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Clinical Trial Results:
A Phase IIIb Study to Evaluate the Efficacy, Safety and Tolerability of Subcutaneous (SC) Tocilizumab (TCZ) Given as Monotherapy or in Combination With Methotrexate (MTX) or Other Non Biologics DMARDs in Subjects With Rheumatoid Arthritis

Summary
EudraCT number	2013-002429-52
Trial protocol	ES PT IE
Global end of trial date	09 Mar 2016

Results information
Results version number	v1(current)
This version publication date	29 Jul 2017
First version publication date	29 Jul 2017
Other versions

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

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Trial information

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Sponsor protocol code

ML28709

ISRCTN number

US NCT number

NCT01995201

WHO universal trial number (UTN)

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-roche-genentech-trials@gene.com

Scientific contact

Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global-roche-genentech-trials@gene.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

09 Mar 2016

Is this the analysis of the primary completion data?

Yes

Primary completion date

29 Jul 2015

Global end of trial reached?

Yes

Global end of trial date

09 Mar 2016

Was the trial ended prematurely?

Main objective of the trial

To assess the efficacy of SC TCZ monotherapy or in combination with oral/SC MTX or other non biologic (nb) DMARDs using sustained clinical remission activity (DAS 28-ESR < 2.6) in patients with active RA with inadequate response to nbDMARDs or to one anti-TNF.

Protection of trial subjects

The study was conducted in full conformance with the ICH E6 guideline for good clinical practices (GCP) and the principles of the Declaration of Helsinki, or the laws and regulations of the country in which the research was conducted, whichever afforded the greater protection to the individual. The study complied with the requirements of the ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for Expedited Reporting). This study was conducted in the European Union (EU)/ European Economic Area, so it complied with the EU Clinical Trial Directive (2001/20/EC), in addition to the local regulations.

Background therapy

Evidence for comparator

Actual start date of recruitment

30 Sep 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Ireland: 35

Country: Number of subjects enrolled

Portugal: 39

Country: Number of subjects enrolled

Spain: 327

Worldwide total number of subjects

401

EEA total number of subjects

401

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)

390

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

A total of 461 patients were screened and 401 patients were randomized into Phase 1 of the study (from baseline until week 24). A total of 343 patients were randomized into Phase 2 of the study (from week 24 until week 48).

Period 1 title

From baseline until week 24

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Phase 1: Tocilizumab Monotherapy

Arm description

Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection as a single fixed dose monotherapy once a week for 24 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

162 mg subcutaneously (SC) qw, Weeks 1-24

Phase 1: Combination therapy

Arm description

Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotraxate (MTX) or other non-biologic Disease Modifying Anti Reumatic Drugs (nbDMARDs) once a week for 24 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

162 mg subcutaneously (SC) qw, Weeks 1-24

Investigational medicinal product name

DMARD

Investigational medicinal product code

Other name

non-biological disease-modifying antirheumatic drugs at stable dose

Pharmaceutical forms

Solution for injection, Tablet

Routes of administration

Oral use, Subcutaneous use

Dosage and administration details

As per labelling and physician direction

Investigational medicinal product name

Methotrexate

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection, Tablet

Routes of administration

Oral use, Subcutaneous use

Dosage and administration details

Stable dose as per labelling and physician direction

Number of subjects in period 1	Phase 1: Tocilizumab Monotherapy	Phase 1: Combination therapy
Started	74	327
Completed	64	281
Not completed	10	46
Adverse event, serious fatal	-	1
Consent withdrawn by subject	2	8
Physician decision	-	2
Anaphylaxis or hypersensitivity reaction	-	3
Adverse event, non-fatal	4	15
Lost to follow-up	2	3
Lack of efficacy	2	5
Protocol deviation	-	9

Period 2 title

From week 24 until week 48

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Phase 2 Arm A1: TCZ +/- nbDMARD once per week (qw)

Arm description

Participants who achieved sustained clinical remission (DAS28-ESR <2.6) at Week 20 and Week 24 in Part 1 were randomized to tocilizumab given every week monotherapy or in combination with methotrexate or other non-biologics DMARDs from Week 24 to Week 48.

Arm type

Experimental

Investigational medicinal product name

DMARD

Investigational medicinal product code

Other name

non-biological disease-modifying antirheumatic drugs at stable dose

Pharmaceutical forms

Solution for injection, Tablet

Routes of administration

Oral use, Subcutaneous use

Dosage and administration details

As per labelling and physician direction

Investigational medicinal product name

Methotrexate

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection, Tablet

Routes of administration

Oral use, Subcutaneous use

Dosage and administration details

Stable dose as per labelling and physician direction

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

162 mg subcutaneously (SC) qw, Weeks 24-48

Phase 2 Arm A2: TCZ +/- nbDMARD every two weeks (q2w)

Arm description

Participants who achieved sustained clinical remission (DAS28-ESR <2.6) at Week 20 and Week 24 in Part 1 were randomized to tocilizumab given every 2 weeks monotherapy or in combination with methotrexate or other non-biologics DMARDs from Week 24 to Week 48.

Arm type

Experimental

Investigational medicinal product name

DMARD

Investigational medicinal product code

Other name

non-biological disease-modifying antirheumatic drugs at stable dose

Pharmaceutical forms

Solution for injection, Tablet

Routes of administration

Oral use, Subcutaneous use

Dosage and administration details

As per labelling and physician direction

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

162 mg subcutaneously (SC) q2w, Weeks 24-48

Investigational medicinal product name

Methotrexate

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection, Tablet

Routes of administration

Oral use, Subcutaneous use

Dosage and administration details

Stable dose as per labelling and physician direction

Phase 2 Arm B: Participants With Low Disease Activity

Arm description

Participants who did not achieve sustained clinical remission at Week 20 and Week 24 but achieve low disease activity (DAS 28-ESR ≤ 3.2) at Week 24 continued with initial treatment of tocilizumab as a single fixed dose monotherapy or in combination with methotrexate or other non-biologics DMARDs from Week 24 to Week 48.

Arm type

Experimental

Investigational medicinal product name

DMARD

Investigational medicinal product code

Other name

non-biological disease-modifying antirheumatic drugs at stable dose

Pharmaceutical forms

Solution for injection, Tablet

Routes of administration

Oral use, Subcutaneous use

Dosage and administration details

As per labelling and physician direction

Investigational medicinal product name

Methotrexate

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection, Tablet

Routes of administration

Oral use, Subcutaneous use

Dosage and administration details

Stable dose as per labelling and physician direction

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

162 mg subcutaneously (SC) qw, Weeks 24-48

Phase 2 Arm C: moderate EULAR response at Week 24

Arm description

Patients who achieved moderate EULAR response at Week 24 continued in the study with initial treatment as per investigator’s judgement.

Arm type

Experimental

Investigational medicinal product name

DMARD

Investigational medicinal product code

Other name

non-biological disease-modifying antirheumatic drugs at stable dose

Pharmaceutical forms

Solution for injection, Tablet

Routes of administration

Oral use, Subcutaneous use

Dosage and administration details

As per labelling and physician direction

Investigational medicinal product name

Methotrexate

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection, Tablet

Routes of administration

Oral use, Subcutaneous use

Dosage and administration details

Stable dose as per labelling and physician direction

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

162 mg subcutaneously (SC) qw, Weeks 24-48

Phase 2 Arm D: Non responders

Arm description

Non responders, safety population.

Arm type

Experimental

Investigational medicinal product name

DMARD

Investigational medicinal product code

Other name

non-biological disease-modifying antirheumatic drugs at stable dose

Pharmaceutical forms

Solution for injection, Tablet

Routes of administration

Oral use, Subcutaneous use

Dosage and administration details

As per labelling and physician direction

Investigational medicinal product name

Methotrexate

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection, Tablet

Routes of administration

Oral use, Subcutaneous use

Dosage and administration details

Stable dose as per labelling and physician direction

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

162 mg subcutaneously (SC) qw, Weeks 24-48

Number of subjects in period 2 ^[1]	Phase 2 Arm A1: TCZ +/- nbDMARD once per week (qw)	Phase 2 Arm A2: TCZ +/- nbDMARD every two weeks (q2w)	Phase 2 Arm B: Participants With Low Disease Activity	Phase 2 Arm C: moderate EULAR response at Week 24	Phase 2 Arm D: Non responders
Started	89	90	95	67	2
Completed	84	89	89	59	0
Not completed	5	1	6	8	2
Adverse event, serious fatal	-	-	-	2	-
Consent withdrawn by subject	1	-	1	-	-
Physician decision	-	-	1	-	-
Adverse event, non-fatal	2	1	1	3	1
Lost to follow-up	-	-	1	1	-
Lack of efficacy	1	-	-	2	1
Protocol deviation	1	-	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 those patients who achieved sustained clinical remission in Period 1 were admitted in Period 2 of the study.

Baseline characteristics

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Reporting group title

Phase 1: Tocilizumab Monotherapy

Reporting group description

Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection as a single fixed dose monotherapy once a week for 24 weeks.

Reporting group title

Phase 1: Combination therapy

Reporting group description

Reporting group values	Phase 1: Tocilizumab Monotherapy	Phase 1: Combination therapy	Total
Number of subjects	74	327	401
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	58	258	316
From 65-84 years	16	69	85
85 years and over	0	0	0
Female	0	0	0
Male	0	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	53.5 ± 12.7	53.6 ± 12.2	-
Gender, Male/Female
Units:
Male	12	63	75
Female	62	264	326

End points

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Reporting group title

Phase 1: Tocilizumab Monotherapy

Reporting group description

Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection as a single fixed dose monotherapy once a week for 24 weeks.

Reporting group title

Phase 1: Combination therapy

Reporting group description

Reporting group title

Phase 2 Arm A1: TCZ +/- nbDMARD once per week (qw)

Reporting group description

Reporting group title

Phase 2 Arm A2: TCZ +/- nbDMARD every two weeks (q2w)

Reporting group description

Reporting group title

Phase 2 Arm B: Participants With Low Disease Activity

Reporting group description

Reporting group title

Phase 2 Arm C: moderate EULAR response at Week 24

Reporting group description

Patients who achieved moderate EULAR response at Week 24 continued in the study with initial treatment as per investigator’s judgement.

Reporting group title

Phase 2 Arm D: Non responders

Reporting group description

Non responders, safety population.

Subject analysis set title

Phase 2 Arm A1 - Monotherapy - qw

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants who achieved sustained clinical remission (DAS28-ESR <2.6) at Week 20 and Week 24 in Part 1 were randomized to tocilizumab given every week monotherapy from Week 24 to Week 48.

Subject analysis set title

Phase 2 Arm A1 - Combination Therapy - qw

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants who achieved sustained clinical remission (DAS28-ESR <2.6) at Week 20 and Week 24 in Part 1 were randomized to tocilizumab given every week in combination with methotrexate or other non-biologics DMARDs from Week 24 to Week 48.

Subject analysis set title

Phase 2 Arm A2 - Monotherapy - q2w

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants who achieved sustained clinical remission (DAS28-ESR <2.6) at Week 20 and Week 24 in Part 1 were randomized to tocilizumab given every 2 weeks monotherapy from Week 24 to Week 48.

Subject analysis set title

Phase 2 Arm A2 - Combination Therapy - q2w

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants who achieved sustained clinical remission (DAS28-ESR <2.6) at Week 20 and Week 24 in Part 1 were randomized to tocilizumab given every 2 weeks in combination with methotrexate or other non-biologics DMARDs from Week 24 to Week 48.

Subject analysis set title

Full Analysis Set (FAS)

Subject analysis set type

Full analysis

Subject analysis set description

Participants who received at least one dose of SC TCZ.

Primary: Percentage of Participants Achieving Sustained Clinical Remission, Disease Activity Scale 28 - Erythrocyte Sedimentation Rate <2.6 (DAS28-ESR <2.6) at Week 20 and Week 24

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End point title

Percentage of Participants Achieving Sustained Clinical Remission, Disease Activity Scale 28 - Erythrocyte Sedimentation Rate <2.6 (DAS28-ESR <2.6) at Week 20 and Week 24

End point description

The DAS 28 is a combined index for measuring disease activity in RA. The index includes the assessment of 28 joints for swelling and tenderness, acute phase response (ESR or CRP) and general health status. For this study ESR was used to calculate the DAS 28 score. Analyses were conducted on the Full Analysis Set (FAS), i.e. all patients included in the study who received at least one dose of SC Tocilizumab.

End point type

Primary

End point timeframe

Week 20 and Week 24

End point values	Phase 1: Tocilizumab Monotherapy	Phase 1: Combination therapy
Number of subjects analysed	74	327
Units: Percentage of participants
number (confidence interval 95%)	48.4 (35.75 to 61.27)	52.9 (46.83 to 58.83)

Sustained Clinical Remission

Statistical analysis description

Percentage of Participants Achieving Sustained Clinical Remission Disease Activity Scale 28 - Erythrocyte Sedimentation Rate <26 (DAS28-ESR <2.6) at Week 20 and Week 24

Comparison groups

Phase 1: Tocilizumab Monotherapy v Phase 1: Combination therapy

Number of subjects included in analysis

401

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.5231

Method

Chi-squared

Confidence interval

Secondary: Mean change in Disease Activity Score 28 - erythrocyte sedimentation rate (DAS28-ESR)

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End point title

Mean change in Disease Activity Score 28 - erythrocyte sedimentation rate (DAS28-ESR)

End point description

End point type

Secondary

End point timeframe

From week 24 up to week 48

End point values	Phase 2 Arm A1: TCZ +/- nbDMARD once per week (qw)	Phase 2 Arm A2: TCZ +/- nbDMARD every two weeks (q2w)
Number of subjects analysed	89	90
Units: mm/hr
arithmetic mean (standard deviation)
Week 24 (n = 89, 90)	-4.07 ± 1.03	-4.01 ± 1.13
Week 28 (n = 87, 88)	-3.94 ± 1.22	-3.78 ± 1.31
Week 32 (n = 86, 90)	-3.97 ± 1.38	-3.77 ± 1.17
Week 36 (n = 86, 88)	-3.82 ± 1.53	-3.9 ± 1.16
Week 40 (n = 84, 88)	-3.95 ± 1.26	-3.84 ± 1.19
Week 44 (n = 82, 88)	-4.05 ± 1.17	-3.76 ± 1.17
Week 48 (n = 82, 88)	-4.14 ± 1.24	-3.68 ± 1.32

No statistical analyses for this end point

Secondary: Percentage of patients allocated in Groups A1 and A2 who remain with clinical remission activity (DAS 28 ESR <2.6) up to Week 48

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End point title

Percentage of patients allocated in Groups A1 and A2 who remain with clinical remission activity (DAS 28 ESR <2.6) up to Week 48

End point description

The DAS28 is a combined index for measuring disease activity in RA. The index includes the assessment of 28 joints for swelling and tenderness, acute phase response (ESR or CRP), and general health status. For this study ESR will be used to calculate the DAS28 score. Analyses were conducted on the Full Analysis Set (FAS).

End point type

Secondary

End point timeframe

From week 28 up to week 48

End point values	Phase 2 Arm A1: TCZ +/- nbDMARD once per week (qw)	Phase 2 Arm A2: TCZ +/- nbDMARD every two weeks (q2w)
Number of subjects analysed	89	90
Units: Percentage of participants
number (confidence interval 95%)
Week 28 (n = 89, 90)	88.5 (79.88 to 94.35)	84.1 (74.75 to 91.02)
Week 32 (n = 87, 90)	87.2 (78.27 to 93.44)	81.1 (71.49 to 88.59)
Week 36 (n = 86, 89)	80.2 (70.25 to 88.04)	86.4 (77.39 to 92.75)
Week 40 (n = 84, 88)	82.1 (72.26 to 89.65)	80.7 (70.88 to 88.32)
Week 44 (n = 82, 89)	89 (80.18 to 94.86)	78.4 (68.35 to 86.47)
Week 48 (n = 84, 89)	91.5 (83.2 to 96.5)	73.9 (63.41 to 82.66)

No statistical analyses for this end point

Secondary: Percentage of patients reporting change in DAS 28 ESR >1.2 until week 48

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End point title

Percentage of patients reporting change in DAS 28 ESR >1.2 until week 48

End point description

End point type

Secondary

End point timeframe

From week 28 up to week 48

End point values	Phase 2 Arm A1: TCZ +/- nbDMARD once per week (qw)	Phase 2 Arm A2: TCZ +/- nbDMARD every two weeks (q2w)
Number of subjects analysed	88	90
Units: Percentage of participants
number (confidence interval 95%)
Week 28 (n = 88, 90)	96.6 (90.25 to 99.28)	96.6 (90.36 to 99.29)
Week 32 (n = 87, 90)	96.5 (90.14 to 99.27)	95.6 (89.01 to 98.78)
Week 36 (n = 86, 89)	93 (85.43 to 97.4)	97.7 (92.03 to 99.72)
Week 40 (n = 84, 88)	98.8 (93.54 to 99.97)	98.9 (93.83 to 99.97)
Week 44 (n = 82, 89)	98.8 (93.39 to 99.97)	95.5 (88.77 to 98.75)
Week 48 (n = 84, 89)	100 (0 to 999999)	95.5 (88.77 to 98.75)

No statistical analyses for this end point

Secondary: Percentage of patients with American College of Rheumatology (ACR20, 50, 70, 90) response scores until week 24

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End point title

Percentage of patients with American College of Rheumatology (ACR20, 50, 70, 90) response scores until week 24

End point description

The definition of improvement of ACR core set of outcome measures includes an improvement equal or higher to the 20%, 50%, 70%, 90% compared to Baseline in both Swollen Joint Count (SJC) and Tender Joint Count (TJC) as well as in three out of five additional parameters: Physician’s Global Assessment of disease activity VAS, patient’s Global Assessment of disease activity VAS, patient’s assessment of pain VAS, HAQ-DI, and acute phase reactant (either CRP or erythrocyte sedimentation rate [ESR]). Analyses were conducted on the Full Analysis Set (FAS).

End point type

Secondary

End point timeframe

From week 2 until week 24

End point values	Phase 1: Tocilizumab Monotherapy	Phase 1: Combination therapy
Number of subjects analysed	74	319
Units: Percentage of participants
number (confidence interval 95%)
ACR20 - Week 2 (n = 74, 319)	27 (17.35 to 38.61)	31.7 (26.59 to 37.08)
ACR20 - Week 4 (n = 73, 312)	50.7 (38.72 to 62.6)	49.7 (44 to 55.37)
ACR20 - Week 8 (n = 73, 300)	67.1 (55.13 to 77.67)	67 (61.36 to 72.3)
ACR20 - Week 12 (n = 70, 296)	80 (68.73 to 88.61)	74.7 (69.31 to 79.52)
ACR20 - Week 16 (n = 69, 292)	79.7 (68.31 to 88.44)	75.7 (70.35 to 80.49)
ACR20 - Week 20 (n = 65, 284)	73.8 (61.46 to 83.97)	81 (75.93 to 85.38)
ACR20 - Week 24 (n = 64, 281)	79.7 (67.77 to 88.72)	83.3 (78.39 to 87.44)
ACR20 - LOCF visit (n = 74, 319)	77 (67.77 to 88.72)	79 (78.39 to 87.44)
ACR50 - Week 2 (n = 74, 319)	9.5 (3.89 to 18.52)	13.2 (9.66 to 17.38)
ACR50 - Week 4 (n = 73, 312)	20.5 (11.98 to 31.62)	25.3 (20.59 to 30.53)
ACR50 - Week 8 (n = 73, 300)	37 (25.97 to 49.09)	41.3 (35.7 to 47.14)
ACR50 - Week 12 (n = 70, 296)	51.4 (39.17 to 63.56)	52.7 (46.84 to 58.51)
ACR50 - Week 16 (n = 69, 292)	53.6 (41.2 to 65.72)	52.4 (46.5 to 58.25)
ACR50 - Week 20 (n = 65, 284)	58.5 (45.56 to 70.56)	58.5 (52.48 to 64.24)
ACR50 - Week 24 (n = 64, 281)	59.4 (46.37 to 71.49)	58.7 (52.72 to 64.53)
ACR50 - LOCF visit (n = 74, 319)	55.4 (46.37 to 71.49)	54.2 (52.72 to 64.53)
ACR70 - Week 2 (n = 74, 319)	5.4 (1.49 to 13.27)	2.8 (1.3 to 5.29)
ACR70 - Week 4 (n = 73, 312)	12.3 (5.8 to 22.12)	10.6 (7.39 to 14.53)
ACR70 - Week 8 (n = 73, 300)	17.8 (9.84 to 28.53)	22.7 (18.05 to 27.83)
ACR70 - Week 12 (n = 70, 296)	32.9 (22.09 to 45.12)	27 (22.05 to 32.47)
ACR70 - Week 16 (n = 69, 292)	29 (18.69 to 41.16)	32.2 (26.87 to 37.88)
ACR70 - Week 20 (n = 65, 284)	33.8 (22.57 to 46.65)	36.6 (31.01 to 42.52)
ACR70 - Week 24 (n = 64, 281)	40.6 (28.51 to 53.63)	37.7 (32.03 to 43.67)
ACR70 - LOCF visit (n = 74, 319)	37.8 (28.51 to 53.63)	33.9 (32.03 to 43.67)
ACR90 - Week 2 (n = 74, 319)	1.4 (0.03 to 7.3)	0.9 (0.19 to 2.72)
ACR90 - Week 4 (n = 73, 312)	2.7 (0.33 to 9.55)	1.6 (0.52 to 3.7)
ACR90 - Week 8 (n = 73, 300)	6.8 (2.26 to 15.26)	7.3 (4.65 to 10.89)
ACR90 - Week 12 (n = 70, 296)	12.9 (6.05 to 23.01)	8.8 (5.82 to 12.61)
ACR90 - Week 16 (n = 69, 292)	13 (6.14 to 23.32)	12 (8.49 to 16.27)
ACR90 - Week 20 (n = 65, 284)	13.8 (6.53 to 24.66)	13.7 (9.95 to 18.29)
ACR90 - Week 24 (n = 64, 281)	23.4 (13.75 to 35.69)	16.7 (12.56 to 21.61)
ACR90 - LOCF visit (n = 74, 319)	20.3 (13.75 to 35.69)	15 (12.56 to 21.61)

No statistical analyses for this end point

Secondary: Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 48

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End point title

Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 48

End point description

End point type

Secondary

End point timeframe

From week 28 until week 48

End point values	Phase 2 Arm A1: TCZ +/- nbDMARD once per week (qw)	Phase 2 Arm A2: TCZ +/- nbDMARD every two weeks (q2w)
Number of subjects analysed	89	90
Units: Percentage of participants
number (confidence interval 95%)
ARC20 - Week 28 (n = 88, 90)	90 (82.7 to 95.99)	92.2 (84.63 to 96.82)
ARC20 - Week 32 (n = 87, 90)	93.1 (85.59 to 97.43)	94.4 (87.51 to 98.17)
ARC20 - Week 36 (n = 86, 89)	84.9 (75.54 to 91.7)	91 (83.05 to 96.04)
ARC20 - Week 40 (n = 84, 88)	88.1 (79.19 to 94.14)	93.2 (85.75 to 97.46)
ARC20 - Week 44 (n = 82, 89)	91.5 (83.2 to 96.5)	91 (83.05 to 96.04)
ARC20 - Week 48 (n = 84, 89)	96.4 (89.92 to 99.26)	88.8 (80.31 to 94.48)
ARC20 - LOCF visit (n = 89, 90)	95.5 (88.89 to 98.76)	87.8 (79.18 to 93.74)
ARC50 - Week 28 (n = 88, 90)	79.5 (69.61 to 87.4)	81.1 (71.49 to 88.59)
ARC50 - Week 32 (n = 87, 90)	85.1 (75.8 to 91.8)	83.3 (74 to 90.36)
ARC50 - Week 36 (n = 86, 89)	74.4 (63.87 to 83.22)	83.1 (73.73 to 90.25)
ARC50 - Week 40 (n = 84, 88)	79.8 (69.59 to 87.75)	81.8 (72.16 to 89.24)
ARC50 - Week 44 (n = 82, 89)	80.5 (70.26 to 88.42)	78.7 (68.69 to 86.63)
ARC50 - Week 48 (n = 84, 89)	88.1 (79.19 to 94.14)	79.8 (69.93 to 87.55)
ARC50 - LOCF visit (n = 89, 90)	84.3 (75.02 to 91.12)	78.9 (69.01 to 86.79)
ARC70 - Week 28 (n = 88, 90)	59.1 (48.09 to 69.46)	57.8 (46.91 to 68.12)
ARC70 - Week 32 (n = 87, 90)	65.5 (54.56 to 75.39)	54.4 (43.6 to 64.98)
ARC70 - Week 36 (n = 86, 89)	61.6 (50.51 to 71.92)	62.9 (52.03 to 72.93)
ARC70 - Week 40 (n = 84, 88)	65.5 (54.31 to 75.52)	59.1 (48.09 to 69.46)
ARC70 - Week 44 (n = 82, 89)	67.1 (55.81 to 77.06)	59.6 (48.62 to 69.83)
ARC70 - Week 48 (n = 84, 89)	71.4 (60.53 to 80.76)	65.2 (54.33 to 74.96)
ARC70 - LOCF visit (n = 89, 90)	68.5 (57.83 to 77.97)	64.4 (53.65 to 74.26)
ARC90 - Week 28 (n = 88, 90)	27.3 (18.32 to 37.81)	32.2 (22.75 to 42.9)
ARC90 - Week 32 (n = 87, 90)	35.6 (25.65 to 46.62)	31.1 (21.77 to 41.74)
ARC90 - Week 36 (n = 86, 89)	33.7 (23.88 to 44.72)	30.3 (21.03 to 40.99)
ARC90 - Week 40 (n = 84, 88)	41.7 (31 to 52.94)	29.5 (20.29 to 40.22)
ARC90 - Week 44 (n = 82, 89)	34.1 (24.03 to 45.45)	27 (18.1 to 37.42)
ARC90 - Week 48 (n = 84, 89)	45.2 (34.34 to 56.48)	32.6 (23.02 to 43.34)
ARC90 - LOCF visit (n = 89, 90)	42.7 (32.26 to 53.63)	32.2 (22.75 to 42.9)

No statistical analyses for this end point

Secondary: Number of patients with good and moderate clinical response according to European League Against Rheumatism (EULAR) response scores up to week 24

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End point title

Number of patients with good and moderate clinical response according to European League Against Rheumatism (EULAR) response scores up to week 24

End point description

DAS28-based EULAR response criteria were used to measure individual response as good or moderate depending on the extent of change from baseline and the level of disease activity reached. Good responders: change from baseline >1.2 with DAS28 ≤3.2; moderate responders: change from baseline >1.2 with DAS28 >3.2 to ≤5.1 or change from baseline >0.6 to =<1.2 with DAS28 ≤5.1. Analyses were conducted on the Full Analysis Set (FAS).

End point type

Secondary

End point timeframe

From week 2 until week 24

End point values	Phase 1: Tocilizumab Monotherapy	Phase 1: Combination therapy
Number of subjects analysed	74	327
Units: Number of participants
number (not applicable)
Good response - Week 2 (n = 74, 319)	14	61
Moderate response - Week 2 (n = 74, 319)	36	196
Good response - Week 4 (n = 73, 312)	18	109
Moderate response - Week 4 (n = 73, 312)	49	175
Good response - Week 8 (n = 73, 300)	37	162
Moderate response - Week 8 (n = 73, 300)	32	121
Good response - Week 12 (n = 70, 296)	41	194
Moderate response - Week 12 (n = 70, 296)	27	95
Good response - Week 16 (n = 69, 292)	45	209
Moderate response - Week 16 (n = 69, 292)	22	76
Good response - Week 20 (n = 65, 284)	45	221
Moderate response - Week 20 (n = 65, 284)	18	56
Good response - Week 24 (n = 64, 281)	48	225
Moderate response - Week 24 (n = 64, 281)	16	53
Good response - LOCF visit (n = 74, 327)	54	247
Moderate response - LOCF visit (n = 74, 327)	19	73

No statistical analyses for this end point

Secondary: Number of Patients With Clinical Response According to European League Against Rheumatism (EULAR) Response Scores up to Week 48

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End point title

Number of Patients With Clinical Response According to European League Against Rheumatism (EULAR) Response Scores up to Week 48

End point description

End point type

Secondary

End point timeframe

From week 28 until week 48

End point values	Phase 2 Arm A1: TCZ +/- nbDMARD once per week (qw)	Phase 2 Arm A2: TCZ +/- nbDMARD every two weeks (q2w)
Number of subjects analysed	89	90
Units: Number of participants
number (not applicable)
Good response - Week 28 (n = 88, 90)	82	77
Moderate response - Week 28 (n = 88, 90)	5	10
Good response - Week 32 (n = 87, 90)	79	81
Moderate response - Week 32 (n = 87, 90)	6	9
Good response - Week 36 (n = 86, 89)	75	80
Moderate response - Week 36 (n = 86, 89)	9	8
Good response - Week 40 (n = 84, 88)	75	81
Moderate response - Week 40 (n = 84, 88)	9	7
Good response - Week 44 (n = 82, 89)	78	75
Moderate response - Week 44 (n = 82, 89)	4	13
Good response - Week 48 (n = 84, 89)	78	73
Moderate response - Week 48 (n = 84, 89)	4	15
Good response - LOCF visit (n = 89, 90)	84	74
Moderate response - LOCF visit (n = 89, 90)	5	16

No statistical analyses for this end point

Secondary: Mean change in Clinical Disease Activity Index (CDAI) from baseline up to week 24

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End point title

Mean change in Clinical Disease Activity Index (CDAI) from baseline up to week 24

End point description

Clinical Disease Activity Index (CDAI) is an index for measuring disease activity in rheumatoid arthritis (RA). The index was calculated using the following formula: CDAI = number of swollen joints using the 28-joint count (SJC28) + number of tender joints using the 28-joint count (TJC28) + patient global assessment of disease (PGA) based on 10 centimeter [cm] Visual Analog Scale [VAS] + physician global assessment of disease (PhGA) based on 10 cm VAS. VAS assessments involved a 10 cm horizontal scale from 0 (no disease activity) to 10 (maximum disease activity). Total CDAI scores ranged from 0 to 76, with higher scores indicating increased disease activity. A negative change from baseline indicates an improvement. Analyses were conducted on the Full Analysis Set (FAS).

End point type

Secondary

End point timeframe

From baseline to Week 24

End point values	Phase 1: Tocilizumab Monotherapy	Phase 1: Combination therapy
Number of subjects analysed	74	327
Units: CDAI score
arithmetic mean (standard deviation)
Baseline values (n = 74, 327)	33.06 ± 12.45	32.06 ± 12.28
Week 2 (n = 74, 319)	-7.54 ± 9.57	-8.62 ± 9.22
Week 4 (n = 73, 312)	-13.03 ± 10.91	-13.23 ± 10.65
Week 8 (n = 73, 299)	-18.06 ± 11.05	-18.46 ± 11.61
Week 12 (n = 70, 296)	-21.56 ± 11.77	-20.6 ± 11.42
Week 16 (n = 69, 290)	-23.01 ± 12.33	-21.79 ± 11.57
Week 20 (n = 65, 284)	-24.07 ± 11.97	-22.88 ± 12.1
Week 24 (n = 64, 281)	-25.8 ± 13.31	-23.43 ± 11.62
LOCF visit (n = 74, 327)	-24.42 ± 13.5	-21.58 ± 12.85

No statistical analyses for this end point

Secondary: Mean change from baseline in Clinical Disease Activity Index (CDAI) up to Week 48

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End point title

Mean change from baseline in Clinical Disease Activity Index (CDAI) up to Week 48

End point description

End point type

Secondary

End point timeframe

From week 24 until week 48

End point values	Phase 2 Arm A1: TCZ +/- nbDMARD once per week (qw)	Phase 2 Arm A2: TCZ +/- nbDMARD every two weeks (q2w)
Number of subjects analysed	89	90
Units: CDAI score
arithmetic mean (standard deviation)
Baseline values (n = 89, 90)	29.27 ± 10.9	29.64 ± 12.13
Week 24 (n = 89, 90)	-25.54 ± 10.6	-25.34 ± 12.1
Week 28 (n = 88, 89)	-24.75 ± 10.64	-24.01 ± 12.3
Week 32 (n = 87, 90)	-24.56 ± 12.93	-25.12 ± 11.64
Week 36 (n = 86, 88)	-23.9 ± 11.56	-25.45 ± 11.42
Week 40 (n = 84, 88)	-25.16 ± 10.43	-25.45 ± 11.75
Week 44 (n = 82, 89)	-25.45 ± 10.11	-25.26 ± 11.75
Week 48 (n = 83, 89)	-26.44 ± 11.13	-25.13 ± 12.51
LOCF visit (n = 89, 90)	-25.74 ± 11.29	-24.87 ± 12.67

No statistical analyses for this end point

Secondary: Mean change in Simplified Disease Activity Index (SDAI) from baseline up to week 24

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End point title

Mean change in Simplified Disease Activity Index (SDAI) from baseline up to week 24

End point description

Simplified Disease Activity Index (SDAI) is the numerical sum of five outcome parameters: TJC and SJC (based on a 28-joint assessment), PtGA and PhGA (based on 0-10 cm VAS, where 0 = no disease activity and 10 = worst disease activity), and CRP. SDAI total score ranges from 0 (no disease activity) to 86 (maximal disease activity), where higher scores represents higher disease activity. The SDAI =< 3.3 indicates disease remission, > 3.4 to 11 indicates low disease activity, > 11 to 26 indicates moderate disease activity, and > 26 indicates high disease activity. Analyses were conducted on the Full Analysis Set (FAS).

End point type

Secondary

End point timeframe

From baseline to Week 24

End point values	Phase 1: Tocilizumab Monotherapy	Phase 1: Combination therapy
Number of subjects analysed	74	327
Units: SDAI score
arithmetic mean (standard deviation)
Baseline values (n = 74, 324)	48.66 ± 31.48	44.4 ± 22.91
Week 2 (n = 72, 309)	-20.45 ± 19.01	-19.5 ± 18.75
Week 4 (n = 70, 308)	-27.86 ± 23.54	-24.34 ± 20.98
Week 8 (n = 72, 292)	-32.61 ± 26.84	-29.34 ± 21.96
Week 12 (n = 70, 291)	-36.23 ± 27.04	-30.95 ± 23.58
Week 16 (n = 69, 286)	-37.82 ± 31.09	-32.66 ± 22.79
Week 20 (n = 64, 277)	-36.79 ± 25.47	-33.95 ± 23.05
Week 24 (n = 63, 277)	-41.38 ± 31.51	-34.8 ± 22.44
LOCF visit (n = 74, 324)	-39.15 ± 30.45	-32.73 ± 22.84

No statistical analyses for this end point

Secondary: Mean Change in Simplified Disease Activity Index (SDAI) From Week 24 up to Week 48

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End point title

Mean Change in Simplified Disease Activity Index (SDAI) From Week 24 up to Week 48

End point description

Simplified Disease Activity Index (SDAI) which is the numerical sum of five outcome parameters: TJC and SJC (based on a 28-joint assessment), PtGA and PhGA (based on 0-10 cm VAS, where 0 = no disease activity and 10 = worst disease activity), and CRP. SDAI total score ranges from 0 (no disease activity) to 86 (maximal disease activity), where higher scores represents higher disease activity. The SDAI =< 3.3 indicates disease remission, > 3.4 to 11 indicates low disease activity, > 11 to 26 indicates moderate disease activity, and > 26 indicates high disease activity. Analyses were conducted on the Full Analysis Set (FAS).

End point type

Secondary

End point timeframe

From week 24 until week 48

End point values	Phase 2 Arm A1: TCZ +/- nbDMARD once per week (qw)	Phase 2 Arm A2: TCZ +/- nbDMARD every two weeks (q2w)
Number of subjects analysed	89	90
Units: SDAI score
arithmetic mean (standard deviation)
Baseline values (n = 89, 89)	41.45 ± 24.9	40.92 ± 21.42
Week 24 (n = 88, 90)	-37.02 ± 24.6	-35.88 ± 20.71
Week 28 (n = 86, 87)	-35.15 ± 25.9	-34.5 ± 20.66
Week 32 (n = 86, 90)	-35.6 ± 26.97	-34.88 ± 20.53
Week 36 (n = 86, 88)	-35.29 ± 26.55	-35.35 ± 20.07
Week 40 (n = 83, 88)	-37.26 ± 25.48	-35.7 ± 19.8
Week 44 (n = 82, 89)	-37.09 ± 25.17	-35.06 ± 21.77
Week 48 (n = 82, 88)	-37.93 ± 26.32	-35.02 ± 21.74
LOCF visit (n = 89, 90)	-36.93 ± 25.75	-34.69 ± 21.75

No statistical analyses for this end point

Secondary: Mean change from baseline in total Tender Joint Counts (TJC) until week 24

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End point title

Mean change from baseline in total Tender Joint Counts (TJC) until week 24

End point description

TCJ is a clinical ssessment of 68 joints which are classified as tender/not tender by pressure and joint manipulation on physical examination. Joint prosthesis, arthrodesis or fused joints are not be taken into consideration. Analyses were conducted on the Full Analysis Set (FAS).

End point type

Secondary

End point timeframe

From baseline to Week 24

End point values	Phase 1: Tocilizumab Monotherapy	Phase 1: Combination therapy
Number of subjects analysed	74	327
Units: TJC
arithmetic mean (standard deviation)
Baseline visit (n = 74, 327)	18.05 ± 12.98	19.12 ± 13.38
Week 2 (n = 74, 319)	-4.31 ± 7.56	-5 ± 8.06
Week 4 (n = 73, 312)	-7.04 ± 11.77	-7.96 ± 9.43
Week 8 (n = 73, 300)	-9.81 ± 10.37	-10.9 ± 11.1
Week 12 (n = 70, 296)	-12.27 ± 10.47	-12.01 ± 10.88
Week 16 (n = 69, 291)	-13.43 ± 12.35	-13.09 ± 11.02
Week 20 (n = 65, 284)	-13.65 ± 11.73	-13.7 ± 11.48
Week 24 (n = 64, 281)	-15.47 ± 13.35	-14.2 ± 11.46
LOCF visit (n = 74, 327)	-14.36 ± 12.87	-13.19 ± 11.75

No statistical analyses for this end point

Secondary: Mean Change From Baseline in Total Tender Joint Counts (TJC) Until Week 48

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End point title

Mean Change From Baseline in Total Tender Joint Counts (TJC) Until Week 48

End point description

End point type

Secondary

End point timeframe

From week 24 until week 48

End point values	Phase 2 Arm A1: TCZ +/- nbDMARD once per week (qw)	Phase 2 Arm A2: TCZ +/- nbDMARD every two weeks (q2w)
Number of subjects analysed	89	90
Units: TJC
arithmetic mean (standard deviation)
Baseline values (n = 89, 90)	15.42 ± 9.05	15.97 ± 12.77
Week 28 (n = 88, 90)	-13.66 ± 8.44	-12.88 ± 11.52
Week 32 (n = 87, 90)	-13.4 ± 8.99	-13.88 ± 11.43
Week 36 (n = 86, 89)	-13.13 ± 8.82	-13.78 ± 11.7
Week 40 (n = 84, 88)	-14.06 ± 8.58	-14.49 ± 12.07
Week 44 (n = 82, 89)	-14.32 ± 8.25	-13.93 ± 11.62
Week 48 (n = 84, 89)	-14.4 ± 8.61	-13.43 ± 12.17
LOCF visit (n = 89, 90)	-13.96 ± 8.68	-13.27 ± 12.2

No statistical analyses for this end point

Secondary: Mean Change in total Swollen Joint Counts (SJC) from baseline Until Week 24

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End point title

Mean Change in total Swollen Joint Counts (SJC) from baseline Until Week 24

End point description

SJC is a clinical assessment of 66 joints classified as swollen/not swollen by pressure and joint manipulation on physical examination. Joint prosthesis, arthrodesis or fused joints will not be taken into consideration for swelling. Analyses were conducted on the Full Analysis Set (FAS).

End point type

Secondary

End point timeframe

From baseline to Week 24

End point values	Phase 1: Tocilizumab Monotherapy	Phase 1: Combination therapy
Number of subjects analysed	74	327
Units: SJC
arithmetic mean (standard deviation)
Baseline values (n = 74, 327)	10.05 ± 7.99	9.76 ± 6.64
Week 2 (n = 74, 319)	-3.22 ± 4.4	-3.42 ± 5.1
Week 4 (n = 73, 312)	-5.07 ± 5.58	-5.46 ± 5.41
Week 8 (n = 73, 300)	-7.38 ± 6.47	-6.81 ± 6.03
Week 12 (n = 70, 296)	-7.93 ± 7.13	-7.6 ± 6
Week 16 (n = 69, 290)	-8.35 ± 7.71	-8.01 ± 6.05
Week 20 (n = 65, 284)	-8.72 ± 7.56	-8.37 ± 6.5
Week 24 (n = 64, 281)	-9.13 ± 7.66	-8.38 ± 6.59
LOCF visit (n = 74, 327)	-8.47 ± 7.48	-7.71 ± 6.67

No statistical analyses for this end point

Secondary: Mean Change in Total Swollen Joint Counts (SJC) From Baseline Until Week 48

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End point title

Mean Change in Total Swollen Joint Counts (SJC) From Baseline Until Week 48

End point description

End point type

Secondary

End point timeframe

From week 24 until week 48

End point values	Phase 2 Arm A1: TCZ +/- nbDMARD once per week (qw)	Phase 2 Arm A2: TCZ +/- nbDMARD every two weeks (q2w)
Number of subjects analysed	89	90
Units: SJC
arithmetic mean (standard deviation)
Baseline values (n = 89, 90)	9.28 ± 6.52	9.23 ± 7.55
Week 28 (n = 88, 90)	-8.64 ± 6.19	-8.14 ± 6.81
Week 32 (n = 87, 90)	-8.54 ± 7.02	-8.62 ± 7.13
Week 36 (n = 86, 89)	-8.48 ± 6.5	-8.38 ± 6.76
Week 40 (n = 84, 88)	-8.85 ± 6.4	-8.51 ± 6.59
Week 44 (n = 82, 89)	-8.73 ± 6.62	-8.62 ± 6.97
Week 48 (n = 84, 89)	-9.06 ± 6.58	-8.72 ± 7.34
LOCF visit (n = 89, 90)	-8.82 ± 6.51	-8.64 ± 7.33

No statistical analyses for this end point

Secondary: Percentages of patients who achieve DAS28-ESR remission (DAS28 < 2.6) up to Week 48

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End point title

Percentages of patients who achieve DAS28-ESR remission (DAS28 < 2.6) up to Week 48

End point description

The DAS 28 is a combined index for measuring disease activity in RA. The index includes the assessment of 28 joints for swelling and tenderness, acute phase response (ESR or CRP) and general health status. For this study ESR was used to calculate the DAS 28 score. The CI of 0 to 100 is presented, but is not applicable as the central value is 100%. Analyses were conducted on the Full Analysis Set (FAS).

End point type

Secondary

End point timeframe

Week 48

End point values	Phase 2 Arm A1 - Monotherapy - qw	Phase 2 Arm A1 - Combination Therapy - qw	Phase 2 Arm A2 - Monotherapy - q2w	Phase 2 Arm A2 - Combination Therapy - q2w
Number of subjects analysed	23 ^[1]	66	23	67
Units: Percentage of participants
arithmetic mean (confidence interval 95%)
Week 28 (n = 23, 65, 23, 67)	82.6 (61.22 to 95.05)	90.6 (80.7 to 96.48)	87 (66.41 to 97.22)	83.1 (71.73 to 91.24)
Week 32 (n = 22, 65, 23, 67)	81.8 (59.72 to 94.81)	89.1 (78.75 to 95.49)	78.3 (56.3 to 92.54)	82.1 (70.8 to 90.39)
Week 36 (n = 21, 65, 23, 67)	90.5 (69.62 to 98.83)	76.9 (64.81 to 86.47)	86.4 (65.09 to 97.09)	86.4 (75.69 to 93.57)
Week 40 (n = 20, 64, 23, 67)	85 (62.11 to 96.79)	81.3 (69.54 to 89.92)	77.3 (54.63 to 92.18)	81.8 (70.39 to 90.24)
Week 44 (n = 19, 63, 23, 67)	94.7 (73.97 to 99.87)	87.3 (76.5 to 94.35)	77.3 (54.63 to 92.18)	78.8 (66.98 to 87.89)
Week 48 (n = 20, 64, 23, 67)	100 (0 to 100)	89.1 (78.75 to 95.49)	77.3 (54.63 to 92.18)	72.7 (60.36 to 82.97)
LOCF Visit (n = 23, 66, 23, 67)	91.3 (71.96 to 98.93)	89.4 (79.63 to 95.63)	73.9 (51.59 to 89.77)	73.1 (60.9 to 83.24)

Notes
[1] - 00000 has been entered as this information is not applicable as the central value is 100%.

No statistical analyses for this end point

Secondary: Percentages of patients with remission (CDAI<2.8) until week 24

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End point title

Percentages of patients with remission (CDAI<2.8) until week 24

End point description

End point type

Secondary

End point timeframe

From baseline to Week 24

End point values	Phase 1: Tocilizumab Monotherapy	Phase 1: Combination therapy
Number of subjects analysed	74	327
Units: Percentage of participants
number (confidence interval 95%)
Baseline visit (n = 74, 327)	0 (0 to 0)	0 (0 to 0)
Week 2 (n = 74, 319)	2.7 (0.33 to 9.42)	1.6 (0.51 to 3.62)
Week 4 (n = 73, 312)	2.7 (0.33 to 9.55)	5.1 (2.96 to 8.19)
Week 8 (n = 73, 300)	11 (4.85 to 20.46)	14.4 (10.61 to 18.88)
Week 12 (n = 70, 296)	15.7 (8.11 to 26.38)	19.3 (14.92 to 24.22)
Week 16 (n = 69, 292)	18.8 (10.43 to 30.06)	22.8 (18.06 to 28.02)
Week 20 (n = 65, 284)	27.7 (17.31 to 40.19)	26.8 (21.7 to 32.31)
Week 24 (n = 64, 281)	29.7 (18.91 to 42.42)	30.2 (24.93 to 35.99)
LOCF visit (n = 74, 327)	29.7 (19.66 to 41.48)	29.4 (24.48 to 34.62)

No statistical analyses for this end point

Secondary: Percentages of Patients With Remission (CDAI<2.8) Until Week 48

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End point title

Percentages of Patients With Remission (CDAI<2.8) Until Week 48

End point description

End point type

Secondary

End point timeframe

From week 28 until week 48

End point values	Phase 2 Arm A1: TCZ +/- nbDMARD once per week (qw)	Phase 2 Arm A2: TCZ +/- nbDMARD every two weeks (q2w)
Number of subjects analysed	89	90
Units: Percentage of participants
number (confidence interval 95%)
Week 28 (n = 88, 90)	46.6 (35.88 to 57.54)	48.3 (37.59 to 59.16)
Week 32 (n = 87, 90)	48.3 (37.42 to 59.25)	45.6 (35.02 to 56.4)
Week 36 (n = 86, 89)	52.3 (41.27 to 63.21)	46.6 (35.88 to 57.54)
Week 40 (n = 84, 88)	52.4 (41.19 to 63.4)	45.5 (34.8 to 56.42)
Week 44 (n = 82, 89)	50 (38.75 to 61.25)	50.6 (39.75 to 61.33)
Week 48 (n = 84, 89)	59 (47.69 to 69.72)	53.9 (43.04 to 64.56)
LOCF Visit (n = 89, 90)	57.8 (46.91 to 68.12)	60.3 (52.77 to 67.56)

No statistical analyses for this end point

Secondary: Percentages of Patients With Remission (SDAI<3.3) Until Week 24

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End point title

Percentages of Patients With Remission (SDAI<3.3) Until Week 24

End point description

End point type

Secondary

End point timeframe

From baseline to Week 24

End point values	Phase 1: Tocilizumab Monotherapy	Phase 1: Combination therapy
Number of subjects analysed	74	327
Units: Percentage of participants
number (confidence interval 95%)
Baseline visit (n = 74, 327)	0 (0 to 0)	0 (0 to 0)
Week 2 (n = 74, 319	1.4 (0.04 to 7.5)	1.9 (0.71 to 4.14)
Week 4 (n = 73, 312)	2.9 (0.35 to 9.94)	4.8 (2.72 to 7.83)
Week 8 (n = 73, 300)	11.1 (4.92 to 20.72)	14.6 (10.75 to 19.13)
Week 12 (n = 70, 296)	14.3 (7.07 to 24.71)	18.8 (14.47 to 23.72)
Week 16 (n = 69, 292)	17.4 (9.32 to 28.41)	22.2 (17.56 to 27.47)
Week 20 (n = 65, 284)	28.1 (17.6 to 40.76)	25.8 (20.77 to 31.36)
Week 24 (n = 64, 281)	31.7 (20.58 to 44.69)	28.8 (23.53 to 34.49)
LOCF visit (n = 74, 327)	28.4 (18.5 to 40.05)	25.4 (20.75 to 30.46)

No statistical analyses for this end point

Secondary: Percentages of Patients With Remission (SDAI<3.3) Until Week 48

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End point title

Percentages of Patients With Remission (SDAI<3.3) Until Week 48

End point description

End point type

Secondary

End point timeframe

From week 28 until week 48

End point values	Phase 2 Arm A1: TCZ +/- nbDMARD once per week (qw)	Phase 2 Arm A2: TCZ +/- nbDMARD every two weeks (q2w)
Number of subjects analysed	89	90
Units: Percentage of participants
number (confidence interval 95%)
Week 28 (n = 88, 90)	50 (39.02 to 60.98)	46 (35.23 to 57)
Week 32 (n = 87, 90)	48.8 (37.9 to 59.86)	45.6 (35.02 to 56.4)
Week 36 (n = 86, 89)	53.5 (42.41 to 64.32)	47.7 (36.96 to 58.65)
Week 40 (n = 84, 88)	55.4 (44.1 to 66.34)	44.3 (33.73 to 55.3)
Week 44 (n = 82, 89)	50 (38.75 to 61.25)	47.2 (36.51 to 58.06)
Week 48 (n = 84, 89)	52.4 (41.11 to 63.59)	47.7 (36.96 to 58.65)
LOCF visit (n = 89, 90)	51.7 (40.48 to 62.41)	47.8 (37.13 to 58.57)

No statistical analyses for this end point

Secondary: Percentage of patients who achieve low disease activity based on DAS28-ESR criteria (DAS28-ESR </=3.2) up to week 24

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End point title

Percentage of patients who achieve low disease activity based on DAS28-ESR criteria (DAS28-ESR </=3.2) up to week 24

End point description

The DAS28 is a combined index for measuring disease activity in RA. The index includes the assessment of 28 joints for swelling and tenderness, acute phase response (ESR or CRP), and general health status. For this study ESR is used to calculate the DAS28 score. Analyses were conducted on the Full Analysis Set (FAS).

End point type

Secondary

End point timeframe

From baseline to Week 24

End point values	Phase 1: Tocilizumab Monotherapy	Phase 1: Combination therapy
Number of subjects analysed	74	327
Units: Percentage of participants
number (confidence interval 95%)
Week 2 (n = 74, 319)	21.6 (12.89 to 32.72)	21.5 (17.12 to 26.47)
Week 4 (n = 73, 300)	26 (16.45 to 37.62)	36.8 (31.39 to 42.41)
Week 8 (n = 74, 327)	50.7 (38.72 to 62.6)	55.4 (49.54 to 61.16)
Week 12 (n = 70, 296)	58.6 (46.17 to 70.23)	67.7 (62.01 to 73)
Week 16 (n = 69, 292)	66.7 (54.29 to 77.56)	72.4 (66.89 to 77.48)
Week 20 (n = 65, 284)	67.7 (54.95 to 78.77)	78.2 (72.91 to 82.83)
Week 24 (n = 64, 281)	75 (62.6 to 84.98)	81.1 (75.98 to 85.49)
LOCF visit (n = 74, 327)	73 (61.39 to 82.65)	74 (68.9 to 78.68)

No statistical analyses for this end point

Secondary: Percentage of Patients Who Achieve Low Disease Activity Based on DAS28-ESR Criteria (DAS28-ESR </=3.2) up to Week 48

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End point title

Percentage of Patients Who Achieve Low Disease Activity Based on DAS28-ESR Criteria (DAS28-ESR </=3.2) up to Week 48

End point description

The DAS28 is a combined index for measuring disease activity in RA. The index includes the assessment of 28 joints for swelling and tenderness, acute phase response (ESR or CRP), and general health status. For this study ESR was used to calculate the DAS28 score. Analyses were conducted on the Full Analysis Set (FAS).

End point type

Secondary

End point timeframe

From week 28 until week 48

End point values	Phase 2 Arm A1: TCZ +/- nbDMARD once per week (qw)	Phase 2 Arm A2: TCZ +/- nbDMARD every two weeks (q2w)
Number of subjects analysed	89	90
Units: Percentage of participants
number (confidence interval 95%)
Week 28 (n = 88, 90)	95.4 (88.64 to 98.73)	88.6 (80.09 to 94.41)
Week 32 (n = 87, 90)	91.9 (83.95 to 96.66)	92.2 (84.63 to 96.82)
Week 36 (86, 89)	87.2 (78.27 to 93.44)	92 (84.3 to 96.74)
Week 40 (n = 84, 88)	89.3 (80.63 to 94.98)	92 (84.3 to 96.74)
Week 44 (n = 82, 89)	96.3 (89.68 to 99.24)	87.5 (78.73 to 93.59)
Week 48 (n = 84, 89)	95.1 (87.98 to 98.66)	86.4 (77.39 to 92.75)
LOCF Visit (n = 89, 90)	94.4 (87.37 to 98.15)	85.6 (76.57 to 92.08)

No statistical analyses for this end point

Secondary: Percentage of Patients Who Achieve Low Disease Activity Based on CDAI score (CDAI<10) until week 24

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End point title

Percentage of Patients Who Achieve Low Disease Activity Based on CDAI score (CDAI<10) until week 24

End point description

End point type

Secondary

End point timeframe

From baseline to Week 24

End point values	Phase 1: Tocilizumab Monotherapy	Phase 1: Combination therapy
Number of subjects analysed	74	327
Units: Percentage of participants
number (confidence interval 95%)
Week 2 (n = 74, 319)	13.5 (6.68 to 23.45)	16.9 (12.98 to 21.5)
Week 4 (n = 73, 312)	24.7 (15.32 to 36.14)	26.9 (22.08 to 32.21)
Week 8 (n = 73, 300)	41.1 (29.71 to 53.23)	47.5 (41.71 to 53.32)
Week 12 (n = 70, 296)	57.1 (44.75 to 68.91)	52.4 (46.51 to 58.17)
Week 16 (n = 69, 292)	62.3 (49.83 to 73.71)	60.7 (54.81 to 66.35)
Week 20 (n = 65, 284)	66.2 (53.35 to 77.43)	65.1 (59.29 to 70.68)
Week 24 (n = 64, 281)	71.9 (59.24 to 82.4)	66.9 (61.07 to 72.38)
LOCF visit (n = 74, 327)	66.2 (54.28 to 76.81)	61.2 (55.64 to 66.48)

No statistical analyses for this end point

Secondary: Percentage of Patients Who Achieve Low Disease Activity Based on CDAI Score (CDAI<10) Until Week 48

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End point title

Percentage of Patients Who Achieve Low Disease Activity Based on CDAI Score (CDAI<10) Until Week 48

End point description

End point type

Secondary

End point timeframe

From week 28 until week 48

End point values	Phase 2 Arm A1: TCZ +/- nbDMARD once per week (qw)	Phase 2 Arm A2: TCZ +/- nbDMARD every two weeks (q2w)
Number of subjects analysed	89	90
Units: Percentage of participants
number (confidence interval 95%)
Week 28 (n = 88, 90)	86.4 (77.39 to 92.75)	85.4 (76.32 to 91.99)
Week 32 (n = 87, 90)	89.7 (81.27 to 95.16)	86.7 (77.87 to 92.92)
Week 36 (n = 86, 89)	80.2 (70.25 to 88.04)	89.8 (81.47 to 95.22)
Week 40 (n = 84, 88)	86.9 (77.78 to 93.28)	88.6 (80.9 to 94.41)
Week 44 (n = 82, 89)	89 (80.18 to 94.86)	85.4 (76.32 to 91.99)
Week 48 (n = 84, 89)	92.8 (84.93 to 97.3)	87.6 (78.96 to 93.67)
LOCF Visit (n = 89, 90)	91 (83.05 to 96.04)	87.8 (79.18 to 93.74)

No statistical analyses for this end point

Secondary: Percentage of patients who achieved low disease activity (LDA) based on SDAI score (SDAI<11) until week 24

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End point title

Percentage of patients who achieved low disease activity (LDA) based on SDAI score (SDAI<11) until week 24

End point description

End point type

Secondary

End point timeframe

From baseline to Week 24

End point values	Phase 1: Tocilizumab Monotherapy	Phase 1: Combination therapy
Number of subjects analysed	74	327
Units: Percentage of participants
number (confidence interval 95%)
Week 2 (n = 74, 319)	16.7 (8.92 to 27.3)	17.6 (13.56 to 22.32)
Week 4 (n = 73, 312)	27.1 (17.2 to 39.1)	28.3 (23.36 to 33.65)
Week 8 (n = 73, 300)	41.7 (30.15 to 53.89)	48.1 (42.31 to 54)
Week 12 (n = 70, 296)	58.6 (46.17 to 70.23)	55.6 (49.74 to 61.41)
Week 16 (n = 69, 292)	63.8 (51.31 to 75.01)	62.5 (56.63 to 68.11)
Week 20 (n = 65, 284)	65.6 (52.7 to 77.05)	66.3 (60.43 to 71.83)
Week 24 (n = 64, 281)	74.6 (62.06 to 84.73)	67.3 (61.41 to 72.75)
LOCF visit n = 74, 327)	63.5 (51.51 to 74.4)	56.9 (51.32 to 62.32)

No statistical analyses for this end point

Secondary: Percentage of patients who achieved low disease activity (LDA) based on SDAI score (SDAI<11) until week 48

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End point title

Percentage of patients who achieved low disease activity (LDA) based on SDAI score (SDAI<11) until week 48

End point description

End point type

Secondary

End point timeframe

From week 28 until week 48

End point values	Phase 2 Arm A1: TCZ +/- nbDMARD once per week (qw)	Phase 2 Arm A2: TCZ +/- nbDMARD every two weeks (q2w)
Number of subjects analysed	89	90
Units: Percentage of participants
number (confidence interval 95%)
Week 28 (n = 88, 90)	84.9 (75.54 to 91.7)	83.89 (74.48 to 90.91)
Week 32 (n = 87, 90)	89.5 (81.06 to 95.1)	85.6 (76.57 to 92.08)
Week 36 (n = 86, 89)	79.1 (68.95 to 87.1)	87.5 (78.73 to 93.59)
Week 40 (n = 84, 88)	86.7 (77.52 to 93.19)	86.4 (77.39 to 92.75)
Week 44 (n = 82, 89)	91.5 (83.2 to 96.5)	82 (72.45 to 89.36)
Week 48 (n = 84, 89)	93.9 (86.34 to 97.99)	81.8 (72.16 to 89.24)
LOCF visit (n = 89, 90)	91 (83.05 to 96.04)	81.1 (71.49 to 88.59)

No statistical analyses for this end point

Secondary: Safety: Number of patients reporting adverse events up to week 24

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End point title

Safety: Number of patients reporting adverse events up to week 24

End point description

Number of patients reporting any treatment emergent adverse event (TEAE), at least one TEAE of special interest, at least one serious TEAE, at least one TEAE leading to dose modification, at least one TEAE leading to discontinuation up to week 24. Analyses were conducted on the Full Analysis Set (FAS).

End point type

Secondary

End point timeframe

From baseline to Week 24

End point values	Phase 1: Tocilizumab Monotherapy	Phase 1: Combination therapy
Number of subjects analysed	74	327
Units: Number of participants
number (not applicable)
Any treatment emergent adverse event (TEAE)	52	254
At least one TEAE of special interest	2	13
At least one serious TEAE	3	10
At least one TEAE leading to dose modification	24	103
At least one TEAE leading to discontinuation	4	21

No statistical analyses for this end point

Secondary: Safety: Number of Patients Reporting Adverse Events up to Week 48

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End point title

Safety: Number of Patients Reporting Adverse Events up to Week 48

End point description

Number of patients reporting any treatment emergent adverse event (TEAE), at least one TEAE of special interest, at least one serious TEAE, at least one TEAE leading to dose modification, at least one TEAE leading to discontinuation up to week 48. Analyses were conducted on the Full Analysis Set (FAS).

End point type

Secondary

End point timeframe

From week 24 until week 48

End point values	Phase 2 Arm A1: TCZ +/- nbDMARD once per week (qw)	Phase 2 Arm A2: TCZ +/- nbDMARD every two weeks (q2w)	Phase 2 Arm B: Participants With Low Disease Activity	Phase 2 Arm C: moderate EULAR response at Week 24	Phase 2 Arm D: Non responders
Number of subjects analysed	89	90	95	67	2
Units: Number of participants
number (not applicable)
Any TEAE	50	63	68	46	1
At least one TEAE of special interest	1	2	2	4	0
At least one serious TEAE	2	1	2	5	1
At least one TEAE leading to dose modification	15	23	23	21	1
At least one TEAE leading to discontinuation	0	0	0	2	0

No statistical analyses for this end point

Secondary: Immunogenicity: Number of patients with anti-tocilizumab antibodies up to week 24

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End point title

Immunogenicity: Number of patients with anti-tocilizumab antibodies up to week 24

End point description

Number of patients resulting positive to anti-tocilizumab antibodies test are reported. Analyses were conducted on the Full Analysis Set (FAS).

End point type

Secondary

End point timeframe

From baseline to Week 24

End point values	Phase 1: Tocilizumab Monotherapy	Phase 1: Combination therapy
Number of subjects analysed	74	327
Units: Number of participants
number (not applicable)
Screen - Baseline	6	13
Screen - Week 12	1	2
Screen - Week 24	3	9
Confirmatory - Baseline	4	5
Confirmatory - Week 12	1	0
Confirmatory - Week 24	1	3

No statistical analyses for this end point

Secondary: Immunogenicity: Number of Patients With Anti-tocilizumab Antibodies up to Week 48

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End point title

Immunogenicity: Number of Patients With Anti-tocilizumab Antibodies up to Week 48

End point description

Number of patients resulting positive to anti-tocilizumab antibodies test are reported. Analyses were conducted on the Full Analysis Set (FAS).

End point type

Secondary

End point timeframe

From week 24 until week 48

End point values	Phase 2 Arm A1: TCZ +/- nbDMARD once per week (qw)	Phase 2 Arm A2: TCZ +/- nbDMARD every two weeks (q2w)	Phase 2 Arm B: Participants With Low Disease Activity	Phase 2 Arm C: moderate EULAR response at Week 24	Phase 2 Arm D: Non responders
Number of subjects analysed	89	90	95	67	2 ^[2]
Units: Number of participants
number (not applicable)
Screen - Week 36 (n = 86, 89, 91, 59, 0)	0	0	0	2	11111
Screen - Week 48 (n = 84. 89, 89, 59, 0)	1	3	2	3	11111
Confirmatory - Week 36 (n = 86, 89, 88, 59, 0)	0	0	0	1	11111
Confirmatory - Week 48 (n = 84, 89, 88, 59, 0)	0	0	0	1	11111

Notes
[2] - 11111 is not applicable as n = 0.

No statistical analyses for this end point

Secondary: Immunogenicity: TCZ levels up to week 24

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End point title

Immunogenicity: TCZ levels up to week 24

End point description

Mean concentrations of TCZ in patients' blood are reported. Analyses were conducted on the Full Analysis Set (FAS). 00000 has been entered as this information is not applicable as the analysis was done for one participant only.

End point type

Secondary

End point timeframe

From baseline to Week 24

End point values	Phase 1: Tocilizumab Monotherapy	Phase 1: Combination therapy
Number of subjects analysed	74	327
Units: mcg/ml
arithmetic mean (standard deviation)
Baseline (n = 1, 4)	0.49 ± 0	0.67 ± 0.34
Week 12 (n = 67, 285)	37.97 ± 20.11	41.23 ± 20.89
Week 24 (n = 62, 273)	46.42 ± 28.35	46.87 ± 27.65

No statistical analyses for this end point

Secondary: Immunogenicity: TCZ levels at week 36 and early withdrawal visit

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End point title

Immunogenicity: TCZ levels at week 36 and early withdrawal visit

End point description

End point type

Secondary

End point timeframe

Week 36 and early withdrawal visit

End point values	Phase 2 Arm A1: TCZ +/- nbDMARD once per week (qw)	Phase 2 Arm A2: TCZ +/- nbDMARD every two weeks (q2w)	Phase 2 Arm B: Participants With Low Disease Activity	Phase 2 Arm C: moderate EULAR response at Week 24	Phase 2 Arm D: Non responders
Number of subjects analysed	89	90	95	67	2
Units: mcg/ml
arithmetic mean (standard deviation)
Week 36 (n = 84, 86, 86, 55, 0)	48.47 ± 30.17	16.77 ± 16.1	41.89 ± 28.82	48.33 ± 25.79	11111 ± 11111
Early withdrawal visit (n = 2, 1, 4, 2, 1)	36.45 ± 18.03	19.2 ± 0	24.43 ± 20.83	13.75 ± 4.6	1.78 ± 0

No statistical analyses for this end point

Secondary: Immunogenicity: SIL-6R Levels up to Week 24

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End point title

Immunogenicity: SIL-6R Levels up to Week 24

End point description

Mean concentration of SIL-6R in patients' blood are reported. Analyses were conducted on the Full Analysis Set (FAS).

End point type

Secondary

End point timeframe

From baseline to Week 24

End point values	Phase 1: Tocilizumab Monotherapy	Phase 1: Combination therapy
Number of subjects analysed	74	327
Units: mcg/ml
arithmetic mean (standard deviation)
Baseline (n = 74, 321)	42.85 ± 16.26	39.29 ± 11.1
Week 12 (n = 69, 290)	566.47 ± 210.49	570.34 ± 228.54
Week 24 (n = 63, 279)	570.49 ± 198.26	565.34 ± 198.32

No statistical analyses for this end point

Secondary: Immunogenicity: SIL-6R Levels at Week 36 and Early Withdrawal Visit

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End point title

Immunogenicity: SIL-6R Levels at Week 36 and Early Withdrawal Visit

End point description

Mean concentration of SIL-6R in patients' blood are reported. Analyses were conducted on the Full Analysis Set (FAS). 00000 has been entered as this information is not applicable as the analysis was done for one participant only. 11111 indicates not applicable as n = 0.

End point type

Secondary

End point timeframe

Baseline, Week 36 and Early Withdrawal Visit

End point values	Phase 2 Arm A1: TCZ +/- nbDMARD once per week (qw)	Phase 2 Arm A2: TCZ +/- nbDMARD every two weeks (q2w)	Phase 2 Arm B: Participants With Low Disease Activity	Phase 2 Arm C: moderate EULAR response at Week 24	Phase 2 Arm D: Non responders
Number of subjects analysed	89	90	95	67	2
Units: mcg/ml
arithmetic mean (standard deviation)
Baseline (n = 88, 88, 94, 67, 2)	39.87 ± 10.46	39.7 ± 16.46	39.39 ± 11.24	43.11 ± 11.85	37.3 ± 11.46
Week 36 (n = 86, 89, 88, 59, 0)	539.89 ± 152.71	476.28 ± 156.5	542.99 ± 168.3	552.65 ± 184.21	11111 ± 11111
Early withdrawal visit (n = 3, 1, 6, 5, 1)	412.53 ± 323.49	643 ± 0	338.38 ± 230.82	217.74 ± 236.21	513 ± 0

No statistical analyses for this end point

Secondary: Patient Global Assessment of Disease activity visual analogue scale (VAS) up to Week 24

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End point title

Patient Global Assessment of Disease activity visual analogue scale (VAS) up to Week 24

End point description

This patient reported outcome assessment represents the patient’s overall assessment of their current disease activity on a 100 mm horizontal VAS. The extreme left end of the line should be described as “no disease activity” (symptom-free and no arthritis symptoms) and the extreme right end as “maximum disease activity” (maximum arthritis disease activity). The line was marked by the participant and the distance from the left edge was recorded and the mean values are reported. Analyses were conducted on the Full Analysis Set (FAS).

End point type

Secondary

End point timeframe

From baseline to Week 24

End point values	Phase 1: Tocilizumab Monotherapy	Phase 1: Combination therapy
Number of subjects analysed	74	327
Units: Millimeters
arithmetic mean (standard deviation)
Baseline (n = 74, 319)	65.26 ± 19.77	59.4 ± 17.61
Week 2 (n = 74, 319)	49.53 ± 22.78	44.16 ± 21.97
Week 4 (n = 73, 312)	38.21 ± 22.92	35.19 ± 20.83
Week 8 (n = 73, 300)	30.03 ± 21.65	26.04 ± 20.59
Week 12 (n = 70, 296)	22.71 ± 18.56	22.24 ± 17.97
Week 16 (n = 69, 291)	19.28 ± 18.22	20.71 ± 18.65
Week 20 (n = 65, 284)	16.8 ± 16.68	18.79 ± 17.79
Week 24 (n = 64, 281)	16.63 ± 15.19	19 ± 18.36
LOCF visit (n = 74, 327)	20.36 ± 19.25	22.23 ± 20.86

No statistical analyses for this end point

Secondary: Patient Global Assessment of Disease Activity Visual Analogue Scale (VAS) up to Week 48

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End point title

Patient Global Assessment of Disease Activity Visual Analogue Scale (VAS) up to Week 48

End point description

End point type

Secondary

End point timeframe

Baseline, from week 28 until week 48

End point values	Phase 2 Arm A1: TCZ +/- nbDMARD once per week (qw)	Phase 2 Arm A2: TCZ +/- nbDMARD every two weeks (q2w)
Number of subjects analysed	89	90
Units: Millimeters
arithmetic mean (standard deviation)
Baseline (n = 89, 90)	58.97 ± 17.4	60.96 ± 20.13
Week 28 (n = 88, 90)	11.97 ± 14.1	12.74 ± 15.07
Week 32 (n = 87, 90)	10.78 ± 15.33	10.8 ± 11.36
Week 36 (n = 86, 89)	11.99 ± 16.23	10.3 ± 13.2
Week 40 (n = 84, 88)	10.62 ± 13.49	10.94 ± 14.12
Week 44 (n = 82, 89)	9.5 ± 11.3	10.06 ± 12.14
Week 48 (n = 84, 89)	8.13 ± 10.52	9.99 ± 13.88
LOCF visit (n = 89, 90)	8.97 ± 11.63	10.21 ± 13.96

No statistical analyses for this end point

Secondary: Assessment of pain reported by the patient (VAS) until week 24

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End point title

Assessment of pain reported by the patient (VAS) until week 24

End point description

This patient reported outcome assessment represents the patient’s assessment of his/her current level of pain on a 100 mm horizontal VAS. The extreme left end of the line should be described as “no pain” and the extreme right end as “unbearable pain”. Analyses were conducted on the Full Analysis Set (FAS).

End point type

Secondary

End point timeframe

From baseline to Week 24

End point values	Phase 1: Tocilizumab Monotherapy	Phase 1: Combination therapy
Number of subjects analysed	74	327
Units: Millimeters
arithmetic mean (standard deviation)
Baseline (n = 74, 327)	66.38 ± 20.7	58.59 ± 23.7
Week 2 (n = 74, 319)	53.2 ± 24.43	47.46 ± 25.14
Week 4 (n = 73, 312)	43.11 ± 24.69	42.88 ± 24.57
Week 8 (n = 73, 300)	35.95 ± 24.62	34.28 ± 25.94
Week 12 (n = 70, 296)	29.44 ± 22.37	31.07 ± 24.97
Week 16 (n = 69, 292)	32.17 ± 22.01	30.18 ± 24
Week 20 (n = 65, 284)	26.58 ± 22.13	28.26 ± 24.16
Week 24 (n = 64, 281)	23.56 ± 21.17	26.43 ± 23.3
LOCF visit (n = 74, 327)	27.34 ± 24.41	29.78 ± 25.18

No statistical analyses for this end point

Secondary: Assessment of Pain Reported by the Patient (VAS) Until Week 48

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End point title

Assessment of Pain Reported by the Patient (VAS) Until Week 48

End point description

End point type

Secondary

End point timeframe

Baseline, from week 28 until week 48

End point values	Phase 2 Arm A1: TCZ +/- nbDMARD once per week (qw)	Phase 2 Arm A2: TCZ +/- nbDMARD every two weeks (q2w)
Number of subjects analysed	89	90
Units: Millimeters
arithmetic mean (standard deviation)
Baseline (n = 89, 90)	55.73 ± 21.68	56 ± 23.56
Week 28 (n = 88, 90)	17.33 ± 20.14	15.67 ± 17.65
Week 32 (n = 87, 90)	17.08 ± 20.47	17.27 ± 17.69
Week 36 (n = 86, 88)	18.81 ± 23.88	14.36 ± 15.65
Week 40 (n = 84, 88)	16.96 ± 20.89	17.07 ± 17.86
Week 44 (n = 82, 89)	15.05 ± 18.02	16.27 ± 17.7
Week 48 (n = 84, 89)	11.9 ± 15.56	16.31 ± 19.85
LOCF visit (n = 89, 90)	12.74 ± 15.99	16.41 ± 19.76

No statistical analyses for this end point

Secondary: Health Assessment Questionnaire-Disability Index (HAQ-DI) up to Week 24

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End point title

Health Assessment Questionnaire-Disability Index (HAQ-DI) up to Week 24

End point description

The Stanford HAQ-DI is a patient-oriented outcome assessment questionnaire specific for RA. It consists of 20 questions referring to eight component sets: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. To respond to each question, a four-level response (score of 0 to 3 points), with higher scores showing larger functional limitations, was chosen. Scoring was as follows with respect to performance of participant’s everyday activities: 0 (equals)=without difficulties; 1=with some difficulties; 2=with great difficulties; and 3=unable to perform these actions at all. Minimum score was 0, maximum score was 3. Analyses were conducted on the Full Analysis Set (FAS).

End point type

Secondary

End point timeframe

From baseline to Week 24

End point values	Phase 1: Tocilizumab Monotherapy	Phase 1: Combination therapy
Number of subjects analysed	74	327
Units: HAQ-DI score
arithmetic mean (standard deviation)
Baseline (n = 74, 324)	1.49 ± 0.76	1.36 ± 0.7
Week 2 (n = 73, 317)	1.39 ± 0.74	1.18 ± 0.69
Week 4 (n = 72, 309)	1.2 ± 0.74	1.05 ± 0.69
Week 8 (n = 73, 300)	1.1 ± 0.75	0.95 ± 0.71
Week 12 (n = 69, 295)	0.99 ± 0.74	0.91 ± 0.71
Week 16 (n = 69, 292)	0.99 ± 0.72	0.87 ± 0.7
Week 20 (n = 65, 283)	0.88 ± 0.7	0.83 ± 0.71
Week 24 (n = 63, 281)	0.85 ± 0.71	0.82 ± 0.7
LOCF visit (n = 74, 327)	0.97 ± 0.76	0.88 ± 0.73

No statistical analyses for this end point

Secondary: Health Assessment Questionnaire-Disability Index (HAQ-DI) up to Week 48

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End point title

Health Assessment Questionnaire-Disability Index (HAQ-DI) up to Week 48

End point description

End point type

Secondary

End point timeframe

Baseline, from week 28 until week 48

End point values	Phase 2 Arm A1: TCZ +/- nbDMARD once per week (qw)	Phase 2 Arm A2: TCZ +/- nbDMARD every two weeks (q2w)
Number of subjects analysed	89	90
Units: HAQ-DI score
arithmetic mean (standard deviation)
Baseline (n = 88, 89)	1.21 ± 0.68	1.2 ± 0.7
Week 28 (n = 88, 90)	0.58 ± 0.56	0.57 ± 0.64
Week 32 (n = 87, 90)	0.55 ± 0.58	0.57 ± 0.63
Week 36 (n = 86, 88)	0.6 ± 0.6	0.56 ± 0.64
Week 40 (n = 84, 88)	0.55 ± 0.56	0.61 ± 0.67
Week 44 (n = 82, 89)	0.53 ± 0.57	0.58 ± 0.66
Week 48 (n = 84, 89)	0.53 ± 0.61	0.57 ± 0.66
LOCF visit (n = 89, 90)	0.55 ± 0.61	0.56 ± 0.66

No statistical analyses for this end point

Secondary: Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F) up to Week 24

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End point title

Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F) up to Week 24

End point description

The symptom-specific measure FACIT-F assesses chronic illness therapy with special emphasis on fatigue in the past 7 days and consists of 5 dimensions: 1) physical well- being, 2) social/family well-being, 3) emotional well-being, 4) functional well-being, and 5) additional concerns. Each of the questions is categorically answered using the scales 0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, and 4=very much for a total possible FACIT-F score of 0 to 160. The figures are reversed during score calculations, so that higher score values indicate more favorable conditions. Analyses were conducted on the Full Analysis Set (FAS).

End point type

Secondary

End point timeframe

From baseline to Week 24

End point values	Phase 1: Tocilizumab Monotherapy	Phase 1: Combination therapy
Number of subjects analysed	74	327
Units: FACIT-F score
arithmetic mean (standard deviation)
Baseline (n = 74, 327)	81.72 ± 24.75	89.16 ± 24.49
Week 2 (n = 74, 319)	86.64 ± 25	95.82 ± 25.42
Week 4 (n = 73, 312)	92.26 ± 25.3	99.54 ± 27.15
Week 8 (n = 73, 300)	96.45 ± 25.88	103.46 ± 27.25
Week 12 (n = 70, 296)	98.29 ± 25.47	104.08 ± 26.79
Week 16 (n = 69, 292)	98.41 ± 27.08	105.51 ± 26.94
Week 20 (n = 65, 284)	102.46 ± 27.24	104.91 ± 27.47
Week 24 (n = 64, 281)	104.36 ± 27.16	107.01 ± 27.6
LOCF visit (n = 74, 327)	101.38 ± 28.24	104.65 ± 28.07

No statistical analyses for this end point

Secondary: Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F) up to Week 48

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End point title

Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F) up to Week 48

End point description

End point type

Secondary

End point timeframe

Baseline, from week 28 until week 48

End point values	Phase 2 Arm A1: TCZ +/- nbDMARD once per week (qw)	Phase 2 Arm A2: TCZ +/- nbDMARD every two weeks (q2w)
Number of subjects analysed	89	90
Units: FACIT-F score
arithmetic mean (standard deviation)
Baseline (n = 89, 90)	17.36 ± 5.16	17.13 ± 5.67
Week 28 (n = 88, 90)	23.5 ± 3.82	23.12 ± 4.47
Week 32 (n = 87, 90)	23.62 ± 4.16	22.98 ± 4.86
Week 36 (n = 86, 88)	23.23 ± 4.21	22.9 ± 4.64
Week 40 (n = 84, 88)	23.39 ± 4.4	23.02 ± 4.38
Week 44 (n = 82, 89)	23.48 ± 4.21	23.13 ± 4.45
Week 48 (n = 84, 89)	23.95 ± 3.79	22.87 ± 4.87
LOCF visit (n = 89, 90)	23.69 ± 4.07	22.88 ± 4.85

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure.

Adverse event reporting additional description

In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. In Non Serious Adverse events section data was calculated separately according to the two different phases of the study, i.e. Phase 1 mono-therapy and Phase 1 combination therapy groups, and the Phase 2 groups.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

18.1

Reporting group title

Phase 1: Tocilizumab Monotherapy

Reporting group description

Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection as a single fixed dose monotherapy once a week for 24 weeks.

Reporting group title

Phase 1: Combination therapy

Reporting group description

Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotraxate (MTX) or other non-biologic Diesase Modifying Anti Reumatic Drugs (nbDMARDs) once a week for 24 weeks.

Reporting group title

Phase 2 Arm A2: TCZ +/- nbDMARD every two weeks (q2w)

Reporting group description

Reporting group title

Phase 2 Arm A1: TCZ +/- nbDMARD once per week (qw)

Reporting group description

Reporting group title

Phase 2 Arm B: Participants With Low Disease Activity

Reporting group description

Reporting group title

Phase 2 Arm D: Non responders

Reporting group description

Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.

Reporting group title

Phase 2 Arm C: moderate EULAR response at Week 24

Reporting group description

Patients who achieved moderate EULAR response at Week 24 continued in the study with initial treatment as per investigator’s judgement.

Serious adverse events	Phase 1: Tocilizumab Monotherapy	Phase 1: Combination therapy	Phase 2 Arm A2: TCZ +/- nbDMARD every two weeks (q2w)	Phase 2 Arm A1: TCZ +/- nbDMARD once per week (qw)	Phase 2 Arm B: Participants With Low Disease Activity	Phase 2 Arm D: Non responders	Phase 2 Arm C: moderate EULAR response at Week 24
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 74 (4.05%)	10 / 327 (3.06%)	1 / 90 (1.11%)	2 / 89 (2.25%)	2 / 95 (2.11%)	1 / 2 (50.00%)	5 / 67 (7.46%)
number of deaths (all causes)	0	1	0	0	0	0	2
number of deaths resulting from adverse events	0	1	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastatic malignant melanoma
subjects affected / exposed	0 / 74 (0.00%)	0 / 327 (0.00%)	0 / 90 (0.00%)	1 / 89 (1.12%)	0 / 95 (0.00%)	0 / 2 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	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
Invasive ductal breast carcinoma
subjects affected / exposed	0 / 74 (0.00%)	1 / 327 (0.31%)	0 / 90 (0.00%)	0 / 89 (0.00%)	0 / 95 (0.00%)	0 / 2 (0.00%)	0 / 67 (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
Urinary tract neoplasm
subjects affected / exposed	0 / 74 (0.00%)	1 / 327 (0.31%)	0 / 90 (0.00%)	0 / 89 (0.00%)	0 / 95 (0.00%)	0 / 2 (0.00%)	0 / 67 (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
Injury, poisoning and procedural complications
Spinal fracture
subjects affected / exposed	0 / 74 (0.00%)	0 / 327 (0.00%)	0 / 90 (0.00%)	0 / 89 (0.00%)	0 / 95 (0.00%)	0 / 2 (0.00%)	1 / 67 (1.49%)
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
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	1 / 74 (1.35%)	0 / 327 (0.00%)	0 / 90 (0.00%)	0 / 89 (0.00%)	0 / 95 (0.00%)	0 / 2 (0.00%)	0 / 67 (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
Thrombophlebitis
subjects affected / exposed	0 / 74 (0.00%)	1 / 327 (0.31%)	0 / 90 (0.00%)	0 / 89 (0.00%)	0 / 95 (0.00%)	0 / 2 (0.00%)	0 / 67 (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
Hypertensive crisis
subjects affected / exposed	0 / 74 (0.00%)	0 / 327 (0.00%)	0 / 90 (0.00%)	0 / 89 (0.00%)	0 / 95 (0.00%)	0 / 2 (0.00%)	1 / 67 (1.49%)
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
Cardiac disorders
Pericarditis
subjects affected / exposed	1 / 74 (1.35%)	0 / 327 (0.00%)	0 / 90 (0.00%)	0 / 89 (0.00%)	0 / 95 (0.00%)	0 / 2 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	1 / 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
Acute coronary syndrome
subjects affected / exposed	0 / 74 (0.00%)	0 / 327 (0.00%)	0 / 90 (0.00%)	0 / 89 (0.00%)	1 / 95 (1.05%)	0 / 2 (0.00%)	0 / 67 (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
Coronary artery disease
subjects affected / exposed	0 / 74 (0.00%)	0 / 327 (0.00%)	0 / 90 (0.00%)	0 / 89 (0.00%)	0 / 95 (0.00%)	0 / 2 (0.00%)	1 / 67 (1.49%)
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 / 1
Myocardial infarction
subjects affected / exposed	0 / 74 (0.00%)	0 / 327 (0.00%)	0 / 90 (0.00%)	0 / 89 (0.00%)	0 / 95 (0.00%)	0 / 2 (0.00%)	1 / 67 (1.49%)
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 / 1
Nervous system disorders
Headache
subjects affected / exposed	1 / 74 (1.35%)	0 / 327 (0.00%)	0 / 90 (0.00%)	0 / 89 (0.00%)	0 / 95 (0.00%)	0 / 2 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	1 / 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
Blood and lymphatic system disorders
Neutropenia
subjects affected / exposed	0 / 74 (0.00%)	1 / 327 (0.31%)	0 / 90 (0.00%)	0 / 89 (0.00%)	0 / 95 (0.00%)	0 / 2 (0.00%)	0 / 67 (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
Gastrointestinal disorders
Duodenal perforation
subjects affected / exposed	0 / 74 (0.00%)	1 / 327 (0.31%)	0 / 90 (0.00%)	0 / 89 (0.00%)	0 / 95 (0.00%)	0 / 2 (0.00%)	0 / 67 (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
Intestinal obstruction
subjects affected / exposed	0 / 74 (0.00%)	1 / 327 (0.31%)	0 / 90 (0.00%)	0 / 89 (0.00%)	0 / 95 (0.00%)	0 / 2 (0.00%)	0 / 67 (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
Ascites
subjects affected / exposed	0 / 74 (0.00%)	0 / 327 (0.00%)	0 / 90 (0.00%)	0 / 89 (0.00%)	0 / 95 (0.00%)	1 / 2 (50.00%)	0 / 67 (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
Diverticular perforation
subjects affected / exposed	0 / 74 (0.00%)	0 / 327 (0.00%)	1 / 90 (1.11%)	0 / 89 (0.00%)	0 / 95 (0.00%)	0 / 2 (0.00%)	0 / 67 (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 / 74 (0.00%)	0 / 327 (0.00%)	0 / 90 (0.00%)	1 / 89 (1.12%)	0 / 95 (0.00%)	0 / 2 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	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
Hepatobiliary disorders
Biliary fistula
subjects affected / exposed	0 / 74 (0.00%)	1 / 327 (0.31%)	0 / 90 (0.00%)	0 / 89 (0.00%)	0 / 95 (0.00%)	0 / 2 (0.00%)	0 / 67 (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, thoracic and mediastinal disorders
Interstitial lung disease
subjects affected / exposed	0 / 74 (0.00%)	1 / 327 (0.31%)	0 / 90 (0.00%)	0 / 89 (0.00%)	0 / 95 (0.00%)	0 / 2 (0.00%)	0 / 67 (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 embolism
subjects affected / exposed	0 / 74 (0.00%)	2 / 327 (0.61%)	0 / 90 (0.00%)	0 / 89 (0.00%)	0 / 95 (0.00%)	0 / 2 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 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
Musculoskeletal and connective tissue disorders
Rheumatoid arthritis
subjects affected / exposed	0 / 74 (0.00%)	0 / 327 (0.00%)	0 / 90 (0.00%)	0 / 89 (0.00%)	0 / 95 (0.00%)	0 / 2 (0.00%)	1 / 67 (1.49%)
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
Back pain
subjects affected / exposed	0 / 74 (0.00%)	1 / 327 (0.31%)	0 / 90 (0.00%)	0 / 89 (0.00%)	0 / 95 (0.00%)	0 / 2 (0.00%)	0 / 67 (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
Breast abscess
subjects affected / exposed	0 / 74 (0.00%)	0 / 327 (0.00%)	0 / 90 (0.00%)	0 / 89 (0.00%)	1 / 95 (1.05%)	0 / 2 (0.00%)	0 / 67 (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
Abscess limb
subjects affected / exposed	0 / 74 (0.00%)	1 / 327 (0.31%)	0 / 90 (0.00%)	0 / 89 (0.00%)	0 / 95 (0.00%)	0 / 2 (0.00%)	0 / 67 (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
Pneumonia
subjects affected / exposed	0 / 74 (0.00%)	2 / 327 (0.61%)	0 / 90 (0.00%)	0 / 89 (0.00%)	0 / 95 (0.00%)	0 / 2 (0.00%)	0 / 67 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	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
Pyelonephritis acute
subjects affected / exposed	0 / 74 (0.00%)	1 / 327 (0.31%)	0 / 90 (0.00%)	0 / 89 (0.00%)	0 / 95 (0.00%)	0 / 2 (0.00%)	0 / 67 (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

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

Non-serious adverse events	Phase 1: Tocilizumab Monotherapy	Phase 1: Combination therapy	Phase 2 Arm A2: TCZ +/- nbDMARD every two weeks (q2w)	Phase 2 Arm A1: TCZ +/- nbDMARD once per week (qw)	Phase 2 Arm B: Participants With Low Disease Activity	Phase 2 Arm D: Non responders	Phase 2 Arm C: moderate EULAR response at Week 24
Total subjects affected by non serious adverse events
subjects affected / exposed	24 / 74 (32.43%)	119 / 327 (36.39%)	25 / 90 (27.78%)	17 / 89 (19.10%)	30 / 95 (31.58%)	0 / 2 (0.00%)	23 / 67 (34.33%)
Investigations
Transaminases increased
subjects affected / exposed	1 / 74 (1.35%)	37 / 327 (11.31%)	0 / 90 (0.00%)	0 / 89 (0.00%)	0 / 95 (0.00%)	0 / 2 (0.00%)	0 / 67 (0.00%)
occurrences all number	1	42	0	0	0	0	0
Vascular disorders
Hypertension
subjects affected / exposed	0 / 74 (0.00%)	0 / 327 (0.00%)	1 / 90 (1.11%)	2 / 89 (2.25%)	5 / 95 (5.26%)	0 / 2 (0.00%)	1 / 67 (1.49%)
occurrences all number	0	0	1	2	5	0	1
Nervous system disorders
Headache
subjects affected / exposed	0 / 74 (0.00%)	0 / 327 (0.00%)	1 / 90 (1.11%)	2 / 89 (2.25%)	0 / 95 (0.00%)	0 / 2 (0.00%)	4 / 67 (5.97%)
occurrences all number	0	0	1	2	0	0	5
Blood and lymphatic system disorders
Neutropenia
subjects affected / exposed	4 / 74 (5.41%)	18 / 327 (5.50%)	5 / 90 (5.56%)	1 / 89 (1.12%)	3 / 95 (3.16%)	0 / 2 (0.00%)	2 / 67 (2.99%)
occurrences all number	4	22	5	1	6	0	2
Thrombocytopenia
subjects affected / exposed	4 / 74 (5.41%)	9 / 327 (2.75%)	0 / 90 (0.00%)	0 / 89 (0.00%)	0 / 95 (0.00%)	0 / 2 (0.00%)	0 / 67 (0.00%)
occurrences all number	4	9	0	0	0	0	0
General disorders and administration site conditions
Injection site erythema
subjects affected / exposed	6 / 74 (8.11%)	10 / 327 (3.06%)	0 / 90 (0.00%)	0 / 89 (0.00%)	0 / 95 (0.00%)	0 / 2 (0.00%)	0 / 67 (0.00%)
occurrences all number	7	12	0	0	0	0	0
Oedema peripheral
subjects affected / exposed	0 / 74 (0.00%)	0 / 327 (0.00%)	1 / 90 (1.11%)	0 / 89 (0.00%)	3 / 95 (3.16%)	0 / 2 (0.00%)	4 / 67 (5.97%)
occurrences all number	0	0	1	0	3	0	4
Gastrointestinal disorders
Nausea
subjects affected / exposed	1 / 74 (1.35%)	18 / 327 (5.50%)	0 / 90 (0.00%)	0 / 89 (0.00%)	0 / 95 (0.00%)	0 / 2 (0.00%)	0 / 67 (0.00%)
occurrences all number	1	21	0	0	0	0	0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	4 / 74 (5.41%)	15 / 327 (4.59%)	0 / 90 (0.00%)	0 / 89 (0.00%)	0 / 95 (0.00%)	0 / 2 (0.00%)	0 / 67 (0.00%)
occurrences all number	4	16	0	0	0	0	0
Rheumatoid arthritis
subjects affected / exposed	0 / 74 (0.00%)	0 / 327 (0.00%)	3 / 90 (3.33%)	2 / 89 (2.25%)	6 / 95 (6.32%)	0 / 2 (0.00%)	3 / 67 (4.48%)
occurrences all number	0	0	3	2	6	0	3
Infections and infestations
Upper respiratory tract infection
subjects affected / exposed	2 / 74 (2.70%)	23 / 327 (7.03%)	7 / 90 (7.78%)	9 / 89 (10.11%)	3 / 95 (3.16%)	0 / 2 (0.00%)	4 / 67 (5.97%)
occurrences all number	2	24	9	10	4	0	5
Urinary tract infection
subjects affected / exposed	6 / 74 (8.11%)	23 / 327 (7.03%)	2 / 90 (2.22%)	3 / 89 (3.37%)	8 / 95 (8.42%)	0 / 2 (0.00%)	3 / 67 (4.48%)
occurrences all number	8	29	3	4	9	0	3
Nasopharyngitis
subjects affected / exposed	0 / 74 (0.00%)	0 / 327 (0.00%)	4 / 90 (4.44%)	2 / 89 (2.25%)	5 / 95 (5.26%)	0 / 2 (0.00%)	4 / 67 (5.97%)
occurrences all number	0	0	4	2	5	0	4
Respiratory tract infection
subjects affected / exposed	0 / 74 (0.00%)	0 / 327 (0.00%)	3 / 90 (3.33%)	2 / 89 (2.25%)	5 / 95 (5.26%)	0 / 2 (0.00%)	3 / 67 (4.48%)
occurrences all number	0	0	3	2	5	0	3

More information

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Were there any global substantial amendments to the protocol? Yes

22 Jan 2014

The purpose of the protocol amendment was to add a description of post-trial access to subcutaneous Tocilizumab (SC TCZ), to clarify that only 1 DMARD was allowed in combination with SC TCZ at the beginning of the study, to clarify that follow-up visits 4 and 8 weeks after the end of treatment was only done after study visit Week 48 and not after early withdrawal visit. The protocol was amended to explain how SC TCZ dose reduction would be done in case it was required. There was an addition of a pregnant partner release form.

22 Feb 2016

The purpose of the protocol amendment was to change the requirement for post-study adverse events reporting. There was also a change in the Country Study Manager.

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

Clinical Trial Results: A Phase IIIb Study to Evaluate the Efficacy, Safety and Tolerability of Subcutaneous (SC) Tocilizumab (TCZ) Given as Monotherapy or in Combination With Methotrexate (MTX) or Other Non Biologics DMARDs in Subjects With Rheumatoid Arthritis

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Participants Achieving Sustained Clinical Remission, Disease Activity Scale 28 - Erythrocyte Sedimentation Rate <2.6 (DAS28-ESR <2.6) at Week 20 and Week 24

Primary: Percentage of Participants Achieving Sustained Clinical Remission, Disease Activity Scale 28 - Erythrocyte Sedimentation Rate <2.6 (DAS28-ESR <2.6) at Week 20 and Week 24

Secondary: Mean change in Disease Activity Score 28 - erythrocyte sedimentation rate (DAS28-ESR)

Secondary: Mean change in Disease Activity Score 28 - erythrocyte sedimentation rate (DAS28-ESR)

Secondary: Percentage of patients allocated in Groups A1 and A2 who remain with clinical remission activity (DAS 28 ESR <2.6) up to Week 48

Secondary: Percentage of patients allocated in Groups A1 and A2 who remain with clinical remission activity (DAS 28 ESR <2.6) up to Week 48

Secondary: Percentage of patients reporting change in DAS 28 ESR >1.2 until week 48

Secondary: Percentage of patients reporting change in DAS 28 ESR >1.2 until week 48

Secondary: Percentage of patients with American College of Rheumatology (ACR20, 50, 70, 90) response scores until week 24

Secondary: Percentage of patients with American College of Rheumatology (ACR20, 50, 70, 90) response scores until week 24

Secondary: Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 48

Secondary: Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 48

Secondary: Number of patients with good and moderate clinical response according to European League Against Rheumatism (EULAR) response scores up to week 24

Secondary: Number of patients with good and moderate clinical response according to European League Against Rheumatism (EULAR) response scores up to week 24

Secondary: Number of Patients With Clinical Response According to European League Against Rheumatism (EULAR) Response Scores up to Week 48

Secondary: Number of Patients With Clinical Response According to European League Against Rheumatism (EULAR) Response Scores up to Week 48

Secondary: Mean change in Clinical Disease Activity Index (CDAI) from baseline up to week 24

Secondary: Mean change in Clinical Disease Activity Index (CDAI) from baseline up to week 24

Secondary: Mean change from baseline in Clinical Disease Activity Index (CDAI) up to Week 48

Secondary: Mean change from baseline in Clinical Disease Activity Index (CDAI) up to Week 48

Secondary: Mean change in Simplified Disease Activity Index (SDAI) from baseline up to week 24

Secondary: Mean change in Simplified Disease Activity Index (SDAI) from baseline up to week 24

Secondary: Mean Change in Simplified Disease Activity Index (SDAI) From Week 24 up to Week 48

Secondary: Mean Change in Simplified Disease Activity Index (SDAI) From Week 24 up to Week 48

Secondary: Mean change from baseline in total Tender Joint Counts (TJC) until week 24

Secondary: Mean change from baseline in total Tender Joint Counts (TJC) until week 24

Secondary: Mean Change From Baseline in Total Tender Joint Counts (TJC) Until Week 48

Secondary: Mean Change From Baseline in Total Tender Joint Counts (TJC) Until Week 48

Secondary: Mean Change in total Swollen Joint Counts (SJC) from baseline Until Week 24

Secondary: Mean Change in total Swollen Joint Counts (SJC) from baseline Until Week 24

Secondary: Mean Change in Total Swollen Joint Counts (SJC) From Baseline Until Week 48

Secondary: Mean Change in Total Swollen Joint Counts (SJC) From Baseline Until Week 48

Secondary: Percentages of patients who achieve DAS28-ESR remission (DAS28 < 2.6) up to Week 48

Secondary: Percentages of patients who achieve DAS28-ESR remission (DAS28 < 2.6) up to Week 48

Secondary: Percentages of patients with remission (CDAI<2.8) until week 24

Secondary: Percentages of patients with remission (CDAI<2.8) until week 24

Secondary: Percentages of Patients With Remission (CDAI<2.8) Until Week 48

Secondary: Percentages of Patients With Remission (CDAI<2.8) Until Week 48

Secondary: Percentages of Patients With Remission (SDAI<3.3) Until Week 24

Secondary: Percentages of Patients With Remission (SDAI<3.3) Until Week 24

Secondary: Percentages of Patients With Remission (SDAI<3.3) Until Week 48

Secondary: Percentages of Patients With Remission (SDAI<3.3) Until Week 48

Secondary: Percentage of patients who achieve low disease activity based on DAS28-ESR criteria (DAS28-ESR </=3.2) up to week 24

Secondary: Percentage of patients who achieve low disease activity based on DAS28-ESR criteria (DAS28-ESR </=3.2) up to week 24

Secondary: Percentage of Patients Who Achieve Low Disease Activity Based on DAS28-ESR Criteria (DAS28-ESR </=3.2) up to Week 48

Secondary: Percentage of Patients Who Achieve Low Disease Activity Based on DAS28-ESR Criteria (DAS28-ESR </=3.2) up to Week 48

Secondary: Percentage of Patients Who Achieve Low Disease Activity Based on CDAI score (CDAI<10) until week 24

Secondary: Percentage of Patients Who Achieve Low Disease Activity Based on CDAI score (CDAI<10) until week 24

Secondary: Percentage of Patients Who Achieve Low Disease Activity Based on CDAI Score (CDAI<10) Until Week 48

Secondary: Percentage of Patients Who Achieve Low Disease Activity Based on CDAI Score (CDAI<10) Until Week 48

Secondary: Percentage of patients who achieved low disease activity (LDA) based on SDAI score (SDAI<11) until week 24

Secondary: Percentage of patients who achieved low disease activity (LDA) based on SDAI score (SDAI<11) until week 24

Secondary: Percentage of patients who achieved low disease activity (LDA) based on SDAI score (SDAI<11) until week 48

Secondary: Percentage of patients who achieved low disease activity (LDA) based on SDAI score (SDAI<11) until week 48

Secondary: Safety: Number of patients reporting adverse events up to week 24

Secondary: Safety: Number of patients reporting adverse events up to week 24

Secondary: Safety: Number of Patients Reporting Adverse Events up to Week 48

Secondary: Safety: Number of Patients Reporting Adverse Events up to Week 48

Secondary: Immunogenicity: Number of patients with anti-tocilizumab antibodies up to week 24

Secondary: Immunogenicity: Number of patients with anti-tocilizumab antibodies up to week 24

Secondary: Immunogenicity: Number of Patients With Anti-tocilizumab Antibodies up to Week 48

Secondary: Immunogenicity: Number of Patients With Anti-tocilizumab Antibodies up to Week 48

Secondary: Immunogenicity: TCZ levels up to week 24

Secondary: Immunogenicity: TCZ levels up to week 24

Secondary: Immunogenicity: TCZ levels at week 36 and early withdrawal visit

Secondary: Immunogenicity: TCZ levels at week 36 and early withdrawal visit

Secondary: Immunogenicity: SIL-6R Levels up to Week 24

Secondary: Immunogenicity: SIL-6R Levels up to Week 24

Secondary: Immunogenicity: SIL-6R Levels at Week 36 and Early Withdrawal Visit

Secondary: Immunogenicity: SIL-6R Levels at Week 36 and Early Withdrawal Visit

Clinical Trial Results:
A Phase IIIb Study to Evaluate the Efficacy, Safety and Tolerability of Subcutaneous (SC) Tocilizumab (TCZ) Given as Monotherapy or in Combination With Methotrexate (MTX) or Other Non Biologics DMARDs in Subjects With Rheumatoid Arthritis