A Pharmacokinetic and Pharmacodynamic Study of MabThera (Rituximab) Plus Methotrexate in Patients With Rheumatoid Arthritis (RA)

Rheumatoid Arthritis Clinical Trial

Official title:

An Open-label, Exploratory Study of the Pharmacokinetic and Pharmacodynamic Activity of MabThera in Combination With Methotrexate in Synovial Tissue and in Peripheral Blood of Patients With Active Rheumatoid Arthritis.

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00422942
• Other study ID #: WA19078
• Status: Terminated
• Phase: Phase 2
• First received: January 15, 2007
• Last updated: July 14, 2014
• Start date: January 2006
• Est. completion date: June 2010

Study information

• Verified date: July 2014
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: Central Committee on Research inv. Human Subjects (CCMO)
• Study type: Interventional

Clinical Trial Summary

This single arm study will investigate the pattern of B cell depletion in synovial tissue and peripheral blood of patients with active RA, after MabThera (1000mg iv x 2 on days 1 and 15) + methotrexate (10-25mg/week po) treatment. The clinical efficacy and pharmacokinetic profile of MabThera after treatment and retreatment will also be investigated. The anticipated time on study treatment is 2+ years, and the target sample size is <100 individuals.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 3
• Est. completion date: June 2010
• Est. primary completion date: June 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

• adult patients 18-80 years of age;

• RA for >=3 months;

• receiving outpatient treatment;

• failed treatment with >=1 DMARD (but not anti TNF or other biologic therapy);

• inadequate response to methotrexate, having taken and tolerated it for >=12 weeks, with a stable dose for >=4 weeks.

Exclusion Criteria:

• rheumatic autoimmune disease other than RA, or significant systemic involvement secondary to RA;

• history of, or current, inflammatory joint disease other than RA, or other systemic autoimmune disorder;

• diagnosis of RA before the age of 16;

• bone/joint surgery within 12 weeks of study;

• prior use of anti-TNF or other biologic therapy, an anti-alpha 4 integrin, or any cell-depleting therapies.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Rheumatoid Arthritis

Intervention

Drug:
• rituximab [MabThera/Rituxan]
1000mg iv on days 1 and 15
• Methotrexate
10-25mg po weekly

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline in Absolute B Cell Cluster Differential 19 Positive (CD19+) Counts in Synovial Tissues	The change from baseline in absolute B cell (CD19+) counts at each visit calculated as (B cell count at visit minus B cell count at baseline) for synovial tissues.	Weeks 12, 24, and 36	No
Primary	Change From Baseline in Absolute B Cell CD19+ Counts in Peripheral Blood	The change from baseline in absolute B cell (CD19+) count at each visit calculated as (B cell count at visit minus B cell count at baseline) for peripheral blood.	Weeks 4, 12, 24, 36, and 48	No
Secondary	Change From Baseline in Absolute Counts of Cells Expressing CD20+ and CD22+ in Absolute B Cell (CD19+) Counts in Synovial Tissues	The change in absolute counts of cells expressing the key B cell markers (CD20+ and CD22+) in absolute B cell (CD19+) counts in synovial tissues at Weeks 12, 24, and 36, relative to baseline.	Weeks 12, 24, and 36	No
Secondary	Change From Baseline in Absolute Counts of Cells Expressing CD20+ and CD22+ in Absolute B Cell (CD19+) Counts in Peripheral Blood	The change in absolute counts of cells expressing the key B cell markers (CD20+ and CD22+) in absolute B cell (CD19+) counts in peripheral blood at Weeks 4,12, 24, 36, and 48, relative to baseline.	Weeks 4,12, 24, 36, and 48	No
Secondary	Change From Baseline in Levels of Key Cytokines (Interleukin [IL]-1beta [ß], Tumor Necrosis Factor [TNF]-Alpha [a], IL-4, IL-6, IL-10, and IL-13) in Blood (Serum)	The change in levels of key cytokines (IL-1ß, TNF-a, IL-4, IL-6, IL-10, and IL-13) in blood (serum) on Days 15 and 183 and at Weeks 4, 12, 24, 36, and 48, relative to baseline.	Days 15 and 183 and Weeks 4, 12, 24, 36, and 48	No
Secondary	Change From Baseline in Levels of Key Cytokines in (IL-1ß, TNF-a, IL-6, and IL-10) in Synovial Tissues	The change in levels of key cytokines in (IL-1ß, TNF-a, IL-6, and IL-10) in synovial tissues at Weeks 12, 24, and 36, relative to baseline.	Weeks 12, 24, and 36	No
Secondary	Change From Baseline in Myelocytomatosis Oncogene (C-myc) and BCL2-associated X Protein (BAX) in Peripheral Blood	The change in ribonucleic acid (RNA) expression of markers of apoptosis (C-myc and BAX) in peripheral blood at Days 15 and 183, relative to baseline.	Days 15 and 183	No
Secondary	Percentage of Participants Achieving American College of Rheumatology 20 Percent (20%) 50%, and 70% (ACR20/50/70) Response	ACR20/50/70 response is greater than or equal to (=) 20%, 50%, or 70% improvement, respectively, in tender joint count (TJC) and swollen joint count (SJC); and improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and C-Reactive Protein (CRP).	Week 48	No
Secondary	Change From Baseline in Disease Activity Score Based on 28 Joint Count (DAS28) Erythrocyte Sedimentation Rate (ESR) Score	The change in DAS28-ESR at Weeks 12, 24, 36, and 48, relative to baseline. DAS28-ESR was calculated from SJC and TJC using 28-joint count, ESR (millimeters per hour [mm/hour]) and patient global assessment of disease activity (participant-rated arthritis activity assessment). Total score range: 0-9.4, higher score equals (=) more disease activity. DAS28-ESR less than or equal to (=) 3.2 implied low disease activity and greater than (>)3.2 to 5.1 implied moderate to high disease activity, and DAS28-ESR <2.6 = remission.	Weeks 12, 24, 36, and 48	No
Secondary	Percentage of Participants Achieving Response by European League Against Rheumatism (EULAR) Category	The DAS28-based EULAR response criteria were used to measure individual response as none, good, and moderate, depending on the extent of change from baseline and the level of disease activity reached. Good responders: change from baseline >1.2 with DAS28 = 3.2; moderate responders: change from baseline >1.2 with DAS28 >3.2 to = 5.1 or change from baseline >0.6 to = 1.2 with DAS28 = 5.1; non-responders: change from baseline = 0.6 or change from baseline >0.6 and = 1.2 with DAS28 >5.1.	Weeks 24, 36, and 48	No
Secondary	Change From Baseline in ACR Core Set	The changes from baseline in the ACR core set parameters at Week 48. Change from baseline to Week 48 over time in ACR core set: SJC, TJC, physician's global assessment of disease activity, patient's global assessment of disease activity, patient's assessment of pain, HAQ, ESR, and CRP. ACR20/50/70 response: =20%/50%/70% improvement in SJC; =20%/50%/70% improvement in TJC; and =20%/50%/70% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; physician's global assessment of disease activity, participant's assessment of disease activity, participant assessment of functional disability via a HAQ, and CRP at each visit.	Week 48	No
Secondary	Change From Baseline in Modified Total Sharp Score (mTSS)	mTSS = sum of erosion and Joint Space Narrowing (JSN) scores for 44 joints (16 per hand and 6 per foot). mTSS scores ranged from 0 (normal) to 448 (worst possible total score). Change: scores at observation minus score at baseline. An increase in mTSS from baseline. An increase in mTSS from baseline represented disease progression and/or joint worsening, no change represented halting of disease progression, and a decrease represented improvement.	Weeks 24 and 48	No
Secondary	Change From Baseline in Erosion Score	Changes from baseline in modified Sharp radiographic erosion score from baseline to Weeks 24 and 48. The change in score at week X (where X=Week 24 or Week 48, as appropriate) calculated as: Change = week X score minus screening score.	Weeks 24 and 48	No
Secondary	Change From Baseline in Joint Space Narrowing (JSN) Score	Changes from baseline in modified Sharp radiographic JSN score from baseline to Weeks 24 and 48. The change in score at week X (where X=Week 24 or Week 48, as appropriate) calculated as: Change = week X score minus screening score.	Weeks 24 and 48	No