RACAT: Rheumatoid Arthritis: Comparison of Active Therapies in Patients With Active Disease Despite Methotrexate Therapy

• Sponsor: US Department of Veterans Affairs (U.S. Fed)
• Overall Status: Completed
• CT.gov ID: NCT00405275
• Collaborator: Canadian Institutes of Health Research (CIHR) (Other), Rheumatoid Arthritis Investigational Network (RAIN) (Other), National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) (NIH)
• Enrollment: 353
• Locations: 37
• Arms: 2
• Duration (Months): 58
• Patients Per Site: 9.5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

Rheumatoid arthritis (RA) is a chronic inflammatory disease of the joints leading to joint destruction, with significant long-term morbidity and mortality. Early treatment of RA patients with disease-modifying antirheumatic drugs (DMARDs) significantly decreases these complications. Methotrexate (MTX) is an excellent, economical first-line DMARD used to treat a majority of RA patients. While most patients respond well to MTX, many continue to have active disease. Therefore, understanding how to best treat RA patients with active disease despite MTX therapy is critically important. Although a number of therapies with significantly different economic implications have been shown to be effective when added to MTX, no trial has directly compared active therapies. This study will compare therapeutic strategies using two regimens with proven efficacy when added to MTX therapy; a) hydroxychloroquine and sulfasalazine (cost ~ $1000 per year); b) the tumor necrosis factor inhibitor, etanercept (cost ~ $12,000 per year).

We propose a bi-national multi-center randomized, double-blind equivalency trial comparing (A) the strategy of initially adding hydroxychloroquine and sulfasalazine to MTX in patients with active disease despite MTX, with a switch at 24 weeks to etanercept in nonresponders to (B) a strategy of adding etanercept to MTX, with a switch to hydroxychloroquine and sulfasalazine in nonresponders at 24 weeks. If we find that the strategy of first adding hydroxychloroquine and sulfasalazine to MTX identifies a subset of responsive patients and that there is no harm to nonresponders because of early rescue with etanercept, then this less expensive option should become the standard treatment for MTX resistant patients.

Four hundred and fifty RA patients with active disease despite treatment with MTX as indicated by a Disease Activity Score with 28 joints (DAS28) of >4.4 units will be randomized. A DAS improvement of <1.2 (validated as clinically significant) at 24 weeks will be used to identify early nonresponder who will switch therapy. Subjects with a DAS28 improvement of > 1.2 at 24 weeks will remain on their initial therapy. The primary endpoint is the change of DAS 28 scores from baseline to 48 weeks. The secondary endpoint is comparison of radiographic progression of disease at 48 weeks, as measured by the change in Sharp score. Economic and functional outcomes will be assessed and a serum and DNA bank will be established to evaluate potential biomarkers predictive of treatment response/toxicity and disease progression. This trial will recruit 450 subjects over 40 months. At the end of the 48 week blinded active therapy portion of the trial, the blind will be broken and data will be collected in an open fashion until all 450 patients have completed the 48 week portion of the trial.

Condition or Disease	Intervention/Treatment	Phase
Rheumatoid Arthritis	Drug: Etanercept; Drug: methotrexate; Drug: Sulfasalazine; Drug: Hydroxychloroquine; Drug: Placebo, triple; Drug: Placebo, etanercept	N/A

Detailed Description

The main objective of this proposal is to compare two successful treatment strategies that have significantly different economic implications head-to-head in patients with rheumatoid arthritis who have active disease despite methotrexate therapy.

Rheumatoid arthritis (RA) is a chronic inflammatory disease of the joints leading to joint destruction, with significant long-term morbidity and mortality. Early treatment of RA patients with disease-modifying antirheumatic drugs (DMARDs) significantly decreases these complications. Methotrexate (MTX) is an excellent, economical first-line DMARD used to treat a majority of RA patients. While most patients respond well to MTX, many continue to have active disease. Therefore, understanding how to best treat RA patients with active disease despite MTX therapy is critically important. Although a number of therapies with significantly different economic implications have been shown to be effective when added to MTX, no trial has directly compared active therapies. This study will compare therapeutic strategies using two regimens with proven efficacy when added to MTX therapy; a) hydroxychloroquine and sulfasalazine (cost ~ $1000 per year); b) the tumor necrosis factor inhibitor, etanercept (cost ~ $12,000 per year).

We propose a bi-national multi-center randomized, double-blind equivalency trial comparing (A) the strategy of initially adding hydroxychloroquine and sulfasalazine to MTX in patients with active disease despite MTX, with a switch at 24 weeks to etanercept in nonresponders to (B) a strategy of adding etanercept to MTX, with a switch to hydroxychloroquine and sulfasalazine in nonresponders at 24 weeks. If we find that the strategy of first adding hydroxychloroquine and sulfasalazine to MTX identifies a subset of responsive patients and that there is no harm to nonresponders because of early rescue with etanercept, then this less expensive option should become the standard treatment for MTX resistant patients.

Four hundred and fifty RA patients with active disease despite treatment with MTX as indicated by a Disease Activity Score with 28 joints (DAS28) of greater than or equal to 4.4 units will be randomized. A DAS improvement of greater than or equal to 1.2 (validated as clinically significant) at 24 weeks will be used to identify early nonresponder who will switch therapy. Subjects with a DAS28 improvement of ≥ 1.2 at 24 weeks will remain on their initial therapy. The primary endpoint is the change of DAS 28 scores from baseline to 48 weeks. The secondary endpoint is comparison of radiographic progression of disease at 48 weeks, as measured by the change in Sharp score. Economic and functional outcomes will be assessed and a serum and DNA bank will be established to evaluate potential biomarkers predictive of treatment response/toxicity and disease progression. This trial will recruit 450 subjects over 40 months. At the end of the 48 week blinded active therapy portion of the trial, the blind will be broken and data will be collected in an open fashion until all 450 patients have completed the 48 week portion of the trial.

Study Design

• Study Type: Interventional
• Actual Enrollment: 353 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: CSP #551 - Rheumatoid Arthritis: Comparison of Active Therapies in Patients With Active Disease Despite Methotrexate Therapy
• Study Start Date: Jul 1, 2007
• Actual Primary Completion Date: Dec 1, 2011
• Actual Study Completion Date: May 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Arm 1 Etanercept and Methotrexate. Participants also received placebo hydroxychloroquine and sulfasalazine	Drug: Etanercept; etanercept, subcutaneous injection; Other Names: Enbrel ; Drug: methotrexate; baseline methotrexate is maintained throughout the study and is not provided by the sponsor; Drug: Placebo, triple; Participants in Etanercept arm (Arm 1) were given placebo hydroxychloroquine and sulfasalazine pills.
Active Comparator: Arm 2 Hydroxychloroquine, sulfasalazine and methotrexate. Participants also received placebo etanercept.	Drug: methotrexate; baseline methotrexate is maintained throughout the study and is not provided by the sponsor; Drug: Sulfasalazine; sulfasalazine, oral; Drug: Hydroxychloroquine; hydroxychloroquine, oral; Other Names: Plaquenil ; Drug: Placebo, etanercept; Participants in triple arm (Arm 2) were given placebo etanercept injections.

Outcome Measures

Primary Outcome Measures

1. Mean 48-week Change in DAS28 [48 weeks after baseline assessment]

   Average difference between 48-week and Baseline DAS28. The Disease Activity Score for 28 Joints (DAS28) is a well-validated composite outcome measure ranging from 2-10 (higher scores indicating more disease) that incorporates a tender and swollen joint count of 28 joints, a laboratory measure of systemic inflammation (ESR) and a patient-reported general assessment of health on a visual analog scale (ranging from 0-10cm) all into one measure. Low disease activity is defined as DAS28 ≤ 3.2 units.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• All patients must fulfill ACR classification criteria for rheumatoid arthritis.

• All patients must have been 16 years of age or older at time of diagnosis of rheumatoid arthritis.

• All patients must be 18 years of age or older at the time of entry into the study.

• All patients will have been receiving oral or subcutaneous methotrexate 15 to 25 mg/week (unless intolerant and on a minimum 10 mg/week) at a constant dose for at least 4 weeks, and on any methotrexate for no less than 12 weeks.

• All patients will have active disease as defined by a DAS28 of greater than or equal to 4.4.

• If patients are receiving corticosteroids, they must have been on stable dose (less than or equal to 10 mg prednisone or equivalent) for at least two weeks prior to screening.

• If patients are using non-steroidal anti-inflammatory drugs (NSAIDs), they must be on stable doses for at least one week prior to screening.

• If patients have taken leflunomide, cyclosporine, gold, Anakinra, azathioprine, or penicillamine in combination with methotrexate, they must have stopped this therapy at least 8 weeks prior to randomization.

• Laboratory tests must meet the following criteria within 2 weeks of randomization:

• Serum creatinine 1.8 mg/dL

• Hemoglobin 9 g/dL

• WBC 3000 mc/L

• Neutrophils 1000 mc/L

• Platelets 100,000 mc/L

• Serum transaminase level (AST or ALT, whichever is followed at the site) not exceeding 1.2 times upper limit of normal.

• Albumin no less than 1.0 g/dL (10 g/L) below lower limit of normal. Anything below lower limit of normal must have been stable (or improving) for no less than 90 days. Stable is defined as changes of no more than 0.2 g/dL (2 g/L).

• All patients must be capable of giving informed consent and able to adhere to study visit schedule.

• Subject or designee must have the ability to self-inject investigational product or have a caregiver who can inject subcutaneous injections

• Subjects must meet one of the following criteria with regard to tuberculosis. PPD must be within 180 days of randomization if the patient has no recent exposure/travel history, or within 90 days if the patient has a recent exposure/travel history.

• Negative PPD; or

• Positive PPD <5 mm, with a negative chest x-ray; or

• Positive PPD >5mm, treated for at least 28 days with INH.

• Subjects with an Erythrocyte sedimentation rate (ESR) of less than or equal to 10 and a tender and swollen joint count of at least 10 and does not qualify for the study using the DAS28, will be allowed to use the DAS28-CRP rather than the traditional DAS28 to determine eligibility.

Exclusion Criteria:

• Previous intolerance to methotrexate (unless able to tolerate at least 10 mg/week)

• Sensitivity to study medications

• Previous treatment with methotrexate, sulfasalazine or hydroxychloroquine in combination with each other for longer than 4 weeks duration. No combination use is allowed within 4 weeks of screening.

• No bed or wheelchair-bound patients

• Previous treatment with a TNF- inhibitor (etanercept, infliximab or adalimumab) for more than 5 weeks of therapy. Previous treatment with TNF- inhibitor must have been stopped for reasons other than toxicity or efficacy. No TNF- inhibitor therapy is allowed within the following time frames:

• Last dose of etanercept must have been at least 4 weeks before screening.

• Last dose of adalimumab or infliximab must have been at least 8 weeks prior to screening.

Example of an eligible patient: A patient found he could not afford the co-pays for a TNF inhibitor after two doses and stopped taking the medication two months before being evaluated for this trial.

• Evidence of important acute or chronic infections (no IV antibiotics within 1 month, and no PO antibiotics within 2 weeks)

• Pregnant or nursing women

• Women of childbearing potential or their partners who are not practicing an acceptable form of birth control as defined by investigator

• Active substance abuse or psychiatric illness likely to interfere with protocol completion

• History of multiple sclerosis, transverse myelitis, or optic neuritis

• History of macular degeneration unless patient has letter from their ophthalmologist that will allow for participation in trial

• New York Heart Association Class III or IV congestive heart failure

• Active malignancy (other than in situ cervical cancer or non-melanoma skin cancer), or history of lymphoma

• History of HIV

• History of any opportunistic infection - to include but not limited to Pneumocystis carinii, aspergillosis, histoplasmosis, or atypical mycobacterium

• History of porphyria

• Diagnosis of SLE or seronegative spondyloarthropathy or any other form of concomitant arthritis (osteoarthritis is permitted)

• Diagnosis of psoriasis unless rheumatoid factor positive

• Any significant unstable medical condition considered a contraindication by investigator

• Any participation in another investigational drug study during the 90 days preceding randomization.

• Receipt of a live vaccine within 90 days of study entry.

