A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction

Abstract

Objectives: Our aim was to investigate the safety and efficacy of intravenous allogeneic human mesenchymal stem cells (hMSCs) in patients with myocardial infarction (MI).

Background: Bone marrow-derived hMSCs may ameliorate consequences of MI, and have the advantages of preparation ease, allogeneic use due to immunoprivilege, capacity to home to injured tissue, and extensive pre-clinical support.

Methods: We performed a double-blind, placebo-controlled, dose-ranging (0.5, 1.6, and 5 million cells/kg) safety trial of intravenous allogeneic hMSCs (Prochymal, Osiris Therapeutics, Inc., Baltimore, Maryland) in reperfused MI patients (n=53). The primary end point was incidence of treatment-emergent adverse events within 6 months. Ejection fraction and left ventricular volumes determined by echocardiography and magnetic resonance imaging were exploratory efficacy end points.

Results: Adverse event rates were similar between the hMSC-treated (5.3 per patient) and placebo-treated (7.0 per patient) groups, and renal, hepatic, and hematologic laboratory indexes were not different. Ambulatory electrocardiogram monitoring demonstrated reduced ventricular tachycardia episodes (p=0.025), and pulmonary function testing demonstrated improved forced expiratory volume in 1 s (p=0.003) in the hMSC-treated patients. Global symptom score in all patients (p=0.027) and ejection fraction in the important subset of anterior MI patients were both significantly better in hMSCs versus placebo subjects. In the cardiac magnetic resonance imaging substudy, hMSC treatment, but not placebo, increased left ventricular ejection fraction and led to reverse remodeling.

Conclusions: Intravenous allogeneic hMSCs are safe in patients after acute MI. This trial provides pivotal safety and provisional efficacy data for an allogeneic bone marrow-derived stem cell in post-infarction patients. (Safety Study of Adult Mesenchymal Stem Cells [MSC] to Treat Acute Myocardial Infarction; NCT00114452).

Figure 1. Time After MI to Infusion of Study Agent

Human mesenchymal stem cells = solid bars; placebo = open bars. MI = myocardial infarction.

Figure 2. Percentage of Patients With >10 PVCs per Hour

Human mesenchymal stem cells = green line (n = 32 at 3 months, n = 33 at 6 months); placebo = red line (n = 19 at 3 months, n = 16 at 6 months). *p = 0.001 by repeated measure analysis of variance; †p < 0.05 versus days 1 and 90; ‡p = 0.017 versus placebo. PVC = premature ventricular contraction.

Figure 3. Increase From Baseline Values in Percent LVEF at 3 and 6 Months Post-Treatment in Patients With Anterior MI

Human mesenchymal stem cells = solid bars (n = 17 at 3 months, n = 15 at 6 months); placebo = open bars (n = 10 at 3 months, n = 9 at 6 months). *p = 0.0436 at 6 months for human mesenchymal stem cell-treated patients versus baseline, analysis of variance. LVEF = left ventricular ejection fraction; MI = myocardial infarction.

Figure 4. Impact of hMSC Treatment on LVEF Evaluated by Cardiac MRI

Human mesenchymal stem cells (hMSCs) = green line (n = 21 at 3 months, n = 18 at 6 and 12 months); placebo = red line (n = 13 at 3 months, n = 11 at 6 and 12 months). *p = 0.003 by repeated measure analysis of variance; †p = 0.005 versus baseline. Abbreviations as in Figure 3.

Figure 5. Impact of hMSC Treatment on LV Remodeling

Changes in left ventricular (LV) ejection fraction (EF) are plotted against the changes in LV end-systolic volume (ESV) (A) and end-diastolic volume (EDV) (B) during follow-up. Human mesenchymal stem cell (hMSC) patients (n = 21 at 3 months, n = 18 at 6 and 12 months) exhibit evidence of reverse remodeling with no increase in LV EDV and a decline in LV ESV, whereas placebo patients (n = 13 at 3 months, n = 11 at 6 and 12 months) demonstrate evidence of LV chamber enlargement. *p = 0.005 versus baseline.

Figure 6. Difference From Baseline in FEV1 % Predicted

Human mesenchymal stem cells = green line (n = 31); placebo = red line (n = 18). Error bars represent standard error of the mean. *p = 0.003 by repeated measure analysis of variance; †p = 0.01 versus placebo. FEV1 = forced expiratory volume in 1 s.

Figure 7. Percentage of Patients With Improved Global Assessment

Human mesenchymal stem cells = green line; placebo = red line. *p = 0.027 between groups, Fisher exact test; †p = 0.016 versus day 10, Fisher exact test.