Phase 4 N=196 Randomized Single-blind Treatment

Intensive Urate Lowering Therapy of Febuxostat Compared to Allopurinol on Cardiovascular Risk in Patients With Gout

Gout

Bottom Line

View on ClinicalTrials.gov: NCT02500641 ↗

Enrolled (actual)

196

Serious AEs

9.2%

Results posted

Jun 2019

Primary outcome: Primary: Pulse Wave Velocity — 9.0; 9.05 m/s — p=0.5298

Study Design & Population

Study type: Interventional
Phase: Phase 4
Interventions: Febuxostat 80/120mg/day (Drug); Allopurinol 100 up to 600mg/day (Drug); Colchicine (Drug); Naproxen (Drug); Omeprazole (Drug)
Age: Adult, Older Adult · 18+ yrs
Sex: All
Sponsor: Menarini International Operations Luxembourg SA
Primary completion: May 2017

Outcome Measures

Outcome	Result	p-value
PRIMARY Pulse Wave Velocity	9.0; 9.05	0.5298

Summary

There is a mounting and clear association between hyperuricaemia, gout and the presence of traditional cardiovascular (CV) risk factors and CV event-equivalent conditions such as chronic kidney disease, metabolic syndrome, and diabetes. Gout is associated with increased risk of CV events such as myocardial infarction and CV death. Furthermore hyperuricaemia is clearly associated with an increased arterial stiffness, a marker of pre-clinical atherosclerosis. Carotid-femoral pulse wave velocity (PWV) is the "gold standard" measurement of arterial stiffness and it is considered, in this trial, as a valid surrogate endpoint with clearly established relevance to predict cardiovascular disease (CVD) clinical outcome In this randomised trial conducted on adult subjects with a history of gout, we use surrogate endpoints to investigate the efficacy of febuxostat compared with allopurinol to predict (CVD) clinical outcome. Eligible subjects were randomised in a 1:1 ratio to the following treatment groups: * Test product: febuxostat 80 mg or 120 mg once daily (120 mg daily, if serum urate was >6 mg/dL after 2 weeks of treatment at 80 mg daily). * Active comparator: allopurinol 100 mg once daily (up to a maximum dose of 600 mg daily escalated in 100 mg increments every 2 weeks, if serum urate acid (sUA) was >6 mg/dL after 2 weeks of treatment at the previous dose). The study duration was 39 weeks, which included the: * Run-in/screening period: 1 week (extendable up to a maximum of 30 days according to variability of sUA levels); * Treatment period: 36 weeks; * Safety follow-up period: 2 weeks.

Eligibility Criteria

Inclusion Criteria

Male or female patients 18 years and older;
History of gout, flare free in the 4 weeks prior to study entry
History of crystal (joint liquid) proven diagnosis or anamnestic diagnosis of gout according to Wallace at el. To be eligible, a subject had to present at least 6 of the following 12 clinical, laboratory, and x-ray phenomena:
Maximum inflammation developed within 1 day, 2. More than one attack of acute arthritis, 3. Monoarticular arthritis attack, 4. Redness observed over joints, 5. First metatarsophalangeal (MTP) pain or swelling, 6. Unilateral first MTP joint attack, 7. Unilateral tarsal joint attack, 8. Suspected or proven tophus, 9. Hyperuricemia, 10. Asymmetric swelling within a joint on a X ray, 11. Subcortical cysts without erosions on X ray, 12. Negative organisms on culture of joint fluid; 4. Naive to ULT or previously treated with ULT, but with no ULT treatment in the last 1 month prior to study entry and only if reason for ULT interruption was not due to safety concerns.
Patients at study entry have elevated serum urate level >8 mg/dl. 6. Overall Cardiovascular (CV) risk based on the scoring proposed by the Joint Task Force of the European Society of Cardiology and other European Societies on cardiovascular disease prevention in clinical practice between 5 and 15-% (inclusive). Patients with diabetes mellitus type 2 could be included in the study if their CV risk score is calculated as ≤7%.
Allowed concomitant medications should be maintained stable during the last 2 weeks before randomisation

Exclusion Criteria

Severe chronic renal failure (creatinine clearance 2 times the upper limit of normal.
Diabetes mellitus type1
Life-threatening co-morbidity or with a significant medical condition and/or conditions that would interfere with the treatment, the safety or the compliance with the protocol
Diagnosis of, or receiving treatment for malignancy (excluding basalioma skin cancer) in the previous 5 years
Patients who have experienced either myocardial infarction or stroke
Patients with inflammatory based arthritis (e.g.: rheumatoid arthritis, etc.)
Patients with congestive heart failure, New York Heart Association (NYHA) Class III or IV
Patients with untreated/uncontrolled thyroid function
Patients with clinically severe peripheral arterial disease
Concomitant administration of any of the following: azathioprine, mercaptopurine, theophylline, meclofenamate, sulfinpyrazone, trimethoprim-sulfamethoxazole, cyclophosphamide, benzbromarone, pyrazinamide, captopril and enalapril (for Allopurinol), tegafur, pegloticase and tacrolimus.
Hypersensitivity to any one of the active substances or to any of the excipients
Any contraindication to febuxostat or allopurinol (with reference to the summary of product characteristics).
Subject is unable to take either of the protocol-required gout flare prophylactic medications (NSAID or colchicine) due to contraindications or intolerance, e.g. hypersensitivity, active gastric ulcer disease, renal impairment and/or changes in liver enzymes
Participation in another trial of an investigational drug or device within 30 days prior to screening, or prior treatment with investigational product(s)
Women of childbearing potential (WOCBP), including peri-menopausal women who have had a menstrual period within 1 year, not willing to use highly effective method of birth control throughout the study period and for 4 weeks after study completion defined as a method which results in a failure rate of less than 1% per year such as:
combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal),
progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable),
intrauterine device (IUD),
intrauterine hormone-releasing system (IUS),
bilateral tubal occlusion,
vasectom

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Data sourced from ClinicalTrials.gov (NCT02500641). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.