Evaluation of Sacubitril/Valsartan Versus Ramipril on Left Ventricular Function in Ischemic Heart Failure with Mid-Range Ejection Fraction
- Trial ID
- 2024-518239-12-00
- Protocol
- DW.0701.005.2020P
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the effect of **sacubitril/valsartan** versus **ramipril** on the change in left ventricular end-systolic volume, as measured by magnetic resonance imaging (MRI), in patients with ischemic heart failure with moderately reduced ejection fraction (HFmrEF) after 12 months of treatment. This objective is clinically relevant as it aims to assess the potential benefits of sacubitril/valsartan in improving cardiac function and remodeling, which are critical factors in the management of heart failure.
Secondary objectives include:
- Assessment of the effect of sacubitril/valsartan compared to ramipril on the change in left ventricular end-diastolic volume measured by MRI.
- Change in indexed left ventricular end-systolic and end-diastolic volumes measured by MRI.
- Change in left ventricular ejection fraction measured by MRI.
- Occurrence of the endpoint of death from cardiovascular causes or first hospitalization for heart failure (HF).
- Occurrence of the endpoint of death from cardiovascular causes or first or subsequent hospitalization for HF.
- Occurrence of death from cardiovascular causes.
- First hospitalization due to HF.
- Occurrence of the first or subsequent hospitalization due to HF.
- Time to death from cardiovascular causes or first hospitalization for HF.
- Occurrence of death from any cause in patients with ischemic HFmrEF over a 12-month treatment period.
Participants
The clinical trial involves participants diagnosed with **heart failure with moderately reduced ejection fraction (HFmrEF)**. The study population includes both male and female subjects aged 18 and over, with symptomatic heart failure classified as NYHA class II to IV of ischemic etiology. Participants are required to have a left ventricular ejection fraction ranging from 40-49%, confirmed by echocardiography, and elevated NT-proBNP natriuretic peptide levels. The trial population was selected based on specific inclusion criteria, including optimal pharmacotherapy with ACE inhibitors or angiotensin receptor blockers and beta-blockers, unless contraindicated. The sponsor has not provided the total number of participants. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, indicating careful consideration of ethical standards in participant selection.
Plans and Procedures
The clinical trial is designed to evaluate the effect of **sacubitril/valsartan** versus **ramipril** on left ventricular remodeling and function in patients with ischemic heart failure with moderately reduced ejection fraction (HFmrEF). This is a randomized, double-blind, controlled trial with a duration of 12 months. Participants will be randomly assigned to receive either sacubitril/valsartan or ramipril, with the primary endpoint being the change in left ventricular end-systolic volume as measured by magnetic resonance imaging (MRI) after 12 months of treatment. Secondary endpoints include changes in left ventricular end-diastolic volume, ejection fraction, and cardiovascular outcomes such as hospitalization and mortality.
The trial will commence with a screening visit to confirm eligibility, which includes criteria such as age 18 and over, symptomatic heart failure in NYHA class II to IV, and specific echocardiographic and biomarker thresholds. Following successful screening, participants will undergo a randomization visit to confirm left ventricular ejection fraction and initiate treatment. Study visits will occur at regular intervals to monitor safety, adherence, and efficacy, with MRI assessments scheduled at baseline and at the end of the study to evaluate cardiac remodeling.
The expected length of participant involvement is approximately 12 months, with the possibility of early termination if significant adverse events occur or if the participant withdraws consent. The trial is anticipated to conclude by April 2026, with recruitment having started in December 2022. Participants will be closely monitored throughout the study to ensure compliance with the protocol and to address any potential safety concerns promptly.
Treatment
The clinical trial involves the administration of **valsartan and sacubitril**, a combination medication used to evaluate its effects on left ventricular function and remodeling in patients with ischemic heart failure with mid-range ejection fraction (HFmrEF). The pharmaceutical form of this medication is identified as PHF00082MIG, and it is administered orally. The maximum daily dose is 400 mg, with a total maximum dose of 151,200 mg over a treatment period of 54 weeks. The medication is repackaged from blisters into HDPE bottles with a capacity of 70 ml for the trial. The active substances, **valsartan** and **sacubitril**, are of chemical origin and are classified under the ATC code C09DX04.
In addition to the experimental medication, a **placebo** is used as a comparator in the study. The placebo is designed to match the experimental medication in appearance and is administered in a similar manner. The placebo for **valsartan and sacubitril** is labeled as "Placebo to VALSARTAN AND SACUBITRIL PL1 PL2" and does not contain any active substances. It serves as a control to assess the efficacy and safety of the experimental treatment.
Another treatment used in the trial is **ramipril**, combined with **hydrochlorothiazide**, which serves as a comparator to the experimental medication. This combination is administered orally in a pharmaceutical form identified as PHF00245MIG. The maximum daily dose for this treatment is 10 mg, with a total maximum dose of 3,780 mg over the same 54-week treatment period. Similar to the experimental medication, the tablets are repackaged into HDPE bottles. The active substances, **ramipril** and **hydrochlorothiazide**, are also of chemical origin, with **ramipril** classified under the ATC code C09AA05.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment regimen. The study aims to provide a comprehensive evaluation of the effects of the experimental medication compared to the standard-of-care therapy and placebo, focusing on changes in left ventricular end-systolic volume as measured by magnetic resonance imaging (MRI) after 12 months of treatment.
Efficacy
The efficacy of the clinical trial will be assessed by evaluating the effect of **sacubitril/valsartan** versus **ramipril** on left ventricular remodeling and function in patients with ischemic heart failure with mid-range ejection fraction (HFmrEF). The primary endpoint for efficacy is the change in left ventricular end-systolic volume, which will be measured using magnetic resonance imaging (MRI) after 12 months of treatment. Secondary endpoints include changes in left ventricular end-diastolic volume, indexed left ventricular end-systolic and end-diastolic volumes, and left ventricular ejection fraction, all measured by MRI after 12 months of treatment. Additionally, the trial will assess cardiovascular outcomes such as death from cardiovascular causes, first or subsequent hospitalization due to heart failure, and all-cause mortality over the 12-month treatment period.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Written consent to participate in the study, expressed prior to any procedures related to the study.
- Age 18 and over.
- Symptomatic HF in NYHA class II to IV of ischemic etiology at screening visit.
- Left ventricular ejection fraction at screening visit ranged from 40- 49%, confirmed by echocardiography at a randomization visit.
- Elevated concentration of NT-proBNP natriuretic peptide≥125 pg / ml at screening visit(if sinus rhythm during the visit).
- Elevated NT-proBNP natriuretic peptide concentration≥350 pg/ml at the screening visit (if atrial fibrillation or flutter during the visit).
- Features of a structural / functional disease of the left ventricle.
- Optimal pharmacotherapy with ACEI or ARB and beta-blocker, unless they are contraindicated.
Exclusion Criteria
- History of hypersensitivity or allergy to any of the drugs tested or drugs of similar chemical class, ACEIs, ARBs or neprilysin inhibitors.
- Previous history of intolerance to recommended ACEI or ARB target doses.
- Known history of angioedema.
- Requirement of simultaneous treatment with ACEI and ARB.
- Acute decompensated HF within 6 weeks prior to screening visit.
- Symptomatic hypotension systolic blood pressure <95 mmHg at screening visit.
- Current or previous treatment with sacubitril / valsartan not related to participation in the clinical trial.
- Estimated creatinine clearance <30 ml / min / 1,73 m2 at screening visit.
- Serum potassium >5.2 mmol / L at screening visit.
- Acute coronary syndrome or elective revascularization within 6 weeks prior to screening.
- Stroke, transient ischemic attack, carotid angioplasty, heart surgery, or any other major cardiovascular surgery in the 3 months prior to screening.
- Implantation of a cardioverter defibrillator, pacemaker, or resynchronization therapy device incompatible with MRI.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Poland | Recruiting | 01 Dec 2022 | 666 |
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 |
|---|---|---|---|---|---|---|
Placebo to RAMIPRIL PL3 PL4 | Placebo | N/A | — | — | — | N/A |
RAMIPRIL | Comparator | PHF00245MIG | ORAL USE | 10 | 54 | SCP10361725 |
VALSARTAN AND SACUBITRIL | Test | PHF00082MIG | ORAL USE | 400 | 54 | SCP77807446 |
Placebo to VALSARTAN AND SACUBITRIL PL1 PL2 | Placebo | N/A | — | — | — | N/A |