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    Summary
    EudraCT Number:2013-002005-59
    Sponsor's Protocol Code Number:156-08-276
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2015-01-05
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2013-002005-59
    A.3Full title of the trial
    A Phase 3b, Multicenter, Open-label, Randomized Withdrawal Trial of the Effects of Titrated Oral SAMSCA® (Tolvaptan) on Serum Sodium, Pharmacokinetics, and Safety in Children and Adolescent Subjects Hospitalized With Euvolemic or Hypervolemic Hyponatremia
    Estudio de fase 3b, multicéntrico, abierto con discontinuación aleatorizada de los efectos de las dosis orales ajustadas de SAMSCA® (tolvaptán) en el sodio sérico, la farmacocinética y la seguridad en niños y adolescentes hospitalizados con hiponatremia euvolémica o hipervolémica
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 3b, Multicenter, Trial of the Effects of Oral Tolvaptan on Blood Sodium, Pharmacokinetics, and Safety in Children and Adolescent Patients Hospitalized With Euvolemic or Hypervolemic Hyponatremia
    Estudio de fase 3b, multicéntrico, para el estudio de los efectos de las dosis orales de tolvaptán en el sodio sérico, la farmacocinética y la seguridad en niños y adolescentes hospitalizados con hiponatremia euvolémica o hipervolémica.
    A.4.1Sponsor's protocol code number156-08-276
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorOtsuka Pharmaceutical Development & Commercialization, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportOtsuka Pharmaceutical Development & Commercialization, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationOtsuka Pharmaceutical Development & Commercialization, Inc.
    B.5.2Functional name of contact pointDorothee Oberdhan
    B.5.3 Address:
    B.5.3.1Street Address2440 Research Boulevard, Rockville,
    B.5.3.2Town/ cityMaryland
    B.5.3.3Post code20850
    B.5.3.4CountryUnited States
    B.5.4Telephone number+12406833517
    B.5.5Fax number+13017217517
    B.5.6E-mailDorothee.Oberdhan@otsuka-us.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTolvaptan 3.75 mg Tablet
    D.3.2Product code OPC-41061
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTolvaptan
    D.3.9.1CAS number 150683-30-0
    D.3.9.2Current sponsor codeOPC-41061
    D.3.9.3Other descriptive nameTOLVAPTAN (OPC-41061)
    D.3.9.4EV Substance CodeSUB31691
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3.75
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTolvaptan 7.5 mg Tablet
    D.3.2Product code OPC-41061
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTolvaptan
    D.3.9.1CAS number 150683-30-0
    D.3.9.2Current sponsor codeOPC-41061
    D.3.9.3Other descriptive nameTOLVAPTAN (OPC-41061)
    D.3.9.4EV Substance CodeSUB31691
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number7.5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name SAMSCA® 15mg Tablet
    D.2.1.1.2Name of the Marketing Authorisation holderOtsuka Pharmaceutical Europe Ltd.
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTolvaptan 15 mg Tablet
    D.3.2Product code OPC-41061
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTolvaptan
    D.3.9.1CAS number 150683-30-0
    D.3.9.2Current sponsor codeOPC-41061
    D.3.9.3Other descriptive nameTOLVAPTAN (OPC-41061)
    D.3.9.4EV Substance CodeSUB31691
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 4
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name SAMSCA® 30 Tablet
    D.2.1.1.2Name of the Marketing Authorisation holderOtsuka Pharmaceutical Europe Ltd
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTolvaptan 30 mg Tablet
    D.3.2Product code OPC-41061
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTolvaptan
    D.3.9.1CAS number 150683-30-0
    D.3.9.2Current sponsor codeOPC-41061
    D.3.9.3Other descriptive nameTOLVAPTAN (OPC-41061)
    D.3.9.4EV Substance CodeSUB31691
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Euvolemic or Hypervolemic Hyponatremia
    Hiponatremia euvolémica o hipervolémica.
    E.1.1.1Medical condition in easily understood language
    Low amount of sodium or salt in the blood
    Baja cantidad de sodio o sal en la sangre.
    E.1.1.2Therapeutic area Diseases [C] - Nutritional and Metabolic Diseases [C18]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.1
    E.1.2Level LLT
    E.1.2Classification code 10021038
    E.1.2Term Hyponatremia
    E.1.2System Organ Class 100000004861
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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.2.2Secondary 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.2.3Trial contains a sub-study No
    E.3Principal 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.4Principal 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.5.1Primary 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.5.1.1Timepoint(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.5.2Secondary 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.5.2.1Timepoint(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.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Ensayo con retirada aleatorizada.
    Randomized Withdrawal Trial
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA33
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If 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.8.7Trial 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.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 100
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 5
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 45
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 50
    F.1.2Adults (18-64 years) No
    F.1.2.1Number of subjects for this age range: 0
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Children and Adolescent Subjects are incapable of giving consent personally, hence it is related to their age ONLY.
    Pacientes niños y adolescentes incapaces de dar el consentimiento personalmente, por lo tanto está relacionado únicamente con la edad.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 66
    F.4.2.2In the whole clinical trial 100
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Subjects will be proposed to roll-over into the 156-11-294 study for a 6 month safety follow-up. There is an optional tolvaptan treatment component if it is determined that there is a need for additional treatment.
    Se propondrá a los pacientes que participen en el estudio 156-11-294 para el seguimiento de la seguridad durante 6 meses. Hay un componente de tratamiento opcional con tolvaptán si se determina que hay necesidad de tratamiento adicional.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-03-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-01-15
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2017-07-24
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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