Columbia University

Funding for Human Subjects Research:

DOE: Office of Biological and Environmental Research (OBER)

$392,478.00 (Est.) for: Fiscal Year 2006
No human subjects enrolled as we continue to work on perfecting the labeling technique.
Percent of funding associated with the use of human subjects: 0

Information on Use of Human Subjects:

This project does not involve the use of multiple protocols/subprojects.

Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: Columbia University
Most recent approval: 09/27/05
IRB approval number: AAAB5728
Explanation of IRB approval:
We were not performing human studies in calendar year 2006 and were concentrated on animal and in vivo studies to perfect the labeling technique.

Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 0
Reporting period for number of human subjects: Fiscal Year 2006

Type(s) of Human Subjects Involvement:

Abstract:

(a. Objectives, b. Methodology, c. Ionizing Radiation, Radioactive Substances, or Chemical Substances to which human subjects are exposed, d. Involvement of Human Subjects [d.1. procedures used, d.2. risks if any])

a. Objectives

The objective of this research grant is to develop an approach for labeling progenitor cells, specifically those that we have identified as being able to replace ischemic heart cells, so that the distribution can be followed non-invasively. In addition, the research is aimed at determining whether administration of progenitor cells results in improved myocardial perfusion and function. The efficiency and toxicity of radiolabeling of progenitor cells is also evaluated. We are also evaluating whether improved perfusion can be detected with contrast perfusion echocardiography.

b. Methodology

Briefly, subjects with end-stage ischemic coronary artery disease undergo a screening cardiac positron emission tomography (PET) scan using N-13 ammonia to delineate myocardial perfusion and function. If they qualify based on their PET scan, they undergo an in-hospital protocol where by CD34+ cells are stimulated by the administration of granulocytes-colony stimulating factor (G-CSF). CD34+ cells are then isolated by apharesis, and labeled with indium-111 oxine. Cells are re-infused and subjects undergo single photon emission computed tomography (SPECT) scanning to evaluate uptake and distribution of labeled progenitor cells. Three months after administration of progenitor cells, a cardiac PET scan is repeated to evaluate changes in myocardial perfusion and/or function.

c. Ionizing Radiation

Patients are exposed to nitrogen-13 ammonia and indium-111 oxine labeled progenitor cells.

d. Involvement of Human Subjects

If subjects qualify for this study based on the PET scan and agree to participate, they will be admitted to the Columbia Presbyterian Medical Center on a Monday morning to start the procedure. Subjects will be given subcutaneous injections of G-CSF on Monday, Tuesday, and Wednesday. On Thursday the subject will undergo a procedure called apharesis.

Apharesis is a procedure in which some white blood cells are removed from blood circulation. CD34+ progenitor cells are found in the white blood cell portion of the blood circulation. The procedure involves inserting a needle in each arm by a nurse or physician. The needles are connected to plastic tubing that is connected to the apharesis machine. Once the procedure begins, blood comes from the body through the needle and enters the bowl of the machine where a centrifuge separates the various blood components. The desired amount of white blood cells is collected in a separate bag attached to the apharesis machine and the remainder of plasma, red blood cells, and replacement fluid is returned to the subject. The procedure takes place over a predetermined amount of blood volume determined by weight, height, and blood count. An apharesis treatment lasts from 90 to 120 minutes. Specially trained apharesis personnel perform treatments in the apharesis laboratory.

CD34+ progenitor cells will be separated from collected white blood cells. Purified CD34+ progenitor cells will be re-infused to the subject via a needle in the arm following the apharesis course. Six to 24 hours before the cells are given back to the subject, in order to aid in the ability of the CD34+ progenitor cells to go to damaged heart muscle, the subject will have a treadmill exercise test. This test involves walking on the treadmill until the subject cannot walk any more due to chest discomfort, general tiredness, or shortness of breath. During this time changes in the heart will be monitored. The CD34+ progenitor cells will be labeled with a small amount of another radioactive material called indium-111 oxine. The cells are labeled to determine how many of them go to the heart. Approximately 24 and 48 hours after the administration of the cells, the subject will undergo a brief (20 to 30 minute) scan of the heart to determine how many cells went to the heart. Three months after the CD34+ progenitor cell injection, the subject will undergo another adenosine perfusion imaging test using PET and nitrogen-13 ammonia in order to take pictures of the heart and look at heart blood flow and function. The subjects will also have another exercise stress test to see how far they can walk without chest pain. All participants will have blood drawn for standard clinical and experimental reasons prior to the procedures (approximately 3 to 4 tablespoons) and also during their admission to the Research Unit (approximately 20 to 30 tablespoons). Thus, the total amount of blood to be drawn will be approximately 25 to 35 tablespoons for the entire study.

e. Risks
G-CSF and Apharesis:
The injection of G-CSF into the arm and the drawing of blood samples by inserting a needle into a vein may cause bruising (black and blue marks) and discomfort at the site where the injection/blood is given/taken. There is also the possibility of infection. The injection of G-CSF may be associated with bone pain and, in people with coronary artery disease, chest pain, and perhaps even a heart attack or death. The potential risks of fluid shifts as blood is being removed and re-infused during apharesis may potentially worsen with heart disease. There is a risk of congestive heart failure, unstable angina, heart attack, or death. Study participants may be at greater risk as a result of the severity of their disease state and their general health status. This risk will be evaluated on an individual basis by the doctor and discussed with the subject. An intravenous line will also be required for each drug infusion. Starting the intravenous line may cause a mild degree of discomfort, and there is a small risk of bleeding, infection, or development of a blood clot with any intravenous catheter.

f. Radiation Exposure
This study involves exposure to radiation from radioactive tracers used to image the heart. The amount of radiation exposure is within accepted limits for studies of this kind and the study will be conducted in compliance with the standard procedures of the institution's Joint Radiation Safety Committee. Although the levels of radiation used in this study are within federal guidelines for research of this type, radiation risks are cumulative over a lifetime, so any additional exposure should be carefully considered.

There may be unforeseeable consequences if the subject is or becomes pregnant and has participated in this study. These unforeseeable risks may affect the subject as well as the fetus. If the subject is pregnant, lactating, or becomes pregnant during this study, she will be excluded from receiving radioactivity and participating in this study. The possibility also exists that complications and unwanted side effects, which are unknown at this time, could occur.

During the calendar year we did not do human studies as we were continuing to perfect the labeling techniques.

g. Confidentiality
Any information that is obtained in connection with this study and that can be identified with the subject will remain confidential and will be disclosed only with his/her permission to people not connected with this study.