Clinical Trials Register

Summary
EudraCT Number:	2014-004850-32
Sponsor's Protocol Code Number:	EFC13794
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:	2016-06-22
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

Spain - AEMPS

A.2

EudraCT number

2014-004850-32

A.3

Full title of the trial

A 26-week open-label study assessing the efficacy and safety of the insulin glargine/lixisenatide fixed ratio combination in adults with Type 2 Diabetes inadequately controlled on GLP-1 receptor agonist and metformin ± pioglitazone

Estudio abierto, de 26 semanas de duración, para evaluar la eficacia y seguridad de la combinación en proporción fija de insulina glargina/lixisenatida en adultos con Diabetes Tipo 2 no controlados adecuadamente con un agonista del receptor de GLP-1 y metformina ± pioglitazona

A.3.1

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

Efficacy and Safety of the Insulin Glargine/Lixisenatide Fixed Ratio Combination Versus GLP-1 Receptor Agonist in Patients With Type 2 Diabetes

Eficacia y seguridad de la combinación en proporción fija de insulina glargina/lixisenatida con un agonista del receptor de GLP-1 en adultos con Diabetes Tipo 2

A.3.2

Name or abbreviated title of the trial where available

LixiLan-G

A.4.1

Sponsor's protocol code number

EFC13794

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1168-4639

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	sanofi-aventis recherche & développement
B.1.3.4	Country	France
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	sanofi-aventis recherche & développement
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	sanofi-aventis, s.a.
B.5.2	Functional name of contact point	Unidad de Estudios Clínicos
B.5.3	Address:
B.5.3.1	Street Address	c/ Josep Pla nº2, 4ª planta
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08019
B.5.3.4	Country	Spain
B.5.4	Telephone number	93 485 94 00
B.5.6	E-mail	ES-unidadestudiosclinicos@sanofi.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	No
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	Insulin glargine and lixisenatide in fixed ratio combination
D.3.2	Product code	HOE901/AVE0010
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	Lixisenatide
D.3.9.1	CAS number	320367-13-3
D.3.9.2	Current sponsor code	AVE0010
D.3.9.4	EV Substance Code	SUB32251
D.3.10	Strength
D.3.10.1	Concentration unit	µg/ml microgram(s)/millilitre
D.3.10.2	Concentration type	not less then
D.3.10.3	Concentration number	33
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	INSULIN GLARGINE
D.3.9.1	CAS number	160337-95-1
D.3.9.2	Current sponsor code	HOE901
D.3.9.4	EV Substance Code	SUB08196MIG
D.3.10	Strength
D.3.10.1	Concentration unit	U/ml 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	Yes
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	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	No
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	Insulin glargine and lixisenatide in fixed ratio combination
D.3.2	Product code	HOE901/AVE0010
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	Lixisenatide
D.3.9.1	CAS number	320367-13-3
D.3.9.2	Current sponsor code	AVE0010
D.3.9.4	EV Substance Code	SUB32251
D.3.10	Strength
D.3.10.1	Concentration unit	µg/ml microgram(s)/millilitre
D.3.10.2	Concentration type	not less then
D.3.10.3	Concentration number	50
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	INSULIN GLARGINE
D.3.9.1	CAS number	160337-95-1
D.3.9.2	Current sponsor code	HOE901
D.3.9.4	EV Substance Code	SUB08196MIG
D.3.10	Strength
D.3.10.1	Concentration unit	U/ml 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	Yes
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	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	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	European Union
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	Liraglutide
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	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	range
D.3.10.3	Concentration number	1.2 to 1.8
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: 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	BYETTA
D.2.1.1.2	Name of the Marketing Authorisation holder	Astra Zeneca
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Exenatide
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	EXENATIDE
D.3.9.1	CAS number	141758-74-9
D.3.9.4	EV Substance Code	SUB21818
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	5 to 10
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.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	BYDUREON
D.2.1.1.2	Name of the Marketing Authorisation holder	Astra Zeneca AB
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Exenatide extended release
D.3.4	Pharmaceutical form	Powder and solvent for 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	EXENATIDE
D.3.9.1	CAS number	141758-74-9
D.3.9.4	EV Substance Code	SUB21818
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	not less then
D.3.10.3	Concentration number	2
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.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	EPERZAN
D.2.1.1.2	Name of the Marketing Authorisation holder	Glaxo Smith Kline Trading Services Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Albiglutide
D.3.4	Pharmaceutical form	Powder and solvent for 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	NA
D.3.9.1	CAS number	782500-75-8
D.3.9.3	Other descriptive name	ALBIGLUTIDE
D.3.9.4	EV Substance Code	SUB120850
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	50
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: 7
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	TRULICITY
D.2.1.1.2	Name of the Marketing Authorisation holder	Eli Lilly
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Dulaglutide
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	NA
D.3.9.3	Other descriptive name	DULAGLUTIDE
D.3.9.4	EV Substance Code	SUB130484
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	0.75 to 1.5
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.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

