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

NCT00298272 | Terminated Phase 2 Results

• 1 other identifier: 102-RA-201
• Study Type: interventional
• Target: 54
• Locations: 1 country
• Sites: 18

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.

Conditions

Rheumatoid Arthritis

Outcome Measures

Primary Outcomes (5)

• 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.

  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.

  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.

  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.

  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).

  Through Week 24

Secondary Outcomes (3)

• Proportion of Participants Achieving an American College of Rheumatology 20 (ACR20) Response at Week 24

  Week 24

• Proportion of Participants Achieving an American College of Rheumatology 50 (ACR50) Response at Week 24

  Week 24

• Proportion of Participants Achieving an American College of Rheumatology 70 (ACR70) Response at Week 24

  Week 24

Study Arms (2)

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.

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.

Drug: Placebo; Drug: Methotrexate; Drug: Etanercept; Drug: Adalimumab; Drug: Methylprednisolone; Dietary Supplement: Folate

Interventions

IDEC-C2B8 (rituximab) BIOLOGICAL

Participants will receive 500 mg rituximab on Day 1 and Day 15

Also known as: Rituxan

Double-blind/Open Label Rituximab

Placebo DRUG

Participants will receive placebo on Day 1 and Day 15

Double-blind Placebo/Open Label Rituximab

Methotrexate DRUG

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.

Double-blind Placebo/Open Label Rituximab; Double-blind/Open Label Rituximab

Etanercept DRUG

Participants must have been treated with etanercept at 50 mg per week (25 mg twice per week or 50 mg once per week).

Also known as: Enbrel

Double-blind Placebo/Open Label Rituximab; Double-blind/Open Label Rituximab

Adalimumab DRUG

Participants must have been treated with adalimumab at 40 mg every other week for at least 12 weeks immediately prior to Day 1.

Also known as: Humira

Double-blind Placebo/Open Label Rituximab; Double-blind/Open Label Rituximab

Methylprednisolone DRUG

Methylprednisolone 100 mg IV was administered by slow infusion to be completed at least 30 minutes prior to each infusion of rituximab or placebo.

Double-blind Placebo/Open Label Rituximab; Double-blind/Open Label Rituximab

Folate DIETARY_SUPPLEMENT

All subjects also received a stable dose of folate (≥5 mg per week).

Double-blind Placebo/Open Label Rituximab; Double-blind/Open Label Rituximab

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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.
• 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).

Sponsors & Collaborators

• Biogen: lead
• Hoffmann-La Roche: collaborator
• Genentech, Inc.: collaborator

Study Sites (18)

Research Site

Huntsville, Alabama, 35801, United States

Location

Research Site

Paradise Valley, Arizona, 85253, United States

Location

Research Site

Palm Desert, California, 92260, United States

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Research Site

Jupiter, Florida, 33458, United States

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Sarasota, Florida, 34239, United States

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Boise, Idaho, 83702, United States

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Kalamazoo, Michigan, 49048, United States

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Research Site

St Louis, Missouri, 63141, United States

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Research site

Chardon, Ohio, 44024, United States

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Mayfield Village, Ohio, 44143, United States

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Oklahoma City, Oklahoma, 73103, United States

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Tulsa, Oklahoma, 74135, United States

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Research Site

Duncansville, Pennsylvania, 16635, United States

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Dallas, Texas, 75231, United States

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Research Site

Houston, Texas, 77074, United States

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San Antonio, Texas, 78217, United States

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Salt Lake City, Utah, 84132, United States

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Research Site

Burlington, Vermont, 05401, United States

Location

Related Publications (1)

• 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.

  PMID: 21360491 RESULT

MeSH Terms

Conditions

Arthritis, Rheumatoid

Interventions

Rituximab; Methotrexate; Etanercept; Adalimumab; Methylprednisolone; Folic Acid

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Immunoglobulin Fc Fragments; Immunoglobulin Fragments; Peptide Fragments; Peptides; Immunoglobulin Constant Regions; Receptors, Tumor Necrosis Factor; Receptors, Cytokine; Receptors, Immunologic; Receptors, Cell Surface; Membrane Proteins; Antibodies, Monoclonal, Humanized; Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Limitations and 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.

Results Point of Contact

• Title: Biogen Idec Study Medical Director
• Organization: Biogen Idec

clinicaltrials@biogenidec.com

Study Officials

• Medical Director

  Biogen

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 1, 2006
• First Posted: March 2, 2006
• Study Start: May 1, 2006
• Primary Completion: April 1, 2009
• Study Completion: July 1, 2011
• Last Updated: September 28, 2015
• Results First Posted: November 17, 2010

Record last verified: 2015-08

Locations

US (18)