title: Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID): a phase 2 trial of intracoronary gene therapy of sarcoplasmic reticulum Ca2+-ATPase in patients with advanced heart failure.
abstract: BACKGROUND
  Adeno-associated virus type 1/sarcoplasmic reticulum Ca(2+)-ATPase was assessed in a randomized, double-blind, placebo-controlled, phase 2 study in patients with advanced heart failure.
  
  
  RESULTS
  Thirty-nine patients received intracoronary adeno-associated virus type 1/sarcoplasmic reticulum Ca(2+)-ATPase or placebo. Seven efficacy parameters were assessed in 4 domains: symptoms (New York Heart Association class, Minnesota Living With Heart Failure Questionnaire), functional status (6-minute walk test, peak maximum oxygen consumption), biomarker (N-terminal prohormone brain natriuretic peptide), and left ventricular function/remodeling (left ventricular ejection fraction, left ventricular end-systolic volume), plus clinical outcomes. The primary end point success criteria were prospectively defined as achieving efficacy at 6 months in the group-level (concordant improvement in 7 efficacy parameters and no clinically significant worsening in any parameter), individual-level (total score for predefined clinically meaningful changes in 7 efficacy parameters), or outcome end points (cardiovascular hospitalizations and time to terminal events). Efficacy in 1 analysis had to be associated with at least a positive trend in the other 2 analyses. This combination of requirements resulted in a probability of success by chance alone of 2.7%. The high-dose group versus placebo met the prespecified criteria for success at the group-level, individual-level, and outcome analyses (cardiovascular hospitalizations) at 6 months (confirmed at 12 months) and demonstrated improvement or stabilization in New York Heart Association class, Minnesota Living With Heart Failure Questionnaire, 6-minute walk test, peak maximum oxygen consumption, N-terminal prohormone brain natriuretic peptide levels, and left ventricular end-systolic volume. Significant increases in time to clinical events and decreased frequency of cardiovascular events were observed at 12 months (hazard ratio=0.12; P=0.003), and mean duration of cardiovascular hospitalizations over 12 months was substantially decreased (0.4 versus 4.5 days; P=0.05) on high-dose treatment versus placebo. There were no untoward safety findings.
  
  
  CONCLUSIONS
  The Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) study demonstrated safety and suggested benefit of adeno-associated virus type 1/sarcoplasmic reticulum Ca(2+)-ATPase in advanced heart failure, supporting larger confirmatory trials.
  
  
  BACKGROUND
  http://www.clinicaltrials.gov. Unique identifier: NCT00454818.
authors.affiliation: Heart Failure/Transplant Program, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA. jessupm@uphs.upenn.edu
authors.forename: Mariell
authors.initials: M
authors.lastname: Jessup
authors.forename: Barry
authors.initials: B
authors.lastname: Greenberg
authors.forename: Donna
authors.initials: D
authors.lastname: Mancini
authors.forename: Thomas
authors.initials: T
authors.lastname: Cappola
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Pauly
authors.forename: Brian
authors.initials: B
authors.lastname: Jaski
authors.forename: Alex
authors.initials: A
authors.lastname: Yaroshinsky
authors.forename: Krisztina M
authors.initials: KM
authors.lastname: Zsebo
authors.forename: Howard
authors.initials: H
authors.lastname: Dittrich
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000328:Adult; D000368:Aged; D002118:Calcium / Q000378:metabolism*; D018450:Disease Progression; D004311:Double-Blind Method; D005080:Exercise Test; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D006331:Heart Diseases / Q000503:physiopathology / Q000628:therapy*; D006333:Heart Failure / Q000628:therapy*; D006801:Humans; D007269:Injections, Intra-Arterial; D008297:Male; D008875:Middle Aged; D010101:Oxygen Consumption / Q000502:physiology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics*; D012720:Severity of Illness Index; D016896:Treatment Outcome; D015854:Up-Regulation / Q000502:physiology*
chemical_list: D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium