ROSE: A Study of Tocilizumab in Combination With DMARDs in Patients With Moderate to Severe Rheumatoid Arthritis

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00531817
• Collaborator: (none)
• Enrollment: 619
• Locations: 157
• Arms: 2
• Duration (Months): 41
• Patients Per Site: 3.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This 2-arm study assessed the safety and efficacy of tocilizumab versus placebo, both in combination with disease modifying antirheumatic drugs (DMARDs), in regard to reduction in signs and symptoms, in patients with moderate to severe active rheumatoid arthritis with an inadequate response to DMARDs. Patients were randomized in a ratio of 2:1 to receive either tocilizumab 8 mg/kg intravenously (IV) or placebo IV every 4 weeks. All patients also received stable antirheumatic therapy, including permitted DMARDs. The anticipated time on study treatment was 3-12 months and the target sample size was 500+ individuals.

Condition or Disease	Intervention/Treatment	Phase
Rheumatoid Arthritis	Drug: Tocilizumab; Drug: Placebo; Drug: Permitted DMARDs	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 619 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Parallel-group Study to Evaluate the Safety and Efficacy of Tocilizumab (TCZ) Versus Placebo in Combination With Disease Modifying Antirheumatic Drugs (DMARDs) in Patients With Moderate to Severe Active Rheumatoid Arthritis (RA)
• Study Start Date: Oct 1, 2007
• Actual Primary Completion Date: Jun 1, 2009
• Actual Study Completion Date: Mar 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tocilizumab 8 mg/kg + DMARDs	Drug: Tocilizumab; Tocilizumab intravenously at a dose of 8 mg/kg over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.; Other Names: Actemra RoActemra ; Drug: Permitted DMARDs; As prescribed. The following DMARDs were permitted in this study: methotrexate (MTX), chloroquine, hydroxychloroquine, parenteral gold, sulfasalazine, azathioprine, and leflunomide. These DMARDs could be used alone or in combination, except for the combination of MTX and leflunomide, which was not allowed.
Placebo Comparator: Placebo + DMARDs	Drug: Placebo; Placebo IV over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.; Drug: Permitted DMARDs; As prescribed. The following DMARDs were permitted in this study: methotrexate (MTX), chloroquine, hydroxychloroquine, parenteral gold, sulfasalazine, azathioprine, and leflunomide. These DMARDs could be used alone or in combination, except for the combination of MTX and leflunomide, which was not allowed.

Outcome Measures

Primary Outcome Measures

1. Percentage of Patients With an Improvement of at Least 50% in American College of Rheumatology (ACR) Score (ACR50) From Baseline at Week 24 [Baseline to Week 24]

   Improvement must be seen in tender and swollen joint counts and in at least 3 of the following 5 parameters. Patient and physician assessment of patient disease activity (DA) in previous 24 hours on a visual analog scale (VAS, no DA to maximum DA); patient assessment of pain in previous 24 hours on a VAS (none to unbearable); Health Assessment Questionnaire-Disability Index (20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do); and C-reactive protein or, if missing, erythrocyte sedimentation rate.

Secondary Outcome Measures

1. Percentage of Patients With an Improvement of at Least 20%, 50%, or 70% in American College of Rheumatology (ACR) Score (ACR20, ACR50, ACR70) From Baseline at Weeks 4, 8, 12, 16, 20, and 24 [Baseline to Weeks 4, 8, 12, 16, 20, 24]

   Improvement must be seen in tender and swollen joint counts and in at least 3 of the following 5 parameters. Patient and physician assessment of patient disease activity (DA) in previous 24 hours on a visual analog scale (VAS, no DA to maximum DA); patient assessment of pain in previous 24 hours on a VAS (none to unbearable); Health Assessment Questionnaire-Disability Index (20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do); and C reactive protein or, if missing, erythrocyte sedimentation rate.

2. Mean Change From Baseline in Disease Activity Score 28 (DAS28) at Weeks 4, 8, 12, 16, 20, and 24 [Baseline to Weeks 4, 8, 12, 16, 20, 24]

   DAS28 was calculated using the following formula: 0.56 × sqrt(TJC) + 0.28 × sqrt(SJC) + 0.70 × ln(ESR) + 0.014 × GH, where TJC = tender joint count on 28 joints, SJC = swollen joint count on 28 joints, ESR = erythrocyte sedimentation rate at the current visit (mm/hr), and GH = general health, ie, the patient's global assessment of disease activity (DA) in the previous 24 hours on a 100 mm visual analog scale (no DA to maximum DA). The DAS28 score ranges from 0 to 10, with higher scores indicating more rheumatoid arthritis. A negative change score indicates improvement.

3. Percentage of Patients With European League Against Rheumatism (EULAR) Good, Moderate, or no Response at Weeks 4, 8, 12, 16, 20, and 24 [Baseline to Weeks 4, 8, 12, 16, 20, and 24]

   Change of the DAS28 score from baseline was used to determine the EULAR responses of good, moderate, or no response. For a post-baseline score ≤ 3.2, a change from baseline of < -1.2 was a good response, < -0.6 to ≥ -1.2 was a moderate response, and ≥ -0.6 was no response. For a post-baseline score > 3.2 to ≤ 5.1, a change from baseline of < -0.6 was a moderate response and ≥ -0.6 was no response. For a post-baseline score > 5.1, a change from baseline < -1.2 was a moderate response and ≥ -1.2 was no response. A good response could not be achieved for post-baseline scores > 3.2.

4. Mean Change From Baseline in the Routine Assessment Patient Index Data (RAPID) Score at Weeks 4, 8, 12, 16, 20, and 24 [Baseline to Weeks 4, 8, 12, 16, 20, and 24]

   Derived from the Multidimensional Health Assessment Questionnaire (MDHAQ), the RAPID includes 3 domains that assess disease activity in rheumatoid arthritis: A physical function score (MDHAQ items 1a-j), a pain visual analog scale score (VAS, item 2 in the MDHAQ), and a global assessment of disease activity VAS score (item 6 in the MDHAQ). Each domain is scored on a scale of 0-10. The RAPID score is the sum of the 3 domain scores divided by 3 resulting in a total score on a scale of 0-10. Higher scores indicate more disease activity and a negative change from baseline indicates improvement.

5. Mean Change From Baseline in 12-Item Short Form Health Survey v2 (SF-12) Scores at Weeks 4, 8, 12, 16, 20, and 24 [Baseline to Weeks 4, 8, 12, 16, 20, and 24]

   The SF-12 is a self-report measure of general health status with 1 or 2 items for each of 8 domains: Physical functioning, role limitations due to physical health problems, bodily pain, general health, vitality, social functioning, role limitations due to emotional problems, and mental health. Two component summaries, physical (PCS-12) and mental (MCS-12) were calculated using norm-based scoring, resulting in means of 50 and standard deviations of 10 in the 1998 general United States population. Higher scores represent better health and a positive change from baseline represents improvement.

6. Mean Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Weeks 4, 8, 12, 16, 20, and 24 [Baseline to Weeks 4, 8, 12, 16, 20, and 24]

   The FACIT-F is a 13-item patient self-report questionnaire that assesses fatigue over the previous 7 days by scoring each item on a 5-point scale (0=Not at all, 1=A little bit, 2=Somewhat, 3=Quite a bit, 4=Very much). An overall FACIT-F score was obtained by summing the scores of all 13 items. The overall score ranged from 0 to 52. A lower score indicates less fatigue. A negative change score indicates improvement.

7. Mean Change From Baseline in the Medical Outcomes Study (MOS) Sleep Scale Score at Weeks 4, 8, 12, 16, 20, and 24 [Baseline to Weeks 4, 8, 12, 16, 20, and 24]

   The MOS Sleep Scale is a 12-item patient self-report instrument that assesses the quality and quantity of sleep over the previous 4 weeks. A sleep problems index (SLP9) was generated using 9 of the 12 items (1, 3, 4, 5, 6, 7, 8, 9, 12). Each item was normalized so that the lowest and highest possible scores were set to 0 and 100, respectively. The SLP9 score is the average of the recoded 9 items. The SLP9 score ranged from 0 to 100. Higher scores represent greater sleep problems. A negative change score indicates improvement.

8. Mean Change From Baseline in Individual Components of the Routine Assessment Patient Index Data (RAPID) at Each Day During the First 7 Days of Treatment [Baseline through Day 7]

   Derived from the Multidimensional Health Assessment Questionnaire (MDHAQ), the RAPID includes 3 domains that assess disease activity in rheumatoid arthritis: A physical function score (0-10), a pain visual analog scale score (VAS, 0-100), and a global assessment of disease activity VAS score (0-100). Each domain was assessed with the Patient Take Home Form (PTHF). Higher scores indicate more disease activity. A negative change score indicates improvement.

9. Percentage of Patients With an Improvement of at Least 20%, 50%, or 70% in American College of Rheumatology (ACR) Score (ACR20, ACR50, ACR70) From Baseline at Day 7 [Baseline to Day 7]

   Improvement must be seen in tender and swollen joint counts and in at least 3 of the following 5 parameters. Patient and physician assessment of patient disease activity (DA) in previous 24 hours on a visual analog scale (VAS, no DA to maximum DA); patient assessment of pain in previous 24 hours on a VAS (none to unbearable); Health Assessment Questionnaire-Disability Index (20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do); and C reactive protein or, if missing, erythrocyte sedimentation rate.

10. Mean Change From Baseline in C-reactive Protein (CRP) at Days 3 and 7 [Baseline to Days 3 and 7]

    Serum concentration of CRP (high-sensitivity CRP [hsCRP] test) was analyzed by a central laboratory.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Adult patients, ≥18 years of age

• Active rheumatoid arthritis of >6 months duration

• Received permitted DMARDs each at a stable dose for at least 7 weeks prior to baseline

Exclusion Criteria:

• Rheumatic autoimmune disease or inflammatory joint disease other than rheumatoid arthritis

• Major surgery within 8 weeks prior to screening or planned within 6 months following randomization

