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A Study of MabThera (Rituximab) in Combination With Methotrexate in Patients With Rheumatoid Arthritis Who Have Had an Inadequate Response to Anti-TNF Therapies.

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT00462345
First received: April 18, 2007
Last updated: October 30, 2014
Last verified: October 2014
  Purpose

This single arm study will evaluate the efficacy and safety of MabThera in combination with methotrexate in patients with rheumatoid arthritis who have had an inadequate response to one or more anti-TNF therapies. Patients will receive MabThera 1000mg i.v. on days 1 and 15, and methotrexate (10-25mg/week p.o. or parenteral), together with methylprednisolone 100mg i.v. prior to infusion of MabThera. After week 24, eligible patients may receive re-treatment. The anticipated time on study treatment is 3-12 months, and the target sample size is <100 individuals.


Condition Intervention Phase
Rheumatoid Arthritis
Drug: rituximab
Drug: Methotrexate
Drug: Corticosteroid or NSAID
Dietary Supplement: Folate
Phase 4

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An Open-label Study to Evaluate the Effect of MabThera in Combination With Methotrexate on Treatment Response in Patients With Active Rheumatoid Arthritis Who Have Had an Inadequate Response to Anti-TNF Therapies

Resource links provided by NLM:


Further study details as provided by Hoffmann-La Roche:

Primary Outcome Measures:
  • Percentage of Participants With An American College of Rheumatology 20 Percent (%) Improvement Criteria (ACR20) Response at Week 24 [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
    ACR20 response: ≥20% improvement in tender joint count; ≥20% improvement in swollen joint count; and ≥20% improvement in at least 3 of 5 remaining ACR core measures: Patient Assessment of Pain; Patient Global Assessment of Disease Activity (PtGA); Physician Global Assessment of Disease Activity (PGA); self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ-DI]); and either C-Reactive Protein (CRP) or erythrocyte sedimentation rate (ESR).


Secondary Outcome Measures:
  • Percentage of Participants With An American College of Rheumatology 50% Improvement Criteria (ACR50) Response at Week 24 [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
    ACR50 response: ≥50% improvement in tender joint count; ≥50% improvement in swollen joint count; and ≥50% improvement in at least 3 of 5 remaining ACR core measures: Patient Assessment of Pain; PtGA; PGA; self-assessed disability (HAQ-DI); and either CRP or ESR.

  • Percentage of Participants With An American College of Rheumatology 70% Improvement Criteria (ACR70) Response at Week 24 [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
    ACR70 response: ≥70% improvement in tender joint count; ≥70% improvement in swollen joint count; and ≥70% improvement in at least 3 of 5 remaining ACR core measures: Patient Assessment of Pain; PtGA; PGA; self-assessed disability (HAQ-DI); and either CRP or ESR.

  • Disease Activity Score Based on 28-Joint Count (DAS-28) [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    DAS28 was calculated from the number of swollen joints and tender joints using the 28 joints count, the ESR (millimeters per hour [mm/hr]) and PtGA of disease activity with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity. DAS28 ≤3.2 equals (=) low disease activity, DAS28 greater than (>)3.2 to 5.1 = moderate to high disease activity.

  • Percentage of Participants With Change in DAS-28 From BL to Week 24 of ≥1.2 [ Time Frame: Baseline, Week 24 ] [ Designated as safety issue: No ]
    DAS28 was calculated from the number of swollen joints and tender joints using the 28 joints count, the ESR (mm/hr) and PtGA of disease activity with transformed scores ranging 0 to 10; higher scores indicated greater affectation due to disease activity.

  • Percentage of Participants With DAS Response by European League Against Rheumatism (EULAR) Category at Week 24 [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
    The percentage of participants categorized as good, moderate, or nonresponders according to the EULAR response criteria at Week 24. Participants were categorized as good responders if the intensity of their symptoms was in the "low disease activity (DAS28 less than [<]3.2)" category after treatment, and their symptoms significantly decreased to >1.2. Participants were categorized as moderate responders if the intensity of their symptoms was in the "moderate or high disease activity (DAS28 >3.2)" category after treatment, and the symptoms significantly decreased to >1.2; or if the intensity of their symptoms was in the "low or moderate disease activity (DAS28 <5.1)" category, and the DAS28 score changed more than 0.6 or 1.2 or less. Participants were categorized as non-responders if they did not fall into the good or moderate categories.

  • Swollen Join Count (SJC) [ Time Frame: Baseline, Weeks 24 and 48 ] [ Designated as safety issue: No ]
    Number of swollen joints was determined by examination of 66 joints (as assessed through pressing and palpating during the physical examination) and identifying when swelling was present. The number of swollen joints was recorded on the joint assessment form at each visit as swollen or not swollen.

  • Tender Joint Count (TJC) [ Time Frame: Baseline, Weeks 24 and 48 ] [ Designated as safety issue: No ]
    Number of tender joints was determined by examination of 68 joints (as assessed through pressing and palpating during the physical examination) and identifying when swelling was present. The number of tender joints was recorded on the joint assessment form at each visit as either tender or not tender.

  • Patient Global Assessment of Disease Activity (VAS) [ Time Frame: Baseline, Weeks 24 and 48 ] [ Designated as safety issue: No ]
    The mean score of the symptoms of rheumatoid arthritis (RA) at Week 0 (baseline) and the change from Week 0 to Weeks 24 and 48 as assessed by participants using a 100 mm horizontal VAS, where the left endpoint indicated "No disease activity" (no symptom, or no symptom of RA), and the right endpoint indicated "Maximum disease activity" (maximum RA activity). A negative change from Baseline indicated improvement.

  • Physician Global Assessment of Disease Activity (VAS) [ Time Frame: Baseline, Weeks 24 and 48 ] [ Designated as safety issue: No ]
    The mean score of the symptoms of RA at Week 0 and the change from Week 0 (baseline) to Weeks 24 and 48 as assessed by investigators using a 100-mm horizontal VAS, where the left endpoint indicated "No disease activity" (no symptom, or no symptom of RA), and the right endpoint indicated "Maximum disease activity" (maximum RA activity). A negative change from Baseline indicated improvement.

  • Patient Assessment of Pain (VAS) [ Time Frame: Baseline, Weeks 24 and 48 ] [ Designated as safety issue: No ]
    The mean score of pain at Week 0 (baseline) and the change from Week 0 to Weeks 24 and 48 as assessed by participants using a 100-mm horizontal VAS, where the left endpoint indicated "No pain," and the right endpoint indicated "Unbearable pain." A negative change indicated improvement.

  • C-reactive Protein (CRP) Level [ Time Frame: Baseline, Weeks 24 and 48 ] [ Designated as safety issue: No ]
    The mean level of CRP in milligrams per liter (mg/L), an acute phase reactant, at Week 0 and the change from Week 0 to Weeks 24 and 48.

  • Erythrocyte Sedimentation Rate (ESR) [ Time Frame: Baseline, Weeks 24 and 48 ] [ Designated as safety issue: No ]
    The mean level of ESR (in mm/hr), an acute phase reactant, at Week 0 and the change from Week 0 to Weeks 24 and 48.

  • HAQ-DI Score [ Time Frame: Baseline, Weeks 24 and 48 ] [ Designated as safety issue: No ]
    HAQ-DI: participant-reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week. Each item scored on 4-point scale from 0 to 3: 0=no difficulty; 1=some difficulty; 2=much difficulty; 3=unable to do. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0-3 where 0 = least difficulty and 3 = extreme difficulty.

  • Physical Function as Assessed by Short Form 36 (SF-36) [ Time Frame: Screening, Weeks 24 and 48 ] [ Designated as safety issue: No ]
    SF-36 is a standardized survey evaluating 8 aspects of functional health and well being: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, mental health. The score for a section is an average of the individual question scores, which are scaled 0-100 (100=highest level of functioning).

  • SF-36 Mental Component Scores [ Time Frame: Screening, Weeks 24 and 48 ] [ Designated as safety issue: No ]
    SF-36 is a standardized survey evaluating 8 aspects of functional health and well being: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, mental health. The score for a section is an average of the individual question scores, which are scaled 0-100 (100=highest level of functioning).

  • Modified Total Sharp-Genant Score (mTSS) [ Time Frame: Screening and Weeks 24 and 48 ] [ Designated as safety issue: No ]
    Posterior-anterior (PA) radiograph of each hand and anterior-posterior (AP) radiograph of each foot were taken separately and assessed according to Genant's method as modified from Sharp's method. The Sharp-Genant score=total of the erosion score and the joint space narrowing (JSN) score of all the hands and feet. Erosion Score: 14 locations in each hand and wrist and 6 joints in the foot were evaluated for erosion using an 8-point scale where 0=Normal to 3.5=very severe erosion. JSN Score:13 locations in each hand and wrist and 6 joints in the foot were evaluated for joint narrowing score using a 9-point scale where 0=Normal to 4.0=definite ankylosis (stiffness or fixation of a joint). Maximum total erosion score in hands=100 and in feet=42; maximum scores for JSN in the hands=100 and in feet=48. Maximum modified Sharp score achievable is 290. A lower number change from Baseline indicated a better score. Change in scores was calculated as change=final score minus initial score.

  • Modified Sharp Radiographic Erosion Score (ES) [ Time Frame: Screening, Weeks 24 and 48 ] [ Designated as safety issue: No ]
    Erosion Score: A total of 14 locations in each hand and wrist and 6 joints in the foot were evaluated for erosion using an 8-point scale where 0=Normal to 3.5=very severe erosion. Maximum total erosion score in the hands was 100 and in the feet was 42, for a maximum overall score of 142. Total erosion score was for both hands and feet.

  • Modified Sharp Radiographic Joint Space Narrowing Score (JSN) [ Time Frame: Screening, Weeks 24 and 48 ] [ Designated as safety issue: No ]
    JSN Score: A total of 13 locations in each hand and wrist and 6 joints in the foot were evaluated for joint narrowing score using a 9-point scale where 0=Normal to 4.0=definite ankylosis (stiffness or fixation of a joint). Maximum total scores for JSN in the hands was 100 and in the feet was 48, for a maximum overall score of 148. Total JSN was for both hands and feet.


Enrollment: 40
Study Start Date: June 2007
Study Completion Date: July 2009
Primary Completion Date: July 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Rituximab, Methotrexate
Participants received rituximab 1000 milligrams (mg), intravenously (IV), on Day 1 and Day 15. Participants also received methylprednisolone 100 mg, IV, 30 minutes before the infusion of rituximab. Participants also received methotrexate (MTX) 10 to 25 milligrams per week (mg/week), orally (PO) or parenterally, and folate greater than or equal to (≥) 5 mg/week, PO, folate greater than or equal to (≥) 5 mg/week, PO, either as a single dose or as divided daily doses from Day 1 through Week 24. Participants also received prednisone less than or equal to (≤) 10 milligrams per day (mg/day), PO, OR equivalent corticosteroid, OR non-steroidal anti-inflammatory drugs (NSAIDs), PO, from Day 1 through Week 24. Eligible participants who completed the first 24-week course were entered into a second course.
Drug: rituximab
1000 mg i.v. on Days 1 and 15
Other Names:
  • MabThera
  • Rituxan
Drug: Methotrexate
10 to 25 mg/week p.o. or parenteral from Day 1 through Week 24
Drug: Corticosteroid or NSAID
≤10 mg/day prednisone p.o., or equivalent corticosteroid, or NSAIDs p.o. from Day 1 through Week 24
Dietary Supplement: Folate
≥5 mg/week, once daily or b.i.d. from Day 1 through Week 24

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • adult patients, 18-80 years of age;
  • rheumatoid arthritis for >=6 months;
  • receiving outpatient treatment;
  • an inadequate response to at least one anti-TNF therapy;
  • stable methotrexate for >=12 weeks.

Exclusion Criteria:

  • other rheumatic autoimmune disease or inflammatory joint disease;
  • previous treatment with MabThera;
  • concurrent treatment with any DMARD (apart from methotrexate), anti-TNF alpha therapy, or other biologic agent.
  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: NCT00462345

Locations
Korea, Republic of
Seoul, Korea, Republic of, 110-744
Seoul, Korea, Republic of, 137701
Seoul, Korea, Republic of, 133-792
Seoul, Korea, Republic of, 138-736
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: NCT00462345     History of Changes
Other Study ID Numbers: ML20934
Study First Received: April 18, 2007
Results First Received: May 8, 2014
Last Updated: October 30, 2014
Health Authority: Korea: Food and Drug Administration

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 November 20, 2014