International Journal of Rheumatic Diseases 2015; 18: 669–678
ORIGINAL ARTICLE
A phase 3, multicenter, randomized, allopurinol-controlled study assessing the safety and efficacy of oral febuxostat in Chinese gout patients with hyperuricemia Shaoyong XU,1 Xiangyang LIU,1 Jie MING,1 Shenren CHEN,2 Yangang WANG,3 Xiumei LIU,4 Hong LIU,5 Yongde PENG,6 Jianqin WANG,7 Jinying LIN,8 Haiwang JI,9 Bin LIU,10 Ying LU,11 Peng LIU,12 Yonghong ZHANG13 and Qiuhe JI1 1 Department of Endocrinology, Xijing Hospital, Fourth Military Medical University, Xi’an, 2Department of Endocrinology, the Second Affiliated Hospital of Shantou University Medical College, Shantou, 3Department of Endocrinology, the Affiliated Hospital of Qingdao University, Qingdao, 4Department of Rheumatology, the First Hospital of Shanxi Medical University, Taiyuan, 5 Department of Endocrinology, the First Affiliated Hospital of Guangxi Medical University, Nanning, 6Department of Endocrinology, Shanghai General Hospital, Shanghai, 7Department of Nephrology, Lanzhou University Second Hospital, Lanzhou, 8Department of Hematology, the People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, 9Department of Traditional Chinese Medicine and Rheumatology, Shaanxi Provincial People’s Hospital, Xi’an, 10Department of Hand and Foot Surgery, the First Hospital of Jilin University, Jilin, 11Department of Nephrology, Zhejiang Provincial Tongde Hospital, Hangzhou, 12Department of Endocrinology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, and 13Department of Rheumatology, Luoyang Orthopedic-Traumatological Hospital, Luoyang, China
Abstract Aim: To compare the efficiency and safety of febuxostat with those of allopurinol in Chinese patients with gout and hyperuricemia. Methods: The trial which was conducted at 13 centers in China during 2011–2013 included a 2-week run-in and a 24-week treatment period. A total of 504 eligible participants with gout and with serum urate ≥ 480 lmol/L were randomly assigned 1 : 1 : 1 to febuxostat 40 mg/day, febuxostat 80 mg/day and allopurinol 300 mg/day groups. The primary efficacy endpoint was the percentage of subjects whose last three serum urate levels were < 360 lmol/L. Results: The primary efficacy endpoint was reached by 33.5% of subjects taking febuxostat 80 mg/day, 22.5% of those taking febuxostat 40 mg/day and 17.0% of those taking allopurinol 300 mg/day (P < 0.001 for the comparison between febuxostat 80 mg/day and allopurinol 300 mg/day groups; P = 0.216 for the comparison between febuxostat 40 mg/day and allopurinol 300 mg/day groups). The incidence of gout flare was relatively high in each group during the first 8 weeks and gradually decreased thereafter. There was no statistically significant difference between the three groups (P > 0.05). The incidence of adverse events was similar in the three treatment groups. The most frequent treatment-related adverse events were liver function test abnormalities. Conclusions: Febuxostat 80 mg/day had superior urate-lowering efficacy to that of febuxostat 40 mg/day or allopurinol 300 mg/day, which was comparable in Chinese gout patients with hyperuricemia. Febuxostat, at a daily dose of 40 or 80 mg, was safe and well tolerated. Key words: allopurinol, febuxostat, gout, hyperuricemia.
Correspondence: Professor Qiuhe Ji, Department of Endocrinology, Xijing Hospital, Fourth Military Medical University, 169 Changle Road West, 710032 Xi’an, China. Email: [email protected]
© 2015 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
S. Xu et al.
BACKGROUND
METHODS
Gout as an increasingly common disorder is characterized by hyperuricemia, episodic gout flares, deforming gouty arthropathy, tophi and urolithiasis.1,2 The primary management of gout requires long-term uratelowering therapy with aim at maintaining serum urate concentration (sUA) below 360 lmol/L (6.0 mg/dL), which results in eventual cessation and even reversal of urate crystal deposition and clinical signs and symptoms.3,4 Previous studies have suggested that urate-lowering therapy leads to the elimination of gout flares and reduction in the size and number of tophi present.5,6 The most commonly employed approaches to uratelowering therapy involve reducing urate production with a xanthine oxidase (XO) inhibitor and enhancing urinary excretion of uric acid with a uricosuric agent. The most widely used XO inhibitor is allopurinol (available since 1965),7 which is recommended by the US Food and Drug Administration (FDA) and the European League Against Rheumatism with a maximum dosage of 800 mg/day and commonly administered at 300 mg/day in clinical practice. Febuxostat, the orally administered nonpurine selective inhibitor of XO,8,9 is a newly adopted urate-lowering agent and has been available for many years for the management of hyperuricemia in patients with gout.10 Published data from randomized controlled trials have demonstrated the superior urate-lowering efficacy of febuxostat at 80 mg daily compared with commonly prescribed doses of allopurinol (300 mg daily) or with placebo.11–16 In contrast to allopurinol, febuxostat inhibits both reduced and oxidized forms of XO and has little effect on other purine- and pyrimidine-metabolizing enzymes.9,14,17 In addition, febuxostat is effective and well tolerated even in patients with mild to moderate renal and hepatic impairment, because it is metabolized mainly in the liver and has its dual (urinary and fecal) pathways to excretion.18 However, although febuxostat was first approved in Japan in 2004 and then by the European League Against Rheumatism in 2008 and by the FDA in 2009,19 and although it has been administered in clinics for many years worldwide, there was no randomized controlled trials in China until 2011, at which time we designed and commenced the present allopurinol-controlled, multicenter, randomized, double-blinded and paralleled study. Here we report the results of the study which aimed to compare the efficiency and safety of febuxostat with those of allopurinol in Chinese patients with gout and hyperuricemia.
The study was a phase 3, multicenter, randomized, double-blinded, triple-dummy, allopurinol-controlled, parallel trial which was conducted at 13 centers in China between July 2011 and October 2013. The study was approved by the Ethics Committee of Xijing Hospital, Fourth Military Medical University and all subjects provided written informed consent prior to any studyrelated procedure.
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Patient population Eligible participants were of either sex and 18–70 years of age, inclusive, with gout (defined by the American Rheumatism Association [ARA] criteria20), hyperuricemia (defined for the study as a serum urate level ≥ 480 lmol/L), normal renal function (serum creatinine concentration ≤ 135 lmol/L [1.5 mg/dL]), and free of gout flare 2 weeks beforehand and during the 2-week run-in period. The exclusion criteria included: pregnancy or lactation; concurrent therapy with azathioprine, 6-mercaptopurine, thiazide diuretics, or medications containing aspirin (> 325 mg) or other salicylates; a history of active liver disease, or hepatic dysfunction (alanine aminotransferase and aspartate aminotransferase values > 1.5 times the upper limit of normal); a history of bronchial asthma; a history of renal calculi or thyroid disease; secondary gout joint diseases induced by rheumatoid arthritis, psoriatic arthritis and bone tumor; intolerance to allopurinol and ibuprofen; alcohol intake of ≥ 14 drinks/week; and clinically significant medical conditions.
Randomization, blinding and allocation The randomization code which was stratified according to centers with a 1 : 1 : 1 allocation was created by the study biostatistician using SAS 9.1.3 software (SAS Institute Inc., Cary, NC, USA). The research pharmacist who was not associated with the study received the randomization list, dispensed the study medications in packs provided by the manufacturer, and then enclosed the medications in numbered boxes according to the randomization list. The investigators in each center administered study medications to the eligible patients in sequence. All parties involved in the present study (investigators, patients and biostatistician) were blinded to the allocation of the study medications.
