E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Autosomal Recessive Polycystic Kidney Disease (ARPKD) |
Poliquistosis renal autosómica recesiva (ARPKD) |
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E.1.1.1 | Medical condition in easily understood language |
Genetic disorder that causes numerous cysts to grow in the kidneys. |
Trastorno genético por el que se forman numerosos quistes en los riñones. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10036047 |
E.1.2 | Term | Polycystic kidney, autosomal recessive |
E.1.2 | System Organ Class | 100000004850 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the effect of tolvaptan on the need for RRT in pediatric subjects with ARPKD |
Evaluar el efecto del tolvaptán sobre la necesidad de RRT en sujetos pediátricos con ARPKD |
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E.2.2 | Secondary objectives of the trial |
Evaluate changes in eGFR and palatability and acceptability of formulation |
Evaluar los cambios en la eGRF, así como la palatabilidad y aceptación de la formulación |
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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 |
Further research will be conducted on the remainder of the samples that are collected during the trial to understand the genetics of ARPKD |
Se llevará a cabo una investigación adicional en las partes restantes de las muestras que se recojan durante el ensayo, para conocer mejor la genética de la poliquistosis renal autosómica recesiva |
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E.3 | Principal inclusion criteria |
1. Male or female subjects between 28 days and < 12 weeks of age, inclusive. 2. Must have clinical and imaging features that are consistent with a diagnosis of ARPKD with all the following characteristics: - Nephromegaly (> 2 standard deviations from age appropriate standard via ultrasound) - Multiple renal cysts - History of oligohydramnios or anhydramnios 3. Ability for parent or guardian to provide written, informed consent prior to initiation of any trial related procedures, and ability, in the opinion of the principal investigator, to comply with all the requirements of the trial. |
1. Sujetos de uno u otro sexo y edad comprendida entre 28 días y menos de 12 semanas, incluidos ambos extremos. 2. Debe de tener características clínicas y de diagnóstico por imagen compatibles con diagnóstico de ARPKD con todas las características siguientes: - nefromegalia (> 2 desviaciones estándar frente a lo normal según la edad, por ecografía) - múltiples quistes renales - historia de oligohidramnios o anhidramnios. 3. Capacidad de los progenitores o tutores de otorgar el consentimiento informado por escrito antes del inicio de los procedimientos del ensayo, y capacidad, en opinión del investigador principal, de cumplir con todos los requisitos del ensayo. |
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E.4 | Principal exclusion criteria |
1. Premature birth (≤ 32 weeks gestational age) 2. Anuria or RRT defined as intermittent or continuous hemodialysis, peritoneal dialysis, hemofiltration, hemodiafiltration, or history of kidney transplantation 3. Evidence of syndromic conditions associated with renal cysts (other than ARPKD) 4. Abnormal liver function tests including ALT and AST, > 1.2 × ULN 5. Parents with renal cystic disease 6. Receiving chronic diuretic that could not be adjusted after tolvaptan initiation 7. Cannot be monitored for fluid balance 8. Has or at risk of having sodium and potassium electrolyte imbalances, as determined by the investigator 9. Has or at risk of having significant hypovolemia (eg, subjects that lack free access to water, without adequate fluid monitoring and management) as determined by investigator 10. Clinically significant anemia, as determined by investigator 11. Severe systolic dysfunction defined as ejection fraction < 14% 12. Serum sodium levels < 130 mmol/L or >145 mmol/L (or the ULN of the local laboratory, whichever is lower). 13. Taking any other experimental medications 14. Require ventilator support 15. Taking medications known to induce CYP3A4 16. Having an infection including viral that would require therapy disruptive to IMP dosing 17. Platelet count <50,000 µL 18. Has findings consistent with clinically significant portal hypertension (eg, varices, variceal bleeding, hypersplenism indicated by thrombocytopenia). 19. Bladder dysfunction and/or difficulty voiding 20. Taking a vasopressin agonist (eg, desmopressin) 21. Having concomitant illnesses or taking medications likely to confound endpoint assessments, including taking approved (ie, marketed) therapies for the purpose of affecting PKD cysts such as tolvaptan, vasopressin antagonists, anti-sense RNA therapies, rapamycin, sirolimus, everolimus, or somatostatin analogs (ie, octreotide, sandostatin) 22. History of cholangitis 23. Received or are scheduled to receive a liver transplant |
1. Prematuridad (edad gestacional <= 32 semanas) 2. Anuria o RRT -definido como la práctica intermitente o continua de hemodiálisis, diálisis peritoneal, hemofiltración o hemodiafiltración o historia de trasplante renal 3. Evidencia de procesos sindrómicos por quistes renales (distintos de la ARPKD) 4. Anomalías de las pruebas funcionales hepáticas, tales como ALT y AST > 1,2 × límite superior de la normalidad. 5. Progenitores con nefopatía quística 6. En tratamiento diurético prolongado que no pueda ajustarse tras el inicio del tolvaptán 7. Imposibilidad de vigilar el balance hídrico 8. Presencia o riesgo de presentar desequilibrios electrolíticos de sodio y potasio, a juicio del investigador 9. Presencia o riesgo de presentar hipovolemia importante (p. ej., sujetos que carecen de libre acceso al agua, sin vigilancia y administración adecuadas de líquidos), a juicio del investigador 10. Anemia clínicamente importante, a juicio del investigador 11. Disfunción sistólica severa, definida como fracción de eyección <14% 12. Niveles de sodio sérico <130 mmol/L o >145 mmol/L (o el límite superior de la normalidad del laboratorio del centro, el que sea menor) 13. En tratamiento con cualquier otro medicamento experimental 14. Necesidad de soporte ventilatorio 15. En tratamiento con medicamentos con efecto conocido de inducción de CYP3A4 16. Presencia de una infección, incluidas las víricas, que requiera un tratamiento no compatible con la administración del medicamento en investigación 17. Cifra de plaquetas <50.000 µL 18. Presencia de signos compatibles con hipertensión portal clínicamente importante (p. ej., várices esofágicas, hemorragia digestiva por varices esofágicas, hiperesplenismo indicado por trombocitopenia) 19. Disfunción vesical y/o dificultad miccional 20. En tratamiento con un agonista de la vasopresina (p. ej., desmopresina) 21. Presencia de enfermedades concomitantes o recepción de medicamentos que puedan dificultar la interpretación de las evaluaciones de los criterios de valoración, incluidos los medicamentos aprobados (es decir, comercializados) que se administren para tratar los quistes de la poliquistosis renal, como tolvaptán, antagonistas de la vasopresina, tratamientos con ácido ribonucleico antisentido, rapamicina/sirolimús, everólimus o análogos de la somatostatina (como octreotida, Sandostatin) 22. Antecedentes de colangitis 23. Trasplante de hígado, recibido o programado |
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E.5 End points |
E.5.1 | Primary end point(s) |
Percentage of subjects having RRT by 1 year of age |
Porcentaje de sujetos con RRT en 1 año de vida |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
- Rate of change of eGFR (eGFR Schwartz formula = 0.413 × height [or length, cm] /serum creatinine mg/dL) from pretreatment to post-treatment after 2 years of treatment - Age-appropriate assessment of acceptability and palatability of formulation |
- Tasa de cambio de la eGFR (eGFR según la fórmula de Schwartz = 0.413 × altura [o talla, en cm]/ creatinina sérica, en mg/dL) desde antes del tratamiento a después del tratamiento tras 2 años de tratamiento - Evaluación, conforme a la edad, de la palatabilidad y aceptación de la formulación en suspensión |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
pre-treatment to post treatment after 2 years of treatment |
desde antes del tratamiento a después del tratamiento tras 2 años de tratamiento |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
Tolerabiltiy |
Tolerabilidad |
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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) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
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 | No |
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 | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 10 |
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 |
United States |
France |
Poland |
Spain |
Czechia |
Germany |
Italy |
Belgium |
United Kingdom |
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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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Expected trial participation duration for each subject to be approximately 2 years with the option to continue to receive tolvaptan treatment for 12 additional months |
La duración prevista de la participación en el ensayo de cada sujeto es de aproximadamente 2 años, con la opción de proseguir el tratamiento con tolvaptán durante 12 meses adicionales |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |