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.

METHODS AND 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.

CLINICAL TRIAL REGISTRATION:

http://www.clinicaltrials.gov. Unique identifier: NCT00454818.

• Authors: Mariell Jessup, Barry Greenberg, Donna Mancini, Thomas Cappola, Daniel F Pauly, Brian Jaski, Alex Yaroshinsky, Krisztina M Zsebo, Howard Dittrich, Roger J Hajjar, Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) Investigators
• Journal: Circulation (Circulation) Vol. 124 Issue 3 Pg. 304-13 (Jul 19 2011) ISSN: 1524-4539 [Electronic] United States
• PMID: 21709064 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Sarcoplasmic Reticulum Calcium-Transporting ATPases
• Calcium

Topics

• Adenoviridae (genetics)
• Adult
• Aged
• Calcium (metabolism)
• Disease Progression
• Double-Blind Method
• Exercise Test
• Female
• Genetic Therapy (adverse effects, methods)
• Heart Diseases (physiopathology, therapy)
• Heart Failure (therapy)
• Humans
• Injections, Intra-Arterial
• Male
• Middle Aged
• Oxygen Consumption (physiology)
• Sarcoplasmic Reticulum Calcium-Transporting ATPases (genetics)
• Severity of Illness Index
• Treatment Outcome
• Up-Regulation (physiology)