Trial DesignRationale 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
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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Cited by (0)
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).