Clinical Trials Register

Summary
EudraCT Number:	2015-001596-48
Sponsor's Protocol Code Number:	NN9068-4229
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:	2016-02-08
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

2015-001596-48

A.3

Full title of the trial

A clinical trial comparing glycaemic control and safety of insulin degludec/liraglutide (IDegLira) versus insulin glargine (IGlar) as add-on therapy to SGLT2i in subjects with type 2 diabetes mellitus

Ensayo clínico para comparar el control glucémico y la seguridad de insulina degludec/liraglutida (IDegLira) frente a insulina glargina (IGlar) como tratamiento complementario a SGLT2i en sujetos con diabetes mellitus tipo 2.

A.3.1

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

A.3.2

Name or abbreviated title of the trial where available

DUAL? IX

A.4.1

Sponsor's protocol code number

NN9068-4229

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1168-9343

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	Novo Nordisk A/S
B.1.3.4	Country	Denmark
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	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	Novo Nordisk A/S
B.5.2	Functional name of contact point	Global Clinical Registry (GCR,1452)
B.5.3	Address:
B.5.3.1	Street Address	Novo Allé
B.5.3.2	Town/ city	Bagsværd
B.5.3.3	Post code	2880
B.5.3.4	Country	Denmark
B.5.6	E-mail	clinicaltrials@novonordisk.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	Xultophy
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.3.4	Pharmaceutical form	Solution for injection
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 DEGLUDEC
D.3.9.1	CAS number	844439-96-9
D.3.9.4	EV Substance Code	SUB96394
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.3.8 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/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	3.6
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	Lantus
D.2.1.1.2	Name of the Marketing Authorisation holder	Sanofi-Aventis
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.3.4	Pharmaceutical form	Solution for injection
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 GLARGINE
D.3.9.1	CAS number	160337-95-1
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	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

Diabetes Mellitus, Type 2

Diabetes Mellitus tipo 2

E.1.1.1

Medical condition in easily understood language

Type 2 diabetes

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	18.1
E.1.2	Level	LLT
E.1.2	Classification code	10045242
E.1.2	Term	Type II diabetes mellitus
E.1.2	System Organ Class	100000004861

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 confirm the effect of insulin degludec/liraglutide (IDegLira) in terms of glycaemic control in subjects with type 2 diabetes mellitus (T2DM) on previous treatment with sodium-glucose cotransporter 2 inhibitors (SGLT2i) ± oral anti-diabetic drug (OAD) therapy. This is done by comparing the difference in change from baseline in HbA1c after 26 weeks to a non-inferiority margin of 0.3% for IDegLira versus insulin glargine (IGlar), both in combination with SGLT2i ± OAD.

Confirmar el efecto de IDegLira en términos de control glucémico en sujetos con DMT2 en tratamiento previo con SGLT2i ± ADO. Esto se hará comparando la diferencia en la variación de la HbA1c con respecto al valor basal después de 26 semanas de tratamiento, con un margen de no inferioridad del 0,3% para IDegLira frente a IGlar, las dos en combinación con un SGLT2i ± ADO.

E.2.2

Secondary objectives of the trial

To confirm superiority of IDegLira versus IGlar after 26 weeks in subjects with T2DM on previous treatment with SGLT2i ± OAD therapy in terms of one or more of the following:

1. Weight change
2. Treatment-emergent hypoglycaemic episodes (severe or blood glucose [BG] confirmed symptomatic)
3. Glycaemic control
4. Insulin dose

To compare the effect and safety of IDegLira versus IGlar after 26 weeks

Confirmar la superioridad de IDegLira frente a IGlar tras 26 semanas en sujetos con DMT2 en tratamiento previo con un SGLT2i ± ADO en términos de uno o más de los siguientes:
1. Variación del peso
2. Episodios de hipoglucemia surgidos durante el tratamiento (graves o sintomáticos confirmados por el valor de glucosa sanguínea [GS])
3. Control de la glucemia
4. Dosis de insulina
Comparar el efecto y la seguridad de IDegLira frente a IGlar tras 26 semanas.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female, age higher or equal to 18 years at the time of signing informed consent
2. Subjects diagnosed (clinically) with type 2 diabetes mellitus
3. HbA1c 7.0-11.0% [53-97 mmol/mol] (both inclusive) by central laboratory analysis
4. Body mass index (BMI) higher or equal to 20 kg/m^2 and less than 40 kg/m^2
5. Insulin naïve subjects; however short term insulin treatment for a maximum of 14 days prior to the day of screening is allowed, as well as prior insulin treatment for gestational diabetes
6. A stable daily dose for at least 90 days prior to the day of screening of any SGLT2i in monotherapy or in combination with metformin ± DPP4i ± pioglitazone. Use of pioglitazone is not allowed in subjects treated with dapagliflozin

1. Sujetos de ambos sexos, mayor o igual a 18 años de edad en el momento de la firma del consentimiento informado.
2. Sujetos con diagnóstico (clínico) de diabetes mellitus tipo 2.
3. HbA1c del 7,0%-11,0% (ambos inclusive) según el análisis de laboratorio central.
4. Índice de masa corporal (IMC) mayor o igual a 20 kg/m2 y menor de 40 kg/m2.
5. Sujetos no tratados previamente con insulina; no obstante, se permite un tratamiento con insulina de corta duración, durante un máximo de 14 días previos al día de la selección, así como el tratamiento previo con insulina para la diabetes gestacional.
6. Dosis diaria estable, durante al menos los 90 días previos al día de la selección, de cualquier SGLT2i en monoterapia o en combinación con metformina ± DPP4i ± pioglitazona. El uso de pioglitazona no se permite en los sujetos tratados con dapagliflozina.

E.4

Principal exclusion criteria

1. Receipt of any investigational medicinal product within 90 days prior to screening
2. Use of any OADs (other than SGLT2i in monotherapy or in combination with metformin or DPP4i or pioglitazone as described in the inclusion criteria) within 90 days prior to the day of screening
3. Use of glucagon-like peptide-1 (GLP-1) receptor agonist (e.g., exenatide or liraglutide) within 90 days prior to the day of screening
4. Acute decompensation of glycaemic control requiring immediate intensification of treatment to prevent severe metabolic dysregulation (e.g., diabetes ketoacidosis) in the previous 90 days prior to the day of the screening
5. Subjects presently classified as being in NYHA Class III or IV
6. Renal impairment estimated Glomerular Filtration Rate less than 60 mL/min/1.73 m^2 as per CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration)
7. Impaired liver function, defined as ALT higher or equal to 2.5 times upper normal limit at screening
8. Known or suspected hypersensitivity to trial product(s) or related products

1. Tratamiento con cualquier producto en investigación en los 90 días previos al día de la selección.
2. Uso de cualquier ADO (salvo SGLT2i en monoterapia o en combinación con metformina o DPP4i o pioglitazona, según se describe en los criterios de inclusión) en los 90 días previos al día de la selección.
3. Uso de agonistas del receptor del péptido glucagonoide 1 (GLP-1) (por ejemplo, exenatida o liraglutida) en los 90 días previos al día de la selección.
4. Descompensación aguda del control de la glucemia que requiere una intensificación inmediata del tratamiento para prevenir alteraciones graves de la regulación metabólica (por ejemplo, cetoacidosis diabética) en los 90 días previos al día de la selección.
5. Sujetos clasificados actualmente en las clases III o IV de la NYHA1.
6. Insuficiencia renal, con una filtración glomerular estimada menor de 60 ml/min/1,73 m2 según la fórmula de la CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration).
7. Disfunción hepática, definida como ALT mayor o igual a 2,5 veces el límite superior de la normalidad en la selección.
8. Hipersensibilidad conocida o sospechada a los productos del ensayo o a productos relacionados.

E.5 End points

E.5.1

Primary end point(s)

Change from baseline in HbA1c

Variación de la HbA1c con respecto al valor basal

E.5.1.1

Timepoint(s) of evaluation of this end point

After 26 weeks

después de 26 semanas de tratamiento.

E.5.2

Secondary end point(s)

1. Change from baseline in body weight
2. Number of treatment-emergent severe or BG confirmed symptomatic hypoglycaemic episodes
3. Insulin dose, total daily dose (U)
4. Responder (Yes/No) for HbA1c less than 7.0%
5. Change from baseline in fasting plasma glucose (FPG)
6. Number of treatment-emergent adverse events

1. Variación del peso corporal con respecto al valor basal
2. Número de episodios de hipoglucemia surgidos durante el tratamiento, graves o sintomáticos confirmados por GS
3. Dosis de insulina, dosis diaria total (U).
4.Sujeto con respuesta (sí/no) para
HbA1c menor de 7,0%
5. Variación con respecto al momento basal de Glucosa plasmática en ayunas (GPA)
6. Número de acontecimientos adversos surgidos con el tratamiento

E.5.2.1

Timepoint(s) of evaluation of this end point

1. After 26 weeks
2. During 26 weeks
3. After 26 weeks
4. After 26 weeks
5. After 26 weeks
6. During 26 weeks

1. después de 26 semanas
2. durante las 26 semanas
3. después de 26 semanas
4. después de 26 semanas
5. después de 26 semanas
6. durante 26 semanas

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

Yes

E.6.13.1

Other scope of the trial description

To confirm superiority of trial drug

Confirmar la superioridad del producto de ensayo

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

Yes

E.8.1.7.1

Other trial design description

tratamiento por objetivo

Treat to target

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

Argentina

Canada

European Union

India

Switzerland

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

LVLS

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 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:

376

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

212

F.4.2.2

In the whole clinical trial

416

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

2016-04-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-04-18

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-10-23

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