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  • Lesinurad in combination with allopurinol: a randomised, double-blind, placebo-controlled study in patients with gout with inadequate response to standard of care (the multinational CLEAR 2 study)

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Clinical and epidemiological research
Extended report
Lesinurad in combination with allopurinol: a randomised, double-blind, placebo-controlled study in patients with gout with inadequate response to standard of care (the multinational CLEAR 2 study)
  1. Thomas Bardin1,
  2. Robert T Keenan2,
  3. Puja P Khanna3,
  4. Jeff Kopicko4,
  5. Maple Fung5,
  6. Nihar Bhakta5,
  7. Scott Adler6,
  8. Chris Storgard5,
  9. Scott Baumgartner7,
  10. Alexander So8
  1. 1Rhumatologie, Lariboisière Hospital, and Université Paris Diderot Sorbonne Cité, Paris, France
  2. 2Division of Rheumatology, Duke University School of Medicine, Durham, North Carolina, USA
  3. 3Division of Rheumatology, University of Michigan, Ann Arbor, Michigan, USA
  4. 4Biometrics, Ardea Biosciences, Inc., San Diego, California, USA
  5. 5Research & Development, Ardea Biosciences, Inc., San Diego, California, USA
  6. 6Research & Development, AstraZeneca Pharmaceuticals, Gaithersburg, Maryland, USA
  7. 7Medical Affairs, Ardea Biosciences, Inc., San Diego, California, USA
  8. 8Service de rhumatologie, Université de Lausanne, Lausanne, Switzerland
  1. Correspondence to Professor Thomas Bardin, Rhumatologie, Hôpital Lariboisière, Assistance Publique Hôpitaux de Paris, 2, rue A Paré, 75010 Paris; thomas.bardin{at}aphp.fr

Abstract

Objectives Determine the efficacy and safety of daily lesinurad (200 or 400 mg orally) added to allopurinol in patients with serum uric acid (sUA) above target in a 12-month, randomised, phase III trial.

Methods Patients on allopurinol ≥300 mg (≥200 mg in moderate renal impairment) had sUA level of ≥6.5 mg/dL (≥387 µmol/L) at screening and two or more gout flares in the prior year. Primary end point was the proportion of patients achieving sUA level of <6.0 mg/dL (<357 µmol/L) (month 6). Key secondary end points were mean gout flare rate requiring treatment (months 7 through 12) and proportions of patients with complete resolution of one or more target tophi (month 12). Safety assessments included adverse events and laboratory data.

Results Patients (n=610) were predominantly male, with mean (±SD) age 51.2±10.90 years, gout duration 11.5±9.26 years and baseline sUA of 6.9±1.2 mg/dL (410±71 µmol/L). Lesinurad at 200 and 400 mg doses, added to allopurinol, significantly increased proportions of patients achieving sUA target versus allopurinol-alone therapy by month 6 (55.4%, 66.5% and 23.3%, respectively, p<0.0001 both lesinurad+allopurinol groups). In key secondary end points, there were no statistically significant treatment-group differences favouring lesinurad. Lesinurad was generally well tolerated; the 200 mg dose had a safety profile comparable with allopurinol-alone therapy. Renal-related adverse events occurred in 5.9% of lesinurad 200 mg+allopurinol, 15.0% of lesinurad 400 mg+allopurinol and 4.9% of allopurinol-alone groups, with serum creatinine elevation of ≥1.5× baseline in 5.9%, 15.0% and 3.4%, respectively. Serious treatment-emergent adverse events occurred in 4.4% of lesinurad 200 mg+allopurinol, in 9.5% of lesinurad 400 mg+allopurinol and in 3.9% of allopurinol-alone groups, respectively.

Conclusion Lesinurad added to allopurinol demonstrated superior sUA lowering versus allopurinol-alone therapy and lesinurad 200 mg was generally well tolerated in patients with gout warranting additional therapy.

Trial registration number NCT01493531.

  • Gout
  • Inflammation
  • Outcomes research

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/annrheumdis-2016-209213

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    Footnotes

    • Handling editor Tore K Kvien

    • JK and CS are former employees.

    • Contributors TB, RTK, PPK and AS: Criterion 1: (1) substantial contributions to study conception and design and/or (2) substantial contributions to analysis and interpretation of data; criterion 2: drafting the article or revising it critically for important intellectual content and criterion 3: final approval of the version of the article to be published. JK, MF, NB, CS and SB: Criterion 1: (1) substantial contributions to study conception and design and/or (2) substantial contributions to acquisition of data and/or (3) substantial contributions to analysis and interpretation of data; criterion 2: drafting the article or revising it critically for important intellectual content and criterion 3: final approval of the version of the article to be published. SA: criterion 1: (1) substantial contributions to acquisition of data and/or (2) substantial contributions to analysis and interpretation of data; criterion 2: drafting the article or revising it critically for important intellectual content and criterion 3: final approval of the version of the article to be published.

    • Funding This clinical study was funded by Ardea Biosciences, a member of the AstraZeneca group. The study sponsor had a role in the design and conduct of the study; collection, management, analysis and interpretation of the data and review and approval of the manuscript.

    • Competing interests TB: grant/research support from Ipsen, Menarini and consultant for AstraZeneca, Ipsen, Menarini, Novartis, Savient, Sobi, Takeda and Cymabay. RTK: consultant for AstraZeneca, Crealta Pharmaceuticals and Takeda. PPK: research grant: AstraZeneca. JK (former employee), MF, NB, CS (former employee) and SB: full-time employees of Ardea Biosciences, a member of the AstraZeneca Group. SA: full-time employee of AstraZeneca Pharmaceuticals. AS: consultant for Novartis, AstraZeneca, Menarini.

    • Patient consent Obtained.

    • Provenance and peer review Not commissioned; externally peer reviewed.

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