Clinical trial NCT00282308: A Study to Evaluate the Effects of Rituximab on Immune Responses in Subjects With Active Rheumatoid Arthritis Receiving Background Methotrexate
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Rheumatoid Arthritis
Keywords: RA
Rituxan
SIERRA
Lead sponsor: Genentech, Inc.
Sponsor class: INDUSTRY
First posted: 2006-01-26
Enrollment: 103
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

Eligibility 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.

Primary outcomes:
measure: Percentage of Patients With a Positive Immune Response to Tetanus Toxoid Adsorbed Booster Vaccine
timeFrame: Week 24 to Week 28 for Group A and Day 1 to Week 4 for Group B
Secondary outcomes:
measure: 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
timeFrame: Week 24 to Week 28 for Group A and Day 1 to Week 4 for Group B
measure: 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
timeFrame: Week 28 to Week 32 for Group A and Week 4 to Week 8 for Group B
measure: 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
timeFrame: Week 28 to Week 32 for Group A and Week 4 to Week 8 for Group B
measure: 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
timeFrame: Week 28 to Week 32 for Group A and Week 4 to Week 8 for Group B
measure: Serum Level of Anti-tetanus Antibody Measured Immediately Prior to and 4 Weeks After Administration of a Tetanus Toxoid Adsorbed Booster Vaccine
timeFrame: Week 24 to Week 28 for Group A and Day 1 to Week 4 for Group B
measure: Serum Level of Anti-pneumococcal Antibody Measured Immediately Prior to and 4 Weeks After Administration of a 23-valent Pneumococcal Polysaccharide Vaccine
timeFrame: Week 28 to Week 32 for Group A and Week 4 to Week 8 for Group B
measure: Serum Level of Anti-keyhole Limpet Hemocyanin Antibody Measured Immediately Prior to and 4 Weeks After the First Administration of Keyhole Limpet Hemocyanin
timeFrame: Week 32 to Week 36 for Group A and Week 8 to Week 12 for Group B
measure: 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
timeFrame: Day 1 to Week 24 for Group A and Day 1 to Week 12 for Group B
measure: 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
timeFrame: Week 24
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Univ of Alabama at Birmingham
state: Alabama
city: Paradise Valley
country: United States
facility: Arizona Arthritis & Rheumatology Research, Pllc
state: Arizona
city: Peoria
country: United States
facility: Sun Valley Arthritis Center
state: Arizona
city: Palm Desert
country: United States
facility: Desert Medical Advances
state: California
city: Upland
country: United States
facility: Inland Rheumatology; Clinical Trials, Inc.
state: California
city: Delray Beach
country: United States
facility: Arthritis Associates of South Florida
state: Florida
city: Palm Harbor
country: United States
facility: The Arthritis Center
state: Florida
city: South Miami
country: United States
facility: Center For Arthritis; Research Dept
state: Florida
city: Boise
country: United States
facility: Intermountain Orthopaedics
state: Idaho
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: Univ of Chicago
state: Illinois
city: Evanston
country: United States
facility: Evanston Northwestern Healthcare
state: Illinois
city: Springfield
country: United States
facility: Springfield Clinic
state: Illinois
city: Louisville
country: United States
facility: Kentuckiana Center For Better Bone & Joint Healthx
state: Kentucky
city: Slidell
country: United States
facility: Clinical Research Network
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins University; Rheumatology
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Kalamazoo
country: United States
facility: Rheumatology, P.C.; Medical Arts Building
state: Michigan
city: Kalamazoo
country: United States
facility: Borgess Research Institute
state: Michigan
city: Lansing
country: United States
facility: Justus Fiechtner MD - PP
state: Michigan
city: Albany
country: United States
facility: Center for Rheumatology, State Uni. of New York
state: New York
city: Rochester
country: United States
facility: Aair Research Center
state: New York
city: Rochester
country: United States
facility: University of Rochester - Strong Memorial Hospital
state: New York
city: Greenville
country: United States
facility: Physicians East Pa
state: North Carolina
city: Oklahoma City
country: United States
facility: Health Research of Oklahoma, Llc
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health Sciences Uni
state: Oregon
city: Duncansville
country: United States
facility: Altoona Arthritis & Osteo Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Charleston
country: United States
facility: Rheumatology Associates
state: South Carolina
city: Charleston
country: United States
facility: Medical University of S. Carolina
state: South Carolina
city: Hixson
country: United States
facility: Arthritis Associates
state: Tennessee
city: Dallas
country: United States
facility: Arthritis Care & Diagnostic Center
state: Texas
city: Arlington
country: United States
facility: Arthritis Clinic of Northern Virginia
state: Virginia
city: Spokane
country: United States
facility: Arthritis Northwest, Spokane
state: Washington
Study officials:
affiliation: Genentech, Inc.
name: Ariella Kelman, M.D.
role: STUDY_DIRECTOR
References:
citation: 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.