A Study to Evaluate the Effects of Rituximab on Immune Responses in Subjects With Active Rheumatoid Arthritis Receiving Background Methotrexate

Study Overview
=================
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).

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

Conditions
-----------------
Rheumatoid Arthritis

Intervention / Treatment
-----------------
* 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


Participation Criteria
=================
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rituximab + methotrexate (Group A)<br>Patients received 2 intravenous infusions of rituximab 1000 mg, 14 days apart + methotrexate 10-25 mg/wk orally or subcutaneously during the Treatment Period. | Drug: Rituximab<br>* Rituximab was supplied in single-use vials.<br>* Other names: MabThera;Drug: Methotrexate<br> <br> Drug: Methylprednisone<br>* Patients received methylprednisolone 100 mg intravenously before each infusion of rituximab.<br>Biological: C. albicans<br>* Patients received an intradermal injection of C. albicans (0.1 mL) on the volar surface of the forearm.<br>Biological: Tetanus toxoid adsorbed booster vaccine<br>* Patients received an intramuscular injection of the tetanus toxoid adsorbed booster vaccine (1 mg in 0.5 mL) in the deltoid muscle.<br>Biological: 23-valent pneumococcal polysaccharide vaccine<br>* Patients received an intramuscular injection of the 23-valent pneumococcal polysaccharide vaccine (0.5 mL) in the deltoid muscle.<br>Biological: Keyhole limpet hemocyanin<br>* Patients received a subcutaneous injection of keyhole limpet hemocyanin (1 mg)<br>|
| Active Comparator: Methotrexate (Group B)<br>Patients received methotrexate 10-25 mg/wk orally or subcutaneously during the Treatment Period. | Drug: Methotrexate<br> <br> Biological: C. albicans<br>* Patients received an intradermal injection of C. albicans (0.1 mL) on the volar surface of the forearm.<br>Biological: Tetanus toxoid adsorbed booster vaccine<br>* Patients received an intramuscular injection of the tetanus toxoid adsorbed booster vaccine (1 mg in 0.5 mL) in the deltoid muscle.<br>Biological: 23-valent pneumococcal polysaccharide vaccine<br>* Patients received an intramuscular injection of the 23-valent pneumococcal polysaccharide vaccine (0.5 mL) in the deltoid muscle.<br>Biological: Keyhole limpet hemocyanin<br>* Patients received a subcutaneous injection of keyhole limpet hemocyanin (1 mg)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients With a Positive Immune Response to Tetanus Toxoid Adsorbed Booster Vaccine | 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. | Week 24 to Week 28 for Group A and Day 1 to Week 4 for Group B | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | Week 24 to Week 28 for Group A and Day 1 to Week 4 for Group B | 
| 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 | 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. | Week 28 to Week 32 for Group A and Week 4 to Week 8 for Group B | 
| 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 | 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. | Week 28 to Week 32 for Group A and Week 4 to Week 8 for Group B | 
| 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 | 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. | Week 28 to Week 32 for Group A and Week 4 to Week 8 for Group B | 
| Serum Level of Anti-tetanus Antibody Measured Immediately Prior to and 4 Weeks After Administration of a Tetanus Toxoid Adsorbed Booster Vaccine | 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. | Week 24 to Week 28 for Group A and Day 1 to Week 4 for Group B | 
| Serum Level of Anti-pneumococcal Antibody Measured Immediately Prior to and 4 Weeks After Administration of a 23-valent Pneumococcal Polysaccharide Vaccine | 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. | Week 28 to Week 32 for Group A and Week 4 to Week 8 for Group B | 
| Serum Level of Anti-keyhole Limpet Hemocyanin Antibody Measured Immediately Prior to and 4 Weeks After the First Administration of Keyhole Limpet Hemocyanin | 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. | Week 32 to Week 36 for Group A and Week 8 to Week 12 for Group B | 
| 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 | 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. | Day 1 to Week 24 for Group A and Day 1 to Week 12 for Group B | 
| 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 | 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. | Week 24 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
RA, Rituxan, SIERRA