Investigator-Initiated, Pilot Study Evaluating The Efficacy Of Etanercept In Acute Gout
Phase: PHASE4
Conditions: Gout Attack
Sponsor: Rutgers, The State University of New Jersey

 
 
Study Protocol 
 
 
 
Protocol Title:  
Investigator-Initiated, Pilot Study Evaluating the 
Efficacy of Etanercept in Acute Gout 
 
 
ClinicalTrials.gov #: NCT03636373 
 
 
Date: 22 Oct 2020 
 

Investigator-Initiated, Pilot Study Evaluating The Efficacy Of Etanercept In Acute Gout
PI: Naomi Schlesinger, MD
Protocol Version and Date: 3.1, 10 March 2020 
                        
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INTERVENTIONAL
RESEARCH PROTOCOL
(HRP-503a)
Title:
Investigator-Initiated, Pilot Study Evaluating the Efficacy of Etanercept in 
Acute Gout
Study Sponsor: Rutgers, The State University of New Jersey 
Responsible Party: Principal Investigator
Funding has been provided by Amgen Inc.
Principal Investigator (PI):
Naomi Schlesinger, MD
Professor and Chief, Division of Rheumatology Department of Medicine
Rutgers—Robert Wood Johnson Medical School
One Robert Wood Johnson Place, New Brunswick, NJ 08901
Office: 732-235-8378
schlesna@rwjms.rutgers.edu
Co-Investigators:
Robert Eisenstein, MD
Chair Department of Emergency Medicine
Rutgers—Robert Wood Johnson Medical School
One Robert Wood Johnson Place, New Brunswick, NJ 08901
eisensrm@rwjms.rutgers.edu
Amanda Borham, MD
Assistant Professor of Rheumatology
Rheumatology Center of New Jersey
56, Union Avenue, Somerville, NJ 08876
borhamam@rutgers.edu 
Ahmed Abdel-Megid, MD
Rheumatology Center of New Jersey
56, Union Avenue, Somerville, NJ 08876
ahmedmegid@rhcnj.com 
Vivien Hsu, MD 
Rutgers—Robert Wood Johnson Medical School
Rm 458, Medical Education Building
125, Paterson Street, New Brunswick, NJ 08901
hsuvm@rwjms.rutgers.edu
Dirk F. Moore, Ph.D
Associate Professor
Rutgers School of Public Health, Room 215,
683 Hoes Lane West, Piscataway NJ 08854
mooredf@sph.rutgers.edu 
Protocol Version and Date:   3.1; 10 January 2020
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Table of Contents 
1.0
Research Introduction
1.1
Purpose/Specific Aims
1.2
Research Significance
1.3
Research Design and Methods
1.4
Preliminary Data
1.5
Sample Size Justification
1.6
Study Variables
1.7
Drugs/Devices/Biologics
1.8
Primary Specimen Collection
1.9
Interviews, Focus Groups, or Surveys
1.10
Timetable/Schedule of Events
2.0
Project Management
2.1
Research Staff and Qualifications
2.2
Resources Available
2.3
Research Sites
3.0
Multi-Site Research Communication & Coordination
3.1
Outside Research
4.0
Research Data Source/s
4.1
Primary Data – Subjects and Specimens
4.2
Subject Selection and Enrollment Considerations
4.3
Subject Randomization
4.4
Secondary Subjects
4.5
Number of Subjects
4.6
Consent Procedures
4.7
Special Consent Populations
4.8
Economic Burden and/or Compensation For Subjects
4.9
Risks to Subjects
4.10
Secondary Data – Record/Chart Reviews, Databases, Tissue Banks, Etc.
4.11
Chart/Record Review Selection
4.12
Secondary Specimen Collection
5.0
Special Considerations
5.1
Health Insurance Portability and Accountability Act (HIPAA)
5.2
Family Educational Rights and Privacy Act (FERPA)
5.3
NJ Access to Medical Research Act
5.4
Code of Federal Regulations Title 45 Part 46 (Vulnerable Populations)
6.0
Research Data Protection and Reporting
6.1
Data Management and Confidentiality
6.2
Data Security
6.3
Data Safety And Monitoring
6.4
Reporting Results
6.5
Data Sharing
7.0
Data and/or Specimen Banking
8.0
Other Approvals/Authorizations
9.0
Bibliography
10.0
Appendix A
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1.0 Research Introduction
1.1 Purpose/Specific Aims
The purpose of this pilot study is to investigate the safety and efficacy of etanercept (Enbrel™; 
Amgen) for the treatment of an acute gout attack. Etanercept is a chimeric protein containing 
the ligand-binding region of the tumor necrosis factor (TNF) receptor (TNFr), fused to the 
constant (Fc) region of a human IgG1 antibody.1 Etanercept binds to TNFα, preventing its 
interaction with TNFr.
The study is designed to demonstrate that a single dose of etanercept 50 mg subcutaneously 
(SC), given at the onset of an acute gout attack, will be non-inferior to a single dose of 
triamcinolone acetonide 40 mg intramuscularly (IM), for relief of signs and symptoms, including 
pain.
A. Objectives 
1.
Primary objective—demonstrate that etanercept 50 mg SC is non-inferior to 
triamcinolone acetonide 40 mg IM, with respect to patient self-assessment of joint pain 
intensity in the most affected (target) baseline joint, at 72 hours post-dose.
2.
Secondary objectives
(a) Evaluate the efficacy of etanercept, compared to triamcinolone acetonide, with 
respect to the treatment of the signs and symptoms of an acute gout attack.
(b) Compare the use of rescue medications in patients treated with etanercept or 
triamcinolone acetonide.
(c) Compare the time to 100%, 80%, and 50% resolution of pain in etanercept- and 
triamcinolone acetonide-treated patients.
(d) Evaluate the safety and tolerability of etanercept.
3.
Exploratory objectives—compare etanercept and triamcinolone acetonide with respect 
to laboratory measures of acute inflammation and patient self-assessment of quality of 
life during an acute gout attack.
B. Hypotheses / Research Question(s)
Etanercept 50 mg SC, given at the onset of an acute gout attack, will be non-inferior to 
triamcinolone acetonide 40 mg IM, with respect to the relief of signs and symptoms, 
including pain.  
1.2 Research Significance
Gout results from the crystallization of uric acid and deposition of monosodium urate (MSU) 
crystals in and around joints, and is the most common inflammatory arthritis in humans.2 The 
2007-2008 National Health and Nutrition Examination Survey (NHANES) gave a prevalence of 8.3 
million adults with gout in the United States.3 Important risk factors for hyperuricemia and gout 
include increasing age, male gender (4:1 male-to-female ratio prior to age 65, and 3:1 
thereafter), obesity (prevalence doubles at BMI >30 kg/m2), hypertension, chronic kidney 
disease (CKD), alcohol use, dietary fructose or animal purines, and the use of loop or thiazide 
diuretics.4-6 Not surprisingly, clinically relevant comorbidities often complicate drug selection 
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and use in the gout population. The 2007-2008 NHANES survey of gout patients revealed 
hypertension in 74%, Stage 2 or greater chronic kidney disease (CKD) in 71%, obesity in 53%, 
diabetes in 26%, and heart failure in 11% of gout patients in the United States.2,6,7
The pathophysiology of acute gout is multifaceted, and involves a number of innate and 
adaptive immune cells, soluble inflammatory mediators, cytokines, and chemokines.8 MSU 
crystals are directly cytotoxic to resident synoviocytes, inducing necroptosis (via the RIPK3-MLKL 
necrosome pathway).8 Necrotic cells also release histones and related DAMPs, thereby 
activating resident macrophages via the NLRP3 inflammasome. The subsequent release of 
interleukin (IL)-1 triggers a cascade of events that stimulate the infiltration of neutrophils and 
monocytes into the affected joints. Monocytes differentiate into an M1 phenotype, and along 
with infiltrating neutrophils release a number of pro-inflammatory cytokines, including IL-6, IL-8, 
and TNFα. Under the influence of IL-8, TNFα, DAMPs, and MSU crystals themselves, neutrophils 
greatly amplify the inflammatory process through the formation of neutrophil extracellular traps 
(NETs), which contain lysosomal enzymes and reactive oxygen species (ROS). NET formation can 
also result in the destruction of infiltrating neutrophils, an event that may be involved in the 
resolution of inflammation.8
For reasons that are still incompletely understood, acute gout resolves spontaneously, even 
without treatment and the continuing presence of MSU crystals in the synovium, within 
approximately 7-10 days.9-12 As with any inflammatory process, negative feedback mechanisms 
are critical for preventing run-away tissue damage and autoimmunity. Anti-inflammatory 
mediators identified in the synovial fluid of patients with acute gout include IL-10; IL-1 receptor 
antagonist (IL-1RA); transforming growth factor-beta1 (TGF-1), which stimulates the release of 
IL-1RA; and soluble TNF receptors I and II (sTNFR-I/II).9 In a murine model, the intraneural 
injection of neutralizing antibodies to both TNFα and IL-1β reduced neuropathic pain.10 In 
contrast, in murine models of RA, such as collagen-induced arthritis, IL-1β blockade appears to 
be more effective than TNFα blockade in ameliorating the disease process.13 One theory with 
respect to the resolution of inflammation involves the phagocytosis of necrotic neutrophils by 
macrophages.9 As acute gout proceeds, infiltrating monocytes differentiate into a stronger  M2 
phenotype, associated with greater phagocytic capacity, and the secretion of TGF-1.9
The role of TNFα in pain generation and propagation is best studied in inflammatory 
neuropathic pain.14-19 TNFα is released by local Schwann cells, mast cells, fibroblasts, and 
endothelial cells in response to acute nerve injury, then amplifies the pain response via 
recruitment of circulating macrophages and neutrophils, which subsequently release IL-1β and 
other inflammatory cytokines. The specific role of TNFα in acute gout is not fully understood, 
but appears to involve the “priming” of neutrophils to secrete IL-1 in response to MSU crystal-
induced cellular necrosis. IL-1 and IL-8 appear to play the central role in the subsequent 
recruitment and activation of inflammatory cells within the affected joint, including neutrophils, 
monocytes, and dendritic cells. Neutrophils greatly enhance the emerging inflammatory 
response via the release of additional inflammatory mediators, such as prostaglandin E2, nitric 
oxide, leukotriene B4 (LTB4), ROS, and the calcium-binding proteins S100A8 and S100A9. 
Crystal-induced activation of the classical complement cascade induces affected endothelial 
cells to release additional IL-8, along with the nociceptive stimulants bradykinin, substance P, 
and LTB4. This latter process helps to explain the sudden, intense pain associated with an acute 
gout attack. 
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The management of acute gout attacks has traditionally centered around the use of non-steroidal 
anti-inflammatory drugs (NSAIDs), colchicine, and systemic or interarticular corticosteroids.9,20,21 The 
ACP 2017 guidelines recommend that clinicians choose corticosteroids, nonsteroidal anti-
inflammatory drugs (NSAIDs), or colchicine to treat patients with acute gout.  Corticosteroids should 
be considered as first-line therapy in patients without contraindications because they are generally 
safer and a low-cost treatment option. 22
NSAIDs or colchicine should be used with caution in patients with renal or gastrointestinal disease, 
while corticosteroids can be problematic in patients with diabetes. Clinicians may be forced to 
choose a corticosteroid in patients with contraindications to NSAIDs and/or colchicine. 
Intramuscular (IM) triamcinolone acetonide (Kenalog®; Bristol-Myers Squibb) is a popular choice in 
patients that cannot receive oral therapy.  A 2008 meta-analysis of three trials found IM 
triamcinolone acetonide to be equally effective to IM adrencorticotropic hormone, oral 
indomethacin, and oral prednisolone.20  Triamcinolone acetonide IM 40 mg was chosen as the 
comparator in the large acute gout trials canakinumab studies comparing a single injection of 
canakinumab (10 to 150 mg) with a single 40 mg IM  injection of triamcinolone acetonide. The 
studies were  based on the experience of the investigators and the fact that in two countries in 
which the canakinumab trials24-25 were  performed, the 40 mg IM dose is labelled as the initial dose 
or usual dose and higher doses were not considered to be acceptable to investigators or the health 
authorities. Furthermore, according to a  survey, 72% of prescriptions for triamcinolone acetonide in 
France, Germany and the UK in 2008 to 2009 were for the 40 mg dosage.26
A single 40 mg dose of IM triamcinolone acetonide is a popular treatment choice for an acute gout 
attack because it is effective, has a superior short-term safety profile compared to colchicine or 
NSAIDs, and offers the potential for effective treatment with single-dose drug administration.21 In a 
study of 20 patients with acute gout exacerbation, patients were randomized to either oral 
indomethacin 50 mg three times daily for a minimum of 2 days, or IM triamcinolone acetonide as a 
single 60 mg dose.23 Follow-up visits occurred at days 1-2, 3-4, 10-14, and 30. A second 
triamcinolone acetonide dose was allowed at the initial follow-up visit if symptoms had not 
improved by at least 50%. There was no difference in the mean time to total symptom resolution 
(8.34.3 versus 7.44.6 days, respectively, for indomethacin and triamcinolone acetonide; P=0.66). 
Respective mean clinical joint scores (0=complete resolution, 1=greater than 50% improvement, 
2=less than 50% improvement, 3=no improvement, 4=worsening of symptoms or involvment of 
additional joints) at days 1-2, 3-4, and 10-14, were 1.50.85, 0.650.63, and 0.20.37 for 
indomethacin, compared to 1.00.72, 0.620.78, and 0.50.16 for triamcinolone acetonide (none of 
the differences between indomethacin and triamcinolone acetonide were significant). Only three 
out of ten patients randomized to triamcinolone acetonide required a second injection at the initial 
follow-up visit.23 A separate study compared oral diclofenac 50 mg three times daily for 3 days, 
followed by 25 mg orally three times daily for 3 days (n=10), to single-dose IM betamethasone 7 mg 
(n=10) or intravenous (IV) methylprednisolone 125 mg (n=7) in 27 patients with acute gout attack.27 
Follow-up visits occurred at days 1, 3, 6, and 15, and no additional analgesic or antiinflammatory 
medications were allowed prior to the day 6 follow-up visit. The median patient self-assessment 
score for percentage improvement in symptoms at 24 hours was 75%, 75%, and 71% , respectively, 
for diclofenac, betamethasone, and methylprednisolone. At 72 hour follow-up, respective median 
scores were 85%, 90%, and 95%, compared to 100%, 100%, and 90% at study day 6. Overall, 67.7%, 
90%, and 100% of patients, respectively, reported at least a 50% improvement in symptoms at 24 
hours, compared to 100%, 90%, and 85.7% of patients, respectively, at both 72 hours and day 6.27
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Newer biologic agents that target pro-inflammatory cytokines offer an alternative choice in patients 
unable to take first-line agents. Anti-IL-1 agents, such as anakinra (recombinant IL-1RA), 
canakinumab (human monoclonal anti-IL-1), and rilonacept (soluble IL-1RA) have been studied for 
gout, but are not FDA-approved, although they are used off-label.24,25,28 There is considerable 
evidence that TNFα inhibition is effective in the management of a range of human arthritides and 
musculoskeletal disorders, namely rheumatoid arthritis (RA), juvenile RA (JRA), ankylosing 
spondylitis, and psoriatic arthritis. Hence, in light of a major unmet need, a clinical study is 
warranted to further define the effect of TNFα blockade in patients with an acute gout attack.
For a number of reasons, the infection risk associated with etanercept is lower than that associated 
with the other approved TNFα blockers available in the United States (the monoclonal antibodies 
infliximab, adalimumab, certolizumab pegol, and golimumab:29

Etanercept is a fully human fusion protein, in which the extracellular ligand-binding region 
of the TNF-alpha receptor is linked to the constant (Fc) fragment of an IgG1 antibody. Unlike 
the 4 monoclonal antibodies mentioned above, etanercept only binds to soluble TNF-alpha. 
Since it cannot bind membrane-bound receptor, the Fc region of etanercept does not 
initiate complement-mediated cell lysis (ie., in contrast to infliximab, activated T cells and 
macrophages expressing membrane-bound TNF-alpha receptors are not lysed by 
etanercept).29,30

TNF-alpha (both soluble, and in particular membrane-bound) is essential for the formation 
of, and integrity of granulomas, and therefore for protection against tuberculosis (TB) and 
other granulomatous diseases.31 In murine models of chronic TB, monoclonal antibody TNF-
alpha receptor blockers penetrate granulomas more completely than etanercept, which may 
help to explain the lower TB risk associated with etanercept. In comparison to etanercept, 
the Odds Ratio (95% Confidence Interval) of TB with infliximab and adalimumab was 13.3 
(2.6-69) and 17.1 (3.6-80.6), respectively.31 Dixon WG et al reported a TB rate of 39/100,000 
patient-years for etanercept, compared to 136/100,000 for infliximab (an incident ratio of 
3.1 [1-9.5] versus etanercept), and 144/100,000 for adalimumab (incident ratio of 4.2 [1.4-
12.4]).32

The onset of TB tends to occur much later with etanercept than with the monoclonal 
antibodies, and may not involve the reactivation of latent TB, but rather spontaneous 
exposure/new infection.33,34 The authors reported a TB infection rate of 28.3/100,000 
patients treated with etanercept, versus 53.8/100,000 with infliximab (P<0.0001). With 
infliximab, 44% of infections occurred within the first 90 days of treatment, as opposed to 
only 10% with etanercept (P<0.001). The cumulative proportion of TB infections suggests an 
early cluster infections with infliximab, representing reactivation of latent TB, as opposed to 
a nearly linear pattern over time with etanercept (new infections as opposed to 
reactivation).33,34
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
In the setting of hepatitis B (HBV) infection, TNF-alpha is essential for the production of 
HBV-specific cytotoxic T cells, which in turn destroy HBV-infected hepatocytes.35 Most of the 
information regarding HBV reactivation in patients treated with TNF-alpha blockers is 
limited to case reports.35 Cantini and colleagues reported a prevalence (95% confidence 
interval) of HBV reactivation of 4.6% (0.5-12.5%) with adalimumab, and 3.9% (1.1-8.4%) with 
etanercept.36

In contrast to chronic HBV, the role of TNF-alpha in chronic hepatitis C (HCV) infection is not 
well established.37 In theory, TNF-alpha blockade could permit increased viral replication, 
since it is involved in triggering apoptosis of HCV-infected hepatocytes. However, this is not 
supported by current observations. Pompili and colleagues reported on 216 chronic HCV 
patients treated with TNF-alpha blockers over a median period of 1.2 years and 260 
cumulative patient-years of exposure, and observed only 3 cases of suspected HCV-related 
liver disease progression.37 The authors concluded that the use of these agents in patients 
with chronic HCV infection appears to be safe in the short term, more evidence is required 
to assess long-term safety. The authors also questioned the value of HCV screening prior to 
initiation of TNF-alpha blocker therapy, as active HCV is not a treatment contraindication.37
1.3 Research Design and Methods
This is a 4-week, multi-center, double-blind, double-dummy, active-controlled clinical study 
designed to compare the safety and effectiveness of etanercept and triamcinolone acetonide in 
patients with acute attacks of gout. 
A. There will be 4 visits to a study site and one follow up phone call. Visits will occur at either the 
adult Clinical Research Center (CRC) at RWJMS in New Brunswick, the Emergency Department at 
Robert Wood Johnson University Hospital (RWJUH) in New Brunswick, the office of Dr. Borham 
at 56 Union Avenue in Somerville, or the clinic of Dr. Schlesinger at RWJMS in New Brunswick. 
Visit 1 (Day 1):  Informed consent and screening (physical examination/medical history/urine 
pregnancy test, as indicated) will be completed. In subjects who qualify, baseline assessments 
will be completed and study drug administered.  
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Visits 2 (Day 41), 3 (Day 71), and 4 (Day 142):  All study procedures listed on Table 2 will 
occur at each Visit. A second dose of study drug will be administered if the pain intensity is ≥5 at 
Visit 2.
Follow-up telephone call (Day 303):  The study will end with the follow-up telephone call,  
designed to record adverse events, and learn whether there were recurrent gout attacks during 
treatment.
Table 1. Outline of study design
Screening and Baseline
Treatment Follow-up
End of Study
  Efficacy and Safety Assessments  
Study Day 1
(Visit 1)
Study Day 4±1
(Visit 2)
Study Day 7±1
(Visit 3)
Study Day 14±2
(Visit 4)
Study Day 30±3
Informed consent
Screening
Randomization
Dosing
Single dose of Etanercept 50 mg SC
or
Single dose of Triamcinolone 
acetonide 40mg IM
72-hour re-dose 
if Pain Score ≥ 5
Follow-up
Follow-up
(Follow-up telephone 
interview)
Table 2. Study procedures
Screening and 
Randomization
Baseline 
assessments
Treatment
Phone 
Call
Visit
1
1
2
3
4
Study Day
1
1
4±1
7±1
14±2
30±3
Informed consent
X
Inclusion/exclusion criteria
X
Demographics
X
Employment status
X
Diagnosis of gout
X
History of gout
X
Medical history and current medical condition
X
X
X
X
Concomitant medications
X
X
X
X
Adverse events
X
X
X
X
X
Blood pressure and pulse
X
X
X
X
Weight
X
X
X
X
Height
X
Physical examination
X
X
X
X
Identification of the target joint of the current gout 
attack
X
Record all affected joints of the current gout attack
X
X
X
X
Pregnancy test (for women with childbearing 
potential)
X
Hematology
X
X
Blood chemistry
X
X
Serum urate
X
X
hSCRP
X
X
Patient’s assessment of gout pain in the target joint 
(Pain Score)
X*
X
X
X
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Screening and 
Randomization
Baseline 
assessments
Treatment
Phone 
Call
Visit
1
1
2
3
4
Study Day
1
1
4±1
7±1
14±2
30±3
Patient’s assessment of gout pain in the target joint 
(Likert)
X*
X
X
X
Patient’s global assessment of response to treatment 
(Likert)
X
X
X
Physician’s global assessment of response to 
treatment (Likert)
X
X
X
Physician’s assessment of Tenderness, Swelling and 
Erythema (Likert)
X*
X
X
X
Physician’s assessment of range of motion (Likert)
X*
X
X
X
HAQ
X
X
X
SF-36v2 ®
X
X
Study drug administration
X
X** 
Dispense rescue medication diary
X
X
X
Check use of rescue medication/ review diary
X
X
X
Pain Score  ≥ 5
X
X
X
X
Patient-reported attack
X
* Assessments will be done prior to dosing
** Second dose of study medication will be administered only if pain intensity still  5 
B.  Data Points collected including long-term follow-up
N/A. The study ends with the follow-up telephone call.
C.
Duration of the Study and Length of Subject Participation
Dosing will occur at the conclusion of Visit 1 (Study Day 1), the Screening/Baseline visit. Visits 2-
4 take place on Study Days 41, 71, and 142. The study will end with a follow-up telephone 
call on Study Day 303 designed to record adverse events (AEs), and learn whether there were 
recurrent gout attacks during treatment. 
D.  Primary and Secondary endpoints
i.
Primary Outcome—pain intensity in the most affected baseline joint measured by the 
numeric 0-10 pain scale at 72 hours (Visit 2). 
ii.
Secondary Outcomes
[1] Patient’s assessment of joint pain intensity in the most affected baseline joint on a 0-
10 numeric pain scale, at Baseline and post-dose Visits 2, 3, and 4;
[2] Patient’s assessment of joint pain intensity in the most affected baseline joint on a 
Likert scale, at Baseline and post-dose Visits 2, 3, and 4;
[3] Change in pain intensity from baseline to 72 hours
[4] Patient’s global assessment of response to treatment, on a Likert scale at post-dose 
Visits 2, 3 and 4;
[5] Physician’s assessment of Tenderness, Swelling and Erythema in the most affected 
joint, at post-dose Visits 2 and 3, using:
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— Tenderness on a 0-3 point scale (“no pain”, “there is pain”, “there is pain and 
patient winces”, and “there is pain, patient winces, and then withdraws on 
palpation or passive movement of the affected study joint”);
— Swelling on a 0-3 point scale (“no swelling”, “palpable”, “visible”, and “bulging 
beyond the joint margins”;
— Erythema (“present”, “absent”, or “not assessable”), and;
[6] Physician’s assessment of range of motion on a Likert scale (“normal”, “mildly 
restricted”, “moderately restricted”, “severely restricted”, and “immobilized”;
[7] Physician’s global assessment of response to treatment, on a Likert scale, at post-dose 
Visits 2, 3 and 4.
[8] Compare the use of rescue medication in etanercept and triamcinolone acetonide 
patients:
(a) Time to first rescue medication intake;
(b) Total number of patients taking rescue medication, and;
(c) Total milligram dose of rescue medication taken.
[9] Time to complete 100%/80%/50% resolution of pain
[10]Safety and tolerability of etanercept
iii.
Exploratory objectives:
[1] Quality of life, as measured by the Health Assessment Questionnaire Disability Index 
(HAQ-DI) and Medical Outcome Short Form (SF)-36v2™ Health Survey (acute version), 
and;
[2] Laboratory results at Baseline (Study Day 1) and Study Visit 3:
(a) Complete blood count (CBC) and differential;
(b) Comprehensive metabolic panel (CMP);
(c) High-sensitivity C-reactive protein (hSCRP), and; 
(d) Serum urate.
1.4 Preliminary Data
None
1.5 Sample Size Justification
The sample size will be 20 patients per arm, for a total of 40 patients, based on a non-inferiority design. 
Details are given in Section 4.5.
1.6 Study Variables
A. Independent Variables, Interventions, or Predictor Variables 
In randomized, double-blind, double-dummy fashion, subjects will receive a single dose of IM 
triamcinolone acetonide and SC placebo, or SC etanercept and IM placebo.
B. Dependent Variables or Outcome Measures 
(1) Primary Outcome—joint pain intensity in the most affected baseline joint.
(2) Secondary Outcomes—see 1.3(D) above
1.7 Drugs/Devices/Biologics 
At the completion of Visit 1 (Study Day 1), subjects will receive one SC injection and one IM 
injection. According to the study design and randomization schedule, each patient will be receiving 
either:
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Etanercept 50 mg SC and placebo IM, or;
Triamcinolone acetonide 40 mg IM and placebo SC. 
The Research Pharmacist at RWJMS is not blinded, and will be responsible for storage, inventory, 
preparation, and dispensing of all study medications:
AMGEN will supply etanercept and its matching placebo in individual prefilled syringes. Thirty 
minutes before injection, prefilled syringes should be taken out from cold storage to 
equilibrate the injection solution with room temperature. The SC injection should be 
administered into the arm or thigh. 

Triamcinolone acetonide 40mg (1 mL) (or 1 mL of matching placebo) will be given as an IM 
injection. The vial should be shaken before use to ensure a uniform suspension. Prior to 
withdrawal, the suspension should be inspected for clumping or granular appearance 
(agglomeration). An agglomerated product results from exposure to freezing temperatures 
and should not be used. The matching placebo for triamcinolone acetonide will be 0.9% 
Normal Saline, supplied as 10 mL vials. One milliliter of 0.9% Normal Saline will be drawn up 
for the placebo injection. An amber colored tape will be placed on each syringe (active drug 
and placebo) to maintain blinding. The amber tape is see-through, it is tinted, to mask the 
color of the injection.  The gradations on the syringe will still be visible. After withdrawal, 
the triamcinolone acetonide/matching placebo should be injected without delay to prevent 
settling in the syringe. IM injection should be made deeply into the gluteal muscle; for 
adults, a minimum needle length of 1½ inches is recommended.
Study drug dose adjustments and/or interruptions will not be permitted.
Rescue medications
Patients who have difficulty tolerating their pain, despite the treatment, are allowed to take 
acetaminophen (paracetamol) 500 mg orally as needed as rescue medication for pain. A maximum 
of 1 g/dose or 3 g/day of acetaminophen is allowed. 
If there is insufficient pain relief, patients are allowed to take 20 mg of prednisone per day for up to 
7 days.
A paper diary will be given to each patient in order to record time of intake of rescue medication 
and the amount taken. At the next visit or early discontinuation/termination the patient diary will be 
reviewed. 
Concomitant treatment
Concomitant medications and/or non-drug therapy before the administration of study medication, 
and after start of study drug, will be collected, including medication name, dose, route of 
administration, and indication.
Prohibited medications or treatments not allowed after screening/randomization: 

any anti-inflammatory or analgesic treatment within the first 7 days after dosing for a gout 
attack, except rescue medication as defined above; 

any biologic agent other than etanercept, and;

any live vaccination.
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A. Drug/Device Accountability and Storage Methods
The Investigational Drug Service (IDS) of the Rutgers-Robert Wood Johnson Medical School is a 
cooperative service with the Department of Pharmacy of the Robert Wood Johnson University 
Hospital. The IDS is responsible for the storage, preparation and proper labeling of 
investigational drugs in use at the hospital and the medical school. The service is involved in 
creation of pharmacy portions of investigator-initiated protocols and in the acquisition of drug 
product for studies within the medical school community. In addition, the IDS provides the 
necessary information and education about investigational drugs to the pharmacy and nursing 
staffs in both institutions. The IDS is located on the 8th floor of the East Tower in the Clinical 
Research Center, Room ET-893. 
The Research Pharmacy in the Clinical Research Center will control all of the IP and will supply 
the IP for the site in already prepared randomized kits in numerical order. An unblinded RN will 
be administering the injections at Dr.Borham’s site.  This person will pull the next numbered kit 
for each subject and monitor such things as supply usage to report back to the CRC pharmacy. 
Also, this person will record the daily temperature logs for both the entanercept or placebo 
(refrigerated), and triamcinolone or normal saline for placebo, ambient temperature.
1.8 Primary Specimen Collection
A. Blood and urine samples will be collected for blood chemistry, hematology, serum urate, hSCRP, 
and pregnancy testing at baseline. All except pregnancy testing will be repeated at visit 3. All 
specimens will be collected at the location of subject screening or follow-up visit. All samples 
collected at all sites will be processed by LabCorp. Clinical specimens will not be used for this 
study. The expenses for these lab tests will be covered by study funds.
1.9 Interviews, Focus Groups, or Surveys 
N/A
1.10 Timetable/Schedule of Events
Please see Tables 1 and 2 in (1.3.A) above.
2.0 Project Management
2.1 Research Staff and Qualifications
Principal Investigator
Naomi Schlesinger, MD, Professor and Chief, Division of Rheumatology and Director, Rutgers Robert 
Wood Johnson Medical School- (RWJMS) Gout Center, Rutgers—RWJMS. Dr. Schlesinger is a 
previous President of the NJ Rheumatology Association and was the recipient of the   2015 
Rheumatologist of The Year award by the Arthritis Foundation - New Jersey Chapter. She is a noted 
authority in the field of gout, having published many papers regarding the diagnosis, treatment, and 
pathogenesis. She is the author of over 200 scientific articles, abstracts, book chapters and reviews.  
Dr.Schlesinger is a co- Editor, with Dr.Lipsky of the soon to be published book “Gout’, 1st Edition by 
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Elsevier and has written the chapter on ‘Clinical features of gout” for the main text book in 
Rheumatology:  “Rheumatology’, published April, 2018. 
Dr.Schlesinger’s research has won recognition, including the work titled: Efficacy of canakinumab 
(ACZ885), a fully human  anti-Interleukin (IL)-1beta monoclonal antibody, in the  prevention of flares 
in gout patients initiating allopurinol therapy, which was  selected as one of the 5 highest ranking 
abstracts   that will likely shape our treatment paradigms for years to come in the 2010 ACR/ ARHP 
Annual Scientific Meeting and the work titled: Erectile dysfunction is common among gout patients, 
which  was  selected (one of 13) for inclusion in   the official 2014 EULAR Press Conference from over 
4000 abstracts.  Other pioneering work includes treatment of gout with topical ice, seasonality of 
gout, diagnosing gout using ultrasound, understanding the pathogenesis of bone erosions in gout 
and the importance of anti-inflammatory treatment in gout. Dr. Schlesinger has been recognized 
among the world's top ten experts in gout research and treatment:  PubMed, March 4, 2014 and 
Expertscape, March 10, 2014.
Dr. Schlesinger served as a scientific advisor, Consortium of Rheumatology Researchers of North 
America (CORRONA) gout registry, the Co-chair of the ACR- Crystal Study Group, as well as the Co-
chair of the ACR abstract reviewer selection process: metabolic and crystal arthropathies. In 
addition, Dr. Schlesinger served on the newly formed American College of Rheumatology (ACR) 
Division Directors Special Committee (DDSC). She has a special interest in Evidence-Based Medicine 
and served as a Co-facilitator of the acute gout review group for the Cochrane International 
Collaboration as well as a member of the Outcome Measures in Rheumatology (OMERACT) gout 
special interest organizing group. 
Dr.Schlesinger served as a leading International Consultant / PI (with Prof. Alexander So Lausanne, 
Switzerland) for the Novartis phases II and III Canakinumab gout trials 5/2007-6/2013. She serves as 
a consultant to pharmaceutical companies and contract research organizations (CROs) on gout drug 
development. 
Co-Investigators
Robert Eisenstein, MD, Chair Department of Emergency Medicine, Rutgers—Robert Wood Johnson 
Medical School, New Brunswick, NJ
Amanda Borham, MD, Assistant Professor, Division of Rheumatology, Department of Medicine, 
Rutgers—Robert Wood Johnson Medical School, New Brunswick, NJ
Ahmed Abdel-Megid, MD, Volunteer Faculty, Division of Rheumatology, Department of Medicine, 
Rutgers—RWJMS. Dr. Abdel-Megid is an expert in the management of both localized and 
generalized pain and has specific training in the diagnosis and treatment of arthritis and 
rheumatism. He treats localized pain in the back, neck, shoulders and hands, including 
osteoarthritis, tendonitis and bursitis, as well as complex systemic pain caused by diseases like 
rheumatoid arthritis or systemic lupus. Dr. Abdel-Megid also treats clinical problems involving joints, 
soft tissues, autoimmune diseases, vasculitis, and heritable connective tissue disorders.
Vivien Hsu, MD, Professor, Division of Rheumatology, Department of Medicine, Rutgers—Robert 
Wood Johnson Medical School, New Brunswick, NJ
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Dirk F. Moore, Ph.D, Rutgers School of Public Health and Rutgers Cancer Institute of New Jersey. Dr. 
Moore’s expertise concerns the application of biostatistical methods to the study of human disease, 
including cancer. He has more than 90 peer-review publications. Dr. Moore uses case series and 
administrative databases to study factors associated with incidence and outcomes of breast and 
prostate cancer. He is experienced in the statistical analysis of proteomics and genetics data in 
human disease, having worked extensively with using biostatistical analyses to elucidate the effects 
of genes and proteins on disease.
2.2 Resources Available
The Clinical Research Center (CRC) will be supporting the study with regulatory, nursing, data 
management and operational support.
The CRC will work with Dr.Schlesinger and personnel at Dr. Borham’s site to provide the training 
necessary for uniform data collection, protocol compliance, and data collection and entry. Major 
elements to be covered are inclusion and exclusion criteria, study procedures, randomization 
procedures, medication storage and dispensing, and data collection. 
Initiation training will be conducted prior to first patient screened.  The CRC will provide the 
following training to Dr. Borham’s site.
CRC will coordinate and conduct the Site Initiation Visit with Dr. Schlesinger for both sites including:  
a.
Study specific aims
b.
Background and significance
c.
Patient population – Inclusion and Exclusion Criteria
d.
Study drug review and specific dosing instruction
e.
Recruitment of patients
f.
Patient Consent
g.
REDCap system orientation
h.
Electronic Data Entry
i.
Randomization   
The CRC, with Dr. Schlesinger, will provide training of any amendments or modifications to the 
protocol or any study specific procedures as they occur to both sites.
2.3 Research Sites
Subjects will be seen at the CRC at RWJMS in New Brunswick, the clinic office of Dr. Schlesinger (her 
outpatient clinic at RWJMS in New Brunswick), the Emergency Department at RWJUH in New 
Brunswick, and the office of Dr. Borham (her office Rheumatology center of New Jersey at 56 Union 
Avenue in Somerville). These patients will be consented, screened, dosed, and evaluated for the 
duration of the study at these respective sites. The follow up visits for subjects enrolled in the 
Emergency Department and Dr. Schlesinger outpatient clinic will take place in the CRC. 
3.0 Multi-Site Research Communication & Coordination 
A. Document Consistency
The PI or PI’s qualified designee will oversee both sites to ensure that both sites have the most 
current versions of study documents and HIPAA authorization. 
B. Site Approvals
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       PI or PI’s qualified designee will oversee all study sites to assure if the required approvals have 
been obtained and maintained as per institutional policy and FDA guidelines.   
C. Modifications
PI or PI’s qualified designee will oversee that the modifications have been communicated to all 
study sites, and the IRB of Record has approved the modification prior to implementation. On-
going regular conference calls will be conducted with the coordinators at both sites to discuss 
issues that arise and data collections. Any modifications or changes to research will be 
communicated during the conference calls.     
D.
Data Security
PI or PI’s qualified designee will oversee that the sites engaged in the study will safeguard data 
as required by FDA and local institutional security policies.  REDCap Database is FDA CFR 21 Part 
11 compliant. Data transmission will not include any personal health identifiers. 
E. Legal Obligation
Local site investigators have completed CITI biomedical training required by the IRB of record 
and aware of federal regulations on conducting clinical research. They will also be trained on 
any applicable local laws required to conduct the research.   
F. Adherence to Policy and Reporting of Non-Compliance
        Study team will make all efforts to conduct the research as per the study protocol. Any non-
compliance with the study protocol will be promptly reported to the proper authorities as 
required by institutional policy.     
3.1 Outside Research
N/A
4.0 Research Data Source/s
4.1 Primary Data-Subjects and Specimens
4.2 Subject Selection and Enrollment Considerations 
A. Recruitment Details
Subjects will be recruited from the practices of Dr. Schlesinger (her outpatient clinic at RWJMS 
Clinical Academic Building Suite 5200A, 125 Paterson Street, New Brunswick, NJ), Dr. Borham 
(her office at 56 Union Avenue in Somerville), and the Emergency Department at RWJUH in New 
Brunswick. Gout classification criteria ACR EULAR 2015 will be used for recruiting patients in the 
study. These patients will be consented, screened, dosed, and evaluated for the duration of the 
study at these respective sites. CITI certified site staff will be consenting the patients.
B. Source of Subjects 
Please see 4.2A.
C. Method to Identify Potential Subjects
Please see 4.2A.
D. Subject Screening
Subjects will be screened for study eligibility by study staff at their respective locations listed 
above. 
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Inclusion Criteria
Patients eligible for inclusion in this study must fulfill all of the following criteria:
1.Male or female patients age ≥18 to ≤85 year
2.History of established gout, as proposed by the American College of 
Rheumatology/European League Against Rheumatism (ACR/EULAR) provisional 
definition of gout (confirmed diagnosis of crystal-proven gout, and/or a score of ≥8 on 
the 2015 ACR/EULAR Gout Classification Criteria)38;
3.Onset of current acute gout attack within 4 days prior to randomization (an acute attack 
in patients with established gout will be defined using modified 2015 ACR/EULAR 
criteria38;  
(a) Presence of any warm joint;
(b) Swollen joint;
(c) Pain score at rest ≥5 on the 0-10 pain scale, and;1
(d) Patient self-report of acute gout attack;
4.Baseline pain intensity ≥5 on a 0-10 pain scale;
5.Tender (≥1 on a 0-4-point Likert scale) and swollen (≥1 on a 0-4-point Likert scale) index 
joint;
6.Subject must be able to give informed consent, and must authorize release and use of 
collected health information;
7.If on urate-lowering therapy, a stable dose and regimen for at least 2 weeks prior to 
randomization, and expectance to remain on a stable dose and regimen for the 
duration of the double-blind treatment period, and;
8.Body mass index (BMI) ≤45 kg/m2.
Exclusion Criteria
Patients fulfilling any of the following criteria will not be eligible for inclusion in this study:
1.Use of intra-articular or IM corticosteroids within 14 days prior to screening;
2.Use of an IL-1 inhibitor, TNF inhibitor or other biologic or investigational drug within     
30 days prior to screening;
3.History of a drug allergy to either study drug;
4.Diagnosis or history of:
(a) rheumatoid arthritis (RA); 
(b) infectious/septic or other inflammatory arthritis; 
(c) alcoholic hepatitis or nonalcoholic steatohepatitis; 
(d) immunodeficiency syndromes, including Human Immunodeficiency Virus (HIV) 
infection; 
(e) Stage IIIb, IV, or V chronic kidney disease;
(f) idiopathic thrombocytopenic purpura; 
(g) active, severe chronic pulmonary disease (eg, requiring oxygen therapy); 
(h) uncontrolled hypertension (≥ 200/105 mmHg);
(i)
symptomatic (New York Heart Association Class II, III, or IV) congestive heart 
failure;
(j) uncontrolled diabetes Type I or II (recent blood glucose > 300 mg/dL); 
1The 2015 ACR/EULAR provisional definition uses a pain score at rest of >3 on a 0-10 scale, along with criteria (a), 
(b), and (d). The combination of all 4 criteria provided 96% specificity and 85% sensitivity. The combination criteria (c) 
and (d) had the best diagnostic characteristics (sensitivity 83% and specificity 90%) (16). 
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(k) myocardial infarction, unstable cardiac arrhythmias or unstable symptomatic 
coronary ischemia, within the past 12 months before randomization;
(l)
history of malignancy of any organ system within the past 5 years;
(m) multiple sclerosis or any other demyelinating disease, or;
(n) major chronic inflammatory disease or connective tissue disease other than RA 
or psoriatic arthritis (PsA), including but not limited to fibromyalgia or systemic 
lupus erythematosus (with the exception of secondary Sjögrens syndrome, etc.);
5.Contraindication to IM injection; 
6.Donation or loss of ≥400 milliliters (mL) of blood in the 8 weeks before dosing; 
7.Any live vaccination in the 3 months before the start of the study;
8.Active infection (including chronic or localized infections) for which anti-infectives were 
indicated within 4 weeks before screening;
9.Any serious infection, defined as requiring hospitalization or intravenous anti-infectives, 
within 8 weeks before first dose of investigational product;
10. Prosthetic joint infection within 5 years of screening, or native joint infection within 1 
year of screening;
11. Known alcohol addiction or dependency, daily alcohol use, or current substance use or 
abuse;
12. Positive medical history for hepatitis B or C (subjects with a history of hepatitis B 
vaccination without history of hepatitis B infection are allowed to enroll);
13. History of active tuberculosis; 
14. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a 
female after conception and until the termination of gestation, confirmed by a 
positive pregnancy test (guide regarding pregnancy attached), or;
15. Female patients who are physiologically capable of becoming pregnant must use an 
acceptable method of contraception with a Pearl Index (PI) failure rate <1 throughout 
the study, and for 4 weeks after study drug discontinuation: the following female 
patients are excluded from using contraception:
(a) female patients whose career, lifestyle, or sexual orientation precludes 
intercourse with a male partner, and;
(b) female patients whose male partners have been sterilized by vasectomy or 
other means.
E. Recruitment Materials 
A “flyer” or paper advertisement (attached) will be posted in the waiting rooms of Drs. 
Schlesinger and Borham.
F. Lead Site Recruitment Methods
N/A
4.3 Subject Randomization
Treatments will be assigned using permuted blocks and stratified by enrollment site. The 
randomization tables will be provided by the Rutgers Department of Biostatistics.  Research 
pharmacist at Clinical Research Center will supply the study medication for the site in already 
prepared randomized kits in numerical order.  The subjects will be identified by the PI in her clinic at 
RWJMS and the Co-Investigator or Sub-investigator at Emergency Department in the RWJUH and 
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Rheumatology center of NJ (RHCNJ). The subjects will be administered the study medication in 
numerical order.
4.4 Secondary Subjects
N/A
4.5 Number of Subjects
The primary aim of this study is to show that Etanercept is an effective therapy for gouty arthritis, by 
which we mean that it is at least as effective as Tiamconolone acetonide at reducing pain at the  72 
hour (visit 2) time point. Thus, the study is powered to determine non-inferiority of the Etanercept 
arm. To this end, we will compute a 95% Students t confidence interval  for the difference in VAS 
scores at 72 hours. If the lower limit of this confidence interval is above a specified non-inferiority 
limit, we will concluded that Etanercept is as effective as Triamcinolone acetonide.  Of course, if the 
lower limit of this confidence interval were to exceed zero, then Etanercept would be shown to be 
superior, which would be an even stronger outcome.39
Based on a 2012 study of gout (Schlesinger et al. 2012)24, the mean VAS pain scores at 72 hours 
were found to be 25.0 and 35.7 in the Canakinumab and Triamcinolone acetonide arms, 
respectively, for a difference of -10.7. The standard deviation in each group was approximately 12.5.  
This information is based on Table 1 and Figure 2C of Schlesinger et al. 2012). For the current study, 
pain will be assessed and reported on a 10-point scale rather than the 100-poing scale typically used 
for VAS pain indication. Hence, we scale down these measures by a factor of 10 to adapt them to 
this study.
Using this information, we have the following information for 80% power for a non-inferiority 
outcome for three plausible values of the standard deviation:
Non-inferiority 
limit
Standard
Deviation
Power
-1.04
1.15
80%
-1.07
1.20
80%
-1.11
1.25
80%
For example, if the standard deviation is found to be 1.20, and if the true VAS scores for the two 
arms are the same, we will have 80% power to find that the lower limit of the 95% confidence 
interval for VAS scores exceeds -1.07, on the 10-point scale we use in this study.
We will follow up this analysis with a linear regression analysis of the change in pain scores at 72 
hours and at other time points at which numeric scores are collected, adjusted for clinical and 
patient characteristics. Changes in pain score with successive visits will be modelled using standard 
longitudinal data analysis methods in order to provide a comparison of the full profile of pain 
measurements.
A. Total Number of Subjects
40
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B. Total Number of Subjects If Multicenter Study
40
C. Required Number of Subjects to Complete Research
 All 40 subjects enrolled will be followed with intent to treat analysis.
D. Feasibility of Recruiting
Clinical practices of Dr. Schlesinger and Borham see approximately 140 patients annually with an 
acute gout attack. Emergency Department see approximately 40 subjects annually with an acute 
gout attack. We expect recruitment to require approximately 16 months.
4.6 Consent Procedures
A. Consent
Documenting Consent
A written Informed Consent Document will be used.
Waiver of Documentation Of Consent
N/A
Waiver or Alteration of Consent Process 
N/A
B. Consent Process
Dr. Borham’s site study coordinator and study staff will be provided with training in 
obtaining informed consent for research purposes. The CRC staff will reference GCP 
guidelines and the CRC SOP for Obtaining Informed Consent and provide a copy of the SOP 
for filing and reference on site. Since the Study Coordinator is new to Clinical Trials, the CRC 
nurse manager, or experienced designee, will provide oversight of the first informed 
consent process to ensure the process is in accordance with the SOP and GCP guidelines. 
Observations and oversight will be provided until the study coordinator and the CRC Nurse 
Manager have ensured these process guidelines are adhered to.  As detailed in the CRC SOP, 
the site coordinator will be trained to emphasize that consent is voluntary and that the 
medical care the patient receives will not be influenced by his or her decision and that, 
should the patient agree to participate, he or she is free to withdraw from the study at any 
time. 
Dr. Eisenstein and CRC study nurse will introduce the study to potential subjects enrolled in 
the Emergency department. Study nurse will complete the Department of Emergency 
Medicine Consent Checklist to determine that the potential subject is able to voluntarily 
reason, understand and appreciate the nature and consequences of the research 
interventions. Potential subjects will be allowed as much time as needed to adequately read 
and consider the consent form and to decide whether or not to enroll in the study. The 
consent form will be reviewed with the subject in a private room prior to signing the form. If 
any subject is determined to be under the influence of pain medications that would affect 
their ability to consent, that subject will not be approached by the study staff.    
Location of Consent Process
Consent process will take place on the adult Clinical Research Center (CRC) or the office of 
Dr. Schlesinger (her outpatient clinic at RWJMS Clinical Academic Building Suite 5200A, 125 
Paterson Street, New Brunswick, NJ), or in the Emergency Department of RWJUH, or the 
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office of Dr. Borham (her office at 56 Union Avenue in Somerville, NJ), depending on the 
location of the patient. 
Ongoing Consent
Subjects will be informed of any new findings or information that arise, after the consent 
process that may affect their willingness to continue study participation.
Individual Roles for Researchers Involved in Consent
1. Consent Discussion Duration
On a case-by-case basis, adequate time to ensure subject comprehension.
2. Coercion or Undue Influence
The discussion will take place in a private examination room. Subjects will be 
informed that the decision to participate is purely voluntary, and in no way 
influences his/her treatment.
3. Subject Understanding
The investigator obtaining consent will go through the consent form line by line, 
making certain the subject fully comprehends any potential risks or benefits 
associated with study participation.
4.7 Special Consent/Populations
N/A
4.8 Economic Burden and/or Compensation for Subjects
A. Expenses 
None. There is no cost to the study subject.
B. Compensation/Incentives
Subjects may earn a total of $220 for study participation. Compensation will be based on the 
amount of completed study visits:  $70 for the screening (Visit 1), $30 for Visit 2, $30 for Visit 3, 
$70 for Visit 4, and $20 for the follow-up telephone call.
4.9 Risks to Subjects
A. Description of Subject Risk
Etanercept
Very common adverse effects (approximately 10% or greater):
a.
Injection site reactions—erythema, tenderness, pain, bruising, warmth, swelling, 
itching and/or infection at the injection site. These reactions are most common 
during the first month following injection, and disappear despite continued 
etanercept treatment.
b.
Infections—can include viral, bacterial (including tuberculosis), and fungal 
infections. Serious infections have been rare (approximately 0.1-1%).
Common adverse effects (approximately 1-10% of patients):
a.
Allergic reactions—may include headache, flushing, shortness of breath, itching 
and rash, hives, or more severe reactions such as dizziness, difficulty breathing, 
hypotension, or angioedema.
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b.
Development of autoantibodies—some patients do develop autoantibodies. 
Rarely (approximately 0.1-1% of patients), these autoantibodies may be 
associated with a lupus-like syndrome. 
c.
Other common side effects include fever.
Uncommon adverse effects (approximately 0.1-1% of patients):
a.
Non-melanoma skin cancer—Non-melanoma skin cancers are cancers that form in 
squamous cells (the top layer of skin cells) or basal cells (the round cells just under 
the squamous cells). Symptoms of non-melanoma skin cancers may include a 
change in the appearance of your skin, such as a new growth or a sore that will not 
heal.
Non-melanoma skin cancers have been reported with etanercept use and are more 
common in patients with psoriasis. These skin cancers rarely spread to other parts 
of the body. In clinical studies, patients with psoriasis treated with etanercept, were 
at a higher risk of getting squamous cell and basal cell skin cancers. Non-melanoma 
skin cancers have also been reported uncommonly in patients with rheumatoid 
arthritis, juvenile idiopathic arthritis, ankylosing spondylitis and psoriatic arthritis.
•  Non-cancer side effects
a.
Psoriasis—may include new or worsening of psoriasis.
b.
Eye disease
i.
Uveitis (a type of eye inflammation) has been reported with etanercept use. 
Symptoms may include: in one or both eyes, blurred or cloudy vision, eye 
redness and/or eye pain especially when looking at bright lights.
ii.
Scleritis, a type of eye inflammation affecting the white outer coating of the 
eye (known as the sclera), can occur in association with rheumatoid 
arthritis, ankylosing spondylitis and psoriatic arthritis and has been reported 
with etanercept use. Symptoms may include: in one or both eyes, blurred or 
cloudy vision, redness in the whites of the eye, eye pain, sensitivity to light 
and irreversible damage to the eye.
c.
Blood problems—low blood counts have been reported with etanercept use. 
Reports have included low white blood cells, low platelets, and low red blood 
cells. Symptoms of a low blood count may include fever that does not go away, 
bruising, bleeding, or very pale skin.
d.
Heart failure—congestive heart failure (CHF) and worsening of CHF in patients 
who already have it, occurred in patients treated with etanercept. In a clinical trial 
to treat CHF with etanercept, the results suggested a possible chance that 
etanercept worsened CHF. Symptoms of heart failure may include shortness of 
breath and ankle swelling.
e.
Systemic and Cutaneous vasculitis—systemic vasculitis (inflammation of blood 
vessels in the body) and cutaneous vasculitis (inflammation of blood vessels in the 
skin) have been reported with etanercept use. Symptoms of vasculitis may include 
fever, loss of appetite, weight loss, feeling tired, general aches and pains. Systemic 
vasculitis is uncommon (which may affect between 1 and 10 people in every 
1,000). Cutaneous vasculitis is rare (which may affect between 1 and 10 people in 
every 10,000).
f.
Elevated liver enzymes—elevated liver enzymes on blood tests have been 
reported with etanercept use
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
Rare side effects (which may affect between 1 and 10 people in every 10,000):
a.
Cancer—There have been reports of cancer in adults, adolescents, and children 
following etanercept use. It is possible that etanercept may increase the risk of 
getting lymphoma (cancer of the lymph nodes), leukemia (cancer of the blood) or 
other cancers. It is unknown if etanercept might influence the development and 
course of cancer (spreading, the effect of treatment of the cancer, or the cancer 
coming back after treatment). There have been cases of unusual cancers in children 
and teenage patients who started using TNF-blocking agents at less than 18 years of 
age.
Overall cancers occurred in about 1% (1 in 100) of patients with rheumatoid arthritis 
treated with etanercept in clinical studies for up to 5 years. This is similar to the rate 
of cancer that would be expected for rheumatoid arthritis or psoriasis patients if 
they were not receiving etanercept.
Lymphoma
It is known that subjects with rheumatoid arthritis and psoriasis, whether on 
etanercept or other treatments, are at a higher risk (up to several times higher) 
compared with the general population of developing lymphoma (a type of cancer of 
the lymph nodes). It is also known that those with more active (worse) disease have 
the highest risk. In rheumatoid arthritis clinical studies, patients treated with 
etanercept were three times more likely to develop lymphoma than people in 
general (without rheumatoid arthritis). They were no more likely to develop 
lymphoma, however, than moderate to severe rheumatoid arthritis patients overall. 
The role of etanercept and other TNF-blocking therapies in the development of 
lymphoma is not known.
Leukemia
Cases of leukemia have been reported in association with TNF-blocker use. Even in 
the absence of TNF-blocker therapy, patients with rheumatoid arthritis may have 
approximately twice the risk of developing leukemia than people without 
rheumatoid arthritis.
b.
Melanoma skin cancer—melanoma (an aggressive form of skin cancer) has been 
reported in patients taking etanercept. Melanoma develops in the cells that produce 
melanin which is the pigment that gives skin its color. The first melanoma symptoms 
often are a change in an existing mole and/or the development of a new, unusual-
looking growth on skin. 
c.
Non-cancer side effects
— Opportunistic infections—opportunistic infections are unusual infections 
that occur most commonly when immune system is weakened.
— Serious skin reactions—severe skin reactions that can be life-threatening 
rarely occur. These reactions can cause rashes, blistering (on skin, inside the 
mouth, nose or other areas), and shedding of the skin.
— Nervous system problems—Nervous system events, including multiple 
sclerosis, convulsions and inflammation of the nerve in the eye, Guillain-
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Barré syndrome (inflammation of the peripheral nerve in your arms and 
legs) and inflammation of the spinal cord have been reported in patients 
taking etanercept. You may experience numbness or tingling, dizziness, 
weakness in your arms and/or legs, or problems with your vision if you are 
having a neurologic problem
— Sarcoidosis—sarcoidosis is a disease that causes inflammation in the lungs 
and other tissues, and has been reported with etanercept use.
— Other rare side effects—other rare side effects include swelling of the 
lymph nodes, diarrhea, chest pain, fever, interstitial lung disease (lung 
scarring), and liver problems such as hepatitis (injury of the liver).

Very Rare side effects (which may affect less than 1 person in 10,000):
a.
Blood problems—aplastic anemia (the body stops producing all blood cells) have 
been reported with etanercept use. Some of the patients with aplastic anemia died. 
Symptoms of a low blood count may include fever that does not go away, bruising, 
bleeding, or very pale skin.

Other Risks
a.
Inflammatory bowel disease (IBD)—inflammatory bowel disease (is the name of a 
group of disorders in which the intestines [small and large intestines or bowels] 
become inflamed, causing redness) has been reported in patients taking etanercept. 
Symptoms of IBD may include pain in the belly, diarrhea (may be bloody), 
unexplained weight loss, loss of appetite, bleeding from the rectum, and fever.
b.
Hepatitis B Virus (HBV) Reactivation—reactivation (to make active again) of 
hepatitis B virus in patients who have had prior hepatitis B virus infection and 
worsening of chronic hepatitis, have been reported with etanercept use. 
Reactivation can occur spontaneously (without warning), but more often is triggered 
when using other medications that suppress (stop) the immune system.
c.
Merkel cell skin cancer—Merkel cell skin cancer (an aggressive type of non-
melanoma skin cancer) has been reported in patients taking etanercept. Merkel cell 
cancer affects touch sensitive cells deep in the skin, and often spreads if it is not 
caught early.
1.
What are the risks of using etanercept in combination with other drugs?
While we do not know the side effects of using etanercept in combination with all drugs, we do 
know the following drugs may affect how etanercept works or that etanercept may affect how they 
work.
a.
Live vaccines should not be given while subjects are taking etanercept.
b.
Subjects with rheumatoid arthritis taking a drug called sulfasalazine with etanercept 
commonly (which may affect between 1 and 10 people in every 100) had lower numbers of 
white blood cells (white blood cells help to fight infection). Using these two drugs together 
could increase risk of an infection.
c.
Hypoglycemia (low blood sugar levels) has been reported rarely (which may affect between 
1 and 10 people in every 10,000) in patients who start taking etanercept and are on 
medicine for diabetes. 
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d.
Using a drug called anakinra with etanercept can increase your risk of getting an infection 
and lower numbers of white blood cells (cells that help to fight infection).
e.
Using a drug called abatacept with etanercept can increase your risk of getting an infection.
2.
What are the risks of taking the other drugs required by this study?
Triamcinolone acetonide is a corticosteroid, and can cause any of the following side effects:
1.
High blood pressure, salt and water retention, weight gain, and potassium deficiency.
2.
High blood sugar (glucose).
3.
Adrenal gland suppression.
4.
Viral, bacterial, fungal, protozoan or helminthic (intestinal worm) infections.
5.
Reactivation or worsening of infections such as Candida, Cryptococcus, Mycobacterium 
(TB), Nocardia, Pneumocystis, or Toxoplasma.
6.
Development or worsening of cataracts and/or glaucoma.
7.
Worsening (including a tear in the stomach or intestine) of peptic ulcers, diverticulitis, or 
ulcerative colitis.
8.
Aseptic necrosis (cell death and loss) of bone, muscle weakness and loss, osteoporosis 
(including bone fracture and spine compression), and tendon rupture.
9.
Seizures, depression, giddiness, headache, trouble sleeping, mood swings, tingling or 
numbness in fingers, toes, and/or extremities, personality changes, psychiatric disorders, 
and dizziness.
B. Procedures for Risks to Embryo, Fetus, and/or Pregnant Subjects
Etanercept has been reported to cross (the placenta) from a pregnant mother into the unborn baby. 
The effects of this on the baby are unknown; however, infants may be at an increased risk of 
infection. Therefore, the administration of live vaccines to infants for 16 weeks after the pregnant 
mother’s last dose of etanercept is generally not recommended.
Etanercept has been reported to be transferred into breast milk. Babies should not be fed breast 
milk produced during treatment with etanercept and for an additional 4 weeks after the end of the 
mother’s treatment with etanercept.
Triamcinolone acetonide should only be used during pregnancy when the possible benefits are 
greater than the risk. There is no evidence in humans that the drug harms the unborn fetus. 
However, in animal studies corticosteroids have been shown to cause birth defects.
Since the effect of etanercept in not known, and triamcinolone acetonide is known to cause birth 
defects in some animals, it is possible that these drugs may cause birth defects in people. For this 
reason, no one can be in this study who is pregnant or who could get pregnant while taking the 
study drug. Women of childbearing age who are sexually active, must use an acceptable method of 
effective birth control as listed below:

Hormonal method (tablets, implants placed under the skin by a health care provider, 
injections, or transdermal patches)

Intrauterine device (IUD)

Intrauterine hormonal-releasing system (IUS)

Surgery to tie both fallopian tubes (bilateral tubal ligation/occlusion)
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
Male partner has had a vasectomy and testing shows there is no sperm in the semen

Sexual abstinence (not having sex)

Two barrier methods (male partner must use a condom, and the female must use a 
diaphragm, cervical cap, or contraceptive sponge); the female partner must also use 
spermicide in addition to a barrier method
C. Risks to Non-Subjects
N/A
D. Assessment of Social Behavior Considerations
N/A
E. Minimizing Risks
Subjects will be given sufficient time to read the consent form and understand study procedures 
prior to signing the consent. Study personnel will spend the time needed to thoroughly explain 
and respond to questions potential subjects may have about the study. 
Study personnel will be educated and trained on study procedures to minimize any discomforts 
or inconveniences to the subjects. No vulnerable populations will be enrolled in this study. Both 
study sites are located within 5 minutes from major hospitals, which will help to provide 
subjects with prompt medical care in the event of an emergency.  
Study data will never be stored on mobile computers or flash drives. Staff is well trained on 
protecting the privacy and confidentiality of study subject health information. PHI will not be 
collected as data or transmitted via email. Data collected will be limited to that necessary to 
conduct the research.
F. Certificate of Confidentiality
N/A
G. Potential Benefits to Subjects
Subjects may or may not experience acute pain relief if receiving etanercept. Triamcinolone 
acetonide is approved for use in this patient population.
H. Provisions to Protect the Privacy Interests of Subjects
To keep subject participation in this study confidential, all study records will be stored in a 
secure location. The institutions where the information is collected will be listed in the consent 
form. Sharing of information will be limited as required by law or as required to conduct the 
research. The data will be de-identified and coded with a study ID to minimize subject 
identification.   
 
I.
Research Team Access to Subject Data
Research team will have access to study files and research data. Access will be limited to 
research personnel through password protection.  User authentication will be enforced in 
REDCap system to limit access to the minimum required to perform the tasks. No data with 
personal identifies will be captured by the system. 
4.10 Secondary Data – Records/Chart Reviews/Databases/Tissue Banks/etc.
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N/A
 
4.11 Chart/Record Review Selection
The study personnel at each site will have access to their subject medical records and will enter all 
relevant data into the REDCap database. 
4.12 Secondary Specimen Collection
N/A
5.0 Special Considerations
5.1 Health Insurance Portability and Accountability Act (HIPAA)
The database does not capture any PHI. A unique Study ID will be assigned to the subject and this will be 
used to identify the subject in the study. All efforts will be made to protect collected data.  Only the 
study personnel at the local site will have access to study data for the subjects that are enrolled at that 
site.  However, PHI will be collected in order to complete phone call on day 30.
Study coordinators will collect the Name, Address and Telephone number of each subject for the 
purpose of communication with the subject during study participation.    
5.2 Family Educational Rights and Privacy Act (FERPA)
N/A
5.3 NJ Access to Medical Research Act
N/A
5.4 Code of Federal Regulations Title 45 Part 46 (Vulnerable Populations)
N/A
6.0 Research Data Protection and Reporting
6.1 Data Management and Confidentiality
A. We will calculate the mean (and 95 percent confidence interval) difference in Pain scores for 
etancercept compared to triamcinolone acetonide. If the upper limit of the confidence 
interval is less than zero, then we will have demonstrated superiority. If the upper limit is 
greater than zero, but less than 20% above zero, then etanercept will have been shown to be 
non-inferior to triamcinolone acetonide.
B.
The primary objective of the study is to determine if etanercept is non-inferior to the current 
standard of care (triamcinolone acetonide) at reducing the pain associated with an acute gout 
attack, as measured by the Pain scale. Based on a 2012 study of gout compazring 
canakinumab vs triamcinolone acetonide, the mean difference in pain scores at 72 hours was 
10.7, with a standard deviation of 36.21. Assuming a Type I error rate of 5%, 20 patients per 
cohort would give us 80% power to detect a reduction in pain scores of 32.92, which we 
consider to be a clinically significant reduction in pain (6).
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C.
The database will be created and maintained in REDCap electronic data capture (EDC) system 
hosted at Rutgers Robert Wood Johnson Medical School. REDCap is a secure web application 
for building and managing online surveys and databases which is US FDA 21 CFR Part 11 
compliant, specifically geared to support online or offline data capture for research studies 
and operations. Procedures for securing the data include password protection, limited access 
to study computers, encryption, authorization of access based on user roles.
Study personnel will be provided with adequate training on how to use the system and secure 
data. The study personnel will maintain all study records according to ICH GCP guidelines.
Patient contact information will be maintained by the study team and will be stored in a 
secure location. Only study team members will have access to the subject study files.         
D. The investigators or their qualified designee will ensure that the source documents and 
subject study files are legible and complete. The investigators will be responsible for the 
regular review of the conduct of the study, for verifying adherence to the protocol and for 
confirming completeness, consistency and accuracy of all documented data and accuracy of 
source documentation verification. 
E. Data Handling:

Data 
Data will be collected on subject demographics, employment status, history of gout, 
medical history including medication, assessments of gout pain, current medical 
conditions, physical examination, AEs, vital signs, laboratory tests, study drug 
administration, questionnaires, etc. 

Data Storage
The data will be collected at the 2 sites listed above by the study personnel. Study data 
will be collected at the study visits and entered into the REDCap system by study 
personnel. All research related data will be stored for 10 years from study closure in 
Rutgers University Records Center in Livingston Campus located at 7 Kilmer Road, 
Edison, NJ. Subject binders/folders at Dr. Schlesinger’s site will be stored in the study 
coordinator’s office, RM ET-876, 8th floor East Tower, Clinical Research Center and 
Dr.Borham’s site will be stored in Rheumatology center of NJ, 56 Union Ave, Somerville.  

Data Access
Study team will have access to the data until the day of the data lock, which will occur at 
the end of data collection and entry, and after addressing all open queries and 
thereafter the data will be analyzed by the Statistician and archived. 

Data Transmission
Data will be entered by study personnel directly into the REDCap database. Data will not 
be transmitted or received via email or any other application other that the database 
created to collect data. RWJMS will collect the Study files from Dr. Borham’s site after 
completion of the study for archiving. 

Data Transporting and Sharing
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Sites will have access to the same REDCap database. In addition, the statistician will 
have access to the REDCap database. PHI and patient information from Dr.Borham’s site 
will not be transferred. Any remaining PHI will be removed from the study materials 
prior to transfer. 
6.2 Data Security
Refer to 6.1.C above
6.3 Data and Safety Monitoring 
A. Periodic Data Evaluation
There will be no interim data analysis for this study. Safety and efficacy data will be analyzed at 
the end of the study, during statistical analysis. Potential adverse events, will be reviewed in 
real-time by the PI and other study personnel, as indicated.
B. Type of Data Evaluated
All post randomization data will be reviewed for safety and efficacy. 
C. Collection of Safety Information
Nature of adverse events:

Severity:  The intensity of an adverse event and is categorized as 1) Mild; asymptomatic or 
mild symptoms; clinical or diagnostic observations only; intervention not indicated 2) 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
activities of daily living 3) Severe; medically significant but not immediately life 
threatening  

Relationship: The extent to which an adverse event is considered to be related to the 
intervention of study procedures. An adverse event is considered suspected if there is a 
reasonable possibility that the event may have been caused by the procedure. Suspected 
also means possible, probably or definitely related to the intervention or the study 
procedure.   Not- suspected means the adverse event is clearly due to an extraneous 
event. 
Serious Adverse events will be classified as follows:

A SAE is defined as any untoward medical occurrence that meets any of the following 
criteria:

Results in death

Is life-threatening

Requires inpatient hospitalization or prolongation of existing hospitalization

Is a congenital anomaly or birth defect

Is an important medical event
Study Safety data will be reported to the Amgen Inc. and the IRB as mandated by the law 
and as stated in executed research agreement.
D. Frequency of Data Collection
Please see section 1.3, Research Design and Methods 
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E. Reviewer of Data
Please see section 6.3.A above 
F. Schedule of Review of Cumulative Data
Please see section 1.3, Research Design and Methods 
G. Tests for Safety Data
Please see section 1.3, Research Design and Methods 
H. Suspension of Research
Serious adverse events that occur during the study period will be reported according to IRB 
guidelines. Study procedures may be stopped if the investigators believe the safety of study 
subjects is threatened. 
6.4 Reporting Results
A. Sharing of Results with Subjects 
There are no plans to share study results with study participants, beyond the reporting to 
individual subjects of any signs of therapeutic response or possible adverse event.
B. Individual Results 
Subjects will be informed of any signs of therapeutic response or possible adverse event. 
  
C. Aggregate Results 
Please see section 6.4.A above
 
D. Professional Reporting
Study results will be presented at scientific meetings as research poster or platform 
presentations. The investigators plan to publish the results of the study in the scientific 
literature.
E. ClinicalTrials.Gov Registration and Data Reporting
The trial  has been registered on ClinicalTrials.gov, as required by U.S. law. 
6.5 Data Sharing  
N/A
7.0 Data and/or Specimen Banking
N/A
8.0 Other Approvals/Authorizations
N/A 
9.0 Bibliography
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Immunex Corp., revised 11/2017.
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Desai J, Steiger S, Anders H-J. Molecular Pathophysiology of Gout. Trends in Molecular Medicine 
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10. Schafers M, Brinkhoff J, Neukirchen S, Marziniak M, Sommer C. Combined epineurial therapy with 
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17. Chapman PT, Yarwood H, Harrison AA,  et al. Endothelial activation in monosodium urate 
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18. Tonussi CR, Ferreira SH. Tumour necrosis factor-alpha mediates carrageenin-induced knee-joint 
incapacitation and also triggers overt nociception in previously inflamed rat knee-joints. Pain 
1999;82(1):81-7.
19. Williams RO, Marinova-Mutafchieva L, Feldmann M, Maini RN. Evaluation of TNF-alpha and IL-1 
blockade in collagen-induced arthritis and comparison with combined anti-TNF-alpha/anti-CD4 
therapy. J IMmunol 2000;165(12):7240-5.
20. Lucassen JHJ, Van de Laar FA, Van de Lisdonk EH. Systemic corticosteroids for acute gout. Cochrane 
Database of Systematic Reviews 2008; Issue 2. Art. No.:CD005521.
21. Cronstein BN, Terkeltaub R. The inflammatory process of gout and its treatment. Arthritis Research 
& Therapy 2006;8(Suppl 1):S3(DOI:10.1186/ar1908)
22. Qaseem A, Harris RP, Forciea MA, for the Clinical Guidelines Committee of the American College of 
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23. Alloway JA, Moriarty MJ, Hoogland YT, et al. Comparison of triamcinolone acetonide with 
indomethacin in the treatment of acute gouty arthritis. J Rheumatol 1993;20:111-3.
24. Schlesinger N, Mysler E, Lin  HY, et al. Canakinumab reduces the risk of acute gouty arthritis attacks 
during initiation of allopurinol therapy: results of a double-blind, randomised study. Ann Rheum Dis  
2011;70(7):1264-71;11.
25. Schlesinger N, Alten R,  Bardin T,  et al. Canakinumab for acute gouty arthritis in patients with 
lIMited treatment options: results from two randomised, multicentre, active-controlled, double-
blind trials and their extensions. Ann Rheum Dis 2012;71:1839-1848.
26. IMS Disease Analyser: Prescriptions of triamcinolone acetonide in France, and Germany for August 
2009 to August 2010 and in the UK for December 2008 to December 2009, personal communication. 
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28. Cavagna L, Taylor WJ. The emerging role of biotechnological drugs in the treatment of gout. Biomed 
Res Int. 2014;2014:264859.  
29. Goffe B, Cather JC. Etanercept: an overview. J Am Acad Dermatol 2003;49(2):S105-11.
30. Conner V. Anti-TNF therapies: a comprehensive analysis of adverse effects associated with 
immunosuppression. Rheum Int 2009;31(3):327-37.
31. Tubach F, Salmon D, Ravaud P, et al. Risk of tuberculosis is mhigher with anti-tumor necrosis factor 
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32. Dixon WG, Hyrich KL, Watson KD, et al. Drug-specific risk of tuberculosis in patients with rheumatoid 
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Investigator-Initiated, Pilot Study Evaluating The Efficacy Of Etanercept In Acute Gout
PI: Naomi Schlesinger, MD
Protocol Version and Date: 3.1, 10 March 2020 
                        
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APPENDIX A:   ACR/EULAR 2015 Gout Classification Criteria  
Presence of MSU crystals in symptomatic joint/bursa or tophus sufficient criterion for gout diagnosis (no 
further scoring needed).
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