title: Design of a phase 2b trial of intracoronary administration of AAV1/SERCA2a in patients with advanced heart failure: the CUPID 2 trial (calcium up-regulation by percutaneous administration of gene therapy in cardiac disease phase 2b).
abstract: OBJECTIVE
  Impaired cardiac isoform of sarco(endo)plasmic reticulum Ca(2+) ATPase (SERCA2a) activity is a key abnormality in heart failure patients with reduced ejection fraction. The CUPID 2 (Calcium Up-Regulation by Percutaneous Administration of Gene Therapy in Cardiac Disease Phase 2b) trial is designed to evaluate whether increasing SERCA2a activity via gene therapy improves clinical outcome in these patients.
  
  
  BACKGROUND
  Intracoronary delivery of recombinant adeno-associated virus serotype 1 (AAV1)/SERCA2a improves intracellular Ca(2+) handling by increasing SERCA2a protein levels and, as a consequence, restores systolic and diastolic function. In a previous phase 2a trial, this therapy improved symptoms, functional status, biomarkers, and left ventricular function, and reduced cardiovascular events in advanced heart failure patients.
  
  
  METHODS
  CUPID 2 is a phase 2b, double-blind, placebo-controlled, multinational, multicenter, randomized event-driven study in up to 250 patients with moderate-to-severe heart failure with reduced ejection fraction and New York Heart Association functional class II to IV symptoms despite optimal therapy. Enrolled patients will be at high risk for recurrent heart-failure hospitalizations by virtue of having elevated N-terminal pro-B-type natriuretic peptide/BNP (>1,200 pg/ml, or >1,600 pg/ml if atrial fibrillation is present) and/or recent heart failure hospitalization. The primary endpoint of time-to-recurrent event (heart failure-related hospitalizations in the presence of terminal events [all-cause death, heart transplant, left ventricular assist device implantation or ambulatory worsening heart failure]) will be assessed using the joint frailty model. This ongoing trial is expected to complete recruitment in 2014, with the required number of 186 recurrent events estimated to occur by mid 2015.
  
  
  RESULTS
  Available data indicate that calcium up-regulation by AAV1/SERCA2a gene therapy is safe and of potential benefit in advanced heart failure patients.
  
  
  CONCLUSIONS
  The CUPID 2 trial is designed to study the effects of this therapy on clinical outcome in these patients. (Calcium Up-Regulation by Percutaneous Administration of Gene Therapy in Cardiac Disease Phase 2b [CUPID-2b]; NCT01643330).
authors.affiliation: Division of Cardiovascular Medicine, University of California at San Diego, San Diego, California. Electronic address: bgeenberg@ucsd.edu.
authors.forename: Barry
authors.initials: B
authors.lastname: Greenberg
authors.affiliation: AY Statistical Consulting, San Andreas, California.
authors.forename: Alex
authors.initials: A
authors.lastname: Yaroshinsky
authors.affiliation: Celladon Corporation, San Diego, California.
authors.forename: Krisztina M
authors.initials: KM
authors.lastname: Zsebo
authors.affiliation: Emory Clinical Cardiovascular Research Institute, Atlanta, Georgia.
authors.forename: Javed
authors.initials: J
authors.lastname: Butler
authors.affiliation: Division of Cardiology, Duke University School of Medicine, Durham, North Carolina.
authors.forename: G Michael
authors.initials: GM
authors.lastname: Felker
authors.affiliation: Department of Cardiology, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Adriaan A
authors.initials: AA
authors.lastname: Voors
authors.affiliation: Celladon Corporation, San Diego, California.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Rudy
authors.affiliation: Celladon Corporation, San Diego, California.
authors.forename: Kim
authors.initials: K
authors.lastname: Wagner
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai School of Medicine, New York, New York.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
mesh_terms: D000256:Adenoviridae; D000279:Administration, Cutaneous; D002118:Calcium / Q000378:metabolism; D004311:Double-Blind Method; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006333:Heart Failure / Q000628:therapy*; D006801:Humans; D036502:Infusions, Intralesional; D011994:Recombinant Proteins / Q000008:administration & dosage; D012008:Recurrence; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome; D015854:Up-Regulation
chemical_list: D011994:Recombinant Proteins; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506946:ATP2A2 protein, human; D002118:Calcium
keywords: SERCA2a; clinical trial; heart failure; joint frailty model; recurrent events