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

Primary Purpose

Left Ventricular Dysfunction

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Adult stem cells

Placebo

About this trial

This is an interventional treatment trial for Left Ventricular Dysfunction focused on measuring Acute Myocardial Infarction, Global Left Ventricular Ejection Fraction, Regional Left Ventricular Ejection Fraction, Left Ventricular Mass, Infarct Size, End Systolic Volume, End Diastolic Volume

Eligibility Criteria

21 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion criteria

Patients at least 21 years of age
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.
No contraindications to undergoing cell therapy procedure within three to seven days following AMI and PCI.
Hemodynamic stability as defined as no requirement for IABP, inotropic or blood pressure supporting medications.
Ejection fraction following reperfusion with PCI <=45% as assessed by echocardiography.
Consent to protocol and agree to comply with all follow-up visits and studies.
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:

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).
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).
History of any malignancy within the past five years excluding non-melanoma skin cancer or cervical cancer in-situ.
History of chronic anemia (hemoglobin (Hb) <9.0 mg/dl).
History of thrombocytosis (platelets >500k).
History of thrombocytopenia in the absence of recent evidence that platelet counts are normal
Known history of elevated INR (PT) or PTT.
Life expectancy less than one year.
History of untreated alcohol or drug abuse.
Currently enrolled in another investigational drug or device trial
Previous CABG.
Previous MI resulting in LV dysfunction (LVEF <55%)
History of stroke or transient ischemic attack (TIA) within the past six months.
History of severe valvular heart disease (aortic valve area <1.0 cm2 or >3+ mitral regurgitation).
Pregnancy or breast feeding
Subjects with a known history of HIV, or has active hepatitis B,active hepatitis C, or active TB
Patients with active inflammatory or autoimmune disease on chronic immuno-suppressive therapy.
Contraindications to cMRI.
Previous radiation to the pelvis with white blood cell count (WBC) and platelet counts below hospital specific normal values.
Women child bearing potential not willing to practice an active form of birth control.
Chronic liver disease that might interfere with survival or treatment with cell therapy.
Chronic renal insufficiency as defined by a creatinine ≥ 2.0 mg/dL or requires chronic dialysis.

Sites / Locations

University of Florida-Department of Medicine
Minneapolis Heart Institute Foundation
Cleveland Clinic
Vanderbilt University Medical Center
Texas Heart Institute

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Arm Description

Participants will receive active adult stem cell infusion 3 days after percutaneous coronary intervention (PCI).

Participants will receive active adult stem cell infusion 7 days after PCI.

Participants will receive placebo infusion (5% human serum albumin [HSA]) 3 days after PCI.

Participants will receive placebo infusion (5% HSA) 7 days after PCI.

Outcomes

Primary Outcome Measures

Global Left Ventricular Function

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)

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)

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

Clincal and Safety Outcomes

Number of events -death, reinfarction, repeat revascularizations (target and nontarget vessels) hospitalizations for heart failure, ICD placements

Left Ventricular Mass

Left ventricular mass (LV mass. Values reported represent the change in LV mass from baseline to six months.

End Diastolic Volume Index

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

Left ventricular end systolic volume index. Values reported represent the change in LV end systolic volume index from baseline to six months.

Infarct Volume

Infarct volume(mL). Values reported represent the change in infarct volume from baseline to six months.

Full Information

NCT ID

NCT00684021

First Posted

May 22, 2008

Last Updated

June 2, 2015

Sponsor

The University of Texas Health Science Center, Houston

Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

1. Study Identification

Unique Protocol Identification Number

NCT00684021

Brief Title

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

2. Study Status

Record Verification Date

June 2015

Overall Recruitment Status

Completed

Study Start Date

July 2008 (undefined)

Primary Completion Date

May 2012 (Actual)

Study Completion Date

November 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

The University of Texas Health Science Center, Houston

Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

120 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm Type

Active Comparator

Arm Description

Participants will receive active adult stem cell infusion 3 days after percutaneous coronary intervention (PCI).

Arm Title

Arm Type

Active Comparator

Arm Description

Participants will receive active adult stem cell infusion 7 days after PCI.

Arm Title

Arm Type

Placebo Comparator

Arm Description

Participants will receive placebo infusion (5% human serum albumin [HSA]) 3 days after PCI.

Arm Title

Arm Type

Placebo Comparator

Arm Description

Participants will receive placebo infusion (5% HSA) 7 days after PCI.

Intervention Type

Biological

Intervention Name(s)

Adult stem cells

Other Intervention Name(s)

Adult autologous stem cells, Bone marrow mononucleated cells

Intervention Description

One time infusion of approximately 150 million total nucleated cells (TNC) in 30 ml of 5% HSA/saline solution

Intervention Type

Biological

Intervention Name(s)

Placebo

Other Intervention Name(s)

HSA

Intervention Description

One time infusion of 30 ml of HSA (5%)

Primary Outcome Measure Information:

Title

Global Left Ventricular Function

Description

Left ventricular ejection fraction (global) as assessed via cardiac MRI. Values reported represent the change in Global EF from baseline to six months.

Time Frame

Measured at Baseline and Month 6

Title

Regional Left Ventricular Function (Infarct Zone Wall Motion)

Description

Time Frame

Measured at Baseline and Month 6

Title

Regional Left Ventricular Function (Border Zone Wall Motion)

Description

Time Frame

Measured at Baseline and Month 6

Secondary Outcome Measure Information:

Title

Clincal and Safety Outcomes

Description

Number of events -death, reinfarction, repeat revascularizations (target and nontarget vessels) hospitalizations for heart failure, ICD placements

Time Frame

Measured from baseline to six months.

Title

Left Ventricular Mass

Description

Left ventricular mass (LV mass. Values reported represent the change in LV mass from baseline to six months.

Time Frame

Measured at Baseline and Month 6

Title

End Diastolic Volume Index

Description

Left ventricular end diastolic volume index. Values reported represent the change in LV end diastolic index from baseline to six months.

Time Frame

Measured at Baseline and Month 6

Title

End Systolic Volume Index

Description

Left ventricular end systolic volume index. Values reported represent the change in LV end systolic volume index from baseline to six months.

Time Frame

Measured at Baseline and Month 6

Title

Infarct Volume

Description

Infarct volume(mL). Values reported represent the change in infarct volume from baseline to six months.

Time Frame

Measured at Baseline and Month 6

10. Eligibility

Sex

All

Minimum Age & Unit of Time

21 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion criteria Patients at least 21 years of age 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. No contraindications to undergoing cell therapy procedure within three to seven days following AMI and PCI. Hemodynamic stability as defined as no requirement for IABP, inotropic or blood pressure supporting medications. Ejection fraction following reperfusion with PCI <=45% as assessed by echocardiography. Consent to protocol and agree to comply with all follow-up visits and studies. 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: 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). 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). History of any malignancy within the past five years excluding non-melanoma skin cancer or cervical cancer in-situ. History of chronic anemia (hemoglobin (Hb) <9.0 mg/dl). History of thrombocytosis (platelets >500k). History of thrombocytopenia in the absence of recent evidence that platelet counts are normal Known history of elevated INR (PT) or PTT. Life expectancy less than one year. History of untreated alcohol or drug abuse. Currently enrolled in another investigational drug or device trial Previous CABG. Previous MI resulting in LV dysfunction (LVEF <55%) History of stroke or transient ischemic attack (TIA) within the past six months. History of severe valvular heart disease (aortic valve area <1.0 cm2 or >3+ mitral regurgitation). Pregnancy or breast feeding Subjects with a known history of HIV, or has active hepatitis B,active hepatitis C, or active TB Patients with active inflammatory or autoimmune disease on chronic immuno-suppressive therapy. Contraindications to cMRI. Previous radiation to the pelvis with white blood cell count (WBC) and platelet counts below hospital specific normal values. Women child bearing potential not willing to practice an active form of birth control. Chronic liver disease that might interfere with survival or treatment with cell therapy. Chronic renal insufficiency as defined by a creatinine ≥ 2.0 mg/dL or requires chronic dialysis.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Robert Simari, MD

Organizational Affiliation

Cardiovascular Cell Therapy Research Network

Official's Role

Study Chair

Facility Information:

Facility Name

University of Florida-Department of Medicine

City

Gainesville

State/Province

Florida

ZIP/Postal Code

32610

Country

United States

Facility Name

Minneapolis Heart Institute Foundation

City

Minneapolis

State/Province

Minnesota

ZIP/Postal Code

55407

Country

United States

Facility Name

Cleveland Clinic

City

Cleveland

State/Province

Ohio

ZIP/Postal Code

44195

Country

United States

Facility Name

Vanderbilt University Medical Center

City

Nashville

State/Province

Tennessee

ZIP/Postal Code

37232

Country

United States

Facility Name

Texas Heart Institute

City

Houston

State/Province

Texas

ZIP/Postal Code

77030

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

19699857

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. Erratum In: Am Heart J. 2009 Dec;158(6):1045. Vaughn, Douglas E [corrected to Vaughan, Douglas E].

Results Reference

background

PubMed Identifier

20524773

Citation

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.

Results Reference

background

PubMed Identifier

22137069

Citation

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.

Results Reference

background

PubMed Identifier

23129008

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. Erratum In: JAMA. 2013 Jan 23;309(4):343. JAMA. 2015 Jul 7;314(1):86.

Results Reference

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PubMed Identifier

29208679

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.

Results Reference

derived

PubMed Identifier

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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.

Results Reference

derived

PubMed Identifier

25136078

Citation

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.

Results Reference

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PubMed Identifier

24247415

Citation

Traverse JH, Henry TD, Pepine CJ, Willerson JT, Ellis SG. One-year follow-up of intracoronary stem cell delivery on left ventricular function following ST-elevation myocardial infarction. JAMA. 2014 Jan 15;311(3):301-2. doi: 10.1001/jama.2013.282674. No abstract available. Erratum In: JAMA. 2015 Jul 7;314(1):86.

Results Reference

derived

PubMed Identifier

20844613

Citation

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.

Results Reference

derived

Links:

URL

http://www.cctrn.org

Description

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

URL

http://www.nhlbi.nih.gov/

Description

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

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

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