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

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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. Tophi were mea- appropriate) from 300 mg/day (or at least 200 mg/day in patients sured with digital Vernier calipers every 3 months. with moderate renal impairment [estimated creatinine clearance Other secondary efficacy end points included the propor- of 30–59 ml/minute]) up to 800 mg/day (16) as the sole urate- tion of patients with serum UA levels of ,6.0 mg/dl, ,5.0 mg/dl, lowering therapy for $8 weeks prior to screening. A serum UA and ,4.0 mg/dl at each monthly visit, as well as the mean abso- level of $6.5 mg/dl at screening and $6.0 mg/dl ;7dayspriorto lute change and the mean percentage change from baseline in the start of treatment on day 1 was required. Patients must also serum UA levels at each visit. Patients were assessed at baseline have reported $2 gout flares during the previous 12 months. (day 1) and from month 1 through month 12 for serum UA levels Complete exclusion criteria are shown in Supplementary and were assessed daily by diary for gout flare data. Table 1 (available on the Arthritis & Rheumatology web site at Safety assessments included treatment-emergent adverse http://onlinelibrary.wiley.com/doi/10.1002/art.39840/abstract). A events (TEAEs; coded according to the Medical Dictionary for history of kidney stones was not a criterion for study exclusion. Regulatory Activities [MedDRA], version 14.0), clinical laboratory LESINURAD IN COMBINATION WITH ALLOPURINOL IN GOUT PATIENTS 205

Figure 1. Design of the Combining Lesinurad with Allopurinol Standard of Care in Inadequate Responders (CLEAR 1) trial. Randomization on day 27 was stratified according to renal function (estimated creatinine clearance $60 ml/minute versus ,60 ml/minute, as calculated by the Cockcroft-Gault formula using the ideal body weight) and tophus status ($1 tophus versus no tophi) during screening. * Allopurinol doses of 300–800 mg/day were permitted, but 200 mg of allopurinol was allowed in patients with moderate renal impairment. sUA 5 serum urate; 18 5 primary; 28 5 secondary. data, physical examination findings, electrocardiogram findings, and the allopurinol-alone group were performed using the and vital signs. Adverse events of special interest included Cochran-Mantel-Haenszel test statistic, stratified by day 27 assessments of renal and cardiovascular (CV) safety. Renal safety renal function and tophus status during screening. A assessments were included because renal impairment is a common Bonferroni correction was used for the primary end point for comorbid condition in patients with gout (7). Renal safety is also a each of the 2 treatment comparisons with allopurinol alone at topic of special interest because of the uricuresis that is caused by an a level of 0.025. Testing of the key secondary end points lesinurad (12). Increases in the excretion of urinary uric acid have hierarchically at an a level of 0.05 was gated on both dosage the potential to induce microcrystallization in the renal tubules contrasts being statistically significant for the primary end and/or urinary system, which could manifest as acute uric acid point. If only 1 of the primary end point dosage contrasts was nephropathy or kidney stones. Assessments of renal safety significant, then a 5 0.025 for each key secondary end point included renal-related and kidney stone TEAEs (Supplementary within the surviving dosage. All other efficacy end points were Table 2, available at http://onlinelibrary.wiley.com/doi/10.1002/art. evaluated at a 5 0.05 (nominal P value), 2-sided, without 39840/abstract) and clinical laboratory data, including serum creati- adjustment for multiple comparisons. nine, creatine kinase, urinary protein-to-creatinine ratio, and esti- Results for the primary end point of serum UA response mated creatinine clearance levels. are expressed as proportions, corresponding adjusted 95% confi- Another area of special interest was CV safety, dence intervals for the difference between proportions, and P val- because of the known high rates of CV risk factors (e.g., ues. Patients with missing values for any reason at month 6 were hypertension, hyperlipidemia, and diabetes mellitus) in considered nonresponders (nonresponder imputation) (20). patients with gout (17,18). An independent Cardiovascular Key secondary end points were analyzed using nega- Events Adjudication Committee (CEAC) routinely assessed tive binomial regression (gout flares) or the Cochran-Mantel- adverse events for a potential CV relationship, with categori- Haenszel test (tophus response). Mean rates of gout flares zation into major adverse CV event (MACE) and non-MACE were adjusted for day 27 renal function, tophus status at end points (Supplementary Table 3, available at http:// screening, and duration of exposure to randomized study med- onlinelibrary.wiley.com/doi/10.1002/art.39840/abstract) (19). ication. Safety data are presented by treatment arm and were Patients who completed the double-blind treatment not subjected to statistical testing. TEAEs are coded by system period in the CLEAR 1 trial were eligible to enroll in a separate organ class and preferred term and are listed according to extension study of lesinurad in combination with allopurinol. their incidence, severity, relation to study medication, and Those who did not enter the extension study attended a follow-up relation to discontinuation. In order to better identify poten- visit within 14 days of completing the double-blind treatment. tial clinically relevant changes in serum creatinine levels Statistical analysis. The study consisted of a 12- related to lesinurad by minimizing any discrepancies due to month treatment period, with the primary end point evaluated intrasubject variability, the baseline serum creatinine level was at month 6 and key secondary end points at month 12. Com- defined as the highest value within 14 days prior to the first dose of parisons of proportions of responders based on serum UA study medication. Relative increases in serum creatinine levels (i.e., levels between each of the 2 lesinurad plus allopurinol groups $1.5 times and $2.0 times the baseline level) were calculated 206 SAAG ET AL

Figure 2. Flow chart showing the distribution of the study participants. a Screened was defined as signing an informed consent form. b Completed study was defined as study completion with or without completing the randomized study medication. Twenty-six additional patients were screened, 4 of whom were randomized and received study medication; these patients were excluded from all analyses (25 because of non- compliance with Good Clinical Practice and 1 because of missing informed consent). ALLO 5 allopurinol; LESU 5 lesinurad.

(21,22). Resolution of serum creatinine elevation was defined as a prior to randomization, including 1,709 who failed the serum creatinine level that returned to #1.2 times the baseline level. screening step and 61 who withdrew their consent. Of A sample size of ;600 subjects to be recruited was the 607 randomized patients, 603 received at least 1 planned, to yield an allocation of ;200 to each treatment arm. This sample size was calculated to provide .90% power to dose of study medication. Four patients withdrew prior detect a difference in the response rate between treatment to receiving study medication: 2 because they were non- groups if the allopurinol-alone group had a 30% response rate compliant/deviated from the protocol and 2 because and the lesinurad groups had response rates as low as 48% they withdrew their consent. A total of 150 patients using Fisher’s exact test, adjusting for multiplicity with (24.9%) withdrew during the study, with similar rates in a 5 0.025, 2-sided, for each test. A previous 4-week, phase IIb the group taking allopurinol alone (24.4%), lesinurad study of lesinurad in combination with allopurinol showed response rates (i.e., serum UA ,6.0 mg/dl) of ;30% for the 200 mg plus allopurinol (24.9%), and lesinurad 400 mg allopurinol-alone arm versus $70% for the lesinurad (200 mg, plus allopurinol (25.4%) (Figure 2). 400 mg, and 600 mg) plus allopurinol arms (13). Demographic characteristics and clinical history. All randomized patients who received $1 dose of ran- domized study medication were included in the intent-to-treat The study patients were predominantly male (94.0%) population, which was the primary population for the efficacy and white (76.3%), with a mean 6 SD age of 51.90 6 and safety assessments. 11.28 years and a mean 6 SD body mass index of 34.77 6 6.66 kg/m2 (Table 1). The study population had, in gen- eral, longstanding symptomatic gout, with a mean 6 SD RESULTS time since diagnosis of 11.84 6 9.37 years. The mean 6 Distribution of the study subjects. Of 2,377 SD baseline serum UA level was 6.94 6 1.27 mg/dl. Only patients screened, 607 were randomized at 138 study 86 patients (14.3%) had tophi at screening, and 54 (9.0%) sites. The remaining 1,770 patients were withdrawn had $1 target tophus (i.e., measurable on hands/wrists or LESINURAD IN COMBINATION WITH ALLOPURINOL IN GOUT PATIENTS 207

Table 1. Demographic and baseline disease characteristics (intent-to-treat population)* Allopurinol Lesinurad 200 mg Lesinurad 400 mg alone plus allopurinol plus allopurinol Total (n 5 201) (n 5 201) (n 5 201) (n 5 603) Demographic characteristics Sex, no. (%) Men 189 (94.0) 192 (95.5) 186 (92.5) 567 (94.0) Women 12 (6.0) 9 (4.5) 15 (7.5) 36 (6.0) Race, no. (%) White 153 (76.1) 151 (75.1) 156 (77.6) 460 (76.3) Black or African American 29 (14.4) 31 (15.4) 30 (14.9) 90 (14.9) Asian 10 (5.0) 9 (4.5) 7 (3.5) 26 (4.3) Native Hawaiian or other 5 (2.5) 4 (2.0) 5 (2.5) 14 (2.3) Pacific Islander American Indian or Alaska native 1 (0.5) 2 (1.0) 0 3 (0.5) Other 3 (1.5) 4 (2.0) 3 (1.5) 10 (1.7) Age, years Mean 6 SD 51.7 6 11.70 51.6 6 10.69 52.3 6 11.47 51.90 6 11.28 Range 22–81 25–77 23–77 22–81 BMI, kg/m2 Mean 6 SD 34.31 6 6.44 35.02 6 6.17 34.96 6 7.33 34.77 6 6.66 Range 15.91–50.99 17.79–59.38 15.77–83.65 15.77–83.65 Baseline disease characteristics Time since gout diagnosis, years Mean 6 SD 11.59 6 8.75 12.76 6 10.04 11.16 6 9.23 11.84 6 9.37 Range 0.2–40.4 0.2–45.2 0.0–43.0 0.0–45.2 Tophi at screening, no. (%) Yes 27 (13.4) 30 (14.9) 29 (14.4) 86 (14.3) No 174 (86.6) 171 (85.1) 172 (85.6) 517 (85.7) $1 target tophus at baseline, no. (%) Yes 17 (8.5) 18 (9.0) 19 (9.5) 54 (9.0) No 184 (91.5) 183 (91.0) 182 (90.5) 549 (91.0) No. of target tophi at baseline Mean 6 SD 1.8 6 1.47 1.8 6 1.06 2.1 6 1.45 1.9 6 1.32 Range 1–5 1–5 1–5 1–5 No. of gout flares in the last 12 months Mean 6 SD 4.8 6 4.09 4.8 6 3.16 4.9 6 3.49 4.8 6 3.60 Range 2–36 2–20 2–20 2–36 Estimated creatinine clearance, no. (%) $90 ml/minute 77 (38.3) 83 (41.3) 76 (37.8) 236 (39.1) ,90 ml/minute 123 (61.2) 117 (58.2) 124 (61.7) 364 (60.4) ,60 ml/minute 40 (19.9) 45 (22.4) 41 (20.4) 126 (20.9) Cardiovascular risk factors, no. (%) Hypertension 134 (66.7) 129 (64.2) 142 (70.6) 405 (67.2) Hyperlipidemia 99 (49.3) 102 (50.7) 98 (48.8) 299 (49.6) Type 2 diabetes 35 (17.4) 44 (21.9) 38 (18.9) 117 (19.4) History of kidney stones, no. (%) 38 (18.9) 20 (10.0) 22 (10.9) 80 (13.3) Serum uric acid Mean 6 SD mg/dl 6.99 6 1.25 7.01 6 1.32 6.83 6 1.24 6.94 6 1.27 ,8.0 mg/dl, no. (%) 165 (82.1) 164 (81.6) 169 (84.1) 498 (82.6) $8.0 mg/dl, no. (%) 36 (17.9) 37 (18.4) 32 (15.9) 105 (17.4) Gout flare prophylaxis, no. (%) Colchicine 166 (82.6) 170 (84.6) 168 (83.6) 504 (83.6) NSAID 34 (16.9) 28 (13.9) 33 (16.4) 95 (15.8) Both 1 (0.5) 2 (1.0) 3 (1.5) 6 (1.0) Allopurinol dosage, mg/day Mean 6 SD 310.0 6 70.00 309.5 6 59.67 300.2 6 46.50 306.6 6 59.58 Range 200–600 200–600 200–600 200–600

* BMI 5 body mass index; NSAID 5 nonsteroidal antiinflammatory drug. feet/ankles) at baseline; the mean 6 SD number of target months prior to study entry. Demographic and disease tophi in these patients was 1.9 6 1.32. The study patients characteristics at baseline were similar between treatment self-reported a mean 6 SD of 4.8 6 3.60 flares in the 12 groups (Table 1). 208 SAAG ET AL

Figure 3. Proportion of patients achieving serum urate (sUA) target levels of ,6.0 mg/dl, ,5.0 mg/dl, and ,4.0 mg/dl by months 6 and 12 (intent- to-treat population). The primary end point was the proportion of patients achieving a serum UA target level of ,6.0 mg/dl by month 6. Those with a missing serum UA result at the assessment time were treated as nonresponders. Values are the mean 6 SE. * 5 P , 0.0001; ** 5 P , 0.01 versus allo- purinol (ALLO) alone, by 2-sided Cochran-Mantel Haenszel test stratified by day 27 renal function and day 27 serum UA status (randomized strati- fication factor values), with nonresponder imputation and no adjustment for multiple comparisons. LESU 5 lesinurad.

The dosage range of allopurinol administered at for each comparison; nonresponder imputation). The pro- baseline was from 200 mg/day (permitted only for those portion of patients who achieved serum UA levels of with moderate renal impairment) to 600 mg/day, com- ,5.0 mg/dl and ,4.0 mg/dl was also greater in both groups pared with the maximum permitted dosage of 800 mg/ taking lesinurad plus allopurinolascomparedwiththegroup day. Most patients (90.5%) received allopurinol at a daily taking allopurinol alone, starting at month 1 and at each dose of 300 mg, consistent with general clinical practice monthly visit through month 12 (serum UA target ,5.0 mg/ (23); another 4.8% received a daily dose of 200 mg to dl, P , 0.0001 for each comparison; serum UA target ,300 mg and 4.6% took .300 mg/day. One or more pre- ,4.0 mg/dl, P , 0.01 for lesinurad 200 mg plus allopurinol defined comorbid conditions (i.e., CV risk factors or kid- and P , 0.0001 for lesinurad 400 mg plus allopurinol). The ney stones) were recorded in 82.1% of patients. proportions of patients at each serum UA threshold by Study medications. The overall proportions of months 6 and 12 are shown in Figure 3. patients exhibiting $80% compliance with study medi- Mean serum UA levels were lower in both groups cations were 95.0%, 93.5%, and 93.0%, respectively, in taking lesinurad plus allopurinol as compared with allo- the groups taking allopurinol alone, lesinurad 200 mg purinol alone at all time points assessed (P , 0.0001 for plus allopurinol, and lesinurad 400 mg plus allopurinol. each comparison of the percentage change in serum UA Efficacy assessments. Primary end point of serum levels from baseline) (Figure 4). UA response and secondary serum UA end points. The Secondary end point: gout flare rate. The gout proportions of patients achieving a serum UA level of flare rate and the proportion of patients with gout flares ,6.0 mg/dl by month 6 (the primary end point) were 27.9%, requiring treatment were low and were similar in all groups 54.2%, and 59.2% in the groups taking allopurinol alone, throughout the study. The mean 6 SEM rates of gout flares lesinurad 200 mg plus allopurinol, and lesinurad 400 mg requiring treatment from the end of month 6 to the end of plus allopurinol, respectively. This represents a significant month 12 were 0.58 6 0.10 for the group taking allopurinol difference for each of the groups taking lesinurad plus allo- alonecomparedwith0.576 0.10 and 0.51 6 0.09 in the purinol as compared with allopurinol alone (P , 0.0001 for groups taking lesinurad 200 mg plus allopurinol and each comparison; nonresponder imputation) (Figure 3). lesinurad 400 mg plus allopurinol (P 5 0.98 and P 5 0.61), Subgroup analyses based on age, sex, race, baseline respectively. serum UA levels, comorbid conditions, renal function, and Secondary end point: tophus resolution. The thiazide diuretic use provided results consistent with those numbers of patients with $1 target tophus at baseline from the primary analysis in the intent-to-treat population. were low: 17 (8.5%), 18 (9.0%), and 19 (9.5%), respec- For the renal function and thiazide diuretic analyses, see tively, in the groups taking allopurinol alone, versus Supplementary Figure 1 (available at http://onlinelibrary. lesinurad 200 mg plus allopurinol, and lesinurad 400 mg wiley.com/doi/10.1002/art.39840/abstract). plus allopurinol. Of these patients, 5 (29.4%), 0 (0%), The proportion of patients achieving a serum UA and 4 (21.1%), respectively, achieved complete resolu- target level of ,6.0 mg/dl was greater in both the lesinurad tion of a target tophus by month 12 (P 5 0.02 for allopu- 200 mg plus allopurinol and the lesinurad 400 mg plus allo- rinol alone versus lesinurad 200 mg plus allopurinol and purinol groups than in the allopurinol-alone group at all P 5 0.60 for allopurinol alone versus lesinurad 400 mg monthly assessments from month 1 to month 12 (P , 0.0001 plus allopurinol). LESINURAD IN COMBINATION WITH ALLOPURINOL IN GOUT PATIENTS 209

(5.5%,10.9%, and 9.0%), increased blood creatine phos- phokinase levels (2.5%, 4.5%, and 8.0%), sinusitis (2.0%, 4.5%, and 6.0%), increased blood creatinine levels (1.0%, 3.5%, and 7.0%), and headache (2.5%, 3.5%, and 6.0%). The most common grade 3 or 4 TEAEs in the respective groups were influenza (0%, 1.5%, and 1.0%) and acute myocardial infarction (0%, 0.5%, and 1.5%). Serious TEAEs were reported in 5.5%, 4.5%, and 8.0% of the patients, respectively. Serious TEAEs occur- ring in more than 1 patient in any treatment group included cerebrovascular accident (2 patients) in those tak- ing allopurinol alone, coronary artery disease (2 patients) inthosetakinglesinurad200mgplusallopurinol,and acute myocardial infarction (3 patients) and congestive heart failure (2 patients) in those taking lesinurad 400 mg plus allopurinol. One death due to cardiac arrest was Figure 4. Serum urate (sUA) levels at each study visit (observed reported in the lesinurad 200 mg plus allopurinol group. cases, intent-to-treat population). The mean change from baseline Renal safety analyses. Renal-related TEAEs for each group receiving lesinurad (LESU) plus allopurinol (ALLO) was compared with that in the group receiving allopurinol alone by occurred in 3.5%, 4.0%, and 10.0% of the allopurinol- analysis of covariance, yielding significant differences (P , 0.0001) at alone, lesinurad 200 mg plus allopurinol, and lesinurad each time point tested. Values are the mean 6 SEM. 400 mg plus allopurinol groups, respectively. The most common renal-related TEAEs in these respective groups Safety assessments. Adverse events. TEAEs were increased blood creatinine levels (1.0%, 3.5%, and were reported in 68.7%, 73.1%, and 77.6% of those taking 7.0%), increased blood urea nitrogen levels (1.0%, 1.0%, allopurinol alone, lesinurad 200 mg plus allopurinol, and and 1.5%), and renal failure (1.5%, 0.5%, and 1.5%). One lesinurad 400 mg plus allopurinol, respectively (Table 2). serious renal-related TEAE (renal failure) was reported in The majority of TEAEs in each group had a maximum 1 patient (0.5%) in the lesinurad 400 mg plus allopurinol severity of grade 1 or 2, based on Rheumatology Common group. Kidney stone TEAEs were reported in 2.0%, 1.0%, Toxicity Criteria (RCTC) (24). Grade 3 or 4 TEAEs and 2.5% of patients, respectively. occurred in 6.0%, 10.9%, and 14.4% of patients in the 3 Serum creatinine elevations $1.5 times the base- groups, respectively. TEAEs led to discontinuation of line levels occurred in 1.0% (n 5 2), 6.0% (n 5 12), and study medication in 4.0%, 8.0%, and 7.0% of patients in 15.9% (n 5 32) of patients in the groups taking allopurinol the respective groups. The most common individual alone, lesinurad 200 mg plus allopurinol, and lesinurad TEAEs in the groups taking allopurinol alone, lesinurad 400 mg plus allopurinol, respectively. Such elevations were 200 mg plus allopurinol, and lesinurad 400 mg plus allopu- transient and reversible in most cases during the study, and rinol, respectively, were upper respiratory tract infection the majority had resolved by the time of the next assessment.

Table 2. Overall summary of treatment-emergent adverse events (safety population)*

Lesinurad Lesinurad Allopurinol 200 mg plus 400 mg alone allopurinol plus allopurinol Adverse event (n 5 201) (n 5 201) (n 5 201) Any TEAE 138 (68.7) 147 (73.1) 156 (77.6) Any TEAE with RCTC 12 (6.0) 22 (10.9) 29 (14.4) toxicity grade 3 or 4 Any TEAE possibly related 19 (9.5) 33 (16.4) 41 (20.4) to randomized study medication Any serious TEAE 11 (5.5) 9 (4.5) 16 (8.0) Any fatal TEAE 0 1 (0.5) 0 Any TEAE leading to discontinuation 8 (4.0) 16 (8.0) 14 (7.0) of randomized study medication Any TEAE leading to study withdrawal 7 (3.5) 9 (4.5) 8 (4.0)

* Values are the number (%). TEAE 5 treatment-emergent adverse event; RCTC 5 Rheumatology Common Toxicity Criteria. 210 SAAG ET AL

There were 2 unresolved serum creatinine elevations in the DISCUSSION lesinurad 200 mg plus allopurinol group and 9 unresolved In the CLEAR 1 trial, we investigated the efficacy elevations in the lesinurad 400 mg plus allopurinol group at and safety of lesinurad (200 mg and 400 mg) in combina- the last study visit. Serum creatinine elevations $2.0 times tion with allopurinol in patients who had a suboptimal the baseline levels were reported in 0%, 1.0% (n 5 2), and response to standard-of-care allopurinol. Consistent with 6.0% (n 5 12) of patients in the respective groups. Again, treatment patterns currently seen in clinical practice, the most cases were transient and reversible. No serum creati- mean allopurinol dosage was 306.6 mg/day (range 200–600) nine elevations $2.0 times baseline levels were unresolved (25,26). Lesinurad at a dosage of 200 mg/day is now at the last study visit in the lesinurad 200 mg plus allopuri- approved by the US Food and Drug Administration and nol group and 2 cases were unresolved in the lesinurad European Medicines Agency for the treatment of hyperuri- 400 mg plus allopurinol group. In approximately two-thirds cemia associated with gout in combination with a xanthine of the cases, resolution of elevated serum creatinine levels oxidase inhibitor in patients who have not achieved target occurred without interruption of the study medication. serum UA levels with a xanthine oxidase inhibitor alone. In subgroups categorized according to baseline Lesinurad at both doses (200 or 400 mg) in combi- renal function (estimated creatinine clearance ,60, ,90, nation with allopurinol significantly increased the propor- and $90 ml/minute), treatment-group differences in tions of patients achieving a serum UA target level of TEAE and serum creatinine elevation rates were consistent ,6.0 mg/dl by month 6 (the primary end point) (P , 0.0001 with those in the overall study population (data not shown). for each comparison), with approximately twice as many Renal function remained stable over the study patients in the lesinurad 200 mg group reaching target lev- across the treatment groups. Mean 6 SD changes in esti- els when compared with allopurinol alone. The onset of mated creatinine clearance in the allopurinol-alone, serum UA reduction achieved with lesinurad plus allopuri- lesinurad 200 mg plus allopurinol, and lesinurad 400 mg nol therapy was rapid, with significant differences from the plus allopurinol groups, respectively, were 3.07 6 10.54, levels achieved with allopurinol alone by the first serum 20.53 6 10.98, and 23.56 6 12.14 ml/minute from base- UA assessment at month 1. The significant increase in the line to the last visit on treatment and were 2.15 6 8.34, proportion of patients who achieved the serum UA target 3.26 6 10.69, and 2.32 6 10.12 ml/minute from baseline to in both lesinurad plus allopurinol groups versus the allopu- the last visit off treatment. Mean changes in the urinary rinol alone group was sustained over the 12-month study. protein-to-creatinine ratio in the 3 study groups were For the key secondary end points, including rates of 0.05 6 0.39, 0.03 6 0.14, and 0.05 6 0.40, respectively. gout flare requiring treatment and complete resolution of Cardiovascular safety analyses. TEAEs were adju- tophi, there were no statistically significant treatment dif- dicated as CV events in 3.5% (n 5 7), 4.5% (n 5 9), and ferences favoring the lesinurad treatment groups. The 4.0% (n 5 8), respectively, of those taking allopurinol mean rate of gout flares requiring treatment was low ini- alone, lesinurad 200 mg plus allopurinol, and lesinurad tially and declined in all groups during the study, favoring 400 mg plus allopurinol. CEAC-adjudicated criteria for lesinurad but without significant between-group differ- MACE were met by 2 patients (3 events) in the allopurinol- ences during the 6-month period from the end of month 6 alone, 2 patients (2 events) in the lesinurad 200 mg plus to the end of month 12. Notably, discontinuation of prophy- allopurinol, and 3 patients (3 events) in the lesinurad laxis at month 5 was not followed by an increase in the rate 400 mg plus allopurinol groups. Non-MACE CV end of gout flares requiring treatment in the lesinurad groups points were reported in 4 patients (5 events), 2 patients (2 compared with the allopurinol-alone group. In the assess- events), and 3 patients (4 events) in the respective groups. ment of complete resolution of tophi, the proportion of Other clinical laboratory tests and vital signs. Clinical evaluable patients with target tophi was low at baseline laboratory test results, including hematologic analyses, liver (9.0%), which affected the interpretation of this secondary function tests, other serum chemistry parameters (exclud- end point. In relation to both gout flare rates and tophus ing renal laboratory results reported above), and urinalysis, resolution, a treatment duration of .12 months may be demonstrated no notable differences between the treat- required for the full effects to be observed (25). ment groups over time. Elevations in creatine kinase levels Lesinurad was generally well tolerated, particularly .5 times the upper limit of normal occurred in 3.5%, at the 200-mg dose, where the AE profile was comparable 5.5%, and 3.0%, respectively, in those taking allopurinol to that of allopurinol alone. The majority of TEAEs were alone, lesinurad 200 mg plus allopurinol, and lesinurad grade 1 or 2, and the proportions of patients with serious 400 mg plus allopurinol. There were no notable changes in adverse events and TEAEs leading to study withdrawal vital signs from baseline in any group during the study. were comparable across treatment groups. LESINURAD IN COMBINATION WITH ALLOPURINOL IN GOUT PATIENTS 211

In renal safety analyses, the incidence of renal- proportions of patients with TEAEs classified as CV events related TEAEs was comparable in the lesinurad 200 mg during the study were low and were similar in the treatment plus allopurinol and allopurinol-alone groups, with groups (range 3.5–4.5%), and all except 1 of these patients higher rates for lesinurad 400 mg plus allopurinol. had at least 1 baseline CV comorbid condition or a history Laboratory assessments revealed that serum creati- of CV disease. Incidences of MACE events were also simi- nine elevations occurred at higher rates in the lesinurad larly low and comparable across the 3 treatment groups. plus allopurinol groups (particularly the 400-mg dose) ver- Low rates of MACE events in association with gout treat- sus allopurinol alone. In the majority of cases, elevated ment have also been reported in the recent open-label serum creatinine levels resolved during the study, without Long-Term Allopurinol Safety Study Evaluating Outcomes interruption of the study medications and without adverse in Gout Patients (LASSO) study, which provided an event effects on renal function over the course of the study. The rate of 0.58% for MACE over 6 months (incidence rate mechanism of the serum creatinine elevation associated 1.42 per 100 patient-years) during allopurinol treatment with lesinurad is believed to be due to increased excretion (4), and in the double-blind CONFIRMS study, which of urinary uric acid, which has the potential to induce uric reported a 0.4% rate of MACE with allopurinol (32). acid microcrystallization in the renal tubules, which could Limitations of the CLEAR 1 trial include the limited manifest clinically as transient and reversible elevations in data on allopurinol doses .300 mg, the exclusion of allopuri- serum creatinine levels. There was no evidence that patients nol dosage adjustments during the study, the low number of with impaired renal function at baseline were at increased patients with evaluable tophi, and the relatively short follow- risk of serum creatinine elevations during the study. up period that limits the ability to adequately study flares There was also no apparent association between and tophi. Lesinurad was developed as an add-on treatment serum creatinine elevations and either of the gout flare for patients in whom serum UA target levels were not prophylaxis medications (colchicine or NSAID) (data achieved with allopurinol alone. The majority of patients in not shown). The urinary protein-to-creatinine ratios and the CLEAR 1 study were receiving allopurinol 300 mg. It is urinalysis results did not change during the study, sug- thus unclear whether further up-titration of allopurinol, as gesting that serum creatinine elevations were not associ- recommended by treatment guidelines (1), would have been ated with renal parenchymal sequelae. an effective option for these patients. A post hoc pooled Of note, the US prescribing information for analysis of both replicate studies on lesinurad in combination lesinurad recommends assessing renal function prior to the with allopurinol demonstrated similar serum UA–lowering initiation of lesinurad therapy and periodically thereafter, and response rates regardless of the allopurinol dose (33). particularly in patients with creatinine clearance values In conclusion, lesinurad is a novel selective uric acid between 30 ml/minute and ,45 ml/minute. Lesinurad treat- reabsorption inhibitor for the treatment of gout in combi- ment should be discontinued in patients with creatinine nation with xanthine oxidase inhibitors. Combination ther- , clearance values persistently 30 ml/minute and is con- apy with lesinurad and allopurinol may represent a traindicated in patients with end-stage renal disease, kidney treatment option for patients with gout in whom target lev- transplant recipients, and patients undergoing dialysis. els of serum UA cannot be achieved with a xanthine oxidase Few kidney stone TEAEs were reported during the inhibitor alone and additional therapy is warranted. study, and the incidence did not differ significantly between treatment groups. Other therapies that inhibit URAT1 have been associated with the development of kidney stones AUTHOR CONTRIBUTIONS (26,27). The lack of increase in kidney stone events during All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved lesinurad therapy is possibly explained by the fact that by the final version to be published. Dr. Saag had full access to all of the decreasing the production of uric acid, allopurinol reduced data in the study and takes responsibility for the integrity of the data the amount of uric acid excreted by the kidneys, as reported and the accuracy of the data analysis. Study conception and design. Saag, Fitz-Patrick, Kopicko, Fung, previously for xanthine oxidase inhibitors (28,29). The tim- Bhakta, Adler, Storgard, Baumgartner, Becker. ing of lesinurad administration may also have contributed to Acquisition of data. Kopicko, Fung, Bhakta, Adler, Storgard, the low rate of nephrolithiasis, as once-daily dosing in the Baumgartner. Analysis and interpretation of data. Saag, Fitz-Patrick, Kopicko, morning increases urinary uric acid levels during the period Fung, Bhakta, Adler, Storgard, Baumgartner, Becker. when urine volume and urine pH are highest and the poten- tial for uric acid precipitation is therefore lowest (30,31). ROLE OF THE STUDY SPONSOR In CV safety analyses, CV comorbidities and risk Ardea Biosciences, Inc., a member of the AstraZeneca group, factors were present in 80% of patients at baseline, played a role in the design and conduct of the study, the collection, reflecting the high rates of CV disease in gout patients. The management, analysis, and interpretation of the data, and the review 212 SAAG ET AL

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