Trial Outcomes & Findings for A Study of RoActemra/Actemra (Tocilizumab) in Combination With Methotrexate in Patients With Severe Active Rheumatoid Arthritis, Comparing Tapering Versus Maintaining the Methotrexate Dosage (NCT NCT01661140)

Last Updated: 2016-10-14

Results Overview

Response was determined using EULAR criteria based upon (Disease Activity Score In 28 Joints) DAS28 absolute scores at the assessment visit and the DAS28 reduction from the reference visit. Participants with a score lesser than or equal to (\<=) 3.2 and reduction of greater than (\>) 1.2 points were assessed as having a 'good' response. Participants with a score \>3.2 with reduction of \>1.2 points, or a score \<=5.1 with reduction of \>0.6 to \<=1.2 points, were assessed as having a 'moderate' response. Participants with a score \>5.1 with reduction of \>0.6 to \<=1.2 points, or any score with reduction \<=0.6 points, were assessed as non-responders with response recorded as 'none.'

Recruitment status

TERMINATED

Study phase

PHASE4

Target enrollment

427 participants

Primary outcome timeframe

From randomization to Week 60

Results posted on

2016-10-14

Participant Flow

The initial open label period of the study consisted of one group of 427 participants. After completion of the initial phase only participants, who achieved a good/moderate disease response, were randomized into the double blind period. 272 participants were randomized into the two arms entering the double-blind period of the study.

Participant milestones

Participant milestones
Measure	Initial Phase At Week 0 participants started open-label tocilizumab and open-label methotrexate (MTX) for 24 weeks, which was the initial phase of the study.	Methotrexate (MTX) Tapering Group After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group participants received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, participants continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.	Methotrexate (MTX) Maintenance Group After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group participants continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, participants continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.
Open-Label Period STARTED	427	0	0
Open-Label Period COMPLETED	351	0	0
Open-Label Period NOT COMPLETED	76	0	0
Double-Blind Period STARTED	0	136	136
Double-Blind Period COMPLETED	0	95	86
Double-Blind Period NOT COMPLETED	0	41	50

Reasons for withdrawal

Reasons for withdrawal
Measure	Initial Phase At Week 0 participants started open-label tocilizumab and open-label methotrexate (MTX) for 24 weeks, which was the initial phase of the study.	Methotrexate (MTX) Tapering Group After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group participants received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, participants continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.	Methotrexate (MTX) Maintenance Group After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group participants continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, participants continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.
Open-Label Period Adverse Event	44	0	0
Open-Label Period Protocol Violation	3	0	0
Open-Label Period Withdrawal by Subject	5	0	0
Open-Label Period Investigator Decision	3	0	0
Open-Label Period Death	1	0	0
Open-Label Period Administrative/Other	1	0	0
Open-Label Period Sponsor termination	16	0	0
Open-Label Period Did not meet EULAR criteria	1	0	0
Open-Label Period Lost to Follow-up	2	0	0
Double-Blind Period Refused Treatment	0	0	1
Double-Blind Period Adverse Event	0	16	18
Double-Blind Period Protocol Violation	0	2	3
Double-Blind Period Withdrawal by Subject	0	1	3
Double-Blind Period Investigator's Decision	0	1	2
Double-Blind Period Sponsor Termination	0	14	17
Double-Blind Period Administrative/Other	0	7	6

Baseline Characteristics

A Study of RoActemra/Actemra (Tocilizumab) in Combination With Methotrexate in Patients With Severe Active Rheumatoid Arthritis, Comparing Tapering Versus Maintaining the Methotrexate Dosage

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Initial Phase n=427 Participants At Week 0 participants started open-label tocilizumab and open-label MTX for 24 weeks.
Age, Continuous	55.0 years STANDARD_DEVIATION 12.03 • n=93 Participants
Sex: Female, Male Female	326 Participants n=93 Participants
Sex: Female, Male Male	101 Participants n=93 Participants

PRIMARY outcome

Timeframe: From randomization to Week 60

Population: Intention to treat (ITT) population included all randomized participants.

Outcome measures

Outcome measures
Measure	Methotrexate (MTX) Tapering Group n=136 Participants After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group participants received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, participants continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.	Methotrexate (MTX) Maintenance Group n=136 Participants After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group participants continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, participants continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.
Percentage of Participants Maintaining Previous Disease Activity (European League Against Rheumatism [EULAR] Response) From Week 24 (Time of Randomization) to Week 60	76.5 percentage of participants	65.4 percentage of participants

SECONDARY outcome

Timeframe: Randomization (Week 24), Week 60

Population: ITT population included all randomized participants. Here, number of participants analyzed signifies those participants who were evaluable for this end point.

The DAS28 defined as a combined index for measuring disease activity in rheumatoid arthritis (RA). The index included swollen (range 0-28) and tender joint counts (TJC) (range 0-28), acute phase response Erythrocyte Sedimentation Rate (ESR), and general health status (range 1-100). The index was calculated using the following formula: The DAS28 was calculated as \[0.28 x the square root of number of swollen joints\] + \[0.56 x the square root of number of tender joints\] + \[0.7 x the natural log of ESR\] + \[0.014 x patient global assessment of disease activity\]. The DAS28 scale ranges from 0 to 10, where higher scores represent higher disease activity.

Outcome measures

Outcome measures
Measure	Methotrexate (MTX) Tapering Group n=136 Participants After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group participants received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, participants continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.	Methotrexate (MTX) Maintenance Group n=136 Participants After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group participants continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, participants continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.
Change From Baseline in Disease Activity Score In 28 Joints (DAS28) Score at Week 60 Change at Week 60 (n= 134, 135)	-0.179 units on a scale Standard Deviation 1.1702	-0.233 units on a scale Standard Deviation 1.5156
Change From Baseline in Disease Activity Score In 28 Joints (DAS28) Score at Week 60 Baseline (n= 135, 136)	2.572 units on a scale Standard Deviation 1.3218	2.573 units on a scale Standard Deviation 1.3017

SECONDARY outcome

Timeframe: Randomization (Week 24), Week 72

Population: ITT population included all randomized participants. Here, number of participants analyzed signifies those participants who were evaluable for this outcome measure.

Outcome measures

Outcome measures
Measure	Methotrexate (MTX) Tapering Group n=134 Participants After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group participants received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, participants continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.	Methotrexate (MTX) Maintenance Group n=135 Participants After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group participants continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, participants continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.
Change From Baseline in Disease Activity Score In 28 Joints (DAS28) Score at Week 72	-0.105 units on a scale Standard Deviation 1.2262	-0.224 units on a scale Standard Deviation 1.4961

SECONDARY outcome

Timeframe: Week 60, 72

Population: ITT population included all randomized participants.

Percentage of participants who achieve score of =1 in TJC and SJC at week 60 and 72 were reported. The number of swollen joints was recorded on the joint assessment form at each visit, no swelling = 0, swelling =1; total was calculated by adding all the joints for a maximum score of 28. The number of tender joints was recorded on the joint assessment form at each visit, no tenderness = 0, tenderness = 1; total was calculated by adding all the joints for a maximum score of 28.

Outcome measures

Outcome measures
Measure	Methotrexate (MTX) Tapering Group n=136 Participants After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group participants received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, participants continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.	Methotrexate (MTX) Maintenance Group n=136 Participants After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group participants continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, participants continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.
Percentage of Participants Who Achieve Score of <=1 in Tender Joint Count (TJC) and Swollen Joint Count (SJC) at Week 60 and 72 TJC <=1, Week 60	39.0 percentage of participants	39.0 percentage of participants
Percentage of Participants Who Achieve Score of <=1 in Tender Joint Count (TJC) and Swollen Joint Count (SJC) at Week 60 and 72 SJC <=1, Week 72	55.9 percentage of participants	60.3 percentage of participants
Percentage of Participants Who Achieve Score of <=1 in Tender Joint Count (TJC) and Swollen Joint Count (SJC) at Week 60 and 72 SJC <=1, Week 60	44.1 percentage of participants	58.1 percentage of participants
Percentage of Participants Who Achieve Score of <=1 in Tender Joint Count (TJC) and Swollen Joint Count (SJC) at Week 60 and 72 TJC <=1, Week 72	37.5 percentage of participants	40.4 percentage of participants

SECONDARY outcome

Timeframe: Week 60, 72

Population: ITT population included all randomized participants.

The DAS28 index was calculated using the following formula: The DAS28 was calculated as \[0.28 x the square root of number of swollen joints\] + \[0.56 x the square root of number of tender joints\] + \[0.7 x the natural log of ESR\] + \[0.014 x patient global assessment of disease activity\]. Participants who achieve score \<=3.2 at weeks 60 and 72 were reported.

Outcome measures

Outcome measures
Measure	Methotrexate (MTX) Tapering Group n=136 Participants After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group participants received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, participants continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.	Methotrexate (MTX) Maintenance Group n=136 Participants After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group participants continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, participants continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.
Percentage of Participants Who Achieve a Disease Activity Score In 28 Joints (DAS28) <= 3.2 Week 60	59.6 percentage of participants	62.5 percentage of participants
Percentage of Participants Who Achieve a Disease Activity Score In 28 Joints (DAS28) <= 3.2 Week 72	61.0 percentage of participants	60.3 percentage of participants

SECONDARY outcome

Timeframe: Week 60, 72

Population: ITT population included all randomized participants.

Outcome measures

Outcome measures
Measure	Methotrexate (MTX) Tapering Group n=136 Participants After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group participants received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, participants continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.	Methotrexate (MTX) Maintenance Group n=136 Participants After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group participants continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, participants continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.
Percentage of Participants Who Achieve DAS28 Remission (DAS28 < 2.6) Week 60	51.5 percentage of participants	47.1 percentage of participants
Percentage of Participants Who Achieve DAS28 Remission (DAS28 < 2.6) Week 72	50.0 percentage of participants	51.5 percentage of participants

SECONDARY outcome

Timeframe: Week 60, 72

Population: ITT population included all randomized participants.

Outcome measures

Outcome measures
Measure	Methotrexate (MTX) Tapering Group n=136 Participants After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group participants received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, participants continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.	Methotrexate (MTX) Maintenance Group n=136 Participants After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group participants continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, participants continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.
Percentage of Participants Who Achieve Change in Disease Activity Score (cDAS) >=1.2 Week 60	9.6 percentage of participants	16.2 percentage of participants
Percentage of Participants Who Achieve Change in Disease Activity Score (cDAS) >=1.2 Week 72	9.6 percentage of participants	15.4 percentage of participants

SECONDARY outcome

Timeframe: Randomization (Week 24), Week 60, 72

Population: ITT population included all randomized participants.

Clinical Disease Activity Index (CDAI) was an index for measuring disease activity in RA. The index was calculated using the following formula: CDAI: SJC28 + TJC28 + patient global assessment of disease (PGA) 10 centimeter \[cm\] Visual Analog Scale \[VAS\] + physician global assessment of disease (PhGA) 10 cm VAS. VAS assessments involved a 10 cm horizontal scale from 'no disease activity' to 'maximum disease activity.' CDAI scores ranged from 0 to 76, with higher scores indicating increased disease activity.

Outcome measures

Outcome measures
Measure	Methotrexate (MTX) Tapering Group n=136 Participants After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group participants received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, participants continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.	Methotrexate (MTX) Maintenance Group n=136 Participants After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group participants continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, participants continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.
Percentage of Participants Who Achieve Clinical Disease Activity Index (CDAI) Remission (CDAI < 2.8) at Week 60 and 72 Week 60	2.9 percentage of participants	1.5 percentage of participants
Percentage of Participants Who Achieve Clinical Disease Activity Index (CDAI) Remission (CDAI < 2.8) at Week 60 and 72 Week 72	1.5 percentage of participants	3.7 percentage of participants

SECONDARY outcome

Timeframe: Randomization (Week 24), Week 60, 72

Population: ITT population included all randomized participants.

Simplified Disease Activity Index (SDAI) was an index for measuring disease activity in RA. The index was calculated using the following formula: CDAI: SJC28 + TJC28 + PGA (10 cm VAS) + PhGA (10 cm VAS + C-Reactive Protein (CRP). VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity. Scores ranged from 0 to 86, with higher scores also indicating increased disease activity.

Outcome measures

Outcome measures
Measure	Methotrexate (MTX) Tapering Group n=136 Participants After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group participants received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, participants continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.	Methotrexate (MTX) Maintenance Group n=136 Participants After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group participants continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, participants continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.
Percentage of Participants Who Achieve Simplified Disease Activity Index (SDAI) Remission (SDAI < 3.3) at Week 60 and 72 Week 60	2.9 percentage of participants	0.7 percentage of participants
Percentage of Participants Who Achieve Simplified Disease Activity Index (SDAI) Remission (SDAI < 3.3) at Week 60 and 72 Week 72	2.9 percentage of participants	0.7 percentage of participants

SECONDARY outcome

Timeframe: Randomization (Week 24), Week 60, 72

Population: ITT population included all randomized participants.

The HAQ-disability index (DI) evaluates participant-reported quality of life using 8 categories: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and other common activities such as running errands and performing household chores and 20 questions. Each category contains multiple questions, which were answered using a 4-point scale from 0 to 3. The overall index score was an average of the individual item responses and may range from 0 to 3, where higher scores indicate more difficulty in daily living activities. Improvement was defined as a decrease from Week 24 to Week 60 and 72. Reported is the percentage of participants with an improvement in HAQ-DI score.

Outcome measures

Outcome measures
Measure	Methotrexate (MTX) Tapering Group n=136 Participants After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group participants received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, participants continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.	Methotrexate (MTX) Maintenance Group n=136 Participants After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group participants continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, participants continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.
Percentage of Participants With Improvement in Physical Function Using Health Assessment Questionnaire [HAQ] at Week 60 and 72 Improvement at Week 60	27.0 percentage of participants	39.6 percentage of participants
Percentage of Participants With Improvement in Physical Function Using Health Assessment Questionnaire [HAQ] at Week 60 and 72 Improvement at Week 72	40.5 percentage of participants	50.0 percentage of participants

SECONDARY outcome

Timeframe: Randomization (Week 24), Week 60, 72

Population: ITT population included all randomized participants.

The FACIT-fatigue assessment was a 13-item questionnaire with participants scoring each item on a 5-point scale (not at all; a little bit; somewhat; quite a bit and very much). The total score ranges from 0 to 65 and higher scores indicate more fatigue. Improvement was defined as a decrease from Week 24 to Week 60 and 72. Reported is the percentage of subjects with an improvement in total FACIT score.

Outcome measures

Outcome measures
Measure	Methotrexate (MTX) Tapering Group n=136 Participants After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group participants received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, participants continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.	Methotrexate (MTX) Maintenance Group n=136 Participants After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group participants continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, participants continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.
Percentage of Participants With Improvement in Physical Function Using Functional Assessment of Chronic Illness Therapy - Fatigue [FACIT-F] at Week 60 and 72 Improvement at Week 60	54.0 percentage of participants	50.0 percentage of participants
Percentage of Participants With Improvement in Physical Function Using Functional Assessment of Chronic Illness Therapy - Fatigue [FACIT-F] at Week 60 and 72 Improvement at Week 72	45.2 percentage of participants	56.3 percentage of participants

SECONDARY outcome

Timeframe: Randomization (Week 24), Week 60, 72

Population: ITT population included all randomized participants.

Quality of life questionnaire (SF-12) scores were computed using the scores of 12 questions and ranged from 0 to 100, where a 0 score indicated the lowest level of health measured by the scales and 100 indicated the highest level of health. Improvement was defined as a decrease from Week 24 to Week 60 and 72. Reported is the percentage of subjects with an improvement in SF-12 score.

Outcome measures

Outcome measures
Measure	Methotrexate (MTX) Tapering Group n=136 Participants After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group participants received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, participants continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.	Methotrexate (MTX) Maintenance Group n=136 Participants After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group participants continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, participants continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.
Percentage of Participants With Improvement in Physical Function Using 12-item Short Form Health Survey [SF-12]) at Week 60 and 72 Improvement at Week 60	22.2 percentage of participants	10.4 percentage of participants
Percentage of Participants With Improvement in Physical Function Using 12-item Short Form Health Survey [SF-12]) at Week 60 and 72 Improvement at Week 72	23.8 percentage of participants	15.6 percentage of participants

SECONDARY outcome

Timeframe: Week 0 up to Week 72

Population: Safety population included all the randomized participants.

Outcome measures

Outcome measures
Measure	Methotrexate (MTX) Tapering Group n=136 Participants After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group participants received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, participants continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.	Methotrexate (MTX) Maintenance Group n=136 Participants After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group participants continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, participants continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.
Percentage of Participants With Anemia	1.5 percentage of participants	0.7 percentage of participants

SECONDARY outcome

Timeframe: Week 0 up to Week 72

Population: Safety population included all the randomized participants.

An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE was any adverse event that can be fatal, life threatening, requires long or prolong hospitalization, results in persistent or significant disability/incapacity, congenital anomaly or significant medical event in the investigator's judgment.

Outcome measures

Outcome measures
Measure	Methotrexate (MTX) Tapering Group n=136 Participants After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group participants received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, participants continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.	Methotrexate (MTX) Maintenance Group n=136 Participants After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group participants continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, participants continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) AEs	98 participants	98 participants
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) SAEs	9 participants	3 participants

SECONDARY outcome

Timeframe: Week 0 up to Week 60

Population: Data were not collected for this outcome measure.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Randomization (Week 24), Week 60, 72

Population: ITT population included all randomized participants.

Outcome measures

Outcome measures
Measure	Methotrexate (MTX) Tapering Group n=136 Participants After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group participants received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, participants continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.	Methotrexate (MTX) Maintenance Group n=136 Participants After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group participants continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, participants continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.
Number of Subjects Employed Assessed Using the Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI-SHP) Week 60	33 participants	17 participants
Number of Subjects Employed Assessed Using the Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI-SHP) Week 72	23 participants	14 participants

SECONDARY outcome

Timeframe: Randomization (Week 24), Week 60, Week 72

Population: Participants in the ITT population with available data were analyzed.

The WPAI-SHP questionnaire assesses work productivity and activity impairment. It is a patient-reported assessment regarding hours missed and hours worked at employment and degree to which a specified health problem affected work productivity and regular activities. It consists of 6 questions to assess the impact of a specific health problem on work productivity and on regular daily activities. Reported here are hours actually worked, work hours missed due to rheumatoid arthritis (RA), work hours missed due to other reasons and the change from Week 24 for each of these parameters reported at Week 60 and Week 72.

Outcome measures

Outcome measures
Measure	Methotrexate (MTX) Tapering Group n=136 Participants After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group participants received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, participants continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.	Methotrexate (MTX) Maintenance Group n=136 Participants After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group participants continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, participants continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.
Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP Hours actually worked (HAW), Week 60 (n=33, 17)	25.0 hours Interval 0.0 to 58.0	28.0 hours Interval 0.0 to 40.0
Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP Change from Week 24 in HAW, Week 60 (n=29, 17)	-1.0 hours Interval -47.0 to 40.0	2.0 hours Interval -43.0 to 38.0
Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP Work hours missed (WHM) to RA, Week 60 (n=33, 17)	0.0 hours Interval 0.0 to 15.0	0.0 hours Interval 0.0 to 35.0
Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP Change from Week 24 in WHM RA, Week 60 (n=30, 16)	0.0 hours Interval -30.0 to 15.0	0.0 hours Interval -7.0 to 21.0
Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP WHM other, Week 60 (n=33, 17)	0.0 hours Interval 0.0 to 46.0	0.0 hours Interval 0.0 to 35.0
Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP Change from Week 24 WHM other, Week 60 (n=30, 16)	0.0 hours Interval -56.0 to 46.0	0.0 hours Interval -38.0 to 35.0
Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP HAW, Week 72 (n=23, 13)	30.0 hours Interval 0.0 to 48.0	16.0 hours Interval 0.0 to 40.0
Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP Change from Week 24 in HAW, Week 72, (n=20, 12)	0.0 hours Interval -37.0 to 23.0	2.5 hours Interval -30.0 to 40.0
Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP WHM to RA, Week 72 (n=23, 13)	0.0 hours Interval 0.0 to 37.0	0.0 hours Interval 0.0 to 35.0
Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP Change from Week 24 in WHM RA, Week 72 (n=21, 11)	0.0 hours Interval -30.0 to 37.0	0.0 hours Interval -7.0 to 21.0
Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP WHM other, Week 72 (n=23, 13)	0.0 hours Interval 0.0 to 30.0	0.0 hours Interval 0.0 to 8.0
Hours Actually Worked and Work Hours Missed Assessed Using the WPAI-SHP Change from Week 24 WHM other, Week 72 (n=21, 11)	0.0 hours Interval -56.0 to 30.0	0.0 hours Interval -38.0 to 2.0

SECONDARY outcome

Timeframe: Randomization (Week 24), Week 60, 72

Population: Participants in the ITT population with available data at the respective time points were analyzed.

The WPAI-SHP questionnaire assesses work productivity and activity impairment. It is a patient-reported assessment regarding hours missed and hours worked at employment and degree to which a specified health problem affected work productivity and regular activities. It consists of 6 questions to assess the impact of a specific health problem on work productivity and on regular daily activities. Assessments were made using a visual analogue scale ranging from 0 to 10 where 0 = minimum impact and 10 = maximum impact.

Outcome measures

Outcome measures
Measure	Methotrexate (MTX) Tapering Group n=136 Participants After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group participants received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, participants continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.	Methotrexate (MTX) Maintenance Group n=136 Participants After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group participants continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, participants continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy.
Change in Productivity and Regular Daily Activities Affected by Rheumatoid Arthritis Assessed Using the WPAI-SHP Productivity (P), Week 60 (n=34, 18)	2.0 units on a scale Interval 0.0 to 8.0	2.0 units on a scale Interval 0.0 to 10.0
Change in Productivity and Regular Daily Activities Affected by Rheumatoid Arthritis Assessed Using the WPAI-SHP Change in P from Week 24 at Week 60 (n=30, 16)	1.0 units on a scale Interval -6.0 to 8.0	0.0 units on a scale Interval -5.0 to 7.0
Change in Productivity and Regular Daily Activities Affected by Rheumatoid Arthritis Assessed Using the WPAI-SHP Regular Daily Activities (RDA), Week 60 (n=60, 45)	3.0 units on a scale Interval 0.0 to 9.0	3.0 units on a scale Interval 0.0 to 9.0
Change in Productivity and Regular Daily Activities Affected by Rheumatoid Arthritis Assessed Using the WPAI-SHP Change in RDA from Week 24 at Week 60 (n=59, 44)	0.0 units on a scale Interval -5.0 to 7.0	0.0 units on a scale Interval -6.0 to 6.0
Change in Productivity and Regular Daily Activities Affected by Rheumatoid Arthritis Assessed Using the WPAI-SHP Productivity (P), Week 72 (n=24, 12)	3.0 units on a scale Interval 0.0 to 8.0	3.0 units on a scale Interval 0.0 to 9.0
Change in Productivity and Regular Daily Activities Affected by Rheumatoid Arthritis Assessed Using the WPAI-SHP Change in P from Week 24 at Week 72 (n=21, 11)	0.0 units on a scale Interval -3.0 to 4.0	0.0 units on a scale Interval -5.0 to 7.0
Change in Productivity and Regular Daily Activities Affected by Rheumatoid Arthritis Assessed Using the WPAI-SHP Regular Daily Activities (RDA), Week 72 (n=42, 31)	3.0 units on a scale Interval 0.0 to 10.0	3.0 units on a scale Interval 0.0 to 9.0
Change in Productivity and Regular Daily Activities Affected by Rheumatoid Arthritis Assessed Using the WPAI-SHP Change in RDA from Week 24 at Week 72 (n=41, 29)	0.0 units on a scale Interval -5.0 to 4.0	-1.0 units on a scale Interval -5.0 to 7.0

Adverse Events

Initial Phase

Serious events: 21 serious events

Other events: 263 other events

Deaths: 0 deaths

Methotrexate (MTX) Tapering Group

Serious events: 9 serious events

Other events: 62 other events

Deaths: 0 deaths

Methotrexate (MTX) Maintenance Group

Serious events: 3 serious events

Other events: 70 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Communications

Hoffmann-La Roche

Phone: 800 821-8590

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER

Measure	Initial Phase n=427 participants at risk At Week 0 participants will start open-label tocilizumab and open-label MTX for 24 weeks, which is the initial phase of the study. Adverse events in this reporting group are those occurring in the open-label phase only.	Methotrexate (MTX) Tapering Group n=136 participants at risk After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group participants received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, participants continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy. Adverse events in this reporting group are those occurring in the double-blind phase only.	Methotrexate (MTX) Maintenance Group n=136 participants at risk After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group participants continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, participants continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy. Adverse events in this reporting group are those occurring in the double-blind phase only.
Infections and infestations Diverticulitis	0.00% 0/427 • From start of treatment to unscheduled visit (up to Week 72)	1.5% 2/136 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)
Infections and infestations Pneumonia	0.47% 2/427 • From start of treatment to unscheduled visit (up to Week 72)	1.5% 2/136 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)
Infections and infestations Abdominal Sepsis	0.00% 0/427 • From start of treatment to unscheduled visit (up to Week 72)	0.74% 1/136 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)
Infections and infestations Bursitis Infective	0.00% 0/427 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)	0.74% 1/136 • From start of treatment to unscheduled visit (up to Week 72)
Infections and infestations Lymph Node Tuberculosis	0.00% 0/427 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)	0.74% 1/136 • From start of treatment to unscheduled visit (up to Week 72)
Infections and infestations Necrotising Fasciitis	0.00% 0/427 • From start of treatment to unscheduled visit (up to Week 72)	0.74% 1/136 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)
General disorders Device Dislocation	0.00% 0/427 • From start of treatment to unscheduled visit (up to Week 72)	0.74% 1/136 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)
Injury, poisoning and procedural complications Ankle Fracture	0.00% 0/427 • From start of treatment to unscheduled visit (up to Week 72)	0.74% 1/136 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)
Injury, poisoning and procedural complications Joint Dislocation	0.00% 0/427 • From start of treatment to unscheduled visit (up to Week 72)	0.74% 1/136 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)
Musculoskeletal and connective tissue disorders Back Pain	0.00% 0/427 • From start of treatment to unscheduled visit (up to Week 72)	0.74% 1/136 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon Neoplasm	0.00% 0/427 • From start of treatment to unscheduled visit (up to Week 72)	0.74% 1/136 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)
Skin and subcutaneous tissue disorders Telangiectasia	0.00% 0/427 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)	0.74% 1/136 • From start of treatment to unscheduled visit (up to Week 72)
Infections and infestations Arthritis Infective	0.23% 1/427 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)
Infections and infestations Bronchitis	0.23% 1/427 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)
Infections and infestations Cellulitis	0.47% 2/427 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)
Infections and infestations Clostridium Difficile Infection	0.23% 1/427 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)
Infections and infestations Lower Respiratory Tract Infection	0.23% 1/427 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)
Infections and infestations Pneumocystis Jirovecii Pneumonia	0.23% 1/427 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)
Infections and infestations Pyelonephritis	0.23% 1/427 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)
Infections and infestations Tooth Infection	0.23% 1/427 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)
Infections and infestations Urinary Tract Infection	0.23% 1/427 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)
Infections and infestations Viral Labyrinthitis	0.23% 1/427 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)
General disorders Chest Pain	0.23% 1/427 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)
Injury, poisoning and procedural complications Fall	0.23% 1/427 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)
Injury, poisoning and procedural complications Multiple Fractures	0.23% 1/427 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)
Musculoskeletal and connective tissue disorders Arthralgia	0.23% 1/427 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)
Musculoskeletal and connective tissue disorders Costochondritis	0.23% 1/427 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)
Musculoskeletal and connective tissue disorders Pain In Extremity	0.23% 1/427 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Carcinoid Tumour Of The Gastrointestinal Tract	0.23% 1/427 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)
Gastrointestinal disorders Enterovesical Fistula	0.23% 1/427 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)
Gastrointestinal disorders Rectal Haemorrhage	0.23% 1/427 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)
Immune system disorders Hypersensitivity	0.47% 2/427 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)
Investigations Blood Bilirubin Increased	0.47% 2/427 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)
Nervous system disorders Carotid Artery Dissection	0.23% 1/427 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)
Nervous system disorders Migraine	0.23% 1/427 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.23% 1/427 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)
Respiratory, thoracic and mediastinal disorders Interstitial Lung Disease	0.47% 2/427 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)
Respiratory, thoracic and mediastinal disorders Pleurisy	0.23% 1/427 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)
Respiratory, thoracic and mediastinal disorders Pneumonitis	0.23% 1/427 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)
Respiratory, thoracic and mediastinal disorders Pulmonary Fibrosis	0.23% 1/427 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)
Respiratory, thoracic and mediastinal disorders Respiratory Failure	0.23% 1/427 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)	0.00% 0/136 • From start of treatment to unscheduled visit (up to Week 72)

Measure	Initial Phase n=427 participants at risk At Week 0 participants will start open-label tocilizumab and open-label MTX for 24 weeks, which is the initial phase of the study. Adverse events in this reporting group are those occurring in the open-label phase only.	Methotrexate (MTX) Tapering Group n=136 participants at risk After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Tapering Group participants received a double-blind MTX dose according to the MTX tapering scheme between Week 24 and Week 56. In addition, participants continued to receive open-label tocilizumab between Week 24 and Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy. Adverse events in this reporting group are those occurring in the double-blind phase only.	Methotrexate (MTX) Maintenance Group n=136 participants at risk After the open-label period ended at Week 24, participants achieving a good/moderate European League Against Rheumatism (EULAR) disease response were randomized to the MTX Tapering Group or MTX Maintenance Group. In the MTX Maintenance Group participants continued to be administered the same dose of MTX in a double-blind fashion from Week 25 to Week 56. In addition, participants continued to receive open-label tocilizumab from Week 25 to Week 56. From Week 56 to Week 72 participants received tocilizumab monotherapy. Adverse events in this reporting group are those occurring in the double-blind phase only.
Infections and infestations Nasopharyngitis	14.3% 61/427 • From start of treatment to unscheduled visit (up to Week 72)	11.8% 16/136 • From start of treatment to unscheduled visit (up to Week 72)	12.5% 17/136 • From start of treatment to unscheduled visit (up to Week 72)
Infections and infestations Lower Respiratory Tract Infection	9.6% 41/427 • From start of treatment to unscheduled visit (up to Week 72)	8.1% 11/136 • From start of treatment to unscheduled visit (up to Week 72)	8.8% 12/136 • From start of treatment to unscheduled visit (up to Week 72)
Infections and infestations Upper Respiratory Tract Infection	5.4% 23/427 • From start of treatment to unscheduled visit (up to Week 72)	8.8% 12/136 • From start of treatment to unscheduled visit (up to Week 72)	5.1% 7/136 • From start of treatment to unscheduled visit (up to Week 72)
Infections and infestations Urinary Tract Infection	4.4% 19/427 • From start of treatment to unscheduled visit (up to Week 72)	6.6% 9/136 • From start of treatment to unscheduled visit (up to Week 72)	4.4% 6/136 • From start of treatment to unscheduled visit (up to Week 72)
Gastrointestinal disorders Diarrhoea	12.6% 54/427 • From start of treatment to unscheduled visit (up to Week 72)	5.1% 7/136 • From start of treatment to unscheduled visit (up to Week 72)	8.1% 11/136 • From start of treatment to unscheduled visit (up to Week 72)
Gastrointestinal disorders Mouth Ulceration	11.2% 48/427 • From start of treatment to unscheduled visit (up to Week 72)	3.7% 5/136 • From start of treatment to unscheduled visit (up to Week 72)	6.6% 9/136 • From start of treatment to unscheduled visit (up to Week 72)
Gastrointestinal disorders Nausea	6.6% 28/427 • From start of treatment to unscheduled visit (up to Week 72)	3.7% 5/136 • From start of treatment to unscheduled visit (up to Week 72)	5.9% 8/136 • From start of treatment to unscheduled visit (up to Week 72)
Musculoskeletal and connective tissue disorders Arthralgia	3.7% 16/427 • From start of treatment to unscheduled visit (up to Week 72)	5.9% 8/136 • From start of treatment to unscheduled visit (up to Week 72)	6.6% 9/136 • From start of treatment to unscheduled visit (up to Week 72)
Musculoskeletal and connective tissue disorders Musculoskeletal Pain	3.0% 13/427 • From start of treatment to unscheduled visit (up to Week 72)	5.1% 7/136 • From start of treatment to unscheduled visit (up to Week 72)	4.4% 6/136 • From start of treatment to unscheduled visit (up to Week 72)
Musculoskeletal and connective tissue disorders Back Pain	3.7% 16/427 • From start of treatment to unscheduled visit (up to Week 72)	1.5% 2/136 • From start of treatment to unscheduled visit (up to Week 72)	5.1% 7/136 • From start of treatment to unscheduled visit (up to Week 72)
Respiratory, thoracic and mediastinal disorders Oropharyngeal Pain	5.4% 23/427 • From start of treatment to unscheduled visit (up to Week 72)	6.6% 9/136 • From start of treatment to unscheduled visit (up to Week 72)	5.9% 8/136 • From start of treatment to unscheduled visit (up to Week 72)
Respiratory, thoracic and mediastinal disorders Cough	6.8% 29/427 • From start of treatment to unscheduled visit (up to Week 72)	5.9% 8/136 • From start of treatment to unscheduled visit (up to Week 72)	4.4% 6/136 • From start of treatment to unscheduled visit (up to Week 72)
Injury, poisoning and procedural complications Contusion	3.7% 16/427 • From start of treatment to unscheduled visit (up to Week 72)	5.1% 7/136 • From start of treatment to unscheduled visit (up to Week 72)	4.4% 6/136 • From start of treatment to unscheduled visit (up to Week 72)
Injury, poisoning and procedural complications Fall	3.5% 15/427 • From start of treatment to unscheduled visit (up to Week 72)	5.9% 8/136 • From start of treatment to unscheduled visit (up to Week 72)	2.9% 4/136 • From start of treatment to unscheduled visit (up to Week 72)
Nervous system disorders Headache	8.9% 38/427 • From start of treatment to unscheduled visit (up to Week 72)	5.9% 8/136 • From start of treatment to unscheduled visit (up to Week 72)	4.4% 6/136 • From start of treatment to unscheduled visit (up to Week 72)
Investigations Alanine Aminotransferase Increased	11.9% 51/427 • From start of treatment to unscheduled visit (up to Week 72)	4.4% 6/136 • From start of treatment to unscheduled visit (up to Week 72)	5.1% 7/136 • From start of treatment to unscheduled visit (up to Week 72)
Skin and subcutaneous tissue disorders Rash	7.5% 32/427 • From start of treatment to unscheduled visit (up to Week 72)	2.2% 3/136 • From start of treatment to unscheduled visit (up to Week 72)	5.1% 7/136 • From start of treatment to unscheduled visit (up to Week 72)