Gout: Allopurinol vs. Febuxostat

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.

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