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

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT00796705
• Collaborator: (none)
• Enrollment: 13
• Locations: 16
• Arms: 2
• Duration (Months): 23
• Patients Per Site: 0.8
• Patients Per Site Per Month: 0

Study Details

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
• 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: Nov 1, 2008
• Actual Primary Completion Date: Oct 1, 2010
• Actual Study Completion Date: Oct 1, 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 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

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. [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. [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 [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 [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) [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 [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 [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 [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

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

	Site	City	State	Country	Postal Code
1	University of Alabama	Birmingham	Alabama	United States	35294
2	Stanford University	Palo Alto	California	United States	94304
3	Yale New Haven Hospital	New Haven	Connecticut	United States	06520
4	Sarasota Arthritis Research Center	Sarasota	Florida	United States	34239
5	Tampa Medical Group	Tampa	Florida	United States	33614
6	University of Chicago Medical Center	Chicago	Illinois	United States	60637
7	Justus Fiechtner, MD, PC	Lansing	Michigan	United States	48910
8	Feinstein Institute for Medical Research NS-LIJ	Manhassett	New York	United States	14642
9	University of Rochester	Rochester	New York	United States	14642
10	Carolina Bone and Joint	Charlotte	North Carolina	United States	28210
11	Duke University Medical Center	Durham	North Carolina	United States	27710
12	Oklahoma Medical Research Foundation	Oklahoma City	Oklahoma	United States	73104
13	Altoona Center for Clinical Research	Duncansville	Pennsylvania	United States	16635
14	University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15260
15	Baylor Research Institute	Dallas	Texas	United States	75231
16	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

Study Documents (Full-Text)

None provided.

More Information

Publications

• 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:S1. doi: 10.1186/ar2666. Epub 2009 Apr 6. Review.
• 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.
• 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. Review.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT00796705
• Other Study ID Numbers: DAIT ARA05
• First Posted: Nov 24, 2008
• Last Update Posted: Oct 4, 2012
• Last Verified: Aug 1, 2012

• Additional relevant MeSH terms: Arthritis; Arthritis, Rheumatoid; Adalimumab; Etanercept

Study Results

Participant Flow

Recruitment Details	Subject recruitment occurred between November 2008 and November 2010 at 16 sites located in the United States. All sites utilized a rheumatology clinic and outside referrals for recruitment.
Pre-assignment Detail	Each subject signed an informed consent prior to undergoing any screening procedures. At the screening visit, subjects underwent procedures to establish inclusion/exclusion criteria.

Arm/Group Title	Non-Switcher/Adalimumab Alternating With Placebo	Non-Switcher/Etanercept	Switcher/Adalimumab to Etanercept	Switcher/Etanercept to Adalimumab Alternating With Placebo
Arm/Group Description	Participants defined as adalimumab failures [1] at screening who were randomized to remain on adalimumab (one 40 milligram [mg] subcutaneous [SQ] injection) alternating with adalimumab placebo (1.0 millilitre [mL] SQ injection of normal saline 0.9%) once weekly for a total of 12 weeks in a blinded (masked) fashion. [1] Adalimumab failures: participants with rheumatoid arthritis [RA] on adalimumab treatment for at least 12 weeks prior to treatment randomization that experienced inadequate clinical response to adalimumab.	Participants defined as etanercept failures [1] at screening who were randomized to receive etanercept (one 50 mg subcutaneous injection) once weekly for a total of 12 weeks in a blinded (masked) fashion. [1] Etanercept failures: participants with rheumatoid arthritis [RA] on etanercept treatment for at least 12 weeks prior to randomization that experienced inadequate clinical response to etanercept.	Participants defined as adalimumab failures [1] at screening who were randomized to switch from adalimumab to etanercept (one 50 mg subcutaneous injection) once weekly for a total of 12 weeks in a blinded (masked) treatment fashion. [1] Adalimumab failures: participants with rheumatoid arthritis [RA] on adalimumab treatment for at least 12 weeks prior to treatment randomization that experienced inadequate clinical response to adalimumab.	Participants defined as etanercept failures [1] at screening who were randomized to switch from etanercept to adalimumab (one 40 mg subcutaneous [SQ] injection) alternating with adalimumab placebo (1.0 mL SQ injection of normal saline 0.9%) once weekly for a total of 12 weeks in a blinded (masked) fashion. [1] Etanercept failures: participants with rheumatoid arthritis [RA] on etanercept treatment for at least 12 weeks prior to randomization that experienced inadequate clinical response to etanercept.
Period Title: Overall Study
STARTED	3	4	4	2
COMPLETED	3	4	4	2
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Non-Switcher/Adalimumab Alternating With Placebo	Non-Switcher/Etanercept	Switcher/Adalimumab to Etanercept	Switcher/Etanercept to Adalimumab Alternating With Placebo	Total
Arm/Group Description	Participants defined as adalimumab failures [1] at screening who were randomized to remain on adalimumab (one 40 milligram [mg] subcutaneous [SQ] injection) alternating with adalimumab placebo (1.0 millilitre [mL] SQ injection of normal saline 0.9%) once weekly for a total of 12 weeks in a blinded (masked) fashion. [1] Adalimumab failures: participants with rheumatoid arthritis [RA] on adalimumab treatment for at least 12 weeks prior to treatment randomization that experienced inadequate clinical response to adalimumab.	Participants defined as etanercept failures [1] at screening who were randomized to receive etanercept (one 50 mg subcutaneous injection) once weekly for a total of 12 weeks in a blinded (masked) fashion. [1] Etanercept failures: participants with rheumatoid arthritis [RA] on etanercept treatment for at least 12 weeks prior to randomization that experienced inadequate clinical response to etanercept.	Participants defined as adalimumab failures [1]at screening who were randomized to switch from adalimumab to etanercept (one 50 mg subcutaneous injection) once weekly for a total of 12 weeks in a blinded (masked) treatment fashion. [1] Adalimumab failures: participants with rheumatoid arthritis [RA] on adalimumab treatment for at least 12 weeks prior to treatment randomization that experienced inadequate clinical response to adalimumab.	Participants defined as etanercept failures [1] at screening who were randomized to switch from etanercept to adalimumab (one 40 mg subcutaneous [SQ] injection) alternating with adalimumab placebo (1.0 mL SQ injection of normal saline 0.9%) once weekly for a total of 12 weeks in a blinded (masked) fashion. [1] Etanercept failures: participants with rheumatoid arthritis [RA] on etanercept treatment for at least 12 weeks prior to randomization that experienced inadequate clinical response to etanercept.	Total of all reporting groups
Overall Participants	3	4	4	2	13
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	3 100%	2 50%	4 100%	2 100%	11 84.6%
>=65 years	0 0%	2 50%	0 0%	0 0%	2 15.4%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53 (4.0)	65 (9.4)	39 (13.7)	60 (6.4)	53 (14.0)
Sex: Female, Male (Count of Participants)
Female	3 100%	4 100%	4 100%	2 100%	13 100%
Male	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	3 100%	4 100%	4 100%	2 100%	13 100%
Disease Activity Score Using C-reactive Protein (DAS28[CRP]) (Scores on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Scores on a scale]	5.6 (0.66)	5.4 (0.44)	4.8 (0.62)	5.3 (0.19)	5.3 (0.56)

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Non-Switcher/ Adalimumab or Etanercept	Switcher/ Adalimumab to Etanercept or Etanercept to Adalimuma
Arm/Group Description	Participants defined as adalimumab failures [1] at screening who were randomized to remain on adalimumab (one 40 milligram [mg] subcutaneous [SQ] injection) alternating with adalimumab placebo (1.0 millilitre [mL] SQ injection of normal saline 0.9%) once weekly for a total of 12 weeks in a blinded (masked) fashion and participants defined as etanercept failures [2] at screening who were randomized to receive etanercept (one 50 mg SQ injection) once weekly for a total of 12 weeks in a blinded (masked) fashion. Adalimumab failures: participants with rheumatoid arthritis [RA] on adalimumab treatment for at least 12 weeks prior to treatment randomization that experienced inadequate clinical response to adalimumab. Etanercept failures: participants with rheumatoid arthritis [RA] on etanercept treatment for at least 12 weeks prior to randomization that experienced inadequate clinical response to etanercept.	Participants defined as adalimumab failures [1]at screening who were randomized to switch from adalimumab to etanercept (one 50 mg SQ injection) once weekly for a total of 12 weeks in a blinded (masked) treatment fashion and participants defined as etanercept failures [2] at screening who were randomized to switch from etanercept to adalimumab (one 40 mg SQ injection) alternating with adalimumab placebo (1.0 mL SQ injection of normal saline 0.9%) once weekly for a total of 12 weeks in a blinded (masked) fashion. Adalimumab failures: participants with rheumatoid arthritis [RA] on adalimumab treatment for at least 12 weeks prior to treatment randomization that experienced inadequate clinical response to adalimumab. Etanercept failures: participants with rheumatoid arthritis [RA] on etanercept treatment for at least 12 weeks prior to randomization that experienced inadequate clinical response to etanercept.
Measure Participants	7	6
Mean (Standard Deviation) [Scores on a scale]	-1.4 (0.90)	-1.7 (1.09)

2. Primary Outcome

Title	Change in the Disease Activity Score Using C-reactive Protein (DAS28[CRP]) From Baseline to Week 12.
Description	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).
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Non-Switcher/Adalimumab Alternating With Placebo	Non-Switcher/Etanercept	Switcher/Adalimumab to Etanercept	Switcher/Etanercept to Adalimumab Alternating With Placebo
Arm/Group Description	Participants defined as adalimumab failures [1] at screening who were randomized to remain on adalimumab (one 40 milligram [mg] subcutaneous [SQ] injection) alternating with adalimumab placebo (1.0 millilitre [mL] SQ injection of normal saline 0.9%) once weekly for a total of 12 weeks in a blinded (masked) fashion. [1] Adalimumab failures: participants with rheumatoid arthritis [RA] on adalimumab treatment for at least 12 weeks prior to treatment randomization that experienced inadequate clinical response to adalimumab.	Participants defined as etanercept failures [1] at screening who were randomized to receive etanercept (one 50 mg subcutaneous injection) once weekly for a total of 12 weeks in a blinded (masked) fashion. [1] Etanercept failures: participants with rheumatoid arthritis [RA] on etanercept treatment for at least 12 weeks prior to randomization that experienced inadequate clinical response to etanercept.	Participants defined as adalimumab failures [1]at screening who were randomized to switch from adalimumab to etanercept (one 50 mg subcutaneous injection) once weekly for a total of 12 weeks in a blinded (masked) treatment fashion. [1] Adalimumab failures: participants with rheumatoid arthritis [RA] on adalimumab treatment for at least 12 weeks prior to treatment randomization that experienced inadequate clinical response to adalimumab.	Participants defined as etanercept failures [1] at screening who were randomized to switch from etanercept to adalimumab (one 40 mg subcutaneous [SQ] injection) alternating with adalimumab placebo (1.0 mL SQ injection of normal saline 0.9%) once weekly for a total of 12 weeks in a blinded (masked) fashion. [1] Etanercept failures: participants with rheumatoid arthritis [RA] on etanercept treatment for at least 12 weeks prior to randomization that experienced inadequate clinical response to etanercept.
Measure Participants	3	4	4	2
Mean (Standard Deviation) [Scores on a scale]	-2.0 (0.22)	-0.9 (0.92)	-1.7 (0.94)	-1.5 (1.81)

3. Secondary Outcome

Title	Participants With a Disease Activity Score Using C-reactive Protein (DAS28[CRP]) Value <= 3.2 (Low Disease Activity) at Week 12
Description	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).
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Non-Switcher/Adalimumab Alternating With Placebo	Non-Switcher/Etanercept	Switcher/Adalimumab to Etanercept	Switcher/Etanercept to Adalimumab Alternating With Placebo
Arm/Group Description	Participants defined as adalimumab failures [1] at screening who were randomized to remain on adalimumab (one 40 milligram [mg] subcutaneous [SQ] injection) alternating with adalimumab placebo (1.0 millilitre [mL] SQ injection of normal saline 0.9%) once weekly for a total of 12 weeks in a blinded (masked) fashion. [1] Adalimumab failures: participants with rheumatoid arthritis [RA] on adalimumab treatment for at least 12 weeks prior to treatment randomization that experienced inadequate clinical response to adalimumab.	Participants defined as etanercept failures [1] at screening who were randomized to receive etanercept (one 50 mg subcutaneous injection) once weekly for a total of 12 weeks in a blinded (masked) fashion. [1] Etanercept failures: participants with rheumatoid arthritis [RA] on etanercept treatment for at least 12 weeks prior to randomization that experienced inadequate clinical response to etanercept.	Participants defined as adalimumab failures [1]at screening who were randomized to switch from adalimumab to etanercept (one 50 mg subcutaneous injection) once weekly for a total of 12 weeks in a blinded (masked) treatment fashion. [1] Adalimumab failures: participants with rheumatoid arthritis [RA] on adalimumab treatment for at least 12 weeks prior to treatment randomization that experienced inadequate clinical response to adalimumab.	Participants defined as etanercept failures [1] at screening who were randomized to switch from etanercept to adalimumab (one 40 mg subcutaneous [SQ] injection) alternating with adalimumab placebo (1.0 mL SQ injection of normal saline 0.9%) once weekly for a total of 12 weeks in a blinded (masked) fashion. [1] Etanercept failures: participants with rheumatoid arthritis [RA] on etanercept treatment for at least 12 weeks prior to randomization that experienced inadequate clinical response to etanercept.
Measure Participants	3	4	4	2
Number [participants]	1 33.3%	1 25%	2 50%	1 50%

4. Secondary Outcome

Title	Participants With a Disease Activity Score Using C-reactive Protein (DAS28[CRP]) Value < 2.6 (Remission) at Week 12
Description	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).
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Non-Switcher/Adalimumab Alternating With Placebo	Non-Switcher/Etanercept	Switcher/Adalimumab to Etanercept	Switcher/Etanercept to Adalimumab Alternating With Placebo
Arm/Group Description	Participants defined as adalimumab failures [1] at screening who were randomized to remain on adalimumab (one 40 milligram [mg] subcutaneous [SQ] injection) alternating with adalimumab placebo (1.0 millilitre [mL] SQ injection of normal saline 0.9%) once weekly for a total of 12 weeks in a blinded (masked) fashion. [1] Adalimumab failures: participants with rheumatoid arthritis [RA] on adalimumab treatment for at least 12 weeks prior to treatment randomization that experienced inadequate clinical response to adalimumab.	Participants defined as etanercept failures [1] at screening who were randomized to receive etanercept (one 50 mg subcutaneous injection) once weekly for a total of 12 weeks in a blinded (masked) fashion. [1] Etanercept failures: participants with rheumatoid arthritis [RA] on etanercept treatment for at least 12 weeks prior to randomization that experienced inadequate clinical response to etanercept.	Participants defined as adalimumab failures [1]at screening who were randomized to switch from adalimumab to etanercept (one 50 mg subcutaneous injection) once weekly for a total of 12 weeks in a blinded (masked) treatment fashion. [1] Adalimumab failures: participants with rheumatoid arthritis [RA] on adalimumab treatment for at least 12 weeks prior to treatment randomization that experienced inadequate clinical response to adalimumab.	Participants defined as etanercept failures [1] at screening who were randomized to switch from etanercept to adalimumab (one 40 mg subcutaneous [SQ] injection) alternating with adalimumab placebo (1.0 mL SQ injection of normal saline 0.9%) once weekly for a total of 12 weeks in a blinded (masked) fashion. [1] Etanercept failures: participants with rheumatoid arthritis [RA] on etanercept treatment for at least 12 weeks prior to randomization that experienced inadequate clinical response to etanercept.
Measure Participants	3	4	4	2
Number [participants]	0 0%	0 0%	1 25%	1 50%

5. Secondary Outcome

Title	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)
Description	The EULAR definition of a Moderate Response is a decrease from baseline in the DAS28[CRP] value of ≥ 1.2.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Non-Switcher/Adalimumab Alternating With Placebo	Non-Switcher/Etanercept	Switcher/Adalimumab to Etanercept	Switcher/Etanercept to Adalimumab Alternating With Placebo
Arm/Group Description	Participants defined as adalimumab failures [1] at screening who were randomized to remain on adalimumab (one 40 milligram [mg] subcutaneous [SQ] injection) alternating with adalimumab placebo (1.0 millilitre [mL] SQ injection of normal saline 0.9%) once weekly for a total of 12 weeks in a blinded (masked) fashion. [1] Adalimumab failures: participants with rheumatoid arthritis [RA] on adalimumab treatment for at least 12 weeks prior to treatment randomization that experienced inadequate clinical response to adalimumab.	Participants defined as etanercept failures [1] at screening who were randomized to receive etanercept (one 50 mg subcutaneous injection) once weekly for a total of 12 weeks in a blinded (masked) fashion. [1] Etanercept failures: participants with rheumatoid arthritis [RA] on etanercept treatment for at least 12 weeks prior to randomization that experienced inadequate clinical response to etanercept.	Participants defined as adalimumab failures [1]at screening who were randomized to switch from adalimumab to etanercept (one 50 mg subcutaneous injection) once weekly for a total of 12 weeks in a blinded (masked) treatment fashion. [1] Adalimumab failures: participants with rheumatoid arthritis [RA] on adalimumab treatment for at least 12 weeks prior to treatment randomization that experienced inadequate clinical response to adalimumab.	Participants defined as etanercept failures [1] at screening who were randomized to switch from etanercept to adalimumab (one 40 mg subcutaneous [SQ] injection) alternating with adalimumab placebo (1.0 mL SQ injection of normal saline 0.9%) once weekly for a total of 12 weeks in a blinded (masked) fashion. [1] Etanercept failures: participants with rheumatoid arthritis [RA] on etanercept treatment for at least 12 weeks prior to randomization that experienced inadequate clinical response to etanercept.
Measure Participants	3	4	4	2
Number [participants]	3 100%	1 25%	2 50%	1 50%

6. Secondary Outcome

Title	Participants With an ACR 20 Response at Week 12
Description	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)
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Non-Switcher/Adalimumab Alternating With Placebo	Non-Switcher/Etanercept	Switcher/Adalimumab to Etanercept	Switcher/Etanercept to Adalimumab Alternating With Placebo
Arm/Group Description	Participants defined as adalimumab failures [1] at screening who were randomized to remain on adalimumab (one 40 milligram [mg] subcutaneous [SQ] injection) alternating with adalimumab placebo (1.0 millilitre [mL] SQ injection of normal saline 0.9%) once weekly for a total of 12 weeks in a blinded (masked) fashion. [1] Adalimumab failures: participants with rheumatoid arthritis [RA] on adalimumab treatment for at least 12 weeks prior to treatment randomization that experienced inadequate clinical response to adalimumab.	Participants defined as etanercept failures [1] at screening who were randomized to receive etanercept (one 50 mg subcutaneous injection) once weekly for a total of 12 weeks in a blinded (masked) fashion. [1] Etanercept failures: participants with rheumatoid arthritis [RA] on etanercept treatment for at least 12 weeks prior to randomization that experienced inadequate clinical response to etanercept.	Participants defined as adalimumab failures [1]at screening who were randomized to switch from adalimumab to etanercept (one 50 mg subcutaneous injection) once weekly for a total of 12 weeks in a blinded (masked) treatment fashion. [1] Adalimumab failures: participants with rheumatoid arthritis [RA] on adalimumab treatment for at least 12 weeks prior to treatment randomization that experienced inadequate clinical response to adalimumab.	Participants defined as etanercept failures [1] at screening who were randomized to switch from etanercept to adalimumab (one 40 mg subcutaneous [SQ] injection) alternating with adalimumab placebo (1.0 mL SQ injection of normal saline 0.9%) once weekly for a total of 12 weeks in a blinded (masked) fashion. [1] Etanercept failures: participants with rheumatoid arthritis [RA] on etanercept treatment for at least 12 weeks prior to randomization that experienced inadequate clinical response to etanercept.
Measure Participants	3	4	4	2
Number [participants]	3 100%	2 50%	3 75%	1 50%

7. Secondary Outcome

Title	Participants With an ACR 50 Response at Week 12
Description	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)
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Non-Switcher/Adalimumab Alternating With Placebo	Non-Switcher/Etanercept	Switcher/Adalimumab to Etanercept	Switcher/Etanercept to Adalimumab Alternating With Placebo
Arm/Group Description	Participants defined as adalimumab failures [1] at screening who were randomized to remain on adalimumab (one 40 milligram [mg] subcutaneous [SQ] injection) alternating with adalimumab placebo (1.0 millilitre [mL] SQ injection of normal saline 0.9%) once weekly for a total of 12 weeks in a blinded (masked) fashion. [1] Adalimumab failures: participants with rheumatoid arthritis [RA] on adalimumab treatment for at least 12 weeks prior to treatment randomization that experienced inadequate clinical response to adalimumab.	Participants defined as etanercept failures [1] at screening who were randomized to receive etanercept (one 50 mg subcutaneous injection) once weekly for a total of 12 weeks in a blinded (masked) fashion. [1] Etanercept failures: participants with rheumatoid arthritis [RA] on etanercept treatment for at least 12 weeks prior to randomization that experienced inadequate clinical response to etanercept.	Participants defined as adalimumab failures [1]at screening who were randomized to switch from adalimumab to etanercept (one 50 mg subcutaneous injection) once weekly for a total of 12 weeks in a blinded (masked) treatment fashion. [1] Adalimumab failures: participants with rheumatoid arthritis [RA] on adalimumab treatment for at least 12 weeks prior to treatment randomization that experienced inadequate clinical response to adalimumab.	Participants defined as etanercept failures [1] at screening who were randomized to switch from etanercept to adalimumab (one 40 mg subcutaneous [SQ] injection) alternating with adalimumab placebo (1.0 mL SQ injection of normal saline 0.9%) once weekly for a total of 12 weeks in a blinded (masked) fashion. [1] Etanercept failures: participants with rheumatoid arthritis [RA] on etanercept treatment for at least 12 weeks prior to randomization that experienced inadequate clinical response to etanercept.
Measure Participants	3	4	4	2
Number [participants]	2 66.7%	0 0%	1 25%	0 0%

8. Secondary Outcome

Title	Participants With an ACR 70 Response at Week 12
Description	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)
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Non-Switcher/Adalimumab Alternating With Placebo	Non-Switcher/Etanercept	Switcher/Adalimumab to Etanercept	Switcher/Etanercept to Adalimumab Alternating With Placebo
Arm/Group Description	Participants defined as adalimumab failures [1] at screening who were randomized to remain on adalimumab (one 40 milligram [mg] subcutaneous [SQ] injection) alternating with adalimumab placebo (1.0 millilitre [mL] SQ injection of normal saline 0.9%) once weekly for a total of 12 weeks in a blinded (masked) fashion. [1] Adalimumab failures: participants with rheumatoid arthritis [RA] on adalimumab treatment for at least 12 weeks prior to treatment randomization that experienced inadequate clinical response to adalimumab.	Participants defined as etanercept failures [1] at screening who were randomized to receive etanercept (one 50 mg subcutaneous injection) once weekly for a total of 12 weeks in a blinded (masked) fashion. [1] Etanercept failures: participants with rheumatoid arthritis [RA] on etanercept treatment for at least 12 weeks prior to randomization that experienced inadequate clinical response to etanercept.	Participants defined as adalimumab failures [1]at screening who were randomized to switch from adalimumab to etanercept (one 50 mg subcutaneous injection) once weekly for a total of 12 weeks in a blinded (masked) treatment fashion. [1] Adalimumab failures: participants with rheumatoid arthritis [RA] on adalimumab treatment for at least 12 weeks prior to treatment randomization that experienced inadequate clinical response to adalimumab.	Participants defined as etanercept failures [1] at screening who were randomized to switch from etanercept to adalimumab (one 40 mg subcutaneous [SQ] injection) alternating with adalimumab placebo (1.0 mL SQ injection of normal saline 0.9%) once weekly for a total of 12 weeks in a blinded (masked) fashion. [1] Etanercept failures: participants with rheumatoid arthritis [RA] on etanercept treatment for at least 12 weeks prior to randomization that experienced inadequate clinical response to etanercept.
Measure Participants	3	4	4	2
Number [participants]	0 0%	0 0%	0 0%	0 0%

