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NCT00282308: SIERRA

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

Completed Phase 2 Results posted Last updated 10 August 2017
What this trial tests

Phase 2 trial testing Rituximab in Rheumatoid Arthritis in 103 participants. Completed in 28 May 2012.

Timeline
23 January 2006
Primary endpoint
31 January 2008
28 May 2012

Quick facts

Lead sponsorGenentech, Inc.
PhasePhase 2
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingnone
Primary purposetreatment
Enrollment103
Start date23 January 2006
Primary completion31 January 2008
Estimated completion28 May 2012
Sites34 locations across United States

Drugs / interventions tested

Conditions studied

Sponsor

Genentech, Inc. — full company profile →

Who can join

Adults 18 to 65, any sex, with Rheumatoid Arthritis. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Percentage of Patients With a Positive Immune Response to Tetanus Toxoid Adsorbed Booster Vaccine Primary · 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

GroupValue95% CI
Rituximab + Methotrexate (Group A)39.1
Methotrexate (Group B)42.3
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 Secondary · 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.

GroupValue95% CI
Rituximab + Methotrexate (Group A)54.7
Methotrexate (Group B)61.5
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 Secondary · 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-vaccin

Serotype 1-146 (1)
GroupValue95% CI
Rituximab + Methotrexate (Group A)12.7
Methotrexate (Group B)42.9
Serotype 3-146 (3)
GroupValue95% CI
Rituximab + Methotrexate (Group A)9.5
Methotrexate (Group B)28.6
Serotype 4-146 (4)
GroupValue95% CI
Rituximab + Methotrexate (Group A)12.7
Methotrexate (Group B)60.7
Serotype 6/26-146 (6B)
GroupValue95% CI
Rituximab + Methotrexate (Group A)38.1
Methotrexate (Group B)60.7
Serotype 8-146 (8)
GroupValue95% CI
Rituximab + Methotrexate (Group A)33.3
Methotrexate (Group B)57.1
Serotype 9-146 (9N)
GroupValue95% CI
Rituximab + Methotrexate (Group A)22.2
Methotrexate (Group B)60.7
Serotype 12-146 (12F)
GroupValue95% CI
Rituximab + Methotrexate (Group A)11.1
Methotrexate (Group B)50.0
Serotype 14-146 (14)
GroupValue95% CI
Rituximab + Methotrexate (Group A)30.2
Methotrexate (Group B)60.7
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 Secondary · 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-vaccin

GroupValue95% CI
Rituximab + Methotrexate (Group A)19.0
Methotrexate (Group B)60.7
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 Secondary · 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-vaccin

1 serotype
GroupValue95% CI
Rituximab + Methotrexate (Group A)57.1
Methotrexate (Group B)82.1
2 serotypes
GroupValue95% CI
Rituximab + Methotrexate (Group A)42.9
Methotrexate (Group B)82.1
3 serotypes
GroupValue95% CI
Rituximab + Methotrexate (Group A)38.1
Methotrexate (Group B)78.6
4 serotypes
GroupValue95% CI
Rituximab + Methotrexate (Group A)33.3
Methotrexate (Group B)75.0
5 serotypes
GroupValue95% CI
Rituximab + Methotrexate (Group A)23.8
Methotrexate (Group B)67.9
Serum Level of Anti-tetanus Antibody Measured Immediately Prior to and 4 Weeks After Administration of a Tetanus Toxoid Adsorbed Booster Vaccine Secondary · 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.

Pre-vaccination
GroupValue95% CI
Rituximab + Methotrexate (Group A)1.20.88 – 1.69
Methotrexate (Group B)1.00.49 – 2.14
4 weeks post-vaccination
GroupValue95% CI
Rituximab + Methotrexate (Group A)4.02.72 – 5.74
Methotrexate (Group B)5.22.25 – 12.00
Serum Level of Anti-pneumococcal Antibody Measured Immediately Prior to and 4 Weeks After Administration of a 23-valent Pneumococcal Polysaccharide Vaccine Secondary · 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.

Pre-vaccination
GroupValue95% CI
Rituximab + Methotrexate (Group A)0.80.64 – 1.06
Methotrexate (Group B)1.00.68 – 1.47
4 weeks post-vaccination
GroupValue95% CI
Rituximab + Methotrexate (Group A)1.00.76 – 1.37
Methotrexate (Group B)2.31.39 – 3.89
Serum Level of Anti-keyhole Limpet Hemocyanin Antibody Measured Immediately Prior to and 4 Weeks After the First Administration of Keyhole Limpet Hemocyanin Secondary · 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.

Pre-vaccination
GroupValue95% CI
Rituximab + Methotrexate (Group A)345.7312.25 – 382.76
Methotrexate (Group B)388.0NA – NA
4 weeks post-vaccination
GroupValue95% CI
Rituximab + Methotrexate (Group A)539.5461.54 – 630.61
Methotrexate (Group B)1585.51065.15 – 2360.17
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 Secondary · 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.

GroupValue95% CI
Rituximab + Methotrexate (Group A)77.4
Methotrexate (Group B)70.0
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 Secondary · 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 I

ACR 20%
GroupValue95% CI
Rituximab + Methotrexate (Group A)36.4
ACR 50%
GroupValue95% CI
Rituximab + Methotrexate (Group A)21.2
ACR 70%
GroupValue95% CI
Rituximab + Methotrexate (Group A)4.5

Adverse events — posted to ClinicalTrials.gov

Time frame: Adverse events were reported from Weeks 1-36 for Group A and Weeks 1-24 for Group B of the treatment period, Weeks 1-6 of the optional extension retreatment period, and Weeks 1-48 of the safety follow-up period (maximum of up to 90 weeks).. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Rituximab + Methotrexate (Group A) - Treatment Period
Serious: 3/68 (4%)
Deaths:
Methotrexate (Group B) - Treatment Period
Serious: 2/32 (6%)
Deaths:
Group A - Optional Extension Re-treatment Period
Serious: 2/52 (4%)
Deaths:
Group B - Optional Extension Re-treatment Period
Serious: 2/26 (8%)
Deaths:
Group A - Safety Follow-up Period
Serious: 3/68 (4%)
Deaths:
Group B - Safety Follow-up Period
Serious: 1/32 (3%)
Deaths:

Serious adverse events (11 terms)

ReactionSystemRituximab + Methotrexate (…Methotrexate (Group B) - T…Group A - Optional Extensi…Group B - Optional Extensi…Group A - Safety Follow-up…Group B - Safety Follow-up…
Coronary artery diseaseCardiac disorders
Chest painGeneral disorders
Hip fractureInfections and infestations
Rheumatoid arthritisMusculoskeletal and connective tissue disorders
Ovarian cystReproductive system and breast disorders
Amaurosis fugaxEye disorders
PyelonephritisInfections and infestations
Ovarian cancerNeoplasms benign, malignant and unspecified (incl cysts and polyps)
Thyroid cancerNeoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinomaNeoplasms benign, malignant and unspecified (incl cysts and polyps)
Bipolar disorderPsychiatric disorders
Other adverse events (32 terms — click to expand)

ReactionSystemRituximab + Methotrexate (…Methotrexate (Group B) - T…Group A - Optional Extensi…Group B - Optional Extensi…Group A - Safety Follow-up…Group B - Safety Follow-up…
Rheumatoid arthritisMusculoskeletal and connective tissue disorders
HeadacheNervous system disorders
PruritusSkin and subcutaneous tissue disorders
Upper respiratory tract infectionInfections and infestations
ArthralgiaMusculoskeletal and connective tissue disorders
NauseaGastrointestinal disorders
SinusitisInfections and infestations
CoughRespiratory, thoracic and mediastinal disorders
Urinary tract infectionInfections and infestations
DiarrhoeaGastrointestinal disorders
InfluenzaInfections and infestations
Throat irritationRespiratory, thoracic and mediastinal disorders
Oropharyngeal painRespiratory, thoracic and mediastinal disorders
UrticariaSkin and subcutaneous tissue disorders
Muscle spasmsMusculoskeletal and connective tissue disorders
FatigueGeneral disorders
Oedema peripheralGeneral disorders
BursitisMusculoskeletal and connective tissue disorders
DizzinessNervous system disorders
ErythemaSkin and subcutaneous tissue disorders
FlushingVascular disorders
InsomniaPsychiatric disorders
BronchitisInfections and infestations
Ear pruritusEar and labyrinth disorders
Respiratory tract congestionRespiratory, thoracic and mediastinal disorders
Rash macularSkin and subcutaneous tissue disorders
Pain in extremityMusculoskeletal and connective tissue disorders
Feeling hotGeneral disorders
Genital herpesInfections and infestations
Viral upper respiratory tract infectionInfections and infestations
Neck painMusculoskeletal and connective tissue disorders
Sinus congestionRespiratory, thoracic and mediastinal disorders

Most-reported serious reactions: Coronary artery disease, Chest pain, Hip fracture, Rheumatoid arthritis, Ovarian cyst, Amaurosis fugax, Pyelonephritis, Ovarian cancer.

Data from ClinicalTrials.gov NCT00282308 adverse events section.

Sponsor's own description

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).

Publications & conference data

2 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Biologics or tofacitinib for people with rheumatoid arthritis naive to methotrexate: a systematic review and network meta-analysis.
    Singh JA, Hossain A, Mudano AS, Tanjong Ghogomu E, et al · · 2017 · cited 44× · PMID 28481462 · DOI 10.1002/14651858.cd012657
  2. Biologics or tofacitinib for people with rheumatoid arthritis unsuccessfully treated with biologics: a systematic review and network meta-analysis.
    Singh JA, Hossain A, Tanjong Ghogomu E, Mudano AS, et al · · 2017 · cited 38× · PMID 28282491 · DOI 10.1002/14651858.cd012591

Verify or expand the search:

Other trials of Rituximab

Trials testing the same drug.

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Trials by the same sponsor.

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Data sources for this page

Drug Landscape aggregates and links these public records for informational use only. Always verify against the primary source before clinical or regulatory decisions. Canonical URL: https://druglandscape.com/trial/NCT00282308.

Primary sources · FDA · ClinicalTrials.gov · EMA · SEC EDGAR · ChEMBL · Wikidata · full sourcing