Inclusion and Exclusion Criteria: TEVA C41750/3100 (DREAM-HF) Study

Inclusion Criteria

  • The patient is 18 to 80 years of age, inclusive; both men and women will be enrolled.
  • 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 CAD defined as documented stenosis of at least 50% in one or more major epicardial coronary arteries or documented prior MI.
  • The patient is on stable, optimally tolerated dosages of HF therapies including beta-blockers, ACE inhibitors or angiotensin-receptor blockers (ARBs), and/or aldosterone antagonists, without change in dose for at least 1 month prior to study intervention (ie, hospitalization on day 0 for index cardiac catheterization with or without intracardiac mapping and cell delivery).
  • 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.
  • 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.
  • The patient may be on the cardiac transplant list. However, he/she must have low priority status with low probability of having a transplant procedure performed over the next 12 months (ie, cannot be UNOS status 1A or 1B).
  • The patient has a LVEF of 40% or less as measured by 2-D echocardiogram, or 35% or less as measured by 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).
  • 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-pro-BNP greater than 1000 pg/mL or 1200 pg/mL for patients with atrial fibrillation
  • If the patient has an AICD in place, the procedure must have occurred at least 1 month before initiation of screening procedures.
  • If the patient has had CRT, the procedure must have occurred at least 3 months before screening.
  • The patient has an LV diastolic wall thickness of at least 8 mm at the potential target site for cell injection.
  • Women must be surgically sterile, 1 year post-menopausal, or must have a negative urine pregnancy test at screening.
  • Women must be surgically sterile, 2 years post-menopausal, or, if of child-bearing 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 a medically accepted method of contraception and must agree to continue to use this method of contraception after initiation of screening 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 2 years post-menopausal. In addition, men may not donate sperm for 16 weeks after study intervention.
  • The patient must be willing to return for required follow-up visits.
  • Written informed consent is obtained for the study before any study-specific procedures are performed. A separate written informed consent for the exploratory PGx substudy is 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.
  • 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.


Exclusion Criteria

  • The patient has NYHA Functional Class I or Functional Class IV symptoms.
  • The patient has had an acute MI within 1 month before initiation of the screening procedures.
  • The patient has unstable angina pectoris within1 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.
  • The patient has peri-/postpartum cardiomyopathy.
  • The patient has ischemic or hemorrhagic stroke as diagnosed by CT or MRI within 3 months prior to study enrollment.
  • The patient has had coronary arterial or peripheral arterial revascularization procedure within 2 months before initiation of screening procedures.
  • 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.
  • The patient, who in the absence of an AICD, 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.
  • The patient has restrictive, obstructive, or infiltrative CM, pericardial constriction, amyloidosis, or uncorrected thyroid disease.
  • The patient has moderate to severe aortic stenosis as determined by echocardiography-Doppler assessment with a valve area less than 1.0 cm2.
  • The patient requires valve or other cardiac (eg, pericardectomy) surgery.
  • The patient has had LV reduction surgery, implanted LVAD, or cardiac transplantation. The patient maybe on the cardiac transplant list, but must have low probability of having a transplant procedure over the next 12 months.
  • The patient has an LV thrombus diagnosed by echocardiography, left ventriculogram, or other imaging.
  • 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 mmHg.
  • The patient is known to have unprotected left main coronary artery disease (CAD) greater than 50%.
  • 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 or DMSO, who may be pretreated with corticosteroids and/or antihistamines.
  • 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.
  • 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.
  • Patients with severe chronic obstructive pulmonary disease (COPD) or patients 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 RV dilatation and dysfunction on echocardiogram may be included in the study if they have a documented HF history that meets qualifying HF criteria. A patient who has a forced expiratory volume (FEV1) in one second 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). Patients with clinically meaningful COPD will be excluded from serial 6MWT evaluations if their exercise limitation is thought to be due predominantly to their intrinsic pulmonary disease rather than from the patient’s HF state.
  • 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).
  • The patient has 1 or more clinical laboratory test value(s) 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 lab abnormalities may be permitted after consultation with the medical monitor):
    • aspartate aminotransferase (AST/SGOT)/alanine aminotransferase (ALT/SGPT) greater than 3 times ULN range
    • total bilirubin greater than 1.5 times ULN
    • eGFR less than 30 mL/min/1.73 m2 (calculated by the central clinical Laboratory using the MDRD formula); measures to minimize the risk of contrast-induced nephropathy will be taken at the discretion of the investigator
    • hemoglobin less than 9g/dL
    • platelets consistently less than 100×103/mm3
    • HbA1c of 10% or greater
  • 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.
  • The patient has previously participated in any stem cell or regenerative medicine study in which he/she received active agent.
  • 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).
  • 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).
  • The patient has hemodynamically compromised, complex congenital heart disease.
  • A patient with an AICD in place who has had an AICD firing within 1 month of day 0.
  • A patient has had angina on the average of more than 3 times per week.

NOTE: patients who experience an event that triggers an exclusion criterion after randomization but before the day 0 procedure must be discontinued from the study and cannot be re-screened.

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