Clinical Trials Register

Summary
EudraCT Number:	2012-001371-37
Sponsor's Protocol Code Number:	GDM-TREAT
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-07-09
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

Denmark - DHMA

A.2

EudraCT number

2012-001371-37

A.3

Full title of the trial

The impact of liraglutide on glucose tolerance and the risk of type 2 diabetes in women with previous gestational diabetes mellitus

Effekten af liraglutide på glukosetolerancen og risikoen for type 2 diabetes i kvinder med tidligere gestationel diabetes

A.3.1

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

The impact of liraglutide on glucose tolerance and the risk of type 2 diabetes in women with previous gestational diabetes mellitus

Effekten af liraglutide på glukosetolerancen og risikoen for type 2 diabetes i kvinder med tidligere graviditetsbetinget sukkersyge

A.4.1

Sponsor's protocol code number

GDM-TREAT

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	Dr. med. Tina Vilsbøll
B.1.3.4	Country	Denmark
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	Novo Nordisk A/S
B.4.2	Country	Denmark
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Gentofte Hospital, University of Copenhagen
B.5.2	Functional name of contact point	Center for diabetesforskning
B.5.3	Address:
B.5.3.1	Street Address	Kildegårdsvej 28
B.5.3.2	Town/ city	Hellerup
B.5.3.3	Post code	2900
B.5.3.4	Country	Denmark
B.5.4	Telephone number	4538672461
B.5.5	Fax number	4538677661
B.5.6	E-mail	t.vilsboll@dadlnet.dk

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	Victoza
D.2.1.1.2	Name of the Marketing Authorisation holder	Novo Nordisk A/S
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
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	Suspension 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	LIRAGLUTIDE
D.3.9.1	CAS number	204656-20-2
D.3.9.4	EV Substance Code	SUB25238
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	1.8
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Suspension for injection in pre-filled pen
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Gestational diabetes mellitus
Non-alcoholic fatty liver disease

Gestationel diabetes mellitus
Non-alcoholic fatty liver disease

E.1.1.1

Medical condition in easily understood language

Diabetes mellitus during pregnancy
Steatosis

Graviditetsbetinget sukkersyge
Fedtlever

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10018210
E.1.2	Term	Gestational diabetes mellitus
E.1.2	System Organ Class	100000004868

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	PT
E.1.2	Classification code	10029530
E.1.2	Term	Non-alcoholic fatty liver
E.1.2	System Organ Class	10019805 - Hepatobiliary 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 investigate the effect of the glucagon-like peptide-1 receptor agonist liraglutide on patophysiological characteristics and the risk of type 2 diabetes mellitus in women with previous gestational diabetes mellitus (GDM).

At undersøge effekten af glucagon-like peptide-1 (GLP-1) receptor agonisten liraglutide på patofysiologiske karakteristika og risikoen for type 2 diabetes mellitus i kvinder med tidligere gestationel diabetes mellitus

E.2.2

Secondary objectives of the trial

To investigate if liraglutide has an effect on appetite which is different during OGTT and IIGI, if liraglutide improves the subjects' quality of life and bone mineral density.
To investigate if the quality of life in women with prior GDM and non-alcoholic fatty liver (NAFLD) is better or worse than women with prior GDM without NAFLD, women without prior GDM and without NAFLD and women with NAFLD who attend an outpatient clinic due to their liver disease.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Women with previous GDM:
• Informed oral and written consent
• Previous diagnosis of GDM according to current Danish guidelines (plasma glucose concentration at 120 min after 75 g oral glucose tolerance test ≥9.0 mM) during pregnancy within the last 10 years
• Age >18 years
• 25 kg/m2 < body mass index < 45 kg/m2
• Normal glucose tolerance (NGT), impaired fasting glycaemia (IFG), or impaired glucose tolerance (IGT)
• Safe contraception and negative pregnancy test

Women without previous GDM
• Informed oral and written consent
• Normal glucose tolerance (fasting PG ≤ 6.0 mM and PG concentration at 120 min after 75 g-OGTT < 7.8 mM)
• Age >18 years
• 25 kg/m2 < BMI < 45 kg/m2
• Pregnancy within the last ten years without GDM

Women without previous GDM and without NAFLD
• Informed oral and written consent
• Normal glucose tolerance (fasting PG < 6.1 mM and HbA1c < 43 mmol/mol)
• Age >18 years
• 25 kg/m2 < BMI < 45 kg/m2
• At least one pregnancy within the last ten years without GDM

Women with biopsi-verified NAFLD
• Informed oral and written consent
• Women with known NAFLD or NASH
• 25 kg/m2 < BMI < 45 kg/m2
• Age >18 years
• At least one prior pregnancy

E.4

Principal exclusion criteria

Women with previous GDM
• Patients with diabetes
• HbA1c ≥6.5%
• Patients with previous pancreatitis or previous neoplasia
• Pregnant or breast feeding women
• Anaemia (haemoglobin <7 mM)
• Women planning to become pregnant within the next 5 years
• Women using other contraception than intrauterine device (IUD) or oral contraceptives. Women who do not use safe contraception will be offered application of an IUD.
• Women treated with statins, corticosteroids or other hormone therapy (except estrogens and gestagens)
• Ongoing abuse of alcohol or narcotics
• Impaired hepatic function (liver transaminases >3 times upper normal limit)
• Impaired renal function (se-creatinine >120 μM and/or albuminuria)
• Uncontrolled hypertension (systolic blood pressure >180 mmHg, diastolic blood pressure >100 mmHg)
• Any condition that the investigator feels would interfere with trial participation
• Receiving any investigational drug within the last 3 months

Women without previous GDM
• Pregnant or breast feeding women
• Anaemia (haemoglobin <7 mM)

Women without previous GDM and without NAFLD
• Pregnant or breast feeding women
• Anaemia (haemoglobin <7 mM)
• Steatosis as assessed by ultrasound scanning
• Receiving any investigational drug within the last 3 months
• Any condition that the investigator feels would interfere with trial participation

Women with biopsi-verified NAFLD
• Women with established cirrhosis
• Pregnant or breast feeding women
• Anaemia (haemoglobin <7 mM)
• Women treated with statins, corticosteroids or other hormone therapy (except oestrogens and gestagens)
• Ongoing abuse of alcohol or narcotics
• Impaired renal function (se-creatinine >120 μM and/or albuminuria)
• Uncontrolled hypertension (systolic blood pressure >180 mmHg, diastolic blood pressure >100 mmHg)
• Any condition that the investigator feels would interfere with trial participation

E.5 End points

E.5.1

Primary end point(s)

Primary endpoint is the change in glucose tolerance from baseline to week 52 as measured by area under the curve (AUC) for the PG excursion following a 4-hour 75 g-oral glucose tolerance test (OGTT). Additional endpoints regarding glucose tolerance includes changes from baseline to week 53 (after trial medication wash-out) and at end of the study (260 weeks and 261 weeks (liraglutide-treated).

E.5.1.1

Timepoint(s) of evaluation of this end point

After 52, 53, 260, and 261 weeks

E.5.2

Secondary end point(s)

1) Percentage of subjects in each treatment arm with normal glucose tolerance (NGT: FPG ≤ 6.0 mM and 2h PG < 7.8 mM) at inclusion who develop prediabetes (impaired fasting glucose (IFG): (6.1 mM ≤ fasting PG (FPG) < 7.0 mM and 2h PG after 75 g-OGTT < 7.8 mM) and/or impaired glucose tolerance (IGT): (FPG < 6.1 mM and 7.8 mM ≤ 2h PG after 75 g-OGTT ≤ 11.0 mM) or T2DM (FPG≥ 7mM or 2h PG ≥ 11.1 mM)
2) Improvement in glycaemic status, as percentage of patients in each treatment arm going from:
• IFG to normal glucose tolerance (FPG ≤ 6.0 mM and 2h PG < 7.8 mM)
• IGT to NGT
• Combined IFG and IGT to IFG, IGT, or NGT
3) Progression of isolated IFG or isolated IGT (at inclusion) to combined IFG/IGT or type 2 diabetes mellitus (T2DM), and progression of combined IFG/IGT (at inclusion) to T2DM
4) Changes in glycosylated haemoglobin (HbA1c) as percentage of patients who progress from:
• Normoglycaemic to prediabetic (HbA1c <6.0  6.0-6.4)
• Normoglycaemic to T2DM (HbA1c <6.0  ≥ 6.5)
• Prediabetic to T2DM (HbA1c 6.0-6.4  ≥ 6.5)
or improves from:
• Prediabetic to normoglycaemic (HbA1c 6.0-6.4  <6.0)
5) Changes in anthropometric measurements (BMI, absolute body weight (kg) and waist:hip ratio)
6) Changes in beta cell secretory responses (AUC for insulin and C-peptide) during OGTT and IIGI, the homeostatic model assessment (HOMA) and pro-insulin to insulin ratio)
7) Changes in insulin sensitivity (assessment of insulin resistance (HOMAIR ) and Matsuda insulin sensitivity index)
8) Changes in incretin hormone secretion (fasting plasma concentrations and plasma responses of GLP-1, GLP-2 and GIP) and plasma glucagon during OGTT
9) Changes in incretin effect (insulin and C-peptide responses after OGTT vs. IIGI)
10) Changes in gamma-glutamyltransferase (GGT), intra-hepatic fat, FGF-21, whole body and visceral fat mass/fat-free mass, circulating lipids and cardiovascular biomarkers (e.g.highly sensitive C-reactive protein (hs-CRP), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), tumor necrosis factor-alpha (TNF-α), adiponectin and plasminogen activator inhibitor-1 (PAI-1) and RNA-oxidation)
11) Changes in gut microbiota (optional to the main protocol)
12) Changes in subjective appetite (measured by visual analogue scale (VAS))
13) Safety and tolerability
14) Evaluation of QoL will be judged by validated questionnaires
15) Evaluation of alcohol consumption will be judged by validated questionnaires
16) Evaluation of the predictive value of biomarkers for detection of microalbuminuria
17) Evaluation of blindedness of participant and investigators by questionnaire and the end of the blinded part of the trial
18) Changes in bone markers

E.5.2.1

Timepoint(s) of evaluation of this end point

All secondary endpoints will be assessed as changes from baseline until 52 weeks, and until end of the study (260 weeks). In addition, some endpoints (including 1, 2, 3, 6, 7, 8, 9, 10, 12 and 18 - above) will also be assessed as changes from baseline until week 53 and week 261 (after trial medication wash-out).

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

Yes

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)

E.7.4

Therapeutic use (Phase IV)

Yes

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

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

Yes

E.8.4

The trial involves multiple sites in the 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

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

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:

160

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

Yes

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

Yes

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

160

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)

None

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Center for Pregnant Women with Diabetes, Center of Obstetrics, Rigshospitalet, University of Copenhagen
G.4.3.4	Network Country	Denmark
G.4 Investigator Network to be involved in the Trial: 2
G.4.1	Name of Organisation	Center for Pregnant Women with Diabetes, Department of Endocrinology, Rigshospitalet, University of Copenhagen
G.4.3.4	Network Country	Denmark
G.4 Investigator Network to be involved in the Trial: 3
G.4.1	Name of Organisation	Department of Endocrinology Research, Faculty of Health Sciences, University of Copenhagen
G.4.3.4	Network Country	Denmark
G.4 Investigator Network to be involved in the Trial: 4
G.4.1	Name of Organisation	Department of Gynaecology and obstetrics, Copenhagen University Hospital Herlev
G.4.3.4	Network Country	Denmark
G.4 Investigator Network to be involved in the Trial: 5
G.4.1	Name of Organisation	Department of Gynaecology and Obstetrics, Copenhagen University Hospital Nordsjælland
G.4.3.4	Network Country	Denmark
G.4 Investigator Network to be involved in the Trial: 6
G.4.1	Name of Organisation	Department of Gynaecology and obstetrics, Copenhagen University Hospital Nordsjælland
G.4.3.4	Network Country	Denmark

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2012-07-09

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-07-10

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-09-02

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