PRIME-HFrEF Trial: a randomized, double-blind, multi-dose umbilical cord-derived mesenchymal stem cell regimen for heart failure.

The safety of multi-dose mesenchymal stem cell (MSC) regimens has seldom been systematically investigated. The PRIME-HFrEF (Prospective Randomized Controlled Study of Multiple Intravenous Infusions of Umbilical Cord-derived MSCs in Patients with Heart Failure and Reduced Ejection Fraction) trial was a single-center, randomized, placebo-controlled, investigator-initiated study (ClinicalTrials.gov identifier: NCT04992832) that enrolled 40 patients. The trial aimed to evaluate the safety of three intravenous infusions of Umbilical Cord-derived MSCs (UC-MSCs) administered at six-week intervals in patients with heart failure and reduced ejection fraction (HFrEF), while also collecting exploratory efficacy data. The primary safety endpoint was the incidence of serious adverse events (SAEs), and the primary efficacy endpoint was the change (Δ) in left ventricular ejection fraction (LVEF). Secondary efficacy endpoints included changes in right ventricular (RV) end-systolic and end-diastolic volumes (ESV and EDV). Thirty-nine patients completed 12 study visits over a 360-day follow-up period or until death. The incidence of SAEs did not differ significantly between treatment groups. However, UC-MSC-treated patients exhibited elevated D-dimer levels, suggesting a treatment-associated increase in coagulability. D-dimer levels were negatively correlated with LVEF, and no significant difference in ΔLVEF was observed between groups. In contrast, the improvement in ΔRVESV was significantly greater in the UC-MSC group than in placebo-treated patients (P = 0.033). In summary, multi-dose UC-MSC infusions were safely administered to patients with HFrEF and were associated with improvements in RV volumes. However, these benefits were accompanied by transient increases in coagulability, which may have attenuated potential improvements in left ventricular contractile function.