CSP594 Comparative Effectiveness in Gout: Allopurinol vs. Febuxostat

Chronic Kidney Diseases Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02579096
• Other study ID #: 594
• Status: Completed
• Phase: Phase 4
• Start date: March 6, 2017
• Est. completion date: April 15, 2021

Study information

• Verified date: March 2024
• Source: VA Office of Research and Development
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 950
• Est. completion date: April 15, 2021
• Est. primary completion date: February 1, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Chronic Kidney Diseases
• Gout
• Kidney Diseases
• Renal Insufficiency, Chronic

Intervention

Drug:
• allopurinol capsule, 100-800 mg by mouth once daily
Patients will be up-titrated up to the dose required to reach target uric acid levels.
• febuxostat tablet 40-120 mg by mouth once daily
Patients will be up-titrated to the dose required to reach target uric acid levels.
• Placebo, vehicle control (febuxostat-shaped)
Placebo tablets resembling febuxostat will be given with allopurinol.
• Placebo, vehicle control (allopurinol-shaped)
Placebo capsules resembling allopurinol will be given with febuxostat.

Locations

Country	Name	City	State
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	Cincinnati VA Medical Center, Cincinnati, OH	Cincinnati	Ohio
United States	VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX	Dallas	Texas
United States	Edward Hines Jr. VA Hospital, Hines, IL	Hines	Illinois
United States	Kansas City VA Medical Center, Kansas City, MO	Kansas City	Missouri
United States	VA Loma Linda Healthcare System, Loma Linda, CA	Loma Linda	California
United States	Miami VA Healthcare System, Miami, FL	Miami	Florida
United States	Minneapolis VA Health Care System, Minneapolis, MN	Minneapolis	Minnesota
United States	Manhattan Campus of the VA NY Harbor Healthcare System, New York, NY	New York	New York
United States	Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE	Omaha	Nebraska
United States	University of Nebraska Medical Center ? RAIN 5	Omaha	Nebraska
United States	Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA	Philadelphia	Pennsylvania
United States	VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA	Pittsburgh	Pennsylvania
United States	VA Portland Health Care System, Portland, OR	Portland	Oregon
United States	Mayo Clinic Rochester MN ? RAIN 1	Rochester	Minnesota
United States	Salem VA Medical Center, Salem, VA	Salem	Virginia
United States	VA Salt Lake City Health Care System, Salt Lake City, UT	Salt Lake City	Utah
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	White River Junction VA Medical Center, White River Junction, VT	White River Junction	Vermont
United States	Yankton Medical Clinic ? RAIN 3	Yankton	South Dakota

Sponsors (1)

Lead Sponsor	Collaborator
VA Office of Research and Development

Country where clinical trial is conducted

United States, 

References & Publications (2)

O'Dell JR, Brophy MT, Pillinger MH, Neogi T, Palevsky PM, Wu H, Davis-Karim A, Newcomb JA, Ferguson R, Pittman D, Cannon GW, Taylor T, Terkeltaub R, Cannella AC, England BR, Helget LN, Mikuls TR. Comparative Effectiveness of Allopurinol and Febuxostat in — View Citation

Timilsina S, Brittan K, O'Dell JR, Brophy M, Davis-Karim A, Henrie AM, Neogi T, Newcomb J, Palevsky PM, Pillinger MH, Pittman D, Taylor TH, Wu H, Mikuls TR. Design and Rationale for the Veterans Affairs "Cooperative Study Program 594 Comparative Effectiveness in Gout: Allopurinol vs. Febuxostat" Trial. Contemp Clin Trials. 2018 May;68:102-108. doi: 10.1016/j.cct.2018.03.015. Epub 2018 Mar 27. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)