Clinical Trials Register

Summary
EudraCT Number:	2005-000899-40
Sponsor's Protocol Code Number:	Guid/05/Met-GDM/001
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2006-08-03
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2005-000899-40

A.3

Full title of the trial

ASSESSMENT OF EFFECTS OF A 12-MONTH TREATMENT WITH METFORMIN ON INSULIN ACTION AND SECRETION IN WOMEN WITH PRIOR GESTATIONAL DIABETES MELLITUS (GDM)

A.4.1

Sponsor's protocol code number

Guid/05/Met-GDM/001

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	GUIDOTTI
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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	METFORAL*50CPR RIV 500MG
D.2.1.1.2	Name of the Marketing Authorisation holder	LAB.GUIDOTTI SpA *
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.3.4	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	Metformin
D.3.9.1	CAS number	1115-70-4
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.3	Concentration number	500
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	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
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	Yes
D.3.11.13.1	Other medicinal product type	Non Applicabile
D.IMP: 2
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	METFORAL*30CPR RIV 850MG
D.2.1.1.2	Name of the Marketing Authorisation holder	LAB.GUIDOTTI SpA *
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.3.4	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	Metformin
D.3.9.1	CAS number	1115-70-4
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.3	Concentration number	850
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	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
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	Yes
D.3.11.13.1	Other medicinal product type	Non Applicabile

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

previous gestational diabetes (GDM) and altered glucose metabolism in the post-partum period (Impaired Fasting Glucose or Impaired Gluocse Tolerance)

pregresso diabete gestazionale (GDM) e alterazione del metabolismo glucidico nel post-partum (alterata glicemia a digiuno e/o ridotta tolleranza glucidica).

E.1.1.2

Therapeutic area

Diseases [C] - Hormonal diseases [C19]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	PT
E.1.2	Classification code	10018429
E.1.2	Term	Glucose tolerance impaired
E.1.2	System Organ Class	10027433 - Metabolism and nutrition disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the effects of a 12-month treatment with metformin on insulin action and secretion in women with prior GDM and impaired glucose tolerance (IGT) or impaired fasting glucose (IFG). Primary outcome variable will be whole body insulin sensitivity index (ISI-Matsuda) at endpoint.

Valutazione degli effetti di un trattamento di 12 mesi con metformina sull'azione e secrezione insulinica in un campione di donne con pregresso GDM e alterazione del metabolismo glucidico nel post-partum (alterata glicemia a digiuno e/o ridotta tolleranza glucidica). Il parametro primario di valutazione sara' il 'Whole body insulin sensitivity index (ISI-Matsuda)'

E.2.2

Secondary objectives of the trial

To assess the effects of metformin on HOMA-Index, beta-index, fasting plasma glucose (FPG), glucose tolerance, HbA1c, physio-pathologic (phenotype) and immunologic features associated with previous GDM and with its outcome.

Obiettivo secondario dello studio sara' la valutazione degli effetti della metformina sull'indice HOMA,il beta-index,il glucosio plasmatico a digiuno,la tolleranza glicidica,l'emoglobina glicosilata,le caratteristiche fisiopatologiche (fenotipo),genetiche ed immunologiche che si associano al diabete gestazionale e ne condizionano l'evoluzione.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Female subjects aged ≥ 18 and ≤ 45 years;
2) Caucasian race;
3) History of prior GDM (in the screening) during pregnancy, defined according to Carpenter and Coustan (7) criteria, i.e. a FPG value ≥ 126 mg/dl or 2 or more of the following conditions after a 100-g oral glucose load in the oral glucose tolerance test (OGTT): 0' ≥ 95 mg/dl, 1h PG ≥ 180 mg/dl, 2h PG ≥ 155 mg/dl, 3h PG ≥ 140 mg/dl (2); or 2 or more of the following conditions after a 75-g OGTT: 0' ≥ 95 mg/dl, 1h PG ≥ 180 mg/dl, 2h PG ≥ 155 mg/dl ; or 1h PG ≥ 198 mg/dl after a screening test with (8) 50-g oral glucose load.
4) Altered Glucose Regulation (IFG or IGT) confirmed at the first post-partum follow-up after a 75-g oral glucose load in the OGTT, performed at entry in the time-window of 10 to 48 months after delivery, defined as a FPG value ≥ 100 mg/dl and < 126 mg/dl (IFG) according with latest classification (9) and/or or a PG value ≥ 140 mg/dl and < 200 mg/dl 2 hours after the glucose load.
5) Female of childbearing potential must use effective contraceptive measures for at least 1 month prior to the entry into the study and should continue to use the same contraceptive method during the overall study period. A pregnancy test at study entry is to be performed in childbearing potential women.
6) Written informed consent obtained.

1) Donne ≥ 18 e ≤ 45 anni;
2) Razza caucasica;
3) Pregresso GDM (allo screening) durante la gravidanza, definito secondo i criteri di Carpenter e Coustan (7).Valore di glucosio plasmatico a digiuno (FPG) ≥ 126 mg/dl o 2 o piu' delle seguenti condizioni dopo un carico orale di 100-g di glucosio nel test (OGTT): 0' ≥ 95 mg/dl, 1h PG ≥ 180 mg/dl, 2h PG ≥ 155 mg/dl, 3h PG ≥ 140 mg/dl; o 2 o piu' delle seguenti condizioni dopo un carico orale di 75-g di glucosio nel test (OGTT): 0' ≥ 95 mg/dl, 1h PG ≥ 180 mg/dl, 2h PG ≥ 155 mg/dl; oppure 1h PG ≥ 198 mg/dl (8) dopo un carico orale di 50-g di glucosio.
4) Regolazione glucidica alterata (IFG o IGT) confermata al primo follow-up post-partum, con test da carico orale di 75 g di glucosio (OGTT) effettuato alla visita iniziale a distanza di 10-48 mesi dal parto, definita come un valore di FPG ≥ 100 mg/dl e < 126 mg/dl (IFG) secondo le piu' recenti classificazioni (9), e/o un valore di PG ≥ 140 mg/dl e < 200 mg/dl a 2h dal carico di glucosio;
5) Donne fertili devono usare adeguate misure contraccettive da almeno 1 mese prima dell'entrata dello studio e continuare ad usare lo stesso metodo per tutta la durata dello studio. Alla visita iniziale un test di gravidanza sara' effettuato in tutte le donne potenzialmente fertili
6) Ottenimento del Consenso Informato scritto.

E.4

Principal exclusion criteria

1) Patients diagnosed with type 1 insulin dependent diabetes mellitus (i.e. positivity for anti-GAD and for anti-IA2); in the event that results are not available at the end of run-in, patients with positivity to antibodies will be withdrawn from the study within the first post-baseline visit. In the case of availability of results obtained in the previous 48 months, they will be considered as valid confirmatory results and the test is not to be repeated at visit 1;

2) Diagnosis of diabetes in the 75-g OGTT performed at entry, defined as a FPG value ≥ 126 mg/dl and/or or a PG value ≥ 200 mg/dl 2 hours after the glucose load;
3) Impaired renal function as shown by serum creatinine ³ 135 μmol/l in males and ³ 110 μmol/l in females;
4) Impaired liver function as shown by transaminase levels ³ twice above the upper normal range;
5) History of hypersensitivity to metformin;
6) Pregnant or breast-feeding women, or women planning to become pregnant during the study;
7) Failure to use adequate contraception (women of current reproductive potential only);
8) Mental condition rendering the subject unable to understand the nature, scope, and possible consequences of the study;
9) Any clinically significant major organ system disease such as relevant cardiovascular, gastrointestinal, hepatic, neurological, endocrine, haematological or other major systemic diseases or infective diseases making implementation of the protocol or interpretation of the study results difficult;
10) Patients with underlying concomitant medications requiring a long-term use of drugs potentially acting on glucose metabolism (e.g. corticosteroids, diuretics, beta-adrenergic drugs or others);
11) Treatment or likelihood of requiring treatment during the study period with drugs not permitted by the clinical study protocol;
12) History of drug or alcohol abuse within the last 2 years or current addiction to substances of abuse;
13) Any disease or condition that in the opinion of the investigator may interfere with the completion of the study;
14) Subject unlikely to comply with protocol, e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of understanding or completing the study procedures;
15) Receipt of an experimental drug or device within 12 weeks prior to study entry;
16) Previous enrolment in the present study.

1) Pazienti con diagnosi di diabete mellito tipo 1 insulino-dipendente, definito dalla positivita' agli anticorpi anti-GAD e anti-IA2. Qualora i risultati non fossero disponibili alla fine del run-in, le pazienti con positivita' saranno fatte uscire dallo studio alla prima visita dopo il basale. Qualora vi siano gia' risultati disponibili nei 48 mesi precedenti l'arruolamento, il risultato sara' considerato valido e non sara' necessario ripetere il test alla visita iniziale (Visita 1);
2) Diagnosi di diabete nell'OGTT da 75-g effettuato alla visita iniziale, definita da un valore di FPG ≥ 126 mg/dl e/o un valore di PG ≥ 200 mg/dl 2 ore dopo il test da carico;
3) Ridotta funzionalita' renale: creatinina serica ³ 1.4 mg/dl;
4) Ridotta funzionalita' epatica: livelli di transaminasi ³ 2 volte il range superiore di normalita';
5) Ipersensibilita' alla metformina;
6) Donne in gravidanza o allattamento, o donne che hanno intenzione di intraprendere una gravidanza durante il periodo dello studio;
7) Fallimento nell'utilizzo di adeguati metodi contraccettivi (applicabile per le donne fertili);
8) Condizione mentale che renda il soggetto non in grado di comprendere la natura, lo scopo e possibili conseguenze dello studio;
9) Qualsiasi patologia clinicamente significativa associata ad un organo maggiore, come patologie sistemiche cardiovascolari, gastrointestinali, epatiche, neurologiche, endocrine, ematiche o di altri sistemi maggiori o patologie infettive che rendano difficoltosa l'applicazione del protocollo o l'interpretazione dei risultati dello studio;
10) Pazienti con malattie concomitanti di fondo che richiedano l'impiego a lungo termine di farmaci potenzialmente in grado di interferire con il metabolismo glicidico (es. corticosteroidi, diuretici, farmaci beta-adrenergici o altri);
11) Trattamento in corso o probabilita' di richiedere un trattamento durante il periodo dello studio con farmaci non permessi dal protocollo di studio;
12) Eventuale precedente abuso di farmaci o alcol negli ultimi due anni o concomitante abuso di sostanze che creano dipendenza;
13) Qualsiasi patologia o condizione che a giudizio dello sperimentatore puo' interferire con il completamento dello studio;
14) Soggetti che difficilmente possono seguire il protocollo, es. mancanza di collaborazione, impossibilita' di tornare alle visite di follow-up e alta probabilita' di non portare a termine le procedure dello studio;
15) Ricevimento di un farmaco o dispositivo sperimentale nelle 12 settimane prima dell'entrata nello studio;
16) Precedente arruolamento nello studio.

E.5 End points

E.5.1

Primary end point(s)

· Primary variable:
Whole body insulin sensitivity index (ISI) will be the primary variable of the study.
Whole body ISI will be calculated from the OGTT using the following formula:
_______10.000________
√(FPG + FPI) x (PG x PI)

where FPI = fasting plasma insulin (μU/ml), FPG = fasting plasma glucose (mg/dl) and PG and PI represent the mean plasma glucose and plasma insulin concentration during OGTT.

La variabile primaria dello studio e' l'indice di sensibilita' all'insulina misurato come 'whole body insulin sensitivity index (ISI)'

Il 'Whole body ISI' sara' calcolato utilizzando dati provenienti dall'OGTT (oral glucose tolerance test) utilizzando la seguente formula:

_______10.000________
√(FPG + FPI) x (PG x PI)

dove FPI = fasting plasma insulin (μU/ml), FPG = fasting plasma glucose (mg/dl) e PG e PI rappresentano il valore medio di glicemia plasmatica e insulinemia durante l'esame OGTT.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

E.6.4

Safety

E.6.5

Efficacy

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

placebo controllato

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

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

E.8.7

Trial has a data monitoring committee

Information not present in EudraCT

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

La conclusione dello studio coincide con l'ultima visita (follow-up) dell'ultimo soggetto arruolato. Ulteriori visite sono possibili per seguire il decorso di un evento avverso.

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1

Number of subjects for this age range:

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.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

Yes

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

140

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)

dieta ed esercizio fisico

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

2006-08-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2006-06-01

P. End of Trial
P.	End of Trial Status	Completed

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