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

• Status: Completed
• Trial end date: 2017-05-10
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 4
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Menarini International Operations Luxembourg SA
• Treatments: Allopurinol; Colchicine; Febuxostat; Naproxen; Omeprazole; Uric Acid

Criteria

Inclusion Criteria:

1. Male or female patients 18 years and older;

2. History of gout, flare free in the 4 weeks prior to study entry

3. 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:

1. 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.

5. 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%.

7. Allowed concomitant medications should be maintained stable during the last 2 weeks before randomisation

Exclusion Criteria:

1. Severe chronic renal failure (creatinine clearance < 30 ml/min)

2. Hepatic failure

3. Active liver disease or hepatic dysfunction, defined as both alanine aminotransferase (ALT) and aspartate aminotransferase (AST) >2 times the upper limit of normal.

4. Diabetes mellitus type1

5. 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

6. Diagnosis of, or receiving treatment for malignancy (excluding basalioma skin cancer) in the previous 5 years

7. Patients who have experienced either myocardial infarction or stroke

8. Patients with inflammatory based arthritis (e.g.: rheumatoid arthritis, etc.)

9. Patients with congestive heart failure, New York Heart Association (NYHA) Class III or IV

10. Patients with untreated/uncontrolled thyroid function

11. Patients with clinically severe peripheral arterial disease

12. 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.

13. Hypersensitivity to any one of the active substances or to any of the excipients

14. Any contraindication to febuxostat or allopurinol (with reference to the summary of product characteristics).

15. 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

16. Participation in another trial of an investigational drug or device within 30 days prior to screening, or prior treatment with investigational product(s)

17. 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,

• vasectomised partner (provided that partner is the sole sexual partner of the trial participant and that the vasectomised partner has received medical assessment of the surgical success),

• sexual abstinence;

18. Severe psychiatric disorders/neurological disorders

19. Severe concurrent pathology, including terminal illness (cancer, AIDS, etc)

20. Abuse of alcohol, analgesics, or psychotropic drugs

21. Inability or unwillingness, in the investigator's opinion, to follow study procedures including, but not limited to the ability to obtain adequate PWV/Pulse Wave Analysis (PWA) recordings. Special attention was made to any physical abnormalities which could affect quality of PWV/PWA measurement:

• Neck region- neck flexibility and accessibility of carotid artery,

• Upper arm and thigh region- exclude any abnormalities which would prevent adequate placement of the cuff;

22. Inability or unwillingness to issue the informed consent