ARTHRITIS & RHEUMATISM
Vol. 64, No. 3, March 2012, pp 876–884
© 2012, American College of Rheumatology
Rilonacept (Interleukin-1 Trap) in the Prevention of Acute
Gout Flares During Initiation of Urate-Lowering Therapy
Results of a Phase II Randomized, Double-Blind, Placebo-Controlled Trial
H. Ralph Schumacher Jr.,1John S. Sundy,2Robert Terkeltaub,3
Howard R. Knapp,4Scott J. Mellis,5Neil Stahl,5George D. Yancopoulos,5
Yuhwen Soo,5Shirletta King-Davis,5Steven P. Weinstein,5and Allen R. Radin,5
on behalf of the 0619 Study Group
Objective. To evaluate the interleukin-1 inhibitor
rilonacept (Interleukin-1 Trap) for prevention of gout
flares occurring in the first few months following initi-
ation of urate-lowering therapy.
Methods. In this double-blind study, adult pa-
tients with hyperuricemia and gout were randomized to
receive rilonacept administered subcutaneously once
per week (loading dose 320 mg followed by 160 mg
weekly) or placebo, and started on allopurinol (300 mg/
day, titrated to serum urate <6 mg/dl). At study visits,
physical and laboratory assessments were performed
and information on any adverse events was ascertained.
Results. Baseline characteristics were similar be-
tween the rilonacept and placebo groups (n ? 41 and
n ? 42, respectively). The mean number of gout flares
per patient through week 12 (primary efficacy end
point) was markedly lower in the rilonacept group than
in the placebo group (0.15 [6 flares] versus 0.79 [33
flares]; P ? 0.0011). Fewer flares were observed with
rilonacept as early as 4 weeks after initiation of treat-
ment (P ? 0.007). The proportion of patients experienc-
ing a flare during the 12 weeks was lower in the
rilonacept group than in the placebo group (14.6%
versus 45.2%; P ? 0.0037). No rebound in the flare rate
was observed for 6 weeks after discontinuation of rilona-
cept or placebo at week 16. Adverse events were similar
between groups, and no deaths or serious infectious
adverse events were reported; the most common adverse
events were infections (14.6% and 26.2% of rilonacept-
and placebo-treated patients, respectively) and muscu-
loskeletal disorders (14.6% and 21.4%, respectively). A
higher percentage of rilonacept-treated patients (98%)
compared with placebo-treated patients (79%) com-
pleted the primary 12-week evaluation period (P ?
Conclusion. The current findings indicate that
rilonacept significantly reduces the frequency of gout
flares during the initial period of treatment with urate-
lowering therapy, with a favorable safety profile.
Gout is caused by deposition of monosodium
urate monohydrate (MSU) crystals in soft tissue in the
ClinicalTrials.gov identifier: NCT00610363.
Supported by Regeneron Pharmaceuticals, Inc.
1H. Ralph Schumacher Jr., MD: University of Pennsylvania
and Philadelphia VA Medical Center, Philadelphia, Pennsylvania;
2John S. Sundy, MD: Duke University Medical Center, Durham,
North Carolina;3Robert Terkeltaub, MD: University of California at
San Diego and San Diego VA Medical Center, San Diego, California;
4Howard R. Knapp, MD, PhD: Montana State University, Billings;
5Scott J. Mellis, MD, PhD, Neil Stahl, PhD, George D. Yancopoulos,
MD, PhD, Yuhwen Soo, PhD, Shirletta King-Davis, RN, MS, Steven
P. Weinstein, MD, PhD, Allen R. Radin, MD: Regeneron Pharma-
ceuticals, Inc., Tarrytown, New York.
Dr. Schumacher has received consulting fees, speaking fees,
and/or honoraria from Regeneron, Takeda, Savient, Ardea, Pfizer,
Xoma, and Novartis (less than $10,000 each). Dr. Sundy has received
consulting fees from Regeneron and Novartis (less than $10,000 each)
and receives sponsored research grants from Regeneron through
Duke University. Dr. Terkeltaub has received consulting fees, speak-
ing fees, and/or honoraria from Regeneron, Novartis, and URL
Pharma (less than $10,000 each) and has served as a paid consultant to
the investment analysts Guidepoint Global and the Coleman Group.
Drs. Mellis, Stahl, Yancopoulos, Soo, Weinstein, and Radin and
Ms King-Davis own stock in Regeneron. Dr. Mellis holds a patent,
licensed to Regeneron, for the use of interleukin-1 antagonists to treat
Address correspondence to H. Ralph Schumacher Jr., MD,
VA Medical Center, 151K, University and Woodland Avenues, Phil-
adelphia, PA 19104. E-mail: firstname.lastname@example.org.
Submitted for publication January 21, 2011; accepted in
revised form October 6, 2011.
setting of hyperuricemia. The presence of MSU crystals
in and around joints can initiate an inflammatory re-
sponse that may lead to recurrent episodes of acute
gouty arthritis, which are characterized by debilitating
inflammation and pain. Gout attacks typically resolve
spontaneously over a period of several days, but MSU
crystals remain in the joint space. Recurrent attacks and
persistent low-grade inflammation leave patients vulner-
able to progressive disease; without treatment, perma-
nent joint destruction can occur (1).
The goal of long-term treatment of gout is to
reverse urate crystal deposition, which requires reducing
serum urate levels (2). Paradoxically, initiation of urate-
lowering therapy can elicit a gout attack, likely due to
remodeling of crystal deposits during dissolution (3). It
has been suggested that these acute flares contribute to
low rates of adherence to long-term treatment regimens
(4,5), preventing control of the clinical manifestations of
gout. Concomitant treatment with colchicine or non-
steroidal antiinflammatory drugs (NSAIDs) to prevent
gout flares (prophylaxis) is recommended during the
first several months of urate-lowering therapy (2,6).
However, class- or drug-specific side effects, drug–drug
interactions, and contraindications can complicate or
limit use of these prophylactic agents in many gout pa-
tients, particularly in older adults and those receiving
multiple medications and with comorbidities such as
renal insufficiency and cardiovascular disease (1,7).
Gout shares pathogenetic features with other
autoinflammatory disorders, and recent research has
provided important new insights into the potential role
of the proinflammatory cytokine interleukin-1 (IL-1) in
crystal-induced arthritides. Urate crystals induce an
inflammatory response in part by promoting activation
of the multiprotein NLRP3 inflammasome in macro-
phages, which results in caspase 1 cleavage and activa-
tion, and processing and release of IL-1? (8). In turn,
IL-1? induces expression of adhesion molecules and
chemokines critical to the recruitment of neutrophils
and development of the acute inflammatory response.
Blockade of IL-1 action in animal models by receptor
knockout as well as with pharmacologic inhibition has
confirmed a role of IL-1? in these models of crystal-
induced joint pain and inflammation, neutrophil influx,
and inflammatory cytokine/chemokine up-regulation
(9). Small pilot trials of IL-1 inhibitors in patients with
gout have provided preliminary evidence that IL-1?
might indeed be important in gouty inflammation in
Other conditions mediated by the NLRP3 inflam-
masome include a rare group of genetic diseases known
as cryopyrin-associated periodic syndromes (CAPS)
(13). In 2 sequential, placebo-controlled studies, efficacy
of the IL-1 inhibitor rilonacept in the treatment of
symptoms of CAPS was demonstrated (13). Rilonacept
is a recombinant fusion protein consisting of the extra-
cellular ligand-binding domains of human IL-1 type I
receptor and IL-1 receptor accessory protein, fused to
the Fc portion of human IgG1 (14). It acts as a soluble
decoy receptor, trapping both IL-1? and IL-1? with
high affinity, and has thus been termed an IL-1 Trap.
The demonstrated efficacy of rilonacept in CAPS, dis-
eases caused by IL-1 overproduction (13), as well as the
efficacy of a murine version of IL-1 Trap in animal
models of gout (9), prompted a pilot study in patients
with chronic active gouty arthritis (12). The encouraging
results of that study motivated this further investigation.
We evaluated rilonacept for its efficacy in pre-
venting acute gout flares during initiation of urate-
lowering therapy. Results of this first placebo-controlled
study of IL-1–targeted therapy in gout flare prophylaxis
are reported herein.
