Dataset Information

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

ABSTRACT: 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.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.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.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.ClinicalTrials.gov, https://clinicaltrials.gov, NCT02317861.

SUBMITTER: Shiramoto M

PROVIDER: S-EPMC6105922 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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

Shiramoto Masanari M Liu Sha S Shen Zancong Z Yan Xiaohong X Yamamoto Amy A Gillen Michael M Ito Yasushi Y Hall Jesse J

Rheumatology (Oxford, England) 20180901 9

<h4>Objectives</h4>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.<h4>Methods</h4>Japanese male subjects aged 21-65 years with gout (n = 37) or asymptomatic hyperuricaemia (n = ...[more]

PMID: 29868853

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Project description:BACKGROUND: This study aimed to identify patient-reported outcomes and clinician-assessed characteristics of the first metatarsophalangeal joint (1MTPJ) in people with gout and with asymptomatic hyperuricaemia by comparing them to normouricaemic controls. METHODS: Twenty four people with gout (without current symptoms of acute arthritis), 29 with asymptomatic hyperuricaemia and 34 age- and sex-matched controls participated in this cross-sectional observational study. Patient-reported outcomes included 1MTPJ pain, foot pain and disability, body pain, lower limb function, activity limitation and overall wellbeing. Clinician-assessed characteristics of the 1MTPJ included range of motion (ROM), plantar- and dorsi-flexion force, foot posture, temperature and hallux valgus severity. RESULTS: Compared to controls, participants with gout reported greater 1MTPJ pain (p?=?0.014), greater foot pain and disability (p?<?0.001), increased odds of having disabling foot pain (odds ratio (OR) 13.4, p?<?0.001), decreased lower limb function for daily living (p?=?0.002) and recreational (p?<?0.001) activities, increased activity limitation (p?=?0.002), reduced overall wellbeing (p?=?0.034), reduced ROM (p?<?0.001), reduced plantarflexion force (p?=?0.012), increased 1MTPJ plantar (p?=?0.004), dorsal (p?=?0.003) and medial (p?=?0.004) temperature and had increased odds of having more severe hallux valgus (OR 0.3 p?=?0.041). Compared to controls, participants with asymptomatic hyperuricaemia had increased odds of having disabling foot pain (OR 4.2, p?=?0.013), increased activity limitation (p?=?0.033), decreased lower limb function for daily living (p?=?0.026) and recreational (p?=?0.010) activities, increased 1MTPJ plantarflexion force (p?=?0.004) and a more pronated foot type (p?=?0.036). CONCLUSIONS: People with gout demonstrate 1MTPJ-specific changes indicative of subclinical inflammation, even in the absence of acute arthritis. People with asymptomatic hyperuricaemia, who exhibit no features or symptoms of gout, also report high levels of foot- and lower limb-related pain and disability.

Project description:Rationale & objectiveHyperuricemia 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 designPhase 2, multicenter, prospective, randomized, double-blind, parallel-group, placebo-controlled trial.Setting & participantsPatients 18 years or older with hyperuricemia, albuminuria, and T2DM.InterventionPatients randomly assigned 1:1 to verinurad (9mg) plus febuxostat (80mg) or matched placebo once daily for 24 weeks.OutcomesThe 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.Results60 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.LimitationsSample 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.ConclusionsVerinurad 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.FundingThis study was supported by AstraZeneca.Trial registrationRegistered at ClinicalTrials.gov with study number NCT03118739.

Project description:INTRODUCTION:Gout affects 2.5% of the UK's adult population and is now the most common type of inflammatory arthritis. The long-term management of gout requires reduction of serum urate levels and this is most often achieved with use of xanthine oxidase inhibitors, such as allopurinol. Febuxostat is the first new xanthine oxidase inhibitor since allopurinol and was licensed for use in 2008. The European Medicines Agency requested a postlicensing cardiovascular safety study of febuxostat versus allopurinol, which has been named the Febuxostat versus Allopurinol Streamlined trial (FAST). METHODS AND ANALYSIS:FAST is a cardiovascular safety study using the prospective, randomised, open, blinded endpoint design. FAST is recruiting in the UK and Denmark. Recruited patients are aged over 60?years, prescribed allopurinol for symptomatic hyperuricaemia and have at least one additional cardiovascular risk factor. After an allopurinol lead-in phase where the dose of allopurinol is optimised to achieve European League against Rheumatism (EULAR) urate targets (serum urate <357?µmol/L), patients are randomised to either continue optimal dose allopurinol or to use febuxostat. Patients are followed-up for an average of 3?years. The primary endpoint is first occurrence of the Anti-Platelet Trialists' Collaboration (APTC) cardiovascular endpoint of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. Secondary endpoints are all cause mortality and hospitalisations for heart failure, unstable, new or worsening angina, coronary or cerebral revascularisation, transient ischaemic attack, non-fatal cardiac arrest, venous and peripheral arterial vascular thrombotic event and arrhythmia with no evidence of ischaemia. The primary analysis is a non-inferiority analysis with a non-inferiority upper limit for the HR for the primary outcome of 1.3. ETHICS AND DISSEMINATION:FAST (ISRCTN72443728) has ethical approval in the UK and Denmark, and results will be published in a peer reviewed journal. TRIAL REGISTRATION NUMBER:FAST is registered in the EU Clinical Trials Register (EUDRACT No: 2011-001883-23) and International Standard Randomised Controlled Trial Number Register (ISRCTN No: ISRCTN72443728).

Project description:SummaryBackgroundGout flares are driven by interleukin (IL)-1β. Dapansutrile inhibits the NLRP3 inflammasome and subsequent activation of IL-1β. In this study we aimed to investigate the safety and efficacy of orally administered dapansutrile in patients with a gout flare.MethodsIn this open-label, proof-of-concept, phase 2a trial, adult patients (aged 18-80 years) with a monoarticular monosodium urate crystal-proven gout flare were enrolled at an outpatient clinic in the Netherlands and sequentially assigned using a dose-adaptive design to receive 100 mg/day, 300 mg/day, 1000 mg/day, or 2000 mg/day oral dapansutrile for 8 days. The coprimary outcomes were change in patient-reported target joint pain from baseline to day 3 and from baseline to day 7, assessed in the per-protocol population (all patients who received at least 80% of the study drug and had no major protocol deviations). Safety was assessed in the intention-to-treat population. This trial is registered with the EU Clinical Trials Register, EudraCT 2016-000943-14, and is completed.FindingsBetween May 18, 2017, and Jan 21, 2019, 144 patients were assessed for eligibility, of whom 34 were enrolled and 29 were included in the per-protocol population (three patients were excluded due to receiving <80% of study drug and two had major protocol deviations): eight patients received 100 mg/day, seven received 300 mg/day, six received 1000 mg/day, and eight received 2000 mg/day. Between baseline and day 3, there was a mean reduction in patient-reported target joint pain of 52·4% (SD 32·94; p=0∙016) for the 100 mg/day group, 68·4% (34·29; p=0∙016) for the 300 mg/day group, 55·8% (44·90; p=0∙063) for the 1000 mg/day group, and 57·6% (38·72; p=0∙016) for the 2000 mg/day group. At day 7, there was a mean reduction of 82·1% (22·68; p=0∙031) for the 100 mg/day group, 84·2% (16·33; p=0∙016) for the 300 mg/day group, 68·9% (34·89; p=0∙031) for the 1000 mg/day group, and 83·9% (15·44; p=0∙008) for the 2000 mg/day group, compared to baseline. 25 (73·5%) of 34 patients reported a total of 45 treatment-emergent adverse events, most of which were metabolism and nutrition disorders (17 [37·8%]) and gastrointestinal disorders (ten [22·2%]). Two serious adverse events occurred during the study, admission to hospital because of worsening of gout flare at day 3, and admission to hospital because of coronary stenosis 18 days after the patient received their last dose; these were considered moderate in severity and unrelated to the study drug.InterpretationDapansutrile is a specific NLRP3 inflammasome inhibitor with a satisfactory safety profile and efficacy in the reduction of target joint pain in this study. Future studies are needed to confirm the clinical potential of dapansutrile.

Dataset Information

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

Publications

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

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