Anti-TNF Agents for the Treatment of Rheumatoid Arthritis

• Frequency of adverse events [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
• Frequency of serious adverse events [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
• Frequency of treatment-related AEs of National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) Grade 3 or higher [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
• Change in DAS28 score [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
• ACR20 and ACR50 responses [ Time Frame: At Weeks 12 and 24 ] [ Designated as safety issue: No ]
• DAS28 responder status [ Time Frame: At Weeks 12 and 24 ] [ Designated as safety issue: No ]
• B-cell subset fractions in peripheral blood [ Time Frame: At Weeks 12 and 24 ] [ Designated as safety issue: No ]
• T-cell subset fraction in peripheral blood [ Time Frame: At Weeks 12 and 24 ] [ Designated as safety issue: No ]
• Changes in autoantibody status [ Time Frame: At study entry and Weeks 12 and 24 ] [ Designated as safety issue: No ]

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.

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 arms. Participants in Arm 1 will receive a subcutaneous injection of etanercept once every week for 24 weeks. Participants in Arm 2 will receive a subcutaneous injection 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 can be found in the protocol.

• Drug: Etanercept
  0.98 mL of 50 mg/mL solution of etanercept with 10 mg/mL sucrose, 5.8 mg/mL sodium chloride, 5.3 mg/mL L-arginine hydrochloride, 2.6 mg/mL sodium phosphate monobasic monohydrate, and 0.9 mg/mL sodium phosphate dibasic anhydrous
  Other Name: Enbrel
• Drug: Adalimumab
  0.8 mL of 40 mg/mL solution of adalimumab with 4.93 mg sodium chloride, 0.69 mg monobasic sodium phosphate dehydrate, 1.22 mg dibasic sodium phosphate dehydrate, 0.24 mg sodium citrate, 1.04 mg citric acid monohydrate, 9.6 mg mannitol, 0.8 mg polysorbate 80, and water
  Other Name: Humira

• Experimental: Etanercept Injection
  Participants will receive a subcutaneous injection of etanercept once every week for 24 weeks
  Intervention: Drug: Etanercept
• Experimental: Adalimumab Injection
  Participants will receive a subcutaneous injection of adalimumab once every 2 weeks for 24 weeks
  Intervention: Drug: Adalimumab

• Bingham CO 3rd. Emerging therapeutics for rheumatoid arthritis. Bull NYU Hosp Jt Dis. 2008;66(3):210-5. Review.
• Otomo K, Koike T. [TNF inhibitors for treatment of rheumatoid arthritis] Nippon Naika Gakkai Zasshi. 2008 Oct 10;97(10):2405-12. Review. Japanese. No abstract available.
• Soen S. [Daily practice using the guidelines for prevention and treatment of osteoporosis. The effects of anti-TNF therapy on bone and joint manifestations in rheumatoid arthritis] Clin Calcium. 2008 Aug;18(8):1169-75. Review. Japanese.

Inclusion Criteria:

• Diagnosis of RA. More information on this criterion can be found in the protocol.
• 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 this criterion can be found in the protocol.

Exclusion Criteria:

• Positive PPD (> 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. More information on this criterion can be found in the protocol.
• Concomitant use of DMARDSs. More information on this criterion can be found in the protocol.
• Any immunosuppressive therapy other than MTX, NSAIDs, or corticosteroids. More information on this criterion can be found in the protocol.
• Current or previous use of any biologic agent
• Presence of open leg ulcers
• Chronic or persistent infection that might be worsened by immunosuppressive treatment. More information on this criterion can be found in the protocol.
• Active infection or severe infections requiring hospitalization or treatment with 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. More information on this criterion can be found in the protocol.
• 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