E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Body processes [G] - Metabolic Phenomena [G03] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10018627 |
E.1.2 | Term | Gout |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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E.2.2 | Secondary objectives of the trial |
• Pulse Wave Analysis
• Brain natriuretic peptide and in N-terminal prohormone of brain natriuretic peptide (BNP and NTproBNP)
• Markers of inflammation (hsCRP, TNF-α, plasma fibrinogen)
• Markers of endothelial activation (sVCAM, sICAM, vWF, e-selectine)
• Oxidative stress parameters: MDA, MPO, Ox-LDL, PON1 and PON2
• sUA, eGFR, Serum creatinine and urine albumin to creatinine ratio
• Lipid profile
• Safety and tolerability
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 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 factor 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
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E.4 | Principal 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 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 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
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
22. Inability or unwillingness to issue the informed consent |
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E.5 End points |
E.5.1 | Primary end point(s) |
Comparison of the effects of febuxostat and allopurinol on Pulse Wave Velocity (PWV) after 36 weeks of treatment. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
after 36 weeks of treatment |
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E.5.2 | Secondary end point(s) |
• Changes in BNP and NTproBNP values after 12, 24 and 36 weeks of treatment;
• Changes in inflammation markers (hsCRP, TNF-α, sUA, and plasma fibrinogen) after 12, 24 and 36 weeks of treatment;
• Changes in oxidative stress parameters [Malondialdehyde (MDA), Myeloperoxidase (MPO) Oxidized low-density lipoprotein (Ox-LDL), Paraoxonase 1 and 2 (PON1, PON2)] after 12, 24 and 36 weeks of treatment;
• Changes in lipid profile after 12, 24 and 36 weeks of treatment;
• Percentage of gout patients with a serum urate concentration of less than 6 mg/dl after 12, 24 and 36 weeks of treatment.
• Time to achieve sUA target levels for patients stratified for sUA levels at baseline as follows: 8.1-8.8 mg/dl, 8.9-9.6 mg/dl, 9.7-10.3 mg/dl, 10.4-11.0 mg/dl, >11 mg/dl.
• Changes in eGFR with CKD-EPI formula after 12, 24 and 36 weeks of treatment;
• Changes in urine albumin excretion as evaluated by first morning urine albumin/creatinine ratio (mg/g) after 12, 24 and 36 weeks of treatment;
• Percentage of patients above the sUA target levels at Week 12, Week 24 and Week 36 after having reached the sUA target levels at Week 2;
• Tender and swollen joint count;
• Pulse Wave Analysis (including modifications of PWV, arterial stiffness, central blood pressure and augmentation index) after 12, 24 and 36 weeks of treatment;
• Changes in endothelial activation/adhesion markers (sVCAM, sICAM, vWF, e-selectine) after 12, 24 and 36 weeks of treatment (These parameters will be evaluated in a subset of patients enrolled in selected centres only)
The following laboratory parameters will be performed in central lab:
• BNP, NTproBNP
• Markers of inflammation: hsCRP, TNF-α, plasma fibrinogen
• Oxidative stress parameters: MDA, MPO, Ox-LDL, PON1, PON2
• Markers of endothelial activation/adhesion: sVCAM, sICAM, vWF, e-selectine
• sUA, eGF, Serum creatinine and urine albumin to creatinine ratio
• Lipid profile
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
after 12, 24 and 36 weeks of treatment |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Croatia |
Germany |
Italy |
Netherlands |
Poland |
Romania |
Serbia |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 3 |