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Clinical Trial Results:
A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel Group Study of CNTO 136 (sirukumab), a Human Anti-IL-6 Monoclonal Antibody, Administered Subcutaneously, in Subjects with Active Rheumatoid Arthritis Despite DMARD Therapy

Summary
EudraCT number	2010-022242-24
Trial protocol	LT BG
Global end of trial date	06 Dec 2016

Results information
Results version number	v1(current)
This version publication date	22 Dec 2017
First version publication date	22 Dec 2017
Other versions

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

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Trial information

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Sponsor protocol code

CR100866

ISRCTN number

US NCT number

NCT01604343

WHO universal trial number (UTN)

Sponsor organisation name

Janssen-Cilag International N.V.

Sponsor organisation address

Archimedesweg 29, Leiden, Netherlands, 2333

Public contact

Clinical Registry Group, Janssen-Cilag International N.V, ClinicalTrialsEU@its.jnj.com

Scientific contact

Clinical Registry Group, Janssen-Cilag International N.V, ClinicalTrialsEU@its.jnj.com

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

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

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

Analysis stage

Final

Date of interim/final analysis

06 Dec 2016

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

06 Dec 2016

Was the trial ended prematurely?

Main objective of the trial

The main objective of this study was to assess the efficacy of sirukumab as measured by the reduction of the signs and symptoms of rheumatoid arthritis (RA) and inhibition of radiographic progression in subjects with moderately to severely active RA who were refractory to disease-modifying antirheumatic drugs (DMARDs).

Protection of trial subjects

Safety assessment was evaluated throughout the study based on reported adverse events (AEs), clinical laboratory tests, vital sign measurements, physical examinations, and concomitant medication review.

Background therapy

Evidence for comparator

Actual start date of recruitment

24 Jul 2012

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

4 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Bulgaria: 18

Country: Number of subjects enrolled

Canada: 11

Country: Number of subjects enrolled

Chile: 68

Country: Number of subjects enrolled

Colombia: 41

Country: Number of subjects enrolled

Croatia: 10

Country: Number of subjects enrolled

Japan: 168

Country: Number of subjects enrolled

Korea, Republic of: 68

Country: Number of subjects enrolled

Lithuania: 98

Country: Number of subjects enrolled

Mexico: 115

Country: Number of subjects enrolled

Malaysia: 7

Country: Number of subjects enrolled

Poland: 169

Country: Number of subjects enrolled

Romania: 15

Country: Number of subjects enrolled

Russian Federation: 201

Country: Number of subjects enrolled

Serbia: 144

Country: Number of subjects enrolled

Taiwan: 24

Country: Number of subjects enrolled

Ukraine: 152

Country: Number of subjects enrolled

United States: 261

Country: Number of subjects enrolled

South Africa: 100

Worldwide total number of subjects

1670

EEA total number of subjects

310

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

1422

From 65 to 84 years

248

85 years and over

Subject disposition

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Recruitment details

Screening details

A total of 2746 subjects were screened of which 1670 subjects were randomized and received at least one administration of study treatment.

Period 1 title

Prior to W52 administration(through W52)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Placebo

Arm description

Subjects received placebo subcutaneously (SC) every 2 weeks (q2w) from Week 0 up to Week 50. Subjects who met early escape (EE) criteria at Week 18, or late escape (LE) at Week 40, or crossover (CO) at Week 52 were re-randomized to receive sirukumab 50 or 100 mg through Week 104. Subjects who completed study agent administration up to Week 104 and did not elect for long term extension (LTE) were followed up for safety from Week 104 up to Week 120.

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

Subject received placebo subcutaneously (SC) every 2 weeks (q2w) from Week 0 up to Week 50.

Sirukumab 50 mg q4w

Arm description

All subjects received 50 mg of sirukumab subcutaneously every 4 weeks (q4w) for 104 Weeks and in between placebo SC injections was received at Weeks 2, 6, and q4w through Week 104.

Arm type

Experimental

Investigational medicinal product name

Sirukumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects received 50 mg of sirukumab subcutaneously every 4 weeks (q4w) for 104 weeks.

Sirukumab 100 mg q2w

Arm description

All subjects received 100 mg of sirukumab SC injections at Weeks 0, 2, and q2w through Week 104. Subjects who completed study agent administration up to Week 104 and did not elect for long term extension (LTE) were followed up for safety from Week 104 up to Week 120.

Arm type

Experimental

Investigational medicinal product name

Sirukumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects received 100 mg of sirukumab SC injections at Weeks 0, 2, and q2w through Week 104.

Number of subjects in period 1	Placebo	Sirukumab 50 mg q4w	Sirukumab 100 mg q2w
Started	556	557	557
Completed	247	481	470
Not completed	309	76	87
Adverse event, serious fatal	5	3	5
Consent withdrawn by subject	19	12	16
Physician decision	4	1	2
Re-randomized at Week 18/40	211	-	-
Adverse event, non-fatal	25	40	41
Other	15	10	6
Pregnancy	1	1	-
Lost to follow-up	5	4	3
Lack of efficacy	24	5	14

Period 2 title

Week 52 to Week 104

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Placebo to 50 mg q4w due to EE/LE/CO

Arm description

All subjects who were assigned to placebo group and who met EE at Week 18 or LE at Week 40 or CO at Week 52 were re- randomized to receive subcutaneous (SC) sirukumab 50 mg dose regimen q4w up to Week 104.

Arm type

Experimental

Investigational medicinal product name

Sirukumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects who were assigned to placebo group and who met early escape (EE) at Week 18 or LE at Week 40 or CO at Week 52 were re-randomized to receive subcutaneous (SC) sirukumab 50 mg dose regimen q4w up to Week 104.

Sirukumab 50 mg q4w

Arm description

All subjects received 50 mg of sirukumab subcutaneously every 4 weeks (q4w) for 104 weeks and in between placebo SC injections was received at Weeks 2, 6, and q4w through week 104.

Arm type

Experimental

Investigational medicinal product name

Sirukumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects received 50 mg of sirukumab subcutaneously every 4 weeks (q4w) for 104 weeks.

Placebo to 100 mg q2w due to EE/LE/CO

Arm description

All subjects who were assigned to placebo group and who met EE at Week 18 or LE at Week 40 or CO at Week 52 were re-randomized to receive subcutaneous (SC) sirukumab 100 mg dose regimen q2w up to Week 104.

Arm type

Experimental

Investigational medicinal product name

Sirukumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects who were assigned to placebo group and who met EE at Week 18 or LE at Week 40 or CO at Week 52 were re-randomized to receive subcutaneous (SC) sirukumab 100 mg dose regimen q2w up to Week 104.

Sirukumab 100 mg q2w

Arm description

All subjects received 100 mg of sirukumab SC injections at Weeks 0, 2, and q2w through Week 104.

Arm type

Experimental

Investigational medicinal product name

Sirukumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects received 100 mg of sirukumab SC injections at Weeks 0, 2, and q2w through Week 104.

Number of subjects in period 2	Placebo to 50 mg q4w due to EE/LE/CO	Sirukumab 50 mg q4w	Placebo to 100 mg q2w due to EE/LE/CO	Sirukumab 100 mg q2w
Started	243	481	241	470
Treated	242	481	241	470
Completed	200	414	195	429
Not completed	43	67	46	41
Adverse event, serious fatal	4	2	5	-
Consent withdrawn by subject	7	12	8	4
Physician decision	1	-	-	2
Adverse event, non-fatal	12	26	21	27
Other	11	11	6	3
Pregnancy	-	1	2	1
Lost to follow-up	2	4	2	1
Lack of efficacy	6	11	2	3

Period 3 title

Post Treatment Safety Follow Up

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Placebo

Arm description

Subjects who completed study agent administration up to Week 104 and did not elect for long term extension (LTE) were followed up for safety from Week 104 up to Week 120.

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

Subject received placebo subcutaneously (SC) every 2 weeks (q2w) from Week 0 up to Week 50.

Placebo to 50 mg q4w due to EE/LE/CO

Arm description

Subjects who completed study agent administration up to Week 104 and did not elect for long term extension (LTE) were followed up for safety from Week 104 up to Week 120.

Arm type

Experimental

Investigational medicinal product name

Placebo, Sirukumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Sirukumab 50 mg q4w

Arm description

Subjects who completed study agent administration up to Week 104 and did not elect for long term extension (LTE) were followed up for safety from Week 104 up to Week 120.

Arm type

Experimental

Investigational medicinal product name

Sirukumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects received 50 mg of sirukumab subcutaneously every 4 weeks (q4w) for 104 weeks.

Placebo to Sirukumab 100 mg q2w due to EE/LE/CO

Arm description

Subjects who completed study agent administration up to Week 104 and did not elect for long term extension (LTE) were followed up for safety from Week 104 up to Week 120.

Arm type

Experimental

Investigational medicinal product name

Placebo, Sirukumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Sirukumab 100 mg q2w

Arm description

Subjects who completed study agent administration up to Week 104 and did not elect for long term extension (LTE) were followed up for safety from Week 104 up to Week 120.

Arm type

Experimental

Investigational medicinal product name

Sirukumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects received 100 mg of sirukumab SC injections at Weeks 0, 2, and q2w through Week 104.

Number of subjects in period 3	Placebo	Placebo to 50 mg q4w due to EE/LE/CO	Sirukumab 50 mg q4w	Placebo to Sirukumab 100 mg q2w due to EE/LE/CO	Sirukumab 100 mg q2w
Started	109	27	105	36	114
Safety Population	109	26	105	36	114
Completed	79	20	72	26	85
Not completed	30	7	33	10	29
Consent withdrawn by subject	12	4	11	3	14
Other	15	2	20	6	14
Lost to follow-up	3	1	2	1	1

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Reporting group title

Sirukumab 50 mg q4w

Reporting group description

All subjects received 50 mg of sirukumab subcutaneously every 4 weeks (q4w) for 104 Weeks and in between placebo SC injections was received at Weeks 2, 6, and q4w through Week 104.

Reporting group title

Sirukumab 100 mg q2w

Reporting group description

Reporting group values	Placebo	Sirukumab 50 mg q4w	Sirukumab 100 mg q2w	Total
Number of subjects	556	557	557	1670
Title for AgeCategorical
Units: subjects
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	466	478	478	1422
From 65 to 84 years	90	79	79	248
85 years and over	0	0	0	0
Title for AgeContinuous
Units: years
arithmetic mean (standard deviation)	52.9 ( 11.85 )	52.9 ( 11.8 )	53 ( 11.31 )	-
Title for Gender
Units: subjects
Female	436	447	452	1335
Male	120	110	105	335

End points

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Reporting group title

Placebo

Reporting group description

Reporting group title

Sirukumab 50 mg q4w

Reporting group description

All subjects received 50 mg of sirukumab subcutaneously every 4 weeks (q4w) for 104 Weeks and in between placebo SC injections was received at Weeks 2, 6, and q4w through Week 104.

Reporting group title

Sirukumab 100 mg q2w

Reporting group description

Reporting group title

Placebo to 50 mg q4w due to EE/LE/CO

Reporting group description

Reporting group title

Sirukumab 50 mg q4w

Reporting group description

All subjects received 50 mg of sirukumab subcutaneously every 4 weeks (q4w) for 104 weeks and in between placebo SC injections was received at Weeks 2, 6, and q4w through week 104.

Reporting group title

Placebo to 100 mg q2w due to EE/LE/CO

Reporting group description

Reporting group title

Sirukumab 100 mg q2w

Reporting group description

All subjects received 100 mg of sirukumab SC injections at Weeks 0, 2, and q2w through Week 104.

Reporting group title

Placebo

Reporting group description

Subjects who completed study agent administration up to Week 104 and did not elect for long term extension (LTE) were followed up for safety from Week 104 up to Week 120.

Reporting group title

Placebo to 50 mg q4w due to EE/LE/CO

Reporting group description

Subjects who completed study agent administration up to Week 104 and did not elect for long term extension (LTE) were followed up for safety from Week 104 up to Week 120.

Reporting group title

Sirukumab 50 mg q4w

Reporting group description

Subjects who completed study agent administration up to Week 104 and did not elect for long term extension (LTE) were followed up for safety from Week 104 up to Week 120.

Reporting group title

Placebo to Sirukumab 100 mg q2w due to EE/LE/CO

Reporting group description

Subjects who completed study agent administration up to Week 104 and did not elect for long term extension (LTE) were followed up for safety from Week 104 up to Week 120.

Reporting group title

Sirukumab 100 mg q2w

Reporting group description

Subjects who completed study agent administration up to Week 104 and did not elect for long term extension (LTE) were followed up for safety from Week 104 up to Week 120.

Primary: Percentage of Subjects With an American College of Rheumatology (ACR) 20 Response at Week 16

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End point title

Percentage of Subjects With an American College of Rheumatology (ACR) 20 Response at Week 16

End point description

ACR 20 response is defined as greater than or equal to (>=) 20 percent (%) improvement in both tender joint count (TJC, 68 joints) and swollen joint count (SJC, 66 joints) and >= 20% improvement in 3 of following 5 assessments: Subject's assessment of pain using visual analog scale (VAS) (0-10 scale, 0=no pain and 10=worst possible pain), Subject's global assessment of disease activity by using VAS (scale ranges from 0 to 10, [0=very well to 10=very poor]), Physician’s global assessment of disease activity using VAS (scale ranges from 0 to 10, [0=no arthritis activity to 10=extremely active arthritis]), Subject’s assessment of physical function as measured by Health Assessment Questionnaire-Disability Index (HAQ-DI) (scale ranges from 0-no difficulty, to 3-inability to perform a task in that area), and Serum C-reactive protein (CRP). Full analysis set included all randomized subjects. Subjects were set to non-responders if meeting TF criteria prior to week 16 or having data missing.

End point type

Primary

End point timeframe

Week 16

End point values	Placebo	Sirukumab 50 mg q4w	Sirukumab 100 mg q2w
Number of subjects analysed	556	557	557
Units: Percentage of Subjects
number (not applicable)	26.4	54.8	53.5

Statistical Analysis-1

Comparison groups

Placebo v Sirukumab 50 mg q4w

Number of subjects included in analysis

1113

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

Cochran-Mantel-Haenszel

Parameter type

Percentage Difference

Point estimate

28.4

Confidence interval

level

95%

sides

2-sided

lower limit

22.8

upper limit

33.8

Statistical Analysis-2

Comparison groups

Placebo v Sirukumab 100 mg q2w

Number of subjects included in analysis

1113

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

Cochran-Mantel-Haenszel

Parameter type

Percentage Difference

Point estimate

27.1

Confidence interval

level

95%

sides

2-sided

lower limit

21.6

upper limit

32.6

Primary: Change from Baseline in van der Heijde-modified Sharp (vdH-S) Score at Week 52

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End point title

Change from Baseline in van der Heijde-modified Sharp (vdH-S) Score at Week 52

End point description

vdH-S score is sum of joint erosion score and joint space narrowing (JSN) score. Joint erosion assessment is scored according to the surface area involved, from 0 to 5, with 0 indicating no erosion and 5 indicating complete collapse of bone whereas the JSN assessment including subluxation, is scored from 0 (normal) to 4 (bony ankylosis or complete luxation). Total score ranges from 0 (best) to 448 (worst) with higher scores indicating more joint damage. Efficacy FAS for radiographic assessment includes all randomized subjects who received at least 1 (partial or complete) dose of study agent and who had non-missing baseline vdH-S score. Subjects were analyzed according to randomized treatments they were assigned to, regardless of the treatment groups they actually received. This score was based on imputed value by EE Rules (set scores after EE to missing for placebo arm) and then missing data rules in all treatment groups (imputed using linear extrapolation method).

End point type

Primary

End point timeframe

Baseline, Week 52

End point values	Placebo	Sirukumab 50 mg q4w	Sirukumab 100 mg q2w
Number of subjects analysed	550	553	551
Units: Units on a Scale
arithmetic mean (standard deviation)	3.69 ( 9.245 )	0.50 ( 2.961 )	0.46 ( 3.258 )

Statistical Analysis-2

Comparison groups

Placebo v Sirukumab 100 mg q2w

Number of subjects included in analysis

1101

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

van der waerden ANOVA

Confidence interval

Statistical Analysis-1

Comparison groups

Placebo v Sirukumab 50 mg q4w

Number of subjects included in analysis

1103

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

van der waerden ANOVA

Confidence interval

Secondary: Change from Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 24

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End point title

Change from Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 24

End point description

The HAQ-DI score is an evaluation of the functional status for a subject. The 20- question instrument assesses the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities of daily living). Responses in each functional area are scored from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range: 0-3 where 0 = least difficulty and 3 = extreme difficulty. Full analysis set included all randomized subjects. Subjects were analyzed according to randomized treatment groups they were assigned to, regardless of the treatments they actually received. Last Observation Carried Forward (LOCF) method was used to impute missing values. Last Observation at or prior EE was used to replace the data after EE for subjects who met EE criteria.

End point type

Secondary

End point timeframe

Baseline, Week 24

End point values	Placebo	Sirukumab 50 mg q4w	Sirukumab 100 mg q2w
Number of subjects analysed	556	557	557
Units: Units on Scale
arithmetic mean (standard deviation)	-0.2179 ( 0.53081 )	-0.4262 ( 0.57631 )	-0.4610 ( 0.56784 )

Statistical Analysis-1

Comparison groups

Placebo v Sirukumab 50 mg q4w

Number of subjects included in analysis

1113

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

Least Square (LS) mean difference

Point estimate

-0.226

Confidence interval

level

95%

sides

2-sided

lower limit

-0.29

upper limit

-0.17

Statistical Analysis-2

Comparison groups

Placebo v Sirukumab 100 mg q2w

Number of subjects included in analysis

1113

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

ANCOVA

Parameter type

LS mean difference

Point estimate

-0.256

Confidence interval

level

95%

sides

2-sided

lower limit

-0.32

upper limit

-0.2

Secondary: Percentage of Subjects With an American College of Rheumatology (ACR) 50 Response at Week 24

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End point title

Percentage of Subjects With an American College of Rheumatology (ACR) 50 Response at Week 24

End point description

ACR 50 response is defined as >= 50% improvement in both TJC (68 joints) and SJC (66 joints) and >= 50% improvement in 3 of the following 5 assessments: Subject’s assessment of pain using VAS (0-10 scale, 0=no pain and 10=worst possible pain), Subject’s global assessment of disease activity by using VAS (the scale ranges from 0 to 10, [0 =very well to 10 =very poor]), Physician’s global assessment of disease activity using VAS (the scale ranges from 0 to 10, [0=no arthritis activity to 10=extremely active arthritis]), Subject’s assessment of physical function as measured by HAQ-DI (the scale ranges from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area), and Serum CRP. FAS included all randomized subjects. Subjects were analyzed according to randomized treatment groups they were assigned to, regardless of the treatments they actually received. Subjects were set to non-responders if meeting EE or TF criteria prior to week 24 or having data missing.

End point type

Secondary

End point timeframe

Week 24

End point values	Placebo	Sirukumab 50 mg q4w	Sirukumab 100 mg q2w
Number of subjects analysed	556	557	557
Units: Percentage of Subjects
number (not applicable)	12.4	30.2	33.2

Statistical Analysis-1

Comparison groups

Placebo v Sirukumab 50 mg q4w

Number of subjects included in analysis

1113

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

Cochran-Mantel-Haenszel

Parameter type

Percentage Difference

Point estimate

17.8

Confidence interval

level

95%

sides

2-sided

lower limit

13.1

upper limit

22.4

Statistical Analysis-2

Comparison groups

Placebo v Sirukumab 100 mg q2w

Number of subjects included in analysis

1113

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

Cochran-Mantel-Haenszel

Parameter type

Percentage Difference

Point estimate

20.8

Confidence interval

level

95%

sides

2-sided

lower limit

16.1

upper limit

25.6

Secondary: Percentage of Subjects With Disease Activity Index Score 28 (DAS28) (C-reactive protein [CRP]) Remission at Week 24

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End point title

Percentage of Subjects With Disease Activity Index Score 28 (DAS28) (C-reactive protein [CRP]) Remission at Week 24

End point description

The DAS28 based on C-Reactive Protein (CRP) is a statistically derived index combining tender joints (28 joints), swollen joints (28 joints), CRP and patient's global assessment of disease activity. The set of 28 joint count is based on evaluation of the shoulder, elbow, wrist, metacarpophalangeal (MCP) MCP1 to MCP5, proximal interphalangeal (PIP) PIP1 to PIP5 joints of both the upper right extremity and the upper left extremity as well as the knee joints of lower right and lower left extremities. The values are 0=best to 10=worst. The Disease Activity Index Score 28 (DAS28) C-reactive protein (CRP) remission is defined as a DAS28 (CRP) value of less than 2.6 at a visit. Full analysis set included all randomized subjects. Subjects were analyzed according to randomized treatment groups they were assigned to, regardless of the treatments they actually received. Subjects were set to not achieving DAS28 remission if meeting EE or TF criteria prior to week 24 or having data missing.

End point type

Secondary

End point timeframe

Week 24

End point values	Placebo	Sirukumab 50 mg q4w	Sirukumab 100 mg q2w
Number of subjects analysed	556	557	557
Units: Percentage of Subjects
number (not applicable)	5.6	26.0	25.5

Statistical Analysis-1

Comparison groups

Placebo v Sirukumab 50 mg q4w

Number of subjects included in analysis

1113

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

Cochran-Mantel-Haenszel

Parameter type

Percentage Difference

Point estimate

20.5

Confidence interval

level

95%

sides

2-sided

lower limit

16.4

upper limit

24.6

Statistical Analysis-2

Comparison groups

Placebo v Sirukumab 100 mg q2w

Number of subjects included in analysis

1113

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

Cochran-Mantel-Haenszel

Parameter type

Percentage Difference

Point estimate

19.9

Confidence interval

level

95%

sides

2-sided

lower limit

15.8

upper limit

Secondary: Percentage of Subjects With Major Clinical Response (MCR) at Week 52

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End point title

Percentage of Subjects With Major Clinical Response (MCR) at Week 52

End point description

MCR was defined as subject achieving ACR 70 response for 6 continuous months (24 weeks) in study period (i.e., through Week 52). An ACR 70 response is defined as >= 70% improvement in both TJC (68 joints) and SJC (66 joints) and >= 70% improvement in 3 of following 5 assessments Subject’s assessment of pain using VAS, Subject’s global assessment of disease activity by using VAS, Physician’s global assessment of disease activity using VAS, Subject’s assessment of physical function as measured by HAQ-DI and Serum CRP. FAS was defined as all randomized subjects. Subjects were analyzed according to randomized treatment groups they were assigned to, regardless of the treatments they actually received. Subjects were set to non-responders if meeting EE, LE or TF criteria prior to week 52 or having data missing.

End point type

Secondary

End point timeframe

Week 52

End point values	Placebo	Sirukumab 50 mg q4w	Sirukumab 100 mg q2w
Number of subjects analysed	556	557	557
Units: Percentage of Subjects
number (not applicable)	1.8	5.4	9.0

Statistical Analysis-1

Comparison groups

Placebo v Sirukumab 50 mg q4w

Number of subjects included in analysis

1113

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

Cochran-Mantel-Haenszel

Parameter type

Percentage Difference

Point estimate

3.6

Confidence interval

level

95%

sides

2-sided

lower limit

1.4

upper limit

508

Statistical Analysis-2

Comparison groups

Placebo v Sirukumab 100 mg q2w

Number of subjects included in analysis

1113

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.001

Method

Cochran-Mantel-Haenszel

Parameter type

Percentage Difference

Point estimate

7.2

Confidence interval

level

95%

sides

2-sided

lower limit

4.6

upper limit

9.8

Secondary: Percentage of Subjects With an American College of Rheumatology (ACR) 20 Response Through Week 52

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End point title

Percentage of Subjects With an American College of Rheumatology (ACR) 20 Response Through Week 52

End point description

ACR 20 response is defined as >=20% improvement in both TJC(68 joints) and SJC(66 joints) and >=20% improvement in 3 of the following 5 assessments: Subject’s assessment of pain using VAS 0-10 scale, 0=no pain and 10=worst possible pain), Subject’s global assessment of disease activity by using VAS(scale ranges from 0 to 10, [0=very well to 10=very poor]), Physician’s global assessment of disease activity using VAS (scale ranges from 0 to 10, [0=no arthritis activity to 10=extremely active arthritis]), Subject’s assessment of physical function as measured by HAQ-DI (scale ranges from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area), and Serum CRP. FAS included all randomized subjects. Subjects were analyzed according to randomized treatment groups they were assigned to, regardless of the treatments they actually received. Subjects were set to non-responders after meeting EE, LE or TF criteria (whichever is earliest) or if having data missing.

End point type

Secondary

End point timeframe

Week 2, 4, 6, 8, 12, 18, 20, 24, 28, 32, 36, 40, 44, 48, and 52

End point values	Placebo	Sirukumab 50 mg q4w	Sirukumab 100 mg q2w
Number of subjects analysed	556	557	557
Units: Percentage of Subjects
number (not applicable)
Week 2	7.4	18.3	15.4
Week 4	14.2	36.3	33.8
Week 6	20.3	45.8	46.9
Week 8	25.9	47.2	51.3
Week 12	27.3	53.1	53.3
Week 18	29.3	54.4	56.9
Week 20	29.5	53.7	52.8
Week 24	27.0	53.7	56.0
Week 28	31.5	53.1	57.3
Week 32	29.5	53.3	56.7
Week 36	28.4	54.0	58.2
Week 40	28.8	53.3	53.3
Week 44	27.7	49.2	54.0
Week 48	26.8	50.1	54.8
Week 52	26.6	49.9	54.8

No statistical analyses for this end point

Secondary: Percentage of Subjects With an American College of Rheumatology (ACR) 50 Response

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End point title

Percentage of Subjects With an American College of Rheumatology (ACR) 50 Response

End point description

ACR 50 response is defined as >=50% improvement in both TJC(68 joints) and SJC(66 joints) and >=50% improvement in 3 of the following 5 assessments: Subject’s assessment of pain using VAS(0-10 scale, 0=no pain and 10=worst possible pain), Subject’s global assessment of disease activity by using VAS(scale ranges from 0 to 10,[0=very well to 10=very poor]), Physician’s global assessment of disease activity using VAS (scale ranges from 0 to 10, [0=no arthritis activity to 10=extremely active arthritis]), Subject’s assessment of physical function as measured by HAQ-DI(scale ranges from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area) and Serum CRP. FAS was defined as all randomized subjects. Subjects were analyzed according to randomized treatment groups they were assigned to, regardless of the treatments they actually received. Subjects were set to non-responders after meeting EE, LE or TF criteria (whichever is earliest) or if having data missing.

End point type

Secondary

End point timeframe

Week 2, 4, 6, 8, 12, 16, 18, 20, 28, 32, 36, 40, 44, 48 and 52

End point values	Placebo	Sirukumab 50 mg q4w	Sirukumab 100 mg q2w
Number of subjects analysed	556	557	557
Units: Percentage of Subjects
number (not applicable)
Week 2	1.1	3.2	2.0
Week 4	2.5	9.2	9.9
Week 6	4.1	15.6	14.0
Week 8	7.7	20.3	18.9
Week 12	10.1	24.6	28.0
Week 16	10.8	30.0	26.2
Week 18	11.7	31.2	31.2
Week 20	13.5	32.7	33.4
Week 28	15.1	31.6	33.0
Week 32	14.0	33.6	35.0
Week 36	12.2	33.4	34.5
Week 40	13.3	31.1	33.4
Week 44	14.2	31.4	33.9
Week 48	14.4	32.9	34.8
Week 52	13.8	30.3	35.5

No statistical analyses for this end point

Secondary: Percentage of Subjects With an American College of Rheumatology (ACR) 70 Response Through Week 52

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End point title

Percentage of Subjects With an American College of Rheumatology (ACR) 70 Response Through Week 52

End point description

ACR 70 response is defined as >=70% improvement in both TJC(68 joints) and SJC(66 joints) and >=70% improvement in 3 of the following 5 assessments: Subject’s assessment of pain using VAS(0-10 scale, 0=no pain and 10=worst possible pain), Subject’s global assessment of disease activity by using VAS (scale ranges from 0 to 10,[0=very well to 10=very poor]), Physician’s global assessment of disease activity using VAS (scale ranges from 0 to 10,[0=no arthritis activity to 10=extremely active arthritis]), Subject’s assessment of physical function as measured by HAQ-DI(scale ranges from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area) and Serum CRP. FAS was defined as all randomized subjects. Subjects were analyzed according to randomized treatment groups they were assigned to, regardless of the treatments they actually received. Subjects were set to non-responders after meeting EE, LE or TF criteria (whichever is earliest) or if having data missing.

