International Journal of Rheumatic Diseases 2014; 17: 679–686
ORIGINAL ARTICLE
An allopurinol-controlled, multicenter, randomized, doubleblind, parallel between-group, comparative study of febuxostat in Chinese patients with gout and hyperuricemia Xinfang HUANG,1 Hui DU,1 Jieruo GU,2 Dongbao ZHAO,3 Lindi JIANG,4 Xinfu LI,5 Xiaoxia ZUO,6 Yi LIU,7 Zhanguo LI,8 Xiangpei LI,9 Ping ZHU,10 Juan LI,11 Zhiyi ZHANG,12 Anbin HUANG,13 Yuanchao ZHANG14 and Chunde BAO1 1 Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 2The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 3Changhai Hospital, Affiliated to Second Military Medical University, 4Zhongshan Hospital, Affiliated to Fudan University, Shanghai, 5Qilu Hospital, Affiliated to Shandong University, Jinan, 6Xiangya Hospital, Central-South University, Changsha, 7Huaxi Hospital, Affiliated to Sichuan University, Chengdu, 8Peking University People’s Hospital, Beijing, 9Anhui Provincial Hospital, Hefei, 10Xijing Hospital, Fourth Military Medical University, Xi’an, 11Southern Medical University South Hospital, Huangzhou, 12First Affiliated Hospital of Harbin Medical University, Harbin, 13Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan and 14Shandong Provincial Hospital, Qingdao, China
Abstract Aim: Febuxostat, a novel non-purine selective inhibitor of xanthine oxidase, has been identified as a potential alternative to allopurinol in patients with hyperuricemia. The purpose of this study was to compare the urate-lowering (UL) efficacy and safety of daily febuxostat and allopurinol in Chinese gout patients with hyperuricemia. Methods: Gout patients (n = 512) with serum uric acid (sUA) concentrations of at least 8.0 mg/dL were randomized to receive daily febuxostat 40 mg or 80 mg or allopurinol 300 mg for 28 weeks. Prophylaxis against gout flares with meloxicam or colchicine was provided during weeks 1 through 8. The primary endpoint was the percentage of subjects achieving a sUA concentration of 1.5 times the upper limit of normal); patients developing gouty arthritis or recovering from gouty arthritis less than 2 weeks previously; and known allergy to febuxostat, allopurinol, non-steroidal antiinflammatory drugs, colchicine or any ingredient of these prescriptions.
Randomization, blinding and allocation The randomization code was created by the study biostatistician using SAS statistical software (version 8.2; SAS Institute, Cary, NC, USA) and was stratified by center with a 1 : 1 : 1 allocation. The randomization list was then given to the research pharmacist, who was not associated with the study. The research pharmacist dispensed the study medication, which was in packs provided by the manufacturer and enclosed the medication in numbered boxes as per the randomization scheme. All study participants and all study personnel who assessed outcomes, worked with study data, or administered tests or questionnaires were unaware of the randomization list or treatment assignments.
Study design and procedures The study was a multicenter, randomized, doubleblind, parallel between-group, comparative trial conducted in China. Subjects already receiving UL therapy underwent a 2-week washout period before undergoing randomization. Registered patients were randomly assigned 1 : 1 : 1 to the febuxostat 40 mg/day, 80 mg/ day or the allopurinol 300 mg/day groups. sUA levels were measured before beginning drug administration and at weeks 2, 6, 10, 14, 16, 20, 24 and 28 during the study. Each patient underwent a physical examination, and vital signs were recorded. Hematological and blood biochemical examination and urinalysis were conducted, and concomitant medication use, gout flares and adverse events were also recorded. During the 2-week washout period and the first 8 weeks, subjects were given 0.5 mg/day colchicine or 7.5 mg/day meloxicam as prophylaxis for gout flares. Gout flares were regarded as expected gout manifestations rather than as adverse events.
Efficacy endpoints The primary efficacy endpoint was the proportion of subjects in each febuxostat group and in the allopurinol group with sUA < 6.0 mg/dL at the last three monthly visits. Subjects who left the study before at least three clinic visits were considered not to have reached the primary efficacy endpoint. The secondary endpoints
International Journal of Rheumatic Diseases 2014; 17: 679–686
Febuxostat hyperuricemia & gout
were a reduction in the sUA level at the last visit relative to baseline, a change in the number of tophi at the 28week visit relative to baseline, and the rate of subjects requiring treatment for acute gout flares from weeks 9 through 28.
Determination of sample size The sample size was determined using PASS software, version 11 (NCSS, LLC, East Kaysville, UT, USA). A sample of 160 subjects per treatment group was required to achieve 80% power to meet the superiority criteria between febuxostat 80 mg and the allopurinol group and to detect a 20% difference between febuxostat 80 mg and the allopurinol group for the primary efficacy endpoint. The size was also necessary to achieve 80% power to meet the non-inferiority criteria between febuxostat 40 mg and the allopurinol group and to detect a 15% difference between febuxostat 40 mg and the allopurinol group for the primary efficacy endpoint, with a two-sided 5% significant level, given an anticipated dropout rate of 10%.
Statistical analysis Analyses were performed with SAS statistical software, version 9.3 (SAS Institute). All statistical tests and confidence intervals were two-sided, and P-values ≤ 0.05 were considered to be statistically significant. The data were assessed by analysis of variance or a nonparametric test for continuous variables and a chi-square test or Fisher’s exact test for categorical variables. Efficacy analysis was conducted for the full analysis set (FAS). To ensure that the overall false-positive rate, that is, the familywise type I error, was lower than 0.05, multiple tests were performed in which the febuxostat 80 mg group was compared with the allopurinol group for superiority using a Cochran–Mantel–Haenszel (CMH) test with a significance level of 0.01. Additionally, the febuxostat 40 mg group was compared with the allopurinol group for non-inferiority with the lower boundary of the 96% confidence interval > 15%. Fisher’s exact test was used for pairwise comparison of adverse events.
RESULTS Disposition of the subjects Between February 2010 and December 2010, of 679 subjects screened, 516 subjects were randomly 1 : 1 : 1 assigned to the febuxostat 40 mg, 80 mg or the allopurinol 300 mg groups, with 172 subjects in each group. Subjects already receiving UL therapy and undergoing a
International Journal of Rheumatic Diseases 2014; 17: 679–686
2-week washout period enrolled in this study was six for allopurinol group (3.49%), eight for febuxostat 40 mg group (4.65%) and six for febuxostat 80 mg group (3.49%). There was no significant statistical difference between groups. Most of them were received allopurinol therapy. The number of subjects who completed the study was 151 for the allopurinol 300 mg/day group, 146 for the febuxostat 40 mg/day group and 154 for the febuxostat 80 mg/day group (Fig. 1).
Demographic and other baseline characteristics There were no significant differences in demographic characteristics or concurrent disease across treatment groups (Table 1). No differences were found in either the mean sUA levels or the status of gouty tophus before drug administration among groups.
Efficacy Primary efficacy endpoint The primary efficacy endpoint, or the proportion of subjects in each treatment group with sUA < 6.0 mg/dL at the last three monthly measurements, was 27.33%, 44.77%, and 23.84% in the febuxostat 40 mg, febuxostat 80 mg and allopurinol groups, respectively. Greater UL efficacy was found in the febuxostat 80 mg group than in the febuxostat 40 mg and allopurinol groups (P = 0.0008 and < 0.0001, respectively) (Fig. 2). The UL efficacy of febuxostat 40 mg was non-inferior to that of allopurinol. The UL efficacy of febuxostat was dose-dependent. Decreases in sUA levels started at week 2, and lower levels were maintained in the subsequent study period in each group (Fig. 2). Second efficacy endpoint The reduction in sUA levels by the final visit relative to baseline: The reduction in the sUA level (mean [95% CI]) by the final visit relative to baseline for febuxostat 80 mg was 4.17 ( 4.48, 3.86) mg/dL, which was greater than for febuxostat 40 mg ( 3.25 [ 3.57, 2.94] mg/dL) and allopurinol ( 3.25 [ 3.57, 2.94] mg/dL) (P < 0.0001, respectively) (Table 2). The change in the number of tophi by the final visit relative to baseline: No significant change in the number of tophi (mean [95% CI]) was observed during the final visit relative to baseline between the febuxostat 80 mg ( 0.28 [ 0.46, 0.11]), febuxostat 40 mg ( 0.11 [ 0.29, 0.06]), and allopurinol 300 mg ( 0.15 [ 0.33, 0.02]) groups (Table 2).
681
X. Huang et al.
Subjects Screened n = 679
Subjects Randomized n = 516
Febuxostat 40 mg/d group n = 172
Completed n = 146
Discontinued n = 26 Reason: 12 lost to follow-up 11 Adverse event 1 Protocal violation 2 Other reasons
Excluded 163 UA 300 mg/ day. As mentioned before, the daily dose of allopurinol was fixed at 300 mg in previous RCTs except in subjects with renal impairment.19,20,24 Since allopurinol hypersensitivity is rare, in the subjects with known allergy to allopurinol, and a serum creatinine concentration of more than 1.5 mg/dL (135 lmol/L), were ruled out in our trial; thus, we adopted the fixed allopurinol dose of 300 mg/dL in this study. The purpose of this study was to compare the UL efficacy and safety of daily febuxostat and allopurinol in Chinese gout patients with hyperuricemia. A daily dose of febuxostat 80 mg had higher UL efficacy than a daily dose of febuxostat 40 mg or allopurinol 300 mg. A daily dose of febuxostat 40 mg was
683
X. Huang et al.
Table 2 Primary and secondary endpoints Endpoint
Febuxostat 40 mg/day group (N = 172)
Allopurinol
80 mg/day group (N = 172)
Primary efficacy endpoint Serum urate < 6.0 mg/dL at last 3-monthly visits n / (%) 47 (27.33%) 77 (44.77%) P-value 0.0008† < 0.0001‡,¶ Second efficacy endpoint The reduction of sUA level in the final visit against baseline Mean (95% CI) 3.25 ( 3.57, 2.94) 4.17 ( 4.48, 3.86) P-value < 0.0001† < 0.0001‡ The change in the number of tophi at final visit against baseline Mean (95%CI) 0.11 ( 0.29, 0.06) 0.28 ( 0.46, 0.11) P-value 0.3539† 0.1777‡ The rates of subjects requiring treatment for acute gout flares from weeks 9 through 28 n / (%) 9 (5.23%) 7 (4.07%) P-value 0.6086† 0.0521‡
300 mg/day group (N = 172)
41 (23.84%) 0.4584§
3.25 ( 3.57, 0.8844§
2.94)
0.15 ( 0.33, 0.02) 0.6734§ 16 (9.3%) 0.1460§
†The comparison between febuxostat 40 mg/day and febuxostat 80 mg/day. ‡The comparison between febuxostat 80 mg/day and allopurinol 300 mg/day. §The comparison between febuxostat 40 mg/day and allopurinol 300 mg/day. ¶A Cochran–Mantel–Haenszel (CMH) test was used for superiority comparison with a significance level of 0.01.
Table 3 Summary of adverse events Adverse event
Febuxostat 40 mg/day group N = 172 n (%)
Any adverse event 96 (55.81%) Any treatment-related event 55 (31.98%) Any events leading to discontinuation 11 (6.40%) Any serious event 2 (1.16%) Most frequent or important treatment-related adverse event Liver function test abnormalities 5 (2.91%) Hyperlipidemia 8 (4.65%) Serum creatinine > 135 lmol/L 2 (1.16%) Gastrointestinal disorder 0 Lack of strength 0 Hyperthyroidism 1 (0.58%)
Febuxostat 80 mg/Day group N = 172 n (%)
Allopurinol 300 mg/day group N = 172 n (%)
89 (51.74%) 58 (33.72%) 10 (5.81%) 1 (0.58%)
103 (59.88%) 68 (39.53%) 12 (6.98%) 2 (1.16%)
2 (1.16%) 7 (4.07%) 4 (2.32%) 5 (2.92%) 3 (1.74%) 0
6 (3.49%) 10 (5.81%) 2 (1.16%) 1 (0.58%) 1 (0.58%) 0
There were no significant differences among the three groups.
non-inferior to allopurinol 300 mg in UL efficacy. Our result was consistent with the findings of prior reports.19,20,24 The proportion of subjects with sUA < 6.0 mg/dL at the 28-week visit was 61.63% in this study, which was also comparable with the 67.1% value reported by Becker et al.19 However, a higher proportion of subjects with sUA < 6.0 mg/dL in a febuxostat 80 mg group at a 16-week visit was observed in a study in Japan,23 greater than in our study (87.8% vs. 63.95%). The factor most likely contributing to the difference might be the numbers of subjects enrolled in these two trials (42 vs. 172).
684
The rates of subjects requiring treatment for acute gout flares from weeks 9 through 28 were similar between febuxostat and allopurinol groups in our data (Table 2), which is consistent with previous reports.19,24 A greater reduction in the sUA level by the final visit relative to baseline was observed for febuxostat 80 mg than for febuxostat 40 mg, which suggested that the UL efficacy of febuxostat was dose-dependent, consistent with other reports.19,24 A greater dose of febuxostat should be used in patients who have greater uric acid pools.
International Journal of Rheumatic Diseases 2014; 17: 679–686
Febuxostat hyperuricemia & gout
The incidence of treatment-related events was 31.98% for febuxostat 40 mg, 33.72% for febuxostat 80 mg and 39.53% for allopurinol. There was no statistical difference between groups. Most of the adverse events were mild to moderate. There was no dosedependent increase in adverse events found in the febuxostat group, which was consistent with other reports.19,20,22,24 No serious events were judged by the investigators to be related to febuxostat.
CONCLUSION The UL efficacy of a daily dose of febuxostat 80 mg was superior to that of a daily dose of febuxostat 40 mg or allopurinol 300 mg. The UL efficacy of a daily dose of febuxostat 40 mg was non-inferior to that of allopurinol 300 mg. Febuxostat showed high efficacy and tolerability in the treatment of Chinese gout patients with hyperuricemia.
