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Clinical Trial Results:
A Randomized, Placebo Controlled, Double-blind, Parallel Group, International Study to Evaluate the Safety and Efficacy of Rituximab in Combination With Methotrexate, Compared to Methotrexate Monotherapy, in Patients With Active Rheumatoid Arthritis

Summary
EudraCT number	2005-002392-32
Trial protocol	IE GB SE DE SI
Global end of trial date	24 Jul 2013

Results information
Results version number	v1(current)
This version publication date	19 Oct 2016
First version publication date	19 Oct 2016
Other versions

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

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Trial information

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Sponsor protocol code

WA17045

ISRCTN number

US NCT number

NCT00299130

WHO universal trial number (UTN)

Other trial identifiers

Genentech Protocol Identification: U2973g (SERENE)

Sponsor organisation name

F. Hoffmann-La Roche AG

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, CH-4070

Public contact

Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com

Scientific contact

Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, 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

06 Sep 2013

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

24 Jul 2013

Was the trial ended prematurely?

Main objective of the trial

1. To determine the efficacy and safety at Week 24 of rituximab 500 milligrams (mg) intravenous ( IV) times (x) 2 and rituximab 1000 mg IV x 2 when used in combination with methotrexate (MTX) compared to continued MTX monotherapy in participants with active rheumatoid arthritis (RA) that currently have an inadequate clinical response to MTX. 2. To investigate by a population analysis approach the pharmacokinetics (PK) of rituximab in the target RA participant population and the influence of covariates on the PK parameters. 3. To explore a dose separation of rituximab 500 mg IV ×2 from rituximab 1000 mg IV ×2. 4. To explore the long-term efficacy and safety of further courses of rituximab.

Protection of trial subjects

This study was conducted in full conformance with the principles of the “Declaration of Helsinki” or with the laws and regulations of the country in which the research was conducted, whichever afforded the greater protection to the individual. The study fully adhered to the principles outlined in “Guideline for Good Clinical Practice” International Conference on Harmonization (ICH) Tripartite Guideline (January 1997) or with local law if it afforded greater protection to the individual. The investigator additionally ensured that the basic principles of “Good Clinical Practice” as outlined in the current version of the Federal Regulations (CFR) Title 21, subchapter D, part 312, “Responsibilities of Sponsors and Investigators”, part 50, “Protection of Human Patients”, and part 56, “Institutional Review Boards”, were adhered to. In other countries where “Guideline for Good Clinical Practice” exist, the sponsor and the investigators strictly ensured adherence to the stated provisions.

Background therapy

Evidence for comparator

Actual start date of recruitment

27 Oct 2005

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

48 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Slovenia: 23

Country: Number of subjects enrolled

Sweden: 7

Country: Number of subjects enrolled

United Kingdom: 40

Country: Number of subjects enrolled

France: 10

Country: Number of subjects enrolled

Germany: 5

Country: Number of subjects enrolled

Poland: 56

Country: Number of subjects enrolled

Guatemala: 13

Country: Number of subjects enrolled

Mexico: 69

Country: Number of subjects enrolled

Romania: 35

Country: Number of subjects enrolled

United States: 237

Country: Number of subjects enrolled

Canada: 16

Worldwide total number of subjects

511

EEA total number of subjects

176

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)

434

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

A total of 511 participants were recruited and randomized between 27 Oct 2005 and 15 Nov 2006. Of these, 2 participants were randomized but received no infusions (one violated inclusion criteria and the other was randomized to rituximab 2 x 1.0 gram [g] + methotrexate [MTX] but failed to return). A total of 509 participants were treated.

Screening details

Of the 509 participants, one participant was randomized first to rituximab 2 x 1.0 g + MTX and then to rituximab 2 x 0.5 g + MTX. No assessments were recorded or medication given after first randomization and all data used in analyses was following the second randomization; hence, participant is included only in rituximab 2 x 0.5 g + MTX arm.

Period 1 title

Treatment Period (up to 5 Years)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Placebo + MTX

Arm description

Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 milligrams (mg) intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.

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

Placebo to rituximab intravenous infusion.

Rituximab 2 x 0.5 g + MTX

Arm description

Participants received 0.5 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.

Arm type

Experimental

Investigational medicinal product name

Rituximab

Investigational medicinal product code

Ro 45-2294

Other name

MabThera, Rituxan

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Intravenous infusion.

Rituximab 2 x 1.0 g + MTX

Arm description

Participants received 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.

Arm type

Experimental

Investigational medicinal product name

Rituximab

Investigational medicinal product code

Ro 45-2294

Other name

MabThera, Rituxan

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Intravenous infusion.

Number of subjects in period 1	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Started	172	168	171
Treated	172	167	170
Completed 24 Weeks	159	162	166
Completed 48 Weeks	155	157	158
Completed 144 Weeks	133	138	132
Completed	119	125	121
Not completed	53	43	50
Consent withdrawn by subject	-	1	1
Adverse Event	13	8	13
Death	1	3	1
Refused Treatment	12	12	19
Reason Not Specified	4	6	4
Protocol Violation	-	1	-
Failure to Return	4	6	6
Insufficient Therapeutic Response	19	6	6

Period 2 title

Safety Follow-up (SFU) (48 Weeks)

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Placebo + MTX

Arm description

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

Placebo to rituximab intravenous infusion.

Rituximab 2 x 0.5 g + MTX

Arm description

Arm type

Experimental

Investigational medicinal product name

Rituximab

Investigational medicinal product code

Ro 45-2294

Other name

MabThera, Rituxan

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Intravenous infusion.

Rituximab 2 x 1.0 g + MTX

Arm description

Arm type

Experimental

Investigational medicinal product name

Rituximab

Investigational medicinal product code

Ro 45-2294

Other name

MabThera, Rituxan

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Intravenous infusion.

Number of subjects in period 2	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Started	119	125	121
Completed	122	120	123
Not completed	45	45	45
Death	4	5	3
Withdrawal by Subject	22	22	21
Administrative/Other	4	9	4
Failure to Return	14	7	15
No SFU Week 48 Date Recorded	-	1	-
Did not Co-operate	1	1	2
Joined	48	40	47
Discontinued Treatment, Entered SFU	48	40	47

Period 3 title

Extended SFU (ESFU) (up to 5.1 Years)

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Rituximab 2 x 0.5 g + MTX

Arm description

Arm type

Experimental

Investigational medicinal product name

Rituximab

Investigational medicinal product code

Ro 45-2294

Other name

MabThera, Rituxan

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Intravenous infusion.

Rituximab 2 x 1.0 g + MTX

Arm description

Arm type

Experimental

Investigational medicinal product name

Rituximab

Investigational medicinal product code

Ro 45-2294

Other name

MabThera, Rituxan

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Intravenous infusion.

Number of subjects in period 3 ^[1]	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Started	82	44
Completed	74	38
Not completed	8	6
Death	3	-
'Did not Co-operate/Withdrew Consent '	3	4
Failure to Return	2	2

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Only participants whose peripheral CD20+ B cells remained depleted (less than the laboratory lower limit of normal) after the week 48 SFU visit, participated in the ESFU period, with the safety assessments described for SFU week 48 being performed at 12 week intervals until peripheral B cells returned to within normal ranges or baseline levels, whichever was lower.

Baseline characteristics

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Reporting group title

Placebo + MTX

Reporting group description

Reporting group title

Rituximab 2 x 0.5 g + MTX

Reporting group description

Reporting group title

Rituximab 2 x 1.0 g + MTX

Reporting group description

Reporting group values	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX	Total
Number of subjects	172	168	171	511
Age categorical
Units: Subjects
Age continuous
Age data was reported for safety population (N = 509).
Units: years
arithmetic mean (standard deviation)	52.16 ( 12.39 )	51.91 ( 12.93 )	51.3 ( 12.64 )	-
Gender categorical
Units: Subjects
Male	25	34	32	91
Female	147	133	138	418
Not Available	0	1	1	2

End points

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Reporting group title

Placebo + MTX

Reporting group description

Reporting group title

Rituximab 2 x 0.5 g + MTX

Reporting group description

Reporting group title

Rituximab 2 x 1.0 g + MTX

Reporting group description

Reporting group title

Placebo + MTX

Reporting group description

Reporting group title

Rituximab 2 x 0.5 g + MTX

Reporting group description

Reporting group title

Rituximab 2 x 1.0 g + MTX

Reporting group description

Reporting group title

Rituximab 2 x 0.5 g + MTX

Reporting group description

Reporting group title

Rituximab 2 x 1.0 g + MTX

Reporting group description

Subject analysis set title

Rituximab + MTX

Subject analysis set type

Safety analysis

Subject analysis set description

Participants received 0.5 g or 1.0 g rituximab administered by intravenous infusion on Days 1 and 15. After Week 24, participants received further courses of rituximab every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of methotrexate and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.

Primary: Percentage of Participants With American College of Rheumatology (ACR) 20 Response at Week 24

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End point title

Percentage of Participants With American College of Rheumatology (ACR) 20 Response at Week 24

End point description

Achieving ACR20 required a ≥20 percent (%) improvement compared with Baseline in tender joint counts (68 joints assessed for tenderness) and swollen joint counts (66 joints assessed for swelling), and a 20% improvement in three of the following five additional measurements: •Physician's global assessment of disease activity (assessed using a 100 millimeter (mm) Visual Analog Scale [VAS]) •Participant's global assessment of disease activity (assessed using a 100 mm VAS) •Participant's assessment of pain (assessed using a 100 mm VAS) •Health Assessment Questionnaire (HAQ; a participant-completed questionnaire consisting of 20 questions, scored from 0-3) •Acute phase reactant: C-reactive protein (CRP) or, if CRP was missing, erythrocyte sedimentation rate (ESR) Participants who withdrew prematurely from the study prior to week 24, who received rescue therapy or had insufficient data in order to calculate a clinical response were considered to be non-responders. ITT Population

End point type

Primary

End point timeframe

Baseline and Week 24 Each component calculated using the last observation carried forward (LOCF).

End point values	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Number of subjects analysed	172	167	170
Units: Percentage of Participants
number (not applicable)	23.3	54.5	50.6

Statistical Analysis 1

Comparison groups

Placebo + MTX v Rituximab 2 x 0.5 g + MTX

Number of subjects included in analysis

339

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Weighted Difference

Point estimate

0.31

Confidence interval

level

95%

sides

2-sided

lower limit

0.21

upper limit

0.41

Statistical Analysis 2

Comparison groups

Placebo + MTX v Rituximab 2 x 1.0 g + MTX

Number of subjects included in analysis

342

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Weighted Difference

Point estimate

0.27

Confidence interval

level

95%

sides

2-sided

lower limit

0.17

upper limit

0.37

Secondary: Percentage of Participants With an ACR50 Response at Week 24

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End point title

Percentage of Participants With an ACR50 Response at Week 24

End point description

Achieving ACR50 required at least a 50% improvement compared with Baseline in both tender joint counts (68 joints assessed for tenderness) and swollen joint counts (66 joints assessed for swelling), as well as a 50% improvement in three of the following five additional measurements: •Physician's global assessment of disease activity (assessed using a 100 mm VAS); •Patient's global assessment of disease activity (assessed using a 100 mm VAS); •Patient's assessment of pain (assessed using a 100 mm VAS); •HAQ; a patient completed questionnaire consisting of 20 questions, scored from 0-3; •Acute phase reactant: CRP or, if CRP was missing, ESR. Participants who withdrew prematurely from the study prior to week 24, who received rescue therapy or had insufficient data in order to calculate a clinical response were considered to be non-responders. ITT Population

End point type

Secondary

End point timeframe

Baseline and Week 24 Each component calculated using the LOCF.

End point values	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Number of subjects analysed	172	167	170
Units: Percentage of Participants
number (not applicable)	9.3	26.3	25.9

No statistical analyses for this end point

Secondary: Percentage of Participants With an ACR70 Response at Week 24

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End point title

Percentage of Participants With an ACR70 Response at Week 24

End point description

To achieve an ACR70 required at least a 70% improvement compared with Baseline in both tender joint counts (68 joints assessed for tenderness) and swollen joint counts (66 joints assessed for swelling), as well as a 70% improvement in three of the following five additional measurements: •Physician's global assessment of disease activity (assessed using a 100 mm VAS); •Participant's global assessment of disease activity (assessed using a 100 mm VAS); •Participant's assessment of pain (assessed using a 100 mm VAS); •HAQ; a patient completed questionnaire consisting of 20 questions, scored from 0-3; •Acute phase reactant: CRP or, if CRP was missing, ESR. Participants who withdrew prematurely from the study prior to week 24, who received rescue therapy or had insufficient data in order to calculate a clinical response were considered to be non-responders. ITT Population

End point type

Secondary

End point timeframe

Baseline and Week 24 Each component calculated using the LOCF.

End point values	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Number of subjects analysed	172	167	170
Units: Percentage of Participants
number (not applicable)	5.2	9	10

No statistical analyses for this end point

Secondary: Change From Baseline in Disease Activity Score (DAS28-ESR) at Week 24

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End point title

Change From Baseline in Disease Activity Score (DAS28-ESR) at Week 24

End point description

The DAS28 is a composite score to measure disease activity in patients with rheumatoid arthritis, derived from the following variables: •The number of swollen and tender joints assessed using the 28-joint count; •ESR; •Participant's global assessment of disease activity measured on a 100 mm visual analog scale. The DAS28 score ranges from zero to ten. A DAS28 score above 5.1 means high disease activity whereas a DAS28 less than or equal to 3.2 indicates low disease activity. Remission is achieved by a DAS28 lower than 2.6. ITT population.

End point type

Secondary

End point timeframe

Baseline and Week 24 Each component calculated using the LOCF.

End point values	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Number of subjects analysed	171	166	168
Units: DAS28-ESR
arithmetic mean (standard deviation)	-0.76 ( 1.304 )	-1.71 ( 1.334 )	-1.68 ( 1.342 )

No statistical analyses for this end point

Secondary: Percentage of Participants With European League Against Rheumatism (EULAR) Response at Week 24

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End point title

Percentage of Participants With European League Against Rheumatism (EULAR) Response at Week 24

End point description

A EULAR response reflects an improvement in disease activity and an attainment of a lower degree of disease activity based on the DAS28 score. The DAS28 score ranges from 0-10, with higher scores indicating more disease activity. A Good Response is defined as an improvement (decrease) in the DAS28 of more than 1.2 compared with Baseline and attainment of a DAS28 score of less than or equal to (≤)3.2. A Moderate Response is defined as either: •an improvement (decrease) in the DAS28 of greater than (>)0.6 and ≤1.2 from Baseline and attainment of a DAS28 score of ≤5.1 or, •an improvement (decrease) in the DAS28 of >1.2 from Baseline and attainment of a DAS28 score of >3.2. No Response is defined as either an improvement (decrease) in the DAS28 of ≤0.6, or an improvement (decrease) in the DAS28 of >0.6 and ≤1.2 and attainment of a DAS28 of >5.1. ITT Population

End point type

Secondary

End point timeframe

Baseline and Week 24 Each component calculated using the LOCF.

End point values	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Number of subjects analysed	172	167	170
Units: Percentage of Participants
number (not applicable)
No Response	66.3	33.5	37.1
Moderate Response	29.1	49.1	51.2
Good Response	4.7	17.4	11.8

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Swollen Joint Count at Week 24 and Week 48

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End point title

Percent Change From Baseline in Swollen Joint Count at Week 24 and Week 48

End point description

Sixty-six joints were assessed and classified as swollen/not swollen by pressure and joint manipulation on physical examination. The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value] times (*)100. A negative percentage change from baseline score indicates an improvement. For each parameter and treatment group, n equals the number of analyzed participants. ITT Population

End point type

Secondary

End point timeframe

Baseline, Week 24, and Week 48 Each component calculated using the LOCF.

End point values	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Number of subjects analysed	172	166	170
Units: Percent Change
arithmetic mean (standard deviation)
Week 24 [n=172, 166, 170]	-21.6 ( 65.82 )	-47.4 ( 43.49 )	-49.1 ( 38.59 )
Week 48 [n=172, 166, 170]	-38.9 ( 66.83 )	-54 ( 38.66 )	-59.3 ( 37.04 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Tender Joint Count at Week 24 and Week 48

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End point title

Percent Change From Baseline in Tender Joint Count at Week 24 and Week 48

End point description

Sixty-eight joints were assessed and classified as tender/not tender by pressure and joint manipulation on physical examination. The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100. A negative percentage change from baseline score indicates an improvement. For each parameter and treatment group, n equals the number of analyzed participants. ITT Population

End point type

Secondary

End point timeframe

Baseline, Week 24 and Week 48 Each component calculated using the LOCF.

End point values	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Number of subjects analysed	172	166	170
Units: Percent Change
arithmetic mean (standard deviation)
Week 24 [n=172, 166, 170]	-14.2 ( 69.2 )	-42.5 ( 64.41 )	-31.5 ( 66.52 )
Week 48 [n=172, 166, 170]	-37.1 ( 55.08 )	-50.2 ( 62.74 )	-45.1 ( 62.64 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Participant's Global Assessment of Disease Activity

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End point title

Percent Change From Baseline in Participant's Global Assessment of Disease Activity

End point description

The participant's overall assessment of their current disease activity measured on a 100 mm horizontal VAS. The left-hand extreme of the line (0 mm) was described as "no disease activity" (symptom-free and no arthritis symptoms) and the right-hand extreme (100 mm) as "maximum disease activity" (maximum arthritis disease activity). The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100. A negative percentage change from baseline score indicates an improvement. For each parameter and treatment group, n equals the number of analyzed participants. ITT Population

End point type

Secondary

End point timeframe

Baseline, Week 24 and Week 48 Each component calculated using the LOCF.

End point values	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Number of subjects analysed	171	166	169
Units: Percent Change
arithmetic mean (standard deviation)
Week 24 [n=171, 166, 169]	-14 ( 48.94 )	-31.5 ( 46.4 )	-29.1 ( 54.43 )
Week 48 [n=171, 166, 169]	-28 ( 50.78 )	-39.7 ( 40.53 )	-36.6 ( 47.6 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Participant’s Pain Assessment

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End point title

Percent Change From Baseline in Participant’s Pain Assessment

End point description

The participant’s assessment of their current level of pain on a 100 mm horizontal VAS, where the left-hand extreme of the line (0 mm) was described as "no pain" and the right-hand extreme (100 mm) as "unbearable pain". The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100. A negative percentage change from baseline score indicates an improvement. For each parameter and treatment group, n equals the number of analyzed participants. ITT Population

End point type

Secondary

End point timeframe

Baseline, Week 24 and Week 48 Each component calculated using the LOCF.

