Anti-TNF Agents for the Treatment of Rheumatoid Arthritis

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

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: Etanercept; Drug: Adalimumab

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 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.

• Study Type: Interventional
• Enrollment (Actual): 63
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama
  • California
    • San Francisco, California, United States, 94143
      • University of California, San Francisco
  • Connecticut
    • New Haven, Connecticut, United States, 06519
      • Yale University School Medicine
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University Of Chicago
  • New York
    • Manhasset, New York, United States, 11030
      • Feinstein Institute for Medical Research
    • Rochester, New York, United States, 14642
      • University of Rochester
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Etanercept; Participants receive a subcutaneous injection of etanercept once every week for 24 weeks	Drug: Etanercept; 50 mg dose of etanercept by subcutaneous injection; Other Names: Enbrel®
EXPERIMENTAL: Adalimumab; Participants receive a subcutaneous injection of adalimumab once every 2 weeks for 24 weeks	Drug: Adalimumab; 40 mg dose of adalimumab by subcutaneous injection; Other Names: Humira®)

What is the study measuring?

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

Collaborators and Investigators

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

Publications and helpful links

General Publications

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

Helpful Links

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

Study record dates

Study Major Dates

• Study Start: March 1, 2009
• Primary Completion (ACTUAL): November 1, 2013
• Study Completion (ACTUAL): January 1, 2014

Study Registration Dates

• First Submitted: February 3, 2009
• First Submitted That Met QC Criteria: February 3, 2009
• First Posted (ESTIMATE): February 5, 2009

Study Record Updates

• Last Update Posted (ACTUAL): September 22, 2021
• Last Update Submitted That Met QC Criteria: August 31, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: tumor necrosis factor (TNF) blockade; inflammatory autoimmune disorder
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Immunosuppressive Agents; Immunologic Factors; Gastrointestinal Agents; Etanercept; Adalimumab
• Other Study ID Numbers: DAIT ARA06; NIAID CRMS ID#: 20001 (OTHER: DAIT NIAID)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The plan is to share data upon completion of the study in: Immunology Database and Analysis Portal (ImmPort), a long-term archive of clinical and mechanistic data from DAIT-funded grants and contracts.
• IPD Sharing Time Frame: On average, within 24 months after database lock for the trial.
• IPD Sharing Access Criteria: Open access.

Study Data/Documents

1. Individual Participant Data Set
   Information identifier: SDY824
   Information comments: The Immunology Database and Analysis Portal (ImmPort) is a long-term archive of clinical and mechanistic data from DAIT-funded grants and contracts. The portal includes available analysis tools for researchers.
2. Study Protocol
   Information identifier: SDY824
   Information comments: ImmPort study identifier is SDY824.
3. Study summary, -design, -adverse event(s), -summary of participant assessments, -medications, -demographics, -lab tests, -mechanistic assays, -study files et al.
   Information identifier: SDY824
   Information comments: ImmPort study identifier is SDY824.