Reverse Remodeling Effects of CDR132L in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction and Cardiac Hypertrophy

Study Overview
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Brief Summary
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This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled study including approximately 130 randomized HF patients with heart failure with mildly reduced or preserved ejection fraction (LVEF ≥45%), to assess efficacy and safety of CDR132L on reverse remodeling. In this study, patients with HFpEF (EF ≥50%) or HFmrEF (LVEF 45-49%) will be included.

Official Title
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Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled Safety and Efficacy Study of CDR132L on Reverse Cardiac Remodeling in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction and Cardiac Hypertrophy

Conditions
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Heart Failure With Preserved Ejection Fraction

Intervention / Treatment
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* Drug: CDR132L
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: Provision of signed informed consent prior to any study-specific procedures. Male or female of non-childbearing potential patients age ≥40 and <85 years. Documented diagnosis of symptomatic heart failure (NYHA class II-IV) at enrollment, and a medical history of typical symptoms/signs of heart failure ≥6 weeks before enrollment with at least intermittent need for diuretic treatment. Ejection fraction ≥ 45% (determined by echocardiography at site laboratory) Increased intraventricular wall thickness (≥11 mm for female and ≥12 mm for male patients by echocardiography at site laboratory) NT-proBNP > 300 pg/ml (sinus rhythm); >900 pg/ml (atrial fibrillation at time of screening/inclusion or documented with the last 6 months) BMI between 22 kg/m² and 45 kg/m². Main Exclusion Criteria: Hemoglobin A1C (A1C) ≥10.5% eGFR <35 mL/min/1.73m² Systolic blood pressure (BP) <90 mmHg on 2 consecutive measurements at 5-minute intervals, at Screening. Systolic BP≥180 mmHg on 2 consecutive measurements at 5-minute intervals, at Screening. Planned coronary revascularization, ablation of atrial flutter/fibrillation and valve repair/replacement. Stroke or transient ischemic attack (TIA) within 12 weeks prior to enrolment.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CDR132L 4.52 mg<br>Six times CDR132L 4.52 mg/kg body weight intravenous in single dose. | Drug: CDR132L<br>* CDR132L is a synthetic antisense oligonucleotide (ASO) and a selective inhibitor of microRNA-132-3p (miR-132). miR-132 in cardiomyocytes is a central switch affecting the expression of genes that are crucially involved in maladaptive cardiac remodeling, transformation, and pathological cardiac growth (hypertrophy), contributing to adverse cardiac remodeling and heart failure (HF).1-5 Aberrant expression of miR-132 in cardiac cells is causally associated with cardiac remodeling and HF progression.<br>|
| Placebo Comparator: Placebo<br>Six times Placebo intravenous in single dose. | Drug: Placebo<br>* Placebo to CDR132L<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Left ventricular mass | Left ventricular mass measured by cardiac magnetic resonance imaging (indexed to the height in meters raised to the power of 2) | 6 months | 
| Left atrial maximum volume | Left atrial maximum volume (measured by cardiac magnetic resonance imaging in end systole(indexed to the height in meters raised to the power of 2)) | 6 months | 
| Total cardiac extracellular volume | Total cardiac extracellular volume (mL) measured by cardiac magnetic resonance imaging | 6 months | 
| Left atrial strain | Left atrial strain measured by cardiac magnetic resonance imaging | 6 months | 
| Maximum left ventricular wall thickness | Maximum left ventricular wall thickness measured by cardiac magnetic resonance imaging | 6 months | 
| Age-adjusted e' velocity | Age-adjusted e' velocity measured by doppler echocardiography. With e´velocity being the maximal velocity of mitral annular motion (E-wave). | 6 months | 
| Global longitudinal strain | Global longitudinal strain measured by echocardiography | 6 months | 
| E/e' | E/e' measured by doppler echocardiography to evaluate the LV filling pressure. | 6 months | 
| Concentration of N-terminal pro B-type natriuretic peptide | Concentration measured as biomarker from blood samples. | 6 months | 
| Concentration of high-sensitivity cardiac troponin T | Concentration measured as biomarker from blood samples. | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HFpEF, Heart failure, Cardiac Hypertrophy