Heart Failure Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) A Phase 2 Trial of Intracoronary Gene Therapy of Sarcoplasmic Reticulum Ca -ATPase in Patients With Advanced Heart Failure

Background—Adeno-associated virus type 1/sarcoplasmic reticulum Ca 2ϩ-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 2ϩ-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 ratioϭ0.12; Pϭ0.003), and mean duration of cardiovascular hospitalizations over 12 months was substantially decreased (0.4 versus 4.5 days; Pϭ0.05) 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 2ϩ-ATPase in advanced heart failure, supporting larger confirmatory trials. Key Words: cardiomyopathy Ⅲ cardiovascular diseases Ⅲ gene therapy Ⅲ heart failure Ⅲ SERCA2a C hronic heart failure accounts for excessive morbidity and mortality, hospitalizations, and medical care costs throughout the world. 1,2 Deficient sarcoplasmic reticulum calcium uptake has been identified in cardiomyocytes from failing human hearts and has been associated with a decrease in the expression and activity of the enzyme responsible for reloading the sarcoplasmic reticulum with calcium during relaxation , the sarcoplasmic reticulum Ca …