Danheart

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Aarhus Universitetshospital

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

completed 18 Feb 2026

Decision date (initial)

2024-09-10

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

The Aase and Ejnar Danielsens Foundation. 0.03 million Euro. · The Independent Research Fund Denmark (grant no. DFF 6110-00263). 0.34 million Euro. · The Novo Nordisk Foundation (grants no. NNF15OC0017450 and no. NNF18OC0052509). 0.5 million Euro. · The Danish Health Regions Research Fund (grant no. 15/1716). 0.33 million Euro. · The Danish Heart Foundation (grant no. 15-R100-A6113-93104). 3.7 million Euro.

External identifiers

EU CT number

2024-514212-27-00

EudraCT number

2015-002150-12

ClinicalTrials.gov

NCT03514108

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

In patients with chronic heart failure and reduced LVEF (40 % or less) on optimal treatment:

Hypothesis 1 (H-HeFT):
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).

Hypothesis 2 (Met-HeFT):
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

Secondary objectives 6

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

Conditions and MedDRA coding

Heart failure

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. 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.

Exclusion criteria 1

1. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. H-HeFT: 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).
2. Met-HeFT: A composite of total (first and recurrent) events in the primary 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 LVAD or acute myocardial infarction or stroke

Secondary endpoints 10

1. H-HeFT: 1. Individual components of the primary endpoint
2. H-HeFT: 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)
3. Met-HeFT: 1. Extended clinical endpoint: The primary endpoint or coronary revascularization or non-coronary revascularization or limb amputation.
4. Met-HeFT: 2. New diagnosis of diabetes mellitus
5. Met-HeFT: 3. Hospitalization/ death due to lactate acidosis
6. Met-HeFT: 4. Individual components of the primary endpoint
7. H-HeFT: Change in NT-proBNP from baseline to final follow-up
8. Met-HeFT: Change in NT-proBNP from baseline to final follow-up
9. Met-HeFT: Combined endpoint, first event: 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 LVAD or acute myocardial infarction or stroke
10. Met-HeFT: Total hospitalizations

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Aarhus Universitetshospital

Sponsor organisation

Aarhus Universitetshospital

Address

Palle Juul-Jensens Boulevard 99

City

Aarhus

Postcode

8200 N

Country

Denmark

Scientific contact point

Organisation

Aarhus Universitetshospital

Contact name

Henrik Wiggers

Public contact point

Organisation

Aarhus Universitetshospital

Contact name

Henrik Wiggers

Third parties 1

Locations

1 EU/EEA country · 20 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 14 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications