E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Heart failure occurs when the heart muscle is weakened and cannot pump enough blood to meet the body's needs for blood and oxygen |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10010684 |
E.1.2 | Term | Congestive heart failure |
E.1.2 | System Organ Class | 100000011679 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the ability of elamipretide compared to placebo to improve cardiac function measured by a reduction in N-terminal pro-brain natriuretic peptide (NT-proBNP) up to Day 8 (or at discharge if earlier) in patients hospitalized with congestion due to heart failure |
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E.2.2 | Secondary objectives of the trial |
_To evaluate the effect of elamipretide on changes between baseline and both Day 3 and Day8/Earlier Discharge on: o renal function (eGFR as per MDRD) o body weight o body weight per mg of furosemide administered _ Clinical status (e.g patients and physician global assessment and treatment failures) at Day 3 and Day 8 _The average daily dose of diuretic (furosemide – adjusted for thiazide dose if administered) between baseline and Day 3 and Day 8/Early Discharge _The safety and tolerability of elamipretide _The plasma pharmacokinetics (PK) of elamipretide, its metabolites, and furosemide following a single dose and multiple doses of elamipretide in a selected number of patients |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Willing and able to provide signed informed consent form (ICF) prior to participation in any study-related procedures 2. Aged ≥18 years 3. history of chronic heart failure for at least 1 month 4. Treated with ≥40 mg/day of furosemide or bumetanide ≥1 mg/day or torasemide ≥10 mg/day for at least 1 month 5. In-hospital observation/admission and treatment for ≤72 hours and primary cause for admission is heart failure with persistent congestion in the opinion of the Investigator (i.e. at least +2 pitting oedema and/or an estimated 8 kg gain in weight over baseline over the past 4 weeks) requiring intravenous loop diuretic therapy 6. Able to be weighed 7. Sufficiently severe oedema to justify treatment by an intravenous infusion of furosemide of 10 mg/hour for at least 48 hours 8. Systolic blood pressure ≥90 mmHg and considered to be haemodynamically stable, in the opinion of the Investigator 9. History of left ventricular ejection fraction (LVEF) ≤40% confirmed in the last 18 months 10. NT-proBNP >1500 pg/ml or BNP >500 pg/ml 11. An eGFR of ≥30mL/min/1.73 m2 using the MDRD study equation 12. 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 drug: a. Abstinence, when it is in line with the preferred and usual lifestyle of the subject. Subject agrees to use an acceptable method of contraception should they become sexually active b. Maintenance of a relationship with a male partner who has been surgically sterilized by vasectomy (the vasectomy procedure must have been conducted at least 60 days prior to the Screening Visit or confirmed via sperm analysis) c. Barrier method (e.g., condom or occlusive cap) with spermicidal foam/gel/film/cream AND either hormonal contraception (oral, implanted, or injectable) or an intrauterine device or system 13. Willing to adhere to the study requirements for the length of the trial |
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E.4 | Principal exclusion criteria |
1. Completely bedridden for >2 weeks prior to admission. Patients should at least have been able to go the toilet and back and to get out of bed for meals at some time during this period 2. Known intolerance of furosemide 3. Acute coronary syndrome, stroke, or transient ischemic attack (TIA), coronary or peripheral revascularization procedures, valve procedures, OR any major surgical procedure within the previous 6 weeks 4. Invasive cardiac investigation and/or treatment (i.e. coronary angiography, percutaneous coronary intervention [PCI] or surgery) or other surgical procedure planned in the next 4 weeks 5. Use of intravenous radiographic contrast agent within 72 hours prior to screening or planned use during the study 6. Severe, in the investigators opinion, uncorrected valve disease or congenital heart disease as the cause for cardiac decompensation 7. Acute mechanical cause of decompensated heart failure such as papillary muscle rupture 8. Obstructive or infiltrative cardiomyopathy (e.g. amyloid, sarcoid, etc), suspected acute myocarditis, or heart failure related to an untreated metabolic condition (e.g. haemochromatosis) 9. Second or third degree heart block unless the subject has a ventricular pacemaker 10. Atrial fibrillation/flutter with sustained ventricular response of >130 bpm 11. Placement of a ventricular resynchronization device within the previous 6 weeks 12. Treatment or planned treatment with intravenous inotropic agents other than digoxin at any time on this admission 13. Receipt of intravenous vasodilator therapy ≤ 6 hours prior to randomization 14. The presence of any mechanical assist device or listed for or a history of a heart transplant 15. Suspected systemic infection or pneumonia and/or the need for antibiotic treatment between admission and time of consent. Patients given antibiotics without clear justification can be included as long as it is appropriate to discontinue the antibiotics 16. Severe respiratory disease or anticipated need for mechanical respiratory support (i.e. mechanical ventilation) 17. Anuric in the previous 24 hours 18. Haemoglobin <9 g/dL at screening or planned blood transfusions in the next 30 days 19. Serum potassium >5.5 mEq/L 20. Marked proteinuria suggestive of nephrotic syndrome 21. Estimated GFR (eGFR) as per MDRD equation <30 ml/min 22. Serum albumin of < 2.8 g/dL 23. Liver enzymes (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST]) elevation >5 times the upper limit of normal (ULN) 24. Total bilirubin >2.0 times ULN in the absence of Gilbert’s Syndrome 25. Known active hepatitis B, hepatitis C or Human Immunodeficiency Virus (HIV) infection, or diagnosis of immunodeficiency 26. Known active drug or alcohol abuse within 1 year of the Screening Visit at the discretion of the Investigator (i.e. 15 or more drinks for men per week or 8 or more for women). 27. Currently receiving treatment with chemotherapeutic agents or immunosuppressant agents or having received prior radiation therapy to the chest 28. Current or planned ultrafiltration, paracentesis, haemofiltration or dialysis 29. Currently receiving treatment of any intravenous steroid or > 5 mg of oral prednisone (or equivalent) 30. Recipient of stem cell or gene therapy or current therapeutic investigational devices 31. Participation in another clinical trial with an investigative product within 3 months prior to the Screening Visit 32. Any significant acute or chronic medical or psychiatric illness or social situation that, in the judgment of the Investigator, could compromise a subject’s safety, limit subject’s ability to complete the study and follow-up period, and/or compromise the objectives of the study 33. Women who are pregnant, planning to become pregnant, or lactating 34. Currently receiving treatment with therapeutic doses of any of the novel or direct oral anticoagulants (vitamin K antagonist are permitted) 35. Currently receiving treatment with sacubitril (Entresto™) 36. Hypersensitivity to elamipretide or any of its excipients |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in NT-proBNP between Baseline and Day 8/Early Discharge |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At Day 8 or early discharge |
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E.5.2 | Secondary end point(s) |
_Clinical Improvement a. Renal function (eGFR as per MDRD) b. Body weight c. Body weight per mg of furosemide administered d. Clinical status (e.g. patients and physician global assessment and treatment failures) e. The average dose of diuretic (furosemide – adjusted for thiazide dose if administered) _The plasma pharmacokinetics (PK) of elamipretide, its metabolites, and furosemide following a single dose and multiple doses of elamipretide in a selected number of patients _Pharmacokinetics The following plasma PK parameters will be determined for elamipretide (MTP-131), its metabolites (M1 and M2), and furosemide where possible and appropriate: Day 1: Cmax, Tmax, AUC(0-last), AUC(0-inf), AUC%extrap, t½, Cl, Vd, MRT Day 7: Cmin,ss, Cmax,ss, Tmax, AUC(0-tau),ss, AUC(0-last), AUC(0-inf), AUC%extrap, t½, Vd Additional Parameters: Cmax, Cmin on Days 2 - 6, P/T fluctuation (%) under steady state conditions, accumulation ratio for Cmax and AUC(0-tau) _ Treatment failures will be defined as any of the following criteria, should they occur before the assessment on Day 8/Early Discharge: a. Cardiovascular Death b. The need to increase the dose of IV furosemide to >10 mg/hour or equivalent c. The need to add new therapy or increase therapy of a thiazide or thiazide-like diuretic to a loop diuretic d. The need for intravenous inotropic agents (not including digoxin) e. The need for mechanical circulatory support f. The need for intubation and mechanical ventilation g. The need for renal replacement therapy or ultrafiltration h. Not medically fit for discharge at Safety Follow-Up Visit |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
All secondary efficacy endpoints will assess changes from baseline to Day 3 and Day 8 or Early Discharge |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 65 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Bulgaria |
France |
Hungary |
Latvia |
Netherlands |
Poland |
Serbia |
Spain |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |