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

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ClinicalTrials.gov Identifier: NCT02093026
Recruitment Status : Completed
First Posted : March 20, 2014
Results First Posted : March 13, 2017
Last Update Posted : March 13, 2017
Sponsor:
Collaborator:
Genentech, Inc.
Information provided by (Responsible Party):
Hoffmann-La Roche

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Rheumatoid Arthritis Drug: Rituximab Drug: Methotrexate Drug: Methylprednisolone Drug: Folic Acid Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 465 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-label Study of the Efficacy and Safety of Re-treatments With Rituximab (MabThera®/Rituxan®) in Patients With Active Rheumatoid Arthritis
Study Start Date : August 2002
Actual Primary Completion Date : December 2012
Actual Study Completion Date : December 2012

Resource links provided by the National Library of Medicine

Drug Information available for: Rituximab

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:
  • MabThera
  • Rituxan

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.




Primary Outcome Measures :
  1. Percentage of Participants With an American College of Rheumatology 20 (ACR20) Response After First Course [ Time Frame: 24 weeks after first course of rituximab (up to approximately 26 weeks) ]
    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.

  2. Percentage of Participants With ACR20 Response After Second Course [ Time Frame: 24 weeks after second course of rituximab (median duration of 90.9 weeks) ]
    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.

  3. Percentage of Participants With ACR20 Response After Third Course [ Time Frame: 24 weeks after third course of rituximab (median duration of 162.9 weeks) ]
    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.

  4. Percentage of Participants With ACR20 Response After Fourth Course [ Time Frame: 24 weeks after fourth course of rituximab (median duration of 232 weeks) ]
    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.

  5. Percentage of Participants With ACR20 Response After Fifth Course [ Time Frame: 24 weeks after fifth course of rituximab (median duration of 297.3 weeks) ]
    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.

  6. Percentage of Participants With ACR20 Response After Sixth Course [ Time Frame: 24 weeks after sixth course of rituximab (median duration of 354.4 weeks) ]
    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.

  7. Percentage of Participants With ACR20 Response After Seventh Course [ Time Frame: 24 weeks after seventh course of rituximab (median duration of 406.7 weeks) ]
    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.


Secondary Outcome Measures :
  1. Percentage of Participants With ACR50 and ACR70 Response [ Time Frame: 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) ]
    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.

  2. American College of Rheumatology Index of Improvement (ACRn) Response [ Time Frame: 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) ]
    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.

  3. Percentage of Participants With Low Disease Activity and Clinical Remission Based on DAS28-ESR [ Time Frame: 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) ]
    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.

  4. Percentage of Participants With European League Against Rheumatism (EULAR) Response of 'Good' or 'Moderate' [ Time Frame: 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) ]
    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.

  5. Change From Baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at 24 Weeks Following Each Course [ Time Frame: 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) ]
    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.

  6. Change From Baseline in Total Rheumatoid Factors (RF) at 24 Weeks Following Each Course [ Time Frame: 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) ]
  7. Percentage of Participants Who Discontinued Treatment Due to Insufficient Response [ Time Frame: 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) ]
  8. Time Since Last Treatment Course [ Time Frame: Baseline up to 10 years ]
    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.



Information from the National Library of Medicine

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Layout table for eligibility information
Ages Eligible for Study:   21 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02093026


  Show 92 Study Locations
Sponsors and Collaborators
Hoffmann-La Roche
Genentech, Inc.
Investigators
Layout table for investigator information
Study Chair: Clinical Trials Hoffmann-La Roche

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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT02093026     History of Changes
Other Study ID Numbers: WA16855
U2653g ( Other Identifier: Genentech Inc. )
First Posted: March 20, 2014    Key Record Dates
Results First Posted: March 13, 2017
Last Update Posted: March 13, 2017
Last Verified: January 2017

Additional relevant MeSH terms:
Layout table for MeSH terms
Connective Tissue Diseases
Methylprednisolone Hemisuccinate
Prednisolone
Methylprednisolone
Methylprednisolone Acetate
Prednisolone acetate
Prednisolone hemisuccinate
Prednisolone phosphate
Arthritis
Arthritis, Rheumatoid
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Autoimmune Diseases
Immune System Diseases
Rituximab
Methotrexate
Folic Acid
Vitamin B Complex
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action