E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic kidney disease and hyperuricaemia |
Chronic kidney disease and hyperuricaemia |
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E.1.1.1 | Medical condition in easily understood language |
Chronic kidney disease and hyperuricaemia |
Chronic kidney disease and hyperuricaemia |
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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 | 20.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10018067 |
E.1.2 | Term | General nutritional disorders NEC |
E.1.2 | System Organ Class | 100000004861 |
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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 |
To assess the effects of treatment with verinurad and allopurinol, allopurinol alone, and placebo on UACR at 6 months |
Valutare gli effetti del trattamento con verinurad e allopurinolo, con allopurinolo da solo e con placebo sull’UARC a 6 mesi |
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E.2.2 | Secondary objectives of the trial |
To assess the effects of treatment with verinurad and allopurinol, allopurinol alone, and placebo on UACR at 12 months To assess the effects of verinurad and allopurinol, allopurinol alone, and placebo on sUA To estimate the dose-response relationship among 3 doses of verinurad and allopurinol and placebo on UACR and sUA To assess the effects of verinurad and allopurinol versus placebo on kidney function. |
Valutare gli effetti del trattamento con verinurad e allopurinolo, con allopurinolo da solo e con placebo sull’UACR a 12 mesi Valutare gli effetti di verinurad e allopurinolo, di allopurinolo da solo e del placebo sul livello di AUs Stimare la relazione dose-risposta fra 3 dosi di verinurad e allopurinolo e placebo su UACR e AUs Valutare gli effetti sulla funzionalità renale di verinurad e allopurinolo rispetto a placebo |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Other types of substudies Specify title, date and version of each substudy with relative objectives: PK sub-study vascular reactivity sub-study
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Altre tipologie di sottostudi specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: PK sub-study vascular reactivity sub-study
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E.3 | Principal inclusion criteria |
- Provision of signed and dated, written ICF. - Provision of signed and dated written genetic informed consent prior to collection of sample for genetic analysis - Patient must be =18 years of age at the time of signing the ICF. - CKD as defined in the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines; ie, there must be a documented occurrence at least 3 months before randomisation of eGFR <60 mL/min/1.73 m2, UACR = 30 mg/g, and/or other markers of kidney damage (including urine protein dipstick =1+, positive urine albumin dipstick, or urinary protein to creatinine ratio =84 mg/g) - Patients should receive background standard of care treatment for albuminuria and/or T2DM and be treated according to locally recognised guidelines, as appropriate. Guideline-recommended medications should be used at recommended doses. Therapy should have been optimised and stable for =4 weeks before study entry and include an ACEi or anARB, unless contraindicated, not tolerated, or in the opinion of the investigator not practically available or suitable. - If treated with a sodium-glucose transport protein (SGLT2) inhibitor, the SGLT2 inhibitor dose must have been stable for =4 weeks before randomisation. - Meeting screening criteria for sUA and eGFR (Visit 2) (a) sUA =6.0 mg/dL (b) eGFR =25 mL/min/1.73 m2 (CKD-EPI formula) - Mean UACR between 30 mg/g and 5000 mg/g inclusive. At least 2 first morning void samples collected before randomisation will be required. - Male or female |
- Provision of signed and dated, written ICF. - Provision of signed and dated written genetic informed consent prior to collection of sample for genetic analysis - Patient must be =18 years of age at the time of signing the ICF. - Patients with CKD. CKD as defined in the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines as abnormalities in kidney structure or function present for >3 months; ie, there must be a documented occurrence at least 3 months before randomisation of either of the following eGFR <60 mL/min/1.73 m2, UACR =30 mg/g, and/or one or more other markers of kidney damage (including abnormalities detected by histology or imaging, urine sediments, urine protein dipstick =1+, positive urine albumin dipstick, or urinary protein to creatinine ratio =84 mg/g). - Patients should receive background standard of care treatment for albuminuria and/or T2DM and be treated according to locally recognisedguidelines, as appropriate. Guideline-recommended medications should be used at recommended doses. Therapy should have been optimised and stable for =4 weeks before study entry and include an ACEi or an ARB, unless contraindicated, not tolerated, or in the opinion of the investigator not practically available or suitable. - If treated with a sodium-glucose transport protein (SGLT2) inhibitor, the SGLT2 inhibitor dose must have been stable for =4 weeks before randomisation. - Meeting screening criteria for sUA and eGFR (Visit 2) (a) sUA =6.0 mg/dL (b) eGFR =25 mL/min/1.73 m2 (CKD-EPI formula) - Mean UACR between 30 mg/g and 5000 mg/g inclusive. At least 2 first morning void samples collected before randomisation will be required. - Male or female |
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E.4 | Principal exclusion criteria |
- Autosomal dominant or autosomal recessive polycystic kidney disease, lupus nephritis or anti-neutrophil cytoplasmic antibody (ANCA)- associated vasculitis - History of renal transplantation - Known carrier of the (HLA-B) *58:01 allele. - Patients diagnosed with tumor lysis syndrome or Lesch-Nyhan syndrome - History of stroke, myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft in the past 6 months - Uncontrolled hypertension presenting with systolic blood pressure >180 mm Hg and/or diastolic blood pressure >100 mm Hg - Diagnosed with heart failure and (NYHA) Class IV at the time of randomisation - QT interval corrected by the Fridericia formula (QTcF) >470 msec; patients diagnosed with long QT syndrome; patients with a family history of long QT syndrome - Receiving cytotoxic therapy, immunosuppressive therapy or other immunotherapy for primary or secondary renal disease within 6 months prior to enrolment - Treated with any drug for hyperuricaemia in the 6 months preceding randomisation. - Dose of ACEi, ARBs, fenofibrate, guaifenesin, or SGLT2 inhibitors changed within 4 weeks of randomisation or further dose titration expected after randomisation - Treated with strong or moderate (OATP) inibitors - Participation in another clinical study with an investigational product administered during the last month prior to randomisation - Patients who are pregnant, lactating, or planning to become pregnant. - Left ventricular hypertrophy with the left ventricular septum exceeding 14 mm during diastole, assessed by echocardiogramm within 6 months of screening (Mozaffarian et al 2016, Shenasa and Shenasa 2017, Williams et al 2018) |
- Autosomal dominant or autosomal recessive polycystic kidney disease, lupus nephritis or anti-neutrophil cytoplasmic antibody (ANCA)- associated vasculitis (granulomatosis with polyangiitis [Wegener's granulomatosis], microscopic polyangiitis, or eosinophilic granulomatosis with polyangiitis [Churg-Strauss syndrome]). - History of renal transplantation - Known carrier of the (HLA-B) *58:01 allele. - Patients diagnosed with tumor lysis syndrome or Lesch-Nyhan syndrome - History of stroke, myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft in the past 6 months - Uncontrolled hypertension presenting with systolic blood pressure >180 mm Hg and/or diastolic blood pressure >100 mm Hg - Diagnosed with heart failure and (NYHA) Class IV at the time of randomisation - QT interval corrected by the Fridericia formula (QTcF) >470 msec; patients diagnosed with long QT syndrome; patients with a family history of long QT syndrome - Subjects with severe hepatic impairment, as judged by the investigator, of Child-Pugh Class C (decompensated cirrhosis), or with major cirrhosis complications (eg, hepatorenal syndrome) - Receiving cytotoxic therapy, immunosuppressive therapy or other immunotherapy for primary or secondary renal disease within 6 months prior to enrolment - Treated with any drug for hyperuricaemia in the 6 months preceding randomisation. - Dose of ACEi, ARBs, fenofibrate, guaifenesin, or SGLT2 inhibitors changed within 4 weeks of randomisation or further dose titration expected after randomisation - Treated with strong or moderate (OATP) inibitors - Participation in another clinical study with an investigational product administered during the last month prior to randomisation - Patients who are pregnant, lactating, or planning to become pregnant. - Left ventricular hypertrophy with the left ventricular septum exceeding 14 mm during diastole, assessed by echocardiogramm within 6 months of screening (Mozaffarian et al 2016, Shenasa and Shenasa 2017, Williams et al 2018) |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline in UACR at 6 months |
UACR a 6 mesi |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From baseline at 6 months |
Da basale a 6 mesi |
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E.5.2 | Secondary end point(s) |
• Change from baseline in UACR at 12 months, end of treatment and end of study • Change from baseline in sUA at 6 and 12 months, end of treatment and end of study • Change from baseline in estimated glomerular filtration rate at 6 and 12 months, end of treatment and end of study• Change from baseline in creatinine at 6 and 12 months, end of treatment and end of study • Change from baseline in cystatin-C at 6 and 12 months end of treatment and end of study |
• Change from baseline in UACR at 12 months, end of treatment and end of study • Change from baseline in sUA at 6 and 12 months, end of treatment and end of study • Change from baseline in estimated glomerular filtration rate at 6 and 12 months, end of treatment and end of study• Change from baseline in creatinine at 6 and 12 months, end of treatment and end of study • Change from baseline in cystatin-C at 6 and 12 months end of treatment and end of study |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• From baseline at 12 months, end of treatment and end of study • From baseline at 6 and 12 months, end of treatment and end of study • From baseline at 6 and 12 months, end of treatment and end of study • From baseline at 6 and 12 months, end of treatment and end of study • From baseline at 6 and 12 months, end of treatment and end of study |
• From baseline at 12 months, end of treatment and end of study • From baseline at 6 and 12 months, end of treatment and end of study • From baseline at 6 and 12 months, end of treatment and end of study • From baseline at 6 and 12 months, end of treatment and end of study • From baseline at 6 and 12 months, end of treatment and end of study |
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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 | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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E.8.2.4 | Number of treatment arms in the trial | 5 |
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 | 12 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 107 |
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 | Information not present in EudraCT |
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 |
Canada |
Israel |
Mexico |
South Africa |
United States |
Czechia |
France |
Hungary |
Italy |
Poland |
Romania |
Slovakia |
Spain |
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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
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The end of study is defined as the last expected visit/contact of the last patient undergoing the study. |
The end of study is defined as the last expected visit/contact of the last patient undergoing the study. |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |