Evaluation of Hydralazine Hydrochloride, Isosorbide Dinitrate, and Metformin Hydrochloride in Chronic Heart Failure with Reduced Ejection Fraction
- Trial ID
- 2024-514212-27-00
- Protocol
- DANHEART
Trial statistics
Diseases & Conditions
Objectives
The primary objective of the study is to evaluate the efficacy of **Hydralazine-ISDN** and **Metformin** in patients with chronic **heart failure** and reduced left ventricular ejection fraction (LVEF) of 40% or less, who are on optimal treatment. The study aims to test two hypotheses: firstly, that Hydralazine-ISDN reduces the incidence of death and hospitalization due to worsening heart failure, urgent visits requiring intravenous or metolazone therapy, heart transplantation, or implantation of a left ventricular assist device (LVAD); and secondly, that Metformin reduces the incidence of death and cardiovascular hospitalizations, including events such as worsening heart failure, heart transplantation, LVAD implantation, acute myocardial infarction, or stroke, as well as urgent visits requiring intravenous or metolazone therapy for heart failure. These objectives are clinically relevant as they address critical outcomes in the management of heart failure, potentially improving patient survival and reducing hospitalizations.
The secondary objectives include: - H-HeFT: Evaluation of individual components of the primary endpoint and a combined endpoint of death or cardiovascular hospitalizations, including events such as worsening heart failure, heart transplantation, LVAD implantation, acute myocardial infarction, or stroke. - Met-HeFT: Assessment of an extended clinical endpoint, including the primary endpoint or coronary and non-coronary revascularization or limb amputation, new diagnosis of diabetes mellitus, and hospitalization or death due to lactate acidosis, as well as evaluation of individual components of the primary endpoint.
Participants
The clinical trial focuses on patients with **chronic heart failure** and reduced left ventricular ejection fraction (LVEF) of 40% or less, who are on optimal treatment. The study population includes both male and female participants, with an age range that encompasses adults and the elderly. The trial does not involve a vulnerable population. The sponsor has not provided the total number of participants. Participants were selected based on specific inclusion criteria, such as having chronic heart failure classified as NYHA class II, III, or IV, and an LVEF of 40% or less within 12 months prior to screening. Additionally, participants must be on a maximally tolerated dose of heart failure medications, including ACE inhibitors, ARBs, or ARNIs, and beta-blockers, unless contraindicated. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data. The trial does not focus on a specific gender, and both male and female subjects are included. The study does not target a vulnerable population, and the selection criteria ensure that participants are clinically stable and on optimal heart failure treatment.
Plans and Procedures
The clinical trial is designed as a **randomized**, 2 x 2 factorial, **double-blind**, placebo-controlled study to evaluate the effects of **hydralazine hydrochloride** and **isosorbide dinitrate** in patients with chronic heart failure. The trial also investigates the impact of **metformin hydrochloride** in patients with chronic heart failure and either diabetes or insulin resistance. The study aims to assess the reduction in incidence of death and hospitalization due to worsening heart failure, as well as other cardiovascular events. The trial is expected to run from March 2018 to April 2028, with a maximum treatment period of 120 days for each participant.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as NYHA-class II, III, or IV heart failure and a left ventricular ejection fraction (LVEF) of 40% or less. Specific criteria for the Met-HeFT arm include a diagnosis of diabetes or insulin resistance. Following randomization, participants will be assigned to receive either the active treatment or placebo. The study includes regular follow-up visits to monitor the participants' health status, adherence to the treatment regimen, and any adverse events. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted.
The expected length of participant involvement is up to 120 days, with conditions for early termination including significant adverse events, withdrawal of consent, or non-compliance with the study protocol. The primary endpoints for the H-HeFT arm include death or hospitalization due to worsening heart failure, while the Met-HeFT arm focuses on death or cardiovascular hospitalizations. Secondary endpoints encompass individual components of the primary endpoints and additional clinical outcomes. The trial's methodology ensures rigorous assessment of the investigational treatments' efficacy and safety in the target population.
Treatment
The clinical trial involves the administration of **BiDil**, a combination medication consisting of **hydralazine hydrochloride** and **isosorbide dinitrate**. BiDil is formulated as a tablet and is administered orally. The maximum daily dose is 345 mg, with a total maximum dose of 1.26 kg over the treatment period. The treatment duration is set for a maximum of 120 days. BiDil is utilized in this study to evaluate its efficacy in reducing the incidence of death and hospitalization due to worsening heart failure in patients with chronic heart failure and reduced left ventricular ejection fraction (LVEF).
Another experimental treatment in the trial is **Metformin Hydrochloride**, a glucose-lowering drug. Metformin is also administered in tablet form and taken orally. The maximum daily dose for Metformin is 2000 mg, with a total maximum dose of 10 kg over the treatment period, which is also set for a maximum of 120 days. The study aims to assess Metformin's potential in reducing the incidence of death and cardiovascular hospitalizations in patients with chronic heart failure and diabetes or insulin resistance.
The trial includes two placebo groups. One placebo is designed to match the BiDil treatment, and the other is for the Metformin treatment. These placebos are used to maintain the double-blind nature of the study, ensuring that neither the participants nor the investigators know which treatment the participants are receiving. The placebo for BiDil and the placebo for Metformin do not contain any active substances and are administered in a manner consistent with the respective active treatments.
Efficacy
Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints for the Hydralazine-ISDN in Patients With Chronic Heart Failure (H-HeFT) trial include the incidence of death or hospitalization due to worsening heart failure, urgent visits resulting in intravenous therapy or metolazone therapy, heart transplantation, or implantation of a left ventricular assist device (LVAD). For the Metformin in Patients with Chronic Heart Failure and Diabetes or Insulin Resistance (Met-HeFT) trial, the primary endpoints are death or cardiovascular hospitalizations, which include hospitalization due to worsening heart failure, heart transplantation, LVAD implantation, acute myocardial infarction, or stroke.
Secondary endpoints for H-HeFT include the individual components of the primary endpoint and a combined endpoint of death or cardiovascular hospitalizations. For Met-HeFT, secondary endpoints include an extended clinical endpoint encompassing the primary endpoint or coronary revascularization, non-coronary revascularization, or limb amputation, as well as new diagnoses of diabetes mellitus, hospitalization or death due to lactate acidosis, and the individual components of the primary endpoint.
The trial employs a randomized, double-blind, placebo-controlled design with a 2 x 2 factorial approach. Patients are randomized through an internet-based module, allowing allocation to both treatment arms or to one of the two arms. The trial is designed to evaluate the efficacy of **Hydralazine Hydrochloride** and **Isosorbide Dinitrate** in combination, as well as **Metformin Hydrochloride**, in improving clinical outcomes for patients with chronic heart failure. The trial is expected to conclude by April 2028, with recruitment having started in March 2018.
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 (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) if treatment with ACE-inhibitor/ ARB is switched to treatment with Entresto, no new echocardiography is required and (iiiii) 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). NT-proBNP or BNP should be measured (i) within 12 months prior to screening (ii) after uptitration of heart failure medication and at least 3 months after CRT implantation and (iii) the latest measurement before screening must be used. (iiii) If no NT-proBNP or BNP measurement is available that fulfils the above criteria, the NT-proBNP or BNP at screening must be used. Specific inclusion criteria for only Met-HeFT: Patients must have a diagnosis of diabetes or insulin resistance or diabetes risk. This includes 1 or more of any of the following: - A previous diagnosis of Diabetes type 2 at any time without Metformin treatment during the last 3 months - HbA1c ≥ 5.5 % (≥ 37 mmol/mol) measured either (i) within 12 months prior to screening or (ii) at screening - Fasting P-glucose ≥ 5.6 mmol/l measured either (i) within 12 months prior to screening or (ii) at 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 screening: 2 hour P-glucose ≥ 7.8 mmol/l - In addition, patients in Met-HeFT must have eGFR ≥ 35 ml/min (MDRD). eGFR can be measured within 4 weeks prior to screening if the patient at the time of measurement is uptitrated to maximally tolerated/ recommended heart failure medication and clinically stable. Patients in Met-HeFT can be included regardless of NT-proBNP / BNP levels Patients are randomized to R1 and R2 through an internet based randomization module. Patients can be allocated to a) both R1 and R2 or to b) only R1 or to c) only R2.
Exclusion Criteria
- For both H-HeFT and Met-HeFT - Acute myocardial infarction, unstable angina or revascularization < 1 month at the time of randomization - Planned coronary artery bypass grafting or cardiac valve replacement - Severe, symptomatic, uncorrected aortic valve stenosis or primary, severe mitral valve disease - Atrial fibrillation with poorly controlled ventricular rate at rest (> 110 beats/min) - Known hypertrophic or restrictive cardiomyopathy, infiltrative or storage myocardial disease, active myocarditis, or pericardial disease. - Listed for heart transplantation. - Female patients who are pregnant, nursing, or of childbearing potential while not practicing effective chemical contraceptive methods (i.e. oral, implanted, injectable, or transdermal contraceptive hormones; intrauterine device) - Age < 18 years - Stroke within the last 1 month - Significant liver disease and/ or P-ALAT >3 times upper normal limit (it is possible to repeat this measurement within 3 months) - Significant comorbidity or issue which makes the patient unsuitable for participation as judged by the investigator - Participation in another double blind drug trial (participation in device studies is allowed) Only for H-HeFT - Severe, symptomatic hypotension - Contraindications to the use of hydralazine therapy - African descent - Treatment with Viagra or other PDE-5-inhibitor or soluble guanylate cyclase stimulator that cannot be discontinued - Treatment with long-acting mono- or di-nitrates, that cannot be discontinued Only for Met-HeFT - Known allergy to Metformin or major side effects to Metformin treatment - Type 1 diabetes
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Denmark | Not Recruiting | 01 Mar 2018 | 1500 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
BiDil | Test | TABLET | ORAL | 345 | 120 | PRD11381764 |
Placeboto Hydralazine / Isosorbide dinitrate | Placebo | N/A | — | — | — | N/A |
PlaceboTo Metformin hydrochloride | Placebo | N/A | — | — | — | N/A |
METFORMIN HYDROCHLORIDE | Test | — | ORAL | 2000 | 120 | SUB03200MIG |