Clinical Trials Register

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

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A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2018-000477-77

A.3

Full 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.3.1

Title 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.3.2

Name or abbreviated title of the trial where available

METROPOLIS

A.4.1

Sponsor's protocol code number

AIFA-2016-02365060

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	U.O. NEFROLOGIA, DIALISI E TRAPIANTO AZIENDA OSPEDALIERO UNIVERSITARIA POLICLINICO DI BARI
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	AIFA - Italian Medicines Agency
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Azienda ospedaliero universitaria policlinico di Bari
B.5.2	Functional name of contact point	U.O Nefrologia, Dialisi e Trapianto
B.5.3	Address:
B.5.3.1	Street Address	Piazza G. Cesare, 11
B.5.3.2	Town/ city	Bari
B.5.3.3	Post code	70124
B.5.3.4	Country	Italy
B.5.4	Telephone number	+390805592778
B.5.5	Fax number	+390805592778
B.5.6	E-mail	trialnefrobari@gmail.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	ZUGLIMET - 500 MG COMPRESSE RIVESTITE CON FILM 30 COMPRESSE IN BLISTER PVC/AL
D.2.1.1.2	Name of the Marketing Authorisation holder	ZENTIVA ITALIA S.R.L.
D.2.1.2	Country which granted the Marketing Authorisation	Italy
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	METFORMINA
D.3.2	Product code	[METFORMINA]
D.3.4	Pharmaceutical form	Coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	METFORMINA
D.3.9.1	CAS number	657-24-9
D.3.9.2	Current sponsor code	METFORMINA
D.3.9.3	Other descriptive name	METFORMIN
D.3.9.4	EV Substance Code	SUB08831MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	500 to 1500
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	JINARC - 15 MG - COMPRESSA - USO ORALE - BLISTER (ALU/PVC) - 28 COMPRESSE
D.2.1.1.2	Name of the Marketing Authorisation holder	OTSUKA PHARMACEUTICAL EUROPE LTD
D.2.1.2	Country which granted the Marketing Authorisation	Italy
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	TOLVAPTAN 15
D.3.2	Product code	[TOLVAPTAN 15]
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	TOLVAPTAN
D.3.9.1	CAS number	150683-30-0
D.3.9.2	Current sponsor code	TOLVAPTAN
D.3.9.3	Other descriptive name	TOLVAPTAN
D.3.9.4	EV Substance Code	SUB31691
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	60 to 120
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	JINARC - 30 MG - COMPRESSA - USO ORALE - BLISTER (ALU/PVC) - 28 COMPRESSE
D.2.1.1.2	Name of the Marketing Authorisation holder	OTSUKA PHARMACEUTICAL EUROPE LTD
D.2.1.2	Country which granted the Marketing Authorisation	Italy
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	TOLVAPTAN 30
D.3.2	Product code	[TOLVAPTAN 30]
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	TOLVAPTAN
D.3.9.1	CAS number	150683-30-0
D.3.9.2	Current sponsor code	TOLVAPTAN
D.3.9.3	Other descriptive name	TOLVAPTAN
D.3.9.4	EV Substance Code	SUB31691
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	60 to 120
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 4
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade 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.2.1.1.2	Name of the Marketing Authorisation holder	OTSUKA PHARMACEUTICAL EUROPE LTD
D.2.1.2	Country which granted the Marketing Authorisation	Italy
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	TOLVAPTAN 45/15
D.3.2	Product code	[TOLVAPTAN 45/15]
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	TOLVAPTAN
D.3.9.1	CAS number	150683-30-0
D.3.9.2	Current sponsor code	TOLVAPTAN
D.3.9.3	Other descriptive name	TOLVAPTAN
D.3.9.4	EV Substance Code	SUB13691
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	60 to 120
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 5
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade 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.2.1.1.2	Name of the Marketing Authorisation holder	OTSUKA PHARMACEUTICAL EUROPE LTD
D.2.1.2	Country which granted the Marketing Authorisation	Italy
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	TOLVAPTAN 60/30
D.3.2	Product code	[TOLVAPTAN 60/30]
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	TOLVAPTAN
D.3.9.1	CAS number	150683-30-0
D.3.9.2	Current sponsor code	TOLVAPTAN
D.3.9.3	Other descriptive name	TOLVAPTAN
D.3.9.4	EV Substance Code	SUB31691
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	60 to 120
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 6
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade 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.2.1.1.2	Name of the Marketing Authorisation holder	OTSUKA PHARMACEUTICAL EUROPE LTD
D.2.1.2	Country which granted the Marketing Authorisation	Italy
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	TOLVAPTAN 90/30
D.3.2	Product code	[TOLVAPTAN 90/30]
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	TOLVAPTAN
D.3.9.1	CAS number	150683-30-0
D.3.9.2	Current sponsor code	TOLVAPTAN
D.3.9.3	Other descriptive name	TOLVAPTAN
D.3.9.4	EV Substance Code	SUV31691
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	60 to 120
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another 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.1.1

Medical condition(s) being investigated

Autosomal Dominant Polycystic Kidney Disease

Rene Policistico Autosomico Dominante

E.1.1.1

Medical condition in easily understood language

Hereditary Bilateral Polycystic Kidney

Rene Policistico Bilaterale Ereditario

E.1.1.2

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10036046
E.1.2	Term	Polycystic kidney, autosomal dominant
E.1.2	System Organ Class	100000004850

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main 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.2.2

Secondary 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.2.3

Trial contains a sub-study

E.3

Principal 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.4

Principal 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.5.1

Primary 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.5.1.1

Timepoint(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.5.2

Secondary 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.5.2.1

Timepoint(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.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.7

Trial has a data monitoring committee

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

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

150

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

150

F.4.2

For a multinational trial

F.4.2.1

In the EEA

150

F.4.2.2

In 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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-08-01

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-11-08

P. End of Trial
P.	End of Trial Status	Ongoing

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