Type 2 Diabetes Mellitus

Diabetes Mellitus Tipo 2

E.1.1.1

Medical condition in easily understood language

Type 2 Diabetes Mellitus

Diabetes Mellitus Tipo 2

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	19.0
E.1.2	Level	PT
E.1.2	Classification code	10067585
E.1.2	Term	Type 2 diabetes mellitus
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 demonstrate the superiority of the insulin glargine/lixisenatide fixed ratio combination (FRC) versus GLP-1 receptor agonist (GLP-1 RA) in hemoglobin A1c (HbA1c) change.

Demostrar la superioridad de la combinación en proporción fija (CPF) de insulina glargina/lixisenatida frente al agonista del receptor del péptido 1 similar al glucagón (AR de GLP-1) en el cambio de la hemoglobina A1c (HbA1c)

E.2.2

Secondary objectives of the trial

To compare the overall efficacy and safety of the insulin glargine/lixisenatide fixed ratio combination (FRC) to GLP-1 receptor agonist (GLP-1 RA) on top of metformin (with or without pioglitazone) in patients with type 2 diabètes.

Comparar la eficacia global y la seguridad de la insulina glargina / lixisenatida en combinación fija (FRC) para los agonistas de los receptores GLP-1 (GLP-1 RA) más metformina (con o sin pioglitazona) en pacientes con diabetes tipo 2.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

-Patients with type 2 diabetes mellitus diagnosed at least 1 year prior to screening visit.
-Patients who have been treated with one of the following glucagon-like peptide 1 (GLP-1) receptor agonists for at least 4 months prior to screening visit (V1), and with stable dose for at least 3 months prior to screening visit (V1):
-Liraglutide (Victoza®) 1.8 mg QD or 1.2 mg QD, if the 1.8 mg QD dose is not well tolerated according to the Investigator's judgment or
-Exenatide (Byetta®) 10 ?g BID or of 5 ?g BID, if 10 ?g BID dose is not well tolerated according to the Investigator's judgment in combination with metformin (daily dose ?1500 mg/day or maximum tolerated dose [MTD]), with or without pioglitazone, both at stable dose for at least 3 months prior to screening.
or
Patients who have been treated with stable dose of one of the following GLP-1 receptor agonists for at least 6 months prior to screening visit (V1):
-Exenatide extended-release (Bydureon®) 2 mg once weekly (QW), if well tolerated according to Investigator?s judgment,
-Albiglutide (Tanzeum®, Eperzan®) 50 mg QW or 30 mg QW, if 50 mg QW is not well tolerated according to Investigator?s judgment,
-Dulaglutide (Trulicity®) 1.5 mg QW or 0.75 mg QW, if 1.5 mg QW is not well tolerated according to Investigator?s judgment in combination with metformin (daily dose ?1500 mg/day or MTD), with or without pioglitazone, both at stable dose for at least 3 months prior to screening;
-Signed written informed consent.

-Pacientes con diabetes mellitus tipo 2 diagnosticada al menos un año antes de la visita de selección (V1);
-Pacientes que han recibido tratamiento con uno de los siguientes agonistas del receptor de GLP-1 durante al menos 4 meses antes de la visita de selección (V1), y que están recibiendo una dosis estable desde al menos los 3 meses anteriores a la visita de selección (V1):
- Liraglutida (Victoza®) 1,8 mg una vez al día (1 v/d), o 1,2 mg 1 v/d cuando, según el criterio del Investigador, no se tolere bien la dosis de 1,8 mg 1 v/d
- o exenatida dos veces al día (2 v/d), (Byetta®) 10 μg 2 v/d o 5 μg 2 v/d cuando, según el criterio del Investigador, no se tolere bien la dosis de 10 μg 2 v/d en combinación con metformina (dosis diaria ≥1500 mg/día o Dosis Máxima Tolerada (DMT)), con o sin pioglitazona, los dos fármacos administrados a una dosis estable como mínimo en los 3 meses anteriores a la selección;
o
Pacientes que han recibido tratamiento con una dosis estable de uno de los siguientes agonistas del receptor de GLP-1 durante al menos 6 meses antes de la visita de selección (V1):
- Exenatida de liberación prolongada (Bydureon®) 2 mg una vez a la semana (1 v/s), cuando, según el criterio del Investigador, se tolere bien
- Albiglutida (Tanzeum®, Eperzan®) 50 mg 1 v/s o 30 mg 1 v/s cuando, según el criterio del Investigador, no se tolere bien 50 mg 1 v/s
- Dulaglutida (Trulicity®) 1,5 mg 1 v/s o 0,75 mg 1 v/s cuando, según el criterio del Investigador, no se tolere bien 1,5 mg 1 v/s en combinación con metformina (dosis diaria ≥1500 mg/día o DMT), con o sin pioglitazona, los dos fármacos administrados a una dosis estable como mínimo en los 3 meses anteriores a la selección;
Consentimiento informado por escrito y firmado.

E.4

Principal exclusion criteria

-At screening visit, age <18.
-Screening HbA1c <7% and >9%.
-Pregnancy or lactation, women of childbearing potential with no effective contraceptive method.
-Any use of oral antidiabetic drugs within 3 months prior to the screening visit other than those described in the inclusion criteria.
-Previous treatment with insulin in the year prior to screening visit (note: short-term treatment with insulin [?10 days] due to intercurrent illness including gestational diabetes is allowed at the discretion of the study physician).
-Laboratory findings at the time of screening, including:
-Fasting plasma glucose (FPG) >250 mg/dL (13.9 mmol/L),
-Amylase and/or lipase >3 times the upper limit of the normal laboratory range (ULN),
-Alanine transaminase or aspartate transaminase >3 ULN,
-Calcitonin ?20 pg/mL (5.9 pmol/L),
-Positive pregnancy test.
-Patient who has renal function impairment with estimated glomerular filtration rate <30 mL/min (using the Modification of Diet in Renal Disease formula) or end-stage renal disease.
-Contraindication to use of insulin glargine, or lixisenatide or GLP-1 receptor agonist (Victoza®, Byetta®, Bydureon®, Tanzeum®/Eperzan® or Trulicity®) according to local labeling.
-Any contraindication to metformin or pioglitazone use, according to local labeling.
-History of hypersensitivity to insulin glargine, or to any of the excipients.
-History of allergic reaction to any GLP-1 receptor agonist or to meta-cresol.
-Personal or immediate family history of medullary thyroid cancer (MTC) or genetic condition that predisposes to MTC (eg, multiple endocrine neoplasia type 2 syndromes).
-History of pancreatitis (unless pancreatitis was related to gallstones and cholecystectomy was already performed), chronic pancreatitis, pancreatitis during a previous treatment with incretin therapies, pancreatectomy, stomach/gastric surgery.
-Body mass index ?20 or >40 kg/m^2.

-En la visita de selección (V1), no haber alcanzado la mayoría de edad;
-HbA1c en la selección <7 % (53 mmol/mol) y >9 % (75 mmol/mol);
-Embarazo o lactancia, mujeres con posibilidad de quedar embarazadas que no usan un método anticonceptivo eficaz;
-Cualquier uso de antidiabéticos orales (ADO) en los 3 meses anteriores a la visita de selección (V1), diferentes a los mencionados en los criterios de inclusión;
-Tratamiento anterior con insulina en el año anterior a la visita de selección (V1) (nota: está permitido, según el criterio del médico del estudio, el tratamiento a corto plazo con insulina (≤10 días) como consecuencia de una enfermedad intercurrente, entre otras la diabetes gestacional);
Resultados de laboratorio en el momento de la selección, entre otros:
- Glucosa plasmática en ayunas (GPA) >250 mg/dl (13,9 mmol/l);
- Amilasa y/o lipasa >3 veces el límite superior de la normalidad del intervalo analítico (LSN);
- Alanina aminotransferasa (ALT) o aspartato aminotransferasa (AST) >3 LSN;
- Calcitonina >20 pg/ml (5,9 pmol/l);
- Prueba de embarazo en suero positiva.
Paciente con deterioro de la función renal con una tasa de filtración glomerular (TFG) <30 ml/min (según la fórmula MDRD) o enfermedad renal en estadío terminal;
Contraindicación al uso de insulina glargina, o lixisenatida o un agonista del receptor de GLP-1 (Victoza®, Byetta®, Bydureon®, Tanzeum®/Eperzan® o Trulicity®) de acuerdo a la ficha técnica local;
Cualquier contraindicación al uso de metformina o pioglitazona (cuando sea aplicable), de acuerdo a la ficha técnica local;
Antecedentes de hipersensibilidad a la insulina glargina o a cualquiera de los excipientes;
Antecedentes de reacción alérgica con cualquier agonista del receptor de GLP-1 o con Metacresol;
Antecedentes personales o familiares inmediatos de cáncer medular tiroideo (CMT) o afecciones genéticas que predisponen al CMT (p. ej., síndromes de neoplasia endocrina múltiple de tipo 2);
Antecedentes de pancreatitis (a menos que la pancreatitis se relacione con litiasis biliar y se haya realizado una colecistectomía), pancreatitis crónica, pancreatitis durante tratamiento previo con incretinas, pancreatectomía, cirugía gástrica;
Índice de Masa Corporal (IMC) ≤20 o >40 kg/m2.

E.5 End points

E.5.1

Primary end point(s)

Change from baseline in HbA1c

Cambio en la HbA1c

E.5.1.1

Timepoint(s) of evaluation of this end point

Baseline to 26 weeks

desde el momento basal hasta la Semana 26.

E.5.2

Secondary end point(s)

1- Percentage of participants reaching HbA1c targets
2- Change from baseline in FPG
3- Change from baseline in 7-point self-monitored plasma glucose
(SMPG) profiles
4- Change from baseline in 2-hour postprandial glucose (PPG)
during standardized meal test
5- Change from baseline in blood glucose excursion during
standardized meal test
6- Change from baseline in body weight
7- Percentage of participants with symptomatic hypoglycemia
8- Number of adverse events

1 -Porcentaje de pacientes que alcanzan valores de HbA1c <7 % (53 mmol/mol) o ≤6,5 % (48 mmol/mol) 
2 -Cambio en la GPA
3 -Cambio en el perfil de SMPG de 7 puntos
4 -Cambio en la GPP a las 2 horas
5 -Cambio en la oscilación glucémica durante una prueba de comida estandarizada
6 -Cambio en el peso corporal
7- Porcentaje de participantes con hipoglucemia sintomática
8- Número de eventos adversos

E.5.2.1

Timepoint(s) of evaluation of this end point

1- 26 weeks
2-3-4-5-6 Baseline to 26 weeks
7-8 26 weeks

1- en la Semana 26;
2-3-4-5-6 desde el momento basal hasta la Semana 26;
7-8 en la Semana 26;

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

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Canada

Estonia

France

Germany

Hungary

Israel

Italy

Portugal

Romania

Slovakia

Spain

United States

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

Date of database lock (database is planned to be locked approximately 4 weeks after last patient last visit)

Fecha del cierre de la base de datos (la base de datos está previsto que se cierre aproximadamente 4 semanas después de la última visita del último paciente)

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 months

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:

616

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

154

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

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

360

F.4.2.2

In the whole clinical trial

770

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

Ninguno

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

2016-06-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-05-10

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-11-17

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