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 Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Left Ventricular Dysfunction
• Interventions: Biological: Adult stem cells; Biological: Placebo
• Enrollment: 87

Participant Flow

Recruitment Details	Enrollment took place at five Network centers and their associated satellite facilities between July 8, 2008 and February 28, 2011. The main centers are located in Ohio, Texas, Florida, Minnesota, and Tennessee. Study brochures, patient informational DVDs, and clinical trials.gov were among the tools used for recruitment.
Pre-assignment Details

Arm/Group Title	Stem Cell Arm	Placebo Arm
Arm/Group Description	Participants will receive active stem cell infusion 2 to 3 weeks after a percutaneous coronary intervention (PCI).	Participants will receive placebo infusion (5% human serum albumin [HSA]) 2 to 3 weeks after a PCI.
Period Title: Overall Study
Started	58	29
Completed	55	26
Not Completed	3	3
Reason Not Completed
Lost to Follow-up	1	0
New stenosis identified	1	0
Unable to collect MRI	1	2
Death	0	1

Baseline Characteristics

Arm/Group Title		Stem Cell Arm	Placebo Arm	Total
Arm/Group Description		Participants will receive active stem cell infusion 2 to 3 weeks after a percutaneous coronary intervention (PCI).	Participants will receive placebo infusion (5% human serum albumin [HSA]) 2 to 3 weeks after a PCI.	Total of all reporting groups
Overall Number of Baseline Participants		58	29	87
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	58 participants	29 participants	87 participants
		57.6 (11)	54.6 (11)	57 (11)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	58 participants	29 participants	87 participants
	Female	12 20.7%	3 10.3%	15 17.2%
	Male	46 79.3%	26 89.7%	72 82.8%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	58 participants	29 participants	87 participants
		58	29	87

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Only participants with both baseline and 6 month MRI images available are included.

Values reported represent the change in Global EF from baseline to six months.

Arm/Group Title	Stem Cell Arm	Placebo Arm
Arm/Group Description:	Participants will receive active stem cell infusion 2 to 3 weeks after a percutaneous coronary intervention (PCI).	Participants will receive placebo infusion (5% human serum albumin [HSA]) 2 to 3 weeks after a PCI.
Overall Number of Participants Analyzed	55	26
Mean (Standard Deviation); Unit of Measure: percentage of ejection fraction
	0.5 (8.2)	3.6 (9.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stem Cell Arm, Placebo Arm
	Comments	Comparison of change in global LVEF in the active group minus change in global LVEF in the control group. 80 percent power based on BOOST results
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.05
	Comments	Threshold 0.05
	Method	t-test, 2 sided
	Comments	No adjustment for multiple comparisons
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-3.0
	Confidence Interval	(2-Sided) 95%; -7.05 to .95
	Parameter Dispersion	Type: Standard Error of the mean; Value: 8.6
	Estimation Comments	[Not Specified]

2. Primary Outcome

Title	Regional Left Ventricular Function (Infarct Zone Wall Motion)
Description	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.
Time Frame	Measured at Baseline and Month 6

Outcome Measure Data

Analysis Population Description

Only participants with both baseline and 6 month MRI images available are included. One patient was excluded from the analysis due to incomplete signal intensity enhancement data.

Values reported represent the change in wall motion over time in the infarct zone from baseline to six months.

Arm/Group Title	Stem Cell Arm	Placebo Arm
Arm/Group Description:	Participants will receive active stem cell infusion 2 to 3 weeks after a percutaneous coronary intervention (PCI).	Participants will receive placebo infusion (5% human serum albumin [HSA]) 2 to 3 weeks after a PCI.
Overall Number of Participants Analyzed	55	25
Mean (Standard Deviation); Unit of Measure: mm
	0.3 (4.3)	1.0 (4.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stem Cell Arm, Placebo Arm
	Comments	Comparison of change in infarct zone wall motion in the active group minus change in global LVEF in the control group. 80 percent power based on BOOST results
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.05
	Comments	Unadjusted
	Method	t-test, 2 sided
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.7
	Confidence Interval	(2-Sided) 95%; -2.8 to 1.3
	Parameter Dispersion	Type: Standard Error of the mean; Value: 4.4
	Estimation Comments	[Not Specified]

3. Primary Outcome

Title	Regional Left Ventricular Function (Border Zone Wall Motion)
Description	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.
Time Frame	Measured at Baseline and Month 6

Outcome Measure Data

Analysis Population Description

Five patients were excluded from analysis due to incomplete signal intensity enhancement data (1) or lack of a signal intensity enhancement signal in the border zone (4).

