Clinical Trial Results:
Efficacy and Safety Study of a Sequential Therapy of Tocilizumab (TCZ) and, if Initially Inadequately Responded to Tocilizumab (TCZ), Followed by Rituximab (RTX) in DMARD-IR Patients With Rheumatoid Arthritis (MIRAI)
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Summary
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EudraCT number |
2010-022049-88 |
Trial protocol |
DE |
Global end of trial date |
19 Feb 2014
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Results information
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Results version number |
v2(current) |
This version publication date |
21 Jul 2016
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First version publication date |
16 Mar 2016
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Other versions |
v1 |
Version creation reason |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
ML22985
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01332994 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
F. Hoffmann-La Roche AG
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Sponsor organisation address |
Grenzacherstrasse 124, Basel, Switzerland, CH-4070
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Public contact |
Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
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Scientific contact |
Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
19 Feb 2014
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
19 Feb 2014
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
This open-label, national, multicenter, two-arm, non-controlled, nonrandomized study evaluated the efficacy and safety of TCZ with or without sequential RTX in participants with moderate to severe active rheumatoid arthritis (RA) with inadequate response to disease-modifying antirheumatic drugs (DMARD-IR) at the time of enrollment. Participants were treated with TCZ and, if applicable, with subsequent RTX in combination with traditional disease-modifying antirheumatic drugs (DMARDs) taken before study entry.
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Protection of trial subjects |
The study was conducted in accordance with the principles of the Declaration of Helsinki (version 1996) as amended, international Good Clinical Practice (ICH-GCP) standards, and local laws and regulations concerning clinical studies.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
18 Mar 2011
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety | ||
Long term follow-up duration |
9 Months | ||
Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Germany: 519
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Worldwide total number of subjects |
519
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EEA total number of subjects |
519
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
388
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From 65 to 84 years |
131
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
After a screening period of up to 4 weeks, eligible participants were treated according to a predefined treatment algorithm based on disease response. In certain cases a re-screening was allowed. Participants were enrolled into the study with the administration of their first dose. | ||||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||||
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Arms
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Arm title
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TCZ/TCZ or TCZ/RTX | ||||||||||||||||||||||||||||||||
Arm description |
All participants were assigned to receive TCZ 8 milligrams per kilogram (mg/kg) via intravenous (IV) infusion every 4 weeks for a total of 4 infusions from Baseline to Week 12. Clinical response was assessed at Week 16 using Disease Activity Score Based on 28-Joint Count (DAS28) to determine subsequent treatment assignment. Participants who achieved early remission, defined as a DAS28 score of less than (<) 2.6, were transferred to clinical routine care and no longer received study medication. Participants who were considered partial responders, defined as a decrease from Baseline in DAS28 score greater than (>) 1.2 or a score between 2.6 and 3.2, inclusive, received TCZ 8 mg/kg via IV infusion every 4 weeks for a total of 4 additional infusions from Week 16 to 28. Those with assessed as having no response, defined as a decrease from Baseline in DAS28 score less than or equal to (≤) 1.2 or a score >3.2, received RTX 1000 milligrams (mg) via IV infusion at Weeks 16 and 18. | ||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Tocilizumab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Participants received TCZ 8 mg/kg via IV infusion every 4 weeks for a total of 4 infusions from Baseline to Week 12. Participants with a partial response received an additional 4 infusions of TCZ 8 mg/kg every 4 weeks from Week 16 to 28.
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Investigational medicinal product name |
Rituximab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Participants assessed as having no response received RTX 1000 mg via IV infusion at Weeks 16 and 18.
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| Notes [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: Only select participants continued assessment visits through the end of safety follow-up (Week 66). Participants achieving early remission or partial response could complete the study earlier. [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: Only select participants continued assessment visits through the end of safety follow-up (Week 66). Participants achieving early remission or partial response could complete the study earlier. [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: Only select participants continued assessment visits through the end of safety follow-up (Week 66). Participants achieving early remission or partial response could complete the study earlier. |
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Baseline characteristics reporting groups
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Reporting group title |
TCZ/TCZ or TCZ/RTX
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Reporting group description |
All participants were assigned to receive TCZ 8 milligrams per kilogram (mg/kg) via intravenous (IV) infusion every 4 weeks for a total of 4 infusions from Baseline to Week 12. Clinical response was assessed at Week 16 using Disease Activity Score Based on 28-Joint Count (DAS28) to determine subsequent treatment assignment. Participants who achieved early remission, defined as a DAS28 score of less than (<) 2.6, were transferred to clinical routine care and no longer received study medication. Participants who were considered partial responders, defined as a decrease from Baseline in DAS28 score greater than (>) 1.2 or a score between 2.6 and 3.2, inclusive, received TCZ 8 mg/kg via IV infusion every 4 weeks for a total of 4 additional infusions from Week 16 to 28. Those with assessed as having no response, defined as a decrease from Baseline in DAS28 score less than or equal to (≤) 1.2 or a score >3.2, received RTX 1000 milligrams (mg) via IV infusion at Weeks 16 and 18. | |||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
TCZ/TCZ or TCZ/RTX
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Reporting group description |
All participants were assigned to receive TCZ 8 milligrams per kilogram (mg/kg) via intravenous (IV) infusion every 4 weeks for a total of 4 infusions from Baseline to Week 12. Clinical response was assessed at Week 16 using Disease Activity Score Based on 28-Joint Count (DAS28) to determine subsequent treatment assignment. Participants who achieved early remission, defined as a DAS28 score of less than (<) 2.6, were transferred to clinical routine care and no longer received study medication. Participants who were considered partial responders, defined as a decrease from Baseline in DAS28 score greater than (>) 1.2 or a score between 2.6 and 3.2, inclusive, received TCZ 8 mg/kg via IV infusion every 4 weeks for a total of 4 additional infusions from Week 16 to 28. Those with assessed as having no response, defined as a decrease from Baseline in DAS28 score less than or equal to (≤) 1.2 or a score >3.2, received RTX 1000 milligrams (mg) via IV infusion at Weeks 16 and 18. | ||
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End point title |
Percentage of Participants Achieving Remission at Week 16 According to DAS28 [1] | ||||||||
End point description |
The DAS28 was calculated as [0.28 times (x) the square root of number of swollen joints] plus (+) [0.56 x the square root of number of tender joints] + [0.7 x the natural log of erythrocyte sedimentation rate (ESR)] + [0.014 x Visual Analog Scale (VAS) patient global assessment of disease activity]. VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity.' DAS28 scores ranged from 0 to 10, with higher scores indicating increased disease activity. Remission was defined as a DAS28 score <2.6 at the assessment visit. Main Intent-to-Treat (ITT) Population: All participants who received at least one dose of TCZ.
