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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)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00282308
Recruitment Status : Completed
First Posted : January 26, 2006
Results First Posted : October 21, 2013
Last Update Posted : August 10, 2017
Sponsor:
Information provided by (Responsible Party):
Genentech, Inc.

Tracking Information
First Submitted Date  ICMJE January 24, 2006
First Posted Date  ICMJE January 26, 2006
Results First Submitted Date  ICMJE June 5, 2013
Results First Posted Date  ICMJE October 21, 2013
Last Update Posted Date August 10, 2017
Actual Study Start Date  ICMJE January 23, 2006
Actual Primary Completion Date January 31, 2008   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 19, 2013)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: January 24, 2006)
To characterize the humoral immune response to tetanus toxoid vaccine in subjects with active rheumatoid arthritis treated with rituximab in combination with methotrexate compared with that of subjects treated with methotrexate alone.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 19, 2013)
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 24, 2006)
To collect additional data on the safety and tolerability of rituximab in subjects who receive vaccines, and to collect open-label efficacy data for rituximab by measuring American College of Rheumatology 20/50/70 scores.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study to Evaluate the Effects of Rituximab on Immune Responses in Subjects With Active Rheumatoid Arthritis Receiving Background Methotrexate
Official Title  ICMJE 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
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).
Detailed Description

Patients were randomized to 2 groups in this study: Group A (active group) and Group B (control group). Patients with active rheumatic arthritis treated with rituximab in combination with methotrexate (Group A) were compared with patients treated with methotrexate alone (Group B).

Group A

Group A patients received rituximab 1000 mg intravenously (IV) on Days 3 and 17 of the 36 week treatment period.

At Day 1 and at Week 24, patients received an intradermal injection of 0.1 mL of C. albicans on the volar surface of the forearm. Forty-eight to 72 hours after each injection, patients were evaluated for a delayed-type hypersensitivity response by measuring the diameter of induration (palpable raised, hardened area of the forearm skin).

At Week 24, patients received a tetanus toxoid adsorbed booster vaccine (1 mg in 0.5 mL) intramuscular (IM) injection in the deltoid muscle. Serum levels of tetanus toxoid titers were obtained at Day 3 immediately prior to the first administration of rituximab, and immediately prior to and 4 weeks after administration of the tetanus toxoid adsorbed vaccine.

At Week 28, patients received an IM injection of the 23-valent pneumococcal polysaccharide vaccine (0.5 mL) in the deltoid muscle. Serum levels for antibodies to 12 pneumococcal serotypes were measured at Day 3 immediately prior to the first administration of rituximab, and immediately prior to and 4 weeks after administration of the pneumococcal vaccine.

At Weeks 32 and 33, patients received subcutaneous (SC) keyhole limpet hemocyanin 1 mg. Serum anti-keyhole limpet hemocyanin antibody levels were measured at Day 3 immediately prior to the first administration of rituximab, and immediately prior to and 4 weeks after the first administration of keyhole limpet hemocyanin.

Samples were obtained for the determination of serum rituximab concentration (pharmacokinetics), peripheral blood CD19 counts (pharmacodynamics), and the presence of human anti-chimeric antibodies from all patients in Group A.

Group A patients completed the treatment period at Week 36 and, if qualified, had the option of entering the optional extension re-treatment period. Patients who did not qualify for or who did not choose to receive the optional extension re-treatment entered the approximately 1-year safety follow-up period. After the safety follow-up period, patients who remained peripherally CD19-positive B-cell depleted entered the B-cell follow-up period where they were followed every 12 weeks until their peripheral CD19-positive B cells returned to baseline values or the lower limit of normal, whichever was lower.

Group B

Because the immune response to vaccines was not likely to be influenced by the knowledge of treatment assignment or the time-of-year administration, vaccinations of Group B patients were administered sooner than in the Group A 36 week treatment period.

At Day 1 and at Week 12, patients received an intradermal injection of 0.1 mL of C. albicans on the volar surface of the forearm. Forty-eight to 72 hours after each injection, patients were evaluated for a delayed-type hypersensitivity response by measuring the diameter of induration (palpable raised, hardened area of the forearm skin).

On Day 1, patients received a tetanus toxoid adsorbed booster vaccine (1 mg in 0.5 mL) IM injection in the deltoid muscle. Serum levels of tetanus toxoid titers were obtained immediately prior to and 4 weeks after administration of the tetanus toxoid adsorbed vaccine.

At Week 4, patients received an IM injection of the 23-valent pneumococcal polysaccharide vaccine (0.5 mL) in the deltoid muscle. Serum levels for antibodies to 12 pneumococcal serotypes were measured at Day 1, and immediately prior to and 4 weeks after administration of the pneumococcal vaccine.

At Weeks 8 and 9, patients received SC keyhole limpet hemocyanin 1 mg. Serum anti-keyhole limpet hemocyanin antibody levels were measured at Day 1, and immediately prior to and 4 weeks after the first administration of keyhole limpet hemocyanin.

Upon completion of the Week 12 visit, Group B patients with active rheumatic arthritis, defined as a swollen joint count (SJC) ≥ 4 (66 joint count) and a tender joint count (TJC) ≥ 6 (68 joint count) were eligible for treatment with 2 infusions of rituximab 1000 mg IV, 14 days apart. Patients received the first infusion of rituximab within 2 weeks after completing the Week 12 visit and after the second C. albicans skin test had been read. Patients received methylprednisolone 100 mg IV before each infusion of rituximab.

Group B patients who received treatment with rituximab completed the treatment period through Week 36 and, if qualified, had the option of entering the optional extension re-treatment period. Patients who did not qualify for or who did not choose to receive the optional extension re-treatment entered the approximately 1-year safety follow-up period. After the safety follow-up period, patients who remained peripherally CD19-positive B-cell depleted entered the B-cell follow-up period where they were followed every 12 weeks until their peripheral CD19-positive B cells returned to baseline values or the lower limit of normal, whichever was lower.

Group B patients who did not qualify for and/or did not choose treatment with rituximab completed the study at the end of the primary study period (Week 12).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Rheumatoid Arthritis
Intervention  ICMJE
  • 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)
Study Arms  ICMJE
  • 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.
    Interventions:
    • 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
  • Active Comparator: Methotrexate (Group B)
    Patients received methotrexate 10-25 mg/wk orally or subcutaneously during the Treatment Period.
    Interventions:
    • Drug: Methotrexate
    • Biological: C. albicans
    • Biological: Tetanus toxoid adsorbed booster vaccine
    • Biological: 23-valent pneumococcal polysaccharide vaccine
    • Biological: Keyhole limpet hemocyanin
Publications * Bingham CO 3rd, Looney RJ, Deodhar A, Halsey N, Greenwald M, Codding C, Trzaskoma B, Martin F, Agarwal S, Kelman A. Immunization responses in rheumatoid arthritis patients treated with rituximab: results from a controlled clinical trial. Arthritis Rheum. 2010 Jan;62(1):64-74. doi: 10.1002/art.25034.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 14, 2012)
103
Original Enrollment  ICMJE
 (submitted: January 24, 2006)
100
Actual Study Completion Date  ICMJE May 28, 2012
Actual Primary Completion Date January 31, 2008   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00282308
Other Study ID Numbers  ICMJE U3374g
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Genentech, Inc.
Study Sponsor  ICMJE Genentech, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Ariella Kelman, M.D. Genentech, Inc.
PRS Account Genentech, Inc.
Verification Date July 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP