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

Sponsor
Biogen (Industry)
Overall Status
Terminated
CT.gov ID
NCT00298272
Collaborator
Hoffmann-La Roche (Industry), Genentech, Inc. (Industry)
54
Enrollment
18
Locations
2
Arms
62
Duration (Months)
3
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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 or Disease Intervention/Treatment Phase
Phase 2

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).

Study Design

Study Type:
Interventional
Actual Enrollment :
54 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Triple (Participant, Care Provider, 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
Study Start Date :
May 1, 2006
Actual Primary Completion Date :
Apr 1, 2009
Actual Study Completion Date :
Jul 1, 2011

Arms and Interventions

Arm Intervention/Treatment
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 Names:
  • 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 Names:
  • 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 Names:
  • 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).
    Other: 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 Names:
  • 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 Names:
  • 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).

    Outcome Measures

    Primary Outcome Measures

    1. Proportion of Participants With at Least One Serious Infection Through Week 24 [Through Week 24]

      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.

    2. Number of Participants With Any Infections or Any Grade 3/4 Infections Through Week 24 [Through Week 24]

      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.

    3. Maximum Duration of Infections Through Week 24 [Week 24]

      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.

    4. Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) Through Week 24 [Through Week 24]

      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.

    5. Number of Participants With Clinically Significant Immunological and Laboratory Assessment Findings [Through Week 24]

      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

    1. Proportion of Participants Achieving an American College of Rheumatology 20 (ACR20) Response at Week 24 [Week 24]

      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.

    2. Proportion of Participants Achieving an American College of Rheumatology 50 (ACR50) Response at Week 24 [Week 24]

      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.

    3. Proportion of Participants Achieving an American College of Rheumatology 70 (ACR70) Response at Week 24 [Week 24]

      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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 65 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    1. 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.

    2. Functional Class IV as defined by the ACR Classification of Functional Status in Rheumatoid Arthritis.

    3. 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).

    4. Diagnosis of juvenile idiopathic arthritis, also known as juvenile RA, and/or RA before age 16.

    Exclusions Related to General Health

    1. 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.

    2. Lack of peripheral venous access.

    3. Pregnancy or breast feeding.

    4. Significant cardiac or pulmonary disease (including obstructive pulmonary disease).

    5. History of chronic heart failure (CHF), SLE-like syndrome, neuropathy or myelitis, optic neuritis, or pancytopenia while on etanercept or adalimumab.

    6. 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.

    7. Primary or secondary immunodeficiency (history of, or currently active), including known history of human immunodeficiency virus (HIV) infection.

    8. 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.

    9. History of positive purified protein derivative (PPD) not adequately treated.

    10. History of deep space/tissue infection (e.g., fasciitis, abscess, osteomyelitis) within 52 weeks of Day 1.

    11. 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).

    12. History of seizures.

    13. 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).

    14. 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).

    15. 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

    1. History of a severe allergic or anaphylactic reaction to a biologic agent or known hypersensitivity to any component of rituximab or to murine proteins.

    2. Previous treatment with an anti alpha 4 integrin agent or costimulation modulator.

    3. 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).

    4. 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).

    5. Treatment with another investigational drug within 4 weeks prior to Day 1 or 5 half lives of the investigational drug (whichever is the longer).

    6. Receipt of a live/attenuated vaccine within 4 weeks prior to Day 1.

    7. Intra-articular or parenteral glucocorticoids within 4 weeks prior to Day 1.

    8. Intolerance or contraindications to IV glucocorticoids.

    Exclusions Related to Laboratory Findings

    1. For women of childbearing potential, a positive serum pregnancy test at screening and/or a positive urine pregnancy test on Day 1.

    2. Positive hepatitis B surface antigen (HBsAg).

    3. Positive hepatitis B core antibody (HBcAb) associated with positive hepatitis B viral DNA (HBV DNA).

    4. Positive hepatitis C antibody.

    5. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 times upper limit of normal.

    6. Hemoglobin <8.0 g/dL.

    7. Levels of immunoglobulin G (IgG) and/or immunoglobulin M (IgM) below 5.0 and 0.4 mg/mL, respectively.

    8. Absolute neutrophil count (ANC) <1500/mL.

    Miscellaneous Exclusions

    1. Current enrollment in any other investigational or other drug study.

    2. Treatment with IV Gamma Globulin or the Prosorba® Column within 6 months of the Screening visit.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Research Site Huntsville Alabama United States 35801
    2 Research Site Paradise Valley Arizona United States 85253
    3 Research Site Palm Desert California United States 92260
    4 Research Site Jupiter Florida United States 33458
    5 Research Site Sarasota Florida United States 34239
    6 Research Site Boise Idaho United States 83702
    7 Research Site Kalamazoo Michigan United States 49048
    8 Research Site St. Louis Missouri United States 63141
    9 Research site Chardon Ohio United States 44024
    10 Research Site Mayfield Village Ohio United States 44143
    11 Research Site Oklahoma City Oklahoma United States 73103
    12 Research Site Tulsa Oklahoma United States 74135
    13 Research Site Duncansville Pennsylvania United States 16635
    14 Research Site Dallas Texas United States 75231
    15 Research Site Houston Texas United States 77074
    16 Research Site San Antonio Texas United States 78217
    17 Research Site Salt Lake City Utah United States 84132
    18 Research Site Burlington Vermont United States 05401

    Sponsors and Collaborators

    • Biogen
    • Hoffmann-La Roche
    • Genentech, Inc.

    Investigators

    • Study Director: Medical Director, Biogen

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Biogen
    ClinicalTrials.gov Identifier:
    NCT00298272
    Other Study ID Numbers:
    • 102-RA-201
    First Posted:
    Mar 2, 2006
    Last Update Posted:
    Sep 28, 2015
    Last Verified:
    Aug 1, 2015
    Additional relevant MeSH terms:
    Arthritis
    Arthritis, Rheumatoid
    Methylprednisolone
    Adalimumab
    Etanercept
    Rituximab
    Methotrexate

    Study Results

    Participant Flow

    Recruitment Details Participants were enrolled at 17 sites in the United States.
    Pre-assignment Detail After 24 weeks, 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 prior to the 48-week SFU.
    Arm/Group Title Double-blind/Open Label Rituximab Double-blind Placebo/Open Label Rituximab
    Arm/Group Description 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. 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.
    Period Title: Double-blind Phase
    STARTED 36 18
    Safety Population 33 18
    Completed to Week 24 31 18
    Completed to Week 56 8 3
    COMPLETED 28 18
    NOT COMPLETED 8 0
    Period Title: Double-blind Phase
    STARTED 22 16
    Completed to Week 24 22 15
    Completed to Week 56 13 12
    COMPLETED 13 12
    NOT COMPLETED 9 4
    Period Title: Double-blind Phase
    STARTED 22 17
    COMPLETED 18 13
    NOT COMPLETED 4 4

    Baseline Characteristics

    Arm/Group Title Double-blind/Open Label Rituximab Double-blind Placebo/Open Label Rituximab Total
    Arm/Group Description 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. 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. Total of all reporting groups
    Overall Participants 33 18 51
    Age (Years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Years]
    49.7
    (12.1)
    50.4
    (11.4)
    50.0
    (11.7)
    Sex: Female, Male (Count of Participants)
    Female
    28
    84.8%
    17
    94.4%
    45
    88.2%
    Male
    5
    15.2%
    1
    5.6%
    6
    11.8%
    Years since rheumatoid arthritis (RA) diagnosis (Years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Years]
    10.3
    (6.7)
    10.7
    (7.5)
    10.5
    (6.9)
    Number of Prior Tumor Necrosis Factor (TNF) Inhibitors (participants) [Number]
    1
    32
    97%
    18
    100%
    50
    98%
    2
    1
    3%
    0
    0%
    1
    2%
    C-Reactive Protein (mg/dL) [Mean (Full Range) ]
    Mean (Full Range) [mg/dL]
    0.97
    0.83
    0.92
    Swollen and Tender Joints (Joint counts) [Mean (Full Range) ]
    Swollen joints
    16.9
    14.2
    16.0
    Tender joints
    25.6
    22.8
    24.6

    Outcome Measures

    1. Primary Outcome
    Title Proportion of Participants With at Least One Serious Infection Through Week 24
    Description 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.
    Time Frame Through Week 24

    Outcome Measure Data

    Analysis Population Description
    The Safety Population consisted of all participants who received any part of an infusion of rituximab or placebo.
    Arm/Group Title Rituximab Placebo
    Arm/Group Description The rituximab treatment group received rituximab 500 mg by intravenous infusion (IV) on Day 1 and Day 15. Prior to rituximab infusion, participants were premedicated with methylprednisolone 100 mg IV. Participants were also to receive a stable dose of folate ≥5 mg weekly. The placebo treatment group received saline solution IV on Day 1 and Day 15. Prior to each infusion of placebo, participants were premedicated with methylprednisolone 100 mg IV. Participants were also to receive a stable dose of folate ≥5 mg weekly.
    Measure Participants 33 18
    Number [proportion of participants]
    0.03
    0.1%
    0.00
    0%
    2. Secondary Outcome
    Title Proportion of Participants Achieving an American College of Rheumatology 20 (ACR20) Response at Week 24
    Description 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.
    Time Frame Week 24

    Outcome Measure Data

    Analysis Population Description
    The Safety Population consisted of all participants who received any part of an infusion of rituximab or placebo. Missing data were imputed using the nonresponder method, in which a participant with missing data at the visit being analyzed was considered a nonresponder.
    Arm/Group Title Rituximab Placebo
    Arm/Group Description The rituximab treatment group received rituximab 500 mg by intravenous infusion (IV) on Day 1 and Day 15. Prior to rituximab infusion, participants were premedicated with methylprednisolone 100 mg IV. Participants were also to receive a stable dose of folate ≥5 mg weekly. The placebo treatment group received saline solution IV on Day 1 and Day 15. Prior to each infusion of placebo, participants were premedicated with methylprednisolone 100 mg IV. Participants were also to receive a stable dose of folate ≥5 mg weekly.
    Measure Participants 33 18
    Number [proportion of participants]
    0.30
    0.9%
    0.17
    0.9%
    3. Secondary Outcome
    Title Proportion of Participants Achieving an American College of Rheumatology 50 (ACR50) Response at Week 24
    Description 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.
    Time Frame Week 24

    Outcome Measure Data

    Analysis Population Description
    The Safety Population consisted of all participants who received any part of an infusion of rituximab or placebo. Missing data were imputed using the nonresponder method, in which a participant with missing data at the visit being analyzed was considered a nonresponder.
    Arm/Group Title Rituximab Placebo
    Arm/Group Description The rituximab treatment group received rituximab 500 mg by intravenous infusion (IV) on Day 1 and Day 15. Prior to rituximab infusion, participants were premedicated with methylprednisolone 100 mg IV. Participants were also to receive a stable dose of folate ≥5 mg weekly. The placebo treatment group received saline solution IV on Day 1 and Day 15. Prior to each infusion of placebo, participants were premedicated with methylprednisolone 100 mg IV. Participants were also to receive a stable dose of folate ≥5 mg weekly.
    Measure Participants 33 18
    Number [proportion of participants]
    0.12
    0.4%
    0.06
    0.3%
    4. Secondary Outcome
    Title Proportion of Participants Achieving an American College of Rheumatology 70 (ACR70) Response at Week 24
    Description 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.
    Time Frame Week 24

    Outcome Measure Data

    Analysis Population Description
    The Safety Population consisted of all participants who received any part of an infusion of rituximab or placebo. Missing data were imputed using the nonresponder method, in which a participant with missing data at the visit being analyzed was considered a nonresponder.
    Arm/Group Title Rituximab Placebo
    Arm/Group Description The rituximab treatment group received rituximab 500 mg by intravenous infusion (IV) on Day 1 and Day 15. Prior to rituximab infusion, participants were premedicated with methylprednisolone 100 mg IV. Participants were also to receive a stable dose of folate ≥5 mg weekly. The placebo treatment group received saline solution IV on Day 1 and Day 15. Prior to each infusion of placebo, participants were premedicated with methylprednisolone 100 mg IV. Participants were also to receive a stable dose of folate ≥5 mg weekly.
    Measure Participants 33 18
    Number [proportion of participants]
    0.00
    0%
    0.00
    0%
    5. Primary Outcome
    Title Number of Participants With Any Infections or Any Grade 3/4 Infections Through Week 24
    Description 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.
    Time Frame Through Week 24

    Outcome Measure Data

    Analysis Population Description
    The Safety Population consisted of all participants who received any part of an infusion of rituximab or placebo.
    Arm/Group Title Double-blind/Open Label Rituximab Double-blind Placebo/Open Label Rituximab
    Arm/Group Description 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. 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.
    Measure Participants 33 18
    Any Infection
    18
    54.5%
    11
    61.1%
    Any Grade 3/4 Infection
    3
    9.1%
    0
    0%
    6. Primary Outcome
    Title Maximum Duration of Infections Through Week 24
    Description 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.
    Time Frame Week 24

    Outcome Measure Data

    Analysis Population Description
    Participants in the Safety Population with at least 1 infection. The Safety Population consisted of all participants who received any part of an infusion of rituximab or placebo.
    Arm/Group Title Double-blind/Open Label Rituximab Double-blind Placebo/Open Label Rituximab
    Arm/Group Description 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. 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.
    Measure Participants 18 11
    Mean (Standard Deviation) [days]
    12.6
    (9.6)
    14.5
    (5.2)
    7. Primary Outcome
    Title Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) Through Week 24
    Description 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.
    Time Frame Through Week 24

    Outcome Measure Data

    Analysis Population Description
    The Safety Population consisted of all participants who received any part of an infusion of rituximab or placebo.
    Arm/Group Title Double-blind/Open Label Rituximab Double-blind Placebo/Open Label Rituximab
    Arm/Group Description 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. 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.
    Measure Participants 33 18
    Any AE
    31
    93.9%
    15
    83.3%
    Any SAE
    2
    6.1%
    0
    0%
    8. Primary Outcome
    Title Number of Participants With Clinically Significant Immunological and Laboratory Assessment Findings
    Description 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).
    Time Frame Through Week 24

    Outcome Measure Data

    Analysis Population Description
    The Safety Population consisted of all participants who received any part of an infusion of rituximab or placebo.
    Arm/Group Title Double-blind/Open Label Rituximab Double-blind Placebo/Open Label Rituximab
    Arm/Group Description 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. 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.
    Measure Participants 33 18
    Number [participants]
    0
    0%
    0
    0%

    Adverse Events

    Time Frame For Double-Blind Rituximab and Double-Blind Placebo reporting groups, nonserious AE data and SAE data are presented through the Week 24 treatment phase (primary endpoint completion). See Additional Description (below) for Cumulative Rituximab time frame.
    Adverse Event Reporting Description For Cumulative Rituximab reporting group, nonserious AEs were captured only through Week 56. Serious adverse events (SAEs) were captured during treatment and post-treatment periods, through the safety follow-up (SFU) period (48 weeks) and the extended safety follow-up (ESFU; 1760 days).
    Arm/Group Title Double-Blind Rituximab Double-Blind Placebo Cumulative Rituximab
    Arm/Group Description The rituximab treatment group received rituximab 500 mg by intravenous infusion (IV) on Day 1 and Day 15. Prior to rituximab infusion, participants were premedicated with methylprednisolone 100 mg IV. Participants were also to receive a stable dose of folate ≥5 mg weekly. The placebo treatment group received saline solution IV on Day 1 and Day 15. Prior to each infusion of placebo, participants were premedicated with methylprednisolone 100 mg IV. Participants were also to receive a stable dose of folate ≥5 mg weekly. The cumulative rituximab treatment group included all participants who received rituximab at any time during the study, including participants who received rituximab in the double-blind period and did not participate in the OL period, those who received placebo in the double-blind period and rituximab in the OL, and those who received rituximab in the double-blind and OL periods. Prior to rituximab infusion, participants were premedicated with methylprednisolone 100 mg IV. Participants were also to receive a stable dose of folate ≥5 mg weekly.
    All Cause Mortality
    Double-Blind Rituximab Double-Blind Placebo Cumulative Rituximab
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Double-Blind Rituximab Double-Blind Placebo Cumulative Rituximab
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 2/33 (6.1%) 0/18 (0%) 8/49 (16.3%)
    Blood and lymphatic system disorders
    Neutropenia 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Cardiac disorders
    Coronary Artery Occlusion 1/33 (3%) 0/18 (0%) 1/49 (2%)
    Gastrointestinal disorders
    Impaired Gastric Emptying 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Nausea 0/33 (0%) 0/18 (0%) 1/49 (2%)
    General disorders
    Asthenia 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Infections and infestations
    Pneumonia 1/33 (3%) 0/18 (0%) 1/49 (2%)
    Arthritis Infective 0/33 (0%) 0/18 (0%) 4/49 (8.2%)
    Cellulitis 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Osteomyelitis 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Musculoskeletal and connective tissue disorders
    Systemic Lupus Erythematosus 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Nervous system disorders
    Dizziness 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Headache 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Respiratory, thoracic and mediastinal disorders
    Interstitial Lung Disease 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Other (Not Including Serious) Adverse Events
    Double-Blind Rituximab Double-Blind Placebo Cumulative Rituximab
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 31/33 (93.9%) 15/18 (83.3%) 48/49 (98%)
    Blood and lymphatic system disorders
    Neutropenia 1/33 (3%) 0/18 (0%) 1/49 (2%)
    Iron Deficiency Anaemia 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Cardiac disorders
    Tachycardia 1/33 (3%) 0/18 (0%) 1/49 (2%)
    Coronary Artery Atherosclerosis 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Congenital, familial and genetic disorders
    Dermoid Cyst 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Ear and labyrinth disorders
    Ear Discomfort 0/33 (0%) 1/18 (5.6%) 0/49 (0%)
    Ear Pruritus 1/33 (3%) 0/18 (0%) 1/49 (2%)
    Tinnitus 0/33 (0%) 1/18 (5.6%) 1/49 (2%)
    Endocrine disorders
    Hypothyroidism 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Eye disorders
    Eyelid Oedema 1/33 (3%) 0/18 (0%) 1/49 (2%)
    Conjunctivitis 0/33 (0%) 0/18 (0%) 3/49 (6.1%)
    Dry Eye 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Gastrointestinal disorders
    Diarrhea 3/33 (9.1%) 1/18 (5.6%) 5/49 (10.2%)
    Mouth ulceration 2/33 (6.1%) 0/18 (0%) 2/49 (4.1%)
    Nausea 5/33 (15.2%) 2/18 (11.1%) 7/49 (14.3%)
    Vomiting 3/33 (9.1%) 0/18 (0%) 5/49 (10.2%)
    Abdominal Adhesions 1/33 (3%) 0/18 (0%) 1/49 (2%)
    Abdominal Pain 0/33 (0%) 1/18 (5.6%) 1/49 (2%)
    Abdominal Pain Upper 1/33 (3%) 0/18 (0%) 2/49 (4.1%)
    Diverticulum 1/33 (3%) 0/18 (0%) 1/49 (2%)
    Dry Mouth 0/33 (0%) 1/18 (5.6%) 1/49 (2%)
    Dyspepsia 0/33 (0%) 1/18 (5.6%) 2/49 (4.1%)
    Dysphagia 1/33 (3%) 0/18 (0%) 1/49 (2%)
    Gastrooesophageal Reflux Disease 1/33 (3%) 0/18 (0%) 3/49 (6.1%)
    Rectocele 1/33 (3%) 0/18 (0%) 1/49 (2%)
    Tooth Fracture 0/33 (0%) 1/18 (5.6%) 1/49 (2%)
    Colonic Polyp 0/33 (0%) 0/18 (0%) 2/49 (4.1%)
    Colitis 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Constipation 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Gastric Disorder 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Gastric Ulcer 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Gastroduodenitis 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Impaired Gastric Emptying 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Irritable Bowel Syndrome 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Oesophageal Polyp 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Reflux Oesophagitis 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Salivary Gland Calculus 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Swollen Tongue 0/33 (0%) 0/18 (0%) 1/49 (2%)
    General disorders
    Edema peripheral 3/33 (9.1%) 2/18 (11.1%) 5/49 (10.2%)
    Asthenia 2/33 (6.1%) 1/18 (5.6%) 2/49 (4.1%)
    Infusion-related reaction 2/33 (6.1%) 1/18 (5.6%) 5/49 (10.2%)
    Fatigue 4/33 (12.1%) 0/18 (0%) 5/49 (10.2%)
    Pyrexia 1/33 (3%) 1/18 (5.6%) 1/49 (2%)
    Chest Pain 1/33 (3%) 0/18 (0%) 1/49 (2%)
    Oedema 0/33 (0%) 1/18 (5.6%) 0/49 (0%)
    Venipuncture Site Inflammation 1/33 (3%) 0/18 (0%) 1/49 (2%)
    Localised Oedema 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Non-Cardiac Chest Pain 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Immune system disorders
    Seasonal Allergy 1/33 (3%) 0/18 (0%) 2/49 (4.1%)
    Infections and infestations
    Upper respiratory tract infection 6/33 (18.2%) 5/18 (27.8%) 15/49 (30.6%)
    Nasopharyngitis 2/33 (6.1%) 1/18 (5.6%) 4/49 (8.2%)
    Vaginal mycosis 2/33 (6.1%) 1/18 (5.6%) 4/49 (8.2%)
    Urinary tract infection 2/33 (6.1%) 1/18 (5.6%) 6/49 (12.2%)
    Sinusitis 3/33 (9.1%) 3/18 (16.7%) 14/49 (28.6%)
    Bronchitis 1/33 (3%) 1/18 (5.6%) 5/49 (10.2%)
    Gastroenteritis 1/33 (3%) 1/18 (5.6%) 2/49 (4.1%)
    Herpes Simplex 0/33 (0%) 1/18 (5.6%) 0/49 (0%)
    Infected Insect Bite 0/33 (0%) 1/18 (5.6%) 1/49 (2%)
    Influenza 1/33 (3%) 0/18 (0%) 2/49 (4.1%)
    Postoperative Infection 1/33 (3%) 0/18 (0%) 1/49 (2%)
    Tooth Abscess 1/33 (3%) 0/18 (0%) 3/49 (6.1%)
    Tooth Infection 1/33 (3%) 0/18 (0%) 1/49 (2%)
    Cellulitis 0/33 (0%) 0/18 (0%) 3/49 (6.1%)
    Gastroenteritis Viral 0/33 (0%) 0/18 (0%) 3/49 (6.1%)
    Acute Sinusitis 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Arthritis Infective 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Bronchitis Acute 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Dental Caries 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Dermatophytosis 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Diverticulitis 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Dry Socket 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Ear Infection 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Eye Infection 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Laryngitis 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Oral Candidiasis 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Oral Fungal Infection 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Osteomyelitis 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Otitis Media 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Parotitis 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Pharyngitis 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Pneumonia 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Respiratory Tract Infection 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Tinea Infection 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Tinea Pedis 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Viral Infection 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Viral Upper Respiratory Tract Infection 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Injury, poisoning and procedural complications
    Arthropod Bite 1/33 (3%) 0/18 (0%) 2/49 (4.1%)
    Contusion 1/33 (3%) 0/18 (0%) 2/49 (4.1%)
    Excoriation 1/33 (3%) 0/18 (0%) 3/49 (6.1%)
    Foot Fracture 0/33 (0%) 1/18 (5.6%) 1/49 (2%)
    Skin Injury 1/33 (3%) 0/18 (0%) 1/49 (2%)
    Stress Fracture 0/33 (0%) 1/18 (5.6%) 0/49 (0%)
    Thermal Burn 1/33 (3%) 0/18 (0%) 1/49 (2%)
    Incision Site Complication 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Joint Sprain 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Ligament Injury 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Muscle Strain 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Tendon Rupture 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Wrist Fracture 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Investigations
    Blood glucose increased 2/33 (6.1%) 0/18 (0%) 2/49 (4.1%)
    Bacteria Sputum Identified 0/33 (0%) 1/18 (5.6%) 0/49 (0%)
    Blood Calcium Increased 1/33 (3%) 0/18 (0%) 1/49 (2%)
    Blood Phosphorus Decreased 1/33 (3%) 0/18 (0%) 1/49 (2%)
    Heart Rate Increased 0/33 (0%) 1/18 (5.6%) 0/49 (0%)
    Lymphocyte Count Increased 1/33 (3%) 0/18 (0%) 1/49 (2%)
    Monocyte Count Increased 1/33 (3%) 0/18 (0%) 1/49 (2%)
    Aspartate Aminotransferase Increased 0/33 (0%) 0/18 (0%) 2/49 (4.1%)
    Alanine Aminotransferase Increased 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Blood Pressure Increased 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Hepatic Enzyme Increased 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Mean Cell Volume Increased 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Platelet Count Increased 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Weight Increased 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Metabolism and nutrition disorders
    Hyperglycaemia 1/33 (3%) 1/18 (5.6%) 3/49 (6.1%)
    Hyperlipidaemia 1/33 (3%) 0/18 (0%) 1/49 (2%)
    Hypokalaemia 0/33 (0%) 1/18 (5.6%) 0/49 (0%)
    Glucose Tolerance Impaired 0/33 (0%) 0/18 (0%) 2/49 (4.1%)
    Diabetes Mellitus 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Diabetes Mellitus Non-Insulin-Dependent 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Hypercholesterolaemia 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Musculoskeletal and connective tissue disorders
    Back pain 2/33 (6.1%) 1/18 (5.6%) 3/49 (6.1%)
    Bursitis 1/33 (3%) 1/18 (5.6%) 5/49 (10.2%)
    Rheumatoid arthritis 3/33 (9.1%) 3/18 (16.7%) 14/49 (28.6%)
    Neck pain 2/33 (6.1%) 1/18 (5.6%) 3/49 (6.1%)
    Arthralgia 3/33 (9.1%) 2/18 (11.1%) 6/49 (12.2%)
    Muscle Spasms 1/33 (3%) 2/18 (11.1%) 4/49 (8.2%)
    Joint Swelling 1/33 (3%) 1/18 (5.6%) 2/49 (4.1%)
    Fibromyalgia 0/33 (0%) 1/18 (5.6%) 0/49 (0%)
    Muscular Weakness 1/33 (3%) 0/18 (0%) 1/49 (2%)
    Plantar Fasciitis 1/33 (3%) 0/18 (0%) 2/49 (4.1%)
    Rotator Cuff Syndrome 1/33 (3%) 0/18 (0%) 1/49 (2%)
    Bone Pain 0/33 (0%) 0/18 (0%) 2/49 (4.1%)
    Osteoarthritis 0/33 (0%) 0/18 (0%) 2/49 (4.1%)
    Rheumatoid Nodule 0/33 (0%) 0/18 (0%) 2/49 (4.1%)
    Ganglion 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Intervertebral Disc Protrusion 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Musculoskeletal Discomfort 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Myalgia 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Pain In Extremity 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Shoulder Pain 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Spinal Osteoarthritis 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Systemic Lupus Erythematosus 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Tendonitis 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign Neoplasm Of Skin 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Haemangioma 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Nervous system disorders
    Headache 3/33 (9.1%) 2/18 (11.1%) 8/49 (16.3%)
    Dizziness 3/33 (9.1%) 1/18 (5.6%) 4/49 (8.2%)
    Dysgeusia 1/33 (3%) 0/18 (0%) 1/49 (2%)
    Lethargy 1/33 (3%) 0/18 (0%) 1/49 (2%)
    Paraesthesia 1/33 (3%) 0/18 (0%) 1/49 (2%)
    Restless Legs Syndrome 1/33 (3%) 0/18 (0%) 1/49 (2%)
    Migraine 0/33 (0%) 0/18 (0%) 3/49 (6.1%)
    Hypoaesthesia 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Lumbar Radiculopathy 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Neuropathy 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Somnolence 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Tremor 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Psychiatric disorders
    Insomnia 3/33 (9.1%) 0/18 (0%) 4/49 (8.2%)
    Anxiety 3/33 (9.1%) 0/18 (0%) 4/49 (8.2%)
    Irritability 1/33 (3%) 0/18 (0%) 1/49 (2%)
    Stress 0/33 (0%) 1/18 (5.6%) 1/49 (2%)
    Depression 0/33 (0%) 0/18 (0%) 2/49 (4.1%)
    Renal and urinary disorders
    Cystocele 1/33 (3%) 0/18 (0%) 2/49 (4.1%)
    Proteinuria 1/33 (3%) 0/18 (0%) 1/49 (2%)
    Haematuria 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Reproductive system and breast disorders
    Genital Pruritus Female 0/33 (0%) 1/18 (5.6%) 0/49 (0%)
    Menstruation Irregular 1/33 (3%) 0/18 (0%) 1/49 (2%)
    Ovarian Cyst 1/33 (3%) 0/18 (0%) 1/49 (2%)
    Menometrorrhagia 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Uterine Polyp 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Respiratory, thoracic and mediastinal disorders
    Sinus Congestion 1/33 (3%) 1/18 (5.6%) 4/49 (8.2%)
    Cough 0/33 (0%) 1/18 (5.6%) 2/49 (4.1%)
    Dyspnoea 1/33 (3%) 0/18 (0%) 1/49 (2%)
    Pharyngolaryngeal Pain 0/33 (0%) 1/18 (5.6%) 2/49 (4.1%)
    Postnasal Drip 1/33 (3%) 0/18 (0%) 1/49 (2%)
    Rhinitis Allergic 0/33 (0%) 1/18 (5.6%) 1/49 (2%)
    Emphysema 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Respiratory Tract Congestion 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Skin and subcutaneous tissue disorders
    Pruritus 4/33 (12.1%) 0/18 (0%) 4/49 (8.2%)
    Urticaria 2/33 (6.1%) 0/18 (0%) 3/49 (6.1%)
    Rash erythematous 2/33 (6.1%) 1/18 (5.6%) 4/49 (8.2%)
    Alopecia 1/33 (3%) 1/18 (5.6%) 2/49 (4.1%)
    Dermatitis Contact 1/33 (3%) 0/18 (0%) 3/49 (6.1%)
    Rash 0/33 (0%) 1/18 (5.6%) 0/49 (0%)
    Rash Pruritic 1/33 (3%) 0/18 (0%) 3/49 (6.1%)
    Skin Lesion 1/33 (3%) 0/18 (0%) 1/49 (2%)
    Rash Macular 0/33 (0%) 0/18 (0%) 2/49 (4.1%)
    Rosacea 0/33 (0%) 0/18 (0%) 2/49 (4.1%)
    Blister 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Ecchymosis 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Eczema 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Erythema 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Heat Rash 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Idiopathic Urticaria 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Pruritus Generalised 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Rash Vesicular 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Sebaceous Hyperplasia 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Skin Ulcer 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Telangiectasia 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Vascular disorders
    Flushing 2/33 (6.1%) 0/18 (0%) 2/49 (4.1%)
    Hypertension 1/33 (3%) 1/18 (5.6%) 1/49 (2%)
    Hypotension 1/33 (3%) 0/18 (0%) 1/49 (2%)
    Raynaud's Phenomenon 0/33 (0%) 1/18 (5.6%) 0/49 (0%)
    Lymphoedema 0/33 (0%) 0/18 (0%) 1/49 (2%)
    Phlebitis 0/33 (0%) 0/18 (0%) 1/49 (2%)

    Limitations/Caveats

    Sponsor made a business decision to terminate study on 28 July 2011, after completion of the primary endpoint and during the long-term extension phase. One participant was still in extended safety follow-up and was referred for appropriate care.

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    Our agreement is subject to confidentiality but generally the PI can publish, for noncommercial purposes only, results and methods of the trial, but no other Sponsor Confidential Information. PI must give Sponsor no less than 60 days to review any manuscript for a proposed publication and must delay publication for up to an additional 90 days thereafter if Sponsor needs to file any patent application to protect any of Sponsor's intellectual property contained in the proposed publication.

    Results Point of Contact

    Name/Title Biogen Idec Study Medical Director
    Organization Biogen Idec
    Phone
    Email clinicaltrials@biogenidec.com
    Responsible Party:
    Biogen
    ClinicalTrials.gov Identifier:
    NCT00298272
    Other Study ID Numbers:
    • 102-RA-201
    First Posted:
    Mar 2, 2006
    Last Update Posted:
    Sep 28, 2015
    Last Verified:
    Aug 1, 2015