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End point type |
Primary
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End point timeframe |
Week 16
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis could not be entered due to system limitations for a single-arm study. An exact one-sided binomial test on single proportions was performed, with a significance level of alpha equals (=) 0.025. Null hypothesis: Proportion of participants reaching DAS28 remission (<2.6) at Week 16 is ≤45 percent (%). The result was p-value = 0.1648. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants Achieving Remission According to DAS28 at Weeks 4, 8, and 12 | ||||||||||||||
End point description |
The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x VAS patient global assessment of disease activity]. VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity.' DAS28 scores ranged from 0 to 10, with higher scores indicating increased disease activity. Remission was defined as a DAS28 score <2.6 at the assessment visit. Main ITT Population.
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End point type |
Secondary
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End point timeframe |
Weeks 4, 8, and 12
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Percentage of Participants Achieving Remission According to DAS28 at Weeks 16, 20, 24, and 28 Among Participants Treated With 8 Courses of Tocilizumab | ||||||||||||||||
End point description |
The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x VAS patient global assessment of disease activity]. VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity.' DAS28 scores ranged from 0 to 10, with higher scores indicating increased disease activity. Remission was defined as a DAS28 score <2.6 at the assessment visit. ITT2 Population: All participants who received at least one dose of TCZ in the first treatment period with at least one efficacy measurement under TCZ, receiving TCZ in the second treatment period.
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End point type |
Secondary
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End point timeframe |
Weeks 16, 20, 24, and 28
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Percentage of Participants Achieving Remission According to DAS28 at Week 32 Among Participants Treated With 8 Courses of Tocilizumab | ||||||||
End point description |
The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x VAS patient global assessment of disease activity]. VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity.' DAS28 scores ranged from 0 to 10, with higher scores indicating increased disease activity. Remission was defined as a DAS28 score <2.6 at the assessment visit. ITT2 Population.
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End point type |
Secondary
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End point timeframe |
Week 32
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants Achieving Low Disease Activity Score (LDAS) According to DAS28 | ||||||||
End point description |
The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x the patient global assessment of disease activity using a VAS]. VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity.' DAS28 scores ranged from 0 to 10, with higher scores indicating increased disease activity. LDAS was defined as a DAS28 score <3.2 at the assessment visit. Main ITT Population.
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End point type |
Secondary
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End point timeframe |
Week 16
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants Achieving a Clinically Relevant Reduction From Baseline in DAS28 at Week 16 | ||||||||
End point description |
The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x VAS patient global assessment of disease activity]. VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity.' DAS28 scores ranged from 0 to 10, with higher scores indicating increased disease activity. Reductions >1.2 points from Baseline to the assessment visit were considered clinically relevant. Main ITT Population.
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End point type |
Secondary
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End point timeframe |
Baseline and Week 16
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Participants Achieving a Clinically Relevant Reduction From Baseline in DAS28 at Weeks 4, 8, and 12 | ||||||||||||||
End point description |
The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x VAS patient global assessment of disease activity]. VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity.' DAS28 scores ranged from 0 to 10, with higher scores indicating increased disease activity. Reductions >1.2 points from Baseline to the assessment visit were considered clinically relevant. Main ITT Population.
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End point type |
Secondary
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End point timeframe |
Baseline and Weeks 4, 8, and 12
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Percentage of Participants Achieving a Clinically Relevant Reduction in DAS28 From Week 16 to Week 32 Among Nonresponding Participants Treated With Rituximab | ||||||||
End point description |
The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x VAS patient global assessment of disease activity]. VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity.' DAS28 scores ranged from 0 to 10, with higher scores indicating increased disease activity. Reductions >1.2 points from the reference visit (Week 16) to the assessment visit were considered clinically relevant. ITT3 Population: All participants who received at least one dose of TCZ in the first treatment period and at least one dose of RTX in the second treatment period with at least one efficacy measurement under RTX.
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End point type |
Secondary
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End point timeframe |
Weeks 16 and 32
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| No statistical analyses for this end point | |||||||||
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End point title |
DAS28 Scores During and After Treatment | ||||||||||||||||||
End point description |
The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x VAS patient global assessment of disease activity]. VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity.' DAS28 scores ranged from 0 to 10, with higher scores indicating increased disease activity. Main ITT Population.
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End point type |
Secondary
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End point timeframe |
Baseline and Weeks 4, 8, 12, 16
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| Notes [2] - Participants with evaluable data at the designated visit (number shown = n) were included. |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
DAS28 Scores During Safety Follow-Up Among Nonresponding Participants Treated With Rituximab | ||||||||||||||||
End point description |
The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x VAS patient global assessment of disease activity]. VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity.' DAS28 scores ranged from 0 to 10, with higher scores indicating increased disease activity. ITT3 Population.
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End point type |
Secondary
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End point timeframe |
Weeks 40, 48, 56, and 66
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| Notes [3] - Participants with evaluable data at the designated visit (number shown = n) were included. |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Percentage of Participants Achieving a Response According to European League Against Rheumatism (EULAR) Criteria at Weeks 4, 8, 12 and 16 | ||||||||||||||||||||||||||||||||
End point description |
Response was determined using EULAR criteria based upon DAS28 absolute scores at the assessment visit and the DAS28 reduction from Baseline. Participants with a score ≤3.2 and reduction of >1.2 points were assessed as having a 'good' response. Participants with a score >3.2 with reduction of >1.2 points, or a score ≤5.1 with reduction of >0.6 to ≤1.2 points, were assessed as having a 'moderate' response. Participants with a score >5.1 with reduction of >0.6 to ≤1.2 points, or any score with reduction ≤0.6 points, were assessed as nonresponders with response recorded as 'none.' Main ITT Population.