• History of oral or IV cyclophosphamide use

• Life expectancy less than 2 years

• Receipt of steroid injection, intravenous, intramuscular, or intraarticular, within 30 days of randomization.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	VA Medical Center, Loma Linda	Loma Linda	California	United States	92357
2	VA Medical Center, Long Beach	Long Beach	California	United States	90822
3	VA Medical Center, San Francisco	San Francisco	California	United States	94121
4	Pacific Arthritis Center (RAIN)	Santa Maria	California	United States	93454-6945
5	VA Greater Los Angeles HCS, Sepulveda	Sepulveda	California	United States	91343
6	VA Medical Center, DC	Washington	District of Columbia	United States	20422
7	St. Mary's/ Duluth Clinic Health System (RAIN)	Duluth	Minnesota	United States	55804
8	Park Nicollet (RAIN)	Minneapolis	Minnesota	United States	55417
9	VA Medical Center, Minneapolis	Minneapolis	Minnesota	United States	55417
10	Mayo Clinic	Rochester	Minnesota	United States	55905
11	VA Medical Center, St Louis	St Louis	Missouri	United States	63106
12	Lincoln Medical Center	Lincoln	Nebraska	United States	68506
13	VA Medical Center, Omaha	Omaha	Nebraska	United States	68105-1873
14	Univesity of Nebraska Medical Center	Omaha	Nebraska	United States	68198
15	Bone, Spine Sports Clinic (RAIN)	Bismarck	North Dakota	United States	58501
16	VA Medical Center, Fargo	Fargo	North Dakota	United States	58102
17	VA Medical Center, Portland	Portland	Oregon	United States	97201
18	Geisinger Medical Center	Danville	Pennsylvania	United States	17822
19	VA Medical Center, Philadelphia	Philadelphia	Pennsylvania	United States	19104
20	VA Pittsburgh Health Care System	Pittsburgh	Pennsylvania	United States	15240
21	Geisinger Medical Group - State College	State College	Pennsylvania	United States	16801
22	Geisinger Medical Group- Wilkes Barre	Wyoming Valley	Pennsylvania	United States	18711
23	Ralph H Johnson VA Medical Center, Charleston	Charleston	South Carolina	United States	29401-5799
24	Rapid City Medical Center (RAIN)	Rapid City	South Dakota	United States	57701
25	Avera Research Institute (RAIN)	Sioux Falls	South Dakota	United States	57117-5046
26	VA North Texas Health Care System, Dallas	Dallas	Texas	United States	75216
27	VA Salt Lake City Health Care System, Salt Lake City	Salt Lake City	Utah	United States	84148
28	VA Medical & Regional Office Center, White River	White River Junction	Vermont	United States	05009-0001
29	University of Calgary (CRRC)	Calgary	Alberta	Canada	T2N 4N1
30	University of Manitoba (CRRC)	Winnipeg	Manitoba	Canada	R3A 1M4
31	Brampton (CRRC)	Brampton	Ontario	Canada	L6T 3J1
32	Credit Valley Rheumatology	Missassauga	Ontario	Canada	L5M 2V8
33	Newmarket (CRRC)	Newmarket	Ontario	Canada	L3Y 3R7
34	Mount Sinai Hospital (CRRC)	Toronto	Ontario	Canada	M5T 3L9
35	Clinical Research and Arthritis Center	Windsor	Ontario	Canada	N8X 5A6
36	Hopital Notre Dame (CRRC)	Montreal	Quebec	Canada	H2L 4M1
37	Crc-Chus (Crrc)	Sherbrooke	Quebec	Canada	J1H 5N4

Sponsors and Collaborators

• US Department of Veterans Affairs
• Canadian Institutes of Health Research (CIHR)
• Rheumatoid Arthritis Investigational Network (RAIN)
• National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Investigators

• Study Chair: James R. O'Dell, VA Medical Center, Omaha

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: US Department of Veterans Affairs
• ClinicalTrials.gov Identifier: NCT00405275
• Other Study ID Numbers: 551; Y1-AR-0048-01
• First Posted: Nov 30, 2006
• Last Update Posted: Dec 3, 2013
• Last Verified: Nov 1, 2013

• Keywords provided by US Department of Veterans Affairs: antineoplastic; antiparasitics; antirheumatics; chronic diseases; clinical trial; connective tissue; double-blind; drug treatment; gastric medications; joint; multi-site trial; musculoskeletal; randomized; rheumatoid arthritis
• Additional relevant MeSH terms: Arthritis; Arthritis, Rheumatoid; Hydroxychloroquine; Sulfasalazine; Etanercept; Methotrexate

Study Results

Participant Flow

Recruitment Details	Bi-national, multi-center 3.5 year recruitment at 16 VA, 12 RAIN and 8 Canadian medical centers.

Arm/Group Title	Triple	Etanercept
Arm/Group Description	Hydroxychloroquine (400mg daily); Sulfasalazine (1g daily for 6 weeks, then increased to 2g daily; Methotrexate (maintaining baseline dose, 10-25mg weekly); Placebo, etanercept (subcutaneous injection). Nonresponders (change in DAS28 < 1.2units at 24 weeks) were switched to Etanercept at 24 weeks. This is denoted in results table below as "switch". "No switch" participants remained on Triple therapy throughout the trial.	Etanercept (50mg subcutaneous injections weekly); Methotrexate (maintaining baseline dose, 10-25mg weekly); Placebo, triple: placebo hydroxychloroquine (tablets daily) and placebo sulfasalazine (tablets daily). Nonresponders (change in DAS28 < 1.2units at 24 weeks) were switched to Triple. This is denoted in results table below as "switch". "No switch" participants remained on Etanercept therapy throughout the trial.
Period Title: Overall Study
STARTED	178	175
24 Weeks (Total)	163	165
24 Week (no Switch)	119	121
24 Week (Switch)	44	44
COMPLETED	155	156
NOT COMPLETED	23	19

Baseline Characteristics

Arm/Group Title	Triple	Etanercept	Total
Arm/Group Description	Hydroxychloroquine, sulfasalazine and methotrexate	Etanercept and Methotrexate	Total of all reporting groups
Overall Participants	178	175	353
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.8 (13.0)	56.0 (13.2)	56.9 (13.1)
Sex/Gender, Customized (participants) [Number]
Female	77 43.3%	85 48.6%	162 45.9%
Male	101 56.7%	89 50.9%	190 53.8%
Unknown	0 0%	1 0.6%	1 0.3%
Region of Enrollment (participants) [Number]
United States	134 75.3%	130 74.3%	264 74.8%
Canada	44 24.7%	45 25.7%	89 25.2%

Outcome Measures

1. Primary Outcome

Title	Mean 48-week Change in DAS28
Description	Average difference between 48-week and Baseline DAS28. The Disease Activity Score for 28 Joints (DAS28) is a well-validated composite outcome measure ranging from 2-10 (higher scores indicating more disease) that incorporates a tender and swollen joint count of 28 joints, a laboratory measure of systemic inflammation (ESR) and a patient-reported general assessment of health on a visual analog scale (ranging from 0-10cm) all into one measure. Low disease activity is defined as DAS28 ≤ 3.2 units.
Time Frame	48 weeks after baseline assessment

Outcome Measure Data

Analysis Population Description

Intention to treat analysis was performed on participants with Week 48 DAS28 data.

Arm/Group Title	Triple	Etanercept
Arm/Group Description	Hydroxychloroquine, sulfasalazine and methotrexate	Etanercept and Methotrexate
Measure Participants	154	155
Mean (Standard Deviation) [units on a scale]	-2.12 (1.28)	-2.29 (1.30)

Adverse Events

Time Frame	Beginning at Informed Consent until each participant's last study follow-up contact (expected to be 48 weeks), including a period of 30 days after last contact for SAE reporting.
Adverse Event Reporting Description	Serious and non-serious Adverse Events are reported according to treatment at the time of event. Participants that switched therapies are represented in both treatments. Participants were seen every 6 weeks for adverse event monitoring.
Arm/Group Title	Triple		Etanercept
Arm/Group Description	Hydroxychloroquine, sulfasalazine and methotrexate		Etanercept and Methotrexate
All Cause Mortality
	Triple		Etanercept
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Triple		Etanercept
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	38/222 (17.1%)		43/219 (19.6%)
Blood and lymphatic system disorders
Anaemia	0/222 (0%)	0	1/219 (0.5%)	1
Lymphadenopathy	1/222 (0.5%)	1	0/219 (0%)	0
Retroperitoneal lymphadenopathy	0/222 (0%)	0	1/219 (0.5%)	1
Cardiac disorders
Angina unstable	0/222 (0%)	0	1/219 (0.5%)	1
Atrial fibrillation	1/222 (0.5%)	1	0/219 (0%)	0
Cardiac failure congestive	0/222 (0%)	0	3/219 (1.4%)	3
Coronary artery disease	1/222 (0.5%)	1	0/219 (0%)	0
Coronary artery occlusion	2/222 (0.9%)	2	0/219 (0%)	0
Intracardiac thrombus	0/222 (0%)	0	1/219 (0.5%)	1
Myocardial infarction	0/222 (0%)	0	2/219 (0.9%)	2
Congenital, familial and genetic disorders
Gastrointestinal arteriovenous malformation	0/222 (0%)	0	1/219 (0.5%)	1
Eye disorders
Glaucoma	1/222 (0.5%)	1	0/219 (0%)	0
Retinal detachment	0/222 (0%)	0	1/219 (0.5%)	1
Gastrointestinal disorders
Colitis ulcerative	1/222 (0.5%)	1	0/219 (0%)	0
Duodenitis haemorrhagic	0/222 (0%)	0	1/219 (0.5%)	1
Dyspepsia	0/222 (0%)	0	1/219 (0.5%)	1
Gastric ulcer	1/222 (0.5%)	1	0/219 (0%)	0
Gastritis	1/222 (0.5%)	1	0/219 (0%)	0
Gastrointestinal haemorrhage	0/222 (0%)	0	1/219 (0.5%)	1
Gastrointestinal ulcer haemorrhage	1/222 (0.5%)	1	0/219 (0%)	0
Ileus	0/222 (0%)	0	1/219 (0.5%)	1
Intestinal obstruction	1/222 (0.5%)	1	0/219 (0%)	0
Pancreatitis acute	2/222 (0.9%)	2	0/219 (0%)	0
Upper gastrointestinal haemorrhage	0/222 (0%)	0	1/219 (0.5%)	1
General disorders
Adverse drug reaction	1/222 (0.5%)	1	0/219 (0%)	0
Chest discomfort	1/222 (0.5%)	1	0/219 (0%)	0
Chest pain	2/222 (0.9%)	2	0/219 (0%)	0
Non-cardiac chest pain	1/222 (0.5%)	1	1/219 (0.5%)	1
Infections and infestations
Appendicitis	0/222 (0%)	0	1/219 (0.5%)	1
Bronchitis	1/222 (0.5%)	1	1/219 (0.5%)	1
Bronchopulmonary aspergillosis	1/222 (0.5%)	1	0/219 (0%)	0
Cellulitis	2/222 (0.9%)	2	1/219 (0.5%)	1
Clostridium difficile colitis	1/222 (0.5%)	1	1/219 (0.5%)	1
Diverticulitis	0/222 (0%)	0	1/219 (0.5%)	1
Localised infection	1/222 (0.5%)	1	0/219 (0%)	0
Lung abscess	0/222 (0%)	0	1/219 (0.5%)	1
Pneumonia	5/222 (2.3%)	6	7/219 (3.2%)	7
Tooth abscess	0/222 (0%)	0	1/219 (0.5%)	1
Upper respiratory tract infection	1/222 (0.5%)	1	0/219 (0%)	0
Urinary tract infection	0/222 (0%)	0	1/219 (0.5%)	1
Viral infection	1/222 (0.5%)	1	0/219 (0%)	0
Viral tracheitis	0/222 (0%)	0	1/219 (0.5%)	1
Injury, poisoning and procedural complications
Cardiac procedure complication	0/222 (0%)	0	1/219 (0.5%)	1
Deep vein thrombosis postoperative	1/222 (0.5%)	1	0/219 (0%)	0
Fall	2/222 (0.9%)	2	0/219 (0%)	0
Post procedural complication	1/222 (0.5%)	1	2/219 (0.9%)	3
Investigations
Catheterisation cardiac normal	0/222 (0%)	0	1/219 (0.5%)	1
Haemoglobin decreased	0/222 (0%)	0	1/219 (0.5%)	1
Metabolism and nutrition disorders
Hyponatraemia	0/222 (0%)	0	1/219 (0.5%)	2
Musculoskeletal and connective tissue disorders
Intervertebral disc disorder	0/222 (0%)	0	1/219 (0.5%)	1
Musculoskeletal pain	0/222 (0%)	0	1/219 (0.5%)	1
Osteoarthritis	1/222 (0.5%)	1	6/219 (2.7%)	6
Rheumatoid arthritis	1/222 (0.5%)	1	1/219 (0.5%)	1
Spondylolisthesis	1/222 (0.5%)	1	0/219 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder cancer stage II	0/222 (0%)	0	1/219 (0.5%)	1
Cerebellopontine angle tumour	0/222 (0%)	0	1/219 (0.5%)	1
Diffuse large B-cell lymphoma	0/222 (0%)	0	1/219 (0.5%)	1
Endometrial cancer	0/222 (0%)	0	1/219 (0.5%)	1
Lung cancer metastatic	2/222 (0.9%)	2	1/219 (0.5%)	1
Lung neoplasm malignant	0/222 (0%)	0	1/219 (0.5%)	1
Non-small cell lung cancer metastatic	0/222 (0%)	0	1/219 (0.5%)	1
Prostate cancer	1/222 (0.5%)	1	1/219 (0.5%)	1
Small cell lung cancer extensive stage	1/222 (0.5%)	1	0/219 (0%)	0
Nervous system disorders
Intracranial hypotension	0/222 (0%)	0	1/219 (0.5%)	1
Ischaemic stroke	1/222 (0.5%)	1	0/219 (0%)	0
Transient ischaemic attack	1/222 (0.5%)	1	0/219 (0%)	0
Psychiatric disorders
Depression	1/222 (0.5%)	1	0/219 (0%)	0
Depression suicidal	0/222 (0%)	0	1/219 (0.5%)	2
Suicidal ideation	0/222 (0%)	0	2/219 (0.9%)	2
Renal and urinary disorders
Bladder prolapse	0/222 (0%)	0	1/219 (0.5%)	1
Haematuria	0/222 (0%)	0	1/219 (0.5%)	1
Nephritic syndrome	1/222 (0.5%)	1	0/219 (0%)	0
Nephrolithiasis	1/222 (0.5%)	1	0/219 (0%)	0
Renal failure	1/222 (0.5%)	1	0/219 (0%)	0
Renal failure acute	0/222 (0%)	0	1/219 (0.5%)	1
Urethral stenosis	0/222 (0%)	0	1/219 (0.5%)	1
Reproductive system and breast disorders
Benign prostatic hyperplasia	0/222 (0%)	0	1/219 (0.5%)	1
Epididymitis	1/222 (0.5%)	1	0/219 (0%)	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	2/222 (0.9%)	2	2/219 (0.9%)	2
Pleural effusion	0/222 (0%)	0	1/219 (0.5%)	1
Pleurisy	1/222 (0.5%)	1	0/219 (0%)	0
Pleuritic pain	1/222 (0.5%)	1	0/219 (0%)	0
Pulmonary embolism	2/222 (0.9%)	2	1/219 (0.5%)	1
Pulmonary hypertension	1/222 (0.5%)	1	0/219 (0%)	0
Respiratory failure	0/222 (0%)	0	1/219 (0.5%)	1
Skin and subcutaneous tissue disorders
Angioedema	1/222 (0.5%)	1	0/219 (0%)	0
Social circumstances
Treatment noncompliance	0/222 (0%)	0	1/219 (0.5%)	1
Surgical and medical procedures
Rotator cuff repair	0/222 (0%)	0	1/219 (0.5%)	1
Transurethral prostatectomy	1/222 (0.5%)	1	0/219 (0%)	0
Vascular disorders
Aortic dissection	0/222 (0%)	0	1/219 (0.5%)	1
Femoral arterial stenosis	0/222 (0%)	0	1/219 (0.5%)	1
Peripheral vascular disorder	0/222 (0%)	0	1/219 (0.5%)	1
Other (Not Including Serious) Adverse Events
	Triple		Etanercept
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	40/222 (18%)		55/219 (25.1%)
Gastrointestinal disorders
Nausea	16/222 (7.2%)	23	17/219 (7.8%)	18
Infections and infestations
Nasopharyngitis	8/222 (3.6%)	8	14/219 (6.4%)	16
Upper respiratory tract infection	12/222 (5.4%)	17	19/219 (8.7%)	23
Nervous system disorders
Headache	17/222 (7.7%)	20	14/219 (6.4%)	15

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Dr. O'Dell is an employee of the Sponsor. Dr. Edward Keystone is not. Per the signed Investigator Agreement, PIs agreed to "maintaining the confidentiality of study data and not publishing study data without prior approval of the study's Executive Committee".