Clinical trial NCT00578305: A Study of Rituximab (MabThera®/Rituxan®) in Patients With Rheumatoid Arthritis and Inadequate Response to Methotrexate
Official title: A Randomized, Placebo Controlled, Multicenter Clinical Study Investigating Efficacy of Rituximab in the Inhibition of Joint Structural Damage Assessed by Magnetic Resonance Imaging in Patients With Rheumatoid Arthritis and Inadequate Response to Methotrexate
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Rheumatoid Arthritis
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2007-12-21
Enrollment: 185
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This 3 arm study assessed the efficacy of rituximab (MabThera®/Rituxan®) in the prevention of progression of structural joint damage in participants with active rheumatoid arthritis who had an inadequate clinical response to methotrexate. Participants were randomized to receive rituximab 500 mg intravenously (iv), rituximab 1000 mg iv, or placebo iv on days 1 and 15 every 24 weeks in the main study; all participants received concomitant methotrexate at a stable dose of 12.5-25 mg/week throughout the study. Further courses of rituximab were provided to eligible participants. Structural joint damage was assessed by magnetic resonance imaging (MRI) at baseline and at intervals during the study.

Detailed description: There were 3 phases in the study: A 52 week long main study, a study extension phase, and a 48 week long safety follow-up phase.

The first course of treatment with placebo or rituximab was initiated on Day 1 of the 52 week long main study. A second course of treatment was initiated after Week 24, if the participant met eligibility criteria. After Week 52, eligible participants received further treatment courses at intervals ≥ 6 months in the study extension phase. No treatments were administered in the safety follow-up phase.

Participants had to meet the following eligibility criteria to receive rituximab in the study extension phase.

* Minimum of 24 weeks had passed since the first infusion of the last course of study medication.
* C-reactive protein-based Disease Activity Score 28 (DAS28-CRP) ≥ 2.6.
* Absolute neutrophil count not below 1.5 x 103/μL.
* Patient had not developed contraindications for receiving rituximab, such as:

  1. Any new or uncontrolled concomitant disease such as, but not limited to, cardiovascular disease, nervous system, pulmonary, renal, hepatic, endocrine or gastrointestinal disorders.
  2. Primary or secondary immunodeficiency (history of, or currently active), including known history of HIV infection.
  3. Known active infection of any kind (excluding fungal infections of nail beds), or any major episode of infection requiring hospitalization, or treatment with iv anti-infectives within 4 weeks prior to infusion or completion of oral anti-infectives within 2 weeks prior to infusion.
* Patient was not pregnant or breast feeding.
* Patients who entered the study and were found to be hepatitis B surface antigen (HBsAg) negative, hepatitis B core antibody (HBcAb) positive, were to be negative for hepatitis B viral DNA (\< 29 IU/mL) and were to have aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN) results within the last 12 weeks.

Eligibility criteria: Inclusion Criteria:

* Adult patients, 18-80 years of age.
* Active rheumatoid arthritis for ≥ 3 months and ≤ 10 years.
* Evidence of erosive disease and/or clinical synovitis in a signal joint.
* Inadequate response to 12.5-25 mg/week methotrexate for ≥ 12 weeks.

Exclusion Criteria:

* Rheumatic autoimmune disease or inflammatory joint disease other than rheumatoid arthritis. - Any surgical procedure within 12 weeks prior to baseline.
* Previous treatment with a biologic agent or with a B cell modulating or cell depleting therapy.

Primary outcomes:
measure: Change in Magnetic Resonance Imaging (MRI) Erosion Score From Baseline to Week 24
timeFrame: Baseline to Week 24
Secondary outcomes:
measure: Change in Magnetic Resonance Imaging (MRI) Erosion Score From Baseline to Weeks 12 and 52
timeFrame: Baseline to Week 52
measure: Change in Magnetic Resonance Imaging (MRI) Synovitis Score From Baseline to Weeks 12, 24, and Week 52
timeFrame: Baseline to Week 52
measure: Change in Magnetic Resonance Imaging (MRI) Osteitis Score From Baseline to Weeks 12, 24, and Week 52
timeFrame: Baseline to Week 52
measure: Percentage of Participants With no Newly Eroded Joints at Weeks 24 and 52
timeFrame: Baseline to Week 52
measure: Percentage of Participants With no Progression/no Worsening in Bone Erosion at Weeks 24 and 52
timeFrame: Baseline to Week 52
measure: Percentage of Participants With Improvement in Synovitis at Weeks 24 and 52
timeFrame: Baseline to Week 52
measure: Percentage of Participants With Improvement in Osteitis at Weeks 24 and 52
timeFrame: Baseline to Week 52
measure: Change From Baseline in the Disease Activity Score 28 (DAS28) at Weeks 24 and 52
timeFrame: Baseline to Week 52
measure: Percentage of Participants With European League Against Rheumatism (EULAR) Good, Moderate, or no Response at Weeks 24 and 52
timeFrame: Baseline to Week 52
measure: Percentage of Participants With Low Disease Activity (Disease Activity Score 28 [DAS28] ≤ 3.2) at Weeks 24 and 52
timeFrame: Baseline to Week 52
measure: Percentage of Participants in Remission Response (Disease Activity Score 28 [DAS28] < 2.6) at Weeks 24 and 52
timeFrame: Baseline to Week 52
measure: Percentage of Participants With an Improvement of at Least 20%, 50%, or 70% in the American College of Rheumatology (ACR) Score (ACR20/50/70) From Baseline at Weeks 24 and 52
timeFrame: Baseline to Week 52
measure: Percentage of Participants Achieving a Major Clinical Response at Week 52
timeFrame: Baseline to Week 52
measure: Correlation of Magnetic Resonance Imaging Assessments and Clinical Outcome Measures
timeFrame: Baseline to Week 52
measure: Change From Baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Weeks 24 and 52
timeFrame: Baseline to Week 52
measure: Adverse Events (AEs), Laboratory Parameters, C-reactive Protein, ESR.
timeFrame: Throughout study
Other outcomes:
Locations:
city: Buenos Aires
country: Argentina
city: Goiania
country: Brazil
state: GO
city: Curtiba
country: Brazil
state: PR
city: Porto Alegre
country: Brazil
state: RS
city: Sao Paulo
country: Brazil
state: SP
city: Winnipeg
country: Canada
state: Manitoba
city: St John's
country: Canada
state: Newfoundland and Labrador
city: Ottawa
country: Canada
state: Ontario
city: Ottawa
country: Canada
state: Ontario
city: Toronto
country: Canada
state: Ontario
city: Montreal
country: Canada
state: Quebec
city: Montreal
country: Canada
state: Quebec
city: Montreal
country: Canada
state: Quebec
city: Quebec City
country: Canada
state: Quebec
city: Saskatoon
country: Canada
state: Saskatchewan
city: Brno
country: Czech Republic
city: Ceské Budejovice
country: Czech Republic
city: Praha
country: Czech Republic
city: Hillerod
country: Denmark
city: Hvidovre
country: Denmark
city: København
country: Denmark
city: Tallinn
country: Estonia
city: Tallinn
country: Estonia
city: Montpellier
country: France
city: Nice
country: France
city: Orleans
country: France
city: Toulouse
country: France
city: Bad Aibling
country: Germany
city: Berlin
country: Germany
city: Dresden
country: Germany
city: Erlangen
country: Germany
city: Halle
country: Germany
city: Hannover
country: Germany
city: Athens
country: Greece
city: Patras
country: Greece
city: Thessaloniki
country: Greece
city: Riga
country: Latvia
city: Riga
country: Latvia
city: Vilnius
country: Lithuania
city: Amsterdam
country: Netherlands
city: Oslo
country: Norway
city: Bucharest
country: Romania
city: Cluj-napoca
country: Romania
city: Kazan
country: Russian Federation
city: Moscow
country: Russian Federation
city: Saint-Petersburg
country: Russian Federation
city: Voronezh
country: Russian Federation
city: Belgrade
country: Serbia
city: Niska Banja
country: Serbia
city: Barcelona
country: Spain
city: Barcelona
country: Spain
city: Madrid
country: Spain
city: Malaga
country: Spain
city: Sevilla
country: Spain
city: Valencia
country: Spain
city: Bern
country: Switzerland
city: Adana
country: Turkey
city: Ankara
country: Turkey
city: Istanbul
country: Turkey
city: Izmir
country: Turkey
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Peterfy C, Emery P, Tak PP, Ostergaard M, DiCarlo J, Otsa K, Navarro Sarabia F, Pavelka K, Bagnard MA, Gylvin LH, Bernasconi C, Gabriele A. MRI assessment of suppression of structural damage in patients with rheumatoid arthritis receiving rituximab: results from the randomised, placebo-controlled, double-blind RA-SCORE study. Ann Rheum Dis. 2016 Jan;75(1):170-7. doi: 10.1136/annrheumdis-2014-206015. Epub 2014 Oct 29.