|Principal Investigator: Craig Selzman|
|Keywords: Stem Cells||Department: Cardiothoracic Division|
|IRB Number: 00057349|
|Specialty: Cardiology, Cardiology, Cardiothoracic Surgery, Cardiothoracic Surgery, Cardiothoracic Surgery|
|Sub Specialties: Heart Failure, Heart Stem Cell Therapy, Heart Failure|
|Recruitment Status: Completed|
The objective of this study is to assess the efficacy, safety and tolerability of ixmyelocel-Tcompared to placebo (vehicle control) when administered via transendocardial catheter-based injections to subjects with end stage heart failure due to IDCM, who have no reasonable revascularization options (either surgical or percutaneous interventional) likely to provide clinical benefit.
Ixmyelocel-T is a patient-specific (autologous), expanded, multicellular therapy manufactured in an automated closed-cultured system developed by Aastrom Biosciences, Inc. All cells obtained from the manufacturing process comprise a single-unit dose for a single patient. The ixmyelocel-T manufacturing process expands cells that express the surface marker CD90 (mesenchymal cells), and also expands a CD14+ monocyte/macrophage subset of CD45+ hematopoetic cells.The precise mechanism of action for ixmyelocel-T is not known; however, current investigation into a multimodal effect of ixmyelocel-T, including beneficial effects to endothelial function, is ongoing. Because of the mixed composition of ixmyelocel-T, a wide range of biological activities relevant to the repair and regeneration of ischemic tissue have been demonstrated. These include tissue remodeling and immunomodulation, which may promote and support angiogenesis in a synergistic manner.To produce ixmyelocel-T, 50-60 mL of bone marrow is aspirated from the patient’s iliac crest under conscious sedation in an outpatient setting. The bone marrow is shipped overnight to Aastrom where it is processed and cultured for 12 ±1 days. The cells are harvested, prepared as the ixmyelocel-T product, and shipped overnight back to the treatment site where they are administered to the patient via multiple injections.In nonclinical studies, there have been no in-life signs or postmortem pathologic findings indicative of toxicity observed in immunodeficient rats that have been treated with ixmyelocel-T via intramuscular or intramyocardial injection in models of limb and cardiac ischemia. No reproductive/developmental toxicity, genotoxicity, or carcinogenicity studies have been conducted due to the autologous nature and intended use of the product.Present indications under study are the prevention and reduction of events associated with critical limb ischemia (CLI), the most severe form of peripheral artery disease (PAD), and the improvement of ischemic or non-ischemic dilated cardiomyopathy (DCM). Past indications no longer under study by Aastrom but reported in this investigator brochure include long bone fracture healing, osteonecrosis, edentulism, spinal fusion, and diabetic ulcer. These are no longer being pursued due to business reasons and not safety concerns.To date, ixmyelocel-T has been studied in 215 patients, including 91 patients in CLI and DCM patients. In the RESTORE-CLI study, adverse event (AE) and serious adverse event (SAE) rates were similar between ixmyelocel-T and control CLI patients. In addition, the intramuscular injection sites were monitored for 2 hours post-injection and there do not appear to be any safety concerns with ixmyelocel-T administration including local or systemic immunological reactions.Summarizing this CLI final data with the data from the 2 ongoing DCM trials, ixmyelocel-T injected into cardiac muscle appears to be well-tolerated. Most of the AEs and SAEs observed to date have been associated with underlying disease progression, or, in the case of the surgical DCM program, were associated with procedural risks related to the thoracotomy required for ixmyelocel-T administration.
Inclusion criteria remains in place for any participant wishing to be part of the open label extension.
1. Males and non-pregnant, non-lactating females. Females of childbearing potential must use an appropriate form of contraception while participating in the study and be at least 12 months post-pregnancy;
2. Age 30 to 86 years of age at screening;
3. Diagnosis of ischemic dilated cardiomyopathy according to WHO criteria:
- Ischemic dilated cardiomyopathy is defined as dilated cardiomyopathy in a subject with a history of myocardial infarction or evidence of clinically significant (≥70% narrowing of a major epicardial artery) coronary artery disease.
