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    Summary
    EudraCT Number:2018-000477-77
    Sponsor's Protocol Code Number:AIFA-2016-02365060
    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:2020-11-04
    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 number2018-000477-77
    A.3Full title of the trial
    Metformin versus Tolvaptan in adults with Autosomal Dominant Polycystic Kidney Disease (ADPKD): a phase 3a, independent, multi-centre, 2 parallel arms randomized controlled trial
    Metformin versusTolvaptan in adulti con rene policistico autosomico dominante (ADPKD): studio multicentrico indipendente randomizzato controllato di fase 3a a due bracci paralleli
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Evaluation of Metformin and Tolvaptan in slowing disease progression of Autosomal Dominant Polycystic Kidney Disease (ADPKD)
    Confronto tra Metformina e Tolvaptan nel rallentare la progressione del danno renale nel rene policistico autosomico dominante (ADPKD)
    A.3.2Name or abbreviated title of the trial where available
    METROPOLIS
    METROPOLIS
    A.4.1Sponsor's protocol code numberAIFA-2016-02365060
    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 SponsorU.O. NEFROLOGIA, DIALISI E TRAPIANTO AZIENDA OSPEDALIERO UNIVERSITARIA POLICLINICO DI BARI
    B.1.3.4CountryItaly
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAIFA - Italian Medicines Agency
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAzienda ospedaliero universitaria policlinico di Bari
    B.5.2Functional name of contact pointU.O Nefrologia, Dialisi e Trapianto
    B.5.3 Address:
    B.5.3.1Street AddressPiazza G. Cesare, 11
    B.5.3.2Town/ cityBari
    B.5.3.3Post code70124
    B.5.3.4CountryItaly
    B.5.4Telephone number+390805592778
    B.5.5Fax number+390805592778
    B.5.6E-mailtrialnefrobari@gmail.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 Yes
    D.2.1.1.1Trade name ZUGLIMET - 500 MG COMPRESSE RIVESTITE CON FILM 30 COMPRESSE IN BLISTER PVC/AL
    D.2.1.1.2Name of the Marketing Authorisation holderZENTIVA ITALIA S.R.L.
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 nameMETFORMINA
    D.3.2Product code [METFORMINA]
    D.3.4Pharmaceutical form Coated 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 INNMETFORMINA
    D.3.9.1CAS number 657-24-9
    D.3.9.2Current sponsor codeMETFORMINA
    D.3.9.3Other descriptive nameMETFORMIN
    D.3.9.4EV Substance CodeSUB08831MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number500 to 1500
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 RoleComparator
    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 JINARC - 15 MG - COMPRESSA - USO ORALE - BLISTER (ALU/PVC) - 28 COMPRESSE
    D.2.1.1.2Name of the Marketing Authorisation holderOTSUKA PHARMACEUTICAL EUROPE LTD
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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
    D.3.2Product code [TOLVAPTAN 15]
    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 codeTOLVAPTAN
    D.3.9.3Other descriptive nameTOLVAPTAN
    D.3.9.4EV Substance CodeSUB31691
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number60 to 120
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 RoleComparator
    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 JINARC - 30 MG - COMPRESSA - USO ORALE - BLISTER (ALU/PVC) - 28 COMPRESSE
    D.2.1.1.2Name of the Marketing Authorisation holderOTSUKA PHARMACEUTICAL EUROPE LTD
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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
    D.3.2Product code [TOLVAPTAN 30]
    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 codeTOLVAPTAN
    D.3.9.3Other descriptive nameTOLVAPTAN
    D.3.9.4EV Substance CodeSUB31691
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number60 to 120
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 RoleComparator
    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 JINARC - 15 MG +45 MG - COMPRESSA - USO ORALE - BLISTER(ALU/PVC) IN CONFEZIONE A PORTAFOGLIO - 56 COMPRESSE (28X15 MG + 28 X 45 MG)
    D.2.1.1.2Name of the Marketing Authorisation holderOTSUKA PHARMACEUTICAL EUROPE LTD
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 45/15
    D.3.2Product code [TOLVAPTAN 45/15]
    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 codeTOLVAPTAN
    D.3.9.3Other descriptive nameTOLVAPTAN
    D.3.9.4EV Substance CodeSUB13691
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number60 to 120
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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: 5
    D.1.2 and D.1.3IMP RoleComparator
    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 JINARC - 30 MG + 60 MG - COMPRESSA - USO ORALE - BLISTER(ALU/PVC) IN CONFEZIONE A PORTAFOGLIO - 56 COMPRESSE (28 X 30 MG + 28 X 60 MG)
    D.2.1.1.2Name of the Marketing Authorisation holderOTSUKA PHARMACEUTICAL EUROPE LTD
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 60/30
    D.3.2Product code [TOLVAPTAN 60/30]
    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 codeTOLVAPTAN
    D.3.9.3Other descriptive nameTOLVAPTAN
    D.3.9.4EV Substance CodeSUB31691
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number60 to 120
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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: 6
    D.1.2 and D.1.3IMP RoleComparator
    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 JINARC - 30 MG +90 MG - COMPRESSA - USO ORALE - BLISTER(ALU/PVC) IN CONFEZIONE A PORTAFOGLIO - 56 COMPRESSE (28 X 30 MG + 28 X 90 MG)
    D.2.1.1.2Name of the Marketing Authorisation holderOTSUKA PHARMACEUTICAL EUROPE LTD
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 90/30
    D.3.2Product code [TOLVAPTAN 90/30]
    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 codeTOLVAPTAN
    D.3.9.3Other descriptive nameTOLVAPTAN
    D.3.9.4EV Substance CodeSUV31691
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number60 to 120
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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
    Rene Policistico Autosomico Dominante
    E.1.1.1Medical condition in easily understood language
    Hereditary Bilateral Polycystic Kidney
    Rene Policistico Bilaterale Ereditario
    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 20.0
    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
    Primary objective of the study is to define if a two years course of 1500 mg a day of metformin is equivalent or not inferior to tolvaptan in reducing eGFR decline in patients affected by ADPKD.
    Obiettivo primario dello studio è definire se un trattamento con Metformina (alla dose di 1500 mg) della durata di due anni sia equivalente o non inferiore al Tolvaptan nel ridurre il declino dell’eGFR in pazienti affetti da ADPKD.
    E.2.2Secondary objectives of the trial
    Secondary objectives are to define if Metformin tratment for ADPKD is safe and effective in reducing kidney volume enlargement and in reducing symptoms related to this pathology.
    Obiettivo secondario è quello di definire se il trattamento con Metformina dell’ADPKD sia sicuro ed efficace nel ridurre l’aumento volumetrico dei reni (valutato mediante TC renale senza mezzo di contrasto) e nel ridurre i sintomi correlati a questa patologia.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) Men and women aged between 18 and 50 years
    2) eGFR (CKD-epi) = 45 ml/min/1,73 m2
    3) Genetic Diagnosis of Type I ADPKD truncating mutation
    4) Signed and dated informed consent
    1)Uomini e donne d’eta compresa tra 18 e 50 anni,
    2)eGFR (CKD-epi) = 45 ml/min/1,73 m2,
    3)Diagnosi genetica di ADPKD causato da mutazione troncante di PKD1,
    4)Consenso informato scritto, datato e firmato.
    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 implant, condom, or sponge with spermicide. Non-childbearing potential in women is defined as female subjects who are surgically sterile (ie, have undergone bilateral oophorectomy or hysterectomy) or female subjects who have been postmenopausal for at least 12 consecutive months.
    2) Women who are breast-feeding and/or who have a positive pregnancy test result prior to receiving investigational medical product (IMP).
    3) Treatment with acarbose, guar gum, cimetidin, phenprocoumon, oral anticoagulants, thrombolytic drugs, diuretics, ranolazin, cephalexin.
    4) Evidence of active systemic or localized major infection at the time of screening.
    5) Hepatic impairment or liver function abnormalities other than that expected for ADPKD with typical cystic liver disease during the screening period as defined by:
    o AST O ALT >8x UNL
    o AST O ALT >5x UNL >2 WEEKS
    o AST O ALT >3x UNL E BT >2x UNL OR INR >1,5
    o AST O ALT >3x UNL E SIGNS AND SYMPTOMS OF LIVER DAMAGE (fatigue, anorexy, nausea, vomiting, right hypocondrium pain, fever, jaundice, skin rash, itching)
    6) Acute or chronic disease causing tissue hypoxia (e.g.: myocardial failure, severe arythmias, myocardial infarction, respiratory failure, liver failure, alcohol acute intoxication, alcoholism, dehydration).
    7) Previously diagnosed diabetes already in treatment with other hypoglycemic drugs.
    8) Ongoing breast feeding.
    9) Use of any other investigational drug or treatment up to 4 weeks before enrollment and during the treatment phase.
    10) Known hypersensitivity to metformin and its derivatives.
    11) Psychiatric disorders and any condition that might prevent full comprehension of the purposes and risks of the study.
    12) Malignancies within three years before enrolment in the study.
    13) HIV, HBV, HCV infection.
    14) Urinary tract obstruction.
    1) Donne in età fertile che non accettino di praticare due metodi contraccettivi o di rimanere astinenti dall'attività sessuale per la durata del trial e fino a 30 giorni dopo l'ultima dose di IMP. Se adottati metodi di controllo delle nascite, devono essere adottate due delle seguenti precauzioni: vasectomia del partner, legatura delle tube,diaframma vaginale, spirale endo-uterina, preservativo, spugna con spermicida. Si definisce non fertile una donna con sterilità chirurgica (ovariectomia bilaterale o isterectomia) o in menopausa da almeno 12 mesi consecutivi.
    2) Donne in allattamento o co test di gravidanza positivo prima di iniziare IMP.
    3) Terapia con acarbosio, gomma di guar, cimetidina, fenprocumone, anticoagulanti orali, farmaci trombolitici, diuretici, ranolazina, cefalessina.
    4) Evidenza, al momento dello screening, di infezioni attive sistemiche o localizzate maggiori
    5) Insufficienza epatica o anomalie degli indici di funzione epatica diversi da quelli attesi per ADPKD con tipche cisti epatiche durante il priodo di screening, come definito da:
    o AST O ALT >8x UNL
    o AST O ALT >5x UNL >2 settimane
    o AST O ALT >3x UNL E BT >2x UNL o INR >1,5
    o AST O ALT >3x UNL e segni e sintomi di danno epatico (affaticabilità, anoressia, nausea, vomito, dolore in ipocondrio destro, febbre, rash cutaneo, prurito)
    6) Malattie acute o croniche determinanti ipossia tissutale(infarto miocardico, insufficienza cardiaca, aritmie severe, insufficienza respiratoria, insufficienza epatica, intossicazione acuta da alcool, disidratazione)
    7) Diagnosi precedente di diabete, già in trattamento con altri ipoglicemizzanti.
    8) Allattamento in corso.
    9) Impiego di altri IMP nelle 4 settimane precedenti l'arruolamento o durante il periodo di trattamento.
    10) Ipersensibilità nota alla metformina ed ai suoi derivati.
    11) Malattie psichiatriche e qualsiasi altra condizione che possa impedire di comprendere pienamente gli scopi e i rischi dello studio
    12) Neoplasie maligne nei tre anni precedenti l'arruolamento
    13) Infezione da HIV, HBV, HCV
    14) Ostruzioni del tratto urinario
    E.5 End points
    E.5.1Primary end point(s)
    Primary outcome of the study is to evaluate the treatments difference (between Metformin and Tolvaptan) in annualized slope of eGFR (CKD-epi) for individual subjects will be calculated using an appropriate baseline and post-randomization assessment.
    L’endpoint primario dello studio è la differenza tra i due gruppi di trattamento nello slope annualizzato dell’eGFR stimato con equazione CKD-Epi, calcolato usando un valore basale e dopo il termine del trattamento.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Throughout study up to the Follow up period (3 week post treatment end).
    Attraverso tutto lo studio fino al termine del periodo di follow-up (3 settimane dopo la fine dei 24 mesi di trattamento)
    E.5.2Secondary end point(s)
    The key secondary endpoint is the percent change from baseline in htTKV as measured by CT-scan at 12 and 24 months.
    L’endpoint secondario più importante è la percentuale di variazione rispetto al basale del TKV normalizzato per altezza (htTKV), misurato mediante TAC renale eseguita al basale e dopo 24 mesi di terapia.
    E.5.2.1Timepoint(s) of evaluation of this end point
    At the end of the treatment period
    Alla fine dei 24 mesi di 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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    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 Yes
    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 Yes
    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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned 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 concerned11
    E.8.5The trial involves multiple Member States No
    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 Information not present in EudraCT
    E.8.7Trial has a data monitoring committee No
    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
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 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: 150
    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 No
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state150
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 150
    F.4.2.2In the whole clinical trial 150
    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)
    3 weeks follow up at the end of the study
    FOLLOW UP DI 3 SETTIMANE AL TERMINE DEL TRATTAMENTO
    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 Decision2018-08-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-11-08
    P. End of Trial
    P.End of Trial StatusOngoing
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