Anti-TNF Agents for the Treatment of Rheumatoid Arthritis

NCT00837434 | Completed Phase 4 Results DMC

• 2 other identifiers: DAIT ARA06NIAID CRMS ID#: 20001
• Study Type: interventional
• Target: 63
• Locations: 1 country
• Sites: 7

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.

Conditions

Rheumatoid Arthritis

Keywords

tumor necrosis factor (TNF) blockade; inflammatory autoimmune disorder

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• Percentage of Participants Fulfilling DAS-28-CRP "Good or Moderate Response" Criteria at Week 12

  Week 12

• Percentage of Participants Fulfilling DAS-28-CRP "Good or Moderate Response" Criteria at Week 24

  Week 24

• Percentage of Participants Meeting ACR20 Response Criteria at Week 12

  Week 12

• Percentage of Participants Meeting ACR20 Response Criteria at Week 24

  Week 24

• Percentage of Participants Meeting ACR50 Response Criteria at Week 12

  Week 12

Study Arms (2)

Etanercept

EXPERIMENTAL

Participants receive a subcutaneous injection of etanercept once every week for 24 weeks

Drug: Etanercept

Adalimumab

EXPERIMENTAL

Participants receive a subcutaneous injection of adalimumab once every 2 weeks for 24 weeks

Drug: Adalimumab

Interventions

Etanercept DRUG

50 mg dose of etanercept by subcutaneous injection

Also known as: Enbrel®

Etanercept

Adalimumab DRUG

40 mg dose of adalimumab by subcutaneous injection

Also known as: Humira®)

Adalimumab

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead
• Autoimmunity Centers of Excellence: collaborator
• Rho Federal Systems Division, Inc.: collaborator

Study Sites (7)

University of Alabama

Birmingham, Alabama, 35294, United States

Location

University of California, San Francisco

San Francisco, California, 94143, United States

Location

Yale University School Medicine

New Haven, Connecticut, 06519, United States

Location

University of Chicago

Chicago, Illinois, 60637, United States

Location

Feinstein Institute for Medical Research

Manhasset, New York, 11030, United States

Location

University of Rochester

Rochester, New York, 14642, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

Related Publications (4)

• Bingham CO 3rd. Emerging therapeutics for rheumatoid arthritis. Bull NYU Hosp Jt Dis. 2008;66(3):210-5.

  PMID: 18937634 BACKGROUND

• Otomo K, Koike T. [TNF inhibitors for treatment of rheumatoid arthritis]. Nihon Naika Gakkai Zasshi. 2008 Oct 10;97(10):2405-12. doi: 10.2169/naika.97.2405. No abstract available. Japanese.

  PMID: 19149036 BACKGROUND

• 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. Japanese.

  PMID: 18677056 BACKGROUND

• Meednu N, Barnard J, Callahan K, Coca A, Marston B, Thiele R, Tabechian D, Bolster M, Curtis J, Mackay M, Graf J, Keating R, Smith E, Boyle K, Keyes-Elstein L, Welch B, Goldmuntz E, Anolik JH. Activated Peripheral Blood B Cells in Rheumatoid Arthritis and Their Relationship to Anti-Tumor Necrosis Factor Treatment and Response: A Randomized Clinical Trial of the Effects of Anti-Tumor Necrosis Factor on B Cells. Arthritis Rheumatol. 2022 Feb;74(2):200-211. doi: 10.1002/art.41941. Epub 2021 Dec 27.

  PMID: 34347945 RESULT

Related Links

• National Institute of Allergy and Infectious Diseases (NIAID)
• Division of Allergy, Immunology, and Transplantation (DAIT)

MeSH Terms

Conditions

Arthritis, Rheumatoid

Interventions

Etanercept; Adalimumab

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Immunoglobulin Fc Fragments; Immunoglobulin Fragments; Peptide Fragments; Peptides; Amino Acids, Peptides, and Proteins; Immunoglobulin Constant Regions; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Serum Globulins; Globulins; Receptors, Tumor Necrosis Factor; Receptors, Cytokine; Receptors, Immunologic; Receptors, Cell Surface; Membrane Proteins; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies

Results Point of Contact

• Title: Director, Clinical Research Program
• Organization: DAIT/NIAID

DAITClinicalTrialsGov@niaid.nih.gov

301-594-7669

Study Officials

• 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

  STUDY CHAIR

• Meggan Mackay, MD

  The Feinstein Institute for Medical Research NS-LIJ Health System

  PRINCIPAL INVESTIGATOR

• Jeffrey Curtis, MD

  University of Alabama at Birmingham

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 3, 2009
• First Posted: February 5, 2009
• Study Start: March 1, 2009
• Primary Completion: November 1, 2013
• Study Completion: January 1, 2014
• Last Updated: September 22, 2021
• Results First Posted: April 14, 2015

Record last verified: 2021-08

Data Sharing

• IPD Sharing: Will share
• Time Frame: On average, within 24 months after database lock for the trial.
• Access Criteria: Open access.

Locations

US (7)