Effect of Elamipretide on Left Ventricular Function in Subjects With Stable Heart Failure With Reduced Ejection Fraction

Study Overview
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Brief Summary
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This was a randomized, double-blinded, placebo-controlled, multiple-dose study in subjects with stable heart failure (HF) with reduced ejection fraction (HFrEF).

Detailed Description
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This was a randomized, double-blinded, placebo-controlled, multiple-dose study in subjects with stable heart failure (HF) with reduced ejection fraction (HFrEF). After completing the Screening period, a total of 71 subjects were randomized, in a 1:1:1 ratio, to receive either placebo, 4 mg elamipretide, or 40 mg elamipretide once daily for 28 consecutive days. Each treatment group went through 3 distinct periods: Screening, Treatment, and Follow up.

Official Title
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A Phase 2 Randomized, Double-Blinded, Placebo-Controlled Study to Evaluate the Effects of Multiple Subcutaneous Injections of Elamipretide on Left Ventricular Function in Subjects With Stable Heart Failure With Reduced Ejection Fraction

Conditions
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Heart Failure

Intervention / Treatment
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* Drug: 4 mg elamipretide
* Drug: 40 mg elamipretide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to provide signed informed consent form (ICF) prior to participation in any study-related procedures. Age ≥40 and ≤80 years. A known history of chronic ischemic or non-ischemic cardiomyopathy of at least 6 months duration from the time of the initial diagnosis. Receiving heart failure (HF) treatment, including, but not limited to, angiotensin converting enzyme inhibitors (ACEI) and/or angiotensin receptor blockers (ARB), and an evidence-based beta blocker for the treatment of HF. Subjects who cannot tolerate ACEI or ARB due to reduced renal function or hypotension are eligible. Subjects may be receiving aldosterone antagonists, but this is not a requirement for the study. HF is considered to be stable in the judgment of the Investigator AND doses of HF treatment have been stable for at least 1 month prior to the Screening Visit. In normal sinus rhythm (electrocardiogram documented) at Screening and Day 1 and no history of atrial fibrillation in the past 12 months No hospitalization related to HF within 1 month prior to the Screening Visit. Left Ventricular Ejection Fraction (LVEF) ≤ 40% by 2-D echocardiography at Screening. At least 3 viable segments (hyperenhancement ≤ 25%) by a qualifying delayed gadolinium-enhanced cardiac MRI examination at Screening (confirmed by independent core lab). Women of childbearing potential must agree to use 1 of the following methods of birth control from the date they sign the ICF until two months after the last dose of study medication: Abstinence, maintenance of monogamous relationship with a male partner who has been surgically sterilized by vasectomy, or barrier method AND either hormonal contraception or an intrauterine device or system. Exclusion Criteria: History of any concurrent medical condition which, in the opinion of the Investigator, significantly increased the potential risks associated with administration of study medication or any other aspect of study participation. Any contraindication to MRI scanning. Left ventricular end diastolic dimension (LVEDD) indexed to Body Surface Area is > 45 mm/m2. Coronary or peripheral revascularization procedures, valvular procedures, OR any major surgical procedure within 3 months prior to the Screening Visit. Acute coronary syndrome, stroke or transient ischemic attack (TIA) within 3 months prior to the Screening Visit. Obstructive or restrictive cardiomyopathy, infiltrative diseases of the myocardium (e.g., amyloid, sarcoid, etc.) myocarditis, or reductions in LV function thought to be secondary primarily to valvular heart disease, prior cardiac valve surgery or known aortic stenosis. The presence or anticipated placement of any pacemaker, implantable cardioverter defibrillator (ICD), or cardiac resynchronization therapy (CRT) devices during the ensuing 6-week study period. Presence of second degree or advanced heart block. Uncontrolled hypertension defined as a systolic blood pressure > 160 mmHg or a diastolic blood pressure > 110 mmHg on at least two consecutive readings. Presence of any left ventricular thrombus, pericardial disease, uncorrected thyroid disease or a dyskinetic left ventricular aneurysm. History of cancer that causes symptoms, disabilities, or is likely to lead to hospitalization or treatment in the next 12 months. Currently receiving treatment with chemotherapeutic agents or immunosuppressant agents or has received prior radiation therapy to the chest. Liver enzymes (alanine aminotransferase [ALT] AND/OR aspartate. aminotransferase [AST]) elevation > 3 times the upper limit of normal (ULN). Total bilirubin > 1.5 times ULN in the absence of Gilbert's Syndrome. Bleeding diathesis or any known blood dyscrasia. Anemia, defined as hemoglobin < 9 g/dL or planned blood transfusions in the next 6 weeks. Estimated glomerular filtration rate (eGFR) < 30 mL/min, using the Modification of Diet in Renal Disease (MDRD) Study equation. History of hepatitis B, hepatitis C or Human Immunodeficiency Virus (HIV) infection, or diagnosis of immunodeficiency. Known active drug or alcohol abuse within 1 year of the Screening Visit. Alcohol abuse is defined as 15 or more drinks for men per week or 8 or more for women. Recipient of any investigational drugs, stem cell or gene therapies, or devices OR participation in another clinical trial, within 3 months prior to the Screening Visit. Female subjects who are pregnant, planning to become pregnant, or lactating. Requiring any change in doses of cardiovascular medication (including diuretics) in order to control worsening of HF symptoms. Known allergy to gadolinium. Currently receiving treatment with therapeutic doses of anticoagulants. Antiplatelet therapy used to prevent cardiovascular disease (primary prevention) or to treat chronic disease (secondary prevention) is permitted. Currently receiving treatment with sacubitril/valsartan or trimetazidine. Hyponatremia defined as plasma Na+ level <125 mEq/L (UK only).

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 4 mg elamipretide<br>4 mg elamipretide once daily for 28 consecutive days | Drug: 4 mg elamipretide<br>* Subcutaneous injection of 4 mg elamipretide administered once daily for 28 consecutive days<br>* Other names: Bendavia;|
| Experimental: 40 mg elamipretide<br>40 mg elamipretide once daily for 28 consecutive days | Drug: 40 mg elamipretide<br>* Subcutaneous injection of 40 mg elamipretide administered once daily for 28 consecutive days<br>* Other names: Bendavia;|
| Placebo Comparator: Placebo<br>Placebo once daily for 28 consecutive days | Drug: Placebo<br>* Subcutaneous injection of placebo administered once daily for 28 consecutive days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Left Ventricular End Systolic Volume (ml) | Change in left ventricular end systolic volume as measured by ml from baseline (last assessment prior to start of study) to Week 4 (end of treatment visit) as assessed by MRI. | Baseline to Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Left Ventricular Ejection Fraction (% of Blood Volume) | Change in Left Ventricular Ejection Fraction as measured by percentage of blood volume from baseline (last assessment prior to start of study) to Week 4 (end of treatment visit) as assessed by MRI. | Baseline to Week 4 | 
| Change in Left Ventricular End Diastolic Volume (ml) as Measured by MRI | Change from baseline in Left Ventricular End Diastolic Volume as measured by ml from baseline (last assessment prior to start of study) to Week 4 (end of treatment visit) as assessed by MRI. | Baseline to Week 4 | 
| Change in Left Ventricular Stroke Volume (ml) | Change in Left Ventricular Stroke Volume as measured by ml from baseline (last assessment prior to start of study) to Week 4 (end of treatment visit) as assessed by MRI. | Baseline to Week 4 | 
| Change in Left Ventricular Cardiac Output (L/Min) | Change in Left Ventricular Cardiac Output as measured by L/min from baseline (last assessment prior to start of study) to Week 4 (end of treatment visit) as assessed by MRI. | Baseline to Week 4 | 
| Change in Left Ventricular Myocardial Mass (g) | Change in Left Ventricular Myocardial Mass as measured by grams from baseline (last assessment prior to start of study) to Week 4 (end of treatment visit) as assessed by MRI. | Baseline to Week 4 | 
| Change in Right Ventricular End Systolic Volume (mL) | Change in Right Ventricular End Systolic Volume as measured by mL from baseline (last assessment prior to start of study) to Week 4 (end of treatment visit) as assessed by MRI. | Baseline to Week 4 | 
| Change in Right Ventricular End Diastolic Volume (mL) | Change in Right Ventricular End Diastolic Volume as measured by ml from baseline (last assessment prior to start of study) to Week 4 (end of treatment visit) as assessed by MRI. | Baseline to Week 4 | 
| Change in Right Ventricular Ejection Fraction (% Blood Volume) | Change in Right Ventricular Ejection Fraction as measured by percentage of blood volume from baseline (last assessment prior to start of study) to Week 4 (end of treatment visit) as assessed by MRI. | Baseline to Week 4 | 
| Change in Early and Late Mitral Inflow Velocity Ratio | Change in Early and Late Mitral Inflow Velocity Ratio from baseline (last assessment prior to start of study) to Week 4 (end of treatment visit) as assessed by echocardiography. | Baseline to Week 4 | 
| Change in Early Mitral Inflow Velocity and Mitral Annular Early Diastolic Velocity Ratio (E/e') | Change in Early Mitral Inflow Velocity and Mitral Annular Early Diastolic Velocity Ratio as measured by E/e' from baseline (last assessment prior to start of study) to Week 4 (end of treatment visit) as assessed by echocardiography. | Baseline to Week 4 | 
| Change in Left Atrial Volume (mL) | Change in Left Atrial Volume as measured by ml from baseline (last assessment prior to start of study) to Week 4 (end of treatment visit) as assessed by echocardiography. | Baseline to Week 4 | 
| Change in Left Ventricular Global Longitudinal Strain Assessment (%) | Change in Left Ventricular Global Longitudinal Strain Assessment as measured by ml from baseline (last assessment prior to start of study) to Week 4 (end of treatment visit) as assessed by echocardiography. | Baseline to Week 4 | 
| Change in Left Ventricular End Diastolic Volume (mL) as Measured by Echocardiography | Change in Left Ventricular End Diastolic Volume as measured by ml from baseline (last assessment prior to start of study) to Week 4 (end of treatment visit) as assessed by echocardiography. | Baseline to Week 4 | 
| Change in Left Ventricular End Systolic Volume (mL) as Measured by Echocardiography | Change in Left Ventricular End Systolic Volume as measured by ml from baseline (last assessment prior to start of study) to Week 4 (end of treatment visit) as assessed by echocardiography. | Baseline to Week 4 | 
| Change in Biplane Ejection Fraction (mL) | Change in Biplane Ejection Fraction as measured by ml from baseline (last assessment prior to start of study) to Week 4 (end of treatment visit) as assessed by echocardiography. | Baseline to Week 4 | 
| Left Ventricular Mass Assessment (g) | Change in Left Ventricular Mass Assessment as measured by grams from baseline (last assessment prior to start of study) to Week 4 (end of treatment visit) as assessed by echocardiography. | Baseline to Week 4 | 
| Change in Tricuspid Regurgitation Severity Assessment (cm²) | Change in Tricuspid Regurgitation Severity Assessment as measured by cm from baseline (last assessment prior to start of study) to Week 4 (end of treatment visit) as assessed by echocardiography. | Baseline to Week 4 | 
| Change in Right Ventricular Fractional Area (%) | Change Right Ventricular Fractional Area in as measured by percentage from baseline (last assessment prior to start of study) to Week 4 (end of treatment visit) as assessed by echocardiography. | Baseline to Week 4 | 
| Change in Right Ventricular Systolic Pressure (mmHg) | Change in Change in Right Ventricular Systolic Pressure as measured by mmHg from baseline (last assessment prior to start of study) to Week 4 (end of treatment visit) as assessed by echocardiography. | Baseline to Week 4 | 
| Change in Mitral Regurgitation Severity (cm²) | Change in Mitral Regurgitation Severity as measured by cm² from baseline (last assessment prior to start of study) to Week 4 (end of treatment visit) as assessed by echocardiography. | Baseline to Week 4 |