Use of Adult Autologous Stem Cells in Treating People Who Have Had a Heart Attack (The TIME Study)

• Global Left Ventricular Function [ Time Frame: Measured at Baseline and Month 6 ] [ Designated as safety issue: No ]
  Left ventricular ejection fraction (global) as assessed via cardiac MRI. Values reported represent the change in Global EF from baseline to six months.
• Regional Left Ventricular Function (Infarct Zone Wall Motion) [ Time Frame: Measured at Baseline and Month 6 ] [ Designated as safety issue: No ]
  One of two calculated values of regional left ventricular function as assessed via cardiac MRI. The infarct zone is defined as the cMRI segments with the largest 2 signal intensity enhancement measures with gadolinium (using a 17-segment model).Values reported represent the change in wall motion over time in the infarct zone from baseline to six months.
• Regional Left Ventricular Function (Border Zone Wall Motion) [ Time Frame: Measured at Baseline and Month 6 ] [ Designated as safety issue: No ]
  Two of two calculated values of regional left ventricular function assessed via cardiac MRI. The border zone is defined as those regions adjacent to the infarct zone in which the cMRI signal intensity enhancement were in the 10%-75% range. Values reported represent the change in wall motion over time in the border zone of the infarct from baseline to six months.

• Clincal and Safety Outcomes [ Time Frame: Measured from baseline to six months. ] [ Designated as safety issue: Yes ]
  Number of participants who experienced either death, reinfarction, repeat revascularizations (target and nontarget vessels) hospitalizations for heart failure, ICD placements
• Left Ventricular Mass [ Time Frame: Measured at Baseline and Month 6 ] [ Designated as safety issue: No ]
  Left ventricular mass (LV mass. Values reported represent the change in LV mass from baseline to six months.
• End Diastolic Volume Index [ Time Frame: Measured at Baseline and Month 6 ] [ Designated as safety issue: No ]
  Left ventricular end diastolic volume index. Values reported represent the change in LV end diastolic index from baseline to six months.
• End Systolic Volume Index [ Time Frame: Measured at Baseline and Month 6 ] [ Designated as safety issue: No ]
  Left ventricular end systolic volume index. Values reported represent the change in LV end systolic volume index from baseline to six months.
• Infarct Volume [ Time Frame: Measured at Baseline and Month 6 ] [ Designated as safety issue: No ]
  Infarct volume(mL). Values reported represent the change in infarct volume from baseline to six months.

• Combined endpoint: first of death, reinfarction, repeat revascularization, or hospitalization for heart failure [ Time Frame: Measured at Month 6 ] [ Designated as safety issue: Yes ]
• Left ventricular mass [ Time Frame: Measured at Month 6 ] [ Designated as safety issue: Yes ]
• End diastolic volume [ Time Frame: Measured at Month 6 ] [ Designated as safety issue: Yes ]
• End systolic volume [ Time Frame: Measured at Month 6 ] [ Designated as safety issue: Yes ]
• Infarct size [ Time Frame: Measured at Month 6 ] [ Designated as safety issue: Yes ]

Heart attacks are a leading cause of death for both men and women in the United States. A heart attack occurs when blood flow to the heart is restricted, commonly due to a blood clot that has formed in one of the coronary arteries. If the clot becomes large enough, blood flow to the heart can be blocked almost completely and the heart muscle in that area can suffer permanent injury or death. Although a percutaneous coronary intervention (PCI) can be used to open up the blocked artery and restore blood flow to the heart muscle, there may be a significant amount of heart tissue that has been irreversibly damaged. Recent studies have shown that adult stem cells from bone marrow may be able to improve heart function after a heart attack. This study will evaluate the safety and effectiveness of using adult stem cells for improving heart function in people who have had a recent heart attack and a PCI.

More than 1 million Americans suffer a heart attack each year, resulting in about a 38% mortality rate. Although current treatments are able to stabilize the condition of the heart, none is able to restore heart function as it was prior to the heart attack. The permanent damage to the heart can lead to more severe problems, such as heart failure and irregular heartbeat, making the discovery of treatments to improve heart function after a heart attack important. Adult stem cells, which are immature cells that can become many different types of cells, may offer a potential means of reversing or preventing permanent damage caused by a heart attack. These specialized cells may have the ability to promote blood vessel growth, prevent cell death, and transform themselves into a number of tissues, including muscle. Recent studies have shown promise in using adult stem cells from bone marrow to reverse damage to the heart muscle caused by a heart attack, but more research is needed to assess the safety and effectiveness of stem cell use and to discover the best time to administer treatment. This study will evaluate the safety and effectiveness of placing adult stem cells into injured heart muscle for improving heart function in people who have had a recent heart attack and a PCI. Additionally, this study will help determine the best time to insert stem cells after a heart attack.

Participation in this study will last 24 months. All participants will first undergo baseline assessments that will include a medical history, a physical exam, an electrocardiogram (ECG), blood draws, an echocardiogram, and a magnetic resonance imaging (MRI) test. Participants will then be assigned randomly to receive stem cells or placebo either 3 or 7 days after their heart attack. The morning of the stem cell or placebo infusion, participants will undergo a blood draw and a bone marrow aspiration procedure of the hip bone to collect the stem cells. Later the same day, either stem cells or placebo will be infused through a catheter and into the damaged area of the heart.

For the first 24 hours following the infusion, participants will be asked to wear a small ECG machine called a Holter monitor. Participants will also be asked to record their temperature twice a day for a month after the infusion. Participants will return for follow-up visits at Months 1, 3, 6, 12, and 24 and will repeat many of the baseline assessments.

• Biological: Adult stem cells
  One time infusion of approximately 150 million total nucleated cells (TNC) in 30 ml of 5% HSA/saline solution
  Other Names:

  • Adult autologous stem cells
  • Bone marrow mononucleated cells
• Biological: Placebo
  One time infusion of 30 ml of HSA (5%)
  Other Name: HSA

• Active Comparator: 1
  Participants will receive active adult stem cell infusion 3 days after percutaneous coronary intervention (PCI).
  Intervention: Biological: Adult stem cells
• Active Comparator: 2
  Participants will receive active adult stem cell infusion 7 days after PCI.
  Intervention: Biological: Adult stem cells
• Placebo Comparator: 3
  Participants will receive placebo infusion (5% human serum albumin [HSA]) 3 days after PCI.
  Intervention: Biological: Placebo
• Placebo Comparator: 4
  Participants will receive placebo infusion (5% HSA) 7 days after PCI.
  Intervention: Biological: Placebo

• Traverse JH, Henry TD, Pepine CJ, Willerson JT, Zhao DX, Ellis SG, Forder JR, Anderson RD, Hatzopoulos AK, Penn MS, Perin EC, Chambers J, Baran KW, Raveendran G, Lambert C, Lerman A, Simon DI, Vaughan DE, Lai D, Gee AP, Taylor DA, Cogle CR, Thomas JD, Olson RE, Bowman S, Francescon J, Geither C, Handberg E, Kappenman C, Westbrook L, Piller LB, Simpson LM, Baraniuk S, Loghin C, Aguilar D, Richman S, Zierold C, Spoon DB, Bettencourt J, Sayre SL, Vojvodic RW, Skarlatos SI, Gordon DJ, Ebert RF, Kwak M, Moyé LA, Simari RD; Cardiovascular Cell Therapy Research Network (CCTRN). Effect of the use and timing of bone marrow mononuclear cell delivery on left ventricular function after acute myocardial infarction: the TIME randomized trial. JAMA. 2012 Dec 12;308(22):2380-9.
• Traverse JH, Henry TD, Vaughn DE, Ellis SG, Pepine CJ, Willerson JT, Zhao DX, Piller LB, Penn MS, Byrne BJ, Perin EC, Gee AP, Hatzopoulos AK, McKenna DH, Forder JR, Taylor DA, Cogle CR, Olson RE, Jorgenson BC, Sayre SL, Vojvodic RW, Gordon DJ, Skarlatos SI, Moye' LA, Simari RD; Cardiovascular Cell Therapy Research Network (CCTRN). Rationale and design for TIME: A phase II, randomized, double-blind, placebo-controlled pilot trial evaluating the safety and effect of timing of administration of bone marrow mononuclear cells after acute myocardial infarction. Am Heart J. 2009 Sep;158(3):356-63. Epub 2009 Jul 23.
• Gee AP, Richman S, Durett A, McKenna D, Traverse J, Henry T, Fisk D, Pepine C, Bloom J, Willerson J, Prater K, Zhao D, Koç JR, Ellis S, Taylor D, Cogle C, Moyé L, Simari R, Skarlatos S. Multicenter cell processing for cardiovascular regenerative medicine applications: the Cardiovascular Cell Therapy Research Network (CCTRN) experience. Cytotherapy. 2010 Sep;12(5):684-91.
• Zierold C, Carlson MA, Obodo UC, Wise E, Piazza VA, Meeks MW, Vojvodic RW, Baraniuk S, Henry TD, Gee AP, Ellis SG, Moyé LA, Pepine CJ, Cogle CR, Taylor DA. Developing mechanistic insights into cardiovascular cell therapy: Cardiovascular Cell Therapy Research Network Biorepository Core Laboratory rationale. Am Heart J. 2011 Dec;162(6):973-80.
• Traverse JH, Henry TD, Vaughan DE, Ellis SG, Pepine CJ, Willerson JT, Zhao DX, Simpson LM, Penn MS, Byrne BJ, Perin EC, Gee AP, Hatzopoulos AK, McKenna DH, Forder JR, Taylor DA, Cogle CR, Baraniuk S, Olson RE, Jorgenson BC, Sayre SL, Vojvodic RW, Gordon DJ, Skarlatos SI, Moyè LA, Simari RD; Cardiovascular Cell Therapy Research Network. LateTIME: a phase-II, randomized, double-blinded, placebo-controlled, pilot trial evaluating the safety and effect of administration of bone marrow mononuclear cells 2 to 3 weeks after acute myocardial infarction. Tex Heart Inst J. 2010;37(4):412-20.

Inclusion criteria

1. Patients at least 21 years of age
2. Patients with first acute MI with successful primary percutaneous coronary intervention (PCI) in an artery at least 2.5 mm in diameter within 24 hours of onset of symptoms.
3. No contraindications to undergoing cell therapy procedure within three to seven days following AMI and PCI.
4. Hemodynamic stability as defined as no requirement for IABP, inotropic or blood pressure supporting medications.
5. Ejection fraction following reperfusion with PCI <=45% as assessed by echocardiography.
6. Consent to protocol and agree to comply with all follow-up visits and studies.
7. Women of child bearing potential willing to use an active form of birth control.

Exclusion criteria

Patients will be excluded from the study if they meet any of the following conditions:

1. History of sustained ventricular arrhythmias not related to their AMI (evidenced by previous holter monitoring and/or medication history for sustained ventricular arrhythmias in patient's medical chart).
2. Require CABG or PCI due to the presence of residual coronary stenosis >70% luminal obstruction in the non-infarct related vessel (Additional PCI of non-culprit vessels may be performed prior to enrollment).
3. History of any malignancy within the past five years excluding non-melanoma skin cancer or cervical cancer in-situ.
4. History of chronic anemia (hemoglobin (Hb) <9.0 mg/dl).
5. History of thrombocytosis (platelets >500k).
6. History of thrombocytopenia in the absence of recent evidence that platelet counts are normal
7. Known history of elevated INR (PT) or PTT.
8. Life expectancy less than one year.
9. History of untreated alcohol or drug abuse.
10. Currently enrolled in another investigational drug or device trial
11. Previous CABG.
12. Previous MI resulting in LV dysfunction (LVEF <55%)
13. History of stroke or transient ischemic attack (TIA) within the past six months.
14. History of severe valvular heart disease (aortic valve area <1.0 cm2 or >3+ mitral regurgitation).
15. Pregnancy or breast feeding
16. Subjects with a known history of HIV, or has active hepatitis B,active hepatitis C, or active TB
17. Patients with active inflammatory or autoimmune disease on chronic immuno-suppressive therapy.
18. Contraindications to cMRI.
19. Previous radiation to the pelvis with white blood cell count (WBC) and platelet counts below hospital specific normal values.
20. Women child bearing potential not willing to practice an active form of birth control.
21. Chronic liver disease that might interfere with survival or treatment with cell therapy.
22. Chronic renal insufficiency as defined by a creatinine ≥ 2.0 mg/dL or requires chronic dialysis.