End point values	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Number of subjects analysed	171	166	169
Units: Percent Change
arithmetic mean (standard deviation)
Week 24 [n=171, 166, 169]	-9.7 ( 52.58 )	-25.7 ( 58.52 )	-29.1 ( 53.11 )
Week 48 [n=171, 166, 169]	-24.4 ( 60.22 )	-35.5 ( 50.45 )	-36.3 ( 47.87 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Physician’s Global Assessment of Disease Activity

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End point title

Percent Change From Baseline in Physician’s Global Assessment of Disease Activity

End point description

The physician’s assessment of the participant's current disease activity on a 100 mm horizontal VAS, where the left-hand extreme of the line (0 mm) was described as "no disease activity" (symptom-free and no arthritis symptoms) and the right-hand extreme (100 mm) as "maximum disease activity". The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100. A negative percentage change from baseline score indicates an improvement. For each parameter and treatment group, n equals the number of analyzed participants. ITT Population

End point type

Secondary

End point timeframe

Baseline, Week 24 and Week 48 Each component calculated using the LOCF.

End point values	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Number of subjects analysed	172	166	170
Units: Percent Change
arithmetic mean (standard deviation)
Week 24 [n=172, 166, 170]	-25.3 ( 38.52 )	-36.9 ( 61.26 )	-35.4 ( 46.99 )
Week 48 [n=172, 166, 170]	-39.4 ( 39.95 )	-40.5 ( 74.54 )	-49 ( 40.01 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score

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End point title

Percent Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score

End point description

The Stanford Health Assessment Questionnaire disability index is a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants choose from four response categories, ranging from 'without any difficulty' (Score=0) to 'unable to do' (Score=3). The overall score is the average of each of the 8 category scores and ranges from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100. A negative percentage change from baseline score indicates an improvement. For each parameter and treatment group, n equals the number of analyzed participants. ITT Population

End point type

Secondary

End point timeframe

Baseline, Week 24 and Week 48 Each component calculated using the LOCF.

End point values	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Number of subjects analysed	172	165	170
Units: Percent Change
arithmetic mean (standard deviation)
Week 24 [n=172, 165, 170]	-14.7 ( 38.41 )	-26.9 ( 40.89 )	-23.4 ( 49.52 )
Week 48 [n=172, 165, 170]	-22.6 ( 39.63 )	-30.2 ( 41.64 )	-30.6 ( 39.95 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in C-Reactive Protein

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End point title

Percent Change From Baseline in C-Reactive Protein

End point description

CRP was measured from blood samples by a central laboratory as a marker for inflammation. The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100. A negative percentage change from baseline score indicates an improvement. For each parameter and treatment group, n equals the number of analyzed participants. ITT Population

End point type

Secondary

End point timeframe

Baseline, Week 24 and Week 48 Each component calculated using the LOCF.

End point values	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Number of subjects analysed	172	166	170
Units: Percent Change
arithmetic mean (standard deviation)
Week 24 [n=172, 166, 170]	58.1 ( 385.23 )	-27.5 ( 84.36 )	-23.1 ( 119.75 )
Week 48 [n=172, 166, 170]	40.1 ( 402.67 )	-37.3 ( 94.65 )	-34.9 ( 82.4 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Erythrocyte Sedimentation Rate

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End point title

Percent Change From Baseline in Erythrocyte Sedimentation Rate

End point description

ESR indirectly measures how much inflammation is in the body. A higher ESR is indicative of increased inflammation. The percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100. A negative percentage change from baseline score indicates an improvement. For each parameter and treatment group, n equals the number of analyzed participants. ITT Population

End point type

Secondary

End point timeframe

Baseline, Week 24 and Week 48 Each component calculated using the LOCF.

End point values	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Number of subjects analysed	172	166	169
Units: Percent Change
arithmetic mean (standard deviation)
Week 24 [n=172, 166, 169]	8 ( 130.71 )	-28 ( 42.2 )	-29.2 ( 52.32 )
Week 48 [n=172, 166, 169]	-14.5 ( 68.55 )	-31.3 ( 49.72 )	-36.7 ( 51.49 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Short Form 36 Health Survey (SF-36) Summary Scores (Physical and Mental Components)

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End point title

Percent Change From Baseline in Short Form 36 Health Survey (SF-36) Summary Scores (Physical and Mental Components)

End point description

SF-36 measured impact of disease on overall quality of life and consists of 36 questions split into 2 major components: physical health and mental health. Physical health includes four domains: physical health, bodily pain, physical functioning and physical role limitations. Under the mental health domain there are four domains; mental health, vitality, social functioning, and emotional role limitation. Individual domain scores are aggregated to derive a physical-component summary score and a mental-component summary score which range from 0 to 100, with higher scores indicating a better level of functioning. Percentage change from baseline at each post-baseline visit was calculated as: [(post-baseline value minus baseline value) divided by Baseline value]*100. A positive percentage change from baseline score indicates an improvement. For each parameter/ treatment group, n equals the number of analyzed participants. ITT Population: included participants with available data.

End point type

Secondary

End point timeframe

Baseline, Week 24 and Week 48

End point values	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Number of subjects analysed	154	154	162
Units: Percent Change
arithmetic mean (standard deviation)
Physical Component: Week 24 [n=147, 152, 155]	11.1 ( 27.63 )	23.7 ( 31.63 )	22.8 ( 33.09 )
Physical Component: Week 48 [n=154, 154, 162]	21.3 ( 30.99 )	26.4 ( 35.81 )	27.4 ( 31.93 )
Mental Component: Week 24 [n=147, 152, 155]	8.4 ( 29.43 )	12.6 ( 29.13 )	19.6 ( 56.64 )
Mental Component: Week 48 [n=154, 154, 162]	12.7 ( 30.52 )	18.4 ( 38.87 )	18.7 ( 57.34 )

No statistical analyses for this end point

Secondary: Change From Baseline in Short Form 36 Health Survey (SF-36) General Health Domain Score

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End point title

Change From Baseline in Short Form 36 Health Survey (SF-36) General Health Domain Score

End point description

The SF-36 measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The individual domain scores are calculated and transformed to range from 0 to 100, with higher scores indicating a better level of functioning. A positive change from baseline score indicates an improvement. For each parameter and treatment group, n equals the number of analyzed participants. ITT Population: included participants with available data.

End point type

Secondary

End point timeframe

Baseline, Week 24 and Week 48

End point values	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Number of subjects analysed	138	154	155
Units: Scores on a Scale
arithmetic mean (standard deviation)
Week 24 [n=138, 154, 155]	2.078 ( 7.3032 )	3.532 ( 8.2747 )	3.866 ( 9.2154 )
Week 48 [n=137, 148, 147]	4.214 ( 8.2352 )	4.165 ( 9.5894 )	4.362 ( 8.1242 )

No statistical analyses for this end point

Secondary: Change From Baseline in Short Form 36 Health Survey (SF-36) Bodily Pain Domain Score

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End point title

Change From Baseline in Short Form 36 Health Survey (SF-36) Bodily Pain Domain Score

End point description

End point type

Secondary

End point timeframe

Baseline, Week 24 and Week 48

End point values	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Number of subjects analysed	138	152	156
Units: Scores on a Scale
arithmetic mean (standard deviation)
Week 24 [n=138, 152, 156]	3.304 ( 8.5631 )	6.931 ( 8.2254 )	7.604 ( 8.5238 )
Week 48 [n=137, 147, 147]	8.449 ( 9.3543 )	8.079 ( 9.5435 )	8.964 ( 8.989 )

No statistical analyses for this end point

Secondary: Change From Baseline in Short Form 36 Health Survey (SF-36) Physical Functioning Domain Score

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End point title

Change From Baseline in Short Form 36 Health Survey (SF-36) Physical Functioning Domain Score

End point description

End point type

Secondary

End point timeframe

Baseline, Week 24 and Week 48

End point values	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Number of subjects analysed	138	154	154
Units: Scores on a Scale
arithmetic mean (standard deviation)
Week 24 [n=138, 154, 154]	3.553 ( 8.4181 )	5.46 ( 8.3099 )	5.653 ( 9.6817 )
Week 48 [n=137, 148, 146]	6.212 ( 9.6882 )	6.778 ( 8.7117 )	6.854 ( 9.3833 )

No statistical analyses for this end point

Secondary: Change From Baseline in Short Form 36 Health Survey (SF-36) Physical Role Limitations Domain Score

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End point title

Change From Baseline in Short Form 36 Health Survey (SF-36) Physical Role Limitations Domain Score

End point description

End point type

Secondary

End point timeframe

Baseline, Week 24 and Week 48

End point values	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Number of subjects analysed	137	153	156
Units: Scores on a Scale
arithmetic mean (standard deviation)
Week 24 [n=136, 153, 156]	2.713 ( 8.7263 )	5.618 ( 9.0459 )	5.175 ( 8.8018 )
Week 48 [n=137, 148, 147]	6.423 ( 9.6752 )	6.812 ( 9.8633 )	6.497 ( 8.482 )

No statistical analyses for this end point

Secondary: Change From Baseline in Short Form 36 Health Survey (SF-36) Mental Health Domain Score

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End point title

Change From Baseline in Short Form 36 Health Survey (SF-36) Mental Health Domain Score

End point description

End point type

Secondary

End point timeframe

Baseline, Week 24 and Week 48

End point values	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Number of subjects analysed	137	153	156
Units: Scores on a Scale
arithmetic mean (standard deviation)
Week 24 [n=137, 153, 156]	3.278 ( 8.685 )	2.77 ( 9.9943 )	4.486 ( 9.493 )
Week 48 [n=135, 147, 147]	3.89 ( 8.7493 )	4.583 ( 10.5625 )	4.224 ( 9.9831 )

No statistical analyses for this end point

Secondary: Change From Baseline in Short Form 36 Health Survey (SF-36) Vitality Domain Score

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End point title

Change From Baseline in Short Form 36 Health Survey (SF-36) Vitality Domain Score

End point description

End point type

Secondary

End point timeframe

Baseline, Week 24 and Week 48

End point values	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Number of subjects analysed	137	154	156
Units: Scores on a Scale
arithmetic mean (standard deviation)
Week 24 [n=137, 154, 156]	3.631 ( 8.7662 )	4.23 ( 9.3631 )	5.91 ( 9.5802 )
Week 48 [n=135, 147, 147]	6.853 ( 9.8221 )	5.925 ( 10.1495 )	5.869 ( 9.6168 )

No statistical analyses for this end point

Secondary: Change From Baseline in Short Form 36 Health Survey (SF-36) Social Functioning Domain Score

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End point title

Change From Baseline in Short Form 36 Health Survey (SF-36) Social Functioning Domain Score

End point description

End point type

Secondary

End point timeframe

Baseline, Week 24 and Week 48

End point values	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Number of subjects analysed	138	154	156
Units: Scores on a Scale
arithmetic mean (standard deviation)
Week 24 [n=138, 154, 156]	2.529 ( 9.6435 )	5.985 ( 10.2986 )	6.468 ( 10.8868 )
Week 48 [n=137, 148, 147]	6.569 ( 10.6674 )	7.112 ( 11.5329 )	6.159 ( 11.0244 )

No statistical analyses for this end point

Secondary: Change From Baseline in Short Form 36 Health Survey (SF-36) Emotional Role Limitations Domain Score

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End point title

Change From Baseline in Short Form 36 Health Survey (SF-36) Emotional Role Limitations Domain Score

End point description

End point type

Secondary

End point timeframe

Baseline, Week 24 and Week 48

End point values	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Number of subjects analysed	137	151	155
Units: Scores on a Scale
arithmetic mean (standard deviation)
Week 24 [n=136, 151, 155]	1.829 ( 11.5405 )	4.634 ( 11.6419 )	4.464 ( 13.6883 )
Week 48 [n=137, 146, 146]	4.724 ( 12.2649 )	6.257 ( 12.964 )	4.446 ( 13.4036 )

No statistical analyses for this end point

Secondary: Change From Baseline in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Scores

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End point title

Change From Baseline in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Scores

End point description

The FACIT questionnaire is a self-administered patient questionnaire that consists of 13 questions designed to measure the degree of fatigue experienced by participants in the previous 7 days. Participants respond to the questions using a value in the range of 0 (not at all) to 4 (very much). The scale score is computed by summing the item scores, after reversing those items that are worded in the negative direction. The FACIT subscale score ranges from 0 to 52, where higher scores represent less fatigue. A positive change from baseline score indicates an improvement. For each parameter and treatment group, n equals the number of analyzed participants. ITT Population: included participants with available data.

End point type

Secondary

End point timeframe

Baseline, Week 24 and Week 48 Each component calculated using the LOCF.

End point values	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Number of subjects analysed	170	165	169
Units: Scores on a Scale
arithmetic mean (standard deviation)
Week 24 [n=170, 165, 168]	2.661 ( 9.5093 )	5.564 ( 9.7438 )	6.398 ( 10.2143 )
Week 48 [170, 165, 169]	5.506 ( 10.9651 )	6.269 ( 9.7495 )	6.203 ( 9.7833 )

No statistical analyses for this end point

Secondary: Percentage of Participants With DAS28-ESR Low Disease Activity Score and Clinical Remission at Week 24

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End point title

Percentage of Participants With DAS28-ESR Low Disease Activity Score and Clinical Remission at Week 24

End point description

The DAS28 is a composite score to measure disease activity in participants with rheumatoid arthritis, derived from the following variables: •The number of swollen and tender joints assessed using the 28-joint count; •ESR; •Patient's global assessment of disease activity measured on a 100 mm VAS. The DAS28 score ranges from zero to ten. DAS28 above 5.1 indicates high disease activity. Low disease activity is defined by a DAS28 score less than or equal to 3.2. Remission is defined by a DAS28 score less than 2.6. ITT Population: included participants with available data.

End point type

Secondary

End point timeframe

Week 24 Each component calculated using the LOCF.

End point values	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Number of subjects analysed	172	166	170
Units: Percentage of Participants
number (not applicable)
Low Disease Activity	4.7	17.5	12.4
Clinical Remission	2.3	9.6	9.4

No statistical analyses for this end point

Secondary: Percentage of Participants With HAQ-DI Improved, Unchanged or Worsened at Week 24

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End point title

Percentage of Participants With HAQ-DI Improved, Unchanged or Worsened at Week 24

End point description

The Stanford Health Assessment Questionnaire disability index is a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants choose from four response categories, ranging from 'without any difficulty' (Score=0) to 'unable to do' (Score=3). The overall score is the average of each of the 8 category scores and ranges from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. A negative change from baseline score indicates an improvement. Improved HAQ-DI is defined as a change from Baseline score ≤-0.22. An Unchanged HAQ-DI is defined as a change from Baseline score >-0.22 and <0.22. A worsened HAQ-DI score is defined as a change from Baseline score of ≥0.22. ITT Population: included participants with available data.

End point type

Secondary

End point timeframe

Baseline and Week 24 Each component calculated using the LOCF.

End point values	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Number of subjects analysed	172	165	170
Units: Percentage of Participants
number (not applicable)
Improved	47.7	66.1	58.2
No Change	32.6	23.6	32.4
Worsened	19.8	10.3	9.4

No statistical analyses for this end point

Secondary: Percentage of Participants With HAQ-DI Improved, Unchanged or Worsened at Week 48

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End point title

Percentage of Participants With HAQ-DI Improved, Unchanged or Worsened at Week 48

End point description

The Stanford Health Assessment Questionnaire disability index is a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants choose from four response categories, ranging from 'without any difficulty' (Score=0) to 'unable to do' (Score=3). The overall score is the average of each of the 8 category scores and ranges from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. A negative change from baseline score indicates an improvement. Improved HAQ-DI is defined as a change from Baseline score ≤-0.22. An Unchanged HAQ-DI is defined as a change from Baseline score >-0.22 and <0.22. A worsened HAQ-DI score is defined as a change from Baseline score of ≥0.22. ITT Population: included participants with available data.

End point type

Secondary

End point timeframe

Baseline and Week 48 Each component calculated using the LOCF.

End point values	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Number of subjects analysed	172	165	170
Units: Percentage of Participants
number (not applicable)
Improved	54.7	73.3	68.8
No Change	29.1	17	25.3
Worsened	16.3	9.7	5.9

No statistical analyses for this end point

Secondary: Percentage of Participants With European League Against Rheumatism (EULAR) Response at Week 48

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End point title

Percentage of Participants With European League Against Rheumatism (EULAR) Response at Week 48

End point description

A EULAR response reflects an improvement in disease activity and an attainment of a lower degree of disease activity based on the DAS28 score. A Good Response is defined as an improvement (decrease) in the DAS28 of >1.2 compared with Baseline and attainment of a DAS28 score ≤3.2. A Moderate Response is defined as either: •an improvement (decrease) in the DAS28 >0.6 and ≤1.2 and attainment of a DAS28 score of ≤5.1 or, •an improvement (decrease) in the DAS28 of >1.2 and attainment of a DAS28 score of >3.2. No Response is defined as either an improvement (decrease) in the DAS28 of ≤0.6, or an improvement (decrease) in the DAS28 of >0.6 and ≤1.2 and attainment of a DAS28 score of 5.1 or higher. ITT Population: included participants with available data.

End point type

Secondary

End point timeframe

Baseline and Week 48 Each component calculated using the LOCF.

End point values	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Number of subjects analysed	172	167	170
Units: Percentage of Participants
number (not applicable)
No Response	41.3	26.9	31.8
Moderate Response	41.9	53.3	47.6
Good Response	16.9	19.8	20.6

No statistical analyses for this end point

Secondary: Percentage of Participants With DAS28-ESR Low Disease Activity Score and Clinical Remission at Week 48

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End point title

Percentage of Participants With DAS28-ESR Low Disease Activity Score and Clinical Remission at Week 48

End point description

The DAS28 is a composite score to measure disease activity in participants with rheumatoid arthritis, derived from the following variables: •The number of swollen and tender joints assessed using the 28-joint count; •ESR; •Patient's global assessment of disease activity measured on a 100 mm VAS. The DAS28 score ranges from zero to ten. DAS28 above 5.1 indicates high disease activity. Low disease activity is defined by a DAS28 score ≤3.2. Remission is defined by a DAS28 score <2.6. ITT Population: included participants with available data.

End point type

Secondary

End point timeframe

Week 48 Each component calculated using the LOCF.

End point values	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Number of subjects analysed	171	165	169
Units: Percentage of Participants
number (not applicable)
Low Disease Activity	18.1	20	24.3
Clinical Remission	7	9.1	11.2

No statistical analyses for this end point

Secondary: Percentage of Participants With an ACR50 Response at Week 48

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End point title

Percentage of Participants With an ACR50 Response at Week 48

End point description

To achieve an ACR50 required at least a 50% improvement compared with Baseline in both tender joint counts (68 joints assessed for tenderness) and swollen joint counts (66 joints assessed for swelling), as well as a 50% improvement in three of the following five additional measurements: •Physician's global assessment of disease activity (assessed using a 100 mm VAS); •Patient's global assessment of disease activity (assessed using a 100 mm VAS); •Patient's assessment of pain (assessed using a 100 mm VAS); •HAQ; a patient completed questionnaire consisting of 20 questions, scored from 0-3; •Acute phase reactant: CRP or, if CRP was missing, ESR. Participants who withdrew prematurely from the study prior to week 48, who received rescue therapy or had insufficient data in order to calculate a clinical response were considered to be non-responders. ITT Population

End point type

Secondary

End point timeframe

Baseline and Week 48 Each component calculated using the LOCF.

End point values	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Number of subjects analysed	172	167	170
Units: Percentage of Participants
number (not applicable)	18.6	32.9	34.1

No statistical analyses for this end point

Secondary: Percentage of Participants With an ACR70 Response at Week 48

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End point title

Percentage of Participants With an ACR70 Response at Week 48

End point description

To achieve an ACR70 required at least a 70% improvement compared with baseline in both tender joint counts (68 joints assessed for tenderness) and swollen joint counts (66 joints assessed for swelling), as well as a 70% improvement in three of the following five additional measurements: •Physician's global assessment of disease activity (assessed using a 100 mm VAS); •Patient's global assessment of disease activity (assessed using a 100 mm VAS); •Patient's assessment of pain (assessed using a 100 mm VAS); •HAQ; a patient completed questionnaire consisting of 20 questions, scored from 0-3; •Acute phase reactant: CRP or, if CRP was missing, ESR. Participants who withdrew prematurely from the study prior to Week 48, who received rescue therapy or had insufficient data in order to calculate a clinical response were considered to be non-responders. ITT Population

End point type

Secondary

End point timeframe

Baseline and Week 48

End point values	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Number of subjects analysed	172	167	170
Units: Percentage of Participants
number (not applicable)	9.3	12.6	13.5

No statistical analyses for this end point

Post-hoc: Time to Repletion of Peripheral CD19+ B-cells

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End point title

Time to Repletion of Peripheral CD19+ B-cells

End point description

Peripheral CD19+ B-cell repletion was defined as a CD19+ B-cell count that returned to the Baseline value or returned to ≥ the LLN, whichever was lower. ESFU Population

End point type

Post-hoc

End point timeframe

Beginning of the first infusion (Day 1) in the last treatment cycle until repletion or the end of the study (up to 3 years, 6 months)

End point values	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX
Number of subjects analysed	80	43
Units: Weeks
median (confidence interval 95%)	110.3 (89.6 to 148.3)	109.6 (94.1 to 134.9)

No statistical analyses for this end point

Post-hoc: Percentage of Participants With Low Immunoglobulin Concentrations Pre- and Post-Rituximab Treatment

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End point title

Percentage of Participants With Low Immunoglobulin Concentrations Pre- and Post-Rituximab Treatment

End point description

A low immunoglobulin concentration was defined as a concentration below the lower level of normal. Safety follow-up population.

End point type

Post-hoc

End point timeframe

Baseline (pre-rituximab), Beginning of the safety follow-up period to the end of the study (approximately 6 years) (post-rituximab)

End point values	Rituximab + MTX
Number of subjects analysed	491
Units: Percentage of Participants
number (not applicable)
Pre-Rituximab (N=490)	0.2
Post-Rituximab (N=491)	5.1

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Up to 5.1 years after last dose in treatment period (treatment period = up to 5 years)

Adverse event reporting additional description

During the 5-year treatment period, all adverse events (AEs) regardless of seriousness were reported. During the standard 48-week safety follow-up (SFU) and extended safety follow-up (ESFU), all serious adverse events (SAEs) and all non-serious infections were reported.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

14.1

Reporting group title

Placebo + MTX

Reporting group description

Includes all data for participants who remained on placebo, and data up to the point of switch if the participant switched to treatment with rituximab. Participants received placebo intravenous infusion on Days 1 and 15. From Week 16 onwards, participants could switch to receive rituximab 0.5 g (on Days 1 and 15) every 24 weeks for up to 5 years if they were not in clinical remission and safety criteria were met. Placebo and rituximab infusions were preceded with 100 mg intravenous methylprednisolone. Participants also received a stable dose of 10-25 mg/week of MTX and ≥ 5 mg/week folic acid for the duration of their participation in the study. All participants entered a 48-week safety follow-up (SFU) period following the treatment period.

Reporting group title

Rituximab 2 x 0.5 g + MTX

Reporting group description

Reporting group title

Rituximab 2 x 1.0 g + MTX

Reporting group description

Reporting group title

Switch Population: Placebo + MTX

Reporting group description

Includes all data up to the point of switch for participants in the Placebo + Methotrexate treatment group who switched to treatment with rituximab after Week 24.

Reporting group title

Switch Population: Rituximab

Reporting group description

Includes all data from the point of switch for participants who switched from Placebo + Methotrexate to treatment with rituximab.

Reporting group title

Rituximab 2 x 0.5 g + MTX - Extended Safety Follow-up Period

Reporting group description

Participants received no treatment during the extended safety follow-up period.

Reporting group title

Rituximab 2 x 1.0 g + MTX - Extended Safety Follow-up Period

Reporting group description

Participants received no treatment during the extended safety follow-up period.

Serious adverse events	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX	Switch Population: Placebo + MTX	Switch Population: Rituximab	Rituximab 2 x 0.5 g + MTX - Extended Safety Follow-up Period	Rituximab 2 x 1.0 g + MTX - Extended Safety Follow-up Period
Total subjects affected by serious adverse events
subjects affected / exposed	16 / 172 (9.30%)	52 / 167 (31.14%)	46 / 170 (27.06%)	12 / 155 (7.74%)	45 / 155 (29.03%)	8 / 82 (9.76%)	2 / 44 (4.55%)
number of deaths (all causes)	2	6	3	0	3	3	0
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung adenocarcinoma
subjects affected / exposed	1 / 172 (0.58%)	0 / 167 (0.00%)	0 / 170 (0.00%)	1 / 155 (0.65%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung squamous cell carcinoma stage unspecified
subjects affected / exposed	0 / 172 (0.00%)	1 / 167 (0.60%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Uterine leiomyoma
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	1 / 170 (0.59%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bladder cancer
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Meningioma
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Non-small cell lung cancer
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Non-small cell lung cancer metastatic
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal adenocarcinoma
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	1 / 170 (0.59%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal carcinoma
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	1 / 170 (0.59%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatic carcinoma
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	1 / 170 (0.59%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma of the cervix
subjects affected / exposed	0 / 172 (0.00%)	1 / 167 (0.60%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
T-cell prolymphocytic leukaemia
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	1 / 170 (0.59%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colon cancer
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	1 / 82 (1.22%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Aortic stenosis
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	1 / 170 (0.59%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intra-abdominal haematoma
subjects affected / exposed	0 / 172 (0.00%)	1 / 167 (0.60%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombosis
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	1 / 170 (0.59%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abortion threatened
subjects affected / exposed	0 / 172 (0.00%)	1 / 167 (0.60%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	0 / 172 (0.00%)	2 / 167 (1.20%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Death
subjects affected / exposed	0 / 172 (0.00%)	1 / 167 (0.60%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Device failure
subjects affected / exposed	0 / 172 (0.00%)	1 / 167 (0.60%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fibrosis
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	1 / 170 (0.59%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hernia obstructive
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Vaginal prolapse
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	1 / 170 (0.59%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cystocele
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	1 / 170 (0.59%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Menorrhagia
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	1 / 170 (0.59%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian cyst
subjects affected / exposed	0 / 172 (0.00%)	1 / 167 (0.60%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Postmenopausal haemorrhage
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Testicular necrosis
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	1 / 170 (0.59%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Uterine haemorrhage
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism
subjects affected / exposed	0 / 172 (0.00%)	2 / 167 (1.20%)	0 / 170 (0.00%)	0 / 155 (0.00%)	2 / 155 (1.29%)	1 / 82 (1.22%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	0 / 172 (0.00%)	1 / 167 (0.60%)	1 / 170 (0.59%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute respiratory failure
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Asthma
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	1 / 170 (0.59%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung disorder
subjects affected / exposed	0 / 172 (0.00%)	1 / 167 (0.60%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Major depression
subjects affected / exposed	0 / 172 (0.00%)	1 / 167 (0.60%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Hepatitis B DNA increased
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	1 / 170 (0.59%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	1 / 172 (0.58%)	4 / 167 (2.40%)	3 / 170 (1.76%)	0 / 155 (0.00%)	3 / 155 (1.94%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 5	0 / 3	0 / 0	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Incisional hernia
subjects affected / exposed	0 / 172 (0.00%)	1 / 167 (0.60%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Road traffic accident
subjects affected / exposed	0 / 172 (0.00%)	1 / 167 (0.60%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ankle fracture
subjects affected / exposed	0 / 172 (0.00%)	1 / 167 (0.60%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Foot fracture
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	1 / 170 (0.59%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infusion related reaction
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Limb injury
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	1 / 170 (0.59%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower limb fracture
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	1 / 170 (0.59%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed	1 / 172 (0.58%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Stress fracture
subjects affected / exposed	0 / 172 (0.00%)	1 / 167 (0.60%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	0 / 172 (0.00%)	1 / 167 (0.60%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Synovial rupture
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tendon rupture
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thoracic vertebral fracture
subjects affected / exposed	0 / 172 (0.00%)	1 / 167 (0.60%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Traumatic coma
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Coronary artery disease
subjects affected / exposed	2 / 172 (1.16%)	3 / 167 (1.80%)	1 / 170 (0.59%)	2 / 155 (1.29%)	3 / 155 (1.94%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 3	1 / 8	1 / 1	0 / 3	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 172 (0.00%)	4 / 167 (2.40%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	0 / 172 (0.00%)	1 / 167 (0.60%)	1 / 170 (0.59%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	1 / 170 (0.59%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	1 / 44 (2.27%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	1 / 170 (0.59%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Angina unstable
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	1 / 170 (0.59%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aortic valve incompetence
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	1 / 170 (0.59%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 172 (0.00%)	1 / 167 (0.60%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	0 / 172 (0.00%)	1 / 167 (0.60%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	0 / 172 (0.00%)	1 / 167 (0.60%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	1 / 82 (1.22%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Pleuropericarditis
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	1 / 82 (1.22%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Palpitations
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	1 / 82 (1.22%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	1 / 172 (0.58%)	0 / 167 (0.00%)	0 / 170 (0.00%)	1 / 155 (0.65%)	3 / 155 (1.94%)	1 / 82 (1.22%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	1 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Demyelination
subjects affected / exposed	1 / 172 (0.58%)	0 / 167 (0.00%)	0 / 170 (0.00%)	1 / 155 (0.65%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Benign intracranial hypertension
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diabetic hyperosmolar coma
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	1 / 170 (0.59%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	1 / 170 (0.59%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Radiculopathy
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	1 / 170 (0.59%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	1 / 170 (0.59%)	0 / 155 (0.00%)	0 / 155 (0.00%)	1 / 82 (1.22%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Neutropenia
subjects affected / exposed	0 / 172 (0.00%)	1 / 167 (0.60%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	0 / 172 (0.00%)	1 / 167 (0.60%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Cataract
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	2 / 170 (1.18%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Pancreatitis
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	2 / 170 (1.18%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diverticular perforation
subjects affected / exposed	1 / 172 (0.58%)	0 / 167 (0.00%)	0 / 170 (0.00%)	1 / 155 (0.65%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulum intestinal
subjects affected / exposed	1 / 172 (0.58%)	0 / 167 (0.00%)	0 / 170 (0.00%)	1 / 155 (0.65%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	2 / 170 (1.18%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	2 / 155 (1.29%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	2 / 170 (1.18%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	2 / 170 (1.18%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal perforation
subjects affected / exposed	0 / 172 (0.00%)	2 / 167 (1.20%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Duodenal ulcer
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Femoral hernia, obstructive
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	1 / 170 (0.59%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ileal ulcer
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	1 / 170 (0.59%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	1 / 170 (0.59%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Inguinal hernia, obstructive
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	1 / 170 (0.59%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 172 (0.00%)	1 / 167 (0.60%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Retroperitoneal haemorrhage
subjects affected / exposed	0 / 172 (0.00%)	1 / 167 (0.60%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Volvulus
subjects affected / exposed	0 / 172 (0.00%)	1 / 167 (0.60%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal wall haematoma
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	1 / 82 (1.22%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Rectal haemorrhage
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	1 / 82 (1.22%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	2 / 172 (1.16%)	0 / 167 (0.00%)	0 / 170 (0.00%)	1 / 155 (0.65%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	0 / 172 (0.00%)	2 / 167 (1.20%)	1 / 170 (0.59%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholangitis
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	1 / 170 (0.59%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	0 / 172 (0.00%)	1 / 167 (0.60%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Lichen planus
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	1 / 172 (0.58%)	1 / 167 (0.60%)	0 / 170 (0.00%)	1 / 155 (0.65%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Vertigo
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	1 / 170 (0.59%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Goitre
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Osteoarthritis
subjects affected / exposed	1 / 172 (0.58%)	4 / 167 (2.40%)	5 / 170 (2.94%)	1 / 155 (0.65%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 5	0 / 5	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rheumatoid arthritis
subjects affected / exposed	1 / 172 (0.58%)	2 / 167 (1.20%)	1 / 170 (0.59%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cervical spinal stenosis
subjects affected / exposed	0 / 172 (0.00%)	1 / 167 (0.60%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteonecrosis
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	2 / 155 (1.29%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	1 / 170 (0.59%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	1 / 82 (1.22%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	0 / 172 (0.00%)	1 / 167 (0.60%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar spinal stenosis
subjects affected / exposed	0 / 172 (0.00%)	1 / 167 (0.60%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	0 / 172 (0.00%)	1 / 167 (0.60%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal column stenosis
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal osteoarthritis
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spondyloarthropathy
subjects affected / exposed	0 / 172 (0.00%)	1 / 167 (0.60%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	1 / 172 (0.58%)	3 / 167 (1.80%)	4 / 170 (2.35%)	1 / 155 (0.65%)	3 / 155 (1.94%)	1 / 82 (1.22%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	1 / 1	2 / 3	4 / 5	1 / 1	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	2 / 172 (1.16%)	1 / 167 (0.60%)	1 / 170 (0.59%)	2 / 155 (1.29%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 1	0 / 1	2 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 172 (0.00%)	3 / 167 (1.80%)	1 / 170 (0.59%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	1 / 1	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 172 (0.00%)	3 / 167 (1.80%)	1 / 170 (0.59%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 3	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	0 / 172 (0.00%)	2 / 167 (1.20%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 172 (0.00%)	2 / 167 (1.20%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 172 (0.00%)	2 / 167 (1.20%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	1 / 82 (1.22%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 3	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Postoperative wound infection
subjects affected / exposed	1 / 172 (0.58%)	1 / 167 (0.60%)	0 / 170 (0.00%)	1 / 155 (0.65%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchopneumonia
subjects affected / exposed	1 / 172 (0.58%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	0 / 172 (0.00%)	2 / 167 (1.20%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal abscess
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	1 / 170 (0.59%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal sepsis
subjects affected / exposed	0 / 172 (0.00%)	1 / 167 (0.60%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abscess soft tissue
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis infective
subjects affected / exposed	0 / 172 (0.00%)	1 / 167 (0.60%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Enterocolitis infectious
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	1 / 170 (0.59%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenic sepsis
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	1 / 170 (0.59%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	0 / 172 (0.00%)	1 / 167 (0.60%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary sepsis
subjects affected / exposed	0 / 172 (0.00%)	1 / 167 (0.60%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary tuberculosis
subjects affected / exposed	0 / 172 (0.00%)	1 / 167 (0.60%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	1 / 172 (0.58%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 172 (0.00%)	1 / 167 (0.60%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	1 / 170 (0.59%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Sinusitis
subjects affected / exposed	0 / 172 (0.00%)	1 / 167 (0.60%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin infection
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Soft tissue infection
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tubo-ovarian abscess
subjects affected / exposed	0 / 172 (0.00%)	1 / 167 (0.60%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 172 (0.00%)	1 / 167 (0.60%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Diabetes mellitus
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	2 / 170 (1.18%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	1 / 170 (0.59%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Failure to thrive
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	1 / 155 (0.65%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	0 / 172 (0.00%)	0 / 167 (0.00%)	0 / 170 (0.00%)	0 / 155 (0.00%)	0 / 155 (0.00%)	0 / 82 (0.00%)	1 / 44 (2.27%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Placebo + MTX	Rituximab 2 x 0.5 g + MTX	Rituximab 2 x 1.0 g + MTX	Switch Population: Placebo + MTX	Switch Population: Rituximab	Rituximab 2 x 0.5 g + MTX - Extended Safety Follow-up Period	Rituximab 2 x 1.0 g + MTX - Extended Safety Follow-up Period
Total subjects affected by non serious adverse events
subjects affected / exposed	112 / 172 (65.12%)	149 / 167 (89.22%)	151 / 170 (88.82%)	99 / 155 (63.87%)	131 / 155 (84.52%)	5 / 82 (6.10%)	2 / 44 (4.55%)
Vascular disorders
Hypertension
subjects affected / exposed	3 / 172 (1.74%)	28 / 167 (16.77%)	18 / 170 (10.59%)	2 / 155 (1.29%)	15 / 155 (9.68%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences all number	3	30	21	2	19	0	0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	1 / 172 (0.58%)	13 / 167 (7.78%)	11 / 170 (6.47%)	0 / 155 (0.00%)	8 / 155 (5.16%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences all number	1	16	13	0	8	0	0
Oedema peripheral
subjects affected / exposed	2 / 172 (1.16%)	9 / 167 (5.39%)	12 / 170 (7.06%)	2 / 155 (1.29%)	5 / 155 (3.23%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences all number	2	11	13	2	6	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	7 / 172 (4.07%)	13 / 167 (7.78%)	22 / 170 (12.94%)	7 / 155 (4.52%)	11 / 155 (7.10%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences all number	7	13	25	7	15	0	0
Rhinitis allergic
subjects affected / exposed	0 / 172 (0.00%)	6 / 167 (3.59%)	10 / 170 (5.88%)	0 / 155 (0.00%)	6 / 155 (3.87%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences all number	0	6	11	0	6	0	0
Psychiatric disorders
Insomnia
subjects affected / exposed	7 / 172 (4.07%)	9 / 167 (5.39%)	8 / 170 (4.71%)	6 / 155 (3.87%)	5 / 155 (3.23%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences all number	7	10	8	6	7	0	0
Depression
subjects affected / exposed	0 / 172 (0.00%)	15 / 167 (8.98%)	7 / 170 (4.12%)	0 / 155 (0.00%)	7 / 155 (4.52%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences all number	0	16	7	0	7	0	0
Injury, poisoning and procedural complications
Infusion related reaction
subjects affected / exposed	33 / 172 (19.19%)	59 / 167 (35.33%)	59 / 170 (34.71%)	28 / 155 (18.06%)	39 / 155 (25.16%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences all number	44	160	148	38	105	0	0
Fall
subjects affected / exposed	5 / 172 (2.91%)	14 / 167 (8.38%)	5 / 170 (2.94%)	4 / 155 (2.58%)	18 / 155 (11.61%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences all number	5	22	6	4	23	0	0
Laceration
subjects affected / exposed	1 / 172 (0.58%)	2 / 167 (1.20%)	10 / 170 (5.88%)	1 / 155 (0.65%)	6 / 155 (3.87%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences all number	1	2	10	1	6	0	0
Nervous system disorders
Headache
subjects affected / exposed	6 / 172 (3.49%)	18 / 167 (10.78%)	15 / 170 (8.82%)	5 / 155 (3.23%)	16 / 155 (10.32%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences all number	6	28	21	5	24	0	0
Dizziness
subjects affected / exposed	4 / 172 (2.33%)	11 / 167 (6.59%)	10 / 170 (5.88%)	3 / 155 (1.94%)	0 / 155 (0.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences all number	4	11	11	3	0	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	5 / 172 (2.91%)	9 / 167 (5.39%)	12 / 170 (7.06%)	4 / 155 (2.58%)	7 / 155 (4.52%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences all number	5	9	13	4	7	0	0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	2 / 172 (1.16%)	8 / 167 (4.79%)	6 / 170 (3.53%)	2 / 155 (1.29%)	9 / 155 (5.81%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences all number	2	9	7	2	9	0	0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	7 / 172 (4.07%)	27 / 167 (16.17%)	20 / 170 (11.76%)	7 / 155 (4.52%)	20 / 155 (12.90%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences all number	8	33	30	8	26	0	0
Nausea
subjects affected / exposed	4 / 172 (2.33%)	21 / 167 (12.57%)	17 / 170 (10.00%)	4 / 155 (2.58%)	12 / 155 (7.74%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences all number	4	22	21	4	12	0	0
Dyspepsia
subjects affected / exposed	3 / 172 (1.74%)	4 / 167 (2.40%)	4 / 170 (2.35%)	3 / 155 (1.94%)	11 / 155 (7.10%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences all number	3	4	6	3	12	0	0
Gastrooesophageal reflux disease
subjects affected / exposed	2 / 172 (1.16%)	7 / 167 (4.19%)	10 / 170 (5.88%)	2 / 155 (1.29%)	4 / 155 (2.58%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences all number	2	8	10	2	4	0	0
Hepatobiliary disorders
Hepatotoxicity
subjects affected / exposed	2 / 172 (1.16%)	8 / 167 (4.79%)	7 / 170 (4.12%)	2 / 155 (1.29%)	8 / 155 (5.16%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences all number	2	12	9	2	9	0	0
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	1 / 172 (0.58%)	9 / 167 (5.39%)	7 / 170 (4.12%)	1 / 155 (0.65%)	6 / 155 (3.87%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences all number	1	12	8	1	6	0	0
Alopecia
subjects affected / exposed	1 / 172 (0.58%)	9 / 167 (5.39%)	6 / 170 (3.53%)	0 / 155 (0.00%)	3 / 155 (1.94%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences all number	1	10	6	0	3	0	0
Musculoskeletal and connective tissue disorders
Rheumatoid arthritis
subjects affected / exposed	30 / 172 (17.44%)	49 / 167 (29.34%)	36 / 170 (21.18%)	26 / 155 (16.77%)	31 / 155 (20.00%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences all number	42	71	49	38	49	0	0
Back pain
subjects affected / exposed	3 / 172 (1.74%)	22 / 167 (13.17%)	14 / 170 (8.24%)	3 / 155 (1.94%)	10 / 155 (6.45%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences all number	3	28	18	3	10	0	0
Arthralgia
subjects affected / exposed	3 / 172 (1.74%)	9 / 167 (5.39%)	15 / 170 (8.82%)	2 / 155 (1.29%)	7 / 155 (4.52%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences all number	3	16	22	2	8	0	0
Muscle spasms
subjects affected / exposed	4 / 172 (2.33%)	7 / 167 (4.19%)	7 / 170 (4.12%)	4 / 155 (2.58%)	10 / 155 (6.45%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences all number	4	9	7	4	14	0	0
Osteoarthritis
subjects affected / exposed	1 / 172 (0.58%)	8 / 167 (4.79%)	10 / 170 (5.88%)	1 / 155 (0.65%)	8 / 155 (5.16%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences all number	1	12	10	1	8	0	0
Pain in extremity
subjects affected / exposed	1 / 172 (0.58%)	9 / 167 (5.39%)	9 / 170 (5.29%)	1 / 155 (0.65%)	7 / 155 (4.52%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences all number	1	11	10	1	8	0	0
Infections and infestations
Upper respiratory tract infection
subjects affected / exposed	13 / 172 (7.56%)	59 / 167 (35.33%)	50 / 170 (29.41%)	13 / 155 (8.39%)	39 / 155 (25.16%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences all number	14	100	84	14	74	0	0
Nasopharyngitis
subjects affected / exposed	17 / 172 (9.88%)	43 / 167 (25.75%)	42 / 170 (24.71%)	16 / 155 (10.32%)	34 / 155 (21.94%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences all number	22	82	77	20	61	0	0
Urinary tract infection
subjects affected / exposed	12 / 172 (6.98%)	41 / 167 (24.55%)	25 / 170 (14.71%)	9 / 155 (5.81%)	34 / 155 (21.94%)	5 / 82 (6.10%)	2 / 44 (4.55%)
occurrences all number	23	72	45	10	50	7	3
Sinusitis
subjects affected / exposed	6 / 172 (3.49%)	24 / 167 (14.37%)	21 / 170 (12.35%)	6 / 155 (3.87%)	29 / 155 (18.71%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences all number	6	39	36	6	46	0	0
Bronchitis
subjects affected / exposed	3 / 172 (1.74%)	27 / 167 (16.17%)	25 / 170 (14.71%)	2 / 155 (1.29%)	24 / 155 (15.48%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences all number	3	39	30	2	37	0	0
Gastroenteritis
subjects affected / exposed	8 / 172 (4.65%)	15 / 167 (8.98%)	14 / 170 (8.24%)	7 / 155 (4.52%)	17 / 155 (10.97%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences all number	8	16	17	7	23	0	0
Pharyngitis
subjects affected / exposed	10 / 172 (5.81%)	15 / 167 (8.98%)	11 / 170 (6.47%)	10 / 155 (6.45%)	9 / 155 (5.81%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences all number	10	17	13	10	10	0	0
Influenza
subjects affected / exposed	1 / 172 (0.58%)	17 / 167 (10.18%)	20 / 170 (11.76%)	1 / 155 (0.65%)	13 / 155 (8.39%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences all number	1	26	30	1	15	0	0
Tooth abscess
subjects affected / exposed	0 / 172 (0.00%)	9 / 167 (5.39%)	8 / 170 (4.71%)	0 / 155 (0.00%)	7 / 155 (4.52%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences all number	0	12	9	0	7	0	0
Herpes zoster
subjects affected / exposed	2 / 172 (1.16%)	10 / 167 (5.99%)	4 / 170 (2.35%)	2 / 155 (1.29%)	5 / 155 (3.23%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences all number	2	10	4	2	5	0	0
Lower respiratory tract infection
subjects affected / exposed	1 / 172 (0.58%)	2 / 167 (1.20%)	8 / 170 (4.71%)	1 / 155 (0.65%)	9 / 155 (5.81%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences all number	1	3	17	1	19	0	0
Metabolism and nutrition disorders
Diabetes mellitus
subjects affected / exposed	4 / 172 (2.33%)	13 / 167 (7.78%)	6 / 170 (3.53%)	3 / 155 (1.94%)	7 / 155 (4.52%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences all number	4	14	6	3	8	0	0
Hypercholesterolaemia
subjects affected / exposed	1 / 172 (0.58%)	7 / 167 (4.19%)	9 / 170 (5.29%)	1 / 155 (0.65%)	5 / 155 (3.23%)	0 / 82 (0.00%)	0 / 44 (0.00%)
occurrences all number	1	7	9	1	6	0	0

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

06 Mar 2006

The first amendment, B, made three main changes: 1. Correction of the dose of pre-infusion antihistamine from diphenhydramine 100 mg to diphenhydramine 50 mg (or equivalent), in accordance with clinical practice. 2. Removal of immunoglobulin concentrations from the eligibility criteria for retreatment. 3. Extended the screening period to 42 days for participants requiring vaccination. The other items were minor changes, clarifications and corrections that did not affect the study conduct.

22 Mar 2007

The second amendment, C, made the following changes: 1. The addition of a comparison of the efficacy of two courses of 2 x 0.5 g rituximab with two courses of 2 x 1.0 g rituximab. This required the addition of study objective No. 3: “to explore a dose separation of rituximab 0.5 g IV x 2 from rituximab 1.0 g IV x 2 at Week 48”, and additions to the assessments and statistical analysis sections. Blinding was extended from Week 24 to Week 48; i.e., although after Week 24 all retreatment infusions were of rituximab, investigators, participants, and study team remained blinded to the dose, and also to the previous first course of treatment. 2. Hepatitis monitoring was added for Hepatitis B core antigen (HBcAg)-positive participants who might have been admitted to the study if they were Hepatitis surface antigen (HBsAb)-negative (HBsAb-positive participants were excluded from the study). Further courses of rituximab for these participants would only be allowed if their hepatitis B viral load was negative and their aspartate aminotransferase (AST) or alanine aminotransferase (ALT) were ≤2.5 x the upper limit of normal (ULN). 3. The rituximab warnings and precautions were updated in line with the latest Investigator’s Brochure. 4. The assessment of eligibility for retreatment was clarified, especially the timing of assessment and the maximum time from assessment to initiation of retreatment. 5. Addition of the proportion of participants with a minimal clinically important difference (MCID) in the health assessment questionnaire (HAQ) as a secondary endpoint. The other changes including corrections, updates and clarifications did not affect the study conduct.

19 Nov 2008

The third amendment, D, made the following changes: 1. Extension of study to provide additional information on the safety of long-term treatment with rituximab in RA participants. 2. Update to safety information (including PML update). 3. Update of study procedures.

31 Aug 2012

The fourth amendment, E, made the following changes: 1. Discontinuation of extended B-cell follow up following the safety follow-up period. 2. Administrative updates.

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/20488885

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Clinical trials

Clinical Trial Results: A Randomized, Placebo Controlled, Double-blind, Parallel Group, International Study to Evaluate the Safety and Efficacy of Rituximab in Combination With Methotrexate, Compared to Methotrexate Monotherapy, in Patients With Active Rheumatoid Arthritis

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Participants With American College of Rheumatology (ACR) 20 Response at Week 24

Primary: Percentage of Participants With American College of Rheumatology (ACR) 20 Response at Week 24

Secondary: Percentage of Participants With an ACR50 Response at Week 24

Secondary: Percentage of Participants With an ACR50 Response at Week 24

Secondary: Percentage of Participants With an ACR70 Response at Week 24

Secondary: Percentage of Participants With an ACR70 Response at Week 24

Secondary: Change From Baseline in Disease Activity Score (DAS28-ESR) at Week 24

Secondary: Change From Baseline in Disease Activity Score (DAS28-ESR) at Week 24

Secondary: Percentage of Participants With European League Against Rheumatism (EULAR) Response at Week 24

Secondary: Percentage of Participants With European League Against Rheumatism (EULAR) Response at Week 24

Secondary: Percent Change From Baseline in Swollen Joint Count at Week 24 and Week 48

Secondary: Percent Change From Baseline in Swollen Joint Count at Week 24 and Week 48

Secondary: Percent Change From Baseline in Tender Joint Count at Week 24 and Week 48

Secondary: Percent Change From Baseline in Tender Joint Count at Week 24 and Week 48

Secondary: Percent Change From Baseline in Participant's Global Assessment of Disease Activity

Secondary: Percent Change From Baseline in Participant's Global Assessment of Disease Activity

Secondary: Percent Change From Baseline in Participant’s Pain Assessment

Secondary: Percent Change From Baseline in Participant’s Pain Assessment

Secondary: Percent Change From Baseline in Physician’s Global Assessment of Disease Activity

Secondary: Percent Change From Baseline in Physician’s Global Assessment of Disease Activity

Secondary: Percent Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score

Secondary: Percent Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) Score

Secondary: Percent Change From Baseline in C-Reactive Protein

Secondary: Percent Change From Baseline in C-Reactive Protein

Secondary: Percent Change From Baseline in Erythrocyte Sedimentation Rate

Secondary: Percent Change From Baseline in Erythrocyte Sedimentation Rate

Secondary: Percent Change From Baseline in Short Form 36 Health Survey (SF-36) Summary Scores (Physical and Mental Components)

Secondary: Percent Change From Baseline in Short Form 36 Health Survey (SF-36) Summary Scores (Physical and Mental Components)

Secondary: Change From Baseline in Short Form 36 Health Survey (SF-36) General Health Domain Score

Secondary: Change From Baseline in Short Form 36 Health Survey (SF-36) General Health Domain Score

Secondary: Change From Baseline in Short Form 36 Health Survey (SF-36) Bodily Pain Domain Score

Secondary: Change From Baseline in Short Form 36 Health Survey (SF-36) Bodily Pain Domain Score

Secondary: Change From Baseline in Short Form 36 Health Survey (SF-36) Physical Functioning Domain Score

Secondary: Change From Baseline in Short Form 36 Health Survey (SF-36) Physical Functioning Domain Score

Secondary: Change From Baseline in Short Form 36 Health Survey (SF-36) Physical Role Limitations Domain Score

Secondary: Change From Baseline in Short Form 36 Health Survey (SF-36) Physical Role Limitations Domain Score

Secondary: Change From Baseline in Short Form 36 Health Survey (SF-36) Mental Health Domain Score

Secondary: Change From Baseline in Short Form 36 Health Survey (SF-36) Mental Health Domain Score

Secondary: Change From Baseline in Short Form 36 Health Survey (SF-36) Vitality Domain Score

Secondary: Change From Baseline in Short Form 36 Health Survey (SF-36) Vitality Domain Score

Secondary: Change From Baseline in Short Form 36 Health Survey (SF-36) Social Functioning Domain Score

Secondary: Change From Baseline in Short Form 36 Health Survey (SF-36) Social Functioning Domain Score

Secondary: Change From Baseline in Short Form 36 Health Survey (SF-36) Emotional Role Limitations Domain Score

Secondary: Change From Baseline in Short Form 36 Health Survey (SF-36) Emotional Role Limitations Domain Score

Secondary: Change From Baseline in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Scores

Secondary: Change From Baseline in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Scores

Secondary: Percentage of Participants With DAS28-ESR Low Disease Activity Score and Clinical Remission at Week 24

Secondary: Percentage of Participants With DAS28-ESR Low Disease Activity Score and Clinical Remission at Week 24

Secondary: Percentage of Participants With HAQ-DI Improved, Unchanged or Worsened at Week 24

Secondary: Percentage of Participants With HAQ-DI Improved, Unchanged or Worsened at Week 24

Secondary: Percentage of Participants With HAQ-DI Improved, Unchanged or Worsened at Week 48

Secondary: Percentage of Participants With HAQ-DI Improved, Unchanged or Worsened at Week 48

Secondary: Percentage of Participants With European League Against Rheumatism (EULAR) Response at Week 48

Secondary: Percentage of Participants With European League Against Rheumatism (EULAR) Response at Week 48

Secondary: Percentage of Participants With DAS28-ESR Low Disease Activity Score and Clinical Remission at Week 48

Secondary: Percentage of Participants With DAS28-ESR Low Disease Activity Score and Clinical Remission at Week 48

Secondary: Percentage of Participants With an ACR50 Response at Week 48

Secondary: Percentage of Participants With an ACR50 Response at Week 48

Secondary: Percentage of Participants With an ACR70 Response at Week 48

Secondary: Percentage of Participants With an ACR70 Response at Week 48

Post-hoc: Time to Repletion of Peripheral CD19+ B-cells

Post-hoc: Time to Repletion of Peripheral CD19+ B-cells

Post-hoc: Percentage of Participants With Low Immunoglobulin Concentrations Pre- and Post-Rituximab Treatment

Post-hoc: Percentage of Participants With Low Immunoglobulin Concentrations Pre- and Post-Rituximab Treatment

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Clinical Trial Results:
A Randomized, Placebo Controlled, Double-blind, Parallel Group, International Study to Evaluate the Safety and Efficacy of Rituximab in Combination With Methotrexate, Compared to Methotrexate Monotherapy, in Patients With Active Rheumatoid Arthritis