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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Adalimumab
* Drug: Adalimumab placebo
* Drug: Etanercept


Participation Criteria
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Eligibility Criteria
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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: Methotrexate - maximum dose of 25 mg per os (PO), intra-muscular (IM), or SQ weekly. Leflunomide - maximum dose of 20 mg PO daily. Sulfasalazine - maximum dose of 1,500 mg PO twice daily. 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Adalimumab / Adalimumab Placebo<br>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<br>* 40 mg injection of adalimumab administered subcutaneously<br>* Other names: Humira;Drug: Adalimumab placebo<br>* 1.0 ml .9% saline placebo administered subcutaneously<br>* Other names: Humira placebo;|
| Experimental: Etanercept<br>Participants will receive 1 SQ injection of etanercept each week for 12 weeks | Drug: Etanercept<br>* 50 mg dimeric fusion protein administered subcutaneously<br>* Other names: Enbrel;|

What is the study measuring?
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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 |