Switching Anti-TNF-Alpha Agents in Rheumatoid Arthritis (RA)

Switching Anti-TNF-alpha Agents in Patients With RA With An Inadequate Response to TNF-alpha Inhibition

Rheumatoid Arthritis (RA) is a systemic inflammatory autoimmune disorder that leads to inflammation and progressive joint damage affecting 2.5 million people in the United States. The primary purpose of this study is to determine the effectiveness of switching to an alternative Tumor Necrosis Factor (TNF) alpha inhibitor in comparison to continuing treatment with an existing TNF-alpha inhibitor in adults suffering from RA in a setting of inadequate clinical response to etanercept or adalimumab.

Study Overview

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

Detailed Description

Over the past 10 years, advancements in biotechnology have revolutionized Rheumatoid Arthritis (RA) therapeutics with biologically-derived immunomodulating compounds. Tumor Necrosis Factor (TNF) alpha inhibitors constitute the largest class of these new biologic therapies. The purpose of this study is to determine the effectiveness of switching to an alternative TNF-alpha inhibitor in comparison to continuing treatment with an existing TNF-alpha inhibitor in adults suffering from RA who have had inadequate clinical response to the study drugs etanercept and adalimumab.

This study will last approximately 16 weeks. Participants will be randomized into two arms and receive injections once per week for 12 weeks. Participants in the adalimumab arm will receive alternating subcutaneous adalimumab and adalimumab placebo injections. Participants in the etanercept arm will receive subcutaneous etanercept injections.

This study consists of thirteen study visits after randomization. Study visits will occur on a weekly basis for 12 weeks prior to a follow-up visit at Week 16. A vital signs measurement and adverse event assessment will occur at each visit. A physical exam, assessment of tender and swollen joints, medication assessment, and blood collection will occur at Weeks 4, 8, 12, and 16.

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama
  • California
    • Palo Alto, California, United States, 94304
      • Stanford University
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale New Haven Hospital
  • Florida
    • Sarasota, Florida, United States, 34239
      • Sarasota Arthritis Research Center
    • Tampa, Florida, United States, 33614
      • Tampa Medical Group
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Medical Center
  • Michigan
    • Lansing, Michigan, United States, 48910
      • Justus Fiechtner, MD, PC
  • New York
    • Manhassett, New York, United States, 14642
      • Feinstein Institute for Medical Research NS-LIJ
    • Rochester, New York, United States, 14642
      • University of Rochester
  • North Carolina
    • Charlotte, North Carolina, United States, 28210
      • Carolina Bone and Joint
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Oklahoma Medical Research Foundation
  • Pennsylvania
    • Duncansville, Pennsylvania, United States, 16635
      • Altoona Center For Clinical Research
    • Pittsburgh, Pennsylvania, United States, 15260
      • University of Pittsburgh
  • Texas
    • Dallas, Texas, United States, 75231
      • Baylor Research Institute
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of Rheumatoid Arthritis
• Current treatment with either etanercept or adalimumab for at least 12 weeks prior to randomization
• Disease Activity Score (DAS) C-reactive Protein (CRP) 28 ≥ 4.4

• Treatment with concomitant Disease-Modifying Anti-Rheumatic Drugs (DMARDs) is permitted but not required as described below:

  1. Methotrexate - maximum dose of 25 mg per os (PO), intra-muscular (IM), or SQ weekly.
  2. Leflunomide - maximum dose of 20 mg PO daily.
  3. Sulfasalazine - maximum dose of 1,500 mg PO twice daily.
  4. Hydroxychloroquine - maximum dose of 400 mg PO daily.
• If taking DMARD(s), subjects must be on stable doses for at least 12 weeks prior to randomization.
• If treated with prednisone (or equivalent corticosteroid), on a stable dose of <= 10 mg/day for 28 days prior to randomization.
• Agree to use appropriate form of contraception. More information on this criterion can be found in the protocol.

Exclusion Criteria:

• Diagnosis of another autoimmune disease likely to require immunosuppression. More information on this criterion can be found in the protocol.
• Failing treatment with etanercept if previously treated with adalimumab
• Failing treatment with adalimumab if previously treated with etanercept
• Intraarticular injection within 4 weeks prior to randomization
• Concomitant use of DMARDs other than those described in Inclusion Criteria within 12 weeks of randomization.
• Concurrent use of any biologic agent other than etanercept or adalimumab
• Concomitant immunosuppressive therapy other than the Disease-Modifying Anti-Rheumatic Drugs (DMARDs), non-steroidal anti-inflammatory drugs (NSAIDs), or corticosteroids specified in the protocol
• Presence of open leg ulcers
• Chronic or persistent infection that may 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 intravenous antibiotics, antivirals, or antifungals within 30 days prior to randomization
• History of positive Purified Protein Derivative (PPD) or chest x-ray findings indicative of prior tuberculosis infection
• Any medical condition or treatment that, in the opinion of the investigator, would put the subject at risk by participation in the study
• History of malignancy. More information on this criterion can be found in the protocol.
• Certain abnormal laboratory values. More information on this criterion can be found in the protocol.
• Investigational biological or chemical agents within 4 weeks prior to randomization.
• History of drug or alcohol abuse within a year prior to randomization
• Treatment with natalizumab, rituximab, or another B-cell depleting therapy within a year prior to randomization
• Treatment with infliximab, abatacept, tocilizumab, golimumab, or certolizumab pegol within 12 weeks prior to randomization.
• Known allergy or hypersensitivity to study products
• Any psychiatric disorder that prevents the participant from providing informed consent
• Inability to follow protocol instructions
• Pregnant or breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Adalimumab / Adalimumab Placebo; 1 sub-cutaneous (SQ) injection of adalimumab or 1 SQ injection of placebo will be given in a blinded and alternating fashion for a total of 12 weeks	Drug: Adalimumab; 40 mg injection of adalimumab administered subcutaneously; Other Names: Humira; Drug: Adalimumab placebo; 1.0 ml .9% saline placebo administered subcutaneously; Other Names: Humira placebo
Experimental: Etanercept; Participants will receive 1 SQ injection of etanercept each week for 12 weeks	Drug: Etanercept; 50 mg dimeric fusion protein administered subcutaneously; Other Names: Enbrel

