Rheumatoid Arthritis
Conditions
Keywords
RA, Rituxan, SIERRA
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).
Interventions
DRUGRituximab
Rituximab was supplied in single-use vials.
DRUGMethotrexate
DRUGMethylprednisone
Patients received methylprednisolone 100 mg intravenously before each infusion of rituximab.
BIOLOGICALC. albicans
Patients received an intradermal injection of C. albicans (0.1 mL) on the volar surface of the forearm.
BIOLOGICALTetanus 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.
Patients received an intramuscular injection of the 23-valent pneumococcal polysaccharide vaccine (0.5 mL) in the deltoid muscle.
BIOLOGICALKeyhole limpet hemocyanin
Patients received a subcutaneous injection of keyhole limpet hemocyanin (1 mg)
Sponsors
Genentech, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With a Positive Immune Response to Tetanus Toxoid Adsorbed Booster Vaccine | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 68 |
| Methotrexate (Group B) Patients received methotrexate 10-25 mg/wk orally or subcutaneously during the Treatment Period. | 32 |
| Total | 100 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Optional Extension Re-treatment Period | Adverse Event | 0 | 0 | 4 |
| Optional Extension Re-treatment Period | Physician's Decision to Withdraw | 0 | 0 | 1 |
| Optional Extension Re-treatment Period | Subject/Guardian Decision to Withdraw | 0 | 0 | 1 |
| Safety Follow-up Period | Adverse Event | 0 | 0 | 1 |
| Safety Follow-up Period | Lost to Follow-up | 0 | 0 | 5 |
| Safety Follow-up Period | Physician Decision to Withdraw | 0 | 0 | 1 |
| Safety Follow-up Period | Subject/Guardian Decision to Withdraw | 0 | 0 | 12 |
| Treatment Period | Adverse Event | 0 | 2 | 0 |
| Treatment Period | Lost to Follow-up | 1 | 0 | 0 |
| Treatment Period | Not Treated with Study Drug | 1 | 0 | 0 |
| Treatment Period | Subject/Guardian Decision to Withdraw | 2 | 4 | 0 |
Baseline characteristics
| Characteristic | Rituximab + Methotrexate (Group A) | Methotrexate (Group B) | Total |
|---|---|---|---|
| Age, Continuous | 49.7 years STANDARD_DEVIATION 9.6 | 49.7 years STANDARD_DEVIATION 10.51 | 49.7 years STANDARD_DEVIATION 9.85 |
| Sex: Female, Male Female | 51 Participants | 25 Participants | 76 Participants |
| Sex: Female, Male Male | 17 Participants | 7 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 51 / 68 | 19 / 32 | 7 / 52 | 13 / 26 | 19 / 68 | 11 / 32 |
| serious Total, serious adverse events | 3 / 68 | 2 / 32 | 2 / 52 | 2 / 26 | 3 / 68 | 1 / 32 |
Outcome results
Primary
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.
Time frame: Week 24 to Week 28 for Group A and Day 1 to Week 4 for Group B
Population: Immune response per-protocol population: Group A - All patients randomized to Group A who received any rituximab infusion and any vaccine and had pre-vaccination and 4-week post-vaccination blood samples. Group B - All patients randomized to Group B who received any vaccine and had pre-vaccination and 4-week post-vaccination blood samples.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab + Methotrexate (Group A) | Percentage of Patients With a Positive Immune Response to Tetanus Toxoid Adsorbed Booster Vaccine | 39.1 Percentage of patients |
| Methotrexate (Group B) | Percentage of Patients With a Positive Immune Response to Tetanus Toxoid Adsorbed Booster Vaccine | 42.3 Percentage of patients |
Secondary
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.
Time frame: Week 24
Population: Safety population: All patients who received any amount of rituximab or any vaccine. Since only limited efficacy data were collected in this study, the parameters necessary to calculate the ACR20/50/70 responses were only available for patients in Group A.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rituximab + Methotrexate (Group A) | 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 | ACR 20% | 36.4 Percentage of patients |
| Rituximab + Methotrexate (Group A) | 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 | ACR 50% | 21.2 Percentage of patients |
| Rituximab + Methotrexate (Group A) | 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 | ACR 70% | 4.5 Percentage of patients |
Secondary
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.
Time frame: Day 1 to Week 24 for Group A and Day 1 to Week 12 for Group B
Population: Skin test per-protocol population: Group A - All patients randomized to Group A who received any rituximab infusion, had Day 1 and Week 24 skin tests, and who provided complete diameter of induration readings. Group B - All patients randomized to Group B who had Day 1 and Week 12 skin tests and who provided complete diameter of induration readings.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab + Methotrexate (Group A) | 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 | 77.4 Percentage of patients |
| Methotrexate (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 | 70.0 Percentage of patients |
Secondary
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.
