A Study of Retreatment With MabThera (Rituximab) in Combination With Methotrexate in Patients With Rheumatoid Arthritis (RA)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT00422383
First received: January 15, 2007
Last updated: April 16, 2015
Last verified: April 2015
  Purpose

This study will evaluate the efficacy and safety of various treatment and retreatment regimens of MabThera. All patients will receive concomitant methotrexate, 10-25mg once weekly either orally or parenterally. The anticipated time on study treatment is 2+ years, and the target sample size is 100-500 individuals.


Condition Intervention Phase
Rheumatoid Arthritis
Drug: rituximab [MabThera/Rituxan]
Phase 3

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, Double-blind Study to Evaluate the Effect of Various Re-treatment Regimens of MabThera in Combination With Methotrexate on Treatment Response in Rheumatoid Arthritis Patients With an Inadequate Response to Methotrexate.

Resource links provided by NLM:


Further study details as provided by Hoffmann-La Roche:

Primary Outcome Measures:
  • Percentage of Participants With a Response as Determined by American College of Rheumatology (ACR) 20% Improvement (ACR20) [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    ACR20 defined as overall score of ≥20 in ACR number (ACRn) calculation. Overall score defined as lowest percent improvement from baseline (BL) of following 3 measures: tender joint count (TJC; 68 joints), swollen joint count (SJC: 66 joints), and the 3rd lowest improvement achieved by at least 3 of 5 remaining ACR core parameters: physician's global assessment of disease activity, participant's global assessment of disease activity, participant's assessment of pain (visual analog assessment [VAS]), Health Assessment Questionnaire (HAQ), and C-Reactive Protein (CRP). If CRP missing, erythrocyte sedimentation rate (ESR) was used. In order for improvements in the ACRn score to be expressed as a positive result, rather than the negative changes that improvements represent, the final ACRn results were multiplied by negative 1. Last observation carried forward (LOCF) for TJC/SJC, HAQ, CRP/ESR, VAS. If change in CRP incalculable, change in ESR used. ACR20 set to Non-Responder if ACRn missing


Secondary Outcome Measures:
  • Percentage of Participants With ACR 50% Improvement Criteria (ACR50) Response at Week 48 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    ACR50 was defined as an overall score of 50 in the ACRn calculation. Overall score defined as lowest percent improvement from BL of following 3 measures: TJC (68 joints), SJC (66 joints), and the 3rd lowest improvement achieved by at least 3 of 5 remaining ACR core parameters: physician's global assessment of disease activity, participant's global assessment of disease activity, participant's assessment of pain (VAS), HAQ, and CRP. If CRP missing, ESR was used. In order for improvements in the ACRn score to be expressed as a positive result, rather than the negative changes that improvements represent, the final ACRn results were multiplied by negative 1. LOCF for TJC/SJC, HAQ, CRP/ESR, VAS. If change in CRP incalculable, change in ESR used. ACR50 set to Non-Responder if ACRn missing.

  • Percentage of Participants With a ACR 70% Improvement Criteria (ACR70) Response at Week 48 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    ACR70 was defined as an overall score of 70 in the ACRn calculation. The Overall score defined as lowest percent improvement from BL of following 3 measures: TJC (68 joints), SJC (66 joints), and the 3rd lowest improvement achieved by at least 3 of 5 remaining ACR core parameters: physician's global assessment of disease activity, participant's global assessment of disease activity, participant's assessment of pain (VAS), HAQ, and CRP. If CRP missing, ESR was used. In order for improvements in the ACRn score to be expressed as a positive result, rather than the negative changes that improvements represent, the final ACRn results were multiplied by negative 1. LOCF for TJC/SJC, HAQ, CRP/ESR, VAS. If change in CRP incalculable, change in ESR used. ACR70 set to Non-Responder if ACRn missing.

  • Disease Activity Score Based on 28-Joint Count and Erythrocyte Sedimentation Rate (DAS28-ESR): Adjusted Mean Change From BL at Week 48 [ Time Frame: BL, Week 48 ] [ Designated as safety issue: No ]
    DAS28 was calculated according to the following formula: DAS28 equals (=) [0.56 multiplied by (*) the square root (√) of TJC] plus (+) [0.28 * √ of SJC] + (0.70 * the natural logarithm (ln) ESR in millimeters per hour (mm/h)] + [0.014 * participant's global assessment of disease activity (GH)]. DAS28-ESR ≥ 5.1 = high disease activity, DAS28-ESR less than or equal to (≤) 3.2 = low disease activity, DAS28-ESR less than (<) 2.6 = remission.

  • Percentage of Participants With a Response at Week 48 by European League Against Rheumatism (EULAR) Category [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    EULAR responses were categorized according to DAS28-ESR score. DAS28-ESR ≤ 3.2 at Week 48 and a change from BL to Week 48 < -1.2 = good response, DAS28-ESR ≤ 3.2 or greater than (>) 3.2 and ≤ 5.1 at Week 48 and a change from BL to Week 48 < -0.6 and ≥ -1.2 = moderate response, DAS28-ESR > 3.2 and ≤ 5.1 at Week 48 and a change from BL to Week 48 < -1.2 = moderate response, DAS28-ESR > 5.1 at Week 48 and a change from BL to Week 48 < -1.2 = moderate response, DAS28-ESR ≤ 3.2 or > 3.2 and ≤ 5.1 at Week 48 and a change from BL to Week 48 ≥ -0.6 = no response, DAS28-ESR > 5.1 at Week 48 and a change from BL to Week 48 < -0.6 and ≥ -1.2 or ≥ -0.6 = no response.

  • Change in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Score From BL at Week 48 [ Time Frame: BL, Week 48 ] [ Designated as safety issue: No ]
    FACIT-F scores were obtained from a 13 question self-administered participant questionnaire designed to measure the degree of fatigue experienced by participants in the previous 7 days. Participants responded to the questions using a value between 0 and 4, where 0 indicated "not at all" and 4 indicated "very much." 11 of the 13 questions were negatively stated; indicating the higher the score of the participant's response, the greater their fatigue. These questions were calculated as 4 minus the participants' response, so that a higher score indicated an improvement in health. The scores for the 2 positively stated questions were not changed. The participants' responses were summed to result in an overall score, which are scored 0 to 52 (52 = highest level of functioning). A positive change from BL indicated improvement.

  • Short-Form 36 Health Survey (SF-36) Score [ Time Frame: BL, Week (Wk) 24 and 48 ] [ Designated as safety issue: No ]
    SF-36 scores were obtained by scoring participants' responses to a 36 item questionnaire. SF-36 evaluated 8 aspects of functional health and well being: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, mental health from a range of 1 (better) to 5 (worst). The score for each section was an average of the individual question scores, which were scaled 0-100 (100=highest level of functioning). These 8 aspects were summarized as physical and mental component scores.

  • Change in SF-36 Score From BL [ Time Frame: BL, Weeks 24 and 48 ] [ Designated as safety issue: No ]
    SF-36 scores were obtained by scoring participants' responses to a 36 item questionnaire. SF-36 evaluated 8 aspects of functional health and well being: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, mental health from a range of 1 (better) to 5 (worst). The score for each section was an average of the individual question scores, which were scaled 0-100 (100=highest level of functioning). These 8 aspects were summarized as physical and mental component scores.

  • Maximum Observed Serum Concentrations Following the 1st Infusion of Rituximab (Cfirst) in the 1st and 2nd Courses of Treatment in Micrograms Per mL (µg/mL) [ Time Frame: Days 1 and 15 (before infusion and 30 minutes following infusion) and Weeks 4, 8, 16, 24, 26, 28, 32, 40, and 48 or early withdrawal and at Weeks 24 and 48 of safety follow-up (1 year period following the completion of study treatment). ] [ Designated as safety issue: No ]
    Cfirst values were estimated from rituximab serum concentrations by non-compartmental methods using the software WinNonlin Enterprise Version 5.2.

  • Maximum Observed Serum Concentrations Following the 2nd Infusion of Rituximab (Csecond) in the 1st and 2nd Courses of Treatment in µg/mL [ Time Frame: Days 1 and 15 (before infusion and 30 minutes following infusion) and Weeks 4, 8, 16, 24, 26, 28, 32, 40, and 48 or early withdrawal and at Weeks 24 and 48 of safety follow-up (1 year period following the completion of study treatment). ] [ Designated as safety issue: No ]
    Csecond values were estimated from rituximab serum concentrations by non-compartmental methods using the software WinNonlin Enterprise Version 5.2.

  • Terminal Elimination Half-Life (t1/2) in the 1st and 2nd Courses of Treatment in Days [ Time Frame: Days 1 and 15 (before infusion and 30 minutes following infusion) and Weeks 4, 8, 16, 24, 26, 28, 32, 40, and 48 or early withdrawal and at Weeks 24 and 48 of safety follow-up (1 year period following the completion of study treatment). ] [ Designated as safety issue: No ]
    t1/2 values were estimated from rituximab serum concentrations by non-compartmental methods using the software WinNonlin Enterprise Version 5.2.

  • Peripheral Cluster of Differentiation (CD) 19 Positive (+) B Cell Count at BL in Cells Per Microliter (Cells/µL) [ Time Frame: BL ] [ Designated as safety issue: No ]
    Surface expression of CD19 was assessed by fluorescence-activated cell sorting (FACS) analysis as a marker of absolute B lymphocyte count.

  • Percentage of Participants With Peripheral CD19+ B Cell Counts Above BL or the Lower Limit of Normal (LLN) [ Time Frame: BL, Days 1 and 15, Weeks 4, 8, 16, 24, 28, 32, 40, and 48 ] [ Designated as safety issue: No ]
    Surface expression of CD19 was assessed by FACS analysis as a marker of absolute B lymphocyte count. The LLN was defined as < 80 cells/µL.

  • Peripheral CD20+ B Cell Count in Cells/µL [ Time Frame: BL, Day 15, Weeks 4, 8, 16, 24, 28, 32, 40, and 48 ] [ Designated as safety issue: No ]
    Surface expression of CD20 was assessed by FACS analysis as a marker of mature and memory B lymphocyte count.

  • Peripheral CD22+ B Cell Count in Cells/µL [ Time Frame: BL, Day 15, Weeks 4, 8, 16, 24, 28, 32, 40, and 48 ] [ Designated as safety issue: No ]
    Surface expression of CD22 was assessed by FACS analysis as a marker of mature lymphocyte count.

  • Peripheral CD19+CD27+ B Cell Count in Cells/µL [ Time Frame: BL, Day 15, Weeks 4, 8, 16, 24, 28, 32, 40, and 48 ] [ Designated as safety issue: No ]
    Simultaneous surface expression of CD19 and CD27 was assessed by FACS analysis as a marker of memory B lymphocyte count.

  • Peripheral CD19+CD27 Negative (-) B Cell Count in Cells/µL [ Time Frame: BL, Day 15, Weeks 4, 8, 16, 24, 28, 32, 40, and 48 ] [ Designated as safety issue: No ]
    Surface expression of CD19 in the absence of CD27 expression was assessed by FACS analysis as a marker of naive B lymphocyte count.

  • Peripheral CD3+ T Cell Count in Cells/µL [ Time Frame: BL, Day 15, Weeks 4, 8, 16, 24, 28, 32, 40, and 48 ] [ Designated as safety issue: No ]
    Surface expression of CD3 was assessed by FACS analysis as a marker of absolute T lymphocyte count. The normal range of CD3+ T cells was defined as 723-2737 cells/µL.

  • Change From BL in Peripheral CD3+ T Cell Count [ Time Frame: BL, Day 15, Weeks 4, 8, 16, 24, 28, 32, 40, and 48 ] [ Designated as safety issue: No ]
    Surface expression of CD3 was assessed by FACS analysis as a marker of absolute T lymphocyte count. The normal range of CD3+ T cells was defined as 723-2737 cells/µL.

  • Peripheral CD4+ T Cell Count in Cells/µL [ Time Frame: BL, Day 15, Weeks 4, 8, 16, 24, 28, 32, 40, and 48 ] [ Designated as safety issue: No ]
    Surface expression of CD4 was assessed by FACS analysis as a marker of T helper cell count. The normal range of CD4+ T cells was defined as 404-1612 cells/µL.

  • Change From BL in Peripheral CD4+ T Cell Count [ Time Frame: BL, Day 15, Weeks 4, 8, 16, 24, 28, 32, 40, and 48 ] [ Designated as safety issue: No ]
    Surface expression of CD4 was assessed by FACS analysis as a marker of T helper cell count. The normal range of CD4+ T cells was defined as 404-1612 cells/µL.

  • Peripheral CD8+ T Cell Count in Cells/µL [ Time Frame: BL, Day 15, Weeks 4, 8, 16, 24, 28, 32, 40, and 48 ] [ Designated as safety issue: No ]
    Surface expression of CD8 was assessed by FACS analysis as a marker of cytotoxic T lymphocyte count. The normal range of CD8+ T cells was defined as 220-1129 cells/µL.

  • Change From BL in Peripheral CD8+ Cell Count [ Time Frame: BL, Day 15, Weeks 4, 8, 16, 24, 28, 32, 40, and 48 ] [ Designated as safety issue: No ]
    Surface expression of CD8 was assessed by FACS analysis as a marker of cytotoxic T lymphocyte count. The normal range of CD8+ T cells was defined as 220-1129 cells/µL.

  • Peripheral CD16+56+ Natural Killer (NK) Cell Count in Cells/µL [ Time Frame: BL, Day 15, Weeks 4, 8, 16, 24, 28, 32, 40, and 48 ] [ Designated as safety issue: No ]
    Simultaneous surface expression of CD16 and CD56 was assessed by FACS analysis as a marker of NK cell count.

  • Change From BL in Peripheral CD16+56+ Cell Count [ Time Frame: BL, Day 15, Weeks 4, 8, 16, 24, 28, 32, 40, and 48 ] [ Designated as safety issue: No ]
    Simultaneous surface expression of CD16 and CD56 was assessed by FACS analysis as a marker of NK cell count.

  • Percentage of Participants With Total Immunoglobin (Ig), IgA, IgG, and IgM Results Below the LLN [ Time Frame: BL, Weeks 24 and 48 ] [ Designated as safety issue: No ]
    The LLNs for total Ig, IgA, IgG, and IgM were defined as 6.75 grams per liter (g/L), 0.70 g/L, 65 g/L, and 0.40 g/L, respectively.

  • Percentage of Participants Who Were Rheumatoid Factor (RF) - Seronegative [ Time Frame: BL, Weeks 8, 24, and 48 ] [ Designated as safety issue: No ]
    Percentage of participants who were RF seropositive at BL who became RF seronegative over the course of the study. RF seropositive status was defined as RF ≥ 20 international units (IU) per mL. RF seronegative status was defined as RF < 20 IU/mL.

  • Anti-Cyclic Citrullinated Peptide (CCP) Antibody Titers at BL in Units Per mL (U/mL) [ Time Frame: BL ] [ Designated as safety issue: No ]
  • Change From BL in Anti-CCP Antibody Titers in U/mL [ Time Frame: Weeks 8, 24, and 48 ] [ Designated as safety issue: No ]
  • Percentage of Participants With Complement Component 3 (C3) Protein Level ≤ LLN [ Time Frame: BL, Day 15, Weeks 4, 8, 16, 24, 28, 32, 40, and 48 ] [ Designated as safety issue: No ]
    The LLN for C3 protein was defined as <0.9 grams per liter (g/L).

  • Change From BL in Complement C3 Protein Level in g/L [ Time Frame: BL, Day 15, Weeks 4, 8, 16, 24, 28, 32, 40, and 48 ] [ Designated as safety issue: No ]
    The LLN of C3 protein was defined as <0.9 g/L.

  • Change From BL in Activated Complement Component 3a (C3a) Protein Level in g/L [ Time Frame: BL, Day 15, Weeks 4, 8, 16, 24, 28, 32, 40, and 48 ] [ Designated as safety issue: No ]
  • Percentage of Participants With Complement Component 4 (C4) Protein Level ≤ LLN [ Time Frame: BL, Day 15, Weeks 4, 8, 16, 24, 28, 32, 40, and 48 ] [ Designated as safety issue: No ]
    The LLN of C4 protein was defined as < 0.1 g/L.

  • Change From BL in Complement C4 Protein Level in g/L [ Time Frame: BL, Day 15, Weeks 4, 8, 16, 24, 28, 32, 40, and 48 ] [ Designated as safety issue: No ]
  • Change From BL in Activated Complement Component 4a (C4a) Protein Level in g/L [ Time Frame: BL, Day 15, Weeks 4, 8, 16, 24, 28, 32, 40, and 48 ] [ Designated as safety issue: No ]
  • Percentage of Participants With Positive Human Anti-Chimeric Antibody (HACA) Titers [ Time Frame: BL, Weeks 24 and 48 ] [ Designated as safety issue: No ]
    A participant was defined as being HACA positive if the HACA serum level was ≥ 5 relative units (RU) per mL and the physician comment read that participant was "immunodepletable with rituximab".

  • Percentage of Participants With a Change From BL by Category in Anti-Nuclear Antibodies (ANA) Titers [ Time Frame: BL, Weeks 24 and 48 ] [ Designated as safety issue: No ]
    ANA titers were obtained by the following serum dilution schema: negative = negative, borderline = 1 diluted to (:) 40 or 1:80, and positive ≥ 1:160. The change categories were defined for the change from BL to Weeks 24 and 48 according to this schema. Negative to borderline was defined as any change from negative to borderline as no dilution is given for negative results. Negative to positive was defined as at least a two-fold positive change in dilution from BL. Borderline to negative was defined as any change from borderline to negative as no dilution is given for negative results. Borderline to positive was defined as at least a two-fold positive change in dilution from BL. Positive to borderline was defined as at least a two-fold negative change in dilution from BL. Positive to negative was defined as at least a two-fold negative change in dilution from BL. Unchanged was defined as any difference in dilution less than two-fold.

  • Percentage of Participants With Positive Recall Antigen Antibody Titers [ Time Frame: BL, Weeks 24 and 48 ] [ Designated as safety issue: No ]
    A positive titer result to recall antigens was defined as a serum antibody level equal to or above the following protective levels: tetanus toxoid ≥ 0.1 IU/mL, influenza A > 12 U/mL, influenza B > 12 U/mL, and streptococcus (S.) pneumococcus ≥ 1.0 mg/L.


Enrollment: 378
Study Start Date: February 2006
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]
500mg iv in days 1 and 15, and 500mg iv on days 168 and 182
Experimental: 2 Drug: rituximab [MabThera/Rituxan]
500mg iv on days 1 and 15, and 1000mg iv on days 168 and 182
Experimental: 3 Drug: rituximab [MabThera/Rituxan]
1000mg iv on days 1 and 15 and 1000mg iv (or placebo in UK)on days 168 and 182

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • adult patients >=18 years of age;
  • RA for >=6 months;
  • receiving outpatient treatment;
  • inadequate response to methotrexate, having received and tolerated it for >=12 weeks, with a stable dose for >=4 weeks.

Exclusion Criteria:

  • rheumatic autoimmune disease other than RA, or significant systemic involvement secondary to RA;
  • inflammatory joint disease other than RA, or other systemic autoimmune disorder;
  • diagnosis of juvenile arthritis, or RA before the age of 16;
  • previous treatment with >1 biologic agent, any cell-depleting therapies, or concurrent treatment with any biologic agent or DMARD other than methotrexate.
  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: NCT00422383

  Show 91 Study Locations
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director: Clinical Trials Hoffmann-La Roche
  More Information

No publications provided by Hoffmann-La Roche

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT00422383     History of Changes
Other Study ID Numbers: WA17044
Study First Received: January 15, 2007
Results First Received: December 9, 2014
Last Updated: April 16, 2015
Health Authority: Italy: Ministry of Health

Additional relevant MeSH terms:
Arthritis
Arthritis, Rheumatoid
Autoimmune Diseases
Connective Tissue Diseases
Immune System Diseases
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Methotrexate
Rituximab
Abortifacient Agents
Abortifacient Agents, Nonsteroidal
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antirheumatic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors
Pharmacologic Actions
Physiological Effects of Drugs
Reproductive Control Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on July 29, 2015