| 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) |
|
| 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. |
|
| 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 |
|
| 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 safety of tolvaptan in pediatric subjects with ARPKD |
| Evaluar la seguridad del tolvaptán en sujetos pediátricos con ARPKD |
|
| E.2.2 | Secondary objectives 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 |
|
| 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 |
| This is optional further research performed on the remainder of the samples collected during the study to understand the genetics of ARPKD |
| Se trata de una investigación adicional, de carácter opcional, en las partes restantes de las muestras recogidas durante el estudio, para conocer mejor la genética de la ARPKD |
|
| E.3 | Principal inclusion criteria |
1. Male or female subjects between 28 days and less than 18 years of age, with 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; and a history of oligohydramnios or anhydramnios in utero.
2. Ability for parent/legal 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. Ability to provide written informed assent from all subjects old enough per local laws to provide assent. |
1. Sujetos de uno u otro sexo y edad comprendida entre 28 días y menos de 18 años, con 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; e historia de oligohidramnios o anhidramnios intrauterino.
2. 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. Capacidad para proporcionar el asentimiento informado por escrito de todos los sujetos con edad suficiente para hacerlo según la legislación del país |
|
| E.4 | Principal exclusion criteria |
1. Premature birth (≤ 32 weeks gestational age) for infants 28 days to <12 weeks of 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. Has splenomegaly or portal hypertension
6. Parents with renal cystic disease
7. Receiving chronic diuretic that could not be adjusted after tolvaptan initiation.
8. Cannot be monitored for fluid balance
9. Has or at risk of having sodium and potassium electrolyte imbalances, as determined by the investigator
10. Has or at risk of having significant hypovolemia (e.g. subjects that lack free access to water
[inability to respond to thirst, depending on age], without adequate fluid monitoring and
management) as determined by investigator
11. Clinically significant anemia, as determined by investigator
12. Platelets < 50000 μL
13. Severe systolic dysfunction defined as ejection fraction < 14%
14. Serum sodium levels < 130 mmol/L or >145 mmol/L (or the ULN of the local laboratory, whichever is lower)
15. Taking any other experimental medications
16. Require ventilator support
17. Taking medications known to induce CYP3A4
18. Having an active infection including viral that would require therapy disruptive to IMP dosing
19. Females who are breast-feeding or who have a positive pregnancy test result prior to receiving IMP.
20. Subjects with a history of substance abuse within the last 6 months (depending on age).
21. Subjects who have bladder dysfunction and/or difficulty voiding.
22. Subjects taking a vasopressin agonist (eg, desmopressin).
23. Subjects with a history of persistent non-compliance with antihypertensive or other important medical therapy
24. Subjects 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).
25. Subjects who do not agree to remain abstinent or assent to use a combination of two of the
following highly effective birth control methods for at least 28 days before the first dose of IMP,
during the trial (including during IMP dose interruptions), and for at least 30 days after the last
dose of IMP:
Barrier method of contraception: condoms (male or female) with or without a spermicidal agent, diaphragm or cervical cap with spermicide, Intrauterine device, Hormone-based contraceptives which are associated with inhibition of ovulation.
26. Received or are scheduled to receive a liver transplant.
27. History of cholangitis within the last 6 months
28. Has findings consistent with clinically significant portal hypertension (eg, varices, variceal
bleeding, hypersplenism indicated by thrombocytopenia). |
1. Prematuridad (edad gestacional <= 32 semanas) en lactantes de 28 días a <12 semanas de edad.
2. Anuria o tratamiento sustitutivo renal (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 × ULN.
5. Presencia de esplenomegalia o hipertensión portal
6. Progenitores con nefopatía quística
7. En tratamiento diurético prolongado que no pueda ajustarse tras el inicio del tolvaptán
8. Imposibilidad de vigilar el balance hídrico
9. Presencia o riesgo de presentar desequilibrios electrolíticos de sodio y potasio, a juicio del investigador
10. Presencia o riesgo de presentar hipovolemia importante (p. ej., sujetos que carecen de libre acceso al agua [incapacidad para responder a la sed, según la edad], sin vigilancia y administración adecuadas de líquidos), a juicio del investigador
11. Anemia clínicamente importante, a juicio del investigador
12. Paquetas < 50000 μL
13. Disfunción sistólica severa, definida como fracción de eyección <14%
14. 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)
15. En tratamiento con cualquier otro medicamento experimental
16. Necesidad de soporte ventilatorio
17. En tratamiento con medicamentos con efecto conocido de inducción de CYP3A4
18. Presencia de una infección, incluidas las víricas, que requiera un tratamiento no compatible con la administración del medicamento en investigación
19. Mujeres en periodo de lactancia o con prueba de embarazo positiva antes de recibir el medicamento en investigación
20. Sujetos con antecedentes de abuso de sustancias en los últimos 6 meses (según la edad)
21. Sujetos con disfunción vesical y/o dificultad miccional
22. Sujetos en tratamiento con un agonista de la vasopresina (p. ej., desmopresina)
23. Sujetos con antecedentes de incumplimiento persistente del tratamiento antihipertensivo u otra terapia médica importante
24. Sujetos con 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)
25. Sujetos que no acepten mantener la abstinencia sexual o utilizar una combinación de dos de los siguientes métodos anticonceptivos de gran efectividad siguientes desde como mínimo 28 días antes de la primera dosis del medicamento en investigación, durante el ensayo (incluso durante las interrupciones de la dosis del medicamento en investigación) y hasta por lo menos 30 días después de la última dosis del medicamento en investigación:
Método anticonceptivo de barrera: preservativo (masculino o femenino) con o sin espermicida, diafragma o capuchón cervical con espermicida; dispositivo intrauterino; anticonceptivos hormonales para inhibición de la ovulación.
