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

• ClinicalTrials.gov Identifier: NCT00796705
• Recruitment Status: Terminated
• First Posted: November 24, 2008
• Results First Posted: August 13, 2012
• Last Update Posted: October 4, 2012
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Information provided by (Responsible Party): National Institute of Allergy and Infectious Diseases (NIAID)

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Rheumatoid Arthritis	Drug: Adalimumab; Drug: Adalimumab placebo; Drug: Etanercept	Phase 4

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 13 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Switching Anti-TNF-alpha Agents in Patients With RA With An Inadequate Response to TNF-alpha Inhibition
• Study Start Date: November 2008
• Actual Primary Completion Date: October 2010
• Actual Study Completion Date: October 2010

Arms and Interventions

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 Name: Humira; Drug: Adalimumab placebo; 1.0 ml .9% saline placebo administered subcutaneously; Other Name: 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 Name: Enbrel

Outcome Measures

Primary Outcome Measures :

1. Change in the Disease Activity Score Using C-reactive Protein (DAS28[CRP]) From Baseline to Week 12 in Non-Switchers Versus Switchers. [ Time Frame: Baseline, 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).
2. Change in the Disease Activity Score Using C-reactive Protein (DAS28[CRP]) From Baseline to Week 12. [ Time Frame: Baseline, 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).

Secondary Outcome Measures :

1. Participants With a Disease Activity Score Using C-reactive Protein (DAS28[CRP]) Value <= 3.2 (Low Disease Activity) at Week 12 [ Time Frame: 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).
2. Participants With a Disease Activity Score Using C-reactive Protein (DAS28[CRP]) Value < 2.6 (Remission) at Week 12 [ Time Frame: 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).
3. 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) [ Time Frame: Baseline, Week 12 ]
   The EULAR definition of a Moderate Response is a decrease from baseline in the DAS28[CRP] value of ≥ 1.2.
4. Participants With an ACR 20 Response at Week 12 [ Time Frame: 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)
5. Participants With an ACR 50 Response at Week 12 [ Time Frame: 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)
6. Participants With an ACR 70 Response at Week 12 [ Time Frame: 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)

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, Alabama

University of Alabama

Birmingham, Alabama, United States, 35294

United States, California

Stanford University

Palo Alto, California, United States, 94304

United States, Connecticut

Yale New Haven Hospital

New Haven, Connecticut, United States, 06520

United States, Florida

Sarasota Arthritis Research Center

Sarasota, Florida, United States, 34239

Tampa Medical Group

Tampa, Florida, United States, 33614

United States, Illinois

University of Chicago Medical Center

Chicago, Illinois, United States, 60637

United States, Michigan

Justus Fiechtner, MD, PC

Lansing, Michigan, United States, 48910

United States, New York

Feinstein Institute for Medical Research NS-LIJ

Manhassett, New York, United States, 14642

University of Rochester

Rochester, New York, United States, 14642

United States, North Carolina

Carolina Bone and Joint

Charlotte, North Carolina, United States, 28210

Duke University Medical Center

Durham, North Carolina, United States, 27710

United States, Oklahoma

Oklahoma Medical Research Foundation

Oklahoma City, Oklahoma, United States, 73104

United States, Pennsylvania

Altoona Center for Clinical Research

Duncansville, Pennsylvania, United States, 16635

University of Pittsburgh

Pittsburgh, Pennsylvania, United States, 15260

United States, Texas

Baylor Research Institute

Dallas, Texas, United States, 75231

United States, Utah

University of Utah

Salt Lake City, Utah, United States, 84132

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Study Chair: Larry Moreland, MD; University of Pittsburgh
• Study Chair: Mark Genovese, MD; Stanford University

More Information

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.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT00796705
• Other Study ID Numbers: DAIT ARA05
• First Posted: November 24, 2008
• Results First Posted: August 13, 2012
• Last Update Posted: October 4, 2012
• Last Verified: August 2012

Additional relevant MeSH terms:

Arthritis; Arthritis, Rheumatoid; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Adalimumab; Etanercept; Tumor Necrosis Factor Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Immunosuppressive Agents; Immunologic Factors