Effects of Febuxostat Versus Allopurinol and
Placebo in Reducing Serum Urate in Subjects With
Hyperuricemia and Gout: A 28-Week, Phase III,
Randomized, Double-Blind, Parallel-Group Trial
H. RALPH SCHUMACHER, JR.,1MICHAEL A. BECKER,2ROBERT L. WORTMANN,3
PATRICIA A. MACDONALD,4BARBARA HUNT,4JANET STREIT,4CHRISTOPHER LADEMACHER,4
AND NANCY JOSEPH-RIDGE4
Objective. To compare the urate-lowering efficacy and safety of febuxostat, allopurinol, and placebo in a large group of
subjects with hyperuricemia and gout, including persons with impaired renal function.
Methods. Subjects (n ? 1,072) with hyperuricemia (serum urate level >8.0 mg/dl) and gout with normal or impaired
(serum creatinine level >1.5 to <2.0 mg/dl) renal function were randomized to receive once-daily febuxostat (80 mg, 120
mg, or 240 mg), allopurinol (300 or 100 mg, based on renal function), or placebo for 28 weeks.
Results. Significantly (P < 0.05) higher percentages of subjects treated with febuxostat 80 mg (48%), 120 mg (65%), and
240 mg (69%) attained the primary end point of last 3 monthly serum urate levels <6.0 mg/dl compared with allopurinol
(22%) and placebo (0%). A significantly (P < 0.05) higher percentage of subjects with impaired renal function treated with
febuxostat 80 mg (4 [44%] of 9), 120 mg (5 [45%] of 11), and 240 mg (3 [60%] of 5) achieved the primary end point
compared with those treated with 100 mg of allopurinol (0 [0%] of 10). Proportions of subjects experiencing any adverse
event or serious adverse event were similar across groups, although diarrhea and dizziness were more frequent in the
febuxostat 240 mg group. The primary reasons for withdrawal were similar across groups except for gout flares, which
were more frequent with febuxostat than with allopurinol.
Conclusion. At all doses studied, febuxostat more effectively lowered and maintained serum urate levels <6.0 mg/dl than
did allopurinol (300 or 100 mg) or placebo in subjects with hyperuricemia and gout, including those with mild to
moderately impaired renal function.
The primary goal in managing patients with hyperurice-
mia and gout is to reduce or reverse the expression of
clinical events by lowering and maintaining serum urate
levels below the limit of urate solubility (approximately
6.8 mg/dl) (1–9). Lowering serum urate below saturating
levels (?6.0 mg/dl, 0.36 mmoles/liter) over time results in
ClinicalTrials.gov identifier: NCT00174915.
Previously published in abstract form: Schumacher HR,
Becker MA, Wortmann RL, MacDonald PA, Hunt B, Streit J,
et al. Febuxostat vs allopurinol and placebo in subjects with
hyperuricemia and gout: the 28-week APEX study [abstract].
Arthritis Rheum 2005;52 Suppl 9:S680.
Supported by Takeda Global Research & Development
Center, Inc., Deerfield, Illinois. Dr. Schumacher’s work was
supported by grants from Takeda Global Research & Devel-
opment Center, Inc.
1H. Ralph Schumacher, Jr., MD: University of Pennsylva-
nia and VA Medical Center, Philadelphia;
Becker, MD: Pritzker School of Medicine, University of Chi-
cago, Chicago, Illinois;
mouth Medical School, Hanover, New Hampshire;4Patricia
A. MacDonald, BSN, NP, Barbara Hunt, MS, Janet Streit,
MS, Christopher Lademacher, MD, PhD, Nancy Joseph-
3Robert L. Wortmann, MD: Dart-
Ridge, MD: Takeda Global Research & Development Center,
Inc., Deerfield, Illinois (of which TAP Pharmaceuticals, Inc.,
is now a subsidiary).
Dr. Schumacher has received consultant fees, speaking
fees, and/or honoraria (less than $10,000 each) from Takeda
Global Research & Development Center, Inc., and Savient.
Dr. Becker has received consultant fees (more than $10,000)
from Takeda Global Research & Development Center, Inc.
Dr. Wortmann has received consultant fees, speaking fees,
and/or honoraria (less than $10,000 each) from Takeda
Global Research & Development Center, Inc., and Merck &
Company. Dr. Joseph-Ridge owns stock and/or holds stock
options in Abbott Laboratories.
Address correspondence to H. Ralph Schumacher, Jr.,
MD, VA Medical Center, 151K University and Woodland
Avenues, Philadelphia, PA 19104. E-mail: schumacr@mail.
Submitted for publication December 20, 2007; accepted in
revised form June 10, 2008.
Arthritis & Rheumatism (Arthritis Care & Research)
Vol. 59, No. 11, November 15, 2008, pp 1540–1548
© 2008, American College of Rheumatology
reduced frequency of acute gouty attacks (flares) (5,10–13)
and reduced size and/or number of clinically detectable
urate crystal deposits (tophi) (4,10,14).
For most gout patients with repeated acute flares of
gouty arthritis, chronic gouty arthropathy, tophi, or uric
acid urolithiasis, long-term maintenance of serum urate
levels ?6.0 mg/dl requires urate-lowering pharmacother-
apy (2,15–17). Two classes of drug agents are currently
available for this purpose: uricosuric agents, which in-
crease renal excretion of uric acid, and xanthine oxidase
inhibitors, which reduce urate synthesis. For many years,
the most commonly employed urate-lowering agent in the
US has been allopurinol, a hypoxanthine analog. Although
allopurinol is generally safe and effective, it can occasion-
ally induce life-threatening rashes and/or a severe multi-
system allopurinol hypersensitivity syndrome (18–20).
Furthermore, the prolonged half-life (14–26 hours) of the
major allopurinol active oxidation product, oxypurinol,
and its further prolongation in patients with decreased
creatinine clearance has prompted dose reduction in pa-
tients with impaired renal function (19,21,22).
Febuxostat, an orally administered nonpurine selective
inhibitor of xanthine oxidase, is in development for the
management of hyperuricemia in patients with gout. In
contrast to allopurinol, febuxostat inhibits both oxidized
and reduced forms of xanthine oxidase (23,24) and has
minimal effects on other enzymes of purine and pyrimi-
dine metabolism (24,25). After oral administration, febux-
ostat is rapidly and extensively (84%) absorbed (26), with
a half-life ranging from 4–18 hours for doses between 10
and 120 mg (27–29). Febuxostat undergoes hepatic metab-
olism with approximately one-half of administered febux-
ostat (unchanged drug and metabolites) excreted in the
stool and the remainder appearing in the urine (27).
Short-term pharmacokinetic studies performed in non-
gouty subjects with impaired renal function (30,31) sug-
gest that febuxostat dose adjustment may not be required
in these patients. In previous trials conducted in healthy
volunteers and subjects with gout and hyperuricemia
(10,15,27), febuxostat exhibited potent and dose-depen-
dent urate-lowering efficacy. However, none of these trials
were intended to examine the efficacy or safety of febux-
ostat in subjects with impaired renal function, hyperuri-
cemia, and gout.
The objective of this multicenter, Allopurinol- and Pla-
cebo-Controlled, Efficacy Study of Febuxostat (APEX) trial
was to compare the safety and efficacy of orally adminis-
tered febuxostat with placebo and allopurinol in subjects
with hyperuricemia and gout. Furthermore, this study
sought to confirm and expand upon the results observed in
the Febuxostat versus Allopurinol Controlled Trial (FACT)
(10) by assessing the effects of treatment in subjects with
impaired renal function (serum creatinine level ?1.5 to
SUBJECTS AND METHODS
Study population. This phase III, randomized, double-
blind, allopurinol- and placebo-controlled, parallel-group
trial was conducted at 167 sites in the US. The majority of
investigators were primary care physicians. Institutional
review boards at participating sites approved the protocol
and written informed consent that conformed to the Dec-
laration of Helsinki and the Health Insurance Portability
and Accountability Act. Written consent was obtained
from all subjects prior to any study-related procedures.
Eligible participants were of either sex and 18–85 years of
age, inclusive, with gout (defined by the American College
of Rheumatology preliminary criteria ), hyperuricemia
(defined for this study as a serum urate level ?8.0 mg/dl),
and normal (serum creatinine level ?1.5 mg/dl) or im-
paired (serum creatinine level ?1.5 to ?2.0 mg/dl) renal
function at day ?2. Exclusion criteria included intoler-
ance to allopurinol, naproxen, or colchicine; history of
renal calculi; alcohol intake of ?14 drinks/week; hepatic
dysfunction with alanine aminotransferase (ALT) and as-
partate aminotransferase (AST) both ?1.5 times the upper
limit of normal; or any other significant medical condi-
After a 2-week washout period for those receiving pre-
vious urate-lowering therapy, subjects were randomized in
a 2:2:1:2:1 ratio to once-daily febuxostat 80 mg, febuxostat
120 mg, febuxostat 240 mg, allopurinol, or placebo. The
randomization was stratified by renal function. Allopuri-
nol dose was dependent on renal function; subjects with
normal renal function (serum creatinine level ?1.5 mg/dl,
n ? 258) received 300 mg, whereas subjects with renal
impairment (serum creatinine level ?1.5 to ?2.0 mg/dl,
n ? 10) received 100 mg based on Food and Drug Admin-
istration–approved dosing information (21). Results from
these 2 allopurinol doses were analyzed together, and are
referred to as allopurinol unless otherwise noted. There
was no dose adjustment in the febuxostat treatment arms.
Either colchicine 0.6 mg once daily or naproxen 250 mg
twice daily was provided during the washout period for
subjects receiving prior urate-lowering therapies or upon
randomization for subjects not receiving prior urate-low-
ering therapy, and was continued for the first 8 weeks of
the study as prophylaxis for gout flares. The investigator
used his or her judgment in selecting between naproxen
and colchicine, although colchicine was recommended for
subjects with a serum creatinine level ?1.5 mg/dl. Any
gout flares occurring during the first 8 weeks or later were
treated at the investigator’s discretion. Serum urate levels,
laboratory assessments, gout flares, adverse events (AEs),
concomitant medications, and number and size of palpa-
ble tophi were monitored at visits every 4 weeks.
Efficacy end points.
proportion of subjects with the last 3 monthly serum urate
levels ?6.0 mg/dl. The last 3 serum urate levels for each
subject, regardless of whether or not the subject completed
the study, were used to determine if the subject was a
responder. If a subject discontinued the study before ?3
serum urate levels were obtained, the subject was consid-
ered a nonresponder. Secondary end points included the
proportion of subjects with a serum urate level ?6.0 mg/dl
at each visit, the percent reduction of serum urate from
baseline at each visit, the proportion of subjects requiring
treatment for a self-reported gout flare between weeks 8
The primary end point was the
Urate-Lowering Efficacy of Febuxostat Versus Allopurinol1541
and 28, reduction in the number of tophi at each visit for
subjects with palpable tophi at baseline, and the percent
reduction in primary tophus size at each visit in those
subjects with a primary palpable tophus at baseline. Pri-
mary tophi were physically measured by the investigator
or designee according to a published method (33). For
variables summarized by visit, data are shown for both the
week 28 visit and the final visit (defined as each subject’s
last postbaseline visit).
formed on the intent-to-treat population, defined as all
randomized subjects who received ?1 dose of study drug
and had a serum urate level ?8.0 mg/dl at baseline. Com-
parisons for the primary efficacy end point were made
sequentially using a 3-step closed testing process. First,
each febuxostat group was compared with placebo for
superiority using a Cochran-Mantel-Haenszel (CMH) test
(stratified by baseline renal function) with Hochberg’s
method for multiple comparisons to ensure that the overall
P value was ?0.05 (34). Second, if each dose of febuxostat
was shown to be superior to placebo, the febuxostat 80 mg
and 120 mg groups were tested for noninferiority to allo-
purinol using binomial confidence intervals. Noninferior-
ity was declared if the lower limit of the 97.5% confidence
interval for the difference in response rates was greater
than ?10%. Finally, each dose of febuxostat shown to be
noninferior to allopurinol was tested for superiority to
allopurinol using a CMH test stratified by baseline renal
function with Hochberg’s method for multiple compari-
sons. Post hoc pairwise comparisons within the subgroups
of subjects with renal impairment and subjects with nor-
mal renal function were made using Fisher’s exact test.
Pairwise comparisons between groups for the secondary
efficacy end points were made using a CMH test (stratified
by baseline renal function) for the proportion of subjects
with serum urate levels ?6.0 mg/dl at the week 28 and
final visits, and the proportion of subjects requiring treat-
ment for a gout flare between weeks 8 and 28 and during
the prophylaxis period. An analysis of variance for the
percent reduction from baseline in serum urate levels at
week 28 and final visits was performed. Wilcoxon’s rank
sum test was performed for the percent reduction in pri-
mary tophus size and reduction in number of tophi at
week 28 and final visits. Demographic data were analyzed
for differences among groups, using analysis of variance
for continuous variables and chi-square test for categorical
variables. Fisher’s exact test was used for pairwise com-
parison of AEs, liver function test elevations, and primary
reason for withdrawal between the groups.
A sample size of 1,000 subjects was targeted to provide
?80% power to meet noninferiority criteria between fe-
buxostat and allopurinol, ?95% power to detect a ?45%
difference between each febuxostat group and placebo,
and ?90% power to detect a 15% difference between ?1
febuxostat group and the allopurinol group for the primary
end point. The unequal randomization ratio was chosen
because a larger number of subjects was required to show
noninferiority between the febuxostat 80 mg and 120 mg
groups and the allopurinol group than to show a difference
All efficacy analyses were per-
between febuxostat and placebo. Since febuxostat 240 mg
was included for safety assessment only, comparisons of
this febuxostat dose with allopurinol were not powered.
Analyses were performed with SAS statistical software,
version 8.2 (SAS Institute, Cary, NC) with the UNIX oper-
ating system. All statistical tests and confidence intervals
were 2-sided and P values less than or equal to 0.05 were
considered to be statistically significant, unless otherwise
Subject disposition. Between February 2003 and April
2004, 1,072 subjects participated in this 28-week, double-
blind, allopurinol- and placebo-controlled study (Figure
1). Five subjects randomized to febuxostat 80 mg were
excluded from the efficacy analyses because they did not
meet the inclusion criteria of a serum urate level ?8.0
mg/dl on day ?1. Premature withdrawal rates were higher
in the febuxostat 80 mg and 240 mg groups (35% and 36%,
respectively) than in the febuxostat 120 mg (26%) or allo-
purinol (21%) groups (P ? 0.05). The withdrawal rate was
also higher in the febuxostat 80 mg group than in the
placebo group (25%; P ? 0.05). The majority of withdraw-
als from each group (58–69% of withdrawals) occurred
within the first 12 weeks of the study. Primary reasons for
withdrawal were similar across all treatment groups ex-
cept for gout flares, which were more frequently reported
with febuxostat, and significantly so (P ? 0.001) in the
Figure 1. Subject disposition. sUA ? serum urate level; LFTs ?
liver function tests; sCr ? serum creatinine;
received 100 mg and 258 subjects received 300 mg of allopurinol
based on renal function;
withdrawal most often included noncompliance or withdrawal of
a? Ten subjects
b? Other, as a primary reason for
1542Schumacher et al
febuxostat 80 mg and 240 mg treatment groups versus
allopurinol (Figure 1).
Baseline characteristics. The majority of subjects were
male (94%), white (78%), and age 45–65 years (56%). At
baseline, the mean duration of gout was 10.9 years, with
89% of subjects experiencing a gout flare within the past
year. Twenty percent of subjects had a primary palpable
tophus. Tophi had been present for an average of 5.7 years
for those with tophi or a history of tophi at baseline.
Forty-seven percent of subjects had hypertension, 33%
hyperlipidemia, 62% obesity (body mass index ?30 kg/
m2), 4% impaired renal function (serum creatinine level
?1.5 to ?2.0 mg/dl), 66% a current history of alcohol use
(?14 drinks/week), and 13% cardiovascular disease.
Mean ? SD baseline serum urate level was 9.85 ? 1.263
mg/dl, with 39% of subjects having a baseline serum urate
level ?10.0 mg/dl. Baseline characteristics, comorbidities,
and gout history did not differ significantly across treat-
ment groups (Table 1). Mean study drug compliance was
similar among all treatment groups and ranged from 95.8–
Efficacy analysis. Proportion of subjects with last 3
monthly serum urate levels ?6.0 mg/dl.
(P ? 0.001) greater proportion of subjects receiving febux-
ostat at any dose achieved the primary end point of last 3
monthly serum urate levels ?6.0 mg/dl than subjects re-
ceiving allopurinol or placebo (Figure 2). Allopurinol also
produced significantly (P ? 0.001) greater percent de-
creases in serum urate level from baseline than placebo.
Among subjects with a baseline serum urate level ?10.0
mg/dl, 36%, 52%, and 66% of subjects achieved last 3
serum urate levels ?6.0 mg/dl while receiving febuxostat
80 mg, 120 mg, and 240 mg, respectively. In contrast, few
(10%) of these subjects achieved last 3 serum urate levels
?6.0 mg/dl while receiving allopurinol. Interestingly, the
response rate in subjects receiving allopurinol who re-
ported prior allopurinol use was nearly identical to the
rate in those who reported no prior allopurinol use (22.6%
versus 22.2%). The proportions of subjects with impaired
renal function (serum creatinine level ?1.5 to ?2.0 mg/dl)
attaining last 3 monthly serum urate levels ?6.0 mg/dl
were 44% in the febuxostat 80 mg group, 46% in the 120
mg group, and 60% in the 240 mg group. No subject with
Table 1. Baseline characteristics and gout disease history of randomized subjects*
(n ? 134)
(n ? 267)
(n ? 269)
(n ? 134)
(n ? 268)†
Age, mean ? SD years
BMI, mean ? SD kg/m2
Gout history, mean ? SD years
History/presence of tophi
Recent use of allopurinol (within 30 days of
Low-dose aspirin use
Mild to moderate renal impairment‡
52 ? 12
51 ? 12
51 ? 12
54 ? 13
52 ? 12
32 ? 6
10 ? 8
33 ? 6
11 ? 9
33 ? 7
12 ? 9
33 ? 7
11 ? 9
33 ? 6
11 ? 9
* Values are the number (percentage) unless otherwise indicated. BMI ? body mass index.
† Ten subjects received 100 mg and 258 subjects received 300 mg of allopurinol based on renal function.
‡ Serum creatinine level ?1.5 to ?2.0 mg/dl.
Figure 2. Proportion of subjects with last 3 monthly serum urate
levels ?6.0 mg/dl (intent-to-treat population). The treatment
groups that were statistically significantly different for all subjects
were also statistically significantly different for the subset of sub-
jects with normal renal function.a? Ten subjects received 100 mg
and 258 subjects received 300 mg of allopurinol based on renal
function;b? Statistically significant (P ? 0.001) versus placebo in
all subjects;c? Statistically significant (P ? 0.05) versus allopuri-
nol in subjects with impaired renal function;
significant (P ? 0.001) versus allopurinol in all subjects;
Statistically significant (P ? 0.001) versus febuxostat 120 mg in all
subjects;f? Statistically significant (P ? 0.001) versus febuxostat
240 mg in all subjects.
Urate-Lowering Efficacy of Febuxostat Versus Allopurinol1543
renal impairment receiving allopurinol 100 mg or placebo
achieved last 3 monthly serum urate levels ?6.0 mg/dl
Proportion of subjects with serum urate level ?6.0 mg/dl
at week 28 or final visit. At the week 28 visit, 76% of
subjects treated with febuxostat 80 mg, 87% with febux-
ostat 120 mg, and 94% with febuxostat 240 mg achieved
serum urate levels ?6.0 mg/dl, whereas 41% of those
treated with allopurinol and 1% of those treated with
placebo achieved the same goal (Table 2). Similar success
rates were seen at the final visit. None (0 of 10) of the
subjects with renal impairment who received allopurinol
100 mg attained serum urate levels ?6.0 mg/dl at either
the week 28 or final visits.
Percent reduction in serum urate level.
week 28 and final visits, all febuxostat doses produced
significantly (P ? 0.05) greater percent decreases in serum
urate levels from baseline (?48% and ?45% for 80 mg,
?55% and ?52% for 120 mg, and ?68% and ?66% for
240 mg at week 28 and final visits, respectively) compared
with allopurinol (?34% and ?34%, respectively) and pla-
cebo (?4% and ?3%, respectively). Reductions in serum
urate levels were evident at week 2 and persisted through-
out the study.
Proportion of subjects requiring treatment for gout flare.
Between weeks 8 (after the prophylaxis period) and 28,
there were no statistically significant differences in the
proportion of subjects requiring treatment for gout flares
observed between the treatment groups; the proportion of
subjects requiring treatment for gout flares tended to di-
minish with continued treatment. In contrast, during the
first 8 weeks of the study, when gout flare prophylaxis was
provided, greater proportions (P ? 0.05) of subjects receiv-
ing febuxostat 120 mg (97 [36%] of 269) and 240 mg (69
[46%] of 134) required treatment for gout flares compared
with those receiving febuxostat 80 mg (73 [28%] of 262),
allopurinol (61 [23%] of 268), or placebo (27 [20%] of 134).
Total number and size of tophi. No significant differ-
ences in the number of tophi were observed between treat-
ment groups, with the exception of a mean percent de-
crease in the number of tophi observed with febuxostat
At both the
120 mg (?1.2) versus placebo (?0.3) at week 28 (P ? 0.05).
Reductions in median tophus size from baseline were re-
ported in each treatment group, including placebo; how-
ever, there were no significant differences between treat-
Safety analysis. Adverse events. Generally, AEs oc-
curred with similar frequency across treatment groups and
were mild or moderate in severity. The most frequently
reported AEs (?5% of subjects) are listed in Table 3. A
statistically significant increase in the incidence of diar-
rhea was seen in the febuxostat 240 mg group compared
with each of the other active treatment groups, but not
with placebo. The incidence of hypertension was signifi-
cantly higher for subjects treated with febuxostat 80 mg
compared with subjects treated with allopurinol, but not
with placebo. An increased incidence of hypertension was
not seen for the other 2 doses of febuxostat when com-
pared with either allopurinol or placebo. The reported
occurrence of dizziness was significantly greater in sub-
jects receiving febuxostat 240 mg when compared with
subjects receiving febuxostat 80 or 120 mg or allopurinol;
however, the incidence was not significantly higher in any
active treatment group when compared with placebo.
AEs related to abnormal findings on liver function tests,
designated as such by individual investigators, were re-
ported for a total of 51 subjects: 17 (6%) receiving febux-
ostat 80 mg, 10 (4%) receiving febuxostat 120 mg, 6 (4%)
receiving febuxostat 240 mg, 15 (6%) receiving allopuri-
nol, and 3 (2%) receiving placebo. Of these subjects, 12
withdrew due to this AE: 5 receiving febuxostat 80 mg, 3
receiving febuxostat 120 mg, and 4 receiving allopurinol
(Table 3). These events were classified by the investigator
as mild to moderate in severity, and only 1 was not tran-
sient. This subject (receiving febuxostat 80 mg) had con-
current hepatitis C and entered the study with elevated
hepatic enzymes (day ?6) that persisted and led to prema-
ture discontinuation at day 53. In addition to these liver
function test AEs, the proportions of subjects with 1 or
more concurrent ALT and AST value ?1.5 times the upper
limit of normal are shown in Table 4.
All rash-related AEs (i.e., allergic, contact, and exfolia-
tive dermatitis; heat, erythematous, follicular, macular,
maculopapular, papular, pruritic, and scaly rashes; ec-
zema; erythema; rash, not elsewhere classified; and urti-
caria) were combined to assess if there were any differ-
ences among treatment groups. These combined terms of
rash-related events were reported with similar incidence
in all treatment groups: 5% (14 of 267) receiving febux-
ostat 80 mg, 6% (17 of 269) receiving febuxostat 120 mg,
4% (6 of 134) receiving febuxostat 240 mg, 5% (14 of 268)
receiving allopurinol, and 5% (7 of 134) receiving placebo.
However, none of the individual types of rashes occurred
at a rate that qualified as a frequently reported AE (?5% of
subjects in any group). Eight subjects withdrew due to any
of these rash types: 3 receiving febuxostat 80 mg, 3 receiv-
ing febuxostat 120 mg, 0 receiving febuxostat 240 mg, 1
receiving allopurinol, and 1 receiving placebo. Most rash
events were mild or moderate in severity, although 2 sub-
jects reported severe rashes while receiving febuxostat 80
Table 2. Proportion of subjects with serum urate levels
<6.0 mg/dl at week 28 and final visits (intent-to-treat
Week 28, % Final, %
Febuxostat 80 mg
Febuxostat 120 mg
Febuxostat 240 mg
Allopurinol 300 mg§
* Statistically significant versus placebo (P ? 0.05) and versus al-
lopurinol (P ? 0.05).
† Statistically significant versus placebo (P ? 0.05), versus allopuri-
nol (P ? 0.05), and versus febuxostat 80 mg (P ? 0.05).
‡ Statistically significant versus placebo (P ? 0.05), versus allopuri-
nol (P ? 0.05), versus febuxostat 80 mg (P ? 0.05), and versus
febuxostat 120 mg (P ? 0.05).
§ Ten subjects received 100 mg and 258 subjects received 300 mg of
allopurinol based on renal function.
¶ Statistically significant versus placebo (P ? 0.05).
1544 Schumacher et al
mg. One of these subjects experienced a severe papular
rash that led to discontinuation from the study, and the
second subject experienced severe contact dermatitis but
continued in the study.
Serious adverse events. There were no deaths reported
during the study. Subjects experienced serious AEs with
similar frequency in all groups (Table 3). The most fre-
quent serious AEs observed in all treatment groups were
cardiovascular disorders (chest pain, coronary artery dis-
ease, myocardial infarction, and atrial fibrillation). These
subjects each had a history of underlying cardiovascular
disease and/or risk factors. Nine of 34 subjects with seri-
ous AEs withdrew due to the serious AE (Table 3).
Only 1 subject experienced a serious AE that was con-
sidered by the investigator to be related to the study drug.
This subject reported a history of kidney stones and expe-
rienced a gradual increase in serum creatinine while re-
ceiving febuxostat 240 mg (1.1 mg/dl on day 1 to 1.5 mg/dl
on the last day of the study, day 197). The serum creatinine
level returned to within normal limits (1.3 mg/dl) during
treatment with febuxostat 120 mg in a subsequent exten-
Adverse events leading to withdrawal. AEs leading at
least in part to study discontinuation occurred in 78
subjects with similar frequency across treatments (Table
3). These events were generally mild to moderate in
severity, with the most common being abnormal find-
ings on liver function tests (discussed above) and diar-
rhea. Eight subjects withdrew from the study due to
diarrhea: ?1% (2 of 267) in the febuxostat 80 mg group,
?1% (1 of 269) in the febuxostat 120 mg group, 3% (4 of
134) in the febuxostat 240 mg group, 0% (0 of 134) in the
placebo group, and ?1% (1 of 268) in the allopurinol
Table 3. Adverse events (AEs)*
(n ? 134)
(n ? 267)
(n ? 269)
(n ? 134)
(n ? 268)†
Most frequent AEs‡
Upper respiratory tract infections
Musculoskeletal and connective tissue signs and
Joint-related signs and symptoms§
Abnormal findings on liver function test (designated as AE
Influenza viral infections
Nausea and vomiting symptoms
Vascular hypertensive disorders (hypertension)
Gastrointestinal and abdominal pains (excluding oral and
Neurologic signs and symptoms (dizziness)
Muscle-related signs and symptoms (muscle cramps,
muscle twitching, night cramps)
Cardiovascular events (chest pain, coronary artery disease,
myocardial infarction, atrial fibrillation)
AEs leading to withdrawal‡‡
Abnormal findings on liver function test**
Serious AEs leading to withdrawal
Cardiovascular disorders (coronary artery disease, acute
coronary syndrome, myocardial infarction)
Cancer (malignant parathyroid tumor, Hodgkin’s disease)
Miscellaneous (pleuritic pain, nausea, muscular weakness,
vomiting, anemia, hypoglycemic seizure)
97 (72) 181 (68)183 (68) 98 (73) 200 (75)
* Values are the number (percentage).
† Ten subjects received 100 mg and 258 subjects received 300 mg of allopurinol based on renal function.
‡ AEs occurring in ?5% of subjects in any group.
§ Excluding gout flares, which were not considered an AE.
¶ Statistically significant versus febuxostat 240 mg (P ? 0.05).
# Statistically significant versus allopurinol (P ? 0.05).
** Terms that are included: alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, hepatic enzyme
increased, abnormal findings on liver function tests, transaminases increased.
†† Statistically significant versus placebo (P ? 0.05).
‡‡ AEs listed as primary or secondary reasons for withdrawal.
§§ Statistically significant versus allopurinol (P ? 0.05) and versus febuxostat 120 mg (P ? 0.05).
Urate-Lowering Efficacy of Febuxostat Versus Allopurinol 1545
The APEX trial is the largest randomized controlled clin-
ical trial to date comparing febuxostat, allopurinol, and
placebo in hyperuricemic subjects with gout. Employing a
rigorous primary end point of last 3 monthly serum urate
levels ?6.0 mg/dl, this 28-week study demonstrated that
treatment with febuxostat significantly reduced and main-
tained serum urate levels ?6.0 mg/dl in the majority of
subjects, and even in many subjects with a baseline serum
urate level ?10.0 mg/dl. In contrast, the proportion of
subjects responding to allopurinol (22%) was lower than
anticipated based on a review of the literature (35–38), but
was consistent with the results of a previously reported
clinical trial (FACT) (10). Reasons for the limited efficacy
of allopurinol in the FACT have previously been discussed
(10) and likely include the high mean baseline serum urate
levels and the use of fixed rather than titrated doses of
allopurinol. Nevertheless, the urate-lowering responses to
febuxostat 80 mg, 120 mg, or 240 mg were more robust
than the responses to commonly used doses of allopurinol
(11), regardless of baseline serum urate level.
The inclusion of subjects with impaired renal function
in this clinical trial provides additional clinically relevant
insights. In the few subjects with impaired renal function
receiving the recommended allopurinol dose (100 mg),
end points of serum urate levels ?6.0 mg/dl were not
achieved. Titration to higher doses of allopurinol might
have provided better urate-lowering efficacy as recently
reported (39,40); however, there are currently no random-
ized controlled trials using allopurinol dose titration in
patients with gout (7,41).
This study was only 28 weeks in duration and did not
demonstrate a difference among treatment groups in re-
ducing gout flare incidence. A 3-year retrospective study
by Shoji et al (12) found that reduction of serum urate
levels to ?6.0 mg/dl eventually resulted in a reduced
incidence of gout flares. It is likely that differences in flare
rates between urate-lowering therapy and placebo may
become more distinct with longer-term therapy, but doc-
umentation in longer studies is needed.
The occurrence rate for any AE was similar across treat-
ment groups. Incidences of diarrhea and dizziness were
significantly more frequently reported in the febuxostat
240 mg group. No other events showed any stepwise in-
crease in rates with higher doses of febuxostat. Entry cri-
teria limited participation to subjects with no more than 14
alcoholic beverages per week. In practice, it will be impor-
tant for physicians to follow possible liver function effects
in heavier drinkers.
Serious AEs were reported with similar frequencies in
all groups, the most common of which were cardiovascu-
lar disorders. These subjects each had documented under-
lying cardiovascular disease and/or risk factors. As might
have been expected, withdrawals due to gout flares were
more common in the febuxostat groups, possibly due to
urate crystal mobilization with more abrupt lowering of
serum urate with febuxostat compared with allopurinol.
Antiinflammatory prophylaxis may need to be studied fur-
ther and may need to be continued longer than 8 weeks
when using potent urate-lowering agents. In addition,
there is a need to educate patients to be aware of acute
flares and seek prompt treatment.
Limitations to this large and complex study are those
observed in hindsight. Fewer subjects with renal impair-
ment were enrolled than anticipated. Additional clinical
trials are needed to provide guidance on how to best
achieve target serum urate levels in patients with impaired
renal function, including those with more severe renal
impairment, as will likely be seen in practice. In addition,
accurate measurement of tophi continues to be problem-
atic in the clinical setting and highlights the need for a
more reliable measure so that the effects of urate-lowering
therapy can be adequately assessed. Likewise, criteria for
the diagnosis and management of acute gout flares need to
Table 4. Liver function test results*
(n ? 129)
(n ? 258)
(n ? 264)
(n ? 127)
(n ? 262)
ALT ?1.5 times the ULN
AST ?1.5 times the ULN
ALT ?1.5 times the ULN and AST
?1.5 times the ULN
ALT ?1.5 times the ULN and total
bilirubin ?2 mg/dl
AST ?1.5 times the ULN and total
bilirubin ?2 mg/dl
ALT ?1.5 times the ULN and alk.
phos. ?2 times the ULN
AST ?1.5 times the ULN and alk.
phos. ?2 times the ULN
10 (8) 38 (15) 30 (11)12 (9) 24 (9)
1 (?1)1 (?1)0 1 (?1) 1 (?1)
1 (?1) 1 (?1)0 1 (?1) 1 (?1)
0 1 (?1)000
0 2 (?1)000
* Values are the number (percentage). ALT ? alanine aminotransferase; ULN ? upper limit of normal; AST ? aspartate aminotransferase; alk. phos.
? alkaline phosphatase.
† Statistically significant versus placebo (P ? 0.050).
‡ Statistically significant versus placebo (P ? 0.050) and versus febuxostat 240 mg (P ? 0.050).
1546Schumacher et al
be more clearly defined so that flares can be more repro-
ducibly described and quantified.
The results of the current study demonstrate that treat-
ment with febuxostat 80 mg, 120 mg, and 240 mg for 28
weeks effectively reduces serum urate levels in subjects
with hyperuricemia and gout and that these effects are
significantly greater than those produced by the commonly
used doses of up to 300 mg of allopurinol or by placebo.
The efficacy of febuxostat in subjects with renal impair-
ment is promising and warrants further study.
We would like to thank the principal investigators at the
clinical sites in the APEX trial, as well as Susan Ruffalo of
MedWrite, Inc., and Jennifer Jaworski of Takeda Pharma-
ceuticals North America, Inc., for assisting with drafting
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 design. Schumacher, Becker, Wortmann, MacDonald,
Hunt, Streit, Joseph-Ridge.
Acquisition of data. Becker, MacDonald, Streit, Lademacher.
Analysis and interpretation of data. Schumacher, Becker, Wort-
mann, MacDonald, Hunt, Streit, Lademacher, Joseph-Ridge.
Manuscript preparation. Schumacher, Becker, Wortmann, Mac-
Donald, Hunt, Streit, Lademacher, Joseph-Ridge, Joyce N. Riffin
(nonauthor; Takeda Pharmaceuticals, Inc., Deerfield, IL).
Statistical analysis. Hunt, Lademacher.
ROLE OF THE STUDY SPONSOR
The study was designed by the academic authors and the cor-
porate sponsor, Takeda Global Research & Development Center,
Inc. Representatives of Takeda Global Research & Development
Center, Inc., collected the data and statisticians at Takeda Global
Research & Development Center, Inc., conducted all statistical
analyses. All authors had access to the data and vouch for the
veracity and completeness of the data and data analysis.
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