4. LVEF ≤35% by echocardiogram (as determined by the imaging core lab);
5. Symptomatic heart failure in NYHA functional class III or IV defined by:
- NYHA Class III: Subjects with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary physical activity causes fatigue, dyspnea, or pain
-NYHA Class IV: Subjects with cardiac disease resulting in inability to carry on any
physical activity without discomfort. Symptoms of cardiac insufficiency or of angina
syndrome may present even at rest. If any physical activity is undertaken, discomfort is
6. In the opinion of the investigator the subject is not a candidate for reasonable revascularization procedures that will produce clinical improvement, based on coronary angiography. This opinion will be reviewed and confirmation documented by an interventional cardiologist (for percutaneous coronary interventions) and a cardiac surgeon (for coronary artery bypass graft).
7. Subject is receiving appropriate clinical standard of care heart failure therapy, as tolerated
and as dictated by a subject’s current medical condition, for at least 30 days prior to
screening and no new continuous-use medications to treat the disease introduced or discontinued in the last
30 days prior to screening. Standard of care heart failure therapy may include, but is not
a) pharmacologic therapy, such as: angiotensin converting enzyme (ACE) inhibitor, angiotensin II receptor blocker, β-blocker, diuretic, aldosterone antagonist; dosing of these medications must be stable for at least 30 days prior to screening, however, titration (up or down) or diuretics is acceptable, if medically indicated.
b) resynchronization device therapy, if indicated, device must have been implanted at least 3 months prior to screening;
c) life-style counseling, as appropriate: e.g., encouraging smoking cessation,
discouraging alcohol and illicit drug use;
8. Must have an automatic implantable cardioverter defibrillator (AICD) and must be implanted for at least 3 months prior to screening. AICD must be of the type that can be interrogated to obtain firing episodes.
9. Subjects are eligible if they meet one of the following:
− Heart failure-related hospitalization within 6 months of screening; or- an unplanned outpatient or emergency department visit to treat ADHF within 6 months of screening (can include treatment with intravenous medication [diuretic, inotrope or vasoactive] or mechanical fluid removal); OR
− NT-proBNP >2000 pg/mL or BNP >400 pg/mL within 30 days of screening (or at screening visit) OR
− 6 MWT distance ≤400 meters at screening (walk capacity limited only by cardiac fitness and NOT by other comorbidities such as PAD, arthritis, pulmonary disease, prosthesis)
10. Life expectancy of at least 12 months in the opinion of the Investigator;
11. LV wall thickness ≥7mm (by echocardiogram) at anticipated target injection area (investigator determined)
12. Hemodynamic stability without IV vasopressors or support devices; (Note: patients on chronic at-home IV inotropic therapy should not be considered for the trial)
13. Given medical history and concurrent medication, subject is an acceptable candidate for bone marrow aspiration and cardiac catheterization and transendocardial injection procedures in the opinion of the Investigator. Subject must be able to tolerate institutional guidelines including anti-coagulation therapy as they pertain to these procedures;
14. Subject is willing and able to comply with scheduled study visits and is able to tolerate study procedures, including bone marrow aspiration, and transendocardial injection procedures and associated institutional guidelines related to these procedures;
15. Subject must be able to provide a personally-signed and dated informed consent document indicating that the subject (or a legally-acceptable representative, if permitted by the site’s Investigational Review Board [IRB]) has been informed of all pertinent aspects of the study.
16. Subject received the placebo in the first treatment section of this trial.
Exclusion criteria remains in place for any participant wishing to be part of the open label extension.
Subjects presenting with any of the following will not be able to participate:
1. Severe primary valvular heart disease including, but not limited to, aortic valve stenosis and insufficiency; subjects with an aortic valve prosthesis (artificial or animal derived) are also excluded;
2. Any of the following cardiac surgeries: VAD implantation, heart transplantation, cardiomyoplasty, left ventricular reduction surgery, or cardiac shunt implantation;
3. Subject has planned heart failure-related device interventions (e.g., VAD implantation, initial cardiac resynchronization therapy) or planned cardiac procedures (e.g., heart transplant, cardiomyoplasty, valvular repair);
3b. Subjects on heart transplant list who are status 1A or 1B are excluded (but transplant status 2 patients may be considered for the trial);
4. Subject has any current arrhythmias that would prohibit accurate NOGA® electromechanical mapping and NOGA®-guided injections;
5. LV thrombus (as documented on echocardiography or LV angiography);
6. Myocardial infarction within 3 months prior to screening;
7. Percutaneous coronary intervention, valvuloplasty, cardiac surgery, and other major cardiac procedure within 30 days prior to screening;
8. In the opinion of the Investigator, the subject’s left ventricular wall is unsuitable for transendocardial injections (due to thickness or other reasons);
9. Deleted; criteria numbering retained to keep consistent with previous protocol;
10. Stroke or transient ischemic attack (TIA) within 3 months of screening;
11. Hemoglobin A1c (HbA1c) ≥9% at screening;
12. Diabetic subjects with uncontrolled or untreated proliferative retinopathy as determined by dilated eye exam administered by a qualified eye care professional as per American Diabetes Association guidelines;
13. Blood clotting disorder not caused by medication (e.g., thrombophilia);
14. Active malignancy (non-basal cell) including those requiring surgery, chemotherapy, and/or radiation in the
past 12 months;
NOTE: Subjects with localized prostate cancer under a watchful-waiting treatment plan without evidence of disease progression in the past year may participate in the study if approved by the investigator and sponsor or designee;
NOTE: Subjects diagnosed with basal cell carcinoma of the skin within the past 12 months must receive adequate treatment for their basal cell skin carcinoma prior to randomization;
15. Current documented drug or alcohol abuse that would interfere with the subject’s compliance with study procedures;
16. Known allergies to any equine, porcine, or bovine products;
17. Body mass index (BMI) ≥40 kg/m2 at screening;
18. Established chronic kidney disease (CKD) requiring dialysis (Stage 5); estimated creatinine clearance <15 mL/min at screening;
19. Subject has allergy or is unable to tolerate imaging contrast agents (echocardiography or ventriculography); also the inability to get a good quality echocardiogram image at screening (as determined by the imaging core
20. Abnormal laboratory values (performed at central lab) at screening:
a. Platelets <50,000 μL;
b. Hemoglobin <9.0 g/dL
c. Aspartate aminotransferase/alanine aminotransferase (AST/ALT) >3 times the upper limit of normal (ULN);
d. Human immunodeficiency virus-1 (HIV-1), HIV-2, or syphilis positive
e. Active hepatitis B surface antigen (HBsAg) or active hepatitis C virus (HCV) antibodies;
NOTE: Additional lab tests may be performed per local requirements including but not limited to: hepatitis B core antibody, human T lymphotropic virus I/II.
Exclusionary Procedures, Devices, or Medication
21. Subjects receiving anti-angiogenic drugs (e.g., anti-vascular endothelial growth factor [VEGF]);
22. Deleted; criteria numbering retained to keep consistent with previous protocol;
23.Exposure to therapy considered to be cytotoxic in nature (examples include, but are not limited to methotrexate, azathioprine, cyclophosphamide) or radiation in the past 3 months prior to screening or expected requirement over the course of the study;
NOTE: If the subject was taking chronic prednisone equivalent does of > 10mg/day, Screening Visit 1 should be scheduled at least 2 weeks after the last dose of steroid medication >10 mg/day.
24. Concurrent participation in another interventional clinical trial or receiving experimental intervention within
30 days of screening;
24b. Previous exposure to the following:
-Aastrom’s ixmyelocel-T product (previously known as tissue repair cells [TRC], cardiac repair cells [CRC], vascular repair cekks [VRC];
-Allogeneic cell therapy
-Autologous cell therapy grown or cultured in the presence of animal protein;
Note: Prior treatment with gene therapy or autologous cell therapies not cultured with animal proteins is allowed. Screening Visit 1 should be scheduled at least 12 months after prior autologous cell treatment.
25. In the opinion of the Investigator, the subject is unsuitable for cellular therapy or has a food/drug allergy, surgical or medical condition (active or chronic), clinically significant psychiatric disorders (bipolar disorder, major depressive disorder, psychosis, past hospitalization for psychiatric reasons), poor nutritional status, or lab abnormality requiring further medical evaluation that may interfere with the investigational product, interfere with the study results’ interpretation, interfere with the subject’s ability to complete the study or compromise subject’s safety.