Clinical trial NCT02579096: CSP594 Comparative Effectiveness in Gout: Allopurinol vs. Febuxostat
Official title: CSP #594 - Comparative Effectiveness in Gout: Allopurinol vs. Febuxostat
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Gout
Chronic Kidney Diseases
Keywords: Gout
Allopurinol
Febuxostat
CKD
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
First posted: 2015-10-19
Enrollment: 950
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Percentage of Participants Experiencing ≥ 1 Gout Flare During Phase 3
timeFrame: Phase III of the study (weeks 49-72 of study duration)
Secondary outcomes:
Other outcomes:
Locations:
city: Loma Linda
country: United States
facility: VA Loma Linda Healthcare System, Loma Linda, CA
state: California
city: San Diego
country: United States
facility: VA San Diego Healthcare System, San Diego, CA
state: California
city: San Francisco
country: United States
facility: San Francisco VA Medical Center, San Francisco, CA
state: California
city: Miami
country: United States
facility: Miami VA Healthcare System, Miami, FL
state: Florida
city: Hines
country: United States
facility: Edward Hines Jr. VA Hospital, Hines, IL
state: Illinois
city: Boston
country: United States
facility: VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA
state: Massachusetts
city: Minneapolis
country: United States
facility: Minneapolis VA Health Care System, Minneapolis, MN
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic Rochester MN ? RAIN 1
state: Minnesota
city: Kansas City
country: United States
facility: Kansas City VA Medical Center, Kansas City, MO
state: Missouri
city: Omaha
country: United States
facility: Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE
state: Nebraska
city: Omaha
country: United States
facility: University of Nebraska Medical Center ? RAIN 5
state: Nebraska
city: New York
country: United States
facility: Manhattan Campus of the VA NY Harbor Healthcare System, New York, NY
state: New York
city: Asheville
country: United States
facility: Asheville VA Medical Center, Asheville, NC
state: North Carolina
city: Bismarck
country: United States
facility: Sanford Bismarck Medical Center ? RAIN 2
state: North Dakota
city: Cincinnati
country: United States
facility: Cincinnati VA Medical Center, Cincinnati, OH
state: Ohio
city: Portland
country: United States
facility: VA Portland Health Care System, Portland, OR
state: Oregon
city: Philadelphia
country: United States
facility: Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA
state: Pennsylvania
city: Pittsburgh
country: United States
facility: VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA
state: Pennsylvania
city: Yankton
country: United States
facility: Yankton Medical Clinic ? RAIN 3
state: South Dakota
city: Dallas
country: United States
facility: VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX
state: Texas
city: Salt Lake City
country: United States
facility: VA Salt Lake City Health Care System, Salt Lake City, UT
state: Utah
city: White River Junction
country: United States
facility: White River Junction VA Medical Center, White River Junction, VT
state: Vermont
city: Salem
country: United States
facility: Salem VA Medical Center, Salem, VA
state: Virginia
Study officials:
affiliation: Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE
name: James R O'Dell
role: STUDY_CHAIR
References:
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.
citation: 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 Gout Management. NEJM Evid. 2022 Mar;1(3):10.1056/evidoa2100028. doi: 10.1056/evidoa2100028. Epub 2022 Feb 3.