Trial Outcomes & Findings for A Study of Tocilizumab in Combination With DMARDs in Patients With Moderate to Severe Rheumatoid Arthritis (NCT NCT00531817)

Last Updated: 2012-08-20

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

619 participants

Primary outcome timeframe

Baseline to Week 24

Results posted on

2012-08-20

Participant Flow

Participant milestones

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

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Tocilizumab 8 mg/kg + DMARDs n=409 Participants Tocilizumab intravenously at a dose of 8 mg/kg over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.	Placebo + DMARDs n=205 Participants Placebo IV over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.	Total n=614 Participants Total of all reporting groups
Age Continuous	55.2 years STANDARD_DEVIATION 12.06 • n=5 Participants	55.8 years STANDARD_DEVIATION 12.42 • n=7 Participants	55.5 years STANDARD_DEVIATION 12.24 • n=5 Participants
Sex: Female, Male Female	325 Participants n=5 Participants	172 Participants n=7 Participants	497 Participants n=5 Participants
Sex: Female, Male Male	84 Participants n=5 Participants	33 Participants n=7 Participants	117 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline to Week 24

Population: 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.

Outcome measures

Outcome measures
Measure	Tocilizumab 8 mg/kg + DMARDs n=409 Participants Tocilizumab intravenously at a dose of 8 mg/kg over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.	Placebo + DMARDs n=205 Participants Placebo IV over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.
Percentage of Patients With an Improvement of at Least 50% in American College of Rheumatology (ACR) Score (ACR50) From Baseline at Week 24	30.1 Percentage of participants	11.2 Percentage of participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Tocilizumab 8 mg/kg + DMARDs n=409 Participants Tocilizumab intravenously at a dose of 8 mg/kg over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.	Placebo + DMARDs n=205 Participants Placebo IV over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.
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 ACR20, Week 12	49.6 Percentage of participants	28.8 Percentage of participants
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 ACR20, Week 24	44.7 Percentage of participants	25.4 Percentage of participants
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 ACR50, Week 12	25.2 Percentage of participants	14.1 Percentage of participants
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 ACR70, Week 24	15.4 Percentage of participants	1.5 Percentage of participants
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 ACR20, Week 4	34.2 Percentage of participants	17.6 Percentage of participants
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 ACR20, Week 8	46.5 Percentage of participants	25.4 Percentage of participants
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 ACR20, Week 16	47.7 Percentage of participants	28.8 Percentage of participants
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 ACR20, Week 20	45.2 Percentage of participants	25.9 Percentage of participants
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 ACR50, Week 4	12.5 Percentage of participants	3.4 Percentage of participants
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 ACR50, Week 8	20.8 Percentage of participants	5.4 Percentage of participants
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 ACR50, Week 16	26.7 Percentage of participants	15.1 Percentage of participants
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 ACR50, Week 20	28.4 Percentage of participants	12.7 Percentage of participants
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 ACR70, Week 4	4.4 Percentage of participants	1.5 Percentage of participants
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 ACR70, Week 8	6.8 Percentage of participants	0.5 Percentage of participants
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 ACR70, Week 12	11.5 Percentage of participants	4.9 Percentage of participants
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 ACR70, Week 16	12.5 Percentage of participants	3.4 Percentage of participants
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 ACR70, Week 20	16.9 Percentage of participants	5.4 Percentage of participants

SECONDARY outcome

Timeframe: Baseline to Weeks 4, 8, 12, 16, 20, 24

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Tocilizumab 8 mg/kg + DMARDs n=409 Participants Tocilizumab intravenously at a dose of 8 mg/kg over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.	Placebo + DMARDs n=205 Participants Placebo IV over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.
Mean Change From Baseline in Disease Activity Score 28 (DAS28) at Weeks 4, 8, 12, 16, 20, and 24 Week 4, n=391, 194	-1.77 Units on a scale Standard Deviation 1.264	-0.45 Units on a scale Standard Deviation 1.065
Mean Change From Baseline in Disease Activity Score 28 (DAS28) at Weeks 4, 8, 12, 16, 20, and 24 Week 8, n= 382, 190	-2.32 Units on a scale Standard Deviation 1.454	-0.72 Units on a scale Standard Deviation 1.047
Mean Change From Baseline in Disease Activity Score 28 (DAS28) at Weeks 4, 8, 12, 16, 20, and 24 Week 12, n=361, 188	-2.63 Units on a scale Standard Deviation 1.433	-0.97 Units on a scale Standard Deviation 1.242
Mean Change From Baseline in Disease Activity Score 28 (DAS28) at Weeks 4, 8, 12, 16, 20, and 24 Week 16, n=343, 183	-2.63 Units on a scale Standard Deviation 1.605	-0.93 Units on a scale Standard Deviation 1.289
Mean Change From Baseline in Disease Activity Score 28 (DAS28) at Weeks 4, 8, 12, 16, 20, and 24 Week 20, n=273, 120	-3.14 Units on a scale Standard Deviation 1.535	-1.36 Units on a scale Standard Deviation 1.353
Mean Change From Baseline in Disease Activity Score 28 (DAS28) at Weeks 4, 8, 12, 16, 20, and 24 Week 24, n=265, 116	-3.18 Units on a scale Standard Deviation 1.526	-1.23 Units on a scale Standard Deviation 1.273

SECONDARY outcome

Timeframe: Baseline to Weeks 4, 8, 12, 16, 20, and 24

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

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.

Outcome measures

Outcome measures
Measure	Tocilizumab 8 mg/kg + DMARDs n=409 Participants Tocilizumab intravenously at a dose of 8 mg/kg over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.	Placebo + DMARDs n=205 Participants Placebo IV over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.
Percentage of Patients With European League Against Rheumatism (EULAR) Good, Moderate, or no Response at Weeks 4, 8, 12, 16, 20, and 24 Good response, Week 8	23.5 Percentage of participants	1.0 Percentage of participants
Percentage of Patients With European League Against Rheumatism (EULAR) Good, Moderate, or no Response at Weeks 4, 8, 12, 16, 20, and 24 Good response, Week 20	31.5 Percentage of participants	6.8 Percentage of participants
Percentage of Patients With European League Against Rheumatism (EULAR) Good, Moderate, or no Response at Weeks 4, 8, 12, 16, 20, and 24 Moderate response, Week 20	30.6 Percentage of participants	28.8 Percentage of participants
Percentage of Patients With European League Against Rheumatism (EULAR) Good, Moderate, or no Response at Weeks 4, 8, 12, 16, 20, and 24 Good response, Week 4	13.2 Percentage of participants	2.0 Percentage of participants
Percentage of Patients With European League Against Rheumatism (EULAR) Good, Moderate, or no Response at Weeks 4, 8, 12, 16, 20, and 24 Good response, Week 12	28.1 Percentage of participants	5.9 Percentage of participants
Percentage of Patients With European League Against Rheumatism (EULAR) Good, Moderate, or no Response at Weeks 4, 8, 12, 16, 20, and 24 Good response, Week 16	29.8 Percentage of participants	4.9 Percentage of participants
Percentage of Patients With European League Against Rheumatism (EULAR) Good, Moderate, or no Response at Weeks 4, 8, 12, 16, 20, and 24 Good response, Week 24	32.5 Percentage of participants	5.9 Percentage of participants
Percentage of Patients With European League Against Rheumatism (EULAR) Good, Moderate, or no Response at Weeks 4, 8, 12, 16, 20, and 24 Moderate response, Week 4	57.2 Percentage of participants	23.9 Percentage of participants
Percentage of Patients With European League Against Rheumatism (EULAR) Good, Moderate, or no Response at Weeks 4, 8, 12, 16, 20, and 24 Moderate response, Week 8	52.6 Percentage of participants	35.6 Percentage of participants
Percentage of Patients With European League Against Rheumatism (EULAR) Good, Moderate, or no Response at Weeks 4, 8, 12, 16, 20, and 24 Moderate response, Week 12	50.6 Percentage of participants	35.6 Percentage of participants
Percentage of Patients With European League Against Rheumatism (EULAR) Good, Moderate, or no Response at Weeks 4, 8, 12, 16, 20, and 24 Moderate response, Week 16	40.6 Percentage of participants	36.6 Percentage of participants
Percentage of Patients With European League Against Rheumatism (EULAR) Good, Moderate, or no Response at Weeks 4, 8, 12, 16, 20, and 24 Moderate response, Week 24	27.4 Percentage of participants	27.8 Percentage of participants
Percentage of Patients With European League Against Rheumatism (EULAR) Good, Moderate, or no Response at Weeks 4, 8, 12, 16, 20, and 24 No response, Week 4	29.6 Percentage of participants	74.1 Percentage of participants
Percentage of Patients With European League Against Rheumatism (EULAR) Good, Moderate, or no Response at Weeks 4, 8, 12, 16, 20, and 24 No response, Week 8	24.0 Percentage of participants	63.4 Percentage of participants
Percentage of Patients With European League Against Rheumatism (EULAR) Good, Moderate, or no Response at Weeks 4, 8, 12, 16, 20, and 24 No response, Week 12	21.3 Percentage of participants	58.5 Percentage of participants
Percentage of Patients With European League Against Rheumatism (EULAR) Good, Moderate, or no Response at Weeks 4, 8, 12, 16, 20, and 24 No response, Week 16	29.6 Percentage of participants	58.5 Percentage of participants
Percentage of Patients With European League Against Rheumatism (EULAR) Good, Moderate, or no Response at Weeks 4, 8, 12, 16, 20, and 24 No response, Week 20	37.9 Percentage of participants	64.4 Percentage of participants
Percentage of Patients With European League Against Rheumatism (EULAR) Good, Moderate, or no Response at Weeks 4, 8, 12, 16, 20, and 24 No response, Week 24	40.1 Percentage of participants	66.3 Percentage of participants

SECONDARY outcome

Timeframe: Baseline to Weeks 4, 8, 12, 16, 20, and 24

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Tocilizumab 8 mg/kg + DMARDs n=409 Participants Tocilizumab intravenously at a dose of 8 mg/kg over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.	Placebo + DMARDs n=205 Participants Placebo IV over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.
Mean Change From Baseline in the Routine Assessment Patient Index Data (RAPID) Score at Weeks 4, 8, 12, 16, 20, and 24 Week 8, n=392, 191	-1.70 Units on a scale Standard Deviation 2.087	-0.73 Units on a scale Standard Deviation 1.868
Mean Change From Baseline in the Routine Assessment Patient Index Data (RAPID) Score at Weeks 4, 8, 12, 16, 20, and 24 Week 4, n=403, 195	-1.28 Units on a scale Standard Deviation 1.921	-0.50 Units on a scale Standard Deviation 1.666
Mean Change From Baseline in the Routine Assessment Patient Index Data (RAPID) Score at Weeks 4, 8, 12, 16, 20, and 24 Week 12, n=379, 191	-1.89 Units on a scale Standard Deviation 2.244	-0.99 Units on a scale Standard Deviation 1.971
Mean Change From Baseline in the Routine Assessment Patient Index Data (RAPID) Score at Weeks 4, 8, 12, 16, 20, and 24 Week 16, n=358, 187	-1.84 Units on a scale Standard Deviation 2.286	-0.86 Units on a scale Standard Deviation 2.104
Mean Change From Baseline in the Routine Assessment Patient Index Data (RAPID) Score at Weeks 4, 8, 12, 16, 20, and 24 Week 20, n=292, 122	-2.30 Units on a scale Standard Deviation 2.212	-1.51 Units on a scale Standard Deviation 2.213
Mean Change From Baseline in the Routine Assessment Patient Index Data (RAPID) Score at Weeks 4, 8, 12, 16, 20, and 24 Week 24, n=283, 116	-2.33 Units on a scale Standard Deviation 2.294	-1.29 Units on a scale Standard Deviation 2.362

SECONDARY outcome

Timeframe: Baseline to Weeks 4, 8, 12, 16, 20, and 24

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Tocilizumab 8 mg/kg + DMARDs n=409 Participants Tocilizumab intravenously at a dose of 8 mg/kg over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.	Placebo + DMARDs n=204 Participants Placebo IV over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.
Mean Change From Baseline in 12-Item Short Form Health Survey v2 (SF-12) Scores at Weeks 4, 8, 12, 16, 20, and 24 Physical component summary, Week 20, n=289, 123	8.43 Units on a scale Standard Deviation 9.563	4.76 Units on a scale Standard Deviation 8.855
Mean Change From Baseline in 12-Item Short Form Health Survey v2 (SF-12) Scores at Weeks 4, 8, 12, 16, 20, and 24 Mental component summary, Week 4, n=403, 197	2.91 Units on a scale Standard Deviation 10.209	1.42 Units on a scale Standard Deviation 9.379
Mean Change From Baseline in 12-Item Short Form Health Survey v2 (SF-12) Scores at Weeks 4, 8, 12, 16, 20, and 24 Mental component summary, Week 20, n=289, 123	4.33 Units on a scale Standard Deviation 11.503	3.29 Units on a scale Standard Deviation 10.760
Mean Change From Baseline in 12-Item Short Form Health Survey v2 (SF-12) Scores at Weeks 4, 8, 12, 16, 20, and 24 Physical component summary, Week 16, n=358, 185	7.12 Units on a scale Standard Deviation 9.278	2.40 Units on a scale Standard Deviation 8.967
Mean Change From Baseline in 12-Item Short Form Health Survey v2 (SF-12) Scores at Weeks 4, 8, 12, 16, 20, and 24 Physical component summary, Week 24, n=283, 115	8.83 Units on a scale Standard Deviation 9.931	3.57 Units on a scale Standard Deviation 9.116
Mean Change From Baseline in 12-Item Short Form Health Survey v2 (SF-12) Scores at Weeks 4, 8, 12, 16, 20, and 24 Mental component summary, Week 8, n=393, 192	3.53 Units on a scale Standard Deviation 10.719	2.18 Units on a scale Standard Deviation 10.019
Mean Change From Baseline in 12-Item Short Form Health Survey v2 (SF-12) Scores at Weeks 4, 8, 12, 16, 20, and 24 Mental component summary, Week 12, n=376, 192	3.29 Units on a scale Standard Deviation 11.021	2.59 Units on a scale Standard Deviation 10.848
Mean Change From Baseline in 12-Item Short Form Health Survey v2 (SF-12) Scores at Weeks 4, 8, 12, 16, 20, and 24 Mental component summary, Week 16, n=358, 185	3.26 Units on a scale Standard Deviation 10.845	2.23 Units on a scale Standard Deviation 10.453
Mean Change From Baseline in 12-Item Short Form Health Survey v2 (SF-12) Scores at Weeks 4, 8, 12, 16, 20, and 24 Mental component summary, Week 24, n=283, 115	3.76 Units on a scale Standard Deviation 12.284	3.39 Units on a scale Standard Deviation 10.150
Mean Change From Baseline in 12-Item Short Form Health Survey v2 (SF-12) Scores at Weeks 4, 8, 12, 16, 20, and 24 Physical component summary, Week 4, n=403, 197	4.14 Units on a scale Standard Deviation 8.125	1.35 Units on a scale Standard Deviation 7.501
Mean Change From Baseline in 12-Item Short Form Health Survey v2 (SF-12) Scores at Weeks 4, 8, 12, 16, 20, and 24 Physical component summary, Week 8, n=393, 192	5.79 Units on a scale Standard Deviation 8.862	1.95 Units on a scale Standard Deviation 7.523
Mean Change From Baseline in 12-Item Short Form Health Survey v2 (SF-12) Scores at Weeks 4, 8, 12, 16, 20, and 24 Physical component summary, Week 12, n=376, 192	7.17 Units on a scale Standard Deviation 9.250	2.67 Units on a scale Standard Deviation 8.098

SECONDARY outcome

Timeframe: Baseline to Weeks 4, 8, 12, 16, 20, and 24

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Tocilizumab 8 mg/kg + DMARDs n=409 Participants Tocilizumab intravenously at a dose of 8 mg/kg over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.	Placebo + DMARDs n=205 Participants Placebo IV over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.
Mean Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Weeks 4, 8, 12, 16, 20, and 24 Week 16, n=358, 186	6.54 Units on a scale Standard Deviation 10.876	3.62 Units on a scale Standard Deviation 10.611
Mean Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Weeks 4, 8, 12, 16, 20, and 24 Week 20, n=289, 123	8.52 Units on a scale Standard Deviation 11.147	6.24 Units on a scale Standard Deviation 11.000
Mean Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Weeks 4, 8, 12, 16, 20, and 24 Week 4, n=405, 197	3.93 Units on a scale Standard Deviation 8.786	3.06 Units on a scale Standard Deviation 8.011
Mean Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Weeks 4, 8, 12, 16, 20, and 24 Week 8, n=394, 193	5.65 Units on a scale Standard Deviation 10.039	3.85 Units on a scale Standard Deviation 8.598
Mean Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Weeks 4, 8, 12, 16, 20, and 24 Week 12, n=378, 192	6.63 Units on a scale Standard Deviation 10.504	3.91 Units on a scale Standard Deviation 10.081
Mean Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Weeks 4, 8, 12, 16, 20, and 24 Week 24, n=283, 115	8.43 Units on a scale Standard Deviation 11.513	5.89 Units on a scale Standard Deviation 11.316

SECONDARY outcome

Timeframe: Baseline to Weeks 4, 8, 12, 16, 20, and 24

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Tocilizumab 8 mg/kg + DMARDs n=409 Participants Tocilizumab intravenously at a dose of 8 mg/kg over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.	Placebo + DMARDs n=205 Participants Placebo IV over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.
Mean Change From Baseline in the Medical Outcomes Study (MOS) Sleep Scale Score at Weeks 4, 8, 12, 16, 20, and 24 Week 20, n=291, 123	12.31 Units on a scale Standard Deviation 17.991	-10.89 Units on a scale Standard Deviation 20.364
Mean Change From Baseline in the Medical Outcomes Study (MOS) Sleep Scale Score at Weeks 4, 8, 12, 16, 20, and 24 Week 4, n=405, 197	-5.68 Units on a scale Standard Deviation 14.334	-3.87 Units on a scale Standard Deviation 14.892
Mean Change From Baseline in the Medical Outcomes Study (MOS) Sleep Scale Score at Weeks 4, 8, 12, 16, 20, and 24 Week 8, n=394, 193	-8.05 Units on a scale Standard Deviation 14.384	-6.77 Units on a scale Standard Deviation 17.256
Mean Change From Baseline in the Medical Outcomes Study (MOS) Sleep Scale Score at Weeks 4, 8, 12, 16, 20, and 24 Week 12, n=378, 192	-9.27 Units on a scale Standard Deviation 16.824	-4.80 Units on a scale Standard Deviation 18.242
Mean Change From Baseline in the Medical Outcomes Study (MOS) Sleep Scale Score at Weeks 4, 8, 12, 16, 20, and 24 Week 16, n=358, 186	-9.65 Units on a scale Standard Deviation 17.117	-5.42 Units on a scale Standard Deviation 19.433
Mean Change From Baseline in the Medical Outcomes Study (MOS) Sleep Scale Score at Weeks 4, 8, 12, 16, 20, and 24 Week 24, n=283, 115	-12.46 Units on a scale Standard Deviation 19.167	-10.11 Units on a scale Standard Deviation 17.352

SECONDARY outcome

Timeframe: Baseline through Day 7

Population: 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.

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.

Outcome measures

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

SECONDARY outcome

Timeframe: Baseline to Day 7

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Tocilizumab 8 mg/kg + DMARDs n=38 Participants Tocilizumab intravenously at a dose of 8 mg/kg over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.	Placebo + DMARDs n=21 Participants Placebo IV over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.
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 ACR20	21 Percentage of participants	5 Percentage of participants
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 ACR50	5 Percentage of participants	0 Percentage of participants
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 ACR70	5 Percentage of participants	0 Percentage of participants

SECONDARY outcome

Timeframe: Baseline to Days 3 and 7

Population: 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.

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

Outcome measures

Outcome measures
Measure	Tocilizumab 8 mg/kg + DMARDs n=40 Participants Tocilizumab intravenously at a dose of 8 mg/kg over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.	Placebo + DMARDs n=22 Participants Placebo IV over a 1-hour infusion, every 4 weeks, for a total of 6 infusions.
Mean Change From Baseline in C-reactive Protein (CRP) at Days 3 and 7 Day 3, n=38, 21	-2.14 mg/dL Standard Deviation 2.391	-0.52 mg/dL Standard Deviation 1.569
Mean Change From Baseline in C-reactive Protein (CRP) at Days 3 and 7 Day 7, n=38, 20	-2.69 mg/dL Standard Deviation 2.854	-0.31 mg/dL Standard Deviation 1.261

Adverse Events

Tocilizumab + DMARDs

Serious events: 79 serious events

Other events: 259 other events

Deaths: 0 deaths

Placebo/Tocilizumab + DMARDs

Serious events: 27 serious events

Other events: 98 other events

Deaths: 0 deaths

Placebo + DMARDs

Serious events: 11 serious events

Other events: 69 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Communications

Hoffmann-La Roche

Phone: 800-821-8590

Results disclosure agreements

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

Restriction type: OTHER