Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   38164   clinical trials with a EudraCT protocol, of which   6269   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Print Download

    Summary
    EudraCT Number:2014-001582-27
    Sponsor's Protocol Code Number:156-13-207
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2015-09-09
    Trial 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 number2014-001582-27
    A.3Full title of the trial
    A Pilot Phase 3b, Multicenter, Randomized, Double-blind, Placebo-controlled Trial of the Safety, Efficacy, and Pharmacokinetics of Titrated Oral SAMSCA® (Tolvaptan) in Children and Adolescent Subjects With Euvolemic or Hypervolemic Hyponatremia
    Studio pilota di fase 3b, multicentrico, randomizzato, in doppio cieco, controllato da placebo sulla sicurezza, l'efficacia e la farmacocinetica di SAMSCA® (Tolvaptan) orale titolato in bambini e adolescenti con iponatriemia euvolemica o ipervolemica
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Pilot Phase 3b, Multicenter Trial of the Safety, Efficacy, and Pharmacokinetics of Tolvaptan in Children and Adolescent Subjects With low concentration of sodium in the blood
    Studio pilota di fase 3b, multicentrico per la sicurezza, l'efficacia, e
    farmacocinetica di Tolvaptan in bambini e adolescenti con bassa concentrazione di sodio nel sangue
    A.4.1Sponsor's protocol code number156-13-207
    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+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 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 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
    D.3.9.4EV Substance CodeSUB22755
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    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
    ponatriemia euvolemica o ipervolemica
    E.1.1.1Medical condition in easily understood language
    Low amount of sodium or salt in the blood
    Bassa quantità di sodio o sale nel sangue
    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
    The primary objective is to evaluate that tolvaptan effectively maintains an increased level of serum sodium in children and adolescent subjects with euvolemic or hypervolemic hyponatremia.
    valutare che tolvaptan mantenga con efficacia un maggiore livello di sodio sierico in bambini e adolescenti con iponatriemia euvolemica o ipervolemica.
    E.2.2Secondary objectives of the trial
    The main secondary objective is to evaluate safety of tolvaptan in children and adolescent subjects with euvolemic or hypervolemic hyponatremia.
    valutare la sicurezza di tolvaptan in bambini e adolescenti con iponatriemia euvolemica o ipervolemica
    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) 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 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 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 IMP.
    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 protocol- required 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 fully abstinent (periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] or withdrawal are not acceptable methods of contraception) or practice double-barrier birth control during the trial and for 30 days following the last dose of IMP for sexually active females of childbearing potential.




    1. Soggetti di sesso maschile o femminile di età compresa tra > 4 settimane (o età
    gestazionale adeguata > 44 settimane) e < 18 anni
    2. Soggetti ricoverati con iponatriemia euvolemica o ipervolemica resistenti alla terapia
    iniziale standard di background (compresa restrizione dei liquidi ed escluso un
    antagonista della vasopressina) e che lo sperimentatore ritiene abbiano probabilità di
    trarre beneficio da una terapia che alzi i livelli di sodio sierico
    3. Iponatriemia euvolemica o ipervolemica persistente definita come presente e
    documentata per almeno 48 ore, dimostrata da almeno 2 valutazioni del sodio sierico
    < 130 mmol/l ottenuti a una distanza di almeno 12 ore (questi valori possono essere documentati utilizzando valori storici ottenuti precedentemente secondo lo standard di cura); una terza (STAT) valutazione del sodio sierico < 130 mmol/l, che servirà da valore basale per gli endpoint di efficacia, deve essere ottenuta nelle 2-4 ore che precedono la prima dose dell'IMP
    4. Possibilità di assumere farmaci per via orale.
    5. Capacità di mantenere un adeguato apporto di liquidi sia per via orale o via IV supportato con un adeguato monitoraggio.
    6. Capacità di rispettare tutti i requisiti dello studio.
    7. Specifico consenso informato scritto / assenso ottenuto da un genitore / tutore o rappresentante legalmente riconosciuto, applicabile in base all’ età del soggetto o alle normative locali prima dell'inizio di qualsiasi porcedura richiesta dal protocollo Inoltre, il soggetto come richiesto dalle leggi locali deve fornire consenso informato allo screening e deve essere in grado di capire che lui o lei può ritirarsi dalla sperimentazione in qualsiasi momento. Tutte le procedure del consenso informato / assenso devono essere in accordo con il Comitato Etico del centro e requisiti normativi locali.
    8. Possibilità di impegnarsi a rimanere completamente astinenti (astinenza periodica [ad esempio, calendario, ovulazione, metodi sintotermico, posta-ovulazione] o
    interruzione non sono metodi accettabili di contraccezione) o utilizzo contraccettivi a doppia barriera durante lo studio e per 30 giorni successivi all’ ultima dose del pordotto per le femmine sessualmente attive.
    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 level < 120 mmol/L, with or without associated neurologic impairment (ie, symptoms such as apathy, confusion, or seizures).
    3. Subjects ≤ 50 kg taking potent CYP3A4 inhibitors or subjects < 20 kg taking moderate CYP3A4 inhibitors within 72 hours prior to dosing.
    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 from recent medical history (within the last 30 days) 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 medications 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 mmol/L).
    17. Has screening liver function values (ALT/AST) > 3 × ULN.
    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 < 4 years of age, weight < 10 kg, or who cannot swallow an oral tablet are excluded until an alternate formulation becomes available.














    1.Evidenza di ipovolemia o deplezione del volume intravascolare (ad es. ipotensione, evidenza clinica di deplezione del volume, risposta a test salino); se il soggetto ha pressione arteriosa sistolica o frequenza cardiaca al di fuori dell'intervallo normale per l'età, lo stato del volume dovrebbe essere specificamente valutato a livello clinico per escludere deplezioni del volume
    2.Livello di sodio sierico < 120 mmol/l, con o senza disabilità neurologica associata (ovvero sintomi quali apatia, confusione o crisi convulsive)
    3.Uso di potenti inibitori del citocromo P450 (CYP) 3A4 in soggetti < 50 kg o inibitori moderati di CYP3A4 in soggetti < 20 kg
    4.Mancanza libero accesso all'acqua (incapacità di rispondere alla sete) o senza
    ICU-livello di monitoraggio e gestione dei fluidi.
    5.Storia o una diagnosi attuale della sindrome nefrosica.
    6.Iponatriemia transitorio presumibilmente risoluzione (ad esempio, trauma cranico o stato postoperatorio).
    7.ipercaliemia definita come livelli sierici di potassio sopra l'ULN per la fascia di età pediatrica appropriata
    8.Velocità di filtrazione glomerulare stimata (eGFR) < 30 ml/min/1,73 m calcolata eGFR (ml / min / 1,73 m2) = altezza 0,413 X (cm) / creatinina sierica (mg / dl
    9.Recente Insufficienza renale acuta (negli ultimi 30 giorni) definita come:
    Aumento della creatinina sierica di > 0,3 mg/dl (> 26,5 umol/l) entro 48 ore; oppure
    Aumento della creatinina sierica fino a > 1,5 volte il basale, che si sa o si presume si
    sia verificato entro i precedenti 7 giorni; oppure
    Volume di urina < 0,5 ml/kg/h per 6 ore
    10.Sintomi neurologici gravi o acute che richiedono altri interventi (ad esempio,
    iperemesi, ottundimento, convulsioni)
    11.Ha ricevuto trattamento per iponatriemia con:
    Soluzione salina ipertonica (incluso test salino normale) entro 8 ore dalle valutazioni di
    qualificazione del sodio sierico
    Urea, litio, demeclociclina, conivaptan o tolvaptan entro 4 giorni dalle valutazioni di
    qualificazione del sodio sierico
    Altro trattamento allo scopo di aumentare il sodio sierico concomitante con il dosaggio
    del farmaco in studio
    12. Anuria o ostruzione del flusso urinario, a meno che il soggetto è, o può essere, cateterizzato durante il processo.
    13.Sstoria di droga o abuso di farmaci nei 3 mesi precedenti lo screening o abuso di alcol corrente.
    14. Storia di ipersensibilità e / o reazione idiosincratica a benzazepina o derivati benzazepina (quali benazepril).
    15. Polidipsia psicogena (soggetti con altre malattie psichiatriche possono essere inclusi con l'approvazione del Medical Monitor).
    16.Diabete mellito non controllato definito come glicemia a digiuno > 300 mg/dl
    (16,7 mmol/l)
    17.Valori di funzionalità epatica allo screening (ALT/AST) > 3 x ULN
    18.Coagulazione insufficiente (ad es. cirrosi con sanguinamento gastrointestinale [GI]), ivi inclusi soggetti rientranti nei seguenti criteri: sanguinamento GI importante negli ultimi 6 mesi, evidenza di emorragia attiva (ad es. epistassi, petecchie/porpora, ematuria o ematochezia), conta delle piastrine < 50.000/ul o uso di farmaci concomitanti noti per aumentare il rischio di sanguinamento
    19. Iponatremia dovuto al risultato di qualsiasi farmaco che può tranquillamente essere
    sospeso (per esempio, diuretici tiazidici).
    20. Iponatriemia (ad esempio, iponatriemia in un quadro di insufficienza surrenalica,
    ipotiroidismo non trattato, o somministrazione di liquidi ipotonici) che è più
    opportunamente corretto con terapie alternative.
    21. Attualmente in stato di gravidanza o allattamento.
    22. Qualsiasi condizione medica che, a giudizio dello sperimentatore, potrebbe
    interferire con la valutazione degli obiettivi dello studio o con la sicurezza dei soggetti.
    23. Considerato inadatto per la partecipazione alla sperimentazione a giudizio dello
    Sperimentatore
    24. Partecipazione a un altro studio sperimentale negli ultimi 30 giorni, senza previa
    approvazione del Medical Monitor dello Sponsor.
    25. Soggetti <4 anni di età, peso <10 kg, o che non riescono a ingoiare una compressa
    orale sono esclusi fino a quando una formulazione alternativa sarà disponibile.
    E.5 End points
    E.5.1Primary end point(s)
    Primary Efficacy Outcome Variable:
    The primary efficacy outcome is the average daily area under the curve (AUC) of change from baseline in serum sodium level up to Day 4 within the double-blind treatment period.
    Variabili di esito primarie: La variabile primaria è larea giornaliera media sotto la curva (AUC) del cambiamento dal basale nel livello di sodio sierico fino al Giorno 4 entro il periodo di trattamento in doppio cieco
    E.5.1.1Timepoint(s) of evaluation of this end point
    At Day 4 within the double-blind treatment period.
    al Giorno 4 entro il periodo di trattamento in doppio cieco
    E.5.2Secondary end point(s)
    Efficacy Outcome Variables:
    • Average daily AUC of changes from baseline at each visit in serum sodium level up to Day 30 within the double-blind treatment period.
    • Change from baseline in serum sodium concentration at Day 4
    • Change from baseline in serum sodium concentration at Day 30
    • Percentage of subjects who require rescue therapy or fluid restriction at any time during the double-blind treatment period
    Safety Outcome Variables:
    • Liver function test changes from baseline
    • Clinically significant changes in vital signs
    • Incidence of dehydration AEs
    • Change in Tanner stage from baseline to Day 30
    • Percentage of subjects with overly rapid correction in serum sodium (≥12 mmol/L in 24 hours)
    Efficacia:
    •La variabile di esito secondaria principale è l'AUC giornaliera media dei cambiamenti
    dal basale a ogni visita nel livello di sodio sierico fino al Giorno 30 entro il periodo di
    trattamento in doppio cieco
    •Cambiamento dal basale nella concentrazione del sodio sierico al Giorno 4
    •Cambiamento dal basale nella concentrazione del sodio sierico al Giorno 30
    •Percentuale di soggetti che richiedono terapia di soccorso o restrizione dei liquidi in
    qualsiasi momento durante il periodo di trattamento in doppio cieco
    Sicurezza:
    •Cambiamenti dal basale nei test di funzionalità epatica
    •Alterazioni clinicamente significative dei segni vitali
    •Incidenza degli EA di disidratazione
    •Cambiamento nello stadio di Tanner dal basale al Giorno 30
    •Percentuale di soggetti con correzione eccessivamente rapida del sodio sierico (> 12 mmol/l in 24 ore)
    E.5.2.1Timepoint(s) of evaluation of this end point
    For Efficacy Outcome Variables:
    - At the end of each visit up to Day 30 within the double-blind treatment period
    - At the end of Day 4
    - At the end of Day 30
    - At any time during the double-blind treatment period
    For Safety Outcome Variables:
    - Up to Day 30
    Per variabili di efficacia:
    - Alla fine di ogni visita fino al giorno 30, nel periodo di trattamento in doppio cieco
    - Alla fine del Giorno 4
    - Alla fine del Giorno 30
    - In qualsiasi momento durante il periodo di trattamento in doppio cieco
    Per le variabili di di sicurezza:
    - Fino a 30 giorni
    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 Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Studio Pilota
    A Pilot Trial
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo Yes
    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 EEA8
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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 fine della studio viene definita come l'ultima data di contatto o la data dell’ ultimo tentaivo di contatto nel Follow-up post-trattamento per l’ ultimo soggetto che ha completato o interrotto la sperimentazione
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days23
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months9
    E.8.9.2In all countries concerned by the trial days23
    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: 8
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 4
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 4
    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 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 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.
    Bambini adolescenti non in grado di dare il loro consenso personalmente, legato solamente alla loro età
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state3
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 8
    F.4.2.2In the whole clinical trial 0
    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.
    Ai soggetti sarà proposto di partecipare allo studio roll-over 156-11-294 per 6
    mesi di follow-up sulla sicurezza. si determina che vi è la necessità di ulteriore
    trattamento c'è un trattamento tolvaptan opzionale
    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 Decision2015-12-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-02-03
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    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
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2020 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA