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 < 5.0 mg/dl was achieved by 77.1%, 79.2%, 88.5%, and 71.4% of patients, respectively. Exposure-adjusted incidence rates of treatment-emergent adverse events (TEAEs) and renal-related TEAEs in the core study were not increased with prolonged lesinurad exposure in the extension study.

Conclusions: Patients receiving lesinurad plus febuxostat therapy for 2 years continued to be at sUA target. Patients exhibited a progressive increase in CR of at least one target tophus, progressive reduction in tophus size, and reduction of gout flares requiring treatment over the second year, with AEs consistent with those observed in the core study.

Trial registration: ClinicalTrials.gov , NCT01510769 . Registered on 13 January 2012.

Keywords: Extension study; Febuxostat; Gout; Lesinurad; Phase III trial; Serum urate; Tophus.

Conflict of interest statement

Ethics approval and consent to participate

Institutional review boards (IRBs)/ethics committees (ECs) from each country reviewed and approved the protocol. The central IRBs/ECs were Schulman Associates Institutional Review Board, Inc., Cincinnati, OH, USA; Health and Disability Ethics Committees, Wellington, New Zealand; and Komisja Bioetyczna przy Okregowej Izbie Lekarskiej w Gdańsku, Gdańsk, Poland. The study was performed in compliance with the ethical principles of good clinical practice and according to the International Conference on Harmonisation Harmonised Tripartite Guideline. Patients provided written informed consent to participate in the extension study and had the right to withdraw at any time.

Consent for publication

Not applicable.

Competing interests

ND has received grant support from AstraZeneca and Amgen and consulting fees for AstraZeneca, Takeda, Horizon, and Kowa. GJ has received grant support from AbbVie, Ardea, Novartis, and Auxilium and has served on advisory boards for Pfizer, Roche, Hospira, and Janssen and speaker’s bureaus for UCB, Roche, Janssen, AbbVie, Novartis, Mundipharma, Amgen, BMS, and Pfizer. RT has received a research grant from AstraZeneca that was transferred to Ironwood for continued funding and has served as consultant to Selecta, Relburn, and SOBI and on advisory boards for Horizon. DK has no conflicts to report. FPR has received grant support from the Spanish Rheumatology Foundation and Cruces Hospital Rheumatologists Association. FPR is a member of the Pharmacy Advisory Commission of the Health Department, Basque Government. FPR has served on speaker’s bureaus for AstraZeneca and Menarini and advisory boards for Amgen, AstraZeneca, Menarini, Metabolex, Novartis, Pfizer, and SOBI. MF and SB are former employees of Ardea Biosciences, Inc., a member of the AstraZeneca group.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1

Proportion of patients with serum urate (sUA) a) and mean (SE) sUA levels (b) in the core study and extension study: observed cases (intention-to-treat population). CONT Continuation of lesinurad treatment, CROSS Crossover from core study placebo to lesinurad treatment

Fig. 2

Percentage of patients with gout flare requiring treatment in intention-to-treat population receiving lesinurad + febuxostat up to 24 months. CONT Continuation of lesinurad treatment, CROSS Crossover from core study placebo to lesinurad treatment

Fig. 3

Proportion of patients with complete resolution of at least one target tophus (a) and percentage mean change from baseline in target tophus area (b) up to 24 months on lesinurad + febuxostat: observed cases. CONT Continuation of lesinurad treatment, CROSS Crossover from core study placebo to lesinurad treatment