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DANHEART (H-HeFT and Met-HeFT) (DANHEART)

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ClinicalTrials.gov Identifier: NCT03514108
Recruitment Status : Recruiting
First Posted : May 2, 2018
Last Update Posted : July 2, 2019
Sponsor:
Collaborators:
Danish Heart Foundation
Danish Council for Independent Research
The Danish Regions: Foundation for Medical Research
The Novo Nordisk Foundation
The Aase og Ejnar Danielsen Foundation
Information provided by (Responsible Party):
Henrik Wiggers, Aarhus University Hospital

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.
  2. The second hypothesis is that treatment of underlying insulin resistance/ type 2 diabetes with metformin in heart failure patients with moderately to severely reduced LVEF 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.

Condition or disease Intervention/treatment Phase
Heart Failure Diabetes Drug: Hydralazine Isosorbide Dinitrate Drug: Placebo Oral Tablet Drug: Metformin Hydrochloride Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1500 participants
Allocation: Randomized
Intervention Model: Factorial Assignment
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.

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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)
Actual Study Start Date : March 1, 2018
Estimated Primary Completion Date : March 1, 2023
Estimated Study Completion Date : September 1, 2023


Arm Intervention/treatment
Active Comparator: Hydralazine Isosorbide Dinitrate

Tablet BiDil (Hydralazine 37.5 mg/ isosorbide dinitrate (ISDN) 20 mg) 2 tablets x 3 daily.

Average treatment period 4 years.

Drug: Hydralazine Isosorbide Dinitrate
Tablet BiDil (Hydralazine 37.5 mg/ Isosorbide Dinitrate (ISDN) 20 mg) 2 tablets x 3 daily
Other Name: BiDil

Placebo Comparator: Placebo (Hydralazine Isosorbide Dinitrate)
Tablet Placebo 2 tablets x 3 daily. Average treatment period 4 years.
Drug: Placebo Oral Tablet
2 tablets x 3 daily

Active Comparator: Metformin
Tablet Metformin hydrochloride 500 mg 2 tablets x 2 daily (eGFR 35-60 ml/min: 500 mg x 2 daily). Average treatment period 4 years.
Drug: Metformin Hydrochloride
Tablet Metformin hydrochloride 500 mg 2 tablets x 2 daily (eGFR 35-60 ml/min: 500 mg x 2 daily)

Placebo Comparator: Placebo (Metformin)
Tablet Placebo 500 mg 2 tablets x 2 daily (eGFR 35-60 ml/min: 500 mg x 2 daily). Average treatment period 4 years.
Drug: Placebo Oral Tablet
2 tablets x 2 daily (eGFR 35-60 ml/min: 500 mg x 2 daily)




Primary Outcome Measures :
  1. H-HeFT combined endpoint: Death or hospitalization with worsening heart failure. [ Time Frame: Through study completion, an average of 4 years ]
    Death or hospitalization with worsening heart failure.

  2. Met-HeFT combined endpoint: Death or hospitalization with worsening heart failure or acute myocardial infarction or stroke [ Time Frame: Through study completion, an average of 4 years ]
    Death or hospitalization with worsening heart failure or acute myocardial infarction or stroke


Secondary Outcome Measures :
  1. H-HeFT secondary endpoint: Death [ Time Frame: Through study completion, an average of 4 years ]
    Death

  2. H-HeFT secondary endpoint: Hospitalization with worsening heart failure [ Time Frame: Through study completion, an average of 4 years ]
    Hospitalization with worsening heart failure

  3. H-HeFT secondary endpoint: Combined endpoint: Death or cardiovascular hospitalizations (hospitalization with worsening heart failure, acute myocardial infarction, or stroke) [ Time Frame: Through study completion, an average of 4 years ]
    Combined endpoint: Death or cardiovascular hospitalizations (hospitalization with worsening heart failure, acute myocardial infarction, or stroke)

  4. Met-HeFT secondary endpoint: Extended clinical endpoint: The primary endpoint or coronary revascularization or non-coronary revascularization or limb amputation. [ Time Frame: Through study completion, an average of 4 years ]
    Extended clinical endpoint: The primary endpoint or coronary revascularization or non-coronary revascularization or limb amputation.

  5. Met-HeFT secondary endpoint: Death [ Time Frame: Through study completion, an average of 4 years ]
    Death

  6. Met-HeFT secondary endpoint: Hospitalization with worsening heart failure [ Time Frame: Through study completion, an average of 4 years ]
    Hospitalization with worsening heart failure

  7. Met-HeFT secondary endpoint: Acute myocardial infarction [ Time Frame: Through study completion, an average of 4 years ]
    Acute myocardial infarction

  8. Met-HeFT secondary endpoint: Stroke [ Time Frame: Through study completion, an average of 4 years ]
    Stroke

  9. Met-HeFT secondary endpoint: New onset type 2 diabetes [ Time Frame: Through study completion, an average of 4 years ]
    New onset type 2 diabetes

