Achaia Taltoan, Mercer University College of Pharmacy
Tophaceous gout is a form of advanced gout characterized by persistent arthritis, white-yellow intradermal deposits, and frequent recurrent acute attacks. The 2012 American Rheumatology Association and the European League Against Rheumatism (EULAR) guidelines for gout recommend xanthine oxidase inhibitors, allopurinol, or febuxostat as first line treatment for chronic tophaceous gout with a goal serum urate <6 mg/dL. [1,2] The EULAR and American Rheumatology Association guidelines suggest a goal serum urate < 5 mg/dL for patients with severe gout symptoms, including tophi, chronic arthropathy, and frequent attacks.  Evidence shows that approximately 40% of patients treated with allopurinol achieve serum urate levels less than 6 mg/dL, and about 48% of febuxostat patients can maintain target serum urate levels for three consecutive months. [3,4]
Lesinurad is a novel selective urate anion absorption inhibitor approved for combination with a xanthine oxidase inhibitor for gout patients whose serum urate targets are not achieved with xanthine oxidase inhibitor monotherapy. The CLEAR 1 and CLEAR 2 trial assessed the use of lesinurad with allopurinol in patients who failed to meet serum urate goals with monotherapy. [5,6] However, no trial assessed the combination of febuxostat and lesinurad in patients who failed xanthine oxidase monotherapy, until the CRYSTAL trial was conducted. 
|Lesinurad a selective uric acid reabsorption inhibitor in combination with febuxostat in patients with tophaceous gout: findings of a phase III clinical trial (CRYSTAL)|
|Design||Phase III, multinational, multicenter, randomized, double blind, placebo controlled, combination study; N=324|
|Objective||To investigate the efficacy and safety of lesinurad in combination with febuxostat in a 12-month phase III trial in patients with tophaceous gout|
|Study Groups||Febuxostat alone (n=109), lesinurad 200 mg+ febuxostat 80 mg (n=106), lesinurad 400 mg+ febuxostat 80 mg (n=109)|
· Age between18-85
· ≥1 measurable tophus on the hands/wrists and/or feet/ankles ≥5 mm and ≤20 mm in the longest diameter
· Able to take gout flare prophylaxis with colchicine or NSAID (including Cox-2 selective NSAID) ± PPI
· Meets one of the following criteria:
o Not currently taking an approved urate lowering therapy with a serum urate ≥8 mg/dL
o Currently taking a medically appropriate dose of febuxostat or allopurinol with a serum urate ≥6.0 mg/dL
· BMI<45 kg/m2
· Taking any approved urate-lowering medication other than allopurinol or febuxostat that is indicated for the treatment of gout (uricosuric agent) within 8 weeks of the screening visit
· Previously received pegloticase
· Previously participated in a clinical study involving lesinurad (RDEA594) or RDEA806 and received active treatment or placebo
· Pregnant or breastfeeding
· Consumes more than 14 drinks of alcohol per week (e.g., 1 drink = 5 oz. [150 ml] of wine, 12 oz. [360 ml] of beer, or 1.5 oz. [45 ml] of hard liquor)
· History or suspicion of drug abuse within the past 5 years
· Uncontrolled hypertension (systolic pressure above 160 or diastolic pressure above 95 mmHg on repeat measurements on two separate visits during the screening period)
· An estimated creatinine clearance < 30 ml/min calculated by the Cockcroft-Gault formula
The patients underwent a 21-day run-in period before randomization in which all patients began febuxostat 80 mg daily and colchicine 0.5-0.6 mg NSAID daily for gout flare prophylaxis. Patients were randomized in a 1:1:1 ratio for a 12-month study period. Serum urate levels were determined at baseline, week 2, and months 1-6, 8,10, and 12. Tophi were measured every 3 months. Renal and cardiovascular treatment emergent adverse events (TEAE) were recorded. All randomized patients that received ≥1 dose of study medication were included in the intention to treat population. Comparisons of the serum urate levels and tophi responses of the study groups were performed using the Cochran-Mantel-Haenszel test.
|Duration||February 2012-April 2014|
|Primary Outcome Measure||The proportion of patients with a serum uric acid level of <5.0 mg/dL by the 6 month of treatment|
Table 1. Proportion of patients achieving serum uric acid targets of <5.0 mg/dL, <4.0mg/dL, and <3.0mg/dL at month 6 and month 12 (from figure 1)
#=p<0.0001 versus febuxostat alone adjusted for multiple comparisons
^=p<0.01 versus febuxostat alone adjusted for multiple comparisons
Table 2. Percentage change in the sum of the areas of all target tophi versus baseline (mm2) at each study visit in the last observation carried forward (from figure 4)
**=p<0.01 versus febuxostat alone
Table 4. Overall summary of treatment-emergent adverse events and renal-related adverse events (%) (from table 2)
TEAE= Treatment emergent adverse event
RCTC=Rheumatology Common Toxicity Criteria
a All ≥2.0 times baseline elevations were captured in the ≥1.5 times baseline elevations group
b Serum creatinine resolution was defined as return of an elevated serum creatinine level to ≤1.2 times baseline
|Adverse Events||Common Adverse Events: (Febuxostat vs. Lesinurad 200 mg+ Febuxostat vs. Lesinurad 400 mg+ Febuxostat, %)
Nasopharyngitis: 8.3% vs. 9.4% vs. 13.8%
Hypertension: 7.3% vs. 5.7% vs. 11.0%
Headache: 7.3% vs. 9.4% vs. 5.5%
Extremity pain: 3.7% vs. 5.7% vs. 8.3%
Back pain: 4.6% vs. 7.5% vs. 5.5%
|Serious Adverse Events: Febuxostat vs. Lesinurad 200 mg+ Febuxostat vs. Lesinurad 400 mg+ Febuxostat, n%)
Acute Renal Failure: 0.9% vs.0%vs. 0.9%
Chronic Renal Failure: 0% vs.0% vs 0.9%
Serious Cardiovascular Events: 0.9% vs.2.8% vs.3.7%
|Percentage that Discontinued due to Adverse Events:
Febuxostat vs. Lesinurad 200 mg+ Febuxostat vs. Lesinurad 400mg+Febuxostat, n%)
8.3% vs. 8.5% vs. 13.8%
|Study Author Conclusions||Treatment with lesinurad and febuxostat combination showed greater lowering of serum urate when compared with febuxostat monotherapy. Lesinurad 200 mg and febuxostat 80 mg showed clinically relevant effects on tophi response and an acceptable safety profile in patients with tophaceous gout.|
The CRYSTAL trial had a large patient population with homogenous baseline characteristics, strengthening its internal validity, by attempting to minimize the effects of confounding variables on the outcomes. Based on the drug’s pharmacological properties, the 21-day run in period for initiating febuxostat was an adequate time period to ensure acute kidney injury or hypersensitivity to lesinurad was not apparent at the beginning of the study period The initial dose of febuxostat is 40 mg, with suggested titration to 80mg if patients don’t achieve serum urate < 6 mg/dL after two weeks. While 80 mg is not the recommended starting dose, the study included patients already using febuxostat and other urate lowering agents, possibly negating the need for titration. The absence of titration was not addressed in the trial, making the dose regimen a limitation of the trial.
The study required patients to record details of gout flares with a daily electronic patient diary; however, the study did not require patients to record daily diet and alcohol intake. Purine rich diet and frequent alcohol intake can decrease efficacy of medication in lowering serum urate target. The lack of diet records may introduce a confounding variable into the trial. The follow up period for patients ineligible for enrollment in the extension study was 14 days, which is not adequate to observe long-term cardiovascular or renal effects of the therapy. The review of cardiovascular safety was performed by an independent cardiovascular events adjudication committee, limiting bias from the investigators who are affiliated with AstraZeneca, the company manufacturing lesinurad. Also, using the highest serum creatinine within 14 days as a measure of baseline renal function limited the selection bias. Overall, the study presents lesinurad as a safe adjunct therapy for tophaceous gout that lesinurad 200 mg and febuxostat 80 mg may be an appropriate treatment option in those who fail to achieve target serum urate levels with a xanthine oxidase inhibitor alone.
 Khanna D, Fitzgerald JD, Khanna PP, et al. 2012 American College of Rheumatology guidelines for management of gout part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken). 2012;64(10):1431-46.
 Richette P, Doherty M, Pascual E, et al. 2016 updated EULAR evidence-based recommendations for the management of gout. Ann Rheum Dis. 2017;76(1):29-42.
 Becker MA, Schumacher HR Jr, Wortmann RL, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Eng J Med. 2005; 353:2450-61.
 Schumacher HR Jr, Becker MA, Wortmann RL, et al. Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double blind, parallel-group trial. Arthritis Rheum. 2008; 59:1540-8.
 Saag K, Fitz-Patrick D, Kopicko J, et al. Lesinurad combined with allopurinol: a randomized, double-blind, placebo-controlled study in gout patients with an inadequate response to standard-of-care allopurinol. Arthritis Rheumatol. 2017;69(1):203-212.
 Bardin T, Keenan RT, Khanna PP, Kopicko J, et al. Lesinurad in combination with allopurinol: a randomized, double-blind, placebo-controlled study in patients with gout with inadequate response to standard of care (the multinational CLEAR 2 study). Ann Rheum Dis. 2017;76(5):811-820.
 Dalbeth N, Jones G, Robert T, et al. Lesinurad, a selective uric acid reabsorption inhibitor, in combination with febuxostat in patients with tophaceous gout: findings of a phase III clinical trial. Arthritis Rheumatol. 2017; 69(9): 1903–1913.