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).
OBJECTIVE
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.


CONCLUSIONS
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.


BACKGROUND
NCT01493531.
Rhumatologie, Lariboisière Hospital, and Université Paris Diderot Sorbonne Cité, Paris, France.
Thomas
T
Bardin
Division of Rheumatology, Duke University School of Medicine, Durham, North Carolina, USA.
Robert T
RT
Keenan
Division of Rheumatology, University of Michigan, Ann Arbor, Michigan, USA.
Puja P
PP
Khanna
Biometrics, Ardea Biosciences, Inc., San Diego, California, USA.
Jeff
J
Kopicko
Research & Development, Ardea Biosciences, Inc., San Diego, California, USA.
Maple
M
Fung
Research & Development, Ardea Biosciences, Inc., San Diego, California, USA.
Nihar
N
Bhakta
Research & Development, AstraZeneca Pharmaceuticals, Gaithersburg, Maryland, USA.
Scott
S
Adler
Research & Development, Ardea Biosciences, Inc., San Diego, California, USA.
Chris
C
Storgard
Medical Affairs, Ardea Biosciences, Inc., San Diego, California, USA.
Scott
S
Baumgartner
Service de rhumatologie, Université de Lausanne, Lausanne, Switzerland.
Alexander
A
So
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000493:Allopurinol / Q000009:adverse effects / Q000627:therapeutic use*; D002318:Cardiovascular Diseases / Q000139:chemically induced; D003404:Creatinine / Q000097:blood; D004311:Double-Blind Method; D004359:Drug Therapy, Combination / Q000009:adverse effects; D005260:Female; D006073:Gout / Q000097:blood / Q000188:drug therapy*; D006074:Gout Suppressants / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D051437:Renal Insufficiency / Q000097:blood / Q000139:chemically induced; D019233:Retreatment; D000067251:Symptom Flare Up; D013864:Thioglycolates / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D014527:Uric Acid / Q000097:blood; D014528:Uricosuric Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D055815:Young Adult
D006074:Gout Suppressants; D013864:Thioglycolates; D014230:Triazoles; D014528:Uricosuric Agents; C000593471:lesinurad; D014527:Uric Acid; D000493:Allopurinol; D003404:Creatinine
Gout; Inflammation; Outcomes research