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CSP594 Comparative Effectiveness in Gout: Allopurinol vs. Febuxostat

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ClinicalTrials.gov Identifier: NCT02579096
Recruitment Status : Active, not recruiting
First Posted : October 19, 2015
Last Update Posted : January 22, 2021
Sponsor:
Information provided by (Responsible Party):
VA Office of Research and Development

Tracking Information
First Submitted Date  ICMJE October 15, 2015
First Posted Date  ICMJE October 19, 2015
Last Update Posted Date January 22, 2021
Actual Study Start Date  ICMJE March 6, 2017
Estimated Primary Completion Date February 1, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 15, 2015)
Proportion of participants who have at least one gout flare in the allopurinol group compared to the febuxostat group [ Time Frame: Phase III of the study (months 12-18 of study duration) ]
Proportion of participants who have at least one gout flare in the allopurinol group compared to the febuxostat group
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE CSP594 Comparative Effectiveness in Gout: Allopurinol vs. Febuxostat
Official Title  ICMJE CSP #594 - Comparative Effectiveness in Gout: Allopurinol vs. Febuxostat
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Gout
  • Chronic Kidney Diseases
Intervention  ICMJE
  • Drug: Allopurinol
    Patients will be titrated up to the dose that will lower to target uric acid levels.
  • Drug: Febuxostat
    Febuxostat will be titrated up to the dose that will lower to target uric acid levels.
  • Drug: Placebo, vehicle control (Febuxostat-shaped)
    Placebo in the shape of Febuxostat will be given with Allopurinol
  • Drug: Placebo, vehicle control (Allopurinol-shaped)
    Placebo in the shape of Allopurinol will be given with Febuxostat
Study Arms  ICMJE
  • Active Comparator: Allopurinol
    Patients will be titrated up to the dose that will lower to target uric acid levels.
    Interventions:
    • Drug: Allopurinol
    • Drug: Placebo, vehicle control (Febuxostat-shaped)
  • Sham Comparator: Placebo (Febuxostat)
    Placebo in the shape of Febuxostat will be given with allopurinol
    Interventions:
    • Drug: Allopurinol
    • Drug: Placebo, vehicle control (Febuxostat-shaped)
  • Active Comparator: Febuxostat
    Febuxostat will be titrated up to the dose that will lower to target uric acid levels.
    Interventions:
    • Drug: Febuxostat
    • Drug: Placebo, vehicle control (Allopurinol-shaped)
  • Sham Comparator: Placebo (Allopurinol)
    Placebo in the shape of Allopurinol will be given with Febuxostat
    Interventions:
    • Drug: Febuxostat
    • Drug: Placebo, vehicle control (Allopurinol-shaped)
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: October 15, 2015)
950
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 15, 2021
Estimated Primary Completion Date February 1, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 of <30 ml/min
  • 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 g/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 g/dL
    • Ascites
    • Encephalopathy
  • Current use of azathioprine, mercaptopurine, didanosine, cyclophosphamide, or probenecid
  • Patient who are unable to give informed consent
  • Enrollment in another randomized interventional clinical trial
  • Any severe medical condition that, in the enrollee's opinion, is likely to compromise the participant's ability to complete the trial
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02579096
Other Study ID Numbers  ICMJE 594
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party VA Office of Research and Development
Study Sponsor  ICMJE VA Office of Research and Development
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: James R O'Dell Omaha VA Nebraska-Western Iowa Health Care System, Omaha, NE
PRS Account VA Office of Research and Development
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP