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

This study has been terminated.
(Study was terminated after enrollment of 3 participants due to recruitment difficulties.)
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT00422942
First received: January 15, 2007
Last updated: July 14, 2014
Last verified: July 2014
  Purpose

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.


Condition Intervention Phase
Rheumatoid Arthritis
Drug: rituximab [MabThera/Rituxan]
Drug: Methotrexate
Phase 2

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

Resource links provided by NLM:


Further study details as provided by Hoffmann-La Roche:

Primary Outcome Measures:
  • Change From Baseline in Absolute B Cell Cluster Differential 19 Positive (CD19+) Counts in Synovial Tissues [ Time Frame: Weeks 12, 24, and 36 ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Absolute B Cell CD19+ Counts in Peripheral Blood [ Time Frame: Weeks 4, 12, 24, 36, and 48 ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Change From Baseline in Absolute Counts of Cells Expressing CD20+ and CD22+ in Absolute B Cell (CD19+) Counts in Synovial Tissues [ Time Frame: Weeks 12, 24, and 36 ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Absolute Counts of Cells Expressing CD20+ and CD22+ in Absolute B Cell (CD19+) Counts in Peripheral Blood [ Time Frame: Weeks 4,12, 24, 36, and 48 ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Levels of Key Cytokines (Interleukin [IL]-1beta [β], Tumor Necrosis Factor [TNF]-Alpha [α], IL-4, IL-6, IL-10, and IL-13) in Blood (Serum) [ Time Frame: Days 15 and 183 and Weeks 4, 12, 24, 36, and 48 ] [ Designated as safety issue: No ]
    The change in levels of key cytokines (IL-1β, TNF-α, 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.

  • Change From Baseline in Levels of Key Cytokines in (IL-1β, TNF-α, IL-6, and IL-10) in Synovial Tissues [ Time Frame: Weeks 12, 24, and 36 ] [ Designated as safety issue: No ]
    The change in levels of key cytokines in (IL-1β, TNF-α, IL-6, and IL-10) in synovial tissues at Weeks 12, 24, and 36, relative to baseline.

  • Change From Baseline in Myelocytomatosis Oncogene (C-myc) and BCL2-associated X Protein (BAX) in Peripheral Blood [ Time Frame: Days 15 and 183 ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants Achieving American College of Rheumatology 20 Percent (20%) 50%, and 70% (ACR20/50/70) Response [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    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).

  • Change From Baseline in Disease Activity Score Based on 28 Joint Count (DAS28) Erythrocyte Sedimentation Rate (ESR) Score [ Time Frame: Weeks 12, 24, 36, and 48 ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants Achieving Response by European League Against Rheumatism (EULAR) Category [ Time Frame: Weeks 24, 36, and 48 ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in ACR Core Set [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Modified Total Sharp Score (mTSS) [ Time Frame: Weeks 24 and 48 ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Erosion Score [ Time Frame: Weeks 24 and 48 ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Joint Space Narrowing (JSN) Score [ Time Frame: Weeks 24 and 48 ] [ Designated as safety issue: No ]
    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.


Enrollment: 3
Study Start Date: January 2006
Study Completion Date: June 2010
Primary Completion Date: June 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1 Drug: rituximab [MabThera/Rituxan]
1000mg iv on days 1 and 15
Drug: Methotrexate
10-25mg po weekly

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00422942

Locations
Netherlands
Amsterdam, Netherlands, 1105 AZ
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director: Clinical Trials Hoffmann-La Roche
  More Information

No publications provided

Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT00422942     History of Changes
Other Study ID Numbers: WA19078
Study First Received: January 15, 2007
Results First Received: May 7, 2014
Last Updated: July 14, 2014
Health Authority: Netherlands: Central Committee on Research inv. Human Subjects (CCMO)

Additional relevant MeSH terms:
Arthritis
Arthritis, Rheumatoid
Autoimmune Diseases
Connective Tissue Diseases
Immune System Diseases
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Methotrexate
Rituximab
Abortifacient Agents
Abortifacient Agents, Nonsteroidal
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antirheumatic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors
Pharmacologic Actions
Physiological Effects of Drugs
Reproductive Control Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on October 20, 2014