A Study to Evaluate the Effects of Rituximab on Immune Responses in Subjects With Active Rheumatoid Arthritis Receiving Background Methotrexate (SIERRA)
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| ClinicalTrials.gov Identifier: NCT00282308 |
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Recruitment Status :
Completed
First Posted : January 26, 2006
Results First Posted : October 21, 2013
Last Update Posted : August 10, 2017
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Sponsor:
Genentech, Inc.
Information provided by (Responsible Party):
Genentech, Inc.
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Brief Summary:
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 or disease | Intervention/treatment | 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 |
Show Detailed Description
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 103 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (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 |
| Actual Study Start Date : | January 23, 2006 |
| Actual Primary Completion Date : | January 31, 2008 |
| Actual Study Completion Date : | May 28, 2012 |
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Genetics Home Reference related topics:
Rheumatoid arthritis
| Arm | Intervention/treatment |
|---|---|
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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.
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Drug: Rituximab
Rituximab was supplied in single-use vials.
Other Names:
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) |
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Active Comparator: Methotrexate (Group B)
Patients received methotrexate 10-25 mg/wk orally or subcutaneously during the Treatment Period.
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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) |
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 ]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 ]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 ]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 ]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 ]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 ]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 ]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 ]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 ]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 ]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.
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| Ages Eligible for Study: | 18 Years to 65 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| 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.
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00282308
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Sponsors and Collaborators
Genentech, Inc.
Investigators
| Study Director: | Ariella Kelman, M.D. | Genentech, Inc. |
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 |
| First Posted: | January 26, 2006 Key Record Dates |
| Results First Posted: | October 21, 2013 |
| Last Update Posted: | August 10, 2017 |
| Last Verified: | July 2017 |
Keywords provided by Genentech, Inc.:
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RA Rituxan SIERRA |
Additional relevant MeSH terms:
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Arthritis Arthritis, Rheumatoid Joint Diseases Musculoskeletal Diseases Rheumatic Diseases Connective Tissue Diseases Autoimmune Diseases Immune System Diseases Rituximab Methotrexate Vaccines Heptavalent Pneumococcal Conjugate Vaccine Keyhole-limpet hemocyanin Immunologic Factors Physiological Effects of Drugs |
Antineoplastic Agents, Immunological Antineoplastic Agents Antirheumatic Agents Abortifacient Agents, Nonsteroidal Abortifacient Agents Reproductive Control Agents Antimetabolites, Antineoplastic Antimetabolites Molecular Mechanisms of Pharmacological Action Dermatologic Agents Enzyme Inhibitors Folic Acid Antagonists Immunosuppressive Agents Nucleic Acid Synthesis Inhibitors Adjuvants, Immunologic |