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in the Disease Activity Score Using C-reactive Protein (DAS28[CRP]) From Baseline to Week 12 in Non-Switchers Versus Switchers.	The DAS28 is a score on a scale (0 to 10) indicating current activity of rheumatoid arthritis (>5.1=high disease activity; <=3.2=low disease activity; <2.6=remission); a continuous variable which is a composite of 4 variables(the number of tender joints out of 28, the number of swollen joints out of 28 joints, serum C-reactive protein in mg/L (CRP) and subject assessment of disease activity measure on a visual analogue scale (VAS) of 100 mm).	Baseline, Week 12
Change in the Disease Activity Score Using C-reactive Protein (DAS28[CRP]) From Baseline to Week 12.	The DAS28 is a score on a scale (0 to 10) indicating current activity of rheumatoid arthritis (>5.1=high disease activity; <=3.2=low disease activity; <2.6=remission); a continuous variable which is a composite of 4 variables(the number of tender joints out of 28, the number of swollen joints out of 28 joints, serum C-reactive protein in mg/L (CRP) and subject assessment of disease activity measure on a visual analogue scale (VAS) of 100 mm).	Baseline, Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Participants With a Disease Activity Score Using C-reactive Protein (DAS28[CRP]) Value <= 3.2 (Low Disease Activity) at Week 12	The DAS28 is a score on a scale (0 to 10) indicating current activity of rheumatoid arthritis (>5.1=high disease activity; <=3.2=low disease activity; <2.6=remission); a continuous variable which is a composite of 4 variables(the number of tender joints out of 28, the number of swollen joints out of 28 joints, serum C-reactive protein in mg/L (CRP) and subject assessment of disease activity measure on a visual analogue scale (VAS) of 100 mm).	Week 12
Participants With a Disease Activity Score Using C-reactive Protein (DAS28[CRP]) Value < 2.6 (Remission) at Week 12	The DAS28 is a score on a scale (0 to 10) indicating current activity of rheumatoid arthritis (>5.1=high disease activity; <=3.2=low disease activity; <2.6=remission); a continuous variable which is a composite of 4 variables(the number of tender joints out of 28, the number of swollen joints out of 28 joints, serum C-reactive protein in mg/L (CRP) and subject assessment of disease activity measure on a visual analogue scale (VAS) of 100 mm).	Week 12
Participants With a Decrease in Disease Activity Score Using C-reactive Protein (DAS28[CRP]) Value of >1.2 From Baseline to Week 12 (European League Against Rheumatism (EULAR) Definition of a Moderate Response)	The EULAR definition of a Moderate Response is a decrease from baseline in the DAS28[CRP] value of ≥ 1.2.	Baseline, Week 12
Participants With an ACR 20 Response 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)	Week 12
Participants With an ACR 50 Response 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)	Week 12
Participants With an ACR 70 Response at Week 12	The American College of Rheumatology (ACR) 70 Responder Index is defined as someone who achieved at least 70% improvement in the tender and swollen 28- joint count, and 70% improvement in at least three of the following 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)	Week 12

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Study Chair: Larry Moreland, MD, University of Pittsburgh; Study Chair: Mark Genovese, MD, Stanford University

Publications and helpful links

General Publications

• Villeneuve E, Haraoui B. To switch or to change class-the biologic dilemma in rheumatoid arthritis. Nat Rev Rheumatol. 2010 May;6(5):301-5. doi: 10.1038/nrrheum.2010.45. Epub 2010 Apr 13.
• Rubbert-Roth A, Finckh A. Treatment options in patients with rheumatoid arthritis failing initial TNF inhibitor therapy: a critical review. Arthritis Res Ther. 2009;11 Suppl 1(Suppl 1):S1. doi: 10.1186/ar2666. Epub 2009 Apr 6.
• van Gestel AM, Haagsma CJ, van Riel PL. Validation of rheumatoid arthritis improvement criteria that include simplified joint counts. Arthritis Rheum. 1998 Oct;41(10):1845-50. doi: 10.1002/1529-0131(199810)41:103.0.CO;2-K.

Study record dates

Study Major Dates

• Study Start: November 1, 2008
• Primary Completion (Actual): October 1, 2010
• Study Completion (Actual): October 1, 2010

Study Registration Dates

• First Submitted: November 20, 2008
• First Submitted That Met QC Criteria: November 20, 2008
• First Posted (Estimate): November 24, 2008

Study Record Updates

• Last Update Posted (Estimate): October 4, 2012
• Last Update Submitted That Met QC Criteria: September 28, 2012
• Last Verified: August 1, 2012

More Information

Terms related to this study

• 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 ARA05