Back to resultsA Study of Combination Treatment With MabThera (Rituximab) and RoActemra (Tocilizumab) Versus RoActemra in Patients With Rheumatoid Arthritis With an Incomplete Response to Methotrexate
Primary Purpose
Rheumatoid Arthritis
Status
Terminated
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Placebo
rituximab [MabThera/Rituxan]
tocilizumab [RoActemra/Actemra]
Sponsored by
About this trial
This is an interventional treatment trial for Rheumatoid Arthritis
Eligibility Criteria
Inclusion Criteria:
- adult patients, 18-65 years of age;
- rheumatoid arthritis, functional status I-III;
- SJC>=4 (28 joint count) and TJC>=4 (28 joint count) at screening and baseline;
- RF and/or anti-CCP positive;
- may have failed up to 1 approved anti-TNF agent (infliximab, etanercept or adalimumab);
- inadequate response to methotrexate, at a dose of 7.5-25mg weekly for at least 12 weeks, at a stable dose for past 4 weeks.
Exclusion Criteria:
- rheumatic autoimmune disease other than rheumatoid arthritis, or significant systemic involvement secondary to rheumatoid arthritis;
- history of, or current, inflammatory joint disease other than rheumatoid arthritis;
- diagnosis of juvenile idiopathic arthritis and/or rheumatoid arthritis before age 16;
- significant cardiac or pulmonary disease;
- previous treatment with any biologic agent for rheumatoid arthritis (other than infliximab, etanercept or adalimumab).
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
1
2
Arm Description
Outcomes
Primary Outcome Measures
Percentage of Participants Achieving Low Disease Activity (LDA) at Week 16 Assessed Using Disease Activity Score Based on 28 Joint Count and Erythrocyte Sedimentation Rate (DAS28-ESR)
The Disease Activity Score based on 28 joint count (DAS28) and Erythrocyte Sedimentation Rate (ESR), is a measure of the participant's disease activity. It is based on the Tender Joint Count (TJC [28 joints]), Swollen Joint Count (SJC [28 joints]), participant's global assessment of disease activity (PtGA) Visual Analog Scale (VAS) in millimeters (mm), and ESR in millimeters per hour (mm/hour). DAS28-ESR scores range from 0 - 10. Definition of LDA was based on DAS28-ESR scores. To achieve LDA the DAS28-ESR had to be (less than or equal to) ≤ 3.2.
DAS28-ESR equals (=) (0.56 times (*) (square root)√ TJC plus (+) (0.28 * √ SJC + (0.70 * ln(ESR))+(0.014 * (Global Health) GH)
Where:
TJC = based on 28 joints SJC = based on 28 joints ESR = erythrocyte sedimentation rate in mm/hour GH = participant's global assessment of disease activity ln = natural log
Secondary Outcome Measures
Percentage of Participants Achieving Remission at Week 16 Assessed Using DAS28-ESR
The DAS28-ESR score is a measure of the participant's disease activity. It is based on the TJC (28 joints), SJC (28 joints), participant's global assessment of disease activity (mm), and ESR (mm/hour). DAS28-ESR is expressed on a unit on a scale with the minimum score=0 (best) to maximum score=10 (worst). Remission was defined as DAS28-ESR less than (<) 2.6
Percentage of Participants by European League Against Rheumatism (EULAR) Response Category at Week 16
DAS28-based EULAR response criteria were used to measure individual response as none, good, and moderate, depending on the extent of change from baseline and the level of disease activity reached. Good responders: change from baseline (greater than) >1.2 with DAS28 ≤3.2; moderate responders: change from baseline >1.2 with DAS28 >3.2 to ≤5.1 or DAS28-ESR >5.1 or change from baseline >0.6 to ≤1.2 with DAS28 ≤5.1; nonresponders: change from baseline ≤0.6 or change from baseline >0.6 and ≤1.2 with DAS28 >5.1.
Change From Baseline in DAS28-ESR
The DAS28-ESR score is a measure of the participant's disease activity. It is based on the TJC (28 joints), SJC (28 joints), participant's global assessment of disease activity (mm), and ESR (mm/hour). DAS28-ESR is expressed as a score on a scale with the minimum score=0 (best) to maximum score=10 (worst).
DAS28-ESR scores were calculated as follows: DAS28-ESR = (0.56 * √TJC)+(0.28 * √SJC)+(0.70 * ln(ESR))+(0.014 * GH).
No imputation used for tender and swollen joint counts, ESR, and patient's global assessment of disease activity VAS.
Clinical Disease Activity Index Scores
The Clinical Disease Activity Index (CDAI) score was calculated according to the following formula: CDAI = SJC + TJC + GH/10 + EGA/10
Where:
SJC = swollen joint count based on 28 joints; TJC = tender joint count based on 28 joints; GH = Participant's global assessment of disease activity; EGA = evaluator's (physician's) global assessment of disease activity. CDAI scores range from 0-76 and the following cut-off points for different disease activity states have been used: high disease activity >22; moderate disease activity >10 and ≤22; LDA >2.8 and ≤10; and remission ≤ 2.8. No imputation used for TJC, SJC, Patient's Global Assessment of Disease Activity VAS and Physicians global assessment of disease activity VAS.
Simplified Disease Activity Index (SDAI) Scores
The SDAI is the numerical sum of five outcome parameters: TJC and SJC (based on a 28-joint assessment), Participant and Physician assessed global disease activity (assessed on 0-100 mm VAS; higher scores = greater affection due to disease activity), and ESR (mm/hour). SDAI total score ranged from 0 to 86. Higher scores indicated greater disease activity.
Change From Baseline to Week 48 in SJC and TJC
An assessment of 28 joints for swelling and tenderness will be made. Joints will be assessed and classified as swollen (1)/not swollen (0) and tender(1)/not tender (0) by pressure and joint manipulation on physical examination. Joint prosthesis, arthrodesis or fused joints were not taken into consideration for swelling or tenderness. The 28 joints assessed comprise shoulders (2 joints), elbows (2 joints), wrists (2 joints), metacarpophalangeal joints on digits 1-5 (10 joints), interphalangeal on digit 1 (2 joints), proximal interphalangeal joints on digits 2-5 (8 joints), and knees (2 joints).
Change From Baseline to Week 48 in Health Assessment Questionnaire (HAQ)
The Stanford Health Assessment Questionnaire disability index specific for rheumatoid arthritis was completed by the participants for efficacy assessments.
Change From Baseline to Week 48 in C-Reactive Protein (CRP)
CRP is an acute phase reactant and is a measure of inflammation.
Change From Baseline to Week 48 in ESR
ESR is an acute phase reactant and is a measure of inflammation.
Change From Baseline to Week 48 in Physician's Global Assessment of Disease Activity
Physician Global Assessment of Disease Activity was measured on a 0 to 100 mm VAS, with 0 mm = no disease activity and 100 mm= maximum disease activity. The physician marked the line according to their assessment and the distance from the left edge was measured.
Change From Baseline to Week 48 in Participant's Global Assessment of Disease Activity
Participant's Global Assessment of Disease Activity was measured on a 0 to 100 mm VAS, with 0 mm = no disease activity and 100 mm = maximum disease activity. The participant marked the line according to their assessment and the distance from the left edge was measured.
Change From Baseline to Week 48 in Participant's Assessment of Pain
Participant's Global Assessment of Disease Activity was measured on a 0 to 100 mm VAS, with 0 mm = no pain and 100 mm = maximum pain. The participant marked the line according to their assessment and the distance from the left edge was measured.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT00845832
Brief Title
A Study of Combination Treatment With MabThera (Rituximab) and RoActemra (Tocilizumab) Versus RoActemra in Patients With Rheumatoid Arthritis With an Incomplete Response to Methotrexate
Official Title
A Randomized, Active Controlled, Double-blind, Study to Compare the Safety and Reduction in Disease Activity With the Combination of Rituximab (MabThera®)and Tocilizumab (RoActemra®) Versus Tocilizumab in Patients With Active Rheumatoid Arthritis With an Incomplete Response to Methotrexate
Study Type
Interventional
2. Study Status
Record Verification Date
December 2014
Overall Recruitment Status
Terminated
Why Stopped
The study was terminated early because of a related decision to stop the development of ocrelizumab in rheumatoid arthritis.
