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Clinical Trial Results:
A randomized, double-blind, parallel group, international study to evaluate the safety and efficacy of ocrelizumab compared to placebo in patients with active rheumatoid arthritis continuing methotrexate treatment

Summary
EudraCT number	2006-005147-28
Trial protocol	DE BE ES FR AT GR GB
Global end of trial date	22 Apr 2015

Results information
Results version number	v2(current)
This version publication date	06 Jan 2018
First version publication date	04 Aug 2017
Other versions	v1
Version creation reason
Summary report(s)	WA20494_CSR synopsis

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

WA20494

ISRCTN number

US NCT number

NCT00406419

WHO universal trial number (UTN)

Sponsor organisation name

F. Hoffmann-La Roche AG

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, CH-4070

Public contact

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

Scientific contact

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

22 Apr 2015

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

22 Apr 2015

Was the trial ended prematurely?

Main objective of the trial

To determine the efficacy and safety of ocrelizumab versus placebo in reducing the signs and symptoms of rheumatoid arthritis (RA), when used in combination with methotrexate (MTX) in subjects with active RA who have an inadequate response to MTX therapy.

Protection of trial subjects

All study subjects were required to read and sign an Informed Consent Form.

Background therapy

Every patient had to take methotrexate.

Evidence for comparator

Comparator was placebo.

Actual start date of recruitment

30 Nov 2006

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

18 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 44

Country: Number of subjects enrolled

Australia: 6

Country: Number of subjects enrolled

Austria: 6

Country: Number of subjects enrolled

Belgium: 4

Country: Number of subjects enrolled

Brazil: 95

Country: Number of subjects enrolled

Canada: 34

Country: Number of subjects enrolled

China: 22

Country: Number of subjects enrolled

France: 19

Country: Number of subjects enrolled

Germany: 27

Country: Number of subjects enrolled

Greece: 4

Country: Number of subjects enrolled

Guatemala: 8

Country: Number of subjects enrolled

Israel: 18

Country: Number of subjects enrolled

Mexico: 79

Country: Number of subjects enrolled

New Zealand: 9

Country: Number of subjects enrolled

Panama: 9

Country: Number of subjects enrolled

Peru: 32

Country: Number of subjects enrolled

Korea, Republic of: 23

Country: Number of subjects enrolled

Russian Federation: 103

Country: Number of subjects enrolled

Spain: 15

Country: Number of subjects enrolled

Taiwan: 27

Country: Number of subjects enrolled

Thailand: 25

Country: Number of subjects enrolled

Ukraine: 26

Country: Number of subjects enrolled

United States: 360

Country: Number of subjects enrolled

United Kingdom: 20

Worldwide total number of subjects

1015

EEA total number of subjects

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)

878

From 65 to 84 years

135

85 years and over

Subject disposition

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Recruitment details

Screening details

A total of 1015 subjects were enrolled in the study. The study consisted of 3 parts: double-blind treatment period (Day 1 - Week 48); study extension period (during which eligible subjects could receive open-label treatment with ocrelizumab, at the discretion of the investigator); safety follow-up period.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Placebo × 2 IV + MTX

Arm description

Subjects received two intravenous (IV) infusion matching placebo to ocrelizumab on Day 1 and Day 15. A repeat course was administered at Weeks 24 and 26. Methotrexate 7.5-25 milligram (mg) was administered weekly.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Matching placebo to ocrelizumab two IV infusions on Day 1 and Day 15.

Investigational medicinal product name

Methotrexate

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Methotrexate 7.5-25 mg tablet was administered weekly.

Ocrelizumab 200 mg × 2 IV + MTX

Arm description

Subjects received two IV infusion of ocrelizumab 200 mg on Day 1 and Day 15. A repeat course was administered at Weeks 24 and 26. Methotrexate 7.5-25 mg was administered weekly.

Arm type

Experimental

Investigational medicinal product name

Ocrelizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Two IV infusions Ocrelizumab 200 mg on Day 1 and Day 15.

Investigational medicinal product name

Methotrexate

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Methotrexate 7.5-25 mg tablet was administered weekly.

Ocrelizumab 500 mg × 2 IV + MTX

Arm description

Subjects received two IV infusion of ocrelizumab 500 mg on Day 1 and Day 15. A repeat course was administered at Weeks 24 and 26. Methotrexate 7.5-25 mg was administered weekly.

Arm type

Experimental

Investigational medicinal product name

Methotrexate

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Methotrexate 7.5-25mg tablet was administered weekly.

Investigational medicinal product name

Ocrelizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Two IV infusions Ocrelizumab 500 mg on Day 1 and Day 15.

Number of subjects in period 1	Placebo × 2 IV + MTX	Ocrelizumab 200 mg × 2 IV + MTX	Ocrelizumab 500 mg × 2 IV + MTX
Started	324	344	347
Completed	0	0	0
Not completed	324	344	347
Adverse Event	10	12	16
Other	260	288	282
Death	3	1	4
NOn-Compliance with Study Drug	5	6	3
Withdrawal by Subject	17	24	26
Lost to follow-up	11	10	5
Protocol deviation	6	2	5
Lack of efficacy	12	1	6

Baseline characteristics

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Reporting group title

Placebo × 2 IV + MTX

Reporting group description

Reporting group title

Ocrelizumab 200 mg × 2 IV + MTX

Reporting group description

Subjects received two IV infusion of ocrelizumab 200 mg on Day 1 and Day 15. A repeat course was administered at Weeks 24 and 26. Methotrexate 7.5-25 mg was administered weekly.

Reporting group title

Ocrelizumab 500 mg × 2 IV + MTX

Reporting group description

Subjects received two IV infusion of ocrelizumab 500 mg on Day 1 and Day 15. A repeat course was administered at Weeks 24 and 26. Methotrexate 7.5-25 mg was administered weekly.

Reporting group values	Placebo × 2 IV + MTX	Ocrelizumab 200 mg × 2 IV + MTX	Ocrelizumab 500 mg × 2 IV + MTX	Total
Number of subjects	324	344	347	1015
Age Categorical
Units: Subjects
Age Continuous
Units: years
arithmetic mean (standard deviation)	50.5 ( 11.6 )	51.8 ( 12.0 )	50.8 ( 12.3 )	-
Gender Categorical
Units: Subjects
Female	251	284	285	820
Male	73	60	62	195

End points

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Reporting group title

Placebo × 2 IV + MTX

Reporting group description

Reporting group title

Ocrelizumab 200 mg × 2 IV + MTX

Reporting group description

Subjects received two IV infusion of ocrelizumab 200 mg on Day 1 and Day 15. A repeat course was administered at Weeks 24 and 26. Methotrexate 7.5-25 mg was administered weekly.

Reporting group title

Ocrelizumab 500 mg × 2 IV + MTX

Reporting group description

Subjects received two IV infusion of ocrelizumab 500 mg on Day 1 and Day 15. A repeat course was administered at Weeks 24 and 26. Methotrexate 7.5-25 mg was administered weekly.

Primary: Percentage of Subjects with American College of Rheumatology (ACR) 20 Response at Week 24

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End point title

Percentage of Subjects with American College of Rheumatology (ACR) 20 Response at Week 24

End point description

ACR20 is defined as 20 percent improvement respectively in: a) swollen joint count (SJC) and tender joint count (TJC) and b) Three of the following 5 assessments: Subject's global assessment of pain by VAS Subject's global assessment of disease activity (VAS) Investigator/Physician's global assessment of disease activity (VAS) Subject's assessment of disability measured by HAQ-DI Acute phase reactant (ESR or CRP). Intent-to-treat (ITT) population included all randomised subjects who had received any part of an infusion of study medication. Here, the number of subjects analysed signifies subjects evaluated for this endpoint.

End point type

Primary

End point timeframe

Week 24

End point values	Placebo × 2 IV + MTX	Ocrelizumab 200 mg × 2 IV + MTX	Ocrelizumab 500 mg × 2 IV + MTX
Number of subjects analysed	319	343	343
Units: Percentage of Subjects
number (confidence interval 95%)	35.7 (30.5 to 41.0)	56.9 (51.6 to 62.1)	54.5 (49.2 to 59.8)

Ocrelizumab 500 mg vs Placebo

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX

Number of subjects included in analysis

662

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Weighted difference

Point estimate

18.5

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

25.9

Ocrelizumab 200 mg vs Placebo

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX

Number of subjects included in analysis

662

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Weighted difference

Point estimate

21.4

Confidence interval

level

95%

sides

2-sided

lower limit

14.1

upper limit

28.8

Primary: Percentage of Subjects with ACR20 Response at Week 48

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End point title

Percentage of Subjects with ACR20 Response at Week 48

End point description

ACR20 is defined as 20 percent improvement respectively in: a) swollen joint count (SJC) and tender joint count (TJC) and b) Three of the following 5 assessments: Subject's global assessment of pain by VAS Subject's global assessment of disease activity (VAS) Investigator/Physician's global assessment of disease activity (VAS) Subject's assessment of disability measured by HAQ-DI Acute phase reactant (ESR or CRP). ITT population included all randomised subjects who had received any part of an infusion of study medication. Here, the number of subjects analysed signifies subjects evaluated for this endpoint.

End point type

Primary

End point timeframe

Week 48

End point values	Placebo × 2 IV + MTX	Ocrelizumab 200 mg × 2 IV + MTX	Ocrelizumab 500 mg × 2 IV + MTX
Number of subjects analysed	319	343	343
Units: Percentage of Subjects
number (confidence interval 95%)	27.6 (22.7 to 32.5)	58.3 (53.1 to 63.5)	62.1 (57.0 to 67.2)

Ocrelizumab 200 mg vs Placebo

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX

Number of subjects included in analysis

662

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Weighted difference

Point estimate

30.8

Confidence interval

level

95%

sides

2-sided

lower limit

23.7

upper limit

37.9

Ocrelizumab 500 mg vs Placebo

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX

Number of subjects included in analysis

662

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Weighted difference

Point estimate

34.5

Confidence interval

level

95%

sides

2-sided

lower limit

27.4

upper limit

41.5

Primary: Percentage of Subjects With Adverse Events (AEs)

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End point title

Percentage of Subjects With Adverse Events (AEs) ^[1]

End point description

An AE was defined as any untoward medical occurrence in a subject administered a pharmaceutical product which does not necessarily have a causal relationship with the treatment. Pre-existing conditions which worsened during the study were also reported as AEs. The safety population included all subjects who were randomized and received any part of an infusion of study drug and provided at least one assessment of safety.

End point type

Primary

End point timeframe

Up to 8.5 years

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistical analysis was planned to be reported for this endpoint.

End point values	Placebo × 2 IV + MTX	Ocrelizumab 200 mg × 2 IV + MTX	Ocrelizumab 500 mg × 2 IV + MTX
Number of subjects analysed	320	343	343
Units: Percentage of Subjects
number (not applicable)	79.4	82.2	83.7

No statistical analyses for this end point

Secondary: Percentage of Subjects With a Major Clinical Response (ACR70 for ≥ 6 months) at Week 48

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End point title

Percentage of Subjects With a Major Clinical Response (ACR70 for ≥ 6 months) at Week 48

End point description

ACR70 is defined as 70 percent improvement respectively in: a) swollen joint count (SJC) and tender joint count (TJC) and b) Three of the following 5 assessments: Subject's global assessment of pain by VAS Subject's global assessment of disease activity (VAS) Investigator/Physician's global assessment of disease activity (VAS) Subject's assessment of disability measured by HAQ-DI Acute phase reactant (ESR or CRP). ITT population included all randomised subjects who had received any part of an infusion of study medication. Here, the number of subjects analysed signifies subjects evaluated for this endpoint.

End point type

Secondary

End point timeframe

Week 48

End point values	Placebo × 2 IV + MTX	Ocrelizumab 200 mg × 2 IV + MTX	Ocrelizumab 500 mg × 2 IV + MTX
Number of subjects analysed	320	343	343
Units: Percentage of Subjects
number (confidence interval 95%)	0.9 (0.0 to 2.0)	6.1 (3.6 to 8.7)	7.3 (4.5 to 10.0)

Ocrelizumab 200 mg vs Placebo

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX

Number of subjects included in analysis

663

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0007

Method

Cochran-Mantel-Haenszel

Parameter type

Weighted difference

Point estimate

5.1

Confidence interval

level

95%

sides

2-sided

lower limit

2.2

upper limit

8.1

Ocrelizumab 500 mg vs Placebo

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX

Number of subjects included in analysis

663

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Weighted difference

Point estimate

6.3

Confidence interval

level

95%

sides

2-sided

lower limit

3.1

upper limit

9.4

Secondary: Percentage of Subjects Achieving Disease Activity Score 28 (DAS28) Remission (DAS28 < 2.6) at Weeks 24 and 48

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End point title

Percentage of Subjects Achieving Disease Activity Score 28 (DAS28) Remission (DAS28 < 2.6) at Weeks 24 and 48

End point description

The Disease Activity Score (DAS28) score is a measure of the subject's disease activity. It is based on the tender joint count (28 joints), swollen joint count (28 joints), patient's global assessment of disease activity and Erythrocyte Sedimentation Rate (ESR). DAS28 total scores range from 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. A negative change from Baseline indicated improvement. ITT population included all randomised subjects who had received any part of an infusion of study medication. Here, the number of subjects analysed signifies subjects evaluated for this endpoint. 'n' signifies the number of subjects evaluated at a specified time point.

End point type

Secondary

End point timeframe

Week 24, 48

End point values	Placebo × 2 IV + MTX	Ocrelizumab 200 mg × 2 IV + MTX	Ocrelizumab 500 mg × 2 IV + MTX
Number of subjects analysed	320	343	343
Units: Percentage of Subjects
number (confidence interval 95%)
Week 24 (n= 319, 343, 343)	5.3 (2.9 to 7.8)	7.9 (5.0 to 10.7)	10.8 (7.5 to 14.1)
Week 48 (n= 319, 343, 343)	5.3 (2.9 to 7.8)	16.0 (12.2 to 19.9)	17.5 (13.5 to 21.5)

Ocrelizumab 200 mg vs Placebo at Week 24

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX

Number of subjects included in analysis

663

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1472

Method

Cochran-Mantel-Haenszel

Parameter type

Weighted difference

Point estimate

2.9

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

6.7

Ocrelizumab 500 mg vs Placebo at Week 24

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX

Number of subjects included in analysis

663

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0082

Method

Cochran-Mantel-Haenszel

Parameter type

Weighted difference

Point estimate

5.7

Confidence interval

level

95%

sides

2-sided

lower limit

1.5

upper limit

9.9

Ocrelizumab 200 mg vs Placebo at Week 48

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX

Number of subjects included in analysis

663

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Weighted difference

Point estimate

10.7

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

15.4

Ocrelizumab 500 mg vs Placebo at Week 48

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX

Number of subjects included in analysis

663

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Weighted difference

Point estimate

12.1

Confidence interval

level

95%

sides

2-sided

lower limit

7.3

upper limit

Secondary: Change From Baseline in DAS28 at Weeks 24 and 48

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End point title

Change From Baseline in DAS28 at Weeks 24 and 48

End point description

End point type

Secondary

End point timeframe

Baseline, Week 24, 48

End point values	Placebo × 2 IV + MTX	Ocrelizumab 200 mg × 2 IV + MTX	Ocrelizumab 500 mg × 2 IV + MTX
Number of subjects analysed	320	343	343
Units: Units on a Scale
arithmetic mean (standard deviation)
Baseline (n= 316, 340, 336)	6.42 ( 1.103 )	6.40 ( 1.143 )	6.40 ( 1.077 )
Change at Week 24 (n= 227, 299, 300)	-1.33 ( 1.329 )	-2.00 ( 1.248 )	-2.02 ( 1.310 )
Change at Week 48 (n= 187, 271, 278)	-1.38 ( 1.290 )	-2.42 ( 1.504 )	-2.68 ( 1.475 )

Ocrelizumab 200 mg vs Placebo at Week 24

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX

Number of subjects included in analysis

663

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

ANOVA

Parameter type

Adjusted mean difference

Point estimate

-0.6

Confidence interval

level

95%

sides

2-sided

lower limit

-0.9

upper limit

-0.4

Ocrelizumab 500 mg vs Placebo at Week 24

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX

Number of subjects included in analysis

663

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

ANOVA

Parameter type

Adjusted mean difference

Point estimate

-0.7

Confidence interval

level

95%

sides

2-sided

lower limit

-0.9

upper limit

-0.5

Ocrelizumab 200 mg vs Placebo at Week 48

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX

Number of subjects included in analysis

663

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

ANOVA

Parameter type

Adjusted mean difference

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-1.3

upper limit

-0.8

Ocrelizumab 500 mg vs Placebo at Week 48

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX

Number of subjects included in analysis

663

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

ANOVA

Parameter type

Adjusted mean difference

Point estimate

-1.3

Confidence interval

level

95%

sides

2-sided

lower limit

-1.5

upper limit

-1

Secondary: European League Against Rheumatism (EULAR) Response Rates (Categorical DAS Responders) at Weeks 24 and 48

Top of page

End point title

European League Against Rheumatism (EULAR) Response Rates (Categorical DAS Responders) at Weeks 24 and 48

End point description

DAS 28 score is a measure of the subject's disease activity. It is based on the tender joint count (28 joints), swollen joint count (28 joints), patient's global assessment of disease activity and ESR. DAS28 total scores range from 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. A negative change from Baseline indicated improvement. EULAR Good response: DAS28 ≤ 3.2 and a change from Baseline < -1.2. EULAR Moderate response: DAS28 >3.2 to ≤ 5.1 or a change from Baseline < -0.6 to ≥ -1.2. ITT population included all randomised subjects who had received any part of an infusion of study medication. Data for good /moderate response are grouped. Here, the number of subjects analysed signifies subjects evaluated for this endpoint.

End point type

Secondary

End point timeframe

Week 24, 48

End point values	Placebo × 2 IV + MTX	Ocrelizumab 200 mg × 2 IV + MTX	Ocrelizumab 500 mg × 2 IV + MTX
Number of subjects analysed	320	343	343
Units: Percentage of Subjects
number (not applicable)
Week 24	41.6	68.8	70.0
Week 48	35.3	65.9	72.0

Ocrelizumab 200 mg vs Placebo at Week 24

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX

Number of subjects included in analysis

663

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

ANOVA

Parameter type

Odds ratio (OR)

Point estimate

2.83

Confidence interval

level

95%

sides

2-sided

lower limit

2.09

upper limit

3.82

Ocrelizumab 500 mg vs Placebo at Week 24

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX

Number of subjects included in analysis

663

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

ANOVA

Parameter type

Odds ratio (OR)

Point estimate

3.04

Confidence interval

level

95%

sides

2-sided

lower limit

2.24

upper limit

4.11

Ocrelizumab 200 mg vs Placebo at Week 48

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX

Number of subjects included in analysis

663

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

ANOVA

Parameter type

Odds ratio (OR)

Point estimate

3.75

Confidence interval

level

95%

sides

2-sided

lower limit

2.77

upper limit

5.1

Ocrelizumab 500 mg vs Placebo at Week 48

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX

Number of subjects included in analysis

663

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

ANOVA

Parameter type

Odds ratio (OR)

Point estimate

4.58

Confidence interval

level

95%

sides

2-sided

lower limit

3.36

upper limit

6.23

Secondary: Percentage of Subjects Achieving an ACR50 Response at Weeks 24 and 48

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End point title

Percentage of Subjects Achieving an ACR50 Response at Weeks 24 and 48

End point description

ACR50 is defined as 50 percent improvement respectively in: a) swollen joint count (SJC) and tender joint count (TJC) and b) Three of the following 5 assessments: Subject's global assessment of pain by VAS Subject's global assessment of disease activity (VAS) Investigator/Physician's global assessment of disease activity (VAS) Subject's assessment of disability measured by HAQ-DI Acute phase reactant (ESR or CRP). ITT population included all randomised subjects who had received any part of an infusion of study medication. Here, the number of subjects analysed signifies subjects evaluated for this endpoint.

End point type

Secondary

End point timeframe

Week 24, 48

End point values	Placebo × 2 IV + MTX	Ocrelizumab 200 mg × 2 IV + MTX	Ocrelizumab 500 mg × 2 IV + MTX
Number of subjects analysed	320	343	343
Units: percentage of subjects
number (confidence interval 95%)
Week 24 (n= 319, 343, 343)	16.3 (12.2 to 20.4)	31.8 (26.9 to 36.7)	31.2 (26.3 to 36.1)
Week 48 (n= 319, 343, 343)	12.9 (9.2 to 16.5)	39.9 (34.8 to 45.1)	36.7 (31.6 to 41.8)

Ocrelizumab 200 mg vs Placebo at Week 24

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX

Number of subjects included in analysis

663

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Weighted difference

Point estimate

15.8

Confidence interval

level

95%

sides

2-sided

lower limit

9.5

upper limit

22.2

Ocrelizumab 500 mg vs Placebo at Week 24

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX

Number of subjects included in analysis

663

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Weighted difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

8.6

upper limit

21.4

Ocrelizumab 200 mg vs Placebo at Week 48

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX

Number of subjects included in analysis

663

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Weighted difference

Point estimate

27.3

Confidence interval

level

95%

sides

2-sided

lower limit

21.1

upper limit

33.6

Ocrelizumab 500 mg vs Placebo at Week 48

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX

Number of subjects included in analysis

663

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Weighted difference

Point estimate

23.7

Confidence interval

level

95%

sides

2-sided

lower limit

17.4

upper limit

29.9

Secondary: Percentage of Subjects Achieving an ACR70 Response at Weeks 24 and 48

Top of page

End point title

Percentage of Subjects Achieving an ACR70 Response at Weeks 24 and 48

End point description

End point type

Secondary

End point timeframe

Week 24, 48

End point values	Placebo × 2 IV + MTX	Ocrelizumab 200 mg × 2 IV + MTX	Ocrelizumab 500 mg × 2 IV + MTX
Number of subjects analysed	320	343	343
Units: percentage of subjects
number (confidence interval 95%)
Week 24 (n= 319, 343, 343)	5.6 (3.1 to 8.2)	14.3 (10.6 to 18.0)	12.2 (8.8 to 15.7)
Week 48 (n= 319, 343, 343)	6.6 (3.9 to 9.3)	20.7 (16.4 to 25.0)	22.4 (18.0 to 26.9)

Ocrelizumab 200 mg vs Placebo at Week 24

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX

Number of subjects included in analysis

663

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0002

Method

Cochran-Mantel-Haenszel

Parameter type

Weighted difference

Point estimate

8.8

Confidence interval

level

95%

sides

2-sided

lower limit

4.2

upper limit

13.3

Ocrelizumab 500 mg vs Placebo at Week 24

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX

Number of subjects included in analysis

663

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0023

Method

Cochran-Mantel-Haenszel

Parameter type

Weighted difference

Point estimate

6.8

Confidence interval

level

95%

sides

2-sided

lower limit

2.4

upper limit

11.2

Ocrelizumab 200 mg vs Placebo at Week 48

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX

Number of subjects included in analysis

663

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Weighted difference

Point estimate

14.3

Confidence interval

level

95%

sides

2-sided

lower limit

9.2

upper limit

19.4

Ocrelizumab 500 mg vs Placebo at Week 48

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX

Number of subjects included in analysis

663

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Weighted difference

Point estimate

15.7

Confidence interval

level

95%

sides

2-sided

lower limit

10.5

upper limit

20.9

Secondary: Percent Change From Baseline in Swollen Joint Count (SJC) at Weeks 24 and 48

Top of page

End point title

Percent Change From Baseline in Swollen Joint Count (SJC) at Weeks 24 and 48

End point description

66 joints were assessed for swelling and joints are classified as swollen/not swollen giving a total possible swollen joint count score of 0 to 66. ITT population included all randomised subjects who had received any part of an infusion of study medication. Here, the number of subjects analysed signifies subjects evaluated for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Week 24, 48

End point values	Placebo × 2 IV + MTX	Ocrelizumab 200 mg × 2 IV + MTX	Ocrelizumab 500 mg × 2 IV + MTX
Number of subjects analysed	320	343	343
Units: Swollen joints
arithmetic mean (standard deviation)
Change at Week 24 (n= 235, 311, 308)	-38.20 ( 66.127 )	-51.82 ( 80.805 )	-54.76 ( 39.896 )
Change at Week 48 (n= 211, 296, 299)	-39.39 ( 59.184 )	-61.36 ( 44.414 )	-64.22 ( 65.234 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Tender Joint Count (TJC) at Weeks 24 and 48

Top of page

End point title

Percent Change From Baseline in Tender Joint Count (TJC) at Weeks 24 and 48

End point description

68 joints were assessed for tenderness and joints were classified as tender/not tender giving a total possible tender joint count score of 0 to 68. ITT population included all randomised subjects who had received any part of an infusion of study medication. Here, 'n' signifies the number of subjects evaluated at a specified time point.

End point type

Secondary

End point timeframe

Baseline, Weeks 24, 48

End point values	Placebo × 2 IV + MTX	Ocrelizumab 200 mg × 2 IV + MTX	Ocrelizumab 500 mg × 2 IV + MTX
Number of subjects analysed	320	243	243
Units: Tendor joints
arithmetic mean (standard deviation)
Change at Week 24 (n= 235, 311, 308)	-36.97 ( 58.675 )	-55.11 ( 37.962 )	-51.07 ( 49.700 )
Change at Week 48 (n= 211, 296, 299)	-35.91 ( 64.358 )	-61.51 ( 37.229 )	-59.55 ( 48.474 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Patient's Pain Visual Analogue Scale (VAS) at Weeks 24 and 48

Top of page

End point title

Percent Change From Baseline in Patient's Pain Visual Analogue Scale (VAS) at Weeks 24 and 48

End point description

The patient assessed their pain on a 0 to 100 millimeters (mm) horizontal visual analogue scale (VAS). The left-hand extreme of the line equals 0 mm, and is described as “no pain” and the right-hand extreme equals 100 mm as “unbearable pain”. A negative change indicated improvement. ITT population included all randomised subjects who had received any part of an infusion of study medication. Here, 'n' signifies the number of subjects evaluated at a specified time point.

End point type

Secondary

End point timeframe

Baseline, Week 24, 48

End point values	Placebo × 2 IV + MTX	Ocrelizumab 200 mg × 2 IV + MTX	Ocrelizumab 500 mg × 2 IV + MTX
Number of subjects analysed	320	343	343
Units: Units on a scale
arithmetic mean (standard deviation)
Change at Week 24 (n =230, 307, 304)	-9.10 ( 109.646 )	-32.02 ( 88.637 )	-27.73 ( 139.732 )
Change at Week 48 (n =206, 293, 295)	-2.28 ( 148.933 )	-38.86 ( 104.267 )	-32.47 ( 197.692 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Physician’s Global VAS at Weeks 24 and 48

Top of page

End point title

Percent Change From Baseline in Physician’s Global VAS at Weeks 24 and 48

End point description

The physician’s global assessment of disease activity is assessed on a 0 to 100 millimetres (mm) horizontal visual analogue scale (VAS) by the physician. The left-hand extreme of the line equals 0 mm, and is described as “no disease activity” (symptom-free and no arthritis symptoms) and the right-hand extreme equals 100 mm as “maximum disease activity” (maximum arthritis disease activity). ITT population included all randomised subjects who had received any part of an infusion of study medication. Here, 'n' signifies the number of subjects evaluated at a specified time point.

End point type

Secondary

End point timeframe

Baseline, Week 24, 48

End point values	Placebo × 2 IV + MTX	Ocrelizumab 200 mg × 2 IV + MTX	Ocrelizumab 500 mg × 2 IV + MTX
Number of subjects analysed	320	343	343
Units: Units on a scale
arithmetic mean (standard deviation)
Change at Week 24 (n= 234, 311, 307)	-40.23 ( 39.655 )	-51.44 ( 34.669 )	-53.02 ( 34.479 )
Change at Week 48 (n= 210, 296, 298)	-41.60 ( 43.285 )	-61.29 ( 31.543 )	-62.10 ( 30.866 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Patient’s Global VAS at Weeks 24 and 48

Top of page

End point title

Percent Change From Baseline in Patient’s Global VAS at Weeks 24 and 48

End point description

The patient’s global assessment of disease activity is assessed on a 0 to 100 millimeters (mm) horizontal visual analogue scale (VAS) by the patient. The left-hand extreme of the line equals 0 mm, and is described as “no disease activity” (symptom-free and no arthritis symptoms) and the right-hand extreme equals 100 mm, as “maximum disease activity” (maximum arthritis disease activity). A negative change from Baseline indicated improvement. ITT population included all randomised subjects who had received any part of an infusion of study medication. Here, 'n' signifies the number of subjects evaluated at a specified time point.

End point type

Secondary

End point timeframe

Baseline, Week 24, 48

End point values	Placebo × 2 IV + MTX	Ocrelizumab 200 mg × 2 IV + MTX	Ocrelizumab 500 mg × 2 IV + MTX
Number of subjects analysed	320	343	343
Units: Units on a scale
arithmetic mean (standard deviation)
Change at Week 24 (n= 231, 308, 303)	-20.73 ( 74.480 )	-37.96 ( 83.908 )	-36.99 ( 79.130 )
Change at Week 48 (n= 207, 294, 294)	-17.13 ( 100.706 )	-42.02 ( 103.526 )	-55.26 ( 37.873 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in C-Reactive Protein (CRP) at Weeks 24 and 48

Top of page

End point title

Percent Change From Baseline in C-Reactive Protein (CRP) at Weeks 24 and 48

End point description

The serum concentration of C-Reactive Protein (CRP) is measured in milligrams per deciliter (mg/dL). A reduction in the level is considered an improvement. ITT population included all randomised subjects who had received any part of an infusion of study medication. Here, 'n' signifies the number of subjects evaluated at a specified time point.

End point type

Secondary

End point timeframe

Baseline, Week 24, 48

End point values	Placebo × 2 IV + MTX	Ocrelizumab 200 mg × 2 IV + MTX	Ocrelizumab 500 mg × 2 IV + MTX
Number of subjects analysed	320	343	343
Units: Milligrams per deciliter (mg/dL)
arithmetic mean (standard deviation)
Change at Week 24 (n= 235, 311, 308)	11.64 ( 116.697 )	-30.41 ( 109.193 )	-23.07 ( 109.193 )
Change at Week 48 (n= 211, 296, 299)	22.01 ( 190.346 )	-40.89 ( 90.139 )	15.14 ( 820.007 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in the Health Assessment Questionnaire Disability Index (HAQ-DI) at Weeks 24 and 48

Top of page

End point title

Percent Change From Baseline in the Health Assessment Questionnaire Disability Index (HAQ-DI) at Weeks 24 and 48

End point description

HAQ-DI is a self-completed patient questionnaire specific for Rheumatoid Arthritis. It consists of 20 questions referring to 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip; common daily activities. Each domain has at least 2 component questions. There are 4 possible responses for each component 0=without any difficulty 1=with some difficulty 2=with much difficulty 3=unable to do. Calculate HAQ-DI the patient must have a domain score for at least 6 of 8 domains. The HAQ-DI is the sum of the scores, divided by the number of domains that have a score (in range 6-8) for a total possible score minimum/maximum 0 (best) to 3 (worst). A negative change from baseline indicated improvement. ITT population included all randomised subjects who had received any part of an infusion of study medication. Here, 'n' signifies the number of subjects evaluated at a specified time point.

End point type

Secondary

End point timeframe

Baseline, Week 24, 48

End point values	Placebo × 2 IV + MTX	Ocrelizumab 200 mg × 2 IV + MTX	Ocrelizumab 500 mg × 2 IV + MTX
Number of subjects analysed	320	343	343
Units: Units on a scale
arithmetic mean (standard deviation)
Change at Week 24 (n= 231, 301, 305)	-20.11 ( 48.921 )	-30.12 ( 86.217 )	-40.83 ( 38.243 )
Change at Week 48 (n= 207, 286, 296)	-22.67 ( 57.893 )	-35.47 ( 78.670 )	-45.63 ( 39.241 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in the Erythrocyte Sedimentation Rate (ESR) at Weeks 24 and 48

Top of page

End point title

Percent Change From Baseline in the Erythrocyte Sedimentation Rate (ESR) at Weeks 24 and 48

End point description

The Erythrocyte Sedimentation Rate (ESR) was measured in millimeters per hour (mm/hr). A reduction in the level is considered an improvement. ITT population included all randomised subjects who had received any part of an infusion of study medication. Here, 'n' signifies the number of subjects evaluated at a specified time point.

End point type

Secondary

End point timeframe

Baseline, Week 24, 48

End point values	Placebo × 2 IV + MTX	Ocrelizumab 200 mg × 2 IV + MTX	Ocrelizumab 500 mg × 2 IV + MTX
Number of subjects analysed	320	343	343
Units: Millimeters per hour (mm/hr)
arithmetic mean (standard deviation)
Change at Week 24 (n= 234, 311, 308)	-2.51 ( 66.453 )	-20.10 ( 90.059 )	-29.98 ( 57.195 )
Change at Week 48 (n= 211, 296, 299)	-2.72 ( 90.088 )	-27.24 ( 147.973 )	-41.19 ( 55.485 )

No statistical analyses for this end point

Secondary: Change From Baseline in the Modified Total Sharp Score (mTSS) at Weeks 24 and 48

Top of page

End point title

Change From Baseline in the Modified Total Sharp Score (mTSS) at Weeks 24 and 48

End point description

mTSS: measure of joint damage that combines scores for bone erosion and joint space narrowing (JNS). Erosion score: total of 14 locations in each hand and wrist and 6 joints in the foot were evaluated for erosion using an 8-point scale where 0=normal to 3.5=very severe erosion. JNS score: total of 13 locations in each hand and wrist and 6 joints in the foot were evaluated for joint narrowing score using a 9-point scale where 0=normal to 4.0=definite ankylosis (stiffness or fixation of a joint). mTSS scores ranged from 0 (normal) to 292 (worst possible total score). Change= mTSS score at Week 24 minus score at baseline. An increase in mTSS from baseline represents disease progression and/or joint worsening, no change represents halting of disease progression, and a decrease represents improvement. mITT population. Number of subjects analysed signifies subjects who were evaluated for the endpoint. 'n' signifies the number of subjects evaluated at a specified time point.

End point type

Secondary

End point timeframe

Baseline, Week 24, 48

End point values	Placebo × 2 IV + MTX	Ocrelizumab 200 mg × 2 IV + MTX	Ocrelizumab 500 mg × 2 IV + MTX
Number of subjects analysed	305	322	329
Units: Units on a scale
arithmetic mean (standard deviation)
Baseline (n= 305, 322, 329)	33.58 ( 51.106 )	31.45 ( 51.323 )	31.99 ( 49.602 )
Change at Week 24 (n= 268, 308, 313)	1.04 ( 2.842 )	0.34 ( 2.424 )	-0.03 ( 2.534 )
Change at Week 48 (n= 268, 308, 313)	1.74 ( 5.293 )	0.26 ( 2.791 )	-0.03 ( 2.911 )

Ocrelizumab 200 mg vs Placebo at Week 24

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX

Number of subjects included in analysis

627

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0024

Method

Van Elteren's test

Confidence interval

Ocrelizumab 500 mg vs Placebo at Week 24

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX

Number of subjects included in analysis

634

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Van Elteren's test

Confidence interval

Ocrelizumab 200 mg vs Placebo at Week 48

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX

Number of subjects included in analysis

627

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Van Elteren's test

Confidence interval

Ocrelizumab 500 mg vs Placebo at Week 48

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX

Number of subjects included in analysis

634

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Van Elteren's test

Confidence interval

Secondary: Change From Baseline in Modified Erosion Score at Weeks 24 and 48

Top of page

End point title

Change From Baseline in Modified Erosion Score at Weeks 24 and 48

End point description

Erosion score was defined as a total of 14 locations in each hand and wrist and 6 joints in the foot using an 8-point scale where 0=normal to 3.5=very severe erosion. mITT population included all subjects who were in the ITT analysis set and had both baseline radiograph and at least one post-baseline radiograph for campaign 1. Here, the number of subjects analysed signifies subjects who were evaluated for the endpoint. 'n' signifies the number of subjects evaluated at a specified time point.