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End point type |
Secondary
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End point timeframe |
Baseline and Weeks 4, 8, 12, and 16
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||
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End point title |
Percentage of Participants Achieving a Response According to EULAR Criteria at Week 32 Compared to Week 16 Among Nonresponding Participants Treated With Rituximab | ||||||||||||||
End point description |
Response was determined using EULAR criteria based upon DAS28 absolute scores at the assessment visit and the DAS28 reduction from the reference visit (Week 16). Participants with a score ≤3.2 and reduction of >1.2 points were assessed as having a 'good' response. Participants with a score >3.2 with reduction of >1.2 points, or a score ≤5.1 with reduction of >0.6 to ≤1.2 points, were assessed as having a 'moderate' response. Participants with a score >5.1 with reduction of >0.6 to ≤1.2 points, or any score with reduction ≤0.6 points, were assessed as nonresponders with response recorded as 'none.' ITT3 Population.
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End point type |
Secondary
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End point timeframe |
Weeks 16 and 32
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Percentage of Participants Achieving a Response According to EULAR Criteria at Weeks 20, 24, 28, and 32 Among Participants Treated With 8 Courses of Tocilizumab | ||||||||||||||||||||||||||||||||
End point description |
Response was determined using EULAR criteria based upon DAS28 absolute scores at the assessment visit and the DAS28 reduction from Baseline. Participants with a score ≤3.2 and reduction of >1.2 points were assessed as having a 'good' response. Participants with a score >3.2 with reduction of >1.2 points, or a score ≤5.1 with reduction of >0.6 to ≤1.2 points, were assessed as having a 'moderate' response. Participants with a score >5.1 with reduction of >0.6 to ≤1.2 points, or any score with reduction ≤0.6 points, were assessed as nonresponders with response recorded as 'none.' ITT2 Population.
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End point type |
Secondary
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End point timeframe |
Baseline and Weeks 20, 24, 28, and 32
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||
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End point title |
Percentage of Participants Achieving a Response According to American College of Rheumatology (ACR) Criteria at Weeks 4, 8, 12, and 16 | ||||||||||||||||||||||||||||||||
End point description |
Response was determined using ACR criteria based upon assessment of 66 joints for swelling and 68 joints for tenderness; joints were classified dichotomously as swollen or not swollen and tender or not tender. Respectively, these assessments were used to generate a swollen joint count (SJC) ranging from 0 to 66 swollen joints and a tender joint count (TJC) ranging from 0 to 68 tender joints. Response was defined as a reduction from Baseline of at least 20% for one of the following: VAS scores for patient-reported pain, patient global assessment of disease activity, or physician global assessment of disease activity, Health Assessment Questionnaire Disability Index (HAQ-DI), or C-reactive protein (CRP); plus a reduction in individual SJC and TJC of 20% (ACR20), 50% (ACR50), or 70% (ACR70). VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity.' Main ITT Population.
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End point type |
Secondary
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End point timeframe |
Baseline and Weeks 4, 8, 12, and 16
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||
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End point title |
Percentage of Participants Achieving a Response According to ACR Criteria at Week 32 Compared to Week 16 Among Nonresponding Participants Treated With Rituximab | ||||||||||||||
End point description |
Response was determined using ACR criteria based upon assessment of 66 joints for swelling and 68 joints for tenderness; joints were classified dichotomously as swollen or not swollen and tender or not tender. Respectively, these assessments were used to generate an SJC ranging from 0 to 66 swollen joints and a TJC ranging from 0 to 68 tender joints. Response was defined as a reduction from the reference visit (Week 16) of at least 20% for one of the following: VAS scores for patient-reported pain, patient global assessment of disease activity, or physician global assessment of disease activity, HAQDI, or CRP; plus a reduction in individual SJC and TJC of 20% (ACR20), 50% (ACR50), or 70% (ACR70). VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity.' ITT3 Population.
|
||||||||||||||
End point type |
Secondary
|
||||||||||||||
End point timeframe |
Weeks 16 and 32
|
||||||||||||||
|
|||||||||||||||
| No statistical analyses for this end point | |||||||||||||||
|
|||||||||||||||||||||||||||||||||
End point title |
Percentage of Participants Achieving a Response According to ACR Criteria at Weeks 20, 24, 28, and 32 Among Participants Treated With 8 Courses of Tocilizumab | ||||||||||||||||||||||||||||||||
End point description |
Response was determined using ACR criteria based upon assessment of 66 joints for swelling and 68 joints for tenderness; joints were classified dichotomously as swollen or not swollen and tender or not tender. Respectively, these assessments were used to generate an SJC ranging from 0 to 66 swollen joints and a TJC ranging from 0 to 68 tender joints. Response was defined as a reduction from Baseline of at least 20% for one of the following: VAS scores for patient-reported pain, patient global assessment of disease activity, or physician global assessment of disease activity, HAQ-DI, or CRP; plus a reduction in individual SJC and TJC of 20% (ACR20), 50% (ACR50), or 70% (ACR70). VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity.' ITT2 Population.
|
||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||
End point timeframe |
Baseline and Weeks 20, 24, 28, and 32
|
||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Change From Baseline in Clinical Disease Activity Index (CDAI) and Simplified Disease Activity Index (SDAI) Scores at Weeks 4, 8, 12, and 16 | ||||||||||||||||||||||||
End point description |
The CDAI was calculated as [SJC + TJC + VAS patient global assessment of disease activity + VAS physician global assessment of disease activity]. VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity.' CDAI scores ranged from 0 to 76, with higher scores indicating increased disease activity. The SDAI was determined by adding CRP level to the CDAI score. Scores ranged from 0 to 86, with higher scores also indicating increased disease activity. A reduction in either score at the assessment visit reflects improvement in disease. Main ITT Population.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Baseline and Weeks 4, 8, 12, and 16
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| Notes [4] - Participants with evaluable data at the designated visit (number shown = n) were included. |
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||
End point title |
Change From Week 16 to 32 in CDAI and SDAI Scores Among Nonresponding Participants Treated With Rituximab | ||||||||||||
End point description |
The CDAI was calculated as [SJC + TJC + VAS patient global assessment of disease activity + VAS physician global assessment of disease activity]. VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity.' CDAI scores ranged from 0 to 76, with higher scores indicating increased disease activity. The SDAI was determined by adding CRP level to the CDAI score. Scores ranged from 0 to 86, with higher scores also indicating increased disease activity. A reduction in either score at the assessment visit reflects improvement in disease. ITT3 Population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Weeks 16 and 32
|
||||||||||||
|
|||||||||||||
| Notes [5] - Participants with evaluable data at the designated visit (number shown = n) were included. |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||||||||||
End point title |
Change From Baseline in CDAI and SDAI Scores at Weeks 20, 24, 28, and 32 Among Participants Treated With 8 Courses of Tocilizumab | ||||||||||||||||||||||||
End point description |
The CDAI was calculated as [SJC + TJC + VAS patient global assessment of disease activity + VAS physician global assessment of disease activity]. VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity.' CDAI scores ranged from 0 to 76, with higher scores indicating increased disease activity. The SDAI was determined by adding CRP level to the CDAI score. Scores ranged from 0 to 86, with higher scores also indicating increased disease activity. A reduction in either score at the assessment visit reflects improvement in disease. ITT2 Population.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Baseline and Weeks 20, 24, 28, and 32
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| Notes [6] - Participants with evaluable data at the designated visit (number shown = n) were included. |
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||
End point title |
Change From Baseline in Hemoglobin at Weeks 4, 8, 12, and 16 | ||||||||||||||||
End point description |
Blood samples for laboratory assessments, including hemoglobin level, were collected prior to each dose of study medication. The mean hemoglobin level was determined at Baseline and for assessment visits by averaging the observed hemoglobin level among all participants providing evaluable blood samples. Change from Baseline was calculated as [mean hemoglobin at the assessment visit minus mean hemoglobin at Baseline] and expressed in grams per liter (g/L). Main ITT Population.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline and Weeks 4, 8, 12, and 16
|
||||||||||||||||
|
|||||||||||||||||
| Notes [7] - Participants with evaluable data at the designated visit (number shown = n) were included. |
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
Change From Baseline in CRP at Weeks 4, 8, 12, and 16 | ||||||||||||||||
End point description |
Blood samples for laboratory assessments, including CRP level, were collected prior to each dose of study medication. The mean CRP level was determined at Baseline and for assessment visits by averaging the observed CRP level among all participants providing evaluable blood samples. Change from Baseline was calculated as [mean CRP at the assessment visit minus mean CRP at Baseline] and expressed in milligrams per deciliter (mg/dL). Main ITT Population.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline and Weeks 4, 8, 12, and 16
|
||||||||||||||||
|
|||||||||||||||||
| Notes [8] - Participants with evaluable data at the designated visit (number shown = n) were included. |
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
Change From Baseline in ESR at Weeks 4, 8, 12, and 16 | ||||||||||||||||
End point description |
Blood samples for laboratory assessments, including ESR, were collected prior to each dose of study medication. The mean ESR was determined at Baseline and for assessment visits by averaging the observed ESR among all participants providing evaluable blood samples. Change from Baseline was calculated as [mean ESR at the assessment visit minus mean ESR at Baseline] and expressed in millimeters per hour (mm/h). Main ITT Population.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline and Weeks 4, 8, 12, and 16
|
||||||||||||||||
|
|||||||||||||||||
| Notes [9] - Participants with evaluable data at the designated visit (number shown = n) were included. |
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||
End point title |
Change in Hemoglobin From Week 16 to 32 Among Nonresponding Participants Treated With Rituximab | ||||||||
End point description |
Blood samples for laboratory assessments, including hemoglobin level, were collected prior to each dose of study medication. The mean hemoglobin level was determined at Baseline and for assessment visits by averaging the observed hemoglobin level among all participants providing evaluable blood samples. Change was calculated as [mean hemoglobin at Week 32 minus mean hemoglobin at Week 16] and expressed in g/L. ITT3 Population.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Weeks 16 and 32
|
||||||||
|
|||||||||
| Notes [10] - Participants with evaluable data at the designated visit were included. |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Change in CRP From Week 16 to 32 Among Nonresponding Participants Treated With Rituximab | ||||||||
End point description |
Blood samples for laboratory assessments, including CRP level, were collected prior to each dose of study medication. The mean CRP level was determined at Baseline and for assessment visits by averaging the observed CRP level among all participants providing evaluable blood samples. Change was calculated as [mean CRP at Week 32 minus mean CRP at Week 16] and expressed in mg/dL. ITT3 Population.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Weeks 16 and 32
|
||||||||
|
|||||||||
| Notes [11] - Participants with evaluable data at the designated visit were included. |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Change in ESR From Week 16 to 32 Among Nonresponding Participants Treated With Rituximab | ||||||||
End point description |
Blood samples for laboratory assessments, including ESR, were collected prior to each dose of study medication. The mean ESR was determined at Baseline and for assessment visits by averaging the observed ESR among all participants providing evaluable blood samples. Change was calculated as [mean ESR at Week 32 minus mean ESR at Week 16] and expressed in mm/h. ITT3 Population.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Weeks 16 and 32
|
||||||||
|
|||||||||
| Notes [12] - Participants with evaluable data at the designated visit were included. |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||||||
End point title |
Change From Baseline in Hemoglobin at Weeks 20, 24, 28, and 32 Among Participants Treated With 8 Courses of Tocilizumab | ||||||||||||||||
End point description |
Blood samples for laboratory assessments, including hemoglobin level, were collected prior to each dose of study medication. The mean hemoglobin level was determined at Baseline and for assessment visits by averaging the observed hemoglobin level among all participants providing evaluable blood samples. Change from Baseline was calculated as [mean hemoglobin at the assessment visit minus mean hemoglobin at Baseline] and expressed in g/L. ITT2 Population.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline and Weeks 20, 24, 28, and 32
|
||||||||||||||||
|
|||||||||||||||||
| Notes [13] - Participants with evaluable data at the designated visit (number shown = n) were included. |
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
Change From Baseline in CRP at Weeks 20, 24, 28, and 32 Among Participants Treated With 8 Courses of Tocilizumab | ||||||||||||||||
End point description |
Blood samples for laboratory assessments, including CRP level, were collected prior to each dose of study medication. The mean CRP level was determined at Baseline and for assessment visits by averaging the observed CRP level among all participants providing evaluable blood samples. Change from Baseline was calculated as [mean CRP at the assessment visit minus mean CRP at Baseline] and expressed in mg/dL. ITT2 Population.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline and Weeks 20, 24, 28, and 32
|
||||||||||||||||
|
|||||||||||||||||
| Notes [14] - Participants with evaluable data at the designated visit (number shown = n) were included. |
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
Change From Baseline in ESR at Weeks 20, 24, 28, and 32 Among Participants Treated With 8 Courses of Tocilizumab | ||||||||||||||||
End point description |
Blood samples for laboratory assessments, including ESR, were collected prior to each dose of study medication. The mean ESR was determined at Baseline and for assessment visits by averaging the observed ESR among all participants providing evaluable blood samples. Change from Baseline was calculated as [mean ESR at the assessment visit minus mean ESR at Baseline] and expressed in mm/h. ITT2 Population.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline and Weeks 20, 24, 28, and 32
|
||||||||||||||||
|
|||||||||||||||||
| Notes [15] - Participants with evaluable data at the designated visit (number shown = n) were included. |
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||
End point title |
Percentage of Participants Withdrawing From the Study for Insufficient Therapeutic Response | ||||||||
End point description |
Study discontinuation was documented by reason for each participant prematurely withdrawing from the study. The percentage of participants was calculated as the number withdrawing for insufficient therapeutic response divided by the total number of participants who began treatment. Main ITT Population.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline to Week 16
|
||||||||
|
|||||||||
| Notes [16] - Participants who withdrew from the study for other reasons were excluded from the analysis. |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||||||||||||||||||||
End point title |
Percentage of B-Cells at Baseline by B-Cell Subpopulation Among Participants With Early Remission | ||||||||||||||||||||||||||||||
End point description |
Blood samples were collected to analyze total B-cell panel via immunophenotyping. Subpopulations were as follows: transitional (cluster of differentiation [CD] 19-positive, immunoglobulin (Ig) D-positive, CD38 medium, CD10-positive); naive (CD19-positive, IgD-positive, CD38 medium, CD27-negative); preswitch memory (CD19-positive, CD27-positive, IgD-positive); post-switch memory (CD19-positive, CD27-positive, IgD-negative); IgG-positive class-switched (CD19-positive, IgG-positive); IgA-positive class-switched (CD19-positive, IgA-positive); double-negative memory (CD19-positive, IgD-negative, CD27-negative); and plasmablasts (CD19-positive, IgD-negative, CD38 high, CD27 high). Naive B-cell compartment was defined as the sum of transitional and naive B-cells. The sum of memory B-cell subsets with or without double-negative B-cells was also determined. ITT1 Population: Those who received at least one dose of TCZ in the first treatment period and completed at Week 16 reaching remission.
|
||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||
End point timeframe |
Baseline
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
| Notes [17] - Participants with evaluable data at the designated visit (number shown = n) were included. |
|||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||
End point title |
Spearman's Rank Correlation Coefficient Between Percentage of B-Cells at Baseline and Difference in DAS28 Scores Between Baseline and Week 16 Among Participants With Early Remission | ||||||||||||||||||||||||||||
End point description |
Blood samples were collected to analyze total B-cell panel via immunophenotyping. Subpopulations were as follows: transitional, naïve, pre-switch memory, post-switch memory, IgG-positive class-switched, IgA-positive class-switched, double-negative memory, and plasmablasts. Naive B-cell compartment was defined as the sum of transitional and naive B-cells. The sum of memory B-cell subsets with or without double-negative B-cells was also determined. Extent of disease response, using change from Baseline to Week 16 in DAS28 score, was correlated to the percentage of B-cells within each subpopulation at Baseline. Correlation is indicated by a correlation coefficient (r) >0.2, with greater values indicating a stronger correlation. ITT1 Population.
|
||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||
End point timeframe |
Baseline and Week 16
|
||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||
| Notes [18] - n = number of data pairs included in the analysis. |
|||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Spearman's Rank Correlation Coefficient Between Percentage of B-Cells at Baseline and Difference in DAS28 Scores Between Baseline and Weeks 16, 24, and 32 Among Participants Treated With 8 Courses of Tocilizumab | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Blood samples were collected to analyze total B-cell panel via immunophenotyping. Subpopulations were as follows: transitional, naïve, pre-switch memory, post-switch memory, IgG-positive class-switched, IgA-positive class-switched, double-negative memory, and plasmablasts. Naive B-cell compartment was defined as the sum of transitional and naive B-cells. The sum of memory B-cell subsets with or without double-negative B-cells was also determined. Extent of disease response, using change from Baseline in DAS28 score, was correlated to the percentage of B-cells within each subpopulation at Baseline. Correlation is indicated by a correlation coefficient (r) >0.2, with greater values indicating a stronger correlation. ITT2 Population.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline and Weeks 16, 24, and 32
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [19] - n = number of data pairs included in the analysis. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Spearman's Rank Correlation Coefficient Between Percentage of B-Cells at Baseline and Difference in DAS28 Scores Between Baseline and Weeks 16, 32, 40, 48, and 66 Among Nonresponding Participants Treated With Rituximab | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Blood samples were collected to analyze total B-cell panel via immunophenotyping. Subpopulations were as follows: transitional, naïve, pre-switch memory, post-switch memory, IgG-positive class-switched, IgA-positive class-switched, double-negative memory, and plasmablasts. Naive B-cell compartment was defined as the sum of transitional and naive B-cells. The sum of memory B-cell subsets with or without double-negative B-cells was also determined. Extent of disease response, using change from Baseline in DAS28 score, was correlated to the percentage of B-cells within each subpopulation at Baseline. Correlation is indicated by a correlation coefficient (r) >0.2, with greater values indicating a stronger correlation. ITT3 Population. (99999 = not estimable because participants in this population were followed for changes in DAS28 up to Week 16 compared to Baseline, and for changes up to Week 66 compared to Week 16; 9999 = not estimable for 0 pairs; 999 = not estimable for 1 pair.)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline and Weeks 16, 32, 40, 48, and 66
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [20] - n = number of data pairs included in the analysis. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||
End point title |
Mean Number of Work Days Missed Per Week | ||||||||||||||||
End point description |
Work days missed were documented by reason (either RA or other reasons) for each participant over the preceding 7-day period. The mean number of work days missed was calculated by averaging the number of days missed per week among all participants. Main ITT Population.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline and Week 16
|
||||||||||||||||
|
|||||||||||||||||
| Notes [21] - Employed participants with evaluable data at the designated visit (number shown = n) were included. |
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||
End point title |
Quality of Life as Assessed Using Short Form 36 (SF-36) | ||||||||||||||||||||||||||||||||||||||||
End point description |
The SF-36 evaluates participant-rated quality of life using 8 domains: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, and mental health. The score for each section is the average of the individual question scores, which are scaled from 0 to 100, with higher scores indicating better functioning. The mean score at each timepoint was determined by averaging the scores among all participants. Main ITT Population.
|
||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline and Week 16
|
||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||
| Notes [22] - Participants with evaluable data at the designated visit (number shown = n) were included. |
|||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Change From Baseline in Quality of Life as Assessed Using SF-36 at Week 16 | ||||||||||||||||||||||||
End point description |
The SF-36 evaluates participant-rated quality of life using 8 domains: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, and mental health. The score for each section is the average of the individual question scores, which are scaled from 0 to 100, with higher scores indicating better functioning. The mean score at each timepoint was determined by averaging the scores among all participants, and the change in each domain score was calculated as [mean score at Week 16 minus mean score at Baseline]. Main ITT Population.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Baseline and Week 16
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| Notes [23] - Participants with evaluable data at the designated visit (number shown = n) were included. |
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Change From Week 16 to 32 in Quality of Life as Assessed Using SF-36 Scores Among Participants Treated With 8 Courses of Tocilizumab | ||||||||||||||||||||||||
End point description |
The SF-36 evaluates participant-rated quality of life using 8 domains: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, and mental health. The score for each section is the average of the individual question scores, which are scaled from 0 to 100, with higher scores indicating better functioning. The mean score at each timepoint was determined by averaging the scores among all participants, and the change in each domain score was calculated as [mean score at Week 32 minus mean score at Week 16]. ITT2 Population.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Weeks 16 and 32
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| Notes [24] - Participants with evaluable data at the designated visit (number shown = n) were included. |
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||
End point title |
Quality of Life as Assessed Using HAQ-DI | ||||||||||||
End point description |
The HAQ-DI evaluates participant-reported quality of life using 8 categories: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and other common activities such as running errands and performing household chores. Each category contains multiple questions, which are answered using a 4-point scale from 0 to 3. The overall index score is taken as an average of the individual item responses and may range from 0 to 3, where higher scores indicate more difficulty in daily living activities. The mean index score at each timepoint was determined by averaging the scores among all participants. Main ITT Population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline and Week 16
|
||||||||||||
|
|||||||||||||
| Notes [25] - Participants with evaluable data at the designated visit (number shown = n) were included. |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||
End point title |
Change From Baseline in Quality of Life as Assessed Using HAQ-DI at Week 16 | ||||||||
End point description |
The HAQ-DI evaluates participant-reported quality of life using 8 categories: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and other common activities such as running errands and performing household chores. Each category contains multiple questions, which are answered using a 4-point scale from 0 to 3. The overall index score is taken as an average of the individual item responses and may range from 0 to 3, where higher scores indicate more difficulty in daily living activities. The mean index score at each timepoint was determined by averaging the scores among all participants, and the change in score was calculated as [mean score at Week 16 minus mean score at Baseline]. Main ITT Population.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline and Week 16
|
||||||||
|
|||||||||
| Notes [26] - Participants with evaluable data at the designated visit were included. |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Change From Week 16 to 32 in Quality of Life as Assessed Using HAQ-DI Among Participants Treated With 8 Courses of Tocilizumab | ||||||||
End point description |
The HAQ-DI evaluates participant-reported quality of life using 8 categories: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and other common activities such as running errands and performing household chores. Each category contains multiple questions, which are answered using a 4-point scale from 0 to 3. The overall index score is taken as an average of the individual item responses and may range from 0 to 3, where higher scores indicate more difficulty in daily living activities. The mean index score at each timepoint was determined by averaging the scores among all participants, and the change in score was calculated as [mean score at Week 32 minus the mean score at Week 16]. ITT2 Population.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Weeks 16 and 32
