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

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.

Keywords: Chronic heart failure; Endogenous tissue repair; Gene therapy; Stem cell homing.

Figure 1

Consort diagram of patients screened and enrolled between May 2012 and September 2013.

Figure 2

Effect of stromal cell-derived factor-1 over-expression on structural, functional, and clinical measures in patients with chronic heart failure. Mean values of (A) composite score, (B) left ventricular ejection fraction (%), (C) left ventricular end-systolic volume (mL), (D) N-terminal pro BNP (pg/mL) and (D) N-terminal pro BNP at baseline, 4 and 12 months after treatment with placebo (open circles), 15 (grey circles), or 30 mg (black circles) of JVS-100. Box in (A) represents primary endpoint of trial. P-value represents treated vs. placebo at 4 months.

Figure 3

Effect of stromal cell-derived factor-1 over-expression on ejection fraction at 4 and 12 months based on baseline ejection fraction. Data represent change in left ventricular ejection fraction in box-whisker plots with median and interquartile range and minimum and maximum data points. Circles represent individual patient data points for (open circle) placebo, (grey circle) 15, or (black circle) 30 mg treatment cohorts. (A) Patients with EF < 26% at baseline, (B) patients with EF < 32% at baseline, or (C) patients with EF < 40% at baseline. The variable Δ represents the difference between the median in the above-treatment cohort and placebo.

Figure 4

Effect of stromal cell-derived factor-1 over-expression on parameters of chronic heart failure in high-risk heart failure patients. Data represent change in (A) composite endpoint, (B) left ventricular end-systolic volume, and (C) N-terminal pro BNP in the first tertile (left ventricular ejection fraction <26% at baseline) in box-whisker plots with median and interquartile range and minimum and maximum data points. Circles represent individual patient data points for (open circle) placebo, (grey circle) 15, or (black circle) 30 mg treatment cohorts. The variable Δ represents the difference between the median in the above-treatment cohort and placebo.

Figure 5

Effect of stromal cell-derived factor-1 over-expression on stroke volume 12 months after treatment. Mean change in stroke volume from baseline to 12 months following administration of placebo or treatment with 15 or 30 mg of JVS-100 in all patients (open bar) or patients in the first tertile of EF (<26%) at baseline. Data represent mean ± SD.

Figure 6

Effect of age and diabetes on change in stroke volume in response to stromal cell-derived factor-1 over-expression in chronic heart failure. Data represent change in left ventricular ejection fraction in patients from the first tertile of baseline left ventricular ejection fraction (<26%) in box-whisker plots with median and interquartile range and minimum and maximum data points. Circles represent individual patient data points for (open circle) placebo or (black circle) 30 mg treatment cohorts. (A) Analysis in patients based on median age and (B) analyses of patients based on presence or absence of diabetes mellitus. The variable Δ represents the difference between the median in the above-treatment cohort and placebo.