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

This study has been terminated.
(Sponsor decided to end long term extension phase for business reasons unrelated to safety.)
Sponsor:
Collaborators:
Hoffmann-La Roche
Genentech, Inc.
Information provided by (Responsible Party):
Biogen
ClinicalTrials.gov Identifier:
NCT00298272
First received: March 1, 2006
Last updated: August 27, 2015
Last verified: August 2015
  Purpose
The primary objective of this study was to evaluate the tolerability and safety of rituximab in combination with methotrexate (MTX) and etanercept or adalimumab in participants with active rheumatoid arthritis (RA). The secondary objective was to explore the efficacy of rituximab in combination with MTX and etanercept or adalimumab in participants with active RA.

Condition Intervention Phase
Rheumatoid Arthritis
Biological: IDEC-C2B8 (rituximab)
Drug: Placebo
Drug: Methotrexate
Drug: Etanercept
Drug: Adalimumab
Drug: Methylprednisolone
Dietary Supplement: Folate
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:

Primary Outcome Measures:
  • Proportion of Participants With at Least One Serious Infection Through Week 24 [ Time Frame: Through Week 24 ] [ Designated as safety issue: Yes ]
    An infection was considered serious if it required intravenous (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 participant 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.

  • Number of Participants With Any Infections or Any Grade 3/4 Infections Through Week 24 [ Time Frame: Through Week 24 ] [ Designated as safety issue: Yes ]
    Infections were defined as adverse events that map to the Medical Dictionary for Regulatory Activities (MedDRA) system organ class (SOC) of "infections and infestations" and also included other infectious events that do not map to this SOC (e.g., cholecystitis, pleurisy, conjunctivitis, acne, tongue ulceration). Participants with multiple infections were calculated only once. 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.

  • Maximum Duration of Infections Through Week 24 [ Time Frame: Week 24 ] [ Designated as safety issue: Yes ]
    Infections were defined as adverse events that map to the Medical Dictionary for Regulatory Activities (MedDRA) system organ class (SOC) of "infections and infestations" and also included other infectious events that do not map to this SOC (e.g., cholecystitis, pleurisy, conjunctivitis, acne, tongue ulceration). For participants with multiple infections, only the infection with the longest duration was included in this analysis.

  • Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) Through Week 24 [ Time Frame: Through Week 24 ] [ Designated as safety issue: Yes ]
    An AE was any sign (including an abnormal laboratory result that the investigator determined to be clinically significant), symptom, or diagnosis/disease that is unfavorable or unintended, that was new, or if pre-existing, worsened in a participant and that did not necessarily have a causal relationship with the treatment. An SAE was any event that resulted in death, resulted in a congenital anomaly in a child of a participant 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.

  • Number of Participants With Clinically Significant Immunological and Laboratory Assessment Findings [ Time Frame: Through Week 24 ] [ Designated as safety issue: Yes ]
    The following immunological assessments were conducted: autoantibody concentrations for RF, anti-cyclic-citrullinated peptide (CCP) antibody concentrations, quantitative immunoglobulin levels, and lymphocyte assessments of T- and B-cell populations, determined using whole blood expanded fluorescent-activated cell sorter (FACS) analysis. The following laboratory assessments were performed: hemoglobin, hematocrit, red blood cells (RBC), white blood cells (WBC) with differential, and platelet counts; aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, total protein, albumin, total bilirubin, blood urea nitrogen (BUN), uric acid, creatinine, random glucose, potassium, sodium, chloride, calcium, and phosphorous; blood, protein, and glucose (microscopic examination, if abnormal and applicable).


Secondary Outcome Measures:
  • Proportion of Participants Achieving an American College of Rheumatology 20 (ACR20) Response at Week 24 [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
    An ACR20 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: Patient and physician assessment of patient disease activity (DA) in previous 24 hours on a visual analog scale (VAS, no DA to maximum DA); patient assessment of pain in previous 24 hours on a VAS (none to unbearable); Health Assessment Questionnaire-Disability Index (20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do); and C reactive protein or, if missing, erythrocyte sedimentation rate.

  • Proportion of Participants Achieving an American College of Rheumatology 50 (ACR50) Response at Week 24 [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
    An ACR50 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: Patient and physician assessment of patient disease activity (DA) in previous 24 hours on a visual analog scale (VAS, no DA to maximum DA); patient assessment of pain in previous 24 hours on a VAS (none to unbearable); Health Assessment Questionnaire-Disability Index (20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do); and C reactive protein or, if missing, erythrocyte sedimentation rate.

  • Proportion of Participants Achieving an American College of Rheumatology 70 (ACR70) Response at Week 24 [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
    An ACR70 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: Patient and physician assessment of patient disease activity (DA) in previous 24 hours on a visual analog scale (VAS, no DA to maximum DA); patient assessment of pain in previous 24 hours on a VAS (none to unbearable); Health Assessment Questionnaire-Disability Index (20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do); and C reactive protein or, if missing, erythrocyte sedimentation rate.


Enrollment: 54
Study Start Date: May 2006
Study Completion Date: July 2011
Primary Completion Date: April 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Double-blind/Open Label Rituximab

The double-blind rituximab treatment group received rituximab 500 mg by intravenous (IV) infusion on Day 1 and Day 15. After 24 weeks (primary endpoint completion), participants continued post-treatment follow-up (PTFU) visits through Week 56, and entered a 48-week Safety Follow-Up (SFU). At any time between Week 24 and Week 40 of PTFU, eligible participants could enter the rituximab open label (OL) arm, and "restart" the 56-week treatment/follow-up schedule (rituximab 500 mg by IV infusion on Day 1 and Day 15) prior to the 48-week SFU.

Prior to rituximab infusion, participants were premedicated with methylprednisolone 100 mg IV. Participants received folate ≥5 mg weekly. Background therapy (stable dose for the duration of the study) included: a tumor necrosis factor (TNF) inhibitor; either etanercept 50 mg subcutaneous injection (SC) weekly or adalimumab 40 mg SC once every 2 weeks; methotrexate (MTX) 15 to 25 mg by mouth or by intramuscular injection (IM) weekly.

Biological: IDEC-C2B8 (rituximab)
Participants will receive 500 mg rituximab on Day 1 and Day 15
Other Name: Rituxan
Drug: Methotrexate
Participants must have been treated with MTX ≥15 mg per week and ≤25 mg per week (dose may have been 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 and was continued for the study duration.
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).
Other Name: Enbrel
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.
Other Name: Humira
Drug: Methylprednisolone
Methylprednisolone 100 mg IV was administered by slow infusion to be completed at least 30 minutes prior to each infusion of rituximab or placebo.
Dietary Supplement: Folate
All subjects also received a stable dose of folate (≥5 mg per week).
Double-blind Placebo/Open Label Rituximab

The double-blind placebo treatment group received saline solution IV on Day 1 and Day 15. After 24 weeks (primary endpoint completion), participants continued post-treatment follow-up (PTFU) visits through Week 56, and entered a 48-week Safety Follow-Up (SFU). At any time between Week 24 and Week 40 of PTFU, eligible participants could enter the rituximab open label (OL) arm, and "restart" the 56-week treatment/follow-up schedule (rituximab 500 mg by IV infusion on Day 1 and Day 15) prior to the 48-week SFU.

Prior to each infusion of placebo, participants were premedicated with methylprednisolone 100 mg IV. Participants received folate ≥5 mg weekly. Background therapy (stable dose for the duration of the study) included: a tumor necrosis factor (TNF) inhibitor; either etanercept 50 mg subcutaneous injection (SC) weekly or adalimumab 40 mg SC once every 2 weeks; methotrexate (MTX) 15 to 25 mg by mouth or by intramuscular injection (IM) weekly.

Drug: 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 have been 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 and was continued for the study duration.
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).
Other Name: Enbrel
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.
Other Name: Humira
Drug: Methylprednisolone
Methylprednisolone 100 mg IV was administered by slow infusion to be completed at least 30 minutes prior to each infusion of rituximab or placebo.
Dietary Supplement: Folate
All subjects also received a stable dose of folate (≥5 mg per week).

Detailed Description:

The study consists of 4 parts: screening, treatment, post-treatment, and safety follow-up. Prior to Day 1, participants were discontinued from all disease-modifying anti-rheumatic drugs (DMARDs) except MTX and etanercept or adalimumab. All participants who met eligibility criteria and were enrolled in the trial were randomized to receive 500 mg rituximab or placebo on Day 1 and Day 15. A subset of 18 participants was enrolled initially and followed through Week 12 for safety. The remaining 42 participants were to be enrolled after the last participant in the subset completed Week 12 and the Data Safety Monitoring Board (DSMB) conducted a safety review and approved enrollment of these additional participants. Participants were dosed on Day 1 and Day 15 and followed for 56 weeks, while remaining on their current dose of MTX and etanercept or adalimumab throughout the study. The primary endpoint was assessed at Week 24.

All participants in double-blind treatment, including those who received placebo or rituximab, who met the open label inclusion/exclusion criteria anytime from Week 24 through Week 40, were eligible to enter the open label retreatment phase. These participants received open label rituximab on Day 1 and Day 15 of the retreatment phase, and were followed monthly until Week 24 then every 2 months until Week 56, while remaining on their current dose of MTX and etanercept or adalimumab throughout the study. Participants received 1 course of open label treatment only.

All participants were required to return for safety follow-up (SFU) assessments at Weeks 4, 12, 24, 36, and 48 after withdrawal or completion of the study. Participants whose peripheral CD20+ B cells remained depleted at the end of the SFU periods for the primary and OL portions of the study entered extended safety follow-up (ESFU). Assessments for ESFU were performed at 12-week intervals until peripheral B-cell levels returned to within normal range or baseline level (whichever was lower).

  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 protected health information (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 American College of Rheumatology (ACR) criteria for the classification of rheumatoid arthritis (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 methotrexate (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 non-steroidal antiinflammatory drugs (NSAIDs) 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., systemic lupus erythematosus [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 chronic heart failure (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 human immunodeficiency virus (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 purified protein derivative (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 disease-modifying anti-rheumatic drug (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 [alemtuzumab], anti-CD4, anti-CD5, anti-CD3, anti-CD19, anti CD11a, anti-CD22, B lymphocyte stimulator/B-cell activating factor [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 (whichever 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. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 times upper limit of normal.
  42. Hemoglobin <8.0 g/dL.
  43. Levels of immunoglobulin G (IgG) and/or immunoglobulin M (IgM) below 5.0 and 0.4 mg/mL, respectively.
  44. Absolute neutrophil count (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 Site
Sarasota, Florida, United States, 34239
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
Research Site
Mayfield Village, Ohio, United States, 44143
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, 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, 05401
Sponsors and Collaborators
Biogen
Hoffmann-La Roche
Genentech, Inc.
Investigators
Study Director: Medical Director Biogen
  More Information

Publications:
Responsible Party: Biogen
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: August 27, 2015
Health Authority: United States: 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
Adalimumab
Methotrexate
Methylprednisolone
Methylprednisolone Hemisuccinate
Methylprednisolone acetate
Prednisolone
Prednisolone acetate
Prednisolone hemisuccinate
Prednisolone phosphate
Rituximab
TNFR-Fc fusion protein
Vitamin B Complex
Abortifacient Agents
Abortifacient Agents, Nonsteroidal
Analgesics
Analgesics, Non-Narcotic
Anti-Inflammatory Agents
Anti-Inflammatory Agents, Non-Steroidal
Antiemetics
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents

ClinicalTrials.gov processed this record on May 03, 2016