title: 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.
authors.affiliation: Lindner Center at Christ Hospital, Cincinnati, OH, USA.
authors.forename: Eugene S
authors.initials: ES
authors.lastname: Chung
authors.affiliation: Baycare Health System, Clearwater, FL, USA.
authors.forename: Leslie
authors.initials: L
authors.lastname: Miller
authors.affiliation: University of Utah, Salt Lake City, UT, USA.
authors.forename: Amit N
authors.initials: AN
authors.lastname: Patel
authors.affiliation: University of Florida, Gainesville, FL, USA.
authors.forename: Russell David
authors.initials: RD
authors.lastname: Anderson
authors.affiliation: Center for Therapeutic Angiogenesis, Birmingham, AL, USA.
authors.forename: Farrell O
authors.initials: FO
authors.lastname: Mendelsohn
authors.affiliation: Minneapolis Heart Institute, Minneapolis, MN, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Traverse
authors.affiliation: Summa Cardiovascular Institute, Akron, OH, USA.
authors.forename: Kevin H
authors.initials: KH
authors.lastname: Silver
authors.affiliation: Montefiore-Einstein Medical Center, New York, NY, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Shin
authors.affiliation: Washington University, St. Louis, MO, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Ewald
authors.affiliation: Columbia University, New York, NY, USA.
authors.forename: Mary Jane
authors.initials: MJ
authors.lastname: Farr
authors.affiliation: Hospital of University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Saif
authors.initials: S
authors.lastname: Anwaruddin
authors.affiliation: Juventas Therapeutics, Inc., Cleveland, OH, USA.
authors.forename: Francis
authors.initials: F
authors.lastname: Plat
authors.affiliation: Juventas Therapeutics, Inc., Cleveland, OH, USA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Fisher
authors.affiliation: Juventas Therapeutics, Inc., Cleveland, OH, USA.
authors.forename: Alexander T
authors.initials: AT
authors.lastname: AuWerter
authors.affiliation: Juventas Therapeutics, Inc., Cleveland, OH, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Pastore
authors.affiliation: Juventas Therapeutics, Inc., Cleveland, OH, USA.
authors.forename: Rahul
authors.initials: R
authors.lastname: Aras
authors.affiliation: Summa Cardiovascular Institute, Akron, OH, USA Juventas Therapeutics, Inc., Cleveland, OH, USA marc.s.penn@gmail.com.
authors.forename: Marc S
authors.initials: MS
authors.lastname: Penn
mesh_terms: D000368:Aged; D000704:Analysis of Variance; D054377:Chemokine CXCL12 / Q000008:administration & dosage* / Q000009:adverse effects / Q000235:genetics; D002908:Chronic Disease; D004311:Double-Blind Method; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D006333:Heart Failure / Q000473:pathology / Q000628:therapy*; D006801:Humans; D015552:Injections, Intralesional; D008297:Male; D017202:Myocardial Ischemia / Q000473:pathology / Q000628:therapy*; D013318:Stroke Volume / Q000502:physiology; D016896:Treatment Outcome; D020257:Ventricular Remodeling / Q000502:physiology
chemical_list: D054377:Chemokine CXCL12
keywords: Chronic heart failure; Endogenous tissue repair; Gene therapy; Stem cell homing