ARTHRITIS & RHEUMATOLOGY Vol. 69, No. 1, January 2017, pp 203–212 DOI 10.1002/art.39840 VC 2016, American College of Rheumatology Lesinurad Combined With Allopurinol A Randomized, Double-Blind, Placebo-Controlled Study in Gout Patients With an Inadequate Response to Standard-of-Care Allopurinol (a US-Based Study) Kenneth G. Saag,1 David Fitz-Patrick,2 Jeff Kopicko,3 Maple Fung,3 Nihar Bhakta,3 Scott Adler,4 Chris Storgard,3 Scott Baumgartner,3 and Michael A. Becker5 Objective. Lesinurad is a selective uric acid re- serum UA level of <6.0 mg/dl at month 6. Key secondary absorption inhibitor used for the treatment of gout in com- end points were the mean gout flare rate requiring treat- bination with a xanthine oxidase inhibitor. The Combining ment (months 7–12) and the proportions of patients with Lesinurad with Allopurinol Standard of Care in Inade- complete resolution of ‡1 target tophus (month 12). Safety quate Responders (CLEAR 1) study, a 12-month, multi- assessments included adverse events and laboratory data. center, randomized, double-blind, placebo-controlled Results. The study patients (n 5 603) were predom- phase III trial, was conducted to investigate daily lesinurad inantlymaleandhadamean6 SD age of 51.9 6 11.3 (200 mg or 400 mg orally) added to allopurinol versus pla- years, a gout duration of 11.8 6 9.4 years, a baseline serum cebo plus allopurinol in patients with serum urate (UA) UA level of 6.94 6 1.27 mg/dl, and were receiving an allopu- levels above a target of <6.0 mg/dl. rinol dosage of 306.6 6 59.58 mg/day. Lesinurad at doses Methods. Patients receiving ‡300 mg of allopuri- of 200 mg or 400 mg added to allopurinol therapy signifi- nol (‡200 mg in those with moderate renal impairment) cantly increased the proportions of patients who achieved who had serum UA levels ‡6.5 mg/dl at screening and ‡2 serum UA target levels by month 6 as compared with those gout flares during the previous year were studied. The pri- receiving allopurinol alone (54.2%, 59.2%, and 27.9%, mary end point was the proportion of patients achieving a respectively, P < 0.0001). Lesinurad was not significantly superior to allopurinol alone in terms of the secondary end ClinicalTrials.gov identifier: NCT01510158. points: rates of gout flares and complete resolution of Supported by Ardea Biosciences, a member of the AstraZeneca group. tophi. Lesinurad was generally well-tolerated; the safety 1Kenneth G. Saag, MD, MSc: University of Alabama at profile of the 200-mg dose was comparable to that of allo- Birmingham; 2David Fitz-Patrick, MD: East-West Medical Research Institute, Honolulu, Hawaii; 3Jeff Kopicko, MSPH (current address: purinol alone, except for higher incidences of predomi- Receptos Inc., San Diego, California), Maple Fung, MD, Nihar Bhakta, nantly reversible elevations of serum creatinine levels. MD, Chris Storgard, MD (current address: Fate Therapeutics, San Conclusion. Lesinurad added to allopurinol pro- Diego, California), Scott Baumgartner, MD: Ardea Biosciences, San Diego, California; 4Scott Adler, MD: AstraZeneca Pharmaceuticals, vided benefit as compared with allopurinol alone in reduc- Gaithersburg, Maryland; 5Michael A. Becker, MD: University of ing serum UA levels and represents a new treatment option Chicago, Chicago, Illinois. for patients needing additional urate-lowering therapy. Dr. Saag has received consulting fees from Ardea/AstraZeneca (more than $10,000) and Takeda (less than $10,000) and research sup- port from Ardea, Crealta, and Takeda. Dr. Fitz-Patrick has received Current guidelines for the long-term management research support from Takeda, CymaBay Therapeutics, Ardea, BioCryst, of gout recommend a combination of lifestyle management and Regeneron Pharmaceuticals. Dr. Becker has received consulting fees from Ardea/AstraZeneca and Takeda (more than $10,000 each), and/or pharmacotherapy to lower serum urate (UA) levels and from Crealta, CymaBay Therapeutics, BioCryst, and Pfizer (less to ,6.0 mg/dl in most patients or ,5.0 mg/dl in patients than $10,000 each). with more severe disease (1). Allopurinol is the most Address correspondence to Kenneth G. Saag, MD, MSc, Division of Clinical Immunology and Rheumatology, University of widely used xanthine oxidase inhibitor and is recom- Alabama at Birmingham, 820 Faculty Office Tower, 510 20th Street mended in treatment guidelines as a first-line urate-lower- South, Birmingham, AL 35233. E-mail: [email protected]. Submitted for publication January 6, 2016; accepted in ing therapy in patients with gout, with a maximum daily revised form August 4, 2016. dose of 800 mg based on the highest approved dose in the 203 204 SAAG ET AL US (1). As an inhibitor of xanthine oxidase, allopurinol Trial design. Treatment procedures. CLEAR 1 was reduces uric acid production and lowers serum UA levels a 12-month, multicenter, randomized, double-blind, placebo- (2). However, many patients––more than 50% in clinical controlled, US-based phase III trial investigating the efficacy and safety of lesinurad (200 mg or 400 mg orally, once a day) in com- trials––do not achieve the serum UA target of ,6.0 mg/dl bination with allopurinol versus allopurinol in combination with at the most commonly used allopurinol dosage of 300 mg/ placebo (control arm). The study included a screening period of day (3–6). In cases where the serum UA target cannot be ;28 days, which included a run-in period of ;14 days during achieved with allopurinol alone at an appropriate dosage, which gout flare prophylaxis was initiated, and a 12-month treatment guidelines recommend substitution therapy double-blind treatment period (Figure 1). Eligible patients were randomized in a double-blind (e.g., with febuxostat or a uricosuric agent) or combination manner to receive lesinurad 200 mg, lesinurad 400 mg, or pla- therapy that includes allopurinol with a uricosuric agent cebo in a 1:1:1 ratio, added to continued treatment with allopur- (1,7,8). The current US-based study is 1 of 2 replicate ran- inol at the same prestudy dosage (permitted range 300–800 mg/ domized controlled trials where this recommendation is day; 200 mg allowed in those with moderate renal impairment). formally investigated for the first time. Randomization at study sites used a centralized interactive voice-response system/interactive web-response system. Lesinurad (RDEA594) is a novel selective uric Doses of lesinurad or matching placebo were taken once acid reabsorption inhibitor for the treatment of gout in daily in the morning with food and 1 cup of water. Patients were combination with a xanthine oxidase inhibitor. Lesinurad encouraged to drink 2 liters of fluid a day and remain well inhibits the uric acid transporter URAT1, which is respon- hydrated, according to the ACR guidelines (1). Compliance with sible for reabsorption of urate from the renal tubular study medication was determined by assessment of dispensing records and verification of returned medication packaging. Con- lumen (9). By inhibiting URAT1, lesinurad increases the comitant medication use was also recorded at each study visit. excretion of uric acid in the kidney and lowers serum UA Gout flare prophylaxis was initiated at the same time as levels (10,11). Lesinurad in combination with allopurinol sponsor-provided allopurinol (day 214) and consisted of colchi- therefore provides a dual mechanism of action for manag- cine (0.5 mg or 0.6 mg once a day, per protocol and as locally avail- able) or a nonsteroidal antiinflammatory drug (NSAID) if ing the hyperuricemia of gout: increased urinary excretion patients were intolerant of, or had contraindications for, colchi- of uric acid and reduced urate production. cine. Gout flare prophylaxis was continued through month 5 Lesinurad in combination with allopurinol has dem- unless the patient became intolerant or developed toxicity to the onstrated greater reductions in serum UA than allopurinol drug. alone in phase I and II studies (12–14). The current phase The study was conducted in accordance with Indepen- dent Ethics Committee E6 Good Clinical Practice, the Declara- III study, Combining Lesinurad with Allopurinol Standard tion of Helsinki (October 2008), and applicable local regulatory of Care in Inadequate Responders (CLEAR 1), is 1 of 2 rep- requirements (including Institutional Review Board approval and licate, randomized, double-blind, placebo-controlled, multi- Health Insurance Portability and Accountability Act assurances). center studies to investigate lesinurad (200 mg or 400 mg Patients were permitted to withdraw from the medication or the orally, once daily) in combination with allopurinol (at the study at any time. The study was conducted between February 8, 2012 and July 1, 2014. investigator-determined appropriate dosage) in patients Evaluations. The primary efficacy end point was the with gout (ClinicalTrials.gov Identifier: NCT01510158). proportion of patients with a serum UA level of ,6.0 mg/dl by month 6 in each treatment group. There were 2 key secondary PATIENTS AND METHODS end points. First was a mean rate of gout flares requiring treat- ment for the 6-month period from the end of month 6 to the end Study participants. Men and women (ages 18–85 of month 12. Permitted gout flare treatments included colchicine, years; body mass index ,45 kg/m2)withadiagnosisofgoutwere analgesics, and/or antiinflammatory medications, including oral eligible for study inclusion if they had an inadequate response to and intraarticular corticosteroids. Gout flares were reported in a standard-of-care allopurinol (defined below). The diagnosis of daily electronic diary. Second was the proportion of patients with gout was based on the American College of Rheumatology target tophi at baseline who experienced complete resolution of (ACR) criteria for the classification of acute arthritis of primary $1 tophus by month 12. Target tophi (up to 5 per patient) were gout (15). Inclusion criteria were receipt of a stable dosage of those measuring $5mmand#20 mm in the longest diameter allopurinol (judged by the treating physician to be medically located on the hands/wrists and/or feet/ankles.