Clinical trial NCT00684021: Use of Adult Autologous Stem Cells in Treating People Who Have Had a Heart Attack (The TIME Study)
Official title: Transplantation in Myocardial Infarction Evaluation (TIME) Protocol: A Phase II, Randomized, Controlled, Double-Blind Trial Evaluating the Effect of Timing on the Administration of Bone Marrow Mononuclear Cells (BMMNCs) Versus Placebo in Patients With Acute Myocardial Infarction
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Left Ventricular Dysfunction
Keywords: Acute Myocardial Infarction
Global Left Ventricular Ejection Fraction
Regional Left Ventricular Ejection Fraction
Left Ventricular Mass
Infarct Size
End Systolic Volume
End Diastolic Volume
Lead sponsor: The University of Texas Health Science Center, Houston
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2008-05-26
Enrollment: 120
Sex: ALL
Minimum age (years): 21
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Global Left Ventricular Function
timeFrame: Measured at Baseline and Month 6
measure: Regional Left Ventricular Function (Infarct Zone Wall Motion)
timeFrame: Measured at Baseline and Month 6
measure: Regional Left Ventricular Function (Border Zone Wall Motion)
timeFrame: Measured at Baseline and Month 6
Secondary outcomes:
measure: Clincal and Safety Outcomes
timeFrame: Measured from baseline to six months.
measure: Left Ventricular Mass
timeFrame: Measured at Baseline and Month 6
measure: End Diastolic Volume Index
timeFrame: Measured at Baseline and Month 6
measure: End Systolic Volume Index
timeFrame: Measured at Baseline and Month 6
measure: Infarct Volume
timeFrame: Measured at Baseline and Month 6
Other outcomes:
Locations:
city: Gainesville
country: United States
facility: University of Florida-Department of Medicine
state: Florida
city: Minneapolis
country: United States
facility: Minneapolis Heart Institute Foundation
state: Minnesota
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Houston
country: United States
facility: Texas Heart Institute
state: Texas
Study officials:
affiliation: Cardiovascular Cell Therapy Research Network
name: Robert Simari, MD
role: STUDY_CHAIR
References:
citation: Traverse JH, Henry TD, Vaughan 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. doi: 10.1016/j.ahj.2009.06.009. Epub 2009 Jul 23.
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citation: 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, Moye 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. doi: 10.1001/jama.2012.28726.
citation: Traverse JH, Henry TD, Pepine CJ, Willerson JT, Chugh A, Yang PC, Zhao DXM, Ellis SG, Forder JR, Perin EC, Penn MS, Hatzopoulos AK, Chambers JC, Baran KW, Raveendran G, Gee AP, Taylor DA, Moye L, Ebert RF, Simari RD. TIME Trial: Effect of Timing of Stem Cell Delivery Following ST-Elevation Myocardial Infarction on the Recovery of Global and Regional Left Ventricular Function: Final 2-Year Analysis. Circ Res. 2018 Feb 2;122(3):479-488. doi: 10.1161/CIRCRESAHA.117.311466. Epub 2017 Dec 5.
citation: Schutt RC, Trachtenberg BH, Cooke JP, Traverse JH, Henry TD, Pepine CJ, Willerson JT, Perin EC, Ellis SG, Zhao DX, Bhatnagar A, Johnstone BH, Lai D, Resende M, Ebert RF, Wu JC, Sayre SL, Orozco A, Zierold C, Simari RD, Moye L, Cogle CR, Taylor DA; Cardiovascular Cell Therapy Research Network (CCTRN). Bone marrow characteristics associated with changes in infarct size after STEMI: a biorepository evaluation from the CCTRN TIME trial. Circ Res. 2015 Jan 2;116(1):99-107. doi: 10.1161/CIRCRESAHA.116.304710. Epub 2014 Nov 18.
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