Extension Study to Assess the Efficacy and Safety of Repeat Treatment With Rituximab (MabThera) in Participants With Active Rheumatoid Arthritis (RA)

An Open-label Study of the Efficacy and Safety of Re-treatments With Rituximab (MabThera®/Rituxan®) in Patients With Active Rheumatoid Arthritis

This study will assess the long-term safety and efficacy of repeat treatment courses of rituximab, in combination with methotrexate in a disease-modifying anti-rheumatic drug (DMARD) inadequate responder population of participants who were previously randomized into studies WA16291 (NCT02693210) or WA17043/U2644g (NCT00074438). The study permits multiple re-treatments until the protocol-defined end-of-treatment date (31 December 2011). Participants will then enter a safety follow-up (SFU) period of at least 48 weeks. This will provide at least 7 years follow-up data on all participants initially randomized into WA16291 or WA17043/U2644g. Approximately 600 participants will potentially be eligible to enter this open label extension study from their respective feeder studies.

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: Rituximab; Drug: Methotrexate; Drug: Methylprednisolone; Drug: Folic Acid

• Study Type: Interventional
• Enrollment (Actual): 465
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Queensland
    • Maroochydore, Queensland, Australia, 4558
  • Victoria
    • Melbourne, Victoria, Australia, 3168
  • Western Australia
    • Perth, Western Australia, Australia, 6979
• Belgium
  • Gent, Belgium, 9000
• Brazil
  • PR
    • Curtiba, PR, Brazil, 80030-110
  • SP
    • Campinas, SP, Brazil, 13083-888
    • Sao Paulo, SP, Brazil, 04026-000
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4Z6
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1L7
  • Newfoundland and Labrador
    • St John's, Newfoundland and Labrador, Canada, A1A 5E8
  • Ontario
    • London, Ontario, Canada, N6A 4V2
• Czech Republic
  • Praha, Czech Republic, 128 50
• Finland
  • Heinola, Finland, 18120
  • Helsinki, Finland, 00290
• Germany
  • Köln, Germany, 50924
  • Leipzig, Germany, 04103
  • Ratingen, Germany, 40882
  • Regensburg, Germany, 93053
  • Wuerzburg, Germany, 97080
• Israel
  • Haifa, Israel, 3109601
  • Haifa, Israel, 3339419
• Italy
  • Emilia-Romagna
    • Modena, Emilia-Romagna, Italy, 41100
  • Friuli-Venezia Giulia
    • Udine, Friuli-Venezia Giulia, Italy, 33100
  • Liguria
    • Genova, Liguria, Italy, 16132
  • Lombardia
    • Milano, Lombardia, Italy, 20157
• Mexico
  • Mexico, Mexico, 44620
  • Mexico City, Mexico, 06726
  • Mexico City, Mexico, 10700
  • Monterrey, Mexico, 64460
• New Zealand
  • Auckland, New Zealand, 2025
  • Auckland City, New Zealand, 0620
• Poland
  • Bialystok, Poland, 15-351
  • Lublin, Poland, 20-022
  • Poznan, Poland, 61-545
  • Warszawa, Poland, 02-637
  • Wroclaw, Poland, 50-556
• Spain
  • Madrid, Spain, 28006
  • Madrid, Spain, 28046
  • Madrid, Spain, 28007
  • Sevilla, Spain, 41014
  • Badajoz
    • Merida, Badajoz, Spain, 06800
  • La Coruña
    • Santiago de Compostela, La Coruña, Spain, 15706
  • Tenerife
    • La Laguna, Tenerife, Spain, 38320
• Sweden
  • Göteborg, Sweden, 413 45
  • Stockholm, Sweden, 171 76
• United Kingdom
  • Birmingham, United Kingdom, B29 6JD
  • Cambridge, United Kingdom, CB2 2QQ
  • Cannock, United Kingdom, WS11 5XY
  • Leeds, United Kingdom, LS7 4SA
  • Stoke-on-trent, United Kingdom, ST6 7AG
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
  • Arizona
    • Peoria, Arizona, United States, 85381
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
  • California
    • La Jolla, California, United States, 92037
    • Long Beach, California, United States, 92813
    • Rancho Mirage, California, United States, 92270
    • San Diego, California, United States, 92108
  • Colorado
    • Colorado Springs, Colorado, United States, 80920
  • Florida
    • Aventura, Florida, United States, 33180
    • Boca Raton, Florida, United States, 33486
    • Fort Lauderdale, Florida, United States, 33334
    • Largo, Florida, United States, 33773
    • South Miami, Florida, United States, 33143
  • Idaho
    • Boise, Idaho, United States, 83702
  • Illinois
    • Chicago, Illinois, United States, 60637
    • Chicago, Illinois, United States, 60611
  • Indiana
    • Indianapolis, Indiana, United States, 46260
    • Indianapolis, Indiana, United States, 46202-5149
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
  • Minnesota
    • Minneapolis, Minnesota, United States, 55416
  • Missouri
    • Saint Louis, Missouri, United States, 63141
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
  • New Jersey
    • Voorhees, New Jersey, United States, 08043
  • New York
    • Great Neck, New York, United States, 11021
    • Plainview, New York, United States, 11803
    • Rochester, New York, United States, 14618
    • Smithtown, New York, United States, 11787
  • North Carolina
    • Greenville, North Carolina, United States, 27834
    • Winston Salem, North Carolina, United States, 27157
  • Ohio
    • Beachwood, Ohio, United States, 44122
    • Dayton, Ohio, United States, 45402
    • Mayfield, Ohio, United States, 44143
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74104
    • Tulsa, Oklahoma, United States, 74135
  • Oregon
    • Portland, Oregon, United States, 97239
  • Pennsylvania
    • Duncansville, Pennsylvania, United States, 16635
  • Texas
    • Dallas, Texas, United States, 75231
    • Houston, Texas, United States, 77074
  • Utah
    • Salt Lake City, Utah, United States, 84132
  • Washington
    • Seattle, Washington, United States, 98104
  • Wisconsin
    • Glendale, Wisconsin, United States, 53217
    • Wausau, Wisconsin, United States, 54401

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• participants with active RA
• completed 24 weeks of treatment in WA16291 or WA17043
• eligible for re-treatment, based on clinical symptoms (Disease Activity Score in 28 joints >=2.6)
• females of childbearing potential using reliable contraception

Exclusion Criteria:

• participants who participated in rituximab studies WA16291 or WA17043 but withdrew into the safety follow-up phases of these trials
• previous rituximab non-responders
• current treatment with any other disease-modifying drug (apart from methotrexate), or any anti-tumor necrosis factor alfa, anti-interleukin-1, or other biologic therapies
• participants with known active infection of any kind
• evidence of any new or uncontrolled concomitant disease or development of any new contraindications which would preclude repeat treatment with rituximab
• history of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies
• female participants who are pregnant or breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Rituximab; Participants will receive rituximab 1 gram intravenously (IV) on Days 1 and 15 of each course of retreatment. In addition, participants will receive methotrexate 10-25 milligrams per week (mg/week) orally or parenterally, methylprednisolone 100 mg IV 30 minutes prior to both rituximab infusions, and a stable dose of folic acid greater than or equal to (>=) 5 mg/week or equivalent. Participants will receive retreatment (next course of rituximab repeat treatment) within 2 weeks of meeting the retreatment criteria as defined in the protocol (minimum of 24 weeks after the first [Day 1] infusion of the last course of rituximab). Repeat treatment will be based on the investigator's decision of prior clinical response to rituximab, clinical need and evidence of active disease (Disease Activity Score in 28 joints >=2.6). Retreatment with rituximab will be continued until withdrawal of consent or study treatment completion on 31 December 2011, whichever is sooner.

