The effect of intensive urate lowering therapy (ULT) with febuxostat in comparison with allopurinol on cardiovascular risk in patients with gout (short title: the FORWARD trial)
- Conditions
- GoutMedDRA version: 20.0Level: PTClassification code 10018627Term: GoutSystem Organ Class: 10027433 - Metabolism and nutrition disordersTherapeutic area: Body processes [G] - Metabolic Phenomena [G03]
- Registration Number
- EUCTR2014-005567-33-PL
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 182
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 et al. To be eligible a subjects has to present at least 6 out of the twelve clinical, laboratory, and X-ray phenomena listed below:
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 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) as per protocol appendix 2. 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 randomization
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 122
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 60
1. Severe chronic renal failure (creatinine clearance < 30 ml/min)
2. Hepatic failure
3. Active liver disease or hepatic dysfunction, defined as both ALT and 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 one 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 of the active substance 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 perimenopausal
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
In each case of delayed menstrual period (over one month between
menstruations) absence of pregnancy has to be confirmed. This also
applies to WOCBP with infrequent or irregular menstrual cycles.
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 limiting to ability to obtain adequate
PWV/PWA recordings. Special attention should be paid to any physical
abnormalities which could affect quality of PWV/PWA measurement:
• Neck region- flexibility of the neck and accessibility of carotid artery,
•
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: Pulse Wave Velocity;Secondary Objective: • Pulse Wave Analysis<br>• Brain natriuretic peptide and in N-terminal prohormone of brain natriuretic peptide (BNP and NTproBNP)<br>• Markers of inflammation (hsCRP, TNF-a, plasma fibrinogen)<br>• Markers of endothelial activation (sVCAM, sICAM, vWF, e-selectine) <br>• Oxidative stress parameters: MDA, MPO, Ox-LDL, PON1 and PON2 <br>• sUA, eGFR, Serum creatinine and urine albumin to creatinine ratio <br>• Lipid profile <br>• Safety and tolerability<br>;Primary end point(s): Comparison of the effects of febuxostat and allopurinol on Pulse Wave Velocity (PWV) after 36 weeks of treatment. ;Timepoint(s) of evaluation of this end point: after 36 weeks of treatment
- Secondary Outcome Measures
Name Time Method