TEVA CEP-41750

Simple Summary

Primary:􀁸 To assess safety and tolerability of single doses of JVS-100 administered through retrogradecoronary sinus delivery using the Oscor Venos Occlusion Balloon catheterSecondary:􀁸 To investigate the impact of single doses of JVS-100 (30 mg or 45 mg) delivered via retrogradecoronary sinus infusion using the Oscor Venos Occlusion Balloon catheter on 6 minute walk distanceand/or quality of life measured by the Minnesota Living with Heart Failure Questionnaire compared toplacebo at 4 months post-dosing.􀁸 To assess the impact of a single dose of JVS-100 on heart failure symptoms, NYHA class,functional parameters, LV function, NTproBNP levels and morbidity/mortality parameters compared toplacebo at 4 and/or 12 months post-dosing.

Detailed Description

Investigational Product is CEP-41750; it consists of human bone marrow-derived allogeneic MPCs that have been isolated from bone mononuclear cells with anti-STRO 3 antibodies, expanded ex vivo, and cryopreserved.Delivery Method is: Contrast left ventriculography in combination with an electromechanical navigational system (NOGA® XP) will beused to visualize and map myocardial locations targeted for delivery of CEP-41750. Myocardial locations will be defined within the left ventricle by imaging and electromechanical mapping as viable for cell delivery. After the completion of the mapping procedure, 15 to 20 appropriate myocardial sites will be identified with the intent of identifying 20 sites, if possible. Transendocardial delivery to each of these locations will be made with 0.2 mL of CEP-41750 within approximately 30 to 60 seconds, utilizing the MyoStar Injection Catheter. Control: Patients randomly assigned to the control group will undergo a scripted sham intracardiac mapping and cell delivery procedure that includes an index cardiac catheterization with left ventriculography. The sham intracardiac mapping and cell delivery procedure will be staged to script and will not include intracardiac mapping or transendocardial delivery of CEP-41750.

Inclusion Criteria

a. The patient is 18 to 80 years of age, inclusive; both men and women will be enrolled.

b. Inclusion criterion b was replaced by b1.

(b1) The patient has a diagnosis of chronic HF of ischemic or nonischemic etiology for at least

6 months before the initiation of screening procedures, with NYHA Functional Class II or Functional

Class III symptoms. Chronic HF of ischemic etiology includes epicardial coronary artery disease

[CAD] defined as documented stenosis of at least 50% in one or more major epicardial coronary

arteries, documented prior coronary revascularization, or documented prior MI.

c. The patient is on stable, optimally tolerated dosages of HF therapies including beta-blockers (approved

for country-specific usage), angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor

blockers (ARBs), and/or aldosterone antagonists, without change in dose for at least 1 month before

study intervention (ie, hospitalization on day 0 for index cardiac catheterization with or without

intracardiac mapping and cell delivery).

d. The patient is on a stable, outpatient, oral diuretic dosing regimen in which the patient remains

clinically stable during screening (flexible diuretic dosing that allows the patient to titrate the dose or

add a dose of a second diuretic during screening is permitted, provided that the dosing regimen is not

further altered and the patient remains stable during this period) or the patient is not on a regular dose of

diuretics but takes diuretics as needed based on daily weights or the appearance of symptoms.

e. The patient is not a candidate for either percutaneous coronary intervention (PCI) or coronary artery

bypass graft (CABG) surgery as determined by the principal investigator (or designee) during

screening.

f. Inclusion criterion f was replaced by f1.

(f1) The patient may be on the cardiac transplant list. However, the patient must have low priority

status with low probability of having a transplant procedure performed over the next 12 months (ie,

cannot be United Network for Organ Sharing [UNOS] status 1A or 1B).

g. The patient has a LVEF by the Core Cardiac Image Laboratory of 40% or less as measured by 2-D echocardiogram, or 35% or less as

measured by radionuclide ventriculography (RVG) within 42 days prior to study intervention (ie,

hospitalization on day 0 for index cardiac catheterization with or without intracardiac mapping and cell

delivery).

h. The patient has 1 or more of the following:

- at least 1 HF hospitalization more than 1 month, but 9 months or less before initiation of screening

procedures

- at least 1 outpatient visit requiring IV diuretic, vasodilator, and/or positive inotropic therapy more

than 1 month, but 9 months or less before initiation of screening procedures

- plasma levels of NT-proBNP as measured by the central laboratory of greater than 1000 pg/mL (1000 ng/L SI units, 118 pmol/L) or 1200 pg/mL (1200

ng/L SI units, 141.6 pmol/L) for patients with atrial fibrillation

i. If the patient has an ICD (or any implated device capable of defibrillation) in place, the placement must have occurred at least 1 month before

initiation of screening procedures.

j. If the patient has had cardiac resynchronization therapy (CRT), the procedure must have occurred at

least 3 months before screening.

k. The patient has an LV diastolic wall thickness of at least 8 mm at potential target sites for cell delivery.

l. Women must be surgically sterile, 1 year postmenopausal, or must have a negative urine or serum pregnancy

test at screening.

m. Inclusion criterion m was replaced by m2.

(m2) Women must be surgically sterile, 1 years post-menopausal, or, if of childbearing potential,

currently using a medically accepted method of contraception, and must agree to continue to use this

method of contraception after initiation of screening procedures and for 6 months after study

intervention (ie, hospitalization on day 0 for index cardiac catheterization with or without intracardiac

mapping and cell delivery). Acceptable methods of contraception include barrier method with

spermicide, abstinence, intrauterine device (IUD) (known to have a failure rate of less than 1% per

year), or steroidal contraceptive (oral, transdermal, implanted, or injected) in conjunction with a barrier

method. Men must be surgically sterile, or, if capable of producing offspring, currently using an

approved method of contraception and must agree to continue to use this method of contraception

after initiation of screening procedures and for 16 weeks after study intervention. Acceptable methods

of contraception include abstinence, female partner’s use of steroidal contraceptive (oral, implanted or

injected) in conjunction with a barrier method, female partner’s use of an IUD (known to have a failure

rate of less than 1% per year), or if female partner is surgically sterile or 1 years post menopausal. In

addition, men may not donate sperm for 16 weeks after study intervention.

n. The patient must be willing to return for required follow-up visits.

o. Written informed consent is obtained for the study before any study-specific procedures are performed.

A separate written informed consent for an exploratory PGx substudy will be obtained before any

PGx-specific procedures are performed. Participation in the PGx substudy is optional and consent may

be collected at a later stage than screening (though preferred as early as possible). A patient will not be

excluded from participation in the study if he/she chooses not to provide consent for the additional

procedures that are required as part of the exploratory PGx substudy.

p. Prior to the initiation of any procedures on day 0, the cell injection center will ensure that an

institution-specific informed consent document is obtained, if applicable.

q. The patient must be able to receive systemic anticoagulant therapy.

Exclusion Criteria

a. The patient has NYHA Functional Class I or Functional Class IV symptoms.

b. The patient has had an acute MI within 1 month before initiation of the screening procedures.

c. The patient has unstable angina pectoris within 1 month before initiation of screening procedures;

unstable angina is defined as the occurrence of chest pain more frequently than usual, pain at rest or

upon minimal exertion, or protracted episodes of pain without any discernible trigger, and/or chest pain

that persists despite use of vasodilatory therapy (eg, nitroglycerin) and or aggravation of stable angina

or new onset angina.

d. The patient has peri- or postpartum cardiomyopathy (CM).

e. The patient has ischemic or hemorrhagic stroke as diagnosed by computed tomography (CT) or

magnetic resonance imaging (MRI) within 3 months prior to study enrollment.

f. The patient has had a coronary arterial or peripheral arterial revascularization procedure within

2 months before initiation of screening procedures.

g. The patient has had IV therapy with diuretic, vasodilator, and/or positive inotropes or aquapheresis

within 1 month before initiation of screening procedures, and/or during the screening period.

h. The patient, who in the absence of an ICD (or any  implanted device capable of defibrillation), has a history of malignant ventricular arrhythmia or

sustained ventricular tachycardia (VT), with sustained VT demonstrated by QRS complexes wider than

120 milliseconds, lasting more than 30 seconds, and with a rate of more than 100 beats per minute on

screening ECG or other data supporting this diagnosis.

i. The patient has restrictive, obstructive, or infiltrative CM, pericardial constriction, amyloidosis, or

uncorrected thyroid disease.

j. The patient has moderate to severe aortic stenosis as determined by the Core Cardiac Imaging Laboratory echocardiography-Doppler

assessment with a valve area less than 1.0 cm2.

k. The patient requires valve or other cardiac (eg, pericardectomy) surgery.

l. The patient has had LV reduction surgery, implanted LVAD, or cardiac transplantation. The patient

may be on the cardiac transplant list, but must have low probability of having a transplant procedure

over the next 12 months.

m. The patient has an LV thrombus diagnosed by echocardiography, left ventriculogram, or other

imaging.

n. The patient has cardiogenic shock that is dependent upon mechanical or inotropic support at the time

of study intervention (ie, hospitalization on day 0 for index cardiac catheterization with or without

intracardiac mapping and cell delivery), as defined by Killip Class IV physiology indicative of

cardiogenic shock and/or requirement of intra-aortic balloon pump or IV inotropic support for the

maintenance of mean arterial blood pressure at least 60 millimeters of mercury (mmHg).

o. The patient is known to have unprotected left main CAD greater than 50%.

p. Exclusion criterion r was replaced by p1.

(p1) The patient has known hypersensitivity to radiocontrast media or dimethyl sulfoxide (DMSO),

murine, and/or bovine products with the exception of patients with mild hypersensitivity to

radiocontrast media, who may be pretreated with corticosteroids and/or antihistamines.

q. The patient has a known active malignancy within the past 3 years except for localized prostate cancer,

cervical carcinoma in situ, breast cancer in situ, or nonmelanoma skin cancer that has been definitively

treated.

r. Exclusion criterion r was replaced by r1.

(r1) The patient has acute bacterial or viral infectious disease, or acute exacerbation of a chronic

infectious disease at the time that day 0 intervention is planned. However, patients with an upper

respiratory infection diagnosed at screening that is cleared by day 0 (maximum of 42 days from

signing of informed consent form) may undergo the procedure .

s. Exclusion criterion s was replaced by s1.

(s1) Patients with severe chronic obstructive pulmonary disease (COPD) or who require home oxygen

for any kind of pulmonary disease; home oxygen use as part of CPAP (continuous positive airway

pressure) for the indication of sleep apnea in patients living at high altitude is permitted, and as-needed

home oxygen use solely as therapy for HF is permitted. A patient with moderate COPD without severe

right ventricular dilatation and dysfunction on echocardiogram may be included in the study if the

patient has a documented HF history that meets qualifying HF criteria. A patient who has a forced

expiratory volume in one second (FEV1) of less than 1.0 L will be excluded. A given patient will be

excluded from serial echocardiographic imaging assessments if his/her heart is difficult to image

adequately using standard precordial echocardiographic techniques. In that case, RVG estimations of

LVEF will be used for screening inclusion criteria as well as for serial changes in overall cardiac

performance after study intervention (ie, hospitalization on day 0 for index cardiac catheterization with

or without intracardiac mapping and cell delivery). A patient with clinically meaningful COPD will be

excluded from serial 6MWT evaluations if the patient’s exercise limitation is thought to be due

predominantly to the patient’s intrinsic pulmonary disease rather than from the patient’s HF state.

t. The patient has a bleeding diathesis disorder such as abnormal coagulation profile, precluding study

intervention (ie, hospitalization on day 0 for index cardiac catheterization with or without intracardiac

mapping and cell delivery).

u. Exclusion criterion u was replaced by u1.

(u1) The patient has 1 or more clinical laboratory test value(s) performed by the Central Clinical Laboratory that are outside the range for 1 or more of the

tests specified below, or any other clinically significant abnormality as determined by the investigator

or medical monitor as follows (note: repeat of suspected spurious laboratory abnormalities may be

permitted after consultation with the medical monitor):

- aspartate aminotransferase (AST/SGOT)/alanine aminotransferase (ALT/SGPT) greater than

3 times upper limit of normal (ULN) range

- estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73 m2 (calculated by the central

clinical laboratory using the Modification of Diet in Renal Disease (MDRD) formula); measures

to minimize the risk of contrast-induced nephropathy will be taken at the discretion of the

investigator

- hemoglobin less than 9 g/dL

- platelets less than 100 × 103/mm3

- hemoglobin A1c (HBA1c) of 10% or greater

v. The patient has any concurrent disease or condition that in the opinion of the investigator would make

the patient unsuitable for participation in the study.

w. The patient has previously participated in any stem cell or regenerative medicine study, in which

he/she received active agent.

x. The patient has received hematopoietic growth factors within 12 months preceding study intervention

(ie, hospitalization on day 0 for index cardiac catheterization with or without intracardiac mapping and

cell delivery).

y. Exclusion criterion u was replaced by y1.

(y1) The patient has had treatment and/or an uncompleted follow-up treatment of any investigational

therapy within 6 months before study intervention and/or intends to participate in any other

investigational drug or cell therapy study in the 3 years after study intervention (ie, hospitalization on

day 0 for index cardiac catheterization with or without intracardiac mapping and cell delivery).

z. The patient has hemodynamically compromised, complex congenital heart disease.

aa. Exclusion criterion aa was replaced by aa1.

(aa1) A patient with an ICD (or any implanted device capable of defibrillation) in place who has had an ICD firing within 1 month of day 0.

bb. A patient has had angina on the average of more than 3 times per week.

cc. The patient completes two 6MWTs with either test being a distance of > 450 meters.

dd. The patient is unable to perform the 6MWT due to concurrent medical conditions; exception is those patients with NT-proBNP >2000 pg/mL (2000 ng/L SI units, 236pmol/L).

ee. The patient has an aortic valve prosthesis

Participant Reimbursement

Subjects will not be paid to be in the study.