26. Trasplante de hígado, recibido o programado
27. Antecedentes de colangitis en los últimos 6 meses
28. Presencia de signos compatibles con hipertensión portal clínicamente importante (p. ej., varices esofágicas, hemorragia digestiva por varices esofágicas, hiperesplenismo indicado por trombocitopenia) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety assessments which will be summarized by descriptive statistics, and the endpoints will be
- Adverse events
- Vital signs
- Clinical laboratory assessments
- Serum transaminase elevations for frequency (2 ×, 3 ×, 5 × and 10 × ULN), time to onset, time to peak levels, time of offset (< 3 ×, 2 ×, or 1 × ULN), response to de-challenge and re-challenge and frequency of progression to Hy’s laboratory criteria (ALT or AST > 3 × ULN and BT, > 2 × ULN without alkaline phosphatase greater than or equal to 2 × ULN)
- Change from baseline in sNa+ |
Evaluaciones de la seguridad, que se resumirán mediante estadígrafos descriptivos y cuyos criterios de
valoración serán
- Acontecimientos adversos
- Constantes vitales
- Determinaciones de laboratorio
- Elevaciones de las transaminasas séricas según su entidad (2 ×, 3 ×, 5 × y 10 × ULN), tiempo hasta su inicio, tiempo hasta los valores máximos, tiempo hasta su reducción (< 3 ×, 2 × o 1 × ULN), respuesta a la retirada y la reintroducción del medicamento y entidad de progresión a criterios de laboratorio de Hy (ALT o AST > 3 × ULN y BT > 2 × ULN sin fosfatasa alcalina >=2 × ULN)
- Cambio frente al basal en sNa+ |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Months 1, 6, 12, and 18 |
| Meses 1, 6, 12 y 18 |
|
| E.5.2 | Secondary end point(s) |
Annual rate of change of eGFR (eGFR Schwartz formula = 0.413 × height [or length, cm] /serum creatinine mg/dL) from baseline to post-treatment after 18 months of treatment
-Change from baseline of eGFR (eGFR
Schwartz formula = 0.413 × height [or length, cm] /serum creatinine mg/dL) while on treatment at Months 1, 6, 12, and 18
-Time to RRT
-Percentage of subjects who receive RRT |
Tasa anual de cambio de la eGFR (eGFR según la fórmula de Schwartz = 0,413 × altura [o talla, en cm]/ creatinina sérica, en mg/dL) desde el basal a después del tratamiento tras 18 meses de tratamiento
- Cambio frente al basal de la eGFR (eGFR según la fórmula de Schwartz = 0,413 × altura [o talla, en cm]/ creatinina sérica, en mg/dL) durante el tratamiento a los Meses 1, 6, 12 y 18
- Tiempo hasta el RRT
- Porcentaje de sujetos que reciben RRT |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Months 1, 6, 12, and 18 |
| Meses 1, 6, 12 y 18 |
|
| 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 |
| Tolerability |
| Tolerabilidad |
|
| 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 | 3 |
| 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 |
|
| 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 overall trial duration is considered from the time the first ICF is signed to the final subject assessment and is expected to be approximately 3.5 years. All subjects may be followed for 18 months after the first dose of IMP, regardless of continued compliance with taking IMP. |
| La duración total del ensayo, que se cuenta desde el momento en que se firme el primer documento de consentimiento informado hasta la evaluación del último sujeto, se espera que sea de aproximadamente 3,5 años. Se procurará el seguimiento de todos los sujetos durante 18 meses después de la primera dosis del medicamento en investigación, independientemente de su grado de cumplimiento del tratamiento con el medicamento en investigación. |
|
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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