Jay H. Traverse, MDPrincipal Investigator, TIME Study

Minneapolis Heart Institute at Abbott Northwestern HospitalUniversity of Minnesota Medical School

Cardiovascular Cell Therapy Research Network (CCTRN)

2013 Scientific Sessions of the AHA

The TIME Randomized TrialThe TIME Randomized Trial: : One-YearOne-Year Follow-up on the Effect of Follow-up on the Effect of Timing of Intracoronary Delivery of Timing of Intracoronary Delivery of

Autologous Bone Marrow Autologous Bone Marrow Mononuclear Cells on Left Ventricular Mononuclear Cells on Left Ventricular

Function Following STEMIFunction Following STEMI

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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

Baseline Characteristics3 Day 7 Day

BMCN=43

PlaceboN=24

BMCN=36

PlaceboN=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 12 0.992

White (%) 88 83 86 88 0.945

History of: (%)

Diabetes 23 33 11 0 0.007

High Blood Pressure 44 63 64 77 0.087

Hyperlipidemia 65 71 53 65 0.777

Smoking 65 71 53 65 0.510

Preinfarction Angina (%) 23 29 31 41 0.606

Drug Eluting Stent (%) 77 88 81 82 0.745

LAD Infarct Artery 86 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) 180.9 (42.1-1302.0)

133.0 (62.0-432.7)

402.0 (234.0-466.0)

227.0 (76.0-442.0)

0.078

3*N=29 BMC 3 Day, N=19 Placebo 3 Day, N=31 BMC 7 Day, N=15 Placebo 7 Day

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

BMCFicoll

Manual Sepax4

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Cell Characteristics

6-Mo Primary Endpoint: Global

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No difference in the change in LVEF between BMC (n=75) and Placebo (n=37) groups from baseline to 6 months

JAMA 2012; 308 (22):2380-9

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. 7

Change in LVEF over 1-Year

Day 3 vs 1-year: BMC < 0.01; Placebo = NS

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)

Change in Infarct Size

3 Day vs. 1 Year: BMC ( p< 0.001); Placebo (p<0.001)

Change in LV Volumes Over 1 Year

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LVEDV (ml/m2) LVESV (ml/m2)

Day 3 6-Month 1-Year 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

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Clinical/Safety Outcomes at 1 Year

BMC Placebo

Patients with events 18/79 (23%) 9/41 (22%)

Deaths 1 0

Reinfarctions 2 3

Repeat Revascularizations 9 6

Target Vessel 4 4

Non-Target Vessel 5 2

Hospitalization Heart Failure 4 1

ICD Placements 4 5

Stroke 2 2

Total 22 17

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

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Acknowledgements

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• 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 1HL087318-07

• 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)

Sonia I. Skarlatos

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1953 - 2013