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

This study has been completed.

Sponsor:

Information provided by (Responsible Party):

Hoffmann-La Roche

ClinicalTrials.gov Identifier:

NCT00531817

First received: September 18, 2007

Last updated: August 13, 2012

Last verified: August 2012

History of Changes

Results First Received: July 6, 2010

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Investigator); Primary Purpose: Treatment
Condition:	Rheumatoid Arthritis
Interventions:	Drug: Tocilizumab Drug: Placebo Drug: Permitted DMARDs

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups

	Description
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.

Participant Flow for 2 periods

Period 1: Randomized

	Tocilizumab 8 mg/kg + DMARDs	Placebo + DMARDs
STARTED	412	207
Received Study Drug in Core Study	409 ^[1]	205 ^[2]
COMPLETED	353	173
NOT COMPLETED	59	34

[1]	3 patients did not receive any study medication. Intent-to-treat population = 409.
[2]	2 patients did not receive any study medication. Intent-to-treat population = 205.

Period 2: Entered Extended Treatment Period

	Tocilizumab 8 mg/kg + DMARDs	Placebo + DMARDs
STARTED	343 ^[1]	170 ^[1]
COMPLETED	206	113
NOT COMPLETED	137	57

[1]	Eligible patients completing core study could participate in extension at investigator’s discretion.

Baseline Characteristics

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Reporting Groups

	Description
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.
Total	Total of all reporting groups

Baseline Measures

	Tocilizumab 8 mg/kg + DMARDs	Placebo + DMARDs	Total
Number of Participants [units: participants]	409	205	614
Age ^[1] [units: years] Mean ± Standard Deviation	55.2 ± 12.06	55.8 ± 12.42	55.5 ± 12.24
Gender ^[1] [units: participants]
Female	325	172	497
Male	84	33	117

[1]	Intent-to-treat population: Tocilizumab 8 mg/kg + DMARDs, n = 409 and Placebo + DMARDs, n = 205

Outcome Measures

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1. Primary:

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

Measure Type	Primary
Measure Title	Percentage of Patients With an Improvement of at Least 50% in American College of Rheumatology (ACR) Score (ACR50) From Baseline at Week 24
Measure 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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
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.

Measured Values

	Tocilizumab 8 mg/kg + DMARDs	Placebo + DMARDs
Number of Participants Analyzed [units: participants]	409	205
Percentage of Patients With an Improvement of at Least 50% in American College of Rheumatology (ACR) Score (ACR50) From Baseline at Week 24 [units: Percentage of participants]	30.1	11.2

Statistical Analysis 1 for Percentage of Patients With an Improvement of at Least 50% in American College of Rheumatology (ACR) Score (ACR50) From Baseline at Week 24

Groups ^[1]	All groups
Method ^[2]	Fisher Exact
P Value ^[3]	<0.0001
Mean Difference (Final Values) ^[4]	18.85
95% Confidence Interval	( 12.29 to 25.42 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	The p-value was not adjusted. The primary objective was a single comparison with an a priori threshold of 0.05 for statistical significance.
[4]	Other relevant estimation information:
	No text entered.

2. Secondary:

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 [ Time Frame: Baseline to Weeks 4, 8, 12, 16, 20, 24 ]

Measure Type	Secondary
Measure 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
Measure 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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
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.

Measured Values

	Tocilizumab 8 mg/kg + DMARDs	Placebo + DMARDs
Number of Participants Analyzed [units: participants]	409	205
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 [units: Percentage of participants]
ACR20, Week 4	34.2	17.6
ACR20, Week 8	46.5	25.4
ACR20, Week 12	49.6	28.8
ACR20, Week 16	47.7	28.8
ACR20, Week 20	45.2	25.9
ACR20, Week 24	44.7	25.4
ACR50, Week 4	12.5	3.4
ACR50, Week 8	20.8	5.4
ACR50, Week 12	25.2	14.1
ACR50, Week 16	26.7	15.1
ACR50, Week 20	28.4	12.7
ACR70, Week 4	4.4	1.5
ACR70, Week 8	6.8	0.5
ACR70, Week 12	11.5	4.9
ACR70, Week 16	12.5	3.4
ACR70, Week 20	16.9	5.4
ACR70, Week 24	15.4	1.5

No statistical analysis provided for 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

3. Secondary:

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

Measure Type	Secondary
Measure Title	Mean Change From Baseline in Disease Activity Score 28 (DAS28) at Weeks 4, 8, 12, 16, 20, and 24
Measure 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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
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.

Measured Values

	Tocilizumab 8 mg/kg + DMARDs	Placebo + DMARDs
Number of Participants Analyzed [units: participants]	409	205
Mean Change From Baseline in Disease Activity Score 28 (DAS28) at Weeks 4, 8, 12, 16, 20, and 24 [units: Units on a scale] Mean ± Standard Deviation
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

No statistical analysis provided for Mean Change From Baseline in Disease Activity Score 28 (DAS28) at Weeks 4, 8, 12, 16, 20, and 24

4. Secondary:

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

Measure Type	Secondary
Measure Title	Percentage of Patients With European League Against Rheumatism (EULAR) Good, Moderate, or no Response at Weeks 4, 8, 12, 16, 20, and 24
Measure 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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent-to-treat population: All randomized patients who received at least 1 dose of study medication. Missing data was imputed as “no response”.

Reporting Groups

	Description
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.

Measured Values

	Tocilizumab 8 mg/kg + DMARDs	Placebo + DMARDs
Number of Participants Analyzed [units: participants]	409	205
Percentage of Patients With European League Against Rheumatism (EULAR) Good, Moderate, or no Response at Weeks 4, 8, 12, 16, 20, and 24 [units: Percentage of participants]
Good response, Week 4	13.2	2.0
Good response, Week 8	23.5	1.0
Good response, Week 12	28.1	5.9
Good response, Week 16	29.8	4.9
Good response, Week 20	31.5	6.8
Good response, Week 24	32.5	5.9
Moderate response, Week 4	57.2	23.9
Moderate response, Week 8	52.6	35.6
Moderate response, Week 12	50.6	35.6
Moderate response, Week 16	40.6	36.6
Moderate response, Week 20	30.6	28.8
Moderate response, Week 24	27.4	27.8
No response, Week 4	29.6	74.1
No response, Week 8	24.0	63.4
No response, Week 12	21.3	58.5
No response, Week 16	29.6	58.5
No response, Week 20	37.9	64.4
No response, Week 24	40.1	66.3

No statistical analysis provided for Percentage of Patients With European League Against Rheumatism (EULAR) Good, Moderate, or no Response at Weeks 4, 8, 12, 16, 20, and 24

5. Secondary:

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

Measure Type	Secondary
Measure Title	Mean Change From Baseline in the Routine Assessment Patient Index Data (RAPID) Score at Weeks 4, 8, 12, 16, 20, and 24
Measure 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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
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.

Measured Values

	Tocilizumab 8 mg/kg + DMARDs	Placebo + DMARDs
Number of Participants Analyzed [units: participants]	409	205
Mean Change From Baseline in the Routine Assessment Patient Index Data (RAPID) Score at Weeks 4, 8, 12, 16, 20, and 24 [units: Units on a scale] Mean ± Standard Deviation
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

No statistical analysis provided for Mean Change From Baseline in the Routine Assessment Patient Index Data (RAPID) Score at Weeks 4, 8, 12, 16, 20, and 24

6. Secondary:

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

Measure Type	Secondary
Measure 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
Measure 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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
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.

Measured Values

	Tocilizumab 8 mg/kg + DMARDs	Placebo + DMARDs
Number of Participants Analyzed [units: participants]	409	204
Mean Change From Baseline in 12-Item Short Form Health Survey v2 (SF-12) Scores at Weeks 4, 8, 12, 16, 20, and 24 [units: Units on a scale] Mean ± Standard Deviation
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

No statistical analysis provided for Mean Change From Baseline in 12-Item Short Form Health Survey v2 (SF-12) Scores at Weeks 4, 8, 12, 16, 20, and 24

7. Secondary:

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

Measure Type	Secondary
Measure 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
Measure 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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
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.

Measured Values

	Tocilizumab 8 mg/kg + DMARDs	Placebo + DMARDs
Number of Participants Analyzed [units: participants]	409	205
Mean Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Weeks 4, 8, 12, 16, 20, and 24 [units: Units on a scale] Mean ± Standard Deviation
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

No statistical analysis provided for Mean Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Weeks 4, 8, 12, 16, 20, and 24

8. Secondary:

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

Measure Type	Secondary
Measure Title	Mean Change From Baseline in the Medical Outcomes Study (MOS) Sleep Scale Score at Weeks 4, 8, 12, 16, 20, and 24
Measure 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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
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.

Measured Values

	Tocilizumab 8 mg/kg + DMARDs	Placebo + DMARDs
Number of Participants Analyzed [units: participants]	409	205
Mean Change From Baseline in the Medical Outcomes Study (MOS) Sleep Scale Score at Weeks 4, 8, 12, 16, 20, and 24 [units: Units on a scale] Mean ± Standard Deviation
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

No statistical analysis provided for Mean Change From Baseline in the Medical Outcomes Study (MOS) Sleep Scale Score at Weeks 4, 8, 12, 16, 20, and 24

9. Secondary:

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 [ Time Frame: Baseline through Day 7 ]

Measure Type	Secondary
Measure 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
Measure 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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
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.

Measured Values

	Tocilizumab 8 mg/kg + DMARDs	Placebo + DMARDs
Number of Participants Analyzed [units: participants]	409	205
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 [units: Units on a scale] Mean ± Standard Deviation
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

No statistical analysis provided for 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

10. Secondary:

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 [ Time Frame: Baseline to Day 7 ]

Measure Type	Secondary
Measure 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
Measure 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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
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.

Measured Values

	Tocilizumab 8 mg/kg + DMARDs	Placebo + DMARDs
Number of Participants Analyzed [units: participants]	38	21
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 [units: Percentage of participants]
ACR20	21	5
ACR50	5	0
ACR70	5	0

11. Secondary:

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

Measure Type	Secondary
Measure Title	Mean Change From Baseline in C-reactive Protein (CRP) at Days 3 and 7
Measure Description	Serum concentration of CRP (high-sensitivity CRP [hsCRP] test) was analyzed by a central laboratory.
Time Frame	Baseline to Days 3 and 7
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups

	Description
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.

Measured Values

	Tocilizumab 8 mg/kg + DMARDs	Placebo + DMARDs
Number of Participants Analyzed [units: participants]	40	22
Mean Change From Baseline in C-reactive Protein (CRP) at Days 3 and 7 [units: mg/dL] Mean ± Standard Deviation
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

No statistical analysis provided for Mean Change From Baseline in C-reactive Protein (CRP) at Days 3 and 7

Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: 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.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact:

Name/Title: Medical Communications
Organization: Hoffmann-La Roche
phone: 800-821-8590

No publications provided by Hoffmann-La Roche

Publications automatically indexed to this study:

Yazici Y, Curtis JR, Ince A, Baraf H, Malamet RL, Teng LL, Kavanaugh A. Efficacy of tocilizumab in patients with moderate to severe active rheumatoid arthritis and a previous inadequate response to disease-modifying antirheumatic drugs: the ROSE study. Ann Rheum Dis. 2012 Feb;71(2):198-205. Epub 2011 Sep 26.

Responsible Party:	Hoffmann-La Roche
ClinicalTrials.gov Identifier:	NCT00531817 History of Changes
Other Study ID Numbers:	ML21136
Study First Received:	September 18, 2007
Results First Received:	July 6, 2010
Last Updated:	August 13, 2012
Health Authority:	United States: Food and Drug Administration

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