  10. Met-HeFT secondary endpoint: Hospitalization or death caused by lactate acidosis. [ Time Frame: Through study completion, an average of 4 years ]
    Hospitalization or death caused by lactate acidosis.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03514108


Contacts
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Contact: Henrik Wiggers, MD, PhD +45 40136627 henrikwiggers@dadlnet.dk

Locations
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Denmark
Sygehus Sønderjylland, Aabenraa Not yet recruiting
Aabenraa, Denmark
Contact: Bartlomiej Jonczy         
Aalborg University Hospital Recruiting
Aalborg, Denmark
Contact: Søren Vraa         
Aarhus University Hospital Recruiting
Aarhus, Denmark
Contact: Henrik Wiggers    +45 40136627    henrikwiggers@dadlnet.dk   
Sub-Investigator: Anders Jorsal         
Amager Hospital Not yet recruiting
Copenhagen, Denmark
Contact: Margrethe Ege Olsen         
Bispebjerg Hospital Recruiting
Copenhagen, Denmark
Contact: Olav Wendelbo Nielsen         
Gentofte Hospital Recruiting
Copenhagen, Denmark
Contact: Morten Schou         
Glostrup Hospital Recruiting
Copenhagen, Denmark
Contact: Jawdat Abdulla         
Herlev Hospital Recruiting
Copenhagen, Denmark
Contact: Morten Schou         
Hvidovre Hospital Recruiting
Copenhagen, Denmark
Contact: Anette Sjøl         
Rigshospitalet Recruiting
Copenhagen, Denmark
Contact: Lars Køber         
Principal Investigator: Finn Gustafsson         
Sydvestjysk Sygehus, Esbjerg Not yet recruiting
Esbjerg, Denmark
Contact: Kirsten Vilain Mikkelsen         
Herning Hospital Recruiting
Herning, Denmark
Contact: Morten Bøttcher         
Regionshospital Nordjylland, Hjørring Not yet recruiting
Hjørring, Denmark
Contact: Gitte Nielsen         
Holbæk Hospital Not yet recruiting
Holbæk, Denmark
Contact: Ilan Raymond         
Horsens Hospital Recruiting
Horsens, Denmark
Contact: Karen Kaae Dodt         
Kolding Hospital Recruiting
Kolding, Denmark
Contact: Monica Petronela Poenaru         
Nykøbing Falster Hospital Not yet recruiting
Nykøbing Falster, Denmark
Contact: Lisbeth Tingsted         
Odense University Hospital Recruiting
Odense, Denmark
Contact: Mikael Kjær Poulsen         
Sjællands Universitetshospital, Roskilde Recruiting
Roskilde, Denmark
Contact: Niels Eske Bruun         
Silkeborg Hospital Recruiting
Silkeborg, Denmark
Contact: Anne S Knudsen         
Slagelse Sygehus Not yet recruiting
Slagelse, Denmark
Contact: Jens Lomholdt         
Vejle Hospital Recruiting
Vejle, Denmark
Contact: Vibeke Brogaard         
Viborg Hospital Recruiting
Viborg, Denmark
Contact: Anne Pauline Schrøder         
Sponsors and Collaborators
Henrik Wiggers
Danish Heart Foundation
Danish Council for Independent Research
The Danish Regions: Foundation for Medical Research
The Novo Nordisk Foundation
The Aase og Ejnar Danielsen Foundation
Investigators
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Study Chair: Henrik Wiggers, MD, PhD Dept. of Cardiology, Aarhus University Hospital, Aarhus, Denmark
Study Chair: Lars Køber, MD, PhD Dept. of Cardiology, Rigshospitalet, Copenhagen, Denmark
Principal Investigator: Finn Gustafsson, MD, PhD Dept. of Cardiology, Rigshospitalet, Copenhagen, Denmark
Principal Investigator: Søren Mellemkjaer, MD, PhD Dept. of Cardiology, Aarhus University Hospital, Aarhus, Denmark
Study Chair: Gunnar Gislason, MD, PhD The Danish Heart Foundation, Copenhagen, Denmark

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Responsible Party: Henrik Wiggers, Consultant, Associate professor, MD, PhD, DMSc, Aarhus University Hospital
ClinicalTrials.gov Identifier: NCT03514108     History of Changes
Other Study ID Numbers: DANHEART
2015-002150-12 ( EudraCT Number )
First Posted: May 2, 2018    Key Record Dates
Last Update Posted: July 2, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Henrik Wiggers, Aarhus University Hospital:
Heart failure
Diabetes
Insulin resistance
Metformin
Hydralazine
Isosorbide Dinitrate
Additional relevant MeSH terms:
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Heart Failure
Heart Diseases
Cardiovascular Diseases
Metformin
Hydralazine
Isosorbide
Isosorbide Dinitrate
Isosorbide-5-mononitrate
Hypoglycemic Agents
Physiological Effects of Drugs
Diuretics, Osmotic
Diuretics
Natriuretic Agents
Vasodilator Agents
Nitric Oxide Donors
Molecular Mechanisms of Pharmacological Action
Antihypertensive Agents