Clinical trial NCT02788747: Effect of Elamipretide on Left Ventricular Function in Subjects With Stable Heart Failure With Reduced Ejection Fraction
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Heart Failure
Lead sponsor: Stealth BioTherapeutics Inc.
Sponsor class: INDUSTRY
First posted: 2016-06-02
Enrollment: 71
Sex: ALL
Minimum age (years): 40
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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).

Primary outcomes:
measure: Change in Left Ventricular End Systolic Volume (ml)
timeFrame: Baseline to Week 4
Secondary outcomes:
measure: Change in Left Ventricular Ejection Fraction (% of Blood Volume)
timeFrame: Baseline to Week 4
measure: Change in Left Ventricular End Diastolic Volume (ml) as Measured by MRI
timeFrame: Baseline to Week 4
measure: Change in Left Ventricular Stroke Volume (ml)
timeFrame: Baseline to Week 4
measure: Change in Left Ventricular Cardiac Output (L/Min)
timeFrame: Baseline to Week 4
measure: Change in Left Ventricular Myocardial Mass (g)
timeFrame: Baseline to Week 4
measure: Change in Right Ventricular End Systolic Volume (mL)
timeFrame: Baseline to Week 4
measure: Change in Right Ventricular End Diastolic Volume (mL)
timeFrame: Baseline to Week 4
measure: Change in Right Ventricular Ejection Fraction (% Blood Volume)
timeFrame: Baseline to Week 4
measure: Change in Early and Late Mitral Inflow Velocity Ratio
timeFrame: Baseline to Week 4
measure: Change in Early Mitral Inflow Velocity and Mitral Annular Early Diastolic Velocity Ratio (E/e')
timeFrame: Baseline to Week 4
measure: Change in Left Atrial Volume (mL)
timeFrame: Baseline to Week 4
measure: Change in Left Ventricular Global Longitudinal Strain Assessment (%)
timeFrame: Baseline to Week 4
measure: Change in Left Ventricular End Diastolic Volume (mL) as Measured by Echocardiography
timeFrame: Baseline to Week 4
measure: Change in Left Ventricular End Systolic Volume (mL) as Measured by Echocardiography
timeFrame: Baseline to Week 4
measure: Change in Biplane Ejection Fraction (mL)
timeFrame: Baseline to Week 4
measure: Left Ventricular Mass Assessment (g)
timeFrame: Baseline to Week 4
measure: Change in Tricuspid Regurgitation Severity Assessment (cm²)
timeFrame: Baseline to Week 4
measure: Change in Right Ventricular Fractional Area (%)
timeFrame: Baseline to Week 4
measure: Change in Right Ventricular Systolic Pressure (mmHg)
timeFrame: Baseline to Week 4
measure: Change in Mitral Regurgitation Severity (cm²)
timeFrame: Baseline to Week 4
Other outcomes:
Locations:
city: Bergamo
country: Italy
facility: A.O. Papa Giovanni XXIII Cardiologia 1, Torre 5
city: Brescia
country: Italy
facility: A.O. Spedali Civili di Brescia Cardiologia
city: Cagliari
country: Italy
facility: Azienda Ospedaliera Brotzu Cardiologia
city: Milano
country: Italy
facility: Centro Cardiologico Monzino U.O. Scompenso, Cardiologia Clinica e Cardiologia Riabilitativa
city: Milano
country: Italy
facility: Ospedale Niguarda Ca' Granda SC Cardiologia 2
city: Monza
country: Italy
facility: Cardiologia clinica, Unità dello Scompenso e Terapia intensive Reparto Carlo Magno, Faggi Policlinico di Monza
city: Pavia
country: Italy
facility: Dip. Cardiotoracovascolare: Cardiologia Fondazione IRCCS Policlinico San Matteo Pad. Nuovo Ospedale "DEA" Degenza: PIANO +3 Ambulatori: P.T. e P+3
city: Pisa
country: Italy
facility: Fondazione Toscana Gabriele Monasterio per la Ricerca Medica e di Sanità Pubblica
city: Deventer
country: Netherlands
facility: Deventer Hospital, Department of Cardiology
city: Groningen
country: Netherlands
facility: University Medical Centre Groningen
city: Sneek
country: Netherlands
facility: Anthonius Ziekenhuis, Cardiology Department
city: Tilburg
country: Netherlands
facility: Elisabeth Twee Steden Hospital (ETZ), Department of Cardiology
city: Zutphen
country: Netherlands
facility: Gelre Ziekenhuis Zutphen, Department of Cardiology
city: Dundee
country: United Kingdom
facility: Ninewells Hospital and Medical School
city: London
country: United Kingdom
facility: William Harvey Heart Centre CRC, (Barts Health NHS Trust)
Study officials:
affiliation: University of Athens, School of Medicine, Athens, Greece
name: Gerasimos Filippatos, MD
role: STUDY_CHAIR
References: