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Clinical Trial Results:
Open-Label, Phase IIIb Study to Evaluate the Efficacy and Safety of Subcutaneous (SC) Tocilizumab Monotherapy or Combination Therapy with Methotrexate (MTX) or Other Non-Biologic Disease Modifying Anti-Rheumatic Drugs (DMARDs) in Patients With Active Rheumatoid Arthritis (RA) Who Have an Inadequate Response to Current Non-Biologic DMARD Therapy or the First Anti-Tumour Necrosis Factor (Anti-TNF) Biologic Agent

Summary
EudraCT number	2013-000054-22
Trial protocol	GB
Global end of trial date	04 Aug 2016

Results information
Results version number	v1
This version publication date	21 Jul 2017
First version publication date	21 Jul 2017
Other versions	v2

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

ML28641

ISRCTN number

US NCT number

NCT02046603

WHO universal trial number (UTN)

Other trial identifiers

Hoffmann-La Roche: ACT-MOVE

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

04 Aug 2016

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

04 Aug 2016

Was the trial ended prematurely?

Main objective of the trial

The primary objective was to assess the efficacy of switching to subcutaneous (SC) tocilizumab (as monotherapy or in combination with methotrexate or other non-biologic disease modifying antirheumatic drugs [DMARDs]) in participants who had an inadequate response to current non-biologic methotrexate therapy or the first anti-tumor necrosis factor (anti-TNF) biologic agent (as monotherapy or in combination with methotrexate or other non-biologic DMARDs).

Protection of trial subjects

The study was conducted in accordance with the principles of the Declaration of Helsinki and International Council for Harmonisation Good Clinical Practice according to the regulations and procedures described in the study protocol.

Background therapy

Evidence for comparator

Actual start date of recruitment

04 Mar 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 161

Worldwide total number of subjects

161

EEA total number of subjects

161

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)

126

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

A total of 162 participants were enrolled. One participant who did not receive a dose of tocilizumab was excluded from the full analysis set (FAS) and the results are reported for 161 participants.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Tocilizumab Monotherapy

Arm description

Participants received a weekly SC injection of tocilizumab 162 milligrams (mg) as monotherapy for 52 weeks.

Arm type

Experimental

Investigational medicinal product name

Tocilizumab

Investigational medicinal product code

Other name

RoActemra, Actemra

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Tocilizumab 162 mg was administered once a week by SC injection and as a single fixed dose, irrespective of body weight, for the treatment duration of 52 weeks.

Tocilizumab in Combination With Methotrexate or Other DMARDs

Arm description

Participants received a weekly SC injection of tocilizumab 162 mg in combination with methotrexate or other non-biologic DMARDs for 52 weeks.

Arm type

Experimental

Investigational medicinal product name

Tocilizumab

Investigational medicinal product code

Other name

RoActemra, Actemra

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Tocilizumab 162 mg was administered once a week by SC injection and as a single fixed dose, irrespective of body weight, for the treatment duration of 52 weeks.

Number of subjects in period 1	Tocilizumab Monotherapy	Tocilizumab in Combination With Methotrexate or Other DMARDs
Started	21	140
Completed	7	65
Not completed	14	75
Participant/legal guardian decision	1	3
Physician decision	1	1
Adverse Event	-	1
Death	-	1
Unspecified	11	66
Lost to follow-up	1	2
Protocol deviation	-	1

Baseline characteristics

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Reporting group title

Tocilizumab Monotherapy

Reporting group description

Participants received a weekly SC injection of tocilizumab 162 milligrams (mg) as monotherapy for 52 weeks.

Reporting group title

Tocilizumab in Combination With Methotrexate or Other DMARDs

Reporting group description

Participants received a weekly SC injection of tocilizumab 162 mg in combination with methotrexate or other non-biologic DMARDs for 52 weeks.

Reporting group values	Tocilizumab Monotherapy	Tocilizumab in Combination With Methotrexate or Other DMARDs	Total
Number of subjects	21	140	161
Age Categorical
Units: Subjects
Age Continuous
Units: years
arithmetic mean (standard deviation)	53.9 ± 13.63	55.3 ± 10.76	-
Gender Categorical
Units: Subjects
Female	16	104	120
Male	5	36	41

End points

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Reporting group title

Tocilizumab Monotherapy

Reporting group description

Participants received a weekly SC injection of tocilizumab 162 milligrams (mg) as monotherapy for 52 weeks.

Reporting group title

Tocilizumab in Combination With Methotrexate or Other DMARDs

Reporting group description

Participants received a weekly SC injection of tocilizumab 162 mg in combination with methotrexate or other non-biologic DMARDs for 52 weeks.

Primary: Change From Baseline in Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS28-ESR) at Week 2

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End point title

Change From Baseline in Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS28-ESR) at Week 2 ^[1]

End point description

DAS28 was calculated from swollen joint count (SJC) and tender joint count (TJC) using 28 joints count, erythrocyte sedimentation rate (ESR; millimeters per hour [mm/hour]), and patient’s global assessment of disease activity (measured on 0 to 100 mm Visual Analog Scale [VAS] where 0 mm=no disease activity and 100 mm=worst disease activity). DAS28 scores were calculated as [0.56×square root of TJC] + [0.28×square root of SJC] + [0.70×natural log (ESR)] + [0.014×VAS]. Total score range: 0-10, higher score=higher disease activity. DAS28-ESR greater than or equal to (≥) 2.6 to less than or equal to (≤) 3.2 implied low disease activity, greater than (>) 3.2 to ≤5.1 implied moderate disease activity, >5.1 implied high/severe disease, and less than (<)2.6 implied clinical remission. FAS population included all participants who received at least 1 dose of SC tocilizumab. “Number of subjects analysed”=participants evaluable for this outcome. “n”=participants evaluable at specified timepoint.

End point type

Primary

End point timeframe

Baseline, Week 2

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

End point values	Tocilizumab Monotherapy	Tocilizumab in Combination With Methotrexate or Other DMARDs
Number of subjects analysed	21	139
Units: units on a scale
arithmetic mean (standard deviation)
Baseline (n=21, 139)	5.52 ± 1.014	5.53 ± 1.257
Change at Week 2 (n=21, 137)	-1.41 ± 0.994	-1.22 ± 1.131

No statistical analyses for this end point

Primary: Change From Baseline in DAS28-ESR at Week 4

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End point title

Change From Baseline in DAS28-ESR at Week 4 ^[2]

End point description

DAS28 was calculated from SJC and TJC using 28 joints count, ESR (mm/hour), and patient’s global assessment of disease activity (measured on a 0 to 100 mm VAS where 0 mm=no disease activity and 100 mm=worst disease activity). DAS28 scores were calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. Total score range: 0-10, higher score=higher disease activity. DAS28-ESR ≥2.6 to ≤3.2 implied low disease activity, >3.2 to ≤5.1 implied moderate disease activity, >5.1 implied high/severe disease, and <2.6 implied clinical remission. FAS population. Here, “Number of subjects analysed” = participants who were evaluable for this outcome

End point type

Primary

End point timeframe

Baseline, Week 4

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned for this end point.

End point values	Tocilizumab Monotherapy	Tocilizumab in Combination With Methotrexate or Other DMARDs
Number of subjects analysed	21	137
Units: units on a scale
arithmetic mean (standard deviation)	-1.86 ± 1.016	-2.11 ± 1.215

No statistical analyses for this end point

Primary: Change From Baseline in DAS28-ESR at Week 8

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End point title

Change From Baseline in DAS28-ESR at Week 8 ^[3]

End point description

End point type

Primary

End point timeframe

Baseline, Week 8

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned for this end point.

End point values	Tocilizumab Monotherapy	Tocilizumab in Combination With Methotrexate or Other DMARDs
Number of subjects analysed	18	131
Units: units on a scale
arithmetic mean (standard deviation)	-2.42 ± 1.352	-2.62 ± 1.482

No statistical analyses for this end point

Primary: Change From Baseline in DAS28-ESR at Week 12

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End point title

Change From Baseline in DAS28-ESR at Week 12 ^[4]

End point description

End point type

Primary

End point timeframe

Baseline, Week 12

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned for this end point.

End point values	Tocilizumab Monotherapy	Tocilizumab in Combination With Methotrexate or Other DMARDs
Number of subjects analysed	19	128
Units: units on a scale
arithmetic mean (standard deviation)	-2.33 ± 1.522	-2.99 ± 1.51

No statistical analyses for this end point

Primary: Change From Baseline in DAS28-ESR at Week 16

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End point title

Change From Baseline in DAS28-ESR at Week 16 ^[5]

End point description

End point type

Primary

End point timeframe

Baseline, Week 16

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned for this end point.

End point values	Tocilizumab Monotherapy	Tocilizumab in Combination With Methotrexate or Other DMARDs
Number of subjects analysed	18	125
Units: units on a scale
arithmetic mean (standard deviation)	-2.93 ± 1.218	-3.07 ± 1.532

No statistical analyses for this end point

Primary: Change From Baseline in DAS28-ESR at Week 20

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End point title

Change From Baseline in DAS28-ESR at Week 20 ^[6]

End point description

End point type

Primary

End point timeframe

Baseline, Week 20

Notes
[6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned for this end point.

End point values	Tocilizumab Monotherapy	Tocilizumab in Combination With Methotrexate or Other DMARDs
Number of subjects analysed	19	121
Units: units on a scale
arithmetic mean (standard deviation)	-3.17 ± 1.346	-3.13 ± 1.525

No statistical analyses for this end point

Primary: Change From Baseline in DAS28-ESR at Week 24

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End point title

Change From Baseline in DAS28-ESR at Week 24 ^[7]

End point description

End point type

Primary

End point timeframe

Baseline, Week 24

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned for this end point.

End point values	Tocilizumab Monotherapy	Tocilizumab in Combination With Methotrexate or Other DMARDs
Number of subjects analysed	19	117
Units: units on a scale
arithmetic mean (standard deviation)	-3.28 ± 1.379	-3.33 ± 1.47

No statistical analyses for this end point

Primary: Change From Baseline in DAS28-ESR at Week 28

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End point title

Change From Baseline in DAS28-ESR at Week 28 ^[8]

End point description

End point type

Primary

End point timeframe

Baseline, Week 28

Notes
[8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned for this end point.

End point values	Tocilizumab Monotherapy	Tocilizumab in Combination With Methotrexate or Other DMARDs
Number of subjects analysed	19	115
Units: units on a scale
arithmetic mean (standard deviation)	-3.54 ± 1.26	-3.32 ± 1.552

No statistical analyses for this end point

Primary: Change From Baseline in DAS28-ESR at Week 32

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End point title

Change From Baseline in DAS28-ESR at Week 32 ^[9]

End point description

End point type

Primary

End point timeframe

Baseline, Week 32

Notes
[9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned for this end point.

End point values	Tocilizumab Monotherapy	Tocilizumab in Combination With Methotrexate or Other DMARDs
Number of subjects analysed	19	115
Units: units on a scale
arithmetic mean (standard deviation)	-3.19 ± 1.418	-3.54 ± 1.448

No statistical analyses for this end point

Primary: Change From Baseline in DAS28-ESR at Week 36

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End point title

Change From Baseline in DAS28-ESR at Week 36 ^[10]

End point description

End point type

Primary

End point timeframe

Baseline, Week 36

Notes
[10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned for this end point.

End point values	Tocilizumab Monotherapy	Tocilizumab in Combination With Methotrexate or Other DMARDs
Number of subjects analysed	18	114
Units: units on a scale
arithmetic mean (standard deviation)	-3.57 ± 1.358	-3.55 ± 1.589

No statistical analyses for this end point

Primary: Change From Baseline in DAS28-ESR at Week 40

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End point title

Change From Baseline in DAS28-ESR at Week 40 ^[11]

End point description

End point type

Primary

End point timeframe

Baseline, Week 40

Notes
[11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned for this end point.

End point values	Tocilizumab Monotherapy	Tocilizumab in Combination With Methotrexate or Other DMARDs
Number of subjects analysed	17	111
Units: units on a scale
arithmetic mean (standard deviation)	-3.82 ± 1.143	-3.64 ± 1.524

No statistical analyses for this end point

Primary: Change From Baseline in DAS28-ESR at Week 44

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End point title

Change From Baseline in DAS28-ESR at Week 44 ^[12]

End point description

End point type

Primary

End point timeframe

Baseline, Week 44

Notes
[12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned for this end point.

End point values	Tocilizumab Monotherapy	Tocilizumab in Combination With Methotrexate or Other DMARDs
Number of subjects analysed	17	107
Units: units on a scale
arithmetic mean (standard deviation)	-3.61 ± 1.325	-3.65 ± 1.574

No statistical analyses for this end point

Primary: Change From Baseline in DAS28-ESR at Week 48

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End point title

Change From Baseline in DAS28-ESR at Week 48 ^[13]

End point description

End point type

Primary

End point timeframe

Baseline, Week 48

Notes
[13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned for this end point.

End point values	Tocilizumab Monotherapy	Tocilizumab in Combination With Methotrexate or Other DMARDs
Number of subjects analysed	16	107
Units: units on a scale
arithmetic mean (standard deviation)	-3.54 ± 1.146	-3.65 ± 1.552

No statistical analyses for this end point

Primary: Change From Baseline in DAS28-ESR at Week 52

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End point title

Change From Baseline in DAS28-ESR at Week 52 ^[14]

End point description

End point type

Primary

End point timeframe

Baseline, Week 52

Notes
[14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned for this end point.

End point values	Tocilizumab Monotherapy	Tocilizumab in Combination With Methotrexate or Other DMARDs
Number of subjects analysed	15	107
Units: units on a scale
arithmetic mean (standard deviation)	-3.75 ± 1.361	-3.67 ± 1.592

No statistical analyses for this end point

Primary: Change From Baseline in DAS28-ESR at Early Withdrawal

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End point title

Change From Baseline in DAS28-ESR at Early Withdrawal ^[15]

End point description

End point type

Primary

End point timeframe

Baseline, early withdrawal (up to Week 52)

Notes
[15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned for this end point.

End point values	Tocilizumab Monotherapy	Tocilizumab in Combination With Methotrexate or Other DMARDs
Number of subjects analysed	5	28
Units: units on a scale
arithmetic mean (standard deviation)	-2.88 ± 1.236	-1.63 ± 1.48

No statistical analyses for this end point

Secondary: Number of Participants Achieving an American College of Rheumatology Criteria 20 (ACR20) Response

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End point title

Number of Participants Achieving an American College of Rheumatology Criteria 20 (ACR20) Response

End point description

A participant had an ACR20 response if there was at least a 20 percent (%) improvement, ie, reduction from Baseline, in TJC (68 joints) and SJC (66 joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity [VAS: 0 mm=no disease activity to 100 mm=maximum disease activity]; 2) Patient's Global Assessment of Disease Activity [VAS: 0 mm=no disease activity to 100 mm=maximum disease activity]; 3) Patient's Assessment of Pain [VAS: 0 mm=no pain to 100 mm=unbearable pain]; 4) Health Assessment Questionnaire [20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, averaged to 0=without difficulty to 3=unable to do] and 5) an acute-phase reactant (either C-reactive protein [CRP] or ESR). FAS population. “n” = participants who were evaluable at specified timepoint for respective groups.

End point type

Secondary

End point timeframe

Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)

End point values	Tocilizumab Monotherapy	Tocilizumab in Combination With Methotrexate or Other DMARDs
Number of subjects analysed	21	140
Units: participants
number (not applicable)
Week 2 (n=21, 137)	6	23
Week 4 (n=21, 137)	6	68
Week 8 (n=18, 132)	11	69
Week 12 (n=19, 128)	10	83
Week 16 (n=19, 125)	13	83
Week 20 (n=19, 122)	15	86
Week 24 (n=19, 117)	15	90
Week 28 (n=19, 115)	14	87
Week 32 (n=19, 115)	13	89
Week 36 (n=18, 114)	12	92
Week 40 (n=17, 111)	13	91
Week 44 (n=17, 108)	12	88
Week 48 (n=16, 107)	12	87
Week 52 (n=16, 107)	12	88
Early withdrawal (n=5, 29)	3	10

No statistical analyses for this end point

Secondary: Number of Participants Achieving an ACR50 Response

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End point title

Number of Participants Achieving an ACR50 Response

End point description

A participant had an ACR50 response if there was at least a 50% improvement, ie, reduction from Baseline, in TJC (68 joints) and SJC (66 joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity [VAS: 0 mm=no disease activity to 100 mm=maximum disease activity]; 2) Patient's Global Assessment of Disease Activity [VAS: 0 mm=no disease activity to 100 mm=maximum disease activity]; 3) Patient's Assessment of Pain [VAS: 0 mm=no pain to 100 mm=unbearable pain]; 4) Health Assessment Questionnaire [20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, averaged to 0=without difficulty to 3=unable to do] and 5) an acute-phase reactant (either CRP or ESR). FAS population. “n” = participants who were evaluable at specified timepoint for respective groups.

End point type

Secondary

End point timeframe

Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)

End point values	Tocilizumab Monotherapy	Tocilizumab in Combination With Methotrexate or Other DMARDs
Number of subjects analysed	21	140
Units: participants
number (not applicable)
Week 2 (n=21, 137)	0	5
Week 4 (n=21, 137)	3	20
Week 8 (n=18, 132)	6	43
Week 12 (n=19, 128)	8	54
Week 16 (n=19, 125)	7	62
Week 20 (n=19, 122)	9	61
Week 24 (n=19, 117)	9	64
Week 28 (n=19, 115)	13	68
Week 32 (n=19, 115)	8	69
Week 36 (n=18, 114)	9	74
Week 40 (n=17, 111)	9	71
Week 44 (n=17, 108)	10	72
Week 48 (n=16, 107)	11	73
Week 52 (n=16, 107)	8	73
Early withdrawal (n=5, 29)	2	4

No statistical analyses for this end point

Secondary: Number of Participants Achieving an ACR70 Response

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End point title

Number of Participants Achieving an ACR70 Response

End point description

A participant had an ACR70 response if there was at least a 70% improvement, ie, reduction from Baseline, in TJC (68 joints) and SJC (66 joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity [VAS: 0 mm=no disease activity to 100 mm=maximum disease activity]; 2) Patient's Global Assessment of Disease Activity [VAS: 0 mm=no disease activity to 100 mm=maximum disease activity]; 3) Patient's Assessment of Pain [VAS: 0 mm=no pain to 100 mm=unbearable pain]; 4) Health Assessment Questionnaire [20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, averaged to 0=without difficulty to 3=unable to do] and 5) an acute-phase reactant (either CRP or ESR). FAS population. “n” = participants who were evaluable at specified timepoint for respective groups.

End point type

Secondary

End point timeframe

Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)

End point values	Tocilizumab Monotherapy	Tocilizumab in Combination With Methotrexate or Other DMARDs
Number of subjects analysed	21	140
Units: participants
number (not applicable)
Week 2 (n=21, 137)	0	0
Week 4 (n=21, 137)	1	9
Week 8 (n=18, 132)	4	19
Week 12 (n=19, 128)	3	30
Week 16 (n=19, 125)	3	32
Week 20 (n=19, 122)	7	37
Week 24 (n=19, 117)	5	38
Week 28 (n=19, 115)	6	44
Week 32 (n=19, 115)	6	47
Week 36 (n=18, 114)	7	48
Week 40 (n=17, 111)	8	49
Week 44 (n=17, 108)	6	53
Week 48 (n=16, 107)	8	56
Week 52 (n=16, 107)	7	54
Early withdrawal (n=5, 29)	2	1

No statistical analyses for this end point

Secondary: Number of Participants With European League Against Rheumatism (EULAR) Response (Good, Moderate or No Response) Based on DAS28-ESR

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End point title

Number of Participants With European League Against Rheumatism (EULAR) Response (Good, Moderate or No Response) Based on DAS28-ESR

End point description

DAS28-ESR was calculated from SJC and TJC using 28 joints count, ESR (mm/hour), and patient's global assessment of disease activity (VAS: 0 mm=no disease activity to 100 mm=maximum disease activity). DAS28-ESR scores were calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. DAS28-ESR based EULAR response criteria were used to measure individual response as none, good, and moderate, depending on extent of change from baseline and level of disease activity reached. Good responders had a change from baseline >1.2 with a DAS28 score ≤3.2; moderate responders had a change from baseline >1.2 with a DAS28 score >3.2 or a change from baseline >0.6 to ≤1.2 with a DAS28 score ≤5.1. Participants with change from baseline >0.6 to ≤1.2 with a DAS28 score >5.1, or any score with change from baseline ≤0.6, were assessed as non-responders. FAS population. “n”=participants who were evaluable at specified timepoint for respective groups.

End point type

Secondary

End point timeframe

Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)

End point values	Tocilizumab Monotherapy	Tocilizumab in Combination With Methotrexate or Other DMARDs
Number of subjects analysed	21	140
Units: participants
number (not applicable)
Week 2 (n=21, 137): No response	4	56
Week 2 (n=21, 137): Moderate response	10	56
Week 2 (n=21, 137): Good response	7	25
Week 4 (n=21, 137): No response	3	22
Week 4 (n=21, 137): Moderate response	7	58
Week 4 (n=21, 137): Good response	11	57
Week 8 (n=18, 131): No response	1	11
Week 8 (n=18, 131): Moderate response	9	48
Week 8 (n=18, 131): Good response	8	72
Week 12 (n=19, 128): No response	4	11
Week 12 (n=19, 128): Moderate response	3	34
Week 12 (n=19, 128): Good response	12	83
Week 16 (n=18, 125): No response	1	9
Week 16 (n=18, 125): Moderate response	4	30
Week 16 (n=18, 125): Good response	13	86
Week 20 (n=19, 121): No response	0	9
Week 20 (n=19, 121): Moderate response	5	27
Week 20 (n=19, 121): Good response	14	85
Week 24 (n=19, 117): No response	1	7
Week 24 (n=19, 117): Moderate response	2	21
Week 24 (n=19, 117): Good response	16	89
Week 28 (n=19, 115): No response	1	5
Week 28 (n=19, 115): Moderate response	0	24
Week 28 (n=19, 115): Good response	18	86
Week 32 (n=19, 115): No response	1	3
Week 32 (n=19, 115): Moderate response	2	21
Week 32 (n=19, 115): Good response	16	91
Week 36 (n=18, 114): No response	0	4
Week 36 (n=18, 114): Moderate response	3	19
Week 36 (n=18, 114): Good response	15	91
Week 40 (n=17, 111): No response	0	2
Week 40 (n=17, 111): Moderate response	1	15
Week 40 (n=17, 111): Good response	16	94
Week 44 (n=17, 107): No response	0	5
Week 44 (n=17, 107): Moderate response	2	15
Week 44 (n=17, 107): Good response	15	87
Week 48 (n=16, 107): No response	0	4
Week 48 (n=16, 107): Moderate response	2	13
Week 48 (n=16, 107): Good response	14	90
Week 52 (n=15, 107): No response	0	5
Week 52 (n=15, 107): Moderate response	3	12
Week 52 (n=15, 107): Good response	12	90
Early Withdrawal (n=5, 28): No response	0	11
Early Withdrawal (n=5, 28): Moderate response	1	8
Early Withdrawal (n=5, 28): Good response	4	9

No statistical analyses for this end point

Secondary: Change From Baseline in Simplified Disease Activity Index (SDAI) at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at Early Withdrawal

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End point title

Change From Baseline in Simplified Disease Activity Index (SDAI) at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at Early Withdrawal

End point description

The SDAI is the numerical sum of five outcome parameters: TJC and SJC based on a 28-joint assessment, patient and physician global assessment of disease activity assessed on 0-10 centimeter (cm) VAS (0 cm= no disease activity and 10 cm= worst disease activity), and CRP in milligrams per liter (mg/L). SDAI total score = 0-86. SDAI ≤3.3 indicates clinical remission, >3.3 to 11 = low disease activity, >11 to 26 = moderate disease activity, and >26 = high (or severe) disease activity. FAS population. Here, “Number of subjects analysed” = participants who were evaluable for this outcome. “n” = participants who were evaluable at specified timepoint for respective groups.

End point type

Secondary

End point timeframe

Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)

End point values	Tocilizumab Monotherapy	Tocilizumab in Combination With Methotrexate or Other DMARDs
Number of subjects analysed	21	136
Units: units on a scale
arithmetic mean (standard deviation)
Baseline (n=21, 136)	142.45 ± 36.644	143.48 ± 37.13
Change at Week 2 (n=21, 132)	-31.79 ± 35.8	-25.03 ± 34.264
Change at Week 4 (n=19, 131)	-46.13 ± 44.461	-53.05 ± 38.847
Change at Week 8 (n=17, 127)	-76.4 ± 59.317	-70.99 ± 46.601
Change at Week 12 (n=16, 120)	-47.89 ± 59.201	-81.5 ± 45.566
Change at Week 16 (n=16, 118)	-78.38 ± 41.554	-89.08 ± 41.093
Change at Week 20 (n=18, 115)	-95.92 ± 49.834	-84.06 ± 44.498
Change at Week 24 (n=19, 112)	-102.37 ± 40.583	-95.35 ± 45.87
Change at Week 28 (n=19, 109)	-99.76 ± 45.504	-95.33 ± 43.82
Change at Week 32 (n=19, 109)	-99.96 ± 43.236	-99.87 ± 40.741
Change at Week 36 (n=18, 107)	-106.52 ± 49.025	-101.93 ± 43.529
Change at Week 40 (n=17, 106)	-108.08 ± 48.571	-104.16 ± 43.84
Change at Week 44 (n=16, 101)	-111.29 ± 47.389	-104.21 ± 45.773
Change at Week 48 (n=16, 102)	-111.04 ± 54.633	-109.42 ± 41.472
Change at Week 52 (n=15, 104)	-119.25 ± 47.409	-106.94 ± 45.343
Change at early withdrawal (n=5, 28)	-63.76 ± 63.34	-41.98 ± 40.769

No statistical analyses for this end point

Secondary: Change From Baseline in Clinical Disease Activity Index (CDAI) at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at Early Withdrawal

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End point title

Change From Baseline in Clinical Disease Activity Index (CDAI) at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at Early Withdrawal

End point description

The CDAI is the numerical sum of four outcome parameters: TJC and SJC based on a 28-joint assessment, patient and physician’s global assessment of disease activity assessed on 0-10 cm VAS (0 cm= no disease activity and 10 cm= worst disease activity). CDAI total score = 0-76. CDAI ≤2.8 indicates clinical remission, >2.8 to 10 = low disease activity, >10 to 22 = moderate disease activity, and >22 = high (or severe) disease activity. FAS population. Here, “Number of subjects analysed” = participants who were evaluable for this outcome. “n” = participants who were evaluable at specified timepoint for respective groups.

End point type

Secondary

End point timeframe

Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)

End point values	Tocilizumab Monotherapy	Tocilizumab in Combination With Methotrexate or Other DMARDs
Number of subjects analysed	21	139
Units: units on a scale
arithmetic mean (standard deviation)
Baseline (n=21, 139)	140.9 ± 35.82	142.5 ± 36.49
Change at Week 2 (n=21, 137)	-30.3 ± 36.14	-22.4 ± 33.81
Change at Week 4 (n=21, 137)	-45.9 ± 42.7	-51.3 ± 38.73
Change at Week 8 (n=18, 130)	-75.4 ± 57.26	-69.2 ± 45.39
Change at Week 12 (n=19, 128)	-62 ± 65.3	-80.3 ± 44.81
Change at Week 16 (n=19, 125)	-87.6 ± 47.37	-86.1 ± 40.39
Change at Week 20 (n=18, 121)	-94.4 ± 49.7	-82.5 ± 44.2
Change at Week 24 (n=19, 117)	-100.9 ± 39.65	-93.5 ± 44.8
Change at Week 28 (n=19, 115)	-98.3 ± 44.36	-92.3 ± 42.69
Change at Week 32 (n=19, 115)	-98.5 ± 42.28	-98.1 ± 40.06
Change at Week 36 (n=18, 114)	-105.1 ± 48.08	-99.5 ± 44.03
Change at Week 40 (n=17, 111)	-106.5 ± 47.62	-102.5 ± 42.6
Change at Week 44 (n=17, 106)	-107 ± 46.18	-101.9 ± 44.99
Change at Week 48 (n=16, 106)	-109.6 ± 53.85	-107.2 ± 41.12
Change at Week 52 (n=16, 107)	-114.1 ± 47.05	-104.6 ± 45.84
Change at early withdrawal (n=5, 29)	-62.6 ± 62.97	-41.2 ± 39.91

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Total TJC on 68 Joints at Week 52

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End point title

Percent Change From Baseline in Total TJC on 68 Joints at Week 52

End point description

Number of tender joints was determined by examining 68 joints and identified the joints that were painful under pressure or to passive motion. The number of tender joints was recorded on the joint assessment form at each visit, no tenderness = 0, tenderness = 1; total was calculated by adding all the joints for a maximum score of 68. A reduction in number of tender joints compared to baseline indicates improvement. The outcome is reported as the percent change from baseline to end of treatment (52 weeks). FAS population. Here, “Number of subjects analysed” = participants who were evaluable for this outcome.

End point type

Secondary

End point timeframe

Baseline, Week 52

End point values	Tocilizumab Monotherapy	Tocilizumab in Combination With Methotrexate or Other DMARDs
Number of subjects analysed	15	106
Units: percent change
arithmetic mean (standard deviation)	-83.12 ± 26.607	-80.44 ± 41.226

No statistical analyses for this end point

Secondary: Change From Baseline in Total TJC on 28 Joints at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at Early Withdrawal

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End point title

Change From Baseline in Total TJC on 28 Joints at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at Early Withdrawal

End point description

Number of tender joints was determined by examining 28 joints and identified the joints that were painful under pressure or to passive motion. The number of tender joints was recorded on the joint assessment form at each visit, no tenderness = 0, tenderness = 1; total was calculated by adding all the joints for a maximum score of 28. A reduction in number of tender joints compared to baseline indicates improvement. FAS population. Here, “Number of subjects analysed” = participants who were evaluable for this outcome. “n” = participants who were evaluable at specified timepoint for respective groups.

End point type

Secondary

End point timeframe

Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)

End point values	Tocilizumab Monotherapy	Tocilizumab in Combination With Methotrexate or Other DMARDs
Number of subjects analysed	21	139
Units: tender joints
arithmetic mean (standard deviation)
Baseline (n=21, 139)	10.4 ± 6.46	12.9 ± 7.06
Change at Week 2 (n=21, 137)	-3.4 ± 5.62	-2.4 ± 5.63
Change at Week 4 (n=21, 137)	-3.9 ± 5.8	-5.4 ± 6.14
Change at Week 8 (n=18, 132)	-6.6 ± 6.41	-6.4 ± 6.94
Change at Week 12 (n=19, 128)	-6 ± 6.71	-8 ± 7.35
Change at Week 16 (n=19, 125)	-7.9 ± 6.35	-8.2 ± 7.05
Change at Week 20 (n=19, 122)	-8.5 ± 6.59	-8.3 ± 7.09
Change at Week 24 (n=19, 117)	-8.3 ± 7.41	-9.3 ± 7.53
Change at Week 28 (n=19, 115)	-8.7 ± 6.26	-9.2 ± 7.04
Change at Week 32 (n=19, 115)	-7.6 ± 6.64	-10.1 ± 6.76
Change at Week 36 (n=18, 114)	-9.4 ± 6.25	-9.7 ± 7.23
Change at Week 40 (n=17, 111)	-10.1 ± 6.64	-10.3 ± 6.74
Change at Week 44 (n=17, 108)	-9.7 ± 6.46	-10.4 ± 6.63
Change at Week 48 (n=16, 107)	-9.6 ± 6.36	-10.5 ± 6.7
Change at Week 52 (n=16, 107)	-9.4 ± 7.15	-10.4 ± 8.01
Change at early withdrawal (n=5, 29)	-7 ± 6.24	-3.3 ± 7.46

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Total SJC on 66 Joints at Week 52

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End point title

Percent Change From Baseline in Total SJC on 66 Joints at Week 52

End point description

Number of swollen joints was determined by examination of 66 joints and identifying when swelling was present. The number of swollen joints was recorded on the joint assessment form at each visit, no swelling = 0, swelling =1; total was calculated by adding all the joints for a maximum score of 66. A reduction in number of swollen joints compared to baseline indicates improvement. The outcome is reported as the percent change from baseline to end of treatment (52 weeks). FAS population. Here, “Number of subjects analysed” = participants who were evaluable for this outcome.

End point type

Secondary

End point timeframe

Baseline, Week 52

End point values	Tocilizumab Monotherapy	Tocilizumab in Combination With Methotrexate or Other DMARDs
Number of subjects analysed	16	102
Units: percent change
arithmetic mean (standard deviation)	-89.31 ± 20.059	-74.77 ± 66.277

No statistical analyses for this end point

Secondary: Change From Baseline in Total SJC on 28 Joints at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at Early Withdrawal

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End point title

Change From Baseline in Total SJC on 28 Joints at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at Early Withdrawal

End point description

Number of swollen joints was determined by examination of 28 joints and identifying when swelling was present. The number of swollen joints was recorded on the joint assessment form at each visit, no swelling = 0, swelling =1; total was calculated by adding all the joints for a maximum score of 28. A reduction in number of swollen joints compared to baseline indicates improvement. FAS population. Here, “Number of subjects analysed” = participants who were evaluable for this outcome. “n” = participants who were evaluable at specified timepoint for respective groups.

End point type

Secondary

End point timeframe

Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)

End point values	Tocilizumab Monotherapy	Tocilizumab in Combination With Methotrexate or Other DMARDs
Number of subjects analysed	21	139
Units: swollen joints
arithmetic mean (standard deviation)
Baseline (n=21, 139)	7 ± 4.64	5.6 ± 4.43
Change at Week 2 (n=21, 137)	-2.5 ± 4.31	-0.8 ± 3.95
Change at Week 4 (n=21, 137)	-4.2 ± 3.79	-2.5 ± 3.81
Change at Week 8 (n=18, 132)	-4.8 ± 4.21	-3.2 ± 4.4
Change at Week 12 (n=19, 128)	-4.2 ± 4.37	-3.8 ± 4.36
Change at Week 16 (n=19, 125)	-5.3 ± 4.67	-3.9 ± 4.41
Change at Week 20 (n=19, 122)	-5.6 ± 5.08	-4.2 ± 4.6
Change at Week 24 (n=19, 117)	-5.9 ± 5.12	-4.7 ± 4.21
Change at Week 28 (n=19, 115)	-6.4 ± 4.9	-4.4 ± 4.63
Change at Week 32 (n=19, 115)	-5.4 ± 5.1	-4.8 ± 4.37
Change at Week 36 (n=18, 114)	-6.5 ± 4.57	-4.9 ± 4.41
Change at Week 40 (n=17, 111)	-6.6 ± 5.12	-5 ± 4.82
Change at Week 44 (n=17, 108)	-6.6 ± 5.28	-5.2 ± 4.71
Change at Week 48 (n=16, 107)	-6.4 ± 4.83	-5 ± 4.48
Change at Week 52 (n=16, 107)	-6.3 ± 4.81	-5.1 ± 4.51
Change at early withdrawal (n=5, 29)	-5.8 ± 5.59	-1.7 ± 4.43

No statistical analyses for this end point

Secondary: Number of Participants Who Achieved Low Disease Activity as Defined by DAS28-ESR ≤3.2

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End point title

Number of Participants Who Achieved Low Disease Activity as Defined by DAS28-ESR ≤3.2

End point description

DAS28 was calculated from SJC and TJC using 28 joints count, ESR (mm/hour), and patient’s global assessment of disease activity (measured on a 0 to 100 mm VAS where 0 mm=no disease activity and 100 mm=worst disease activity). DAS28 scores were calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. Total score range: 0-10, higher score=higher disease activity. DAS28-ESR ≥2.6 to ≤3.2 implied low disease activity. FAS population. Here, “n” = participants who were evaluable at specified timepoint for respective groups.

End point type

Secondary

End point timeframe

Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)

End point values	Tocilizumab Monotherapy	Tocilizumab in Combination With Methotrexate or Other DMARDs
Number of subjects analysed	21	140
Units: participants
number (not applicable)
Baseline (n=21, 139)	0	5
Week 2 (n=21, 137)	7	18
Week 4 (n=21, 137)	9	30
Week 8 (n=18, 131)	3	25
Week 12 (n=19, 128)	6	23
Week 16 (n=18, 125)	3	20
Week 20 (n=19, 121)	3	15
Week 24 (n=19, 117)	2	15
Week 28 (n=19, 115)	4	15
Week 32 (n=19, 115)	5	14
Week 36 (n=18, 114)	1	14
Week 40 (n=17, 111)	3	14
Week 44 (n=17, 107)	5	10
Week 48 (n=16, 107)	3	12
Week 52 (n=15, 107)	0	11
Early withdrawal (n=5, 29)	2	4

No statistical analyses for this end point

Secondary: Number of Participants Who Achieved Remission as Defined by DAS28-ESR <2.6

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End point title

Number of Participants Who Achieved Remission as Defined by DAS28-ESR <2.6

End point description

DAS28 was calculated from SJC and TJC using 28 joints count, ESR (mm/hour), and patient’s global assessment of disease activity (measured on a 0 to 100 mm VAS where 0 mm=no disease activity and 100 mm=worst disease activity). DAS28 scores were calculated as [0.56 × square root of TJC] + [0.28 × square root of SJC] + [0.70 × natural log (ESR)] + [0.014 × VAS]. Total score range: 0-10, higher score=higher disease activity. DAS28-ESR <2.6 implied clinical remission. FAS population. “n” = participants who were evaluable at specified timepoint for respective groups.

End point type

Secondary

End point timeframe

Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)

End point values	Tocilizumab Monotherapy	Tocilizumab in Combination With Methotrexate or Other DMARDs
Number of subjects analysed	21	140
Units: participants
number (not applicable)
Baseline (n=21, 139)	0	3
Week 2 (n=21, 137)	1	15
Week 4 (n=21, 137)	2	34
Week 8 (n=18, 131)	5	53
Week 12 (n=19, 128)	6	66
Week 16 (n=18, 125)	10	72
Week 20 (n=19, 121)	11	75
Week 24 (n=19, 117)	14	76
Week 28 (n=19, 115)	14	73
Week 32 (n=19, 115)	12	80
Week 36 (n=18, 114)	14	80
Week 40 (n=17, 111)	13	81
Week 44 (n=17, 107)	10	80
Week 48 (n=16, 107)	11	78
Week 52 (n=15, 107)	12	80
Early withdrawal (n=5, 29)	3	7

No statistical analyses for this end point

Secondary: Number of Participants With Non-Biologic DMARD/Corticosteroid Dose Reductions and/or Discontinuation

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End point title

Number of Participants With Non-Biologic DMARD/Corticosteroid Dose Reductions and/or Discontinuation

End point description

Results are reported for number of participants who had non-biologic DMARD/corticosteroid dose reductions and/or discontinuation by reasons for dose reductions or discontinuation (safety reasons, discomfort, lack of efficacy, other reasons, and unknown reasons). Participants may be included under more than one reason. FAS population. Here, “n” = participants who were evaluable at specified timepoint for respective groups.

End point type

Secondary

End point timeframe

Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, at early withdrawal (up to Week 52), follow-up Week 4 (up to Week 56), and follow-up Week 8 (up to Week 60)

End point values	Tocilizumab Monotherapy	Tocilizumab in Combination With Methotrexate or Other DMARDs
Number of subjects analysed	21	140
Units: participants
number (not applicable)
Baseline: Safety (n=21, 140)	0	1
Baseline: Discomfort (n=21, 140)	0	0
Baseline: Lack of efficacy (n=21, 140)	0	1
Baseline: Other (n=21, 140)	0	2
Baseline: Unknown (n=21, 140)	0	0
Week 2: Safety (n=21, 137)	0	4
Week 2: Discomfort (n=21, 137)	0	0
Week 2: Lack of efficacy (n=21, 137)	0	0
Week 2: Other (n=21, 137)	0	7
Week 2: Unknown (n=21, 137)	0	0
Week 4: Safety (n=21, 137)	0	6
Week 4: Discomfort (n=21, 137)	0	0
Week 4: Lack of efficacy (n=21, 137)	0	1
Week 4: Other (n=21, 137)	1	9
Week 4: Unknown (n=21, 137)	0	1
Week 8: Safety (n=18, 132)	0	8
Week 8: Discomfort (n=18, 132)	0	0
Week 8: Lack of efficacy (n=18, 132)	0	0
Week 8: Other (n=18, 132)	1	13
Week 8: Unknown (n=18, 132)	0	1
Week 12: Safety (n=19, 128)	0	6
Week 12: Discomfort (n=19, 128)	0	2
Week 12: Lack of efficacy (n=19, 128)	0	0
Week 12: Other (n=19, 128)	2	14
Week 12: Unknown (n=19, 128)	0	0
Week 16: Safety (n=19, 126)	0	7
Week 16: Discomfort (n=19, 126)	0	0
Week 16: Lack of efficacy (n=19, 126)	0	1
Week 16: Other (n=19, 126)	2	13
Week 16: Unknown (n=19, 126)	0	0
Week 20: Safety (n=19, 122)	0	6
Week 20: Discomfort (n=19, 122)	0	0
Week 20: Lack of efficacy (n=19, 122)	0	0
Week 20: Other (n=19, 122)	2	9
Week 20: Unknown (n=19, 122)	0	1
Week 24: Safety (n=19, 117)	0	5
Week 24:Discomfort (n=19, 117)	0	0
Week 24: Lack of efficacy (n=19, 117)	0	0
Week 24: Other (n=19, 117)	1	13
Week 24: Unknown (n=19, 117)	0	1
Week 28: Safety (n=19, 116)	0	3
Week 28: Discomfort (n=19, 116)	0	0
Week 28: Lack of efficacy (n=19, 116)	0	1
Week 28: Other (n=19, 116)	1	7
Week 28: Unknown (n=19, 116)	0	0
Week 32: Safety (n=19, 115)	0	4
Week 32: Discomfort (n=19, 115)	0	0
Week 32: Lack of efficacy (n=19, 115)	0	2
Week 32: Other (n=19, 115)	1	11
Week 32: Unknown (n=19, 115)	0	0
Week 36: Safety (n=18, 114)	0	3
Week 36: Discomfort (n=18, 114)	0	1
Week 36: Lack of efficacy (n=18, 114)	0	0
Week 36: Other (n=18, 114)	2	3
Week 36: Unknown (n=18, 114)	0	0
Week 40: Safety (n=17, 111)	0	4
Week 40: Discomfort (n=17, 111)	0	1
Week 40: Lack of efficacy (n=17, 111)	0	1
Week 40: Other (n=17, 111)	1	1
Week 40: Unknown (n=17, 111)	0	0
Week 44: Safety (n=17, 108)	0	3
Week 44: Discomfort (n=17, 108)	0	0
Week 44: Lack of efficacy (n=17, 108)	0	0
Week 44: Other (n=17, 108)	0	7
Week 44: Unknown (n=17, 108)	0	0
Week 48: Safety (n=16, 107)	0	3
Week 48: Discomfort (n=16, 107)	0	0
Week 48: Lack of efficacy (n=16, 107)	0	1
Week 48: Other (n=16, 107)	1	3
Week 48: Unknown (n=16, 107)	0	0
Week 52: Safety (n=16, 107)	0	0
Week 52: Discomfort (n=16, 107)	0	0
Week 52: Lack of efficacy (n=16, 107)	0	0
Week 52: Other (n=16, 107)	0	1
Week 52: Unknown (n=16, 107)	0	0
Early withdrawal: Safety (n=5, 30)	0	0
Early withdrawal: Discomfort (n=5, 30)	0	0
Early withdrawal: Lack of efficacy (n=5, 30)	0	0
Early withdrawal: Other (n=5, 30)	1	8
Early withdrawal: Unknown (n=5, 30)	0	0
Follow-up Week 4: Safety (n=8, 70)	0	0
Follow-up Week 4: Discomfort (n=8, 70)	0	0
Follow-up Week 4: Lack of efficacy (n=8, 70)	0	0
Follow-up Week 4: Other (n=8, 70)	0	2
Follow-up Week 4: Unknown (n=8, 70)	0	1
Follow-up Week 8: Safety (n=9, 65)	0	0
Follow-up Week 8: Discomfort (n=9, 65)	0	0
Follow-up Week 8: Lack of efficacy (n=9, 65)	0	0
Follow-up Week 8: Other (n=9, 65)	0	0
Follow-up Week 8: Unknown (n=9, 65)	0	0

No statistical analyses for this end point

Secondary: Percentage of Methotrexate Adherence as Assessed by Methotrexate Adherence Questionnaire

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End point title

Percentage of Methotrexate Adherence as Assessed by Methotrexate Adherence Questionnaire ^[16]

End point description

Methotrexate adherence was determined from responses to the question ‘Over the last 3 months you were prescribed 12 doses of methotrexate, how many (approximately) have you taken?’ Adherence (%) was calculated as: (Approximate number of doses taken/12)*100. FAS population. Here, “Number of subjects analysed” = participants who were evaluable for this outcome. “n” = participants who were evaluable at specified timepoint for respective groups.

End point type

Secondary

End point timeframe

Baseline, Weeks 12, 24, 36, 52, and at early withdrawal (up to Week 52)

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Results are provided for single arm as participants in “Tocilizumab Monotherapy” arm did not receive methotrexate.

End point values	Tocilizumab in Combination With Methotrexate or Other DMARDs
Number of subjects analysed	97
Units: percentage of methotrexate adherence
arithmetic mean (standard deviation)
Baseline (n=97)	96.82 ± 7.747
Week 12 (n=80)	92.92 ± 14.412
Week 24 (n=65)	91.54 ± 20.915
Week 36 (n=60)	90.14 ± 21.456
Week 52 (n=60)	95.28 ± 11.417
Early withdrawal (n=17)	90.69 ± 18.367

No statistical analyses for this end point

Secondary: Patient Global Assessment of Disease Activity VAS Score

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End point title

Patient Global Assessment of Disease Activity VAS Score

End point description

Patient global assessment of disease activity was measured on a 0 to 100 mm horizontal VAS where 0 mm=no disease activity and 100 mm=maximum disease activity. FAS population. “n” = participants who were evaluable at specified timepoint for respective groups.

End point type

Secondary

End point timeframe

Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)

End point values	Tocilizumab Monotherapy	Tocilizumab in Combination With Methotrexate or Other DMARDs
Number of subjects analysed	21	140
Units: mm
arithmetic mean (standard deviation)
Baseline (n=21, 139)	59.6 ± 26.94	62.3 ± 20.72
Week 2 (n=21, 137)	50.3 ± 24.01	54.5 ± 22.12
Week 4 (n=21, 137)	46.4 ± 26.43	42.3 ± 23.22
Week 8 (n=18, 131)	35.8 ± 24.73	36.2 ± 24.43
Week 12 (n=19, 128)	41.3 ± 27.67	32.1 ± 23.91
Week 16 (n=19, 126)	29.6 ± 21.59	29.2 ± 22.55
Week 20 (n=19, 122)	25.7 ± 23.77	29.9 ± 22.99
Week 24 (n=19, 117)	23.8 ± 19.55	26.6 ± 21.92
Week 28 (n=19, 116)	23.2 ± 16.47	26.7 ± 23.12
Week 32 (n=19, 115)	24 ± 17.81	24.3 ± 21.66
Week 36 (n=18, 114)	24.1 ± 19.13	22.3 ± 21.86
Week 40 (n=17, 111)	22.5 ± 19.31	21.4 ± 20.81
Week 44 (n=17, 107)	22.7 ± 20.62	22 ± 22.83
Week 48 (n=16, 107)	22.9 ± 23.31	18.9 ± 20.57
Week 52 (n=16, 107)	20.6 ± 18.96	21.4 ± 23.07
Early withdrawal (n=5, 30)	30.8 ± 28.78	52.4 ± 24.88

No statistical analyses for this end point

Secondary: Patient Pain VAS Score

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End point title

Patient Pain VAS Score

End point description

This assessment represents the participant’s assessment of his/her current level of pain on a 100 mm horizontal VAS where 0 mm= no pain to 100 mm= unbearable pain. FAS population. “n” = participants who were evaluable at specified timepoint for respective groups.

End point type

Secondary

End point timeframe

Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)

End point values	Tocilizumab Monotherapy	Tocilizumab in Combination With Methotrexate or Other DMARDs
Number of subjects analysed	21	140
Units: mm
arithmetic mean (standard deviation)
Baseline (n=21, 139)	50.5 ± 23.78	57.5 ± 21.06
Week 2 (n=21, 137)	46.1 ± 22.43	51.1 ± 22.58
Week 4 (n=21, 137)	47 ± 26.69	42.4 ± 23.8
Week 8 (n=18, 131)	37.8 ± 25.75	35.3 ± 24.3
Week 12 (n=19, 128)	40.9 ± 29.56	30.8 ± 23.29
Week 16 (n=19, 126)	29.7 ± 20.83	26.8 ± 22.61
Week 20 (n=19, 122)	27.6 ± 25.48	28.6 ± 23.74
Week 24 (n=19, 117)	29.9 ± 22.76	25.2 ± 22.16
Week 28 (n=19, 116)	24.8 ± 19.15	25.6 ± 23.18
Week 32 (n=19, 115)	25.1 ± 17.92	22.6 ± 21.3
Week 36 (n=18, 114)	29.6 ± 20.03	22.1 ± 21.68
Week 40 (n=17, 111)	27.6 ± 22.7	20.9 ± 21.24
Week 44 (n=17, 107)	26.7 ± 24.25	20 ± 21.26
Week 48 (n=16, 107)	28.6 ± 28.98	17.6 ± 19.66
Week 52 (n=16, 107)	22.4 ± 19.7	19 ± 19.83
Early withdrawal (n=5, 30)	30.4 ± 29.57	51.6 ± 26.03

No statistical analyses for this end point

Secondary: Health Assessment Questionnaire-Disability Index (HAQ-DI) Score

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End point title

Health Assessment Questionnaire-Disability Index (HAQ-DI) Score

End point description

The HAQ-DI questionnaire measures functional status (disability) and health-related quality of life. It measures the participant's ability to perform everyday tasks. The index consists of 20 questions regarding the function of the upper and lower extremities. These questions are summarized in 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and common activities over past week. Each question is evaluated according to the degree of severity on a 4-point scale. Total score for HAQ-DI was the average of all questions and ranges from 0 = without any difficulty to 3 = unable to do. FAS population. “n” = participants who were evaluable at specified timepoint for respective groups.

End point type

Secondary

End point timeframe

Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)

End point values	Tocilizumab Monotherapy	Tocilizumab in Combination With Methotrexate or Other DMARDs
Number of subjects analysed	21	140
Units: units on a scale
arithmetic mean (standard deviation)
Baseline (n=21, 139)	1.806 ± 0.5551	1.738 ± 0.6406
Week 2 (n=20, 137)	1.558 ± 0.7319	1.659 ± 0.621
Week 4 (n=21, 137)	1.616 ± 0.772	1.546 ± 0.7351
Week 8 (n=18, 132)	1.508 ± 0.7597	1.404 ± 0.8115
Week 12 (n=19, 128)	1.488 ± 0.9304	1.333 ± 0.8272
Week 16 (n=19, 126)	1.351 ± 0.9586	1.312 ± 0.8621
Week 20 (n=19, 119)	1.409 ± 0.9071	1.318 ± 0.8608
Week 24 (n=19, 117)	1.33 ± 0.8379	1.261 ± 0.8915
Week 28 (n=19, 116)	1.33 ± 0.9412	1.221 ± 0.873
Week 32 (n=19, 114)	1.351 ± 0.8816	1.232 ± 0.887
Week 36 (n=18, 113)	1.432 ± 0.9048	1.17 ± 0.8757
Week 40 (n=17, 111)	1.479 ± 0.8975	1.199 ± 0.8908
Week 44 (n=17, 108)	1.442 ± 0.9392	1.13 ± 0.9206
Week 48 (n=16, 107)	1.361 ± 0.9685	1.114 ± 0.8815
Week 52 (n=16, 107)	1.338 ± 0.9796	1.154 ± 0.9187
Early withdrawal (n=5, 30)	1.252 ± 1.1232	1.756 ± 0.782

No statistical analyses for this end point

Secondary: Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score

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End point title

Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score

End point description

The FACIT-F score was calculated according to a 13-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function. FACIT-F is a 13-item questionnaire. Participants scored each item on a 5-point scale: 0 (Not at all) to 4 (Very much). The larger the participant's response to the questions (with the exception of 2 negatively stated), the greater the participant's fatigue. For all questions, except for the 2 negatively stated ones, the code was reversed and a new score was calculated as (4 minus the participant's response). The sum of all responses resulted in the FACIT-F score for a total possible score of 0 (worse score) to 52 (better score). FAS population. “n” = participants who were evaluable at specified timepoint for respective groups.

End point type

Secondary

End point timeframe

Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)

End point values	Tocilizumab Monotherapy	Tocilizumab in Combination With Methotrexate or Other DMARDs
Number of subjects analysed	21	140
Units: units on a scale
arithmetic mean (standard deviation)
Baseline (n=21, 139)	18.4 ± 11.14	24.3 ± 11.55
Week 2 (n=21, 137)	23.1 ± 12.37	27.9 ± 11.03
Week 4 (n=21, 136)	25.1 ± 12.28	30.7 ± 12.1
Week 8 (n=18, 132)	30.2 ± 11.58	32.8 ± 11.91
Week 12 (n=19, 128)	28.4 ± 11.71	33.7 ± 11.85
Week 16 (n=19, 126)	31.3 ± 13.8	34 ± 12.53
Week 20 (n=19, 121)	33.2 ± 13.57	34.1 ± 12.05
Week 24 (n=19, 117)	33.8 ± 15.28	35.3 ± 10.98
Week 28 (n=19, 115)	32.9 ± 12.06	35.5 ± 11.59
Week 32 (n=19, 115)	34.1 ± 12.68	36.2 ± 11.32
Week 36 (n=18, 114)	30.3 ± 13.62	36.8 ± 11.48
Week 40 (n=17, 111)	31.7 ± 12.87	37.1 ± 11.69
Week 44 (n=17, 106)	31 ± 14.02	37.2 ± 11.75
Week 48 (n=16, 107)	31.6 ± 14.63	37.9 ± 11.73
Week 52 (n=16, 106)	33.4 ± 14.17	38.1 ± 11.16
Early withdrawal (n=4, 30)	31.3 ± 2.63	24.5 ± 12.08

No statistical analyses for this end point

Secondary: Number of Participants Compliant to Tocilizumab Treatment as Measured by Diary Cards and Return Records

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End point title

Number of Participants Compliant to Tocilizumab Treatment as Measured by Diary Cards and Return Records

End point description

A diary card was provided to participants to record home injections. Participants were asked to return all empty drug supply boxes, unused pre-filled syringe, and diary cards to the clinic at each visit as a measure of drug accountability and participant compliance. A participant was considered compliant if the participant correctly administered all scheduled doses of SC tocilizumab during the assessment period. FAS population. Here, “n” = participants who were evaluable at specified timepoint for respective groups.

