Changes in ventricular remodelling and clinical status during the year following a single administration of stromal cell-derived factor-1 non-viral gene therapy in chronic ischaemic heart failure patients: The STOP-HF randomized Phase II trial

Eugene S. Chung, Leslie Miller, Amit N. Patel, Russell David Anderson, Farrell O. Mendelsohn, Jay Traverse, Kevin H. Silver, Julia Shin, Gregory Ewald, Mary Jane Farr, Saif Anwaruddin, Francis Plat, Scott J. Fisher, Alexander T. AuWerter, Joseph M. Pastore, Rahul Aras, Marc S. Penn

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Abstract

Background Stromal cell-derived factor-1 (SDF-1) promotes tissue repair through mechanisms of cell survival, endogenous stem cell recruitment, and vasculogenesis. Stromal Cell-Derived Factor-1 Plasmid Treatment for Patients with Heart Failure (STOP-HF) is a Phase II, double-blind, randomized, placebo-controlled trial to evaluate safety and efficacy of a single treatment of plasmid stromal cell-derived factor-1 (pSDF-1) delivered via endomyocardial injection to patients with ischaemic heart failure (IHF). Methods Ninety-three subjects with IHF on stable guideline-based medical therapy and left ventricular ejection fraction (LVEF) ≤40%, completed Minnesota Living with Heart Failure Questionnaire (MLWHFQ) and 6-min walk distance (6 MWD), were randomized 1: 1: 1 to receive a single treatment of either a 15 or 30 mg dose of pSDF-1 or placebo via endomyocardial injections. Safety and efficacy parameters were assessed at 4 and 12 months after injection. Left ventricular functional and structural measures were assessed by contrast echocardiography and quantified by a blinded independent core laboratory. Stromal Cell-Derived Factor-1 Plasmid Treatment for Patients with Heart Failure was powered based on change in 6 MWD and MLWHFQ at 4 months. Results Subject profiles at baseline were (mean ± SD): age 65 ± 9 years, LVEF 28 ± 7%, left ventricular end-systolic volume (LVESV) 167 ± 66 mL, N-terminal pro brain natriuretic peptide (BNP) (NTproBNP) 1120 ± 1084 pg/mL, MLWHFQ 50 ± 20 points, and 6 MWD 289 ± 99 m. Patients were 11 ± 9 years post most recent myocardial infarction. Study injections were delivered without serious adverse events in all subjects. Sixty-two patients received drug with no unanticipated serious product-related adverse events. The primary endpoint was a composite of change in 6 MWD and MLWHFQ from baseline to 4 months follow-up. The primary endpoint was not met (P = 0.89). For the patients treated with pSDF-1, there was a trend toward an improvement in LVEF at 12 months (placebo vs. 15 mg vs. 30 mg ΔLVEF: -2 vs. -0.5 vs. 1.5%, P = 0.20). A pre-specified analysis of the effects of pSDF-1 based on tertiles of LVEF at entry revealed improvements in EF and LVESV from lowest-to-highest LVEF. Patients in the first tertile of EF (<26%) that received 30 mg of pSDF-1 demonstrated a 7% increase in EF compared with a 4% decrease in placebo (ΔLVEF = 11%, P = 0.01) at 12 months. There was also a trend towards improvement in LVESV, with treated patients demonstrating an 18.5 mL decrease compared with a 15 mL increase for placebo at 12 months (ΔLVESV = 33.5 mL, P = 0.12). The change in end-diastolic and end-systolic volume equated to a 14 mL increase in stroke volume in the patients treated with 30 mg of pSDF-1 compared with a decrease of -11 mL in the placebo group (ΔSV = 25 mL, P = 0.09). In addition, the 30 mg-treated cohort exhibited a trend towards improvement in NTproBNP compared with placebo at 12 months (-784 pg/mL, P = 0.23). Conclusions The blinded placebo-controlled STOP-HF trial demonstrated the safety of a single endocardial administration of pSDF-1 but failed to demonstrate its primary endpoint of improved composite score at 4 months after treatment. Through a pre-specified analysis the STOP-HF trial demonstrates the potential for attenuating LV remodelling and improving EF in high-risk ischaemic cardiomyopathy. The safety profile supports repeat dosing with pSDF-1 and the degree of left ventricular remodelling suggests the potential for improved outcomes in larger future trials.

Original languageEnglish
Pages (from-to)2228-2238
Number of pages11
JournalEuropean heart journal
Volume36
Issue number33
DOIs
StatePublished - Sep 1 2015

Keywords

  • Chronic heart failure
  • Endogenous tissue repair
  • Gene therapy
  • Stem cell homing

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    Chung, E. S., Miller, L., Patel, A. N., Anderson, R. D., Mendelsohn, F. O., Traverse, J., Silver, K. H., Shin, J., Ewald, G., Farr, M. J., Anwaruddin, S., Plat, F., Fisher, S. J., AuWerter, A. T., Pastore, J. M., Aras, R., & Penn, M. S. (2015). Changes in ventricular remodelling and clinical status during the year following a single administration of stromal cell-derived factor-1 non-viral gene therapy in chronic ischaemic heart failure patients: The STOP-HF randomized Phase II trial. European heart journal, 36(33), 2228-2238. https://doi.org/10.1093/eurheartj/ehv254