CSP594 Comparative Effectiveness in Gout: Allopurinol vs. Febuxostat

March 27, 2024 updated by: VA Office of Research and Development

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

950

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • Loma Linda, California, United States, 92357
        • VA Loma Linda Healthcare System, Loma Linda, CA
      • San Diego, California, United States, 92161
        • VA San Diego Healthcare System, San Diego, CA
      • San Francisco, California, United States, 94121
        • San Francisco VA Medical Center, San Francisco, CA
    • Florida
      • Miami, Florida, United States, 33125
        • Miami VA Healthcare System, Miami, FL
    • Illinois
      • Hines, Illinois, United States, 60141-5000
        • Edward Hines Jr. VA Hospital, Hines, IL
    • Massachusetts
      • Boston, Massachusetts, United States, 02130
        • VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA
    • Minnesota
      • Minneapolis, Minnesota, United States, 55417
        • Minneapolis VA Health Care System, Minneapolis, MN
      • Rochester, Minnesota, United States, 55905
        • Mayo Clinic Rochester MN ? RAIN 1
    • Missouri
      • Kansas City, Missouri, United States, 64128
        • Kansas City VA Medical Center, Kansas City, MO
    • Nebraska
      • Omaha, Nebraska, United States, 68198-3025
        • University of Nebraska Medical Center ? RAIN 5
      • Omaha, Nebraska, United States, 68105-1850
        • Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE
    • New York
      • New York, New York, United States, 10010
        • Manhattan Campus of the VA NY Harbor Healthcare System, New York, NY
    • North Carolina
      • Asheville, North Carolina, United States, 28805
        • Asheville VA Medical Center, Asheville, NC
    • North Dakota
      • Bismarck, North Dakota, United States, 58506
        • Sanford Bismarck Medical Center ? RAIN 2
    • Ohio
      • Cincinnati, Ohio, United States, 45220
        • Cincinnati VA Medical Center, Cincinnati, OH
    • Oregon
      • Portland, Oregon, United States, 97239
        • VA Portland Health Care System, Portland, OR
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104
        • Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA
      • Pittsburgh, Pennsylvania, United States, 15240
        • VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA
    • South Dakota
      • Yankton, South Dakota, United States, 57078
        • Yankton Medical Clinic ? RAIN 3
    • Texas
      • Dallas, Texas, United States, 75216
        • VA North Texas Health Care System Dallas VA Medical Center, Dallas, TX
    • Utah
      • Salt Lake City, Utah, United States, 84148
        • VA Salt Lake City Health Care System, Salt Lake City, UT
    • Vermont
      • White River Junction, Vermont, United States, 05009-0001
        • White River Junction VA Medical Center, White River Junction, VT
    • Virginia
      • Salem, Virginia, United States, 24153
        • Salem VA Medical Center, Salem, VA

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Allopurinol / Sham Comparator (Febuxostat)
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
Patients will be up-titrated up to the dose required to reach target uric acid levels.
Other Names:
  • Zyloprim; CAS: 315-30-0
Drug: Placebo, vehicle control (febuxostat-shaped)
Placebo tablets resembling febuxostat will be given with allopurinol.
Active Comparator: Febuxostat / Sham Comparator (Allopurinol)
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
Patients will be up-titrated to the dose required to reach target uric acid levels.
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)
Placebo capsules resembling allopurinol will be given with febuxostat.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percentage of Participants Experiencing ≥ 1 Gout Flare During Phase 3
Time Frame: 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
Phase III of the study (weeks 49-72 of study duration)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

VA Office of Research and Development

Investigators

  • Study Chair: James R O'Dell, Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 6, 2017

Primary Completion (Actual)

February 1, 2021

Study Completion (Actual)

April 15, 2021

Study Registration Dates

First Submitted

October 15, 2015

First Submitted That Met QC Criteria

October 15, 2015

First Posted (Estimated)

October 19, 2015

Study Record Updates

Last Update Posted (Actual)

March 29, 2024

Last Update Submitted That Met QC Criteria

March 27, 2024

Last Verified

March 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 594 (Ct Surgery Network Research Group)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Individual Participant Data will be made available after study closure only to research credentialed Veterans Affairs researchers who submit a valid study question to their IRB of record. A Data Use Agreement will be in effect between the researcher and the coordinating center

IPD Sharing Time Frame

After primary and secondary analyses and subsequent publications

IPD Sharing Access Criteria

Executed data use agreement with CSP Coordinating Center approval

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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