Elsevier

American Heart Journal

Volume 158, Issue 3, September 2009, Pages 356-363
American Heart Journal

Trial Design
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

https://doi.org/10.1016/j.ahj.2009.06.009Get rights and content

Several previous studies have demonstrated that administration of autologous bone marrow–derived mononuclear cells (BMMNCs) improves cardiac function in patients after acute myocardial infarction (AMI). However, optimum timing of administration has not been investigated in a clinical trial. The Cardiovascular Cell Therapy Research Network was developed and funded by the National Heart, Lung, and Blood Institute to address important questions such as timing of cell delivery and to accelerate research in the use of cell-based therapies. The TIME trial is a randomized, phase II, double-blind, placebo-controlled clinical trial. The 5 member clinical sites of the Cardiovascular Cell Therapy Research Network will enroll 120 eligible patients with moderate-to-large anterior AMIs who have undergone successful percutaneous coronary intervention of the left anterior descending coronary artery and have a left ventricular (LV) ejection fraction ≤45% by echocardiography. Participants will have bone marrow aspirations and intracoronary infusions of 150 × 106 BMMNCs or placebo on day 3 or day 7 post-AMI. Objectives of this study are (1) to evaluate effects of BMMNCs on regional and global LV function compared to placebo therapy in patients with acute AMI as assessed by cardiac magnetic resonance imaging at 6 months and (2) to assess whether effects of BMMNC infusion on global and regional LV function and safety are influenced by the time of administration. This study will provide further insight into the clinical feasibility and appropriate timing of autologous BMMNC therapy in high-risk patients after AMI and percutaneous coronary intervention.

Section snippets

Organizational structure and oversight

The CCTRN was established by the NHLBI to develop, coordinate, and conduct multiple collaborative protocols testing the effects of stem cell therapy on cardiovascular disease. The Network builds on contemporary findings of the cell therapy basic science community, translating newly acquired information to the cardiac clinical setting in the phase I/II study paradigm. The Network consists of 5 clinical research centers (Cleveland Clinic Foundation, University of Florida, Minneapolis Heart

Objectives and design

The objectives of this study are (1) to evaluate the effect of a single intracoronary infusion of autologous BMMNCs on regional and global LV function when compared to control therapy in patients with an acute anterior myocardial infarction (MI) as assessed by cardiac magnetic resonance imaging (cMRI) and (2) to assess whether the effect of this BMMNC infusion on regional and global LV function is influenced by whether it is given at 3 versus 7 days post-AMI. The primary outcome will be change

Hypotheses and study power

The primary hypotheses of the TIME study are that, as compared with placebo therapy, (1) administration of cell therapy will improve global and regional LV function and (2) this improvement will depend on the timing of cell delivery. The secondary hypotheses are that, in comparison with control therapy, (1) administration of cell therapy will result in smaller end-diastolic and end-systolic volumes (2) and a lower incidence of the composite adverse events of death, reinfarction, repeat

Enrollment and study population

This study is a randomized, double-blind, placebo-controlled clinical study of autologous BMMNC administration to 120 patients after AMI. Patients will be randomized to a 2:1 treatment-versus-placebo therapy ratio at each of the 2 time points. Patients enrolled in this study will be recruited from each of the 5 sites participating in the CCTRN. Enrollment will be limited to patients with moderate-to-large anterior infarctions with no prior history of coronary artery bypass grafting (CABG) and

Randomization to the timing of administration

The clinical center will electronically transmit eligibility criteria to the DCC, at which time a computer-generated scheme will randomly allocate eligible patients (1:1) to an intervention time group (3 or 7 days post-PCI, with day zero defined as the day of incident PCI). This randomization will be not be blinded, and participants will be stratified by clinical center. Patients randomized to day 3 therapy must receive cMRI, bone marrow aspirations, cell processing, and therapy infusions on

Safety monitoring

All CCTRN participants will be closely monitored for adverse events, and this information will be transmitted to institutional review boards of each center by the DCC; to the Food and Drug Administration (FDA), through the University of Texas Health Science Center–held investigational new drug (IND); and by the DSMB. The DSMB will meet at least twice yearly to review performance of the participating sites, to assess accruing safety data, and to ascertain feasibility of continuation of the

Determination of outcomes

A 1.5-T cMRI scanner will be used, with precise magnetic resonance imaging protocols developed by the MRI core laboratory. Because resolution of myocardial stunning and improvement in global and regional LV function often continue to occur between day 3 and day 7, all patients will undergo baseline cMRI measurements at day 3. Commercial Siemens Argus analysis software will be used for measurement of global LV myocardial mass, volumes, and LVEF. Regional systolic wall motion, thickening, and

Statistical methods

The TIME trial is a 2-factor experiment. The 2 factors are therapy (active vs placebo therapy) and timing (3 vs 7 days). The principal interest is whether the effect of cell administration timing influences the relationship between BMMNC infusion and cardiac function. Hypothesis testing for each of the primary end points will be carried out at the 0.05 level in this Phase II study. A total of 120 patients provide satisfactory power for the assessment of the overall effect of BMMNC

Discussion

Recent findings in animals that stem cell therapy significantly reduces the development of LV dysfunction after MI1, 2, 3, 4 have been rapidly translated into clinical trials using a variety of cell types including intracoronary BMMNC administration.7, 8, 9, 10 Importantly, these trials have demonstrated that cell delivery after AMI is safe over several years of follow-up, and meta-analyses review of these trials have found a small but significant improvement in LV function.11, 12 However,

Acknowledgements

We are solely responsible for the design and conduct of this study, all study analyses, and the drafting and editing of the manuscript and its final contents. Technical support for the Sepax System was provided by Biosafe (Eysins, Switzerland).

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    ClinicalTrials.gov no. NCT00684021.

    This study is supported by the NHLBI (U01 HL087318-01) and by the Production Assistance for Cellular Therapies (N01-HB-37164). PTCA and guide catheters and wires were generously supplied by the Boston Scientific Corporation (Natick, MA).

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