Primary: To evaluate the effects of multiple subcutaneous (SC) doses of elamipretide on left ventricular end systolic volume (LV ESV) assessed by cardiac Magnetic Resonance Imaging (MRI)Secondary:* To evaluate the safety and tolerability of multiple…
ID
Source
Brief title
Condition
- Heart failures
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Endpoints
Change from baseline in left ventricular end systolic volume (LV ESV) assessed
by cardiac
MRI
Secondary outcome
Secondary Endpoints
** Adverse events (AEs)
** Changes from baseline in vital signs
** Changes from baseline in electrocardiograms (ECGs)
** Changes from baseline in clinical laboratory evaluations
** Changes from baseline in the following parameters assessed by cardiac MRI:
o LV EF
o LV end diastolic volume (EDV)
** Changes from baseline in the following parameters assessed by
echocardiography:
o E/A (ratio between early and late mitral inflow velocity),
o E/e* (Ratio between early mitral inflow velocity and mitral annular early
diastolic velocity)
o LV EDV, LV ESV and biplane EF
o LV global longitudinal strain
o LA volume
o LV mass
o Mitral regurgitation severity
o Tricuspid regurgitation severity
o RV fractional area change
o RV systolic pressure (RVSP)
Background summary
It is estimated that approximately 1-2% of the adult population in developed
countries has Heart
Failure (HF) and the prevalence is rising to *10% among persons 70 years of age
or older.
HF incidence is continuously increasing.
Despite the significant improvement in symptoms and survival observed with
pharmacologic blockade of the renin-angiotensin and beta adrenergic sys-tems,
such drug therapy generally has had limited impact on exercise capacity.
This has led to the concept that multi-targeted mechanistic approaches to HF
are required to suc-cessfully translate experimental interventions into
protection against the clinical manifestations of the disease state, as well as
beneficially impacting its associated major adverse events, including recurrent
hospitalization and death. Such a broad-based ap-proach must include therapies
that simultaneously impact multiple affected organ systems and cellular
mechanisms.
Elamipretide, with its multi-organ beneficial actions on function and
metabolism in vitro and in animal models, is a promising candidate for
targeting the complex interplay of factors that ultimately result in the
syndrome of clinical HF. The potential of elami-pretide to treat the multiple
organs systems and or-ganelles that contribute to the HF state represents an
important opportunity to address a critical and unmet clinical need.
The study drug has been given as single intravenous (into a vein) dose in heart
failure patients, but not as multiple subcutaneous doses. This will be the
first study where the study drug is being given as multi-ple subcutaneous
injections to patients with chronic heart failure.
Protocol page 15, section 4.1
Study objective
Primary:
To evaluate the effects of multiple subcutaneous (SC) doses of elamipretide on
left ventricular end systolic volume (LV ESV) assessed by cardiac Magnetic
Resonance Imaging (MRI)
Secondary:
* To evaluate the safety and tolerability of multiple SC doses of elamipretide
* To evaluate the effects of multiple SC doses of elamipretide on LV systolic
and diastolic function, LV volumes, LV global longitudinal strain, left atrial
(LA) volume, LV mass, mitral and tricuspid regurgitation severity, and right
ventricular (RV) function
Exploratory:
To evaluate the effects of multiple SC doses of elamipretide on:
- 6-minute walking distance
- Quality of Life
- N-terminal pro-brain natriuretic peptide (NT-pro-BNP) levels
- Change in Borg dyspnea scale
Study design
A Phase 2 Randomized, Double-Blinded, Placebo-Controlled Study
Intervention
Elamipretide (MTP-131) will be supplied as 40 mg/1 mL of sterile solution for
subcutaneous injection. The doses of elamipretide will be 4 mg or 40 mg
administered as a once daily SC injection.
You will be randomly assigned to 1 of 3 treatment groups:
* Group 1 will receive a daily dose of placebo (a sterile solution of salt in
water, otherwise known as saline) for 28 days
* Group 2 will receive a daily dose of 4mg of study drug for 28 days
* Group 3 will receive a daily dose of 40mg of study drug for 28 days
Study burden and risks
- the amount and number of blood samples (seeE6, 11x) ,
- the number of site visits (8x),
- physical examinations or other tests: every visit, incl 3x times an MRI scan
(once with contrast dye, and twice without)
- questionnaires (2 types),
- the risks associated with the investigational product:
Based on the clinical and non-clinical study data, accepatable safety risks are
expected for the proposed current study. Visiting nurses will visit subjects
daily to administer study medication and therefore subjects will have an
opportunity to report any safety concerns on a daily basis.
Common side effects in the phase I study were:
Headache, nausea and low serum sodium values.
When the study drug was injected directly under the skin, the most commonly
observed injection site reaction was mild erythema (redness) and/ or mild
itchiness (pruritis), which generally occurred within 5 minutes of
administration.
Patients with decreased renal function will have higher study drug blood
levels after taking the drug. To dat, there have not been more side effect in
patients with decreased kidney function compared to peaple with normal kidney
function.
MRI scan:
Patients may be allergic to the contrast dye used for the initial MRI scan
(screening visit), or experience claustrophobia during the scanning process.
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US
Listed location countries
Age
Inclusion criteria
1. Willing and able to provide signed informed consent form (ICF) prior to participation in any study-related procedures;
2. Age *40 and *80 years;
3. A known history of chronic ischemic or non-ischemic cardiomyopathy of at least 6 months duration from the time of the initial diagnosis, or signs and symptoms consistent with heart failure;
4. 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;
5. 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;
6. In normal sinus rhythm (electrocardiogram documented) at Screening and Day 1 and no history of atrial fibrillation in the past 12 months;
7. No hospitalization related to HF within 1 month prior to the Screening Visit;
8. Left Ventricular Ejection Fraction (LVEF) * 40% by 2-D echocardiography at Screening;
9. At least 3 viable segments (hyperenhancement * 25%) by a qualifying delayed gadolinium-enhanced cardiac MRI examination at Screening (confirmed by independent core lab);
10. Willing to adhere to the study requirements for the length of the trial;
11. 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 AND either hormonal contraception (oral, implanted, or injectable) or an intrauterine device or system;;Note: Non-childbearing potential is defined as surgical sterilization (e.g., bilateral oophorectomy, hysterectomy, or tubal ligation) or postmenopausal (defined as permanent cessation of menstruation for at least 12 consecutive months prior to the Screening Visit);
Exclusion criteria
1. 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;
2. Any contraindication to MRI scanning as assessed by local MRI safety questionnaire, which may include;
a. History of intra-orbital metal fragments which have not been removed;
b. Severe claustrophobia;
c. Non-MRI safe cochlear implant(s) or intracranial aneurysm clips;
d. Extensive tattoos located on the torso that contain metallic inks;
e. Other non-removable implanted metallic or electronic devices that have not been determined to be MRI safe;
f. Inability to lie flat;
3. Inadequate echocardiogram image quality (defined as poor sound transmission and/or < 10 endocardial segments seen);
4. LVEDD indexed to Body Surface Area is > 45 mm/m2 assessed by 2-D echocardiography;
5. Coronary or peripheral revascularization procedures, valvular procedures, OR any major surgical procedure within 3 months prior to the Screening Visit;
6. Acute coronary syndrome, stroke or transient ischemic attack (TIA) within 3 months prior to the Screening Visit;
7. 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;
8. 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;
9. Presence of second degree or advanced heart block;
10. Uncontrolled hypertension defined as a systolic blood pressure > 160 mmHg or a diastolic blood pressure > 110 mmHg on at least two consecutive readings;
11. Presence of any left ventricular thrombus, pericardial disease, uncorrected thyroid disease or a dyskinetic left ventricular aneurysm;
12. History of cancer that causes symptoms, disabilities, or is likely to lead to hospitalization or treatment in the next 12 months;
13. Currently receiving treatment with chemotherapeutic agents or immunosuppressant agents or has received prior radiation therapy to the chest;
14. Liver enzymes (alanine aminotransferase [ALT] AND/OR aspartate aminotransferase[AST]) elevation > 3 times the upper limit of normal (ULN;
15. Total bilirubin > 1.5 times ULN in the absence of Gilbert*s Syndrome;
16. Bleeding diathesis or any known blood dyscrasia;
17. Anemia, defined as hemoglobin < 9 g/dL or planned blood transfusions in the next 6 weeks;
18. Estimated glomerular filtration rate (eGFR) < 30 mL/min, using the Modification of Diet in Renal Disease (MDRD) Study equation;
eGFR (mL/min/1.73 m2) = 175 x (Scr)^[-1.154] x (Age)^[-0.203] x (0.742 if female) x (1.212 if African American);
19. History of hepatitis B, hepatitis C or Human Immunodeficiency Virus (HIV) infection, or diagnosis of immunodeficiency;
20. 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;
21. 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;
22. Any significant acute or chronic medical or psychiatric illness that, in the judgment of the Investigator, could compromise the subject*s safety, limit subject*s ability to complete the study, and/or compromise the objectives of the study;
23. Female subjects who are pregnant, planning to become pregnant, or lactating;
24. Currently requiring any changes in doses of cardiovascular medication (including diuretics) in order to control worsening of HF symptoms;
25. Known allergy to gadolinium;
26. 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, as well as vitamin K antagonists;
27. Currently receiving treatment with sacubitril/valsartan or trimetazidine.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-005724-10-NL |
| CCMO | NL56002.042.16 |