Multicenter randomized controlled trial of intensive uric acid lowering therapy for CKD patients with hyperuricemia: TARGET-UA.

BACKGROUND: We investigate whether Intensive uric acid (UA)-lowering therapy (ULT) provides increased renal protection compared with standard therapy in chronic kidney disease (CKD) patients. METHODS: This was a multicenter randomized controlled trial. Only CKD patients with hyperuricemia were included in this study. The participants were randomly assigned to either the Intensive therapy group (target serum UA level ≥ 4.0 mg/dL and < 5.0 mg/dL) or the standard therapy group (serum UA level ≥ 6.0 mg/dL and < 7.0 mg/dL). ULT was performed using topiroxostat, a non-purine-type selective xanthine oxidase inhibitor. The primary endpoint was change in the logarithmic value of urine albumin to the creatinine ratio (ACR) between baseline and week 52 of the treatment. RESULTS: Three hundred fifty-two patients were included in the full analysis set. In the Standard therapy group, mean serum UA was 8.23 mg/dL at baseline and 6.13 mg/dL at 52 weeks. In the Intensive therapy group, mean serum UA was 8.15 mg/dL at baseline and 5.25 mg/dL at 52 weeks. There was no significant difference in changes in log ACR at 52 weeks between the Intensive therapy and the Standard therapy groups. CONCLUSION: This study did not reveal the benefit of Intensive ULT to improve albuminuria levels. (UMIN000026741 and jRCTs051180146).

Effect of Topiroxostat on Reducing Oxidative Stress in the Aorta of Streptozotocin-Induced Diabetic Rats.

Xanthine oxidoreductase exists both intracellularly and extracellularly and induces vascular injury by producing reactive oxygen species (ROS). Here, we investigated the effects and mechanism of action of topiroxostat, a xanthine oxidase inhibitor, on ROS using an animal model of type 1 diabetes with persistent hyperglycemia. Six-week-old male Sprague-Dawley rats were administered 50 mg/kg streptozotocin to induce diabetes; at 8 weeks of age, animals were administered topiroxostat (0.3, 1, or 3 mg/kg) for 2 weeks through mixed feeding after which the aorta was sampled. The production of superoxide, a type of ROS, was measured by chemiluminescence and dihydroethidium staining. Cytotoxicity was evaluated by nitrotyrosine staining. Topiroxostat at 3 mg/kg significantly decreased blood urea nitrogen, e-selectin, urinary malondialdehyde, and the urinary albumin/creatinine ratio compared with the streptozotocin group. Superoxide production by xanthine oxidase anchored to the cell membrane was significantly decreased by topiroxostat at both 1 mg/kg and 3 mg/kg compared with the streptozotocin group. Dihydroethidium staining revealed no significant effect of topiroxostat administration on superoxide production. The fluorescence intensity of nitrotyrosine staining was significantly suppressed by 3 mg/kg topiroxostat. Topiroxostat was found to inhibit the production of ROS in the thoracic aorta and suppress vascular endothelial damage. The antioxidant effect of topiroxostat appears to be exerted via the inhibition of anchored xanthine oxidase.

Chronic kidney disease: Which role for xanthine oxidoreductase activity and products?

The present review explores the role of xanthine oxidoreductase (XOR) in the development and progression of chronic kidney disease (CKD). Human XOR is a multi-level regulated enzyme, which has many physiological functions, but that is also implicated in several pathological processes. The main XOR activities are the purine catabolism, which generates uric acid, and the regulation of cell redox state and cell signaling, through the production of reactive oxygen species. XOR dysregulation may lead to hyperuricemia and oxidative stress, which could have a pathogenic role in the initial phases of CKD, by promoting cell injury, hypertension, chronic inflammation and metabolic derangements. Hypertension is common in CKD patients and many mechanisms inducing it (upregulation of renin-angiotensin-aldosterone system, endothelial dysfunction and atherosclerosis) may be influenced by XOR products. High XOR activity and hyperuricemia are also risk factors for obesity, insulin resistance, type 2 diabetes and metabolic syndrome that are frequent CKD causes. Moreover, CKD is common in patients with gout, which is characterized by hyperuricemia, and in patients with cardiovascular diseases, which are associated with hypertension, endothelial dysfunction and atherosclerosis. Although hyperuricemia is undoubtedly related to CKD, controversial findings have been hitherto reported in patients treated with urate-lowering therapies.

Protective Effect of Topiroxostat on Myocardial Injury Induced by Lipopolysaccharide.

BACKGROUND: Myocardial injury induced by sepsis is the most common cause of death. Topiroxostat has been found to have organ protective effects, but its role in septic shock-related cardiomyocyte damage is still unclear and needs further study. MATERIAL AND METHODS: An endotoxemic shock model in rats was constructed. After topiroxostat treatment, hemodynamic parameters, myocardial injury marker enzymes, oxidative stress, myocardial injury, and apoptosis were measured by polyphysiograph, enzyme-linked immunosorbent assay, hematoxylin and eosin staining, TUNEL staining, and western blot. During in vitro experiments, the effect of topiroxostat on cell vitality, oxidative stress, inflammatory factors, apoptosis-related markers, phosphorylated-p65 (p-p65) and p65 expressions were measured by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), flow cytometry, enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction, and western blot. RESULTS: Topiroxostat improved myocardial dysfunction and superoxide dismutase activity while suppressing levels of creatine kinase, lactate dehydrogenase and malondialdehyde in serum of endotoxemic shock rats. Additionally, topiroxostat augmented dry-wet weight ratios of the hearts in rats. Meanwhile, topiroxostat was proved to alleviate interstitial edema and apoptosis in myocardial tissues of endotoxemic shock rats. During in vitro experiments, topiroxostat pretreatment elevated lipopolysaccharide (LPS)-induced H9c2 cell vitality, and alleviated oxidative stress and inflammation. Moreover, topiroxostat pretreatment downregulated apoptosis-related markers, p-p65, and p-p65/p65 levels in LPS-induced H9c2 cells. CONCLUSIONS: Topiroxostat attenuated LPS-induced myocardial injury via repressing apoptosis and oxidative stress.

Development of an In Vivo Predictive Dissolution Methodology of Topiroxostat Immediate-Release Tablet Using In Silico Simulation.

The main objective of this study was to develop an in vivo predictive dissolution (IVPD) model for topiroxostat immediate-release (IR) formulation by the combination of mechanistic absorption model (MAM) deconvolution method with time shifting factor (TSF) adjustment. The in vitro dissolution profiles in different biorelevant dissolution media containing different concentrations of sodium lauryl sulfate (SLS) were obtained from dissolution testing with the paddle method of the US Pharmacopeia, while the human pharmacokinetic profile was taken from the published experimental results. The GastroPlus™ software was used to observe the linear relationship between in vitro drug dissolution and in vivo absorption. The pharmacokinetic profile of topiroxostat IR tablet was first deconvoluted through the MAM method to obtain the fraction absorbed in vivo. Next, Levy plot was constructed to estimate the TSF, and the time scale for both processes of dissolution and absorption was then adjusted to be superimposable. The IVPD modelling was subsequently established with data between in vitro dissolution profiles and fraction absorbed in vivo. Finally, the dissolution profiles of topiroxostat IR tablet were translated into a pharmacokinetic curve in terms of convolution method. The comparison between translated and observed pharmacokinetic data will validate the performance of the developed IVPD model. This new linear IVPD model with high predictive power for the tablet can predict the in vivo pharmacokinetic differences through in vitro dissolution data, and it can be utilized as a risk-control tool for the formulation development of the topiroxostat IR tablet and the quality control of product batches.

Intensive uric acid-lowering therapy in CKD patients: the protocol for a randomized controlled trial.

BACKGROUND: Hyperuricemia would be a risk factor for the development/progression of CKD. However, several studies showed U-shape association between serum uric acid level and renal impairment, suggesting that hypouricemia was rather associated with renal dysfunction. Perhaps, there is the optimal target level of serum UA for renal function. METHODS: The Target-UA study is a multicenter randomized controlled trial. Eligible CKD patients (eGFR ≥ 30, < 60 mL/min/1.73 m2 and urine protein < 0.5 g/gCr or urine albumin to creatinine ratio (ACR) < 300 mg/gCr) with serum UA ≥ 8.0 mg/dL (≥ 7.0 mg/dl: under the treatment) will be enrolled and be randomly assigned to the intensive therapy group (target serum UA level ≥ 4.0 mg/dL, < 5.0 mg/dL) or the standard therapy group (serum UA level ≥ 6.0 mg/dL, < 7.0 mg/dL). Topiroxostat, a new xanthine oxidase inhibitor, will be administered to treat hyperuricemia. The primary endpoint is a change in logarithmic value of urine ACR between baseline and week 52 of treatment. The secondary endpoints include changes in serum UA, eGFR, urine protein, lipid profile, and onset of composite cardiovascular events, renal events, gouty arthritis, and attack of urolithiasis. The number of subjects has been set to be 185 in each group for a total of 370. DISCUSSION: This is the first study, to the best of our knowledge, to determine the optimal target level of serum UA for renal protection and is expected to lead to progress in CKD treatment. TRIAL REGISTRATION: (UMIN000026741 and jRCTs051180146).

Efficacy of xanthine oxidase inhibitor for chronic kidney disease patients with hyperuricemia.

BACKGROUND: Hyperuricemia is a known risk factor for end-stage renal disease. Although xanthine oxidase (XO) inhibitors are expected to protect the kidney function, evidence to this end is insufficient at present. METHODS: This study was a multi-center, open-labeled, randomized study conducted in Mie Prefecture in Japan. Patients were included if they were between 20 and 80 years old and had a serum uric acid (sUA) level ≥ 7.0 mg/dl with or without gout, estimated glomerular filtration rate (eGFR) of 15-60 ml/min/1.73 m2, and urinary protein creatinine ratio (uPCR) of 0.15-3.5 g/gCr. Patients were randomly assigned to a Topiroxostat or Febuxostat group, and the treatment target for the sUA level was < 6.0 mg/dl. The primary outcome was the change in the uPCR after 24 weeks. RESULTS: The change in the median uPCR after 24 weeks was not statistically significant after treatment in the Topiroxostat or Febuxostat group (0.05 g/gCr and - 0.04 g/gCr, respectively). However, the sUA levels decreased significantly in both groups (Topiroxostat group: 8.6 ± 1.1 at baseline to 6.0 ± 1.1 mg/dl at 24 weeks, Febuxostat group: 8.4 ± 1.1 mg/dl at baseline to 5.9 ± 1.3 mg/dl at 24 weeks). No significant change in the eGFR after 24 weeks was noted in either the Topiroxostat or Febuxostat group (- 0.04 ± 4.59 ml/min/1.73 m2 and 0.31 ± 4.70 ml/min/1.73 m2, respectively). CONCLUSIONS: In this study, XO inhibitors did not significantly reduce the uPCR in chronic kidney disease stage 3 and 4 patients with hyperuricemia.

The effect for hyperuricemia inpatient of uric acid overproduction type or in combination with topiroxostat on the pharmacokinetics, pharmacodynamics and safety of dotinurad, a selective urate reabsorption inhibitor.

BACKGROUND: Dotinurad, a novel selective urate reabsorption inhibitor (SURI), increases urinary uric acid excretion. The aim of this study is to examine the pharmacokinetics, pharmacodynamics, and safety of dotinurad according to the type of hyperuricemia, with or without concomitant use of xanthine oxidase inhibitor, in uric acid "overproduction type" patients. METHODS: This open-label clinical pharmacology study was conducted in a hospital. Dotinurad 1 mg was administered for 7 days to hyperuricemic patients with uric acid "overproduction type" (overproduction group, n = 6; and combination group, n = 6) and uric acid "underexcretion type" (underexcretion group, n = 6). In the combination group, topiroxostat 80 mg was used concomitantly. RESULTS: No significant differences were observed in pharmacokinetics and safety between overproduction group and underexcretion group, and the percent change in serum uric acid level and the amount of urinary uric acid excretion after administration were comparable. In "overproduction type" patients of combination group, the percent change in serum uric acid level significantly increased and the amount of urinary uric acid excretion significantly decreased compared to those of overproduction group. No clinically meaningful differences were observed in safety between the overproduction group and the combination group. CONCLUSION: In inpatients, differences in hyperuricemic type did not significantly influence the pharmacokinetics, pharmacodynamics, and safety of dotinurad. Moreover, in "overproduction type", the coadministration of dotinurad and topiroxostat had an add-on serum uric acid lowering effect and suppressed urinary uric acid excretion. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02837198.

Protective Effects of Topiroxostat on an Ischemia-Reperfusion Model of Rat Hearts.

BACKGROUND: Ischemia/reperfusion (I/R) injury triggers cardiac dysfunctions via creating reactive oxygen species (ROS). Because xanthine oxidase (XO) is one of the major enzymes that generate ROS, inhibition of XO is expected to suppress ROS-induced I/R injury. However, it remains unclear whether XO inhibition really yields cardioprotection during I/R. The protective effects of the XO inhibitors, topiroxostat and allopurinol, on cardiac I/R injury were evaluated.Methods and Results:Using isolated rat hearts, ventricular functions, occurrence of arrhythmias, XO activities and thiobarbituric acid reactive substances (TBARS) productions and myocardial levels of adenine nucleotides before and after I/R, and cardiomyocyte death markers during reperfusion, were evaluated. Topiroxostat prevented left ventricular dysfunctions and facilitated recovery from arrhythmias during I/R. Allopurinol and the antioxidant, N-acetylcysteine (NAC), exhibited similar effects at higher concentrations. Topiroxostat inhibited myocardial XO activities and TBARS productions after I/R. I/R decreased myocardial levels of ATP, ADP and AMP, but increased that of xanthine. While topiroxostat, allopurinol or NAC did not change myocardial levels of ATP, ADP or AMP after I/R, all of the agents decreased the level of xanthine. They also decreased releases of CPK and LDH during reperfusion. CONCLUSIONS: Topiroxostat showed protective effects against I/R injury with higher potency than allopurinol or NAC. It dramatically inhibited XO activity and TBARS production, suggesting suppression of ROS generation.

Effects of topiroxostat in hyperuricemic patients with chronic kidney disease.

BACKGROUND: Hyperuricemia is associated with chronic kidney disease (CKD). Although topiroxostat, a novel, non-purine, selective xanthine oxidase inhibitor, has a strong effect against hyperuricemia, limited data are available on its renoprotective effect against CKD. METHODS: This study was conducted between October 2014 and May 2016. Thirty patients (20 male, 10 female) were administered 40 mg/day of topiroxostat twice daily. All patients were followed for a year. To elucidate the effects of topiroxostat, we evaluated the clinically documented primary indication of progression, viz. laboratory evidence of kidney function decline (reference indicator), uric acid, and hypertension in different patient groups, separated according to their baseline uProt levels and baseline eGFR. RESULTS: Topiroxostat treatment resulted in significant reduction in SUA (-1.53 mg/dL), systolic blood pressure (-8.9 mmHg), diastolic blood pressure (-5.0 mmHg), and urinary protein excretion (-795.5 mg/gCr) compared with baseline values. However, serum creatinine and urinary NAG levels, and estimated glomerular filtration rate did not change significantly. CONCLUSIONS: Topiroxostat reduced SUA levels effectively and may exhibit renoprotective effect in hyperuricemic patients with CKD. Further studies are required to clarify whether topiroxostat prevents the progression of renal disease and improves the prognosis of CKD patients.

Uric acid-lowering and renoprotective effects of topiroxostat, a selective xanthine oxidoreductase inhibitor, in patients with diabetic nephropathy and hyperuricemia: a randomized, double-blind, placebo-controlled, parallel-group study (UPWARD study).