ACKNOWLEDGMENTS This study was supported by Wanbang Biopharmaceuticals (ChiCTR: 2009L08759, 2009L11564).
DISCLOSURES none.
AUTHORS CONTRIBUTIONS Study design: Chunde Bao; acquisition of data: Xinfang Huang, Hui Du, Jieruo Gu, Dongbao Zhao, Lindi Jiang, Xinfu Li, Xiaoxia Zuo, Yi Liu, Zhanguo Li, Xiangpei Li, Ping Zhu, Juan Li, Zhiyi Zhang, Anbin Huang, Yuanchao Zhang; statistical analysis: Chunde Bao, Xinfang Huang, Hui Du.
REFERENCES 1 Wortmann RL (2002) Gout and hyperuricemia. Curr Opin Rheumatol 14, 281–6. 2 Perez-Ruiz F, Alonso-Ruiz A, Calabozo M et al. (1998) Efficacy of allopurinol and benzbromarone for the control of hyperuricaemia. A pathogenic approach to the treatment of primary chronic gout. Ann Rheum Dis 57, 545–9. 3 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.
International Journal of Rheumatic Diseases 2014; 17: 679–686
4 Shoji A, Yamanaka H, Kamatani N (2004) A retrospective study of the relationship between serum urate level and recurrent attacks of gouty arthritis: evidence for reduction of recurrent gouty arthritis with antihyperuricemic therapy. Arthritis Rheum 51, 321–5. 5 Hall AP (1965) Correlations among hyperuricemia, hypercholesterolemia, coronary disease and hypertension. Arthritis Rheum 8, 846–52. 6 Abbott RD, Brand FN, Kannel WB, Castelli WP (1988) Gout and coronary heart disease: the Framingham Study. J Clin Epidemiol 41, 237–42. 7 Beard JT (1983) Serum uric acid and coronary heart disease. Am Heart J 106, 397–400. 8 Brand FN, McGee DL, Kannel WB, Stokes J, Castelli WP (1985) Hyperuricemia as a risk factor of coronary heart disease: the Framingham Study. Am J Epidemiol 121, 11–8. 9 Freedman DS, Williamson DF, Gunter EW, Byers T (1995) Relation of serum uric acid to mortality and ischemic heart disease. The NHANES I Epidemiologic Follow-up Study. Am J Epidemiol 141, 637–44. 10 Frohlich ED (1993) Uric acid. A risk factor for coronary heart disease. JAMA 270, 378–9. 11 Kim SY, Guevara JP, Kim KM, Choi HK, Heitjan DF, Albert DA (2010) Hyperuricemia and coronary heart disease: a systematic review and meta-analysis. Arthritis Care Res (Hoboken) 62, 170–80. 12 Li C, Hsieh MC, Chang SJ (2013) Metabolic syndrome, diabetes, and hyperuricemia. Curr Opin Rheumatol 25, 210–6. 13 Ryoo JH, Choi JM, Oh CM, Kim MG (2013) The association between uric acid and chronic kidney disease in Korean men: a 4-year follow-up study. J Korean Med Sci 28, 855–60. 14 Hande KR, Noone RM, Stone WJ (1984) Severe allopurinol toxicity. Description and guidelines for prevention in patients with renal insufficiency. Am J Med 76, 47–56. 15 Schlesinger N (2004) Management of acute and chronic gouty arthritis: present state-of-the-art. Drugs 64, 2399– 416. 16 Terkeltaub RA (2003) Clinical practice. Gout. N Engl J Med 349, 1647–55. 17 Fam AG (1998) Gout in the elderly. Clinical presentation and treatment. Drugs Aging 13, 229–43. 18 Harris MD, Siegel LB, Alloway JA (1999) Gout and hyperuricemia. Am Fam Physician 59, 925–34. 19 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. 20 Becker MA, Schumacher HR, Wortmann RL et al. (2005) Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med 353, 2450–61. 21 Becker MA, Schumacher HR, Wortmann RL et al. (2005) Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase: a twenty-eight-day, multicenter, phase II,
685
X. Huang et al.
randomized, double-blind, placebo-controlled, doseresponse clinical trial examining safety and efficacy in patients with gout. Arthritis Rheum 52, 916–23. 22 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. 23 Naoyuki K, Shin F, Toshikazu H et al. (2011) Placebocontrolled double-blind dose-response study of the nonpurine-selective xanthine oxidase inhibitor febuxostat (TMX-67) in patients with hyperuricemia (including gout patients) in japan: late phase 2 clinical study. J Clin Rheumatol 17, S35–43.
686
24 Schumacher HR, 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. 25 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. 26 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.
