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CSP594 Comparative Effectiveness in Gout: Allopurinol vs. Febuxostat

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02579096
Recruitment Status : Completed
First Posted : October 19, 2015
Results First Posted : January 11, 2022
Last Update Posted : May 17, 2022
Sponsor:
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Gout Chronic Kidney Diseases 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) Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 950 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: CSP #594 - Comparative Effectiveness in Gout: Allopurinol vs. Febuxostat
Actual Study Start Date : March 6, 2017
Actual Primary Completion Date : February 1, 2021
Actual Study Completion Date : April 15, 2021

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Gout
MedlinePlus related topics: Gout

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 Name: 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 Name: 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.




Primary Outcome Measures :
  1. 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




Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02579096


Locations
Show Show 23 study locations
Sponsors and Collaborators
VA Office of Research and Development
Investigators
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Study Chair: James R O'Dell Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE
  Study Documents (Full-Text)

Documents provided by VA Office of Research and Development:
Study Protocol  [PDF] June 23, 2020
Statistical Analysis Plan  [PDF] August 7, 2019
Informed Consent Form  [PDF] April 5, 2019

Publications of Results:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: VA Office of Research and Development
ClinicalTrials.gov Identifier: NCT02579096    
Other Study ID Numbers: 594
First Posted: October 19, 2015    Key Record Dates
Results First Posted: January 11, 2022
Last Update Posted: May 17, 2022
Last Verified: April 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Time Frame: After primary and secondary analyses and subsequent publications
Access Criteria: Executed data use agreement with CSP Coordinating Center approval
URL: https://www.research.va.gov/programs/csp/default.cfm

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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
Keywords provided by VA Office of Research and Development:
Gout
Allopurinol
Febuxostat
CKD
Additional relevant MeSH terms:
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Gout
Kidney Diseases
Renal Insufficiency, Chronic
Urologic Diseases
Renal Insufficiency
Arthritis
Joint Diseases
Musculoskeletal Diseases
Crystal Arthropathies
Rheumatic Diseases
Purine-Pyrimidine Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases
Allopurinol
Febuxostat
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Enzyme Inhibitors
Gout Suppressants
Antirheumatic Agents
Free Radical Scavengers
Antioxidants
Protective Agents
Physiological Effects of Drugs