End point type

Secondary

End point timeframe

Baseline, Week 24, 48

End point values	Placebo × 2 IV + MTX	Ocrelizumab 200 mg × 2 IV + MTX	Ocrelizumab 500 mg × 2 IV + MTX
Number of subjects analysed	305	322	329
Units: Units on a scale
arithmetic mean (standard deviation)
Baseline (n= 305, 322, 329)	17.10 ( 27.256 )	16.22 ( 27.875 )	16.24 ( 26.103 )
Change at Week 24 (n= 268, 308, 313)	0.61 ( 1.778 )	0.18 ( 1.487 )	0.04 ( 1.511 )
Change at week 48 (n= 268, 308, 313)	1.06 ( 3.238 )	0.08 ( 1.690 )	-0.08 ( 1.588 )

Ocrelizumab 200 mg vs Placebo at Week 24

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX

Number of subjects included in analysis

627

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0015

Method

Van Elteren’s test

Confidence interval

Ocrelizumab 500 mg vs Placebo at Week 24

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX

Number of subjects included in analysis

634

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0003

Method

Van Elteren’s test

Confidence interval

Ocrelizumab 200 mg vs Placebo at Week 48

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX

Number of subjects included in analysis

627

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Van Elteren’s test

Confidence interval

Ocrelizumab 500 mg vs Placebo at Week 48

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX

Number of subjects included in analysis

634

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Van Elteren’s test

Confidence interval

Secondary: Change From Baseline in Modified Joint Space Narrowing Score at Weeks 24 and 48

Top of page

End point title

Change From Baseline in Modified Joint Space Narrowing Score at Weeks 24 and 48

End point description

Joint Space Narrowing score was defined as a total of 13 locations in each hand and wrist and 6 joints in the foot using a 9-point scale where 0=normal to 4.0=definite ankylosis (stiffness or fixation of a joint). mITT population included all subjects who were in the ITT analysis set and had both baseline radiograph and at least one post-baseline radiograph for campaign 1. Here, the number of subjects analysed signifies subjects who were evaluated for the endpoint. 'n' signifies the number of subjects evaluated at a specified time point.

End point type

Secondary

End point timeframe

Baseline, Week 24, 48

End point values	Placebo × 2 IV + MTX	Ocrelizumab 200 mg × 2 IV + MTX	Ocrelizumab 500 mg × 2 IV + MTX
Number of subjects analysed	305	322	329
Units: Units on a scale
arithmetic mean (standard deviation)
Baseline (n= 305, 322, 329)	16.47 ( 25.990 )	15.22 ( 25.012 )	15.75 ( 25.118 )
Change at Week 24 (n= 268, 308, 313)	0.43 ( 1.654 )	0.16 ( 1.655 )	-0.07 ( 1.504 )
Change at Week 48 (n= 268, 308, 313)	0.68 ( 2.777 )	0.18 ( 1.471 )	0.05 ( 1.859 )

Ocrelizumab 200 mg vs Placebo at Week 24

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX

Number of subjects included in analysis

627

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0923

Method

Van Elteren’s test

Confidence interval

Ocrelizumab 500 mg vs Placebo at Week 24

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX

Number of subjects included in analysis

634

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Van Elteren’s test

Confidence interval

Ocrelizumab 200 mg vs Placebo at Week 48

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX

Number of subjects included in analysis

627

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1171

Method

Van Elteren’s test

Confidence interval

Ocrelizumab 500 mg vs Placebo at Week 48

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX

Number of subjects included in analysis

634

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0002

Method

Van Elteren’s test

Confidence interval

Secondary: Percentage of Subjects Without Radiographic Progression Defined as Change in mTSS ≤ 0 at Weeks 24 and 48

Top of page

End point title

Percentage of Subjects Without Radiographic Progression Defined as Change in mTSS ≤ 0 at Weeks 24 and 48

End point description

Radiographic progression was defined as a change from baseline in the modified total sharp scale greater than zero. The modified Intent-to-Treat (mITT) population included all subjects who were in the ITT analysis set and had both baseline radiograph and at least one post-baseline radiograph for campaign 1. Here, the number of subjects analysed signifies subjects who were evaluated for the endpoint. 'n' signifies the number of subjects evaluated at a specified time point.

End point type

Secondary

End point timeframe

Weeks 24, 48

End point values	Placebo × 2 IV + MTX	Ocrelizumab 200 mg × 2 IV + MTX	Ocrelizumab 500 mg × 2 IV + MTX
Number of subjects analysed	305	322	329
Units: Percentage of Subjects
number (confidence interval 95%)
Week 24 (n= 305, 322, 329)	47.5 (41.9 to 53.1)	58.7 (53.3 to 64.1)	65.3 (60.2 to 70.5)
Week 48 (n= 305, 322, 329)	37.7 (32.3 to 43.1)	58.7 (53.3 to 64.1)	60.8 (55.5 to 66.1)

Ocrelizumab 200 mg vs Placebo at Week 24

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX

Number of subjects included in analysis

627

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0036

Method

Cochran-Mantel-Haenszel

Parameter type

Weighted Difference

Point estimate

11.5

Confidence interval

level

95%

sides

2-sided

lower limit

3.8

upper limit

19.2

Ocrelizumab 500 mg vs Placebo at Week 24

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX

Number of subjects included in analysis

634

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Weighted Difference

Point estimate

18.2

Confidence interval

level

95%

sides

2-sided

lower limit

10.6

upper limit

25.8

Ocrelizumab 200 mg vs Placebo at Week 48

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX

Number of subjects included in analysis

634

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Weighted Difference

Point estimate

21.3

Confidence interval

level

95%

sides

2-sided

lower limit

13.7

upper limit

28.9

Ocrelizumab 500 mg vs Placebo at Week 48

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX

Number of subjects included in analysis

634

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Weighted Difference

Point estimate

23.6

Confidence interval

level

95%

sides

2-sided

lower limit

16.1

upper limit

31.2

Secondary: Percentage of Subjects With a Reduction in Modified Total Sharp Score (mTSS) From Baseline at Week 48

Top of page

End point title

Percentage of Subjects With a Reduction in Modified Total Sharp Score (mTSS) From Baseline at Week 48

End point description

End point type

Secondary

End point timeframe

Baseline, Week 48

End point values	Placebo × 2 IV + MTX	Ocrelizumab 200 mg × 2 IV + MTX	Ocrelizumab 500 mg × 2 IV + MTX
Number of subjects analysed	305	322	329
Units: Percentage of Subjects
number (confidence interval 95%)	11.8 (8.2 to 15.4)	22.7 (18.1 to 27.2)	29.8 (24.8 to 34.7)

Ocrelizumab 500 mg vs Placebo

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX

Number of subjects included in analysis

634

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Weighted Difference

Point estimate

18.3

Confidence interval

level

95%

sides

2-sided

lower limit

12.1

upper limit

24.4

Ocrelizumab 200 mg vs Placebo

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX

Number of subjects included in analysis

627

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0003

Method

Cochran-Mantel-Haenszel

Parameter type

Weighted Difference

Point estimate

10.9

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

16.8

Secondary: Percentage of Subjects With a Reduction of Greater Than or Equal to 0.25 Units in the HAQ-DI Score at Weeks 24 and 48

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End point title

Percentage of Subjects With a Reduction of Greater Than or Equal to 0.25 Units in the HAQ-DI Score at Weeks 24 and 48

End point description

HAQ-DI is a self-completed patient questionnaire specific for Rheumatoid Arthritis. It consists of 20 questions referring to 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip; common daily activities. Each domain has at least 2 component questions. There are 4 possible responses for each component 0=without any difficulty 1=with some difficulty 2=with much difficulty 3=unable to do. Calculate HAQ-DI the patient must have a domain score for at least 6 of 8 domains. The HAQ-DI is the sum of the scores, divided by the number of domains that have a score (in range 6-8) for a total possible score minimum/maximum 0 (best) to 3 (worst). A negative change from baseline indicated improvement. ITT population included all randomised subjects who had received any part of an infusion of study medication. Here, the number of subjects analysed signifies subjects evaluated for this endpoint. 'n' signifies the number of subjects evaluated at a specified time point.

End point type

Secondary

End point timeframe

Week 24, 48

End point values	Placebo × 2 IV + MTX	Ocrelizumab 200 mg × 2 IV + MTX	Ocrelizumab 500 mg × 2 IV + MTX
Number of subjects analysed	320	343	343
Units: Percentage of Subjects
number (confidence interval 95%)
Week 24 (n= 319, 343, 343)	42.3 (36.9 to 47.7)	59.8 (54.6 to 65.0)	66.5 (61.5 to 71.5)
Week 48 (n= 319, 343, 343)	34.8 (29.6 to 40.0)	58.9 (53.7 to 64.1)	65.9 (60.9 to 70.9)

Ocrelizumab 200 mg vs Placebo at Week 24

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX

Number of subjects included in analysis

663

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Weighted Difference

Point estimate

17.4

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

24.9

Ocrelizumab 500 mg vs Placebo at Week 24

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX

Number of subjects included in analysis

663

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Weighted Difference

Point estimate

23.7

Confidence interval

level

95%

sides

2-sided

lower limit

16.4

upper limit

31.1

Ocrelizumab 200 mg vs Placebo at Week 48

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX

Number of subjects included in analysis

663

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Weighted Difference

Point estimate

24.1

Confidence interval

level

95%

sides

2-sided

lower limit

16.9

upper limit

31.4

Ocrelizumab 500 mg vs Placebo at Week 48

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX

Number of subjects included in analysis

663

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Weighted Difference

Point estimate

30.9

Confidence interval

level

95%

sides

2-sided

lower limit

23.7

upper limit

38.1

Secondary: Change From Baseline in Short Form Health Survey (SF-36) Subscale and Summary Scores at Weeks 24 and 48

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End point title

Change From Baseline in Short Form Health Survey (SF-36) Subscale and Summary Scores at Weeks 24 and 48

End point description

The SF-36 is a questionnaire used to assess physical functioning and is made up of eight domains: Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional and Mental Health. Transforming and standardizing these domains leads to the calculation of the Physical and Mental Component Summary measures. Scores ranging from 0 to 100, with 0=worst score (or quality of life) and 100=best score. A positive change from baseline indicates improvement. ITT population included all randomised subjects who had received any part of an infusion of study medication. Here, the number of subjects analysed signifies subjects evaluated for this endpoint. 'n' signifies the number of subjects evaluated at a specified time point.

End point type

Secondary

End point timeframe

Baseline, Week 24, 48

End point values	Placebo × 2 IV + MTX	Ocrelizumab 200 mg × 2 IV + MTX	Ocrelizumab 500 mg × 2 IV + MTX
Number of subjects analysed	320	343	343
Units: Units on a scale
arithmetic mean (standard deviation)
Baseline:MCS (n= 312, 334, 334)	40.54 ( 12.282 )	39.99 ( 11.863 )	40.48 ( 12.822 )
Change at Week 24:MCS (n= 229, 303, 302)	4.38 ( 10.886 )	6.11 ( 10.082 )	5.80 ( 11.224 )
Change at Week 48:MCS (n= 206, 290, 292)	4.15 ( 10.326 )	6.36 ( 10.212 )	6.43 ( 11.795 )
Baseline:PCS (n= 312, 334, 334)	31.86 ( 7.387 )	32.24 ( 7.401 )	31.58 ( 8.039 )
Change at Week 24:PCS (n= 229, 303, 302)	5.29 ( 8.421 )	6.73 ( 8.385 )	7.71 ( 7.328 )
Change at Week 48:PCS (n= 206, 290, 292)	5.28 ( 8.373 )	8.38 ( 8.347 )	9.15 ( 8.389 )

MCS: Ocrelizumab 200 mg vs Placebo Week 24

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX

Number of subjects included in analysis

663

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1103

Method

ANOVA

Parameter type

Adjusted mean difference

Point estimate

1.2

Confidence interval

level

95%

sides

2-sided

lower limit

-0.3

upper limit

2.8

MCS: Ocrelizumab 500 mg vs Placebo at Week 24

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX

Number of subjects included in analysis

663

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2011

Method

ANOVA

Parameter type

Adjusted mean difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.5

upper limit

2.5

MCS: Ocrelizumab 200 mg vs Placebo at Week 48

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX

Number of subjects included in analysis

663

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0186

Method

ANOVA

Parameter type

Adjusted mean difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

0.3

upper limit

3.6

MCS: Ocrelizumab 500 mg vs Placebo at Week 48

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX

Number of subjects included in analysis

663

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0127

Method

ANOVA

Parameter type

Adjusted mean difference

Point estimate

2.1

Confidence interval

level

95%

sides

2-sided

lower limit

0.5

upper limit

3.7

PCS: Ocrelizumab 200 mg vs Placebo at Week 24

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX

Number of subjects included in analysis

663

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0232

Method

ANOVA

Parameter type

Adjusted mean difference

Point estimate

1.5

Confidence interval

level

95%

sides

2-sided

lower limit

0.2

upper limit

2.8

PCS: Ocrelizumab 500 mg vs Placebo at Week 24

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX

Number of subjects included in analysis

663

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0006

Method

ANOVA

Parameter type

Adjusted mean difference

Point estimate

2.3

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

3.6

PCS: Ocrelizumab 200 mg vs Placebo at Week 48

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 200 mg × 2 IV + MTX

Number of subjects included in analysis

663

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

ANOVA

Parameter type

Adjusted mean difference

Point estimate

3.1

Confidence interval

level

95%

sides

2-sided

lower limit

1.7

upper limit

4.5

PCS: Ocrelizumab 500 mg vs Placebo at Week 48

Comparison groups

Placebo × 2 IV + MTX v Ocrelizumab 500 mg × 2 IV + MTX

Number of subjects included in analysis

663

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

ANOVA

Parameter type

Adjusted mean difference

Point estimate

3.6

Confidence interval

level

95%

sides

2-sided

lower limit

2.2

upper limit

Secondary: Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-F) Fatigue Assessment at Weeks 24 and 48

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End point title

Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-F) Fatigue Assessment at Weeks 24 and 48

End point description

The FACIT-Fatigue score was calculated according to a 13-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function. Participants scored each item on a 5-point scale: 0 (Not at all) to 4 (Very much). The larger the participant's response to the questions (with the exception of 2 negatively stated), the greater the participant's fatigue. For all questions, except for the 2 negatively stated ones, the code was reversed and a new score was calculated as (4 minus the participant's response). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worst score) to 52 (best score). ITT population included all randomised subjects who had received any part of an infusion of study medication. Here, the number of subjects analysed signifies subjects evaluated for this endpoint. 'n' signifies the number of subjects evaluated at a specified time point.

End point type

Secondary

End point timeframe

Baseline, week 24, 48

End point values	Placebo × 2 IV + MTX	Ocrelizumab 200 mg × 2 IV + MTX	Ocrelizumab 500 mg × 2 IV + MTX
Number of subjects analysed	320	343	343
Units: Units on a scale
arithmetic mean (standard deviation)
Baseline (n= 317, 340, 340)	27.25 ( 10.821 )	26.87 ( 10.920 )	26.57 ( 11.194 )
Change at Week 24 (n= 235, 309, 308)	5.14 ( 9.864 )	7.18 ( 9.755 )	7.07 ( 10.269 )
Change at Week 48 (n= 211, 296, 298)	5.39 ( 10.054 )	8.01 ( 10.132 )	8.41 ( 10.682 )

No statistical analyses for this end point

Secondary: Change From Baseline in Pain Quality and Impact of Pain on Daily Function Measured by the Brief Pain Inventory (BPI) Short Form at Weeks 24 and 48

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End point title

Change From Baseline in Pain Quality and Impact of Pain on Daily Function Measured by the Brief Pain Inventory (BPI) Short Form at Weeks 24 and 48

End point description

The modified BPI (short-form) is a short questionnaire to assess the severity of pain and the impact of pain on daily functions. The first two questions relate to average and current pain respectively and are assessed on a scale from 0 to 10, where 0 represents no pain, and 10 represents pain as bad as one can imagine. The degree to which pain has interfered with 7 different aspects is also rated on a scale from 0 to 10, where 0 represents that pain does not interfere and 10 that pain completely interferes. ITT population included all randomised subjects who had received any part of an infusion of study medication. Here, the number of subjects analysed signifies subjects evaluated for this endpoint. 'n' signifies the number of subjects evaluated at a specified time point.

End point type

Secondary

End point timeframe

Baseline, Week 24, 48

End point values	Placebo × 2 IV + MTX	Ocrelizumab 200 mg × 2 IV + MTX	Ocrelizumab 500 mg × 2 IV + MTX
Number of subjects analysed	320	343	343
Units: Units on a Scale
arithmetic mean (standard deviation)
Baseline: average pain (n=316,340,335)	6.39 ( 2.011 )	6.28 ( 2.077 )	6.42 ( 2.194 )
Baseline: pain right now (n=317,340,337)	5.57 ( 2.398 )	5.75 ( 2.495 )	5.82 ( 2.533 )
Change at Week 24: average pain (n=234,304,298)	-1.82 ( 2.441 )	-2.45 ( 2.299 )	-2.48 ( 2.424 )
Change at Week 24: pain right now (n=235,303,299)	-1.57 ( 2.775 )	-2.32 ( 2.659 )	-2.24 ( 2.671 )
Change at Week 48: average pain (n=188,273,280)	-1.78 ( 2.619 )	-2.92 ( 2.442 )	-3.06 ( 2.422 )
Change at Week 48: pain right now (n=188,272,282)	-1.53 ( 2.795 )	-2.66 ( 2.676 )	-2.92 ( 2.681 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Up to 8.5 years

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

16.0

Reporting group title

Placebo × 2 IV + MTX

Reporting group description

Reporting group title

Ocrelizumab 200 mg × 2 IV + MTX

Reporting group description

Subjects received two IV infusion of ocrelizumab 200 mg on Day 1 and Day 15. A repeat course was administered at Weeks 24 and 26. Methotrexate 7.5-25 mg was administered weekly.

Reporting group title

Ocrelizumab 500 mg × 2 IV + MTX

Reporting group description

Subjects received two IV infusion of ocrelizumab 500 mg on Day 1 and Day 15. A repeat course was administered at Weeks 24 and 26. Methotrexate 7.5-25 mg was administered weekly.

Serious adverse events	Placebo × 2 IV + MTX	Ocrelizumab 200 mg × 2 IV + MTX	Ocrelizumab 500 mg × 2 IV + MTX
Total subjects affected by serious adverse events
subjects affected / exposed	73 / 318 (22.96%)	61 / 343 (17.78%)	78 / 345 (22.61%)
number of deaths (all causes)	5	2	8
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
B-cell lymphoma
subjects affected / exposed	1 / 318 (0.31%)	1 / 343 (0.29%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Basal cell carcinoma
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	3 / 345 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Breast cancer
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1
Intraductal proliferative breast lesion
subjects affected / exposed	1 / 318 (0.31%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Non-Hodgkin's lymphoma
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Uterine leiomyoma
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Adenocarcinoma of colon
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bladder transitional cell carcinoma
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchial carcinoma
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cervix carcinoma stage 0
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chronic myeloid leukaemia
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastric cancer
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Inflammatory carcinoma of the breast
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lymphoma
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Malignant melanoma
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metastatic renal cell carcinoma
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myxoid liposarcoma
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ovarian cancer metastatic
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ovarian epithelial cancer
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal cell carcinoma
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma of lung
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma of skin
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
T-cell lymphoma
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thyroid neoplasm
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	2 / 318 (0.63%)	1 / 343 (0.29%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Aortic aneurysm
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Aortic dissection
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rheumatoid vasculitis
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
Thrombosis
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vasculitis necrotising
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Abortion missed
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abortion spontaneous
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune system disorders
Hypersensitivity
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Ovarian cyst
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cervical dysplasia
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endometrial hyperplasia
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endometriosis
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ovarian cyst ruptured
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Uterine polyp
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Uterine prolapse
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	2 / 318 (0.63%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	2 / 345 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 318 (0.00%)	2 / 343 (0.58%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Alveolitis
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Asthma
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchiectasis
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Sinus disorder
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	2 / 345 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Drug dependence
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypomania
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mental status changes
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Haemoglobin abnormal
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Humerus fracture
subjects affected / exposed	0 / 318 (0.00%)	3 / 343 (0.87%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infusion related reaction
subjects affected / exposed	0 / 318 (0.00%)	2 / 343 (0.58%)	2 / 345 (0.58%)
occurrences causally related to treatment / all	0 / 0	2 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	2 / 345 (0.58%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Toxicity to various agents
subjects affected / exposed	2 / 318 (0.63%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	1 / 318 (0.31%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Multiple fractures
subjects affected / exposed	0 / 318 (0.00%)	2 / 343 (0.58%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Multiple injuries
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	2 / 345 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Upper limb fracture
subjects affected / exposed	1 / 318 (0.31%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Accidental overdose
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ankle fracture
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Carbon monoxide poisoning
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Clavicle fracture
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Comminuted fracture
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Joint dislocation
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Laceration
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lower limb fracture
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lumbar vertebral fracture
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Overdose
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tendon rupture
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Myocardial infarction
subjects affected / exposed	3 / 318 (0.94%)	1 / 343 (0.29%)	2 / 345 (0.58%)
occurrences causally related to treatment / all	1 / 3	1 / 1	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	2 / 318 (0.63%)	1 / 343 (0.29%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 2	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1
Coronary artery disease
subjects affected / exposed	2 / 318 (0.63%)	1 / 343 (0.29%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	1 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	2 / 318 (0.63%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pericarditis
subjects affected / exposed	2 / 318 (0.63%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arteriosclerosis coronary artery
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diastolic dysfunction
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mitral valve incompetence
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Palpitations
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Transient ischaemic attack
subjects affected / exposed	0 / 318 (0.00%)	2 / 343 (0.58%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	0 / 318 (0.00%)	2 / 343 (0.58%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Brain oedema
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Cerebral ischaemia
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Convulsion
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dementia
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Grand mal convulsion
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lacunar infarction
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nerve compression
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subarachnoid haemorrhage
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Anaemia of chronic disease
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Inner ear disorder
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Otosalpingitis
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vertigo
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye disorders
Cataract
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	2 / 345 (0.58%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal hernia
subjects affected / exposed	1 / 318 (0.31%)	1 / 343 (0.29%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Umbilical hernia
subjects affected / exposed	1 / 318 (0.31%)	1 / 343 (0.29%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	1 / 1	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diverticular perforation
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diverticulum
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemorrhoidal haemorrhage
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis acute
subjects affected / exposed	2 / 318 (0.63%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 318 (0.00%)	2 / 343 (0.58%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Renal failure acute
subjects affected / exposed	2 / 318 (0.63%)	3 / 343 (0.87%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	2 / 2	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Calculus ureteric
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hydronephrosis
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal colic
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Stag horn calculus
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urogenital fistula
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endocrine disorders
Basedow's disease
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Rheumatoid arthritis
subjects affected / exposed	4 / 318 (1.26%)	1 / 343 (0.29%)	2 / 345 (0.58%)
occurrences causally related to treatment / all	0 / 4	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	1 / 318 (0.31%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Foot deformity
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteochondrosis
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteonecrosis
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rotator cuff syndrome
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	3 / 318 (0.94%)	4 / 343 (1.17%)	10 / 345 (2.90%)
occurrences causally related to treatment / all	4 / 4	3 / 4	6 / 10
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 3
Urinary tract infection
subjects affected / exposed	4 / 318 (1.26%)	1 / 343 (0.29%)	3 / 345 (0.87%)
occurrences causally related to treatment / all	0 / 4	0 / 1	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	3 / 318 (0.94%)	1 / 343 (0.29%)	3 / 345 (0.87%)
occurrences causally related to treatment / all	1 / 3	1 / 1	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	4 / 318 (1.26%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	3 / 4	0 / 1	0 / 0
deaths causally related to treatment / all	2 / 2	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	3 / 318 (0.94%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	2 / 3	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	2 / 318 (0.63%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	2 / 318 (0.63%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	1 / 2	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Postoperative wound infection
subjects affected / exposed	1 / 318 (0.31%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abscess soft tissue
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Acute hepatitis B
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Acute sinusitis
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Appendicitis perforated
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Borrelia infection
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchopneumonia
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cellulitis gangrenous
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dengue fever
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diarrhoea infectious
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Extradural abscess
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fungal oesophagitis
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	1 / 318 (0.31%)	2 / 343 (0.58%)	3 / 345 (0.87%)
occurrences causally related to treatment / all	0 / 1	0 / 2	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Histoplasmosis
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Meningitis aseptic
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mycobacterium kansasii infection
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Paronychia
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pharyngitis
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia staphylococcal
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia viral
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Purulent synovitis
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyelonephritis chronic
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Soft tissue infection
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Staphylococcal bacteraemia
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Wound infection
subjects affected / exposed	0 / 318 (0.00%)	1 / 343 (0.29%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 318 (0.00%)	0 / 343 (0.00%)	1 / 345 (0.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Electrolyte imbalance
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Type 2 diabetes mellitus
subjects affected / exposed	1 / 318 (0.31%)	0 / 343 (0.00%)	0 / 345 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Placebo × 2 IV + MTX	Ocrelizumab 200 mg × 2 IV + MTX	Ocrelizumab 500 mg × 2 IV + MTX
Total subjects affected by non serious adverse events
subjects affected / exposed	228 / 318 (71.70%)	272 / 343 (79.30%)	273 / 345 (79.13%)
Injury, poisoning and procedural complications
Infusion related reaction
subjects affected / exposed	62 / 318 (19.50%)	89 / 343 (25.95%)	96 / 345 (27.83%)
occurrences all number	136	164	168
Vascular disorders
Hypertension
subjects affected / exposed	26 / 318 (8.18%)	42 / 343 (12.24%)	37 / 345 (10.72%)
occurrences all number	28	43	45
Nervous system disorders
Headache
subjects affected / exposed	24 / 318 (7.55%)	29 / 343 (8.45%)	32 / 345 (9.28%)
occurrences all number	29	33	38
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	17 / 318 (5.35%)	13 / 343 (3.79%)	13 / 345 (3.77%)
occurrences all number	19	14	15
General disorders and administration site conditions
Oedema peripheral
subjects affected / exposed	17 / 318 (5.35%)	16 / 343 (4.66%)	14 / 345 (4.06%)
occurrences all number	21	18	15
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	23 / 318 (7.23%)	21 / 343 (6.12%)	23 / 345 (6.67%)
occurrences all number	28	22	29
Dyspepsia
subjects affected / exposed	14 / 318 (4.40%)	17 / 343 (4.96%)	22 / 345 (6.38%)
occurrences all number	15	18	24
Gastritis
subjects affected / exposed	8 / 318 (2.52%)	14 / 343 (4.08%)	18 / 345 (5.22%)
occurrences all number	9	16	18
Nausea
subjects affected / exposed	17 / 318 (5.35%)	15 / 343 (4.37%)	22 / 345 (6.38%)
occurrences all number	21	17	26
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	8 / 318 (2.52%)	13 / 343 (3.79%)	20 / 345 (5.80%)
occurrences all number	8	15	23
Psychiatric disorders
Depression
subjects affected / exposed	19 / 318 (5.97%)	18 / 343 (5.25%)	21 / 345 (6.09%)
occurrences all number	19	20	23
Insomnia
subjects affected / exposed	19 / 318 (5.97%)	19 / 343 (5.54%)	15 / 345 (4.35%)
occurrences all number	19	19	16
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	16 / 318 (5.03%)	19 / 343 (5.54%)	26 / 345 (7.54%)
occurrences all number	17	20	27
Infections and infestations
Bronchitis
subjects affected / exposed	39 / 318 (12.26%)	43 / 343 (12.54%)	40 / 345 (11.59%)
occurrences all number	57	59	47
Gastroenteritis
subjects affected / exposed	16 / 318 (5.03%)	11 / 343 (3.21%)	15 / 345 (4.35%)
occurrences all number	22	12	20
Herpes zoster
subjects affected / exposed	16 / 318 (5.03%)	14 / 343 (4.08%)	12 / 345 (3.48%)
occurrences all number	17	16	13
Influenza
subjects affected / exposed	20 / 318 (6.29%)	31 / 343 (9.04%)	29 / 345 (8.41%)
occurrences all number	26	37	35
Nasopharyngitis
subjects affected / exposed	45 / 318 (14.15%)	43 / 343 (12.54%)	51 / 345 (14.78%)
occurrences all number	60	56	77
Pharyngitis
subjects affected / exposed	18 / 318 (5.66%)	9 / 343 (2.62%)	9 / 345 (2.61%)
occurrences all number	22	14	13
Sinusitis
subjects affected / exposed	18 / 318 (5.66%)	33 / 343 (9.62%)	28 / 345 (8.12%)
occurrences all number	27	48	35
Upper respiratory tract infection
subjects affected / exposed	64 / 318 (20.13%)	79 / 343 (23.03%)	85 / 345 (24.64%)
occurrences all number	130	130	157
Urinary tract infection
subjects affected / exposed	40 / 318 (12.58%)	38 / 343 (11.08%)	48 / 345 (13.91%)
occurrences all number	67	49	69

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Were there any global substantial amendments to the protocol? Yes

21 Dec 2006

1. Provided more information on the definition and incidence of infusion-related reactions (IRRs) as applied to previous studies with ocrelizumab (2004-002132-26 and NCT00077870) 2. Included a statement mandating the signing of informed consent forms by subjects prior to the performance of any screening procedures 3. Defined the period during which subjects who withdrew from the study should continue in safety follow-up and clarified the end of study for individual subjects 4. Included some additional text cautioning the investigator to review safety criteria, which were also added to the text, prior to the administration of subsequent infusions 5. Clarified that randomisation could occur within 24 hours or exceptionally within 72 hours prior to administration of blinded study infusion 6. In the schedule of assessments added an assessment of rheumatoid manifestations; included new safety assessment for Hepatitis B viral DNA and separated inflammatory related biomarkers and Apolipoprotein A1 and B at baseline and every 24 weeks from the blood biochemistry assessments to reduce their collection time points 7. In the schedule of assessments added an assessment of rheumatoid manifestations; included new safety assessment for Hepatitis B viral DNA and separated inflammatory related biomarkers and Apolipoprotein A1 and B at baseline and every 24 weeks from the blood biochemistry assessments to reduce their collection time points 8. Recommended that IV infusion bags containing diluted ocrelizumab solutions be used within 48 hours of preparation for stability reasons 9. Provided guidance on the administration of rescue medication during the study 10. Included detailed information on the Hepatitis B screening process for inclusion into the study including information on viral DNA monitoring and separated the screening process from that for Hepatitis C

28 Aug 2008

1. Reduced the number of samples collected during the double-blind and study extension periods and amended the scheduled of assessments and procedures accordingly 2. Clarified the basis for the administration of Day 15 infusions for patients who develop infections between Day 1 and Day 15 of a course of study treatment 3. Clarified the circumstances under which pregnant patients and subjects who develop skin malignancy during the study could be given study treatment

12 Jul 2010

Terminates treatment and mandates transitioning of all subjects to safety follow up

06 Sep 2012

Terminates the Safety Follow up for all subjects

Were there any global interruptions to the trial? No

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

None reported

http://www.ncbi.nlm.nih.gov/pubmed/21905001
http://www.ncbi.nlm.nih.gov/pubmed/24498318

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Clinical trials

Clinical Trial Results: A randomized, double-blind, parallel group, international study to evaluate the safety and efficacy of ocrelizumab compared to placebo in patients with active rheumatoid arthritis continuing methotrexate treatment

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Subjects with American College of Rheumatology (ACR) 20 Response at Week 24

Primary: Percentage of Subjects with American College of Rheumatology (ACR) 20 Response at Week 24

Primary: Percentage of Subjects with ACR20 Response at Week 48

Primary: Percentage of Subjects with ACR20 Response at Week 48

Primary: Percentage of Subjects With Adverse Events (AEs)

Primary: Percentage of Subjects With Adverse Events (AEs)

Secondary: Percentage of Subjects With a Major Clinical Response (ACR70 for ≥ 6 months) at Week 48

Secondary: Percentage of Subjects With a Major Clinical Response (ACR70 for ≥ 6 months) at Week 48

Secondary: Percentage of Subjects Achieving Disease Activity Score 28 (DAS28) Remission (DAS28 < 2.6) at Weeks 24 and 48

Secondary: Percentage of Subjects Achieving Disease Activity Score 28 (DAS28) Remission (DAS28 < 2.6) at Weeks 24 and 48

Secondary: Change From Baseline in DAS28 at Weeks 24 and 48

Secondary: Change From Baseline in DAS28 at Weeks 24 and 48

Secondary: European League Against Rheumatism (EULAR) Response Rates (Categorical DAS Responders) at Weeks 24 and 48

Secondary: European League Against Rheumatism (EULAR) Response Rates (Categorical DAS Responders) at Weeks 24 and 48

Secondary: Percentage of Subjects Achieving an ACR50 Response at Weeks 24 and 48

Secondary: Percentage of Subjects Achieving an ACR50 Response at Weeks 24 and 48

Secondary: Percentage of Subjects Achieving an ACR70 Response at Weeks 24 and 48

Secondary: Percentage of Subjects Achieving an ACR70 Response at Weeks 24 and 48

Secondary: Percent Change From Baseline in Swollen Joint Count (SJC) at Weeks 24 and 48

Secondary: Percent Change From Baseline in Swollen Joint Count (SJC) at Weeks 24 and 48

Secondary: Percent Change From Baseline in Tender Joint Count (TJC) at Weeks 24 and 48

Secondary: Percent Change From Baseline in Tender Joint Count (TJC) at Weeks 24 and 48

Secondary: Percent Change From Baseline in Patient's Pain Visual Analogue Scale (VAS) at Weeks 24 and 48

Secondary: Percent Change From Baseline in Patient's Pain Visual Analogue Scale (VAS) at Weeks 24 and 48

Secondary: Percent Change From Baseline in Physician’s Global VAS at Weeks 24 and 48

Secondary: Percent Change From Baseline in Physician’s Global VAS at Weeks 24 and 48

Secondary: Percent Change From Baseline in Patient’s Global VAS at Weeks 24 and 48

Secondary: Percent Change From Baseline in Patient’s Global VAS at Weeks 24 and 48

Secondary: Percent Change From Baseline in C-Reactive Protein (CRP) at Weeks 24 and 48

Secondary: Percent Change From Baseline in C-Reactive Protein (CRP) at Weeks 24 and 48

Secondary: Percent Change From Baseline in the Health Assessment Questionnaire Disability Index (HAQ-DI) at Weeks 24 and 48

Secondary: Percent Change From Baseline in the Health Assessment Questionnaire Disability Index (HAQ-DI) at Weeks 24 and 48

Secondary: Percent Change From Baseline in the Erythrocyte Sedimentation Rate (ESR) at Weeks 24 and 48

Secondary: Percent Change From Baseline in the Erythrocyte Sedimentation Rate (ESR) at Weeks 24 and 48

Secondary: Change From Baseline in the Modified Total Sharp Score (mTSS) at Weeks 24 and 48

Secondary: Change From Baseline in the Modified Total Sharp Score (mTSS) at Weeks 24 and 48

Secondary: Change From Baseline in Modified Erosion Score at Weeks 24 and 48

Secondary: Change From Baseline in Modified Erosion Score at Weeks 24 and 48

Secondary: Change From Baseline in Modified Joint Space Narrowing Score at Weeks 24 and 48

Secondary: Change From Baseline in Modified Joint Space Narrowing Score at Weeks 24 and 48

Secondary: Percentage of Subjects Without Radiographic Progression Defined as Change in mTSS ≤ 0 at Weeks 24 and 48

Secondary: Percentage of Subjects Without Radiographic Progression Defined as Change in mTSS ≤ 0 at Weeks 24 and 48

Secondary: Percentage of Subjects With a Reduction in Modified Total Sharp Score (mTSS) From Baseline at Week 48

Secondary: Percentage of Subjects With a Reduction in Modified Total Sharp Score (mTSS) From Baseline at Week 48

Secondary: Percentage of Subjects With a Reduction of Greater Than or Equal to 0.25 Units in the HAQ-DI Score at Weeks 24 and 48

Secondary: Percentage of Subjects With a Reduction of Greater Than or Equal to 0.25 Units in the HAQ-DI Score at Weeks 24 and 48

Secondary: Change From Baseline in Short Form Health Survey (SF-36) Subscale and Summary Scores at Weeks 24 and 48

Secondary: Change From Baseline in Short Form Health Survey (SF-36) Subscale and Summary Scores at Weeks 24 and 48

Secondary: Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-F) Fatigue Assessment at Weeks 24 and 48

Secondary: Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-F) Fatigue Assessment at Weeks 24 and 48

Secondary: Change From Baseline in Pain Quality and Impact of Pain on Daily Function Measured by the Brief Pain Inventory (BPI) Short Form at Weeks 24 and 48

Secondary: Change From Baseline in Pain Quality and Impact of Pain on Daily Function Measured by the Brief Pain Inventory (BPI) Short Form at Weeks 24 and 48

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
A randomized, double-blind, parallel group, international study to evaluate the safety and efficacy of ocrelizumab compared to placebo in patients with active rheumatoid arthritis continuing methotrexate treatment