1. The TIME Randomized Trial:
One-Year Follow-up on the Effect of Timing of Intracoronary Delivery of Autologous Bone Marrow Mononuclear Cells on Left Ventricular Function Following STEMI
Jay H. Traverse, MD
Principal Investigator, TIME Study
Minneapolis Heart Institute at Abbott Northwestern Hospital
University of Minnesota Medical School
Cardiovascular Cell Therapy Research Network (CCTRN)
2013 Scientific Sessions of the AHA
State no conflicts.

2. TIME Study Design
Study Aim: Assess effects of autologous BMCs and timing of delivery (Day 3 vs. 7) post-STEMI on measures of LV function
Target Population: 120 pts w/first ant MI, reperfused by PCI + stent, with residual LV dysfunction (EF≤45%)
Treatment: 150 x 106 autologous BMCs or placebo by intracoronary infusion (Stop Flow)
Primary Endpoints: change in global and regional LV function
from baseline to 6 months by cMRI
Secondary Endpoints: change in infarct size and LV volumes
Subgroups of interest: age, LVEF 2 2

3. Baseline Characteristics
3 Day
7 Day
BMC
N=43
Placebo
N=24
N=36
N=17
P-Value
Age in years, mean (SD)
55.6 (10.8)
57.0 (12.4)
58.2 (11.3)
57.0 (8.0)
0.766
Female (%) 12 13 14
0.992
White (%) 88 83 86
0.945
History of: (%)
Diabetes 23 33 11
0.007
High Blood Pressure 44 63 64 77
0.087
Hyperlipidemia 65 71 53
0.777
Smoking
0.510
Preinfarction Angina (%) 29 31 41
0.606
Drug Eluting Stent (%) 81 82
0.745
LAD Infarct Artery 96 97
100
0.086
Qualifying LVEF (echo), mean (SD)
36.1 (6.1)
37.8 (6.6)
36.5 (6.3)
36.6 (4.1)
0.763
Peak CKMB, median* (IQR)
( )
( )
( )
( )
0.078
*N=29 BMC 3 Day, N=19 Placebo 3 Day, N=31 BMC 7 Day, N=15 Placebo 7 Day

4. Cell Processing of BMCs
Sepax System
Automated local cell processing
No significant RBC Contamination
Only minuscule amounts of heparin in final product (0.1 U/ml)
Sepax vs. Manual Ficoll
No difference in cell recovery, migration or CFU ability
No difference in recovery of perfusion in murine hind-limb ischemia model
No difference in recovery of LV fxn in murine infarct model
BMC
Ficoll
Manual
Sepax

5. Cell Characteristics
Colony-Forming Units-Hill (N=45 BMC; N=23 placebo)
Endothelial Colony-Forming Cells (N=38 BMC; N=21 placebo)
7 patients either declined participation or had insufficient product for the Biorepository

6. 6-Mo Primary Endpoint: Global
No difference in the change in LVEF between BMC (n=75) and Placebo (n=37) groups from baseline to 6 months
Circles= means
I-bars= standard errors 6
JAMA 2012; 308 (22):2380-9 6

7. TIME at 1-Year
Follow-up imaging at 1 and 2-years prospectively declared.
112 of 120 patients had analyzable MRIs at 6-months.
95 of 112 patients had analyzable MRIs at 1-year. (ICD=3, death=1, LTF/refused=2, not performed=1, no-show=10).
Day-3 MRI utilized as baseline for all patients.
Worst-case imputation for incomplete data.
Comment on vital status of no shows
Comment on “worst case” method

8. Change in LVEF over 1-Year
Day 3 vs 1-year: BMC < 0.01; Placebo = NS

9. Changes in Regional LV Function
Infarct Zone
Border Zone
3 Day vs. 1 Year:
BMC ( p< 0.001); Placebo (NS)
3 Day vs. 1 Year:
BMC ( p< 0.001); Placebo (p=0.002)

10. Change in Infarct Size
3 Day vs. 1 Year: BMC ( p< 0.001); Placebo (p<0.001)

11. Change in LV Volumes Over 1 Year
LVEDV (ml/m2)
LVESV (ml/m2)
Day 3
6-Month
1-Year
BMC
77 ± 18
87 ± 25*
89 ± 25*
42 ±14
45 ± 20*
46 ± 21*
PLACEBO
70 ± 17
80 ± 23*
83 ± 22*
38 ± 12
40 ± 18*
43 ± 18*
*P < 0.01 versus Day 3

12. Clinical/Safety Outcomes at 1 Year
BMC
Placebo
Patients with events
18/79 (23%)
9/41 (22%)
Deaths 1
Reinfarctions 2 3
Repeat Revascularizations 9 6
Target Vessel 4
Non-Target Vessel 5
Hospitalization Heart Failure
ICD Placements
Stroke
Total 22 17

13. Conclusions
The recovery of LV function following STEMI is not enhanced by BMCs at any time-point.
The improvement in global and regional function is nearly complete by 6 months.
Infarct size and LV Mass in both groups decreased by 30% over the first 6-months, with a smaller, ongoing decrease out to 1-year.
There is a small, ongoing increase in LV volumes 13

14. Acknowledgements
We would like to acknowledge partial funding for this work through the following grants: NIH NHLBI Cardiovascular Cell Therapy Network (CCTRN) under grant# 5 UM 1HL
Industry partners: Biosafe and Boston Scientific
The Clinical Centers, and DCC (Cleveland Clinic, Minneapolis Heart Institute, Texas Heart Institute, University of Florida, and Vanderbilt University, University of Texas School of Public Health), their satellites (University Hospitals, United Heart & Vascular Clinic, Metropolitan Cardiology Consultants, University of Minnesota, Mayo Clinic, DeBakey VA, and Pepin Heart Institute) and their research teams
Core labs (Center for Cell & Gene Therapy, Baylor College of Medicine, University of Florida cMRI and Cleveland Clinic Echo Core Labs, University of Minnesota and University of Florida Biorepositories)

15. Sonia I. Skarlatos