Estimation of adherence to urate-lowering therapy in people living with gout using Australia's Pharmaceutical Benefits Scheme and patient-reported dosing.

AIMS: The aim of this study was to estimate adherence to urate-lowering therapy (ULT), predominately allopurinol, from Australia's Pharmaceutical Benefits Scheme (PBS) claims database in association with (1) patient-reported doses and (2) World Health Organization's (WHO) defined daily doses (DDD), namely, allopurinol (400 mg/day) or febuxostat (80 mg/day). METHODS: Proportion of days covered (PDC) was calculated in 108 Gout App (Gout APP) trial participants with at least two recorded ULT dispensings in an approximately 12-month period before provision of intervention or control apps. Adherence was defined as PDC ≥80%. We measured the correlation between the two methods of calculating PDC using a Wilcoxon signed rank test. Agreement between ULT-taking status (self-reports) and ULT-dispensed status (PBS records) was tested with Cohen's kappa (κ), and positive and negative percent agreement. RESULTS: Allopurinol was prescribed in 93.5% of participants taking ULT. Their self-reported mean daily dose (SD) was 291 (167) mg/day. Mean PDC (SD) for allopurinol was 83% (21%) calculated using self-reported dose, and 63% (24%) using WHO's DDD. Sixty-three percent of allopurinol users were identified as adherent (PDC ≥80%) using self-reported dose. There was good agreement between self-reported ULT use and PBS dispensing claims (κ = 0.708, P < .001; positive percent agreement = 90%, negative percent agreement = 82%). CONCLUSIONS: Participant-reported allopurinol daily doses, in addition to PBS dispensing claims, may enhance confidence in estimating PDC and adherence compared to using DDD. This approach improves adherence estimations from pharmaceutical claims datasets for medications where daily doses vary between individuals or where there is a wide therapeutic dose range.

Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial.

BACKGROUND: Febuxostat and allopurinol are urate-lowering therapies used to treat patients with gout. Following concerns about the cardiovascular safety of febuxostat, the European Medicines Agency recommended a post-licensing study assessing the cardiovascular safety of febuxostat compared with allopurinol. METHODS: We did a prospective, randomised, open-label, blinded-endpoint, non-inferiority trial of febuxostat versus allopurinol in patients with gout in the UK, Denmark, and Sweden. Eligible patients were 60 years or older, already receiving allopurinol, and had at least one additional cardiovascular risk factor. Those who had myocardial infarction or stroke in the previous 6 months or who had severe congestive heart failure or severe renal impairment were excluded. After a lead-in phase in which allopurinol dose was optimised towards achieving a serum urate concentration of less than 0·357 mmol/L (<6 mg/dL), patients were randomly assigned (1:1, with stratification according to previous cardiovascular events) to continue allopurinol (at the optimised dose) or start febuxostat at 80 mg/day, increasing to 120 mg/day if necessary to achieve the target serum urate concentration. The primary outcome was a composite of hospitalisation for non-fatal myocardial infarction or biomarker-positive acute coronary syndrome; non-fatal stroke; or cardiovascular death. The hazard ratio (HR) for febuxostat versus allopurinol in a Cox proportional hazards model (adjusted for the stratification variable and country) was assessed for non-inferiority (HR limit 1·3) in an on-treatment analysis. This study is registered with the EU Clinical Trials Register (EudraCT 2011-001883-23) and ISRCTN (ISRCTN72443728) and is now closed. FINDINGS: From Dec 20, 2011, to Jan 26, 2018, 6128 patients (mean age 71·0 years [SD 6·4], 5225 [85·3%] men, 903 [14·7%] women, 2046 [33·4%] with previous cardiovascular disease) were enrolled and randomly allocated to receive allopurinol (n=3065) or febuxostat (n=3063). By the study end date (Dec 31, 2019), 189 (6·2%) patients in the febuxostat group and 169 (5·5%) in the allopurinol group withdrew from all follow-up. Median follow-up time was 1467 days (IQR 1029-2052) and median on-treatment follow-up was 1324 days (IQR 870-1919). For incidence of the primary endpoint, on-treatment, febuxostat (172 patients [1·72 events per 100 patient-years]) was non-inferior to allopurinol (241 patients [2·05 events per 100 patient-years]; adjusted HR 0·85 [95% CI 0·70-1·03], p<0·0001). In the febuxostat group, 222 (7·2%) of 3063 patients died and 1720 (57·3%) of 3001 in the safety analysis set had at least one serious adverse event (with 23 events in 19 [0·6%] patients related to treatment). In the allopurinol group, 263 (8·6%) of 3065 patients died and 1812 (59·4%) of 3050 had one or more serious adverse events (with five events in five [0·2%] patients related to treatment). Randomised therapy was discontinued in 973 (32·4%) patients in the febuxostat group and 503 (16·5%) patients in the allopurinol group. INTERPRETATION: Febuxostat is non-inferior to allopurinol therapy with respect to the primary cardiovascular endpoint, and its long-term use is not associated with an increased risk of death or serious adverse events compared with allopurinol. FUNDING: Menarini, Ipsen, and Teijin Pharma Ltd.

Effect of Intensive Urate Lowering With Combined Verinurad and Febuxostat on Albuminuria in Patients With Type 2 Diabetes: A Randomized Trial.

RATIONALE & OBJECTIVE: Hyperuricemia has been implicated in the development and progression of chronic kidney disease. Verinurad is a novel, potent, specific urate reabsorption inhibitor. We evaluated the effects on albuminuria of intensive urate-lowering therapy with verinurad combined with the xanthine oxidase inhibitor febuxostat in patients with hyperuricemia and type 2 diabetes mellitus (T2DM). STUDY DESIGN: Phase 2, multicenter, prospective, randomized, double-blind, parallel-group, placebo-controlled trial. SETTING & PARTICIPANTS: Patients 18 years or older with hyperuricemia, albuminuria, and T2DM. INTERVENTION: Patients randomly assigned 1:1 to verinurad (9mg) plus febuxostat (80mg) or matched placebo once daily for 24 weeks. OUTCOMES: The primary end point was change in urinary albumin-creatinine ratio (UACR) from baseline after 12 weeks' treatment. Secondary end points included safety and tolerability and effect on glomerular filtration. RESULTS: 60 patients were enrolled (n=32, verinurad and febuxostat; n=28, placebo). UACRs after treatment with verinurad plus febuxostat were lower than after placebo at 1, 12, and 24 weeks: -38.6% (90% CI, -60.9% to-3.6%), -39.4% (90% CI, -61.8% to-3.8%), and-49.3% (90% CI, -68.2% to-19.0%), respectively. Serum urate levels after treatment with verinurad plus febuxostat were 59.6% and 63.7% lower than after placebo at 12 and 24 weeks, respectively. No clinically meaningful changes were observed in estimated glomerular filtration rate or serum creatinine or serum cystatin C concentrations. Verinurad plus febuxostat was well tolerated. LIMITATIONS: Sample size and study duration were insufficient to evaluate definitive effects of verinurad plus febuxostat on UACR and glomerular filtration. Generalizability was limited by exclusion of patients with stages 4 and 5 chronic kidney disease. CONCLUSIONS: Verinurad plus febuxostat reduced albuminuria and lowered serum urate concentrations in patients with T2DM, albuminuria, and hyperuricemia. Definitive assessment of their combined impact on preservation of kidney function awaits larger clinical studies. FUNDING: This study was supported by AstraZeneca. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT03118739.

Comparative efficacy of low-dose versus regular-dose colchicine to prevent flares in gout patients initiated on urate-lowering therapies.

OBJECTIVE: The objective of this study was to compare the prophylactic effect of regular-dose (RD, 1.2 mg/day) vs low-dose (LD, 0.6 mg/day) colchicine on gout flare when initiating urate-lowering therapy. METHODS: In this retrospective cohort study, we included gout patients who were initiated on either allopurinol or febuxostat, in combination with colchicine therapy and followed them up for 3 months. We analysed the rates of gout flare and adverse events according to the dose of colchicine. We performed the inverse probability of treatment weighting (IPTW) and weighted logistic regression analysis to assess the treatment effect. Analysis of gout flares and adverse events was performed on an intention-to-treat (ITT) and per-protocol (PP) basis. RESULTS: Of the total of 419 patients with gout, 177 patients (42.2%) received LD colchicine, whereas 242 patients (57.8%) received RD colchicine. Lower BMI and estimated glomerular filtration rate, and higher incidence of cardiovascular disease were seen in the LD group than in the RD group. In IPTW-adjusted analysis, events of gout flare were not significantly different between the LD and RD groups [ITT: 14.3% vs 11.3%; odds ratio (OR): 1.309, 95% CI: 0.668, 2.566, P = 0.432; PP: 15.3% vs 10.0%; OR: 1.623, 95% CI: 0.765, 3.443, P = 0.207]. However, LD colchicine was associated with a lower rate of adverse events than RD colchicine [ITT: 8.2% vs 17.9%; OR: 0.410, 95% CI: 0.217, 0.777; P < 0.05; PP: 8.4% vs 17.2%; OR: 0.442, 95% CI: 0.223, 0.878; P < 0.05]. CONCLUSION: Our data suggest that LD colchicine can adequately prevent gout flare with fewer adverse events compared with RD colchicine.

A formula predicting the effective dose of febuxostat in chronic kidney disease patients with asymptomatic hyperuricemia based on a retrospective study and a validation cohort
.

AIM: Febuxostat is initiated in chronic kidney disease (CKD) patients to lower uric acid but without any renal dosing scheme. This study aimed to determine a formula that predicts the effective dose of febuxostat in patients with an estimated glomerular filtration rate (eGFR) < 60 mL/min and asymptomatic hyperuricemia. MATERIALS AND METHODS: This is a retrospective analysis of 100 CKD patients treated with febuxostat for asymptomatic hyperuricemia in two private Lebanese clinics. Patients with gout were excluded. Collected variables were age, sex, weight, serum creatinine, serum uric acid (sUA) before and after febuxostat, dose of febuxostat used, and diuretic use. Multiple regression analysis was used to derive a formula predicting the dose of febuxostat based on eGFR (2009 Chronic Kidney Disease Epidemiology Collaboration equation), baseline sUA, and sUA reduction ratio. A prospective cohort of 24 patients was then used to validate the derived model. RESULTS: 100 patients were included with a median age of 71.5 years (interquartile range (IQR), 64.2 - 79.0); 69% were men. Median baseline sUA was 9.1 mg/dL (IQR, 8.4 - 10.1). Mean eGFR was 31.80 ± 12.96 mL/min/1.73m2. Of the included patients, 18% had CKD stage 3a, 36% had CKD stage 3b, 38% had CKD stage 4, and 8% had non-dialysis CKD stage 5. A formula was computed to predict febuxostat dosing. Variables that were predictive of febuxostat dose and used in the final equation were eGFR, diuretic use, baseline sUA, and sUA reduction ratio. The validation cohort showed no significant difference between the expected sUA and the measured one (p = 0.16). CONCLUSION: With this new formula, physicians can initiate febuxostat in CKD patients at an effective dose for any desired sUA reduction ratio.

Association between long-term prescription of febuxostat and the progression of heart failure with preserved ejection fraction in patients with hypertension and asymptomatic hyperuricemia.

Both hypertension and hyperuricemia are closely associated with the morbidity and mortality of heart failure. This study was designed to evaluate the influences of long-term xanthine oxidase inhibitor (febuxostat) prescription on left ventricular hypertrophy (LVH), left ventricular (LV) diastolic function, and new-onset heart failure with preserved ejection fraction (HFpEF) in these patients. Using a propensity score matching of 1:2 ratio, this retrospective claims database study compared febuxosatat prescription (n = 96) and non-urate-lowering therapy (n = 192) in patients with hypertensive left ventricular hypertrophy (LVH) and asymptomatic hyperuricemia. With a follow-up of 36 months, febuxostat significantly decreased the level of serum uric acid as well as generated more prominent improvement in LVH and LV diastolic function. Besides, the new-onset symptomatic HFpEF occurred in 2 of 96 patients in febuxostat group and 13 of 192 patients in non-urate-lowering group (P = 0.091). No increased risk for major adverse cardiovascular events in patients prescribed with febuxostat was noted. In conclusion, long-term febuxostat exposure was associated with protective effects in terms of LVH or LV diastolic dysfunction in patients with hypertensive LVH and asymptomatic hyperuricemia. Febuxostat also displayed a trend for reduced risk of new-onset HFpEF in this population.

A non-inferiority study of the novel selective urate reabsorption inhibitor dotinurad versus febuxostat in hyperuricemic patients with or without gout.

BACKGROUND: Dotinurad is a novel, selective urate reabsorption inhibitor, which reduces serum uric acid levels by selective inhibition of the urate transporter 1. We evaluated the efficacy and safety of dotinurad versus febuxostat, a widely used drug in Japan, in hyperuricemic Japanese patients with or without gout. METHODS: This was a multicenter, randomized, double-blind, active-controlled, parallel-group, forced-titration study in hyperuricemic patients. Study treatment in the dotinurad and febuxostat groups was initiated at 0.5 and 10 mg/day, followed by dose titration to 2 and 40 mg/day, respectively, over 14 weeks. The primary endpoint was the percent change in serum uric acid level from the baseline to the final visit. RESULTS: A total of 203 hyperuricemic patients with or without gout were enrolled in the study and randomized to receive dotinurad or febuxostat. The percent change in serum uric acid level from the baseline to the final visit was 41.82% in the dotinurad group and 44.00% in the febuxostat group. The mean difference was - 2.17% (two-sided 95% confidence interval - 5.26% to 0.92%). The lower limit of the interval was above the non-inferiority margin (- 10%), demonstrating the non-inferiority of dotinurad to febuxostat. The profiles of adverse events and adverse drug reactions raised no noteworthy safety concerns in either group. CONCLUSION: The non-inferiority of dotinurad to febuxostat in terms of serum uric acid lowering effect was confirmed. No noteworthy safety concerns arose.

Development of an optimized febuxostat self-nanoemulsified loaded transdermal film: in-vitro, ex-vivo and in-vivo evaluation.

Febuxostat (FBX) is used to treat gout and chronic hyperuricemia. However, its bioavailability is moderate (49%) as a result of low solubility and first-pass metabolism. Therefore, the aim of our study is to improve FBX bioavailability by enhancement its solubility using self-nanoemulsifying drug delivery system (SNEDDS) technique in the form of transdermal film to avoid hepatic metabolism. To accomplish this goal, Eight SNEDDS formulae were prepared according to a three-factor, two-level D-Optimal mixture design to evaluate the effect of different ratios of the Lemon oil (X1), the surfactant Tween-20 (X2), and the co-surfactant PEG-400 (X3) on the globule size in order to reach smallest globular size. Results revealed that SNEDDS globule size ranged from 177 to 454 nm. The optimized formula consisted of 20% oil, 40% surfactant and 40% co-surfactant. Diffusion study showed improved enhancement in skin permeation that was confirmed by imaging using fluorescence microscope. In vivo plasma data showed significant (p < 0.05) difference in FBX plasma levels and pharmacokinetic parameters when compared with raw FBX loaded film. In conclusion, FBX-SNEDDS loaded transdermal film could be a successful way to improve solubility and skin permeability that would lead to improvement in patient's compliance.

Enhanced Physical Stability and Synchronized Release of Febuxostat and Indomethacin in Coamorphous Solids.

Coamorphous formulation, a homogeneous monophasic amorphous system composed of multiple components, has been demonstrated as an effective approach for delivering drugs with poor aqueous solubility. In this study, we prepared the coamorphous system composed of two poorly soluble drugs febuxostat (FEB) and indomethacin (IMC) by using cryogenic milling. The combination of these two drugs in the coamorphous form can attain a synergistic effect, especially on gout therapy. Coamorphous solid of FEB and IMC in 1:1 molar ratio exhibited superior physical stability compared with the individual amorphous components, as evidenced by X-ray powder diffractions after 30 days of storage at ambient and elevated temperature. In addition, the FEB-IMC coamorphous system has been demonstrated to show enhanced dissolution performance. The intrinsic dissolution rates of two components in the coamorphous system exhibited the synchronized drug release. Based on the FT-IR spectroscopy, the excellent physical stability and synchronized release of FEB-IMC coamorphous system could be attributed to the heterodimer structure formed by strong hydrogen bonding interactions between these drugs. Furthermore, the supersaturation potential of FEB-IMC coamorphous solids was also investigated through the cosolvent quenching method. The FEB-IMC coamorphous system can effectively inhibit the fast crystallization of FEB in the supersaturated solution. However, the maximum achievable supersaturation of IMC in the coamorphous system decreases to only one fifth of that achieved for the pure amorphous IMC. These results are relevant for understanding the physical stability and complex solution behaviors of the coamorphous formulation.

Treatment of two mitochondrial disease patients with a combination of febuxostat and inosine that enhances cellular ATP.

Since mitochondria are energy-generating micro-organisms, most of the disorders in patients with mitochondrial diseases (mt-disease) are considered secondary to defects in ATP synthesis, although some other factors such as reactive oxygen species may be involved. A simultaneous oral administration of febuxostat and inosine was reported to elevate both hypoxanthine and ATP levels in peripheral blood. Based on those results, we attempted co-administration of febuxostat and inosine in two patients with mitochondrial disease: one patient with mitochondrial cardiomyopathy and the other patient with mitochondrial diabetes. In the former case, brain natriuretic peptide (BNP), which is a specific marker for heart failure, was decreased by 31%, and in the latter case, the insulinogenic index increased 3.1 times, suggesting the favorable action of the treatment. Considering that there is no effective treatment available for this disorder, the present therapy may be quite useful for the management of patients with mitochondrial diseases.

A novel strategy for treatment of cancer cachexia targeting xanthine oxidase in the brain.

Cancer cachexia is a systemic wasting syndrome characterized by anorexia and loss of body weight. The xanthine oxidase (XO) inhibitor febuxostat is one of the promising candidates for cancer cachexia treatment. However, cachexic symptoms were not alleviated by oral administration of febuxostat in our cancer cachexia model. Metabolomic analysis with brains of our cachexic model showed that purine metabolism was activated and XO activity was increased, and thus suggested that febuxostat would not reach the brain. Accordingly, targeting XO in the brain, which controls appetite, may be an effective strategy for treatment of cancer cachexia.

Febuxostat administration for the prevention of tumour lysis syndrome: A meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: Tumour lysis syndrome is an oncological emergency, characterized by rapid cytolysis leading to an abrupt rise of serum uric acid levels. The aim of the present meta-analysis is to evaluate the efficacy and safety of febuxostat as a preventive measure in patients at risk of tumour lysis syndrome development, by comparing it with allopurinol administration. METHODS: MEDLINE, Scopus, Cochrane Central Register of Controlled Trials, Clinicaltrials.gov and Google Scholar databases were searched from inception to 15 December 2018. All studies evaluating the effectiveness of febuxostat in preventing tumour lysis syndrome were held eligible. RESULTS AND DISCUSSION: Six studies were included with a total of 658 patients. Compared to allopurinol, febuxostat achieved a similar response rate (OR: 1.39, 95% CI: [0.55, 3.51]) and tumour lysis syndrome incidence (OR: 1.01, 95% CI: [0.56, 1.81]). Serum uric acid levels did not differ between the investigated groups at the second (MD: -0.21 mg/dL, 95% CI: [-1.30, 0.88]) and seventh (MD: -0.43 mg/dL, 95% CI: [-1.38, 0.51]) day of treatment. Elevation of liver function tests was the most common adverse effect, although its incidence was similar among patients treated with allopurinol and febuxostat. WHAT IS NEW AND CONCLUSIONS: The present meta-analysis suggests that febuxostat may serve as an effective alternative to allopurinol in the prevention of tumour lysis syndrome. Future large-scale studies should define the optimal febuxostat dosage, explore the most appropriate population for its administration and better define its safety profile.

Switching from allopurinol to febuxostat: efficacy and safety in the treatment of hyperuricemia in renal transplant recipients.

The aim of this study was to evaluate the efficacy and tolerability of febuxostat in renal transplant recipients who were previously treated with allopurinol (the daily oral dose is 100 mg). A 6-month cohort study was conducted with 46 renal transplant recipients who had hyperuricemia. In 22 patients, treatment was changed from allopurinol to febuxostat (febuxostat was given at an oral dose of 20 mg once a day), and the other 24 patients continued the allopurinol treatment (the daily oral dose is 100 mg). The serum levels of uric acid (UA), creatinine, other biochemical parameters, estimated glomerular filtration rate (eGFR), and adverse events were measured at baseline as well as at 1, 3, and 6 months after the switch to febuxostat. Serum UA levels significantly decreased from 470.82 ± 34.37 to 378.77 ± 51.97 µmol/L in the febuxostat group, and decreased from 469.46 ± 33.47 to 428.21 ± 23.37 µmol/L in the allopurinol group. The eGFR increased from 75.55 to 85.23 mL/min in the febuxostat group, and decreased from 78.79 to 70.31 mL/min in the allopurinol group. In renal transplant recipients, febuxostat reduced the serum UA levels resulting in minor short-term improvement of renal function with no changes in the other biochemical parameters.

Formulation and Characterization of Nanosized Ethosomal Formulations of Antigout Model Drug (Febuxostat) Prepared by Cold Method: In Vitro/Ex Vivo and In Vivo Assessment.

Febuxostat (FXT) is a xanthine oxidase (XO) drug which indicated for the treatment of gout. FXT loaded nanosized ethosomes were prepared using cold method with varied concentrations of ethyl alcohol and soya lecithin (SL). The prepared ethosomes were characterized by size, entrapment efficiency (DEE), FT-IR, in vitro release, kinetic studies of in vitro release profile, in vitro skin permeation and deposition, and stability study. The selected ethosomal formulation was incorporated in HPMC gel and characterized for drug content, ex vivo diffusion study through rat skin, and in vivo study and determination of pharmacokinetic parameters using HPLC technique. The results of size analysis showed that minimum size was 124.2 ± 16.77 nm with PDI values between 0.2 and 0.6. The zeta potential was from - 43.5 ± 3.0 to - 20.6 ± 1.42 mV. DEE ranged from 48 to 86%. The results of in vitro skin permeation showed that the amount FXT permeated ranged from 43.33 ± 5.3 to 82.14 ± 5.8%, flux ranged from 14.85 to 28.02. The results of ex vivo study showed that the amount of FXT permeated from unprocessed FXT gel was 49.42 ± 3.29% which was lesser than from FXT ethosomal gel. The results of in vivo study showed that Cmax and tmax were significantly different and higher for transdermal administration of FXT than oral administration. The developed FXT nanosized selected ethosome-based transdermal drug delivery gel system would provide a promising method for better management of gout.

Quality by Design Approach for the Development of Self-Emulsifying Systems for Oral Delivery of Febuxostat: Pharmacokinetic and Pharmacodynamic Evaluation.

The goal of the present investigation is to formulate febuxostat (FXT) self-nanoemulsifying delivery systems (liquid SNEDDS, solid SNEDDS, and pellet) to ameliorate the solubility and bioavailability. To determine the self-nanoemulsifying region, ternary plot was constructed utilizing Capmul MCM C8 NF® as an oil phase, Labrasol® as principal surfactant, and Transcutol HP® being the co-surfactant. Liquid SNEDDS (L-SNEDDS) were characterized by evaluating droplet size, zeta potential, % transmission, and for thermodynamic stability. In vitro dissolution study of FXT loaded L-SNEDDS (batch F7) showed increased dissolution (about 48.54 ± 0.43% in 0.1 N HCl while 86.44 ± 0.16% in phosphate buffer pH 7.4 within 30 min) compared to plain drug (19.65 ± 2.95% in 0.1 N HCl while about 17.61 ± 2.63% in phosphate buffer pH 7.4 within 30 min). Single pass intestinal permeability studies revealed fourfold increase in the intestinal permeability of F7 compared to plain drug. So, for commercial aspects, F7 was further transformed into solid SNEDDS (S-SNEDDS) as readily nanoemulsifying powder form (SNEP) as well as pellets prepared by application of extruder spheronizer. The developed formulation was found superior to pure FXT with enhanced oral bioavailability and anti-gout activity (with reduced uric acid levels), signifying a lipidic system being an efficacious substitute for gout treatment.

Long-term adherence and persistence with febuxostat among male patients with gout in a routine clinical setting.

Objectives: To assess long-term adherence and persistence to febuxostat (FBX) and factors that might contribute to non-adherence and non-persistence to FBX in male patients with gout during a 3-year period. Methods: Adherence to FBX was assessed by the clinic nurses through pill counts at the scheduled visits and non-adherence was defined as less than 80% of the prescribed dose taken. Non-persistence was defined as discontinuation of FBX longer than 60 days. Results: A total of 220 patients were recruited. The percentage of adherence and persistence was 71.8% and 80.9% at 1 year, 65.5% and 68.2% at 2 years and 58.2% and 56.4% at 3 years, respectively. The logistic regression analysis identified high income status, current smoking, absence of hypertension and previous history of non-persistence with urate-lowering therapy (ULT) as the independent factors associated with non-adherence, and the unmarried, absence of hypertension and previous history of non-persistence with ULT as the independent factors associated with non-persistence. Conclusion: Variable risk factors that are correlated with poor adherence or persistence and easily assessed can be used to identify patients at a particular risk of poor adherence or persistence.

The influence of febuxostat on coronary artery endothelial dysfunction in patients with coronary artery disease: A phase 4 randomized, placebo-controlled, double-blind, crossover trial.

BACKGROUND: The xanthine oxidase (XO) system is a significant source of vascular oxidative stress, which is believed to impair endothelial function, an important contributor to atherosclerotic disease. We tested whether febuxostat, a potent XO inhibitor, improves coronary endothelial function (CEF) in patients with stable coronary artery disease (CAD) in a single-center, randomized, placebo-controlled, double-blind crossover trial. METHODS: CEF was measured using noninvasive magnetic resonance imaging (MRI) assessment of changes in 30 patients with stable CAD and baseline impaired CEF. Patients received either febuxostat or placebo for 6 weeks and then were crossed over to the alternative for an additional 6 weeks. MRI-detected changes in coronary flow and in coronary cross-sectional area from rest to isometric handgrip exercise, a known endothelial-dependent stressor, were measured at the end of each 6 week period. RESULTS: Mean serum urate levels were lower at the end of the 6-week febuxostat period (2.9±0.8mg/dL) than at the end of the 6-week placebo period (5.9±0.04, P<.001). However, there were no significant differences in any of the CEF parameters measured at the end of the febuxostat and placebo periods. CONCLUSIONS: In summary, although XO inhibition with febuxostat was well tolerated and lowered serum urate, it did not improve the primary end point of the study, CEF measured using MRI after 6 weeks of treatment. In conclusion, these findings suggest that short-term inhibition of XO does not significantly improve impaired CEF in patients with stable CAD.

Stepwise dose increase of febuxostat is comparable with colchicine prophylaxis for the prevention of gout flares during the initial phase of urate-lowering therapy: results from FORTUNE-1, a prospective, multicentre randomised study.

OBJECTIVES: To determine whether febuxostat with stepwise dose increase is as useful as colchicine prophylaxis in reducing gout flares during the initial introduction of urate-lowering therapy in patients with gout in comparison with febuxostat with no dose titration. METHODS: In this prospective, multicentre, randomised open-label comparative study, patients were randomised to group A (stepwise dose increase of febuxostat from 10 to 40 mg/day), group B (fixed-dose febuxostat 40 mg/day plus colchicine 0.5 mg/day) or group C (fixed-dose febuxostat 40 mg/day) and observed for 12 weeks. Gout flare was defined as non-steroidal anti-inflammatory drug use for gout symptoms. RESULTS: A total of 255 patients were randomised, and 241 patients were treated. Among the treated patients, gout flares were experienced by 20/96 (20.8%) in group A, 18/95 (18.9%) in group B and 18/50 (36.0%) in group C. The incidence of flare was significantly lower in groups A and B than that in group C (P=0.047 and P=0.024, respectively), although the differences were not significant after correction for multiple comparisons. No significant difference was noted between the incidence of gout flare in groups A and B. CONCLUSIONS: Our data suggested that stepwise dose increase of febuxostat and low-dose colchicine prophylaxis effectively reduced gout flares in comparison with fixed-dose febuxostat alone. Stepwise dose increase of febuxostat may be an effective alternative to low-dose colchicine prophylaxis during the introduction of urate-lowering therapy. TRIAL REGISTRATION NUMBER: UMIN 000008414.

Febuxostat Therapy for Patients With Stage 3 CKD and Asymptomatic Hyperuricemia: A Randomized Trial.

RATIONALE & OBJECTIVE: Epidemiologic and clinical studies have suggested that urate-lowering therapy may slow the progression of chronic kidney disease (CKD). However, definitive evidence is lacking. STUDY DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING & PARTICIPANTS: 467 patients with stage 3 CKD and asymptomatic hyperuricemia at 55 medical institutions in Japan. INTERVENTION: Participants were randomly assigned in a 1:1 ratio to receive febuxostat or placebo for 108 weeks. OUTCOMES: The primary end point was the slope (in mL/min/1.73m2 per year) of estimated glomerular filtration rate (eGFR). Secondary end points included changes in eGFRs and serum uric acid levels at 24, 48, 72, and 108 weeks of follow-up and the event of doubling of serum creatinine level or initiation of dialysis therapy. RESULTS: Of 443 patients who were randomly assigned, 219 and 222 assigned to febuxostat and placebo, respectively, were included in the analysis. There was no significant difference in mean eGFR slope between the febuxostat (0.23±5.26mL/min/1.73m2 per year) and placebo (-0.47±4.48mL/min/1.73m2 per year) groups (difference, 0.70; 95% CI, -0.21 to 1.62; P=0.1). Subgroup analysis demonstrated a significant benefit from febuxostat in patients without proteinuria (P=0.005) and for whom serum creatinine concentration was lower than the median (P=0.009). The incidence of gouty arthritis was significantly lower (P=0.007) in the febuxostat group (0.91%) than in the placebo group (5.86%). Adverse events specific to febuxostat were not observed. LIMITATIONS: GFR was estimated rather than measured, and patients with stages 4 and 5 CKD were excluded. CONCLUSIONS: Compared to placebo, febuxostat did not mitigate the decline in kidney function among patients with stage 3 CKD and asymptomatic hyperuricemia. FUNDING: Funded by Teijin Pharma Limited. TRIAL REGISTRATION: Registered at the UMIN (University Hospital Medical Information Network) Clinical Trials Registry with study number UMIN000008343.

Verinurad combined with febuxostat in Japanese adults with gout or asymptomatic hyperuricaemia: a phase 2a, open-label study.

Objectives: Verinurad (RDEA3170) is a high-affinity inhibitor of the URAT1 transporter in clinical development for treating gout and asymptomatic hyperuricaemia. The aim of this Phase 2a, randomized, open-label study was to investigate the multiple-dose pharmacodynamics, pharmacokinetics and safety of oral verinurad combined with febuxostat vs febuxostat alone and verinurad alone. Methods: Japanese male subjects aged 21-65 years with gout (n = 37) or asymptomatic hyperuricaemia (n = 35) and serum urate (sUA) ⩾8 mg/dl were randomized to febuxostat (10, 20, 40 mg) in combination with verinurad (2.5-10 mg), verinurad alone (2.5-15 mg), febuxostat alone (10, 20, 40 mg) or benzbromarone alone (50 mg). There were four treatment periods per cohort and each treatment period was 7 days. Study drugs were administered once-daily after breakfast. Plasma, serum and urine samples were measured at pre-set intervals on days -1, 7, 14, 21 and 28. Results: Verinurad combined with febuxostat decreased sUA in dose-dependent manner, providing greater sUA lowering than febuxostat alone at the same dose (P < 0.001). Urinary uric acid excretion rate was increased by verinurad, reduced by febuxostat and comparable to baseline for verinurad combined with febuxostat. Verinurad from 2.5 mg to 15 mg was well tolerated, with no withdrawals due to adverse events. Laboratory assessments showed no clinically meaningful changes during combination treatment. Conclusion: Verinurad combined with febuxostat decreased sUA dose-dependently while maintaining uric acid excretion similar to baseline. All dose combinations of verinurad and febuxostat were generally well tolerated. These data support continued investigation of oral verinurad in patients with gout. Trial registration: ClinicalTrials.gov, https://clinicaltrials.gov, NCT02317861.