Dose Comparison Study of Allogeneic Mesenchymal Stem Cells in Patients With Ischemic Cardiomyopathy (The TRIDENT Study)

Abstract

Rationale: Cell dose and concentration play crucial roles in phenotypic responses to cell-based therapy for heart failure.

Objective: To compare the safety and efficacy of 2 doses of allogeneic bone marrow-derived human mesenchymal stem cells identically delivered in patients with ischemic cardiomyopathy.

Methods and results: Thirty patients with ischemic cardiomyopathy received in a blinded manner either 20 million (n=15) or 100 million (n=15) allogeneic human mesenchymal stem cells via transendocardial injection (0.5 cc per injection × 10 injections per patient). Patients were followed for 12 months for safety and efficacy end points. There were no treatment-emergent serious adverse events at 30 days or treatment-related serious adverse events at 12 months. The Major Adverse Cardiac Event rate was 20.0% (95% confidence interval [CI], 6.9% to 50.0%) in 20 million and 13.3% (95% CI, 3.5% to 43.6%) in 100 million (P=0.58). Worsening heart failure rehospitalization was 20.0% (95% CI, 6.9% to 50.0%) in 20 million and 7.1% (95% CI, 1.0% to 40.9%) in 100 million (P=0.27). Whereas scar size reduced to a similar degree in both groups: 20 million by -6.4 g (interquartile range, -13.5 to -3.4 g; P=0.001) and 100 million by -6.1 g (interquartile range, -8.1 to -4.6 g; P=0.0002), the ejection fraction improved only with 100 million by 3.7 U (interquartile range, 1.1 to 6.1; P=0.04). New York Heart Association class improved at 12 months in 35.7% (95% CI, 12.7% to 64.9%) in 20 million and 42.9% (95% CI, 17.7% to 71.1%) in 100 million. Importantly, proBNP (pro-brain natriuretic peptide) increased at 12 months in 20 million by 0.32 log pg/mL (95% CI, 0.02 to 0.62; P=0.039), but not in 100 million (-0.07 log pg/mL; 95% CI, -0.36 to 0.23; P=0.65; between group P=0.07).

Conclusions: Although both cell doses reduced scar size, only the 100 million dose increased ejection fraction. This study highlights the crucial role of cell dose in the responses to cell therapy. Determining optimal dose and delivery is essential to advance the field, decipher mechanism(s) of action and enhance planning of pivotal Phase III trials.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02013674.

Keywords: bone marrow; cell-based therapy; heart failure; hospitalization; stem cells.

© 2017 American Heart Association, Inc.

Figures

Figure 1.. Study Flow Chart.

Following screening, 30 patients were enrolled and randomized 1:1 to receive allogeneic hMSC treatment. Following safety evaluation at 30 day TE-SAEs and secondary endpoints.

Figure 2.. Changes in LV Function from Baseline to 12 months post-TESI.

(A) Ejection fraction increased from baseline in 100 M but not in 20 M: 3.7 units (IQR, 1.09, 6.10, p=0.04), between groups (p=0.68). (B) End diastolic volume, (C) end systolic volume, and (D) stroke volume did not improve from baseline. *within-group p≤0.05.

Figure 2.. Changes in LV Function from Baseline to 12 months post-TESI.

(A) Ejection fraction increased from baseline in 100 M but not in 20 M: 3.7 units (IQR, 1.09, 6.10, p=0.04), between groups (p=0.68). (B) End diastolic volume, (C) end systolic volume, and (D) stroke volume did not improve from baseline. *within-group p≤0.05.

Figure 2.. Changes in LV Function from Baseline to 12 months post-TESI.

(A) Ejection fraction increased from baseline in 100 M but not in 20 M: 3.7 units (IQR, 1.09, 6.10, p=0.04), between groups (p=0.68). (B) End diastolic volume, (C) end systolic volume, and (D) stroke volume did not improve from baseline. *within-group p≤0.05.

Figure 2.. Changes in LV Function from Baseline to 12 months post-TESI.

(A) Ejection fraction increased from baseline in 100 M but not in 20 M: 3.7 units (IQR, 1.09, 6.10, p=0.04), between groups (p=0.68). (B) End diastolic volume, (C) end systolic volume, and (D) stroke volume did not improve from baseline. *within-group p≤0.05.

Figure 3.. Changes in Scar Size from Baseline to 12 months post-TESI.

Both group reduced scar size and scar size as a fraction of LV mass by similar degree. (A) Scar size reduction in 20M by −6.4g (IQR, 13.5g, −3.4g, p=0.001) and 100M by −6.1g (IQR, −8.1g, −4.6g, p=0.0002), between groups (p=0.91). (B) Scar size as a percentage of LV mass decreased in 20M by 3.30% (−5.82%, −2.48%, p=0.0005) and 100M by 4.34% (−9.32%, −1.84%, p=0.0015), between groups (p=0.6). **Within-group p≤0.005, ***within-group p≤0.0005.

Figure 3.. Changes in Scar Size from Baseline to 12 months post-TESI.

Both group reduced scar size and scar size as a fraction of LV mass by similar degree. (A) Scar size reduction in 20M by −6.4g (IQR, 13.5g, −3.4g, p=0.001) and 100M by −6.1g (IQR, −8.1g, −4.6g, p=0.0002), between groups (p=0.91). (B) Scar size as a percentage of LV mass decreased in 20M by 3.30% (−5.82%, −2.48%, p=0.0005) and 100M by 4.34% (−9.32%, −1.84%, p=0.0015), between groups (p=0.6). **Within-group p≤0.005, ***within-group p≤0.0005.

Figure 4.. Functional Capacity and Quality of Life in ICM Patients.

Depicted are changes in functional capacity, quality of life, and sexual quality of life. (A) 6MWT distance increased in 20M by 13.5m (95% CI, −34.48m, 61.46m, p=0.57) and in 100M by 25.2m (95% CI, −23.20m, 73.58m, p=0.30), between groups (p=0.64). (B) NYHA class improved to a similar degree in both dose groups: 35.7% in 20M and 42.9% in 100M after 1 year post-TESI. (C) MLHFQ score didn’t change over time (20M p=0.22, 100M p=0.23). (D) pro-BNP was maintained in 100M while it increased by 0.32 log pg/mL (p=0.038) in 20M. *Within-group p≤0.05.

Figure 4.. Functional Capacity and Quality of Life in ICM Patients.

Depicted are changes in functional capacity, quality of life, and sexual quality of life. (A) 6MWT distance increased in 20M by 13.5m (95% CI, −34.48m, 61.46m, p=0.57) and in 100M by 25.2m (95% CI, −23.20m, 73.58m, p=0.30), between groups (p=0.64). (B) NYHA class improved to a similar degree in both dose groups: 35.7% in 20M and 42.9% in 100M after 1 year post-TESI. (C) MLHFQ score didn’t change over time (20M p=0.22, 100M p=0.23). (D) pro-BNP was maintained in 100M while it increased by 0.32 log pg/mL (p=0.038) in 20M. *Within-group p≤0.05.

Figure 4.. Functional Capacity and Quality of Life in ICM Patients.

Depicted are changes in functional capacity, quality of life, and sexual quality of life. (A) 6MWT distance increased in 20M by 13.5m (95% CI, −34.48m, 61.46m, p=0.57) and in 100M by 25.2m (95% CI, −23.20m, 73.58m, p=0.30), between groups (p=0.64). (B) NYHA class improved to a similar degree in both dose groups: 35.7% in 20M and 42.9% in 100M after 1 year post-TESI. (C) MLHFQ score didn’t change over time (20M p=0.22, 100M p=0.23). (D) pro-BNP was maintained in 100M while it increased by 0.32 log pg/mL (p=0.038) in 20M. *Within-group p≤0.05.

Figure 4.. Functional Capacity and Quality of Life in ICM Patients.

Depicted are changes in functional capacity, quality of life, and sexual quality of life. (A) 6MWT distance increased in 20M by 13.5m (95% CI, −34.48m, 61.46m, p=0.57) and in 100M by 25.2m (95% CI, −23.20m, 73.58m, p=0.30), between groups (p=0.64). (B) NYHA class improved to a similar degree in both dose groups: 35.7% in 20M and 42.9% in 100M after 1 year post-TESI. (C) MLHFQ score didn’t change over time (20M p=0.22, 100M p=0.23). (D) pro-BNP was maintained in 100M while it increased by 0.32 log pg/mL (p=0.038) in 20M. *Within-group p≤0.05.

Figure 5.. Effects of hMSCs on serum TNF-α in ICM Patients.

Cell treatment improved serum TNF-α at 6 months post-TESI by −5.96pg/mL in 20M (p=0.01) and −9.37pg/mL in 100M (p=0.0004), between groups (p=0.96). *Within-group p≤0.05, ***within-group p≤0.0005.