Clinical trial NCT00282308
Conditions: Rheumatoid Arthritis
Keywords: RA Rituxan SIERRA
Sponsor: Genentech, Inc.
Start date: 2006-01-23; Completion date: 2012-05-28
Enrollment: 103 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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).

Arms: arm 1: Patients received 2 intravenous infusions of rituximab 1000 mg, 14 days apart + methotrexate 10-25 mg/wk orally or subcutaneously during the Treatment Period. arm 2: Patients received methotrexate 10-25 mg/wk orally or subcutaneously during the Treatment Period.
Interventions: intervention 1: Rituximab intervention 2: Methotrexate intervention 3: Methylprednisone intervention 4: C. albicans intervention 5: Tetanus toxoid adsorbed booster vaccine intervention 6: 23-valent pneumococcal polysaccharide vaccine intervention 7: Keyhole limpet hemocyanin
Intervention descriptions: intervention 1: Rituximab was supplied in single-use vials. intervention 2: None intervention 3: Patients received methylprednisolone 100 mg intravenously before each infusion of rituximab. intervention 4: Patients received an intradermal injection of C. albicans (0.1 mL) on the volar surface of the forearm. intervention 5: Patients received an intramuscular injection of the tetanus toxoid adsorbed booster vaccine (1 mg in 0.5 mL) in the deltoid muscle. intervention 6: Patients received an intramuscular injection of the 23-valent pneumococcal polysaccharide vaccine (0.5 mL) in the deltoid muscle. intervention 7: Patients received a subcutaneous injection of keyhole limpet hemocyanin (1 mg)

Protocol documents: