Trial Outcomes & Findings for A Study of Subcutaneous RoActemra/Actemra (Tocilizumab) as Monotherapy or in Combination With Methotrexate or Other Non-Biologic DMARDs in Patients With Active Rheumatoid Arthritis (NCT NCT01995201)

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

401 participants

Primary outcome timeframe

Week 20 and Week 24

Results posted on

2018-01-26

Participant Flow

Participant milestones

Participant milestones
Measure	Phase 1: Tocilizumab Monotherapy Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection as a single fixed dose monotherapy once a week for 24 weeks.	Phase 1: Combination Therapy Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) 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.	Phase 2 Arm A2: TCZ +/- nbDMARD Every Two Weeks (q2w) 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.	Phase 2 Arm B: Participants With Low Disease Activity 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.	Phase 2 Arm C: Moderate EULAR Response at Week 24 Patients who achieved moderate EULAR response at Week 24 continued in the study with initial treatment as per investigator's judgement.	Phase 2 Arm D: Non Responders Non responders, safety population.
From Baseline Until Week 24 STARTED	74	327	0	0	0	0	0
From Baseline Until Week 24 COMPLETED	64	281	0	0	0	0	0
From Baseline Until Week 24 NOT COMPLETED	10	46	0	0	0	0	0
From Week 24 Until Week 48 STARTED	0	0	89	90	95	67	2
From Week 24 Until Week 48 COMPLETED	0	0	84	89	89	59	0
From Week 24 Until Week 48 NOT COMPLETED	0	0	5	1	6	8	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Phase 1: Tocilizumab Monotherapy Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection as a single fixed dose monotherapy once a week for 24 weeks.	Phase 1: Combination Therapy Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) 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.	Phase 2 Arm A2: TCZ +/- nbDMARD Every Two Weeks (q2w) 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.	Phase 2 Arm B: Participants With Low Disease Activity 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.	Phase 2 Arm C: Moderate EULAR Response at Week 24 Patients who achieved moderate EULAR response at Week 24 continued in the study with initial treatment as per investigator's judgement.	Phase 2 Arm D: Non Responders Non responders, safety population.
From Baseline Until Week 24 Adverse Event	4	15	0	0	0	0	0
From Baseline Until Week 24 Anaphylaxis or hypersensitivity reaction	0	3	0	0	0	0	0
From Baseline Until Week 24 Death	0	1	0	0	0	0	0
From Baseline Until Week 24 Lack of Efficacy	2	5	0	0	0	0	0
From Baseline Until Week 24 Lost to Follow-up	2	3	0	0	0	0	0
From Baseline Until Week 24 Withdrawal by Subject	2	8	0	0	0	0	0
From Baseline Until Week 24 Physician Decision	0	2	0	0	0	0	0
From Baseline Until Week 24 Protocol Violation	0	9	0	0	0	0	0
From Week 24 Until Week 48 Adverse Event	0	0	2	1	1	3	1
From Week 24 Until Week 48 Death	0	0	0	0	0	2	0
From Week 24 Until Week 48 Lack of Efficacy	0	0	1	0	0	2	1
From Week 24 Until Week 48 Lost to Follow-up	0	0	0	0	1	1	0
From Week 24 Until Week 48 Withdrawal by Subject	0	0	1	0	1	0	0
From Week 24 Until Week 48 Physician Decision	0	0	0	0	1	0	0
From Week 24 Until Week 48 Protocol Violation	0	0	1	0	2	0	0

Baseline Characteristics

A Study of Subcutaneous RoActemra/Actemra (Tocilizumab) as Monotherapy or in Combination With Methotrexate or Other Non-Biologic DMARDs in Patients With Active Rheumatoid Arthritis

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Phase 1: Tocilizumab Monotherapy n=74 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection as a single fixed dose monotherapy once a week for 24 weeks.	Phase 1: Combination Therapy n=327 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Total n=401 Participants Total of all reporting groups
Age, Continuous	53.5 years STANDARD_DEVIATION 12.7 • n=5 Participants	53.6 years STANDARD_DEVIATION 12.2 • n=7 Participants	53.6 years STANDARD_DEVIATION 12.3 • n=5 Participants
Sex: Female, Male Female	62 Participants n=5 Participants	264 Participants n=7 Participants	326 Participants n=5 Participants
Sex: Female, Male Male	12 Participants n=5 Participants	63 Participants n=7 Participants	75 Participants n=5 Participants

PRIMARY outcome

Timeframe: Week 20 and Week 24

Population: 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 TCZ.

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.

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=327 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=74 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w 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.	Phase 2 Arm A2 - Combination Therapy - q2w 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.	Phase 2 Arm D: Non Responders Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
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	52.9 Percentage of participants Interval 46.83 to 58.83	48.4 Percentage of participants Interval 35.75 to 61.27	—	—	—

SECONDARY outcome

Timeframe: From week 24 up to week 48

Population: Analysis was conducted on the FAS

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.

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=90 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=89 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w 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.	Phase 2 Arm A2 - Combination Therapy - q2w 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.	Phase 2 Arm D: Non Responders Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Mean Change in Disease Activity Score 28 - Erythrocyte Sedimentation Rate(DAS28-ESR) Week 24	-4.01 mm/hr Standard Deviation 1.13	-4.07 mm/hr Standard Deviation 1.03	—	—	—
Mean Change in Disease Activity Score 28 - Erythrocyte Sedimentation Rate(DAS28-ESR) Week 28	-3.78 mm/hr Standard Deviation 1.31	-3.94 mm/hr Standard Deviation 1.22	—	—	—
Mean Change in Disease Activity Score 28 - Erythrocyte Sedimentation Rate(DAS28-ESR) Week 32	-3.77 mm/hr Standard Deviation 1.17	-3.97 mm/hr Standard Deviation 1.38	—	—	—
Mean Change in Disease Activity Score 28 - Erythrocyte Sedimentation Rate(DAS28-ESR) Week 36	-3.90 mm/hr Standard Deviation 1.16	-3.82 mm/hr Standard Deviation 1.53	—	—	—
Mean Change in Disease Activity Score 28 - Erythrocyte Sedimentation Rate(DAS28-ESR) Week 40	-3.84 mm/hr Standard Deviation 1.19	-3.95 mm/hr Standard Deviation 1.26	—	—	—
Mean Change in Disease Activity Score 28 - Erythrocyte Sedimentation Rate(DAS28-ESR) Week 44	-3.76 mm/hr Standard Deviation 1.17	-4.05 mm/hr Standard Deviation 1.17	—	—	—
Mean Change in Disease Activity Score 28 - Erythrocyte Sedimentation Rate(DAS28-ESR) Week 48	-3.68 mm/hr Standard Deviation 1.32	-4.14 mm/hr Standard Deviation 1.24	—	—	—

SECONDARY outcome

Timeframe: From week 28 up to week 48

Population: Analysis was conducted on the FAS

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.

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=90 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=89 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w 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.	Phase 2 Arm A2 - Combination Therapy - q2w 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.	Phase 2 Arm D: Non Responders Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Percentage of Patients Allocated in Groups A1 and A2 Who Remain With Clinical Remission Activity (DAS 28 ESR <2.6) up to Week 48 Week 28	84.1 Percentage of participants Interval 74.75 to 91.02	88.5 Percentage of participants Interval 79.88 to 94.35	—	—	—
Percentage of Patients Allocated in Groups A1 and A2 Who Remain With Clinical Remission Activity (DAS 28 ESR <2.6) up to Week 48 Week 32	81.1 Percentage of participants Interval 71.49 to 88.59	87.2 Percentage of participants Interval 78.27 to 93.44	—	—	—
Percentage of Patients Allocated in Groups A1 and A2 Who Remain With Clinical Remission Activity (DAS 28 ESR <2.6) up to Week 48 Week 36	86.4 Percentage of participants Interval 77.39 to 92.75	80.2 Percentage of participants Interval 70.25 to 88.04	—	—	—
Percentage of Patients Allocated in Groups A1 and A2 Who Remain With Clinical Remission Activity (DAS 28 ESR <2.6) up to Week 48 Week 40	80.7 Percentage of participants Interval 70.88 to 88.32	82.1 Percentage of participants Interval 72.26 to 89.65	—	—	—
Percentage of Patients Allocated in Groups A1 and A2 Who Remain With Clinical Remission Activity (DAS 28 ESR <2.6) up to Week 48 Week 44	78.4 Percentage of participants Interval 68.35 to 86.47	89.0 Percentage of participants Interval 80.18 to 94.86	—	—	—
Percentage of Patients Allocated in Groups A1 and A2 Who Remain With Clinical Remission Activity (DAS 28 ESR <2.6) up to Week 48 Week 48	73.9 Percentage of participants Interval 63.41 to 82.66	91.5 Percentage of participants Interval 83.2 to 96.5	—	—	—

SECONDARY outcome

Timeframe: From week 28 up to week 48

Population: Analysis was conducted on the FAS

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.

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=90 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=89 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w 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.	Phase 2 Arm A2 - Combination Therapy - q2w 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.	Phase 2 Arm D: Non Responders Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Percentage of Patients Reporting Change in DAS 28 ESR >1.2 Until Week 48 Week 28	96.6 Percentage of participants Interval 90.36 to 99.29	96.6 Percentage of participants Interval 90.25 to 99.28	—	—	—
Percentage of Patients Reporting Change in DAS 28 ESR >1.2 Until Week 48 Week 32	95.6 Percentage of participants Interval 89.01 to 98.78	96.5 Percentage of participants Interval 90.14 to 99.27	—	—	—
Percentage of Patients Reporting Change in DAS 28 ESR >1.2 Until Week 48 Week 36	97.7 Percentage of participants Interval 92.03 to 99.72	93.0 Percentage of participants Interval 85.43 to 97.4	—	—	—
Percentage of Patients Reporting Change in DAS 28 ESR >1.2 Until Week 48 Week 40	98.9 Percentage of participants Interval 93.83 to 99.97	98.8 Percentage of participants Interval 93.54 to 99.97	—	—	—
Percentage of Patients Reporting Change in DAS 28 ESR >1.2 Until Week 48 Week 44	95.5 Percentage of participants Interval 88.77 to 98.75	98.8 Percentage of participants Interval 93.39 to 99.97	—	—	—
Percentage of Patients Reporting Change in DAS 28 ESR >1.2 Until Week 48 Week 48	95.5 Percentage of participants Interval 88.77 to 98.75	100.0 Percentage of participants NA because the central value is 100%	—	—	—

SECONDARY outcome

Timeframe: From week 2 until week 24

Population: Analysis was conducted on the FAS

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 \[ESR\]).

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=327 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=74 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w 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.	Phase 2 Arm A2 - Combination Therapy - q2w 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.	Phase 2 Arm D: Non Responders Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 24 ACR90 - week 16	12.0 Percentage of participants Interval 8.49 to 16.27	13.0 Percentage of participants Interval 6.14 to 23.32	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 24 ACR20 - Week 2	31.7 Percentage of participants Interval 26.59 to 37.08	27.0 Percentage of participants Interval 17.35 to 38.61	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 24 ACR20 - Week 4	49.7 Percentage of participants Interval 44.0 to 55.37	50.7 Percentage of participants Interval 38.72 to 62.6	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 24 ACR20 - Week 8	67.0 Percentage of participants Interval 61.36 to 72.3	67.1 Percentage of participants Interval 55.13 to 77.67	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 24 ACR20 - Week 12	74.7 Percentage of participants Interval 69.31 to 79.52	80.0 Percentage of participants Interval 68.73 to 88.61	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 24 ACR20 - Week 16	75.7 Percentage of participants Interval 70.35 to 80.49	79.7 Percentage of participants Interval 68.31 to 88.44	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 24 ACR20 - Week 20	81.0 Percentage of participants Interval 75.93 to 85.38	73.8 Percentage of participants Interval 61.46 to 83.97	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 24 ACR20 - Week 24	83.3 Percentage of participants Interval 78.39 to 87.44	79.7 Percentage of participants Interval 67.77 to 88.72	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 24 ACR20 - LOCF visit	79.0 Percentage of participants Interval 78.39 to 87.44	77.0 Percentage of participants Interval 67.77 to 88.72	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 24 ACR50 - week 2	13.2 Percentage of participants Interval 9.66 to 17.38	9.5 Percentage of participants Interval 3.89 to 18.52	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 24 ACR50 - week 4	25.3 Percentage of participants Interval 20.59 to 30.53	20.5 Percentage of participants Interval 11.98 to 31.62	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 24 ACR50 - week 8	41.3 Percentage of participants Interval 35.7 to 47.14	37.0 Percentage of participants Interval 25.97 to 49.09	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 24 ACR50 - week 12	52.7 Percentage of participants Interval 46.84 to 58.51	51.4 Percentage of participants Interval 39.17 to 63.56	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 24 ACR50 - week 16	52.4 Percentage of participants Interval 46.5 to 58.25	53.6 Percentage of participants Interval 41.2 to 65.72	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 24 ACR50 - week 20	58.5 Percentage of participants Interval 52.48 to 64.24	58.5 Percentage of participants Interval 45.56 to 70.56	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 24 ACR50 - week 24	58.7 Percentage of participants Interval 52.72 to 64.53	59.4 Percentage of participants Interval 46.37 to 71.49	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 24 ACR50 - LOCF visit	54.2 Percentage of participants Interval 52.72 to 64.53	55.4 Percentage of participants Interval 46.37 to 71.49	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 24 ACR70 - week 2	2.8 Percentage of participants Interval 1.3 to 5.29	5.4 Percentage of participants Interval 1.49 to 13.27	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 24 ACR70 - week 4	10.6 Percentage of participants Interval 7.39 to 14.53	12.3 Percentage of participants Interval 5.8 to 22.12	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 24 ACR70 - week 8	22.7 Percentage of participants Interval 18.05 to 27.83	17.8 Percentage of participants Interval 9.84 to 28.53	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 24 ACR70 - week 12	27.0 Percentage of participants Interval 22.05 to 32.47	32.9 Percentage of participants Interval 22.09 to 45.12	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 24 ACR70 - week 16	32.2 Percentage of participants Interval 26.87 to 37.88	29.0 Percentage of participants Interval 18.69 to 41.16	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 24 ACR70 - week 20	36.6 Percentage of participants Interval 31.01 to 42.52	33.8 Percentage of participants Interval 22.57 to 46.65	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 24 ACR70 - week 24	37.7 Percentage of participants Interval 32.03 to 43.67	40.6 Percentage of participants Interval 28.51 to 53.63	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 24 ACR70 - LOCF visit	33.9 Percentage of participants Interval 32.03 to 43.67	37.8 Percentage of participants Interval 28.51 to 53.63	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 24 ACR90 - week 2	0.9 Percentage of participants Interval 0.19 to 2.72	1.4 Percentage of participants Interval 0.03 to 7.3	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 24 ACR90 - week 4	1.6 Percentage of participants Interval 0.52 to 3.7	2.7 Percentage of participants Interval 0.33 to 9.55	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 24 ACR90 - week 8	7.3 Percentage of participants Interval 4.65 to 10.89	6.8 Percentage of participants Interval 2.26 to 15.26	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 24 ACR90 - week 12	8.8 Percentage of participants Interval 5.82 to 12.61	12.9 Percentage of participants Interval 6.05 to 23.01	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 24 ACR90 - week 20	13.7 Percentage of participants Interval 9.95 to 18.29	13.8 Percentage of participants Interval 6.53 to 24.66	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 24 ACR90 - week 24	16.7 Percentage of participants Interval 12.56 to 21.61	23.4 Percentage of participants Interval 13.75 to 35.69	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 24 ACR90 - LOCF visit	15.0 Percentage of participants Interval 12.56 to 21.61	20.3 Percentage of participants Interval 13.75 to 35.69	—	—	—

SECONDARY outcome

Timeframe: From week 28 until week 48

Population: Analysis was conducted on the FAS

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 \[ESR\]).

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=90 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=89 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w 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.	Phase 2 Arm A2 - Combination Therapy - q2w 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.	Phase 2 Arm D: Non Responders Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 48 ACR20 - Week 28	92.2 Percentage of participants Interval 84.63 to 96.82	90.0 Percentage of participants Interval 82.7 to 95.99	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 48 ACR20 - LOCF visit	87.8 Percentage of participants Interval 79.18 to 93.74	95.5 Percentage of participants Interval 88.89 to 98.76	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 48 ACR20 - Week 32	94.4 Percentage of participants Interval 87.51 to 98.17	93.1 Percentage of participants Interval 85.59 to 97.43	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 48 ACR20 - Week 36	91.0 Percentage of participants Interval 83.05 to 96.04	84.9 Percentage of participants Interval 75.54 to 91.7	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 48 ACR20 - Week 40	93.2 Percentage of participants Interval 85.75 to 97.46	88.1 Percentage of participants Interval 79.19 to 94.14	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 48 ACR20 - Week 44	91.0 Percentage of participants Interval 83.05 to 96.04	91.5 Percentage of participants Interval 83.2 to 96.5	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 48 ACR20 - Week 48	88.8 Percentage of participants Interval 80.31 to 94.48	96.4 Percentage of participants Interval 89.92 to 99.26	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 48 ACR50 - Week 28	81.1 Percentage of participants Interval 71.49 to 88.59	79.5 Percentage of participants Interval 69.61 to 87.4	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 48 ACR50 - Week 32	83.3 Percentage of participants Interval 74.0 to 90.36	85.1 Percentage of participants Interval 75.8 to 91.8	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 48 ACR50 - Week 36	83.1 Percentage of participants Interval 73.73 to 90.25	74.4 Percentage of participants Interval 63.87 to 83.22	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 48 ACR50 - Week 40	81.8 Percentage of participants Interval 72.16 to 89.24	79.8 Percentage of participants Interval 69.59 to 87.75	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 48 ACR50 - Week 44	78.7 Percentage of participants Interval 68.69 to 86.63	80.5 Percentage of participants Interval 70.26 to 88.42	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 48 ACR50 - Week 48	79.8 Percentage of participants Interval 69.93 to 87.55	88.1 Percentage of participants Interval 79.19 to 94.14	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 48 ACR50 - LOCF visit	78.9 Percentage of participants Interval 69.01 to 86.79	84.3 Percentage of participants Interval 75.02 to 91.12	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 48 ACR70 - Week 28	57.8 Percentage of participants Interval 46.91 to 68.12	59.1 Percentage of participants Interval 48.09 to 69.46	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 48 ACR70 - Week 32	54.4 Percentage of participants Interval 43.6 to 64.98	65.5 Percentage of participants Interval 54.56 to 75.39	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 48 ACR70 - Week 36	62.9 Percentage of participants Interval 52.03 to 72.93	61.6 Percentage of participants Interval 50.51 to 71.92	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 48 ACR70 - Week 40	59.1 Percentage of participants Interval 48.09 to 69.46	65.5 Percentage of participants Interval 54.31 to 75.52	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 48 ACR70 - Week 44	59.6 Percentage of participants Interval 48.62 to 69.83	67.1 Percentage of participants Interval 55.81 to 77.06	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 48 ACR70 - Week 48	65.2 Percentage of participants Interval 54.33 to 74.96	71.4 Percentage of participants Interval 60.53 to 80.76	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 48 ACR70 - LOCF visit	64.4 Percentage of participants Interval 53.65 to 74.26	68.5 Percentage of participants Interval 57.83 to 77.97	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 48 ACR90 - Week 28	32.2 Percentage of participants Interval 22.75 to 42.9	27.3 Percentage of participants Interval 18.32 to 37.81	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 48 ACR90 - Week 32	31.1 Percentage of participants Interval 21.77 to 41.74	35.6 Percentage of participants Interval 25.65 to 46.62	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 48 ACR90 - Week 36	30.3 Percentage of participants Interval 21.03 to 40.99	33.7 Percentage of participants Interval 23.88 to 44.72	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 48 ACR90 - Week 40	29.5 Percentage of participants Interval 20.29 to 40.22	41.7 Percentage of participants Interval 31.0 to 52.94	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 48 ACR90 - Week 44	27.0 Percentage of participants Interval 18.1 to 37.42	34.1 Percentage of participants Interval 24.03 to 45.45	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 48 ACR90 - Week 48	32.6 Percentage of participants Interval 23.02 to 43.34	45.2 Percentage of participants Interval 34.34 to 56.48	—	—	—
Percentage of Patients With American College of Rheumatology (ACR20, 50, 70, 90) Response Scores Until Week 48 ACR90 - LOCF visit	32.2 Percentage of participants Interval 22.75 to 42.9	42.7 Percentage of participants Interval 32.26 to 53.63	—	—	—

SECONDARY outcome

Timeframe: From week 2 until week 24

Population: Analysis was conducted on the FAS

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.

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=327 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=74 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w 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.	Phase 2 Arm A2 - Combination Therapy - q2w 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.	Phase 2 Arm D: Non Responders Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Number of Patients With Good and Moderate Clinical Response According to European League Against Rheumatism (EULAR) Response Scores up to Week 24 Good response - week 2	61 Number of participants	14 Number of participants	—	—	—
Number of Patients With Good and Moderate Clinical Response According to European League Against Rheumatism (EULAR) Response Scores up to Week 24 Moderate response - week 2	196 Number of participants	36 Number of participants	—	—	—
Number of Patients With Good and Moderate Clinical Response According to European League Against Rheumatism (EULAR) Response Scores up to Week 24 Good response - week 4	109 Number of participants	18 Number of participants	—	—	—
Number of Patients With Good and Moderate Clinical Response According to European League Against Rheumatism (EULAR) Response Scores up to Week 24 Moderate response - week 4	175 Number of participants	49 Number of participants	—	—	—
Number of Patients With Good and Moderate Clinical Response According to European League Against Rheumatism (EULAR) Response Scores up to Week 24 Good response - week 8	162 Number of participants	37 Number of participants	—	—	—
Number of Patients With Good and Moderate Clinical Response According to European League Against Rheumatism (EULAR) Response Scores up to Week 24 Moderate response - week 8	121 Number of participants	32 Number of participants	—	—	—
Number of Patients With Good and Moderate Clinical Response According to European League Against Rheumatism (EULAR) Response Scores up to Week 24 Good response - week 12	194 Number of participants	41 Number of participants	—	—	—
Number of Patients With Good and Moderate Clinical Response According to European League Against Rheumatism (EULAR) Response Scores up to Week 24 Moderate response - week 12	95 Number of participants	27 Number of participants	—	—	—
Number of Patients With Good and Moderate Clinical Response According to European League Against Rheumatism (EULAR) Response Scores up to Week 24 Good response - week 16	209 Number of participants	45 Number of participants	—	—	—
Number of Patients With Good and Moderate Clinical Response According to European League Against Rheumatism (EULAR) Response Scores up to Week 24 Moderate response - week 16	76 Number of participants	22 Number of participants	—	—	—
Number of Patients With Good and Moderate Clinical Response According to European League Against Rheumatism (EULAR) Response Scores up to Week 24 Good response - week 20	221 Number of participants	45 Number of participants	—	—	—
Number of Patients With Good and Moderate Clinical Response According to European League Against Rheumatism (EULAR) Response Scores up to Week 24 Moderate response - week 20	56 Number of participants	18 Number of participants	—	—	—
Number of Patients With Good and Moderate Clinical Response According to European League Against Rheumatism (EULAR) Response Scores up to Week 24 Good response - week 24	225 Number of participants	48 Number of participants	—	—	—
Number of Patients With Good and Moderate Clinical Response According to European League Against Rheumatism (EULAR) Response Scores up to Week 24 Moderate response - week 24	53 Number of participants	16 Number of participants	—	—	—
Number of Patients With Good and Moderate Clinical Response According to European League Against Rheumatism (EULAR) Response Scores up to Week 24 Good response - LOCF visit	247 Number of participants	54 Number of participants	—	—	—
Number of Patients With Good and Moderate Clinical Response According to European League Against Rheumatism (EULAR) Response Scores up to Week 24 Moderate response - LOCF visit	73 Number of participants	19 Number of participants	—	—	—

SECONDARY outcome

Timeframe: From week 28 until week 48

Population: Analysis was conducted on the FAS.

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.

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=90 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=89 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w 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.	Phase 2 Arm A2 - Combination Therapy - q2w 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.	Phase 2 Arm D: Non Responders Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Number of Patients With Clinical Response According to European League Against Rheumatism (EULAR) Response Scores up to Week 48 Good response - week 28	77 Number of participants	82 Number of participants	—	—	—
Number of Patients With Clinical Response According to European League Against Rheumatism (EULAR) Response Scores up to Week 48 Moderate response - week 28	10 Number of participants	5 Number of participants	—	—	—
Number of Patients With Clinical Response According to European League Against Rheumatism (EULAR) Response Scores up to Week 48 Good response - week 32	81 Number of participants	79 Number of participants	—	—	—
Number of Patients With Clinical Response According to European League Against Rheumatism (EULAR) Response Scores up to Week 48 Moderate response - week 32	9 Number of participants	6 Number of participants	—	—	—
Number of Patients With Clinical Response According to European League Against Rheumatism (EULAR) Response Scores up to Week 48 Good response - week 36	80 Number of participants	75 Number of participants	—	—	—
Number of Patients With Clinical Response According to European League Against Rheumatism (EULAR) Response Scores up to Week 48 Moderate response - week 36	8 Number of participants	9 Number of participants	—	—	—
Number of Patients With Clinical Response According to European League Against Rheumatism (EULAR) Response Scores up to Week 48 Good response - week 40	81 Number of participants	75 Number of participants	—	—	—
Number of Patients With Clinical Response According to European League Against Rheumatism (EULAR) Response Scores up to Week 48 Moderate response - week 40	7 Number of participants	9 Number of participants	—	—	—
Number of Patients With Clinical Response According to European League Against Rheumatism (EULAR) Response Scores up to Week 48 Good response - week 44	75 Number of participants	78 Number of participants	—	—	—
Number of Patients With Clinical Response According to European League Against Rheumatism (EULAR) Response Scores up to Week 48 Moderate response - week 44	13 Number of participants	4 Number of participants	—	—	—
Number of Patients With Clinical Response According to European League Against Rheumatism (EULAR) Response Scores up to Week 48 Good response - week 48	73 Number of participants	78 Number of participants	—	—	—
Number of Patients With Clinical Response According to European League Against Rheumatism (EULAR) Response Scores up to Week 48 Moderate response - week 48	15 Number of participants	4 Number of participants	—	—	—
Number of Patients With Clinical Response According to European League Against Rheumatism (EULAR) Response Scores up to Week 48 Good response - LOCF visit	74 Number of participants	84 Number of participants	—	—	—
Number of Patients With Clinical Response According to European League Against Rheumatism (EULAR) Response Scores up to Week 48 Moderate response - LOCF visit	16 Number of participants	5 Number of participants	—	—	—

SECONDARY outcome

Timeframe: From baseline to Week 24

Population: Analysis was conducted on the FAS.

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.

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=327 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=74 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w 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.	Phase 2 Arm A2 - Combination Therapy - q2w 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.	Phase 2 Arm D: Non Responders Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Mean Change in Clinical Disease Activity Index (CDAI) From Baseline up to Week 24 Baseline values	32.06 CDAI score Standard Deviation 12.28	33.06 CDAI score Standard Deviation 12.45	—	—	—
Mean Change in Clinical Disease Activity Index (CDAI) From Baseline up to Week 24 Week 2	-8.62 CDAI score Standard Deviation 9.22	-7.54 CDAI score Standard Deviation 9.57	—	—	—
Mean Change in Clinical Disease Activity Index (CDAI) From Baseline up to Week 24 Week 4	-13.23 CDAI score Standard Deviation 10.65	-13.03 CDAI score Standard Deviation 10.91	—	—	—
Mean Change in Clinical Disease Activity Index (CDAI) From Baseline up to Week 24 Week 8	-18.46 CDAI score Standard Deviation 11.61	-18.06 CDAI score Standard Deviation 11.05	—	—	—
Mean Change in Clinical Disease Activity Index (CDAI) From Baseline up to Week 24 Week 12	-20.60 CDAI score Standard Deviation 11.42	-21.56 CDAI score Standard Deviation 11.77	—	—	—
Mean Change in Clinical Disease Activity Index (CDAI) From Baseline up to Week 24 Week 16	-21.79 CDAI score Standard Deviation 11.57	-23.01 CDAI score Standard Deviation 12.33	—	—	—
Mean Change in Clinical Disease Activity Index (CDAI) From Baseline up to Week 24 Week 20	-22.88 CDAI score Standard Deviation 12.10	-24.07 CDAI score Standard Deviation 11.97	—	—	—
Mean Change in Clinical Disease Activity Index (CDAI) From Baseline up to Week 24 Week 24	-23.43 CDAI score Standard Deviation 11.62	-25.80 CDAI score Standard Deviation 13.31	—	—	—
Mean Change in Clinical Disease Activity Index (CDAI) From Baseline up to Week 24 LOCF visit	-21.58 CDAI score Standard Deviation 12.85	-24.42 CDAI score Standard Deviation 13.50	—	—	—

SECONDARY outcome

Timeframe: From week 24 until week 48

Population: Analysis was conducted on the FAS.

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.

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=90 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=89 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w 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.	Phase 2 Arm A2 - Combination Therapy - q2w 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.	Phase 2 Arm D: Non Responders Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Mean Change From Baseline in Clinical Disease Activity Index (CDAI) up to Week 48 Baseline values	29.64 CDAI score Standard Deviation 12.13	29.27 CDAI score Standard Deviation 10.90	—	—	—
Mean Change From Baseline in Clinical Disease Activity Index (CDAI) up to Week 48 Week 24	-25.34 CDAI score Standard Deviation 12.10	-25.54 CDAI score Standard Deviation 10.60	—	—	—
Mean Change From Baseline in Clinical Disease Activity Index (CDAI) up to Week 48 Week 28	-24.01 CDAI score Standard Deviation 12.30	-24.75 CDAI score Standard Deviation 10.64	—	—	—
Mean Change From Baseline in Clinical Disease Activity Index (CDAI) up to Week 48 Week 32	-25.12 CDAI score Standard Deviation 11.64	-24.56 CDAI score Standard Deviation 12.93	—	—	—
Mean Change From Baseline in Clinical Disease Activity Index (CDAI) up to Week 48 Week 36	-25.45 CDAI score Standard Deviation 11.42	-23.90 CDAI score Standard Deviation 11.56	—	—	—
Mean Change From Baseline in Clinical Disease Activity Index (CDAI) up to Week 48 Week 40	-25.45 CDAI score Standard Deviation 11.75	-25.16 CDAI score Standard Deviation 10.43	—	—	—
Mean Change From Baseline in Clinical Disease Activity Index (CDAI) up to Week 48 Week 44	-25.26 CDAI score Standard Deviation 11.75	-25.45 CDAI score Standard Deviation 10.11	—	—	—
Mean Change From Baseline in Clinical Disease Activity Index (CDAI) up to Week 48 Week 48	-25.13 CDAI score Standard Deviation 12.51	-26.44 CDAI score Standard Deviation 11.13	—	—	—
Mean Change From Baseline in Clinical Disease Activity Index (CDAI) up to Week 48 LOCF visit	-24.87 CDAI score Standard Deviation 12.67	-25.74 CDAI score Standard Deviation 11.29	—	—	—

SECONDARY outcome

Timeframe: From baseline to Week 24

Population: Analysis was conducted on the FAS

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.

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=327 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=74 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w 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.	Phase 2 Arm A2 - Combination Therapy - q2w 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.	Phase 2 Arm D: Non Responders Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Mean Change in Simplified Disease Activity Index (SDAI) From Baseline up to Week 24 Baseline values	44.40 SDAI score Standard Deviation 22.91	48.66 SDAI score Standard Deviation 31.48	—	—	—
Mean Change in Simplified Disease Activity Index (SDAI) From Baseline up to Week 24 Week 2	-19.50 SDAI score Standard Deviation 18.75	-20.45 SDAI score Standard Deviation 19.01	—	—	—
Mean Change in Simplified Disease Activity Index (SDAI) From Baseline up to Week 24 Week 4	-24.34 SDAI score Standard Deviation 20.98	-27.86 SDAI score Standard Deviation 23.54	—	—	—
Mean Change in Simplified Disease Activity Index (SDAI) From Baseline up to Week 24 Week 8	-29.34 SDAI score Standard Deviation 21.96	-32.61 SDAI score Standard Deviation 26.84	—	—	—
Mean Change in Simplified Disease Activity Index (SDAI) From Baseline up to Week 24 Week 12	-30.95 SDAI score Standard Deviation 23.58	-36.23 SDAI score Standard Deviation 27.04	—	—	—
Mean Change in Simplified Disease Activity Index (SDAI) From Baseline up to Week 24 Week 16	-32.66 SDAI score Standard Deviation 22.79	-37.82 SDAI score Standard Deviation 31.09	—	—	—
Mean Change in Simplified Disease Activity Index (SDAI) From Baseline up to Week 24 Week 20	-33.95 SDAI score Standard Deviation 23.05	-36.79 SDAI score Standard Deviation 25.47	—	—	—
Mean Change in Simplified Disease Activity Index (SDAI) From Baseline up to Week 24 Week 24	-34.80 SDAI score Standard Deviation 22.44	-41.38 SDAI score Standard Deviation 31.51	—	—	—
Mean Change in Simplified Disease Activity Index (SDAI) From Baseline up to Week 24 LOCF visit	-32.73 SDAI score Standard Deviation 22.84	-39.15 SDAI score Standard Deviation 30.45	—	—	—

SECONDARY outcome

Timeframe: From week 24 until week 48

Population: Analysis was conducted on the FAS

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.

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=90 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=89 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w 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.	Phase 2 Arm A2 - Combination Therapy - q2w 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.	Phase 2 Arm D: Non Responders Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Mean Change in Simplified Disease Activity Index (SDAI) From Week 24 up to Week 48 Baseline values	40.92 SDAI score Standard Deviation 21.42	41.45 SDAI score Standard Deviation 24.90	—	—	—
Mean Change in Simplified Disease Activity Index (SDAI) From Week 24 up to Week 48 Week 24	-35.88 SDAI score Standard Deviation 20.71	-37.02 SDAI score Standard Deviation 24.60	—	—	—
Mean Change in Simplified Disease Activity Index (SDAI) From Week 24 up to Week 48 Week 28	-34.50 SDAI score Standard Deviation 20.66	-35.15 SDAI score Standard Deviation 25.90	—	—	—
Mean Change in Simplified Disease Activity Index (SDAI) From Week 24 up to Week 48 Week 32	-34.88 SDAI score Standard Deviation 20.53	-35.60 SDAI score Standard Deviation 26.97	—	—	—
Mean Change in Simplified Disease Activity Index (SDAI) From Week 24 up to Week 48 Week 36	-35.35 SDAI score Standard Deviation 20.07	-35.29 SDAI score Standard Deviation 26.55	—	—	—
Mean Change in Simplified Disease Activity Index (SDAI) From Week 24 up to Week 48 Week 40	-35.70 SDAI score Standard Deviation 19.80	-37.26 SDAI score Standard Deviation 25.48	—	—	—
Mean Change in Simplified Disease Activity Index (SDAI) From Week 24 up to Week 48 Week 44	-35.06 SDAI score Standard Deviation 21.77	-37.09 SDAI score Standard Deviation 25.17	—	—	—
Mean Change in Simplified Disease Activity Index (SDAI) From Week 24 up to Week 48 Week 48	-35.02 SDAI score Standard Deviation 21.74	-37.93 SDAI score Standard Deviation 26.32	—	—	—
Mean Change in Simplified Disease Activity Index (SDAI) From Week 24 up to Week 48 LOCF visit	-34.69 SDAI score Standard Deviation 21.75	-36.93 SDAI score Standard Deviation 25.75	—	—	—

SECONDARY outcome

Timeframe: From baseline to Week 24

Population: Analysis was conducted on the FAS.

TCJ is a clinical assessment 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.

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=327 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=74 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w 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.	Phase 2 Arm A2 - Combination Therapy - q2w 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.	Phase 2 Arm D: Non Responders Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Mean Change From Baseline in Total Tender Joint Counts (TJC) Until Week 24 Baseline visit	19.12 TJC Standard Deviation 13.38	18.05 TJC Standard Deviation 12.98	—	—	—
Mean Change From Baseline in Total Tender Joint Counts (TJC) Until Week 24 Week 2	-5.00 TJC Standard Deviation 8.06	-4.31 TJC Standard Deviation 7.56	—	—	—
Mean Change From Baseline in Total Tender Joint Counts (TJC) Until Week 24 Week 4	-7.96 TJC Standard Deviation 9.43	-7.04 TJC Standard Deviation 11.77	—	—	—
Mean Change From Baseline in Total Tender Joint Counts (TJC) Until Week 24 Week 8	-10.90 TJC Standard Deviation 11.10	-9.81 TJC Standard Deviation 10.37	—	—	—
Mean Change From Baseline in Total Tender Joint Counts (TJC) Until Week 24 Week 12	-12.01 TJC Standard Deviation 10.88	-12.27 TJC Standard Deviation 10.47	—	—	—
Mean Change From Baseline in Total Tender Joint Counts (TJC) Until Week 24 Week 16	-13.09 TJC Standard Deviation 11.02	-13.43 TJC Standard Deviation 12.35	—	—	—
Mean Change From Baseline in Total Tender Joint Counts (TJC) Until Week 24 Week 20	-13.70 TJC Standard Deviation 11.48	-13.65 TJC Standard Deviation 11.73	—	—	—
Mean Change From Baseline in Total Tender Joint Counts (TJC) Until Week 24 Week 24	-14.20 TJC Standard Deviation 11.46	-15.47 TJC Standard Deviation 13.35	—	—	—
Mean Change From Baseline in Total Tender Joint Counts (TJC) Until Week 24 LOCF visit	-13.19 TJC Standard Deviation 11.75	-14.36 TJC Standard Deviation 12.87	—	—	—

SECONDARY outcome

Timeframe: From week 24 until week 48

Population: Analysis was conducted on the FAS.

TCJ is a clinical assessment 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.

