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

Study Overview
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Brief Summary
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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.

Detailed Description
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The study physician, responsible for randomization and drug supply handling, is unblinded to study medications and therefore will not be 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) will be blind to study treatments. Key efficacy variables will be performed by an independent centralized laboratory. Trial was conducted in a detailed and orderly manner in accordance with established research principles, International Conference on Harmonization (ICH), Good Clinical Practice (GCP) Guidelines and with Clinical Research Organization (CRO) Standard Operating Procedures (SOPs). As part of a concerted effort to fulfill these obligations, the authorised CRO study monitor visited investigative sites prior to and during the trial in addition to maintaining telephone and written communication. Data from each subject were reviewed and source verified as the study progressed. In accordance with audit plans, this trial may have been selected for audits. The investigators committed to permit independent audits by auditors assigned by the Sponsor at a reasonable notice. Audits included, but were not limited to, drug supply, presence of required documents, the informed consent process, protection of rights and well-being of subjects and verification of Electronic case report form (eCRF) entries against source documents. Regulatory authorities worldwide had the right to inspect the investigative sites during or after the trial. In such cases, the investigators were required to contact the Sponsor immediately and to fully cooperate with the inspectors. Copies of written correspondence between the investigators, CRO, Sponsor, Competent Authorities, Institutional Review Board (IRB) and Independent Ethic Committee (IEC) are on file with the Sponsor and investigators. Adverse events were according to the Medical Dictionary for Regulatory Activities (MedDRA, version 18.0) thesaurus. Statistical analysis were conducted according the Statistical Analysis Plan (SAP) describing the analytical principles and statistical techniques employed in order to address the objectives specified in the Protocol. A Data Management Plan was present for missing data, to address situations where variables are reported as missing, unavailable, non-reported, uninterpretable, or considered missing because of data inconsistency or out-of-range results.

Official Title
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The Effect of Intensive Urate Lowering Therapy (ULT) With Febuxostat in Comparison With Allopurinol on Cardiovascular Risk in Patients With Gout Using Surrogate Markers: a Randomized, Controlled Trial

Conditions
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Gout

Intervention / Treatment
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* Drug: Febuxostat 80/120mg/day
* Drug: Allopurinol 100 up to 600mg/day
* Drug: Colchicine
* Drug: Naproxen
* Drug: Omeprazole


Participation Criteria
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Eligibility Criteria
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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: 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: Severe chronic renal failure (creatinine clearance < 30 ml/min) Hepatic failure Active liver disease or hepatic dysfunction, defined as both alanine aminotransferase (ALT) and aspartate aminotransferase (AST) >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, 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; Severe psychiatric disorders/neurological disorders Severe concurrent pathology, including terminal illness (cancer, AIDS, etc) Abuse of alcohol, analgesics, or psychotropic drugs 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; Inability or unwillingness to issue the informed consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Febuxostat 80/120 mg/day<br>Febuxostat 80/120 mg film coated tablets.The initial daily dose is 80 mg given orally. In case a patient has serum urate level 6 mg/dl after 2 weeks of treatment the dose will be escalated to 120 mg and if tolerated will be maintained during the study treatment period. To prevent flares in the initial stages of treatment, patients will be treated for at least 6 months with colchicine 0.5 - 1 mg quaque die (QD ) or in case of colchicine intolerance, Naproxen 550 mg bis in die (BID) with Omeprazole (20-40 mg once daily), if indicated to be used. | Drug: Febuxostat 80/120mg/day<br>* 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.<br>* Other names: Adenuric;Drug: Colchicine<br>* 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<br>Drug: Naproxen<br>* 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.<br>* Other names: Synflex;Drug: Omeprazole<br>* Omeprazole 20 mg capsules, co-administered to patients for gastric protection.<br>* Other names: Omeprazen;|
| Active Comparator: Allopurinol 100 up to 600 mg/day<br>Allopurinol 100/300 mg tablets.The initial daily allopurinol dose is 100 mg given orally, to be escalated of 100 mg every 2 weeks in patients with serum urate concentration >6 mg/dl. The maximum dose of allopurinol achievable in the study will depend on kidney function and tolerability, but will not exceed 600 mg daily.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 or in case of colchicine intolerance, Naproxen 550 mg BID with Omeprazole (20-40 mg once daily), if indicated to be used. | Drug: Allopurinol 100 up to 600mg/day<br>* 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.<br>* Other names: Allopurinol;Drug: Colchicine<br>* 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<br>Drug: Naproxen<br>* 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.<br>* Other names: Synflex;Drug: Omeprazole<br>* Omeprazole 20 mg capsules, co-administered to patients for gastric protection.<br>* Other names: Omeprazen;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pulse Wave Velocity | Comparison of the effects of Febuxostat and Allopurinol on Pulse Wave Velocity (PWV) after 36 weeks of treatment. | 36 weeks of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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