International Journal of Rheumatic Diseases 2014; 17: 679–686
ORIGINAL ARTICLE
An allopurinol-controlled, multicenter, randomized, doubleblind, parallel between-group, comparative study of febuxostat in Chinese patients with gout and hyperuricemia Xinfang HUANG,1 Hui DU,1 Jieruo GU,2 Dongbao ZHAO,3 Lindi JIANG,4 Xinfu LI,5 Xiaoxia ZUO,6 Yi LIU,7 Zhanguo LI,8 Xiangpei LI,9 Ping ZHU,10 Juan LI,11 Zhiyi ZHANG,12 Anbin HUANG,13 Yuanchao ZHANG14 and Chunde BAO1 1 Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 2The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 3Changhai Hospital, Affiliated to Second Military Medical University, 4Zhongshan Hospital, Affiliated to Fudan University, Shanghai, 5Qilu Hospital, Affiliated to Shandong University, Jinan, 6Xiangya Hospital, Central-South University, Changsha, 7Huaxi Hospital, Affiliated to Sichuan University, Chengdu, 8Peking University People’s Hospital, Beijing, 9Anhui Provincial Hospital, Hefei, 10Xijing Hospital, Fourth Military Medical University, Xi’an, 11Southern Medical University South Hospital, Huangzhou, 12First Affiliated Hospital of Harbin Medical University, Harbin, 13Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan and 14Shandong Provincial Hospital, Qingdao, China
Abstract Aim: Febuxostat, a novel non-purine selective inhibitor of xanthine oxidase, has been identified as a potential alternative to allopurinol in patients with hyperuricemia. The purpose of this study was to compare the urate-lowering (UL) efficacy and safety of daily febuxostat and allopurinol in Chinese gout patients with hyperuricemia. Methods: Gout patients (n = 512) with serum uric acid (sUA) concentrations of at least 8.0 mg/dL were randomized to receive daily febuxostat 40 mg or 80 mg or allopurinol 300 mg for 28 weeks. Prophylaxis against gout flares with meloxicam or colchicine was provided during weeks 1 through 8. The primary endpoint was the percentage of subjects achieving a sUA concentration of 1.5 times the upper limit of normal); patients developing gouty arthritis or recovering from gouty arthritis less than 2 weeks previously; and known allergy to febuxostat, allopurinol, non-steroidal antiinflammatory drugs, colchicine or any ingredient of these prescriptions.
Randomization, blinding and allocation The randomization code was created by the study biostatistician using SAS statistical software (version 8.2; SAS Institute, Cary, NC, USA) and was stratified by center with a 1 : 1 : 1 allocation. The randomization list was then given to the research pharmacist, who was not associated with the study. The research pharmacist dispensed the study medication, which was in packs provided by the manufacturer and enclosed the medication in numbered boxes as per the randomization scheme. All study participants and all study personnel who assessed outcomes, worked with study data, or administered tests or questionnaires were unaware of the randomization list or treatment assignments.
Study design and procedures The study was a multicenter, randomized, doubleblind, parallel between-group, comparative trial conducted in China. Subjects already receiving UL therapy underwent a 2-week washout period before undergoing randomization. Registered patients were randomly assigned 1 : 1 : 1 to the febuxostat 40 mg/day, 80 mg/ day or the allopurinol 300 mg/day groups. sUA levels were measured before beginning drug administration and at weeks 2, 6, 10, 14, 16, 20, 24 and 28 during the study. Each patient underwent a physical examination, and vital signs were recorded. Hematological and blood biochemical examination and urinalysis were conducted, and concomitant medication use, gout flares and adverse events were also recorded. During the 2-week washout period and the first 8 weeks, subjects were given 0.5 mg/day colchicine or 7.5 mg/day meloxicam as prophylaxis for gout flares. Gout flares were regarded as expected gout manifestations rather than as adverse events.
Efficacy endpoints The primary efficacy endpoint was the proportion of subjects in each febuxostat group and in the allopurinol group with sUA < 6.0 mg/dL at the last three monthly visits. Subjects who left the study before at least three clinic visits were considered not to have reached the primary efficacy endpoint. The secondary endpoints
International Journal of Rheumatic Diseases 2014; 17: 679–686
Febuxostat hyperuricemia & gout
were a reduction in the sUA level at the last visit relative to baseline, a change in the number of tophi at the 28week visit relative to baseline, and the rate of subjects requiring treatment for acute gout flares from weeks 9 through 28.
Determination of sample size The sample size was determined using PASS software, version 11 (NCSS, LLC, East Kaysville, UT, USA). A sample of 160 subjects per treatment group was required to achieve 80% power to meet the superiority criteria between febuxostat 80 mg and the allopurinol group and to detect a 20% difference between febuxostat 80 mg and the allopurinol group for the primary efficacy endpoint. The size was also necessary to achieve 80% power to meet the non-inferiority criteria between febuxostat 40 mg and the allopurinol group and to detect a 15% difference between febuxostat 40 mg and the allopurinol group for the primary efficacy endpoint, with a two-sided 5% significant level, given an anticipated dropout rate of 10%.
Statistical analysis Analyses were performed with SAS statistical software, version 9.3 (SAS Institute). All statistical tests and confidence intervals were two-sided, and P-values ≤ 0.05 were considered to be statistically significant. The data were assessed by analysis of variance or a nonparametric test for continuous variables and a chi-square test or Fisher’s exact test for categorical variables. Efficacy analysis was conducted for the full analysis set (FAS). To ensure that the overall false-positive rate, that is, the familywise type I error, was lower than 0.05, multiple tests were performed in which the febuxostat 80 mg group was compared with the allopurinol group for superiority using a Cochran–Mantel–Haenszel (CMH) test with a significance level of 0.01. Additionally, the febuxostat 40 mg group was compared with the allopurinol group for non-inferiority with the lower boundary of the 96% confidence interval > 15%. Fisher’s exact test was used for pairwise comparison of adverse events.
RESULTS Disposition of the subjects Between February 2010 and December 2010, of 679 subjects screened, 516 subjects were randomly 1 : 1 : 1 assigned to the febuxostat 40 mg, 80 mg or the allopurinol 300 mg groups, with 172 subjects in each group. Subjects already receiving UL therapy and undergoing a
International Journal of Rheumatic Diseases 2014; 17: 679–686
2-week washout period enrolled in this study was six for allopurinol group (3.49%), eight for febuxostat 40 mg group (4.65%) and six for febuxostat 80 mg group (3.49%). There was no significant statistical difference between groups. Most of them were received allopurinol therapy. The number of subjects who completed the study was 151 for the allopurinol 300 mg/day group, 146 for the febuxostat 40 mg/day group and 154 for the febuxostat 80 mg/day group (Fig. 1).
Demographic and other baseline characteristics There were no significant differences in demographic characteristics or concurrent disease across treatment groups (Table 1). No differences were found in either the mean sUA levels or the status of gouty tophus before drug administration among groups.
Efficacy Primary efficacy endpoint The primary efficacy endpoint, or the proportion of subjects in each treatment group with sUA < 6.0 mg/dL at the last three monthly measurements, was 27.33%, 44.77%, and 23.84% in the febuxostat 40 mg, febuxostat 80 mg and allopurinol groups, respectively. Greater UL efficacy was found in the febuxostat 80 mg group than in the febuxostat 40 mg and allopurinol groups (P = 0.0008 and < 0.0001, respectively) (Fig. 2). The UL efficacy of febuxostat 40 mg was non-inferior to that of allopurinol. The UL efficacy of febuxostat was dose-dependent. Decreases in sUA levels started at week 2, and lower levels were maintained in the subsequent study period in each group (Fig. 2). Second efficacy endpoint The reduction in sUA levels by the final visit relative to baseline: The reduction in the sUA level (mean [95% CI]) by the final visit relative to baseline for febuxostat 80 mg was 4.17 ( 4.48, 3.86) mg/dL, which was greater than for febuxostat 40 mg ( 3.25 [ 3.57, 2.94] mg/dL) and allopurinol ( 3.25 [ 3.57, 2.94] mg/dL) (P < 0.0001, respectively) (Table 2). The change in the number of tophi by the final visit relative to baseline: No significant change in the number of tophi (mean [95% CI]) was observed during the final visit relative to baseline between the febuxostat 80 mg ( 0.28 [ 0.46, 0.11]), febuxostat 40 mg ( 0.11 [ 0.29, 0.06]), and allopurinol 300 mg ( 0.15 [ 0.33, 0.02]) groups (Table 2).
681
X. Huang et al.
Subjects Screened n = 679
Subjects Randomized n = 516
Febuxostat 40 mg/d group n = 172
Completed n = 146
Discontinued n = 26 Reason: 12 lost to follow-up 11 Adverse event 1 Protocal violation 2 Other reasons
Excluded 163 UA 300 mg/ day. As mentioned before, the daily dose of allopurinol was fixed at 300 mg in previous RCTs except in subjects with renal impairment.19,20,24 Since allopurinol hypersensitivity is rare, in the subjects with known allergy to allopurinol, and a serum creatinine concentration of more than 1.5 mg/dL (135 lmol/L), were ruled out in our trial; thus, we adopted the fixed allopurinol dose of 300 mg/dL in this study. The purpose of this study was to compare the UL efficacy and safety of daily febuxostat and allopurinol in Chinese gout patients with hyperuricemia. A daily dose of febuxostat 80 mg had higher UL efficacy than a daily dose of febuxostat 40 mg or allopurinol 300 mg. A daily dose of febuxostat 40 mg was