PATIENTS AND METHODS
Study design and patient population. This phase II
randomized, double-blind, placebo-controlled trial was per-
formed at 27 study centers in the US. The principal investi-
gators are listed in Appendix A. The study was conducted
in accordance with the revised Declaration of Helsinki, and
approval was obtained from the appropriate institutional re-
view boards or independent ethics committees. All patients
provided written informed consent prior to enrollment.
To be eligible for enrollment, patients had to be ?18
years of age and to have previously met the American College
of Rheumatology preliminary criteria for the classification
of acute arthritis of primary gout (15), based on clinical
features and/or demonstration of MSU crystals in joint fluid.
A serum uric acid concentration of ?7.5 mg/dl and a self-
reported history of ?2 gout flares within the prior year were
also required for study inclusion.
Exclusion criteria included the occurrence of an acute
gout flare within the 2 weeks prior to screening, recent
treatment with anakinra or investigational drugs, previous
exposure to rilonacept, chronic or active infections or recent
use of anti-infective agents, evidence of tuberculosis at screen-
ing, use of allopurinol, probenecid, or sulfinpyrazone in the
prior 3 months, history of allopurinol intolerance, use of
colchicine or parenteral glucocorticoids in the prior month or
NSAIDs in the prior 2 weeks, dialysis or other confirmed
evidence of severe renal impairment (estimated glomerular
filtration rate ?30 ml/minute), or current use of immuno-
suppressive therapy; pregnant or lactating women were also
Eligible patients were randomized 1:1 to begin treat-
ment with placebo or rilonacept 160 mg (2 ml) administered
subcutaneously once weekly for 16 weeks, and oral allopurinol
RILONACEPT FOR GOUT FLARE PREVENTION877
300 mg/day was initiated in all patients. A loading dose of
rilonacept (320 mg [2 doses of 2 ml]) or placebo was adminis-
tered on study day 1. Placebo was supplied in vials that were
matched for appearance and content except that they did not
contain the rilonacept protein.
The allopurinol dosage was titrated monthly during the
study in 100-mg increments, up to 800 mg/day, to attain a
serum urate level of ?6 mg/dl. For patients with impaired
renal function, the initial daily dose of allopurinol was adjusted
as recommended by Hande et al (16), based on estimated
creatinine clearance. Patients continued treatment with allo-
purinol after the last dose of blinded study drug at week 16,
and were followed up for the subsequent 6 weeks.
Gout flares were treated at the investigator’s discretion
for up to 10 days with NSAIDs or oral glucocorticoids. Flares
were self-reported and assessed using a daily diary that was
recorded via a telephone-based Interactive Voice Response
System starting on day 1 of a flare until resolution of all
symptoms. Patients phoned the study center upon first symp-
toms of an acute gout flare and continued with daily reports for
the duration of the flare. These daily reports, which included
assessment of pain and global well-being (0–10 numerical
rating scale, recall period 24 hours for both measures), also
enabled determination of when a flare ended (i.e., when pain
returned to baseline) and estimation of flare duration. For
analysis, a flare was defined as patient-reported acute articular
pain typical of a gout attack that required treatment with an
Study visits occurred every 4 weeks during the treat-
ment period, with a 6-week posttreatment followup visit.
Assessments included physical examination, determination of
serum urate levels and other laboratory assessments, and
review of flare diary and reported adverse events. Between
visits, patient clinical status was assessed via telephone.
End points. The primary efficacy variable was the
number of gout flares per patient from day 1 through week 12.
Secondary end points, also assessed from day 1 through week
12, included the proportion of patients with flares, the number
of gout flare days per patient, and the number of days per
patient with a pain score of ?5. The values for all efficacy
variables were also determined for day 1 to week 16, the full
period of double-blind treatment. In addition, patients were
assessed for flares during the 6-week followup period after the
last dose of study drug administered during the blinded
Safety and tolerability were evaluated based on the
incidence of adverse events. A treatment-emergent event was
defined as an adverse event that occurred during the period
from the first dose to 42 days (6 weeks) after the final dose of
the study drug. Serious adverse events were defined as events
that were life-threatening or that resulted in death, hospital-
ization, prolongation of hospitalization, persistent disability or
incapacity, or a congenital anomaly or birth defect. Severity
and relationship of adverse events to study drug were deter-
mined by the investigator.
Statistical analysis. All analyses were performed on
the full analysis set using SAS version 9 (SAS Institute). The
full analysis set included all randomized patients who received
study medication and had at least 1 postbaseline assessment.
For the primary efficacy analysis, Wilcoxon’s 2-sided
rank sum test was used to compare the mean number of gout
flares assessed from day 1 to week 12 between the 2 treatment
groups. For secondary end points, continuous variables were
analyzed by Wilcoxon’s 2-sided rank sum test, and variables
that were proportions were analyzed by Fisher’s exact test.
Time to flare was calculated based on Kaplan-Meier estima-
tion. Mean ? SD values are reported. Because pain scores
were not always reported on all days during which gout flare
occurred, sensitivity analyses using 3 different imputation
methods (as prespecified in the statistical analysis plan) were
performed for the secondary outcome of mean number of days
per patient with pain score ?5 during the treatment period,
including first observation carried forward, worst observation
carried forward, and last observation carried forward. For
other continuous variable end point inferential analyses, Stu-
dent’s t-test was used. P values (2-sided) less than 0.05 were
Patient disposition and baseline characteristics.
Of 154 patients screened, 83 were randomized (42 to the
placebo group; 41 to the rilonacept group); all 83
received at least 1 dose of the study drug, had at least 1
postbaseline assessment, and were included in the ana-
lyses (Figure 1). Nine patients in the placebo group had
withdrawn from the study by week 12, compared with
only 1 in the rilonacept group (P ? 0.015 by Fisher’s
exact test), and this had increased to a total of 11
withdrawals in the placebo group and 3 in the rilonacept
group at the end of double-blind treatment period at
week 16 (P ? 0.0377 by Fisher’s exact test).
Demographic and clinical characteristics were
generally similar between the 2 treatment groups
(Table 1), although the proportion of patients with tophi
was higher in the placebo group than in the rilonacept
group (14.3% and 4.9%, respectively). The study popu-
lation was predominantly non-Hispanic white and male,
with a mean age of 51.0 years. On average, the baseline
serum uric acid level was 9.1 mg/dl, the time from gout
diagnosis was 9.7 years, and the number of flares re-
ported for the previous year was 4.5. Fifty-nine percent
of the patients had not previously received allopurinol.
Study drug utilization and adherence. The mean
daily study doses of allopurinol were comparable be-
tween treatment groups and were similar at 12 weeks
(mean ? SD [observed data] 318.9 ? 56.6 mg in the
placebo group [n ? 41] and 326.5 ? 43.1 mg in the
rilonacept group [n ? 41]) and 16 weeks (observed data
332.1 ? 65.7 mg in the placebo group [n ? 41] and
336.9 ? 54.0 mg in the rilonacept group [n ? 41]). While
allopurinol could be titrated once a month and physi-
cians were reminded to titrate to target urate level, the
target serum urate level of ?6 mg/dl was achieved in
878SCHUMACHER ET AL
only ?60–70% of the patients during the study treat-
ment period (observed data 62.5% in the placebo group,
73.7% in the rilonacept group at week 12; 58.1% in the
placebo group, 56.8% in the rilonacept group at week
16). Observed urate levels during the study treatment
period were similar in the 2 treatment groups at week 12
(mean ? SD 5.9 ? 1.4 mg/dl in the placebo group [n ?
32] and 5.5 ? 1.4 mg/dl in the rilonacept group [n ? 38])
and week 16 (6.0 ? 1.2 mg/dl in the placebo group [n ?
31] and 5.9 ? 1.4 mg/dl in the rilonacept group [n ? 37]).
When patients who withdrew from the study
early were also included in the analysis using last obser-
vation carried forward imputation, the mean serum
urate level was greater in the placebo group compared
with the rilonacept group at week 12 (6.3 ? 1.7 mg/dl
[n ? 42] versus 5.6 ? 1.4 mg/dl [n ? 41]) and week 16
(6.4 ? 1.6 mg/dl [n ? 42] versus 5.9 ? 1.4 mg/dl [n ?
41]). In addition, as noted above, a higher proportion of
placebo-treated patients withdrew from the study and
thus may have terminated their allopurinol treatment.
Although adherence with study drug injections was
high in both groups, the adherence rate was significantly
greater in the rilonacept group compared with the
placebo group through week 12 (mean ? SD 97.9 ?
5.4% of doses versus 92.4% ? 14.5%; P ? 0.026 by
Student’s t-test) and week 16 (97.3 ? 4.7% versus
91.3% ? 14.0%; P ? 0.011 by Student’s t-test).
Efficacy. The mean number of acute gout flares
per patient over the 12-week period (primary end point)
was significantly lower in the rilonacept group (0.15
Figure 1. Enrollment and disposition of the study patients.
Baseline demographic and clinical characteristics of the patients*
(n ? 42)
(n ? 41)
(n ? 83)
Male, no. (%)
Race or ethnic group, no. (%)
Body mass index, kg/m2
Duration of gout, years
Serum urate concentration, mg/dl
Presence of tophi, no. (%) of patients
No. of gout flares/year
50.1 ? 11.6
51.9 ? 10.6
51.0 ? 11.1
32.53 ? 5.75
8.6 ? 7.0
9.35 ? 1.33
4.4 ? 4.0
33.31 ? 7.74
10.7 ? 9.1
8.92 ? 1.22
4.7 ? 3.2
32.92 ? 6.78
9.7 ? 8.1
9.14 ? 1.29
4.5 ? 3.6
* Except where indicated otherwise, values are the mean ? SD.
RILONACEPT FOR GOUT FLARE PREVENTION879
[representing 6 total flares at 12 weeks]) compared to
the placebo group (0.79 [representing 33 total flares])
(P ? 0.0011) (Figure 2A). This difference corresponds
to an 81% decrease in flares with rilonacept at 12 weeks,
and the difference was maintained through the 4-week
on-treatment extension, as well as through the 6-week
posttreatment followup period (Figure 2A). Significantly
fewer flares were observed in the rilonacept-treated
patients as early as 4 weeks after initiation of treatment
(P ? 0.007), the earliest prespecified analysis time point.
No increase (i.e., “rebound”) of flare frequency was
observed during the posttreatment followup period.
The proportion of patients with at least 1 gout
flare through week 12, an important secondary end
point, was significantly lower in the rilonacept group
(14.6% [95% confidence interval 6–29%]) compared to
the placebo group (45.2% [95% confidence interval
30–61%]) (P ? 0.0037) (Table 2). The proportion of
patients who reported flares was also lower with rilona-
cept compared to placebo throughout the 16-week
double-blind treatment period (22.0% [95% confidence
interval 11–38%] versus 47.6% [95% confidence interval
32–64%]; P ? 0.021) (Table 2). Significant divergence
between groups was detected as early as week 4, with
4.9% of the rilonacept-treated patients reporting a flare,
versus 26.2% of the placebo-treated patients (P ?
0.013). All other secondary end points showed a sta-
tistically significant difference in favor of rilonacept
(Table 3). Kaplan-Meier analysis (Figure 2B) revealed
that the median time to first gout flare in the placebo
group (estimated at 77 days) was significantly earlier
(P ? 0.001) than that in the rilonacept group, for which
the median time to flare could not be estimated over the
Post hoc analysis was performed to determine
the proportion of patients who reported multiple gout
flares (?2) (Table 2). While 26.2% of placebo-treated
patients reported multiple flares by week 16, no
Figure 2. A, Mean number of gout flares per patient through week 22 (end of the followup period), by treatment group. Bars show the 95%
confidence interval. P values were determined by Wilcoxon’s rank sum test. B, Kaplan-Meier curve of the time to first gout flare from day 1 to week
16 (full analysis set).
week 16 (end of double-blind treatment)
Proportion of patients reporting gout flares through week 12 (primary efficacy end point) and
% of patients with flare
(n ? 42)
(n ? 41)P*
12 weeks (primary end point)
16 weeks (end of treatment)
* ND ? not determined.
† Post hoc analysis.
880SCHUMACHER ET AL
rilonacept-treated patients reported more than 1 flare
during this period (P ? 0.001).
Safety and tolerability. The incidence of all-
cause and treatment-related adverse events was similar
in the 2 treatment groups (Table 4), and no deaths
or serious infectious adverse events were reported.
Serious adverse events were reported in 3 patients: 1 in
the rilonacept group (prostate cancer), and 2 in the
placebo group (1 with angina and 1 with alterations
in renal function). None of these was considered related
Results obtained using primary and secondary efficacy measures*
(n ? 42)
(n ? 41)P
Primary efficacy variable based on day 1 through week 12
Gout flares per patient, mean ? SD
Secondary efficacy variables based on day 1 through week 12
Patients with at least 1 gout flare, no. (%)
Gout flare days per patient, mean ? SD
Days with pain score ?5 per patient, mean ? SD‡
0.79 ? 1.07 0.15 ? 0.36 0.0011*81.0
5.17 ? 8.02
2.02 ? 4.51
1.41 ? 5.23
0.22 ? 0.79
* By Wilcoxon’s rank sum test.
† By Fisher’s exact test.
‡ Results of sensitivity analyses: first observation carried forward 3.33 ? 6.78 placebo, 0.51 ? 1.82 rilonacept; worst observation
carried forward 3.40 ? 6.79 placebo, 0.51 ? 1.82 rilonacept; last observation carried forward 3.05 ? 6.31 placebo, 0.51 ? 1.82
rilonacept (all P ? 0.05 by Wilcoxon’s rank sum test).
Summary of adverse events
No. (%) of patients
(n ? 42)
(n ? 41)
Any treatment-emergent event*
Any serious adverse event†
Alterations in renal function
Any treatment-related adverse event‡
Discontinuations due to treatment-emergent events
Most frequent treatment-emergent adverse events
By system organ class (in ?15% of patients)§
Infections and infestations
Musculoskeletal and connective tissue disorders
By high-level term (in ?5% of patients)¶
Upper respiratory tract infections
Lower respiratory tract and lung infections
Musculoskeletal and connective tissue signs and symptoms NEC
Joint-related signs and symptoms
Liver function abnormalities
Purine metabolism disorders NEC
Injection and infusion site reactions
Nasal congestion and inflammation
* An adverse event that occurred during the period from the first dose to 42 days (6 weeks) after the final dose of the study
† An event that was life-threatening or resulted in death, hospitalization or prolongation of hospitalization, persistent or
significant disability or incapacity, or congenital anomaly or birth defect.
‡ An adverse event that was considered by the investigator to be possibly, probably, or definitely related to the study drug.
§ Adverse events by system organ class, the highest-level adverse event grouping (in Medical Dictionary for Regulatory Activities;
version 10), independent of relationship to study drug and occurring in ?15% of patients in either treatment group.
¶ Adverse events by high-level term (Medical Dictionary for Regulatory Activities; version 10) independent of relationship to
study drug and occurring in ?5% of patients in either treatment group. NEC ? not elsewhere classified.
RILONACEPT FOR GOUT FLARE PREVENTION 881
to study treatment, and none resulted in treatment
Adverse events were generally rated mild or
moderate in severity. The most common adverse events
overall were infections (14.6% and 26.2% in the rilona-
cept and placebo groups, respectively) and musculo-
skeletal disorders (14.6% and 21.4%, respectively). In-
jection site reactions (all rated mild) were the most
common treatment-related adverse events (9.8% of
patients in the rilonacept group and 2.4% in the pla-
cebo group). Supplementary Table 1 (available on the
Arthritis & Rheumatism web site at http://onlinelibrary.
wiley.com/journal/10.1002/(ISSN)1529-0131) lists all
treatment-emergent adverse events reported between
the first dose of rilonacept or placebo through 42 days
after the last dose.
Two patients in each group reported adverse
events that were defined as severe by the investigators,
with a total of 6 severe adverse events. One severe
adverse event was considered to be treatment related: a
worsening of gout flare, considered by the investigator as
an exacerbation of the underlying disease, in a patient in
the placebo group. In the rilonacept group, 1 patient
discontinued the study treatment due to an adverse
event (diarrhea, lower extremity weakness, tremor, and
altered mental status) deemed not related to study
treatment (the patient did not initially disclose a prior
history of weakness, tremor, and altered mental status),
whereas in the placebo group, 3 patients discontinued
due to adverse events (1 patient due to an infected
tophus and 2 patients due to joint-related symptoms).
Further, as noted above, the proportion of pa-
tients who had withdrawn from the study at the 12-week
analysis was smaller among those treated with rilonacept
than among those treated with placebo. Only 1 of the 41
patients in the rilonacept group (2.4%) had discontinued
by 12 weeks, compared with 9 of 42 in the placebo group
(21.4%) (P ? 0.015 by Fisher’s exact test).
Class- or drug-specific limitations of colchicine
and NSAIDs, agents that are currently recommended
for gout flare prophylaxis, indicate a need for alterna-
tives in some patients. The results of this phase II
double-blind, placebo-controlled study of rilonacept
provide rigorous proof of principle, validating the IL-1
axis as a potential target in developing new treatments to
prevent flares of gouty arthritis. In gout patients who are
starting urate-lowering therapy and are thus at increased
risk of gout attacks, rilonacept substantially reduced the
occurrence of acute gout flares compared to placebo, as
calculated on the basis of both the number of flares and
the proportion of patients with flares. Over a 12-week
period, patients treated with rilonacept experienced
significantly fewer acute gout flares than placebo-treated
patients (0.15 versus 0.79 flares per patient). In addition,
a significantly lower proportion of patients experienced
1 or more gout flares in the rilonacept group (14.6%)
versus the placebo group (45.2%). Efficacy was robust,
observed early during the course of therapy, and main-
tained over the duration of treatment (16 weeks). Posi-
tive results of a phase II study comparing canakinumab,
a monoclonal antibody specific for IL-1?, to the active
comparator colchicine 0.5 mg daily for gout flare pro-
phylaxis in patients initiating urate-lowering therapy
were reported recently (17). This further strengthens the
evidence that IL-1 has a key role in the pathophysiology
of gout flares.
With current approaches to gout flare prophy-
laxis using colchicine or NSAIDs, reported flare rates
have ranged from 22% to 33% (6,18,19), and up to 14%
of patients experience multiple flares during initiation of
urate-lowering therapy (6). In the phase III multicenter
Febuxostat versus Allopurinol Controlled Trial (FACT),
in which gout flare prophylaxis with colchicine or
NSAIDs was included during the initial 8 weeks, 22%
and 21% of patients treated with febuxostat 80 mg daily
and allopurinol 300 mg daily, respectively, needed treat-
ment for a gout flare during the 8-week prophylaxis
period (18). Flare rates increased substantially shortly
after prophylaxis ended. In contrast to the FACT, an
increase in flare rate was not seen in the current study
when prophylaxis with rilonacept was discontinued after
week 16, suggesting that a 16-week period of prophylaxis
with rilonacept was sufficient for some patients in this
Rilonacept was generally well tolerated in these
patients with gout who were taking allopurinol and other
concomitant medications. No serious drug-related ad-
verse events were reported, and injection site reactions
(none leading to withdrawal) were the most common
treatment-related event. Infections, including tubercu-
losis and other opportunistic infections, have been a
concern with some biologic agents targeting inflamma-
tory cytokines (20,21). While rilonacept treatment was
not associated with a higher rate of infections compared
with placebo in this modest-sized study, it remains
possible that, as with other IL-1 inhibitors, rilonacept
might be associated with an increased risk of certain
types of infections.
During the prespecified 12-week primary end
882 SCHUMACHER ET AL
point period, there was a 21.4% dropout rate in the
placebo group compared to a 2.4% dropout rate in the
rilonacept group. Although results from clinical trials
are not always generalizable to daily practice, the higher
proportion of patients completing the study in the
rilonacept group suggests that IL-1 blockade might have
the potential to facilitate disease management in pa-
tients beginning urate-lowering therapy, and ultimately
allow a greater proportion of patients to adhere to
urate-lowering treatment. The difference in the rate of
early withdrawals between treatment groups, with more
withdrawals in the placebo group, had the potential to
cause underestimation of treatment effects on flare
frequency if dropouts had unreported flares, and also
had the potential to cause underestimation of the benefit
of prophylaxis on adherence with urate-lowering ther-
apy, since allopurinol treatment and urate levels could
not be monitored in many of the patients who withdrew
from the study. Confirmation, in larger studies, of the
difference in the rate of early withdrawals observed here
would better clarify the utility of gout flare prophylaxis
in disease management.
One potential limitation of this study is the
initiation of allopurinol starting at a dosage of 300 mg
daily (in patients with normal renal function). Initiating
allopurinol at 300 mg daily has been considered to
potentially increase the risk of flares relative to a lower
starting dosage, so that lower initial dosages are some-
times recommended. However, there are no studies
confirming the utility of these lower dosages, while there
is support for initial use of 300 mg per day (22), which
is the dosage often initiated in clinical practice. Despite
an average daily allopurinol dose of ?330 mg in this
study at weeks 12 and 16, the target urate level was not
achieved in 30–40% of patients; in contrast, in the
FACT trial, serum urate levels ?6 mg/dl were not
achieved in 64% of patients treated with allopurinol
300 mg daily (18). Another factor that should be con-
sidered when interpreting the present study results is the
somewhat higher number of patients with tophi in the
placebo group (n ? 6) compared to the rilonacept group
(n ? 2). However, these numbers of patients were too
small to allow meaningful analysis incorporating tophi as
a covariate. Last, there is not yet an established defini-
tion of gout flare (23). While the definition of flare used
in our analyses is relevant for patients and has previously
been used in studies of urate-lowering strategies, it may
lack specificity (17). However, the robust results pre-
sented here suggest that any potential limitation due to
the analytic definition used in this study was small.
In summary, this well-controlled study provides
evidence supporting the notion that IL-1 inhibition has a
role in the prevention of flares of acute gout. Prevention
of gout flares with an agent that has an acceptable safety
and tolerability profile could potentially contribute to
increased long-term adherence with urate-lowering ther-
apy and thus better maintenance of reduced serum urate
levels and better disease control (24–26). Further eval-
uation of the use of IL-1 blockade for both the preven-
tion and the treatment of acute gout flares is warranted.
All authors were involved in drafting the article or revising it
critically for important intellectual content, and all authors approved
the final version to be published. Dr. Schumacher had full access to all
of the data in the study and takes responsibility for the integrity of the
data and the accuracy of the data analysis.
Study conception and design. Schumacher, Sundy, Mellis, Stahl,
Yancopoulos, Weinstein, Radin.
Acquisition of data. Knapp, Mellis, Soo, King-Davis, Weinstein, Radin.
Analysis and interpretation of data. Schumacher, Terkeltaub, Stahl,
Yancopoulos, Soo, Weinstein, Radin.
ROLE OF THE STUDY SPONSOR
Regeneron Pharmaceuticals, Inc. designed the study in col-
laboration with the academic authors. Data were collected by the
investigators and retained and analyzed by the sponsor. The lead
authors reviewed and contributed to the interpretation of the results
and agreed to prepare and submit the manuscript for publication, with
technical writing and editorial assistance from a professional medical
writer, E. Jay Bienen, PhD, and Regeneron. Funding for publication
support services rendered by the professional medical writer was
provided by Regeneron Pharmaceuticals, Inc. All authors assume
responsibility for the overall content and vouch for the validity and
completeness of the reported results.
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APPENDIX A: PRINCIPAL INVESTIGATORS
The principal investigators in this trial were as follows:
H. S. B. Baraf (Wheaton, MD), J. Butler (Spokane, WA), S. Clevinger
(Ocala, FL), P. Collins (Boise, ID), M. D’Ambrosio (Colorado
Springs, CO), D. J. Dionne (Spokane, WA), D. Fitz-Patrick (Hono-
lulu, HI), G. Gottschlich (Cincinnati, OH), W. Harper (Raleigh, NC),
G. Hill (Simpsonville, SC), J. Hill (DeLand, FL), D. Johnson
(Owensboro, KY), S. Kardatzke (Indianapolis, IN), H. Knapp (Bill-
ings, MT), K. Kolba (Santa Maria, CA), D. Mandel (Mayfield Village,
OH), F. Murphy (Duncansville, PA), G. Niemer (Charleston, SC),
W. Palmer (Omaha, NE), N. Patterson (Great Neck, NY), J. E. Poiley
(Orlando, FL), A. J. Porges (Roslyn, NY), H. M. Prupas (Salt Lake
City, UT), N. Romanoff (Albany, NY), J. Silverfield (Tampa, FL),
N. Straniero (Southbend, IN), and L. Willis (Oklahoma City, OK).
884 SCHUMACHER ET AL