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    Summary
    EudraCT Number:2014-001516-19
    Sponsor's Protocol Code Number:156-13-211
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2014-10-16
    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 ConcernedItaly - Italian Medicines Agency
    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
    Sperimentazione multicentrica in aperto, di fase 3b, per la valutazione della sicurezza a lungo termine di tolvaptan a rilascio immediato (OPC 41061, da 30 a 120 mg/giorno, in dosi separate) titolato in soggetti affetti da rene policistico autosomico 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.
    Studio per la valutazione della sicurezza a lungo termine di Tolvaptan in adulti affetti da malattia renale cronica.
    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)
    rene policistico autosomico dominante
    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.
    il rene policistico è una malattia ereditaria che causa la formazione di cisti nel rene con conseguente ingrossamento del rene e danno renale.
    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 17.0
    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.
    valutare e descrivere la sicurezza a lungo termine di tolvaptan.
    E.2.2Secondary objectives of the trial
    Not Applicable
    non applicabile
    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.
    • Soggetti di sesso maschile e femminile di età  18 anni con diagnosi confermata di ADPKD (durante la partecipazione a precedenti sperimentazioni su tolvaptan) che
    • provengano da e abbiano completato la sperimentazione in doppio cieco 156-13-210 (periodo di 12 mesi comprendente il follow-up post-trattamento, indipendentemente dal fatto che abbiano ricevuto il trattamento) oppure
    • abbiano completato la sperimentazione 156-08-271 o una precedente sperimentazione per la cura dell'ADPKD a base di tolvaptan oppure
    • abbiano interrotto o sospeso il trattamento in una precedente sperimentazione per la cura dell'ADPKD tramite tolvaptan, diversa dalla sperimentazione 156-13-210. I soggetti potranno essere arruolati previa approvazione di un responsabile del monitoraggio medico, e all'inizio della sperimentazione potrebbe essere richiesto un ulteriore e più rigoroso monitoraggio.
    • Tasso di filtrazione glomerulare stimato (estimated Glomerular Filtration Rate, eGFR)  20 ml/min/1,73 m2 entro 45 giorni dalla visita basale. I soggetti con eGFR tra 15 e 19 ml/min/1,73 m2 potranno essere arruolati previa approvazione di un responsabile del monitoraggio medico.
    • La funzionalità renale verrà valutata durante lo screening sulla base dei precedenti valori degli esami di laboratorio (relativi agli ultimi 30 giorni) con riferimento ai livelli di creatinina sierica per il calcolo dell'eGFR. I valori dell’eGFR saranno calcolati secondo la formula dell’epidemiologia della malattia renale cronica (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.
    • Necessità di impiego cronico di diuretici
    • Insufficienza epatica calcolata sulla base di esami di laboratorio (alanina aminotransferasi [alanine aminotransferase, ALT], aspartato aminotransferasi [aspartate aminotransferase, AST], bilirubina totale [bilirubin total, BT]) con valori discrepanti da quelli previsti per l'ADPKD con malattia epatica cistica.
    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.
    lo studio non avrà endpoint formali. Le variabili di sicurezza saranno riassunte con metodi di statistica descrittiva (ad es. proporzione, media, mediana, deviazione standard, valori minimo e massimo). In generale, il riassunto delle statistiche, incluse le variazioni dal basale, saranno fornite per le variabili di di sicurezza sulla base di tutti i dati disponibili . Gli endpoint di sicurezza saranno i seguenti:
    - eventi avversi
    - segni vitali
    - valutazioni cliniche di laboratorio
    - aumento delle transaminasi seriche per frequenza (2x, 3x, 5x, e 10x ULN), tempo di comparsa, tempo per il raggiungimento del picco, tempo di spostamento (<3x, 2x, o 1x ULN), risposta alla sospensione del farmaco e alla ripresa e frequenza di progressione secondo i criteri di laboratorio di Hy (ALT o AST >3x ULN e bilirubina, totale (BT), >2x ULN senza fosfatasi alcalina ≥2x ULN).
    - variazioni di sodio nel siero al di sopra di 145, 150 o 155 mmol/L o sotto 135, 130 o 125 mmol/L.
    Endpoint di farmacocinetica: concentrazioni plasmatiche del metabolita DM-4103 di tolvaptan, di tolvaptan e altri metaboliti.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Throughout Study up to end of treatment and follow up visit.
    nel corso dello studio fino al termine del trattamento e visita di follow up.
    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
    Endpoint esplorativi:
    - esiti della valutazione della malattia del rene policistico
    - ricorso al pronto soccorso, ricoveri, procedure e terapie) e perdita di giornate produttive a causa della patologia come parte della survey sulla malattia
    (da analizzare e riportare separatamente dal clinical study report)
    - concentrazione del biomarcatore nel plasma e nelle urinenei soggetti con anomalie epatiche
    - DNA potrà essere valutato nei soggetti con anomalie epatiche
    E.5.2.1Timepoint(s) of evaluation of this end point
    Throughout Study up to end of treatment visit.
    nel corso dello studio fino alla visita di fine trattamento.
    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 concerned10
    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.
    la data dell’ultimo contatto o la data dell’ultimo tentativo di contatto estrapolata dalla pagina di CRF relativa al follow up post trattamento per l’ultimo soggetto che ha completato il trattamento o che si è ritirato dallo studio.
    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.1.3.1Number of subjects for this age range: 100
    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 state91
    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
    nessuno
    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 Decision2014-12-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-12-09
    P. End of Trial
    P.End of Trial StatusOngoing
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