A Study to Evaluate the Effects of Rituximab on Immune Responses in Subjects With Active Rheumatoid Arthritis Receiving Background Methotrexate
Condition: Rheumatoid Arthritis
MeSH terms: Arthritis; Arthritis, Rheumatoid
Study type: Interventional
Phase: Phase 2

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).
    

Intervention name(s): Rituximab; Methotrexate; Methylprednisone; C. albicans; Tetanus toxoid adsorbed booster vaccine; 23-valent pneumococcal polysaccharide vaccine; Keyhole limpet hemocyanin
Intervention type(s): Drug; Drug; Drug; Biological; Biological; Biological; Biological
Intervention description(s): Rituximab was supplied in single-use vials.; Patients received methylprednisolone 100 mg intravenously before each infusion of rituximab.; Patients received an intradermal injection of C. albicans (0.1 mL) on the volar surface of the forearm.; Patients received an intramuscular injection of the tetanus toxoid adsorbed booster vaccine (1 mg in 0.5 mL) in the deltoid muscle.; Patients received an intramuscular injection of the 23-valent pneumococcal polysaccharide vaccine (0.5 mL) in the deltoid muscle.; Patients received a subcutaneous injection of keyhole limpet hemocyanin (1 mg)
Other intervention name(s): Rituxan; MabThera
Intervention MeSH terms: Rituximab; Methotrexate; Vaccines; Heptavalent Pneumococcal Conjugate Vaccine; Keyhole-limpet hemocyanin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: RA; Rituxan; SIERRA