Clinical Trials Register

Summary
EudraCT Number:	2015-004825-14
Sponsor's Protocol Code Number:	D1680C00016
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2016-03-18
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

2015-004825-14

A.3

Full title of the trial

A 24-Week, Multicenter, Randomized, Double-blind, Parallel Group,
Placebo-controlled Study to Investigate the Effects of Saxagliptin,
Saxagliptin Combined with Dapagliflozin, and Sitagliptin in Patients with
Type 2 Diabetes Mellitus and Heart Failure

Ensayo de 24 semanas, multicéntrico, aleatorizado, doble ciego con grupos paralelos y controlado con placebo para investigar los efectos de saxagliptina, saxagliptina combinada con dapagliflozina, y sitagliptina en pacientes con diabetes mellitus tipo 2 e insuficiencia cardíaca

A.3.1

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

A 24-Week study to investigate the effects of saxagliptin,saxagliptin combined with dapagliflozin, sitagliptin and placebo in patients with type 2 diabetes mellitus and heart failure.

Ensayo de 24 semanas para investigar los efectos de saxagliptina, saxagliptina combinada con dapagliflozina, sitagliptina y placebo en pacientes con diabetes mellitus tipo 2 e insuficiencia cardíaca

A.3.2

Name or abbreviated title of the trial where available

MEASURE-HF

MEASURE

A.4.1

Sponsor's protocol code number

D1680C00016

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	AstraZeneca AB
B.1.3.4	Country	Sweden
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	AstraZeneca AB
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AstraZeneca Farmacéutica Spain, S.A.
B.5.2	Functional name of contact point	Unidad de Investigación Clínica
B.5.3	Address:
B.5.3.1	Street Address	C/ Serrano Galvache, 56; Parque Norte, Edificio Álamo
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	28033
B.5.3.4	Country	Spain
B.5.4	Telephone number	900 200 444
B.5.6	E-mail	informacionEECC-Spain@astrazeneca.com

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	Forxiga
D.2.1.1.2	Name of the Marketing Authorisation holder	AstraZeneca 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	Dapagliflozin
D.3.4	Pharmaceutical form	Film-coated 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	DAPAGLIFLOZIN PROPANEDIOL
D.3.9.1	CAS number	960404-48-2
D.3.9.3	Other descriptive name	DAPAGLIFLOZIN PROPANEDIOL MONOHYDRATE
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	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: 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	Onglyza
D.2.1.1.2	Name of the Marketing Authorisation holder	AstraZeneca 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	Saxagliptin
D.3.4	Pharmaceutical form	Film-coated 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	SAXAGLIPTIN
D.3.9.1	CAS number	361442-04-8
D.3.9.3	Other descriptive name	SAXAGLIPTIN
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	5
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: 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	Onglyza
D.2.1.1.2	Name of the Marketing Authorisation holder	AstraZeneca 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	Saxagliptin
D.3.4	Pharmaceutical form	Film-coated 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	SAXAGLIPTIN
D.3.9.1	CAS number	361442-04-8
D.3.9.3	Other descriptive name	SAXAGLIPTIN
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	2.5
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: 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	Januvia
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Sharp & Dohme 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	Sitagliptin
D.3.4	Pharmaceutical form	Capsule
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	Sitagliptin phosphate
D.3.9.1	CAS number	654671-77-9
D.3.9.3	Other descriptive name	Sitagliptin phosphate
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	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	Januvia
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Sharp & Dohme 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	Sitagliptin
D.3.4	Pharmaceutical form	Capsule
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	Sitagliptin phosphate
D.3.9.1	CAS number	654671-77-9
D.3.9.3	Other descriptive name	Sitagliptin phosphate
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	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)	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	Film-coated 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	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 3
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule
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

Patients with type 2 diabetes mellitus and heart failure

Pacientes con diabetes mellitus tipo 2 e insuficiencia cardíaca.

E.1.1.1

Medical condition in easily understood language

Type 2 diabetes mellitus and heart failure

Diabetes mellitus tipo 2 e insuficiencia cardíaca

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.1
E.1.2	Level	PT
E.1.2	Classification code	10011078
E.1.2	Term	Coronary artery disease
E.1.2	System Organ Class	10007541 - Cardiac 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 exclude an increase in left ventricular end diastolic volume (LVEDV) index of greater than 10% (non-inferiority margin of 6.5 mL/m2) in patients with T2DM and HFtreated with saxagliptin for 24 weeks,compared to placebo.

