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Rheumatoid ArthritisPhase 4NCT00837434

Anti-TNF Agents for the Treatment of Rheumatoid Arthritis

A Phase 4 study testing Etanercept and Adalimumab in people with Rheumatoid Arthritis, run by National Institute of Allergy and Infectious Diseases (NIAID) at 7 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 75 years
Conditions the study is for
Rheumatoid Arthritis
What is being tested?
Etanercept and Adalimumab
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
63 participants
Where
7 sitesUnited States
Study dates
Mar 2009to Jan 2014
Phase
Phase 4
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 75 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.

Who cannot join

  • 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*
Show all 20Show fewer
  • 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.

Trial locations and contacts

7 sites in 1 country.

7 sites in 1 country

United States7 sites

  • University of Alabama

    Birmingham, Alabama, 35294

  • Medical University of South Carolina

    Charleston, South Carolina, 29425

  • University of Chicago

    Chicago, Illinois, 60637

  • Feinstein Institute for Medical Research

    Manhasset, New York, 11030

  • Yale University School Medicine

    New Haven, Connecticut, 06519

  • University of Rochester

    Rochester, New York, 14642

  • University of California, San Francisco

    San Francisco, California, 94143

Other trials in United States

About this study

Official title: 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.
Read the 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.

Being tested
Etanercept, Adalimumab
Keywords
tumor necrosis factor (TNF) blockade, inflammatory autoimmune disorder
Medical subject headings
Arthritis, Rheumatoid

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • EtanerceptDrug

    Also called Enbrel®

    50 mg dose of etanercept by subcutaneous injection

  • AdalimumabDrug

    Also called Humira®)

    40 mg dose of adalimumab by subcutaneous injection

Study groups in NCT00837434
Study groupRoleWhat they receive
EtanerceptExperimentalParticipants receive a subcutaneous injection of etanercept once every week for 24 weeks
Receives: Drug: Etanercept
AdalimumabExperimentalParticipants receive a subcutaneous injection of adalimumab once every 2 weeks for 24 weeks
Receives: Drug: Adalimumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: Week 12

Secondary outcomes (6)

  1. 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].

    Measured: Week 12

  2. 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.

    Measured: Week 24

  3. 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.

    Measured: Week 12

  4. 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.

    Measured: Week 24

  5. 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.

    Measured: Week 12

  6. 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.

    Measured: Week 24

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted5 Feb 2009 (estimated)
  2. Study startMar 2009
  3. Primary completionNov 2013
  4. Study completionJan 2014

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Single blind
Who is masked
Investigator
Enrolment
63 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00837434
Sponsor's protocol ID
DAIT ARA06
Other IDs
NIAID CRMS ID#: 20001
Status last verified
Aug 2021
First submitted
3 Feb 2009
Last updated
22 Sep 2021
Data monitoring committee
Yes
Individual data sharing
Yes: 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.

Publications

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

    PubMed 18937634

  • 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.

    PubMed 19149036

  • 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.

    PubMed 18677056

  • 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.

    PubMed 34347945

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Etanercept and Adalimumab in people with Rheumatoid Arthritis, run by National Institute of Allergy and Infectious Diseases (NIAID) at 7 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 22 Sep 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 7 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 14 Apr 2015). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Percentage of CD27+ Switched Memory B Cells at Week 12 (time frame: Week 12). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00837434, which also lists 4 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Sep 2021.

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