Clinical Trials Register

Summary
EudraCT Number:	2015-000361-31
Sponsor's Protocol Code Number:	FIM-MET-2015-01
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-07-10
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

Spain - AEMPS

A.2

EudraCT number

2015-000361-31

A.3

Full title of the trial

Efficacy of metformin in gestational diabetes not controlled by diet compared to the use of insulin

Eficacia del tratamiento con metformina en diabetes gestacional no controlada con dieta frente al uso de insulinoterapia

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Efficacy of metformin in gestational diabetes

Eficacia del tratamiento con metformina en diabetes gestacional

A.3.2

Name or abbreviated title of the trial where available

MeDiGes

A.4.1

Sponsor's protocol code number

FIM-MET-2015-01

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	Fundación Pública Andaluza para la Investigación de Málaga en Biomedicina y Salud (FIMABIS)
B.1.3.4	Country	Spain
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	FIMABIS
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	FIMABIS
B.5.2	Functional name of contact point	Clinical Studies Platform
B.5.3	Address:
B.5.3.1	Street Address	Avda Carlos Haya s/n
B.5.3.2	Town/ city	Malaga
B.5.3.3	Post code	29010
B.5.3.4	Country	Spain
B.5.4	Telephone number	34951291977
B.5.5	Fax number	34951440263
B.5.6	E-mail	gloria.luque@fimabis.org

D. IMP Identification
D.IMP: 1
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	LEVEMIR
D.2.1.1.2	Name of the Marketing Authorisation holder	Novo Nordisk
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Solution for injection in pre-filled pen
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	INSULIN DETEMIR
D.3.9.1	CAS number	169148-63-4
D.3.9.4	EV Substance Code	SUB02692MIG
D.3.10	Strength
D.3.10.1	Concentration unit	IU/ml international unit(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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	NovoRapid
D.2.1.1.2	Name of the Marketing Authorisation holder	Novo Nordisk
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Solution for injection in pre-filled pen
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	INSULIN ASPART
D.3.9.1	CAS number	116094-23-6
D.3.9.4	EV Substance Code	SUB08195MIG
D.3.10	Strength
D.3.10.1	Concentration unit	IU/ml international unit(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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	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	Metformine
D.2.1.1.2	Name of the Marketing Authorisation holder	TEVA
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Metformine
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 HYDROCHLORIDE
D.3.9.1	CAS number	9100L32L2N
D.3.9.3	Other descriptive name	METFORMIN HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB03200MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
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	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

Gestational diabetes (GD)

Diabetes gestacional

E.1.1.1

Medical condition in easily understood language

Gestational diabetes

Diabetes gestacional

E.1.1.2

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	PT
E.1.2	Classification code	10018209
E.1.2	Term	Gestational diabetes
E.1.2	System Organ Class	10036585 - Pregnancy, puerperium and perinatal conditions

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Demonstrate that treatment with metformin in women with GD (not controlled with diet) can get no lower obstetric and perinatal outcomes to standard treatment with insulin.

Demonstrate that glycemic control with metformin in women obtained properly selected can be equivalent to that obtained with insulin.

Demostrar que el tratamiento con metformina en mujeres con DG (no controladascon dieta) puede obtener resultados obstétricos y perinatales no inferiores al tratamiento de referencia con insulina.

Demostrar que el control glucémico obtenido con metformina en mujeres apropiadamente
seleccionadaspuede ser equivalente al obtenido con insulina.

E.2.2

Secondary objectives of the trial

State that the adverse effect profile of treatment is safe and can favor the
metformin, at least in a lower risk of hypoglycemia, and that digestive intolerance will not be a limitant factor in most pregnant.

Demonstrate that women treated with metformin have a weight gain
significant lower than those treated with insulin.

State If fructosamine may be a marker of insulinization need in patients treated with metformin.

Women treated with metformin will found more satisfied than those treated with insulin

Check for differences in parameters of inflammation, endothelial injury and oxidativge stress as well as in lipid profile, between groups and based on metabolic control and
perinatal outcomes.

Demostrar que el perfil de efectos adversos del tratamiento es seguro y puede favorecer a la
metformina, al menos en un menor riesgo de hipoglucemias, y que la intolerancia digestiva
no será un factor limitanteen la mayoría de gestantes.

-Demostrar que las mujeres tratadas con metformina tendrán una ganancia ponderal
significativamentemenor que las tratadas con insulina.

Testar si la fructosamina puede ser marcador de necesidad de insulinización en la rama de
metformina.

Las mujeres tratadas con metformina se encontrara más satisfecha con el tratamiento que las tratadas con insulina

Comprobar si existen diferencias en parámetros de inflamación, lesión endotelial y estrés oxidativo, así como en perfil lipídico, entre los grupos y en función del control metabólico y los resultados perinatales

E.2.3

Trial contains a sub-study

E.2.3.1

Full title, date and version of each sub-study and their related objectives

E.3

Principal inclusion criteria

1) 18-45 years old.
2) Diagnosis of GD, with fasting glucose <120 mg / dL.
3) not controlled by diet: fasting capillary blood glucose> 95 mg / dl in at least 2-3 times or 1 hour postprandial >140 mg / dl on, at least 2-3 times a week.
4) 2nd or 3rd trimesters of pregnancy.
5) Able to give informed consent.

1) 18-45 años.
2) Diagnóstico de DG, con glucemia basal < 120 mg/dL.
3) No controlada con dieta: glucemias capilares en ayunas >95 mg/dl en al menos 2-3 ocasiones o 1h postprandial>140 mg/dl en al menos 2-3 ocasiones, en una semana.
4) 2º o 3º trimestres de embarazo.
5) Capaz de dar consentimiento informado.

E.4

Principal exclusion criteria

1) Psychopathological situations that do not guarantee proper adhesion to follow up
2) 1st trimester of pregnancy
3) gastrointestinal diseases that may cause poorer tolerance or increased
symptoms with metformin.
4) Patients who can not attend the scheduled consultation.
5) Language barrier limiting for understanding treatment settings
6) Twin pregnancy.

1) Alteraciones psicopatológicas que no garanticen adherencia apropiada a seguimiento.
2) 1º trimestre de gestación.
3) Enfermedades gastrointestinales que puedan provocar peor tolerancia o aumento de
síntomas con la metformina.
4) Pacientes que no puedan acudir con la frecuencia prevista a consulta programada.
5) Barrera idiomática limitante para la comprensión de los ajustes de tratamiento
6) Gestación gemelar.

E.5 End points

E.5.1

Primary end point(s)

E.5.1.1

Timepoint(s) of evaluation of this end point

Selection visit, subsequent visits (every 1-3 weeks), 36-37 week pregnancy, 8-10 weeks after delivery

Visita de selección, visitas sucesivas (cada 1-3 semanas), semana 36.37 de gestación, semana 8-10 postparto

E.5.2

Secondary end point(s)

Demostrar que el perfil de efectos adversos del tratamiento es seguro y puede favorecer a la
metformina, al menos en un menor riesgo de hipoglucemias, y que la intolerancia digestiva
no será un factor limitanteen la mayoría de gestantes.

-Demostrar que las mujeres tratadas con metformina tendrán una ganancia ponderal
significativamentemenor que las tratadas con insulina.

Testar si la fructosamina puede ser marcador de necesidad de insulinización en la rama de
metformina.

Las mujeres tratadas con metformina se encontrara más satisfecha con el tratamiento que las tratadas con insulina
Comprobar si existen diferencias en parámetros de inflamación, lesión endotelial y estrés oxidativo, así como en perfil lipídico, entre los grupos y en función del control metabólico y los resultados perinatales

E.5.2.1

Timepoint(s) of evaluation of this end point

Selection visit, subsequent visits, 36-37 week pregnancy, 8-10 weeks after delivery

Visita de selección, visitas sucesivas, semana 36.37 de gestación, semana 8-10 postparto

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

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

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

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

Reclassification of glucose metabolism disorder diagnosis based on the result of
oral glucose overload, and recommendations will be given to the patient. Physical examination: weight, circumference waist and blood pressure. From this onwardpatient will be followed in primary or specialized care, according to clinical practice based on the results of such reclassification.

Se procederá a la reclalificación del diagnóstico de disglucosis en función del resultado de Sobrecarga Oral de Glucosa y se darán recomendaciones al alta. Exploración física: peso, circunferencia de la cintura y tensión arterial. A partir de ahí se hará el seguimiento de la paciente en atención primaria o especializada, según la práctica clínica habitual en función de los resultados de dicha recalificación.

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.1.1.1

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:

200

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

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

Yes

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

200

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)

Expected norrmal care

Práctica clínica habitual

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

2015-09-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-02-27

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

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