End point type

Secondary

End point timeframe

Week 2, 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48 and 52

End point values	Placebo	Sirukumab 50 mg q4w	Sirukumab 100 mg q2w
Number of subjects analysed	556	557	557
Units: Percentage of Subjects
number (not applicable)
Week 2	0.4	0.7	0.4
Week 4	0.5	2.0	3.1
Week 6	1.6	4.7	4.5
Week 8	1.6	7.2	7.2
Week 12	3.1	10.4	10.6
Week 16	4.0	13.5	13.5
Week 18	4.3	12.6	14.7
Week 20	4.0	13.1	16.0
Week 24	3.4	14.9	16.3
Week 28	5.2	16.0	16.5
Week 32	4.7	17.4	17.2
Week 36	4.7	15.8	16.2
Week 40	5.0	16.9	17.6
Week 44	5.2	16.3	17.1
Week 48	6.8	18.5	17.8
Week 52	5.4	16.5	18.5

No statistical analyses for this end point

Secondary: Percentage of Subjects With an American College of Rheumatology (ACR) 90 Response Through Week 52

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End point title

Percentage of Subjects With an American College of Rheumatology (ACR) 90 Response Through Week 52

End point description

ACR 90 response is defined as >=90% improvement in both TJC(68 joints) and SJC(66 joints) and >=90% improvement in 3 of the following 5 assessments: Subject’s assessment of pain using VAS(0-10 scale, 0=no pain and 10=worst possible pain), Subject’s global assessment of disease activity by using VAS(scale ranges from 0 to 10, [0=very well to 10=very poor]), Physician’s global assessment of disease activity using VAS(scale ranges from 0 to 10,[0=no arthritis activity to 10=extremely active arthritis]), Subject’s assessment of physical function as measured by HAQ-DI (scale ranges from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area) and Serum CRP. FAS was defined as all randomized subjects. Subjects were analyzed according to randomized treatment groups they were assigned to, regardless of the treatments they actually received. Subjects were set to non-responders after meeting EE, LE or TF criteria (whichever is earliest) or if having data missing.

End point type

Secondary

End point timeframe

Week 2, 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48 and 52

End point values	Placebo	Sirukumab 50 mg q4w	Sirukumab 100 mg q2w
Number of subjects analysed	556	557	557
Units: Percentage of Subjects
number (not applicable)
Week 2	0	0	0
Week 4	0	0.2	0.2
Week 6	0.2	0.2	0.2
Week 8	0.2	1.1	0.5
Week 12	0.5	2.2	1.8
Week 16	0.9	2.5	2.9
Week 18	1.1	2.5	2.5
Week 20	0.5	3.6	4.1
Week 24	0.5	3.4	5.2
Week 28	0.4	4.5	4.7
Week 32	1.1	4.1	5.7
Week 36	0.9	4.8	5.4
Week 40	0.7	5.4	6.1
Week 44	0.5	5.0	6.6
Week 48	0.7	4.7	6.3
Week 52	1.3	4.5	5.6

No statistical analyses for this end point

Secondary: Percentage of Subjects With Disease Activity Index Score 28 (DAS28) C-reactive Protein (CRP) Response Through Week 52

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End point title

Percentage of Subjects With Disease Activity Index Score 28 (DAS28) C-reactive Protein (CRP) Response Through Week 52

End point description

DAS28 based on CRP is a statistically derived index combining tender joints (28 joints), swollen joints (28 joints), CRP and patient's global assessment of disease activity. The values are 0=best to 10=worst. Good responders: improvement from baseline greater than (>) 1.2 with DAS28 less than or equal to (<=) 3.2; moderate responders: improvement from baseline >1.2 with DAS28 >3.2 to <=5.1 or improvement from baseline >0.6 to <=1.2 with DAS28 <=5.1; non-responders: improvement from baseline <=0.6 or improvement from baseline >0.6 and <=1.2 with DAS28 >5.1. FAS included all randomized subjects. Subjects were analyzed according to randomized treatment groups they were assigned to, regardless of the treatments they actually received. Subjects were set to non-responders after meeting EE, LE or TF criteria (whichever is earliest) or if having data missing.

End point type

Secondary

End point timeframe

Week 2, 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48 and 52

End point values	Placebo	Sirukumab 50 mg q4w	Sirukumab 100 mg q2w
Number of subjects analysed	556	557	557
Units: Percentage of Subjects
number (not applicable)
Week 2	18.5	72.0	72.4
Week 4	28.1	80.1	78.3
Week 6	36.7	82.4	80.3
Week 8	38.5	81.7	81.3
Week 12	43.7	83.3	81.3
Week 16	42.6	80.4	79.5
Week 18	41.5	79.7	79.4
Week 20	41.5	73.8	72.5
Week 24	37.9	71.5	72.2
Week 28	41.2	69.7	72.2
Week 32	41.4	68.2	70.6
Week 36	39.7	67.7	69.8
Week 40	39.2	66.8	67.9
Week 44	37.6	63.2	64.6
Week 48	36.7	61.9	64.6
Week 52	35.6	62.5	64.3

No statistical analyses for this end point

Secondary: Change From Baseline in Disease Activity Index Score 28 (DAS28) C-reactive Protein (CRP) Through Week 52

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End point title

Change From Baseline in Disease Activity Index Score 28 (DAS28) C-reactive Protein (CRP) Through Week 52

End point description

DAS28 based on C-Reactive Protein (CRP) is a statistically derived index combining tender joints (28 joints), swollen joints (28 joints), CRP and patient's global assessment of disease activity. The values are 0=best to 10=worst. A negative change from baseline in DAS28 (CRP) (that is, a decrease from baseline) indicates improvement from baseline. FAS included all randomized subjects. Subjects were analyzed according to randomized treatment groups they were assigned to, regardless of the treatments they actually received. Last Observation Carried Forward (LOCF) method was used to impute missing values. Last Observation at or prior EE/LE was used to replace the data after EE/LE for subjects who met EE/LE criteria.

End point type

Secondary

End point timeframe

Baseline, Week 2, 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48 and 52

End point values	Placebo	Sirukumab 50 mg q4w	Sirukumab 100 mg q2w
Number of subjects analysed	556	557	557
Units: Units on a Scale
arithmetic mean (standard deviation)
Change at Week 2	-0.319 ( 0.7677 )	-1.316 ( 0.7776 )	-1.284 ( 0.7605 )
Change at Week 4	-0.515 ( 0.9287 )	-1.638 ( 0.9759 )	-1.627 ( 0.9529 )
Change at Week 6	-0.707 ( 1.0599 )	-1.886 ( 1.0622 )	-1.888 ( 1.0340 )
Change at Week 8	-0.754 ( 1.1013 )	-2.016 ( 1.1183 )	-2.031 ( 1.1138 )
Change at Week 12	-0.881 ( 1.1727 )	-2.187 ( 1.1995 )	-2.185 ( 1.1950 )
Change at Week 16	-0.908 ( 1.2834 )	-2.264 ( 1.2443 )	-2.282 ( 1.2283 )
Change at Week 18	-0.895 ( 1.2986 )	-2.286 ( 1.2690 )	-2.335 ( 1.2314 )
Change at Week 20	-0.920 ( 1.2973 )	-2.367 ( 1.3368 )	-2.380 ( 1.3158 )
Change at Week 24	-0.912 ( 1.3180 )	-2.356 ( 1.3599 )	-2.402 ( 1.3048 )
Change at Week 28	-0.979 ( 1.3752 )	-2.417 ( 1.4068 )	-2.440 ( 1.3245 )
Change at Week 32	-1.010 ( 1.3904 )	-2.451 ( 1.4141 )	-2.479 ( 1.3304 )
Change at Week 36	-1.019 ( 1.4020 )	-2.461 ( 1.3951 )	-2.497 ( 1.3231 )
Change at Week 40	-0.985 ( 1.4054 )	-2.462 ( 1.4180 )	-2.459 ( 1.3901 )
Change at Week 44	-0.994 ( 1.4117 )	-2.442 ( 1.4364 )	-2.477 ( 1.4381 )
Change at Week 48	-1.026 ( 1.4755 )	-2.482 ( 1.4630 )	-2.488 ( 1.3783 )
Change at Week 52	-0.992 ( 1.4431 )	-2.491 ( 1.4305 )	-2.476 ( 1.4109 )

No statistical analyses for this end point

Secondary: Percentage of Subjects with Disease Activity Index Score 28 (DAS28) (C-reactive protein [CRP]) Remission Through Week 52

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End point title

Percentage of Subjects with Disease Activity Index Score 28 (DAS28) (C-reactive protein [CRP]) Remission Through Week 52

End point description

DAS28 based on C-Reactive Protein (CRP) is a statistically derived index combining tender joints (28 joints), swollen joints (28 joints), CRP and patient's global assessment of disease activity. The set of 28 joint count is based on evaluation of the shoulder, elbow, wrist, metacarpophalangeal (MCP) MCP1 to MCP5, proximal interphalangeal (PIP) PIP1 to PIP5 joints of both the upper right extremity and the upper left extremity as well as the knee joints of lower right and lower left extremities. The values are 0=best to 10=worst. DAS28 (CRP) remission is defined as a DAS28 (CRP) value of less than 2.6 at a visit. Full analysis set included all randomized subjects. Subjects were analyzed according to randomized treatment groups they were assigned to, regardless of the treatments they actually received. Subjects were set to not achieving DAS28 remission after meeting EE, LE or TF criteria (whichever is earliest) or if having data missing.

End point type

Secondary

End point timeframe

Week 2, 4, 6, 8, 12, 16, 18, 20, 28, 32, 36, 40, 44, 48 and 52

End point values	Placebo	Sirukumab 50 mg q4w	Sirukumab 100 mg q2w
Number of subjects analysed	556	557	557
Units: Percentage of Subjects
number (not applicable)
Week 2	0.5	2.5	2.7
Week 4	1.6	7.9	9.3
Week 6	3.1	10.2	12.6
Week 8	3.2	13.6	17.8
Week 12	4.3	18.3	19.6
Week 16	5.8	21.2	21.9
Week 18	6.1	22.8	23.7
Week 20	5.8	26.4	25.5
Week 24	5.6	26.0	25.5
Week 28	7.7	27.5	27.1
Week 32	7.7	29.6	28.4
Week 36	8.5	29.1	28.0
Week 40	7.2	27.8	27.3
Week 44	8.5	28.2	27.5
Week 48	9.0	29.6	30.2
Week 52	8.8	30.0	29.1

No statistical analyses for this end point

Secondary: Change From Baseline in Simplified Disease Activity Index (SDAI) Score Through Week 52

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End point title

Change From Baseline in Simplified Disease Activity Index (SDAI) Score Through Week 52

End point description

SDAI score is a derived score combining tender joints (28 joints), swollen joints (28 joints), patient's global assessment of disease activity, physician's global assessments of disease activity, and CRP. The total score range is from 0 to 86 with a lower score indicating less disease activity. A negative change from baseline indicates an improvement and a positive change from baseline indicates a worsening. FAS included all randomized subjects. Subjects were analyzed according to randomized treatment groups they were assigned to, regardless of the treatments they actually received. Last Observation Carried Forward (LOCF) method was used to impute missing values. Last Observation at or prior EE/LE was used to replace the data after EE/LE for subjects who met EE/LE criteria. Last Observation at or prior EE/LE was used to replace the data after EE/LE for subjects who met EE/LE criteria.

End point type

Secondary

End point timeframe

Baseline, Week 2, 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48 and 52

End point values	Placebo	Sirukumab 50 mg q4w	Sirukumab 100 mg q2w
Number of subjects analysed	556	557	557
Units: Units on a Scale
arithmetic mean (standard deviation)
Change at Week 2	-4.5129 ( 9.68032 )	-9.1095 ( 9.64598 )	-7.9649 ( 9.58765 )
Change at Week 4	-7.3134 ( 11.87959 )	-13.3976 ( 12.00410 )	-12.2156 ( 11.65262 )
Change at Week 6	-9.5833 ( 13.15531 )	-16.1013 ( 12.80166 )	-15.4404 ( 12.18642 )
Change at Week 8	-10.0752 ( 13.54599 )	-17.6624 ( 12.98109 )	-17.1302 ( 12.92830 )
Change at Week 12	-11.5975 ( 14.53181 )	-19.6639 ( 13.67016 )	-19.0635 ( 13.63444 )
Change at Week 16	-11.3507 ( 15.72864 )	-20.3221 ( 14.14177 )	-20.0652 ( 13.85171 )
Change at Week 18	-10.6805 ( 16.31549 )	-20.1215 ( 14.75683 )	-20.4858 ( 13.72370 )
Change at Week 20	-11.0425 ( 16.42770 )	-20.8300 ( 15.31245 )	-20.8508 ( 14.44400 )
Change at Week 24	-11.1443 ( 16.37909 )	-20.7459 ( 15.48312 )	-21.0858 ( 14.57962 )
Change at Week 28	-11.7828 ( 17.04652 )	-21.3535 ( 15.98762 )	-21.5524 ( 14.69362 )
Change at Week 32	-12.0835 ( 17.11297 )	-21.8176 ( 16.15549 )	-21.8530 ( 14.58393 )
Change at Week 36	-12.2107 ( 17.24703 )	-21.9077 ( 15.95251 )	-22.1040 ( 14.54871 )
Change at Week 40	-11.9185 ( 17.32206 )	-21.7862 ( 16.12260 )	-21.6692 ( 15.33635 )
Change at Week 44	-11.8730 ( 17.41934 )	-21.4843 ( 16.33985 )	-21.5514 ( 15.78476 )
Change at Week 48	-11.9055 ( 17.91398 )	-21.7238 ( 16.45520 )	-21.7991 ( 15.34514 )
Change at Week 52	-11.7647 ( 17.61074 )	-21.9130 ( 16.32611 )	-21.7344 ( 15.64620 )

No statistical analyses for this end point

Secondary: Change From Baseline in Clinical Disease Activity Index (CDAI) Score Through Week 52

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End point title

Change From Baseline in Clinical Disease Activity Index (CDAI) Score Through Week 52

End point description

CDAI score is a derived score of 4 components: tender joints (28 joints), swollen joints (28 joints), patient's global assessment of disease activity, and physician's global assessments of disease activity. Total score ranges from 0 to 76 with a lower score indicating less disease activity. A negative change in CDAI score indicates an improvement in disease activity and a positive change in score indicates a worsening of disease activity. FAS included all randomized subjects. Subjects were analyzed according to randomized treatment groups they were assigned to, regardless of the treatments they actually received. Last Observation Carried Forward (LOCF) method was used to impute missing values. Last Observation at or prior EE/LE was used to replace the data after EE/LE for subjects who met EE/LE criteria.

End point type

Secondary

End point timeframe

Baseline, Week 2, 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48 and 52

End point values	Placebo	Sirukumab 50 mg q4w	Sirukumab 100 mg q2w
Number of subjects analysed	556	557	557
Units: Units on a Scale
arithmetic mean (standard deviation)
Change at Week 2	-4.38 ( 9.210 )	-6.82 ( 9.350 )	-5.65 ( 9.014 )
Change at Week 4	-7.09 ( 11.241 )	-11.13 ( 11.699 )	-9.88 ( 11.166 )
Change at Week 6	-9.24 ( 12.407 )	-13.79 ( 12.416 )	-13.10 ( 11.599 )
Change at Week 8	-9.72 ( 12.714 )	-15.37 ( 12.593 )	-14.79 ( 12.438 )
Change at Week 12	-11.19 ( 13.625 )	-17.36 ( 13.223 )	-16.74 ( 13.098 )
Change at Week 16	-10.86 ( 14.716 )	-18.04 ( 13.651 )	-17.75 ( 13.261 )
Change at Week 18	-10.24 ( 15.245 )	-17.82 ( 14.291 )	-18.17 ( 13.204 )
Change at Week 20	-10.57 ( 15.338 )	-18.53 ( 14.809 )	-18.57 ( 13.910 )
Change at Week 24	-10.68 ( 15.302 )	-18.45 ( 14.936 )	-18.80 ( 14.075 )
Change at Week 28	-11.27 ( 15.926 )	-19.06 ( 15.395 )	-19.27 ( 14.168 )
Change at Week 32	-11.55 ( 15.950 )	-19.57 ( 15.549 )	-19.56 ( 14.095 )
Change at Week 36	-11.70 ( 16.099 )	-19.66 ( 15.455 )	-19.80 ( 14.084 )
Change at Week 40	-11.46 ( 16.236 )	-19.54 ( 15.640 )	-19.3 ( 14.833 )
Change at Week 44	-11.41 ( 16.126 )	-19.24 ( 15.888 )	-19.26 ( 15.264 )
Change at Week 48	-11.47 ( 16.594 )	-19.47 ( 15.951 )	-19.50 ( 14.871 )
Change at Week 52	-11.38 ( 16.348 )	-19.67 ( 15.834 )	-19.44 ( 15.115 )

No statistical analyses for this end point

Secondary: Percentage of Subjects With Simplified Disease Activity Index based (SDAI-based) American College of Rheumatology (ACR)/ European League Against Rheumatism (EULAR) Remission Through Week 52

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End point title

Percentage of Subjects With Simplified Disease Activity Index based (SDAI-based) American College of Rheumatology (ACR)/ European League Against Rheumatism (EULAR) Remission Through Week 52

End point description

SDAI-based ACR/EULAR remission in subject at visit if SDAI score of <= 3.3. SDAI score is derived by combining 5 disease assessments: tender joint (28 joints), swollen joint (28 joints) counts, PGA of disease activity by using VAS (scale ranges from 0 to 10 [0 = very well to 10 = very poor]), PhGA of disease activity using VAS (scale ranges from 0 to 10 [0=no arthritis to 10=extremely active arthritis]) and CRP. Change from baseline measures change in disease activity, negative change shows improvement and positive change shows worsening. FAS included all randomized subjects. Subjects were analyzed according to randomized treatment groups they were assigned to, regardless of the treatments they actually received. Subjects were set to not achieving SDAI-based remission after meeting EE, LE or TF criteria (whichever is earliest) or if having data missing.

End point type

Secondary

End point timeframe

Week 2, 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48 and 52

End point values	Placebo	Sirukumab 50 mg q4w	Sirukumab 100 mg q2w
Number of subjects analysed	556	557	557
Units: Percentage of Subjects
number (not applicable)
Week 2	0.2	0	0
Week 4	0.4	0.2	1.3
Week 6	0.4	1.6	2.3
Week 8	0.7	2.9	2.9
Week 12	1.6	4.8	5.2
Week 16	2.2	5.4	6.6
Week 18	1.6	6.3	6.8
Week 20	1.6	7.5	7.7
Week 24	2.3	8.1	9.5
Week 28	2.3	9.0	8.4
Week 32	2.9	9.7	10.2
Week 36	1.8	10.1	10.6
Week 40	2.5	11.5	11.5
Week 44	2.5	9.7	11.7
Week 48	3.8	11.3	10.4
Week 52	3.2	11.5	10.6

No statistical analyses for this end point

Secondary: Percentage of Subjects With Boolean-based American College of Rheumatology (ACR)/ European League Against Rheumatism (EULAR) Remission Through Week 52

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End point title

Percentage of Subjects With Boolean-based American College of Rheumatology (ACR)/ European League Against Rheumatism (EULAR) Remission Through Week 52

End point description

A subject was considered as having achieved the Boolean-based American College of Rheumatology (ACR)/ European League Against Rheumatism (EULAR) remission at a visit if all of the following 4 criteria were met at that visit: Tender joint count (68 joints) less than or equal to (<=) 1; Swollen joint count (66 joints) <=1; CRP <=1 milligram per deciliter (mg/dL); Patient’s Global Assessment of Disease Activity <=1 on a 0 (very well) to 10 (very poor) VAS. FAS included all randomized subjects. Subjects were analyzed according to randomized treatment groups they were assigned to, regardless of the treatments they actually received. Subjects were set to not achieving Boolean-based remission after meeting EE, LE or TF criteria (whichever is earliest) or if having data missing.

End point type

Secondary

End point timeframe

Week 2, 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48 and 52

End point values	Placebo	Sirukumab 50 mg q4w	Sirukumab 100 mg q2w
Number of subjects analysed	556	557	557
Units: Percentage of Subjects
number (not applicable)
Week 2	0.2	0.4	0
Week 4	0.2	0.4	0.7
Week 6	0	0.9	0.9
Week 8	0.2	1.3	1.8
Week 12	1.3	2.9	3.1
Week 16	1.6	3.2	4.7
Week 18	0.7	3.6	4.7
Week 20	1.3	4.3	5.6
Week 24	0.9	4.3	7.0
Week 28	1.1	5.2	6.1
Week 32	2.3	5.0	6.5
Week 36	1.3	7.0	7.9
Week 40	0.9	5.9	7.9
Week 44	1.4	5.7	7.9
Week 48	1.8	7.0	7.0
Week 52	2.2	7.0	5.7

No statistical analyses for this end point

Secondary: Change from Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score Through Week 52

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End point title

Change from Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score Through Week 52

End point description

The HAQ-DI score is an evaluation of the functional status for a subject. The 20- question instrument assesses the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities of daily living). Responses in each functional area are scored from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range: 0-3 where 0 = least difficulty and 3 = extreme difficulty. Full analysis set included all randomized subjects. Subjects were analyzed according to randomized treatment groups they were assigned to, regardless of the treatments they actually received. LOCF method was used to impute missing values. Last Observation at or prior EE/LE was used to replace the data after EE/LE for subjects who met EE/LE criteria.

End point type

Secondary

End point timeframe

Baseline, Week 2, 4, 6, 8, 12, 16, 18, 20, 28, 32, 36, 40, 44, 48 and 52

End point values	Placebo	Sirukumab 50 mg q4w	Sirukumab 100 mg q2w
Number of subjects analysed	556	557	557
Units: Units on a Scale
arithmetic mean (standard deviation)
Change at Week 2	-0.075 ( 0.3809 )	-0.139 ( 0.3744 )	-0.128 ( 0.3939 )
Change at Week 4	-0.130 ( 0.4444 )	-0.244 ( 0.4498 )	-0.254 ( 0.4184 )
Change at Week 6	-0.170 ( 0.4657 )	-0.318 ( 0.4989 )	-0.360 ( 0.4910 )
Change at Week 8	-0.172 ( 0.4824 )	-0.362 ( 0.5163 )	-0.388 ( 0.5163 )
Change at Week 12	-0.191 ( 0.5055 )	-0.387 ( 0.5512 )	-0.399 ( 0.5364 )
Change at Week 16	-0.201 ( 0.5439 )	-0.409 ( 0.5736 )	-0.433 ( 0.5489 )
Change at Week 18	-0.217 ( 0.5266 )	-0.431 ( 0.5744 )	-0.464 ( 0.5496 )
Change at Week 20	-0.209 ( 0.5275 )	-0.429 ( 0.6074 )	-0.474 ( 0.5797 )
Change at Week 28	-0.232 ( 0.5515 )	-0.438 ( 0.5837 )	-0.471 ( 0.5763 )
Change at Week 32	-0.225 ( 0.5462 )	-0.441 ( 0.6017 )	-0.483 ( 0.5886 )
Change at Week 36	-0.226 ( 0.5585 )	-0.444 ( 0.5961 )	-0.461 ( 0.5810 )
Change at Week 40	-0.230 ( 0.5586 )	-0.447 ( 0.5900 )	-0.431 ( 0.5921 )
Change at Week 44	-0.228 ( 0.5601 )	-0.442 ( 0.6182 )	-0.456 ( 0.5956 )
Change at Week 48	-0.227 ( 0.5727 )	-0.447 ( 0.6207 )	-0.481 ( 0.6043 )
Change at Week 52	-0.225 ( 0.5693 )	-0.453 ( 0.6127 )	-0.470 ( 0.5959 )

No statistical analyses for this end point

Secondary: Area Under the Curve (AUC) of Change from Baseline in HAQ-DI Score From Week 0 Through Week 24 and From Week 0 Through Week 52

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End point title

Area Under the Curve (AUC) of Change from Baseline in HAQ-DI Score From Week 0 Through Week 24 and From Week 0 Through Week 52

End point description

AUC of change from baseline in HAQ-DI score is AUC of change from baseline in HAQ-DI score versus the time. AUC was calculated based on measurement at scheduled visits using trapezoidal rule. Functional status was determined as cumulative measure of HAQ-DI over 1 year by using AUC of change from baseline in HAQ-DI score through week 52. Decreases in AUC of change from baseline in HAQ-DI indicate a greater average improvement in physical function over time. FAS included all randomized subjects. Subjects were analyzed according to randomized treatment groups they were assigned to, regardless of the treatments they actually received. LOCF method was used to impute missing values. Last Observation at or prior EE/LE was used to replace the data after EE/LE for subjects who met EE/LE criteria.

End point type

Secondary

End point timeframe

Week 0 Through Week 24 and 52

End point values	Placebo	Sirukumab 50 mg q4w	Sirukumab 100 mg q2w
Number of subjects analysed	556	557	557
Units: Units on a Scale*Day
arithmetic mean (standard deviation)
Week 0 Through Week 24	-28.85 ( 69.783 )	-57.99 ( 76.384 )	-61.71 ( 75.189 )
Week 0 Through Week 52	-73.55 ( 170.636 )	-145.30 ( 184.630 )	-153.03 ( 180.633 )

No statistical analyses for this end point

Secondary: Percentage of Subjects With Health Assessment Questionnaire-Disability Index (HAQ-DI) Response Through Week 52

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End point title

Percentage of Subjects With Health Assessment Questionnaire-Disability Index (HAQ-DI) Response Through Week 52

End point description

HAQ-DI response was defined as change of less than -0.22 from baseline in HAQ-DI score. HAQ-DI score is a 20-question instrument assesses the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities of daily living). Responses in each functional area are scored from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0-3 where 0 = least difficulty and 3 = extreme difficulty. FAS included all randomized subjects. Subjects were analyzed according to randomized treatment groups they were assigned to, regardless of the treatments they actually received. LOCF method was used to impute missing values. Last Observation at or prior EE/LE was used to replace the data after EE/LE for subjects who met EE/LE criteria.

End point type

Secondary

End point timeframe

Week 2, 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48 and 52

End point values	Placebo	Sirukumab 50 mg q4w	Sirukumab 100 mg q2w
Number of subjects analysed	556	557	557
Units: Percentage of Subjects
number (not applicable)
Week 2	34.4	40.6	37.0
Week 4	38.1	49.2	52.2
Week 6	42.4	56.2	58.0
Week 8	44.1	56.2	61.0
Week 12	44.6	60.1	60.9
Week 16	45.5	60.9	61.9
Week 18	45.9	62.7	65.4
Week 20	46.2	61.4	65.4
Week 24	46.9	63.0	65.4
Week 28	47.8	64.8	63.4
Week 32	46.9	62.8	63.7
Week 36	47.3	63.9	63.7
Week 40	47.3	63.7	61.8
Week 44	47.3	62.1	63.2
Week 48	47.3	61.8	64.6
Week 52	47.1	63.4	64.5

No statistical analyses for this end point

Secondary: Percentage of Subjects With Health Assessment Questionnaire-Disability Index (HAQ-DI) Score of Less Than or Equal to 0.5

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End point title

Percentage of Subjects With Health Assessment Questionnaire-Disability Index (HAQ-DI) Score of Less Than or Equal to 0.5

End point description

HAQ-DI score is an evaluation of the functional status for a subject. The 20- question instrument assesses the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities of daily living). Responses in each functional area are scored from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0-3 where 0 = least difficulty and 3 = extreme difficulty. FAS included all randomized subjects. Subjects were analyzed according to randomized treatment groups they were assigned to, regardless of the treatments they actually received. LOCF method was used to impute missing values. Last Observation at or prior EE/LE was used to replace the data after EE/LE for subjects who met EE/LE criteria.

End point type

Secondary

End point timeframe

Week 2, 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48 and 52

End point values	Placebo	Sirukumab 50 mg q4w	Sirukumab 100 mg q2w
Number of subjects analysed	556	557	557
Units: Percentage of Subjects
number (not applicable)
Week 2	7.9	12.2	11.5
Week 4	9.9	15.6	16.3
Week 6	9.5	18.3	21.2
Week 8	10.6	21.7	21.0
Week 12	12.2	22.8	23.3
Week 16	13.3	24.6	26.8
Week 18	13.7	24.6	25.9
Week 20	13.1	26.0	27.5
Week 24	13.1	25.9	27.5
Week 28	13.8	26.2	28.7
Week 32	13.7	26.0	28.7
Week 36	13.7	27.5	27.5
Week 40	13.7	27.3	26.2
Week 44	13.1	27.8	27.6
Week 48	13.8	28.2	30.0
Week 52	12.4	27.5	29.3

No statistical analyses for this end point

Secondary: Change from Baseline in van der Heijde-modified Sharp (vdH-S) Score at Week 24

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End point title

Change from Baseline in van der Heijde-modified Sharp (vdH-S) Score at Week 24

End point description

End point type

Secondary

End point timeframe

Baseline, Week 24

End point values	Placebo	Sirukumab 50 mg q4w	Sirukumab 100 mg q2w
Number of subjects analysed	550	553	551
Units: Units on a Scale
arithmetic mean (standard deviation)	1.96 ( 5.390 )	0.35 ( 2.149 )	0.30 ( 2.165 )

No statistical analyses for this end point

Secondary: Change From Baseline in van der Heijde-modified Sharp (vdH-S) Sub-score by Type of Damage (erosion or JSN) at Week 24 and 52

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End point title

Change From Baseline in van der Heijde-modified Sharp (vdH-S) Sub-score by Type of Damage (erosion or JSN) at Week 24 and 52

End point description

vdH-S score measures structural damage progression as sum of JE and JSN scores(S).JE is summary of erosion severity in 32 of hands(H) and 12 of feet(F) joints,scored as per surface area-from 0 (no erosion) to 5 (complete(CM) collapse of bone). Maximum (MAX) JES for H-160 (32*5) and MAX JES for F-120 (12*10 [5*2 sides of foot]). MAX JES is 280 whereas JSN is summary of severity of 30 of H and 12 of F joints, scored to subluxation from 0(normal) to 4(bony ankylosis or CM luxation). MAX JSNS for H-120(30*4), and MAX JSS for F-48(12*4). MAX JSNS is 168.Thus MAX JES-280 combined with MAX JSNS-168 gives worst possible vdH-SS of 448.Efficacy FAS population for radiographic assessments included here. Subjects analyzed according to randomized treatment they were assigned to, regardless of treatments they actually received. Imputed value based on EE Rules (set scores after EE to missing for placebo arm) and then missing data rules in all treatment groups (using linear extrapolation method).

End point type

Secondary

End point timeframe

Baseline, Week 24 and 52

End point values	Placebo	Sirukumab 50 mg q4w	Sirukumab 100 mg q2w
Number of subjects analysed	550	553	551
Units: Units on a Scale
arithmetic mean (standard deviation)
Erosion Score: Change at Week 24	1.21 ( 3.348 )	0.10 ( 1.306 )	0.08 ( 1.321 )
JSN Score: Change at Week 24	0.76 ( 2.540 )	0.24 ( 1.404 )	0.21 ( 1.537 )
Erosion Score: Change at Week 52	2.23 ( 5.903 )	0.12 ( 1.809 )	0.08 ( 2.005 )
JSN Score: Change at Week 52	1.46 ( 4.311 )	0.38 ( 1.839 )	0.38 ( 2.184 )

No statistical analyses for this end point

Secondary: Change from Baseline in van der Heijde-modified Sharp (vdH-S) Sub-score by Region Hand or Feet and Type Erosion or JSN at Week 24 and 52

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End point title

Change from Baseline in van der Heijde-modified Sharp (vdH-S) Sub-score by Region Hand or Feet and Type Erosion or JSN at Week 24 and 52

End point description

End point type

Secondary

End point timeframe

Baseline, Week 24 and 52

End point values	Placebo	Sirukumab 50 mg q4w	Sirukumab 100 mg q2w
Number of subjects analysed	550	553	551
Units: Units on a Scale
arithmetic mean (standard deviation)
Change in Hand Erosion Score at Week 24	0.74 ( 2.406 )	0.07 ( 0.920 )	0.03 ( 0.966 )
Change in Hand JSN Score at Week 24	0.51 ( 1.818 )	0.16 ( 1.025 )	0.16 ( 1.021 )
Change in Foot Erosion Score at Week 24	0.46 ( 1.459 )	0.03 ( 0.682 )	0.05 ( 0.754 )
Change in Foot JSN Score at Week 24	0.25 ( 1.207 )	0.09 ( 0.722 )	0.06 ( 1.152 )
Change in Hand Erosion Score at Week 52	1.43 ( 4.378 )	0.09 ( 1.296 )	0.03 ( 1.312 )
Change in Hand JSN Score at Week 52	0.98 ( 3.196 )	0.25 ( 1.378 )	0.28 ( 1.808 )
Change in Foot Erosion Score at Week 52	0.80 ( 2.460 )	0.03 ( 0.955 )	0.06 ( 1.302 )
Change in Foot JSN Score at Week 52	0.48 ( 2.013 )	0.13 ( 0.929 )	0.10 ( 1.171 )

No statistical analyses for this end point

Secondary: Percentage of Subjects With Change From Baseline in van der Heijde Modified Sharp Score (vdH-S Score) Greater Than Smallest Detectable Change (SDC) at Weeks 24 and 52

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End point title

Percentage of Subjects With Change From Baseline in van der Heijde Modified Sharp Score (vdH-S Score) Greater Than Smallest Detectable Change (SDC) at Weeks 24 and 52

End point description

vdH-S score measures structural damage progression as sum of JE and JSNS.JE is summary of erosion(E) severity in 32 of hand(H) and 12 of feet(F) joints, scored as per the surface area- 0(no E) to 5(complete(CM) collapse of bone); JSN-summary of severity of 30 of H12 of F joints, scored as per sub-luxation(L) from 0(normal) to 4(bony ankylosis or CML). SDC is smallest change in S to be assessed correctly as per limits of agreement. SDC for change from baseline in vdH-SS is determined as:SDC=1.96*SD/(root 2*root k), here SD=standard deviation of difference between 2 readers; k= number of readers. Efficacy FAS population for radiographic assessments included here. Subjects analyzed according to randomized treatment they were assigned to, regardless of treatments they actually received. This score was based on imputed value by EE Rules (set scores after EE to missing for placebo arm) and then missing data rules in all treatment groups (imputed using linear extrapolation method).

End point type

Secondary

End point timeframe

Weeks 24 and 52

End point values	Placebo	Sirukumab 50 mg q4w	Sirukumab 100 mg q2w
Number of subjects analysed	550	553	551
Units: Percentage of Subjects
number (not applicable)
Week 24	25.3	8.3	7.6
Week 52	35.5	12.1	12.0

No statistical analyses for this end point

Secondary: Percentage of Subjects With a Change of Less Than or Equal to 0 From Baseline in van der Heijde Modified Sharp (vdH-S) Score at Weeks 24 and 52

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End point title

Percentage of Subjects With a Change of Less Than or Equal to 0 From Baseline in van der Heijde Modified Sharp (vdH-S) Score at Weeks 24 and 52

End point description

End point type

Secondary

End point timeframe

Week 24 and 52

End point values	Placebo	Sirukumab 50 mg q4w	Sirukumab 100 mg q2w
Number of subjects analysed	550	553	551
Units: Percentage of Subjects
number (not applicable)
Week 24	48.4	65.8	68.8
Week 52	45.5	59.0	62.4

No statistical analyses for this end point

Secondary: Change From Baseline in van der Heijde Modified Sharp Score (vdH-S Score) by Reader at Weeks 24 and 52

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End point title

Change From Baseline in van der Heijde Modified Sharp Score (vdH-S Score) by Reader at Weeks 24 and 52

End point description

vdH-S score measures structural damage progression as sum of JE and JSN scores(S).JE is summary of erosion severity in 32 of hands(H) and 12 of feet(F) joints,scored as per surface area-from 0 (no erosion) to 5 (complete(CM) collapse of bone). Maximum (MAX) JES for H-160 (32*5) and MAX JES for F-120 (12*10 [5*2 sides of foot]). MAX JES is 280 whereas JSN is summary of severity of 30 of H and 12 of F joints, scored to subluxation from 0(normal) to 4(bony ankylosis or CM luxation). MAX JSNS for H-120(30*4), and MAX JSS for F-48(12*4). MAX JSNS is 168.Thus MAX JES-280 combined with MAX JSNS-168 gives worst possible vdH-SS of 448.Efficacy FAS population for radiographic assessments included here. Subjects analyzed according to randomized treatment they were assigned to, regardless of treatments they actually received. Imputed value based on EE Rules (set scores after EE to missing for placebo arm) then missing data rules in all treatment groups (using linear extrapolation method).

End point type

Secondary

End point timeframe

Baseline, Weeks 24 and 52

End point values	Placebo	Sirukumab 50 mg q4w	Sirukumab 100 mg q2w
Number of subjects analysed	550	553	551
Units: Units on a Scale
arithmetic mean (standard deviation)
Reader 1 at Week 24 (n= 550, 551, 550)	2.06 ( 5.616 )	0.21 ( 2.495 )	0.20 ( 2.773 )
Reader 2 at Week 24 (n= 550, 553, 551)	1.65 ( 5.053 )	0.38 ( 1.969 )	0.33 ( 1.830 )
Reader 1 at Week 52 (n= 447, 459, 467)	2.99 ( 7.940 )	0.54 ( 3.285 )	0.29 ( 3.325 )
Reader 2 at Week 52 (n= 447, 460, 467)	2.65 ( 7.331 )	0.54 ( 2.660 )	0.35 ( 2.184 )

No statistical analyses for this end point

Secondary: Change From Baseline in Serum C-reactive protein (CRP) Levels Through Week 52

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End point title

Change From Baseline in Serum C-reactive protein (CRP) Levels Through Week 52

End point description

Serum CRP is a marker of systemic inflammation. A negative change from baseline in CRP represents improvement. FAS included all randomized subjects. Subjects analyzed according to randomized treatment they were assigned to, regardless of treatments they actually received. Last Observation Carried Forward (LOCF) method was used to impute missing values. The last observation at or prior to EE/LE was used to replace the data after EE/LE for subjects who met EE/LE criteria.

End point type

Secondary

End point timeframe

Baseline, Week 2, 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48 and 52

End point values	Placebo	Sirukumab 50 mg q4w	Sirukumab 100 mg q2w
Number of subjects analysed	556	557	557
Units: Milligram per Deciliter
arithmetic mean (standard deviation)
Baseline	2.5148 ( 3.38577 )	2.4145 ( 2.62179 )	2.3952 ( 2.64241 )
Change at Week 2	-0.1339 ( 2.86946 )	-2.2867 ( 2.44604 )	-2.3198 ( 2.64772 )
Change at Week 4	-0.2209 ( 2.94279 )	-2.2707 ( 2.41525 )	-2.3406 ( 2.64584 )
Change at Week 6	-0.3432 ( 2.96865 )	-2.3124 ( 2.44604 )	-2.3451 ( 2.64678 )
Change at Week 8	-0.3561 ( 3.05281 )	-2.2919 ( 2.41368 )	-2.3392 ( 2.65864 )
Change at Week 12	-0.4099 ( 3.22085 )	-2.3038 ( 2.43828 )	-2.3274 ( 2.67383 )
Change at Week 16	-0.4890 ( 3.17554 )	-2.2841 ( 2.43707 )	-2.3166 ( 2.65115 )
Change at Week 18	-0.4375 ( 3.48359 )	-2.3030 ( 2.45255 )	-2.3114 ( 2.65919 )
Change at Week 20	-0.4682 ( 3.21483 )	-2.2973 ( 2.44855 )	-2.2798 ( 2.74939 )
Change at Week 24	-0.4610 ( 3.31445 )	-2.2974 ( 2.45343 )	-2.2891 ( 2.73480 )
Change at Week 28	-0.5108 ( 3.34288 )	-2.2937 ( 2.45419 )	-2.2820 ( 2.73435 )
Change at Week 32	-0.5332 ( 3.39542 )	-2.2474 ( 2.63824 )	-2.2907 ( 2.73375 )
Change at Week 36	-0.5128 ( 3.36374 )	-2.2515 ( 2.62647 )	-2.3085 ( 2.73396 )
Change at Week 40	-0.4623 ( 3.46179 )	-2.2429 ( 2.64450 )	-2.3032 ( 2.73402 )
Change at Week 44	-0.4631 ( 4.00446 )	-2.2398 ( 2.65898 )	-2.2895 ( 2.75035 )
Change at Week 48	-0.4372 ( 4.15311 )	-2.2561 ( 2.62491 )	-2.2944 ( 2.75776 )
Change at Week 52	-0.3854 ( 3.96633 )	-2.2399 ( 2.64267 )	-2.2976 ( 2.73878 )

No statistical analyses for this end point

Secondary: Change From Baseline in the Duration of Morning Stiffness Through Week 52

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End point title

Change From Baseline in the Duration of Morning Stiffness Through Week 52

End point description

Duration of morning stiffness was defined as the time elapsed when subject woke up in the morning and was able to resume normal activities without stiffness in minutes (If none was present = 0; If morning stiffness was continuing at the time of assessment or was unusual compared to the recent past, average of duration of stiffness over the past 3 days was reported; If stiffness persisted the entire day, 1440 minutes was recorded). Negative values for this outcome measure represent improvement, i.e. shortening of duration of morning stiffness. FAS was defined as all randomized subjects. Subjects were analyzed according to randomized treatment groups they were assigned to, regardless of treatment they actually received. Here 'N'(number of subject analyzed) signifies subject who were evaluable for this outcome measure. LOCF method was used to impute missing values. The last observation at or prior to EE/LE was used to replace the data after EE/LE for subjects who met EE/LE criteria.

End point type

Secondary

End point timeframe

Baseline, Week 2, 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48 and 52

End point values	Placebo	Sirukumab 50 mg q4w	Sirukumab 100 mg q2w
Number of subjects analysed	552	552	555
Units: Minutes
arithmetic mean (standard deviation)
Change at Week 2	-22.5 ( 184.96 )	-35.2 ( 212.94 )	-24.0 ( 177.41 )
Change at Week 4	-27.2 ( 202.02 )	-61.6 ( 213.09 )	-45.1 ( 181.13 )
Change at Week 6	-35.3 ( 190.54 )	-81.0 ( 207.07 )	-70.3 ( 206.41 )
Change at Week 8	-41.7 ( 171.05 )	-84.1 ( 232.34 )	-79.6 ( 213.42 )
Change at Week 12	-53.2 ( 179.24 )	-88.1 ( 220.03 )	-89.4 ( 217.48 )
Change at Week 16	-52.2 ( 173.24 )	-82.2 ( 241.75 )	-84.1 ( 224.72 )
Change at Week 18	-60.2 ( 191.68 )	-84.6 ( 239.43 )	-88.5 ( 223.95 )
Change at Week 20	-62.0 ( 193.64 )	-93.5 ( 234.10 )	-90.0 ( 229.08 )
Change at Week 24	-63.7 ( 195.58 )	-96.7 ( 228.31 )	-95.5 ( 234.19 )
Change at Week 28	-68.3 ( 195.42 )	-95.2 ( 230.36 )	-98.0 ( 235.03 )
Change at Week 32	-68.9 ( 196.31 )	-96.5 ( 230.46 )	-96.5 ( 231.25 )
Change at Week 36	-68.8 ( 196.90 )	-96.5 ( 228.71 )	-95.2 ( 226.37 )
Change at Week 40	-68.7 ( 68.7 )	-95.7 ( 243.78 )	-95.9 ( 233.28 )
Change at Week 44	-69.9 ( 197.38 )	-96.6 ( 232.42 )	-97.0 ( 234.63 )
Change at Week 48	-69.6 ( 195.50 )	-97.8 ( 238.36 )	-97.0 ( 230.66 )
Change at Week 52	-67.3 ( 196.98 )	-99.1 ( 233.82 )	-97.7 ( 231.53 )

No statistical analyses for this end point

Secondary: Change From Baseline in Physical and Mental Component Summary (MCS) Scores of 36-Item Short Form Health Survey (SF-36) at Weeks 24 and 52

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End point title

Change From Baseline in Physical and Mental Component Summary (MCS) Scores of 36-Item Short Form Health Survey (SF-36) at Weeks 24 and 52

End point description

SF-36(36 questions),consists of 8 multi-item scales:Limitations(LIM) in physical (PHY) functioning due to health (HEL) problems;LIM in usual role activities due to PHY HEL problems;Bodily pain;General mental HEL(psychological distress/well-being);LIM in usual role activities due to personal/emotional problems;LIM in social functioning due to PHY/mental HEL problems;Vitality;General HEL perception.All 8 scales scored from 0- 100(higher scores(S)=better HEL) Based on scale S,summary S,physical component score (PCS)/MCS will be derived.Scoring is based on algorithm provided by developer.Summary MCS/PCS score is also scaled from 0-100(higher S indicating better HEL).FAS included all randomized subjects.Subjects analyzed according to randomized treatment groups they were assigned to,regardless of treatments they actually received.LOCF method was used to impute missing values.The last observation at/prior to EE/LE was used to replace the data after EE/LE for subjects who met EE/LE criteria

End point type

Secondary

End point timeframe

Baseline, Week 24 and 52

End point values	Placebo	Sirukumab 50 mg q4w	Sirukumab 100 mg q2w
Number of subjects analysed	556	557	557
Units: Units on a Scale
arithmetic mean (standard deviation)
PCS :Change at Week 24	2.290 ( 6.2790 )	5.358 ( 7.3312 )	5.850 ( 7.0677 )
PCS :Change at Week 52	2.423 ( 6.8069 )	5.661 ( 7.7405 )	6.162 ( 7.2277 )
MCS :Change at Week 24	2.892 ( 9.1766 )	4.898 ( 9.6508 )	4.216 ( 9.4819 )
MCS :Change at Week 52	2.690 ( 9.5698 )	5.351 ( 9.6397 )	4.767 ( 9.7991 )

No statistical analyses for this end point

Secondary: Percentage of Subjects With Greater Than or Equal to 4-Point Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Score at Week 8, 16, 24, 36 and 52

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End point title

Percentage of Subjects With Greater Than or Equal to 4-Point Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Score at Week 8, 16, 24, 36 and 52

End point description

Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) is a questionnaire that assesses self-reported tiredness, weakness, and difficulty conducting usual activities due to fatigue. The questionnaire consists of 13 questions that assess a subject’s level of fatigue and tiredness over the last 7 days. Each question is graded on a 5-point scale (0 - 4); and accordingly, the total FACIT Fatigue scores can range from 0 to 52, with lower score reflecting more fatigue and higher scores reflecting less fatigue. FAS was defined as all randomized subjects. Subjects analyzed according to randomized treatment they were assigned to, regardless of treatments they actually received. Last Observation Carried Forward (LOCF) method was used to impute missing values. The last observation at or prior to EE/LE was used to replace the data after EE/LE for subjects who met EE/LE criteria.

End point type

Secondary

End point timeframe

Week 8, 16, 24, 36 and 52

End point values	Placebo	Sirukumab 50 mg q4w	Sirukumab 100 mg q2w
Number of subjects analysed	556	557	557
Units: Percentage of Subjects
number (not applicable)
Week 8	41.0	55.8	54.9
Week 16	42.4	58.0	58.9
Week 24	43.9	61.4	59.4
Week 36	39.7	57.8	56.2
Week 52	41.0	59.1	60.5

No statistical analyses for this end point

Secondary: Change from Baseline in Total Scores of Work Limitations Questionnaire (WLQ) Week 8, 16, 24, 36 and 52

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End point title

Change from Baseline in Total Scores of Work Limitations Questionnaire (WLQ) Week 8, 16, 24, 36 and 52

End point description

The Work Limitations Questionnaire (WLQ) was used to measure the impairment in work-related productivity, with reference to the previous two weeks. Each work-related question is scored from 0 to 4 and the total score ranges from 0-100, with lower scores signifying fewer limitations at work. FAS was defined as all randomized subjects. Subjects analyzed according to randomized treatment they were assigned to, regardless of treatments they actually received. Here 'N'(number of subjects analyzed) signifies subjects who were evaluable for this outcome measure. Last Observation Carried Forward (LOCF) method was used to impute missing values. The last observation at or prior to EE/LE was used to replace the data after EE/LE for subjects who met EE/LE criteria.

End point type

Secondary

End point timeframe

Baseline, Week 8, 16, 24, 36 and 52

End point values	Placebo	Sirukumab 50 mg q4w	Sirukumab 100 mg q2w
Number of subjects analysed	227	223	223
Units: Units on a Scale
arithmetic mean (standard deviation)
Week 8	-0.812 ( 3.6230 )	-1.946 ( 3.8040 )	-2.202 ( 3.8437 )
Week 16	-0.840 ( 4.6414 )	-2.406 ( 4.1403 )	-2.600 ( 4.3066 )
Week 24	-1.019 ( 4.5328 )	-2.765 ( 4.4381 )	-2.884 ( 4.5873 )
Week 36	-0.940 ( 4.7982 )	-2.921 ( 4.4205 )	-2.952 ( 4.5640 )
Week 52	-0.732 ( 5.0288 )	-3.057 ( 4.5290 )	-2.936 ( 4.3940 )

No statistical analyses for this end point

Secondary: Change From Baseline in EuroQol Health State Visual Analogue Scale (EQ VAS)

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End point title

Change From Baseline in EuroQol Health State Visual Analogue Scale (EQ VAS)

End point description

The EuroQol Health State Visual Analogue Scale (EQ VAS) records the respondent’s self-rated health on a vertical line, VAS where the endpoints are labeled as 0= ‘Worst imaginable health state’ and 100= ‘Best imaginable health state’. The EQ VAS can be used as a quantitative measure of health outcome as judged by the individual respondents. FAS included all randomized subjects. Here 'N'(number of subjects analyzed) signifies subjects who were evaluable for this outcome measure. Subjects analyzed according to randomized treatment they were assigned to, regardless of treatments they actually received. Last Observation Carried Forward (LOCF) method was used to impute missing values. The last observation at or prior to EE/LE was used to replace the data after EE/LE for subjects who met EE/LE criteria.

End point type

Secondary

End point timeframe

Baseline, Week 8, 16, 24, and 52

End point values	Placebo	Sirukumab 50 mg q4w	Sirukumab 100 mg q2w
Number of subjects analysed	554	557	556
Units: Units on a Scale
arithmetic mean (standard deviation)
Change at Week 8	5.61 ( 24.415 )	11.64 ( 26.979 )	12.24 ( 26.025 )
Change at Week 16	5.83 ( 26.177 )	14.09 ( 28.581 )	14.36 ( 27.884 )
Change at Week 24	6.71 ( 26.520 )	14.86 ( 28.747 )	16.41 ( 28.830 )
Change at Week 36	8.30 ( 26.144 )	16.80 ( 28.595 )	17.14 ( 28.329 )

No statistical analyses for this end point

Secondary: Change From Baseline in EuroQol EQ-5D-3L Descriptive System

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End point title

Change From Baseline in EuroQol EQ-5D-3L Descriptive System

End point description

The EQ-5D-3L Descriptive System comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension is assessed on a 3-point ordinal scale (1=no problems, 2=some problems, 3=extreme problems). The responses to the five EQ-5D dimensions were scored using a utility-weighted algorithm to derive an EQ-5D health status index score between 0 to 1, with 1.00 indicating "full health" and 0 representing dead. FAS included all randomized subjects. Subjects analyzed according to randomized treatment they were assigned to, regardless of treatments they actually received. LOCF method was used to impute missing values. The last observation at or prior to EE/LE was used to replace the data after EE/LE for subjects who met EE/LE criteria.

End point type

Secondary

End point timeframe

Baseline, Week 8, 16, 24, and 52

End point values	Placebo	Sirukumab 50 mg q4w	Sirukumab 100 mg q2w
Number of subjects analysed	556	557	557
Units: Units on a Scale
arithmetic mean (standard deviation)
Change at Week 8	0.1041 ( 0.31794 )	0.1734 ( 0.32473 )	0.1647 ( 0.30146 )
Change at Week 16	0.1131 ( 0.33788 )	0.1831 ( 0.34875 )	0.1899 ( 0.31149 )
Change at Week 24	0.1263 ( 0.33539 )	0.1885 ( 0.33867 )	0.2057 ( 0.32081 )
Change at Week 52	0.1255 ( 0.34312 )	0.1950 ( 0.33448 )	0.2007 ( 0.32895 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Screening up to Week 120

Adverse event reporting additional description

Safety population included all subjects who received at least 1 partial or complete dose of study agent, analysed in treatment received overtime, regardless randomization.One subject inadvertently received Sirukumab 100 mg instead of Sirukumab 50 mg and therefore reported in Sirukumab 100 mg arm (558) instead of Sirukumab 50 mg (556 subjects).

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

17.0

Reporting group title

W0 to W120-Placebo to Sirukumab 50 mg q4w due to EE/LE or CO

Reporting group description

Subjects who received placebo in the placebo controlled period were rerandomized (due to EE at Week 18 or LE at Week 40 or CO at Week 52) to receive subcutaneous (SC) sirukumab 50 mg q4w dose regimen up to Week 104. Subjects who completed study agent administration up to Week 104 and did not elect for long term extension (LTE) were followed up for safety from Week 104 up to Week 120.

Reporting group title

Week 0 to Week 120-Placebo

Reporting group description

Subjects received matching placebo from week 0 to week 52, every 2 weeks (q2w) until either early escape (EE) at Week 18 or late escape (LE) at Week 40 or crossover (CO) at Week 52 and were rerandomized to subcutaneous (SC) sirukumab 50 mg q4w or sirukumab 100 mg q2w dose regimens up to Week 104. Subjects who completed study agent administration up to Week 104 and did not elect for long term extension (LTE) were followed up for safety from Week 104 up to Week 120.

Reporting group title

W0 to W120- Placebo to Sirukumab 100 mg q2w Due to EE/LE or CO

Reporting group description

Subjects who received placebo in the placebo controlled period were rerandomized (due to EE at Week 18 or LE at Week 40 or CO at Week 52) to receive subcutaneous (SC) sirukumab 100 mg q2w dose up to Week 104. Subjects who completed study agent administration up to Week 104 and did not elect for long term extension (LTE) were followed up for safety from Week 104 up to Week 120.

Reporting group title

W0 to W120-Sirukumab 100 mg q2w

Reporting group description

Subjects received 100 mg of sirukumab SC injections at Weeks 0, 2 and q2w throught Week 104. Subjects who completed study agent administration up to Week 104 and did not elect for long term extension (LTE) were followed up for safety from Week 104 up to Week 120.

Reporting group title

W0 to W120- Sirukumab 50 mg q4w

Reporting group description

Subjects received 50 mg of sirukumab SC injections at Weeks 0, 4, and q4w through Week 104. Subjects who completed study agent administration up to Week 104 and did not elect for long term extension (LTE) were followed up for safety from Week 104 up to Week 120.

Serious adverse events	W0 to W120-Placebo to Sirukumab 50 mg q4w due to EE/LE or CO	Week 0 to Week 120-Placebo	W0 to W120- Placebo to Sirukumab 100 mg q2w Due to EE/LE or CO	W0 to W120-Sirukumab 100 mg q2w	W0 to W120- Sirukumab 50 mg q4w
Total subjects affected by serious adverse events
subjects affected / exposed	30 / 242 (12.40%)	40 / 556 (7.19%)	35 / 241 (14.52%)	97 / 558 (17.38%)	111 / 556 (19.96%)
number of deaths (all causes)	5	1	6	5	7
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute Myeloid Leukaemia
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
Adrenal Adenoma
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Basal Cell Carcinoma
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Benign Neoplasm of Thyroid Gland
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bladder Cancer
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
Bladder Transitional Cell Carcinoma
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Breast Cancer
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	1 / 241 (0.41%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colon Cancer Metastatic
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastric Cancer
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	1 / 241 (0.41%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal Stromal Tumour
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Glioblastoma Multiforme
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intraductal Papilloma of Breast
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Invasive Ductal Breast Carcinoma
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	2 / 558 (0.36%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Leiomyoma
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	1 / 241 (0.41%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung Cancer Metastatic
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
Lung Neoplasm Malignant
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	1 / 241 (0.41%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
Meningioma
subjects affected / exposed	1 / 242 (0.41%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to Bone
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to Central Nervous System
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	1 / 241 (0.41%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neuroendocrine Carcinoma
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oropharyngeal Squamous Cell Carcinoma
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian Clear Cell Carcinoma
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Teratoma
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Uterine Cancer
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Uterine Leiomyoma
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Aortic Aneurysm
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	1 / 241 (0.41%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aortic Dissection
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	1 / 241 (0.41%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
Axillary Vein Thrombosis
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Deep Vein Thrombosis
subjects affected / exposed	1 / 242 (0.41%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Extremity Necrosis
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematoma
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	1 / 242 (0.41%)	1 / 556 (0.18%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	2 / 2	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
Hypotension
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Labile Hypertension
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Necrosis Ischaemic
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral Arterial Occlusive Disease
subjects affected / exposed	1 / 242 (0.41%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral Ischaemia
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Shock
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subclavian Vein Thrombosis
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombosed Varicose Vein
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vasculitis
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Venous Thrombosis Limb
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Abortion Spontaneous
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chest Pain
subjects affected / exposed	1 / 242 (0.41%)	0 / 556 (0.00%)	0 / 241 (0.00%)	2 / 558 (0.36%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Death
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	1 / 241 (0.41%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
Influenza Like Illness
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Medical Device Site Joint Inflammation
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Serositis
subjects affected / exposed	1 / 242 (0.41%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sudden Cardiac Death
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
Immune system disorders
Drug Hypersensitivity
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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
Benign Prostatic Hyperplasia
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	1 / 241 (0.41%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Breast Mass
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cystocele
subjects affected / exposed	1 / 242 (0.41%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endometriosis
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian Cyst
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rectocele
subjects affected / exposed	1 / 242 (0.41%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vaginal Haemorrhage
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Distress Syndrome
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	2 / 558 (0.36%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0
Acute Respiratory Failure
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	1 / 241 (0.41%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Asthma
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	1 / 241 (0.41%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic Obstructive Pulmonary Disease
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	3 / 556 (0.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cough
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Interstitial Lung Disease
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	4 / 556 (0.72%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung Disorder
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural Effusion
subjects affected / exposed	1 / 242 (0.41%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleurisy
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia Aspiration
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax Spontaneous
subjects affected / exposed	1 / 242 (0.41%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary Embolism
subjects affected / exposed	1 / 242 (0.41%)	0 / 556 (0.00%)	2 / 241 (0.83%)	2 / 558 (0.36%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	2 / 2	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary Mass
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary Necrosis
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory Failure
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
Psychiatric disorders
Anxiety
subjects affected / exposed	1 / 242 (0.41%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mental Status Changes
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Suicidal Ideation
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Alanine Aminotransferase Increased
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	1 / 241 (0.41%)	3 / 558 (0.54%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aspartate Aminotransferase Increased
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	2 / 241 (0.83%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood Bilirubin Increased
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	2 / 241 (0.83%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chest X-Ray Abnormal
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic Enzyme Increased
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Liver Function Test Increased
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	1 / 241 (0.41%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Weight Decreased
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Abdominal Injury
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	1 / 241 (0.41%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chemical Peritonitis
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	1 / 241 (0.41%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Concussion
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Contusion
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	1 / 241 (0.41%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Epiphyseal Fracture
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Facial Bones Fracture
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	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 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Femur Fracture
subjects affected / exposed	1 / 242 (0.41%)	1 / 556 (0.18%)	1 / 241 (0.41%)	0 / 558 (0.00%)	2 / 556 (0.36%)
occurrences causally related to treatment / all	1 / 1	1 / 1	1 / 1	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Foot Fracture
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hand Fracture
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hip Fracture
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Humerus Fracture
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Joint Capsule Rupture
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (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
Joint Dislocation
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Kidney Rupture
subjects affected / exposed	1 / 242 (0.41%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Laceration
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ligament Sprain
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower Limb Fracture
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar Vertebral Fracture
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Meniscus Injury
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Multiple Fractures
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Muscle Rupture
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post Procedural Complication
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Postoperative Wound Complication
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Procedural Haemorrhage
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Procedural Pain
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Radius Fracture
subjects affected / exposed	1 / 242 (0.41%)	0 / 556 (0.00%)	0 / 241 (0.00%)	5 / 558 (0.90%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	5 / 5	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rib Fracture
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Road Traffic Accident
subjects affected / exposed	2 / 242 (0.83%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Spinal Compression Fracture
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tendon Injury
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tendon Rupture
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	1 / 241 (0.41%)	1 / 558 (0.18%)	1 / 556 (0.18%)
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
Ulna Fracture
subjects affected / exposed	1 / 242 (0.41%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	1 / 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 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wound Dehiscence
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute Left Ventricular Failure
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Angina Pectoris
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial Fibrillation
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac Failure Congestive
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	1 / 241 (0.41%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiopulmonary Failure
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial Infarction
subjects affected / exposed	1 / 242 (0.41%)	0 / 556 (0.00%)	1 / 241 (0.41%)	1 / 558 (0.18%)	3 / 556 (0.54%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	1 / 1	4 / 4
deaths causally related to treatment / all	1 / 1	0 / 0	1 / 1	1 / 1	0 / 0
Sinus Bradycardia
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Carpal Tunnel Syndrome
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral Infarction
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	1 / 558 (0.18%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
Cerebral Ischaemia
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular Accident
subjects affected / exposed	2 / 242 (0.83%)	0 / 556 (0.00%)	1 / 241 (0.41%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Cervical Myelopathy
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cervical Radiculopathy
subjects affected / exposed	1 / 242 (0.41%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhagic Stroke
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	1 / 242 (0.41%)	1 / 556 (0.18%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertensive Encephalopathy
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intracranial Aneurysm
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic Stroke
subjects affected / exposed	1 / 242 (0.41%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	1 / 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 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	2 / 556 (0.36%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyramidal Tract Syndrome
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Radiculopathy
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reversible Cerebral Vasoconstriction Syndrome
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Transient Ischaemic Attack
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	2 / 558 (0.36%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Trigeminal Neuralgia
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ulnar Nerve Palsy
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	1 / 241 (0.41%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vertebrobasilar Insufficiency
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
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	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	2 / 558 (0.36%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	2 / 558 (0.36%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Amaurosis Fugax
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cataract
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Keratitis
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Retinal Detachment
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Scleritis
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ulcerative Keratitis
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	2 / 556 (0.36%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal Strangulated Hernia
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diverticular Perforation
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Enterocele
subjects affected / exposed	1 / 242 (0.41%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Erosive Duodenitis
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastric Perforation
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastric Polyps
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastric Ulcer
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastric Ulcer Haemorrhage
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	1 / 241 (0.41%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis Erosive
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal Hypomotility
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal Necrosis
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal Perforation
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhoidal Haemorrhage
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Incarcerated Inguinal Hernia
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal Obstruction
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatic Fistula
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Retroperitoneal Haemorrhage
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	1 / 241 (0.41%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	1 / 241 (0.41%)	3 / 558 (0.54%)	2 / 556 (0.36%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	3 / 3	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis Acute
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	1 / 241 (0.41%)	3 / 558 (0.54%)	2 / 556 (0.36%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	3 / 3	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gallbladder Perforation
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	1 / 241 (0.41%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic Cyst
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic Steatosis
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	1 / 241 (0.41%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Jaundice Cholestatic
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Non-Alcoholic Steatohepatitis
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Angioedema
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Decubitus Ulcer
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dermatitis Allergic
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dermatitis Bullous
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dermatitis Contact
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhage Subcutaneous
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	1 / 241 (0.41%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperkeratosis
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin Exfoliation
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin Necrosis
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	1 / 241 (0.41%)	2 / 558 (0.36%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin Ulcer
subjects affected / exposed	1 / 242 (0.41%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Stevens-Johnson Syndrome
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	1 / 241 (0.41%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urticaria
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute Kidney Injury
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	2 / 556 (0.36%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Calculus Urinary
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hydronephrosis
subjects affected / exposed	1 / 242 (0.41%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	1 / 558 (0.18%)	3 / 556 (0.54%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ureterolithiasis
subjects affected / exposed	1 / 242 (0.41%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary Tract Obstruction
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Basedow's Disease
subjects affected / exposed	1 / 242 (0.41%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Goitre
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atlantoaxial Instability
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Back Pain
subjects affected / exposed	1 / 242 (0.41%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bursitis
subjects affected / exposed	1 / 242 (0.41%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chondromalacia
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fistula
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fistula Discharge
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Foot Deformity
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	1 / 241 (0.41%)	2 / 558 (0.36%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral Disc Disorder
subjects affected / exposed	1 / 242 (0.41%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral Disc Protrusion
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar Spinal Stenosis
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal Chest Pain
subjects affected / exposed	1 / 242 (0.41%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	1 / 242 (0.41%)	1 / 556 (0.18%)	1 / 241 (0.41%)	2 / 558 (0.36%)	4 / 556 (0.72%)
occurrences causally related to treatment / all	1 / 1	1 / 1	1 / 1	2 / 2	5 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rheumatoid Arthritis
subjects affected / exposed	0 / 242 (0.00%)	6 / 556 (1.08%)	1 / 241 (0.41%)	5 / 558 (0.90%)	5 / 556 (0.90%)
occurrences causally related to treatment / all	0 / 0	6 / 6	1 / 1	5 / 5	5 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rheumatoid Nodule
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rotator Cuff Syndrome
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal Pain
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spondylolisthesis
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Synovitis
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	1 / 241 (0.41%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Abdominal Abscess
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal Sepsis
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abscess
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abscess Limb
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	4 / 558 (0.72%)	3 / 556 (0.54%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	4 / 4	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abscess Soft Tissue
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	1 / 242 (0.41%)	0 / 556 (0.00%)	0 / 241 (0.00%)	2 / 558 (0.36%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis Perforated
subjects affected / exposed	1 / 242 (0.41%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis Bacterial
subjects affected / exposed	1 / 242 (0.41%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Bacterial Food Poisoning
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bacterial Sepsis
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
Bronchitis
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	2 / 241 (0.83%)	5 / 558 (0.90%)	7 / 556 (1.26%)
occurrences causally related to treatment / all	0 / 0	1 / 1	3 / 3	6 / 6	7 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis Staphylococcal
subjects affected / exposed	1 / 242 (0.41%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Cytomegalovirus Colitis
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dengue Fever
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	1 / 241 (0.41%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Device Related Infection
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	1 / 242 (0.41%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	4 / 556 (0.72%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endophthalmitis
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Epididymitis
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	2 / 556 (0.36%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia Bacteraemia
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Extradural Abscess
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye Infection Fungal
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gangrene
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	1 / 241 (0.41%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	1 / 242 (0.41%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Herpes Zoster
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infected Bite
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infectious Pleural Effusion
subjects affected / exposed	1 / 242 (0.41%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	2 / 556 (0.36%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infective Spondylitis
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral Discitis
subjects affected / exposed	1 / 242 (0.41%)	0 / 556 (0.00%)	1 / 241 (0.41%)	1 / 558 (0.18%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Localised Infection
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung Abscess
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lymphangitis
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Meningitis
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Necrotising Fasciitis
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
Osteomyelitis
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	2 / 558 (0.36%)	2 / 556 (0.36%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteomyelitis Chronic
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Perirectal Abscess
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	2 / 242 (0.83%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	3 / 556 (0.54%)
occurrences causally related to treatment / all	2 / 2	3 / 3	0 / 0	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
Peritonsillar Abscess
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	2 / 556 (0.36%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pharyngitis
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 242 (0.41%)	0 / 556 (0.00%)	1 / 241 (0.41%)	10 / 558 (1.79%)	11 / 556 (1.98%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	12 / 12	11 / 11
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
Pneumonia Bacterial
subjects affected / exposed	1 / 242 (0.41%)	1 / 556 (0.18%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	1 / 1	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 Necrotising
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post Procedural Infection
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Postoperative Wound Infection
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary Tuberculosis
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis Acute
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyoderma
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyonephrosis
subjects affected / exposed	1 / 242 (0.41%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Salpingitis
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	1 / 241 (0.41%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Salpingo-Oophoritis
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	2 / 242 (0.83%)	1 / 556 (0.18%)	1 / 241 (0.41%)	5 / 558 (0.90%)	3 / 556 (0.54%)
occurrences causally related to treatment / all	2 / 2	1 / 1	1 / 1	5 / 5	3 / 3
deaths causally related to treatment / all	1 / 1	0 / 0	1 / 1	0 / 0	1 / 1
Septic Shock
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
Skin Infection
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Soft Tissue Infection
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subcutaneous Abscess
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary Tract Infection
subjects affected / exposed	1 / 242 (0.41%)	0 / 556 (0.00%)	1 / 241 (0.41%)	3 / 558 (0.54%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	4 / 4	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
Varicella
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wound Infection
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatitis E
subjects affected / exposed	0 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	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 / 242 (0.00%)	1 / 556 (0.18%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diabetes Mellitus
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	1 / 556 (0.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	0 / 242 (0.00%)	0 / 556 (0.00%)	0 / 241 (0.00%)	1 / 558 (0.18%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	1 / 242 (0.41%)	0 / 556 (0.00%)	0 / 241 (0.00%)	0 / 558 (0.00%)	0 / 556 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	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	W0 to W120-Placebo to Sirukumab 50 mg q4w due to EE/LE or CO	Week 0 to Week 120-Placebo	W0 to W120- Placebo to Sirukumab 100 mg q2w Due to EE/LE or CO	W0 to W120-Sirukumab 100 mg q2w	W0 to W120- Sirukumab 50 mg q4w
Total subjects affected by non serious adverse events
subjects affected / exposed	113 / 242 (46.69%)	213 / 556 (38.31%)	128 / 241 (53.11%)	353 / 558 (63.26%)	355 / 556 (63.85%)
Investigations
Alanine Aminotransferase Increased
subjects affected / exposed	34 / 242 (14.05%)	23 / 556 (4.14%)	41 / 241 (17.01%)	124 / 558 (22.22%)	108 / 556 (19.42%)
occurrences all number	45	28	57	192	149
Aspartate Aminotransferase Increased
subjects affected / exposed	20 / 242 (8.26%)	17 / 556 (3.06%)	23 / 241 (9.54%)	84 / 558 (15.05%)	63 / 556 (11.33%)
occurrences all number	26	18	30	132	90
Vascular disorders
Hypertension
subjects affected / exposed	14 / 242 (5.79%)	21 / 556 (3.78%)	11 / 241 (4.56%)	45 / 558 (8.06%)	32 / 556 (5.76%)
occurrences all number	15	23	11	55	39
Nervous system disorders
Headache
subjects affected / exposed	8 / 242 (3.31%)	22 / 556 (3.96%)	9 / 241 (3.73%)	28 / 558 (5.02%)	38 / 556 (6.83%)
occurrences all number	9	30	11	46	47
Blood and lymphatic system disorders
Leukopenia
subjects affected / exposed	12 / 242 (4.96%)	7 / 556 (1.26%)	8 / 241 (3.32%)	39 / 558 (6.99%)	37 / 556 (6.65%)
occurrences all number	13	9	11	67	62
Neutropenia
subjects affected / exposed	9 / 242 (3.72%)	5 / 556 (0.90%)	8 / 241 (3.32%)	34 / 558 (6.09%)	40 / 556 (7.19%)
occurrences all number	11	5	12	61	86
General disorders and administration site conditions
Injection Site Erythema
subjects affected / exposed	11 / 242 (4.55%)	6 / 556 (1.08%)	31 / 241 (12.86%)	70 / 558 (12.54%)	50 / 556 (8.99%)
occurrences all number	27	8	126	413	169
Injection Site Pruritus
subjects affected / exposed	3 / 242 (1.24%)	1 / 556 (0.18%)	14 / 241 (5.81%)	34 / 558 (6.09%)	12 / 556 (2.16%)
occurrences all number	5	1	33	135	40
Injection Site Swelling
subjects affected / exposed	3 / 242 (1.24%)	0 / 556 (0.00%)	13 / 241 (5.39%)	27 / 558 (4.84%)	15 / 556 (2.70%)
occurrences all number	5	0	38	66	26
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	2 / 242 (0.83%)	21 / 556 (3.78%)	9 / 241 (3.73%)	23 / 558 (4.12%)	28 / 556 (5.04%)
occurrences all number	2	26	9	28	31
Musculoskeletal and connective tissue disorders
Rheumatoid Arthritis
subjects affected / exposed	9 / 242 (3.72%)	36 / 556 (6.47%)	10 / 241 (4.15%)	29 / 558 (5.20%)	46 / 556 (8.27%)
occurrences all number	11	39	12	37	59
Infections and infestations
Bronchitis
subjects affected / exposed	17 / 242 (7.02%)	27 / 556 (4.86%)	13 / 241 (5.39%)	36 / 558 (6.45%)	48 / 556 (8.63%)
occurrences all number	22	29	14	46	62
Nasopharyngitis
subjects affected / exposed	16 / 242 (6.61%)	53 / 556 (9.53%)	19 / 241 (7.88%)	67 / 558 (12.01%)	70 / 556 (12.59%)
occurrences all number	26	67	24	99	123
Pharyngitis
subjects affected / exposed	5 / 242 (2.07%)	13 / 556 (2.34%)	8 / 241 (3.32%)	24 / 558 (4.30%)	30 / 556 (5.40%)
occurrences all number	9	16	14	28	38
Upper Respiratory Tract Infection
subjects affected / exposed	28 / 242 (11.57%)	63 / 556 (11.33%)	20 / 241 (8.30%)	72 / 558 (12.90%)	76 / 556 (13.67%)
occurrences all number	37	76	31	122	123
Urinary Tract Infection
subjects affected / exposed	8 / 242 (3.31%)	13 / 556 (2.34%)	13 / 241 (5.39%)	23 / 558 (4.12%)	30 / 556 (5.40%)
occurrences all number	10	15	15	31	42

More information

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Were there any global substantial amendments to the protocol? Yes

06 Nov 2012

Clarified that in the event of clinically significant decreases in neutrophils or platelet counts, MTX should be temporarily or permanently discontinued

18 Feb 2014

Increased the total number of subjects to be enrolled to approximately 1,650 with approximately 550 subjects in each of the 3 treatment groups. The sample size of CNTO136ARA3002 was increased to ensure that the overall safety database size of the Phase 3 RA program for sirukumab was maintained despite a reduction in enrollment in CNTO136ARA3003. Along with the increase in subject enrollment, there was an increase in power of the study.

07 May 2014

Added acute diverticulitis requiring antibiotic treatment and GI perforation to the list of conditions that would result in the permanent discontinuation of study agent administrations. Power calculations were revised due to an increase in sample size.

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.

The short pure placebo-controlled period (through Week 18) and the EE at Week 18 and LE at Week 40 for subjects in the placebo group might have affected the ability to directly compare safety between sirukumab and placebo groups through Week 52.

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Clinical trials

Clinical Trial Results: A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel Group Study of CNTO 136 (sirukumab), a Human Anti-IL-6 Monoclonal Antibody, Administered Subcutaneously, in Subjects with Active Rheumatoid Arthritis Despite DMARD Therapy

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Subjects With an American College of Rheumatology (ACR) 20 Response at Week 16

Primary: Percentage of Subjects With an American College of Rheumatology (ACR) 20 Response at Week 16

Primary: Change from Baseline in van der Heijde-modified Sharp (vdH-S) Score at Week 52

Primary: Change from Baseline in van der Heijde-modified Sharp (vdH-S) Score at Week 52

Secondary: Change from Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 24

Secondary: Change from Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 24

Secondary: Percentage of Subjects With an American College of Rheumatology (ACR) 50 Response at Week 24

Secondary: Percentage of Subjects With an American College of Rheumatology (ACR) 50 Response at Week 24

Secondary: Percentage of Subjects With Disease Activity Index Score 28 (DAS28) (C-reactive protein [CRP]) Remission at Week 24

Secondary: Percentage of Subjects With Disease Activity Index Score 28 (DAS28) (C-reactive protein [CRP]) Remission at Week 24

Secondary: Percentage of Subjects With Major Clinical Response (MCR) at Week 52

Secondary: Percentage of Subjects With Major Clinical Response (MCR) at Week 52

Secondary: Percentage of Subjects With an American College of Rheumatology (ACR) 20 Response Through Week 52

Secondary: Percentage of Subjects With an American College of Rheumatology (ACR) 20 Response Through Week 52

Secondary: Percentage of Subjects With an American College of Rheumatology (ACR) 50 Response

Secondary: Percentage of Subjects With an American College of Rheumatology (ACR) 50 Response

Secondary: Percentage of Subjects With an American College of Rheumatology (ACR) 70 Response Through Week 52

Secondary: Percentage of Subjects With an American College of Rheumatology (ACR) 70 Response Through Week 52

Secondary: Percentage of Subjects With an American College of Rheumatology (ACR) 90 Response Through Week 52

Secondary: Percentage of Subjects With an American College of Rheumatology (ACR) 90 Response Through Week 52

Secondary: Percentage of Subjects With Disease Activity Index Score 28 (DAS28) C-reactive Protein (CRP) Response Through Week 52

Secondary: Percentage of Subjects With Disease Activity Index Score 28 (DAS28) C-reactive Protein (CRP) Response Through Week 52

Secondary: Change From Baseline in Disease Activity Index Score 28 (DAS28) C-reactive Protein (CRP) Through Week 52

Secondary: Change From Baseline in Disease Activity Index Score 28 (DAS28) C-reactive Protein (CRP) Through Week 52

Secondary: Percentage of Subjects with Disease Activity Index Score 28 (DAS28) (C-reactive protein [CRP]) Remission Through Week 52

Secondary: Percentage of Subjects with Disease Activity Index Score 28 (DAS28) (C-reactive protein [CRP]) Remission Through Week 52

Secondary: Change From Baseline in Simplified Disease Activity Index (SDAI) Score Through Week 52

Secondary: Change From Baseline in Simplified Disease Activity Index (SDAI) Score Through Week 52

Secondary: Change From Baseline in Clinical Disease Activity Index (CDAI) Score Through Week 52

Secondary: Change From Baseline in Clinical Disease Activity Index (CDAI) Score Through Week 52

Secondary: Percentage of Subjects With Simplified Disease Activity Index based (SDAI-based) American College of Rheumatology (ACR)/ European League Against Rheumatism (EULAR) Remission Through Week 52

Secondary: Percentage of Subjects With Simplified Disease Activity Index based (SDAI-based) American College of Rheumatology (ACR)/ European League Against Rheumatism (EULAR) Remission Through Week 52

Secondary: Percentage of Subjects With Boolean-based American College of Rheumatology (ACR)/ European League Against Rheumatism (EULAR) Remission Through Week 52

Secondary: Percentage of Subjects With Boolean-based American College of Rheumatology (ACR)/ European League Against Rheumatism (EULAR) Remission Through Week 52

Secondary: Change from Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score Through Week 52

Secondary: Change from Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score Through Week 52

Secondary: Area Under the Curve (AUC) of Change from Baseline in HAQ-DI Score From Week 0 Through Week 24 and From Week 0 Through Week 52

Secondary: Area Under the Curve (AUC) of Change from Baseline in HAQ-DI Score From Week 0 Through Week 24 and From Week 0 Through Week 52

Secondary: Percentage of Subjects With Health Assessment Questionnaire-Disability Index (HAQ-DI) Response Through Week 52

Secondary: Percentage of Subjects With Health Assessment Questionnaire-Disability Index (HAQ-DI) Response Through Week 52

Secondary: Percentage of Subjects With Health Assessment Questionnaire-Disability Index (HAQ-DI) Score of Less Than or Equal to 0.5

Secondary: Percentage of Subjects With Health Assessment Questionnaire-Disability Index (HAQ-DI) Score of Less Than or Equal to 0.5

Secondary: Change from Baseline in van der Heijde-modified Sharp (vdH-S) Score at Week 24

Secondary: Change from Baseline in van der Heijde-modified Sharp (vdH-S) Score at Week 24

Secondary: Change From Baseline in van der Heijde-modified Sharp (vdH-S) Sub-score by Type of Damage (erosion or JSN) at Week 24 and 52

Secondary: Change From Baseline in van der Heijde-modified Sharp (vdH-S) Sub-score by Type of Damage (erosion or JSN) at Week 24 and 52

Secondary: Change from Baseline in van der Heijde-modified Sharp (vdH-S) Sub-score by Region Hand or Feet and Type Erosion or JSN at Week 24 and 52

Secondary: Change from Baseline in van der Heijde-modified Sharp (vdH-S) Sub-score by Region Hand or Feet and Type Erosion or JSN at Week 24 and 52

Secondary: Percentage of Subjects With Change From Baseline in van der Heijde Modified Sharp Score (vdH-S Score) Greater Than Smallest Detectable Change (SDC) at Weeks 24 and 52

Secondary: Percentage of Subjects With Change From Baseline in van der Heijde Modified Sharp Score (vdH-S Score) Greater Than Smallest Detectable Change (SDC) at Weeks 24 and 52

Secondary: Percentage of Subjects With a Change of Less Than or Equal to 0 From Baseline in van der Heijde Modified Sharp (vdH-S) Score at Weeks 24 and 52

Secondary: Percentage of Subjects With a Change of Less Than or Equal to 0 From Baseline in van der Heijde Modified Sharp (vdH-S) Score at Weeks 24 and 52

Secondary: Change From Baseline in van der Heijde Modified Sharp Score (vdH-S Score) by Reader at Weeks 24 and 52

Secondary: Change From Baseline in van der Heijde Modified Sharp Score (vdH-S Score) by Reader at Weeks 24 and 52

Secondary: Change From Baseline in Serum C-reactive protein (CRP) Levels Through Week 52

Secondary: Change From Baseline in Serum C-reactive protein (CRP) Levels Through Week 52

Secondary: Change From Baseline in the Duration of Morning Stiffness Through Week 52

Secondary: Change From Baseline in the Duration of Morning Stiffness Through Week 52

Secondary: Change From Baseline in Physical and Mental Component Summary (MCS) Scores of 36-Item Short Form Health Survey (SF-36) at Weeks 24 and 52

Secondary: Change From Baseline in Physical and Mental Component Summary (MCS) Scores of 36-Item Short Form Health Survey (SF-36) at Weeks 24 and 52

Secondary: Percentage of Subjects With Greater Than or Equal to 4-Point Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Score at Week 8, 16, 24, 36 and 52

Secondary: Percentage of Subjects With Greater Than or Equal to 4-Point Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Score at Week 8, 16, 24, 36 and 52

Secondary: Change from Baseline in Total Scores of Work Limitations Questionnaire (WLQ) Week 8, 16, 24, 36 and 52

Secondary: Change from Baseline in Total Scores of Work Limitations Questionnaire (WLQ) Week 8, 16, 24, 36 and 52

Secondary: Change From Baseline in EuroQol Health State Visual Analogue Scale (EQ VAS)

Secondary: Change From Baseline in EuroQol Health State Visual Analogue Scale (EQ VAS)

Secondary: Change From Baseline in EuroQol EQ-5D-3L Descriptive System

Secondary: Change From Baseline in EuroQol EQ-5D-3L Descriptive System

Adverse events

Adverse events

Clinical Trial Results:
A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel Group Study of CNTO 136 (sirukumab), a Human Anti-IL-6 Monoclonal Antibody, Administered Subcutaneously, in Subjects with Active Rheumatoid Arthritis Despite DMARD Therapy