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Efficacy and safety during extended treatment of lesinurad in combination with febuxostat in patients with tophaceous gout: CRYSTAL extension study.

ABSTRACT: BACKGROUND:In gout, long-term urate-lowering therapy (ULT) promotes dissolution of tissue urate crystal deposits. However, no studies using combined xanthine oxidase inhibition and uricosuric ULT have focused on clinical outcomes or adverse events (AEs) beyond 12?months of therapy. Our objective in the present study was to examine efficacy and long-term safety in patients with tophaceous gout receiving febuxostat plus lesinurad as combination therapy. METHODS:Patients receiving combined lesinurad and febuxostat in the 12-month core CRYSTAL study continued at the same doses in the extension study ("200CONT", "400CONT"), whereas those receiving only febuxostat 80?mg were randomized to lesinurad 200 or 400?mg with febuxostat ("200CROSS", "400CROSS"). The primary endpoint was the proportion of patients experiencing complete resolution (CR) of at least one target tophus by extension month (EM) 12. The key secondary endpoint was mean rate of gout flares requiring treatment from the end of EM 2 to the end of EM 12. Secondary endpoints included reduction in the sum of areas for all target tophi. Safety assessments included AEs and laboratory data for the entire extension study (median length of lesinurad exposure, 800?days). RESULTS:Of 235 patients completing the core study, 196 (83.4%) enrolled in the extension: 200CONT (n?=?64), 200CROSS (n?=?33), 400CONT (n?=?65), and 400CROSS (n?=?34). At EM 12, 59.6%, 43.5%, 66.7%, and 50.0% of patients, respectively, had CR of at least one target tophus. The sum of areas for all target tophi was reduced by 76.4%, 58.1%, 77.5%, and 62.8%, respectively. The adjusted mean (SE) rates of gout flares requiring treatment from the end of EM 2 to the end of EM 12 were 0.6 (0.19), 1.3 (0.48), 0.2 (0.08), and 1.9 (0.93), respectively. Target sUA

SUBMITTER: Dalbeth N

PROVIDER: S-EPMC6322285 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Efficacy and safety during extended treatment of lesinurad in combination with febuxostat in patients with tophaceous gout: CRYSTAL extension study.

Dalbeth Nicola N Jones Graeme G Terkeltaub Robert R Khanna Dinesh D Fung Maple M Baumgartner Scott S Perez-Ruiz Fernando F

Arthritis research & therapy 20190107 1

<h4>Background</h4>In gout, long-term urate-lowering therapy (ULT) promotes dissolution of tissue urate crystal deposits. However, no studies using combined xanthine oxidase inhibition and uricosuric ULT have focused on clinical outcomes or adverse events (AEs) beyond 12 months of therapy. Our objective in the present study was to examine efficacy and long-term safety in patients with tophaceous gout receiving febuxostat plus lesinurad as combination therapy.<h4>Methods</h4>Patients receiving co ...[more]

PMID: 30616614

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Project description:BACKGROUND:Febuxostat immediate release (IR), a xanthine oxidase inhibitor, is indicated for the management of hyperuricemia in patients with gout by lowering urate levels. An extended release (XR) formulation of febuxostat was developed to provide equal or superior efficacy on urate lowering compared with the IR formulation and potentially lower the risk of treatment-initiated gout flares due to an altered pattern of drug exposure. The present study evaluated the efficacy and safety of febuxostat XR and IR formulations in patients with gout and moderate renal impairment (estimated glomerular filtrate rate???30 and?<?60 ml/min). METHODS:This was an exploratory, 3-month, phase II, multicenter, placebo-controlled, double-blind proof-of-concept study. Patients (n?=?189) were randomized 1:1:1:1:1 to receive placebo or febuxostat IR 40 mg, XR 40 mg, IR 80 mg, or XR 80 mg once daily. Endpoints included: proportion of patients with serum uric acid (sUA) <?5.0 mg/dl at month 3 (primary endpoint), proportion of patients with sUA <?6.0 mg/dl at month 3, and proportion of patients with ??1 gout flare requiring treatment over 3 months. RESULTS:At month 3, all febuxostat treatment groups were associated with greater proportions of patients achieving sUA <?5.0 mg/dl (p?<?0.05 vs placebo). A greater proportion of patients receiving XR 40 mg achieved sUA <?5.0 mg/dl versus those receiving IR 40 mg (p?=?0.034); proportions were similar in the IR 80 mg and XR 80 mg groups. Higher proportions of febuxostat-treated patients achieved sUA <?6.0 mg/dl at month 3 (p?<?0.05 vs placebo) and experienced ??1 gout flare (significant for all comparisons, except XR 40 mg). Incidences of treatment-related adverse events were low across all treatment groups; the majority were mild or moderate with no apparent trends correlating with IR or XR doses. The most common treatment-emergent adverse event was hypertension. One death (unrelated to the study drug) was reported. CONCLUSIONS:These exploratory data demonstrate that febuxostat (XR and IR) formulations were effective and well tolerated in patients with gout and moderate renal impairment. TRIAL REGISTRATION:ClinicalTrials.gov, NCT02128490 Registered on 29 April 2014.

Dataset Information

Efficacy and safety during extended treatment of lesinurad in combination with febuxostat in patients with tophaceous gout: CRYSTAL extension study.

Publications

Efficacy and safety during extended treatment of lesinurad in combination with febuxostat in patients with tophaceous gout: CRYSTAL extension study.

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