Study to Evaluate the Effect on the Heart and Kidneys of Short Term Treatment with Elamipretide in Patients Hospitalized with Congestion due to Heart Failure

• Register: EUCTR
• Last refreshed on: 22 January 2018
• Main ID: EUCTR2016-000126-19-HU
• Date of registration: 12/09/2016
• Prospective Registration: Yes
• Primary sponsor: Stealth BioTherapeutics Inc.
• Public title: Study to Evaluate the Effect on the Heart and Kidneys of Short Term Treatment with Elamipretide in Patients Hospitalized with Congestion due to Heart Failure
• Scientific title: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Cardiac and Renal Effects of Short Term Treatment with Elamipretide in Patients Hospitalized with Congestion due to Heart Failure
• Date of first enrolment: 15/09/2016
• Target sample size: 300
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-000126-19
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Belgium, Bulgaria, France, Hungary, Latvia, Netherlands, Poland, Serbia, Spain, United Kingdom

Contacts

• Name: Matthew Millstein
• Affiliation: Stealth BioTherapeutics Inc.

• Name: Matthew Millstein
• Affiliation: Stealth BioTherapeutics Inc.

Key inclusion & exclusion criteria

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
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 100
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 200

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 medica

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

Congestive heart failure
MedDRA version: 19.1 Level: LLT Classification code 10010684 Term: Congestive heart failure System Organ Class: 100000004849

Intervention(s)

Product Name: Elamipretide
Product Code: MTP-131
Pharmaceutical Form: Powder and solution for solution for injection
INN or Proposed INN: elamipretide
CAS Number: 736992-21-5
Current Sponsor code: MTP-131
Other descriptive name: BENDAVIA™, MTP-131, SS-31, SPI-31, SBT-31
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 20-
Pharmaceutical form of the placebo: Powder for solution for infusion
Route of administration of the placebo: Intravenous use

Primary Outcome(s)

Primary end point(s): Change in NT-proBNP between Baseline and Day 8/Early Discharge

Timepoint(s) of evaluation of this end point: At Day 8 or early discharge

Secondary Objective: _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

Main Objective: 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

Secondary Outcome(s)

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

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

Secondary ID(s)

2016-000126-19-LV

SPIHF-204

Source(s) of Monetary Support

Stealth BioTherapeutics Inc.