Safety and Tolerability of Rituxan With Methotrexate and Etanercept or Methotrexate and Adalimumab in Patients With Active Rheumatoid Arthritis

This study has been completed.
Sponsor:
Collaborators:
Hoffmann-La Roche
Genentech
Information provided by:
Biogen Idec
ClinicalTrials.gov Identifier:
NCT00298272
First received: March 1, 2006
Last updated: September 12, 2013
Last verified: September 2010
  Purpose

This study is being conducted to see how well participants with rheumatoid arthritis are able to tolerate rituximab in combination with methotrexate and etanercept or methotrexate and adalimumab.


Condition Intervention Phase
Rheumatoid Arthritis
Biological: Rituximab
Other: Placebo
Drug: Methotrexate
Drug: Etanercept
Drug: Adalimumab
Drug: Methylprednisolone
Dietary Supplement: Folate
Drug: Glucocorticoid
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: A Randomized, Double-Blinded, Placebo Controlled Study to Evaluate the Tolerability and Safety of Rituximab When Given in Combination With Methotrexate and Etanercept (Enbrel) or Methotrexate and Adalimumab (Humira) in Subjects With Active Rheumatoid Arthritis

Resource links provided by NLM:


Further study details as provided by Biogen Idec:

Primary Outcome Measures:
  • Proportion of Participants With at Least One Serious Infection [ Time Frame: Through Week 24 ] [ Designated as safety issue: Yes ]
    The primary endpoint was the proportion of participants with ≥1 serious infection. An infection was considered serious if it required IV antibiotics or met the regulatory definition of a serious adverse event (SAE). An SAE was any event that resulted in death, resulted in a congenital anomaly in a child of a subject who participated in the study, caused or prolonged an inpatient hospitalization, resulted in significant or persistent disability, or was considered by the Investigator to be an Important Medical Event that may have required intervention to prevent any of the above-listed outcomes.


Secondary Outcome Measures:
  • Proportion of Participants Achieving an American College of Rheumatology (ACR)20 Response. [ Time Frame: Through Week 24 ] [ Designated as safety issue: No ]
    Improvement in disease activity compared to the placebo-control group was assessed using the ACR 20/50/70 response criteria. An ACR 20 response is defined as a 20% reduction in the number of both swollen and tender joints, and a 20% reduction in the score or results of at least 3 of the following 5 core set measurement tools: Physician Global Assessment of Disease, Patient Global Assessment of Disease, Patient Assessment of Pain, C-reactive protein or erythrocyte sedimentation rate (laboratory test results), and degree of disability in the Health Assessment Questionnaire.

  • Proportion of Participants Achieving an ACR50 Response [ Time Frame: Through Week 24 ] [ Designated as safety issue: No ]
    Improvement in disease activity compared to the placebo-control group was assessed using the ACR 20/50/70 response criteria. An ACR 50 response is defined as a 50% reduction in the number of both swollen and tender joints and a 50% reduction in the score or results of at least 3 of the following 5 core set measurement tools: Physician Global Assessment of Disease, Patient Global Assessment of Disease, Patient Assessment of Pain, C-reactive protein or erythrocyte sedimentation rate, and degree of disability in the Health Assessment Questionnaire.

  • Proportion of Participants Achieving an ACR70 Response [ Time Frame: Through Week 24 ] [ Designated as safety issue: No ]
    Improvement in disease activity compared to the placebo-control group was assessed using the ACR 20/50/70 response criteria. An ACR 70 response is defined as a 70% reduction in the number of both swollen and tender joints and a 70% reduction in the score or results of at least 3 of the following 5 core set measurement tools: Physician Global Assessment of Disease, Patient Global Assessment of Disease, Patient Assessment of Pain, C-reactive protein or erythrocyte sedimentation rate, and degree of disability in the Health Assessment Questionnaire.


Other Outcome Measures:
  • Proportion of Participants With at Least One Grade 3 or Grade 4 Infection [ Time Frame: Through Week 24 ] [ Designated as safety issue: Yes ]
    The severity of all reported adverse events, including infections, was graded and reported according to the National Cancer Institute Common Terminology Criteria for Adverse Events. This scale defines the severity of an adverse event as follows: Grade 1 = a mild adverse event, Grade 2 = a moderate adverse event, Grade 3 = a severe adverse event, and Grade 4 = a life-threatening or disabling adverse event.

  • Duration of Infections [ Time Frame: Through Week 24 ] [ Designated as safety issue: Yes ]
    Mean maximum duration of infections for each treatment group. For participants with multiple infections, only the infection with the longest duration was considered. Infections were identified using the wide RA harmonization MedDRA basket.

  • Proportion of Participants With at Least One Infection [ Time Frame: Through Week 24 ] [ Designated as safety issue: Yes ]

Enrollment: 54
Study Start Date: March 2006
Study Completion Date: October 2011
Primary Completion Date: April 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Rituximab
Participants will receive 500 mg rituximab on Day 1 and Day 15
Biological: Rituximab
Participants will receive 500 mg rituximab on Day 1 and Day 15
Drug: Methotrexate
Participants must have been treated with MTX ≥15 mg per week and ≤25 mg per week (dose may be as low as 10 mg if unable to tolerate higher dose) for at least 12 weeks immediately prior to Day 1, at a stable dose for at least 4 weeks.
Drug: Etanercept
Participants must have been treated with etanercept at 50 mg per week (25 mg twice per week or 50 mg once per week).
Drug: Adalimumab
Participants must have been treated with adalimumab at 40 mg every other week for at least 12 weeks immediately prior to Day 1.
Drug: Methylprednisolone
All participants who meet eligibility criteria and are enrolled in the trial will receive rituximab or placebo. Doses will be given 14 days apart, with pre-medication with methylprednisolone 100 mg IV prior to each dose of rituximab or placebo.
Dietary Supplement: Folate
All subjects will also receive a stable dose of folate (≥5 mg per week). All subjects will also receive a stable dose of folate (≥5 mg per week). All subjects should continue to receive any background oral glucocorticoids (≤10 mg per day prednisone or equivalent) and/or oral nonsteroidal anti-inflammatory drugs (NSAIDs) at a stable dose.
Drug: Glucocorticoid
All subjects should continue to receive any background oral glucocorticoids (≤10 mg per day prednisone or equivalent) and/or oral nonsteroidal anti-inflammatory drugs (NSAIDs) at a stable dose.
Placebo Comparator: Placebo Other: Placebo
Participants will receive placebo on Day 1 and Day 15
Drug: Methotrexate
Participants must have been treated with MTX ≥15 mg per week and ≤25 mg per week (dose may be as low as 10 mg if unable to tolerate higher dose) for at least 12 weeks immediately prior to Day 1, at a stable dose for at least 4 weeks.
Drug: Etanercept
Participants must have been treated with etanercept at 50 mg per week (25 mg twice per week or 50 mg once per week).
Drug: Adalimumab
Participants must have been treated with adalimumab at 40 mg every other week for at least 12 weeks immediately prior to Day 1.
Drug: Methylprednisolone
All participants who meet eligibility criteria and are enrolled in the trial will receive rituximab or placebo. Doses will be given 14 days apart, with pre-medication with methylprednisolone 100 mg IV prior to each dose of rituximab or placebo.
Dietary Supplement: Folate
All subjects will also receive a stable dose of folate (≥5 mg per week). All subjects will also receive a stable dose of folate (≥5 mg per week). All subjects should continue to receive any background oral glucocorticoids (≤10 mg per day prednisone or equivalent) and/or oral nonsteroidal anti-inflammatory drugs (NSAIDs) at a stable dose.
Drug: Glucocorticoid
All subjects should continue to receive any background oral glucocorticoids (≤10 mg per day prednisone or equivalent) and/or oral nonsteroidal anti-inflammatory drugs (NSAIDs) at a stable dose.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Must give written informed consent. If required by local law, candidates must also authorize the release and use of PHI.
  2. Male or female participants, between 18 and 65 years of age, who have a diagnosis of active RA for at least 6 months, diagnosed according to the revised 1987 ACR criteria for the classification of RA.
  3. Must have at least 5 tender and 5 swollen joints at Screening and Day 1.
  4. Must have been treated with etanercept at 50 mg per week (25 mg twice per week or 50 mg once per week) or adalimumab at 40 mg every other week for at least 12 weeks immediately prior to Day 1.
  5. Must have been treated with MTX greater than or equal to 15 mg per week and less than or equal to 25 mg per week (dose may be as low as 10 mg if unable to tolerate higher dose) for at least 12 weeks immediately prior to Day 1, at a stable dose for at least 4 weeks.
  6. Must be willing to receive oral folate.
  7. Oral glucocorticoids must not exceed 10 mg per day of prednisone (or equivalent dose) and must have been administered at a stable dose for at least 4 weeks prior to Day 1.
  8. Any concomitant NSAID must be stable for at least 2 weeks prior to Day 1.
  9. For participants of reproductive potential (males and females), use of a reliable means of contraception (e.g., hormonal contraceptive, patch, intrauterine device, physical barrier) throughout study participation.

    Exclusion Criteria:

    Exclusions Related to RA

  10. Rheumatic autoimmune disease other than RA, or significant systemic involvement secondary to RA (e.g., vasculitis, pulmonary fibrosis, or Felty's syndrome). Secondary Sjögren's syndrome or secondary limited cutaneous vasculitis with RA is permitted.
  11. Functional Class IV as defined by the ACR Classification of Functional Status in Rheumatoid Arthritis.
  12. History of, or current, inflammatory joint disease other than RA (e.g., gout, reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy, Lyme disease) or other systemic autoimmune disorder (e.g., SLE, inflammatory bowel disease, scleroderma, inflammatory myopathy, mixed connective tissue disease, or any overlap syndrome).
  13. Diagnosis of juvenile idiopathic arthritis, also known as juvenile RA, and/or RA before age 16.

    Exclusions Related to General Health

  14. Any surgical procedure, including bone/joint surgery/synovectomy (including joint fusion or replacement) within 12 weeks prior to baseline or planned within 24 weeks of randomization.
  15. Lack of peripheral venous access.
  16. Pregnancy or breast feeding.
  17. Significant cardiac or pulmonary disease (including obstructive pulmonary disease).
  18. History of CHF, SLE like syndrome, neuropathy or myelitis, optic neuritis, or pancytopenia while on etanercept or adalimumab.
  19. Evidence of significant uncontrolled concomitant disease such as, but not limited to, nervous system, renal, hepatic, endocrine, or gastrointestinal disorders which, in the Investigator's opinion, would preclude subject participation.
  20. Primary or secondary immunodeficiency (history of, or currently active), including known history of HIV infection.
  21. Known active infection of any kind (excluding fungal infections of nail beds), or any major episode of infection requiring hospitalization or treatment with IV anti infectives within 4 weeks of Day 1 or completion of oral anti infectives within 2 weeks of Day 1.
  22. History of positive PPD not adequately treated.
  23. History of deep space/tissue infection (e.g., fasciitis, abscess, osteomyelitis) within 52 weeks of Day 1.
  24. History of serious infection or opportunistic infection in the last 2 years (to screen for a chest infection, a chest radiograph will be performed at Screening if one was not performed within 12 weeks prior to Screening).
  25. History of seizures.
  26. History of cancer, including solid tumors, hematologic malignancies, and carcinoma in situ (except basal cell and squamous cell carcinoma of the skin that have been excised and cured).
  27. Any neurological (congenital or acquired), vascular, or systemic disorder that might affect any of the efficacy assessments, in particular, joint pain and swelling (e.g., Parkinsons disease, cerebral palsy, diabetic neuropathy).
  28. Currently active alcohol or drug abuse or history of alcohol or drug abuse (as determined by the Investigator) within 1 year prior to Day 1.

    Exclusions Related to Medications

  29. History of a severe allergic or anaphylactic reaction to a biologic agent or known hypersensitivity to any component of rituximab or to murine proteins.
  30. Previous treatment with an anti alpha 4 integrin agent or costimulation modulator.
  31. Concurrent treatment with any biologic agent other than etanercept or adalimumab, or DMARD other than MTX. Treatment with any biologic or DMARD except etanercept or adalimumab, and MTX must be discontinued 14 days prior to baseline, except for the following: azathioprine for 28 days; leflunomide for 8 weeks (or 14 days after 11 days of standard cholestyramine or activated charcoal washout).
  32. Previous treatment with any cell depleting therapies, including investigational agents (e.g., CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19, anti CD11a, anti-CD22, BLys/BAFF, and anti CD20).
  33. Treatment with another investigational drug within 4 weeks prior to Day 1 or 5 half lives of the investigational drug (which ever is the longer).
  34. Receipt of a live/attenuated vaccine within 4 weeks prior to Day 1.
  35. Intra articular or parenteral glucocorticoids within 4 weeks prior to Day 1.
  36. Intolerance or contraindications to IV glucocorticoids.

    Exclusions Related to Laboratory Findings

  37. For women of childbearing potential, a positive serum pregnancy test at screening and/or a positive urine pregnancy test on Day 1.
  38. Positive hepatitis B surface antigen (HBsAg).
  39. Positive hepatitis B core antibody (HBcAb) associated with positive hepatitis B viral DNA (HBV DNA).
  40. Positive hepatitis C antibody.
  41. AST or ALT >2.5 times upper limit of normal.
  42. Hemoglobin <8.0 g/dL.
  43. Levels of IgG and/or IgM below 5.0 and 0.4 mg/mL, respectively.
  44. ANC <1500/mL.

    Miscellaneous Exclusions

  45. Current enrollment in any other investigational or other drug study.
  46. Treatment with IV Gamma Globulin or the Prosorba® Column within 6 months of the Screening visit
  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: NCT00298272

Locations
United States, Alabama
Research Site
Huntsville, Alabama, United States, 35801
United States, Arizona
Research Site
Paradise Valley, Arizona, United States, 85253
United States, California
Research Site
Palm Desert, California, United States, 92260
United States, Florida
Research Site
Jupiter, Florida, United States, 33458
Research Stie
Sarasota, Florida, United States, 34239
United States, Georgia
Research Site
Atlanta, Georgia, United States, 30342
United States, Idaho
Research Site
Boise, Idaho, United States, 83702
United States, Michigan
Research Site
Kalamazoo, Michigan, United States, 49048
United States, Missouri
Research Site
St. Louis, Missouri, United States, 63141
United States, Ohio
Research site
Chardon, Ohio, United States, 44024
United States, Oklahoma
Research Site
Oklahoma City, Oklahoma, United States, 73103
Research Site
Tulsa, Oklahoma, United States, 74135
United States, Pennsylvania
Research Site
Duncansville, Pennsylvania, United States, 16635
United States, Texas
Research Site
Dallas, Texas, United States, 75235
Research Site
Dallas, Texas, United States, 75231
Research Site
Houston, Texas, United States, 77074
Research Site
San Antonio, Texas, United States, 78217
United States, Utah
Research Site
Salt Lake City, Utah, United States, 84132
United States, Vermont
Research Site
Burlington, Vermont, United States, 5401
United States, Washington
Research Site
Tacoma, Washington, United States, 98405
Sponsors and Collaborators
Biogen Idec
Hoffmann-La Roche
Genentech
  More Information

No publications provided by Biogen Idec

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Biogen Idec MD, Biogen Idec
ClinicalTrials.gov Identifier: NCT00298272     History of Changes
Other Study ID Numbers: 102-RA-201
Study First Received: March 1, 2006
Results First Received: April 20, 2010
Last Updated: September 12, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Arthritis
Arthritis, Rheumatoid
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Anti-Inflammatory Agents, Non-Steroidal
TNFR-Fc fusion protein
Folic Acid
Vitamin B Complex
Glucocorticoids
Methylprednisolone
Methylprednisolone Hemisuccinate
Prednisolone
Prednisolone hemisuccinate
Prednisolone phosphate
Methotrexate
Rituximab
Adalimumab
Methylprednisolone acetate
Prednisolone acetate
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Anti-Inflammatory Agents

ClinicalTrials.gov processed this record on July 20, 2014