• Unsuccessful treatment with a biologic agent, including an anti-TNF agent

• Previous treatment with tocilizumab

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Birmingham	Alabama	United States	35205
2		Birmingham	Alabama	United States	35215
3		Birmingham	Alabama	United States	35294-7201
4		Montgomery	Alabama	United States	36111
5		Lake Havasu City	Arizona	United States	86403
6		Paradise Valley	Arizona	United States	85253
7		Peoria	Arizona	United States	85381
8		Scottsdale	Arizona	United States	85251
9		Scottsdale	Arizona	United States	85258
10		Jonesboro	Arkansas	United States	72401
11		Beverly Hills	California	United States	90211
12		Escondido	California	United States	92025
13		La Jolla	California	United States	92037
14		Long Beach	California	United States	90815
15		Los Angeles	California	United States	90095
16		Pasadena	California	United States	91107
17		Santa Maria	California	United States	93454
18		Santa Monica	California	United States	90404
19		Upland	California	United States	91786
20		Van Nuys	California	United States	91405
21		Walnut Creek	California	United States	94598
22		Whittier	California	United States	90606
23		Colorado Springs	Colorado	United States	80910
24		Trumbull	Connecticut	United States	06611
25		Washington	District of Columbia	United States	20006
26		Dunedin	Florida	United States	34698
27		Fort Lauderdale	Florida	United States	33334
28		Lake Mary	Florida	United States	32746
29		Melbourne	Florida	United States	32901
30		Miami	Florida	United States	33133
31		Ocala	Florida	United States	34474
32		Orange Park	Florida	United States	32073
33		Orlando	Florida	United States	32804
34		Palm Harbor	Florida	United States	34684
35		Plantation	Florida	United States	33317
36		Sarasota	Florida	United States	34239
37		Tamarac	Florida	United States	33321
38		Tampa	Florida	United States	33609
39		Atlanta	Georgia	United States	30342
40		Blue Ridge	Georgia	United States	30513
41		Fort Valley	Georgia	United States	31030
42		Tifton	Georgia	United States	311794
43		Boise	Idaho	United States	83702
44		Idaho Falls	Idaho	United States	83404
45		Nampa	Idaho	United States	83687
46		Downers Grove	Illinois	United States	60515
47		Springfield	Illinois	United States	62704
48		Evansville	Indiana	United States	47714
49		Munster	Indiana	United States	46321
50		South Bend	Indiana	United States	46601
51		Leawood	Kansas	United States	66209
52		Bowling Green	Kentucky	United States	42102
53		Lexington	Kentucky	United States	40515
54		Baton Rouge	Louisiana	United States	70808
55		Baton Rouge	Louisiana	United States	70810
56		Monroe	Louisiana	United States	71203
57		New Orleans	Louisiana	United States	70112
58		Wheaton	Maryland	United States	20902
59		Mansfield	Massachusetts	United States	02048
60		Worcester	Massachusetts	United States	01605
61		Worcester	Massachusetts	United States	01610
62		Kalamazoo	Michigan	United States	49009
63		St Clair Shores	Michigan	United States	48080
64		Eagan	Minnesota	United States	55121
65		Flowood	Mississippi	United States	39232
66		Tupelo	Mississippi	United States	38802
67		Florissant	Missouri	United States	63031
68		St Louis	Missouri	United States	63141
69		Billings	Montana	United States	59101
70		Kalispell	Montana	United States	59907
71		Missoula	Montana	United States	59802
72		Grand Island	Nebraska	United States	68803
73		Las Vegas	Nevada	United States	89106
74		Las Vegas	Nevada	United States	89128
75		Reno	Nevada	United States	89502
76		Dover	New Hampshire	United States	03820
77		Freehold	New Jersey	United States	07728
78		New Brunswick	New Jersey	United States	08903
79		Passaic	New Jersey	United States	07055
80		Teaneck	New Jersey	United States	07666
81		Bronx	New York	United States	10451
82		Mineola	New York	United States	11501
83		New York	New York	United States	10003
84		New York	New York	United States	10029
85		Orchard Park	New York	United States	14127
86		Smithtown	New York	United States	11787
87		Belmont	North Carolina	United States	28012
88		Charlotte	North Carolina	United States	28209
89		Charlotte	North Carolina	United States	28210
90		Durham	North Carolina	United States	27704
91		Greensboro	North Carolina	United States	27408
92		Greenville	North Carolina	United States	27834
93		Hickory	North Carolina	United States	28601
94		Rock Hill	North Carolina	United States	29732
95		Akron	Ohio	United States	44333
96		Beechwood	Ohio	United States	44122
97		Mayfield	Ohio	United States	44143
98		Middleburg Heights	Ohio	United States	44130
99		Perrysburg	Ohio	United States	43551
100		Zanesville	Ohio	United States	43701
101		Norman	Oklahoma	United States	73069
102		Oklahoma City	Oklahoma	United States	73103
103		Oklahoma City	Oklahoma	United States	73104
104		Lake Oswego	Oregon	United States	97035
105		Portland	Oregon	United States	97239
106		Salem	Oregon	United States	97302
107		Bethlehem	Pennsylvania	United States	10817
108		Philadelphia	Pennsylvania	United States	19102
109		Philadelphia	Pennsylvania	United States	19152
110		Pittsburgh	Pennsylvania	United States	15261
111		Wexford	Pennsylvania	United States	15090
112		Willow Grove	Pennsylvania	United States	80045
113		Charleston	South Carolina	United States	29407
114		Columbia	South Carolina	United States	29204
115		Florence	South Carolina	United States	29506
116		Greenville	South Carolina	United States	29601
117		Myrtle Beach	South Carolina	United States	29572
118		Rapid City	South Dakota	United States	57701
119		Rapid City	South Dakota	United States	57702
120		Sioux Falls	South Dakota	United States	57105
121		Watertown	South Dakota	United States	57201
122		Crossville	Tennessee	United States	38555
123		Hendersonville	Tennessee	United States	37073
124		Jackson	Tennessee	United States	38305
125		Knoxville	Tennessee	United States	37909
126		Memphis	Tennessee	United States	38119
127		Nashville	Tennessee	United States	37203
128		Amarillo	Texas	United States	79106
129		Amarillo	Texas	United States	79124
130		Bellaire	Texas	United States	77401
131		Carrollton	Texas	United States	75007
132		Dallas	Texas	United States	75231
133		Fort Worth	Texas	United States	76107
134		Houston	Texas	United States	77004
135		Houston	Texas	United States	77034
136		Houston	Texas	United States	77074
137		Houston	Texas	United States	77090
138		Mesquite	Texas	United States	75150
139		San Antonio	Texas	United States	78217
140		San Antonio	Texas	United States	78229
141		San Antonio	Texas	United States	78258
142		Temple	Texas	United States	76508
143		Waco	Texas	United States	76708
144		Salt Lake City	Utah	United States	84132
145		Burlington	Vermont	United States	05401
146		Burke	Virginia	United States	22015
147		Reston	Virginia	United States	22102
148		Salem	Virginia	United States	24153
149		Seattle	Washington	United States	98133
150		Seattle	Washington	United States	98195
151		Spokane	Washington	United States	99204-2336
152		Beckley	West Virginia	United States	25801
153		Clarksburg	West Virginia	United States	26301
154		Milwaukee	Wisconsin	United States	53209
155		Onalaska	Wisconsin	United States	54605
156		Wausau	Wisconsin	United States	54401
157		San Juan		Puerto Rico	00918

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Clinical Study Report Synopsis

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT00531817
• Other Study ID Numbers: ML21136
• First Posted: Sep 19, 2007
• Last Update Posted: Aug 20, 2012
• Last Verified: Aug 1, 2012

• Additional relevant MeSH terms: Arthritis; Arthritis, Rheumatoid

Study Results

Participant Flow

Arm/Group Title	Tocilizumab 8 mg/kg + DMARDs	Placebo + DMARDs
Arm/Group Description	Tocilizumab intravenously at a dose of 8 mg/kg over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.	Placebo IV over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.
Period Title: Randomized
STARTED	412	207
Received Study Drug in Core Study	409	205
COMPLETED	353	173
NOT COMPLETED	59	34
Period Title: Randomized
STARTED	343	170
COMPLETED	206	113
NOT COMPLETED	137	57

Baseline Characteristics

Arm/Group Title	Tocilizumab 8 mg/kg + DMARDs	Placebo + DMARDs	Total
Arm/Group Description	Tocilizumab intravenously at a dose of 8 mg/kg over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.	Placebo IV over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.	Total of all reporting groups
Overall Participants	409	205	614
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.2 (12.06)	55.8 (12.42)	55.5 (12.24)
Sex: Female, Male (Count of Participants)
Female	325 79.5%	172 83.9%	497 80.9%
Male	84 20.5%	33 16.1%	117 19.1%

Outcome Measures

1. Secondary Outcome

Title	Percentage of Patients With an Improvement of at Least 20%, 50%, or 70% in American College of Rheumatology (ACR) Score (ACR20, ACR50, ACR70) From Baseline at Weeks 4, 8, 12, 16, 20, and 24
Description	Improvement must be seen in tender and swollen joint counts and in at least 3 of the following 5 parameters. Patient and physician assessment of patient disease activity (DA) in previous 24 hours on a visual analog scale (VAS, no DA to maximum DA); patient assessment of pain in previous 24 hours on a VAS (none to unbearable); Health Assessment Questionnaire-Disability Index (20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do); and C reactive protein or, if missing, erythrocyte sedimentation rate.
Time Frame	Baseline to Weeks 4, 8, 12, 16, 20, 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized patients who received at least 1 dose of study medication. In determining ACR status, a last observation carried forward (LOCF) approach was used for missing joint count data. Patients with missing data or who escaped were classified as non-responders.

Arm/Group Title	Tocilizumab 8 mg/kg + DMARDs	Placebo + DMARDs
Arm/Group Description	Tocilizumab intravenously at a dose of 8 mg/kg over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.	Placebo IV over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.
Measure Participants	409	205
ACR20, Week 4	34.2 8.4%	17.6 8.6%
ACR20, Week 8	46.5 11.4%	25.4 12.4%
ACR20, Week 12	49.6 12.1%	28.8 14%
ACR20, Week 16	47.7 11.7%	28.8 14%
ACR20, Week 20	45.2 11.1%	25.9 12.6%
ACR20, Week 24	44.7 10.9%	25.4 12.4%
ACR50, Week 4	12.5 3.1%	3.4 1.7%
ACR50, Week 8	20.8 5.1%	5.4 2.6%
ACR50, Week 12	25.2 6.2%	14.1 6.9%
ACR50, Week 16	26.7 6.5%	15.1 7.4%
ACR50, Week 20	28.4 6.9%	12.7 6.2%
ACR70, Week 4	4.4 1.1%	1.5 0.7%
ACR70, Week 8	6.8 1.7%	0.5 0.2%
ACR70, Week 12	11.5 2.8%	4.9 2.4%
ACR70, Week 16	12.5 3.1%	3.4 1.7%
ACR70, Week 20	16.9 4.1%	5.4 2.6%
ACR70, Week 24	15.4 3.8%	1.5 0.7%

2. Primary Outcome

Title	Percentage of Patients With an Improvement of at Least 50% in American College of Rheumatology (ACR) Score (ACR50) From Baseline at Week 24
Description	Improvement must be seen in tender and swollen joint counts and in at least 3 of the following 5 parameters. Patient and physician assessment of patient disease activity (DA) in previous 24 hours on a visual analog scale (VAS, no DA to maximum DA); patient assessment of pain in previous 24 hours on a VAS (none to unbearable); Health Assessment Questionnaire-Disability Index (20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do); and C-reactive protein or, if missing, erythrocyte sedimentation rate.
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized patients who received at least 1 dose of study medication. In determining ACR status, a last observation carried forward (LOCF) approach was used for missing joint count data. Patients with missing data or who escaped were classified as non-responders.

Arm/Group Title	Tocilizumab 8 mg/kg + DMARDs	Placebo + DMARDs
Arm/Group Description	Tocilizumab intravenously at a dose of 8 mg/kg over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.	Placebo IV over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.
Measure Participants	409	205
Number [Percentage of participants]	30.1 7.4%	11.2 5.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tocilizumab 8 mg/kg + DMARDs, Placebo + DMARDs
	Comments	Power calculation: Assuming placebo+DMARDs response rate of 15% and tocilizumab 8 mg/kg+DMARDs response rate of 28% based on previous trials, a sample size of 570 patients (2:1 ratio, tocilizumab+DMARDs n=380 and placebo+DMARDs n=190) will provide > 90% power to detect a difference between 2 treatment arms with 5% Type I error with a 2-sided Fisher's exact test. Null Hypothesis: The percentage of patients responding in each treatment group (tocilizumab+DMARDs vs placebo+ DMARDs) is the same.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	The p-value was not adjusted. The primary objective was a single comparison with an a priori threshold of 0.05 for statistical significance.
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	18.85
	Confidence Interval	(2-Sided) 95%; 12.29 to 25.42
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Mean Change From Baseline in Disease Activity Score 28 (DAS28) at Weeks 4, 8, 12, 16, 20, and 24
Description	DAS28 was calculated using the following formula: 0.56 × sqrt(TJC) + 0.28 × sqrt(SJC) + 0.70 × ln(ESR) + 0.014 × GH, where TJC = tender joint count on 28 joints, SJC = swollen joint count on 28 joints, ESR = erythrocyte sedimentation rate at the current visit (mm/hr), and GH = general health, ie, the patient's global assessment of disease activity (DA) in the previous 24 hours on a 100 mm visual analog scale (no DA to maximum DA). The DAS28 score ranges from 0 to 10, with higher scores indicating more rheumatoid arthritis. A negative change score indicates improvement.
Time Frame	Baseline to Weeks 4, 8, 12, 16, 20, 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized patients who received at least 1 dose of study medication. No imputation of missing data was made; only observed data are reported.

Arm/Group Title	Tocilizumab 8 mg/kg + DMARDs	Placebo + DMARDs
Arm/Group Description	Tocilizumab intravenously at a dose of 8 mg/kg over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.	Placebo IV over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.
Measure Participants	409	205
Week 4, n=391, 194	-1.77 (1.264)	-0.45 (1.065)
Week 8, n= 382, 190	-2.32 (1.454)	-0.72 (1.047)
Week 12, n=361, 188	-2.63 (1.433)	-0.97 (1.242)
Week 16, n=343, 183	-2.63 (1.605)	-0.93 (1.289)
Week 20, n=273, 120	-3.14 (1.535)	-1.36 (1.353)
Week 24, n=265, 116	-3.18 (1.526)	-1.23 (1.273)

4. Secondary Outcome

Title	Percentage of Patients With European League Against Rheumatism (EULAR) Good, Moderate, or no Response at Weeks 4, 8, 12, 16, 20, and 24
Description	Change of the DAS28 score from baseline was used to determine the EULAR responses of good, moderate, or no response. For a post-baseline score ≤ 3.2, a change from baseline of < -1.2 was a good response, < -0.6 to ≥ -1.2 was a moderate response, and ≥ -0.6 was no response. For a post-baseline score > 3.2 to ≤ 5.1, a change from baseline of < -0.6 was a moderate response and ≥ -0.6 was no response. For a post-baseline score > 5.1, a change from baseline < -1.2 was a moderate response and ≥ -1.2 was no response. A good response could not be achieved for post-baseline scores > 3.2.
Time Frame	Baseline to Weeks 4, 8, 12, 16, 20, and 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized patients who received at least 1 dose of study medication. Missing data was imputed as "no response".

Arm/Group Title	Tocilizumab 8 mg/kg + DMARDs	Placebo + DMARDs
Arm/Group Description	Tocilizumab intravenously at a dose of 8 mg/kg over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.	Placebo IV over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.
Measure Participants	409	205
Good response, Week 4	13.2 3.2%	2.0 1%
Good response, Week 8	23.5 5.7%	1.0 0.5%
Good response, Week 12	28.1 6.9%	5.9 2.9%
Good response, Week 16	29.8 7.3%	4.9 2.4%
Good response, Week 20	31.5 7.7%	6.8 3.3%
Good response, Week 24	32.5 7.9%	5.9 2.9%
Moderate response, Week 4	57.2 14%	23.9 11.7%
Moderate response, Week 8	52.6 12.9%	35.6 17.4%
Moderate response, Week 12	50.6 12.4%	35.6 17.4%
Moderate response, Week 16	40.6 9.9%	36.6 17.9%
Moderate response, Week 20	30.6 7.5%	28.8 14%
Moderate response, Week 24	27.4 6.7%	27.8 13.6%
No response, Week 4	29.6 7.2%	74.1 36.1%
No response, Week 8	24.0 5.9%	63.4 30.9%
No response, Week 12	21.3 5.2%	58.5 28.5%
No response, Week 16	29.6 7.2%	58.5 28.5%
No response, Week 20	37.9 9.3%	64.4 31.4%
No response, Week 24	40.1 9.8%	66.3 32.3%

5. Secondary Outcome

Title	Mean Change From Baseline in the Routine Assessment Patient Index Data (RAPID) Score at Weeks 4, 8, 12, 16, 20, and 24
Description	Derived from the Multidimensional Health Assessment Questionnaire (MDHAQ), the RAPID includes 3 domains that assess disease activity in rheumatoid arthritis: A physical function score (MDHAQ items 1a-j), a pain visual analog scale score (VAS, item 2 in the MDHAQ), and a global assessment of disease activity VAS score (item 6 in the MDHAQ). Each domain is scored on a scale of 0-10. The RAPID score is the sum of the 3 domain scores divided by 3 resulting in a total score on a scale of 0-10. Higher scores indicate more disease activity and a negative change from baseline indicates improvement.
Time Frame	Baseline to Weeks 4, 8, 12, 16, 20, and 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized patients who received at least 1 dose of study medication. No imputation of missing data was made; only observed data are reported.

Arm/Group Title	Tocilizumab 8 mg/kg + DMARDs	Placebo + DMARDs
Arm/Group Description	Tocilizumab intravenously at a dose of 8 mg/kg over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.	Placebo IV over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.
Measure Participants	409	205
Week 4, n=403, 195	-1.28 (1.921)	-0.50 (1.666)
Week 8, n=392, 191	-1.70 (2.087)	-0.73 (1.868)
Week 12, n=379, 191	-1.89 (2.244)	-0.99 (1.971)
Week 16, n=358, 187	-1.84 (2.286)	-0.86 (2.104)
Week 20, n=292, 122	-2.30 (2.212)	-1.51 (2.213)
Week 24, n=283, 116	-2.33 (2.294)	-1.29 (2.362)

6. Secondary Outcome

Title	Mean Change From Baseline in 12-Item Short Form Health Survey v2 (SF-12) Scores at Weeks 4, 8, 12, 16, 20, and 24
Description	The SF-12 is a self-report measure of general health status with 1 or 2 items for each of 8 domains: Physical functioning, role limitations due to physical health problems, bodily pain, general health, vitality, social functioning, role limitations due to emotional problems, and mental health. Two component summaries, physical (PCS-12) and mental (MCS-12) were calculated using norm-based scoring, resulting in means of 50 and standard deviations of 10 in the 1998 general United States population. Higher scores represent better health and a positive change from baseline represents improvement.
Time Frame	Baseline to Weeks 4, 8, 12, 16, 20, and 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized patients who received at least 1 dose of study medication. No imputation of missing data was made; only observed data are reported.

Arm/Group Title	Tocilizumab 8 mg/kg + DMARDs	Placebo + DMARDs
Arm/Group Description	Tocilizumab intravenously at a dose of 8 mg/kg over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.	Placebo IV over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.
Measure Participants	409	204
Physical component summary, Week 4, n=403, 197	4.14 (8.125)	1.35 (7.501)
Physical component summary, Week 8, n=393, 192	5.79 (8.862)	1.95 (7.523)
Physical component summary, Week 12, n=376, 192	7.17 (9.250)	2.67 (8.098)
Physical component summary, Week 16, n=358, 185	7.12 (9.278)	2.40 (8.967)
Physical component summary, Week 20, n=289, 123	8.43 (9.563)	4.76 (8.855)
Physical component summary, Week 24, n=283, 115	8.83 (9.931)	3.57 (9.116)
Mental component summary, Week 4, n=403, 197	2.91 (10.209)	1.42 (9.379)
Mental component summary, Week 8, n=393, 192	3.53 (10.719)	2.18 (10.019)
Mental component summary, Week 12, n=376, 192	3.29 (11.021)	2.59 (10.848)
Mental component summary, Week 16, n=358, 185	3.26 (10.845)	2.23 (10.453)
Mental component summary, Week 20, n=289, 123	4.33 (11.503)	3.29 (10.760)
Mental component summary, Week 24, n=283, 115	3.76 (12.284)	3.39 (10.150)

7. Secondary Outcome

Title	Mean Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Weeks 4, 8, 12, 16, 20, and 24
Description	The FACIT-F is a 13-item patient self-report questionnaire that assesses fatigue over the previous 7 days by scoring each item on a 5-point scale (0=Not at all, 1=A little bit, 2=Somewhat, 3=Quite a bit, 4=Very much). An overall FACIT-F score was obtained by summing the scores of all 13 items. The overall score ranged from 0 to 52. A lower score indicates less fatigue. A negative change score indicates improvement.
Time Frame	Baseline to Weeks 4, 8, 12, 16, 20, and 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized patients who received at least 1 dose of study medication. No imputation of missing data was made; only observed data are reported.

Arm/Group Title	Tocilizumab 8 mg/kg + DMARDs	Placebo + DMARDs
Arm/Group Description	Tocilizumab intravenously at a dose of 8 mg/kg over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.	Placebo IV over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.
Measure Participants	409	205
Week 4, n=405, 197	3.93 (8.786)	3.06 (8.011)
Week 8, n=394, 193	5.65 (10.039)	3.85 (8.598)
Week 12, n=378, 192	6.63 (10.504)	3.91 (10.081)
Week 16, n=358, 186	6.54 (10.876)	3.62 (10.611)
Week 20, n=289, 123	8.52 (11.147)	6.24 (11.000)
Week 24, n=283, 115	8.43 (11.513)	5.89 (11.316)

8. Secondary Outcome

Title	Mean Change From Baseline in the Medical Outcomes Study (MOS) Sleep Scale Score at Weeks 4, 8, 12, 16, 20, and 24
Description	The MOS Sleep Scale is a 12-item patient self-report instrument that assesses the quality and quantity of sleep over the previous 4 weeks. A sleep problems index (SLP9) was generated using 9 of the 12 items (1, 3, 4, 5, 6, 7, 8, 9, 12). Each item was normalized so that the lowest and highest possible scores were set to 0 and 100, respectively. The SLP9 score is the average of the recoded 9 items. The SLP9 score ranged from 0 to 100. Higher scores represent greater sleep problems. A negative change score indicates improvement.
Time Frame	Baseline to Weeks 4, 8, 12, 16, 20, and 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized patients who received at least 1 dose of study medication. No imputation of missing data was made; only observed data are reported.

Arm/Group Title	Tocilizumab 8 mg/kg + DMARDs	Placebo + DMARDs
Arm/Group Description	Tocilizumab intravenously at a dose of 8 mg/kg over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.	Placebo IV over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.
Measure Participants	409	205
Week 4, n=405, 197	-5.68 (14.334)	-3.87 (14.892)
Week 8, n=394, 193	-8.05 (14.384)	-6.77 (17.256)
Week 12, n=378, 192	-9.27 (16.824)	-4.80 (18.242)
Week 16, n=358, 186	-9.65 (17.117)	-5.42 (19.433)
Week 20, n=291, 123	12.31 (17.991)	-10.89 (20.364)
Week 24, n=283, 115	-12.46 (19.167)	-10.11 (17.352)

9. Secondary Outcome

Title	Mean Change From Baseline in Individual Components of the Routine Assessment Patient Index Data (RAPID) at Each Day During the First 7 Days of Treatment
Description	Derived from the Multidimensional Health Assessment Questionnaire (MDHAQ), the RAPID includes 3 domains that assess disease activity in rheumatoid arthritis: A physical function score (0-10), a pain visual analog scale score (VAS, 0-100), and a global assessment of disease activity VAS score (0-100). Each domain was assessed with the Patient Take Home Form (PTHF). Higher scores indicate more disease activity. A negative change score indicates improvement.
Time Frame	Baseline through Day 7

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized patients who received at least 1 dose of study medication. No imputation of missing data was made; only observed data are reported.

Arm/Group Title	Tocilizumab 8 mg/kg + DMARDs	Placebo + DMARDs
Arm/Group Description	Tocilizumab intravenously at a dose of 8 mg/kg over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.	Placebo IV over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.
Measure Participants	409	205
Physical function, Day 1, n=372, 184	-0.26 (1.203)	-0.22 (1.092)
Physical function, Day 2, n=373, 183	-0.35 (1.307)	-0.19 (1.197)
Physical function, Day 3, n=370, 182	-0.46 (1.376)	-0.09 (1.254)
Physical function, Day 4, n=374, 184	-0.50 (1.490)	-0.15 (1.342)
Physical function, Day 5, n=372, 181	-0.57 (1.499)	-0.27 (1.316)
Physical function, Day 6, n=366, 179	-0.65 (1.474)	-0.23 (1.356)
Physical function, Day 7, n=354, 167	-0.68 (1.518)	-0.33 (1.315)
Pain VAS, Day 1, n=371, 183	-10.50 (19.636)	-7.76 (18.498)
Pain VAS, Day 2, n=373, 183	-10.68 (21.439)	-8.79 (19.053)
Pain VAS, Day 3, n=370, 182	-12.60 (22.387)	-7.87 (21.506)
Pain VAS, Day 4, n=374, 183	-13.22 (23.202)	-8.46 (21.637)
Pain VAS, Day 5, n=372, 179	-13.53 (23.915)	-8.47 (21.536)
Pain VAS, Day 6, n=366, 179	-14.33 (24.608)	-7.98 (22.056)
Pain VAS, Day 7, n=354, 166	-14.68 (24.881)	-8.51 (21.148)
Disease activity VAS, Day 1, n=372, 183	-3.44 (19.690)	-1.32 (19.434)
Disease activity VAS, Day 2, n=373, 183	-3.87 (21.574)	-2.54 (19.562)
Disease activity VAS, Day 3, n=370, 182	-5.99 (22.090)	-2.19 (21.105)
Disease activity VAS, Day 4, n=374, 183	-5.72 (22.821)	-2.31 (21.131)
Disease activity VAS, Day 5, n=371, 179	-6.54 (23.256)	-2.93 (22.111)
Disease activity VAS, Day 6, n=366, 179	-7.90 (24.409)	-3.20 (21.936)
Disease activity VAS, Day 7, n=354, 166	-8.54 (23.836)	-3.50 (21.654)

10. Secondary Outcome

Title	Percentage of Patients With an Improvement of at Least 20%, 50%, or 70% in American College of Rheumatology (ACR) Score (ACR20, ACR50, ACR70) From Baseline at Day 7
Description	Improvement must be seen in tender and swollen joint counts and in at least 3 of the following 5 parameters. Patient and physician assessment of patient disease activity (DA) in previous 24 hours on a visual analog scale (VAS, no DA to maximum DA); patient assessment of pain in previous 24 hours on a VAS (none to unbearable); Health Assessment Questionnaire-Disability Index (20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do); and C reactive protein or, if missing, erythrocyte sedimentation rate.
Time Frame	Baseline to Day 7

Outcome Measure Data

Analysis Population Description

C-reactive protein (CRP) population: A subset of patients enrolled at designated study sites who met the CRP entry criteria (CRP ≥ 1 mg/dL), received at least 1 dose of study medication, and attended the Day 3 or Day 7 visit. LOCF was used for missing joint count data. Patients with missing data or who escaped were classified as non-responders.

Arm/Group Title	Tocilizumab 8 mg/kg + DMARDs	Placebo + DMARDs
Arm/Group Description	Tocilizumab intravenously at a dose of 8 mg/kg over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.	Placebo IV over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.
Measure Participants	38	21
ACR20	21 5.1%	5 2.4%
ACR50	5 1.2%	0 0%
ACR70	5 1.2%	0 0%

11. Secondary Outcome

Title	Mean Change From Baseline in C-reactive Protein (CRP) at Days 3 and 7
Description	Serum concentration of CRP (high-sensitivity CRP [hsCRP] test) was analyzed by a central laboratory.
Time Frame	Baseline to Days 3 and 7

Outcome Measure Data

Analysis Population Description

C-reactive protein (CRP) population: A subset of patients enrolled at designated study sites who met the CRP entry criteria (CRP ≥ 1 mg/dL), received at least 1 dose of study medication, and attended the Day 3 or Day 7 visit. No imputation of missing data was made; only observed data are reported.

Arm/Group Title	Tocilizumab 8 mg/kg + DMARDs	Placebo + DMARDs
Arm/Group Description	Tocilizumab intravenously at a dose of 8 mg/kg over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.	Placebo IV over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.
Measure Participants	40	22
Day 3, n=38, 21	-2.14 (2.391)	-0.52 (1.569)
Day 7, n=38, 20	-2.69 (2.854)	-0.31 (1.261)

Adverse Events

Time Frame	Adverse events that occurred in the double-blind treatment period and the extended treatment period are reported.
Adverse Event Reporting Description	Safety analysis population: All patients who received at least 1 dose of study medication and who had at least 1 post-baseline safety assessment. Placebo patients in the core study that received tocilizumab in the extension are reported in 2 groups resulting in a total of 787 patients in the 3 Adverse Events groups; only 619 enrolled in the study.
Arm/Group Title	Tocilizumab + DMARDs		Placebo/Tocilizumab + DMARDs		Placebo + DMARDs
Arm/Group Description	Initially treated with tocilizumab + DMARDs and received ≥ 1 dose of tocilizumab. The tocilizumab + DMARDs group includes all data (double-blind and extended treatment periods) for patients who were initially treated with tocilizumab in the double-blind treatment period. In the extended treatment period, patients received tocilizumab 8 mg/kg 1-hour IV infusion every 4 weeks (q4weeks) for up to 1 month post-commercial availability of tocilizumab in the United States.		Initially treated with placebo + DMARDs then received ≥ 1 dose of tocilizumab. The placebo/tocilizumab + DMARDs group includes all data collected after patients' first infusion of tocilizumab (whether escape therapy or extended treatment) for those who were initially treated with placebo in the double-blind treatment period. In the extended treatment period, patients received tocilizumab 8 mg/kg 1-hour IV infusion every 4 weeks (q4weeks) for up to 1 month post-commercial availability of tocilizumab in the United States.		Initially treated with placebo + DMARDs and received ≥ 1 dose of placebo. The placebo + DMARDs group includes all data collected while patients were on placebo for those who were initially treated with placebo in the double-blind treatment period.
All Cause Mortality
	Tocilizumab + DMARDs		Placebo/Tocilizumab + DMARDs		Placebo + DMARDs
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Tocilizumab + DMARDs		Placebo/Tocilizumab + DMARDs		Placebo + DMARDs
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	79/409 (19.3%)		27/173 (15.6%)		11/205 (5.4%)
Blood and lymphatic system disorders
Anaemia	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Cardiac disorders
Arteriosclerosis Coronary Artery	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Atrial Fibrillation	0/409 (0%)		1/173 (0.6%)		1/205 (0.5%)
Coronary Artery Disease	1/409 (0.2%)		1/173 (0.6%)		1/205 (0.5%)
Myocardial Infarction	2/409 (0.5%)		0/173 (0%)		0/205 (0%)
Pericarditis	0/409 (0%)		0/173 (0%)		1/205 (0.5%)
Acute myocardial infarction	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Angina pectoris	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Bradycardia	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Cardiac arrest	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Ischaemic cardiomyopathy	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Gastrointestinal disorders
Gastritis	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Gastrointestinal Haemorrhage	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Pancreatitis Acute	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Pancreatitis	3/409 (0.7%)		0/173 (0%)		0/205 (0%)
Diverticular perforation	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Diverticulum	0/409 (0%)		1/173 (0.6%)		0/205 (0%)
Retroperitoneal haemorrhage	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Large intestine perforation	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
General disorders
Chest Pain	4/409 (1%)		1/173 (0.6%)		1/205 (0.5%)
Hepatobiliary disorders
Biliary Dyskinesia	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Cholelithiasis	1/409 (0.2%)		1/173 (0.6%)		0/205 (0%)
Cholecystitis	0/409 (0%)		1/173 (0.6%)		0/205 (0%)
Infections and infestations
Cellulitis	4/409 (1%)		3/173 (1.7%)		0/205 (0%)
Pneumonia	8/409 (2%)		3/173 (1.7%)		0/205 (0%)
Anal Abscess	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Enterobacter Sepsis	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Gastroenteritis Viral	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Lung Infection Pseudomonal	0/409 (0%)		0/173 (0%)		1/205 (0.5%)
Pyelonephritis	1/409 (0.2%)		1/173 (0.6%)		0/205 (0%)
Septic Shock	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Staphylococcal Infection	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Urinary Tract Infection	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Urosepsis	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Bacteraemia	1/409 (0.2%)		1/173 (0.6%)		0/205 (0%)
Diverticulitis	1/409 (0.2%)		1/173 (0.6%)		0/205 (0%)
Abdominal abscess	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Appendicitis	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Arthritis bacterial	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Bursitis infective staphylococcal	0/409 (0%)		1/173 (0.6%)		0/205 (0%)
Cellulitis staphylococcal	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Enterocolitis infectious	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Gastroenteritis	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Infection	0/409 (0%)		1/173 (0.6%)		0/205 (0%)
Localised infection	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Osteomyelitis	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Peptostreptococcus	0/409 (0%)		1/173 (0.6%)		0/205 (0%)
Peridiverticular abscess	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Pneumocystis jiroveci pneumonia	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Pneumonia primary atypical	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Puncture site infection	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Sepsis	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Staphylococcal bacteraemia	0/409 (0%)		1/173 (0.6%)		0/205 (0%)
Injury, poisoning and procedural complications
Spinal Compression Fracture	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Thoracic Vertebral Fracture	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Humerus fracture	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Tibia fracture	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Wound dehiscence	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Investigations
Heart Rate Irregular	0/409 (0%)		0/173 (0%)		1/205 (0.5%)
Metabolism and nutrition disorders
Dehydration	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Hyponatraemia	2/409 (0.5%)		0/173 (0%)		0/205 (0%)
Hypocalcaemia	0/409 (0%)		1/173 (0.6%)		0/205 (0%)
Musculoskeletal and connective tissue disorders
Intervertebral Disc Protrusion	1/409 (0.2%)		1/173 (0.6%)		0/205 (0%)
Spondylolisthesis	1/409 (0.2%)		1/173 (0.6%)		1/205 (0.5%)
Osteoarthritis	2/409 (0.5%)		1/173 (0.6%)		0/205 (0%)
Arthralgia	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Back pain	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Musculoskeletal chest pain	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Diffuse Large B-Cell Lymphoma	0/409 (0%)		0/173 (0%)		1/205 (0.5%)
Lipoma	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Renal Cell Carcinoma	0/409 (0%)		0/173 (0%)		1/205 (0.5%)
Squamous Cell Carcinoma	2/409 (0.5%)		0/173 (0%)		1/205 (0.5%)
Breast cancer	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Colon cancer	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Endometrial cancer	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Large cell carcinoma of the respiratory tract stage unspecified	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Malignant melanoma	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Malignant pleural effusion	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Non-small cell lung cancer	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Nervous system disorders
Haemorrhagic Stroke	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Loss of Consciousness	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Syncope	2/409 (0.5%)		1/173 (0.6%)		1/205 (0.5%)
Cardiovascular accident	2/409 (0.5%)		0/173 (0%)		0/205 (0%)
Convulsion	0/409 (0%)		1/173 (0.6%)		0/205 (0%)
Headache	0/409 (0%)		1/173 (0.6%)		0/205 (0%)
VIIIth nerve paralysis	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Pregnancy, puerperium and perinatal conditions
Pregnancy	1/409 (0.2%)		1/173 (0.6%)		0/205 (0%)
Psychiatric disorders
Depression	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Suicidal Ideation	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Anxiety	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Drug abuse	0/409 (0%)		1/173 (0.6%)		0/205 (0%)
Major depression	0/409 (0%)		1/173 (0.6%)		0/205 (0%)
Renal and urinary disorders
Calculus Ureteric	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Nephrolithiasis	0/409 (0%)		0/173 (0%)		1/205 (0.5%)
Renal failure acute	0/409 (0%)		1/173 (0.6%)		0/205 (0%)
Respiratory, thoracic and mediastinal disorders
Interstitial Lung Disease	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Lung Disorder	0/409 (0%)		0/173 (0%)		1/205 (0.5%)
Pleural Effusion	0/409 (0%)		0/173 (0%)		1/205 (0.5%)
Pneumonitis	1/409 (0.2%)		1/173 (0.6%)		0/205 (0%)
Pulmonary embolism	3/409 (0.7%)		1/173 (0.6%)		0/205 (0%)
Dyspnoea	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Skin and subcutaneous tissue disorders
Rash Vesicular	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Swelling Face	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Surgical and medical procedures
Skin graft	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Vascular disorders
Deep Vein Thrombosis	3/409 (0.7%)		3/173 (1.7%)		0/205 (0%)
Haematoma	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Hypertension	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Jugular Vein Thrombosis	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Aneurysm	1/409 (0.2%)		0/173 (0%)		0/205 (0%)
Hypertensive crisis	0/409 (0%)		1/173 (0.6%)		0/205 (0%)
Other (Not Including Serious) Adverse Events
	Tocilizumab + DMARDs		Placebo/Tocilizumab + DMARDs		Placebo + DMARDs
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	259/409 (63.3%)		98/173 (56.6%)		69/205 (33.7%)
Gastrointestinal disorders
Diarrhoea	44/409 (10.8%)		6/173 (3.5%)		10/205 (4.9%)
Nausea	25/409 (6.1%)		9/173 (5.2%)		5/205 (2.4%)
Infections and infestations
Upper Respiratory Tract Infection	70/409 (17.1%)		28/173 (16.2%)		10/205 (4.9%)
Urinary Tract Infection	53/409 (13%)		21/173 (12.1%)		11/205 (5.4%)
Sinusitis	44/409 (10.8%)		17/173 (9.8%)		5/205 (2.4%)
Bronchitis	31/409 (7.6%)		13/173 (7.5%)		6/205 (2.9%)
Nasopharyngitis	30/409 (7.3%)		13/173 (7.5%)		7/205 (3.4%)
Injury, poisoning and procedural complications
Fall	20/409 (4.9%)		10/173 (5.8%)		0/205 (0%)
Investigations
Alanine aminotransferase increased	31/409 (7.6%)		9/173 (5.2%)		3/205 (1.5%)
Blood cholesterol increased	23/409 (5.6%)		6/173 (3.5%)		0/205 (0%)
Metabolism and nutrition disorders
Hyperlipidaemia	25/409 (6.1%)		13/173 (7.5%)		3/205 (1.5%)
Musculoskeletal and connective tissue disorders
Rheumatoid Arthritis	22/409 (5.4%)		9/173 (5.2%)		17/205 (8.3%)
Arthralgia	27/409 (6.6%)		8/173 (4.6%)		3/205 (1.5%)
Back pain	25/409 (6.1%)		7/173 (4%)		3/205 (1.5%)
Nervous system disorders
Headache	27/409 (6.6%)		14/173 (8.1%)		4/205 (2%)
Skin and subcutaneous tissue disorders
Rash	22/409 (5.4%)		5/173 (2.9%)		5/205 (2.4%)
Vascular disorders
Hypertension	23/409 (5.6%)		9/173 (5.2%)		1/205 (0.5%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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