Study Start Date
March 2009 (undefined)
Primary Completion Date
March 2013 (Actual)
Study Completion Date
March 2013 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Hoffmann-La Roche
4. Oversight
5. Study Description
Brief Summary
This 2 part study will investigate the safety, tolerability and efficacy of MabT hera in combination with RoActemra in patients with active rheumatoid arthritis despite a stable dose of methotrexate. In Part 1 of the study, patients will be randomized to receive either MabThera 0.5g iv or placebo on days 1 and 15, follo wed by RoActemra at one of the ascending doses between 2mg/kg and 8mg/kg at week s 4, 8 and 12 (MabThera arm) or 8mg/kg (placebo arm). In Part 2, additional pati ents will be randomized to one of 2 groups to receive MabThera 0.5g on days 1 an d 15 followed by the selected dose (from Part 1)of RoActemra at weeks 4, 8 and 1 2, or placebo on days 1 and 15 followed by RoActemra 8mg/kg at weeks 4,8 and 12.
All patients will then be eligible to receive extension treatment withRoActemra every 4 weeks. The anticipated time on study treatment is 12 months, and the tar get sample size is <100 individuals.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Rheumatoid Arthritis
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
24 (Actual)
8. Arms, Groups, and Interventions
Arm Title
1
Arm Type
Experimental
Arm Title
2
Arm Type
Active Comparator
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
iv on days 1 and 15 (Parts 1 and 2)
Intervention Type
Drug
Intervention Name(s)
rituximab [MabThera/Rituxan]
Intervention Description
0.5g iv on days 1 and 15 (Parts 1 and 2)
Intervention Type
Drug
Intervention Name(s)
tocilizumab [RoActemra/Actemra]
Intervention Description
2mg/kg-8mg/kg iv in Part 1 and selected dose in Part 2, on weeks 4, 8 and 12---Arm 1\n8mg/kg iv on weeks 4,8 and 12 (Parts 1 and 2)--- Arm 2
Primary Outcome Measure Information:
Title
Percentage of Participants Achieving Low Disease Activity (LDA) at Week 16 Assessed Using Disease Activity Score Based on 28 Joint Count and Erythrocyte Sedimentation Rate (DAS28-ESR)
Description
The Disease Activity Score based on 28 joint count (DAS28) and Erythrocyte Sedimentation Rate (ESR), is a measure of the participant's disease activity. It is based on the Tender Joint Count (TJC [28 joints]), Swollen Joint Count (SJC [28 joints]), participant's global assessment of disease activity (PtGA) Visual Analog Scale (VAS) in millimeters (mm), and ESR in millimeters per hour (mm/hour). DAS28-ESR scores range from 0 - 10. Definition of LDA was based on DAS28-ESR scores. To achieve LDA the DAS28-ESR had to be (less than or equal to) ≤ 3.2.
DAS28-ESR equals (=) (0.56 times (*) (square root)√ TJC plus (+) (0.28 * √ SJC + (0.70 * ln(ESR))+(0.014 * (Global Health) GH)
Where:
TJC = based on 28 joints SJC = based on 28 joints ESR = erythrocyte sedimentation rate in mm/hour GH = participant's global assessment of disease activity ln = natural log
Time Frame
Week 16
Secondary Outcome Measure Information:
Title
Percentage of Participants Achieving Remission at Week 16 Assessed Using DAS28-ESR
Description
The DAS28-ESR score is a measure of the participant's disease activity. It is based on the TJC (28 joints), SJC (28 joints), participant's global assessment of disease activity (mm), and ESR (mm/hour). DAS28-ESR is expressed on a unit on a scale with the minimum score=0 (best) to maximum score=10 (worst). Remission was defined as DAS28-ESR less than (<) 2.6
Time Frame
Week 16
Title
Percentage of Participants by European League Against Rheumatism (EULAR) Response Category at Week 16
Description
DAS28-based EULAR response criteria were used to measure individual response as none, good, and moderate, depending on the extent of change from baseline and the level of disease activity reached. Good responders: change from baseline (greater than) >1.2 with DAS28 ≤3.2; moderate responders: change from baseline >1.2 with DAS28 >3.2 to ≤5.1 or DAS28-ESR >5.1 or change from baseline >0.6 to ≤1.2 with DAS28 ≤5.1; nonresponders: change from baseline ≤0.6 or change from baseline >0.6 and ≤1.2 with DAS28 >5.1.
Time Frame
Week 16
Title
Change From Baseline in DAS28-ESR
Description
The DAS28-ESR score is a measure of the participant's disease activity. It is based on the TJC (28 joints), SJC (28 joints), participant's global assessment of disease activity (mm), and ESR (mm/hour). DAS28-ESR is expressed as a score on a scale with the minimum score=0 (best) to maximum score=10 (worst).
DAS28-ESR scores were calculated as follows: DAS28-ESR = (0.56 * √TJC)+(0.28 * √SJC)+(0.70 * ln(ESR))+(0.014 * GH).
No imputation used for tender and swollen joint counts, ESR, and patient's global assessment of disease activity VAS.
Time Frame
Weeks 4, 8, 12, 16, 20, 24, 32, 40 and 48
Title
Clinical Disease Activity Index Scores
Description
The Clinical Disease Activity Index (CDAI) score was calculated according to the following formula: CDAI = SJC + TJC + GH/10 + EGA/10
Where:
SJC = swollen joint count based on 28 joints; TJC = tender joint count based on 28 joints; GH = Participant's global assessment of disease activity; EGA = evaluator's (physician's) global assessment of disease activity. CDAI scores range from 0-76 and the following cut-off points for different disease activity states have been used: high disease activity >22; moderate disease activity >10 and ≤22; LDA >2.8 and ≤10; and remission ≤ 2.8. No imputation used for TJC, SJC, Patient's Global Assessment of Disease Activity VAS and Physicians global assessment of disease activity VAS.
Time Frame
Baseline and Weeks 4, 8, 12, 16, 20, 24, 32, 40 and 48
Title
Simplified Disease Activity Index (SDAI) Scores
Description
The SDAI is the numerical sum of five outcome parameters: TJC and SJC (based on a 28-joint assessment), Participant and Physician assessed global disease activity (assessed on 0-100 mm VAS; higher scores = greater affection due to disease activity), and ESR (mm/hour). SDAI total score ranged from 0 to 86. Higher scores indicated greater disease activity.
Time Frame
Baseline and Weeks 4, 8, 12, 16, 20, 24, 32, 40, and 48
Title
Change From Baseline to Week 48 in SJC and TJC
Description
An assessment of 28 joints for swelling and tenderness will be made. Joints will be assessed and classified as swollen (1)/not swollen (0) and tender(1)/not tender (0) by pressure and joint manipulation on physical examination. Joint prosthesis, arthrodesis or fused joints were not taken into consideration for swelling or tenderness. The 28 joints assessed comprise shoulders (2 joints), elbows (2 joints), wrists (2 joints), metacarpophalangeal joints on digits 1-5 (10 joints), interphalangeal on digit 1 (2 joints), proximal interphalangeal joints on digits 2-5 (8 joints), and knees (2 joints).
Time Frame
Baseline and Week 48
Title
Change From Baseline to Week 48 in Health Assessment Questionnaire (HAQ)
Description
The Stanford Health Assessment Questionnaire disability index specific for rheumatoid arthritis was completed by the participants for efficacy assessments.
Time Frame
Baseline and Week 48
Title
Change From Baseline to Week 48 in C-Reactive Protein (CRP)
Description
CRP is an acute phase reactant and is a measure of inflammation.
Time Frame
Baseline and Week 48
Title
Change From Baseline to Week 48 in ESR
Description
ESR is an acute phase reactant and is a measure of inflammation.
Time Frame
Baseline and Week 48
Title
Change From Baseline to Week 48 in Physician's Global Assessment of Disease Activity
Description
Physician Global Assessment of Disease Activity was measured on a 0 to 100 mm VAS, with 0 mm = no disease activity and 100 mm= maximum disease activity. The physician marked the line according to their assessment and the distance from the left edge was measured.
Time Frame
Baseline and Week 48
Title
Change From Baseline to Week 48 in Participant's Global Assessment of Disease Activity
Description
Participant's Global Assessment of Disease Activity was measured on a 0 to 100 mm VAS, with 0 mm = no disease activity and 100 mm = maximum disease activity. The participant marked the line according to their assessment and the distance from the left edge was measured.
Time Frame
Baseline and Week 48
Title
Change From Baseline to Week 48 in Participant's Assessment of Pain
Description
Participant's Global Assessment of Disease Activity was measured on a 0 to 100 mm VAS, with 0 mm = no pain and 100 mm = maximum pain. The participant marked the line according to their assessment and the distance from the left edge was measured.
Time Frame
Baseline and Week 48
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
adult patients, 18-65 years of age;
rheumatoid arthritis, functional status I-III;
SJC>=4 (28 joint count) and TJC>=4 (28 joint count) at screening and baseline;
RF and/or anti-CCP positive;
may have failed up to 1 approved anti-TNF agent (infliximab, etanercept or adalimumab);
inadequate response to methotrexate, at a dose of 7.5-25mg weekly for at least 12 weeks, at a stable dose for past 4 weeks.
Exclusion Criteria:
rheumatic autoimmune disease other than rheumatoid arthritis, or significant systemic involvement secondary to rheumatoid arthritis;
history of, or current, inflammatory joint disease other than rheumatoid arthritis;
diagnosis of juvenile idiopathic arthritis and/or rheumatoid arthritis before age 16;
significant cardiac or pulmonary disease;
previous treatment with any biologic agent for rheumatoid arthritis (other than infliximab, etanercept or adalimumab).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Clinical Trials
Organizational Affiliation
Hoffmann-La Roche
Official's Role
Study Director
Facility Information:
City
Le Kremlin Bicetre
ZIP/Postal Code
94275
Country
France
City
Montpellier
ZIP/Postal Code
34295
Country
France
City
Paris
ZIP/Postal Code
75679
Country
France
City
Strasbourg
ZIP/Postal Code
67098
Country
France
City
Berlin
ZIP/Postal Code
10117
Country
Germany
City
Berlin
ZIP/Postal Code
14059
Country
Germany
City
Heidelberg
ZIP/Postal Code
69120
Country
Germany
City
Köln
ZIP/Postal Code
50924
Country
Germany
City
Wuerzburg
ZIP/Postal Code
97080
Country
Germany
City
Athens
ZIP/Postal Code
15121
Country
Greece
City
Thessaloniki
ZIP/Postal Code
54636
Country
Greece
City
Amsterdam
ZIP/Postal Code
1105 AZ
Country
Netherlands
City
Leiden
ZIP/Postal Code
2333 ZA
Country
Netherlands
City
Bytom
ZIP/Postal Code
41-902
Country
Poland
City
Lublin
ZIP/Postal Code
20-607
Country
Poland
City
Poznan
ZIP/Postal Code
60-218
Country
Poland
City
Santander
State/Province
Cantabria
ZIP/Postal Code
39008
Country
Spain
City
Santiago de Compostela
State/Province
La Coruña
ZIP/Postal Code
15706
Country
Spain
City
Madrid
ZIP/Postal Code
28007
Country
Spain
City
Sevilla
ZIP/Postal Code
41009
Country
Spain
City
Bern
ZIP/Postal Code
3010
Country
Switzerland
City
Lausanne
ZIP/Postal Code
1011
Country
Switzerland
City
Newcastle Upon Tyne
ZIP/Postal Code
NE1 4LP
Country
United Kingdom
City
Southampton
ZIP/Postal Code
SO16 6YD
Country
United Kingdom
12. IPD Sharing Statement
Learn more about this trial
A Study of Combination Treatment With MabThera (Rituximab) and RoActemra (Tocilizumab) Versus RoActemra in Patients With Rheumatoid Arthritis With an Incomplete Response to Methotrexate
We'll reach out to this number within 24 hrs