End point type

Secondary

End point timeframe

Baseline, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at early withdrawal (up to Week 52)

End point values	Tocilizumab Monotherapy	Tocilizumab in Combination With Methotrexate or Other DMARDs
Number of subjects analysed	21	140
Units: participants
number (not applicable)
Baseline (n=21, 139)	21	137
Week 2 (n=21, 137)	20	126
Week 4 (n=21, 137)	20	132
Week 8 (n=18, 132)	18	124
Week 12 (n=19, 128)	18	121
Week 16 (n=19, 126)	19	120
Week 20 (n=19, 122)	18	114
Week 24 (n=19, 117)	16	107
Week 28 (n=19, 116)	19	112
Week 32 (n=19, 115)	17	111
Week 36 (n=18, 114)	17	105
Week 40 (n=17, 111)	16	104
Week 44 (n=17, 108)	16	102
Week 48 (n=16, 107)	13	107
Week 52 (n=16, 107)	16	98
Early withdrawal (n=5, 30)	4	27

No statistical analyses for this end point

Secondary: Number of Participants With Anti-Tocilizumab Antibodies

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End point title

Number of Participants With Anti-Tocilizumab Antibodies

End point description

FAS population. Here, “n” = participants who were evaluable at specified timepoint for respective groups. "99999" indicates results are not reported as no participants were evaluable at the specified timepoint.

End point type

Secondary

End point timeframe

Baseline, Weeks 12 and 24, at early withdrawal (up to Week 52), and follow-up visit (8 weeks after last dose of tocilizumab, up to 60 weeks)

End point values	Tocilizumab Monotherapy	Tocilizumab in Combination With Methotrexate or Other DMARDs
Number of subjects analysed	21	140
Units: participants
number (not applicable)
Baseline (n=20, 138)	3	6
Week 12 (n=1, 0)	0	99999
Week 24 (n=19, 116)	0	2
Early withdrawal (n=5, 27)	0	0
Follow-up visit (n=3, 21)	0	0

No statistical analyses for this end point

Secondary: Serum Levels of Tocilizumab

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End point title

Serum Levels of Tocilizumab

End point description

FAS population. Here, “n” = participants who were evaluable at specified timepoint for respective groups.

End point type

Secondary

End point timeframe

Baseline, Weeks 12 and 24, at early withdrawal (up to Week 52), and follow-up visit (8 weeks after last dose of tocilizumab, up to 60 weeks)

End point values	Tocilizumab Monotherapy	Tocilizumab in Combination With Methotrexate or Other DMARDs
Number of subjects analysed	21	140
Units: micrograms per milliliter (mcg/mL)
arithmetic mean (standard deviation)
Baseline (n=20, 138)	0 ± 0	0.0082 ± 0.09619
Week 12 (n=18, 125)	35.3953 ± 22.69069	40.2529 ± 21.05801
Week 24 (n=19, 115)	53.0416 ± 39.06367	43.9047 ± 30.41603
Early withdrawal (n=5, 25)	44.716 ± 38.81521	17.616 ± 22.92477
Follow-up visit (n=3, 22)	0.0597 ± 0.10335	2.3123 ± 7.40931

No statistical analyses for this end point

Secondary: Serum Levels of Soluble Interleukin-6 Receptors (sIL-6Rs)

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End point title

Serum Levels of Soluble Interleukin-6 Receptors (sIL-6Rs)

End point description

FAS population. Here, “n” = participants who were evaluable at specified timepoint for respective groups.

End point type

Secondary

End point timeframe

Baseline, Weeks 12 and 24, at early withdrawal (up to Week 52), and follow-up visit (8 weeks after last dose of tocilizumab, up to 60 weeks)

End point values	Tocilizumab Monotherapy	Tocilizumab in Combination With Methotrexate or Other DMARDs
Number of subjects analysed	21	140
Units: nanograms per milliliter (ng/mL)
arithmetic mean (standard deviation)
Baseline (n=8, 48)	43.63 ± 10.947	42.4 ± 12.087
Week 12 (n=12, 57)	577.42 ± 175.649	548.7 ± 131.079
Week 24 (n=12, 80)	602.25 ± 158.541	521.07 ± 160.464
Early withdrawal (n=4, 18)	639.75 ± 99.644	327.95 ± 229.481
Follow-up visit (n=3, 20)	132.23 ± 93.048	125.07 ± 211.038

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Baseline up to Week 60

Adverse event reporting additional description

FAS population

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

19.0

Reporting group title

Tocilizumab Monotherapy

Reporting group description

Participants received a weekly SC injection of tocilizumab 162 mg as monotherapy for 52 weeks.

Reporting group title

Tocilizumab in Combination With Methotrexate or Other DMARDs

Reporting group description

Participants received a weekly SC injection of tocilizumab 162 mg in combination with methotrexate or other non-biologic DMARDs for 52 weeks.

Serious adverse events	Tocilizumab Monotherapy	Tocilizumab in Combination With Methotrexate or Other DMARDs
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 21 (14.29%)	7 / 140 (5.00%)
number of deaths (all causes)	0	1
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Prostate cancer
subjects affected / exposed	1 / 21 (4.76%)	0 / 140 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Accidental overdose
subjects affected / exposed	0 / 21 (0.00%)	1 / 140 (0.71%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Wound
subjects affected / exposed	1 / 21 (4.76%)	0 / 140 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	0 / 21 (0.00%)	1 / 140 (0.71%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
Knee arthroplasty
subjects affected / exposed	1 / 21 (4.76%)	0 / 140 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Vomiting
subjects affected / exposed	1 / 21 (4.76%)	0 / 140 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pulmonary fibrosis
subjects affected / exposed	0 / 21 (0.00%)	1 / 140 (0.71%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Skin and subcutaneous tissue disorders
Drug eruption
subjects affected / exposed	0 / 21 (0.00%)	1 / 140 (0.71%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Costochondritis
subjects affected / exposed	0 / 21 (0.00%)	1 / 140 (0.71%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Arthritis bacterial
subjects affected / exposed	0 / 21 (0.00%)	1 / 140 (0.71%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 21 (0.00%)	1 / 140 (0.71%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 21 (4.76%)	0 / 140 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sinusitis
subjects affected / exposed	1 / 21 (4.76%)	0 / 140 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Subcutaneous abscess
subjects affected / exposed	0 / 21 (0.00%)	1 / 140 (0.71%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Tocilizumab Monotherapy	Tocilizumab in Combination With Methotrexate or Other DMARDs
Total subjects affected by non serious adverse events
subjects affected / exposed	19 / 21 (90.48%)	135 / 140 (96.43%)
Investigations
Alanine aminotransferase increased
subjects affected / exposed	2 / 21 (9.52%)	31 / 140 (22.14%)
occurrences all number	4	50
Neutrophil count decreased
subjects affected / exposed	0 / 21 (0.00%)	13 / 140 (9.29%)
occurrences all number	0	15
Blood cholesterol increased
subjects affected / exposed	3 / 21 (14.29%)	5 / 140 (3.57%)
occurrences all number	3	5
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	2 / 21 (9.52%)	13 / 140 (9.29%)
occurrences all number	2	17
Fall
subjects affected / exposed	1 / 21 (4.76%)	14 / 140 (10.00%)
occurrences all number	1	14
Laceration
subjects affected / exposed	0 / 21 (0.00%)	7 / 140 (5.00%)
occurrences all number	0	10
Nervous system disorders
Headache
subjects affected / exposed	4 / 21 (19.05%)	13 / 140 (9.29%)
occurrences all number	4	20
Dizziness
subjects affected / exposed	2 / 21 (9.52%)	8 / 140 (5.71%)
occurrences all number	2	9
Migraine
subjects affected / exposed	1 / 21 (4.76%)	7 / 140 (5.00%)
occurrences all number	1	13
Paraesthesia
subjects affected / exposed	2 / 21 (9.52%)	6 / 140 (4.29%)
occurrences all number	2	6
Lethargy
subjects affected / exposed	0 / 21 (0.00%)	7 / 140 (5.00%)
occurrences all number	0	7
General disorders and administration site conditions
Injection site bruising
subjects affected / exposed	3 / 21 (14.29%)	12 / 140 (8.57%)
occurrences all number	5	14
Fatigue
subjects affected / exposed	1 / 21 (4.76%)	12 / 140 (8.57%)
occurrences all number	1	12
Injection site erythema
subjects affected / exposed	1 / 21 (4.76%)	11 / 140 (7.86%)
occurrences all number	4	49
Influenza like illness
subjects affected / exposed	1 / 21 (4.76%)	8 / 140 (5.71%)
occurrences all number	1	9
Peripheral swelling
subjects affected / exposed	1 / 21 (4.76%)	8 / 140 (5.71%)
occurrences all number	1	9
Blood and lymphatic system disorders
Neutropenia
subjects affected / exposed	0 / 21 (0.00%)	14 / 140 (10.00%)
occurrences all number	0	15
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	2 / 21 (9.52%)	32 / 140 (22.86%)
occurrences all number	2	41
Nausea
subjects affected / exposed	0 / 21 (0.00%)	21 / 140 (15.00%)
occurrences all number	0	26
Mouth ulceration
subjects affected / exposed	1 / 21 (4.76%)	18 / 140 (12.86%)
occurrences all number	3	23
Vomiting
subjects affected / exposed	2 / 21 (9.52%)	16 / 140 (11.43%)
occurrences all number	2	21
Abdominal pain
subjects affected / exposed	0 / 21 (0.00%)	7 / 140 (5.00%)
occurrences all number	0	9
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain
subjects affected / exposed	3 / 21 (14.29%)	27 / 140 (19.29%)
occurrences all number	4	33
Cough
subjects affected / exposed	4 / 21 (19.05%)	21 / 140 (15.00%)
occurrences all number	5	22
Productive cough
subjects affected / exposed	2 / 21 (9.52%)	3 / 140 (2.14%)
occurrences all number	3	6
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	0 / 21 (0.00%)	18 / 140 (12.86%)
occurrences all number	0	22
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 21 (4.76%)	12 / 140 (8.57%)
occurrences all number	1	13
Back pain
subjects affected / exposed	3 / 21 (14.29%)	10 / 140 (7.14%)
occurrences all number	4	10
Pain in extremity
subjects affected / exposed	0 / 21 (0.00%)	11 / 140 (7.86%)
occurrences all number	0	11
Rheumatoid arthritis
subjects affected / exposed	0 / 21 (0.00%)	11 / 140 (7.86%)
occurrences all number	0	13
Infections and infestations
Nasopharyngitis
subjects affected / exposed	5 / 21 (23.81%)	33 / 140 (23.57%)
occurrences all number	6	40
Lower respiratory tract infection
subjects affected / exposed	6 / 21 (28.57%)	25 / 140 (17.86%)
occurrences all number	11	27
Upper respiratory tract infection
subjects affected / exposed	2 / 21 (9.52%)	20 / 140 (14.29%)
occurrences all number	3	31
Urinary tract infection
subjects affected / exposed	5 / 21 (23.81%)	16 / 140 (11.43%)
occurrences all number	6	25
Oral herpes
subjects affected / exposed	1 / 21 (4.76%)	10 / 140 (7.14%)
occurrences all number	1	13
Lower respiratory tract infection viral
subjects affected / exposed	2 / 21 (9.52%)	0 / 140 (0.00%)
occurrences all number	2	0

More information

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Were there any global substantial amendments to the protocol? Yes

23 Sep 2013

The major changes were corrections to ensure consistent wording for participant withdrawal criteria throughout the protocol and clarification regarding post-study follow-up visits. Minor formatting changes were also made to improve clarity and consistency.

06 May 2014

The major changes were the reduction in sample size from 260 participants to 160 participants, expansion of the target population to include those participants who had not experienced an adequate response to their current non-biologic DMARD therapy or the first anti-TNF agent and clarification that eligible participants were required to have “active” (not severe) rheumatoid arthritis. The reduction in sample size only increased the 95% confidence interval (CI) width by 0.09 for ESR and by 0.8 for CDAI. The expected precision of the CI widths around the mean change from baseline for a sample of 160 participants was still deemed to be clinically sufficient and a reasonable target to be able to draw conclusions from the study. The addition of DMARD inadequate response participants was not expected to compromise the power of the study as data from other studies indicate their responses are no worse and not more variable than those of the original study population. Details regarding study treatment, concomitant medications and assessments were updated for clarification. Administrative changes and additional minor changes were made to improve clarity and consistency.

10 Dec 2014

The major change was amendment of the target participant population to remove the window (previously 12 to 32 weeks) during which a participant who was receiving their first anti-TNF therapy would have to be assessed for an inadequate response to anti-TNF treatment. The rationale for this change was based on the feedback received from the sites, which indicated that such a protocol requirement was extremely difficult to implement and not aligned with local hospital protocols for assessing inadequate response to anti-TNF treatment. It was also clarified that inadequate response to non-biologic DMARD therapy was to be assessed according to local guidelines and that participants needed to be eligible for biologic therapy according to local guidelines. Language regarding pregnancy testing was also clarified in this amendment and names of relevant Roche personnel were updated. Additional minor changes were made to improve clarity and consistency.

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change From Baseline in Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS28-ESR) at Week 2

Primary: Change From Baseline in Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS28-ESR) at Week 2

Primary: Change From Baseline in DAS28-ESR at Week 4

Primary: Change From Baseline in DAS28-ESR at Week 4

Primary: Change From Baseline in DAS28-ESR at Week 8

Primary: Change From Baseline in DAS28-ESR at Week 8

Primary: Change From Baseline in DAS28-ESR at Week 12

Primary: Change From Baseline in DAS28-ESR at Week 12

Primary: Change From Baseline in DAS28-ESR at Week 16

Primary: Change From Baseline in DAS28-ESR at Week 16

Primary: Change From Baseline in DAS28-ESR at Week 20

Primary: Change From Baseline in DAS28-ESR at Week 20

Primary: Change From Baseline in DAS28-ESR at Week 24

Primary: Change From Baseline in DAS28-ESR at Week 24

Primary: Change From Baseline in DAS28-ESR at Week 28

Primary: Change From Baseline in DAS28-ESR at Week 28

Primary: Change From Baseline in DAS28-ESR at Week 32

Primary: Change From Baseline in DAS28-ESR at Week 32

Primary: Change From Baseline in DAS28-ESR at Week 36

Primary: Change From Baseline in DAS28-ESR at Week 36

Primary: Change From Baseline in DAS28-ESR at Week 40

Primary: Change From Baseline in DAS28-ESR at Week 40

Primary: Change From Baseline in DAS28-ESR at Week 44

Primary: Change From Baseline in DAS28-ESR at Week 44

Primary: Change From Baseline in DAS28-ESR at Week 48

Primary: Change From Baseline in DAS28-ESR at Week 48

Primary: Change From Baseline in DAS28-ESR at Week 52

Primary: Change From Baseline in DAS28-ESR at Week 52

Primary: Change From Baseline in DAS28-ESR at Early Withdrawal

Primary: Change From Baseline in DAS28-ESR at Early Withdrawal

Secondary: Number of Participants Achieving an American College of Rheumatology Criteria 20 (ACR20) Response

Secondary: Number of Participants Achieving an American College of Rheumatology Criteria 20 (ACR20) Response

Secondary: Number of Participants Achieving an ACR50 Response

Secondary: Number of Participants Achieving an ACR50 Response

Secondary: Number of Participants Achieving an ACR70 Response

Secondary: Number of Participants Achieving an ACR70 Response

Secondary: Number of Participants With European League Against Rheumatism (EULAR) Response (Good, Moderate or No Response) Based on DAS28-ESR

Secondary: Number of Participants With European League Against Rheumatism (EULAR) Response (Good, Moderate or No Response) Based on DAS28-ESR

Secondary: Change From Baseline in Simplified Disease Activity Index (SDAI) at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at Early Withdrawal

Secondary: Change From Baseline in Simplified Disease Activity Index (SDAI) at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at Early Withdrawal

Secondary: Change From Baseline in Clinical Disease Activity Index (CDAI) at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at Early Withdrawal

Secondary: Change From Baseline in Clinical Disease Activity Index (CDAI) at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at Early Withdrawal

Secondary: Percent Change From Baseline in Total TJC on 68 Joints at Week 52

Secondary: Percent Change From Baseline in Total TJC on 68 Joints at Week 52

Secondary: Change From Baseline in Total TJC on 28 Joints at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at Early Withdrawal

Secondary: Change From Baseline in Total TJC on 28 Joints at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at Early Withdrawal

Secondary: Percent Change From Baseline in Total SJC on 66 Joints at Week 52

Secondary: Percent Change From Baseline in Total SJC on 66 Joints at Week 52

Secondary: Change From Baseline in Total SJC on 28 Joints at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at Early Withdrawal

Secondary: Change From Baseline in Total SJC on 28 Joints at Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and at Early Withdrawal

Secondary: Number of Participants Who Achieved Low Disease Activity as Defined by DAS28-ESR ≤3.2

Secondary: Number of Participants Who Achieved Low Disease Activity as Defined by DAS28-ESR ≤3.2

Secondary: Number of Participants Who Achieved Remission as Defined by DAS28-ESR <2.6

Secondary: Number of Participants Who Achieved Remission as Defined by DAS28-ESR <2.6

Secondary: Number of Participants With Non-Biologic DMARD/Corticosteroid Dose Reductions and/or Discontinuation

Secondary: Number of Participants With Non-Biologic DMARD/Corticosteroid Dose Reductions and/or Discontinuation

Secondary: Percentage of Methotrexate Adherence as Assessed by Methotrexate Adherence Questionnaire

Secondary: Percentage of Methotrexate Adherence as Assessed by Methotrexate Adherence Questionnaire

Secondary: Patient Global Assessment of Disease Activity VAS Score

Secondary: Patient Global Assessment of Disease Activity VAS Score

Secondary: Patient Pain VAS Score

Secondary: Patient Pain VAS Score

Secondary: Health Assessment Questionnaire-Disability Index (HAQ-DI) Score

Secondary: Health Assessment Questionnaire-Disability Index (HAQ-DI) Score

Secondary: Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score

Secondary: Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score

Secondary: Number of Participants Compliant to Tocilizumab Treatment as Measured by Diary Cards and Return Records

Secondary: Number of Participants Compliant to Tocilizumab Treatment as Measured by Diary Cards and Return Records

Secondary: Number of Participants With Anti-Tocilizumab Antibodies

Secondary: Number of Participants With Anti-Tocilizumab Antibodies

Secondary: Serum Levels of Tocilizumab