Use of Adult Autologous Stem Cells in Treating People 2 to 3 Weeks After Having a Heart Attack (The Late TIME Study)

• ClinicalTrials.gov Identifier: NCT00684060
• Recruitment Status: Completed
• First Posted: May 26, 2008
• Results First Posted: May 4, 2012
• Last Update Posted: July 10, 2015
• Sponsor: The University of Texas Health Science Center, Houston
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): Dr Lemuel A Moye III, The University of Texas Health Science Center, Houston

Study Description

Brief Summary:

More than 1 million Americans suffer heart attacks each year. 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. 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. 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 using adult stem cell infusions 2 to 3 weeks after a heart attack for improving heart function in people who have had a recent heart attack and a common procedure called a percutaneous coronary intervention (PCI).

Condition or disease	Intervention/treatment	Phase
Left Ventricular Dysfunction	Biological: Adult stem cells; Biological: Placebo	Phase 2

Detailed Description:

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 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. 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. After an acute heart attack, a remodeling process is initiated in the heart in an attempt to compensate for damaged areas. Consequently, the condition of the heart muscle several weeks after a heart attack may differ considerably from the heart's condition during the acute setting. For some patients, delaying the delivery of the stem cells until 2 to 3 weeks after a heart attack may be better than initiating treatment during the acute phase. This study will evaluate the safety and effectiveness of placing adult stem cells into injured heart muscle 2 to 3 weeks after a heart attack for improving heart function in people who have had a recent heart attack and a PCI.

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 between 2 and 3 weeks 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 after 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 87 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase II, Randomized, Controlled, Double-Blind Pilot Trial Evaluating the Safety and Effect of Administration of Bone Marrow Mononuclear Cells Two to Three Weeks Following Acute Myocardial Infarction
• Study Start Date: July 2008
• Actual Primary Completion Date: August 2011
• Actual Study Completion Date: February 2012

Arms and Interventions

Arm	Intervention/treatment
Experimental: 1; Participants will receive active stem cell infusion 2 to 3 weeks after a percutaneous coronary intervention (PCI).	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
Placebo Comparator: 2; Participants will receive placebo infusion (5% human serum albumin [HSA]) 2 to 3 weeks after a PCI.	Biological: Placebo; One time infusion of 30 ml of HSA (5%); Other Names: Human serum albumin; HSA

Outcome Measures

Primary Outcome Measures :

1. Global Left Ventricular Function [ Time Frame: Measured at Baseline and Month 6 ]
   Left ventricular ejection fraction (global) as assessed via cardiac MRI. Values reported represent the change in Global EF from baseline to six months.
2. Regional Left Ventricular Function (Infarct Zone Wall Motion) [ Time Frame: Measured at Baseline and Month 6 ]
   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.
3. Regional Left Ventricular Function (Border Zone Wall Motion) [ Time Frame: Measured at Baseline and Month 6 ]
   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.

Secondary Outcome Measures :

1. Combined Endpoint [ Time Frame: Measured at Baseline and Month 6 ]
   Combined endpoint: first of death, reinfarction, repeat revascularization, and hospitalization for heart failure. This is measured as the number of events by treatment group over the 6 month follow up period.
2. Left Ventricular Mass [ Time Frame: Measured at Baseline and Month 6 ]
   Left ventricular mass (LV mass. Values reported represent the change in LV mass from baseline to six months.)
3. End Diastolic Volume Index [ Time Frame: Measured at Baseline and Month 6 ]
   Left ventricular end diastolic volume index. Values reported represent the change in LV end diastolic index from baseline to six months.
4. End Systolic Volume Index [ Time Frame: Measured at Baseline and Month 6 ]
   Left ventricular end systolic volume index. Values reported represent the change in LV end systolic volume index from baseline to six months.
5. Infarct Volume [ Time Frame: Measured at Baseline and Month 6 ]
   Infarct volume(mL). Values reported represent the change in infarct volume from baseline to six months.

Eligibility Criteria

• Ages Eligible for Study: 21 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion criteria

1. Patients at least 21 years of age.
2. Patients with first acute MI and subsequent successful primary percutaneous coronary intervention (PCI) in an artery at least 2.5 mm in diameter occurring two to three weeks before recruitment.
3. No contraindications to undergoing cell therapy procedure within two to three weeks 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 tuberculosis (TB)
17. Patients with active inflammatory or autoimmune disease on chronic immunosuppressive 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.

Contacts and Locations

Locations

United States, Florida

University of Florida - Department of Medicine

Gainesville, Florida, United States, 32610

United States, Minnesota

Minneapolis Heart Institute Foundation

Minneapolis, Minnesota, United States, 55407

United States, Ohio

Cleveland Clinic

Cleveland, Ohio, United States, 44195

United States, Tennessee

Vanderbilt University Medical Center

Nashville, Tennessee, United States, 37232

United States, Texas

Texas Heart Institute

Houston, Texas, United States, 77030

Sponsors and Collaborators

The University of Texas Health Science Center, Houston

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Study Chair: Robert Simari, MD; Cardiovascular Cell Therapy Research Network

More Information

Additional Information:

Click here for more information on this study at the Cardiovascular Cell Therapy Research Network (CCTRN) 

Click here for the National Heart, Lung, and Blood Institute 

Publications of Results:

Traverse JH, Henry TD, Ellis SG, Pepine CJ, Willerson JT, Zhao DX, Forder JR, Byrne BJ, Hatzopoulos AK, Penn MS, Perin EC, Baran KW, Chambers J, Lambert C, Raveendran G, Simon DI, Vaughan DE, Simpson LM, Gee AP, Taylor DA, Cogle CR, Thomas JD, Silva GV, Jorgenson BC, Olson RE, Bowman S, Francescon J, Geither C, Handberg E, Smith DX, Baraniuk S, Piller LB, Loghin C, Aguilar D, Richman S, Zierold C, Bettencourt J, Sayre SL, Vojvodic RW, Skarlatos SI, Gordon DJ, Ebert RF, Kwak M, Moye LA, Simari RD; Cardiovascular Cell Therapy ResearchNetwork. Effect of intracoronary delivery of autologous bone marrow mononuclear cells 2 to 3 weeks following acute myocardial infarction on left ventricular function: the LateTIME randomized trial. JAMA. 2011 Nov 16;306(19):2110-9. doi: 10.1001/jama.2011.1670. Epub 2011 Nov 14.

Other Publications:

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, Moye 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.

Gee AP, Richman S, Durett A, McKenna D, Traverse J, Henry T, Fisk D, Pepine C, Bloom J, Willerson J, Prater K, Zhao D, Koc JR, Ellis S, Taylor D, Cogle C, Moye 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. doi: 10.3109/14653249.2010.487900.

Zierold C, Carlson MA, Obodo UC, Wise E, Piazza VA, Meeks MW, Vojvodic RW, Baraniuk S, Henry TD, Gee AP, Ellis SG, Moye 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. doi: 10.1016/j.ahj.2011.05.024.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Shahrivari M, Wise E, Resende M, Shuster JJ, Zhang J, Bolli R, Cooke JP, Hare JM, Henry TD, Khan A, Taylor DA, Traverse JH, Yang PC, Pepine CJ, Cogle CR; Cardiovascular Cell Therapy Research Network (CCTRN). Peripheral Blood Cytokine Levels After Acute Myocardial Infarction: IL-1beta- and IL-6-Related Impairment of Bone Marrow Function. Circ Res. 2017 Jun 9;120(12):1947-1957. doi: 10.1161/CIRCRESAHA.116.309947. Epub 2017 May 10.

Bhatnagar A, Bolli R, Johnstone BH, Traverse JH, Henry TD, Pepine CJ, Willerson JT, Perin EC, Ellis SG, Zhao DX, Yang PC, Cooke JP, Schutt RC, Trachtenberg BH, Orozco A, Resende M, Ebert RF, Sayre SL, Simari RD, Moye L, Cogle CR, Taylor DA; Cardiovascular Cell Therapy Research Network (CCTRN). Bone marrow cell characteristics associated with patient profile and cardiac performance outcomes in the LateTIME-Cardiovascular Cell Therapy Research Network (CCTRN) trial. Am Heart J. 2016 Sep;179:142-50. doi: 10.1016/j.ahj.2016.06.018. Epub 2016 Jul 6.

Cogle CR, Wise E, Meacham AM, Zierold C, Traverse JH, Henry TD, Perin EC, Willerson JT, Ellis SG, Carlson M, Zhao DX, Bolli R, Cooke JP, Anwaruddin S, Bhatnagar A, da Graca Cabreira-Hansen M, Grant MB, Lai D, Moye L, Ebert RF, Olson RE, Sayre SL, Schulman IH, Bosse RC, Scott EW, Simari RD, Pepine CJ, Taylor DA; Cardiovascular Cell Therapy Research Network (CCTRN). Detailed analysis of bone marrow from patients with ischemic heart disease and left ventricular dysfunction: BM CD34, CD11b, and clonogenic capacity as biomarkers for clinical outcomes. Circ Res. 2014 Oct 24;115(10):867-74. doi: 10.1161/CIRCRESAHA.115.304353. Epub 2014 Aug 18.

• Responsible Party: Dr Lemuel A Moye III, Professor - School of Public Health, The University of Texas Health Science Center, Houston
• ClinicalTrials.gov Identifier: NCT00684060
• Other Study ID Numbers: 578; 1U01HL087318 ( U.S. NIH Grant/Contract ); 1 U01-HL-087318-01 (Project 2)
• First Posted: May 26, 2008
• Results First Posted: May 4, 2012
• Last Update Posted: July 10, 2015
• Last Verified: July 2015

Keywords provided by Dr Lemuel A Moye III, The University of Texas Health Science Center, Houston:

Acute Myocardial Infarction; Global Left Ventricular Ejection Fraction; Regional Left Ventricular Ejection Fraction; Left Ventricular Mass; Infarct Size; End Systolic Volume; End Diastolic Volume

Additional relevant MeSH terms:

Ventricular Dysfunction; Ventricular Dysfunction, Left; Heart Diseases; Cardiovascular Diseases