| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Euvolemic or Hypervolemic Hyponatremia |
| Hiponatremia euvolémica o hipervolémica. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Low amount of sodium or salt in the blood |
| Baja cantidad de sodio o sal en la sangre. |
|
| 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 | 17.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10021038 |
| E.1.2 | Term | Hyponatremia |
| E.1.2 | System Organ Class | 100000004861 |
|
| 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 is to demonstrate that tolvaptan effectively and safely increases and maintains serum sodium concentrations in children and adolescent subjects with euvolemic or hypervolemic hyponatremia. |
| Demostrar que tolvaptán aumenta y mantiene de forma eficaz y segura las concentraciones séricas de sodio en niños y adolescentes que presentan hiponatremia euvolémica o hipervolémica. |
|
| E.2.2 | Secondary objectives of the trial |
| The key secondary objective is to assess the PK of tolvaptan and the effect on fluid balance in children and adolescent subjects with euvolemic or hypervolemic hyponatremia. |
| Evaluar la FC de tolvaptán y su efecto en el balance hídrico en niños y adolescentes que presentan hiponatremia euvolémica o hipervolémica. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male and female subjects ? 4 weeks (or ? 44 weeks adjusted gestational age for premature births) to < 18 years old.
2. Subjects hospitalized with euvolemic or hypervolemic hyponatremia resistant to initial standard background therapy (including fluid restriction and excluding a vasopressin antagonist) and who are deemed by the investigator as likely to benefit from a therapy that raises serum sodium levels.
3. Persistent euvolemic or hypervolemic hyponatremia defined as being documented as present for at least 48 hours, evidenced by at least 2 serum sodium assessments < 130 mEq/L (mmol/L) drawn at least 12 hours apart (these values can be documented using historical values previously obtained per standard of care); a third (STAT) serum sodium assessment < 130 mEq/L (mmol/L), which will serve as the baseline value for efficacy endpoints, is to be obtained within 2-4 hours prior to the first dose of tolvaptan.
4. Ability to take oral medication.
5. Ability to maintain adequate fluid intake whether orally or via IV support with adequate monitoring.
6. Ability to comply with all requirements of the trial.
7. Trial-specific written informed consent/assent obtained from a parent/guardian or legally acceptable representative, as applicable per age of subject or local laws, prior to the initiation of any protocolrequired procedures. In addition, the subject as required by local laws must provide informed assent at Screening and must be able to understand that he or she can withdraw from the trial at any time. All informed consent/assent procedures must be in accordance with the trial center?s IRB/IEC and local regulatory requirements.
8. Ability to commit to remain abstinent or practice double-barrier birth control during the trial and for 14 days following the last dose of IMP for sexually active females of childbearing potential |
1. Pacientes de ambos sexos >= 4 semanas (o >= 44 semanas, ajustadas según la edad gestacional) hasta menos de 18 años de edad.
2. Pacientes hospitalizados con hiponatremia euvolémica o hipervolémica resistente al tratamiento de base estándar inicial (que incluye restricción de líquidos y excluye la administración de un antagonista de los receptores de la vasopresina) y que, según el investigador, tengan probabilidades de beneficiarse de un tratamiento que aumenta los niveles de sodio sérico.
3. Hiponatremia euvolémica o hipervolémica persistente, que se define como la presencia documentada durante al menos 48 horas, de al menos 2 evaluaciones de sodio sérico < 130 mEq/l (mmol/l) realizadas con al menos 12 horas de diferencia (estos valores se pueden documentar mediante los valores históricos obtenidos anteriormente durante la atención médica habitual). Se debe obtener una tercera evaluación de sodio sérico (prueba de determinación urgente) < 130 mEq/l (mmol/l), que servirá como valor inicial para los criterios de valoración de eficacia, dentro de las 2-4 horas anteriores a la primera dosis de tolvaptán.
4. Capacidad de tomar el fármaco vía oral. |
|
| E.4 | Principal exclusion criteria |
1. Has evidence of hypovolemia or intravascular volume depletion (eg, hypotension, clinical evidence of volume depletion, response to saline challenge); if the subject has systolic blood pressure or heart rate outside of the normal range for that age volume status should be specifically clinically assessed to rule out volume depletion.
2. Has serum sodium < 120 mEq/L (mmol/L), with or without associated neurologic impairment (ie, symptoms such as apathy, confusion, or seizures).
3. Use of potent CYP3A4 inhibitors in subjects ? 50 kg or moderate CYP3A4 inhibitors in subjects < 20 kg.
4. Lacks free access to water (inability to respond to thirst) or without ICU-level fluid monitoring and management.
5. Has a history or current diagnosis of nephrotic syndrome.
6. Has transient hyponatremia likely to resolve (eg, head trauma or post-operative state).
7. Has hyperkalemia defined as serum potassium above the ULN for the appropriate pediatric age range.
8. Has eGFR < 30 mL/min/1.73 m2 calculated by the following equation:
eGFR (mL/min/1.73 m2) = 0.413 x height (cm)/serum creatinine (mg/dL).
9. Has AKI defined as:
? Increase in serum creatinine by ? 0.3 mg/dL (? 26.5 µmol/L) within 48 hours; or
? Increase in serum creatinine to ? 1.5 times baseline, which is known or presumed to have occurred within the prior 7 days; or
? Urine volume < 0.5 mL/kg/h for 6 hours.
10. Has severe or acute neurological symptoms requiring other intervention (eg, hyperemesis, obtundation, seizures).
11. Has had treatment for hyponatremia with:
? Hypertonic saline (including normal saline challenge) within 8 hours of qualifying serum sodium assessments;
? Urea, lithium, demeclocycline, conivaptan, or tolvaptan within 4 days of qualifying serum sodium assessments;
? Other treatment for the purpose of increasing serum sodium concurrent with dosing of trial medication.
12. Has anuria or urinary outflow obstruction, unless the subject is, or can be, catheterized during the trial.
13. Has a history of drug or medication abuse within 3 months prior to Screening or current alcohol abuse.
14. Has a history of hypersensitivity and/or idiosyncratic reaction to benzazepine or benzazepine derivatives (such as benazepril).
15. Has psychogenic polydipsia (subjects with other psychiatric illness may be included per medical monitor approval).
16. Has uncontrolled diabetes mellitus, defined as fasting glucose > 300 mg/dL (16.7 mEq/L [mmol/L]).
17. Has screening liver function values > 3 x ULN. An IRE will be completed if the subject is a potential Hy?s Law case (any increase of AST or ALT ? 2 x ULN or baseline value with an increase
in total bilirubin ? 2 x ULN or baseline value).
18. Has deficient coagulation (eg, cirrhotic at risk of GI bleed), including subjects who meet any of the following criteria: a major GI bleed within the past 6 months, evidence of active bleeding (eg,
epistaxis, petechiae/purpura, hematuria, or hematochezia), platelet count < 50,000/µL, or use of concomitant medications known to increase bleeding risk.
19. Has hyponatremia due to the result of any medication that can safely be withdrawn (eg, thiazide diuretics).
20. Has hyponatremia (eg, hyponatremia in the setting of adrenal insufficiency, untreated hypothyroidism, or hypotonic fluid administration) that is most appropriately corrected by alternative therapies.
21. Is currently pregnant or breastfeeding.
22. Has any medical condition that, in the opinion of the investigator, could interfere with evaluation of the trial objectives or safety of the subjects.
23. Is deemed unsuitable for trial participation in the opinion of the investigator.
24. Participation in another investigational drug trial within the past 30 days, without prior approval from the sponsor medical monitor.
25. Subjects <2 years of age, weight <10 kg, or who cannot swallow an oral tablet are excluded until an oral suspension formulation becomes available. |
1. Signos de hipovolemia o depleción de volumen intravascular (p. ej., hipotensión, signos clínicos de depleción de volumen o respuesta a la provocación con solución salina). Si la presión arterial sistólica o la frecuencia cardíaca están fuera del intervalo normal para la edad, se evaluará específicamente el cuadro clínico del estado de volumen para descartar la depleción de volumen.
2. Pacientes con sodio sérico menor de 120 mEq/l (mmol/l), con o sin deterioro neurológico asociado (es decir, síntomas como apatía, confusión o convulsiones).
3. Uso de inhibidores potentes del citocromo CYP3A4 en pacientes <= 50 kg o de inhibidores moderados del CYP3A4 en pacientes < 20 kg
4. Carece de acceso libre al agua (incapacidad de responder a la sed) o sin monitorización y control de líquidos a nivel de UCI.
5. Antecedentes o diagnóstico actual de síndrome nefrótico.
6. Hiponatremia transitoria que podría resolverse (p. ej., traumatismo craneal o postoperatorio).
7. Hiperpotasemia definida como un potásico sérico mayor que el LSN en el intervalo adecuado de edad pediátrica.
8. Filtración glomerular estimada (FGe) < 30 ml/min/1,73 m2, calculada mediante la ecuación siguiente:
FGe (ml/min/1,73 m2) = 0,413xestatura (cm)/creatinina sérica (mg/dl).
9. LRA, definida como:
- Incremento de la creatinina sérica >= 0,3 mg/dl (>= 26,5 µmol/l) en un plazo de 48 horas o
- Incremento de la creatinina sérica hasta >= 1,5 veces el valor inicial, que se sabe o se sospecha que se ha producido en los 7 días previos o
- Diuresis < 0,5 ml/kg·h durante 6 horas.
10. Síntomas neurológicos intensos o agudos que requieren otra intervención (p. ej., hiperemesis, obnubilación o convulsiones).
11. Tratamiento para la hiponatremia con:
- Solución salina hipertónica (incluida la provocación con solución salina normal) en las 8 horas anteriores a las evaluaciones de sodio sérico de cualificación
- Urea, litio, demeclociclina, conivaptán o tolvaptán en los 4 días anteriores a las evaluaciones de sodio sérico de cualificación
- Otro tratamiento con el objetivo de incrementar el sodio sérico junto a la administración del fármaco del estudio.
12. Anuria u obstrucción del flujo urinario, salvo cuando el paciente esté o pueda estar sondado durante el estudio.
13. Antecedentes de abuso de alcohol o drogas en los 3 meses previos a la fase de selección o abuso de alcohol actual.
14. Antecedentes de hipersensibilidad y/o reacción idiosincrásica a benzazepinas o sus derivados (como benazepril).
15. Polidipsia psicógena (puede incluirse pacientes con otras enfermedades psiquiátricas si lo aprueba el monitor médico).
16. Diabetes mellitus no controlada, definida como glucosa en ayunas mayor de 300 mg/dl (16,7 mEq/l [mmol/l]).
17. Resultados de las pruebas hepáticas en la selección > 3 veces el LSN. Se completará un ANI si el paciente es un caso posible de ley de Hy (cualquier aumento de la AST o ALT ? 2xLSN o un valor inicial con un aumento de la bilirrubina total >=2 del LSN o del valor inicial).
18. Trastorno de la coagulación (p. ej., cirróticos con riesgo de hemorragia digestiva), incluidos los pacientes que cumplan cualquiera de los siguientes criterios: hemorragia digestiva mayor en los últimos 6 meses, signos de hemorragia activa (p. ej., epistaxis, petequias/púrpura, hematuria o hematoquecia), recuento de plaquetas < 50.000/µl o uso de medicamentos concomitantes que aumentan el riesgo de hemorragia.
19. Hiponatremia debida a cualquier medicamento que pueda retirarse de forma segura (p. ej., diuréticos tiazidas).
20. Hiponatremia (p. ej., hiponatremia en el marco de una insuficiencia suprarrenal, hipotiroidismo no tratado o administración de líquidos hipotónicos) que se corrige de una forma más apropiada mediante tratamientos alternativos.
21. La paciente está embarazada o en período de lactancia.
22. Cualquier afección médica que, en opinión del investigador, pudiera interferir con la evaluación de los objetivos del estudio o la seguridad de los pacientes.
23. El paciente no se considera apto para el estudio por cualquier otra causa, en opinión del investigador.
24. Participación en otro estudio de investigación con el fármaco del estudio en los últimos 30 días, sin aprobación previa del monitor médico del promotor
25. Se excluye a los pacientes < 2 años de edad, que pesen < 10 kg o que no puedan tragar un comprimido por vía oral hasta que se disponga de una formulación oral en suspensión. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint:
For subjects with serum sodium level increases of ? 4 mEq/L (mmol/L) (ie, responders), change in serum sodium concentration from Day 2 (or 2a) at the end of Treatment Phase A to the end of Treatment Phase B for Early compared to Late Withdrawal groups. |
| Para pacientes con aumentos de la concentración del sodio sérico de >= 4 mmol/l (es decir, los pacientes que responden al tratamiento), cambio en la concentración sérica de sodio desde el día 2 (o 2a) al final de la fase A de tratamiento hasta el final de la fase B de tratamiento en los grupos de retirada temprana en comparación con el de los grupos de retirada tardía. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From Day 2 (or 2a) at the end of Treatment Phase A to the end of Treatment Phase B for Early compared to Late Withdrawal groups. |
| Para todos los pacientes, el criterio de valoración secundario clave es el cambio en la concentración sérica de sodio al final del día 2 (o 2a) en la fase A de tratamiento con respecto a la concentración inicial |
|
| E.5.2 | Secondary end point(s) |
Key Secondary Efficacy Endpoint:
For all subjects, the key secondary endpoint is the change in serum sodium concentration at the end of Day 2 (or 2a) in Treatment Phase A from baseline. |
| Para todos los pacientes, el criterio de valoración secundario clave es el cambio en la concentración sérica de sodio al final del día 2 (o 2a) en la fase A de tratamiento con respecto a la concentración inicial. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At the end of Day 2 (or 2a) in Treatment Phase A. |
| Al final del día 2 (o 2a) en la fase A de tratamiento. |
|
| 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 | No |
| 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) | 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 | 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 | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Ensayo con retirada aleatorizada. |
| Randomized Withdrawal Trial |
|
| 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 | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 33 |
| 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 |
| Belgium |
| Canada |
| Czech Republic |
| Germany |
| Italy |
| Poland |
| Romania |
| Spain |
| Turkey |
| United Kingdom |
| 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 Trial Date is defined as the last Date of Contact or the Date of Final Contact Attempt from the Post-treatment Follow-up CRF page for the last subject completing or withdrawing from the trial. |
| La fecha de finalización del estudio (FE) se define como la última fecha de contacto o la fecha del intento de contacto final de la página del CRD de seguimiento posterior al tratamiento para el último paciente que complete el estudio o se retire del mismo. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| 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 | 3 |
| 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 |
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