Cardiovascular Cell Therapy Research Network (CCTRN) 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
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Open BioLINCC Study See bottom of this webpage for request information
July 2008 – November 2012
May 7, 2019
Clinical Trial URLs
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Commercial Use Data Restrictions No
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Specific Consent Restrictions
See also the companion CCTRN-LateTIME study.
To determine 1) the effect of intracoronary autologous bone marrow mononuclear cell (BMC) delivery following ST segment myocardial infarction (STEMI) on recovery of global and regional left-ventricular (LV) function and 2) if timing of BMC delivery (3 versus 7 days following reperfusion) influences this effect.
Cell therapy has been investigated as a therapeutic option for patients following acute myocardial infarction (AMI), with the goal of preventing the transition to end-stage heart failure requiring cardiac transplantation. Meta-analyses of BMC delivery to the infarct zone following AMI have shown small improvements in LV function after successful reperfusion. Myocardium and bone marrow undergo important changes days to weeks following AMI that may affect stem/progenitor cell engraftment and survival. To determine the optimal time to administer BMCs, the NHLBI-sponsored Cardiovascular Cell Therapy Research Network (CCTRN) developed two prospective clinical trials, TIME and LateTIME. The LateTIME trial found BMC administration did not influence the ongoing post-reperfusion recovery of either global or regional LV function when delivered 2-3 weeks following AMI. TIME was performed as a companion trial to investigate influences of timing of cell delivery within the first week following AMI on the course of improving global and regional LV function following reperfusion.
120 adult patients with LV ejection fraction (LVEF) ≤ 45% by echocardiography following successful primary percutaneous coronary intervention (PCI) with stenting of the infarct-related coronary artery were enrolled. 43 patients were randomized to active intervention at day 3, 24 were randomized to placebo at day 3, 36 were randomized to active intervention at day 7, and 17 were randomized to placebo at day 7.
TIME was a randomized, double-blinded, placebo-controlled trial investigating the timing of intracoronary autologous BMCs within the first week following reperfusion in a high-risk STEMI cohort. Enrolled patients were randomized (1:1) to receive therapy on either Day 3 or 7 following primary PCI with stenting. All patients had cardiac magnetic resonance imaging (MRI) at Day 3 (baseline) and those randomized to delivery on Day 7 had another MRI on Day 7 (baseline). Patients underwent bone marrow aspiration on the morning of their treatment day and BMCs were isolated using a closed, automated Ficoll cell processing system to ensure a uniform cellular product. After the cell product passed stipulated lot release criteria, patients were again randomized in a 2:1 ratio to cell therapy or placebo.
Patients randomized to BMCs received a product containing 150 × 106 total nucleated cells (70-80% BMCs). Patients randomized to placebo received a cell-free product of 5% albumin in normal saline, with 100 microliters of autologous blood added to ensure color and consistency matched the BMC group. Within 12 hours of aspiration, the BMCs or placebo was infused in the infarct-related artery in six aliquots of five ml each using stop-flow technique. All patients were heparinized during the procedure to activated clotting time of more than 200 seconds and treated with aspirin and 75 mg of clopidogrel in addition to other guideline-recommended post-MI medications.
Co-primary endpoints were: 1) Change in global (LVEF) and regional (wall motion) LV function in infarct and border zones at 6 months measured by cardiac MRI and 2) Change in LV function as affected by timing of treatment on Day 3 versus Day 7. Secondary endpoints included major adverse cardiovascular events as well as changes in LV volumes and infarct size.
Patients with STEMI, who underwent successful primary PCI and administration of intra-coronary BMCs at either 3 or 7 days following the event, had recovery of global and regional LV function similar to placebo.
Traverse JH, Henry TD, Pepine CJ, et al. Effect of the use and timing of bone marrow mononuclear cell delivery on left ventricular function after acute myocardial infarction: the TIME randomized trial [published correction appears in JAMA. 2013 Jan 23;309(4):343] [published correction appears in JAMA. 2015 Jul 7;314(1):86]. JAMA. 2012;308(22):2380–2389. doi:10.1001/jama.2012.28726
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Resources AvailableStudy Datasets Only
- Data Dictionary (PDF - 147.5 KB)
- TIME Case Report Forms (PDF - 1.1 MB)
- TIME Manual of Operating Procedures (PDF - 1.2 MB)
- TIME Protocol (PDF - 759.9 KB)
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