Anti-TNF Agents for the Treatment of Rheumatoid Arthritis

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00837434
First received: February 3, 2009
Last updated: March 26, 2014
Last verified: March 2014
  Purpose

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.

Condition Intervention Phase
Rheumatoid Arthritis
Drug: Etanercept
Drug: Adalimumab
Phase 4

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • Change in memory B-cells in peripheral blood [ Time Frame: Week 12 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • 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.



Enrollment: 63
Study Start Date: March 2009
Study Completion Date: January 2014
Primary Completion Date: January 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Etanercept Injection
Participants will receive a subcutaneous injection of etanercept once every week for 24 weeks
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
Experimental: Adalimumab Injection
Participants will receive a subcutaneous injection of adalimumab once every 2 weeks for 24 weeks
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

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 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.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  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: NCT00837434

Locations
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
Sponsors and Collaborators
Investigators
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
  More Information

Additional Information:
Publications:
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00837434     History of Changes
Other Study ID Numbers: DAIT ARA06
Study First Received: February 3, 2009
Last Updated: March 26, 2014
Health Authority: United States: Federal Government

Additional relevant MeSH terms:
Arthritis
Arthritis, Rheumatoid
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Adalimumab
TNFR-Fc fusion protein
Anti-Inflammatory Agents
Therapeutic Uses
Pharmacologic Actions
Antirheumatic Agents
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Immunologic Factors
Immunosuppressive Agents
Central Nervous System Agents

ClinicalTrials.gov processed this record on October 01, 2014