Rheumatology 2009;48:188–194 doi:10.

1093/rheumatology/ken457

Febuxostat in the treatment of gout: 5-yr findings of the

FOCUS efficacy and safety study
H. R. Schumacher Jr1, M. A. Becker2, E. Lloyd3, P. A. MacDonald3 and C. Lademacher3

Objectives. This 5-yr study assessed urate-lowering and clinical efficacy and safety of long-term febuxostat therapy in subjects with gout.
The primary efficacy end-point was reduction to and maintenance of serum urate (sUA) levels <6.0 mg/dl.

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Methods. Subjects who completed a previous 28-day study were entered into an open-label extension study and initially received febuxostat
80 mg daily. Between Weeks 4 and 24, dosing could be adjusted to febuxostat 40 or 120 mg. All subjects received gout flare prophylaxis
during the first 4 weeks. Gout flares were recorded and treated throughout the study, and sUA, baseline tophi and safety were monitored.
Results. Among 116 subjects initially enrolled, dose adjustments were made for 44 (38%) subjects. As a result, 8 subjects received
febuxostat 40 mg, 79 received 80 mg, and 29 received 120 mg daily maintenance dose. At 5 yrs, 93% (54/58) of the remaining subjects had
sUA <6.0 mg/dl. Fifty-eight subjects (50%) discontinued prematurely; 38 did so in the first year. Thirteen subjects withdrew due to an adverse
event. Sustained reduction of sUA was associated with nearly complete elimination of gout flares. In 26 subjects with a tophus at baseline,
resolution was achieved in 69% (18/26) by last visit on study drug at any point during the study (Final Visit). There were no deaths reported
during the study.
Conclusions. Long-term treatment with febuxostat resulted in durable maintenance of sUA <6.0 mg/dl for most subjects. There was nearly
complete abolition of gout flares in patients completing the study. Baseline tophi resolved in a majority of subjects.

KEY WORDS: Febuxostat, Gout, Hyperuricaemia, Allopurinol.

Introduction of the administered febuxostat is excreted in the urine, only
10%

Hyperuricaemia, defined as serum urate (sUA) concentration
exceeding the solubility of urate in extracellular fluid (
6.8 mg/dl),
predisposes affected individuals to urate crystal formation and
deposition [1, 2] as well as the clinical features of gout [1–3].
Increasing levels of hyperuricaemia increase the risk for the
occurrence of gouty arthritis [3] and uric acid urolithiasis [4].
Untreated, gout may progress to a chronic disease characterized
by destructive arthropathy and deforming deposits of urate
crystals (tophi).
The primary goal in management of gout is reduction to
and maintenance of sUA in a sub-saturating range (usually
<6.0 mg/dl); it is believed that long-term achievement of this
objective results in a decreased incidence or disappearance of gout
flares and dissolution of tophaceous deposits [3, 5–9]. The two
pharmacological methods currently employed for urate lowering
in gout are reduction of urate production by use of the xanthine
oxidase (XO) inhibitor, allopurinol, and enhancement of urinary
uric acid excretion with a uricosuric agent. A third urate-lowering
strategy, conversion of uric acid to allantoin by administration of
a modified or unmodified recombinant uricase, is in development
for treatment of gout refractory to currently available urate-
lowering agents [10, 11].
Febuxostat is an orally administered selective inhibitor of XO
[12–16] in development for the treatment of hyperuricaemia in
patients with gout. The drug has potent hypouricaemic and
hypouricosuric properties [12, 13, 16] but is not a purine analogue.
Febuxostat is primarily metabolized in the liver to inactive acyl-
glucuronide metabolites and, to a minor extent, by cytochrome
P450 enzymes to active oxidized metabolites [14]. Although
50%
1
University of Pennsylvania and VA Medical Center, Philadelphia, PA, 2University
of Chicago, Pritzker School of Medicine, Chicago and 3Takeda Global Research
and Development Center, Deerfield, IL, USA.
Present address: C. Lademacher, Astellas Pharma US, Deerfield, IL, USA.
Submitted 9 June 2008; revised version accepted 18 November 2008.
Correspondence to: H. R. Schumacher Jr, VA Medical Center, 151K, University
and Woodland Avenues, Philadelphia, PA 19104, USA.
E-mail: schumacr@mail.med.upenn.edu
188
ß The Author 2009. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
is as unchanged drug or active metabolites [17].
Results of three double-blind studies of the safety and efficacy
of febuxostat in subjects with gout and sUA >8.0 mg/dl have
previously been reported: a 28-day Phase 2, placebo-controlled
trial [5]; a 28-week Phase 3 trial comparing febuxostat with
allopurinol and placebo [18]; and a 52-week Phase 3 febuxostat
and allopurinol comparative trial [19]. In all three studies,
febuxostat produced significant dose-dependent decreases in
sUA. Here, we present the results of a 5-yr open-label extension
of the 28-day Phase 2 trial (FOCUS: Febuxostat Open-label
Clinical trial of Urate-lowering efficacy and Safety). Our
objectives were to evaluate the durability of febuxostat urate-
lowering and the clinical efficacy, safety, and tolerability of
febuxostat-induced sUA reduction and maintenance at sub-
saturating levels. Clinical efficacy was assessed by changes in the
incidence of acute gout flares that required treatment and by
resolution of tophi that were palpable at baseline.
Subjects and methods
Study design and procedures
This open-label extension study was conducted at 23 centres in the
United States. Institutional review board approval was obtained,
and all subjects provided written informed consent and Health
Insurance Portability and Accountability Act authorization prior
(as of April 2003) to any study-related procedure. Data from last
visit on study drug at any point during the study (Final Visit)
(Day 28) in the preceding double-blind study were considered Day
1 data for the extension study [5]. Baseline sUA was defined as the
value obtained 2 days prior to the start of the 28-day double-blind
study period. The uric acid production status of each subject,
roughly defined as overproducer (>800 mg/day) or underexcreter
(4800 mg/day), was determined at the time of the initiation of the
28-day Phase 2 study by measurement of 24-h urinary uric acid
excretion.
Inclusion criteria included enrolment and completion of the
28-day Phase 2 study [5]. Subjects with mild or moderate
renal impairment, defined for this study as serum creatinine of
>1.5 mg/dl or creatinine clearance of >50 to 80 ml/min were
included in this extension study. All female subjects had to be
 Long-term safety and efficacy of febuxostat 189

surgically sterile, using acceptable means of contraception or post-
menopausal to be eligible. Females who were nursing or pregnant
were not enrolled. Additional inclusion and exclusion criteria
were as previously described [5]; subjects consuming more than
14 alcoholic drinks/week were excluded. There was no restriction
on purine intake.
Of 145 subjects completing the 28-day Phase 2 trial, 116
enrolled in the extension study. Each subject initially received
febuxostat 80 mg daily for 4 weeks. In the period between Weeks 4
and 24, the dose of febuxostat could be titrated among doses of
40, 80 or 120 mg daily in order to maintain sUA between 3.0 and
<6.0 mg/dl, to respond to an adverse event (AE), or at the
significance was determined by using P-values rounded to three
decimal places. Efficacy and safety variables were analysed by
final stable dose and/or by dose at observation. Final stable dose
reflects the maintenance dose a subject received after dose changes
were no longer allowed. For analyses by dose at observation,
subjects were summarized by the dose they received at the time of
the observation, and the denominator for a dose included all
subjects exposed to the dose for the time interval summarized.
Subjects whose febuxostat doses were titrated between Weeks 4
and 24, and thus received more than one dose, may be
summarized in more than one dose group.

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discretion of the investigator. Dose adjustments could be made up Results
to three times at study visits between Weeks 4 and 24. By Week 28,
subjects were required to have been receiving a stable dose for at Baseline characteristics and concomitant medication use
least 4 weeks. All subjects were provided with colchicine The majority of subjects were Caucasian (85%; 99/116) and male
prophylaxis (0.6 mg twice daily) for the first 4 weeks of this (91%; 105/116). The mean age of the subjects at entry was 53.3
open-label study. yrs. Tophi were identified at baseline in 22% (26/116) of the
Study visits occurred at Weeks 2 and 4, and then every 4 weeks subjects. Impaired renal function was defined in this study as
through Week 56. Visits during Years 2–5 occurred every 8 weeks, serum creatinine >1.5 mg/dl or creatinine clearance 80 ml/min,
except for the end-of-each-year visit, which was 4 weeks after the and was identified in 59% (68/116) of the subjects. Mean sUA
previous visit (i.e. Week 204 and then Week 208). Assessments at at baseline (determined at the time of enrolment into the initial
each visit included efficacy (sUA) and safety. Safety was 4-week Phase 2 double-blind study) was 9.70 mg/dl, 35% of the
monitored by the assessment of AEs and concomitant medication, subjects (41/116) had baseline sUA 10 mg/dl and 76% (88/116)
laboratory tests, physical examination and vital signs. Investiga-
were hyperuricaemic due to underexcretion of uric acid (Table 1).
tors estimated the severity of reported AEs (mild, moderate or
The mean body weight of the study population was 104.5 kg
severe) and their potential relationship to the study drug (related
(230.4 lbs), and mean BMI was 32.9 kg/m2. The most common
or not related).
comorbid conditions were obesity (BMI >30 kg/m2; 67%; 78/116),
At each visit, gout flares experienced since the prior visit were
hypertension (52%; 60/116), hyperlipidaemia (46%; 53/116) and
recorded. Gout flares were treated at the investigators’ discretion,
cardiovascular disease (23%; 27/116).
both during and after the prophylaxis period. Recommended gout
During the study, 98% (114/116) of the subjects used
flare medications included colchicine, NSAIDS, analgesics (i.e. acet-
medications other than febuxostat and colchicine (for
aminophen) and corticosteroids. Only treated flares were ultimately
recorded as flares. Assessments of baseline index tophi were
TABLE 1. Summary of baseline characteristics of the study populationa
performed at Weeks 52, 104, 156, 208 and 260, and at Final Visit.
All subjects
Study end-points Baseline characteristics N ¼ 116
Efficacy analyses were carried out on all subjects who received at Gender, n (%)
least one dose of febuxostat on or after Day 1 of this open-label Male 105 (91)
extension study. The primary efficacy end-point was the propor- Race, n (%)
tion of subjects that achieved and maintained sUA <6.0 mg/dl. Caucasian 99 (85)
The secondary efficacy end-point was the percent reduction Black 9 (8)
Hispanic 3 (3)
from baseline sUA. Additional efficacy end-points included Asian 2 (2)
the proportion of subjects with sUA <5.0 and <4.0 mg/dl, the Other 3 (3)
proportion of subjects requiring treatment for gout flare and
Age, yrs
the resolution of palpable tophi. Mean (S.D.) 53.3 (12.7)
Range 23–78
Study analyses and evaluations
BMI, kg/m2
Study data were obtained between 21 March 2001 and 29 Mean (S.D.) 32.9 (5.7)
December 2006. All subjects who received at least one dose of Range 23–49
30, n (%) 78 (67)
study drug were included in the efficacy and safety analyses.
Baseline data were obtained prior to treatment in the previous Comorbidity history, n (%)b
study. Hypertension 60 (52)
Hyperlipidaemia 53 (46)
The number and percentage of subjects that achieved the Cardiovascular disease 27 (23)
primary efficacy end-point, sUA <6.0 mg/dl, at Weeks 28, 52, 80,
104, 156, 208 and 260 were summarized. Summary statistics were Tophi, n (%)
Present 26 (22)
also generated at each study visit for secondary efficacy end-points.
Analysis of the primary and secondary efficacy end-points sUA, mg/dl
included stratification by baseline sUA, renal function [normal or Mean (S.D.) 9.7 (1.30)
Range 7.7–16.1
impaired (defined as serum creatinine >1.5 mg/dl or calculated
creatinine clearance 80 ml/min)], uric acid production (under- Uric acid production, n (%)
excretion vs overproduction), age, gender, race, BMI at baseline, Underexcretors 88 (76)
Overproducers 26 (22)
tophi present at baseline and history of kidney stones. Missing 2 (2)
The number and percentage of subjects with treatment-
emergent AEs were summarized by system and proposed relation- Renal function, n (%)
Impairedc 68 (59)
ship to the study drug.
All statistical tests were two-sided at the 0.05 significance level. a b
All baseline characteristics from entry into 28-day study. Comorbidity history as self-reported
Computations were performed prior to rounding, and statistical by subjects at enrolment. cSerum creatinine >1.5 mg/dl or creatinine clearance 80 ml/min.
190 H. R. Schumacher et al.

prophylaxis). The most common concomitant medications used
were anti-inflammatory and analgesic drugs. In addition, anti-
hypertension agents, including diuretics and anti-hyperlipidaemic
drugs, were frequently used as ongoing treatment for the common
comorbid conditions of hypertension and hyperlipidaemia.
Subject disposition
In the majority of subjects (62%; 72/116), no change from the
initial febuxostat dose of 80 mg/day was made. Among 44 subjects
receiving dose adjustment, a single change in dose was made in
32 subjects: a reduction from 80 to 40 mg in 4 subjects, and an
terminated prematurely, 22 (19%) subjects were terminated due
to ‘personal reasons’ (not further characterized) and 13 (11.2%)
subjects withdrew because of an AE. Nine subjects withdrew for
‘other reasons,’ eight because of gout flares and five because of
failure to follow-up. One subject was discontinued for a protocol
violation (enrolment in another clinical trial). Fifty-eight subjects
withdrew during the 5-yr study, with 38 withdrawing in the
first year.
Efficacy
The primary end-point was the proportion of subjects with sUA

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increase from 80 to 120 mg in 28 subjects. Eleven subjects had
two adjustments: from 80 to 40 to 80 mg in three subjects; from
80 to 120 to 40 mg in four subjects; and from 80 to 120 to 80 mg
in four subjects. Multiple dose adjustments were made in one
subject: from 80 to 120 to 80 to 40 to 80 to 120 mg; this was
a deviation from protocol, as the subject exceeded the allotted
number of titrations. Distribution of subjects by final stable dose
and premature discontinuation patterns are provided in Fig. 1.
Fifty-nine of the subjects initially enrolled completed at least
5 yrs (260 weeks) of the trial. Fifty-eight subjects (50%)
<6.0 mg/dl. At Week 260, 93% (54/58) of all subjects who
remained in the study had sUA <6.0 mg/dl. Overall, sUA at Final
Visit was <6.0 mg/dl in 83% of all subjects (95/114; two subjects
did not have qualifying post-baseline sUA). The percent of
subjects in each febuxostat dose group that achieved sUA
<6.0 mg/dl at selected study visits is shown in Table 2.
The secondary efficacy end-point was the percent reduction
from baseline sUA at each study visit. Among all subjects, mean
percent sUA reductions from baseline ranged from 45 to 59%
across all visits. Across doses, the percent reductions in sUA were

Completed 28-day
double-blind study
n = 145

Enrolled in FOCUS trial and received

4 Weeks febuxostat 80 mg daily
n = 116

Final Stable
40 mg daily 80 mg daily 120 mg daily
Dose,
n=8 n = 79 n = 29
Week 24

Premature Discontinuation, n = 58
Year 1: 38 (32.8%)
Year 2: 7 (6.0%)
Year 3: 5 (4.3%)
Year 4: 6 (5.2%)
≥Year 5: 2 (1.7%)

Primary Reason for Discontinuation

Personal Reasons: 22 (19.0%)
Adverse Event: 13 (11.2%)
Other: 9 (7.8%)
Gout Flare: 8 (6.9%)
Lost to Follow-up: 5 (4.3%)
Protocol Violation: 1 (<1%)

Completed 40 mg daily 80 mg daily 120 mg daily

Study n=6 n = 41 n = 11

FIG. 1. Subject disposition.

 Long-term safety and efficacy of febuxostat 191

TABLE 2. Percentage of subjects with sUA <6.0 mg/dl

Visit Febuxostat 40 mg/day, n/N (%) Febuxostat 80 mg/day, n/N (%) Febuxostat 120 mg/day, n/N (%) All subjects n/N (%)
Week 28 5/10 (50) 54/58 (93) 11/17 (65) 70/85 (82)
Week 52 4/7 (57) 47/55 (85) 12/18 (67) 63/80 (79)
Week 80 4/8 (50) 41/50 (82) 8/14 (57) 53/72 (74)
Week 104 5/8 (63) 37/49 (76) 12/13 (92) 54/70 (77)
Week 156 4/6 (67) 38/45 (84) 12/13 (92) 54/64 (84)
Week 208 5/6 (83) 36/39 (92) 11/13 (85) 52/58 (90)
Week 260 6/6 (100) 38/41 (93) 10/11 (91) 54/58 (93)
Final Visita 8/8 (100) 65/79 (82) 22/27 (81) 95/114 (83)

a
Two subjects did not have a qualifying post-baseline sUA. sUA levels are summarized under the febuxostat dose taken at time of visit.

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similar at Final Visit, with percent reductions from baseline of 30

49.2, 47.1 and 50.7% for febuxostat doses of 40, 80 and 120 mg,
25
respectively.
Across visits, the proportions of all subjects achieving sUA

Percentage of subjects
20
<5.0 or <4.0 mg/dl were 47–66 and 11–28%, respectively.
Overall, 47% (55/116) of all subjects reported gout flares that 15

required treatment while on their maintenance dose. The

percentage of subjects that received treatment for gout flares 10

throughout the study, by maintenance dose, was 75% (6/8) of 5

those taking febuxostat 40 mg; 47% (37/79) of those taking
febuxostat 80 mg; and 41% (12/29) of those taking febuxostat 0

120 mg. However, over time, the percentage of subjects that Month 2 4 6 8 10 12 14 1 6 18 20 2 2 24 26 28 30 32 3 4 36 38 40 42 44 46 48 50 52 54 56 58 60

required treatment for gout flares declined to zero during the fifth n 27 27 1 9 14 7 12 4 4 5 5 2 4 3 2 3 1 1 1 2 3 1 2 1 3 1 0 1 0 0 0

year of treatment (Fig. 2). N 116 96 89 88 84 83 76 72 71 69 6 9 69 68 66 65 65 6 4 62 61 6 0 59 56 55 55 55 55 55 55 54 54

The incidence (at 6-month intervals) of gout flares in subjects FIG. 2. Percentage of subjects that required treatment for flares while they received
with and without tophi differed. After 12 months of treatment maintenance dose. Time is with respect to duration of treatment with stable
on the maintenance dose, <10% of the subjects without baseline maintenance dose. Months are the end of time intervals and data points represent
tophi reported gout flares compared with as high as 31% of the total incidence of gout flares that required treatment during each 2-month
interval. ‘N’ represents the total number of subjects on a final stable dose of
the subjects with baseline tophi. Within the latter group, the febuxostat for the duration designated and ‘n’ is the total number of subjects that
percent of subjects that reported flares decreased to <10% after reported at least one gout flare that required treatment in the given time interval.
Month 48.
Among the 26 subjects with a palpable tophus at baseline,
resolution of the index tophi occurred in 18 (69%) subjects by
Final Visit. Resolution of index tophi throughout the duration of
the study is shown in Fig. 3.
When analysed individually by age, gender, BMI at baseline,
baseline uric acid production status, tophi present at baseline, or
history of kidney stones, there were no significant differences in
the urate-lowering efficacy of febuxostat between the levels of the
above factors. In addition, there was no significant relationship
between renal function and the urate-lowering efficacy of
febuxostat in the group of subjects with mild to moderate renal
impairment. Across the visits, the percent of subjects with normal
renal function attaining sUA <6.0 mg/dl was 72–92% compared
with 75–97% for subjects with impaired renal function. However,
a statistically significant difference in urate-lowering efficacy of
febuxostat was observed when Caucasian and non-Caucasian
subjects were compared: 87% of Caucasian subjects achieved sUA
<6.0 mg/dl at Final Visit compared with 65% of non-Caucasian
subjects (P ¼ 0.025).

Safety results
AEs were reported by 91% (106/116) of the subjects during the
study. The most frequently reported AEs (occurred in 10% of
total subjects) by study drug dose at the time of occurrence are
shown in Table 3. The majority of AEs were mild or moderate in
severity. In general, there were no increases in the incidence of
AEs over time. AEs were analysed by the dose at the time of the
event; as such, subjects that switched doses could be included in
more than one treatment group. Due to imbalance of treatment
exposure, AEs by dose were summarized by patient-year (PY) of
exposure. There were 349 AEs per 100 PYs overall, with 273.5,
384.7 and 258.7 events per 100 PYs among subjects who received
febuxostat 40, 80 and 120 mg, respectively.
FIG. 3. Persistence of baseline index tophi. ‘N ’ represents the number of subjects
with index tophi at baseline and remaining in the study at specified visits, and ‘n’ is
the number of subjects with index tophi present at specified visit. Data were missing
from one subject at Week 52 and from two subjects at Week 260.
Serious AEs were reported by 18% (21/116) of the subjects; the
majority resulted in hospitalization. Five subjects experienced
atrial fibrillation while on febuxostat 80 mg/day; atrial fibrillation
was the most frequently reported serious AE. The investigators did
not ascribe any of the serious AEs to the study drug. No myocardial
infarctions occurred during the study. Alternate aetiologies for
atrial fibrillation, as proposed by the investigators based on
192 H. R. Schumacher et al.

TABLE 3. Adverse events recommended treatment goal in the management of hyperuric-

aemia in subjects with gout [7, 9, 20]. Maintenance of sUA in this
All subjects range has resulted in clinical benefits of tophus resolution and
N ¼ 116, n (%)
decreased gout flare incidence over the long term [3, 6–8, 21, 22].
Most frequently reported (10%) AEsa The ability of febuxostat to lower and maintain sUA <6.0 mg/dl
Total subjects with at least 1 AE 106 (91) for up to 5 yrs has been demonstrated in this study, which
Upper respiratory tract infections 61 (53)
Musculoskeletal and connective tissue signs and 42 (36) represents the longest febuxostat study to date and one of the few
symptoms long-term studies reported for any urate-lowering therapy [8, 23].
Joint-related signs and symptoms 33 (28) Continued treatment with febuxostat resulted in a decline in
Diarrhoea 24 (21) the incidence of gout flares that required treatment (Fig. 2). After
Influenza 20 (17)
Limb injuries 20 (17) 5 yrs of urate-lowering therapy with febuxostat, the number of
Headache 18 (16) subjects that remained in the study that experienced gout flares

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Paresthesias and dysesthesias
Lower respiratory tract and lung infections
Liver function analyses
Vascular hypertensive disorders
Gastrointestinal and abdominal pains
Rashes, eruptions and exanthems
Skin injuries
Osteoarthropathies
Oedema
Pain and discomfort
Non-site-specific injuries
Tendon disorders
Serious AEsb
Total subjects with at least 1 serious AE
Cardiac disorders (atrioventricular block; atrial
fibrillation)
Gastrointestinal disorders (small intestinal obstruction;
diverticular perforation; appendicitis perforated)
General disorders and administration site conditions
(non-cardiac chest pain)
Hepatobiliary disorders (cholecystitis)
Infections and infestations (diverticulitis; pneumonia;
urosepsis)
Injury, poisoning and procedural complications
(concussion; traumatic fracture; excoriation;
radiation injury)
Musculoskeletal and connective tissue disorders
(intervertebral disc degeneration; rotator cuff
syndrome; OA; osteoporotic fracture; lumbar
spinal stenosis)
Neoplasms benign, malignant and unspecified
(malignant tongue neoplasm; prostate cancer;
benign lung neoplasm; basal cell carcinoma)
Nervous system disorders (Alzheimer;
cerebrovascular accident)
Psychiatric disorders (depression)
Renal and urinary disorders (urinary retention)
a
Classified by MedDRA high-level terms. bClassified by system organ class (preferred term).
medical histories, included concomitant medication use, dehydra-
tion, cellulitis and possible acute coronary syndrome and cardio-
vascular disease. A complete list of serious AEs is included in
Table 3.
Thirteen subjects reported an AE as a primary reason for
premature discontinuation. The most common AEs that led to
withdrawal from the study were abnormal liver function tests
(LFTs; n ¼ 3), cancers (n ¼ 3) and increased serum creatinine
(n ¼ 2). Of these AEs, all three instances of abnormal LFTs and one
instance of increased serum creatinine were considered related to
the study drug treatment. These resolved within 10–106 days. All
subjects with abnormal LFTs had elevated values at baseline prior
to exposure to febuxostat, and two subjects reported regular use of
alcohol (10 drinks per week). Additional AEs that led to dis-
continuation include increased frequency of bowel movements,
non-cardiac chest pain, renal impairment, spondylitic myelopathy
and Alzheimer’s-related dementia (each n ¼ 1). No deaths occurred
during the study.
Discussion
Reduction to and maintenance of sUA <6.0 mg/dl (<360
m/l), a
range below the limit of solubility of urate in serum, is a widely
16 (14) declined to zero. Long-term maintenance of sUA <6.0 mg/dl also
15 (13) resulted in the resolution of baseline tophi in the majority of
15 (13)
15 (13) subjects. Similar results in tophus reduction have been reported
14 (12) elsewhere [8].
14 (12) Acute gout flares frequently occurred during the first few
13 (11) months of urate-lowering treatment, and prophylactic treatment
13 (11)
12 (10) with colchicine or NSAIDs was recommended when urate-
12 (10) lowering therapy was initiated [20, 24]. The observed increase in
12 (10) gout flares after prophylaxis withdrawal was followed by a step-
12 (10) wise decrease in the percentage of subjects that reported flares,
presumably related to continued reduction of body urate pools. In
21 (18) previously reported Phase 3 trials [18, 19], prophylaxis for gout
6 (5) flares was provided for the first 8 weeks, while subjects in this
3 (3) study received colchicine for 4 weeks. The shorter duration of
prophylaxis may have contributed to a higher incidence of gout
1 (<1) flares during the first 6 months than might have been observed if
prophylaxis had been extended.
2 (2)
4 (3) The success of urate-lowering therapy depends on long-term
adherence to medication in order to achieve and maintain an
3 (3) optimal sUA. In several studies, adherence to allopurinol has been
poor [22, 25, 26], resulting in failure to achieve sUAs <6.0 mg/dl
5 (4) and failure to reduce rates of gout flare. Furthermore, additional
studies suggest that many subjects receive sub-optimal manage-
ment with urate-lowering therapy for gout/hyperuricaemia
[27–29].
4 (3)
Significantly higher febuxostat efficacy was observed in
Caucasian subjects compared with non-Caucasian subjects.
2 (2) However, the total number of non-Caucasian subjects was small
(n ¼ 17), which indicates the need for further investigation
1 (<1)
1 (<1) involving greater numbers of minority subjects. It is especially
important to determine the efficacy of febuxostat in these
populations, as black men may be more likely to have gout than
Caucasian men [30]. In addition, higher rates of hyperuricaemia
and gout in other non-Caucasian populations, often in particular
geographic regions, such as the Maoris of New Zealand, are well
known [31].
No significant difference in the urate-lowering efficacy of
febuxostat was observed between subjects with normal and
impaired renal function. Mild to moderate renal impairment has
little impact on the pharmacodynamics and pharmacokinetics of
febuxostat [32–34], and the safety of this drug in these
circumstances has been satisfactory to date. Further studies are
needed to assess safety in such subjects over longer periods of time
and to assess safety in individuals with more advanced kidney
disease.
The majority of AEs were reported as mild to moderate in
severity. Thirteen subjects prematurely discontinued due to an
AE. No hypersensitivity reactions were observed. Investigators
considered all serious AEs unrelated to the study drug. However,
this assessment was subjective and no placebo or active
comparator, as used in previous studies [18, 19], was included in
this study to truly determine if an AE was or was not likely to be
related to the study drug.
Some limitations need to be considered when interpreting the
results of this study. Fifty percent of subjects prematurely
discontinued, possibly skewing the results towards a greater
reduction in gout flares. The reduction in the number of patients
 Long-term safety and efficacy of febuxostat
may negatively impact the power of the subanalyses, and
additional studies with greater numbers of subjects are needed
to verify the trends described. This discontinuation rate may
reflect clinical reality. The retention rate reported here is far higher
than the rate observed in a retrospective analysis of almost 6000
subjects with gout in a managed care cohort. This retrospective
analysis found that among those prescribed allopurinol for urate-
lowering therapy, the mean duration of continuous treatment was
8.5 months (11 months) and 87.1% discontinued treatment
during the 5 yrs for which data were available [26]. The relatively
high level of adherence in this study might have been influenced by
frequent follow-up and monitoring over the course of the trial.
Another potential limitation was the assessment of flares and
tophi. Flares are an important outcome in this study, but a method
to validate flares is still needed. Here, assessment of flares relied on
self-reports and confirmation by documentation of treatment.
Studies addressing gout outcome measures and validation are
currently underway [35]. Assessment of tophi resolution was
subjective and determined by individual investigators. An easy,
reproducible method for measuring tophi has been reported [36],
and future investigators may want to consider employing this
technique when following tophi regression or growth.
Patients were often on treatments for comorbidities. While
some anti-hypertensive and anti-hyperlipidaemia agents are
known to affect sUA [9], the use of these medications during the
study should not have introduced any systematic error.
As subjects were not randomized to dose groups and dose
titration was allowed, meaningful comparisons between dose
groups is not possible. In addition, while clinical benefit from
long-term febuxostat therapy is clearly demonstrated, there is no
control or comparator group to establish how therapy with
febuxostat compares with currently employed urate-lowering
regimens with regard to clinical outcomes. Shorter duration (up
to 1 yr) trials have demonstrated that febuxostat is significantly
better than allopurinol (300 mg) in lowering sUA [18, 19], but
longer term studies comparing various doses of febuxostat and
allopurinol are needed to establish the relative urate lowering and
clinical benefits of these agents.
The findings of this long-term study in subjects with gout
indicate that treatment with febuxostat for up to 5 yrs results in a
sustained reduction in sUA. Subjects that maintain an sUA
<6.0 mg/dl have infrequent gout flares and reduction in the
presence of tophi.
Rheumatology key messages
 Long-term treatment with febuxostat resulted in durable main-
tenance of sUA <6.0 mg/dl for most subjects.
 There was nearly complete abolition of gout flares.
 Baseline tophi resolved in a majority of subjects.
Acknowledgements
The authors would like to thank the principal investigators at the
clinical sites of the FOCUS trial, as well as Nancy Joseph-Ridge,
Takeda Global Research & Development Center, and Meryl
Gersh, AlphaBioCom LLC, for assisting with drafting and
reviewing the manuscript.
Funding: This study was funded by Takeda Global Research &
Development Center, Inc. (TAP Pharmaceutical Products is now a
part of Takeda Global Research & Development Center), and is
registered as NCT00174949.
Disclosure statement: C.L. is a former employee of Takeda Global
Research & Development, E.L. and P.A.M. are employees of
Takeda Global Research and Development Center, H.R.S. and
M.A.B. are consultants for Takeda Global Research &
Development Center.
193
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