| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic symptomatic hyperuricaemic |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| 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 |
|
| 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 |
| The primary objective of the study is to compare the cardiovascular safety profile of febuxostat versus allopurinol when taken for an average of 3 years in patients over 60 years with chronic hyperuricaemia in conditions where urate deposition has already occurred |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary study objectives are to evaluate other cardiovascular adverse events for both products. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female patients aged 60 years or older with at least one additional cardiovascular risk factor: Age ≥70 years (male) or ≥75 years (female); Smoking (current or within the last 2 years); Diabetes mellitus; Impaired glucose tolerance; Hypertension (SBP >140 mmHg and/or DBP >90 mmHg) or receiving treatment to lower blood pressure; Dyslipidaemia (investigator assessment); Chronic kidney disease (CKD); Microalbuminuria or proteinuria; Family history of coronary heart disease or stroke in first degree relative at age <55 years; Inflammatory arthritis (investigator assessment – including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis); Chronic NSAID therapy (investigator assessment); Previous cardiovascular (CV) event (MI, cerebrovascular accident [CVA] or transient ischaemic attack [TIA]); Peripheral vascular disease (investigator / clinical assessment); Chronic obstructive pulmonary disease (COPD); Body mass index >30 kg/m2.
2. Patients who, in the opinion of the recruiting physician, require treatment for chronic hyperuricaemia where urate deposition has already occurred (including a history or presence of tophus and/or gouty arthritis) fulfilling the recommendation for treatment with urate lowering therapy.
3. Patients who have received ≥60 days treatment with allopurinol, or ≥2 allopurinol prescriptions, within the previous 6 months.
4. Patients, who in the opinion of the recruiting physician or study site coordinator, are eligible for treatment (with reference to the summary of product characteristics) with either allopurinol or febuxostat.
5. Patients who are willing to give permission for their paper and electronic medical records, hospitalisation data, prescribing data, and (in the event of their death) their death certification data to be accessed and abstracted by trial investigators.
6. Patients who are willing to be contacted and interviewed by trial investigators or delegates (suitably trained research nurses), should the need arise (e.g., for adverse event [AE] assessment and to determine whether an episode of acute gout has occurred). |
|
| E.4 | Principal exclusion criteria |
1. Patients who have any contraindication to febuxostat or allopurinol (with reference to the summary of product characteristics) or any of the components of their formulations.
2. Patients who are not receiving allopurinol as ULT.
3. Patients with severe renal impairment (eGFR <30 mL/min as defined by the Cockroft-Gault formula (http://www.nephron.com/cgi-bin/CGSI.cgi) according to creatinine, age, sex and body weight).
4. Patients with moderate or severe hepatic impairment i.e. cirrhosis with clinical and/or biological decompensation (i.e. alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3x reference value, ascites, lower limb oedema, icterus or increased prothrombin time >2x reference value).
5. Patients with a life-threatening co-morbidity or with a significant medical condition and/or conditions that would interfere with the treatment, safety or compliance with the protocol.
6. Patients with a diagnosis of, or receiving treatment for malignancy (excluding minor skin cancer and indolent cancers that are not thought to be life threatening and require no treatment) in the previous 5 years. (Investigator opinion)
7. Patients who have experienced either a myocardial infarction or stroke within the 6 months prior to the screening visit.
8. Patients with congestive heart failure, New York Heart Association (NYHA) Class III or IV.
9. Patients whose behaviour or lifestyle would render them less likely to comply with study medication (i.e., abuse of alcohol, substance misuse, debilitating psychiatric conditions or inability to provide informed consent).
10. Patients with a current acute gout flare or who are within 14 days of the resolution of a gout flare.
11. Patients currently participating in another clinical trial or who have participated in a non-interventional clinical trial in the previous 1 month or an interventional clinical trial in the previous 3 months. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary analysis will be time to event and the endpoint will be the first occurrence of hospitalisation or death due to one or more APTC (Anti-Platelet Trialists’ Collaboration) primary events: • non-fatal myocardial infarction • non-fatal stroke • cardiovascular death |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Time from randomisation to first occurence of any event |
|
| E.5.2 | Secondary end point(s) |
| • Hospitalisation for non-fatal MI • Hospitalisation for non-fatal stroke • Cardiovascular death • All cause mortality • Hospitalisation for heart failure • Hospitalisation for unstable, new or worsening angina • Hospitalisation for coronary revascularisation • Hospitalisation for cerebral revascularisation • Hospitalisation for transient ischeamic attack (TIA) • Hospitalisation for non-fatal cardiac arrest • Hospitalisation for venous and peripheral arterial vascular thrombotic event • Hospitalisation for arrhythmia with no evidence of ischaemia |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The secondary endpoints (in rank order of importance) will be evaluated using a time to event analysis The following endpoints will be evaluated as an incidence rate: • Cardiovascular mortality • APTC events in each treatment arm |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| 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 | Yes |
| 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 | No |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
|
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 22 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| The end of the trial will be determined by the steering committee and this will occur when more than the required number of primary endpoints has accrued |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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