Study design Febuxostat tablets (80 or 40 mg) were used as investigational drugs and allopurinol (100 mg) as control drug;
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placebo tablets for each drug were also used. Febuxostat, allopurinol and the placebo tablets were provided by Qingdao Shengbang Pharmaceutical Corporation Limited, Shandong, China. After a 2-week run-in period for those receiving previous urate-lowering therapy, registered patients were randomly assigned in a 1 : 1 : 1 ratio to febuxostat 80 mg/day, febuxostat 40 mg/day and allopurinol 300 mg/day groups. All the study medications were administered at fixed doses for up to 24 weeks. In the screening period, the evaluations included physical examination, vital signs, medical history, laboratory tests, electrocardiogram, assessment for tophi and gout flare, and concomitant medication use. In the treatment period, serum urate level was repeatedly measured by using the uricase oxidase method at monthly visits; physical examination, vital signs, gout flares, concomitant medication use and adverse events were assessed and recorded at monthly visits; and blood biochemical examination, urinalysis and electrocardiogram were performed at bimonthly visits. All the laboratory testing and all urinalyses were provided by a local laboratory in the same standardized method. Throughout the 24-week treatment period, subjects received prophylaxis for gout flares with ibuprofen (Xinhua Pharmaceutical Corporation Limited, Shandong, China), 0.2 g twice daily. If subjects suffered from gout flare, they were permitted to temporarily increase the dose of ibuprofen or change to another medication (e.g., colchicine or celecoxib) for treatment. The gout flare was considered as expected gout manifestations rather than as adverse events.
Efficacy endpoints The primary efficacy endpoint was the percentage of subjects whose last three serum urate levels were < 360 lmol/L. The secondary endpoints were the percentage of subjects whose serum urate levels at the final visit were < 360 lmol/L and the absolute change in the serum urate level at the final visit relative to baseline.
Determination of sample size The sample size was estimated using PASS software, version 11 (NCSS, LLC, East Kaysville, UT, USA). This sample size is considered practical and determined according to the duration and cost issues. Since uratelowering efficacy of febuxostat 80 mg exceeds that of febuxostat 40 mg, febuxostat 80 mg rather than 40 mg was preferred to determine the sample size to guarantee superior urate-lowering efficacy of febuxostat relative to allopurinol. According to the previous studies, the
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proportion of subjects with their last three serum urate levels < 360 lmol/L in the febuxostat 80 group was 48% (126/262)14 and 53% (136/255),11 respectively, the mean of which was 50%. It was 22% (60/268),14 21% (53/251)11 and 42% (318/756)21, respectively, in the allopurinol 300 mg group, the mean of which was 29%. Therefore, with a two-sided 0.025 alpha level and an anticipated drop-out rate of 20%, a sample size of 170 per treatment group was required to achieve a 90% power to meet the superiority criteria between febuxostat 80 mg and the allopurinol group for the primary efficacy variable. The size was also necessary to an 80% power to meet the non-inferiority criteria between 40 mg and the allopurinol group for the primary efficacy endpoint, with a two-sided 0.05 alpha level and a dropout rate of 10%.
Statistical analysis The primary analysis was based on the full analysis set and included all randomized patients who took at least one randomized investigational product dose, and had at least one non-missing baseline and one post-baseline efficacy data assessment, according to the intentionto-treat basis. All supportive analyses were based on per protocol set analysis sets and the safety endpoints were analyzed on safety analysis sets. No interim analysis was involved in the research. All data were entered into SAS 9.1.3 software (SAS Institute). Analyses by actual therapy included only those patients who were continuing to take their allocated therapy. Data were presented as mean and standard deviation (SD), range or percentage. Data were examined for skewness, outliers and systematic missing data. Univariate and multivariate tests for repeated measures analysis of variance (ANOVA) were used to evaluate differences within and between groups over time. Mann–Whitney U-test was used to evaluate differences between groups, whereas Friedman’s test (variance analysis) followed by Wilcoxon paired test was used to evaluate differences within groups. P < 0.05 was considered as significantly different in statistics. For numerical data with more than one post-baseline visits (e.g., serum urate level, blood pressure, body mass index), mixed model for repeated measures (MMRM) was utilized for analysis and a last observation carried forward (LOCF) analysis was presented as sensitivity analysis unless otherwise specified. The safety endpoints were analyzed on safety analysis sets. Adverse events were summarized. The incidence of adverse events was summarized by body system organ class and preferred term. Analyses for safety and tolerability endpoints were
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summarized using descriptive statistics for continuous variables or frequency counts and percentages for categorical variables.
RESULTS
group, 22.8% (36/158) in febuxostat 40 mg/day group and 14.8% (22/149) in allopurinol 300 mg/day group. There was a statistically significant difference across groups (P < 0.001). Subgroup analysis in female subjects was not conducted due to a small sample.
Patient disposition
Secondary efficacy endpoint
Of 762 subjects screened, 504 were randomly 1 : 1 : 1 assigned to febuxostat 80 mg/day, febuxostat 40 mg/day or allopurinol 300 mg/day groups, with 168 in each group. The number of subjects who completed the study was 141 for febuxostat 80 mg/day group, 144 for febuxostat 40 mg/day group and 132 for allopurinol 300 mg/day group (Fig. 1). The percentage of subjects having good compliance (assessed based on returned tablet counts) was 95.2%, 97.6% and 97.6% in febuxostat 80 mg/day group, febuxostat 40 mg/day group and allopurinol 300 mg/day group, separately (P = 0.356 across groups). The primary analysis was based on full analysis sets, which included 158 subjects in febuxostat 80 mg/day group, 160 subjects in febuxostat 40 mg/day group and 159 subjects in allopurinol 300 mg/day group. The details of analysis sets can be seen in Figure 1.
The proportion of subjects with serum urate < 360 lmol/L at the last visit in febuxostat 80 mg/day group was higher than that in febuxostat 40 mg/day group (58.9% vs. 45.0%, P = 0.014) and that in allopurinol 300 mg/day group (58.9% vs. 34.6%, P < 0.001). There was no significant difference between febuxostat 40 mg/day group and allopurinol 300 mg/day group (45.0% vs. 34.6%, P = 0.059) (Table 2). The reduction in serum urate level by the last visit relative to baseline was 216.0 137.2 lmol/L, 182.2 115.6 lmol/L and 170.4 132.6 lmol/L for febuxostat 80 mg/day group, febuxostat 40 mg/day group and allopurinol 300 mg/day group, respectively. Significant difference was found between febuxostat 80 mg/day group and allopurinol 300 mg/day group (P = 0.011) and no significant difference was found between febuxostat 40 mg/day group and allopurinol 300 mg/day group (P = 0.087) (Table 2). Serum urate level in each group was observed as decreased at week 4 (the first visit after randomization) and maintained in the subsequent study period. Greater urate-lowering efficacy was found in febuxostat 80 mg/day group than in the febuxostat 40 mg/day group and allopurinol 300 mg/day group (both P < 0.025 at each visit). The urate-lowering efficacy of febuxostat 40 mg/day was non-inferior to that of allopurinol 300 mg/day (P > 0.05 in each visit) (Fig. 2a).
Patient characteristics There were no significant differences across treatment groups in demographic, gout-related or comorbid characteristics of the subjects, except sex in full analysis set. There were more male subjects in febuxostat 40 mg/day group (98.8%) than in febuxostat 80 mg/day group (92.4%) and in allopurinol 300 mg/day group (93.7%) (P = 0.024) (Table 1). Sex-stratified subgroup analysis was therefore conducted as sensitivity analysis.
EFFICACY Primary efficacy endpoint The primary efficacy endpoint, or the proportion of subjects with serum urate level < 360 lmol/L in the last three visits, was reached by 33.5% (53/158) of subjects taking 80 mg/day of febuxostat, 22.5% (36/160) of those taking 40 mg/day of febuxostat, and 17.0% (27/ 159) of those taking 300 mg/day of allopurinol. Significant difference was discovered between febuxostat 80 mg/day group and allopurinol 300 mg/day group (P < 0.001) and no significant difference was discovered between febuxostat 40 mg/day group and allopurinol 300 mg/day group (P = 0.216) (Table 2). For male subjects, the primary efficacy endpoint was reached by 33.6% (49/146) in febuxostat 80 mg/day
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Gout flares The incidence of gout flare was relative high in each group during the first 8 weeks and then gradually decreased thereafter until the end of the study. There was no statistically significant difference in the incidence of gout flare between the three groups in all visit periods (all P > 0.05) (Fig. 2b).
Adverse events The incidence of adverse events was similar in the three treatment groups. The most frequent treatment-related adverse events were liver function test abnormalities, renal function test abnormalities and gastrointestinal disorders. Most adverse events were mild to moderate in severity. Adverse events related to liver function test abnormalities were reported for a total of 57 subjects:
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Figure 1 Flow of the subjects through the study. sUA, serum urate acid.
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Table 1 Baseline characteristics of subjects (full analysis set) Variable
Febuxostat 80 mg/day
Febuxostat 40 mg/day
Allopurinol 300 mg/day
N Demographic characteristics Age, years Sex (male), n (%) Height, cm Body mass, kg Body mass index, kg/m2 Systolic blood pressure, mmHg Diastolic blood pressure, mmHg Gout-related characteristics Baseline serum urate level, lmol/L Time with gout disease, years History or presence of tophi, n (%) Previous urate-lowering therapy, n (%) Drug allergy, n (%) Coexisting conditions, n (%) Hypertension Diabetes Hyperlipidemia Cardiovascular disease
158
160
159
P-value
48.2 12.0 146 (92.4) 170.7 5.7 73.3 9.6 25.1 2.6 126.4 11.0 77.6 8.1
45.5 11.9 158 (98.8) 171.4 4.7 74.0 8.6 25.3 2.7 126.2 10.0 79.1 8.2
46.6 10.7 149 (93.7) 170.2 6.0 73.6 11.3 25.4 3.3 124.9 10.1 78.7 7.9
0.114 0.024 0.124 0.849 0.681 0.356 0.217
565.1 75.5 3.0 (1.2–5.1) 26 (16.5) 79 (50.0) 7 (4.4)
560.8 73.3 2.7 (1.0–5.8) 24 (15.0) 87 (54.4) 8 (5.0)
574.2 77.8 3.0 (2.0–6.9) 26 (16.4) 83 (52.2) 7 (4.4)
0.269 0.966 0.924 0.737 0.960
32 (20.3) 5 (3.2) 13 (8.2) 2 (1.3)
20 (12.5) 10 (6.3) 15 (9.4) 4 (2.5)
22 (13.8) 9 (5.7) 11 (6.9) 4 (2.5)
0.086 0.124 0.442 0.514
Table 2 Primary and secondary endpoints (full analysis set) Endpoints
Febuxostat 80 mg/day
Febuxostat 40 mg/day
N 158 Primary efficacy endpoint Serum urate level < 360 lmol/L at the last 3 visits No./total no. (%) 53/158 (33.5) P-value† < 0.001 Secondary efficacy endpoint Serum urate level < 360 lmol/L at the last visit No./total no. (%) 93/158 (58.9) P-value† 0.014 Change in the serum urate level at the final visit relative to baseline Mean SD 216.0 137.2 P-value† 0.011
160
Allopurinol 300 mg/day 159
36/160 (22.5) 0.216
27/159 (17.0)
72/160 (45.0) < 0.001
55/159 (34.6)
182.2 115.6 0.087
170.4 132.6
†Versus allopurinol 300 mg/day. SD, standard deviation.
22 (13.1%) receiving febuxostat 80 mg/day, 17 (10.1%) receiving febuxostat 40 mg/day and 18 (10.7%) receiving allopurinol 300 mg/day. Of these subjects, only one patient in febuxostat 80 mg/day group who withdrew from the study at visit 2 stopped the study drugs; 14 patients who encountered liver function test abnormalities at the last visit also stopped the study drugs, and the remaining patients did not
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change their study drugs. Most adverse events related to abnormal findings on liver function tests happened at visit 2 and visit 4-6, and resolved within 3 months. Serious adverse events occurred in only one subject receiving febuxostat 80 mg/day. The subject was diagnosed as having hydronephrosis after a 14-day period of febuxostat administration and thus was hospitalized. Actually, the subject had a kidney stone history which
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(a)
Table 3 Summary of adverse events (safety set) Variable
(b)
Figure 2 Serum urate levels at each visit (a) and incidence of gout flare in each visit period (b).
was not reported to the investigator in the screening period. Therefore, the serious adverse event was classified as due to protocol violation and judged by the investigator as unrelated to the study drug. In addition, no death happened during the study period in any group (Table 3).
Sensitivity analysis The efficacy endpoints were analyzed in per protocol set as supportive analyses and the results were all in accord with those from the full analysis set. For example, the proportion of subjects who reached the primary efficacy endpoint in febuxostat 80 mg/day group was 32.6% (46/141), which was higher than 19.7% (26/132) in allopurinol 300 mg/day group (P = 0.015). The result was similar with that from the full analysis set. Likewise, analysis from the per protocol set showed that there was no significant difference in the proportion of subjects reaching the primary efficacy endpoint between febuxostat 40 mg/day group and allopurinol
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Febuxostat 80 mg/day
Febuxostat 40 mg/day
N 168 168 Any adverse events 61 (36.3) 63 (37.5) Any treat-related 46 (27.4) 45 (26.8) adverse events Most frequent treat-related adverse events Liver function test 22 (13.1) 17 (10.1) abnormalities Renal function 7 (4.2) 2 (1.2) test abnormalities Abnormal 0 (0.0) 4 (2.4) electrocardiograph Abnormal 4 (2.4) 4 (2.4) urine protein Abnormal 1 (0.6) 2 (1.2) urine glucose Skin rashes 1 (0.6) 3 (1.8) Headaches 1 (0.6) 0 (0.0) Upper respiratory 1 (0.6) 0 (0.0) infection Gastrointestinal 2 (1.2) 3 (1.8) disorders 4 (2.4) 2 (1.2) Musculoskeletal and connective tissue signs and symptoms Others 3 (1.8) 7 (4.2) 3 (1.8) 3 (1.8) Any adverse events leading to discontinuation Any serious 1 (0.6) 0 (0.0) adverse events
Allopurinol 300 mg/day 168 54 (32.1) 41 (24.4)
18 (10.7) 2 (1.2) 1 (0.6) 1 (0.6) 1 (0.6) 5 (3.0) 1 (0.6) 0 (0.0) 4 (2.4) 0 (0.0)
8 (4.8) 3 (1.8)
0 (0.0)
There were no significant differences among the three groups.
300 mg/day group (24.3% [35/144] vs. 19.7% [26/ 132], P = 0.357).
DISCUSSION Few randomized controlled clinical trials to date have been conducted comparing febuxostat and allopurinol in Chinese gout patients with hyperuricemia.22 This 26week study demonstrated that a daily dose of febuxostat 80 mg had higher urate-lowering efficacy than a daily dose of febuxostat 40 mg and allopurinol 300 mg. Urate-lowering efficacy of febuxostat 40 mg daily was non-inferior to that of allopurinol 300 mg daily. In addition, results showed that there was only 58.9% of patients in the febuxostat 80 mg/day group achieving targeted sUA levels below 360 lmol/L at the final visit
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and, more importantly, only 22.3% patients with sUA level below 360 lmol/L at the last three visits in febuxostat 80 mg/day group, suggesting that titration to higher dosage of febuxostat (e.g., 120 mg/day) might be required to achieve and maintain recommended sUA levels below 360 lmol/L in Chinese gout patients with hyperuricemia. As expected, in our present study febuxostat 80 mg/ day was more effective in reducing serum urate in gout patients with hyperuricemia compared with allopurinol of common usage (300 mg/day), which was consistent with previous studies.11,14,21 For example, Becker et al.11 reported that the primary end point of sUA < 360 lmol/L at the last 3 months was reached in 53% of patients receiving 80 mg of febuxostat and 21% of those receiving 300 mg of allopurinol (P < 0.001). In a meta-analysis by Peng Ye et al.,23 the pooled proportion of patients who achieved target sUA at the final visit was significantly greater in the febuxostat-treated group (80 mg/day) compared with the allopurinol-treated group (100–300 mg/day) (71.4% vs. 45.6%; odds ratio = 3.27, 95% confidence interval: 2.14–5.00). In addition, our study showed non-inferiority of uratelowering efficacy between febuxostat 40 mg/day and allopurinol 300 mg/day. Our results were opposite from those from Kamatani et al.24 but similar with most of prior studies,21,22,25 particularly a study from China.22 Thus, despite the fact that Peng Ye et al.23 conducted a meta-analysis and indicated that the pooled percentage of patients who achieved target sUA at the final visit was significantly higher in the febuxostat-treated group (40 mg/day) than that in the allopurinoltreated group (100–300 mg/day) (50.9% vs. 45.6%; odds ratio = 1.25, 95% confidence interval: 1.05–1.49), we speculated with caution that febuxostat 40 mg/day had non-superior urate-lowering efficacy relative to allopurinol 300 mg/day in Chinese gout patients with hyperuricemia. Our study, together with another Chinese clinical trial (by Huang et al.),22 had relatively lower proportions of subjects treated with febuxostat and whose sUA levels were < 360 lmol/L, compared with those in US and Japan. For example, the proportion of subjects treated with febuxostat 80 mg at the 26-week visit was 58.9% in ours and 61.6% in Huang’s study,22 while it was 67.1% in Becker’s11 and 76.0% in Schumacher’s14 studies, respectively. Also, the proportion at the 16-week visit was 57.2% in ours and 64.0% in Huang’s study,22 lower than 87.8% in Naoyuki’s study.26 The metabolism of Chinese populations which differs from that of European people could only partly
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explain the results in our opinion, and generic febuxostat products might contribute to the differences to some extent. In addition, we observed a greater reduction in the sUA level by the last visit relative to baseline for febuxostat 80 mg/day than for 40 mg/day, indicating that febuxostat had dose-dependent uratelowering efficacy. Therefore, considering that almost half of patients treated with a daily dose of febuxostat 80 mg in the present study could not achieve and maintain target sUA levels < 360 lmol/L, titration to higher dosage of febuxostat (e.g., 120 mg/day) for Chinese gout patients was suggested and a further future study accessing efficacy and safety of febuxostat 120 or 160 mg/day was needed. The proportion of subjects requiring treatment for gout flares in our study was relatively high in the first 8 weeks and tended to diminish with continued treatment in all treatment groups, and no statistically significant differences were observed between the treatment groups during the 28-week study period. The results were in accord with previous studies.11,21,22 Consistent with prior studies,11,14,21,22,25 the occurrence of treatment-related adverse events was similar between the three treatment groups, most of which were mild to moderate in severity. No treatment-related events showed any stepwise increase in rates with higher doses of febuxostat. No death and serious treatment-related adverse events were judged related to febuxostat. The most frequent treatment-related adverse event in our study was liver function test abnormalities, which was 13.1%, 9.5% and 10.7% in febuxostat 80 mg/day, febuxostat 40 mg/day and allopurinol 300 mg/day groups, respectively. There is a need to educate patients to monitor liver function during uratelowering therapy. Some limitations should be addressed. First, a limited number of female subjects were included in our study and we thus could not perform a sex-stratified subgroup analysis due to data limitation. Further studies should be conducted for the optimal usage of febuxostat in female gout patients. Second, guidelines recommend to start with a low dose of allopurinol and slowly titrate up during the urate-lowering course.3,27 However, most previous randomized controlled trials except in subjects with renal impairment used a fixed daily dose of allopurinol (300 mg).11,14,21,22 Considering that we only included patients with normal renal function and also ruled out subjects with known allergy to allopurinol to avoid the rare severe adverse event of hypersensitivity, the fixed allopurinol dose of 300 mg/day was also adopted in our study. However, we must acknowledge
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that the comparison dose of 300 mg/day is well below full dose and allopurinol may perform better with dose escalation. The allopurinol dose used in this study is no longer considered optimal in patients who have not achieved the target sUA concentration, and this is a limitation of the study. Third, tophus size was not measured and tophus size reduction was not an endpoint in the current trial. This was mainly because we had a relatively short study period of 6 months and prior randomized controlled trials comparing febuxostat and allopurinol did not establish significant differences between these drugs in the clinical outcome of tophus size reductions during the first 6–12 months of treatment.11,14 Furthermore, accurate measurement of tophi was problematic in the clinical setting. Last, while we followed the ARA criteria to diagnose gout, we actually did not require crystal identification and the study group might not definitely represent actual gout.
CONCLUSIONS The results of the current study demonstrated that febuxostat 80 mg daily had superior urate-lowering efficacy to that of febuxostat 40 mg daily or allopurinol 300 mg daily, which were comparable, in Chinese gout patients with hyperuricemia. Febuxostat, at a daily dose of 40 or 80 mg, was safe and well tolerated. In addition, considering that almost half of patients treated with a daily dose of febuxostat 80 mg in the current study could not achieve and maintain recommended target sUA level < 360 lmol/L, titration to a higher dose of febuxostat (e.g., 120 mg/day) might be required in clinical practice among a Chinese population.
ACKNOWLEDGEMENTS This study was funded by Qingdao Shengbang Pharmaceutical Corporation Limited, Shandong, China (ChiCTR: 2010L04287, 2010L04288).
AUTHORS CONTRIBUTIONS SX, XL and JM contributed equally to the manuscript. QJ was involved in study concept and design. SX XL and JM were involved in the acquisition of data, data analysis and interpretation, and preparation of the manuscript. All authors provided final approval to submit the manuscript. The study sponsors, Qingdao Shengbang Pharmaceutical Corporation Limited and DDLD (Beijing) Pharmaceutical Technology Corporation Limited, were involved in the study design, proto-
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cols, subject recruitment, data collections, and analyses (Trial registration: NCT02082769).
COMPETING INTERESTS The authors declare they have no conflict of interests.
REFERENCES 1 Terkeltaub RA (2003) Clinical practice. Gout. N Engl J Med 349, 1647–55. 2 Hamburger M, Baraf HS, Adamson TC III et al. (2011) 2011 recommendations for the diagnosis and management of gout and hyperuricemia. Phys Sportsmed 39, 98–123. 3 Zhang W, Doherty M, Bardin T et al. (2006) EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 65, 1312–24. 4 Perez-Ruiz F, Liote F (2007) Lowering serum uric acid levels: what is the optimal target for improving clinical outcomes in gout? Arthritis Rheum 57, 1324–8. 5 Perez-Ruiz F, Calabozo M, Pijoan JI, Herrero-Beites AM, Ruibal A (2002) Effect of urate-lowering therapy on the velocity of size reduction of tophi in chronic gout. Arthritis Rheum 47, 356–60. 6 Sarawate CA, Patel PA, Schumacher HR, Yang W, Brewer KK, Bakst AW (2006) Serum urate levels and gout flares: analysis from managed care data. J Clin Rheumatol 12, 61–5. 7 Schlesinger N (2004) Management of acute and chronic gouty arthritis: present state-of-the-art. Drugs 64, 2399– 416. 8 Khosravan R, Grabowski BA, Wu JT, Joseph-Ridge N, Vernillet L (2006) Pharmacokinetics, pharmacodynamics and safety of febuxostat, a non-purine selective inhibitor of xanthine oxidase, in a dose escalation study in healthy subjects. Clin Pharmacokinet 45, 821–41. 9 Takano Y, Hase-Aoki K, Horiuchi H et al. (2005) Selectivity of febuxostat, a novel non-purine inhibitor of xanthine oxidase/xanthine dehydrogenase. Life Sci 76, 1835–47. 10 Love BL, Barrons R, Veverka A, Snider KM (2010) Uratelowering therapy for gout: focus on febuxostat. Pharmacotherapy 30, 594–608. 11 Becker MA, Schumacher HR Jr, Wortmann RL et al. (2005) Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med 353, 2450–61. 12 Faruque LI, Ehteshami-Afshar A, Wiebe N, Tjosvold L, Homik J, Tonelli M (2013) A systematic review and metaanalysis on the safety and efficacy of febuxostat versus allopurinol in chronic gout. Semin Arthritis Rheum 43, 367–75. 13 Jackson RL, Hunt B, MacDonald PA (2012) The efficacy and safety of febuxostat for urate lowering in gout patients >/=65 years of age. BMC Geriatr 12, 11.
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14 Schumacher HR Jr, Becker MA, Wortmann RL et al. (2008) 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. Arthritis Rheum 59, 1540–8. 15 Tayar JH, Lopez-Olivo MA, Suarez-Almazor ME (2012) Febuxostat for treating chronic gout. Cochrane Database Syst Rev (11), CD008653. 16 Wells AF, MacDonald PA, Chefo S, Jackson RL (2012) African American patients with gout: efficacy and safety of febuxostat vs allopurinol. BMC Musculoskelet Disord 13, 15. 17 Grabowski BA, Khosravan R, Vernillet L, Mulford DJ (2011) Metabolism and excretion of [14C] febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase, in healthy male subjects. J Clin Pharmacol 51, 189–201. 18 Garcia-Valladares I, Khan T, Espinoza LR (2011) Efficacy and safety of febuxostat in patients with hyperuricemia and gout. Ther Adv Musculoskelet Dis 3, 245–53. 19 Burns CM, Wortmann RL (2011) Gout therapeutics: new drugs for an old disease. Lancet 377, 165–77. 20 Wallace SL, Robinson H, Masi AT, Decker JL, McCarty DJ, Yu TF (1977) Preliminary criteria for the classification of the acute arthritis of primary gout. Arthritis Rheum 20, 895–900. 21 Becker MA, Schumacher HR, Espinoza LR et al. (2010) The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial. Arthritis Res Ther 12, R63. 22 Huang X, Du H, Gu J et al. (2014) An allopurinol-controlled, multicenter, randomized, double-blind, parallel between-group, comparative study of febuxostat in Chinese patients with gout and hyperuricemia. Int J Rheum Dis 17, 679–86. 23 Ye P, Yang S, Zhang W et al. (2013) Efficacy and tolerability of febuxostat in hyperuricemic patients with or without
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gout: a systematic review and meta-analysis. Clin Ther 35, 180–9. Kamatani N, Fujimori S, Hada T et al. (2011) An allopurinol-controlled, randomized, double-dummy, doubleblind, parallel between-group, comparative study of febuxostat (TMX-67), a non-purine-selective inhibitor of xanthine oxidase, in patients with hyperuricemia including those with gout in Japan: phase 3 clinical study. J Clin Rheumatol 17, S13–8. Naoyuki K, Shin F, Toshikazu H et al. (2011) An allopurinol-controlled, multicenter, randomized, open-label, parallel between-group, comparative study of febuxostat (TMX-67), a non-purine-selective inhibitor of xanthine oxidase, in patients with hyperuricemia including those with gout in Japan: phase 2 exploratory clinical study. J Clin Rheumatol 17, S44–9. Naoyuki K, Shin F, Toshikazu H et al. (2011) Placebo-controlled double-blind dose-response study of the non-purine-selective xanthine oxidase inhibitor febuxostat (TMX67) in patients with hyperuricemia (including gout patients) in japan: late phase 2 clinical study. J Clin Rheumatol 17, S35–43. Khanna D, Fitzgerald JD, Khanna PP et al. (2012) 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken) 64, 1431–46.
Supporting Information Additional Supporting Information may be found in the online version of this article:
Appendix S1 Study group field centers and members.
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ORIGINAL ARTICLE
A phase 3, multicenter, randomized, allopurinol-controlled study assessing the safety and efficacy of oral febuxostat in Chinese gout patients with hyperuricemia Shaoyong XU,1 Xiangyang LIU,1 Jie MING,1 Shenren CHEN,2 Yangang WANG,3 Xiumei LIU,4 Hong LIU,5 Yongde PENG,6 Jianqin WANG,7 Jinying LIN,8 Haiwang JI,9 Bin LIU,10 Ying LU,11 Peng LIU,12 Yonghong ZHANG13 and Qiuhe JI1 1 Department of Endocrinology, Xijing Hospital, Fourth Military Medical University, Xi’an, 2Department of Endocrinology, the Second Affiliated Hospital of Shantou University Medical College, Shantou, 3Department of Endocrinology, the Affiliated Hospital of Qingdao University, Qingdao, 4Department of Rheumatology, the First Hospital of Shanxi Medical University, Taiyuan, 5 Department of Endocrinology, the First Affiliated Hospital of Guangxi Medical University, Nanning, 6Department of Endocrinology, Shanghai General Hospital, Shanghai, 7Department of Nephrology, Lanzhou University Second Hospital, Lanzhou, 8Department of Hematology, the People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, 9Department of Traditional Chinese Medicine and Rheumatology, Shaanxi Provincial People’s Hospital, Xi’an, 10Department of Hand and Foot Surgery, the First Hospital of Jilin University, Jilin, 11Department of Nephrology, Zhejiang Provincial Tongde Hospital, Hangzhou, 12Department of Endocrinology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, and 13Department of Rheumatology, Luoyang Orthopedic-Traumatological Hospital, Luoyang, China
Abstract Aim: To compare the efficiency and safety of febuxostat with those of allopurinol in Chinese patients with gout and hyperuricemia. Methods: The trial which was conducted at 13 centers in China during 2011–2013 included a 2-week run-in and a 24-week treatment period. A total of 504 eligible participants with gout and with serum urate ≥ 480 lmol/L were randomly assigned 1 : 1 : 1 to febuxostat 40 mg/day, febuxostat 80 mg/day and allopurinol 300 mg/day groups. The primary efficacy endpoint was the percentage of subjects whose last three serum urate levels were < 360 lmol/L. Results: The primary efficacy endpoint was reached by 33.5% of subjects taking febuxostat 80 mg/day, 22.5% of those taking febuxostat 40 mg/day and 17.0% of those taking allopurinol 300 mg/day (P < 0.001 for the comparison between febuxostat 80 mg/day and allopurinol 300 mg/day groups; P = 0.216 for the comparison between febuxostat 40 mg/day and allopurinol 300 mg/day groups). The incidence of gout flare was relatively high in each group during the first 8 weeks and gradually decreased thereafter. There was no statistically significant difference between the three groups (P > 0.05). The incidence of adverse events was similar in the three treatment groups. The most frequent treatment-related adverse events were liver function test abnormalities. Conclusions: Febuxostat 80 mg/day had superior urate-lowering efficacy to that of febuxostat 40 mg/day or allopurinol 300 mg/day, which was comparable in Chinese gout patients with hyperuricemia. Febuxostat, at a daily dose of 40 or 80 mg, was safe and well tolerated. Key words: allopurinol, febuxostat, gout, hyperuricemia.
Correspondence: Professor Qiuhe Ji, Department of Endocrinology, Xijing Hospital, Fourth Military Medical University, 169 Changle Road West, 710032 Xi’an, China. Email: [email protected]
© 2015 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
S. Xu et al.
BACKGROUND
METHODS
Gout as an increasingly common disorder is characterized by hyperuricemia, episodic gout flares, deforming gouty arthropathy, tophi and urolithiasis.1,2 The primary management of gout requires long-term uratelowering therapy with aim at maintaining serum urate concentration (sUA) below 360 lmol/L (6.0 mg/dL), which results in eventual cessation and even reversal of urate crystal deposition and clinical signs and symptoms.3,4 Previous studies have suggested that urate-lowering therapy leads to the elimination of gout flares and reduction in the size and number of tophi present.5,6 The most commonly employed approaches to uratelowering therapy involve reducing urate production with a xanthine oxidase (XO) inhibitor and enhancing urinary excretion of uric acid with a uricosuric agent. The most widely used XO inhibitor is allopurinol (available since 1965),7 which is recommended by the US Food and Drug Administration (FDA) and the European League Against Rheumatism with a maximum dosage of 800 mg/day and commonly administered at 300 mg/day in clinical practice. Febuxostat, the orally administered nonpurine selective inhibitor of XO,8,9 is a newly adopted urate-lowering agent and has been available for many years for the management of hyperuricemia in patients with gout.10 Published data from randomized controlled trials have demonstrated the superior urate-lowering efficacy of febuxostat at 80 mg daily compared with commonly prescribed doses of allopurinol (300 mg daily) or with placebo.11–16 In contrast to allopurinol, febuxostat inhibits both reduced and oxidized forms of XO and has little effect on other purine- and pyrimidine-metabolizing enzymes.9,14,17 In addition, febuxostat is effective and well tolerated even in patients with mild to moderate renal and hepatic impairment, because it is metabolized mainly in the liver and has its dual (urinary and fecal) pathways to excretion.18 However, although febuxostat was first approved in Japan in 2004 and then by the European League Against Rheumatism in 2008 and by the FDA in 2009,19 and although it has been administered in clinics for many years worldwide, there was no randomized controlled trials in China until 2011, at which time we designed and commenced the present allopurinol-controlled, multicenter, randomized, double-blinded and paralleled study. Here we report the results of the study which aimed to compare the efficiency and safety of febuxostat with those of allopurinol in Chinese patients with gout and hyperuricemia.
The study was a phase 3, multicenter, randomized, double-blinded, triple-dummy, allopurinol-controlled, parallel trial which was conducted at 13 centers in China between July 2011 and October 2013. The study was approved by the Ethics Committee of Xijing Hospital, Fourth Military Medical University and all subjects provided written informed consent prior to any studyrelated procedure.
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Patient population Eligible participants were of either sex and 18–70 years of age, inclusive, with gout (defined by the American Rheumatism Association [ARA] criteria20), hyperuricemia (defined for the study as a serum urate level ≥ 480 lmol/L), normal renal function (serum creatinine concentration ≤ 135 lmol/L [1.5 mg/dL]), and free of gout flare 2 weeks beforehand and during the 2-week run-in period. The exclusion criteria included: pregnancy or lactation; concurrent therapy with azathioprine, 6-mercaptopurine, thiazide diuretics, or medications containing aspirin (> 325 mg) or other salicylates; a history of active liver disease, or hepatic dysfunction (alanine aminotransferase and aspartate aminotransferase values > 1.5 times the upper limit of normal); a history of bronchial asthma; a history of renal calculi or thyroid disease; secondary gout joint diseases induced by rheumatoid arthritis, psoriatic arthritis and bone tumor; intolerance to allopurinol and ibuprofen; alcohol intake of ≥ 14 drinks/week; and clinically significant medical conditions.
Randomization, blinding and allocation The randomization code which was stratified according to centers with a 1 : 1 : 1 allocation was created by the study biostatistician using SAS 9.1.3 software (SAS Institute Inc., Cary, NC, USA). The research pharmacist who was not associated with the study received the randomization list, dispensed the study medications in packs provided by the manufacturer, and then enclosed the medications in numbered boxes according to the randomization list. The investigators in each center administered study medications to the eligible patients in sequence. All parties involved in the present study (investigators, patients and biostatistician) were blinded to the allocation of the study medications.
Study design Febuxostat tablets (80 or 40 mg) were used as investigational drugs and allopurinol (100 mg) as control drug;
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placebo tablets for each drug were also used. Febuxostat, allopurinol and the placebo tablets were provided by Qingdao Shengbang Pharmaceutical Corporation Limited, Shandong, China. After a 2-week run-in period for those receiving previous urate-lowering therapy, registered patients were randomly assigned in a 1 : 1 : 1 ratio to febuxostat 80 mg/day, febuxostat 40 mg/day and allopurinol 300 mg/day groups. All the study medications were administered at fixed doses for up to 24 weeks. In the screening period, the evaluations included physical examination, vital signs, medical history, laboratory tests, electrocardiogram, assessment for tophi and gout flare, and concomitant medication use. In the treatment period, serum urate level was repeatedly measured by using the uricase oxidase method at monthly visits; physical examination, vital signs, gout flares, concomitant medication use and adverse events were assessed and recorded at monthly visits; and blood biochemical examination, urinalysis and electrocardiogram were performed at bimonthly visits. All the laboratory testing and all urinalyses were provided by a local laboratory in the same standardized method. Throughout the 24-week treatment period, subjects received prophylaxis for gout flares with ibuprofen (Xinhua Pharmaceutical Corporation Limited, Shandong, China), 0.2 g twice daily. If subjects suffered from gout flare, they were permitted to temporarily increase the dose of ibuprofen or change to another medication (e.g., colchicine or celecoxib) for treatment. The gout flare was considered as expected gout manifestations rather than as adverse events.
Efficacy endpoints The primary efficacy endpoint was the percentage of subjects whose last three serum urate levels were < 360 lmol/L. The secondary endpoints were the percentage of subjects whose serum urate levels at the final visit were < 360 lmol/L and the absolute change in the serum urate level at the final visit relative to baseline.
Determination of sample size The sample size was estimated using PASS software, version 11 (NCSS, LLC, East Kaysville, UT, USA). This sample size is considered practical and determined according to the duration and cost issues. Since uratelowering efficacy of febuxostat 80 mg exceeds that of febuxostat 40 mg, febuxostat 80 mg rather than 40 mg was preferred to determine the sample size to guarantee superior urate-lowering efficacy of febuxostat relative to allopurinol. According to the previous studies, the
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proportion of subjects with their last three serum urate levels < 360 lmol/L in the febuxostat 80 group was 48% (126/262)14 and 53% (136/255),11 respectively, the mean of which was 50%. It was 22% (60/268),14 21% (53/251)11 and 42% (318/756)21, respectively, in the allopurinol 300 mg group, the mean of which was 29%. Therefore, with a two-sided 0.025 alpha level and an anticipated drop-out rate of 20%, a sample size of 170 per treatment group was required to achieve a 90% power to meet the superiority criteria between febuxostat 80 mg and the allopurinol group for the primary efficacy variable. The size was also necessary to an 80% power to meet the non-inferiority criteria between 40 mg and the allopurinol group for the primary efficacy endpoint, with a two-sided 0.05 alpha level and a dropout rate of 10%.
Statistical analysis The primary analysis was based on the full analysis set and included all randomized patients who took at least one randomized investigational product dose, and had at least one non-missing baseline and one post-baseline efficacy data assessment, according to the intentionto-treat basis. All supportive analyses were based on per protocol set analysis sets and the safety endpoints were analyzed on safety analysis sets. No interim analysis was involved in the research. All data were entered into SAS 9.1.3 software (SAS Institute). Analyses by actual therapy included only those patients who were continuing to take their allocated therapy. Data were presented as mean and standard deviation (SD), range or percentage. Data were examined for skewness, outliers and systematic missing data. Univariate and multivariate tests for repeated measures analysis of variance (ANOVA) were used to evaluate differences within and between groups over time. Mann–Whitney U-test was used to evaluate differences between groups, whereas Friedman’s test (variance analysis) followed by Wilcoxon paired test was used to evaluate differences within groups. P < 0.05 was considered as significantly different in statistics. For numerical data with more than one post-baseline visits (e.g., serum urate level, blood pressure, body mass index), mixed model for repeated measures (MMRM) was utilized for analysis and a last observation carried forward (LOCF) analysis was presented as sensitivity analysis unless otherwise specified. The safety endpoints were analyzed on safety analysis sets. Adverse events were summarized. The incidence of adverse events was summarized by body system organ class and preferred term. Analyses for safety and tolerability endpoints were
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summarized using descriptive statistics for continuous variables or frequency counts and percentages for categorical variables.
RESULTS
group, 22.8% (36/158) in febuxostat 40 mg/day group and 14.8% (22/149) in allopurinol 300 mg/day group. There was a statistically significant difference across groups (P < 0.001). Subgroup analysis in female subjects was not conducted due to a small sample.
Patient disposition
Secondary efficacy endpoint
Of 762 subjects screened, 504 were randomly 1 : 1 : 1 assigned to febuxostat 80 mg/day, febuxostat 40 mg/day or allopurinol 300 mg/day groups, with 168 in each group. The number of subjects who completed the study was 141 for febuxostat 80 mg/day group, 144 for febuxostat 40 mg/day group and 132 for allopurinol 300 mg/day group (Fig. 1). The percentage of subjects having good compliance (assessed based on returned tablet counts) was 95.2%, 97.6% and 97.6% in febuxostat 80 mg/day group, febuxostat 40 mg/day group and allopurinol 300 mg/day group, separately (P = 0.356 across groups). The primary analysis was based on full analysis sets, which included 158 subjects in febuxostat 80 mg/day group, 160 subjects in febuxostat 40 mg/day group and 159 subjects in allopurinol 300 mg/day group. The details of analysis sets can be seen in Figure 1.
The proportion of subjects with serum urate < 360 lmol/L at the last visit in febuxostat 80 mg/day group was higher than that in febuxostat 40 mg/day group (58.9% vs. 45.0%, P = 0.014) and that in allopurinol 300 mg/day group (58.9% vs. 34.6%, P < 0.001). There was no significant difference between febuxostat 40 mg/day group and allopurinol 300 mg/day group (45.0% vs. 34.6%, P = 0.059) (Table 2). The reduction in serum urate level by the last visit relative to baseline was 216.0 137.2 lmol/L, 182.2 115.6 lmol/L and 170.4 132.6 lmol/L for febuxostat 80 mg/day group, febuxostat 40 mg/day group and allopurinol 300 mg/day group, respectively. Significant difference was found between febuxostat 80 mg/day group and allopurinol 300 mg/day group (P = 0.011) and no significant difference was found between febuxostat 40 mg/day group and allopurinol 300 mg/day group (P = 0.087) (Table 2). Serum urate level in each group was observed as decreased at week 4 (the first visit after randomization) and maintained in the subsequent study period. Greater urate-lowering efficacy was found in febuxostat 80 mg/day group than in the febuxostat 40 mg/day group and allopurinol 300 mg/day group (both P < 0.025 at each visit). The urate-lowering efficacy of febuxostat 40 mg/day was non-inferior to that of allopurinol 300 mg/day (P > 0.05 in each visit) (Fig. 2a).
Patient characteristics There were no significant differences across treatment groups in demographic, gout-related or comorbid characteristics of the subjects, except sex in full analysis set. There were more male subjects in febuxostat 40 mg/day group (98.8%) than in febuxostat 80 mg/day group (92.4%) and in allopurinol 300 mg/day group (93.7%) (P = 0.024) (Table 1). Sex-stratified subgroup analysis was therefore conducted as sensitivity analysis.
EFFICACY Primary efficacy endpoint The primary efficacy endpoint, or the proportion of subjects with serum urate level < 360 lmol/L in the last three visits, was reached by 33.5% (53/158) of subjects taking 80 mg/day of febuxostat, 22.5% (36/160) of those taking 40 mg/day of febuxostat, and 17.0% (27/ 159) of those taking 300 mg/day of allopurinol. Significant difference was discovered between febuxostat 80 mg/day group and allopurinol 300 mg/day group (P < 0.001) and no significant difference was discovered between febuxostat 40 mg/day group and allopurinol 300 mg/day group (P = 0.216) (Table 2). For male subjects, the primary efficacy endpoint was reached by 33.6% (49/146) in febuxostat 80 mg/day
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Gout flares The incidence of gout flare was relative high in each group during the first 8 weeks and then gradually decreased thereafter until the end of the study. There was no statistically significant difference in the incidence of gout flare between the three groups in all visit periods (all P > 0.05) (Fig. 2b).
Adverse events The incidence of adverse events was similar in the three treatment groups. The most frequent treatment-related adverse events were liver function test abnormalities, renal function test abnormalities and gastrointestinal disorders. Most adverse events were mild to moderate in severity. Adverse events related to liver function test abnormalities were reported for a total of 57 subjects:
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Figure 1 Flow of the subjects through the study. sUA, serum urate acid.
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Table 1 Baseline characteristics of subjects (full analysis set) Variable
Febuxostat 80 mg/day
Febuxostat 40 mg/day
Allopurinol 300 mg/day
N Demographic characteristics Age, years Sex (male), n (%) Height, cm Body mass, kg Body mass index, kg/m2 Systolic blood pressure, mmHg Diastolic blood pressure, mmHg Gout-related characteristics Baseline serum urate level, lmol/L Time with gout disease, years History or presence of tophi, n (%) Previous urate-lowering therapy, n (%) Drug allergy, n (%) Coexisting conditions, n (%) Hypertension Diabetes Hyperlipidemia Cardiovascular disease
158
160
159
P-value
48.2 12.0 146 (92.4) 170.7 5.7 73.3 9.6 25.1 2.6 126.4 11.0 77.6 8.1
45.5 11.9 158 (98.8) 171.4 4.7 74.0 8.6 25.3 2.7 126.2 10.0 79.1 8.2
46.6 10.7 149 (93.7) 170.2 6.0 73.6 11.3 25.4 3.3 124.9 10.1 78.7 7.9
0.114 0.024 0.124 0.849 0.681 0.356 0.217
565.1 75.5 3.0 (1.2–5.1) 26 (16.5) 79 (50.0) 7 (4.4)
560.8 73.3 2.7 (1.0–5.8) 24 (15.0) 87 (54.4) 8 (5.0)
574.2 77.8 3.0 (2.0–6.9) 26 (16.4) 83 (52.2) 7 (4.4)
0.269 0.966 0.924 0.737 0.960
32 (20.3) 5 (3.2) 13 (8.2) 2 (1.3)
20 (12.5) 10 (6.3) 15 (9.4) 4 (2.5)
22 (13.8) 9 (5.7) 11 (6.9) 4 (2.5)
0.086 0.124 0.442 0.514
Table 2 Primary and secondary endpoints (full analysis set) Endpoints
Febuxostat 80 mg/day
Febuxostat 40 mg/day
N 158 Primary efficacy endpoint Serum urate level < 360 lmol/L at the last 3 visits No./total no. (%) 53/158 (33.5) P-value† < 0.001 Secondary efficacy endpoint Serum urate level < 360 lmol/L at the last visit No./total no. (%) 93/158 (58.9) P-value† 0.014 Change in the serum urate level at the final visit relative to baseline Mean SD 216.0 137.2 P-value† 0.011
160
Allopurinol 300 mg/day 159
36/160 (22.5) 0.216
27/159 (17.0)
72/160 (45.0) < 0.001
55/159 (34.6)
182.2 115.6 0.087
170.4 132.6
†Versus allopurinol 300 mg/day. SD, standard deviation.
22 (13.1%) receiving febuxostat 80 mg/day, 17 (10.1%) receiving febuxostat 40 mg/day and 18 (10.7%) receiving allopurinol 300 mg/day. Of these subjects, only one patient in febuxostat 80 mg/day group who withdrew from the study at visit 2 stopped the study drugs; 14 patients who encountered liver function test abnormalities at the last visit also stopped the study drugs, and the remaining patients did not
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change their study drugs. Most adverse events related to abnormal findings on liver function tests happened at visit 2 and visit 4-6, and resolved within 3 months. Serious adverse events occurred in only one subject receiving febuxostat 80 mg/day. The subject was diagnosed as having hydronephrosis after a 14-day period of febuxostat administration and thus was hospitalized. Actually, the subject had a kidney stone history which
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(a)
Table 3 Summary of adverse events (safety set) Variable
(b)
Figure 2 Serum urate levels at each visit (a) and incidence of gout flare in each visit period (b).
was not reported to the investigator in the screening period. Therefore, the serious adverse event was classified as due to protocol violation and judged by the investigator as unrelated to the study drug. In addition, no death happened during the study period in any group (Table 3).
Sensitivity analysis The efficacy endpoints were analyzed in per protocol set as supportive analyses and the results were all in accord with those from the full analysis set. For example, the proportion of subjects who reached the primary efficacy endpoint in febuxostat 80 mg/day group was 32.6% (46/141), which was higher than 19.7% (26/132) in allopurinol 300 mg/day group (P = 0.015). The result was similar with that from the full analysis set. Likewise, analysis from the per protocol set showed that there was no significant difference in the proportion of subjects reaching the primary efficacy endpoint between febuxostat 40 mg/day group and allopurinol
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Febuxostat 80 mg/day
Febuxostat 40 mg/day
N 168 168 Any adverse events 61 (36.3) 63 (37.5) Any treat-related 46 (27.4) 45 (26.8) adverse events Most frequent treat-related adverse events Liver function test 22 (13.1) 17 (10.1) abnormalities Renal function 7 (4.2) 2 (1.2) test abnormalities Abnormal 0 (0.0) 4 (2.4) electrocardiograph Abnormal 4 (2.4) 4 (2.4) urine protein Abnormal 1 (0.6) 2 (1.2) urine glucose Skin rashes 1 (0.6) 3 (1.8) Headaches 1 (0.6) 0 (0.0) Upper respiratory 1 (0.6) 0 (0.0) infection Gastrointestinal 2 (1.2) 3 (1.8) disorders 4 (2.4) 2 (1.2) Musculoskeletal and connective tissue signs and symptoms Others 3 (1.8) 7 (4.2) 3 (1.8) 3 (1.8) Any adverse events leading to discontinuation Any serious 1 (0.6) 0 (0.0) adverse events
Allopurinol 300 mg/day 168 54 (32.1) 41 (24.4)
18 (10.7) 2 (1.2) 1 (0.6) 1 (0.6) 1 (0.6) 5 (3.0) 1 (0.6) 0 (0.0) 4 (2.4) 0 (0.0)
8 (4.8) 3 (1.8)
0 (0.0)
There were no significant differences among the three groups.