683
X. Huang et al.
Table 2 Primary and secondary endpoints Endpoint
Febuxostat 40 mg/day group (N = 172)
Allopurinol
80 mg/day group (N = 172)
Primary efficacy endpoint Serum urate < 6.0 mg/dL at last 3-monthly visits n / (%) 47 (27.33%) 77 (44.77%) P-value 0.0008† < 0.0001‡,¶ Second efficacy endpoint The reduction of sUA level in the final visit against baseline Mean (95% CI) 3.25 ( 3.57, 2.94) 4.17 ( 4.48, 3.86) P-value < 0.0001† < 0.0001‡ The change in the number of tophi at final visit against baseline Mean (95%CI) 0.11 ( 0.29, 0.06) 0.28 ( 0.46, 0.11) P-value 0.3539† 0.1777‡ The rates of subjects requiring treatment for acute gout flares from weeks 9 through 28 n / (%) 9 (5.23%) 7 (4.07%) P-value 0.6086† 0.0521‡
300 mg/day group (N = 172)
41 (23.84%) 0.4584§
3.25 ( 3.57, 0.8844§
2.94)
0.15 ( 0.33, 0.02) 0.6734§ 16 (9.3%) 0.1460§
†The comparison between febuxostat 40 mg/day and febuxostat 80 mg/day. ‡The comparison between febuxostat 80 mg/day and allopurinol 300 mg/day. §The comparison between febuxostat 40 mg/day and allopurinol 300 mg/day. ¶A Cochran–Mantel–Haenszel (CMH) test was used for superiority comparison with a significance level of 0.01.
Table 3 Summary of adverse events Adverse event
Febuxostat 40 mg/day group N = 172 n (%)
Any adverse event 96 (55.81%) Any treatment-related event 55 (31.98%) Any events leading to discontinuation 11 (6.40%) Any serious event 2 (1.16%) Most frequent or important treatment-related adverse event Liver function test abnormalities 5 (2.91%) Hyperlipidemia 8 (4.65%) Serum creatinine > 135 lmol/L 2 (1.16%) Gastrointestinal disorder 0 Lack of strength 0 Hyperthyroidism 1 (0.58%)
Febuxostat 80 mg/Day group N = 172 n (%)
Allopurinol 300 mg/day group N = 172 n (%)
89 (51.74%) 58 (33.72%) 10 (5.81%) 1 (0.58%)
103 (59.88%) 68 (39.53%) 12 (6.98%) 2 (1.16%)
2 (1.16%) 7 (4.07%) 4 (2.32%) 5 (2.92%) 3 (1.74%) 0
6 (3.49%) 10 (5.81%) 2 (1.16%) 1 (0.58%) 1 (0.58%) 0
There were no significant differences among the three groups.
non-inferior to allopurinol 300 mg in UL efficacy. Our result was consistent with the findings of prior reports.19,20,24 The proportion of subjects with sUA < 6.0 mg/dL at the 28-week visit was 61.63% in this study, which was also comparable with the 67.1% value reported by Becker et al.19 However, a higher proportion of subjects with sUA < 6.0 mg/dL in a febuxostat 80 mg group at a 16-week visit was observed in a study in Japan,23 greater than in our study (87.8% vs. 63.95%). The factor most likely contributing to the difference might be the numbers of subjects enrolled in these two trials (42 vs. 172).
684
The rates of subjects requiring treatment for acute gout flares from weeks 9 through 28 were similar between febuxostat and allopurinol groups in our data (Table 2), which is consistent with previous reports.19,24 A greater reduction in the sUA level by the final visit relative to baseline was observed for febuxostat 80 mg than for febuxostat 40 mg, which suggested that the UL efficacy of febuxostat was dose-dependent, consistent with other reports.19,24 A greater dose of febuxostat should be used in patients who have greater uric acid pools.
International Journal of Rheumatic Diseases 2014; 17: 679–686
Febuxostat hyperuricemia & gout
The incidence of treatment-related events was 31.98% for febuxostat 40 mg, 33.72% for febuxostat 80 mg and 39.53% for allopurinol. There was no statistical difference between groups. Most of the adverse events were mild to moderate. There was no dosedependent increase in adverse events found in the febuxostat group, which was consistent with other reports.19,20,22,24 No serious events were judged by the investigators to be related to febuxostat.
CONCLUSION The UL efficacy of a daily dose of febuxostat 80 mg was superior to that of a daily dose of febuxostat 40 mg or allopurinol 300 mg. The UL efficacy of a daily dose of febuxostat 40 mg was non-inferior to that of allopurinol 300 mg. Febuxostat showed high efficacy and tolerability in the treatment of Chinese gout patients with hyperuricemia.
ACKNOWLEDGMENTS This study was supported by Wanbang Biopharmaceuticals (ChiCTR: 2009L08759, 2009L11564).
DISCLOSURES none.
AUTHORS CONTRIBUTIONS Study design: Chunde Bao; acquisition of data: Xinfang Huang, Hui Du, Jieruo Gu, Dongbao Zhao, Lindi Jiang, Xinfu Li, Xiaoxia Zuo, Yi Liu, Zhanguo Li, Xiangpei Li, Ping Zhu, Juan Li, Zhiyi Zhang, Anbin Huang, Yuanchao Zhang; statistical analysis: Chunde Bao, Xinfang Huang, Hui Du.
REFERENCES 1 Wortmann RL (2002) Gout and hyperuricemia. Curr Opin Rheumatol 14, 281–6. 2 Perez-Ruiz F, Alonso-Ruiz A, Calabozo M et al. (1998) Efficacy of allopurinol and benzbromarone for the control of hyperuricaemia. A pathogenic approach to the treatment of primary chronic gout. Ann Rheum Dis 57, 545–9. 3 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.
International Journal of Rheumatic Diseases 2014; 17: 679–686
4 Shoji A, Yamanaka H, Kamatani N (2004) A retrospective study of the relationship between serum urate level and recurrent attacks of gouty arthritis: evidence for reduction of recurrent gouty arthritis with antihyperuricemic therapy. Arthritis Rheum 51, 321–5. 5 Hall AP (1965) Correlations among hyperuricemia, hypercholesterolemia, coronary disease and hypertension. Arthritis Rheum 8, 846–52. 6 Abbott RD, Brand FN, Kannel WB, Castelli WP (1988) Gout and coronary heart disease: the Framingham Study. J Clin Epidemiol 41, 237–42. 7 Beard JT (1983) Serum uric acid and coronary heart disease. Am Heart J 106, 397–400. 8 Brand FN, McGee DL, Kannel WB, Stokes J, Castelli WP (1985) Hyperuricemia as a risk factor of coronary heart disease: the Framingham Study. Am J Epidemiol 121, 11–8. 9 Freedman DS, Williamson DF, Gunter EW, Byers T (1995) Relation of serum uric acid to mortality and ischemic heart disease. The NHANES I Epidemiologic Follow-up Study. Am J Epidemiol 141, 637–44. 10 Frohlich ED (1993) Uric acid. A risk factor for coronary heart disease. JAMA 270, 378–9. 11 Kim SY, Guevara JP, Kim KM, Choi HK, Heitjan DF, Albert DA (2010) Hyperuricemia and coronary heart disease: a systematic review and meta-analysis. Arthritis Care Res (Hoboken) 62, 170–80. 12 Li C, Hsieh MC, Chang SJ (2013) Metabolic syndrome, diabetes, and hyperuricemia. Curr Opin Rheumatol 25, 210–6. 13 Ryoo JH, Choi JM, Oh CM, Kim MG (2013) The association between uric acid and chronic kidney disease in Korean men: a 4-year follow-up study. J Korean Med Sci 28, 855–60. 14 Hande KR, Noone RM, Stone WJ (1984) Severe allopurinol toxicity. Description and guidelines for prevention in patients with renal insufficiency. Am J Med 76, 47–56. 15 Schlesinger N (2004) Management of acute and chronic gouty arthritis: present state-of-the-art. Drugs 64, 2399– 416. 16 Terkeltaub RA (2003) Clinical practice. Gout. N Engl J Med 349, 1647–55. 17 Fam AG (1998) Gout in the elderly. Clinical presentation and treatment. Drugs Aging 13, 229–43. 18 Harris MD, Siegel LB, Alloway JA (1999) Gout and hyperuricemia. Am Fam Physician 59, 925–34. 19 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. 20 Becker MA, Schumacher HR, Wortmann RL et al. (2005) Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med 353, 2450–61. 21 Becker MA, Schumacher HR, Wortmann RL et al. (2005) Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase: a twenty-eight-day, multicenter, phase II,
685
X. Huang et al.
randomized, double-blind, placebo-controlled, doseresponse clinical trial examining safety and efficacy in patients with gout. Arthritis Rheum 52, 916–23. 22 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. 23 Naoyuki K, Shin F, Toshikazu H et al. (2011) Placebocontrolled double-blind dose-response study of the nonpurine-selective xanthine oxidase inhibitor febuxostat (TMX-67) in patients with hyperuricemia (including gout patients) in japan: late phase 2 clinical study. J Clin Rheumatol 17, S35–43.
686
24 Schumacher HR, 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. 25 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. 26 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.
International Journal of Rheumatic Diseases 2014; 17: 679–686
