A Partially Blinded, Randomized, Multi-Center, Phase IV Trial to Evaluate Mechanism of Action of Anti-TNF Agents in Rheumatoid Arthritis
Overview
- Phase
- Phase 4
- Intervention
- Etanercept
- Conditions
- Rheumatoid Arthritis
- Sponsor
- National Institute of Allergy and Infectious Diseases (NIAID)
- Enrollment
- 63
- Locations
- 7
- Primary Endpoint
- Percentage of CD27+ Switched Memory B Cells at Week 12
- Status
- Completed
- Last Updated
- 4 years ago
Overview
Brief Summary
Rheumatoid arthritis (RA) is a chronic disease that leads to inflammation and progressive joint damage. RA is a systemic inflammatory autoimmune disorder affecting almost 1% of the United States population. Current therapies target the immune system early in the disease process before joint damage occurs, and include drugs such as methotrexate (MTX) and tumor necrosis factor (TNF)-blocking agents. The primary purpose of this study is to determine the effectiveness of two TNF inhibitors, etanercept and adalimumab, on memory B lymphocytes (B-cells) in the peripheral blood of participants with RA.
Additionally, there are 4 optional sub-studies as part of the trial:
- B-Cell Kinetic Sub-Study to look at changes in B-cell subsets over time and how quickly reductions in B-cell memory occur
- Vaccine Response Sub-Study to assess B cell memory in response to immunization with hepatitis B,-hepatitis A, and diphtheria/tetanus vaccines, and to determine whether T-cell vaccine responses are altered with TNF blockade
- Tonsil Biopsy Sub-Study to evaluate how TNF blockade affects memory B-cells in the tonsil dendritic cells and germinal cells
- Synovial Biopsy Sub-Study to evaluate how TNF blockade affects changes in memory B-cells in lymphoid tissue.
Detailed Description
RA is characterized by persistent inflammation of peripheral joints, causing pain, stiffness, swelling and warmth. Over the past 10 years, advancements in biotechnology have revolutionized RA therapeutics with biologically-derived immunomodulating compounds. TNF-alpha inhibitors constitute the largest class of these new biologic therapies. The purpose of this study is to determine the effectiveness two TNF inhibitors, etanercept and adalimumab, on memory B lymphocytes (B-cells) in the peripheral blood of participants with RA. This study will last 24 weeks. Participants will be randomized into one of two treatment groups. Participants in one group will receive a dose of etanercept once every week for 24 weeks. Participants in the other group will receive a dose of adalimumab once every 2 weeks for 24 weeks. This study consists of seven study visits after randomization and will occur at study entry and Weeks 4, 8, 12, 16, 20 and 24. Blood collection will occur at all study visits. A written participant assessment, vital signs, and physical exam will occur at study entry and Weeks 12 and 24. Follow-up calls to assess safety are scheduled for Weeks 4, 8, 16, and 20. Additionally, participants will be offered the opportunity to enter one of four sub-studies as mentioned in the brief summary above: B Cell Kinetic Sub-Study, Vaccine Response Sub-Study, Tonsil Biopsy Sub-Study, and Synovial Biopsy Sub-Study. More information on these sub-studies is in the protocol.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Diagnosis of RA\*
- •Disease duration as defined from the onset of symptoms of at least 3 months prior to study entry
- •Active RA with DAS28 \> 4.4, clinically requiring the addition of anti-TNF therapy
- •Stable dose of MTX between 7.5 mg and 25 mg weekly for at least 8 weeks prior to study entry
- •Able and willing to self-administer subcutaneous injections or have available qualified person(s) or caregiver to administer subcutaneous injections
- •For females, agree to use accepted methods of contraception during the duration of the study and for 150 days after study completion\*. \*More information on these criterion can be found in the protocol.
Exclusion Criteria
- •Positive PPD test - a tuberculosis (TB) skin test: (\> 5 mm induration regardless of prior Bacille Calmette-Guerin \[BCG\] vaccine administration) without evidence of ongoing treatment for at least 30 days or completed treatment
- •History of positive PPD or chest x-ray findings indicative of prior TB infection, without documentation of either treatment for TB infection or chemoprophylaxis for TB exposure
- •Prednisone dose \> 10 mg/day (or equivalent dose of another corticosteroid) within 30 days prior to study entry
- •Definitive diagnosis of another autoimmune disease that may require immunosuppression for treatment\*
- •Concomitant use of DMARDSs (e.g., disease-modifying antirheumatic drugs)\*
- •Any immunosuppressive therapy other than MTX, NSAIDs, or corticosteroids\*
- •Current or previous use of any biologic agent
- •Presence of open leg ulcers
- •Chronic or persistent infection that might be worsened by immunosuppressive treatment\*
- •Active infection or severe infections requiring hospitalization or treatment with intravenous (IV) antibiotics, IV antivirals, or IV antifungals within 30 days prior to study entry
Arms & Interventions
Etanercept
Participants receive a subcutaneous injection of etanercept once every week for 24 weeks
Intervention: Etanercept
Adalimumab
Participants receive a subcutaneous injection of adalimumab once every 2 weeks for 24 weeks
Intervention: Adalimumab
Outcomes
Primary Outcomes
Percentage of CD27+ Switched Memory B Cells at Week 12
Time Frame: Week 12
Analysis of the steady state composition of the B cell compartment were performed using ex-vivo multicolor flow cytometry on Ficoll isolated peripheral blood mononuclear cells (PBMCs). CD27+ switched memory B cells are a subset of B cells and are assessed by flow cytometry. CD27+ switched memory B cells are expressed as a percent of B cells. Lower CD27+ memory B cells indicate a decrease in the generation of B cell memory which may be caused by blocking lymphotoxin (LT) and tumor necrosis factor (TNF) signaling.
Secondary Outcomes
- Percentage of Participants Meeting ACR20 Response Criteria at Week 24(Week 24)
- Percentage of Participants Meeting ACR50 Response Criteria at Week 12(Week 12)
- Percentage of Participants Meeting ACR50 Response Criteria at Week 24(Week 24)
- Percentage of Participants Fulfilling DAS-28-CRP "Good or Moderate Response" Criteria at Week 12(Week 12)
- Percentage of Participants Meeting ACR20 Response Criteria at Week 12(Week 12)
- Percentage of Participants Fulfilling DAS-28-CRP "Good or Moderate Response" Criteria at Week 24(Week 24)