| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic kidney disease and hyperuricaemia |
| Nefropatía crónica e hiperuricemia |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic kidney disease and elevated serum uric acid |
| Enfermedad renal crónica y alto nivel de ácido úrico. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| 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 |
| Evaluar los efectos del tratamiento con verinurad y alopurinol, alopurinol como monoterapia y placebo sobre el valor del CACO a los 6 meses. |
|
| 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. |
Evaluar los efectos del tratamiento con verinurad y alopurinol, alopurinol como monoterapia y placebo sobre el valor del CACO a los 12 meses.
Evaluar los efectos del tratamiento con verinurad y alopurinol, alopurinol como monoterapia y placebo sobre la concentración de AUs.
Calcular la relación dosis-respuesta entre 3 dosis de verinurad y alopurinol y placebo sobre los valores de CACO y AUs.
Evaluar los efectos de verinurad y alopurinol frente al placebo en la función renal. |
|
| 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 |
MRI sub-study
PK sub-study
vascular reactivity sub-study |
Subestudio de Resonancia Magnetica (RM).
Subestudio de Farmatocinética (PK).
Subestudio de reactividad vascular. |
|
| 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 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 |
-Entrega de un FCI por escrito firmado y fechado.
-Entrega de un FCI de muestras genética por escrito firmado y fechado antes de la recogida de muestras en análisis genéticos.
-El paciente debe tener ≥18 años de edad en el momento de la firma del FCI.
-NFC, tal como se define en la nefropatía: Pautas de mejora de resultados clínicos globales (KDIGO); por ejemplo, debe estar documentada la presencia de valores de VFGe <60 ml/min/1,73 m2, CACO ≥30 mg/g al menos tres meses antes de la aleatorización y/u otros marcadores de lesión renal (incluida prueba de proteína en orina con tira reactiva ≥1+, albúmina positiva en orina mediante prueba con tira reactiva o cociente de proteína:creatinina en orina ≥84 mg/g).
-Los pacientes deben recibir el tratamiento de referencia de base para la albuminuria y/o la DMT2 y ser tratados conforme a las directrices reconocidas localmente, según corresponda. Se deben usar los medicamentos recomendados en las directrices en las dosis recomendadas. El tratamiento debe estar optimizado y estable durante ≥ 4 semanas antes de la inclusión en el estudio y debe incluir un IECA o BRA, salvo que esté contraindicado, o que según el criterio del investigador no sea práctico o adecuado.
-Si recibe un inhibidor de la proteína transportadora de sodio-glucosa (SGLT2), la dosis de este inhibidor debe haberse mantenido estable durante ≥4 semanas antes de la aleatorización.
-Cumplir los criterios de selección para AUs y la VFGe (consulta 2)
(a) AUs ≥6,0 mg/dl
(b) VFGe ≥25 ml/min/1,73 m2 (fórmula EPI para la NFC)
-CACO medio entre 30 mg/g y 5000 mg/g (ambos inclusive). Es obligatorio obtener al menos 2 muestras de orina de la primera micción de la mañana antes de la aleatorización.
-Hombre o mujer |
|
| 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. |
- Nefropatía poliquística autosómica recesiva o dominante autosómica, nefritis lúpica o vasculitis asociada con anticuerpos citoplasmáticos antineutrófilos (ACAN).
- Antecedentes de trasplante renal.
- Portador conocido del alelo 58:01 del antígeno B leucocitario humano (HLA-B).
- Los pacientes diagnosticados con síndrome de lisis tumoral o síndrome de Lesch-Nyhan.
- Antecedentes de ictus, infarto de miocardio, intervención coronaria percutánea, derivación de la arteria coronaria en los últimos 6 meses.
- Hipertensión controlada inadecuadamente (definida como tensión arterial sistólica >180 mmHg y/o tensión arterial diastólica >100 mgHg).
- Intervalo QT corregido según la fórmula de Fridericia (QTcF) >470 mseg. Pacientes diagnosticados con síndrome de intervalo QT largo. Pacientes con antecedentes familiares de síndrome de intervalo QT largo.
- Haber recibido tratamiento citotóxico, inmunodepresor u otra inmunoterapia para nefropatía primaria o secundaria en los 6 meses previos a la inscripción.
- Tratamiento con cualquier medicamento para la hiperuricemia en los 6 meses previos a la aleatorización.
- Modificación de la dosis de IECA, BRA, fenofibrato, guaifenesina o inhibidores de SGLT2 en las 4 semanas previas a la aleatorización o cuando se prevé un mayor ajuste de la dosis después de la aleatorización.
- Tratamiento con inhibidores fuertes o moderados del polipéptido transportador aniónico (OATP)
- Participación en otro estudio clínico con un producto en fase de investigación administrado durante el último mes previo a la aleatorización.
- Pacientes que estén embarazadas o dando el pecho o que tengan pensando quedarse embarazadas. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline in UACR at 6 months |
| Variación en el valor del CACO a los 6 meses respecto al inicio. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From baseline at 6 months |
| A los 6 meses desde el inicio. |
|
| 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 |
• Variación en el valor del CACO a los 12 meses, fin del tratamiento y fin del estudio.
• Variación en la concentración de AUs a los 6 y 12 meses, fin del tratamiento y fin del estudio.
• Variación en la velocidad de filtración glomerular estimada a los 6 y 12 meses, fin del tratamiento y fin del estudio.
• Variación en la concentración de creatinina a los 6 y 12 meses, fin del tratamiento y fin del estudio.
• Variación en la concentración de cistatina-C a los 6 y 12 meses, fin del tratamiento y fin del estudio. |
|
| 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 |
• A los 12 meses desde el inicio, fin del tratamiento y fin del estudio.
• A los 6 y 12 meses desde el inicio, fin del tratamiento y fin del estudio.
• A los 6 y 12 meses desde el inicio, fin del tratamiento y fin del estudio.
• A los 6 y 12 meses desde el inicio, fin del tratamiento y fin del estudio.
• A los 6 y 12 meses desde el inicio, fin del tratamiento y fin del estudio. |
|
| 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 |
|
| 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 | 21 |
| 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 | 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 |
| Canada |
| Czech Republic |
| France |
| Hungary |
| Israel |
| Italy |
| Mexico |
| Poland |
| Romania |
| Slovakia |
| South Africa |
| Spain |
| United States |
|
| 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 study is defined as the last expected visit/contact of the last patient undergoing the study. |
| El final del estudio se define como la última visita/contacto previsto del último paciente del estudio. |
|
| 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 |
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