Excluir el aumento del índice de volumen telediastólico ventricular izquierdo (VTDVI) de más del 10 % (margen de ausencia de inferioridad de 6,5 ml/m2) en pacientes con DMT2 e IC tratados con saxagliptina durante 24 semanas, en comparación con placebo.

E.2.2

Secondary objectives of the trial

- Evaluate the effects of saxagliptin compared to placebo on left ventricular end systolic volume (LVESV) index, left ventricular ejection fraction (LVEF), and left ventricular mass (LVM) after 24 weeks in patients with T2DM and HF

- Evaluate the effects of saxagliptin compared to placebo on N-terminal prohormone of brain natriuretic peptide (NT-proBNP) after 24 weeks of treatment

- Evaluar los efectos de saxagliptina en comparación con placebo en el índice de volumen telesistólico ventricular izquierdo (VTSVI), en la fracción de eyección ventricular izquierda (FEVI) y en la masa ventricular izquierda (MVI) después de 24 semanas en pacientes con DMT2 e IC.

- Evaluar los efectos de saxagliptina en comparación con placebo en la prohormona N-terminal del péptido natriurético cerebral (NT-proBNP) tras 24 semanas de tratamiento.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Provision of informed consent prior to any study specific procedure (Pre-screening
ICF and Informed Consent collected at screening)
2. Male or female, aged > o = 18 years at the time of consent
3. Documented, controlled T2DM, as defined by:
-Treatment with stable doses of antidiabetic medications that have not increased or decreased for > o = 8 weeks before screening
-No planned increases or reductions in antidiabetic medications during the study
-With central lab HbA1c > o =7.0% and < o = 9.0% value; for patients treated with sulfonylurea agents, central lab HbA1c > o = 7.5% and < o = 9.0% value; during prescreening or screening
4. HF demonstrated by all 3 of the following criteria:
-History of HF and LVEF < o = 45% within the last 6 months (echocardiogram, MRI, left ventriculography, or other accepted methodology). Patients without a recent assessment of LV function will undergo a local echocardiogram at the time of screening to determine ejection fraction
-Elevated NT-proBNP (>900 pg/mL) during screening
-Stable doses of HF medications (according to local standards of care), that have not increased or decreased (including diuretics, angiotensin converting enzyme [ACE] inhibitors or angiotensin receptor blocking [ARB] agents, beta blockers, and aldosterone antagonists) for > o = 8 weeks prior to screening
5. Stable HF, with no evidence of volume overload (no rales, jugular venous
distention, peripheral edema) at screening
6. Normal sinus rhythm
7. Body mass index 25 to 40 kg/m2, inclusive
8. Women of childbearing potential (WOCBP):
-Must be using appropriate birth control to avoid pregnancy throughout the study and for up to 4 weeks after the last dose of investigational product
-Must have a negative serum or urine pregnancy test within 72 hours prior to the start of investigational product
-Must not be breastfeeding

1. Firma del consentimiento informado antes de que se realice cualquier procedimiento específico del estudio (consentimiento informado de pre-selección y consentimiento informado del estudio en la seleccion).
2. Hombres o mujeres de > o = 18 años en el momento del consentimiento.
3. DMT2 controlada y documentada, definida según lo siguiente:
- Tratamiento con dosis estables de medicamentos antidiabéticos que no hayan aumentado ni disminuido durante > o = 8 semanas anteriores a la selección.
- Reducciones o aumentos no previstos en la medicación antidiabética durante el estudio.
- Resultado en Laboratorio Central de HbA1c > o = 7,0 % y < o = 9,0 %; para pacientes tratados con sulfonilureas, resultado en Laboratorio Central de HbA1c > o = 7,5 % y < o = 9,0 %; durante la preselección o la selección.
4.IC constatada mediante los 3 criterios siguientes:
- Historial de IC y FEVI < o = 45 % en los últimos 6 meses (ecocardiograma, RM, ventriculografía izquierda u otra metodología aceptada). Los pacientes sin evaluación reciente sobre la función del VI se someterán a un ecocardiograma local en el momento de la selección para determinar la fracción de eyección.
- NT-proBNP elevado (>900 pg/ml) durante la selección.
- Dosis estables de medicamentos para IC (según tratamiento de referencia aprobado), que no se hayan aumentado ni reducido (esto incluye diuréticos, inhibidores de la enzima convertidora de la angiotensina [ECA] o agentes bloqueadores del receptor de la angiotensina [BRA], betabloqueantes y antagonistas de la aldosterona) durante > o = 8 semanas anteriores a la selección.
5. IC estable, sin evidencias de hipervolemia (sin estertores, distensión venosa yugular ni edema periférico) en el momento de la selección.
6. Ritmo sinusal normal.
7. Índice de masa corporal de 25 a 40 kg/m2 inclusive.
8. Mujeres fértiles (MF):
- Deben emplear métodos anticonceptivos apropiados para evitar elembarazo durante el estudio y durante las 4 semanas posteriores a la administración de la última dosis del producto en investigación (PI).
- Deben tener una prueba de embarazo negativa en suero o en orina en el plazo de 72 horas antes del inicio de la administración del PI.
- No deben encontrarse en período de lactancia.

E.4

Principal exclusion criteria

1. MRI contraindications: all implanted defibrillators; implanted pacemakers and other
devices/implants that in the judgment of the investigator preclude an MRI evaluation
2. Atrial fibrillation
3. Receiving incretin therapy (DPP4 inhibitors, GLP-1 mimetics), or having received incretin therapy within the previous 3 months of screening
4. Receiving therapy with an SGLT2 inhibitor or having received SGLT2 inhibitor therapy within the previous 3 months of screening
5. Receiving therapy with a TZD or having received TZD therapy within the previous 3 months of screening
6. Type 1 diabetes mellitus
7. History of unstable or rapidly progressing renal disease
8. History of unexplained microscopic or gross hematuria
9. Previously documented bladder cancer
10. Volume depletion as judged by the investigator
11. A central lab eGFR value <45 mL/min/1.73 m2 on pre-screening or screening
12. New York Heart Association (NYHA) Class IV HF
13. Myocardial infarction, stroke, transient ischemic attack, or coronary revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass graft [CABG]) within the past 6 months of screening
14. Inoperable aortic or mitral valvular heart disease. Recent (within 6 months) or planned valvular heart procedure
15. Heart failure secondary to restrictive cardiomyopathy, active myocarditis, constrictive pericarditis, and hypertrophic obstructive cardiomyopathy
16. Previous cardiac transplantation or transplantation indicated or expected within 6 months of randomization
17. Contraindications to saxagliptin therapy as outlined in the saxagliptin Investigator?s Brochure, to dapagliflozin therapy as outlined in the dapagliflozin Investigator?s Brochure, or to sitagliptin therapy as outlined in the sitagliptin prescribing information
18. Current treatment with strong cytochrome P450 (CYP) 3A4/5 inhibitors
19. Involvement in the planning and/or conduct of the study (applies to both AZ staff and/or staff at the study site)
20. Previous enrollment or randomization in the present study
21. Participation in another clinical study with an investigational product during the last 30 days
22. Patients either employed by or immediate relatives of the Sponsor
23. Known human immunodeficiency virus (HIV) infection
24. Severe hepatic disease, including chronic active hepatitis. Positive serologic evidence of current infectious liver disease, including patients who are known to be positive for hepatitis B viral antibody IgM, hepatitis B surface antigen, or hepatitis C virus antibody; or aspartate transaminase (AST) or alanine transaminase (ALT)>3X the upper limit of normal; or total bilirubin (TB) >2 mg/dL
25. History of diabetic ketoacidosis (DKA) requiring medical intervention (eg, emergency room visit and/or hospitalization) within 1 month prior to the Screening visit
26. History of malignancy within the last 5 years, excluding successful treatment of basal or squamous cell skin cancer
27. Patients who, in the judgement of the investigator, may be at risk for dehydration
28. Pregnant, positive pregnancy test, planning to become pregnant during clinical trial or breast feeding
29. History of any clinically significant disease or disorder which, in the opinion of the investigator, may put the patient at risk because of participation in the study, may influence the results, or may limit the patient's ability to participate in or complete the study
30. Unable or unwilling to provide written informed consent

1. Contraindicaciones de la RM: cualquier desfibrilador implantado; marcapasos implantados y otros dispositivos/implantes que, según el criterio del investigador, impidan una evaluación mediante RM.
2. Fibrilación auricular.
3. Recibir tratamiento con incretinas (inhibidores de DPP4, miméticos de GLP-1) o haber recibido tratamiento con incretinas en los 3 meses previos a la selección.
4. Recibir tratamiento con un inhibidor de SGLT2 o haber recibido tratamiento con un inhibidor de SGLT2 en los 3 meses previos a la selección.
5. Recibir tratamiento con un inhibidor de TZD o haber recibido tratamiento con un inhibidor de TZD en los 3 meses previos a la selección.
6. Diabetes mellitus tipo 1.
7. Antecedentes de enfermedad renal inestable o de progreso rápido.
8. Antecedentes de hematuria microscópica o macroscópica sin causa aparente.
9. Cáncer de vejiga documentado previamente.
10. Hipovolemia a criterio del investigador.
11. Resultado en Laboratorio Central de eGFR <45 ml/min/1,73 m2 en el período de preselección o selección.
12. IC de clase IV según la Asociación de cardiología de Nueva York (NYHA).
13. Infarto de miocardio, accidente cerebrovascular, accidente isquémico transitorio o revascularización coronaria (intervención coronaria percutánea [ICP] o cirugía de derivación coronaria con injerto [CDCI]) en los 6 meses previos a la selección.
14. Valvulopatía aórtica o valvulopatía mitral no operables. Intervención quirúrgica por valvulopatía reciente (últimos 6 meses) o prevista.
15. IC secundaria a miocardiopatía restrictiva, miocarditis activa, pericarditis constrictiva o miocardiopatía obstructiva hipertrófica.
16. Trasplante cardíaco previo o trasplante indicado o previsto en un período de 6 meses tras la aleatorización
17. Contraindicaciones relacionadas con el tratamiento con saxagliptina tal como se describe en el manual del investigador (MI) de saxagliptina, con el tratamiento con dapagliflozina tal como se describe en el MI de dapagliflozina o con el tratamiento con sitagliptina tal como se describe en la información de prescripción de sitagliptina.
18. Tratamiento actual con inhibidores potentes del citocromo P450 (CYP) 3A4/5.
19. Implicación en la planificación o la realización del estudio (se aplica al personal de AZ o al personal del centro del estudio).
20. Inclusión o aleatorización previas en el estudio actual.
21. Participación en otro estudio clínico con un PI en los últimos 30 días.
22. Pacientes que trabajan para el promotor o que sean familiares directos.
23. Infección por el virus de la inmunodeficiencia humana (VIH) conocida.
24. Enfermedad hepática grave, incluida la hepatitis activa crónica. Evidencia serológica positiva de enfermedad hepática infecciosa actual, incluidos pacientes con un resultado positivo conocido de anticuerpos IgM contra el virus de la hepatitis B, antígeno de superficie del virus de la hepatitis B o anticuerpo del virus de la hepatitis C; o asparato transaminasa (AST) o alanina aminotransferasa (ALT) >3 x el límite superior de la normalidad; o bilirrubina total (BT) >2 mg/dl.
25. Antecedentes de cetoacidosis diabética (CAD) que haya requerido intervención médica (p. ej., visita a un centro de urgencias u hospitalización) en el mes previo a la visita de selección.
26. Antecedentes de neoplasia maligna en los últimos 5 años, excepto tratamiento con respuesta eficaz de carcinoma basocelular o epidermoide.
27. Pacientes que, según el criterio del investigador, pueden estar en riesgo de sufrir deshidratación.
28. Pacientes embarazadas, con prueba de embarazo positiva o que tengan previsto quedarse embarazadas durante el ensayo clínico o que se encuentren en período de lactancia.
29. Antecedentes de cualquier enfermedad o trastorno de importancia clínica que, según la opinión del investigador, pueda poner en riesgo al paciente debido a su participación en el estudio, pueda afectar a los resultados o limitar la capacidad del paciente para participar o finalizar el estudio.
30. Pacientes que no pueden o que se niegan a otorgar su consentimiento informado por escrito.

E.5 End points

E.5.1

Primary end point(s)

Change from baseline in LVEDV index measured by Magnetic Resonance Imaging (MRI)

Cambio con respecto al valor inicial del índice VTDVI medido mediante resonancia magnética (RM)

E.5.1.1

Timepoint(s) of evaluation of this end point

24 weeks

24 semanas

E.5.2

Secondary end point(s)

-Change from baseline in LVESV index, LVEF, and LVM measured by MRI
- Change from baseline in NT-proBNP

- Cambio con respecto al valor inicial en el índice VTSVI, FEVI y MVI medidos mediante RM.

- Cambio con respecto al valor inicial en NT-proBNP.

E.5.2.1

Timepoint(s) of evaluation of this end point

24 weeks

24 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

Yes

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)

Yes

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

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

Chile

Hungary

Korea, Republic of

Russian Federation

Spain

Taiwan

Thailand

United States

E.8.7

Trial has a data monitoring committee

Yes

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

Last Subject Last Visit (LSLV)

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:

375

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

F.4.2.2

In the whole clinical trial

440

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)

Standard of care

Cuidados standar.

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

2016-05-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-05-02

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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