NCT03514108CompletedPhase 4
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)
Henrik Wiggers50 sites in 1 country1,100 target enrollmentStarted: March 1, 2018Last updated:
Conditions
Interventions
Drugs
Trial Snapshot
- Phase
- Phase 4
- Status
- Completed
- Sponsor
- Enrollment
- 1,100
- Locations
- 50
- Primary Endpoint
- H-HeFT combined primary endpoint
Study Overview
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.
- 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.
- 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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Factorial
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •General inclusion criteria for both H-HeFT and Met-HeFT
- •* Patients with chronic heart failure
- •* NYHA-class II, III or IV
- •* LVEF \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.
Exclusion Criteria
- Not provided
Arms & Interventions
Metformin
Active Comparator
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.
Intervention: Metformin Hydrochloride (Drug)
Placebo (Hydralazine Isosorbide Dinitrate)
Placebo Comparator
Tablet Placebo 2 tablets x 3 daily. Average treatment period 4 years.
Intervention: Placebo Oral Tablet (Drug)
Placebo (Metformin)
Placebo Comparator
Tablet Placebo 500 mg 2 tablets x 2 daily (eGFR 35-60 ml/min: 500 mg x 2 daily). Average treatment period 4 years.
Intervention: Placebo Oral Tablet (Drug)
Hydralazine Isosorbide Dinitrate
Active Comparator
Tablet BiDil (Hydralazine 37.5 mg/ isosorbide dinitrate (ISDN) 20 mg) 2 tablets x 3 daily.
Average treatment period 4 years.
Intervention: Hydralazine Isosorbide Dinitrate (Drug)
Outcomes
Primary Outcomes
H-HeFT combined primary endpoint
Time Frame: Through study completion, an average of 4 years
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 LVAD.
Met-HeFT combined primary endpoint
Time Frame: Through study completion, an average of 4 years
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 LVAD or acute myocardial infarction or stroke
Secondary Outcomes
- H-HeFT: Death or cardiovascular hospitalization(Through study completion, an average of 4 years)
- H-HeFT: Change in NT-proBNP from baseline to final follow-up(Through study completion, an average of 4 years)
- Met-HeFT secondary endpoint: New onset type 2 diabetes(Through study completion, an average of 4 years)
- Met-HeFT: Cardiovascular hospitalizations(Through study completion, an average of 4 years)
- H-HeFT Death(Through study completion, an average of 4 years)
- H-HeFT: Heart failure events(Through study completion, an average of 4 years)
- H-HeFT: Death or cardiovascular hospitalization(Through study completion, an average of 4 years)
- H-HeFT combined primary endpoint of total (first and recurrent) events(Through study completion, an average of 4 years)
- H-HeFT: All-cause, total (first and subsequent) hospitalizations(Through study completion, an average of 4 years)
- H-HeFT: Change in NT-proBNP from baseline to final follow-up(Through study completion, an average of 4 years)
- H-HeFT: Cardiovascular hospitalizations(Through study completion, an average of 4 years)
- Met-HeFT combined endpoint of total (first and recurrent) events in the primary endpoint(Through study completion, an average of 4 years)
- Met-HeFT secondary endpoint: Death(Through study completion, an average of 4 years)
- Met-HeFT: Hospitalization with worsening heart failure or urgent visit resulting in intravenous therapy or metolazone therapy for heart failure or heart transplantation or implantation of a LVAD(Through study completion, an average of 4 years)
- Met-HeFT Extended clinical endpoint (first event analysis): The primary endpoint or coronary revascularization or non-coronary revascularization or limb amputation.(Through study completion, an average of 4 years)
- Met-HeFT secondary endpoint: Acute myocardial infarction(Through study completion, an average of 4 years)
- Met-HeFT secondary endpoint: Stroke(Through study completion, an average of 4 years)
- Met-HeFT secondary endpoint: New onset type 2 diabetes(Through study completion, an average of 4 years)
- Met-HeFT secondary endpoint: Hospitalization or death caused by lactic acidosis.(Through study completion, an average of 4 years)
- Met-HeFT: All-cause, total (first and subsequent) hospitalizations(Through study completion, an average of 4 years)
- Met-HeFT: Change in NT-proBNP from baseline to final follow-up(Through study completion, an average of 4 years)
- Met-HeFT: Cardiovascular hospitalizations(Through study completion, an average of 4 years)
Investigators
Henrik Wiggers
Professor, Consultant, MD, PhD, DMSc
Aarhus University Hospital
Study Sites (50)
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