title: Effect of intracoronary administration of AAV1/SERCA2a on ventricular remodelling in patients with advanced systolic heart failure: results from the AGENT-HF randomized phase 2 trial.
abstract: Restoration of sarco/endoplasmic reticulum Ca2+ATPase (SERCA2a) activity through gene transfer improved cardiac function in experimental and pilot studies in humans with heart failure. The AGENT-HF (NCT01966887) trial investigated the impact of adeno-associated virus (AAV1)/SERCA2a on ventricular remodelling using multimodality non-invasive cardiac imaging.
  
  
  
  AGENT-HF was a single centre, randomized, double-blind, placebo-controlled trial in adult patients with NYHA class III-IV ischaemic or non-ischaemic heart failure and left ventricular ejection fraction ≤35%. Eligible patients were randomized to receive a single intracoronary infusion of either 1 × 1013DNase-resistant particles of AAV1/SERCA2a or placebo. The primary endpoint was change in left ventricular end-systolic volume (LVESV), measured by cardiac computed tomography at 6 month follow-up. We planned to include 40 patients but the trial was terminated prematurely as the sponsor suspended further enrolment following neutral results of the CUPID-2 outcome trial. At the time of termination, nine patients were randomized with five patients infused with AAV1/SERCA2a and four with placebo. At 6 months, LVESV was increased in both groups compared with baseline: median (interquartile range) in AAV1/SERCA2a vs. placebo: 13 (13;14) mL vs. 3.5 (-36;36) mL, P = 0.74, with a mean difference between groups of 11.4 mL in favour of placebo. No safety issues were noted.
  
  
  
  AGENT-HF failed to demonstrate any improvement in ventricular remodelling in response to AAV1/SERCA2a at the dose studied. However, because of premature termination, the study was underpowered to demonstrate an effect of AAV1/SERCA2a and these data should be interpreted with caution.
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, AP-HP, CIC Paris-Est 1421, Institute of Cardiometabolism and Nutrition (ICAN), Pitié-Salpêtrière Hospital, F-75013, Paris, France.
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Hulot
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, AP-HP, CIC Paris-Est 1421, Institute of Cardiometabolism and Nutrition (ICAN), Pitié-Salpêtrière Hospital, F-75013, Paris, France.
authors.forename: Joe-Elie
authors.initials: JE
authors.lastname: Salem
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, AP-HP, CIC Paris-Est 1421, Institute of Cardiometabolism and Nutrition (ICAN), Pitié-Salpêtrière Hospital, F-75013, Paris, France.
authors.forename: Alban
authors.initials: A
authors.lastname: Redheuil
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, AP-HP, CIC Paris-Est 1421, Institute of Cardiometabolism and Nutrition (ICAN), Pitié-Salpêtrière Hospital, F-75013, Paris, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Collet
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, AP-HP, CIC Paris-Est 1421, Institute of Cardiometabolism and Nutrition (ICAN), Pitié-Salpêtrière Hospital, F-75013, Paris, France.
authors.forename: Shaida
authors.initials: S
authors.lastname: Varnous
authors.affiliation: Centre Hospitalier Pontoise, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Jourdain
authors.affiliation: UMR-S 942, Université Paris Diderot, DHU FIRE, Department of Cardiology, Lariboisière Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Logeart
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, AP-HP, CIC Paris-Est 1421, Institute of Cardiometabolism and Nutrition (ICAN), Pitié-Salpêtrière Hospital, F-75013, Paris, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Gandjbakhch
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, AP-HP, Clinical Investigation Center for Biotherapies and Inflammation-Immunopathology-Biotherapy Department, F-75013, Paris, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Bernard
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, AP-HP, CIC Paris-Est 1421, Institute of Cardiometabolism and Nutrition (ICAN), Pitié-Salpêtrière Hospital, F-75013, Paris, France.
authors.forename: Stéphane N
authors.initials: SN
authors.lastname: Hatem
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, AP-HP, CIC Paris-Est 1421, Institute of Cardiometabolism and Nutrition (ICAN), Pitié-Salpêtrière Hospital, F-75013, Paris, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Isnard
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, AP-HP, CIC Paris-Est 1421, Institute of Cardiometabolism and Nutrition (ICAN), Pitié-Salpêtrière Hospital, F-75013, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Cluzel
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, AP-HP, CIC Paris-Est 1421, Institute of Cardiometabolism and Nutrition (ICAN), Pitié-Salpêtrière Hospital, F-75013, Paris, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Le Feuvre
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, AP-HP, CIC Paris-Est 1421, Institute of Cardiometabolism and Nutrition (ICAN), Pitié-Salpêtrière Hospital, F-75013, Paris, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Leprince
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, AP-HP, CIC Paris-Est 1421, Institute of Cardiometabolism and Nutrition (ICAN), Pitié-Salpêtrière Hospital, F-75013, Paris, France.
authors.forename: Nadjib
authors.initials: N
authors.lastname: Hammoudi
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, AP-HP, Clinical Investigation Center for Biotherapies and Inflammation-Immunopathology-Biotherapy Department, F-75013, Paris, France.
authors.forename: François M
authors.initials: FM
authors.lastname: Lemoine
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, AP-HP, Clinical Investigation Center for Biotherapies and Inflammation-Immunopathology-Biotherapy Department, F-75013, Paris, France.
authors.forename: David
authors.initials: D
authors.lastname: Klatzmann
authors.affiliation: ACTION Study Group, Unité de Recherche Clinique, Lariboisière, Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Vicaut
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, AP-HP, CIC Paris-Est 1421, Institute of Cardiometabolism and Nutrition (ICAN), Pitié-Salpêtrière Hospital, F-75013, Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Komajda
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, AP-HP, CIC Paris-Est 1421, Institute of Cardiometabolism and Nutrition (ICAN), Pitié-Salpêtrière Hospital, F-75013, Paris, France.|ACTION Study Group, Unité de Recherche Clinique, Lariboisière, Paris, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Montalescot
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, AP-HP, CIC Paris-Est 1421, Institute of Cardiometabolism and Nutrition (ICAN), Pitié-Salpêtrière Hospital, F-75013, Paris, France.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Lompré
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinaï, New York, NY, USA.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
mesh_terms: D000368:Aged; D003331:Coronary Vessels; D004311:Double-Blind Method; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D054143:Heart Failure, Systolic / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D007261:Infusions, Intra-Arterial; D008297:Male; D008875:Middle Aged; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000008:administration & dosage*; D016896:Treatment Outcome; D020257:Ventricular Remodeling / Q000235:genetics / Q000502:physiology*
chemical_list: D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
keywords: Clinical trial; Gene therapy; Heart failure; Sarcoplasmic reticulum calcium ATPase