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    Summary
    EudraCT Number:2017-004149-26
    Sponsor's Protocol Code Number:METRIS-HF
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2017-004149-26
    A.3Full title of the trial
    Effect of Metformin in insulin resistant patients with heart failure with reduced ejection fraction
    Effekt von Metformin bei insulinresistenten Patienten mit Herzinsuffizienz bei reduzierter Pumpleistung des Herzens
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Effect of Metformin in insulin resistant patients with heart failure with reduced ejection fraction
    Effekt von Metformin bei insulinresistenten Patienten mit Herzinsuffizienz bei reduzierter Pumpleistung des Herzens
    A.4.1Sponsor's protocol code numberMETRIS-HF
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorCharité Universitätsmedizin Berlin
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportDZHK
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCharité Universitätsmedizin
    B.5.2Functional name of contact pointProf. Dr. Wolfram Döhner
    B.5.3 Address:
    B.5.3.1Street AddressAugustenburger Platz 1
    B.5.3.2Town/ cityBerlin
    B.5.3.3Post code13353
    B.5.3.4CountryGermany
    B.5.4Telephone number4930450553507
    B.5.5Fax number49304507553507
    B.5.6E-mailwolfram.doehner@charite.de
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Sifor 1000
    D.2.1.1.2Name of the Marketing Authorisation holderBerlin-Chemie AG
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMetformin
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMetformine
    D.3.9.1CAS number 657-24-9
    D.3.9.3Other descriptive nameMETFORMIN HYDROCHLORIDE PH. EUR.
    D.3.9.4EV Substance CodeSUB172801
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1000
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Sifor 1000
    D.2.1.1.2Name of the Marketing Authorisation holderBerlin Chemie AG
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMetformin
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMetformine
    D.3.9.1CAS number 657-24-9
    D.3.9.3Other descriptive nameMETFORMIN HYDROCHLORIDE PH. EUR.
    D.3.9.4EV Substance CodeSUB172801
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOcular use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Heart Failure with reduced ejection fraction (HFrEF and HFmrEF)
    E.1.1.1Medical condition in easily understood language
    Heart Failure with reduced ejection fraction (HFrEF and HFmrEF)
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Improvement of myocardial contractility and functional capacity in patients with reduced EF (HFrEF and HFmrEF) and insulin resistance.
    E.2.2Secondary objectives of the trial
    Safety aspects of metformin therapy in patients with HFrEF
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full 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.3Principal inclusion criteria
    1. Signed Written Informed Consent prior to any study related measures
    2. Age ≥18 years,
    3. Patients with clinical signs 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.4Principal exclusion criteria
    1.1. Acute decompensated reduced EF (HFrEF and HFmrEF) requiring acute intravenous therapy or acute dehydration,
    2. Current treatment with metformin,
    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.5.1Primary 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.5.1.1Timepoint(s) of evaluation of this end point
    after 24 weeks therapy
    E.5.2Secondary 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):
    • 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.5.2.1Timepoint(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.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    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.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 88
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women 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.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state88
    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
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-06-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-06-26
    P. End of Trial
    P.End of Trial StatusOngoing
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