Anti-TNF Agents for the Treatment of Rheumatoid Arthritis
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.
|Study Design:||Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Investigator)
Primary Purpose: Treatment
|Official Title:||A Partially Blinded, Randomized, Multi-Center, Phase IV Trial to Evaluate Mechanism of Action of Anti-TNF Agents in Rheumatoid Arthritis|
- Change in memory B-cells in peripheral blood [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
- Frequency of adverse events [ Time Frame: Week 24 ] [ Designated as safety issue: Yes ]
- Frequency of serious adverse events [ Time Frame: Week 24 ] [ 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: Week 24 ] [ Designated as safety issue: Yes ]
- Change in DAS28 score from Baseline/Treatment Initiation to Week 12 [ Time Frame: Week 12 ] [ 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 ]
An ordinal measure of response defined at Week 12 and also at Week 24 using DAS28 at each post-baseline time-point and change in DAS28 from baseline accordingly:
DAS28 non-responders are defined as DAS28 change of < 0.6 OR DAS28 change 0.6-1.2 with a DAS28 > 5.1 OR any flare that requires prednisone > 10 mg/day (or equivalent dose of another corticosteroid) beyond Week 8 for the 12 week endpoint and beyond Week 20 for the 24 week endpoint or the inability to taper prednisone to < 10 mg/day (or equivalent dose of another corticosteroid) by Week 8 or Week 20 OR Any subject that requires prednisone > 20 mg/day (or equivalent dose of another corticosteroid) at any time point.
DAS28 good responders are defined as having a DAS28 decrease of > 1.2 and a DAS28 < 3.2 DAS28 moderate responders are defined as all remaining subjects that do not fit in either the non-responder or good responder categories.
|Study Start Date:||March 2009|
|Study Completion Date:||January 2014|
|Primary Completion Date:||January 2014 (Final data collection date for primary outcome measure)|
Experimental: Etanercept Injection
Participants will receive a subcutaneous injection of etanercept once every week for 24 weeks
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
Experimental: Adalimumab Injection
Participants will receive a subcutaneous injection of adalimumab once every 2 weeks for 24 weeks
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
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00837434
|United States, Alabama|
|University of Alabama|
|Birmingham, Alabama, United States|
|United States, California|
|University of California, San Francisco|
|San Francisco, California, United States|
|United States, Connecticut|
|Yale University School Medicine|
|New Haven, Connecticut, United States, 06519|
|United States, Illinois|
|University of Chicago|
|Chicago, Illinois, United States|
|United States, New York|
|Feinstein Institute for Medical Research|
|Manhassett, New York, United States, 11030|
|University of Rochester|
|Rochester, New York, United States|
|United States, South Carolina|
|Medical University of South Carolina|
|Charleston, South Carolina, United States, 29425|
|Study Chair:||Jennifer A. Anolik, MD, PhD||University of Rochester|
|Study Chair:||Inaki Sanz, MD||University of Rochester|
|Study Chair:||R. John Looney, MD||University of Rochester|
|Principal Investigator:||Meggan Mackay, MD||The Feinstein Institute for Medical Research NS-LIJ Health System|
|Principal Investigator:||Jeffrey Curtis, MD||University of Alabama at Birmingham|