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    Summary
    EudraCT Number:2014-001516-19
    Sponsor's Protocol Code Number:156-13-211
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-09-11
    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 number2014-001516-19
    A.3Full title of the trial
    A Phase 3b, Multi-center, Open-label Trial to Evaluate the Long Term Safety of Titrated Immediate-release Tolvaptan (OPC 41061, 30 mg to 120 mg/day, Split dose) in Subjects with Autosomal Dominant Polycystic Kidney Disease
    Ensayo de fase IIIb, multicéntrico y abierto para evaluar la seguridad a largo plazo de tolvaptán de liberación inmediata (OPC-41061, de 30 mg a 120 mg/día, dosis dividida) en sujetos con poliquistosis renal autosómica dominante
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    This is a study to evaluate the long term safety of Tolvaptan in
    adults with chronic kidney disease.
    Estudio para evaluar la seguridad a largo plazo de tolvaptán en sujetos con poliquistosis renal autosómica dominante
    A.4.1Sponsor's protocol code number156-13-211
    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,
    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,
    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 pointOlga Sergeyeva, MD, MPH
    B.5.3 Address:
    B.5.3.1Street Address2440 Research Boulevard
    B.5.3.2Town/ cityRockville,
    B.5.3.3Post codeMaryland 20850
    B.5.3.4CountryUnited States
    B.5.4Telephone number16092496643
    B.5.5Fax number16092490643
    B.5.6E-mailolga.sergeyeva@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 Yes
    D.2.5.1Orphan drug designation numberEU/3/13/1175
    D.3 Description of the IMP
    D.3.1Product nameTolvaptan 15mg
    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.3.9.2Current 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: 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 Yes
    D.2.5.1Orphan drug designation numberEU/3/13/1175
    D.3 Description of the IMP
    D.3.1Product nameTolvaptan 30mg
    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.3.9.2Current 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
    Autosomal Dominant Polycystic Kidney Disease (ADPKD)
    Poliquistosis renal autosómica dominante (PQRAD)
    E.1.1.1Medical condition in easily understood language
    ADPKD is an inherited condition (passed from ones parents) that causes
    cysts (fluid filled sacs) to develop on the kidneys. It causes the kidneys
    to get bigger over time and for the kidneys to fail.
    PQRAD es una afección hereditaria que produce la destrucción progresiva de la estructura normal del riñón y da lugar a una enfermedad renal terminal (ERT).
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level LLT
    E.1.2Classification code 10036046
    E.1.2Term Polycystic kidney, autosomal dominant
    E.1.2System Organ Class 100000004850
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate and describe the long-term safety of tolvaptan.
    Evaluar y describir la seguridad a largo plazo de tolvaptán
    E.2.2Secondary objectives of the trial
    Not Applicable
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male and female subjects aged > 18 years with confirmed diagnosis of ADPKD (during participation in prior tolvaptan trials) who have

    - Completed and transferred from the double-blind Trial 156-13-210 (12-month period including post-treatment follow-up, regardless of whether this was on-treatment or off-treatment), or

    - Completed Trial 156-08-271 or a prior tolvaptan trial, or

    - Interrupted or discontinued treatment in a tolvaptan trial other than Trial 156-13-210. Subjects may be enrolled with the medical monitor approval, and additional close monitoring may be required at the beginning of the trial

    - Renal function will be assessed during screening by using historical laboratory values (in the last 30 days) for serum creatinine levels to calculate the estimated glomerular filtration rate (eGFR). The eGFR values will be estimated based on the Chronic Kidney Disease - Epidemiology (CKD-EPI) formula.

    2. Estimated glomerular filtration rate > 20 mL/min/1.73 m2 (calculated using the CKD-EPI formula) within 45 days prior to the baseline visit. Subjects who have an eGFR between 15 and 19 mL/min/1.73 m2 may be permitted with documented medical monitor approval prior to enrollment.
    ? Sujetos de ambos sexos mayores de 18 años con diagnóstico confirmado de PQRAD (durante su participación en ensayos previos con tolvaptán) que
    ? han completado y han sido transferidos del ensayo doble ciego 156-13-210 (período de 12 meses, incluido el seguimiento posterior al tratamiento, con independencia de si fue en tratamiento o fuera del mismo), o
    ? hayan completado el ensayo 156-08-271 o un ensayo previo de PQRAD con tolvaptán, o
    ? hayan interrumpido o suspendido su participación en un ensayo previo de PQRAD con tolvaptán (distinto del ensayo 156-13-210). Se puede inscribir a los sujetos con la aprobación del supervisor médico y es posible que sea necesaria una atenta supervisión adicional al comienzo del ensayo.
    ? Filtración glomerular estimada (FGe) ?20 ml/min/1,73 m2 en el plazo de 3 meses desde la visita inicial. Los sujetos que tengan una FGe ?20 ml/min/1,73 m2 pueden inscribirse con la aprobación del supervisor médico y del promotor, y un aumento de la frecuencia de supervisión para garantizar la seguridad de los sujetos.
    ? La función renal se evaluará durante la selección mediante el uso de valores analíticos históricos (dentro de los 3 meses previos a la visita de selección) para los niveles séricos de creatinina con el fin de calcular la FGe. Los valores de la FGe se calcularán mediante la fórmula Enfermedad Renal Crónica-Epidemiología (Chronic Kidney Disease-Epidemiology, CKD-EPI)
    E.4Principal exclusion criteria
    1. Women of childbearing potential (WOCBP) who do not agree to practice 2 different methods of birth control or remain abstinent during the trial and for 30 days after the last dose of IMP. If employing birth control, 2 of the following precautions must be used: vasectomy of partner, tubal ligation, vaginal diaphragm, intrauterine device, birth control.

    2. Women who are breast-feeding and/or who have a positive pregnancy test result prior to receiving IMP.

    3. Need for chronic diuretic use.

    4. Hepatic impairment based on liver function abnormalities other than that expected for ADPKD with cystic liver disease during screening.

    5. Subjects with contraindications to required trial assessments (contraindications to optional assessments, eg, MRI are not a limitation).

    6. Subjects who, in the opinion of the investigator or medical monitor, have a medical history or medical finding inconsistent with safety or trial compliance. This includes prior evidence of significant hepatic injury deemed to be related to tolvaptan use.
    1. MEF que no acepten utilizar 2 métodos anticonceptivos diferentes o no mantener relaciones sexuales durante el ensayo y los 30 días posteriores a la última dosis del PEI. Si emplean un método anticonceptivo, deben utilizarse 2 de las siguientes precauciones: vasectomía del compañero, ligadura de las trompas, diafragma vaginal, dispositivo intrauterino, píldora anticonceptiva, implante anticonceptivo, inyección anticonceptiva depot, preservativo o esponja con espermicida.
    2.Mujeres en período de lactancia y/o con resultado positivo en una prueba de embarazo antes de recibir el PEI.
    3. Necesidad de uso crónico de diuréticos.
    4. Alteración hepática basada en anomalías de la función hepática diferentes a la esperada por una PQRAD, con típica enfermedad hepática quística, durante la selección basada en valores analíticos históricos recientes (en los 3 últimos meses).
    5. Los sujetos con contraindicaciones para las evaluaciones obligatorias para el ensayo (las contraindicaciones para las evaluaciones opcionales, p. ej., una RM, no son una limitación).
    6. Sujetos que, en opinión del investigador o del supervisor médico, tienen antecedentes médicos o hallazgos médicos contradictorios de seguridad o del cumplimiento del ensayo. Esto incluye evidencia previa de lesión hepática significativa que se considere relacionada con el uso de tolvaptán
    E.5 End points
    E.5.1Primary end point(s)
    This trial will have no formal endpoints. Safety variables will be summarized by
    descriptive statistics, (eg, proportion, mean, median, standard deviation [SD], minimum,
    and maximum values). In general, summary statistics, including changes from baseline,
    will be provided for safety variables based on all available data. Safety endpoints will be
    as follows:

    - Adverse events

    - Vital signs

    - Clinical laboratory assessments

    - Serum transaminase elevations for frequency (2x, 3x, 5x and 10x ULN), time to onset, time to peak levels, time of offset (< 3x, 2x, or 1x ULN), response to de-challenge and re-challenge and frequency of progression to Hy?s laboratory criteria (ALT or AST > 3x ULN and bilirubin, total (BT), > 2x ULN without alkaline phosphatase ? 2x ULN)

    - Serum sodium excursions above 145, 150, or 155 mmol/L or below 135, 130, or 125 mmol/L


    Pharmacokinetic Endpoints
    Tolvaptan metabolite DM-4103, tolvaptan, and other tolvaptan metabolite plasma concentrations.
    Las variables de la seguridad se resumirán mediante estadísticas descriptivas, (p. ej., proporción, media, mediana, desviación estándar [DE], valores mínimo y máximo). En general, las estadísticas de resumen, incluidos los cambios con respecto al inicio, se proporcionarán para variables de la seguridad basándose en todos los datos disponibles. Los criterios de valoración de la seguridad serán los siguientes:
    ? Acontecimientos adversos
    ? Constantes vitales
    ? Evaluaciones de laboratorio clínico
    ? Elevaciones de las transaminasas séricas por frecuencia (2x, 3x, 5x y 10x LSN), tiempo hasta el inicio, tiempo hasta niveles máximos, tiempo hasta la desaparición (<3x, 2x o 1x LSN), respuesta a la retirada y la reintroducción y frecuencia de progresión hasta los criterios analíticos de Hy (ALT o AST >3x LSN y BT >2x LSN sin fosfatasa alcalina ?2x LSN)
    ? Desviaciones del sodio sérico por encima de 145, 150 o 155 mmol/l o por debajo de 135, 130 o 125 mmol/l
    E.5.1.1Timepoint(s) of evaluation of this end point
    Throughout Study up to end of treatment and follow up visit.
    A lo largo del tratamiento hasta el final del tratamiento y la visita de seguimiento.
    E.5.2Secondary end point(s)
    Exploratory Endpoints

    - Polycystic kidney disease (PKD) outcomes survey

    - Medical resource utilization (office/emergency room healthcare visits, hospital admissions, procedures and therapies) and productive days lost due to PKD outcomes will be reported for subjects as part of the ADPKD outcomes survey

    (To be analyzed and reported separately from the clinical study report).

    - Urine and plasma biomarker concentrations in subjects with liver abnormalities

    - DNA (with separate consent) may be assessed in subjects with liver abnormalities
    ? Encuesta de resultados de la poliquistosis renal (PQR).
    ? La utilización de recursos médicos (visitas a la clínica/urgencias, ingresos hospitalarios, procedimientos y tratamientos) y la pérdida de días laborables por PQR de los sujetos se registrarán en el informe de resultados de PQRAD.
    Seguridad: Estos análisis pueden llevarse a cabo y registrarse de forma independiente del informe del estudio clínico.
    ? Concentraciones de biomarcadores en orina y plasma en sujetos con alteraciones hepáticas.
    ? Se puede evaluar el ADN (con un consentimiento separado) en sujetos con alteraciones hepáticas.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Throughout Study up to end of treatment visit.
    A lo largo del estudio y hasta la visita de final del 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 No
    E.6.4Safety Yes
    E.6.5Efficacy No
    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 No
    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 No
    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.8.3 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.8.4.1Number of sites anticipated in Member State concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA81
    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
    Argentina
    Australia
    Belgium
    Brazil
    Canada
    Chile
    Colombia
    Czech Republic
    Denmark
    France
    Germany
    Hungary
    Israel
    Italy
    Mexico
    Netherlands
    Norway
    Peru
    Poland
    Romania
    Russian Federation
    South Africa
    Spain
    Sweden
    Switzerland
    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.
    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 months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months6
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    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) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 2400
    F.1.3Elderly (>=65 years) No
    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 Yes
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state35
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 688
    F.4.2.2In the whole clinical trial 2500
    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)
    None
    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 Decision2015-10-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-10-14
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-11-09
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