|
||||||||
|
|||||||||
| Notes [27] - Participants with evaluable data at the designated visit were included. |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Percentage of Participants Achieving a Response According to HAQ-DI Criteria | ||||||||
End point description |
The HAQ-DI evaluates participant-reported quality of life using 8 categories: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and other common activities such as running errands and performing household chores. Each category contains multiple questions, which are answered using a 4-point scale from 0 to 3. The overall index score is taken as an average of the individual item responses and may range from 0 to 3, where higher scores indicate more difficulty in daily living activities. Response was defined as a change in index score >0.22 from Baseline to Week 16. Main ITT Population.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline and Week 16
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||||||||||||||
End point title |
Quality of Life as Assessed Using Functional Assessment of Chronic Illness Therapy (FACIT) | ||||||||||||||||||||||||
End point description |
The FACIT-F evaluates quality of life using 5 categories: physical well-being (PWB), social/family well-being (SWB), emotional well-being (EWB), functional well-being (FWB), and fatigue (FS). Participants answer each item on a 5-point scale from 0 to 4. The total score is the sum of individual responses across all 5 categories and may range from 0 to 160. The FACIT-General (FACIT-G; range 0 to 108) is the sum of scores for PWB, SWB, EWB, and FWB; the FACIT-Fatigue (FACIT-F) trial outcome index (TOI; range 0 to 108) is the sum of scores for PWB, FWB, and FS; and the FACIT-F fatigue (range 0 to 52) is the sum of scores for the FS only. For derivations of the FACIT-F reported here, higher scores indicate better quality of life. The mean score at each timepoint was determined by averaging scores among all participants. Main ITT Population.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Baseline and Week 16
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| Notes [28] - Participants with evaluable data at the designated visit (number shown = n) were included. |
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||
End point title |
Change From Baseline in Quality of Life as Assessed Using FACIT at Week 16 | ||||||||||||||||
End point description |
The FACIT-F evaluates quality of life using 5 categories: PWB, SWB, EWB, FWB, and FS. Participants answer each item on a 5-point scale from 0 to 4. The total score is the sum of individual responses across all 5 categories and may range from 0 to 160. The FACIT-G (range 0 to 108) is the sum of scores for PWB, SWB, EWB, and FWB; the FACIT-F TOI (range 0 to 108) is the sum of scores for PWB, FWB, and FS; and the FACIT-F fatigue (range 0 to 52) is the sum of scores for the FS only. For derivations of the FACIT-F reported here, higher scores indicate better quality of life. The mean score at each timepoint was determined by averaging scores among all participants, and the change in score was calculated as [mean score at Week 16 minus mean score at Baseline]. Main ITT Population.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline and Week 16
|
||||||||||||||||
|
|||||||||||||||||
| Notes [29] - Participants with evaluable data at the designated visit (number shown = n) were included. |
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
Change From Week 16 to 32 in Quality of Life as Assessed Using FACIT Among Participants Treated With 8 Courses of Tocilizumab | ||||||||||||||||
End point description |
The FACIT-F evaluates quality of life using 5 categories: PWB, SWB, EWB, FWB, and FS. Participants answer each item on a 5-point scale from 0 to 4. The total score is the sum of individual responses across all 5 categories and may range from 0 to 160. The FACIT-G (range 0 to 108) is the sum of scores for PWB, SWB, EWB, and FWB; the FACIT-F TOI (range 0 to 108) is the sum of scores for PWB, FWB, and FS; and the FACIT-F fatigue (range 0 to 52) is the sum of scores for the FS only. For derivations of the FACIT-F reported here, higher scores indicate better quality of life. The mean score at each timepoint was determined by averaging scores among all participants, and the change in score was calculated as [mean score at Week 32 minus mean score at Week 16]. ITT2 Population.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Weeks 16 and 32
|
||||||||||||||||
|
|||||||||||||||||
| Notes [30] - Participants with evaluable data at the designated visit (number shown = n) were included. |
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||
End point title |
Percentage of Participants Achieving Remission According to DAS28 at Week 32 Among Nonresponding Participants Treated With Rituximab | ||||||||
End point description |
The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x VAS patient global assessment of disease activity]. VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity.' DAS28 scores ranged from 0 to 10, with higher scores indicating increased disease activity. Remission was defined as a DAS28 score <2.6 at the assessment visit. ITT3 Population.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Week 32
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Percentage of Participants Achieving LDAS According to DAS28 Among Nonresponding Participants Treated With Rituximab | ||||||||
End point description |
The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x the patient global assessment of disease activity using a VAS]. VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity.' DAS28 scores ranged from 0 to 10, with higher scores indicating increased disease activity. LDAS was defined as a DAS28 score <3.2 at the assessment visit. ITT3 Population.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Week 32
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||||||||||||||||
End point title |
DAS28 Scores During and After Treatment Among Participants Treated With 8 Courses of Tocilizumab | ||||||||||||||||||||||||||
End point description |
The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x VAS patient global assessment of disease activity]. VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity.' DAS28 scores ranged from 0 to 10, with higher scores indicating increased disease activity. ITT2 Population.
|
||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||
End point timeframe |
Baseline and Weeks 4, 8, 12, 16, 20, 24, 28, and 32
|
||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||
| Notes [31] - Participants with evaluable data at the designated visit (number shown = n) were included. |
|||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||
|
|||||||||||||||||||||||
End point title |
DAS28 Scores During and After Treatment Among Nonresponding Participants Treated With Rituximab | ||||||||||||||||||||||
End point description |
The DAS28 was calculated as [0.28 x the square root of number of swollen joints] + [0.56 x the square root of number of tender joints] + [0.7 x the natural log of ESR] + [0.014 x VAS patient global assessment of disease activity]. VAS assessments involved a 10-cm horizontal scale from 'no disease activity' to 'maximum disease activity.' DAS28 scores ranged from 0 to 10, with higher scores indicating increased disease activity. ITT3 Population.
|
||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||
End point timeframe |
Baseline and Weeks 4, 8, 12, 16, 24, and 32
|
||||||||||||||||||||||
|
|||||||||||||||||||||||
| Notes [32] - Participants with evaluable data at the designated visit (number shown = n) were included. |
|||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
End point title |
Percentage of B-Cells at Baseline by B-Cell Subpopulation Among Participants Treated With 8 Courses of Tocilizumab | ||||||||||||||||||||||||||||||
End point description |
Blood samples were collected to analyze total B-cell panel via immunophenotyping. Subpopulations were as follows: transitional (cluster of differentiation [CD] 19-positive, immunoglobulin (Ig) D-positive, CD38 medium, CD10-positive); naive (CD19-positive, IgD-positive, CD38 medium, CD27-negative); pre-switch memory (CD19-positive, CD27-positive, IgD-positive); post-switch memory (CD19-positive, CD27-positive, IgD-negative); IgG-positive class-switched (CD19-positive, IgG-positive); IgA-positive class-switched (CD19-positive, IgA-positive); double-negative memory (CD19-positive, IgD-negative, CD27-negative); and plasmablasts (CD19-positive, IgD-negative, CD38 high, CD27 high). Naive B-cell compartment was defined as the sum of transitional and naive B-cells. The sum of memory B-cell subsets with or without double-negative B-cells was also determined. ITT2 Population.
|
||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||
End point timeframe |
Baseline
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
| Notes [33] - Participants with evaluable data at the designated visit (number shown = n) were included. |
|||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
End point title |
Percentage of B-Cells at Baseline by B-Cell Subpopulation Among Nonresponding Participants Treated With Rituximab | ||||||||||||||||||||||||||||||
End point description |
Blood samples were collected to analyze total B-cell panel via immunophenotyping. Subpopulations were as follows: transitional (cluster of differentiation [CD] 19-positive, immunoglobulin (Ig) D-positive, CD38 medium, CD10-positive); naive (CD19-positive, IgD-positive, CD38 medium, CD27-negative); pre-switch memory (CD19-positive, CD27-positive, IgD-positive); post-switch memory (CD19-positive, CD27-positive, IgD-negative); IgG-positive class-switched (CD19-positive, IgG-positive); IgA-positive class-switched (CD19-positive, IgA-positive); double-negative memory (CD19-positive, IgD-negative, CD27-negative); and plasmablasts (CD19-positive, IgD-negative, CD38 high, CD27 high). Naive B-cell compartment was defined as the sum of transitional and naive B-cells. The sum of memory B-cell subsets with or without double-negative B-cells was also determined. ITT3 Population.
|
||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||
End point timeframe |
Baseline
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
| Notes [34] - Participants with evaluable data at the designated visit (number shown = n) were included. |
|||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Change From Week 16 to 32 in Quality of Life as Assessed Using SF-36 Scores Among Nonresponding Participants Treated With Rituximab | ||||||||||||||||||||||||
End point description |
The SF-36 evaluates participant-rated quality of life using 8 domains: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, and mental health. The score for each section is the average of the individual question scores, which are scaled from 0 to 100, with higher scores indicating better functioning. The mean score at each timepoint was determined by averaging the scores among all participants, and the change in each domain score was calculated as [mean score at Week 32 minus mean score at Week 16]. ITT3 Population.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Weeks 16 and 32
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| Notes [35] - Participants with evaluable data at the designated visit (number shown = n) were included. |
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||
End point title |
Change From Week 16 to 32 in Quality of Life as Assessed Using HAQ-DI Among Nonresponding Participants Treated With Rituximab | ||||||||
End point description |
The HAQ-DI evaluates participant-reported quality of life using 8 categories: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and other common activities such as running errands and performing household chores. Each category contains multiple questions, which are answered using a 4-point scale from 0 to 3. The overall index score is taken as an average of the individual item responses and may range from 0 to 3, where higher scores indicate more difficulty in daily living activities. The mean index score at each timepoint was determined by averaging the scores among all participants, and the change in score was calculated as [mean score at Week 32 minus the mean score at Week 16]. ITT3 Population.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Weeks 16 and 32
|
||||||||
|
|||||||||
| Notes [36] - Participants with evaluable data at the designated visit were included. |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||||||
End point title |
Change From Week 16 to 32 in Quality of Life as Assessed Using FACIT Among Nonresponding Participants Treated With Rituximab | ||||||||||||||||
End point description |
The FACIT-F evaluates quality of life using 5 categories: PWB, SWB, EWB, FWB, and FS. Participants answer each item on a 5-point scale from 0 to 4. The total score is the sum of individual responses across all 5 categories and may range from 0 to 160. The FACIT-G (range 0 to 108) is the sum of scores for PWB, SWB, EWB, and FWB; the FACIT-F TOI (range 0 to 108) is the sum of scores for PWB, FWB, and FS; and the FACIT-F fatigue (range 0 to 52) is the sum of scores for the FS only. For derivations of the FACIT-F reported here, higher scores indicate better quality of life. The mean score at each timepoint was determined by averaging scores among all participants, and the change in score was calculated as [mean score at Week 32 minus mean score at Week 16]. ITT3 Population.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Weeks 16 and 32
|
||||||||||||||||
|
|||||||||||||||||
| Notes [37] - Participants with evaluable data at the designated visit were included. |
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Up to 66 weeks
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Adverse events (AEs) were assessed at each treatment visit from Baseline to Week 16, at which point participants having achieved early remission completed the study. Those who did not achieve early remission continued to receive treatment, and AEs were assessed until 4 weeks after last dose (TCZ/TCZ) or until Week 66 (TCZ/RTX).
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
17.0
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
TCZ/TCZ or TCZ/RTX
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Reporting group description |
All participants were assigned to receive TCZ 8 mg/kg via IV infusion every 4 weeks for a total of 4 infusions from Baseline to Week 12. Clinical response was assessed at Week 16 using DAS28 to determine subsequent treatment assignment. Participants who achieved early remission, defined as a DAS28 score of <2.6, were transferred to clinical routine care and no longer received study medication. Participants who were considered partial responders, defined as a decrease from Baseline in DAS28 score >1.2 or a score between 2.6 and 3.2, inclusive, received TCZ 8 mg/kg via IV infusion every 4 weeks for a total of 4 additional infusions from Week 16 to 28. Those with assessed as having no response, defined as a decrease from Baseline in DAS28 score ≤1.2 or a score >3.2, received RTX 1000 mg via IV infusion at Weeks 16 and 18. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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16 Feb 2012 |
The protocol was amended to clarify inclusion and exclusion criteria, and to allow the enrollment of participants receiving methotrexate and leflunomide up to 4 weeks prior to Baseline. Safety follow-up was also planned for participants who withdrew from the study early. Definitions and procedures for TCZ-related hypersensitivity were implemented, and the reporting requirements for AEs were also modified. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
