Intensive Urate Lowering Therapy of Febuxostat Compared to Allopurinol on Cardiovascular Risk in Patients With Gout (FORWARD)
Gout
About this trial
This is an interventional treatment trial for Gout focused on measuring 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
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:
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
Sites / Locations
- Medizinische Klinik und Poliklinik III/Rheumatologie Universitätsklinikum "Carl Gustav Carus" Der Technischen Universität
- Presidio Ospedaliero San Filippo e Nicola Università degli Studi dell'Aquila U.O.C Geriatria e Lungodegenza Geriatrica
- Ospedale San Salvatore U.O.C. Medicina Interna e Nefrologia Dipartimento MeSVA Università degli Studi dell'Aquila
- Azienda Ospedaliero-Universitaria Policlinico Sant'Orsola-Malpighi
- Ospedale Policlinico SS. Annunziata Università degli Studi "G. d'Annunzio". Dipartimento di Medicina e Scienze dell'Invecchiamento.
- Reade Clinic
- Gdańskie Centrum Zdrowia Sp.z o.o.
- Specjalistyczna Praktyka Lekarska Piotr Kubalski
- Centrum Medyczne Pratia Katowice
- Centrum Medyczne Plejady
- Krakowski Szpital Specjalistyczny im. Jana Pawła II w Krakowie
- Specjalistyczny Gabinet Dermatologiczno-Kosmetyczny
- Pratia S,A
- Reumatika- Centrum Reumatologii
- Oddział Kardiologiczny, WSS im. W. Biegańskiego w Łodzi
- Polimedica
- Clinica Medicală Data Plus SRL
- Institutul Clinic Fundeni
- S.C. Centrul Medical Sana S.R.L.
- S.C. Cardiomed S.R.L.
- Institutul de Boli Cardiovasculare Clinica de Cardiologie si Recuperare Cardiovasculara
- Cabinet Medical Medicina Interna
- Institut za kardiovaskularne bolesti Dedinje
- Institut za reumatologiju
- Kliničko-bolnički centar "Bežanijska kosa" Klinika za imunologiju i alergologiju
- Vojnomedicinska akademija Klinika za reumatologiju
Arms of the Study
Arm 1
Arm 2
Experimental
Active Comparator
Febuxostat 80/120 mg/day
Allopurinol 100 up to 600 mg/day
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.
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.