A Study of Combination Treatment With MabThera (Rituximab) and RoActemra (Tocilizumab) Versus RoActemra in Patients With Rheumatoid Arthritis With an Incomplete Response to Methotrexate

This study has been terminated.
(The study was terminated early because of a related decision to stop the development of ocrelizumab in rheumatoid arthritis.)
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT00845832
First received: February 17, 2009
Last updated: December 15, 2014
Last verified: December 2014
  Purpose

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.


Condition Intervention Phase
Rheumatoid Arthritis
Drug: Placebo
Drug: rituximab [MabThera/Rituxan]
Drug: tocilizumab [RoActemra/Actemra]
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Hoffmann-La Roche:

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) [ Time Frame: Week 16 ] [ Designated as safety issue: No ]

    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 [ Time Frame: Week 16 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Week 16 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Weeks 4, 8, 12, 16, 20, 24, 32, 40 and 48 ] [ Designated as safety issue: No ]

    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 [ Time Frame: Baseline and Weeks 4, 8, 12, 16, 20, 24, 32, 40 and 48 ] [ Designated as safety issue: No ]

    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 [ Time Frame: Baseline and Weeks 4, 8, 12, 16, 20, 24, 32, 40, and 48 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline and Week 48 ] [ Designated as safety issue: No ]
    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) [ Time Frame: Baseline and Week 48 ] [ Designated as safety issue: No ]
    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) [ Time Frame: Baseline and Week 48 ] [ Designated as safety issue: No ]
    CRP is an acute phase reactant and is a measure of inflammation.

  • Change From Baseline to Week 48 in ESR [ Time Frame: Baseline and Week 48 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline and Week 48 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline and Week 48 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline and Week 48 ] [ Designated as safety issue: No ]
    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.


Enrollment: 24
Study Start Date: March 2009
Study Completion Date: March 2013
Primary Completion Date: March 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1 Drug: rituximab [MabThera/Rituxan]
0.5g iv on days 1 and 15 (Parts 1 and 2)
Drug: tocilizumab [RoActemra/Actemra]
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
Active Comparator: 2 Drug: Placebo
iv on days 1 and 15 (Parts 1 and 2)
Drug: tocilizumab [RoActemra/Actemra]
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

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00845832

Locations
France
Le Kremlin Bicetre, France, 94275
Montpellier, France, 34295
Paris, France, 75679
Strasbourg, France, 67098
Germany
Berlin, Germany, 10117
Berlin, Germany, 14059
Heidelberg, Germany, 69120
Köln, Germany, 50924
Wuerzburg, Germany, 97080
Greece
Athens, Greece, 15121
Thessaloniki, Greece, 54636
Netherlands
Amsterdam, Netherlands, 1105 AZ
Leiden, Netherlands, 2333 ZA
Poland
Bytom, Poland, 41-902
Lublin, Poland, 20-607
Poznan, Poland, 60-218
Spain
Santander, Cantabria, Spain, 39008
Santiago de Compostela, La Coruña, Spain, 15706
Madrid, Spain, 28007
Sevilla, Spain, 41009
Switzerland
Bern, Switzerland, 3010
Lausanne, Switzerland, 1011
United Kingdom
Newcastle Upon Tyne, United Kingdom, NE1 4LP
Southampton, United Kingdom, SO16 6YD
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director: Clinical Trials Hoffmann-La Roche
  More Information

No publications provided

Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT00845832     History of Changes
Other Study ID Numbers: WX21956, 2008-005525-11
Study First Received: February 17, 2009
Results First Received: June 23, 2014
Last Updated: December 15, 2014
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Additional relevant MeSH terms:
Arthritis
Arthritis, Rheumatoid
Autoimmune Diseases
Connective Tissue Diseases
Immune System Diseases
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Rituximab
Antineoplastic Agents
Antirheumatic Agents
Immunologic Factors
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on August 31, 2015