Anti-TNF Agents for the Treatment of Rheumatoid Arthritis

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Partially Blinded, Randomized, Multi-Center, Phase IV Trial to Evaluate Mechanism of Action of Anti-TNF Agents in Rheumatoid Arthritis

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Etanercept
* Drug: Adalimumab


Participation Criteria
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Eligibility Criteria
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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 Received oral antibiotics, antivirals, or antifungals within 14 days prior to study entry Certain abnormal laboratory values* Any medical condition that, in the opinion of the investigator, would interfere with the study History of malignancy other than treated localized carcinoma in situ of the cervix or adequately treated non-metastatic squamous or basal cell skin carcinoma within 10 years prior to study entry Any Investigational agent within the earlier of 4 weeks or 5 half-lives prior to study entry History of drug or alcohol abuse within 6 months prior to study entry Known allergy or hypersensitivity to study products Inability or unwillingness to follow the protocol Any condition or treatment that, in the opinion of the investigator, places the participant at an unacceptable risk Pregnant or breastfeeding *More information on these criterion are in the protocol.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Etanercept<br>Participants receive a subcutaneous injection of etanercept once every week for 24 weeks | Drug: Etanercept<br>* 50 mg dose of etanercept by subcutaneous injection<br>* Other names: Enbrel®;|
| Experimental: Adalimumab<br>Participants receive a subcutaneous injection of adalimumab once every 2 weeks for 24 weeks | Drug: Adalimumab<br>* 40 mg dose of adalimumab by subcutaneous injection<br>* Other names: Humira®);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of CD27+ Switched Memory B Cells at 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. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Fulfilling DAS-28-CRP Good or Moderate Response Criteria at Week 12 | Good responders: change in DAS28-CRP (Baseline-Week12) > 1.2 and Week 12 DAS-CRP score was <\= 3.2. If the conditions for non-response* or good response were not met, the DAS28-CRP response was considered moderate. Participants with measurements for designated time points were included in the analysis. [*Non-responders had any of 4 conditions: change in DAS28-CRP (Baseline -Week 12) <0.6; 0.6 <\= change in DAS28-CRP ( Baseline-Week 12) < 1.2 with Week 12 DAS28-CRP score > 5.1; a flare that required prednisone > 10 mg/day (or equivalent) beyond Week 8 or the inability to taper prednisone to <\= 10 mg/day by Week 8; or the participant required prednisone > 20 mg/day at any time point]. | Week 12 | 
| Percentage of Participants Fulfilling DAS-28-CRP Good or Moderate Response Criteria at Week 24 | Good responders had: change in DAS28-CRP (Baseline-Week 24) > 1.2 and the Week 24 DAS-CRP score was <= 3.2. If the conditions for non-response* or good response were not met then the DAS28-CRP response was considered moderate.[*Non-responders had any of the 4 conditions: change in DAS28-CRP (Baseline -Week 24) <0.6; 0.6 <\= change in DAS28-CRP ( Baseline-Week 24) < 1.2 with Week 24 DAS28-CRP score > 5.1 ; a flare that required prednisone > 10 mg/day (or equivalent) beyond Week 8 or the inability to taper prednisone to <= 10 mg/day by Week 8; or the participant required prednisone > 20 mg/day at any time point]. Participants with measurements for designated time points were included in the analysis. | Week 24 | 
| Percentage of Participants Meeting ACR20 Response Criteria at Week 12 | The American College of Rheumatology (ACR) 20 Responder Index is defined as someone who achieved at least 20% improvement in the tender and swollen 28-joint count, and 20% improvement in at least three of the following 5 measures: Patient's pain assessment (Visual Analogue Scale (VAS) 100 mm) Patient's global assessment of disease activity (VAS 100 mm) Physician's global assessment of disease activity (VAS 100 mm) Patient self-assessed disability (Health Assessment Questionnaire (HAQ) score) Acute phase reactant (CRP). Participants with measurements for designated time points were included in the analysis. | Week 12 | 
| Percentage of Participants Meeting ACR20 Response Criteria at Week 24 | The American College of Rheumatology (ACR) 20 Responder Index is defined as someone who achieved at least 20% improvement in the tender and swollen 28-joint count, and 20% improvement in at least three of the following 5 measures: Patient's pain assessment (Visual Analogue Scale (VAS) 100 mm) Patient's global assessment of disease activity (VAS 100 mm) Physician's global assessment of disease activity (VAS 100 mm) Patient self-assessed disability (Health Assessment Questionnaire (HAQ) score) Acute phase reactant (CRP). Participants with measurements for designated time points were included in the analysis. | Week 24 | 
| Percentage of Participants Meeting ACR50 Response Criteria at Week 12 | The American College of Rheumatology (ACR) 50 Responder Index is defined as someone who achieved at least 50% improvement in the tender and swollen 28-joint count, and 50% improvement in at least three of the following 5 measures: Patient's pain assessment (Visual Analogue Scale (VAS) 100 mm) Patient's global assessment of disease activity (VAS 100 mm) Physician's global assessment of disease activity (VAS 100 mm) Patient self-assessed disability (Health Assessment Questionnaire (HAQ) score) Acute phase reactant (CRP). Participants with measurements for designated time points were included in the analysis. | Week 12 | 
| Percentage of Participants Meeting ACR50 Response Criteria at Week 24 | The American College of Rheumatology (ACR) 50 Responder Index is defined as someone who achieved at least 50% improvement in the tender and swollen 28-joint count, and 50% improvement in at least three of the following 5 measures: Patient's pain assessment (Visual Analogue Scale (VAS) 100 mm) Patient's global assessment of disease activity (VAS 100 mm) Physician's global assessment of disease activity (VAS 100 mm) Patient self-assessed disability (Health Assessment Questionnaire (HAQ) score) Acute phase reactant (CRP). Participants with measurements for designated time points were included in the analysis. | Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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tumor necrosis factor (TNF) blockade, inflammatory autoimmune disorder