Adverse Events

Arm/Group Title	Non-Switcher/Adalimumab		Non-Switcher/Etanercept		Switcher/Adalimumab to Etanercept		Switcher/Etanercept to Adalimumab
Arm/Group Description	Subjects failing Adalimumab at screening who were randomized to remain on Adalimumab		Subjects failing Etanercept at screening who were randomized to remain on Etanercept		Subjects failing Adalimumab at screening who were randomized to switch to Etanercept		Subjects failing Etanercept at screening who were randomized to switch to Adalimumab
All Cause Mortality
	Non-Switcher/Adalimumab		Non-Switcher/Etanercept		Switcher/Adalimumab to Etanercept		Switcher/Etanercept to Adalimumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Non-Switcher/Adalimumab		Non-Switcher/Etanercept		Switcher/Adalimumab to Etanercept		Switcher/Etanercept to Adalimumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/4 (0%)		0/4 (0%)		0/2 (0%)
Other (Not Including Serious) Adverse Events
	Non-Switcher/Adalimumab		Non-Switcher/Etanercept		Switcher/Adalimumab to Etanercept		Switcher/Etanercept to Adalimumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		3/4 (75%)		4/4 (100%)		2/2 (100%)
Gastrointestinal disorders
Abdominal distension	1/3 (33.3%)	1	0/4 (0%)	0	0/4 (0%)	0	0/2 (0%)	0
Constipation	1/3 (33.3%)	1	0/4 (0%)	0	0/4 (0%)	0	0/2 (0%)	0
Diarrhoea	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/2 (50%)	7
Dry mouth	1/3 (33.3%)	1	0/4 (0%)	0	1/4 (25%)	1	0/2 (0%)	0
Nausea	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/2 (0%)	0
Vomiting	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/2 (0%)	0
General disorders
Fatigue	1/3 (33.3%)	1	0/4 (0%)	0	1/4 (25%)	1	0/2 (0%)	0
Influenza like illness	1/3 (33.3%)	1	0/4 (0%)	0	0/4 (0%)	0	0/2 (0%)	0
Injection site haematoma	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/2 (50%)	1
Injection site irritation	0/3 (0%)	0	2/4 (50%)	6	0/4 (0%)	0	1/2 (50%)	1
Injection site pain	0/3 (0%)	0	2/4 (50%)	7	0/4 (0%)	0	0/2 (0%)	0
Injection site reaction	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/2 (0%)	0
Pain	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/2 (0%)	0
Infections and infestations
Bronchitis	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/2 (0%)	0
Gastroenteritis viral	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/2 (0%)	0
Laryngitis	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/2 (0%)	0
Nasopharyngitis	0/3 (0%)	0	1/4 (25%)	1	0/4 (0%)	0	0/2 (0%)	0
Otitis media	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/2 (0%)	0
Rhinitis	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/2 (0%)	0
Tooth abscess	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/2 (0%)	0
Upper respiratory tract infection	1/3 (33.3%)	1	0/4 (0%)	0	1/4 (25%)	1	0/2 (0%)	0
Viral upper respiratory tract infection	1/3 (33.3%)	1	0/4 (0%)	0	0/4 (0%)	0	0/2 (0%)	0
Injury, poisoning and procedural complications
Excoriation	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/2 (0%)	0
Humerus fracture	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/2 (50%)	1
Investigations
Cardiac murmur	0/3 (0%)	0	1/4 (25%)	1	0/4 (0%)	0	0/2 (0%)	0
Gallop rhythm present	0/3 (0%)	0	1/4 (25%)	1	0/4 (0%)	0	0/2 (0%)	0
Haemoglobin decreased	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/2 (0%)	0
White blood cell count decreased	1/3 (33.3%)	1	0/4 (0%)	0	0/4 (0%)	0	0/2 (0%)	0
Metabolism and nutrition disorders
Hyperglycaemia	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/2 (0%)	0
Hypoglycaemia	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/2 (50%)	1
Hypokalaemia	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/2 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	1/3 (33.3%)	1	1/4 (25%)	1	0/4 (0%)	0	0/2 (0%)	0
Musculoskeletal pain	1/3 (33.3%)	2	1/4 (25%)	1	0/4 (0%)	0	0/2 (0%)	0
Rheumatoid arthritis	1/3 (33.3%)	2	0/4 (0%)	0	1/4 (25%)	1	1/2 (50%)	1
Tendonitis	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/2 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/2 (0%)	0
Nervous system disorders
Dizziness	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/2 (0%)	0
Headache	1/3 (33.3%)	1	0/4 (0%)	0	1/4 (25%)	1	1/2 (50%)	2
Respiratory, thoracic and mediastinal disorders
Prolonged expiration	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/2 (50%)	1
Tonsillar hypertrophy	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/2 (0%)	0
Skin and subcutaneous tissue disorders
Rash	0/3 (0%)	0	1/4 (25%)	2	0/4 (0%)	0	0/2 (0%)	0
Skin lesion	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/2 (0%)	0

Limitations/Caveats

The study terminated early due to recruitment feasibility issues. Thirteen subjects were enrolled and received treatment. No mechanistic analyses were performed.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.