Clinical Trials Register

Summary
EudraCT Number:	2017-004149-26
Sponsor's Protocol Code Number:	METRIS-HF(EMPA)
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-03-21
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Germany - BfArM

A.2

EudraCT number

2017-004149-26

A.3

Full title of the trial

Effect of Metformin and Empagliflozin in insulin resistant patients with heart failure with reduced ejection fraction

Effekt von Metformin und Empagliflozin bei insulinresistenten Patienten mit Herzinsuffizienz bei reduzierter Pumpleistung des Herzens

A.3.1

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

Effect of Metformin and Empagliflozin in insulin resistant patients with heart failure with reduced ejection fraction

Effekt von Metformin und Empagliflozin bei insulinresistenten Patienten mit Herzinsuffizienz bei reduzierter Pumpleistung des Herzens

A.4.1

Sponsor's protocol code number

METRIS-HF(EMPA)

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	Charité Universitätsmedizin Berlin
B.1.3.4	Country	Germany
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	DZHK
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Charité Universitätsmedizin
B.5.2	Functional name of contact point	Prof. Dr. Wolfram Döhner
B.5.3	Address:
B.5.3.1	Street Address	Augustenburger Platz 1
B.5.3.2	Town/ city	Berlin
B.5.3.3	Post code	13353
B.5.3.4	Country	Germany
B.5.4	Telephone number	4930450553507
B.5.5	Fax number	49304507553507
B.5.6	E-mail	wolfram.doehner@charite.de

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	Sifor 1000
D.2.1.1.2	Name of the Marketing Authorisation holder	Berlin-Chemie AG
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Metformin
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	Metformine
D.3.9.1	CAS number	657-24-9
D.3.9.3	Other descriptive name	METFORMIN HYDROCHLORIDE PH. EUR.
D.3.9.4	EV Substance Code	SUB172801
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	1000
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	Sifor 1000
D.2.1.1.2	Name of the Marketing Authorisation holder	Berlin Chemie AG
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Metformin
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	Metformine
D.3.9.1	CAS number	657-24-9
D.3.9.3	Other descriptive name	METFORMIN HYDROCHLORIDE PH. EUR.
D.3.9.4	EV Substance Code	SUB172801
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	500
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	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	Jardiance Filmtabletten (10 mg)
D.2.1.1.2	Name of the Marketing Authorisation holder	Boehringer Ingelheim International GmbH
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	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	empagliflozin
D.3.9.1	CAS number	864070-44-0
D.3.9.3	Other descriptive name	EMPAGLIFLOZIN
D.3.9.4	EV Substance Code	SUB35915
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.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	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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Heart Failure with reduced ejection fraction (HFrEF and HFmrEF)

E.1.1.1

Medical condition in easily understood language

Heart Failure with reduced ejection fraction (HFrEF and HFmrEF)

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Improvement of myocardial contractility and functional capacity in patients with reduced EF (HFrEF and HFmrEF) and insulin resistance in comparison with two control groups (empaglifozin and placebo).

E.2.2

Secondary objectives of the trial

Safety aspects of metformin therapy in patients with HFrEF

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

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

MRI substudy (1):
to assess by proton-spectroscopy (MRS) to assessment the change of myocardial triglyceride content (MTG) in comparison to the skeletal muscle before and after treatment with metformin.

MRI substudy (2):
to assess by 31P-MR phosphate spectroscopy the change of energy intermediates (phosphocreatine: ATP ratio) of the skeletal muscle before and after treatment with metformin.

Microdialysis substudy (3):
to assess in skeletal muscle interstitial fluid key intermediates of energy substrates (glycolysis and lipolysis).

Microbiome/immune substudy (4):
to assess in stool samples microbiome and immune cell signature changes before and after metformin therapy.

E.3

Principal inclusion criteria

1. Signed Written Informed Consent prior to any study related measures
2. Age ≥18 years,
3. Patients with Symptoms of heart failure (NYHA II-III) in stable ambulatory condition,
4. Patients with the diagnosis of HF for > 6 months
5. Left ventricular ejection fraction (LVEF) ≤50% ,
6. 6-minute walking distance of <450m,
7. Elevated natriuretic peptides (BNP ≥100pg/mL or N-terminal-pro-BNP ≥300 pg/mL),
8. Current standard medication for reduced EF (HFrEF and HFmrEF) therapy according to guideline recommendations in individually optimized doses,
9. Patients need to be free of signs of acute decompensated HF, but can be recruited at the end of a hospital stay, if clinically stabilised,
10. Presence of insulin resistance (e.g. HOMA-IR ≥ 2.0; SPISE index < 6.87 or Quicky index < 0.32)
11. Willing and capable of providing informed consent, participating in all associated study activities

E.4

Principal exclusion criteria

1.1. Acute decompensated heart failure reduced EF (HFrEF and HFmrEF) requiring acute intravenous therapy or acute dehydration,
2. Current treatment with metformin or empagliflozin
3. Known hypersensitivity or contraindication for Metformin or to any of the excipients of the Investigational Medicinal Product (IMP) or placebo,
4. Type I DM,
5. Diagnosed DM (HbA1c >7.5 or existing medical treatment for DM),
6. Clinical signs or symptoms of dehydration requiring iv volume therapy,
7. impaired kidney function >CKD stage III (GFR <30 ml/min/1.73m2),
8. Acute infection requiring antibiotic therapy,
9. Any clinical condition that limits the life expectancy <1y
10. Incapability to participate in the trial,
11. Acute systemic illness, malignancy, inflammatory disease, requiring, antibiotic therapy, immune-suppressive - or steroid therapy,
12. Lack of willingness to storage and disclosure of pseudonymous disease data in the context of the clinical trial,
13. Subject with participation in another interventional clinical trial during this study or within 30 days (or longer) before entry into this trial (as a minimum; 5 x elimination half-life / terminal elimination of an IMP),
14. Subjects who are legally detained in an official institution,
15. Subjects who may be dependent on the sponsor, the investigator or the trial sites, have to be excluded from the trial,
16. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) urine test,
17. For female patients of reproductive potential: Unwilling to agree to use a highly effective method of contraception (Pearl index <1) throughout the study period,

Exclusion criteria that occur in the course of the study do not necessarily lead to study discontinuation. Depending on the exclusion criterion, the investigator may consider interruption or discontinuation of the IMP if it occurs during the course of IMP intake.

E.5 End points

E.5.1

Primary end point(s)

Change in global longitudinal strain (GLS) of the left ventral (LV) after 24-week therapy. Primary endpoint assessed by Cardiac MR and by echocardiography in patients not eligible for MR.

E.5.1.1

Timepoint(s) of evaluation of this end point

after 24 weeks therapy

E.5.2

Secondary end point(s)

Key secondary endpoints (at 24 weeks):
• Change in 6min-walking distance
• Patient global assessment (PGA)

Other secondary endpoints (at 24 and 52 weeks)
• Change in 6 min walking distance (52w)
• Patient global assessment (52w)
• Change in NYHA functional class
• Change in Quality of life assessed by EQ5-D and Kansas City Cardiomyopathy Questionnaire (KCCQ)
• Change in plasma levels of brain-type natriuretic peptides (BNP)

Other exploratory endpoints (at 24 weeks and at 52 weeks), metformin vs. empaliflozin:
• Change in echocardiographic measures of LV function and morphology
• Change in insulin sensitivity (e.g. HOMA-IR, SPISE index or Quicky index)
• Change in MR measures of LV function and structure at rest and under isometric handgrip exercise (MRI-sub-study, 24 weeks only)
• Change in myocardial and skeletal muscle triglyceride content assessed by MTG MR Spectroscopy (MRI-sub-study, 24 weeks only)
• Change in skeletal muscle phosphocreatinine and ATP levels assessed by 31p MR Spectroscopy
• Change in skeletal muscle glycolytic and lipolytic activity (Microdialysis substudy, 24 weeks)
• Change in plasma profile of energy substrate metabolites (Lipid profile, FFS, glycerol, pyruvate, ketone bodies, lactate)
• Changes in plasma levels of kidney function, liver function and inflammation
• Changes in fecal microbiome after metformin vs. Placebo (microbiome substudy)
• Decrease of lymphocytic pro-inflammatory mediators after metfomin vs. Placebo

E.5.2.1

Timepoint(s) of evaluation of this end point

at week 24 and / or at week 52

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

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

empaliflozin

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LPLV (end of Treatment in week 24)

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:

F.1.3

Elderly (>=65 years)

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

F.3.3.1

Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2018-03-21.

Yes

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.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)

After completing all the protocol treatment and visits, patients will continue with regular medical care according to the usual practice.

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

2018-06-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-06-26

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2024-02-28

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