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

BackgroundStromal 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).MethodsNinety-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.ResultsSubject 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).ConclusionsThe blinded placebo-controlled STOP-HF trial demonstrated the safety of a single ...

Novel Therapies for Heart Failure – Where Do They Stand? –

“…98, 99 In a PHASE 2 study, 93 HFrEF patients with ischemic disease received intramyocardial injection of a single treatment of 15 or 30 mg of plasmid SDF-1 (pSDF-1) or placebo. 100 Although a primary composite endpoint was not met, there was a trend towards improved EF with pSDF-1. Patients in the lowest EF tertile who received 30 mg of drug demonstrated significant placebo adjusted changes in EF after 12 months.…”

Role of Notch, SDF-1 and Mononuclear Cells Recruitment in Angiogenesis

“…The crucial role of SDF-1 for cardiac repair in chronic ischemic heart failure was the reason for conducting clinical trial using SDF-1 nonviral gene therapy via its endomyocardial administration [99]. This blinded placebo-controlled STOP-HF trial demonstrated improvement of clinical status based on composite endpoint of six MWD (6-min walk distance) and MLWHFQ (Minnesota Living with Heart Failure Quality of life Questionnaire).…”

Tripartite Motif Protein 72 Regulates the Proliferation and Migration of Rat Cardiac Fibroblasts via the Transforming Growth Factor-β Signaling Pathway

“…In response to chronic ischemia stimuli, cardiac fibroblasts proliferate, migrate, and excrete ECM to maintain myocardial function. However, if the repair phase is not terminated appropriately, excessive deposition of ECM will result in chronic fibrosis, ultimately leading to worse cardiac function and a poor prognosis [6][7][8] . During the development of cardiac remodeling after myocardial infarction, the proliferation and migration of cardiac fibroblasts play critical roles in heart failure.…”