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    Summary
    EudraCT Number:2013-002810-11
    Sponsor's Protocol Code Number:156-11-294
    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:2015-06-30
    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 number2013-002810-11
    A.3Full title of the trial
    A Phase 3b, Multicenter, Extension Follow-up Trial to Evaluate the Long-term Safety of Children and Adolescent Subjects With Euvolemic or Hypervolemic Hyponatremia Who Have Previously Participated in a Trial of Titrated Oral SAMSCA® (Tolvaptan)
    Estudio de fase 3b, multicéntrico y de extensión del seguimiento para evaluar la seguridad a largo plazo de niños y adolescentes con hiponatremia euvolémica o hipervolémica que han participado con anterioridad en un estudio con dosis orales ajustadas de SAMSCA® (tolvaptán)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 3b, Multicenter, Extension Follow-up Trial to Evaluate the Safety of Children and Adolescent Subjects With Euvolemic or Hypervolemic Hyponatremia Who Have Previously Participated in a Trial of Tolvaptan
    Estudio de fase 3b, multicéntrico y de extensión del seguimiento para evaluar la seguridad de niños y adolescentes con hiponatremia euvolémica o hipervolémica que han participado con anterioridad en un ensayo de tolvaptán
    A.4.1Sponsor's protocol code number156-11-294
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/221/2013
    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+34917088600
    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 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 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® 15 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 18.0
    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
    For all subjects: To evaluate the post-treatment safety follow-up of children and adolescent subjects with dilutional (euvolemic or hypervolemic) hyponatremia who have previously participated in a trial of titrated oral investigational medicinal product (IMP [tolvaptan in Trial 156-08-276, tolvaptan or placebo in Trials 156-13-207 and 156-12-205]).
    For subjects who receive tolvaptan: To demonstrate that tolvaptan safely and effectively achieves and maintains increased serum sodium concentrations in children and adolescent subjects with dilutional (euvolemic or hypervolemic) hyponatremia when used for both multiple short-term treatments and/or longer chronic treatments.
    Para todos los pacientes: Evaluar el seguimiento de la seguridad posterior al tratamiento de voluntarios niños y adolescentes con hiponatremia dilucional (euvolémica o hipervolémica) que han participado anteriormente en un ensayo de dosis orales ajustadas del producto en investigación (PEI [tolvaptán en el estudio 156-08-276, tolvaptán o placebo en los estudios 156-13-207 y 156-12-205]).
    En el caso de los pacientes que reciben tolvaptán:Demostrar que el tolvaptán logra y mantiene con seguridad y eficacia un aumento en las concentraciones del sodio sérico en voluntarios niños y adolescentes con hiponatremia dilucional (euvolémica o hipervolémica), tanto cuando se usa en tratamientos múltiples a corto plazo como en tratamientos crónicos más prolongados.
    E.2.2Secondary objectives of the trial
    Not applicable
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Enrollment in one of the previous tolvaptan pediatric trials for hyponatremia (ie, Trial 156-08-276, 156-13-207, or 156-12-205).
    2. Trial-specific written informed consent/assent obtained from a parent/guardian or legally acceptable representative, as applicable for local laws, prior to the initiation of any protocol-required procedures. In addition, the subject must provide informed assent at baseline 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.
    3. Ability to comply with all requirements of the trial
    4. Willingness to be clinically followed for 6 months
    1. Participación en uno de los ensayos pediátricos anteriores de tolvaptán para la hiponatremia (es decir, los ensayos 156-08-276, 156-13-207 o 156-12-205).
    2. Asentimiento/consentimiento informado por escrito específico del estudio, obtenido del progenitor/el tutor o el representante legal, si corresponde según las leyes locales, antes del inicio de cualquier procedimiento requerido por el protocolo. Además, según lo requieran las leyes locales, el paciente debe dar su asentimiento informado en el momento inicial y debe ser capaz de comprender que puede retirarse del estudio en cualquier momento. Todos los procedimientos del consentimiento/asentimiento informado deben realizarse según los requisitos normativos locales y del CRI/CEIC del centro del estudio.
    3. Capacidad para cumplir todos los requisitos del estudio.
    4. Disposición para someterse a un seguimiento clínico durante 6 meses.
    E.4Principal exclusion criteria
    Safety follow-up component of this trial: There are no exclusion criteria.
    Optional Tolvaptan Treatment Component of this trial:
    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 the pretreatment visit 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 form 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 BT ? 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 an investigational drug trial (other than Trials 156-08-276, or 156-13-207 or 156-12-205) within the past 30 days, without prior approval from the medical monitor
    25. Subjects <2 years of age, weight <10 kg, or who cannot swallow an oral tablet are excluded until an oral liquid formulation becomes available
    No hay criterios de exclusión para la incorporación en el componente principal de seguimiento de la seguridad de este ensayo:
    1. Indicios de hipovolemia o reducción del volumen intravascular (por ej., hipotensión, indicios clínicos de reducción del volumen intravascular, respuesta a sobrecarga de solución salina); si el paciente tiene presión arterial sistólica o frecuencia cardíaca fuera del intervalo normal para la edad, el estado del volumen intravascular debe evaluarse específicamente desde el punto de vista clínico para descartar una reducción del volumen.
    2. Sodio sérico < 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. Falta de acceso libre a agua (incapacidad de responder a la sed) o ausencia de control y manejo de líquidos con nivel de UCI.
    5. Antecedentes o diagnóstico actual de síndrome nefrótico.
    6. Hiponatremia transitoria con probabilidad de resolverse (por ej., traumatismo craneoencefálico o estado posquirúrgico).
    7. Hiperpotasiemia definida como potasio sérico por encima del LSN para el rango de edad pediátrica adecuado.
    8. FGc < 30 ml/min/1,73 m2, calculada mediante la ecuación siguiente:
    FGc (ml/min/1,73 m2) = 0,413 × estatura (cm)/creatinina sérica (mg/dl).
    9. AKI, que se define como:
    - Un aumento de la creatinina sérica >=0,3 mg/dl (>= 26,5 mol/l) en 48 horas
    - Un aumento de la creatinina sérica ? 1,5 veces el valor inicial, que se sabe o se supone que ocurrió en los 7 días anteriores o
    - Volumen de orina < 0,5 ml/kg/h durante 6 horas.
    10. Síntomas neurológicos graves o agudos que requieren otra intervención (por ej., hiperémesis, embotamiento, convulsiones).
    11. Tratamiento para la hiponatremia con:
    - Solución salina hipertónica (incluida la prueba de sobrecarga de solución salina normal) dentro de las 8 horas siguientes a las evaluaciones de sodio sérico que cumplieron los requisitos
    - Urea, litio, demeclociclina, conivaptán o tolvaptán en los 4 días anteriores a las evaluaciones de sodio sérico para la cualificación
    - Otro tratamiento cuyo objetivo sea aumentar el sodio sérico en forma simultánea con la administración del medicamento del estudio.
    12. Anuria u obstrucción del flujo urinario, a menos que el paciente tenga insertada una sonda o pueda insertársele una durante el estudio.
    13. Antecedentes de abuso de drogas o medicamentos en los 3 meses anteriores a la visita pretratamiento o alcoholismo actual.
    14. Antecedentes de hipersensibilidad o reacción idiosincrásica a la benzacepina o a sus derivados (como el benazepril).
    15. Polidipsia psicógena (puede incluirse a pacientes con otra enfermedad psiquiátrica, si se cuenta con la aprobación del monitor médico).
    16. Diabetes mellitus no controlada, que se define como glucosa en ayunas > 300 mg/dl (16,7 mEq/l [mmol/l]).
    17. Valores de la función hepática en el momento de la selección > 3 × LSN Se rellenará un formulario de ANI si el paciente es un posible caso de la ley de Hy (cualquier aumento de la AST o ALT >= 2 × LSN o un valor inicial con un aumento de la BT >=2 × LSN o del valor inicial).
    18. Coagulación deficiente (por ej., cirrosis con riesgo de hemorragia GI), incluidos los pacientes que reúnan alguno de los siguientes criterios: hemorragia GI importante en los 6 meses anteriores, indicios de hemorragia activa (por ej., epistaxis, petequias/púrpura, hematuria o hematoquecia), recuento de plaquetas < 50 000/µl o uso concomitante de medicamentos que se sabe que aumentan el riesgo de sangrado.
    19. Hiponatremia causada por cualquier medicamento que puede retirarse con seguridad (p. ej., diuréticos tiazídicos).
    20. Hiponatremia cuyo tratamiento correctivo más apropiado son los tratamientos alternativos (por ej., hiponatremia en el contexto de una insuficiencia suprarrenal, hipotiroidismo no tratado o administración de líquidos hipotónicos).
    21. Embarazo o lactancia en estos momentos.
    22. Problemas médicos que, en opinión del investigador, podrían interferir en la evaluación de los objetivos del estudio o la seguridad de los pacientes.
    23. Inadecuación para la participación en el estudio, según el criterio del investigador.
    24. Participación en un estudio de un medicamento en fase de investigación (distinto de los estudios 156-08-276, 156-13-207 o 156-12-205) en los últimos 30 días, sin previa aprobación del monitor médico.
    25. Se excluirá del estudio a los pacientes menores de 2 años de edad, que pesen menos de 10 kg o que no puedan tragar el comprimido por vía oral, hasta que se disponga de una formulación líquida oral.
    E.5 End points
    E.5.1Primary end point(s)
    Change from baseline in serum sodium while tolvaptan is being administered.
    Cambios en el sodio sérico con respecto a los valores iniciales mientras se administra tolvaptán.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Change from baseline in serum sodium while tolvaptan is being administered by Visit so there will be several primary end-points depending on the number of visits that the subject will have. Hence, the change in serum sodium at each visit will be measured and the mean value will be the primary end point.
    Cambios en el sodio sérico con respecto a los valores iniciales mientras se administra tolvaptán en cada visita, así habrán varios criterios de valoración principal dependiendo del número de visitas que tenga el paciente.
    Por tanto, se medirá el cambio en el sodio sérico en cada visita y el valor medio será el criterio de valoración principal.
    E.5.2Secondary end point(s)
    Optional Tolvaptan Treatment Component:
    1. Percentage of subjects who require rescue therapy while on tolvaptan treatment
    2. Percentage of subjects requiring continuation of tolvaptan following 30 days of treatment
    3. Percentage of subjects with overly rapid correction in serum sodium
    (?12 mmol/L in 24 hours after the first dose at introduction or reintroduction of tolvaptan)
    4. Changes from baseline in ALT, AST and BT.
    Core Safety Follow up Component:
    1. Frequency of AE reports
    2. Change from baseline in QoL assessments
    3. Change from baseline in growth percentiles
    -for body weight
    - body height
    4. Tanner Staging progression score
    - Change from baseline in serum sodium by visit
    Componente de tratamiento opcional con tolvaptán:
    1. Porcentaje de pacientes que precisan tratamiento de rescate mientras reciben tolvaptán.
    2. Porcentaje de pacientes que requieren continuar el tratamiento con tolvaptán después de 30 días de tratamiento.
    3. Porcentaje de pacientes con corrección excesivamente rápido del sodio sérico (>=12 mEq/l [mmol/l] en 24 horas después de la primera dosis en el inicio o reanudación de tolvaptán)
    ­4. Cambios de la ALT, AST y BT con respecto a los valores iniciales.
    Componente principal de seguimiento de la seguridad:
    1. Frecuencia de notificaciones de AA.
    2. Cambios en las evaluaciones de la CdV con respecto al valor inicial.
    3. Cambio con respecto al valor inicial de los percentiles de crecimiento:
    - peso corporal
    - estatura.
    4. Puntuación de la progresión de los estadios de Tanner (a los 6 meses).
    5. Cambios de la concentración sérica de sodio con respecto a los valores iniciales, por visita.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Optional Tolvaptan Treatment Component:
    1. Percentage of subjects who require rescue therapy while on tolvaptan treatment (Evaluation time point: all trial duration)
    2. Percentage of subjects requiring continuation of tolvaptan following 30 days of treatment (Evaluation timepoint after 30 days of treatment minimum)
    3. Percentage of subjects with overly rapid correction in serum sodium (?12 mmol/L in 24 hours after the first dose at introduction or reintroduction of tolvaptan) (Evaluation timepoint: Any visit with this increase)
    4. Changes from baseline in ALT, AST and BT (Evaluation timepoint: Each visit).
    Core Safety Followup Component:
    Evaluation timepoint for most of the secondary endpoints is Any Visit. For more details, please see Appendix 5 of current protocol amendment1.
    Componente de tratamiento opcional con tolvaptán:
    1. Porcentaje de pacientes que precisan tratamiento de rescate mientras reciben tolvaptán (Evaluación de la administración: toda la duración del ensayo).
    2. Porcentaje de pacientes que requieren continuar el tratamiento con tolvaptán después de 30 días de tratamiento (evaluación después de un mínimo de 30 días de tratamiento).
    3. Porcentaje de pacientes con corrección excesivamente rápida del sodio sérico (>=12 mEq/l [mmol/l] en 24 horas después de la primera dosis en el inicio o reanudación de tolvaptán) (Evaluación : cualquier visita con este aumento).
    ­4. Cambios ALT, AST y BT con respecto a los valores iniciales (Evaluación: cada visita).
    Componente principal de seguimiento de la seguridad:
    Ver Apéndice 5 del protocolo enmienda 1.
    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 No
    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 trial1
    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 EEA49
    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
    Completion of at least 6 months follow-up by all subjects and for those participating in the optional treatment cycles will be the last date of contact following the last treatment cycle.
    Para todos los pacientes será completar al menos 6 meses de seguimiento y para aquellos que participan en los ciclos opcionales de tratamiento será el último día de contacto después del último ciclo de tratamiento.
    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 months5
    E.8.9.1In the Member State concerned days21
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months5
    E.8.9.2In all countries concerned by the trial days21
    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: 140
    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: 7
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 63
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 70
    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 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 state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 86
    F.4.2.2In the whole clinical trial 140
    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)
    The optional tolvaptan treatment component of this trial will last until product is available on the marketed to allow subjects to continue being treated.
    El componente de tratamiento opcional con tolvaptán de este ensayo durará hasta que el producto esté disponible en el mercado para permitir que los pacientes sigan siendo tratados.
    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 Decision2015-03-09
    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
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