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    Summary
    EudraCT Number:2015-002150-12
    Sponsor's Protocol Code Number:DANSVIGT
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2017-06-01
    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 ConcernedDenmark - DHMA
    A.2EudraCT number2015-002150-12
    A.3Full title of the trial
    DanHeart (H-HeFT / Met-HeFT)
    Hydralazine-ISDN in Patients With Chronic Heart Failure - Hydralazine Heart Failure Trial (H-HeFT)

    Metformin in Patients with Chronic Heart Failure and Diabetes or Insulin Resistance -
    Metformin Heart Failure Trial (Met-HeFT)

    A randomized, 2 x 2 factorial designed, double-blind, placebo controlled study
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    DanHeart
    A.3.2Name or abbreviated title of the trial where available
    DanHeart (H-HeFT / Met-HeFT)
    A.4.1Sponsor's protocol code numberDANSVIGT
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03514108
    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 SponsorDanish Society of Cardiology, Heart Failure Working Group
    B.1.3.4CountryDenmark
    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 supportThe Danish Heart Foundation
    B.4.2CountryDenmark
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationDAN-HeFT Study Group
    B.5.2Functional name of contact pointDAN-HeFT Study Group
    B.5.3 Address:
    B.5.3.1Street AddressPalle Juul-Jensens Boulevard 99
    B.5.3.2Town/ cityAarhus
    B.5.3.3Post code8200 N
    B.5.3.4CountryDenmark
    B.5.6E-mailhenrikwiggers@dadlnet.dk
    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 No
    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 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 INNMETFORMIN HYDROCHLORIDE
    D.3.9.1CAS number 1115-70-4
    D.3.9.4EV Substance CodeSUB03200MIG
    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.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 BiDil
    D.2.1.1.2Name of the Marketing Authorisation holderArbor Pharmaceuticals, LCC, Six Concourse Parkway, Suite 1800, Atlanta, Georgia, USA
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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 nameBiDil
    D.3.4Pharmaceutical form 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 INNISOSORBIDE DINITRATE
    D.3.9.1CAS number 87-33-2
    D.3.9.4EV Substance CodeSUB08335MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDIHYDRALAZINE HYDROCHLORIDE
    D.3.9.1CAS number 304-20-1
    D.3.9.4EV Substance CodeSUB01701MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number37.5
    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 placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Heart Failure
    E.1.1.1Medical condition in easily understood language
    Heart Failure
    Heart Failure is a condition where the heart is damaged and cannot deliver sufficient amount of blood flow to the body at rest and/ or during exercise.
    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
    In patients with chronic heart failure and reduced LVEF on optimal treatment:

    R1) Hydralazine-ISDN reduces incidence of death and hospitalization with worsening heart failure or an urgent visit resulting in intravenous therapy or metolazone therapy for heart failure or heart transplantation or implantation of a left ventricular assist device (LVAD).

    R2) Metformin reduces incidence of death and cardiovascular hospitalizations (worsening heart failure or heart transplantation or implantation of a left ventricular assist device (LVAD) or acute myocardial infraction or stroke) and urgent visits resulting in intravenous therapy or metolazone therapy for heart failure
    E.2.2Secondary objectives of the trial
    BiDil:
    1. Individual components of the primary endpoint
    2. Combined endpoint: Death or cardiovascular hospitalizations (hospitalization with worsening heart failure or heart transplantation or implantation of a left ventricular assist device (LVAD) or acute myocardial infarction or stroke) or an urgent visit resulting in intravenous therapy or metolazone therapy for heart failure

    Metformin:
    1. Individual components of the primary endpoint
    2. Extended clinical endpoint: The primary endpoint or coronary revascularization or non-coronary revascularization or limb amputation
    3. New-onset T2D
    4. Hospitalization/ death caused by: lactate acidosis.

    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Substudies are planned. Some are listed below:

    Echocardiography
    Hemodynamics
    Magnetic resonance imaging
    Positron emission tomography
    Muscle strength
    Quality of life
    Biomarkers
    Genetics
    E.3Principal inclusion criteria
    General inclusion criteria for both H-HeFT and Met-HeFT
    - Patients with chronic heart failure
    - NYHA-class II, III or IV
    - LVEF </= 40% within 12 months prior to screening (echocardiography should (i) be performed after uptitration in heart failure medication and (ii) LVEF from the most recently performed echocardiographic study should be used and (iii) LVEF must not be measured during rapid atrial fibrillation, i.e. heart rate >110/min) and (iiii) if treatment with ACE-inhibitor/ ARB is switched to treatment with Entresto, no new echocardiography is required and (iiiii) the echocardiography should be performed at least 3 months after CRT-implantation.
    - Patients should be uptitrated to recommended or maximally tolerated dose of ACE-I/ARB/ARNI (unless contraindicated) and beta-blocker (unless contraindicated). If indicated, an aldosterone receptor antagonist should be given (unless contraindicated).
    - A CRT device should be implanted, if indicated and accepted by the patient and patients with a CRT device should be treated for > 3 months.
    - Implantation of an ICD unit should be planned or already done, if indicated and accepted by the patient. The patient can be included in the study before a planned ICD implantation has been performed.
    - Informed consent

    Specific inclusion criteria for only H-HeFT:
    - Systolic blood pressure ≥100 mmHg
    - NT-proBNP > 350 pg/ml or BNP > 80 pg/ml (in patients treated with ARNI, NT-proBNP must be used). NT-proBNP or BNP should be measured (i) within 12 months prior to screening (ii) after uptitration of heart failure medication and at least 3 months after CRT implantation and (iii) the latest measurement before screening must be used. (iiii) If no NT-proBNP or BNP measurement is available that fulfils the above criteria, the NT-proBNP or BNP at screening must be used.

    Specific inclusion criteria for only Met-HeFT:
    Patients must have a diagnosis of diabetes or insulin resistance or diabetes risk. This includes 1 or more of any of the following:
    - A previous diagnosis of Diabetes type 2 at any time without Metformin treatment during the last 3 months
    - HbA1c ≥ 5.5 % (≥ 37 mmol/mol) measured either (i) within 12 months prior to screening or (ii) at screening
    - Fasting P-glucose ≥ 5.6 mmol/l measured either (i) within 12 months prior to screening or (ii) at screening (measured when the patient in stable condition / has no intercurrent illness)
    - Body mass index ≥ 30 kg/m2
    - If oral glucose tolerance testing (OGTT) has been performed at any time prior to screening: 2 hour P-glucose ≥ 7.8 mmol/l
    - In addition, patients in Met-HeFT must have eGFR ≥ 35 ml/min (MDRD). eGFR can be measured within 4 weeks prior to screening if the patient at the time of measurement is uptitrated to maximally tolerated/ recommended heart failure medication and clinically stable.

    Patients in Met-HeFT can be included regardless of NT-proBNP / BNP levels

    Patients are randomized to R1 and R2 through an internet based randomization module.
    Patients can be allocated to a) both R1 and R2 or to b) only R1 or to c) only R2.
    E.4Principal exclusion criteria
    For both H-HeFT and Met-HeFT
    - Acute myocardial infarction, unstable angina or revascularization < 1 month at the time of randomization
    - Planned coronary artery bypass grafting or cardiac valve replacement
    - Severe, symptomatic, uncorrected aortic valve stenosis or primary, severe mitral valve disease
    - Atrial fibrillation with poorly controlled ventricular rate at rest (> 110 beats/min)
    - Known hypertrophic or restrictive cardiomyopathy, infiltrative or storage myocardial disease, active myocarditis, or pericardial disease.
    - Listed for heart transplantation.
    - Female patients who are pregnant, nursing, or of childbearing potential while not practicing effective chemical contraceptive methods (i.e. oral, implanted, injectable, or transdermal contraceptive hormones; intrauterine device)
    - Age < 18 years
    - Stroke within the last 1 month
    - Significant liver disease and/ or P-ALAT >3 times upper normal limit (it is possible to repeat this measurement within 3 months)
    - Significant comorbidity or issue which makes the patient unsuitable for participation as judged by the investigator
    - Participation in another double blind drug trial (participation in device studies is allowed)

    Only for H-HeFT
    - Severe, symptomatic hypotension
    - Contraindications to the use of hydralazine therapy
    - African descent
    - Treatment with Viagra or other PDE-5-inhibitor or soluble guanylate cyclase stimulator that cannot be discontinued
    - Treatment with long-acting mono- or di-nitrates, that cannot be discontinued

    Only for Met-HeFT
    - Known allergy to Metformin or major side effects to Metformin treatment
    - Type 1 diabetes
    E.5 End points
    E.5.1Primary end point(s)
    BiDil: Combined endpoint: Death or hospitalization with worsening heart failure or an urgent visit resulting in intravenous therapy or metolazone therapy for heart failure or heart transplantation or implantation of a left ventricular assist device (LVAD).

    Metformin: Combined endpoint: Death or cardiovascular hospitalizations (hospitalization with worsening heart failure or heart transplantation or implantation of a left ventricular assist device (LVAD) or acute myocardial infarction or stroke) or an urgent visit resulting in intravenous therapy or metolazone therapy for heart failure

    E.5.1.1Timepoint(s) of evaluation of this end point
    After a mean follow-up of approximately 4 years.
    The study is endpoint driven.
    E.5.2Secondary end point(s)
    H-HeFT
    1. Individual components of the primary endpoint
    2. Combined endpoint: Death or cardiovascular hospitalizations (hospitalization with worsening heart failure or heart transplantation or implantation of a left ventricular assist device (LVAD) or acute myocardial infarction or stroke or acute myocardial infarction or stroke)

    Metformin:
    1. Extended clinical endpoint: The primary endpoint or coronary revascularization or non-coronary revascularization or limb amputation.
    2. New diagnosis of diabetes mellitus
    3. Hospitalization/ death due to lactate acidosis,
    4. Individual components of the primary endpoint

    List of all endpoints evaluated by the endpoint committe:
    • Death (including suspected cause of death)
    • Hospitalization with worsening of heart failure
    - an urgent visit resulting in intravenous therapy or metolazone therapy for heart failure
    - heart transplantation or implantation of a left ventricular assist device (LVAD).
    • Non-fatal acute myocardial infarction
    • Non-fatal stroke
    • Coronary revascularization
    • Non-coronary arterial revascularization / surgery (e.g. peripheral vascular arterial surgery, carotid surgery) and limb amputations
    • New onset diabetes
    • Hospitalization/death due to lactate acidosis
    E.5.2.1Timepoint(s) of evaluation of this end point
    After a mean follow-up of 4 years, except for quality of life
    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 No
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) Yes
    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 Yes
    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.8.2.4Number of treatment arms in the trial6
    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 concerned20
    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 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months
    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: 500
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 1000
    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 Yes
    F.3.3.1Women of childbearing potential not using contraception No
    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 state1500
    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)
    In diabetic patients: plan for future anti-glycemic treatment and control after study medication (Metformin/Placebo) is stopped.

    All patients will be followed in a registry study
    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 Decision2017-10-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-09-15
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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