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A Study to Evaluate the Effects of Rituximab on Immune Responses in Subjects With Active Rheumatoid Arthritis Receiving Background Methotrexate (SIERRA)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Genentech, Inc.
ClinicalTrials.gov Identifier:
NCT00282308
First received: January 24, 2006
Last updated: August 19, 2013
Last verified: August 2013
  Purpose

This was a Phase II, randomized, open-label, multicenter study designed to evaluate the immune response to vaccines after administration of 1000 mg of rituximab in subjects with active rheumatoid arthritis (RA) who were receiving background methotrexate (MTX).


Condition Intervention Phase
Rheumatoid Arthritis
Drug: Rituximab
Drug: Methotrexate
Drug: Methylprednisone
Biological: C. albicans
Biological: Tetanus toxoid adsorbed booster vaccine
Biological: 23-valent pneumococcal polysaccharide vaccine
Biological: Keyhole limpet hemocyanin
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II, Randomized, Parallel-group, Open-label, Multicenter Study to Evaluate the Effects of Rituximab on Immune Responses in Subjects With Active Rheumatoid Arthritis Receiving Background Methotrexate

Resource links provided by NLM:


Further study details as provided by Genentech, Inc.:

Primary Outcome Measures:
  • Percentage of Patients With a Positive Immune Response to Tetanus Toxoid Adsorbed Booster Vaccine [ Time Frame: Week 24 to Week 28 for Group A and Day 1 to Week 4 for Group B ] [ Designated as safety issue: No ]
    The immune response to tetanus toxoid adsorbed booster vaccine was measured in serum samples immediately prior to and 4 weeks after vaccine administration. The tetanus antibody test was an ELISA that used tetanus toxoid as a capturing reagent and alkaline phosphatase-conjugated anti-human IgG (γ) for detection. For patients with pre-vaccination tetanus antibody titers < 0.1 IU/mL, a positive immune response was defined as an antibody titer ≥ 0.2 IU/mL. For patients with pre-vaccination tetanus antibody titers ≥ 0.1 IU/mL, a positive immune response to the booster immunization was defined as a 4-fold increase in antibody titer.


Secondary Outcome Measures:
  • Percentage of Patients With a 2-fold Increase in Tetanus Antibody Titers or With Tetanus Antibody Titers ≥ 0.2 IU/mL in Response to Tetanus Toxoid Adsorbed Booster Vaccine [ Time Frame: Week 24 to Week 28 for Group A and Day 1 to Week 4 for Group B ] [ Designated as safety issue: No ]
    The immune response to tetanus toxoid adsorbed booster vaccine was measured in serum samples immediately prior to and 4 weeks after vaccine administration. The tetanus antibody test was an ELISA that used tetanus toxoid as a capturing reagent and alkaline phosphatase-conjugated anti-human IgG (γ) for detection.

  • Percentage of Patients With a Positive Immune Response to Each of the 12 Anti-pneumococcal Antibody Serotypes in Response to the 23-valent Pneumococcal Polysaccharide Vaccine [ Time Frame: Week 28 to Week 32 for Group A and Week 4 to Week 8 for Group B ] [ Designated as safety issue: No ]
    The immune response to each of the 12 anti-pneumococcal antibody serotypes was measured in serum samples immediately prior to and 4 weeks after vaccine administration. The pneumococcal antibody assay was a fluoroimmunoassay that used a Luminex Multiplex platform. Purified capsular polysaccharides isolated from 12 serotypes of S. pneumonia were covalently attached to microbeads and used as a capturing reagent. Phycoerythrin conjugated anti-human IgG was used for detection. A positive immune response against a serotype was defined as a 2-fold increase or an increase of > 1 μg/mL from pre-vaccination levels.

  • Percentage of Patients With a Positive Immune Response to at Least 50% (≥ 6 of 12) of the 12 Anti-pneumococcal Antibody Serotypes in Response to the 23-valent Pneumococcal Polysaccharide Vaccine [ Time Frame: Week 28 to Week 32 for Group A and Week 4 to Week 8 for Group B ] [ Designated as safety issue: No ]
    The immune response to each of the 12 anti-pneumococcal antibody serotypes was measured in serum samples immediately prior to and 4 weeks after vaccine administration. The pneumococcal antibody assay was a fluoroimmunoassay that used a Luminex Multiplex platform. Purified capsular polysaccharides isolated from 12 serotypes of S. pneumonia were covalently attached to microbeads and used as a capturing reagent. Phycoerythrin conjugated anti-human IgG was used for detection. A positive immune response against a serotype was defined as a 2-fold increase or an increase of > 1 μg/mL from pre-vaccination levels.

  • Percentage of Patients With a Positive Immune Response to at Least k (for k = 1, 2, 3, 4, 5) of the 12 Anti-pneumococcal Antibody Serotypes in Response to the 23-valent Pneumococcal Polysaccharide Vaccine [ Time Frame: Week 28 to Week 32 for Group A and Week 4 to Week 8 for Group B ] [ Designated as safety issue: No ]
    The immune response to each of the 12 anti-pneumococcal antibody serotypes was measured in serum samples immediately prior to and 4 weeks after vaccine administration. The pneumococcal antibody assay was a fluoroimmunoassay that used a Luminex Multiplex platform. Purified capsular polysaccharides isolated from 12 serotypes of S. pneumonia were covalently attached to microbeads and used as a capturing reagent. Phycoerythrin conjugated anti-human IgG was used for detection. A positive immune response against a serotype was defined as a 2-fold increase or an increase of > 1 μg/mL from pre-vaccination levels.

  • Serum Level of Anti-tetanus Antibody Measured Immediately Prior to and 4 Weeks After Administration of a Tetanus Toxoid Adsorbed Booster Vaccine [ Time Frame: Week 24 to Week 28 for Group A and Day 1 to Week 4 for Group B ] [ Designated as safety issue: No ]
    Anti-tetanus antibody was measured in serum samples immediately prior to and 4 weeks after administration of a tetanus toxoid adsorbed booster vaccine. The tetanus antibody test was an ELISA that used tetanus toxoid as a capturing reagent and alkaline phosphatase-conjugated anti-human IgG (γ) for detection.

  • Serum Level of Anti-pneumococcal Antibody Measured Immediately Prior to and 4 Weeks After Administration of a 23-valent Pneumococcal Polysaccharide Vaccine [ Time Frame: Week 28 to Week 32 for Group A and Week 4 to Week 8 for Group B ] [ Designated as safety issue: No ]
    Anti-pneumococcal antibody was measured immediately prior to and 4 weeks after administration of a 23-valent pneumococcal polysaccharide vaccine. The pneumococcal antibody assay was a fluoroimmunoassay that used a Luminex Multiplex platform. Purified capsular polysaccharides isolated from 12 serotypes of S. pneumonia were covalently attached to microbeads and used as a capturing reagent. Phycoerythrin conjugated anti-human IgG was used for detection.

  • Serum Level of Anti-keyhole Limpet Hemocyanin Antibody Measured Immediately Prior to and 4 Weeks After the First Administration of Keyhole Limpet Hemocyanin [ Time Frame: Week 32 to Week 36 for Group A and Week 8 to Week 12 for Group B ] [ Designated as safety issue: No ]
    Anti-keyhole limpet hemocyanin antibody was measured immediately prior to and 4 weeks after the first administration of keyhole limpet hemocyanin. The keyhole limpet hemocyanin antibody ELISA assay used keyhole limpet hemocyanin as the plate coat and anti-human IgG-horseradish peroxidase for detection.

  • Percentage of Patients Who Maintained a Positive Response to the C. Albicans Skin Test From Day 1 to Week 24 for Group A or From Day 1 to Week 12 for Group B [ Time Frame: Day 1 to Week 24 for Group A and Day 1 to Week 12 for Group B ] [ Designated as safety issue: No ]
    Patients received an intradermal injection of C. albicans on the volar surface of the forearm on Day 1 and Week 24 for Group A or on Day 1 and Week 12 for Group B. Forty-eight to 72 hours after injection, patients were evaluated for a delayed-type hypersensitivity response by measuring the diameter of induration (palpable raised, hardened area of the forearm skin). A positive response to the C. albicans skin test was defined as at least 5 mm in diameter of induration.

  • Percentage of Patients in Group A With an Improvement of at Least 20%, 50%, or 70% in American College of Rheumatology (ACR) Score (ACR20/50/70) From Baseline at Week 24 [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
    Improvement must be seen in tender and swollen joint counts (28 assessed joints) and in at least 3 of the following 5 parameters: Separate patient and physician assessments of patient disease activity in the previous 24 hours on a visual analog scale (VAS, the extreme left end of the line "no disease activity" [symptom-free and no arthritis symptoms] and the extreme right end "maximum disease activity"; patient assessment of pain in previous the 24 hours on a VAS (extreme left end of the line "no pain" and the extreme right end "unbearable pain"); Health Assessment Questionnaire-Disability Index (20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities, 0=without difficulty to 3=unable to do); and C reactive protein or, if missing, erythrocyte sedimentation rate.


Enrollment: 103
Study Start Date: January 2006
Study Completion Date: February 2009
Primary Completion Date: January 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Rituximab + methotrexate (Group A)
Patients received 2 intravenous infusions of rituximab 1000 mg, 14 days apart + methotrexate 10-25 mg/wk orally or subcutaneously during the Treatment Period.
Drug: Rituximab
Rituximab was supplied in single-use vials.
Other Names:
  • Rituxan
  • MabThera
Drug: Methotrexate Drug: Methylprednisone
Patients received methylprednisolone 100 mg intravenously before each infusion of rituximab.
Biological: C. albicans
Patients received an intradermal injection of C. albicans (0.1 mL) on the volar surface of the forearm.
Biological: Tetanus toxoid adsorbed booster vaccine
Patients received an intramuscular injection of the tetanus toxoid adsorbed booster vaccine (1 mg in 0.5 mL) in the deltoid muscle.
Biological: 23-valent pneumococcal polysaccharide vaccine
Patients received an intramuscular injection of the 23-valent pneumococcal polysaccharide vaccine (0.5 mL) in the deltoid muscle.
Biological: Keyhole limpet hemocyanin
Patients received a subcutaneous injection of keyhole limpet hemocyanin (1 mg)
Active Comparator: Methotrexate (Group B)
Patients received methotrexate 10-25 mg/wk orally or subcutaneously during the Treatment Period.
Drug: Methotrexate Biological: C. albicans
Patients received an intradermal injection of C. albicans (0.1 mL) on the volar surface of the forearm.
Biological: Tetanus toxoid adsorbed booster vaccine
Patients received an intramuscular injection of the tetanus toxoid adsorbed booster vaccine (1 mg in 0.5 mL) in the deltoid muscle.
Biological: 23-valent pneumococcal polysaccharide vaccine
Patients received an intramuscular injection of the 23-valent pneumococcal polysaccharide vaccine (0.5 mL) in the deltoid muscle.
Biological: Keyhole limpet hemocyanin
Patients received a subcutaneous injection of keyhole limpet hemocyanin (1 mg)

  Show Detailed Description

  Eligibility

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

Inclusion Criteria:

  • Age 18-65 years.
  • Diagnosis of rheumatoid arthritis (RA) for at least 6 months.
  • Receiving treatment for RA on an outpatient basis.
  • Use of methotrexate (MTX) at a dose of 10-25 mg/wk (oral [PO] or subcutaneous [SC]) for at least 12 weeks prior to Day 1, with the dose stable during the last 4 weeks prior to Day 1 (first day of the treatment period).
  • If taking a background corticosteroid, use of the corticosteroid must be for at least 12 weeks prior to Day 1 at a stable dose during the last 4 weeks prior to Day 1.
  • If taking one non-steroidal anti-inflammatory drug (NSAID), use of a stable dose for at least 2 weeks prior to Day 1.

Exclusion Criteria:

  • Rheumatic autoimmune disease other than RA or significant systemic involvement secondary to RA; Sjogren's syndrome with RA is permitted.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00282308

Sponsors and Collaborators
Genentech, Inc.
Investigators
Study Director: Ariella Kelman, M.D. Genentech, Inc.
  More Information

No publications provided by Genentech, Inc.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Genentech, Inc.
ClinicalTrials.gov Identifier: NCT00282308     History of Changes
Other Study ID Numbers: U3374g
Study First Received: January 24, 2006
Results First Received: June 5, 2013
Last Updated: August 19, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Genentech, Inc.:
RA
Rituxan
SIERRA

Additional relevant MeSH terms:
Arthritis
Arthritis, Rheumatoid
Autoimmune Diseases
Connective Tissue Diseases
Immune System Diseases
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Keyhole-limpet hemocyanin
Methotrexate
Rituximab
Abortifacient Agents
Abortifacient Agents, Nonsteroidal
Adjuvants, Immunologic
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antirheumatic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors
Pharmacologic Actions
Physiological Effects of Drugs
Reproductive Control Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on November 20, 2014