BACKGROUND: Hyperuricemia is supposed to be an independent risk factor for kidney dysfunction in diabetic patients. We attempted to examine the uric acid-lowering effect and the renoprotective effect of topiroxostat, a selective xanthine oxidoreductase inhibitor, in patients with diabetic nephropathy and hyperuricemia in this pilot study. METHODS: The study design was randomized, double-blind, placebo-controlled, parallel-group study. A total of 65 patients with hyperuricemia and diabetic nephropathy with microalbuminuria were enrolled and assigned to either the topiroxostat group or the placebo group. Topiroxostat (stepwise dosing from 40 to 160 mg/day) or matching placebo was administered BID for 28 weeks. The primary endpoint was a change in the urinary albumin-to-creatinine ratio in the first-morning-void urine sample. Secondary endpoints were changes in the estimated glomerular filtration rate and the serum uric acid level. RESULTS: At 28 weeks, there was no significant difference in the percent change from baseline in the urinary albumin-to-creatinine ratio between the two groups (topiroxostat: 0 vs. placebo: 17%, p = 0.3206), but the changes in the estimated glomerular filtration rate (- 0.2 vs. - 4.0 mL/min/1.73 m2, p = 0.0303) and the serum uric acid level (- 2.94 vs. - 0.20 mg/dL, p < 0.0001) were significantly different between the topiroxostat and placebo groups. Gouty arthritis occurred in 1 patient in the placebo group and no patients in the topiroxostat group. CONCLUSION: These findings support that diabetic nephropathy combined with hyperuricemia may be associated with kidney dysfunctions. Topiroxostat provides strict control of the serum uric acid level preventing decline of eGFR in these patients.

The effects of xanthine oxidase inhibitor in patients with chronic heart failure complicated with hyperuricemia: a prospective randomized controlled clinical trial of topiroxostat vs allopurinol-study protocol.

BACKGROUND: Hyperuricemia has a close relationship with cardiovascular diseases including heart failure. However, it is controversial whether xanthine oxidase inhibition has benefits for patients with chronic heart failure. We designed the Effect of Xanthine Oxidase Inhibitor in Chronic Heart Failure Patients Complicated with Hyperuricemia study (Excited-UA study) to compare the beneficial effects between a novel xanthine oxidoreductase inhibitor, topiroxostat, and a conventional agent, allopurinol, in patients with chronic heart failure and hyperuricemia. We focus on serum N-terminal pro-brain natriuretic peptide (NT-proBNP) level, echocardiography-based cardiac function, vascular endothelial function, renal function, inflammation, and oxidative stress. METHODS: The excited-UA is a prospective, randomized, open-label, blinded-endpoint clinical trial designed to prove our hypothesis that topiroxostat is more effective than allopurinol in patients with chronic heart failure and hyperuricemia. A total of 140 patients with chronic heart failure and hyperuricemia (plasma brain natriuretic peptide level ≥ 40 pg/mL and serum uric acid level ≥ 7.0 mg/dL) are randomly assigned (ratio 1:1) into either the topiroxostat group (40-160 mg/day) or allopurinol group (100-300 mg/day), to achieve the target uric acid level of 6.0 mg/dL. According to the protocol, all patients are followed up annually for 24 weeks. The primary endpoint is percent change in serum NT-proBNP level at 24 weeks from baseline. CONCLUSIONS: The Excited-UA study would provide novel evidence for the clinical relevancy of xanthine oxidoreductase inhibitor treatment in patients with chronic heart failure and hyperuricemia.

Renoprotective effects of topiroxostat for Hyperuricaemic patients with overt diabetic nephropathy study (ETUDE study): A prospective, randomized, multicentre clinical trial.

AIM: We aimed to evaluate the anti-albuminuric effects of topiroxostat in Japanese hyperuricaemic patients with diabetic nephropathy. METHODS: In this 24-week, multicentre, open-label, randomized (1 : 1) trial, we assigned hyperuricaemic patients with diabetic nephropathy (estimated glomerular filtration rate ≥ 20 mL/min per 1.73m2 ) and overt proteinuria (0.3 ≤ urine protein to creatinine ratio (UPCR) <3.5 g/g Cr) to either high dose (160 mg daily) or low dose (40 mg daily) topiroxostat. The primary endpoint was the change in albuminuria indicated by urine albumin-to-creatinine ratio (UACR) from the baseline at the final time point. RESULTS: A total of 80 patients underwent randomization. The changes in UACR after 24 weeks of treatment (or at the final time point if patients failed to reach 24 weeks) relative to the baseline were -122 mg/gCr (95% CI: -5.1 to -240.1, P = 0.041) in patients treated with high dose, while treatment with low dose topiroxostat could not show significant reduction (P = 0.067). In the linear mixed model including baseline albuminuria, eGFR, age, and sex as covariates, the decreases in UACR were still significant from baseline to 12 weeks by 228.7 ± 83.2 mg/gCr (P = 0.0075) in the high dose group. The adverse-event profile during this study was not different between the groups. CONCLUSION: Topiroxostat 160 mg daily reduced albuminuria in patients with diabetic nephropathy. (Funded by Sanwa Kagaku Kenkyusho; Trial registration, UMIN000015403).

Cross-Over Trial of Febuxostat and Topiroxostat for Hyperuricemia With Cardiovascular Disease (TROFEO Trial).

BACKGROUND: We previously reported that febuxostat was more effective for hyperuricemia than allopurinol. The efficacy, however, of topiroxostat (a novel xanthine oxidase reductase inhibitor similar to febuxostat), for hyperuricemia is unknown.Methods and Results:Patients with cardiovascular disease and hyperuricemia, in whom serum uric acid (s-UA) was controlled at ≤6 mg/dL, were eligible for enrollment. Fifty-five patients were randomized to receive either febuxostat or topiroxostat for 6 months and were switched to the other drug for the following 6 months. The primary endpoint was s-UA. Secondary endpoints included serum creatinine, estimated glomerular filtration rate, urinary albumin, cystatin-C, oxidized low-density lipoprotein, eicosapentaenoic acid/arachidonic acid ratio, lipid biomarkers, high-sensitivity C-reactive protein and B-type natriuretic protein. Although s-UA level was similar for both drugs, significantly more patients required dose escalation during treatment with topiroxostat. There were no differences in renal function, inflammatory and lipid markers between the 2 drugs. A biomarker of oxidative stress was significantly lower after 3 months of febuxostat compared with topiroxostat. CONCLUSIONS: Febuxostat causes more marked and more rapid reduction of s-UA than topiroxostat. With regard to the antioxidant effect, febuxostat was superior to topiroxostat after 3 months. The renal protective and anti-inflammatory effects of both drugs were also similar after 6 months of treatment. Thus, both of these agents were similarly effective for hyperuricemia in patients with cardiovascular disease.

Comparison of Clinical Advantage between Topiroxostat and Febuxostat in Hemodialysis Patients.

To determine the response of hemodialysis (HD) patients to topiroxostat after a switch from febuxostat, we evaluated the efficacy, tolerability, and serum concentration of topiroxostat in HD patients after the switch. In this 16-month prospective observational study, we assessed the serum uric acid (UA) levels, other laboratory data, and serum topiroxostat concentrations of 10 HD patients who had been receiving febuxostat at a dose of 10 mg/d for over 1 year. No statistical difference was observed between the tolerability index at baseline and 16 months after the switch to topiroxostat. Serum UA after the switch in all patients (attained serum UA levels of ≤6 mg/dL) was 5.6±1.7 mg/dL (60%) at baseline, 4.9±0.5 mg/dL (100%) at 6 months and 5.7±0.4 mg/dL (50%) at 16 months (p=0.25), respectively. In patients with baseline serum UA levels >6 mg/dL, serum UA was significantly reduced at 6 and 16 months compared with baseline. Minimum serum concentrations of serum topiroxostat were lower than the limit of quantification (<25 ng/mL). Our results indicate that a switch from febuxostat 10 mg/d to topiroxostat 40 mg/d might reduce serum UA levels, with no change in other clinical laboratory data over the long term. These effects were more frequent in patients with high serum UA levels. Furthermore, topiroxostat therapy was more cost effective than febuxostat therapy. Thus, topiroxostat therapy could be a better treatment option for HD patients who develop high serum UA levels after febuxostat 10 mg/d administration.

Xanthine Oxidase Inhibitors for Improving Renal Function in Chronic Kidney Disease Patients: An Updated Systematic Review and Meta-Analysis.

BACKGROUND: Accruing evidence suggests that Xanthine Oxidase inhibitors (XOis) may bring direct renal benefits, besides those related to their hypo-uricemic effect. We hence aimed at performing a systematic review of randomized controlled trials (RCTs) to verify if treatment with XOis may improve renal outcomes in individuals with chronic kidney disease (CKD). METHODS: Ovid-MEDLINE, PubMed and CENTRAL databases were searched for RCTs comparing any XOi to standard therapy or placebo. The primary endpoint of interest was progression to End-Stage Kidney Disease (ESKD); secondary endpoints were changes in serum creatinine, glomerular filtration rate (eGFR), proteinuria and albuminuria. RESULTS: XOis treatment significantly reduced the risk of ESKD compared to the control (3 studies, 204 pts; RR = 0.42; 95% CI, 0.22, 0.80) and also improved eGFR in data pooled from RCTs with long follow-up times (>3 mo.) (4 studies, 357 pts; mean difference (MD) 6.82 mL/min/1.73 m²; 95% CI, 3.50, 10.15) and high methodological quality (blind design) (3 studies, 400 pts; MD 2.61 mL/min/1.73 m²; 95% CI, 0.23, 4.99). Conversely, no definite effects were apparently noticed on serum creatinine, proteinuria and albuminuria. CONCLUSIONS: XOis may represent a promising tool for retarding disease progression in CKD patients. Future trials are awaited to confirm the generalizability of these findings to the whole CKD population.

Renoprotective effect of the xanthine oxidoreductase inhibitor topiroxostat on adenine-induced renal injury.

The aim of the present study was to reveal the effect of a xanthine oxidoreductase (XOR) inhibitor, topiroxostat (Top), compared with another inhibitor, febuxostat (Feb), in an adenine-induced renal injury model. We used human liver-type fatty acid-binding protein (L-FABP) chromosomal transgenic mice, and urinary L-FABP, a biomarker of tubulointerstitial damage, was used to evaluate tubulointerstitial damage. Male transgenic mice (n = 24) were fed a 0.2% (wt/wt) adenine-containing diet. Two weeks after the start of this diet, renal dysfunction was confirmed, and the mice were divided into the following four groups: the adenine group was given only the diet containing adenine, and the Feb, high-dose Top (Top-H), and low-dose Top (Top-L) groups were given diets containing Feb (3 mg/kg), Top-H (3 mg/kg), and Top-L (1 mg/kg) in addition to adenine for another 2 wk. After withdrawal of the adenine diet, each medication was continued for 2 wk. Serum creatinine levels, the degree of macrophage infiltration, tubulointerstitial damage, renal fibrosis, urinary 15-F2t-isoprostane levels, and renal XOR activity were significantly attenuated in the kidneys of the Feb, Top-L, and Top-H groups compared with the adenine group. Serum creatinine levels in the Top-L and Top-H groups as well as renal XOR in the Top-H group were significantly lower than those in the Feb group. Urinary excretion of L-FABP in both the Top-H and Top-L groups was significantly lower than in the adenine and Feb groups. In conclusion, Top attenuated renal damage in an adenine-induced renal injury model.

Clinical efficacy and safety of topiroxostat in Japanese male hyperuricemic patients with or without gout: an exploratory, phase 2a, multicentre, randomized, double-blind, placebo-controlled study.

WHAT IS KNOWN AND OBJECTIVE: In Japan, although topiroxostat, a selective xanthine oxidoreductase inhibitor, has been used for the treatment of patients with hyperuricemia including gout, no published randomized controlled studies evaluating the dose-dependent relationship with respect to the serum urate-lowering efficacy have been reported. The aim of this study was to evaluate the dose-dependent relationship with serum urate-lowering efficacy and safety of topiroxostat in Japanese hyperuricemic patients including gout. METHODS: We conducted an exploratory, phase 2a, multicentre, randomized, double-blind, 8-week, placebo-controlled study in Japanese hyperuricemic patients with or without gout. The study arms were placebo and topiroxostat 40, 60, 80 or 120 mg/day. The primary efficacy endpoint was the per cent change in serum urate level from baseline to the final visit. RESULTS AND DISCUSSION: One hundred and eighty-seven eligible patients were randomized and 186 received at least one dose of the study drug. The study results demonstrated a dose-dependent serum urate reduction effect ranging from 40 to 120 mg/day (P < 0·001, Jonckheere-Terpstra test). The mean per cent change in serum urate level from baseline at the final visit was -30·8% in the 120-mg group and 1·6% with placebo, with a between-group difference of -32·4% ([95% confidence interval, -38·9% to -25·9%]; P < 0·001). Incidences of overall adverse events (AEs) in the topiroxostat groups were comparable to those in the placebo group; however, the incidence of AEs in the 120-mg group was statistically lower than that in the placebo group. The incidences of gouty arthritis were not statistically but numerically higher in the topiroxostat 80- and 120-mg groups. WHAT IS NEW AND CONCLUSIONS: A dose-dependent serum urate-lowering efficacy of topiroxostat was observed in Japanese hyperuricemic male patients with or without gout. Further clinical studies aimed at evaluating the long-term safety and clinical efficacy are warranted.

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.

WHAT IS KNOWN AND OBJECTIVE: There are no clinical reports that have compared topiroxostat, a selective xanthine oxidase inhibitor, with allopurinol in serum urate-lowering efficacy. The aim of this study was to compare the efficacy and safety of topiroxostat and allopurinol in Japanese hyperuricemic patients with or without gout. METHODS: A phase 3, multicentre, randomized, double-blind, double-dummy, active-controlled, parallel-group study conducted in Japan. Patients who had inadequate serum urate levels (a gout patient: serum urate level ≥416·4 µmol/L; an asymptomatic hyperuricemic patient with specific complications (urinary lithiasis, hypertension, hyperlipidemia and/or diabetes): serum urate level ≥475·8 µmol/L; and an asymptomatic hyperuricemic patient with no specific complications: serum urate level ≥535·3 µmol/L) were randomized to topiroxostat 120 mg/day or allopurinol 200 mg/day, with an equal allocation ratio, for 16 weeks. To prevent the onset of gouty arthritis by rapid serum urate reduction, these doses were increased in a stepwise manner. The primary efficacy endpoint was the per cent change in serum urate level from baseline to the final visit. RESULTS AND DISCUSSION: Overall, 206 patients were randomly assigned to topiroxostat and allopurinol. Two hundred and three patients (allopurinol: n = 105, topiroxostat: n = 98) received at least one dose of the study drug and had their serum urate level assessed at least once. The baseline characteristics were comparable between groups. The mean age of patients was 53·0 ± 11·4 years and 99% of patients were male. The primary efficacy endpoint was -34·3 ± 11·1% in the allopurinol group (n = 105) and -36·3 ± 12·7% in the topiroxostat group (n = 98). Non-inferiority of the serum urate-lowering efficacy of topiroxostat to allopurinol was proved by the predefined non-inferiority margin (95% confidence interval, -5·3 to 1·3%). The overall incidences of adverse events and adverse drug reactions were similar between both groups. WHAT IS NEW AND CONCLUSION: Topiroxostat 120 mg/day provides non-inferior serum urate reduction compared with allopurinol 200 mg/day and is well tolerated in Japanese hyperuricemic patients with or without gout.

Randomized control trial for the assessment of the anti-albuminuric effects of topiroxostat in hyperuricemic patients with diabetic nephropathy (the ETUDE study).

Proteinuria is an established risk factor for diabetic nephropathy. Recent studies indicate that some xanthine oxidase inhibitors have a renoprotective effect. The aim of this study was to assess whether topiroxostat reduces albuminuria in hyperuricemic patients with diabetic nephropathy and overt proteinuria. The ETUDE study is an ongoing 24-week, multicenter, open-label, randomized (1:1), parallel group study involving hyperuricemic patients with diabetic nephropathy (estimated glomerular filtration rate [eGFR] ≥ 20 mL/min/1.73 m(2)) and overt proteinuria (0.3 ≤ urine protein to creatinine ratio (UPCR) < 3.5 g/g Cr). Patients are randomly assigned to high dose (topiroxostat 160 mg daily) or low dose (topiroxostat 40 mg daily) on top of standard of care. The primary endpoint is the change in albuminuria indicated by urine albumin-to-creatinine ratio after 24 treated weeks relative to the baseline values. This trial was registered at the Japanese University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR: UMIN 000015403). The background, rationale, and study design of this trial are presented here. Seventy-six patients from four registered facilities have already been enrolled and received at least one dose of topiroxostat. This trial will end in 2017. The ETUDE trial is the first randomized controlled study of topiroxostat in hyperuricemic patients with diabetic nephropathy and overt proteinuria. We will clarify the pleiotropic function of topiroxostat including an anti-albumiuric effect as well as its effects on safely decreasing serum uric acid levels.