Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease Phase 2b - CUPID 2


Sarcoplasmic/endoplasmic reticulum (SERCA2a) activity is deficient in heart failure. The goal of the trial was to evaluate gene transfer therapy among patients with heart failure.

Contribution to the Literature: The CUPID 2 trial showed that gene transfer therapy failed to improve clinical outcomes.

Study Design

  • Randomized
  • Parallel
  • Placebo
  • Stratified

Patients with heart failure were randomized to gene transfer therapy (n = 123) versus placebo injection (n = 127). Gene therapy was performed by adeno-associated virus 1/SERCA2a.

  • Total number of enrollees: 250
  • Duration of follow-up: mean 17.5 months
  • Mean patient age: 58 years
  • Percentage female: 20%
  • Percentage diabetics: 40%
  • Ischemic etiology: 52%

Inclusion criteria:

  • Patients with heart failure symptoms (New York Heart Association class II-IV)
  • Left ventricular ejection fraction ≤35% (ischemic and nonischemic etiology)

Exclusion criteria:

  • Cardiac surgery, percutaneous coronary intervention, valvuloplasty, or intravenous treatment for heart failure within 30 days

Principal Findings:

The primary outcome, recurrent events (defined as hospital readmission for heart failure or ambulatory treatment for worsening heart failure), occurred in 62.8% of the gene transfer group versus 73.9% of the placebo group (p = 0.81). Findings were similar among all tested subgroups.

 The secondary outcome, death, was 21% versus 16% (p = not significant), respectively, for gene transfer versus placebo.


Among heart failure patients, gene transfer therapy was not beneficial. Although there were no notable safety concerns, gene transfer therapy failed to improve clinical events. The future for this therapy remains unknown.


Greenberg B, Butler J, Felker GM, et al. Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2): a randomized, multinational, double-blind, placebo-controlled, phase 2b trial. Lancet 2016;387:1178-86.

Clinical Topics: Heart Failure and Cardiomyopathies, Prevention, Acute Heart Failure

Keywords: Administration, Cutaneous, Genetic Therapy, Heart Failure, Ischemia, Patient Readmission, Sarcoplasmic Reticulum, Secondary Prevention, Up-Regulation, Ventricular Function, Left

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