Time frame: Week 24 to Week 28 for Group A and Day 1 to Week 4 for Group B
Population: Immune response per-protocol population: Group A - All patients randomized to Group A who received any rituximab infusion and any vaccine and had pre-vaccination and 4-week post-vaccination blood samples. Group B - All patients randomized to Group B who received any vaccine and had pre-vaccination and 4-week post-vaccination blood samples.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab + Methotrexate (Group A) | 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 | 54.7 Percentage of patients |
| Methotrexate (Group B) | 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 | 61.5 Percentage of patients |
Secondary
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.
Time frame: Week 28 to Week 32 for Group A and Week 4 to Week 8 for Group B
Population: Immune response per-protocol population: Group A - All patients randomized to Group A who received any rituximab infusion and any vaccine and had pre-vaccination and 4-week post-vaccination blood samples. Group B - All patients randomized to Group B who received any vaccine and had pre-vaccination and 4-week post-vaccination blood samples.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab + Methotrexate (Group A) | 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 | 19.0 Percentage of patients |
| Methotrexate (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 | 60.7 Percentage of patients |
Secondary
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.
Time frame: Week 28 to Week 32 for Group A and Week 4 to Week 8 for Group B
Population: Immune response per-protocol population: Group A - All patients randomized to Group A who received any rituximab infusion and any vaccine and had pre-vaccination and 4-week post-vaccination blood samples. Group B - All patients randomized to Group B who received any vaccine and had pre-vaccination and 4-week post-vaccination blood samples.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rituximab + Methotrexate (Group A) | 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 | 2 serotypes | 42.9 Percentage of patients |
| Rituximab + Methotrexate (Group A) | 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 | 4 serotypes | 33.3 Percentage of patients |
| Rituximab + Methotrexate (Group A) | 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 | 3 serotypes | 38.1 Percentage of patients |
| Rituximab + Methotrexate (Group A) | 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 | 5 serotypes | 23.8 Percentage of patients |
| Rituximab + Methotrexate (Group A) | 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 | 1 serotype | 57.1 Percentage of patients |
| Methotrexate (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 | 5 serotypes | 67.9 Percentage of patients |
| Methotrexate (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 | 1 serotype | 82.1 Percentage of patients |
| Methotrexate (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 | 2 serotypes | 82.1 Percentage of patients |
| Methotrexate (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 | 3 serotypes | 78.6 Percentage of patients |
| Methotrexate (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 | 4 serotypes | 75.0 Percentage of patients |
Secondary
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.
Time frame: Week 28 to Week 32 for Group A and Week 4 to Week 8 for Group B
Population: Immune response per-protocol population: Group A - All patients randomized to Group A who received any rituximab infusion and any vaccine and had pre-vaccination and 4-week post-vaccination blood samples. Group B - All patients randomized to Group B who received any vaccine and had pre-vaccination and 4-week post-vaccination blood samples.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rituximab + Methotrexate (Group A) | 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 | Serotype 1-146 (1) | 12.7 Percentage of patients |
| Rituximab + Methotrexate (Group A) | 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 | Serotype 3-146 (3) | 9.5 Percentage of patients |
| Rituximab + Methotrexate (Group A) | 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 | Serotype 4-146 (4) | 12.7 Percentage of patients |
| Rituximab + Methotrexate (Group A) | 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 | Serotype 6/26-146 (6B) | 38.1 Percentage of patients |
| Rituximab + Methotrexate (Group A) | 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 | Serotype 8-146 (8) | 33.3 Percentage of patients |
| Rituximab + Methotrexate (Group A) | 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 | Serotype 9-146 (9N) | 22.2 Percentage of patients |
| Rituximab + Methotrexate (Group A) | 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 | Serotype 12-146 (12F) | 11.1 Percentage of patients |
| Rituximab + Methotrexate (Group A) | 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 | Serotype 14-146 (14) | 30.2 Percentage of patients |
| Rituximab + Methotrexate (Group A) | 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 | Serotype 19-146 (19F) | 25.4 Percentage of patients |
| Rituximab + Methotrexate (Group A) | 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 | Serotype 23-146 (23F) | 20.6 Percentage of patients |
| Rituximab + Methotrexate (Group A) | 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 | Serotype 51-146 (7F) | 25.4 Percentage of patients |
| Rituximab + Methotrexate (Group A) | 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 | Serotype 56-146 (18C) | 20.6 Percentage of patients |
| Methotrexate (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 | Serotype 51-146 (7F) | 60.7 Percentage of patients |
| Methotrexate (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 | Serotype 1-146 (1) | 42.9 Percentage of patients |
| Methotrexate (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 | Serotype 12-146 (12F) | 50.0 Percentage of patients |
| Methotrexate (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 | Serotype 3-146 (3) | 28.6 Percentage of patients |
| Methotrexate (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 | Serotype 23-146 (23F) | 35.7 Percentage of patients |
| Methotrexate (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 | Serotype 4-146 (4) | 60.7 Percentage of patients |
| Methotrexate (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 | Serotype 14-146 (14) | 60.7 Percentage of patients |
| Methotrexate (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 | Serotype 6/26-146 (6B) | 60.7 Percentage of patients |
| Methotrexate (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 | Serotype 56-146 (18C) | 57.1 Percentage of patients |
| Methotrexate (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 | Serotype 8-146 (8) | 57.1 Percentage of patients |
| Methotrexate (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 | Serotype 19-146 (19F) | 53.6 Percentage of patients |
| Methotrexate (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 | Serotype 9-146 (9N) | 60.7 Percentage of patients |
Secondary
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.
Time frame: Week 32 to Week 36 for Group A and Week 8 to Week 12 for Group B
Population: Immune response per-protocol population: Group A - All patients randomized to Group A who received any rituximab infusion and any vaccine and had pre-vaccination and 4-week post-vaccination blood samples. Group B - All patients randomized to Group B who received any vaccine and had pre-vaccination and 4-week post-vaccination blood samples.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Rituximab + Methotrexate (Group A) | Serum Level of Anti-keyhole Limpet Hemocyanin Antibody Measured Immediately Prior to and 4 Weeks After the First Administration of Keyhole Limpet Hemocyanin | Pre-vaccination | 345.7 IU/mL |
| Rituximab + Methotrexate (Group A) | Serum Level of Anti-keyhole Limpet Hemocyanin Antibody Measured Immediately Prior to and 4 Weeks After the First Administration of Keyhole Limpet Hemocyanin | 4 weeks post-vaccination | 539.5 IU/mL |
| Methotrexate (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 | Pre-vaccination | 388.0 IU/mL |
| Methotrexate (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 | 4 weeks post-vaccination | 1585.5 IU/mL |
Secondary
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.
Time frame: Week 28 to Week 32 for Group A and Week 4 to Week 8 for Group B
Population: Immune response per-protocol population: Group A - All patients randomized to Group A who received any rituximab infusion and any vaccine and had pre-vaccination and 4-week post-vaccination blood samples. Group B - All patients randomized to Group B who received any vaccine and had pre-vaccination and 4-week post-vaccination blood samples.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Rituximab + Methotrexate (Group A) | Serum Level of Anti-pneumococcal Antibody Measured Immediately Prior to and 4 Weeks After Administration of a 23-valent Pneumococcal Polysaccharide Vaccine | Pre-vaccination | 0.8 µg/mL |
| Rituximab + Methotrexate (Group A) | Serum Level of Anti-pneumococcal Antibody Measured Immediately Prior to and 4 Weeks After Administration of a 23-valent Pneumococcal Polysaccharide Vaccine | 4 weeks post-vaccination | 1.0 µg/mL |
| Methotrexate (Group B) | Serum Level of Anti-pneumococcal Antibody Measured Immediately Prior to and 4 Weeks After Administration of a 23-valent Pneumococcal Polysaccharide Vaccine | Pre-vaccination | 1.0 µg/mL |
| Methotrexate (Group B) | Serum Level of Anti-pneumococcal Antibody Measured Immediately Prior to and 4 Weeks After Administration of a 23-valent Pneumococcal Polysaccharide Vaccine | 4 weeks post-vaccination | 2.3 µg/mL |
Secondary
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.
Time frame: Week 24 to Week 28 for Group A and Day 1 to Week 4 for Group B
Population: Immune response per-protocol population: Group A - All patients randomized to Group A who received any rituximab infusion and any vaccine and had pre-vaccination and 4-week post-vaccination blood samples. Group B - All patients randomized to Group B who received any vaccine and had pre-vaccination and 4-week post-vaccination blood samples.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Rituximab + Methotrexate (Group A) | Serum Level of Anti-tetanus Antibody Measured Immediately Prior to and 4 Weeks After Administration of a Tetanus Toxoid Adsorbed Booster Vaccine | Pre-vaccination | 1.2 IU/mL |
| Rituximab + Methotrexate (Group A) | Serum Level of Anti-tetanus Antibody Measured Immediately Prior to and 4 Weeks After Administration of a Tetanus Toxoid Adsorbed Booster Vaccine | 4 weeks post-vaccination | 4.0 IU/mL |
| Methotrexate (Group B) | Serum Level of Anti-tetanus Antibody Measured Immediately Prior to and 4 Weeks After Administration of a Tetanus Toxoid Adsorbed Booster Vaccine | Pre-vaccination | 1.0 IU/mL |
| Methotrexate (Group B) | Serum Level of Anti-tetanus Antibody Measured Immediately Prior to and 4 Weeks After Administration of a Tetanus Toxoid Adsorbed Booster Vaccine | 4 weeks post-vaccination | 5.2 IU/mL |