Intensive Urate Lowering Therapy of Febuxostat Compared to Allopurinol on Cardiovascular Risk in Patients With Gout
Condition: Gout
MeSH terms: Gout
Intervention: Febuxostat 80/120mg/day; Allopurinol 100 up to 600mg/day; Colchicine; Naproxen; Omeprazole
Intervention description: Starting dose and dose regimen of Febuxostat : the initial daily dose is 80 mg. In case the patient has the serum urate concentration > 6 mg/dl after 2 weeks of treatment the dose will be escalated to 120 mg and if tolerated will be maintained for the duration of the study.; Starting dose and dose regimen of allopurinol : the initial daily allopurinol dose is 100 mg, to be increased by 100 mg every 2 weeks in patients with serum urate concentration >6 mg/dl. The maximum daily dose of allopurinol achievable in the study will depend on kidney function and tolerability, but will not exceed 600 mg.; Colchicine 0.5 mg tablets.To prevent flares in the initial stages of treatment, patients will be treated for at least 6 months with colchicine 0.5 - 1 mg QD; Naproxen sodium 550 mg film coated tablets. In case of colchicine intolerance patients will be treated for at least 6 months with Naproxen 550 mg BID and Omeprazole (20-40 mg once daily), if indicated to be used.; Omeprazole 20 mg capsules, co-administered to patients for gastric protection.
Intervention MeSH terms: Naproxen; Colchicine; Allopurinol; Febuxostat; Omeprazole
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Masking description: The study physician, responsible for randomization and drug supply handling, was unblinded to study medications and therefore not involved in the main efficacy evaluations of each patient randomized in the study.
Conversely, the study physician/s responsible for the main efficacy evaluation (Pulse Wave Velocity) was blinded to study treatments.
Enrollment: 196.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Biological Markers; Cardiovascular disease; Humans; Pulse Wave Velocity; Cardiovascular risk factors; Allopurinol; Pulse Wave Analysis; Thiazoles; Inflammation; Uric acid; Febuxostat; Oxidative stress; Tumor Necrosis Factor; Arthritis; Hyperuricemia

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:

          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