CSP594 Comparative Effectiveness in Gout: Allopurinol vs. Febuxostat

Phase 4

Completed

• Conditions: Chronic Kidney Diseases; Gout
• Interventions: Drug: febuxostat tablet 40-120 mg by mouth once daily; Drug: allopurinol capsule, 100-800 mg by mouth once daily; Drug: Placebo, vehicle control (allopurinol-shaped); Drug: Placebo, vehicle control (febuxostat-shaped)

• Registration Number: NCT02579096
• Lead Sponsor: VA Office of Research and Development

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2015-10-15
• Study First Submitted QC: 2015-10-15
• Study First Posted: 2015-10-19
• Study Start: 2017-03-06
• Primary Completion: 2021-02-01
• Study Completion: 2021-04-15
• Results First Submitted: 2021-12-17
• Results First Submitted QC: 2021-12-17
• Results First Posted: 2022-01-11
• Status Verified: 2024-03
• Last Update Submitted: 2024-03-27
• Last Update Posted: 2024-03-29

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 950

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Febuxostat / Sham Comparator (Allopurinol)	febuxostat tablet 40-120 mg by mouth once daily	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
Allopurinol / Sham Comparator (Febuxostat)	allopurinol capsule, 100-800 mg by mouth once daily	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
Febuxostat / Sham Comparator (Allopurinol)	Placebo, vehicle control (allopurinol-shaped)	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
Allopurinol / Sham Comparator (Febuxostat)	Placebo, vehicle control (febuxostat-shaped)	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

Primary Outcome Measures

Name	Time	Method
Percentage of Participants Experiencing ≥ 1 Gout Flare During Phase 3	Phase III of the study (weeks 49-72 of study duration)	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

Trial Locations

Locations (23)

VA Loma Linda Healthcare System, Loma Linda, CA; 🇺🇸 Loma Linda, California, United States

Asheville VA Medical Center, Asheville, NC; 🇺🇸 Asheville, North Carolina, United States

Sanford Bismarck Medical Center ? RAIN 2; 🇺🇸 Bismarck, North Dakota, United States

VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA; 🇺🇸 Boston, Massachusetts, United States

Manhattan Campus of the VA NY Harbor Healthcare System, New York, NY; 🇺🇸 New York, New York, United States

VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA; 🇺🇸 Pittsburgh, Pennsylvania, United States

Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA; 🇺🇸 Philadelphia, Pennsylvania, United States

Salem VA Medical Center, Salem, VA; 🇺🇸 Salem, Virginia, United States

Edward Hines Jr. VA Hospital, Hines, IL; 🇺🇸 Hines, Illinois, United States

Yankton Medical Clinic ? RAIN 3; 🇺🇸 Yankton, South Dakota, United States

VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX; 🇺🇸 Dallas, Texas, United States

VA San Diego Healthcare System, San Diego, CA; 🇺🇸 San Diego, California, United States

San Francisco VA Medical Center, San Francisco, CA; 🇺🇸 San Francisco, California, United States

Miami VA Healthcare System, Miami, FL; 🇺🇸 Miami, Florida, United States

Cincinnati VA Medical Center, Cincinnati, OH; 🇺🇸 Cincinnati, Ohio, United States

VA Portland Health Care System, Portland, OR; 🇺🇸 Portland, Oregon, United States

VA Salt Lake City Health Care System, Salt Lake City, UT; 🇺🇸 Salt Lake City, Utah, United States

Minneapolis VA Health Care System, Minneapolis, MN; 🇺🇸 Minneapolis, Minnesota, United States

Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE; 🇺🇸 Omaha, Nebraska, United States

Mayo Clinic Rochester MN ? RAIN 1; 🇺🇸 Rochester, Minnesota, United States

Kansas City VA Medical Center, Kansas City, MO; 🇺🇸 Kansas City, Missouri, United States

University of Nebraska Medical Center ? RAIN 5; 🇺🇸 Omaha, Nebraska, United States

White River Junction VA Medical Center, White River Junction, VT; 🇺🇸 White River Junction, Vermont, United States