300 mg/day group (24.3% [35/144] vs. 19.7% [26/ 132], P = 0.357).
DISCUSSION Few randomized controlled clinical trials to date have been conducted comparing febuxostat and allopurinol in Chinese gout patients with hyperuricemia.22 This 26week study demonstrated that a daily dose of febuxostat 80 mg had higher urate-lowering efficacy than a daily dose of febuxostat 40 mg and allopurinol 300 mg. Urate-lowering efficacy of febuxostat 40 mg daily was non-inferior to that of allopurinol 300 mg daily. In addition, results showed that there was only 58.9% of patients in the febuxostat 80 mg/day group achieving targeted sUA levels below 360 lmol/L at the final visit
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and, more importantly, only 22.3% patients with sUA level below 360 lmol/L at the last three visits in febuxostat 80 mg/day group, suggesting that titration to higher dosage of febuxostat (e.g., 120 mg/day) might be required to achieve and maintain recommended sUA levels below 360 lmol/L in Chinese gout patients with hyperuricemia. As expected, in our present study febuxostat 80 mg/ day was more effective in reducing serum urate in gout patients with hyperuricemia compared with allopurinol of common usage (300 mg/day), which was consistent with previous studies.11,14,21 For example, Becker et al.11 reported that the primary end point of sUA < 360 lmol/L at the last 3 months was reached in 53% of patients receiving 80 mg of febuxostat and 21% of those receiving 300 mg of allopurinol (P < 0.001). In a meta-analysis by Peng Ye et al.,23 the pooled proportion of patients who achieved target sUA at the final visit was significantly greater in the febuxostat-treated group (80 mg/day) compared with the allopurinol-treated group (100–300 mg/day) (71.4% vs. 45.6%; odds ratio = 3.27, 95% confidence interval: 2.14–5.00). In addition, our study showed non-inferiority of uratelowering efficacy between febuxostat 40 mg/day and allopurinol 300 mg/day. Our results were opposite from those from Kamatani et al.24 but similar with most of prior studies,21,22,25 particularly a study from China.22 Thus, despite the fact that Peng Ye et al.23 conducted a meta-analysis and indicated that the pooled percentage of patients who achieved target sUA at the final visit was significantly higher in the febuxostat-treated group (40 mg/day) than that in the allopurinoltreated group (100–300 mg/day) (50.9% vs. 45.6%; odds ratio = 1.25, 95% confidence interval: 1.05–1.49), we speculated with caution that febuxostat 40 mg/day had non-superior urate-lowering efficacy relative to allopurinol 300 mg/day in Chinese gout patients with hyperuricemia. Our study, together with another Chinese clinical trial (by Huang et al.),22 had relatively lower proportions of subjects treated with febuxostat and whose sUA levels were < 360 lmol/L, compared with those in US and Japan. For example, the proportion of subjects treated with febuxostat 80 mg at the 26-week visit was 58.9% in ours and 61.6% in Huang’s study,22 while it was 67.1% in Becker’s11 and 76.0% in Schumacher’s14 studies, respectively. Also, the proportion at the 16-week visit was 57.2% in ours and 64.0% in Huang’s study,22 lower than 87.8% in Naoyuki’s study.26 The metabolism of Chinese populations which differs from that of European people could only partly
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explain the results in our opinion, and generic febuxostat products might contribute to the differences to some extent. In addition, we observed a greater reduction in the sUA level by the last visit relative to baseline for febuxostat 80 mg/day than for 40 mg/day, indicating that febuxostat had dose-dependent uratelowering efficacy. Therefore, considering that almost half of patients treated with a daily dose of febuxostat 80 mg in the present study could not achieve and maintain target sUA levels < 360 lmol/L, titration to higher dosage of febuxostat (e.g., 120 mg/day) for Chinese gout patients was suggested and a further future study accessing efficacy and safety of febuxostat 120 or 160 mg/day was needed. The proportion of subjects requiring treatment for gout flares in our study was relatively high in the first 8 weeks and tended to diminish with continued treatment in all treatment groups, and no statistically significant differences were observed between the treatment groups during the 28-week study period. The results were in accord with previous studies.11,21,22 Consistent with prior studies,11,14,21,22,25 the occurrence of treatment-related adverse events was similar between the three treatment groups, most of which were mild to moderate in severity. No treatment-related events showed any stepwise increase in rates with higher doses of febuxostat. No death and serious treatment-related adverse events were judged related to febuxostat. The most frequent treatment-related adverse event in our study was liver function test abnormalities, which was 13.1%, 9.5% and 10.7% in febuxostat 80 mg/day, febuxostat 40 mg/day and allopurinol 300 mg/day groups, respectively. There is a need to educate patients to monitor liver function during uratelowering therapy. Some limitations should be addressed. First, a limited number of female subjects were included in our study and we thus could not perform a sex-stratified subgroup analysis due to data limitation. Further studies should be conducted for the optimal usage of febuxostat in female gout patients. Second, guidelines recommend to start with a low dose of allopurinol and slowly titrate up during the urate-lowering course.3,27 However, most previous randomized controlled trials except in subjects with renal impairment used a fixed daily dose of allopurinol (300 mg).11,14,21,22 Considering that we only included patients with normal renal function and also ruled out subjects with known allergy to allopurinol to avoid the rare severe adverse event of hypersensitivity, the fixed allopurinol dose of 300 mg/day was also adopted in our study. However, we must acknowledge
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that the comparison dose of 300 mg/day is well below full dose and allopurinol may perform better with dose escalation. The allopurinol dose used in this study is no longer considered optimal in patients who have not achieved the target sUA concentration, and this is a limitation of the study. Third, tophus size was not measured and tophus size reduction was not an endpoint in the current trial. This was mainly because we had a relatively short study period of 6 months and prior randomized controlled trials comparing febuxostat and allopurinol did not establish significant differences between these drugs in the clinical outcome of tophus size reductions during the first 6–12 months of treatment.11,14 Furthermore, accurate measurement of tophi was problematic in the clinical setting. Last, while we followed the ARA criteria to diagnose gout, we actually did not require crystal identification and the study group might not definitely represent actual gout.
CONCLUSIONS The results of the current study demonstrated that febuxostat 80 mg daily had superior urate-lowering efficacy to that of febuxostat 40 mg daily or allopurinol 300 mg daily, which were comparable, in Chinese gout patients with hyperuricemia. Febuxostat, at a daily dose of 40 or 80 mg, was safe and well tolerated. In addition, considering that almost half of patients treated with a daily dose of febuxostat 80 mg in the current study could not achieve and maintain recommended target sUA level < 360 lmol/L, titration to a higher dose of febuxostat (e.g., 120 mg/day) might be required in clinical practice among a Chinese population.
ACKNOWLEDGEMENTS This study was funded by Qingdao Shengbang Pharmaceutical Corporation Limited, Shandong, China (ChiCTR: 2010L04287, 2010L04288).
AUTHORS CONTRIBUTIONS SX, XL and JM contributed equally to the manuscript. QJ was involved in study concept and design. SX XL and JM were involved in the acquisition of data, data analysis and interpretation, and preparation of the manuscript. All authors provided final approval to submit the manuscript. The study sponsors, Qingdao Shengbang Pharmaceutical Corporation Limited and DDLD (Beijing) Pharmaceutical Technology Corporation Limited, were involved in the study design, proto-
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cols, subject recruitment, data collections, and analyses (Trial registration: NCT02082769).
COMPETING INTERESTS The authors declare they have no conflict of interests.
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Supporting Information Additional Supporting Information may be found in the online version of this article:
Appendix S1 Study group field centers and members.
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