Rheumatoid ArthritisPhase 2NCT00298272
Safety and Tolerability of Rituxan With Methotrexate and Etanercept or Methotrexate and Adalimumab in Patients With Active Rheumatoid Arthritis
A Phase 2 study testing IDEC-C2B8 (rituximab), Methotrexate and Etanercept in people with Rheumatoid Arthritis, run by Biogen at 18 sites in United States.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Rheumatoid Arthritis
- What is being tested?
- IDEC-C2B8 (rituximab), Methotrexate and Etanercept
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 54 participants
- Where
- 18 sitesUnited States
- Study dates
- May 2006to Jul 2011
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Must give written informed consent. If required by local law, candidates must also authorize the release and use of protected health information (PHI).
- 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).
- Must have at least 5 tender and 5 swollen joints at Screening and Day 1.
- 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.
- 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.
- Must be willing to receive oral folate.
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- 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.
- Any concomitant non-steroidal antiinflammatory drugs (NSAIDs) must be stable for at least 2 weeks prior to Day 1.
- 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.
Who cannot join
- Exclusions Related to RA
- 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.
- Functional Class IV as defined by the ACR Classification of Functional Status in Rheumatoid Arthritis.
- 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).
- Diagnosis of juvenile idiopathic arthritis, also known as juvenile RA, and/or RA before age 16.
- Exclusions Related to General Health
Show all 42Show fewer
- 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.
- Lack of peripheral venous access.
- Pregnancy or breast feeding.
- Significant cardiac or pulmonary disease (including obstructive pulmonary disease).
- History of chronic heart failure (CHF), SLE-like syndrome, neuropathy or myelitis, optic neuritis, or pancytopenia while on etanercept or adalimumab.
- 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.
- Primary or secondary immunodeficiency (history of, or currently active), including known history of human immunodeficiency virus (HIV) infection.
- 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.
- History of positive purified protein derivative (PPD) not adequately treated.
- History of deep space/tissue infection (e.g., fasciitis, abscess, osteomyelitis) within 52 weeks of Day 1.
- 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).
- History of seizures.
- 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).
- 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).
- 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
- History of a severe allergic or anaphylactic reaction to a biologic agent or known hypersensitivity to any component of rituximab or to murine proteins.
- Previous treatment with an anti alpha 4 integrin agent or costimulation modulator.
- 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).
- 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).
- Treatment with another investigational drug within 4 weeks prior to Day 1 or 5 half lives of the investigational drug (whichever is the longer).
- Receipt of a live/attenuated vaccine within 4 weeks prior to Day 1.
- Intra-articular or parenteral glucocorticoids within 4 weeks prior to Day 1.
- Intolerance or contraindications to IV glucocorticoids.
- Exclusions Related to Laboratory Findings
- For women of childbearing potential, a positive serum pregnancy test at screening and/or a positive urine pregnancy test on Day 1.
- Positive hepatitis B surface antigen (HBsAg).
- Positive hepatitis B core antibody (HBcAb) associated with positive hepatitis B viral DNA (HBV DNA).
- Positive hepatitis C antibody.
- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 times upper limit of normal.
- Hemoglobin <8.0 g/dL.
- Levels of immunoglobulin G (IgG) and/or immunoglobulin M (IgM) below 5.0 and 0.4 mg/mL, respectively.
- Absolute neutrophil count (ANC) <1500/mL.
- Miscellaneous Exclusions
- Current enrollment in any other investigational or other drug study.
- Treatment with IV Gamma Globulin or the Prosorba® Column within 6 months of the Screening visit.
Trial locations and contacts
18 sites in 1 country.
18 sites in 1 country
United States18 sites
Research Site
Boise, Idaho, 83702
Research Site
Burlington, Vermont, 05401
Research site
Chardon, Ohio, 44024
Research Site
Dallas, Texas, 75231
Research Site
Duncansville, Pennsylvania, 16635
Research Site
Houston, Texas, 77074
Research Site
Huntsville, Alabama, 35801
Research Site
Jupiter, Florida, 33458
Research Site
Kalamazoo, Michigan, 49048
Research Site
Mayfield Village, Ohio, 44143
Research Site
Oklahoma City, Oklahoma, 73103
Research Site
Palm Desert, California, 92260
Research Site
Paradise Valley, Arizona, 85253
Research Site
Salt Lake City, Utah, 84132
Research Site
San Antonio, Texas, 78217
Research Site
Sarasota, Florida, 34239
Research Site
St Louis, Missouri, 63141
Research Site
Tulsa, Oklahoma, 74135
About this study
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
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.
Read the 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).
- Conditions
- Rheumatoid Arthritis
- Being tested
- IDEC-C2B8 (rituximab), Placebo, Methotrexate, Etanercept, Adalimumab
- Medical subject headings
- Arthritis, Rheumatoid
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
IDEC-C2B8 (rituximab)Biological
Also called Rituxan
Participants will receive 500 mg rituximab on Day 1 and Day 15
PlaceboDrug
Participants will receive placebo on Day 1 and Day 15
MethotrexateDrug
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.
EtanerceptDrug
Also called Enbrel
Participants must have been treated with etanercept at 50 mg per week (25 mg twice per week or 50 mg once per week).
AdalimumabDrug
Also called Humira
Participants must have been treated with adalimumab at 40 mg every other week for at least 12 weeks immediately prior to Day 1.
Methylprednisolone 100 mg IV was administered by slow infusion to be completed at least 30 minutes prior to each infusion of rituximab or placebo.
FolateDietary supplement
All subjects also received a stable dose of folate (≥5 mg per week).
| Study group | Role | What they receive |
|---|---|---|
| Double-blind/Open Label Rituximab | Experimental | 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. Receives: Biological: IDEC-C2B8 (rituximab); Drug: Methotrexate; Drug: Etanercept; Drug: Adalimumab; Drug: Methylprednisolone; Dietary Supplement: Folate |
| Double-blind Placebo/Open Label Rituximab | Other | 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. Receives: Drug: Placebo; Drug: Methotrexate; Drug: Etanercept; Drug: Adalimumab; Drug: Methylprednisolone; Dietary Supplement: Folate |
What is being measured
The primary outcome is the main question the study is designed to answer.
Proportion of Participants With at Least One Serious Infection 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.
Measured: Through Week 24
Number of Participants With Any Infections or Any Grade 3/4 Infections 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.
Measured: Through Week 24
Maximum Duration of Infections 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). For participants with multiple infections, only the infection with the longest duration was included in this analysis.
Measured: Week 24
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) 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.
Measured: Through Week 24
Number of Participants With Clinically Significant Immunological and Laboratory Assessment Findings
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).
Measured: Through Week 24
Secondary outcomes (3)
Proportion of Participants Achieving an American College of Rheumatology 20 (ACR20) Response at 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.
Measured: Week 24
Proportion of Participants Achieving an American College of Rheumatology 50 (ACR50) Response at 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.
Measured: Week 24
Proportion of Participants Achieving an American College of Rheumatology 70 (ACR70) Response at 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.
Measured: Week 24
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Mar 2006 (estimated)
- Study startMay 2006
- Primary completionApr 2009
- Study completionJul 2011
Why it stopped: Sponsor decided to end long term extension phase for business reasons unrelated to safety.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Rheumatoid ArthritisStudies of the same condition, open and under way.
- More trials run by BiogenThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 54 participants (actual)
Sponsor and investigators
- Lead sponsor
- Biogen
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Hoffmann-La Roche, Genentech, Inc.
- Responsible party
- Sponsor
- Investigators
- Medical Director, Study director, Biogen
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00298272
- Sponsor's protocol ID
- 102-RA-201
- Status last verified
- Aug 2015
- First submitted
- 1 Mar 2006
- Last updated
- 28 Sep 2015
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
Greenwald MW, Shergy WJ, Kaine JL, Sweetser MT, Gilder K, Linnik MD. Evaluation of the safety of rituximab in combination with a tumor necrosis factor inhibitor and methotrexate in patients with active rheumatoid arthritis: results from a randomized controlled trial. Arthritis Rheum. 2011 Mar;63(3):622-32. doi: 10.1002/art.30194.
PubMed 21360491
Study at a glance
From the registry record, last updated by the sponsor on 28 Sep 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT00298272
- Acronym / sponsor ID
- 102-RA-201
- Conditions
- Rheumatoid Arthritis
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Sponsor decided to end long term extension phase for business reasons unrelated to safety.
- Enrolment
- 54 participants (actual)
- Lead sponsor
- BiogenIndustry (pharma, biotech, devices)
- Collaborators
- Hoffmann-La Roche, Genentech, Inc.
- Study start
- May 2006
- Primary completion
- Apr 2009 (actual)
- Study completion
- Jul 2011 (actual)
- First posted
- 2 Mar 2006 (estimated)
- Results
- Posted 17 Nov 2010
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Double-blind/Open Label Rituximab | Experimental | Biological: IDEC-C2B8 (rituximab), Drug: Methotrexate, Drug: Etanercept, Drug: Adalimumab, Drug: Methylprednisolone, Dietary Supplement: FolateThe 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. |
| Double-blind Placebo/Open Label Rituximab | Other | Drug: Placebo, Drug: Methotrexate, Drug: Etanercept, Drug: Adalimumab, Drug: Methylprednisolone, Dietary Supplement: FolateThe 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. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- Must give written informed consent. If required by local law, candidates must also authorize the release and use of protected health information (PHI).
- 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).
- Must have at least 5 tender and 5 swollen joints at Screening and Day 1.
- 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.
- 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.
Key exclusion criteria (42 listed)
- Exclusions Related to RA
- 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.
- Functional Class IV as defined by the ACR Classification of Functional Status in Rheumatoid Arthritis.
- 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).
- Diagnosis of juvenile idiopathic arthritis, also known as juvenile RA, and/or RA before age 16.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| IDEC-C2B8 (rituximab)Also: RituxanParticipants will receive 500 mg rituximab on Day 1 and Day 15 | Biological | Double-blind/Open Label Rituximab |
| PlaceboParticipants will receive placebo on Day 1 and Day 15 | Drug | Double-blind Placebo/Open Label Rituximab |
| MethotrexateParticipants 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 | Double-blind Placebo/Open Label Rituximab, Double-blind/Open Label Rituximab |
| EtanerceptAlso: EnbrelParticipants must have been treated with etanercept at 50 mg per week (25 mg twice per week or 50 mg once per week). | Drug | Double-blind Placebo/Open Label Rituximab, Double-blind/Open Label Rituximab |
| AdalimumabAlso: HumiraParticipants must have been treated with adalimumab at 40 mg every other week for at least 12 weeks immediately prior to Day 1. | Drug | Double-blind Placebo/Open Label Rituximab, Double-blind/Open Label Rituximab |
| MethylprednisoloneMethylprednisolone 100 mg IV was administered by slow infusion to be completed at least 30 minutes prior to each infusion of rituximab or placebo. | Drug | Double-blind Placebo/Open Label Rituximab, Double-blind/Open Label Rituximab |
| FolateAll subjects also received a stable dose of folate (≥5 mg per week). | Dietary supplement | Double-blind Placebo/Open Label Rituximab, Double-blind/Open Label Rituximab |
Primary outcome
Proportion of Participants With at Least One Serious Infection Through Week 24
Time frame: 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.
Number of Participants With Any Infections or Any Grade 3/4 Infections Through Week 24
Time frame: 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.
Maximum Duration of Infections Through Week 24
Time frame: 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.
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) Through Week 24
Time frame: 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.
Number of Participants With Clinically Significant Immunological and Laboratory Assessment Findings
Time frame: 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).
3 secondary outcomes
Proportion of Participants Achieving an American College of Rheumatology 20 (ACR20) Response at Week 24
Time frame: Week 24
Proportion of Participants Achieving an American College of Rheumatology 50 (ACR50) Response at Week 24
Time frame: Week 24
Proportion of Participants Achieving an American College of Rheumatology 70 (ACR70) Response at Week 24
Time frame: Week 24
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Sep 2015.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 21360491Greenwald MW, Shergy WJ, Kaine JL, Sweetser MT, Gilder K, Linnik MD. Evaluation of the safety of rituximab in combination with a tumor necrosis factor inhibitor and methotrexate in patients with active rheumatoid arthritis: results from a randomized controlled trial. Arthritis Rheum. 2011 Mar;63(3):622-32. doi: 10.1002/art.30194.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Medical Director study director
Biogen
18 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing IDEC-C2B8 (rituximab), Methotrexate and Etanercept in people with Rheumatoid Arthritis, run by Biogen at 18 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 42 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 28 Sep 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 18 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 17 Nov 2010). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Proportion of Participants With at Least One Serious Infection Through Week 24 (time frame: Through Week 24). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00298272, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Sep 2015.