Clinical trial NCT03514108: DANHEART (H-HeFT and Met-HeFT)
Official title: A Randomized, Double-blind, Placebo Controlled Study (DANHEART): Hydralazine-ISDN in Patients With Chronic Heart Failure - Hydralazine Heart Failure Trial (H-HeFT) and Metformin in Patients With Chronic Heart Failure and Diabetes or Insulin Resistance - Metformin Heart Failure Trial (Met-HeFT)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Heart Failure
Diabetes
Keywords: Heart failure
Diabetes
Insulin resistance
Metformin
Hydralazine
Isosorbide Dinitrate
Lead sponsor: Aarhus University Hospital
Sponsor class: OTHER
Collaborators: name: Danish Heart Foundation
name: Danish Council for Independent Research
name: The Danish Regions: Foundation for Medical Research
name: The Novo Nordisk Foundation
name: The Aase og Ejnar Danielsen Foundation
First posted: 2018-05-02
Enrollment: 1500
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Intervention model description: Patients can be allocated to either

1. both Hydralazine Isosorbide Dinitrate / Placebo and Metformin hydrochloride / Placebo
2. to only Hydralazine Isosorbide Dinitrate / Placebo.
3. to only Metformin hydrochloride / Placebo.

Patient characteristics are entered in an electronic CRF. According to in- and exclusion criteria they are randomized in three blocks:

1. Patients receiving both Hydralazine Isosorbide Dinitrate / Placebo and Metformin hydrochloride / Placebo
2. Patients receiving only Hydralazine Isosorbide Dinitrate / Placebo and
3. Patients receiving only Metformin hydrochloride / Placebo

Analysis will be performed in:

1. all patients who have received Hydralazine Isosorbide Dinitrate / Placebo (H-HeFT) and
2. all patients who have received Metformin hydrochloride / Placebo (Met-HeFT)

The study is event driven. Anticipated: both H-HeFT and Met-HeFT 900, only H-HeFT 400, only Met-HeFT 200 patients.
Primary purpose: TREATMENT

Brief summary: The present study is testing in a combined design to types of drugs in patients with chronic heart failure: 1) Hydralazine in combination with isosorbide dinitrate (BiDil) and 2) Metformin hydrochloride. The study is double blind, placebo controlled.

1. The first hypothesis is that hydralazine in combination with isosorbide dinitrate can reduce mortality and hospitalization with worsening heart failure in chronic heart failure patients with reduced LVEF.
2. The second hypothesis is that treatment with metformin in chronic heart failure patients with reduced LVEF and type 2 diabetes / diabetes risk / insulin resistance can reduce mortality and cardiovascular hospitalizations. Among secondary endpoints are reduction in new-onset diabetes in heart failure patients with insulin resistance and diabetes risk profile and patient safety.


Eligibility criteria: 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. The 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) 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)

Specific inclusion criteria for only Met-HeFT:

Patients must have a diagnosis of type 2 diabetes or insulin resistance or diabetes risk. This includes 1 or more of any of the following:

* A previous diagnosis of type 2 diabetes at any time without Metformin treatment during the last 3 months
* HbA1c ≥ 5.5 % (≥ 37 mmol/mol) within 12 months prior to screening
* Fasting P-glucose ≥ 5.6 mmol/l within 12 months prior to 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 randomization: 2 hour P-glucose ≥ 7.8 mmol/l
* In addition, patients in Met-HeFT must have eGFR ≥ 35 ml/min (MDRD)

Patients are randomized through an internet based randomization module. Patients can be allocated to a) both H-HeFT and Met-HeFT or to b) only H-HeFT or to c) only Met-HeFT.

Primary outcomes:
measure: H-HeFT combined primary endpoint
timeFrame: Through study completion, an average of 4 years
measure: Met-HeFT combined primary endpoint of total (first and recurrent) events
timeFrame: Through study completion, an average of 4 years
Secondary outcomes:
measure: H-HeFT secondary endpoint: Death
timeFrame: Through study completion, an average of 4 years
measure: H-HeFT secondary endpoint: Hospitalization with worsening heart failure or urgent visit resulting in intravenous therapy or metolazone therapy for heart failure
timeFrame: Through study completion, an average of 4 years
measure: H-HeFT secondary endpoint: Combined endpoint: Death or cardiovascular hospitalization or urgent heart failure visit
timeFrame: Through study completion, an average of 4 years
measure: H-HeFT: All-cause, total (first and subsequent) hospitalizations
timeFrame: Through study completion, an average of 4 years
measure: H-HeFT: Recurrent event analysis
timeFrame: Through study completion, an average of 4 years
measure: H-HeFT: Change in NT-proBNP from baseline to final follow-up
timeFrame: Through study completion, an average of 4 years
measure: Met-HeFT secondary endpoint: Combined endpoint of first event
timeFrame: Through study completion, an average of 4 years
measure: Met-HeFT secondary endpoint: Extended clinical endpoint (recurrent events): The primary endpoint or coronary revascularization or non-coronary revascularization or limb amputation.
timeFrame: Through study completion, an average of 4 years
measure: Met-HeFT: Met-HeFT secondary endpoint: Extended clinical endpoint (first event analysis): The primary endpoint or coronary revascularization or non-coronary revascularization or limb amputation.
timeFrame: Through study completion, an average of 4 years
measure: Met-HeFT secondary endpoint: Death
timeFrame: Through study completion, an average of 4 years
measure: Met-HeFT secondary endpoint: Hospitalization with worsening heart failure or urgent visit resulting in intravenous therapy or metolazone therapy for heart failure
timeFrame: Through study completion, an average of 4 years
measure: Met-HeFT secondary endpoint: Acute myocardial infarction
timeFrame: Through study completion, an average of 4 years
measure: Met-HeFT secondary endpoint: Stroke
timeFrame: Through study completion, an average of 4 years
measure: Met-HeFT secondary endpoint: New onset type 2 diabetes
timeFrame: Through study completion, an average of 4 years
measure: Met-HeFT secondary endpoint: Hospitalization or death caused by lactic acidosis.
timeFrame: Through study completion, an average of 4 years
measure: Met-HeFT: All-cause, total (first and subsequent) hospitalizations
timeFrame: Through study completion, an average of 4 years
measure: Met-HeFT: Change in NT-proBNP from baseline to final follow-up
timeFrame: Through study completion, an average of 4 years
Other outcomes:
Locations:
city: Holbæk
country: Denmark
facility: Holbæk Hospital
state: Region Sjælland
city: Aabenraa
country: Denmark
facility: Sygehus Sønderjylland, Aabenraa
city: Aalborg
country: Denmark
facility: Aalborg University Hospital
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
city: Copenhagen
country: Denmark
facility: Amager Hospital
city: Copenhagen
country: Denmark
facility: Bispebjerg Hospital
city: Copenhagen
country: Denmark
facility: Gentofte Hospital
city: Copenhagen
country: Denmark
facility: Glostrup Hospital
city: Copenhagen
country: Denmark
facility: Herlev Hospital
city: Copenhagen
country: Denmark
facility: Hvidovre Hospital
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Esbjerg
country: Denmark
facility: Sydvestjysk Sygehus, Esbjerg
city: Herning
country: Denmark
facility: Herning Hospital
city: Hillerød
country: Denmark
facility: Nordsjællands Hospital Hillerød
city: Hjørring
country: Denmark
facility: Regionshospital Nordjylland, Hjørring
city: Holbæk
country: Denmark
facility: Holbæk Hospital
city: Horsens
country: Denmark
facility: Horsens Hospital
city: Kolding
country: Denmark
facility: Kolding Hospital
city: Nykøbing Falster
country: Denmark
facility: Nykøbing Falster Hospital
city: Odense
country: Denmark
facility: Odense University Hospital
city: Randers
country: Denmark
facility: Randers Hospital
city: Roskilde
country: Denmark
facility: Sjællands Universitetshospital, Roskilde
city: Silkeborg
country: Denmark
facility: Silkeborg Hospital
city: Slagelse
country: Denmark
facility: Slagelse Sygehus
city: Vejle
country: Denmark
facility: Vejle Hospital
city: Viborg
country: Denmark
facility: Viborg Hospital
Study officials:
affiliation: Dept. of Cardiology, Aarhus University Hospital, Aarhus, Denmark
name: Henrik Wiggers, MD, PhD
role: STUDY_CHAIR
affiliation: Dept. of Cardiology, Rigshospitalet, Copenhagen, Denmark
name: Lars Køber, MD, PhD
role: STUDY_CHAIR
affiliation: Dept. of Cardiology, Rigshospitalet, Copenhagen, Denmark
name: Finn Gustafsson, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Dept. of Cardiology, Aarhus University Hospital, Aarhus, Denmark
name: Søren Mellemkjaer, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: The Danish Heart Foundation, Copenhagen, Denmark
name: Gunnar Gislason, MD, PhD
role: STUDY_CHAIR
References:
citation: Wiggers H, Kober L, Gislason G, Schou M, Poulsen MK, Vraa S, Nielsen OW, Bruun NE, Norrelund H, Hollingdal M, Barasa A, Bottcher M, Dodt K, Hansen VB, Nielsen G, Knudsen AS, Lomholdt J, Mikkelsen KV, Jonczy B, Bronnum-Schou J, Poenaru MP, Abdulla J, Raymond I, Mahboubi K, Sillesen K, Serup-Hansen K, Madsen JS, Kristensen SL, Larsen AH, Botker HE, Torp-Petersen C, Eiskjaer H, Moller J, Hassager C, Steffensen FH, Bibby BM, Refsgaard J, Hofsten DE, Mellemkjaer S, Gustafsson F. The DANish randomized, double-blind, placebo controlled trial in patients with chronic HEART failure (DANHEART): A 2 x 2 factorial trial of hydralazine-isosorbide dinitrate in patients with chronic heart failure (H-HeFT) and metformin in patients with chronic heart failure and diabetes or prediabetes (Met-HeFT). Am Heart J. 2021 Jan;231:137-146. doi: 10.1016/j.ahj.2020.09.020. Epub 2020 Oct 9.