Values reported represent the change in wall motion over time in the border zone of the infarct from baseline to six months.

Arm/Group Title	Stem Cell Arm	Placebo Arm
Arm/Group Description:	Participants will receive active stem cell infusion 2 to 3 weeks after a percutaneous coronary intervention (PCI).	Participants will receive placebo infusion (5% human serum albumin [HSA]) 2 to 3 weeks after a PCI.
Overall Number of Participants Analyzed	53	23
Mean (Standard Deviation); Unit of Measure: mm
	0.5 (7.2)	3.2 (6.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stem Cell Arm, Placebo Arm
	Comments	Comparison of change in border zone wall motion in the active group minus change in global LVEF in the control group. 80 percent power based on BOOST results
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.05
	Comments	[Not Specified]
	Method	t-test, 2 sided
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-2.6
	Confidence Interval	95%; -6.0 to 0.8
	Parameter Dispersion	Type: Standard Error of the mean; Value: 6.9
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	Combined Endpoint
Description	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.
Time Frame	Measured at Baseline and Month 6

Outcome Measure Data

Analysis Population Description

All randomized patients were followed for clinical outcomes. However the paucity of events precluded a reliable time to event analysis.

Arm/Group Title	Stem Cell Arm	Placebo Arm
Arm/Group Description:	Participants will receive active stem cell infusion 2 to 3 weeks after a percutaneous coronary intervention (PCI).	Participants will receive placebo infusion (5% human serum albumin [HSA]) 2 to 3 weeks after a PCI.
Overall Number of Participants Analyzed	58	29
Measure Type: Number; Unit of Measure: events
	3	4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stem Cell Arm, Placebo Arm
	Comments	comparison of the proportion of events in patients in the active group to those in patients in the control group
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.05
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.30
	Confidence Interval	95%; 0.08 to 1.17
	Estimation Comments	[Not Specified]

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Only participants with both baseline and 6 month MRI images available are included.

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

Arm/Group Title	Stem Cell Arm	Placebo Arm
Arm/Group Description:	Participants will receive active stem cell infusion 2 to 3 weeks after a percutaneous coronary intervention (PCI).	Participants will receive placebo infusion (5% human serum albumin [HSA]) 2 to 3 weeks after a PCI.
Overall Number of Participants Analyzed	55	26
Mean (Standard Deviation); Unit of Measure: g
	-12.0 (18.1)	-10.8 (15.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stem Cell Arm, Placebo Arm
	Comments	Comparison of change in the active group minus change in global LVEF in the control group.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.05
	Comments	[Not Specified]
	Method	t-test, 2 sided
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.2
	Confidence Interval	(2-Sided) 95%; -9.3 to 6.8
	Parameter Dispersion	Type: Standard Error of the mean; Value: 17.2
	Estimation Comments	[Not Specified]

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Only participants with both baseline and 6 month MRI images available are included.

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

Arm/Group Title	Stem Cell Arm	Placebo Arm
Arm/Group Description:	Participants will receive active stem cell infusion 2 to 3 weeks after a percutaneous coronary intervention (PCI).	Participants will receive placebo infusion (5% human serum albumin [HSA]) 2 to 3 weeks after a PCI.
Overall Number of Participants Analyzed	55	26
Mean (Standard Deviation); Unit of Measure: mL/m2
	3.4 (23.4)	2.7 (18.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stem Cell Arm, Placebo Arm
	Comments	Comparison of change in the active group minus change in global LVEF in the control group.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.05
	Comments	[Not Specified]
	Method	t-test, 2 sided
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.7
	Confidence Interval	(2-Sided) 95%; -9.5 to 10.9
	Parameter Dispersion	Type: Standard Error of the mean; Value: 21.8
	Estimation Comments	[Not Specified]

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Only participants with both baseline and 6 month MRI images available are included.

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

Arm/Group Title	Stem Cell Arm	Placebo Arm
Arm/Group Description:	Participants will receive active stem cell infusion 2 to 3 weeks after a percutaneous coronary intervention (PCI).	Participants will receive placebo infusion (5% human serum albumin [HSA]) 2 to 3 weeks after a PCI.
Overall Number of Participants Analyzed	55	26
Mean (Standard Deviation); Unit of Measure: mL/m2
	0.2 (14.0)	-2.3 (14.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stem Cell Arm, Placebo Arm
	Comments	Comparison of change in the active group minus change in the control group.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.05
	Comments	[Not Specified]
	Method	t-test, 2 sided
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	2.5
	Confidence Interval	(2-Sided) 95%; -4.1 to 9.2
	Parameter Dispersion	Type: Standard Error of the mean; Value: 14.2
	Estimation Comments	[Not Specified]

8. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Only participants with both baseline and 6 month MRI images available are included.

Values reported represent the change in infarct volume from baseline to six months.

Arm/Group Title	Stem Cell Arm	Placebo Arm
Arm/Group Description:	Participants will receive active stem cell infusion 2 to 3 weeks after a percutaneous coronary intervention (PCI).	Participants will receive placebo infusion (5% human serum albumin [HSA]) 2 to 3 weeks after a PCI.
Overall Number of Participants Analyzed	55	25
Mean (Standard Deviation); Unit of Measure: mL
	-3.5 (19.0)	-2.0 (14.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stem Cell Arm, Placebo Arm
	Comments	Comparison of change in the active group minus change in the control group.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.05
	Comments	[Not Specified]
	Method	t-test, 2 sided
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.5
	Confidence Interval	95%; -9.9 to 6.9
	Parameter Dispersion	Type: Standard Error of the mean; Value: 17.7
	Estimation Comments	[Not Specified]

Adverse Events

Time Frame	Events reported are from Randomization Date to the 6 month endpoint data collection window (i.e. 210 days post intervention)
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Stem Cell Arm		Placebo Arm
Arm/Group Description	Participants will receive active stem cell infusion 2 to 3 weeks after a percutaneous coronary intervention (PCI).		Participants will receive placebo infusion (5% human serum albumin [HSA]) 2 to 3 weeks after a PCI.
All-Cause Mortality
	Stem Cell Arm		Placebo Arm
	Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--
Serious Adverse Events
	Stem Cell Arm		Placebo Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/58 (13.79%)		14/29 (48.28%)
Cardiac disorders
Chest Pain †	6/58 (10.34%)	9	8/29 (27.59%)	8
Heart Failure †	2/58 (3.45%)	2	2/29 (6.90%)	2
Left Ventricular Thrombus †	0/58 (0.00%)	0	2/29 (6.90%)	2
Tachycardia †	0/58 (0.00%)	0	2/29 (6.90%)	3
† Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Stem Cell Arm		Placebo Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/58 (22.41%)		14/29 (48.28%)
Blood and lymphatic system disorders
Anemia †	4/58 (6.90%)	4	2/29 (6.90%)	2
Cardiac disorders
Chest Pain †	4/58 (6.90%)	5	4/29 (13.79%)	4
Tachycardia †	0/58 (0.00%)	0	3/29 (10.34%)	3
Syncope †	1/58 (1.72%)	1	2/29 (6.90%)	2
Gastrointestinal disorders
Nausea †	3/58 (5.17%)	3	0/29 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Bronchitis †	1/58 (1.72%)	1	3/29 (10.34%)	3
† Indicates events were collected by systematic assessment

Limitations and Caveats

Lack of in-vivo testing of cell product. While there are several different approaches to measure myocardial strain (myocardial tagging, DENSE, etc.), these were not employed in this study due to the need for specialized expertise at each site.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

Results Point of Contact

• Name/Title: Lemuel Moye, MD, PhD
• Organization: UT-Houston School of Public Health
• Phone: 713-500-9518
• EMail: Lemmoye@msn.com

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, Moyé 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, 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.

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. 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, 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. 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-1β- 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, Moyé 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, Moyé 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, 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 Submitted: May 22, 2008
• First Posted: May 26, 2008
• Results First Submitted: April 9, 2012
• Results First Posted: May 4, 2012
• Last Update Posted: July 10, 2015