DANHEART (H-HeFT and Met-HeFT)

Henrik Wiggers

Status and phase: Enrolling; Phase 4

Conditions: Diabetes; Heart Failure

Treatments: Drug: Metformin Hydrochloride; Drug: Placebo Oral Tablet; Drug: Hydralazine Isosorbide Dinitrate

Study type: Interventional

Funder types: Other

Identifiers

NCT03514108

DANHEART

2015-002150-12 (EudraCT Number)

Details and patient eligibility

About

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.

Enrollment: 1,500 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Factorial Assignment

Masking: Quadruple Blind

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1,500 participants in 4 patient groups, including a placebo group

Hydralazine Isosorbide Dinitrate

Active Comparator group

Description:

Tablet BiDil (Hydralazine 37.5 mg/ isosorbide dinitrate (ISDN) 20 mg) 2 tablets x 3 daily. Average treatment period 4 years.

Treatment:

Drug: Hydralazine Isosorbide Dinitrate

Placebo (Hydralazine Isosorbide Dinitrate)

Placebo Comparator group

Description:

Tablet Placebo 2 tablets x 3 daily. Average treatment period 4 years.

Treatment:

Drug: Placebo Oral Tablet

Drug: Placebo Oral Tablet

Metformin

Active Comparator group

Description:

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.

Treatment:

Drug: Metformin Hydrochloride

Placebo (Metformin)

Placebo Comparator group

Description:

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

Treatment:

Drug: Placebo Oral Tablet

Drug: Placebo Oral Tablet