CSP594 Comparative Effectiveness in Gout: Allopurinol vs. Febuxostat

Study Overview
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Brief Summary
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This trial will compare two effective therapies, allopurinol and febuxostat, to lower serum uric acid and therefore prevent further gout attacks. These therapies have never been compared at appropriate doses. Further, they will be studied in patients with kidney disease for the first time.

Detailed Description
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Gout is the most common form of inflammatory arthritis affecting adults (1), with a disease frequency that continues to increase dramatically (2). Gout is associated with substantial morbidity and mortality which are concentrated in older men and magnified in patients with chronic kidney disease (CKD) (3-6), demographics common to the Veterans Affairs (VA) Health System. Effective gout therapies are readily available and are centered primarily on the use of approved urate lowering therapy (ULT). Despite having excellent ULT options available to patients (7), gout is extremely poorly managed especially in patients with CKD (8-10). The two most widely used ULTs in clinical practice, allopurinol and febuxostat, have recently been endorsed as the two acceptable first-line treatment strategies in chronic gout (7). Although both agents appear to be efficacious and generally well-tolerated, allopurinol and febuxostat have significantly different costs and have never been compared to each other at appropriate doses. Randomized controlled trials completed to date comparing allopurinol with febuxostat in gout have used 'fixed' and, in many cases, insufficient doses of allopurinol (11-13), an approach that is contrary to current guideline recommendations (7). Furthermore, these studies have included only very small proportions of gout patients with CKD even though CKD is present in approximately 1 of every 2 gout sufferers (14). To test the hypothesis that allopurinol is non-inferior to febuxostat in the treatment of gout, the investigators propose a randomized open-label non-inferiority trial, which for the first time compares allopurinol with febuxostat using appropriately titrated doses and a treat-to-target approach. Further, the investigators will assess the comparative effectiveness of these agents in a significant number of gout patients with co-morbid CKD. The investigators plan to enroll 950 participants with a diagnosis of gout, including participants with stage 3 CKD, who are hyperuricemic defined as a serum uric acid concentration (sUA) above 6.8 mg/dl. Participants will be recruited from 18 Veteran Affairs and 5 Rheumatology and Arthritis Investigational Network (RAIN) sites. The total duration of the trial will be 4 years. Recruitment will occur over 24 months. Participants will be followed for 72 weeks. This will include a 24 week Dose Titration Phase (Phase 1) followed by a 24 week Maintenance and Optimization Phase (Phase 2) and then a 24 week Steady State Flare Observation Phase (Phase 3). The investigators will use a treat-to-target approach with specified titration of ULT dosing to obtain goal sUA. Maximal daily drug doses will be 800 mg/day for allopurinol or 120 mg/day for febuxostat. The primary outcome will be the proportion of participants who have at least one gout flare in the allopurinol group compared to the febuxostat group during Phase 3. This primary outcome was endorsed by the patient and VA provider groups that were surveyed (see below). All participants will be followed during Phase 3 regardless of the achievement of sUA goal. The primary hypothesis will test the non-inferiority of allopurinol with regards to proportions of flares. The investigators anticipate that approximately 15 to 20% of patients will flare during Phase 3.

Official Title
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CSP #594 - Comparative Effectiveness in Gout: Allopurinol vs. Febuxostat

Conditions
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Gout, Chronic Kidney Diseases

Intervention / Treatment
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* Drug: allopurinol capsule, 100-800 mg by mouth once daily
* Drug: febuxostat tablet 40-120 mg by mouth once daily
* Drug: Placebo, vehicle control (febuxostat-shaped)
* Drug: Placebo, vehicle control (allopurinol-shaped)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 years History of gout - crystal proven or historical as defined by ACR criteria listed above Serum urate level > 6.8 mg/dl Exclusion Criteria: Stage 4 or 5 Chronic Kidney Disease (CKD) - defined as eGFR < 30 ml/min/1.73 m2 Women less than 50 years of age Patients with a history of prior solid organ / hematopoietic transplantation Previous allergy or intolerance to allopurinol or febuxostat Patients who are not candidates for any of the recommended prophylactic medications (colchicine, naprosyn or glucocorticoids) Patients who in the opinion of the investigator have a high genetic risk for allopurinol hypersensitivity syndrome (AHS*) unless they have been found to be negative for HLA B5801. Previous history of failure to reach target uric acid levels despite therapy with allopurinol at dose > 300 mg/day Prior febuxostat use Patients with malignancies that are currently active with exception of non-melanoma skin cancer Patients with serum uric acid levels >15 mg/dl Patients with myelodysplasia and hemoglobin of < 8.5 mg/dL Patients with chronic liver disease with more than one of the following: INR > 1.7, not on Warfarin therapy Bilirubin 2 mg/dL Serum albumin < 3.5 mg/dL Ascites Encephalopathy Current use of azathioprine, mercaptopurine, didanosine, cyclophosphamide, probenecid, lesinurad or pegloticase Enrollment in another randomized interventional clinical trial Any severe medical condition that, in the enrolleer's opinion, is likely to compromise the participant's ability to complete the trial

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Allopurinol / Sham Comparator (Febuxostat)<br>Patients will be titrated up to the dose that will lower to target uric acid levels. A placebo resembling Febuxostat will be given with allopurinol | Drug: allopurinol capsule, 100-800 mg by mouth once daily<br>* Patients will be up-titrated up to the dose required to reach target uric acid levels.<br>* Other names: Zyloprim; CAS: 315-30-0;Drug: Placebo, vehicle control (febuxostat-shaped)<br>* Placebo tablets resembling febuxostat will be given with allopurinol.<br>|
| Active Comparator: Febuxostat / Sham Comparator (Allopurinol)<br>Febuxostat will be titrated up to the dose that will lower to target uric acid levels. A placebo resembling Allopurinol will be given with Febuxostat | Drug: febuxostat tablet 40-120 mg by mouth once daily<br>* Patients will be up-titrated to the dose required to reach target uric acid levels.<br>* Other names: Uloric; CAS: 144060-53-7; NDCs: 64764-677-11, 64764-677-13, 64764-677-19, 64764-677-30, 64764-918-11, 64764-918-18, 64764-918-30, 64764-918-90;Drug: Placebo, vehicle control (allopurinol-shaped)<br>* Placebo capsules resembling allopurinol will be given with febuxostat.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Experiencing ≥ 1 Gout Flare During Phase 3 | Participants were defined as flaring in Phase 3 if they: -1) met 3 of 4 following participant-reported criteria: a) warm joint(s) b) swollen joint(s) c) pain (>3) at rest on a scale of 0-10 (10 being the worst pain) d) self-identified gout flare OR -2) reported use of medications to treat flare | Phase III of the study (weeks 49-72 of study duration) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CKD, Gout, Allopurinol, Febuxostat