Rev Iss Web Jcpt 12391 41-3 290..297

Journal of Clinical Pharmacy and Therapeutics, 2016, 41,290–297 doi: 10.1111/jcpt.12391

Comparison of topiroxostat and allopurinol in Japanese hyperuricemic patients with or without gout: a phase 3, multicentre, randomized, double-blind, double-dummy, active-controlled, parallel-group study

T. Hosoya* MD PhD, Y. Ogawa† MSc, H. Hashimoto† PhD, T. Ohashi‡ PhD and R. Sakamoto† MSc *Department of Pathophysiology and Therapy in Chronic Kidney Disease, Jikei University School of Medicine, Tokyo, †Drug Development Center, Sanwa Kagaku Kenkyusho Co. Ltd., Aichi, and ‡Medical R&D Division, Fuji Yakuhin Co. Ltd., Saitama, Japan

Received 8 December 2015, Accepted 24 March 2016

Keywords: allopurinol, gout, hyperuricemia, topiroxostat

200 mg/day and is well tolerated in Japanese hyperuricemic SUMMARY patients with or without gout. What is known and objective: There are no clinical reports that have compared topiroxostat, a selective xanthine oxidase WHAT IS KNOWN AND OBJECTIVE inhibitor, with allopurinol in serum urate-lowering efficacy. The aim of this study was to compare the efficacy and safety of Gout is a common disease in adult males, and its acute symptom, the topiroxostat and allopurinol in Japanese hyperuricemic patients so-called gout attack, causes impaired quality of life.1 Because gout is with or without gout. related to monosodium urate crystal deposition, a causative disease Methods: A phase 3, multicentre, randomized, double-blind, of gout is hyperuricemia, which is defined as a serum urate level double-dummy, active-controlled, parallel-group study con- >416Á4 lmol/L in Japan.2 Therefore, it is essential to control hype- ducted in Japan. Patients who had inadequate serum urate levels ruricemia in order to treat gout and its related disorders such as gouty (a gout patient: serum urate level ≥416Á4 lmol/L; an asymptomatic arthritis. Surprisingly, the prevalence of hyperuricemia in male was hyperuricemic patient with specific complications (urinary lithi- approximately 20% in United States and 15–20% in Japan.3,4 asis, hypertension, hyperlipidemia and/or diabetes): serum urate Recent clinical reports have suggested a link between high level ≥475Á8 lmol/L; and an asymptomatic hyperuricemic patient serum urate levels and life-threatening diseases such as cardio- with no specific complications: serum urate level ≥535Á3 lmol/L) vascular disease, chronic kidney disease (CKD) and hyperten- – were randomized to topiroxostat 120 mg/day or allopurinol sion.5 10 Therefore, the management of hyperuricemia has become 200 mg/day, with an equal allocation ratio, for 16 weeks. To increasingly import. In Japan, in consideration of the results of prevent the onset of gouty arthritis by rapid serum urate these observational studies and some interventional studies, reduction, these doses were increased in a stepwise manner. asymptomatic hyperuricemia (serum urate level ≥475Á8 lmol/L) The primary efficacy endpoint was the per cent change in serum with lifestyle-related disease such as CKD, urinary lithiasis, urate level from baseline to the final visit. hypertension, hyperlipidemia or diabetes can be treated with Results and discussion: Overall, 206 patients were randomly urate-lowering drugs according to the individual patient’s clinical assigned to topiroxostat and allopurinol. Two hundred and three condition.2,11,12 This therapeutic policy is significantly different patients (allopurinol: n = 105, topiroxostat: n = 98) received at compared with that of other countries. least one dose of the study drug and had their serum urate level Topiroxostat, formerly known as FYX-051, is a selective assessed at least once. The baseline characteristics were compa- xanthine oxidoreductase (XOR) inhibitor recently approved in rable between groups. The mean age of patients was Japan for the treatment of hyperuricemia with or without gout and 53Á0 Æ 11Á4 years and 99% of patients were male. The primary has been developed for the treatment of diabetic nephropathy efficacy endpoint was À34Á3 Æ 11Á1% in the allopurinol group (UPWARD; NCT02327754).13,14 In contrast to allopurinol, the (n = 105) and À36Á3 Æ 12Á7% in the topiroxostat group (n = 98). pharmacokinetics of topiroxostat was not affected by renal Non-inferiority of the serum urate-lowering efficacy of topirox- function.15,16 Compared with febuxostat, whereas a part of the ostat to allopurinol was proved by the predefined non-inferiority metabolites of febuxostat consists of active oxidative metabolites, margin (95% confidence interval, À5Á3to1Á3%). The overall the major metabolites of topiroxostat (N-glucuronide and N-oxide ≥ l incidences of adverse events and adverse drug reactions were form) were generally inactive to XOR (IC50 10 mol/L), and the similar between both groups. urinary excretion rate of topiroxostat is <0Á1% in patients with – What is new and conclusion: Topiroxostat 120 mg/day provides moderate renal impairment.16 18 In view of the fact that hyper- non-inferior serum urate reduction compared with allopurinol uricemic patients have CKD with relatively high frequency, these pharmacokinetic profiles are useful.19 We previously reported that topiroxostat significantly reduced Correspondence Yoshimi Ogawa, MSc, Sanwa Kagaku Kenkyusho Co. serum urate levels and urinary albumin creatinine ratios in Ltd., 35, Higashisotobori-cho, Higashi-ku, Nagoya, Aichi 461-8631, Japanese hyperuricemic stage 3 CKD patients without dose Japan. Tel.: +81 52 951 8130; fax: +81 52 950 1860; e-mail: adjustment in a 22-week clinical trial.20 However, no clinical trial [email protected] fi The copyright line for this article was changed on 22nd November, has reported that compared the serum urate-lowering ef cacy of 2016 after original online publication. topiroxostat with other XOR inhibitors. This study was designed

© 2016 The Authors. 290 Journal of Clinical Pharmacy and Therapeutics Published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. Phase 3 study of topiroxostat T. Hosoya et al.

fi fi ‘ ’ to test the serum urate-lowering ef cacy and safety of topiroxostat were de ned as urate overproduction type ; (ii) patients with EUA < Á < Á fi ‘ ’ compared with allopurinol in Japanese hyperuricemic patients 0 48 or CUA 7 3 were de ned as urate underexcretion type ; (iii) > Á < Á fi ‘ with or without gout. patients with EUA 0 51 and CUA 7 3 were de ned as combined ’ Á ≤ ≤ Á ≥ Á type ; and (iv) patients with 0 48 EUA 0 51 and CUA 7 3 were defined as ‘normal type’.21 The 24-h urine collection is normally METHODS used for the classification.22 However, we used a 60-min urine collection method in view of difficulties for the 24-h urine Study design collection in outpatient settings. The study design was a phase 3, multicentre, randomized, double- blind, double-dummy, active-controlled, parallel-group study. We Randomization, blinding, intervention and follow-up conducted the study at 21 hospitals in Japan. The institutional review board at each centre approved the study protocol, A randomized block allocation of the study drug was conducted including the informed consent form, related documents and the by an independent organization. Patients, study investigators and implementation of the study. The study was conducted in local sponsor personnel were masked to treatment assignment compliance with the Declaration of Helsinki, the Pharmaceutical until the final database lock. At the end of the run-in period, Affairs Law of Japan, Good Clinical Practice guidelines (GCP) and eligible patients received allopurinol or topiroxostat (ratio 1 : 1) for other applicable regulatory requirements. Written informed con- 16 weeks. To maintain an appropriate double-blinding condition, sent was obtained from all of the participating patients prior to the the serum urate levels after randomization were concealed and a initiation of any study-related procedures. The clinical trial double-dummy design was adopted. information of the study was registered with the Japan Pharma- We chose the dose of topiroxostat on the basis of previous ceutical Information Center on April 2010 (Registration number: results from a dose-ranging phase 2a study, in which topiroxostat JapicCTI-101108). 120 mg/day demonstrated a significant reduction in serum urate levels. On the other hand, although the approved dosage of allopurinol is defined as 200–300 mg/day in Japan, the frequently Inclusion and exclusion criteria prescribed dose of allopurinol is 100 mg/day, and the highest Patients who met all of the inclusion criteria and did not meet any dosage is considered to be 200 mg/day in clinical practice.23 exclusion criteria were enrolled the study. The inclusion criteria of Therefore, we compared topiroxostat 120 mg/day with allopuri- the study were as follows: age 20–74 years at the day of nol 200 mg/day, which is the substantive highest dose of submission of written informed consent; the serum urate level at allopurinol. In this study, we used the dose up-titration method the run-in period was ≥416Á4 lmol/L (in gout or gouty tophus to minimize the risk of gouty arthritis arising in association with patients), ≥475Á8 lmol/L (in patients with asymptomatic hyper- rapid serum urate reduction.24 Specifically, the dosage of allop- uricemia who are being diagnosed as or treated for urinary urinol in the study was set as 100 mg/day for the first 2 weeks lithiasis, hypertension, hyperlipidemia and/or diabetes) or and then 200 mg/day for 14 weeks. The dosage of topiroxostat in ≥535Á3 lmol/L (in asymptomatic hyperuricemic patients who are the study was set as 40 mg/day for the first 2 weeks and then not being diagnosed as or treated for these complications 80 mg/day for 4 weeks, and 120 mg/day for 10 weeks. The study described above); outpatient (included no plan of hospital admis- scheme, including follow-up visit, is shown in Fig. 1. sion); and patients who can provide voluntary informed consent. The exclusion criteria were as follows: an attack of gouty arthritis Efficacy endpoints within 2 weeks prior to the first day of the study drug administration; hyperuricemia secondary to certain disorders; HbA1c The primary efficacy endpoint was the per cent change in serum (NGSP) ≥8Á4%; hepatic function impairment [serum alanine urate level from baseline to the final visit. The secondary efficacy aminotransferase (ALT) and/or aspartate aminotransferase (AST) endpoints were the proportion of patients with serum urate levels ≥100 IU/L]; impaired renal function [estimated glomerular filtra- ≤356Á9 lmol/L at the final visit, and the per cent change and tion rate (eGFR) <50 mL/min/1Á73 m2]; severe hypertension change in serum urate levels from baseline to the each visit. (systolic blood pressure ≥180 mmHg and/or diastolic blood pressure ≥110 mmHg); hypersensitivity to allopurinol; or the Safety evaluations presence of any other clinically significant medical condition that could potentially preclude participation in this study. Patients who During the study, vital signs, 12-lead electrocardiography, clinical had used urate-lowering agents (probenecid, bucolome, benzbro- laboratory tests and clinical examination were recorded at each marone or allopurinol), colchicine, agents potentially affecting the visit. The clinical investigators assessed any adverse events (AEs), serum urate level (pyrazinamide, ethambutol, mizoribine or their severity and the causal relationship with the study drug. AEs cyclosporine) and/or agents that could potentially cause adverse were classified according to system organ class and preferred term drug interaction with the study drug (6-mercaptopurine, azathio- (MEDDRA/J, version 13.0; Japanese Maintenance Organization, prine, vidarabine,warfarin potassium, chlorpropamide, cyclophos- Tokyo, Japan). The incidence of AEs, serious AEs and AEs leading phamide, phenytoin, theophylline, pentostatin, captopril, to discontinuation of the study were summarized as number of hydrochlorothiazide or ampicillin) entered a washout period of patients and percentage in each study group. ≥14 days before the run-in period after providing informed consent. The above-mentioned drugs were prohibited during the Statistical analyses study period. In the run-in period, we classified the type of hyperuricemia into The sample size calculation was based on the result of a phase 2a the following four types: (i) patients with urinary excretion of urate study of topiroxostat and on the result of the clinical study of > Á ≥ Á 25 [EUA (mg/kg/h)] 0 51 and urate clearance [CUA (mL/min)] 7 3 allopurinol. We assumed that the per cent change in serum urate

© 2016 The Authors. 291 Journal of Clinical Pharmacy and Therapeutics, 2016, 41,290–297 Journal of Clinical Pharmacy and Therapeutics Published by John Wiley & Sons Ltd. Phase 3 study of topiroxostat T. Hosoya et al.

Follow-up visit 6 4 02 6 10 14 16 (weeks)

Allopurinol 100 200 Wash mg/day mg/day out Run-in period period1) (1–4 weeks) ( 2 Topiroxostat weeks) 40 80 120 mg/day mg/day mg/day

Informed consent Randomization

Fig. 1. Study schema. 1)In the event, patients had been prescribed urate-lowering agents or agents affecting the serum urate level. level from baseline in topiroxostat was À38Á8% and À33Á9% in both non-inferiority of topiroxostat to allopurinol for the per cent allopurinol, with an assumed standard deviation (SD) of 10Á0% in change in serum urate levels with a one-sided significance level of each group. The non-inferiority margin was predefined as 8Á0%, 0Á025 and the superiority of topiroxostat to allopurinol for the per which was less than a quarter of the difference between allopurinol cent change in serum urate levels with a two-sided significance (À33Á9%) and placebo (0Á0%). An estimated 89 patients per group level of 0Á05. Assuming that some patients would discontinue from would be needed to provide approximately 90% power to show the study, we allocated 100 patients per group.

Enrolment Assessed for eligibility (n = 298) Excluded (n = 92) Did not meet inclusion criteria (n = 67) Met exclusion criteria (n = 23) Did not meet inclusion criteria and met exclusion criteria (n = 2) Randomized (n = 206)

Allocation

n Allocated to allopurinol ( = 106) Allocated to topiroxostat (n = 100) n Received 1 dose of the study drug ( = 105) Received 1 dose of the study drug (n = 100) n Did not receive the study drug ( = 1) Did not receive the study drug (n = 0) - Other reason (n = 1)

Follow-up

Lost to follow-up (n = 2) Lost to follow-up (n = 0) Did not visit the hospital (n = 2) Discontinued intervention (n = 8) Discontinued intervention (n = 9) Adverse event (n = 6) Adverse event (n = 5) Withdrew consent (n = 1) Withdrew consent (n = 2) Other reason (n = 1) Other reason (n = 2)

Analysis

Efficacy analysis: full analysis set (n = 105) Efficacy analysis: full analysis set (n = 98) Excluded from efficacy analysis (n = 1) Excluded from efficacy analysis (n = 2) - Did not receive the study drug (n = 1) - No data on serum urate level (n = 2)

Safety analysis: safety population (n = 105) Safety analysis: safety population (n = 100) Excluded from safety analysis (n = 1) Excluded from safety analysis (n = 0) - Did not receive the study drug (n = 1)

Fig. 2. Flow diagram of the study.

© 2016 The Authors. 292 Journal of Clinical Pharmacy and Therapeutics, 2016, 41,290–297 Journal of Clinical Pharmacy and Therapeutics Published by John Wiley & Sons Ltd. Phase 3 study of topiroxostat T. Hosoya et al.

Table 1. Baseline characteristics (full analysis set) for categorical variables and two-sample t-tests for continuous variables were implemented to test for homogeneity between study groups at baseline. Allopurinol Topiroxostat In the analyses of the primary efficacy endpoint, comparisons of 200 mg/day 120 mg/day (n = 105) (n = 98) P-Value* the mean values between study groups were performed using two-sample t-test. Assessment of non-inferiority of topiroxostat to allopurinol was based on a prespecified non-inferiority margin of Á Æ Á Á Æ Á Á Age (year) 53 7 11 9523 10 903736 8%. If non-inferiority was demonstrated, superiority of topirox- Á Á Á Male, n (%) 104 (99 0) 97 (99 0) 1 0000 ostat to allopurinol was assessed. In this case, the problem of Female, n (%) 1 (1Á0) 1 (1Á0) 26 2 Á Æ Á Á Æ Á Á multiple testing is avoided by a simple closed testing procedure. BMI (kg/m )258 4 2267 4 701683 fi Duration of hyperuricemia 8Á5 Æ 7Á09Á0 Æ 7Á40Á6458 In the analyses of the secondary ef cacy endpoints, two-sample v2 (year) t-tests were used for the continuous outcomes, and test was Have treatment history 88 (83Á8) 78 (79Á6) 0Á4366 used for binary outcomes. of hyperuricemia, n (%) Safety analyses were performed on the safety population, Serum urate (lmol/L) 505Á4 Æ 56Á9 512Á5 Æ 64Á50Á4064 consisting of all randomized patients who receive at least one Estimated glomerular 73Á8 Æ 14Á673Á3 Æ 13Á80Á7750 dose of the study drug and who had no critical GCP violation. v2 fi ltration rate test or Fisher’s exact test was used for the comparison of incidences Á 2 (mL/min/1 73 m ) between study groups. Classification of hyperuricemia, n (%) We performed prespecified subgroup analyses to the per cent Urate overproduction type 11 (10Á5) 11 (11Á2) 0Á9715 Á Á change in serum urate levels and the proportion of patients with Urate underexcretion type 84 (80 0) 79 (80 6) ≤ Á l Combined type 8 (7Á6) 6 (6Á1) serum urate level 356 9 mol/L. The subgroups were as follows: ≥ < Normal type 2 (1Á9) 2 (2Á0) age ( 65 or 65), with or without treatment history of hyper- Have history of gouty 75 (71Á4) 72 (73Á5) 0Á7451 uricemia; baseline serum urate levels; and classification of hype- arthritis, n (%) ruricemia. Two-sample t-tests, v2 test or Fisher’s exact test was Existence of gouty tophus, n (%) 1 (1Á0) 7 (7Á1) 0Á0303 used to make comparisons between study groups. Á Á Á Family history of gout, n (%) 22 (21 0) 14 (14 3) 0 2139 The significance level of all efficacy and safety analyses was set Á Á Á Entered washout period, n (%) 67 (63 8) 64 (65 3) 0 8237 at 0Á05 (two-sided) and all confidence intervals (CI) at a two-sided confidence level of 95%. For assessing the homogeneity of baseline *t-test for continuous variables; Fisher’s exact test for sex, classification of characteristics, the significance level was set at 0Á15 (two-sided). hyperuricemia and existence of gouty tophus; chi-square test for the other The continuous data were summarized as mean Æ SD if not categorical variables. otherwise specified. These statistical analytical approaches were l Á To convert serum urate levels from mol/L to mg/dL, divide by 59 48. prespecified before the final database lock. No interim analyses were performed during the study period. Primary analyses were performed on the full analysis set, consisting of all randomized patients who received at least one RESULTS AND DISCUSSION dose of the study drug, were measured for the efficacy variable (serum urate level) at least once after randomization and had no Patient flow critical GCP violation. For the efficacy analyses, if patients As far as we know, this is the first reported comparative clinical dropped out of the study before completion, the missing data study of the serum urate-lowering effect of topiroxostat and were input based on the last observation carried forward (LOCF) allopurinol. The flow diagram of the study is summarized in method. Fig. 2. From April 2010 to January 2011, 298 patients were The baseline characteristics are summarized by study group assessed for eligibility, and 206 patients were randomized to the using appropriate descriptive statistics. v2 test or Fisher’s exact test study. Of note, one patient in the allopurinol group did not take the study drug at all; therefore, 205 patients were included in the safety population. Of 205 patients, two patients in the topirox- 700 ostat group discontinued the study without their serum urate 600 levels being measured after randomization. As a result, 203 patients were included in the full analysis set. One hundred and 500 mol/L) eighty-six patients (95 patients in the allopurinol group and 91 μ 400 patients in the topiroxostat group) completed the study. The 300 baseline characteristics of the full analysis set were similar between groups except for existence of gouty tophus (Table 1). 200 Allopurinol 200 mg/day Overall, mean age was 53Á0 Æ 11Á4 years, 99% of patients were

Serum urate ( 100 Topiroxostat 120 mg/day male, mean serum urate level was 508Á8 Æ 60Á6 lmol/L, mean 0 body mass index was 26Á3 Æ 4Á4 kg/m2, mean duration of 0 2 4 6 8 10121416 hyperuricemia was 8Á8 Æ 7Á2 years, 80Á3% of patients were Time (weeks) considered to be the urate underexcretion type, and all patients were Japanese. 64Á5% of patients had received serum urate- Fig. 3. Time course of serum urate levels (Full analysis set). Error lowering agents just before entry into the study, and all of these bars indicate standard deviation. To convert serum urate levels patients entered a washout period of ≥2 weeks after providing from lmol/L to mg/dL, divide by 59Á48. informed consent.

© 2016 The Authors. 293 Journal of Clinical Pharmacy and Therapeutics, 2016, 41,290–297 Journal of Clinical Pharmacy and Therapeutics Published by John Wiley & Sons Ltd. Phase 3 study of topiroxostat T. Hosoya et al.

Table 2. Prespeciﬁed subgroup analyses of per cent change in serum urate levels from baseline to the ﬁnal visit (full analysis set)

Allopurinol Topiroxostat

Difference (95% CI) Mean per cent change (95% CI) (number of patients) vs. allopurinol P-value*

Age <65 years À33Á5(À35Á7toÀ31Á2) (84) À35Á2(À38Á0toÀ32Á4) (82) À1Á7(À5Á3to1Á8) 0Á3399 ≥65 years À37Á4(À43Á4toÀ31Á4) (21) À41Á8(À48Á0toÀ35Á7) (16) À4Á4(À12Á9to4Á0) 0Á2906 Treatment history No À32Á2(À37Á5toÀ26Á8) (17) À32Á7(À39Á0toÀ26Á3) (20) À0Á5(À8Á7to7Á7) 0Á9012 of hyperuricemia Yes À34Á7(À37Á0toÀ32Á3) (88) À37Á2(À40Á0toÀ34Á4) (78) À2Á5(À6Á2to1Á1) 0Á1659 Serum urate level ≤416Á4 > 475Á8 lmol/L À28Á9(À33Á0toÀ24Á8) (29) À34Á6(À39Á6toÀ29Á5) (27) À5Á7(À12Á0to0Á7) 0Á0793 at baseline ≤475Á8 > 535Á3 lmol/L À36Á9(À40Á0toÀ33Á9) (51) À36Á7(À41Á0toÀ32Á4) (42) 0Á2(À4Á9to5Á3) 0Á9251 ≤535Á3 > 594Á8 lmol/L À33Á6(À38Á5toÀ28Á7) (19) À38Á4(À44Á7toÀ32Á2) (14) À4Á8(À12Á3to2Á6) 0Á1955 ≥594Á8 lmol/L À39Á5(À48Á1toÀ31Á0) (6) À36Á2(À42Á3toÀ30Á1) (15) 3Á3(À7Á1to13Á8) 0Á5110 Classiﬁcation of Overproduction type À35Á0(À41Á4toÀ28Á5) (11) À45Á8(À52Á7toÀ39Á0) (11) À10Á9(À19Á7toÀ2Á0) 0Á0182 hyperuricemia Underexcretion type À34Á0(À36Á3toÀ31Á6) (84) À34Á9(À37Á6toÀ32Á1) (79) À0Á9(À4Á5to2Á7) 0Á6231 Combined type À38Á1(À51Á8toÀ24Á4) (8) À34Á8(À52Á5toÀ17Á2) (6) 3Á2(À16Á3to22Á7) 0Á7249 Normal type À27Á2(À42Á3toÀ12Á1) (2) À44Á1(À102Á9to14Á6) (2) À16Á9(À37Á4to3Á6) 0Á0712

*Two-sample t-tests. To convert serum urate levels from lmol/L to mg/dL, divide by 59Á48.

Efficacy in the allopurinol group in this study (Fig. 3). Therefore, we believe that the results obtained in this study are reasonable and The primary efficacy endpoint – the per cent change in serum urate practical. The robustness was supported by the result from per- level from baseline to the final visit – was À34Á3 Æ 11Á1% in protocol analysis (Appendix S1). In addition, the results of the allopurinol group (n = 105) and À36Á3 Æ 12Á7% in topiroxostat prespecified subgroup analyses demonstrated that the per cent group (n = 98) with between-group difference À2Á0% (95% CI: change in serum urate level of topiroxostat was numerically À5Á3to1Á3%) (P = 0Á2264; two-sample t-test). Because the upper similar except for the result of the overproduction type (Table 2). limit of 95% CI of the between-group difference was lower than the The reason for that may have been the small sample size; however, prespecified non-inferiority margin, the non-inferiority of the this remains unclear and warrants further studies. serum urate-lowering efficacy of topiroxostat to allopurinol was The proportion of patients with a serum urate level proved. ≤356Á9 lmol/L was not significant with topiroxostat [72Á4% (95% The per cent changes in serum urate levels in the allopurinol CI: 62Á5to81Á0)] compared with allopurinol [73Á3% (95% CI: 63Á8to group after 6 weeks of treatment in this study were generally same 81Á5)], with a between-group difference of À0Á9% (95% CI: À13Á1to with the per cent change of serum urate in the other clinical study 11Á4) (P = 0Á8873, v2 test) (Fig. 4). For each prespecified subgroup of allopurinol.27 In addition, the effect was constant until week 16 analysis, the percentage was similar between groups (Table 3). The per cent change and change in serum urate levels from baseline at P = 0·8873 each visit are shown in Appendix S2 and S3. 100 Safety 73·3 72·4 80 Summary of AEs in this study is shown in Table 4. Sixteen-week treatment with topiroxostat 120 mg/day was well tolerated, in which the incidence of overall AEs was similar to that of 60 allopurinol 200 mg/day (P = 0Á3329, v2 test). The incidence of adverse drug reaction was numerically higher in topiroxostat 2 40 group than in the allopurinol group (P = 0Á1974, v test), but the Patients (%) incidences of AEs that necessitated withdrawal from the study were similar between groups. One death in the allopurinol group 20 and two serious AEs (one prostate cancer and one colon polyp) in the topiroxostat group occurred in the study. No causalities 0 between study drugs and these serious AEs were reported. Five Allopurinol Topiroxostat patients in the topiroxostat group discontinued from the study due 200 mg/day 120 mg/day to AEs. These AEs were drug eruption, urinary b2-microglobulin n = 105 n = 98 increased, upper abdominal pain in one patient each and rash in two patients. In the allopurinol group, six patients (cardiac Fig. 4. Proportion of patients with a serum urate level hypertrophy leading to death, rhabdomyolysis, ALT and AST ≤356Á9 lmol/L (full analysis set). Error bars indicate 95% confi- increased, urticaria in one patient each and gouty arthritis in two dence interval. patients) discontinued from the study due to AEs. Clinical

© 2016 The Authors. 294 Journal of Clinical Pharmacy and Therapeutics, 2016, 41,290–297 Journal of Clinical Pharmacy and Therapeutics Published by John Wiley & Sons Ltd. Phase 3 study of topiroxostat T. Hosoya et al.

Table 3. Prespeciﬁed subgroup analyses of the proportion of patients with a serum urate level ≤356Á9 lmol/L at the ﬁnal visit (full analysis set)

Allopurinol Topiroxostat

Difference (95% CI) no./total no. (%) (95% CI) vs. allopurinol P-value

Age <65 years 59/84 (70Á2) (59Á3to79Á7) 55/82 (67Á1) (55Á8to77Á1) À3Á2(À17Á3to10Á9) 0Á6602* † ≥65 years 18/21 (85Á7) (63Á7to97Á0) 16/16 (100Á0) (79Á4 to 100Á0) 14Á3(À0Á7to29Á3) 0Á2432 † Treatment history of No 14/17 (82Á4) (56Á6to96Á2) 15/20 (75Á0) (50Á9to91Á3) À7Á4(À33Á6to18Á9) 0Á7013 hyperuricemia Yes 63/88 (71Á6) (61Á0to80Á7) 56/78 (71Á8) (60Á5to81Á4) 0Á2(À13Á5to13Á9) 0Á9767* † Serum urate level ≤416Á4 > 475Á8 lmol/L 25/29 (86Á2) (68Á3to96Á1) 26/27 (96Á3) (81Á0to99Á9) 10Á1(À4Á3to24Á5) 0Á3533 at baseline ≤475Á8 > 535Á3 lmol/L 38/51 (74Á5) (60Á4to85Á7) 31/42 (73Á8) (58Á0to86Á1) À0Á7(À18Á6to17Á2) 0Á9387* ≤535Á3 > 594Á8 lmol/L 11/19 (57Á9) (33Á5to79Á7) 8/14 (57Á1) (28Á9to82Á3) À0Á8(À34Á9to33Á4) 0Á9655* † ≥594Á8 lmol/L 3/6 (50Á0) (11Á8to88Á2) 6/15 (40Á0) (16Á3to67Á7) À10Á0(À57Á1to37Á1) 1Á0000 † Classiﬁcation of Overproduction type 9/11 (81Á8) (48Á2to97Á7) 11/11 (100Á0) (71Á5 to 100Á0) 18Á2(À4Á6to41Á0) 0Á4761 hyperuricemia Underexcretion type 63/84 (75Á0) (64Á4to83Á8) 56/79 (70Á9) (59Á6to80Á6) À4Á1(À17Á8to9Á5) 0Á5543* † Combined type 4/8 (50Á0) (15Á7to84Á3) 2/6 (33Á3) (4Á3to77Á7) À16Á7(À67Á9to34Á6) 0Á6270 † Normal type 1/2 (50Á0) (1Á3to98Á7) 2/2 (100Á0) (15Á8 to 100Á0) 50Á0(À19Á3 to 100Á0) 1Á0000

† *v2 test, Fisher’s exact test. To convert serum urate levels from lmol/L to mg/dL, divide by 59Á48.

Table 4. Summary of AEs (safety population) As for the results of liver function test, the incidences of ‘ALT increased’, ‘AST increased’ and ‘c-glutamyltransferase (cGTP) Allopurinol Topiroxostat increased’ were 2- to 3-fold higher in the topiroxostat group than (n = 105) (n = 100) in the allopurinol group (Table 4). The severity of all of these AEs was mild in the topiroxostat group, and these patients did not discontinue from the study. Any AE, n (%) 98 (93Á3) 97 (97Á0) No severe skin-related AE was observed, but some skin-related Any serious AE, n (%) 1 (1Á0) 2 (2Á0) Any adverse drug reaction, n (%) 29 (27Á6) 36 (36Á0) AEs including rash occurred in both groups [allopurinol group: Á Á AEs necessitated withdrawal 6(5Á7) 5 (5Á0) 5 7% (6/105), topiroxostat group: 7 0% (7/100)]. Among these of the patient from the study, n (%) patients, one patient [urticaria (severity: mild)] in allopurinol Frequent AEs (incidence ≥10%), n (%) group and three patients [drug eruption in one patient (severity: Nasopharyngitis 10 (9Á5) 10 (10Á0) moderate) and rash in two patients (severity: mild)] in the Gouty arthritis 8 (7Á6) 12 (12Á0) topiroxostat group discontinued from the study. The severities of Á Á ALT increased 8 (7 6) 24 (24 0) the other skin-related AEs were mild. Five of six patients in Á Á AST increased 12 (11 4) 24 (24 0) allopurinol group and all of seven patients in topiroxostat group b2-microglobulin increased 16 (15Á2) 16 (16Á0) were recovered from skin-related AEs, and one patient in Urinary b2-microglobulin increased 24 (22Á9) 16 (16Á0) Urinary NAG increased 21 (20Á0) 25 (25Á0) allopurinol group was recovering from the skin-related AEs Blood amylase increased 11 (10Á5) 6 (6Á0) (pruritus and eczema). Blood CPK increased 16 (15Á2) 17 (17Á0) It is clinically important to evaluate the safety profile in patients Blood triglycerides increased 40 (38Á1) 42 (42Á0) who took urate-lowering agents before enrolling in the study. cGTP increased 5 (4Á8) 15 (15Á0) Among washout patients in safety population, 6Á0% (4/67) in WBC count increased 11 (10Á5) 5 (5Á0) allopurinol group and 6Á2% (4/65) in topiroxostat group devel- a Á Á Urinary 1-microglobulin increased 33 (31 4) 34 (34 0) oped skin-related AEs. The incidences were numerically similar between groups, but various urate-lowering agents were pre- ALT, alanine aminotransferase; AE, adverse event; AST, aspartate amino- scribed before participation of the study, and these urate-lowering transferase; NAG, b-N-acetyl-D-glucosaminidase; CPK, creatine phosphok- agents were not controlled. Therefore, the profile of the skin- c c inase; GTP, -glutamyltransferase; WBC, white blood cell. related AE in patients who switched from other urate-lowering agents to topiroxostat is uncertain at this time. When prescribing investigators determined that all of these AEs (except for cardiac topiroxostat, clinicians should assume that there may be an hypertrophy leading to death, ALT and AST increased, and occurrence of gouty arthritis, abnormal liver function test results urticaria) were adverse drug reactions. or skin diseases. In spite of the gradual dose up-titration method, the incidence of gouty arthritis was not statistically significant, but tended to have Limitations a higher incidence in the topiroxostat group than in the allopurinol group (P = 0Á2906, v2 test) (Table 4). In detail, all patients had mild Our study had several potential limitations. First, the mean baseline severity of gouty arthritis that occurred in the topiroxostat group serum urate level of the study was relatively low compared with except for one patient who had moderate severity, and none of the that of previous clinical studies conducted in countries other than patients discontinued from the study because of gouty arthritis. Japan.28 Therefore, no conclusion can be made in more severe

© 2016 The Authors. 295 Journal of Clinical Pharmacy and Therapeutics, 2016, 41,290–297 Journal of Clinical Pharmacy and Therapeutics Published by John Wiley & Sons Ltd. Phase 3 study of topiroxostat T. Hosoya et al. hyperuricemic patients. Second, all of the patients who participated CONFLICT OF INTEREST in our study were Japanese, limiting generalizability to other ethnic populations. Third, to avoid the onset of allopurinol TH has received consultant fees and/or speaker’s honoraria from hypersensitivity, the inclusion of renal-impaired patients was Fuji Yakuhin Co., Ltd., and/or Sanwa Kagaku Kenkyusho Co., limited; therefore, the serum urate-lowering efficacy of topiroxostat Ltd., the manufacturer of topiroxostat. YO, HH and RS were 120 mg/day in renal-impaired patients is uncertain. Finally, employees of Sanwa Kagaku Kenkyusho Co., Ltd., at the time of because of the difficulty of the 24-h urine collection, the classifica- the study. TO was an employee of Fuji Yakuhin Co., Ltd., at the tion method in our study was significantly different method in time of the study. outside Japan. Therefore, the result of subgroup analysis by the classification of hyperuricemia in this study may have a different SUPPORTING INFORMATION result from that by the classification of the 24-h urine collection. Additional Supporting Information may be found in the online version of this article: WHAT IS NEW AND CONCLUSION Appendix S1 Summary of primary efficacy endpoint (Per- Topiroxostat 120 mg/day provides non-inferior serum urate protocol set). reduction compared with allopurinol 200 mg/day and is well Appendix S2 Percent change in serum urate levels from tolerated in Japanese hyperuricemic patients with or without gout. baseline to each visit (Full analysis set). Appendix S3 Change in serum urate level from baseline to each visit (Full analysis set). ACKNOWLEDGEMENTS We are grateful to the investigators, local study coordinators and the patients for their valuable contributions to this study. Sanwa Kagaku Kenkyusho Co., Ltd., sponsored this study.

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