Drug: Rituximab; Participants will receive rituximab 1 gram IV on Days 1 and 15 of each course of retreatment.; Other Names: Rituxan; MabThera; Drug: Methotrexate; Participants will receive methotrexate 10-25 mg/week orally or parenterally.; Drug: Methylprednisolone; Participants will receive methylprednisolone 100 mg IV 30 minutes prior to each rituximab infusion.; Drug: Folic Acid; Participants will receive folic acid >= 5 mg/week or equivalent.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With an American College of Rheumatology 20 (ACR20) Response After First Course	A participant had an ACR20 response if there was at least a 20 percent (%) improvement, ie, reduction from Baseline, in tender joint count (TJC) and swollen joint count (SJC) (28 assessed joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity [visual analog scale (VAS): 0=no disease activity to 100=maximum disease activity]; 2) Patient's Global Assessment of Disease Activity [VAS: 0=no disease activity to 100=maximum disease activity]; 3) Patient's Assessment of Pain [VAS: 0=no pain to 100=unbearable pain]; 4) Health Assessment Questionnaire [20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do] and 5) an acute-phase reactant (either C-reactive protein [CRP] or erythrocyte sedimentation rate [ESR]). The ACR20 response was compared to Baseline in the precursor studies WA16291 or WA17043.	24 weeks after first course of rituximab (up to approximately 26 weeks)
Percentage of Participants With ACR20 Response After Second Course	A participant had an ACR20 response if there was at least a 20% improvement, ie, reduction from Baseline, in TJC and SJC (28 assessed joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity [VAS: 0=no disease activity to 100=maximum disease activity]; 2) Patient's Global Assessment of Disease Activity [VAS: 0=no disease activity to 100=maximum disease activity]; 3) Patient's Assessment of Pain [VAS: 0=no pain to 100=unbearable pain]; 4) Health Assessment Questionnaire [20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do] and 5) an acute-phase reactant (either CRP or ESR). The ACR20 response was compared to Baseline in the precursor studies WA16291 or WA17043.	24 weeks after second course of rituximab (median duration of 90.9 weeks)
Percentage of Participants With ACR20 Response After Third Course	A participant had an ACR20 response if there was at least a 20% improvement, ie, reduction from Baseline, in TJC and SJC (28 assessed joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity [VAS: 0=no disease activity to 100=maximum disease activity]; 2) Patient's Global Assessment of Disease Activity [VAS: 0=no disease activity to 100=maximum disease activity]; 3) Patient's Assessment of Pain [VAS: 0=no pain to 100=unbearable pain]; 4) Health Assessment Questionnaire [20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do] and 5) an acute-phase reactant (either CRP or ESR). The ACR20 response was compared to Baseline in the precursor studies WA16291 or WA17043.	24 weeks after third course of rituximab (median duration of 162.9 weeks)
Percentage of Participants With ACR20 Response After Fourth Course	A participant had an ACR20 response if there was at least a 20% improvement, ie, reduction from Baseline, in TJC and SJC (28 assessed joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity [VAS: 0=no disease activity to 100=maximum disease activity]; 2) Patient's Global Assessment of Disease Activity [VAS: 0=no disease activity to 100=maximum disease activity]; 3) Patient's Assessment of Pain [VAS: 0=no pain to 100=unbearable pain]; 4) Health Assessment Questionnaire [20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do] and 5) an acute-phase reactant (either CRP or ESR). The ACR20 response was compared to Baseline in the precursor studies WA16291 or WA17043.	24 weeks after fourth course of rituximab (median duration of 232 weeks)
Percentage of Participants With ACR20 Response After Fifth Course	A participant had an ACR20 response if there was at least a 20% improvement, ie, reduction from Baseline, in TJC and SJC (28 assessed joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity [VAS: 0=no disease activity to 100=maximum disease activity]; 2) Patient's Global Assessment of Disease Activity [VAS: 0=no disease activity to 100=maximum disease activity]; 3) Patient's Assessment of Pain [VAS: 0=no pain to 100=unbearable pain]; 4) Health Assessment Questionnaire [20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do] and 5) an acute-phase reactant (either CRP or ESR). The ACR20 response was compared to Baseline in the precursor studies WA16291 or WA17043.	24 weeks after fifth course of rituximab (median duration of 297.3 weeks)
Percentage of Participants With ACR20 Response After Sixth Course	A participant had an ACR20 response if there was at least a 20% improvement, ie, reduction from Baseline, in TJC and SJC (28 assessed joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity [VAS: 0=no disease activity to 100=maximum disease activity]; 2) Patient's Global Assessment of Disease Activity [VAS: 0=no disease activity to 100=maximum disease activity]; 3) Patient's Assessment of Pain [VAS: 0=no pain to 100=unbearable pain]; 4) Health Assessment Questionnaire [20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do] and 5) an acute-phase reactant (either CRP or ESR). The ACR20 response was compared to Baseline in the precursor studies WA16291 or WA17043.	24 weeks after sixth course of rituximab (median duration of 354.4 weeks)
Percentage of Participants With ACR20 Response After Seventh Course	A participant had an ACR20 response if there was at least a 20% improvement, ie, reduction from Baseline, in TJC and SJC (28 assessed joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of Disease Activity [VAS: 0=no disease activity to 100=maximum disease activity]; 2) Patient's Global Assessment of Disease Activity [VAS: 0=no disease activity to 100=maximum disease activity]; 3) Patient's Assessment of Pain [VAS: 0=no pain to 100=unbearable pain]; 4) Health Assessment Questionnaire [20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do] and 5) an acute-phase reactant (either CRP or ESR). The ACR20 response was compared to Baseline in the precursor studies WA16291 or WA17043.	24 weeks after seventh course of rituximab (median duration of 406.7 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With ACR50 and ACR70 Response	A participant had an ACR50 and ACR70 response if there was at least a 50% or 70% improvement, ie, reduction from Baseline, in TJC and SJC (28 assessed joints) and in at least 3 of the following 5 parameters: 1) Physician's Global Assessment of disease activity [VAS: 0=no disease activity to 100=maximum disease activity]; 2) Patient's Global Assessment of Disease Activity [VAS: 0=no disease activity to 100=maximum disease activity]; 3) Patient's Assessment of Pain [VAS: 0=no pain to 100=unbearable pain]; 4) Health Assessment Questionnaire [20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do] and 5) an acute-phase reactant (CRP or ESR). The ACR50 and ACR70 responses were compared to Baseline in the precursor studies WA16291 or WA17043.	24 weeks after first, second, third, fourth, fifth, sixth, and seventh course of rituximab (median duration of 26, 90.9, 162.9, 232, 297.3, 354.4, and 406.7 weeks, respectively)
American College of Rheumatology Index of Improvement (ACRn) Response	The ACRn is calculated for each participant by taking the lowest percentage improvement in (1) SJC or (2) TJC or (3) the median of the remaining 5 components of the ACR response (patient's assessment of disease activity; patient's global assessment of pain; physician's assessment of disease activity; participant's assessment of physical function; an acute phase reactant value [either CRP or ESR]). The index of improvement in RA, where 0 indicates no improvement and 100 indicates a 100% improvement across all signs and symptoms of RA. ACRn scores were calculated considering the original baseline in the precursor studies WA16291 or WA17043.	24 weeks after first, second, third, fourth, fifth, sixth, and seventh course of rituximab (median duration of 26, 90.9, 162.9, 232, 297.3, 354.4, and 406.7 weeks, respectively)
Percentage of Participants With Low Disease Activity and Clinical Remission Based on DAS28-ESR	DAS28-ESR was calculated from SJC and TJC using 28 joints count, ESR (millimeters per hour [mm/hour]), and Patient's Global Assessment of Disease Activity (VAS: 0=no disease activity to 100=maximum disease activity). DAS28-ESR = 0.56*square root (sqrt)(TJC28) + 0.28*sqrt(SJC28) + 0.70*natural logarithm (ln) (ESR) + 0.014*Patient's Global Assessment of Disease Activity. Total score range: 0-10, higher score=more disease activity. DAS28-ESR <= 3.2 implied low disease activity (LDA) and DAS28-ESR <2.6 = clinical remission.	24 weeks after first, second, third, fourth, fifth, sixth, and seventh course of rituximab (median duration of 26, 90.9, 162.9, 232, 297.3, 354.4, and 406.7 weeks, respectively)
Percentage of Participants With European League Against Rheumatism (EULAR) Response of 'Good' or 'Moderate'	DAS28-ESR was calculated from SJC and TJC using 28 joints count, ESR (mm/hour), and Physician's Global Assessment of Disease Activity (VAS: 0=no disease activity to 100=maximum disease activity). DAS28-ESR = 0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) + 0.70*ln(ESR) + 0.014*Patient's Global Assessment of Disease Activity. The 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 had a change from baseline greater than (>) 1.2 with a DAS28 score less than or equal to (≤) 3.2; moderate responders had a change from baseline >1.2 with a DAS28 score >3.2 to less than or equal to (≤) 5.1 or a change from baseline >0.6 to ≤1.2 with a DAS28 score ≤5.1.	24 weeks after first, second, third, fourth, fifth, sixth, and seventh course of rituximab (median duration of 26, 90.9, 162.9, 232, 297.3, 354.4, and 406.7 weeks, respectively)
Change From Baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at 24 Weeks Following Each Course	The HAQ-DI is a questionnaire specific for rheumatoid arthritis and consists of 20 questions referring to 8 domains: Dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. Participants completed the questionnaire by answering the 20 questions on a scale of 0 (without difficulty) to 3 (unable to do). The total score ranges from 0 (no disability) to 3 (completely disabled). A negative change score indicates improvement.	24 weeks after first, second, third, fourth, fifth, sixth, and seventh course of rituximab (median duration of 26, 90.9, 162.9, 232, 297.3, 354.4, and 406.7 weeks, respectively)
Change From Baseline in Total Rheumatoid Factors (RF) at 24 Weeks Following Each Course		24 weeks after first, second, third, fourth, fifth, sixth, and seventh course of rituximab (median duration of 26, 90.9, 162.9, 232, 297.3, 354.4, and 406.7 weeks, respectively)
Percentage of Participants Who Discontinued Treatment Due to Insufficient Response		First, second, third, fourth, fifth, sixth, and seventh course of rituximab (up to a median of approximately 2, 62, 124, 186, 248, 310, and 372 weeks, respectively)
Time Since Last Treatment Course	Time since last treatment course = The last day of the last dose of rituximab to date of last contact. Date of last contact is the last available date of efficacy, complete medication start date, laboratory, adverse event assessments, early withdrawal visit, date of last contact, or date of death.	Baseline up to 10 years

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche
• Collaborators: Genentech, Inc.

Study record dates

Study Major Dates

• Study Start: August 1, 2002
• Primary Completion (Actual): December 1, 2012
• Study Completion (Actual): December 1, 2012

Study Registration Dates

• First Submitted: March 19, 2014
• First Submitted That Met QC Criteria: March 19, 2014
• First Posted (Estimate): March 20, 2014

Study Record Updates

• Last Update Posted (Actual): March 13, 2017
• Last Update Submitted That Met QC Criteria: January 23, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuroprotective Agents; Protective Agents; Antineoplastic Agents, Immunological; Dermatologic Agents; Micronutrients; Vitamins; Reproductive Control Agents; Vitamin B Complex; Hematinics; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Methylprednisolone; Rituximab; Methotrexate; Folic Acid
• Other Study ID Numbers: WA16855; U2653g (Other Identifier: Genentech Inc.)