Study design
NCT02128490 was a phase II, multicenter, randomized, double-blind, placebo-controlled, exploratory study involving patients at 64 sites across the USA from May 5, 2014 to October 23, 2015. The study design consisted of a 3-week screening/washout period, followed by a 3-month double-blind treatment period (Fig. 1). Patients receiving ULT at enrollment discontinued their medication on the day −21 screening visit; this was followed by a 3-week washout period (day −21 to day −1). A day −4 visit served as a follow-up screening visit for patients washing out ULT, and as the initial screening visit for patients not receiving ULT. All patients had their blood drawn at the day −4 screening visit to determine baseline sUA levels. Patients who did not meet day −4 sUA criteria were allowed to have one retest of the sUA levels at the discretion of the investigator. Patients who met all eligibility criteria received the double-blind study drug from day 1 through the 3-month study duration. Eligible patients underwent physical examinations, clinical assessments, review of concomitant medication usage, and an electrocardiogram (ECG) on day 1. Follow-up visits were scheduled at week 2, month 1, month 2, and month 3 (end of treatment). If applicable, an ECG, urinalysis, and a pregnancy test were performed at the end-of-treatment visit. Each investigator conducted the study according to the Declaration of Helsinki and the International Conference on Harmonisation’s Harmonised Tripartite Guideline for good clinical practices, and in compliance with applicable local or regional regulatory requirements. All patients enrolled in the study provided written informed consent in the manner deemed appropriate by the institutional review board or the independent ethics committees.
Patients
Eligible patients included men and women (aged ≥ 18 years) who: provided informed consent; had a history or presence of gout based on criteria defined by the American Rheumatism Association [18]; had an sUA level ≥ 8.0 mg/dl at the day −4 screening visit or at the retest visit; had moderate renal impairment as defined by an eGFR (Modification of Diet in Renal Disease) ≥ 30 and < 60 ml/min at screening visit on day −21 for patients on ULT and on day −4 for patients not on ULT or at the retest visit; and had a self-reported history of ≥ 1 gout flare within the 12 months prior to the screening visit.
Patients were excluded from the study if they met any of the following criteria: received an investigational compound within 30 days prior to screening, secondary hyperuricemia; history of xanthuria, known hypersensitivity to febuxostat or any components in its formulations, known hypersensitivity to naproxen, any other nonsteroidal anti-inflammatory drug (NSAID), aspirin, lansoprazole, colchicine, or any components in their formulation; had experienced either a myocardial infarction, stroke, hospitalized unstable angina, cardiac or cerebrovascular revascularization procedure, or hospitalized transient ischemic attack; or had a history of cancer (other than basal cell carcinoma of the skin) within 5 years prior to the screening visit, history of drug or alcohol abuse, presence of rheumatoid arthritis, active peptic ulcer disease, or any significant medical condition that would interfere with the treatment, safety, or compliance with the protocol.
Randomization
Eligible patients were randomly assigned in a 1:1:1:1:1 ratio to one of five treatment groups: placebo, febuxostat IR 40 or 80 mg, or febuxostat XR 40 or 80 mg, all QD. Patients were randomized within two population strata: patients with an sUA level ≥ 8.0 and < 10.0 mg/dl at the day −4 visit; and patients with an sUA level ≥ 10.0 mg/dl at the day −4 visit. An interactive voice or web response technology was employed for randomization, and for assigning the study drug.
Treatments
Patients orally self-administered one capsule of the study drug starting from day 1 through the end of study duration (month 3). To maintain blinding, all tablets (febuxostat XR, febuxostat IR, and placebo) were overencapsulated in a similar manner. To maintain consistency, patients were instructed to take the study drug at the same time daily, and to withhold the study drug on days of scheduled follow-up visits (months 1, 2, and/or 3) when samples for trough pharmacokinetic measurements were collected. All patients systematically received gout flare prophylaxis for the duration of double-blind treatment from day 1 to the end of treatment, including colchicine 0.6 mg every other day (QOD); however, if colchicine was contraindicated or not tolerated, naproxen (250 mg BID) or other NSAIDs or prednisone were permitted at the investigator’s discretion. Beginning on the day −21 screening visit, patients receiving ULT discontinued their ULT and entered a washout period during which they received 0.6 mg colchicine QOD for gout flare prophylaxis. From day 1 through to end of treatment, all remaining patients (i.e., those not receiving ULT prior to the study) also began treatment for gout flare prophylaxis.
Study endpoints
The primary efficacy endpoint was percentage of patients with sUA < 5.0 mg/dl at month 3. Secondary efficacy endpoints included the proportion of patients with sUA < 6.0 mg/dl at month 3, and the proportion of patients with ≥ 1 gout flare requiring treatment during the 3-month treatment period.
Safety assessments
Safety and tolerability were assessed by evaluating the incidence of treatment-emergent adverse events (TEAEs), 12-lead ECG findings, clinical laboratory tests, and vital signs. All safety analyses were conducted using the safety analysis set, which included all patients who received ≥ 1 dose of double-blind study drug. A TEAE was defined as any AE, regardless of relationship to the study drug, which occurred on or after the first double-blind dose date and up to 30 days after the last dose date of the double-blind study drug. A pretreatment event was defined as an event with a reported onset date after the patient signed the consent form but prior to the date of randomization. Treatment-related AEs were defined as TEAEs that were identified by the investigator to be related to the study drug. TEAEs were identified as reported by the investigators and summarized using the MedDRA Version 18.0 coding dictionary.
Statistical analyses
Primary efficacy analyses were performed using the full analysis set, and included all patients who received ≥ 1 dose of the double-blind study drug. For the primary analysis, no missing data were imputed. The original protocol was modified (prior to database lock) so that patients who discontinued treatment before the month 3 visit were included in the efficacy analysis as having failed to meet a particular efficacy endpoint. sUA levels obtained > 1 day after the last dose of double-blind study drug were excluded from the analyses.
Efficacy analysis primarily involved comparison of treatment with febuxostat XR 40 and 80 mg QD versus febuxostat IR 40 and 80 mg QD, respectively. In addition, each febuxostat XR treatment group and the placebo group were compared by study visit. Comparisons were also made between febuxostat XR 40 and 80 mg QD, between febuxostat IR 40 and 80 mg QD, and between each febuxostat IR treatment group and placebo.
A gout flare was defined, in agreement with the US Food and Drug Administration, as the presence of all of the following: patient-reported acute articular pain typical of a gout attack that was deemed (by patient and/or investigator) to require treatment (and was treated) with colchicine, NSAIDs, or steroids; presence of at least three or more of joint swelling, redness, tenderness, and pain; and patient experienced at least one or more of rapid onset of pain, decreased range of motion, joint warmth, and other symptoms similar to a prior gout flare. Patients who discontinued the double-blind study drug due to gout flares were considered to have experienced a gout flare during the 3-month treatment period.
The SAS System with the HP-Unix operating system was used to perform the statistical analyses. All statistical tests and confidence intervals (CIs) were two sided and conducted at the 0.05 significance level, with no adjustments for multiple comparisons. Fisher’s exact test was used to compare treatment groups for the analysis of primary and secondary efficacy endpoints. A total of 200 patients (40 per treatment group) were planned for enrollment into this study. Due to the exploratory nature of the proof-of-concept study, the sample size was not based on formal power calculations. The sample size was considered sufficient to characterize the effect of febuxostat XR formulation on lowering of urate levels compared with the febuxostat IR formulation.