Phase II Clinical Research Design in Cardiology Learning the Right Lessons Too Well: Observations and Recommendations From the Cardiovascular Cell Therapy Research Network (CCTRN)

University of Texas School of Public Health, 1200 Herman Pressler W-848, Houston, TX 77030. .
Circulation (Impact Factor: 14.43). 04/2013; 127(15):1630-5. DOI: 10.1161/CIRCULATIONAHA.112.000779
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Available from: Rachel W. Vojvodic, Nov 10, 2014
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    ABSTRACT: The purpose of stem cell therapy for myocardial infarction is to improve clinical outcomes, and detailed information on clinical outcomes is critical to appropriate planning of phase III trials. We have examined data from select phase II trials using autologous bone-marrow-derived stem cells in patients with acute myocardial infarction. We have extracted available definitions and outcome data, and have generated standardized estimates of events to permit summary comparisons. Nine trials (1,040 patients) with results for 6 months to 5 years were evaluated. Adverse outcomes differed widely, and there was a general lack of details in the definitions of these outcomes. Heart-failure-related hospitalizations occurred in only 16 patients (1.5 %) and death occurred in only 43 patients (4.1 %). Ischemia-related outcomes outnumbered heart failure outcomes more than tenfold. Uniform criteria need to be developed to better define clinical outcomes of interest. Furthermore, a refocus from heart failure outcomes to ischemia-related outcomes seems appropriate.
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    ABSTRACT: IMPORTANCE Whether culture-expanded mesenchymal stem cells or whole bone marrow mononuclear cells are safe and effective in chronic ischemic cardiomyopathy is controversial. OBJECTIVE To demonstrate the safety of transendocardial stem cell injection with autologous mesenchymal stem cells (MSCs) and bone marrow mononuclear cells (BMCs) in patients with ischemic cardiomyopathy. DESIGN, SETTING, AND PATIENTS A phase 1 and 2 randomized, blinded, placebo-controlled study involving 65 patients with ischemic cardiomyopathy and left ventricular (LV) ejection fraction less than 50% (September 1, 2009-July 12, 2013). The study compared injection of MSCs (n=19) with placebo (n = 11) and BMCs (n = 19) with placebo (n = 10), with 1 year of follow-up. INTERVENTIONS Injections in 10 LV sites with an infusion catheter. MAIN OUTCOMES AND MEASURES Treatment-emergent 30-day serious adverse event rate defined as a composite of death, myocardial infarction, stroke, hospitalization for worsening heart failure, perforation, tamponade, or sustained ventricular arrhythmias. RESULTS No patient had a treatment-emergent serious adverse events at day 30. The 1-year incidence of serious adverse events was 31.6% (95% CI, 12.6% to 56.6%) for MSCs, 31.6% (95% CI, 12.6%-56.6%) for BMCs, and 38.1% (95% CI, 18.1%-61.6%) for placebo. Over 1 year, the Minnesota Living With Heart Failure score improved with MSCs (-6.3; 95% CI, -15.0 to 2.4; repeated measures of variance, P=.02) and with BMCs (-8.2; 95% CI, -17.4 to 0.97; P=.005) but not with placebo (0.4; 95% CI, -9.45 to 10.25; P=.38). The 6-minute walk distance increased with MSCs only (repeated measures model, P = .03). Infarct size as a percentage of LV mass was reduced by MSCs (-18.9%; 95% CI, -30.4 to -7.4; within-group, P = .004) but not by BMCs (-7.0%; 95% CI, -15.7% to 1.7%; within-group, P = .11) or placebo (-5.2%; 95% CI, -16.8% to 6.5%; within-group, P = .36). Regional myocardial function as peak Eulerian circumferential strain at the site of injection improved with MSCs (-4.9; 95% CI, -13.3 to 3.5; within-group repeated measures, P = .03) but not BMCs (-2.1; 95% CI, -5.5 to 1.3; P = .21) or placebo (-0.03; 95% CI, -1.9 to 1.9; P = .14). Left ventricular chamber volume and ejection fraction did not change. CONCLUSIONS AND RELEVANCE Transendocardial stem cell injection with MSCs or BMCs appeared to be safe for patients with chronic ischemic cardiomyopathy and LV dysfunction. Although the sample size and multiple comparisons preclude a definitive statement about safety and clinical effect, these results provide the basis for larger studies to provide definitive evidence about safety and to assess efficacy of this new therapeutic approach. TRIAL REGISTRATION Identifier: NCT00768066.
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