| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Heart failure with preserved ejection fraction (HFpEF) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Heart failure with preserved ejection fraction (HFpEF) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| 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 effects of 4 weeks of daily subcutaueous administration of elamipretide on
E/e' at rest assessed by transthoracic echocardiography |
| Beurteilung der Wirkungen einer 4-wöchigen täglichen subkutanen Verabreichung von Elamipretid auf das E/e'-Verhältnis in Ruhe , bewertet über transthorakale Herzechokardiographie |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the effects of 4 weeks of daily administration of elamipretide on:
o E/e’ during stress as assessed by transthoracic echocardiography
o LV systolic global longitudinal strain (GLS) at rest and during submaximal stress
o 6-minute walking distance
o NT-proBNP
To evaluate the safety profile of elamipretide in this patient population (including
tolerability assessed by ISR questionnaire) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Age ≥45 and <80 years.
2) Symptomatic heart failure (i.e. NYHA II or III) due to HFpEF for at least 6 months prior to study start
3) Evidence of HFpEF: LVEF ≥45% and E/e´>10 and NT-pro-BNP >220 pg/ml (sinus rhythm) / > 600 pg/mL (atrial fibrillation)
4) An exercise-induced increase in E/e′ of at least 4 units during stress echocardiography assessment.
5) Meeting echocardiographic E/e’ criteria both at screening and at baseline
6) Heart failure is considered to be stable, in the judgment of the investigator, and no hospitalization for HFpEF or changes in dose regimen of pharmacologic treatment for HF has occurred within 1 month prior to the Screening Visit.
7) Treatment with appropriate pharmacologic therapy to manage underlying risk factors according to current guidelines.
8) Ability to complete the study in compliance with the protocol.
9) 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:
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 monogamous 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 (based on non-oil and non-lipid ingredients containing lactic acid or citric acid) AND either hormonal contraception (oral, implanted, or injectable) or an intrauterine device or system.
Note: Non-childbearing potential is defined as surgical sterilization (eg, bilateral oophorectomy, hysterectomy, or tubal ligation) or postmenopausal status (defined as permanent cessation of menstruation for at least 12 consecutive months prior to the Screening Visit).
10) Women of child-bearing potential must have a negative serum pregnancy test at baseline
11) For male subjects with female partners of child-bearing potential, highly effective methods of contraception must be adhered prior to drug administration and for at least 2 months after administration of the last dose of drug. Highly effective methods of contraception are defined as usage by the female partner of any form of hormonal contraception or intra-uterine device (which should be in situ prior to the start of the study) plus usage by one of the partners of an additional spermicide-containing barrier method of contraception.
12) Male subjects with pregnant partners must use a condom with spermicide from the start of treatment until at least 2 months after administration of the last dose of drug.
13) Subjects must not donate sperm or eggs from the start of treatment until 2 months after the administration of the last dose of drug
14) Subject is willing to participate and to provide signed informed consent (ICF) prior to participation in any study-related procedures.
|
|
| E.4 | Principal exclusion criteria |
1) Probable alternative diagnoses that in the opinion of the investigator could account for the patient’s symptoms e.g. severe pulmonary dysfunction or severe asthma as determined by the responsible investigator (COPD class 2 or more), anemia (hemoglobin <10 g/dl), body mass index (BMI) >40 kg/m2
2) LVEF <45% (at the moment of enrollment or in medical history)
3) Atrial fibrillation as soon as 18 subjects with atrial fibrillation have been randomized into the trial
4) Inability to acquire complete echo images (e.g. barrel chested, lung disease, severe obesity)
5) Inability to perform stress echocardiography (e.g. severe peripheral artery disease)
6) History of any concurrent medical condition which, in the opinion of the Investigator, significantly increases the potential risks associated with administration of study medication or any other aspect of study participation.
7) Coronary or peripheral revascularization procedures, valvular procedures, OR any major surgical procedure within 3 months prior to the Screening Visit.
8) Acute coronary syndrome (ACS), stroke or transient ischemic attack (TIA) within 3 months prior to the Screening Visit.
9) Patients with symptomatic coronary artery disease (CAD)
10) Patients presenting with clinically relevant scar burden (>3 segments) at the echo screening resulting in a LVEF <45%
11) Restrictive or obstructive cardiomyopathy or pericardial disease.
12) Severe valvular heart disease defined as aortic stenosis > grade 2, any degree of mitral stenosis, mitral regurgitation > grade 2, aortic regurgitation >grade 2, tricuspid regurgitation > grade 2, pulmonary stenosis and/or pulmonary regurgitation >grade 1
13) Uncontrolled hypertension defined as a systolic blood pressure (BP) >160 mm Hg or a diastolic BP >100 mm Hg on at least 2 consecutive readings that will require a change in anti-hypertensive treatment during the study period.
14) Heart rate at randomization visit >= 100 beats per minute
15) Presence of second degree or advanced heart block
16) Active cancer or undergoing chemotherapy within previous 6 months
17) Total bilirubin >2x the upper limit of normal (ULN) in the absence of Gilbert’s Syndrome (M. Meulengracht) and liver enzymes (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST] and/or alkaline phosphatase) elevation >3xULN
18) Estimated glomerular filtration rate <30 mL/min, by MDRD
19) Bleeding diathesis or any known blood dyscrasia.
20) Expected survival <1 year in the Investigator’s medical opinion.
21) Known active drug or alcohol abuse within 1 year of the Screening Visit.
22) Use of other investigational drugs at the time of enrolment, or within 30 days or 5 half- lives of enrolment
23) Treatment with spironolactone or eplerenone for less than 3 months at study start
24) Treatment with dabigatran
25) Treatment with valsartan/sacubitril
26) Treatment with trimethazine
27) Treament with immunosuppressors
28) Treatment with chemotherapeutic drugs
29) Female subjects who are pregnant, planning to become pregnant, or lactating.
30) Specific contraindications for echo stress testing
• Absolute contraindications:
• acute myocardial infarction
• unstable angina
• cardiac arrhythmias with symptoms and/or impaired haemodynamics
• decompensated heart failure
• acute pulmonary embolism
• acute myocarditis
• acute pericarditis
• acute aortic dissection
• Relative contraindications:
• significant left main coronary artery stenosis
• known electrolyte imbalance
• arterial hypertension (>200/110 mmHg)
• tachyarrhythmia or bradyarrhythmia
• hypertrophic cardiomyopathy and any other forms of obstruction of the outflow tract
• physical and/or psychological impairments
31) Hypersensitivity to MTP-131 (Elamipretide) or any of its excipients.
32) Symptomatic hyponatremia with a sodium Na+ <125 meq/L
Note: Laboratory exclusion criteria, specifically hemoglobin, total platelet count, total bilirubin, alanine
aminotransferase, aspartase aminotransferase, alkaline phosphatase, and serum creatinine should be
measured locally in order to allow randomization based on local laboratory values. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Changes in E/e’ at rest as assessed by transthoracic echocardiography between Baseline and Visit 5 (28 days). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| the Primary endpoint will be evaluated after visit 5 (day 28 + 3 days) |
|
| E.5.2 | Secondary end point(s) |
Changes in E/e’ during submaximal stress assessed by transthoracic echocardiography
between Baseline and V5
Changes from baseline in LV systolic GLS at rest and during submaximal stress
(transthoracic echocardiography)
Adverse events (including tolerability assessed by ISR questionnaire)
Changes from baseline in walking distance (6MWT test)
Changes from baseline in NT-proBNP
Exploratory Endpoints
Changes from baseline in:
SF-36 questionnaire – limited to physical function
Direct and indirect measures of LV structure and function (resting and submaximal
stress echocardiography):
a) LVESVI
b) LVEDVI
c) LVEF
d) Stroke volume
e) LV mass
f) Average E’
g) LAVI
h) TR velocity
Biomarkers: Cystatin C, NGAL, Troponin I. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At any point from baseline through last visit |
|
| 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 | No |
| 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 | No |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 7 |
| 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 |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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