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

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.

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 < 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