DANHEART (H-HeFT and Met-HeFT)

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. 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.

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)

Conditions
-----------------
Heart Failure, Diabetes

Intervention / Treatment
-----------------
* Drug: Hydralazine Isosorbide Dinitrate
* Drug: Placebo Oral Tablet
* Drug: Metformin Hydrochloride
* Drug: Placebo Oral Tablet


Participation Criteria
=================
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: Patients can be allocated to either both Hydralazine Isosorbide Dinitrate / Placebo and Metformin hydrochloride / Placebo to only Hydralazine Isosorbide Dinitrate / Placebo. 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: Patients receiving both Hydralazine Isosorbide Dinitrate / Placebo and Metformin hydrochloride / Placebo Patients receiving only Hydralazine Isosorbide Dinitrate / Placebo and Patients receiving only Metformin hydrochloride / Placebo Analysis will be performed in: all patients who have received Hydralazine Isosorbide Dinitrate / Placebo (H-HeFT) and 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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Hydralazine Isosorbide Dinitrate<br>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<br>* Tablet BiDil (Hydralazine 37.5 mg/ Isosorbide Dinitrate (ISDN) 20 mg) 2 tablets x 3 daily<br>* Other names: BiDil;|
| Placebo Comparator: Placebo (Hydralazine Isosorbide Dinitrate)<br>Tablet Placebo 2 tablets x 3 daily. Average treatment period 4 years. | Drug: Placebo Oral Tablet<br>* 2 tablets x 3 daily<br>|
| Active Comparator: Metformin<br>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<br>* Tablet Metformin hydrochloride 500 mg 2 tablets x 2 daily (eGFR 35-60 ml/min: 500 mg x 2 daily)<br>|
| Placebo Comparator: Placebo (Metformin)<br>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<br>* 2 tablets x 2 daily (eGFR 35-60 ml/min: 500 mg x 2 daily)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| H-HeFT combined endpoint: Death or hospitalization with worsening heart failure or urgent heart failure visit | Death or hospitalization with worsening heart failure or urgent heart failure visit resulting in intravenous therapy or metolazone treatment for heart failure. | Through study completion, an average of 4 years | 
| Met-HeFT combined endpoint: Death or hospitalization with worsening heart failure or acute myocardial infarction or stroke or urgent heart failure visit | Death or hospitalization with worsening heart failure or acute myocardial infarction or stroke or urgent visit resulting in intravenous therapy or metolazone treatment for heart failure | Through study completion, an average of 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| H-HeFT secondary endpoint: Death | Death | Through study completion, an average of 4 years | 
| H-HeFT secondary endpoint: Hospitalization with worsening heart failure or urgent visit resulting in intravenous therapy or metolazone therapy for heart failure | Hospitalization with worsening heart failure or urgent visit resulting in intravenous therapy or metolazone therapy for heart failure | Through study completion, an average of 4 years | 
| H-HeFT secondary endpoint: Combined endpoint: Death or cardiovascular hospitalization or urgent heart failure visit | Combined endpoint: Death or cardiovascular hospitalizations (hospitalization with worsening heart failure, acute myocardial infarction, or stroke) or urgent visit resulting in intravenous therapy or metolazone therapy for heart failure | Through study completion, an average of 4 years | 
| Met-HeFT secondary endpoint: Extended clinical endpoint: The primary endpoint or coronary revascularization or non-coronary revascularization or limb amputation. | Extended clinical endpoint: 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: Death | Death | Through study completion, an average of 4 years | 
| Met-HeFT secondary endpoint: Hospitalization with worsening heart failure or urgent visit resulting in intravenous therapy or metolazone therapy for heart failure | Hospitalization with worsening heart failure or urgent visit resulting in intravenous therapy or metolazone therapy for heart failure | Through study completion, an average of 4 years | 
| Met-HeFT secondary endpoint: Acute myocardial infarction | Acute myocardial infarction | Through study completion, an average of 4 years | 
| Met-HeFT secondary endpoint: Stroke | Stroke | Through study completion, an average of 4 years | 
| Met-HeFT secondary endpoint: New onset type 2 diabetes | New onset type 2 diabetes | Through study completion, an average of 4 years | 
| Met-HeFT secondary endpoint: Hospitalization or death caused by lactate acidosis. | Hospitalization or death caused by lactate acidosis. | Through study completion, an average of 4 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Heart failure, Diabetes, Insulin resistance, Metformin, Hydralazine, Isosorbide Dinitrate