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=90 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=89 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w 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.	Phase 2 Arm A2 - Combination Therapy - q2w 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.	Phase 2 Arm D: Non Responders Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Mean Change From Baseline in Total Tender Joint Counts (TJC) Until Week 48 Baseline values	15.97 TJC Standard Deviation 12.77	15.42 TJC Standard Deviation 9.05	—	—	—
Mean Change From Baseline in Total Tender Joint Counts (TJC) Until Week 48 Week 28	-12.88 TJC Standard Deviation 11.52	-13.66 TJC Standard Deviation 8.44	—	—	—
Mean Change From Baseline in Total Tender Joint Counts (TJC) Until Week 48 Week 32	-13.88 TJC Standard Deviation 11.43	-13.40 TJC Standard Deviation 8.99	—	—	—
Mean Change From Baseline in Total Tender Joint Counts (TJC) Until Week 48 Week 36	-13.78 TJC Standard Deviation 11.70	-13.13 TJC Standard Deviation 8.82	—	—	—
Mean Change From Baseline in Total Tender Joint Counts (TJC) Until Week 48 Week 40	-14.49 TJC Standard Deviation 12.07	-14.06 TJC Standard Deviation 8.58	—	—	—
Mean Change From Baseline in Total Tender Joint Counts (TJC) Until Week 48 Week 44	-13.93 TJC Standard Deviation 11.62	-14.32 TJC Standard Deviation 8.25	—	—	—
Mean Change From Baseline in Total Tender Joint Counts (TJC) Until Week 48 Week 48	-13.43 TJC Standard Deviation 12.17	-14.40 TJC Standard Deviation 8.61	—	—	—
Mean Change From Baseline in Total Tender Joint Counts (TJC) Until Week 48 LOCF visit	-13.27 TJC Standard Deviation 12.20	-13.96 TJC Standard Deviation 8.68	—	—	—

SECONDARY outcome

Timeframe: From baseline to Week 24

Population: Analysis was conducted on the FAS.SJC

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.

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=327 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=74 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w 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.	Phase 2 Arm A2 - Combination Therapy - q2w 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.	Phase 2 Arm D: Non Responders Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Mean Change in Total Swollen Joint Counts (SJC) From Baseline Until Week 24 Baseline values	9.76 SJC Standard Deviation 6.64	10.05 SJC Standard Deviation 7.99	—	—	—
Mean Change in Total Swollen Joint Counts (SJC) From Baseline Until Week 24 Week 2	-3.42 SJC Standard Deviation 5.10	-3.22 SJC Standard Deviation 4.40	—	—	—
Mean Change in Total Swollen Joint Counts (SJC) From Baseline Until Week 24 Week 4	-5.46 SJC Standard Deviation 5.41	-5.07 SJC Standard Deviation 5.58	—	—	—
Mean Change in Total Swollen Joint Counts (SJC) From Baseline Until Week 24 Week 8	-6.81 SJC Standard Deviation 6.03	-7.38 SJC Standard Deviation 6.47	—	—	—
Mean Change in Total Swollen Joint Counts (SJC) From Baseline Until Week 24 Week 12	-7.60 SJC Standard Deviation 6.00	-7.93 SJC Standard Deviation 7.13	—	—	—
Mean Change in Total Swollen Joint Counts (SJC) From Baseline Until Week 24 Week 16	-8.01 SJC Standard Deviation 6.05	-8.35 SJC Standard Deviation 7.71	—	—	—
Mean Change in Total Swollen Joint Counts (SJC) From Baseline Until Week 24 Week 20	-8.37 SJC Standard Deviation 6.50	-8.72 SJC Standard Deviation 7.56	—	—	—
Mean Change in Total Swollen Joint Counts (SJC) From Baseline Until Week 24 Week 24	-8.38 SJC Standard Deviation 6.59	-9.13 SJC Standard Deviation 7.66	—	—	—
Mean Change in Total Swollen Joint Counts (SJC) From Baseline Until Week 24 LOCF visit	-7.71 SJC Standard Deviation 6.67	-8.47 SJC Standard Deviation 7.48	—	—	—

SECONDARY outcome

Timeframe: From week 24 until week 48

Population: Analysis was conducted on the FAS.

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.

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=90 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=89 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w 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.	Phase 2 Arm A2 - Combination Therapy - q2w 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.	Phase 2 Arm D: Non Responders Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Mean Change in Total Swollen Joint Counts (SJC) From Baseline Until Week 48 Baseline values	9.23 SJC Standard Deviation 7.55	9.28 SJC Standard Deviation 6.52	—	—	—
Mean Change in Total Swollen Joint Counts (SJC) From Baseline Until Week 48 Week 28	-8.14 SJC Standard Deviation 6.81	-8.64 SJC Standard Deviation 6.19	—	—	—
Mean Change in Total Swollen Joint Counts (SJC) From Baseline Until Week 48 Week 32	-8.62 SJC Standard Deviation 7.13	-8.54 SJC Standard Deviation 7.02	—	—	—
Mean Change in Total Swollen Joint Counts (SJC) From Baseline Until Week 48 Week 36	-8.38 SJC Standard Deviation 6.76	-8.48 SJC Standard Deviation 6.50	—	—	—
Mean Change in Total Swollen Joint Counts (SJC) From Baseline Until Week 48 Week 40	-8.51 SJC Standard Deviation 6.59	-8.85 SJC Standard Deviation 6.40	—	—	—
Mean Change in Total Swollen Joint Counts (SJC) From Baseline Until Week 48 Week 44	-8.62 SJC Standard Deviation 6.97	-8.73 SJC Standard Deviation 6.62	—	—	—
Mean Change in Total Swollen Joint Counts (SJC) From Baseline Until Week 48 Week 48	-8.72 SJC Standard Deviation 7.34	-9.06 SJC Standard Deviation 6.58	—	—	—
Mean Change in Total Swollen Joint Counts (SJC) From Baseline Until Week 48 LOCF visit	-8.64 SJC Standard Deviation 7.33	-8.82 SJC Standard Deviation 6.51	—	—	—

SECONDARY outcome

Timeframe: Week 48

Population: Analysis was conducted on the FAS

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.

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=66 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=23 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w n=23 Participants 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.	Phase 2 Arm A2 - Combination Therapy - q2w n=67 Participants 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.	Phase 2 Arm D: Non Responders Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Percentages of Patients Who Achieve DAS28-ESR Remission (DAS28 < 2.6) up to Week 48 Week 48	89.1 Percentage of participants Interval 78.75 to 95.49	100 Percentage of participants CI unavailable because the central value is 100%	77.3 Percentage of participants Interval 54.63 to 92.18	72.7 Percentage of participants Interval 60.36 to 82.97	—
Percentages of Patients Who Achieve DAS28-ESR Remission (DAS28 < 2.6) up to Week 48 Week 28	90.6 Percentage of participants Interval 80.7 to 96.48	82.6 Percentage of participants Interval 61.22 to 95.05	87.0 Percentage of participants Interval 66.41 to 97.22	83.1 Percentage of participants Interval 71.73 to 91.24	—
Percentages of Patients Who Achieve DAS28-ESR Remission (DAS28 < 2.6) up to Week 48 Week 32	89.1 Percentage of participants Interval 78.75 to 95.49	81.8 Percentage of participants Interval 59.72 to 94.81	78.3 Percentage of participants Interval 56.3 to 92.54	82.1 Percentage of participants Interval 70.8 to 90.39	—
Percentages of Patients Who Achieve DAS28-ESR Remission (DAS28 < 2.6) up to Week 48 Week 36	76.9 Percentage of participants Interval 64.81 to 86.47	90.5 Percentage of participants Interval 69.62 to 98.83	86.4 Percentage of participants Interval 65.09 to 97.09	86.4 Percentage of participants Interval 75.69 to 93.57	—
Percentages of Patients Who Achieve DAS28-ESR Remission (DAS28 < 2.6) up to Week 48 Week 40	81.3 Percentage of participants Interval 69.54 to 89.92	85.0 Percentage of participants Interval 62.11 to 96.79	77.3 Percentage of participants Interval 54.63 to 92.18	81.8 Percentage of participants Interval 70.39 to 90.24	—
Percentages of Patients Who Achieve DAS28-ESR Remission (DAS28 < 2.6) up to Week 48 Week 44	87.3 Percentage of participants Interval 76.5 to 94.35	94.7 Percentage of participants Interval 73.97 to 99.87	77.3 Percentage of participants Interval 54.63 to 92.18	78.8 Percentage of participants Interval 66.98 to 87.89	—
Percentages of Patients Who Achieve DAS28-ESR Remission (DAS28 < 2.6) up to Week 48 LOCF Visit	89.4 Percentage of participants Interval 79.36 to 95.63	91.3 Percentage of participants Interval 71.96 to 98.93	73.9 Percentage of participants Interval 51.59 to 89.77	73.1 Percentage of participants Interval 60.9 to 83.24	—

SECONDARY outcome

Timeframe: From baseline to Week 24

Population: Analysis was conducted on the FAS

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.

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=327 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=74 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w 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.	Phase 2 Arm A2 - Combination Therapy - q2w 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.	Phase 2 Arm D: Non Responders Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Percentages of Patients With Remission (CDAI<2.8) Until Week 24 Baseline visit	0 Percentage of participants Interval 0.0 to 0.0	0 Percentage of participants Interval 0.0 to 0.0	—	—	—
Percentages of Patients With Remission (CDAI<2.8) Until Week 24 Week 2	1.6 Percentage of participants Interval 0.51 to 3.62	2.7 Percentage of participants Interval 0.33 to 9.42	—	—	—
Percentages of Patients With Remission (CDAI<2.8) Until Week 24 Week 4	5.1 Percentage of participants Interval 2.96 to 8.19	2.7 Percentage of participants Interval 0.33 to 9.55	—	—	—
Percentages of Patients With Remission (CDAI<2.8) Until Week 24 Week 8	14.4 Percentage of participants Interval 10.61 to 18.88	11.0 Percentage of participants Interval 4.85 to 20.46	—	—	—
Percentages of Patients With Remission (CDAI<2.8) Until Week 24 Week 12	19.3 Percentage of participants Interval 14.92 to 24.22	15.7 Percentage of participants Interval 8.11 to 26.38	—	—	—
Percentages of Patients With Remission (CDAI<2.8) Until Week 24 Week 16	22.8 Percentage of participants Interval 18.06 to 28.02	18.8 Percentage of participants Interval 10.43 to 30.06	—	—	—
Percentages of Patients With Remission (CDAI<2.8) Until Week 24 Week 20	26.8 Percentage of participants Interval 21.7 to 32.31	27.7 Percentage of participants Interval 17.31 to 40.19	—	—	—
Percentages of Patients With Remission (CDAI<2.8) Until Week 24 Week 24	30.2 Percentage of participants Interval 24.93 to 35.99	29.7 Percentage of participants Interval 18.91 to 42.42	—	—	—
Percentages of Patients With Remission (CDAI<2.8) Until Week 24 LOCF visit	29.4 Percentage of participants Interval 24.48 to 34.62	29.7 Percentage of participants Interval 19.66 to 41.48	—	—	—

SECONDARY outcome

Timeframe: From week 28 until week 48

Population: Analysis was conducted on the FAS

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.

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=90 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=89 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w 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.	Phase 2 Arm A2 - Combination Therapy - q2w 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.	Phase 2 Arm D: Non Responders Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Percentages of Patients With Remission (CDAI<2.8) Until Week 48 Week 28	48.3 Percentage of participants Interval 37.59 to 59.16	46.6 Percentage of participants Interval 35.88 to 57.54	—	—	—
Percentages of Patients With Remission (CDAI<2.8) Until Week 48 Week 32	45.6 Percentage of participants Interval 35.02 to 56.4	48.3 Percentage of participants Interval 37.42 to 59.25	—	—	—
Percentages of Patients With Remission (CDAI<2.8) Until Week 48 Week 36	46.6 Percentage of participants Interval 35.88 to 57.54	52.3 Percentage of participants Interval 41.27 to 63.21	—	—	—
Percentages of Patients With Remission (CDAI<2.8) Until Week 48 Week 40	45.5 Percentage of participants Interval 34.8 to 56.42	52.4 Percentage of participants Interval 41.19 to 63.4	—	—	—
Percentages of Patients With Remission (CDAI<2.8) Until Week 48 Week 44	50.6 Percentage of participants Interval 39.75 to 61.33	50.0 Percentage of participants Interval 38.75 to 61.25	—	—	—
Percentages of Patients With Remission (CDAI<2.8) Until Week 48 Week 48	53.9 Percentage of participants Interval 43.04 to 64.56	59.0 Percentage of participants Interval 47.69 to 69.72	—	—	—
Percentages of Patients With Remission (CDAI<2.8) Until Week 48 LOCF Visit	60.3 Percentage of participants Interval 52.77 to 67.56	57.8 Percentage of participants Interval 46.91 to 68.12	—	—	—

SECONDARY outcome

Timeframe: From baseline to Week 24

Population: Analysis was conducted on the FAS

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.

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=327 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=74 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w 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.	Phase 2 Arm A2 - Combination Therapy - q2w 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.	Phase 2 Arm D: Non Responders Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Percentages of Patients With Remission (SDAI<3.3) Until Week 24 Baseline visit	0 Percentage of participants Interval 0.0 to 0.0	0 Percentage of participants Interval 0.0 to 0.0	—	—	—
Percentages of Patients With Remission (SDAI<3.3) Until Week 24 Week 2	1.9 Percentage of participants Interval 0.71 to 4.14	1.4 Percentage of participants Interval 0.04 to 7.5	—	—	—
Percentages of Patients With Remission (SDAI<3.3) Until Week 24 Week 4	4.8 Percentage of participants Interval 2.72 to 7.83	2.9 Percentage of participants Interval 0.35 to 9.94	—	—	—
Percentages of Patients With Remission (SDAI<3.3) Until Week 24 Week 8	14.6 Percentage of participants Interval 10.75 to 19.13	11.1 Percentage of participants Interval 4.92 to 20.72	—	—	—
Percentages of Patients With Remission (SDAI<3.3) Until Week 24 Week 12	18.8 Percentage of participants Interval 14.47 to 23.72	14.3 Percentage of participants Interval 7.07 to 24.71	—	—	—
Percentages of Patients With Remission (SDAI<3.3) Until Week 24 Week 16	22.2 Percentage of participants Interval 17.56 to 27.47	17.4 Percentage of participants Interval 9.32 to 28.41	—	—	—
Percentages of Patients With Remission (SDAI<3.3) Until Week 24 Week 20	25.8 Percentage of participants Interval 20.77 to 31.36	28.1 Percentage of participants Interval 17.6 to 40.76	—	—	—
Percentages of Patients With Remission (SDAI<3.3) Until Week 24 Week 24	28.8 Percentage of participants Interval 23.53 to 34.49	31.7 Percentage of participants Interval 20.58 to 44.69	—	—	—
Percentages of Patients With Remission (SDAI<3.3) Until Week 24 LOCF visit	25.4 Percentage of participants Interval 20.75 to 30.46	28.4 Percentage of participants Interval 18.5 to 40.05	—	—	—

SECONDARY outcome

Timeframe: From week 28 until week 48

Population: Analysis was conducted on the FAS

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.

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=90 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=89 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w 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.	Phase 2 Arm A2 - Combination Therapy - q2w 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.	Phase 2 Arm D: Non Responders Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Percentages of Patients With Remission (SDAI<3.3) Until Week 48 Week 28	46.0 Percentage of participants Interval 35.23 to 57.0	50.0 Percentage of participants Interval 39.02 to 60.98	—	—	—
Percentages of Patients With Remission (SDAI<3.3) Until Week 48 Week 32	45.6 Percentage of participants Interval 35.02 to 56.4	48.8 Percentage of participants Interval 37.9 to 59.86	—	—	—
Percentages of Patients With Remission (SDAI<3.3) Until Week 48 Week 36	47.7 Percentage of participants Interval 36.96 to 58.65	53.5 Percentage of participants Interval 42.41 to 64.32	—	—	—
Percentages of Patients With Remission (SDAI<3.3) Until Week 48 Week 40	44.3 Percentage of participants Interval 33.73 to 55.3	55.4 Percentage of participants Interval 44.1 to 66.34	—	—	—
Percentages of Patients With Remission (SDAI<3.3) Until Week 48 Week 44	47.2 Percentage of participants Interval 36.51 to 58.06	50.0 Percentage of participants Interval 38.75 to 61.25	—	—	—
Percentages of Patients With Remission (SDAI<3.3) Until Week 48 Week 48	47.7 Percentage of participants Interval 36.96 to 58.65	52.4 Percentage of participants Interval 41.11 to 63.59	—	—	—
Percentages of Patients With Remission (SDAI<3.3) Until Week 48 LOCF Visit	47.8 Percentage of participants Interval 37.13 to 58.57	51.7 Percentage of participants Interval 40.48 to 62.41	—	—	—

SECONDARY outcome

Timeframe: From baseline to Week 24

Population: Analysis was conducted on the FAS.

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.

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=327 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=74 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w 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.	Phase 2 Arm A2 - Combination Therapy - q2w 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.	Phase 2 Arm D: Non Responders Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Percentage of Patients Who Achieve Low Disease Activity Based on DAS28-ESR Criteria (DAS28-ESR </=3.2) up to Week 24 Week 2	21.5 Percentage of participants Interval 17.12 to 26.47	21.6 Percentage of participants Interval 12.89 to 32.72	—	—	—
Percentage of Patients Who Achieve Low Disease Activity Based on DAS28-ESR Criteria (DAS28-ESR </=3.2) up to Week 24 Week 4	36.8 Percentage of participants Interval 31.39 to 42.41	26.0 Percentage of participants Interval 16.45 to 37.62	—	—	—
Percentage of Patients Who Achieve Low Disease Activity Based on DAS28-ESR Criteria (DAS28-ESR </=3.2) up to Week 24 Week 8	55.4 Percentage of participants Interval 49.54 to 61.16	50.7 Percentage of participants Interval 38.72 to 62.6	—	—	—
Percentage of Patients Who Achieve Low Disease Activity Based on DAS28-ESR Criteria (DAS28-ESR </=3.2) up to Week 24 Week 12	67.7 Percentage of participants Interval 62.01 to 73.0	58.6 Percentage of participants Interval 46.17 to 70.23	—	—	—
Percentage of Patients Who Achieve Low Disease Activity Based on DAS28-ESR Criteria (DAS28-ESR </=3.2) up to Week 24 Week 16	72.4 Percentage of participants Interval 66.89 to 77.48	66.7 Percentage of participants Interval 54.29 to 77.56	—	—	—
Percentage of Patients Who Achieve Low Disease Activity Based on DAS28-ESR Criteria (DAS28-ESR </=3.2) up to Week 24 Week 20	78.2 Percentage of participants Interval 72.91 to 82.83	67.7 Percentage of participants Interval 54.95 to 78.77	—	—	—
Percentage of Patients Who Achieve Low Disease Activity Based on DAS28-ESR Criteria (DAS28-ESR </=3.2) up to Week 24 Week 24	81.1 Percentage of participants Interval 75.98 to 85.49	75.0 Percentage of participants Interval 62.6 to 84.98	—	—	—
Percentage of Patients Who Achieve Low Disease Activity Based on DAS28-ESR Criteria (DAS28-ESR </=3.2) up to Week 24 LOCF visit	74.0 Percentage of participants Interval 68.9 to 78.68	73.0 Percentage of participants Interval 61.39 to 82.65	—	—	—

SECONDARY outcome

Timeframe: From week 28 until week 48

Population: Analysis was conducted on the FAS.

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.

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=90 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=89 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w 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.	Phase 2 Arm A2 - Combination Therapy - q2w 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.	Phase 2 Arm D: Non Responders Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Percentage of Patients Who Achieve Low Disease Activity Based on DAS28-ESR Criteria (DAS28-ESR </=3.2) up to Week 48 Week 32	92.2 Percentage of participants Interval 84.63 to 96.82	91.9 Percentage of participants Interval 83.95 to 96.66	—	—	—
Percentage of Patients Who Achieve Low Disease Activity Based on DAS28-ESR Criteria (DAS28-ESR </=3.2) up to Week 48 Week 28	88.6 Percentage of participants Interval 80.09 to 94.41	95.4 Percentage of participants Interval 88.64 to 98.73	—	—	—
Percentage of Patients Who Achieve Low Disease Activity Based on DAS28-ESR Criteria (DAS28-ESR </=3.2) up to Week 48 Week 36	92.0 Percentage of participants Interval 84.3 to 96.74	87.2 Percentage of participants Interval 78.27 to 93.44	—	—	—
Percentage of Patients Who Achieve Low Disease Activity Based on DAS28-ESR Criteria (DAS28-ESR </=3.2) up to Week 48 Week 40	92.0 Percentage of participants Interval 84.3 to 96.74	89.3 Percentage of participants Interval 80.63 to 94.98	—	—	—
Percentage of Patients Who Achieve Low Disease Activity Based on DAS28-ESR Criteria (DAS28-ESR </=3.2) up to Week 48 Week 44	87.5 Percentage of participants Interval 78.73 to 93.59	96.3 Percentage of participants Interval 89.68 to 99.24	—	—	—
Percentage of Patients Who Achieve Low Disease Activity Based on DAS28-ESR Criteria (DAS28-ESR </=3.2) up to Week 48 Week 48	86.4 Percentage of participants Interval 77.39 to 92.75	95.1 Percentage of participants Interval 87.98 to 98.66	—	—	—
Percentage of Patients Who Achieve Low Disease Activity Based on DAS28-ESR Criteria (DAS28-ESR </=3.2) up to Week 48 LOCF Visit	85.6 Percentage of participants Interval 76.57 to 92.08	94.4 Percentage of participants Interval 87.37 to 98.15	—	—	—

SECONDARY outcome

Timeframe: From baseline to Week 24

Population: Analysis was conducted on the FAS.

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.

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=327 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=74 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w 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.	Phase 2 Arm A2 - Combination Therapy - q2w 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.	Phase 2 Arm D: Non Responders Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Percentage of Patients Who Achieve Low Disease Activity Based on CDAI Score (CDAI<10) Until Week 24 Week 2	16.9 Percentage of participants Interval 12.98 to 21.5	13.5 Percentage of participants Interval 6.68 to 23.45	—	—	—
Percentage of Patients Who Achieve Low Disease Activity Based on CDAI Score (CDAI<10) Until Week 24 Week 4	26.9 Percentage of participants Interval 22.08 to 32.21	24.7 Percentage of participants Interval 15.32 to 36.14	—	—	—
Percentage of Patients Who Achieve Low Disease Activity Based on CDAI Score (CDAI<10) Until Week 24 Week 8	47.5 Percentage of participants Interval 41.71 to 53.32	41.1 Percentage of participants Interval 29.71 to 53.23	—	—	—
Percentage of Patients Who Achieve Low Disease Activity Based on CDAI Score (CDAI<10) Until Week 24 Week 12	52.4 Percentage of participants Interval 46.51 to 58.17	57.1 Percentage of participants Interval 44.75 to 68.91	—	—	—
Percentage of Patients Who Achieve Low Disease Activity Based on CDAI Score (CDAI<10) Until Week 24 Week 16	60.7 Percentage of participants Interval 54.81 to 66.35	62.3 Percentage of participants Interval 49.83 to 73.71	—	—	—
Percentage of Patients Who Achieve Low Disease Activity Based on CDAI Score (CDAI<10) Until Week 24 Week 20	65.1 Percentage of participants Interval 59.29 to 70.68	66.2 Percentage of participants Interval 53.35 to 77.43	—	—	—
Percentage of Patients Who Achieve Low Disease Activity Based on CDAI Score (CDAI<10) Until Week 24 Week 24	66.9 Percentage of participants Interval 61.07 to 72.38	71.9 Percentage of participants Interval 59.24 to 82.4	—	—	—
Percentage of Patients Who Achieve Low Disease Activity Based on CDAI Score (CDAI<10) Until Week 24 LOCF visit	61.2 Percentage of participants Interval 55.64 to 66.48	66.2 Percentage of participants Interval 54.28 to 76.81	—	—	—

SECONDARY outcome

Timeframe: From week 28 until week 48

Population: Analysis was conducted on the FAS.

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.

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=90 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=89 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w 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.	Phase 2 Arm A2 - Combination Therapy - q2w 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.	Phase 2 Arm D: Non Responders Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Percentage of Patients Who Achieve Low Disease Activity Based on CDAI Score (CDAI<10) Until Week 48 Week 28	85.4 Percentage of participants Interval 76.32 to 91.99	86.4 Percentage of participants Interval 77.39 to 92.75	—	—	—
Percentage of Patients Who Achieve Low Disease Activity Based on CDAI Score (CDAI<10) Until Week 48 Week 32	86.7 Percentage of participants Interval 77.87 to 92.92	89.7 Percentage of participants Interval 81.27 to 95.16	—	—	—
Percentage of Patients Who Achieve Low Disease Activity Based on CDAI Score (CDAI<10) Until Week 48 Week 36	89.8 Percentage of participants Interval 81.47 to 95.22	80.2 Percentage of participants Interval 70.25 to 88.04	—	—	—
Percentage of Patients Who Achieve Low Disease Activity Based on CDAI Score (CDAI<10) Until Week 48 Week 40	88.6 Percentage of participants Interval 80.09 to 94.41	86.9 Percentage of participants Interval 77.78 to 93.28	—	—	—
Percentage of Patients Who Achieve Low Disease Activity Based on CDAI Score (CDAI<10) Until Week 48 Week 44	85.4 Percentage of participants Interval 76.32 to 91.99	89.0 Percentage of participants Interval 80.18 to 94.86	—	—	—
Percentage of Patients Who Achieve Low Disease Activity Based on CDAI Score (CDAI<10) Until Week 48 Week 48	87.6 Percentage of participants Interval 78.96 to 93.67	92.8 Percentage of participants Interval 84.93 to 97.3	—	—	—
Percentage of Patients Who Achieve Low Disease Activity Based on CDAI Score (CDAI<10) Until Week 48 LOCF Visit	87.8 Percentage of participants Interval 79.18 to 93.74	91.0 Percentage of participants Interval 83.05 to 96.04	—	—	—

SECONDARY outcome

Timeframe: From baseline to Week 24

Population: Analysis was conducted on the FAS.

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.

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=327 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=74 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w 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.	Phase 2 Arm A2 - Combination Therapy - q2w 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.	Phase 2 Arm D: Non Responders Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Percentage of Patients Who Achieved Low Disease Activity (LDA) Based on SDAI Score (SDAI<11) Until Week 24 Week 2	17.6 Percentage of participants Interval 13.56 to 22.32	16.7 Percentage of participants Interval 8.92 to 27.3	—	—	—
Percentage of Patients Who Achieved Low Disease Activity (LDA) Based on SDAI Score (SDAI<11) Until Week 24 Week 4	28.3 Percentage of participants Interval 23.36 to 33.65	27.1 Percentage of participants Interval 17.2 to 39.1	—	—	—
Percentage of Patients Who Achieved Low Disease Activity (LDA) Based on SDAI Score (SDAI<11) Until Week 24 Week 8	48.1 Percentage of participants Interval 42.31 to 54.0	41.7 Percentage of participants Interval 30.15 to 53.89	—	—	—
Percentage of Patients Who Achieved Low Disease Activity (LDA) Based on SDAI Score (SDAI<11) Until Week 24 Week 12	55.6 Percentage of participants Interval 49.74 to 61.41	58.6 Percentage of participants Interval 46.17 to 70.23	—	—	—
Percentage of Patients Who Achieved Low Disease Activity (LDA) Based on SDAI Score (SDAI<11) Until Week 24 Week 16	62.5 Percentage of participants Interval 56.63 to 68.11	63.8 Percentage of participants Interval 51.31 to 75.01	—	—	—
Percentage of Patients Who Achieved Low Disease Activity (LDA) Based on SDAI Score (SDAI<11) Until Week 24 Week 20	66.3 Percentage of participants Interval 60.43 to 71.83	65.6 Percentage of participants Interval 52.7 to 77.05	—	—	—
Percentage of Patients Who Achieved Low Disease Activity (LDA) Based on SDAI Score (SDAI<11) Until Week 24 Week 24	67.3 Percentage of participants Interval 61.41 to 72.75	74.6 Percentage of participants Interval 62.06 to 84.73	—	—	—
Percentage of Patients Who Achieved Low Disease Activity (LDA) Based on SDAI Score (SDAI<11) Until Week 24 LOCF visit	56.9 Percentage of participants Interval 51.32 to 62.32	63.5 Percentage of participants Interval 51.51 to 74.4	—	—	—

SECONDARY outcome

Timeframe: From week 28 until week 48

Population: Analysis was conducted on the FAS.

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.

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=90 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=89 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w 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.	Phase 2 Arm A2 - Combination Therapy - q2w 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.	Phase 2 Arm D: Non Responders Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Percentage of Patients Who Achieved Low Disease Activity (LDA) Based on SDAI Score (SDAI<11) Until Week 48 Week 28	83.89 Percentage of participants Interval 74.48 to 90.91	84.9 Percentage of participants Interval 75.54 to 91.7	—	—	—
Percentage of Patients Who Achieved Low Disease Activity (LDA) Based on SDAI Score (SDAI<11) Until Week 48 Week 32	85.6 Percentage of participants Interval 76.57 to 92.08	89.5 Percentage of participants Interval 81.06 to 95.1	—	—	—
Percentage of Patients Who Achieved Low Disease Activity (LDA) Based on SDAI Score (SDAI<11) Until Week 48 Week 36	87.5 Percentage of participants Interval 78.73 to 93.59	79.1 Percentage of participants Interval 68.95 to 87.1	—	—	—
Percentage of Patients Who Achieved Low Disease Activity (LDA) Based on SDAI Score (SDAI<11) Until Week 48 Week 40	86.4 Percentage of participants Interval 77.39 to 92.75	86.7 Percentage of participants Interval 77.52 to 93.19	—	—	—
Percentage of Patients Who Achieved Low Disease Activity (LDA) Based on SDAI Score (SDAI<11) Until Week 48 Week 44	82.0 Percentage of participants Interval 72.45 to 89.36	91.5 Percentage of participants Interval 83.2 to 96.5	—	—	—
Percentage of Patients Who Achieved Low Disease Activity (LDA) Based on SDAI Score (SDAI<11) Until Week 48 Week 48	81.8 Percentage of participants Interval 72.16 to 89.24	93.9 Percentage of participants Interval 86.34 to 97.99	—	—	—
Percentage of Patients Who Achieved Low Disease Activity (LDA) Based on SDAI Score (SDAI<11) Until Week 48 LOCF Visit	81.1 Percentage of participants Interval 71.49 to 88.59	91.0 Percentage of participants Interval 83.05 to 96.04	—	—	—

SECONDARY outcome

Timeframe: From baseline to Week 24

Population: Analysis was conducted on the FAS.

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

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=327 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=74 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w 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.	Phase 2 Arm A2 - Combination Therapy - q2w 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.	Phase 2 Arm D: Non Responders Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Safety: Number of Patients Reporting Adverse Events up to Week 24 Any treatment emergent adverse event (TEAE)	254 Number of participants	52 Number of participants	—	—	—
Safety: Number of Patients Reporting Adverse Events up to Week 24 At least one TEAE of special interest	13 Number of participants	2 Number of participants	—	—	—
Safety: Number of Patients Reporting Adverse Events up to Week 24 At least one serious TEAE	10 Number of participants	3 Number of participants	—	—	—
Safety: Number of Patients Reporting Adverse Events up to Week 24 At least one TEAE leading to dose modification	103 Number of participants	24 Number of participants	—	—	—
Safety: Number of Patients Reporting Adverse Events up to Week 24 At least one TEAE leading to discontinuation	21 Number of participants	4 Number of participants	—	—	—

SECONDARY outcome

Timeframe: From week 24 until week 48

Population: Analysis was conducted on the FAS.

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

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=90 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=89 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w n=95 Participants 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.	Phase 2 Arm A2 - Combination Therapy - q2w n=67 Participants 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.	Phase 2 Arm D: Non Responders n=2 Participants Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Safety: Number of Patients Reporting Adverse Events up to Week 48 Any TEAE	63 Number of participants	50 Number of participants	68 Number of participants	46 Number of participants	1 Number of participants
Safety: Number of Patients Reporting Adverse Events up to Week 48 At least one TEAE of special interest	2 Number of participants	1 Number of participants	2 Number of participants	4 Number of participants	0 Number of participants
Safety: Number of Patients Reporting Adverse Events up to Week 48 At least one serious TEAE	1 Number of participants	2 Number of participants	2 Number of participants	5 Number of participants	1 Number of participants
Safety: Number of Patients Reporting Adverse Events up to Week 48 At least one TEAE leading to dose modification	23 Number of participants	15 Number of participants	23 Number of participants	21 Number of participants	1 Number of participants
Safety: Number of Patients Reporting Adverse Events up to Week 48 At least one TEAE leading to discontinuation	0 Number of participants	0 Number of participants	0 Number of participants	2 Number of participants	0 Number of participants

SECONDARY outcome

Timeframe: From baseline to Week 24

Population: Analysis was conducted on the FAS.

Number of patients resulting positive to anti-tocilizumab antibodies test are reported.

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=327 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=74 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w 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.	Phase 2 Arm A2 - Combination Therapy - q2w 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.	Phase 2 Arm D: Non Responders Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Immunogenicity: Number of Patients With Anti-tocilizumab Antibodies up to Week 24 Screen - Baseline	13 Number of participants	6 Number of participants	—	—	—
Immunogenicity: Number of Patients With Anti-tocilizumab Antibodies up to Week 24 Screen - Week 12	2 Number of participants	1 Number of participants	—	—	—
Immunogenicity: Number of Patients With Anti-tocilizumab Antibodies up to Week 24 Screen - Week 24	9 Number of participants	3 Number of participants	—	—	—
Immunogenicity: Number of Patients With Anti-tocilizumab Antibodies up to Week 24 Confirmatory - Baseline	5 Number of participants	4 Number of participants	—	—	—
Immunogenicity: Number of Patients With Anti-tocilizumab Antibodies up to Week 24 Confirmatory - Week 12	0 Number of participants	1 Number of participants	—	—	—
Immunogenicity: Number of Patients With Anti-tocilizumab Antibodies up to Week 24 Confirmatory - Week 24	3 Number of participants	1 Number of participants	—	—	—

SECONDARY outcome

Timeframe: From week 24 until week 48

Population: Analysis was conducted on the FAS.

Number of patients resulting positive to anti-tocilizumab antibodies test are reported.

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=90 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=89 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w n=95 Participants 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.	Phase 2 Arm A2 - Combination Therapy - q2w n=67 Participants 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.	Phase 2 Arm D: Non Responders n=2 Participants Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Immunogenicity: Number of Patients With Anti-tocilizumab Antibodies up to Week 48 Screen - Week 36	0 Number of participants	0 Number of participants	0 Number of participants	2 Number of participants	—
Immunogenicity: Number of Patients With Anti-tocilizumab Antibodies up to Week 48 Screen - Week 48	3 Number of participants	1 Number of participants	2 Number of participants	3 Number of participants	—
Immunogenicity: Number of Patients With Anti-tocilizumab Antibodies up to Week 48 Confirmatory - Week 36	0 Number of participants	0 Number of participants	0 Number of participants	1 Number of participants	—
Immunogenicity: Number of Patients With Anti-tocilizumab Antibodies up to Week 48 Confirmatory - Week 48	0 Number of participants	0 Number of participants	0 Number of participants	1 Number of participants	—

SECONDARY outcome

Timeframe: From baseline to Week 24

Population: Analysis was conducted on the FAS.

Mean concentrations of TCZ in patients' blood are reported.

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=327 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=74 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w 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.	Phase 2 Arm A2 - Combination Therapy - q2w 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.	Phase 2 Arm D: Non Responders Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Immunogenicity: TCZ Levels up to Week 24 Baseline	0.67 mcg/ml Standard Deviation 0.34	0.49 mcg/ml Standard Deviation NA Analysis was done for one participant only.	—	—	—
Immunogenicity: TCZ Levels up to Week 24 Week 12	41.23 mcg/ml Standard Deviation 20.89	37.97 mcg/ml Standard Deviation 20.11	—	—	—
Immunogenicity: TCZ Levels up to Week 24 Week 24	46.87 mcg/ml Standard Deviation 27.65	46.42 mcg/ml Standard Deviation 28.35	—	—	—

SECONDARY outcome

Timeframe: week 36 and early withdrawal visit

Population: Analysis was conducted on the FAS.

Mean concentrations of TCZ in patients' blood are reported.

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=90 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=89 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w n=95 Participants 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.	Phase 2 Arm A2 - Combination Therapy - q2w n=67 Participants 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.	Phase 2 Arm D: Non Responders n=2 Participants Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Immunogenicity: TCZ Levels at Week 36 and Early Withdrawal Visit Week 36	16.77 mcg/ml Standard Deviation 16.10	48.47 mcg/ml Standard Deviation 30.17	41.89 mcg/ml Standard Deviation 28.82	48.33 mcg/ml Standard Deviation 25.79	—
Immunogenicity: TCZ Levels at Week 36 and Early Withdrawal Visit Early withdrawal visit	19.20 mcg/ml Standard Deviation NA Analysis was conducted for one participant only	36.45 mcg/ml Standard Deviation 18.03	24.43 mcg/ml Standard Deviation 20.83	13.75 mcg/ml Standard Deviation 4.60	1.78 mcg/ml Standard Deviation NA Analysis was conducted for one participant only

SECONDARY outcome

Timeframe: From baseline to Week 24

Population: Analysis was conducted on the FAS.

Mean concentration of SIL-6R in patients' blood are reported.

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=327 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=74 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w 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.	Phase 2 Arm A2 - Combination Therapy - q2w 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.	Phase 2 Arm D: Non Responders Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Immunogenicity: SIL-6R Levels up to Week 24 Baseline	39.29 mcg/ml Standard Deviation 11.10	42.85 mcg/ml Standard Deviation 16.26	—	—	—
Immunogenicity: SIL-6R Levels up to Week 24 Week 12	570.34 mcg/ml Standard Deviation 228.54	566.47 mcg/ml Standard Deviation 210.49	—	—	—
Immunogenicity: SIL-6R Levels up to Week 24 Week 24	565.34 mcg/ml Standard Deviation 198.32	570.49 mcg/ml Standard Deviation 198.26	—	—	—

SECONDARY outcome

Timeframe: Baseline, Week 36 and Early Withdrawal Visit

Population: Analysis was conducted on the FAS.

Mean concentration of SIL-6R in patients' blood are reported.

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=90 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=89 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w n=95 Participants 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.	Phase 2 Arm A2 - Combination Therapy - q2w n=67 Participants 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.	Phase 2 Arm D: Non Responders n=2 Participants Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Immunogenicity: SIL-6R Levels at Week 36 and Early Withdrawal Visit Early withdrawal visit	643.00 mcg/ml Standard Deviation NA Analysis was conducted on one participant only.	412.53 mcg/ml Standard Deviation 323.49	338.38 mcg/ml Standard Deviation 230.82	217.74 mcg/ml Standard Deviation 236.21	513.00 mcg/ml Standard Deviation NA Analysis was conducted on one participant only.
Immunogenicity: SIL-6R Levels at Week 36 and Early Withdrawal Visit Baseline	39.70 mcg/ml Standard Deviation 16.46	39.87 mcg/ml Standard Deviation 10.46	39.39 mcg/ml Standard Deviation 11.24	43.11 mcg/ml Standard Deviation 11.85	37.30 mcg/ml Standard Deviation 11.46
Immunogenicity: SIL-6R Levels at Week 36 and Early Withdrawal Visit Week 36	476.28 mcg/ml Standard Deviation 156.50	539.89 mcg/ml Standard Deviation 152.71	542.99 mcg/ml Standard Deviation 168.30	552.65 mcg/ml Standard Deviation 184.21	—

SECONDARY outcome

Timeframe: From baseline to Week 24

Population: Analysis was conducted on the FAS.

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.

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=327 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=74 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w 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.	Phase 2 Arm A2 - Combination Therapy - q2w 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.	Phase 2 Arm D: Non Responders Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Patient Global Assessment of Disease Activity Visual Analogue Scale (VAS) up to Week 24 Baseline	59.40 Millimeters Standard Deviation 17.61	65.26 Millimeters Standard Deviation 19.77	—	—	—
Patient Global Assessment of Disease Activity Visual Analogue Scale (VAS) up to Week 24 Week 2	44.16 Millimeters Standard Deviation 21.97	49.53 Millimeters Standard Deviation 22.78	—	—	—
Patient Global Assessment of Disease Activity Visual Analogue Scale (VAS) up to Week 24 Week 4	35.19 Millimeters Standard Deviation 20.83	38.21 Millimeters Standard Deviation 22.92	—	—	—
Patient Global Assessment of Disease Activity Visual Analogue Scale (VAS) up to Week 24 Week 8	26.04 Millimeters Standard Deviation 20.59	30.03 Millimeters Standard Deviation 21.65	—	—	—
Patient Global Assessment of Disease Activity Visual Analogue Scale (VAS) up to Week 24 Week 12	22.24 Millimeters Standard Deviation 17.97	22.71 Millimeters Standard Deviation 18.56	—	—	—
Patient Global Assessment of Disease Activity Visual Analogue Scale (VAS) up to Week 24 Week 16	20.71 Millimeters Standard Deviation 18.65	19.28 Millimeters Standard Deviation 18.22	—	—	—
Patient Global Assessment of Disease Activity Visual Analogue Scale (VAS) up to Week 24 Week 20	18.79 Millimeters Standard Deviation 17.79	16.80 Millimeters Standard Deviation 16.68	—	—	—
Patient Global Assessment of Disease Activity Visual Analogue Scale (VAS) up to Week 24 Week 24	19.00 Millimeters Standard Deviation 18.36	16.63 Millimeters Standard Deviation 15.19	—	—	—
Patient Global Assessment of Disease Activity Visual Analogue Scale (VAS) up to Week 24 LOCF visit	22.23 Millimeters Standard Deviation 20.86	20.36 Millimeters Standard Deviation 19.25	—	—	—

SECONDARY outcome

Timeframe: Baseline, from week 28 until week 48

Population: Analysis was conducted on the FAS.

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.

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=90 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=89 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w 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.	Phase 2 Arm A2 - Combination Therapy - q2w 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.	Phase 2 Arm D: Non Responders Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Patient Global Assessment of Disease Activity Visual Analogue Scale (VAS) up to Week 48 Baseline	60.96 Millimeters Standard Deviation 20.13	58.97 Millimeters Standard Deviation 17.40	—	—	—
Patient Global Assessment of Disease Activity Visual Analogue Scale (VAS) up to Week 48 Week 28	12.74 Millimeters Standard Deviation 15.07	11.97 Millimeters Standard Deviation 14.10	—	—	—
Patient Global Assessment of Disease Activity Visual Analogue Scale (VAS) up to Week 48 Week 32	10.80 Millimeters Standard Deviation 11.36	10.78 Millimeters Standard Deviation 15.33	—	—	—
Patient Global Assessment of Disease Activity Visual Analogue Scale (VAS) up to Week 48 Week 36	10.30 Millimeters Standard Deviation 13.20	11.99 Millimeters Standard Deviation 16.23	—	—	—
Patient Global Assessment of Disease Activity Visual Analogue Scale (VAS) up to Week 48 Week 40	10.94 Millimeters Standard Deviation 14.12	10.62 Millimeters Standard Deviation 13.49	—	—	—
Patient Global Assessment of Disease Activity Visual Analogue Scale (VAS) up to Week 48 Week 44	10.06 Millimeters Standard Deviation 12.14	9.50 Millimeters Standard Deviation 11.30	—	—	—
Patient Global Assessment of Disease Activity Visual Analogue Scale (VAS) up to Week 48 Week 48	9.99 Millimeters Standard Deviation 13.88	8.13 Millimeters Standard Deviation 10.52	—	—	—
Patient Global Assessment of Disease Activity Visual Analogue Scale (VAS) up to Week 48 LOCF visit	10.21 Millimeters Standard Deviation 13.96	8.97 Millimeters Standard Deviation 11.63	—	—	—

SECONDARY outcome

Timeframe: From baseline to Week 24

Population: Analysis was conducted on the FAS.

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".

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=327 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=74 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w 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.	Phase 2 Arm A2 - Combination Therapy - q2w 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.	Phase 2 Arm D: Non Responders Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Assessment of Pain Reported by the Patient (VAS) Until Week 24 Baseline	58.59 Millimeters Standard Deviation 23.70	66.38 Millimeters Standard Deviation 20.70	—	—	—
Assessment of Pain Reported by the Patient (VAS) Until Week 24 Week 2	47.46 Millimeters Standard Deviation 25.14	53.20 Millimeters Standard Deviation 24.43	—	—	—
Assessment of Pain Reported by the Patient (VAS) Until Week 24 Week 4	42.88 Millimeters Standard Deviation 24.57	43.11 Millimeters Standard Deviation 24.69	—	—	—
Assessment of Pain Reported by the Patient (VAS) Until Week 24 Week 8	34.28 Millimeters Standard Deviation 25.94	35.95 Millimeters Standard Deviation 24.62	—	—	—
Assessment of Pain Reported by the Patient (VAS) Until Week 24 Week 12	31.07 Millimeters Standard Deviation 24.97	29.44 Millimeters Standard Deviation 22.37	—	—	—
Assessment of Pain Reported by the Patient (VAS) Until Week 24 Week 16	30.18 Millimeters Standard Deviation 24.00	32.17 Millimeters Standard Deviation 22.01	—	—	—
Assessment of Pain Reported by the Patient (VAS) Until Week 24 Week 20	28.26 Millimeters Standard Deviation 24.16	26.58 Millimeters Standard Deviation 22.13	—	—	—
Assessment of Pain Reported by the Patient (VAS) Until Week 24 Week 24	26.43 Millimeters Standard Deviation 23.30	23.56 Millimeters Standard Deviation 21.17	—	—	—
Assessment of Pain Reported by the Patient (VAS) Until Week 24 LOCF visit	29.78 Millimeters Standard Deviation 25.18	27.34 Millimeters Standard Deviation 24.41	—	—	—

SECONDARY outcome

Timeframe: Baseline, from week 28 until week 48

Population: Analysis was conducted on the FAS.

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".

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=90 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=89 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w 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.	Phase 2 Arm A2 - Combination Therapy - q2w 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.	Phase 2 Arm D: Non Responders Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Assessment of Pain Reported by the Patient (VAS) Until Week 48 Baseline	56.00 Millimeters Standard Deviation 23.56	55.73 Millimeters Standard Deviation 21.68	—	—	—
Assessment of Pain Reported by the Patient (VAS) Until Week 48 Week 28	15.67 Millimeters Standard Deviation 17.65	17.33 Millimeters Standard Deviation 20.14	—	—	—
Assessment of Pain Reported by the Patient (VAS) Until Week 48 Week 32	17.27 Millimeters Standard Deviation 17.69	17.08 Millimeters Standard Deviation 20.47	—	—	—
Assessment of Pain Reported by the Patient (VAS) Until Week 48 Week 36	14.36 Millimeters Standard Deviation 15.65	18.81 Millimeters Standard Deviation 23.88	—	—	—
Assessment of Pain Reported by the Patient (VAS) Until Week 48 Week 40	17.07 Millimeters Standard Deviation 17.86	16.96 Millimeters Standard Deviation 20.89	—	—	—
Assessment of Pain Reported by the Patient (VAS) Until Week 48 Week 44	16.27 Millimeters Standard Deviation 17.70	15.05 Millimeters Standard Deviation 18.02	—	—	—
Assessment of Pain Reported by the Patient (VAS) Until Week 48 Week 48	16.31 Millimeters Standard Deviation 19.85	11.90 Millimeters Standard Deviation 15.56	—	—	—
Assessment of Pain Reported by the Patient (VAS) Until Week 48 LOCF visit	16.41 Millimeters Standard Deviation 19.76	12.74 Millimeters Standard Deviation 15.99	—	—	—

SECONDARY outcome

Timeframe: From baseline to Week 24

Population: Analysis was conducted on the FAS.

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.

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=327 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=74 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w 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.	Phase 2 Arm A2 - Combination Therapy - q2w 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.	Phase 2 Arm D: Non Responders Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Health Assessment Questionnaire-Disability Index (HAQ-DI) up to Week 24 Baseline	1.36 HAQ-DI score Standard Deviation 0.70	1.49 HAQ-DI score Standard Deviation 0.76	—	—	—
Health Assessment Questionnaire-Disability Index (HAQ-DI) up to Week 24 Week 2	1.18 HAQ-DI score Standard Deviation 0.69	1.39 HAQ-DI score Standard Deviation 0.74	—	—	—
Health Assessment Questionnaire-Disability Index (HAQ-DI) up to Week 24 Week 4	1.05 HAQ-DI score Standard Deviation 0.69	1.20 HAQ-DI score Standard Deviation 0.74	—	—	—
Health Assessment Questionnaire-Disability Index (HAQ-DI) up to Week 24 Week 8	0.95 HAQ-DI score Standard Deviation 0.71	1.10 HAQ-DI score Standard Deviation 0.75	—	—	—
Health Assessment Questionnaire-Disability Index (HAQ-DI) up to Week 24 Week 12	0.91 HAQ-DI score Standard Deviation 0.71	0.99 HAQ-DI score Standard Deviation 0.74	—	—	—
Health Assessment Questionnaire-Disability Index (HAQ-DI) up to Week 24 Week 16	0.87 HAQ-DI score Standard Deviation 0.70	0.99 HAQ-DI score Standard Deviation 0.72	—	—	—
Health Assessment Questionnaire-Disability Index (HAQ-DI) up to Week 24 Week 20	0.83 HAQ-DI score Standard Deviation 0.71	0.88 HAQ-DI score Standard Deviation 0.70	—	—	—
Health Assessment Questionnaire-Disability Index (HAQ-DI) up to Week 24 Week 24	0.82 HAQ-DI score Standard Deviation 0.70	0.85 HAQ-DI score Standard Deviation 0.71	—	—	—
Health Assessment Questionnaire-Disability Index (HAQ-DI) up to Week 24 LOCF visit	0.88 HAQ-DI score Standard Deviation 0.73	0.97 HAQ-DI score Standard Deviation 0.76	—	—	—

SECONDARY outcome

Timeframe: Baseline, from week 28 until week 48

Population: Analysis was conducted on the FAS.

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.

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=90 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=89 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w 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.	Phase 2 Arm A2 - Combination Therapy - q2w 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.	Phase 2 Arm D: Non Responders Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Health Assessment Questionnaire-Disability Index (HAQ-DI) up to Week 48 Baseline	1.20 HAQ-DI score Standard Deviation 0.70	1.21 HAQ-DI score Standard Deviation 0.68	—	—	—
Health Assessment Questionnaire-Disability Index (HAQ-DI) up to Week 48 Week 28	0.57 HAQ-DI score Standard Deviation 0.64	0.58 HAQ-DI score Standard Deviation 0.56	—	—	—
Health Assessment Questionnaire-Disability Index (HAQ-DI) up to Week 48 Week 32	0.57 HAQ-DI score Standard Deviation 0.63	0.55 HAQ-DI score Standard Deviation 0.58	—	—	—
Health Assessment Questionnaire-Disability Index (HAQ-DI) up to Week 48 Week 36	0.56 HAQ-DI score Standard Deviation 0.64	0.60 HAQ-DI score Standard Deviation 0.60	—	—	—
Health Assessment Questionnaire-Disability Index (HAQ-DI) up to Week 48 Week 40	0.61 HAQ-DI score Standard Deviation 0.67	0.55 HAQ-DI score Standard Deviation 0.56	—	—	—
Health Assessment Questionnaire-Disability Index (HAQ-DI) up to Week 48 Week 44	0.58 HAQ-DI score Standard Deviation 0.66	0.53 HAQ-DI score Standard Deviation 0.57	—	—	—
Health Assessment Questionnaire-Disability Index (HAQ-DI) up to Week 48 Week 48	0.57 HAQ-DI score Standard Deviation 0.66	0.53 HAQ-DI score Standard Deviation 0.61	—	—	—
Health Assessment Questionnaire-Disability Index (HAQ-DI) up to Week 48 LOCF visit	0.56 HAQ-DI score Standard Deviation 0.66	0.55 HAQ-DI score Standard Deviation 0.61	—	—	—

SECONDARY outcome

Timeframe: From baseline to Week 24

Population: Analysis was conducted on the FAS

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.

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=327 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=74 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w 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.	Phase 2 Arm A2 - Combination Therapy - q2w 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.	Phase 2 Arm D: Non Responders Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) up to Week 24 Baseline	89.16 FACIT-F score Standard Deviation 24.49	81.72 FACIT-F score Standard Deviation 24.75	—	—	—
Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) up to Week 24 Week 2	95.82 FACIT-F score Standard Deviation 25.42	86.64 FACIT-F score Standard Deviation 25.00	—	—	—
Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) up to Week 24 Week 4	99.54 FACIT-F score Standard Deviation 27.15	92.26 FACIT-F score Standard Deviation 25.30	—	—	—
Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) up to Week 24 Week 8	103.46 FACIT-F score Standard Deviation 27.25	96.45 FACIT-F score Standard Deviation 25.88	—	—	—
Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) up to Week 24 Week 12	104.08 FACIT-F score Standard Deviation 26.79	98.29 FACIT-F score Standard Deviation 25.47	—	—	—
Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) up to Week 24 Week 16	105.51 FACIT-F score Standard Deviation 26.94	98.41 FACIT-F score Standard Deviation 27.08	—	—	—
Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) up to Week 24 Week 20	104.91 FACIT-F score Standard Deviation 27.47	102.46 FACIT-F score Standard Deviation 27.24	—	—	—
Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) up to Week 24 Week 24	107.01 FACIT-F score Standard Deviation 27.60	104.36 FACIT-F score Standard Deviation 27.16	—	—	—
Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) up to Week 24 LOCF visit	104.65 FACIT-F score Standard Deviation 28.07	101.38 FACIT-F score Standard Deviation 28.24	—	—	—

SECONDARY outcome

Timeframe: Baseline, from week 28 until week 48

Population: Analysis was conducted on the FAS.

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.

Outcome measures

Outcome measures
Measure	Phase 1: Combination Therapy n=90 Participants Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=89 Participants Participants who achieve 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.	Phase 2 Arm A2 - Monotherapy - q2w 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.	Phase 2 Arm A2 - Combination Therapy - q2w 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.	Phase 2 Arm D: Non Responders Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) up to Week 48 Baseline	17.13 FACIT-F score Standard Deviation 5.67	17.36 FACIT-F score Standard Deviation 5.16	—	—	—
Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) up to Week 48 Week 28	23.12 FACIT-F score Standard Deviation 4.47	23.50 FACIT-F score Standard Deviation 3.82	—	—	—
Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) up to Week 48 Week 32	22.98 FACIT-F score Standard Deviation 4.86	23.62 FACIT-F score Standard Deviation 4.16	—	—	—
Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) up to Week 48 Week 36	22.90 FACIT-F score Standard Deviation 4.64	23.23 FACIT-F score Standard Deviation 4.21	—	—	—
Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) up to Week 48 Week 40	23.02 FACIT-F score Standard Deviation 4.38	23.39 FACIT-F score Standard Deviation 4.40	—	—	—
Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) up to Week 48 Week 44	23.13 FACIT-F score Standard Deviation 4.45	23.48 FACIT-F score Standard Deviation 4.21	—	—	—
Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) up to Week 48 Week 48	22.87 FACIT-F score Standard Deviation 4.87	23.95 FACIT-F score Standard Deviation 3.79	—	—	—
Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) up to Week 48 LOCF visit	22.88 FACIT-F score Standard Deviation 4.85	23.69 FACIT-F score Standard Deviation 4.07	—	—	—

Adverse Events

Phase 1: Tocilizumab Monotherapy

Serious events: 3 serious events

Other events: 24 other events

Deaths: 0 deaths

Phase 1: Combination Therapy

Serious events: 10 serious events

Other events: 119 other events

Deaths: 1 deaths

Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw)

Serious events: 2 serious events

Other events: 17 other events

Deaths: 0 deaths

Phase 2 Arm A2: TCZ +/- nbDMARD Every Two Weeks (q2w)

Serious events: 1 serious events

Other events: 25 other events

Deaths: 0 deaths

Phase 2 Arm B: Participants With Low Disease Activity

Serious events: 2 serious events

Other events: 30 other events

Deaths: 0 deaths

Phase 2 Arm C: Moderate EULAR Response at Week 24

Serious events: 5 serious events

Other events: 23 other events

Deaths: 2 deaths

Phase 2 Arm D: Non Responders

Serious events: 1 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Phase 1: Tocilizumab Monotherapy n=74 participants at risk Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection as a single fixed dose monotherapy once a week for 24 weeks.	Phase 1: Combination Therapy n=327 participants at risk Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=89 participants at risk 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.	Phase 2 Arm A2: TCZ +/- nbDMARD Every Two Weeks (q2w) n=90 participants at risk 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.	Phase 2 Arm B: Participants With Low Disease Activity n=95 participants at risk 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.	Phase 2 Arm C: Moderate EULAR Response at Week 24 n=67 participants at risk Patients who achieved moderate EULAR response at Week 24 continued in the study with initial treatment as per investigator's judgement.	Phase 2 Arm D: Non Responders n=2 participants at risk Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Blood and lymphatic system disorders Neutropenia	0.00% 0/74 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.31% 1/327 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/89 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/90 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/95 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/67 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/2 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.
Cardiac disorders Pericarditis	1.4% 1/74 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/327 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/89 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/90 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/95 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/67 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/2 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.
Cardiac disorders Acute coronary syndrome	0.00% 0/74 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/327 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/89 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/90 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	1.1% 1/95 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/67 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/2 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.
Cardiac disorders Coronary artery disease	0.00% 0/74 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/327 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/89 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/90 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/95 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	1.5% 1/67 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/2 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.
Cardiac disorders Myocardial infarction	0.00% 0/74 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/327 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/89 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/90 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/95 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	1.5% 1/67 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/2 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.
Gastrointestinal disorders Duodenal perforation	0.00% 0/74 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.31% 1/327 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/89 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/90 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/95 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/67 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/2 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.
Gastrointestinal disorders Intestinal obstruction	0.00% 0/74 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.31% 1/327 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/89 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/90 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/95 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/67 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/2 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.
Gastrointestinal disorders Ascites	0.00% 0/74 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/327 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/89 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/90 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/95 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/67 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	50.0% 1/2 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.
Gastrointestinal disorders Diverticular perforation	0.00% 0/74 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/327 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/89 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	1.1% 1/90 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/95 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/67 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/2 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.
Gastrointestinal disorders Ileus	0.00% 0/74 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/327 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	1.1% 1/89 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/90 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/95 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/67 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/2 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.
Hepatobiliary disorders Biliary fistula	0.00% 0/74 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.31% 1/327 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/89 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/90 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/95 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/67 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/2 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.
Infections and infestations Breast abscess	0.00% 0/74 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/327 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/89 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/90 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	1.1% 1/95 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/67 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/2 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.
Infections and infestations Abscess limb	0.00% 0/74 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.31% 1/327 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/89 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/90 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/95 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/67 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/2 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.
Infections and infestations Pneumonia	0.00% 0/74 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.61% 2/327 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/89 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/90 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/95 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/67 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/2 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.
Injury, poisoning and procedural complications Spinal fracture	0.00% 0/74 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/327 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/89 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/90 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/95 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	1.5% 1/67 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/2 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.
Musculoskeletal and connective tissue disorders Rheumatoid arthritis	0.00% 0/74 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/327 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/89 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/90 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/95 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	1.5% 1/67 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/2 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastatic malignant melanoma	0.00% 0/74 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/327 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	1.1% 1/89 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/90 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/95 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/67 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/2 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.
Nervous system disorders Headache	1.4% 1/74 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/327 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/89 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/90 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/95 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/67 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/2 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.
Respiratory, thoracic and mediastinal disorders Interstitial lung disease	0.00% 0/74 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.31% 1/327 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/89 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/90 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/95 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/67 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/2 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.00% 0/74 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.61% 2/327 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/89 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/90 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/95 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/67 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/2 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.
Infections and infestations Pyelonephritis acute	0.00% 0/74 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.31% 1/327 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/89 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/90 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/95 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/67 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/2 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/74 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.31% 1/327 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/89 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/90 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/95 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/67 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/2 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Invasive ductal breast carcinoma	0.00% 0/74 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.31% 1/327 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/89 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/90 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/95 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/67 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/2 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Urinary tract neoplasm	0.00% 0/74 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.31% 1/327 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/89 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/90 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/95 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/67 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/2 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.
Vascular disorders Deep vein thrombosis	1.4% 1/74 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/327 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/89 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/90 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/95 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/67 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/2 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.
Vascular disorders Thrombophlebitis	0.00% 0/74 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.31% 1/327 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/89 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/90 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/95 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/67 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/2 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.
Vascular disorders Hypertensive crisis	0.00% 0/74 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/327 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/89 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/90 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/95 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	1.5% 1/67 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/2 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.

Other adverse events

Other adverse events
Measure	Phase 1: Tocilizumab Monotherapy n=74 participants at risk Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection as a single fixed dose monotherapy once a week for 24 weeks.	Phase 1: Combination Therapy n=327 participants at risk Participants received Tocilizumab (TCZ), 162mg, by sub-cutaneous injection in combination with oral or sub-cutaneous methotrexate (MTX) or other non-biologic Disease Modifying Anti Rheumatic Drugs (nbDMARDs) once a week for 24 weeks.	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) n=89 participants at risk 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.	Phase 2 Arm A2: TCZ +/- nbDMARD Every Two Weeks (q2w) n=90 participants at risk 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.	Phase 2 Arm B: Participants With Low Disease Activity n=95 participants at risk 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.	Phase 2 Arm C: Moderate EULAR Response at Week 24 n=67 participants at risk Patients who achieved moderate EULAR response at Week 24 continued in the study with initial treatment as per investigator's judgement.	Phase 2 Arm D: Non Responders n=2 participants at risk Patients who didn't achieve any therapeutic response up to week 24 and were discontinued from the study.
Blood and lymphatic system disorders Neutropenia	5.4% 4/74 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	5.5% 18/327 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	1.1% 1/89 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	5.6% 5/90 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	3.2% 3/95 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	3.0% 2/67 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/2 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.
Blood and lymphatic system disorders Thrombocytopenia	5.4% 4/74 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	2.8% 9/327 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/89 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/90 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/95 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/67 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/2 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.
Gastrointestinal disorders Nausea	1.4% 1/74 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	5.5% 18/327 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/89 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/90 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/95 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/67 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/2 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.
General disorders Injection site erythema	8.1% 6/74 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	3.1% 10/327 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/89 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/90 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/95 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/67 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/2 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.
Infections and infestations Upper respiratory tract infection	2.7% 2/74 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	7.0% 23/327 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	10.1% 9/89 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	7.8% 7/90 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	3.2% 3/95 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	6.0% 4/67 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/2 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.
Infections and infestations Urinary tract infection	8.1% 6/74 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	7.0% 23/327 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	3.4% 3/89 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	2.2% 2/90 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	8.4% 8/95 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	4.5% 3/67 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/2 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.
Investigations Transaminases increased	1.4% 1/74 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	11.3% 37/327 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/89 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/90 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/95 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/67 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/2 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.
Musculoskeletal and connective tissue disorders Back pain	5.4% 4/74 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	4.6% 15/327 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/89 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/90 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/95 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/67 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/2 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.
General disorders Oedema peripheral	0.00% 0/74 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/327 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/89 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	1.1% 1/90 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	3.2% 3/95 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	6.0% 4/67 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/2 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.
Infections and infestations Nasopharyngitis	0.00% 0/74 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/327 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	2.2% 2/89 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	4.4% 4/90 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	5.3% 5/95 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	6.0% 4/67 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/2 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.
Infections and infestations Respiratory tract infection	0.00% 0/74 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/327 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	2.2% 2/89 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	3.3% 3/90 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	5.3% 5/95 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	4.5% 3/67 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/2 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.
Musculoskeletal and connective tissue disorders Rheumatoid arthritis	0.00% 0/74 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/327 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	2.2% 2/89 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	3.3% 3/90 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	6.3% 6/95 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	4.5% 3/67 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/2 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.
Nervous system disorders Headache	0.00% 0/74 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/327 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	2.2% 2/89 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	1.1% 1/90 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/95 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	6.0% 4/67 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/2 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.
Vascular disorders Hypertension	0.00% 0/74 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/327 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	2.2% 2/89 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	1.1% 1/90 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	5.3% 5/95 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	1.5% 1/67 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.	0.00% 0/2 • After initiation of study drug, all AEs, regardless of relationship to study drug, are reported until study closure. In this section the arms are not mutually exclusive because they report AE data across two different phases of the study. The patients in phase 2 groups B,C and D were considered in this study for safety reporting purposes only. 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.

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