Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2): a randomised, multinational, double-blind, placebo-controlled, phase 2b trial
File(s)
Accepted version
Author(s)
Type
Journal Article
Abstract
BACKGROUND: Sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase (SERCA2a) activity is deficient in the failing heart. Correction of this abnormality by gene transfer might improve cardiac function. We aimed to investigate the clinical benefits and safety of gene therapy through infusion of adeno-associated virus 1 (AAV1)/SERCA2a in patients with heart failure and reduced ejection fraction. METHODS: We did this randomised, multinational, double-blind, placebo-controlled, phase 2b trial at 67 clinical centres and hospitals in the USA, Europe, and Israel. High-risk ambulatory patients with New York Heart Association class II-IV symptoms of heart failure and a left ventricular ejection fraction of 0·35 or less due to an ischaemic or non-ischaemic cause were randomly assigned (1:1), via an interactive voice and web-response system, to receive a single intracoronary infusion of 1 × 10(13) DNase-resistant particles of AAV1/SERCA2a or placebo. Randomisation was stratified by country and by 6 min walk test distance. All patients, physicians, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was time to recurrent events, defined as hospital admission because of heart failure or ambulatory treatment for worsening heart failure. Primary efficacy endpoint analyses and safety analyses were done by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01643330. FINDINGS: Between July 9, 2012, and Feb 5, 2014, we randomly assigned 250 patients to receive either AAV1/SERCA2a (n=123) or placebo (n=127); 243 (97%) patients comprised the modified intention-to-treat population. Patients were followed up for at least 12 months; median follow-up was 17·5 months (range 1·8-29·4 months). AAV1/SERCA2a did not improve time to recurrent events compared with placebo (104 vs 128 events; hazard ratio 0·93, 95% CI 0·53-1·65; p=0·81). No safety signals were noted. 20 (16%) patients died in the placebo group and 25 (21%) patients died in the AAV1/SERCA2a group; 18 and 22 deaths, respectively, were adjudicated as being due to cardiovascular causes. INTERPRETATION: CUPID 2 is the largest gene transfer study done in patients with heart failure so far. Despite promising results from previous studies, AAV1/SERCA2a at the dose tested did not improve the clinical course of patients with heart failure and reduced ejection fraction. Although we did not find evidence of improved outcomes at the dose of AAV1/SERCA2a studied, our findings should stimulate further research into the use of gene therapy to treat patients with heart failure and help inform the design of future gene therapy trials. FUNDING: Celladon Corporation.
Date Issued
2016-03-19
Date Acceptance
2016-01-20
Citation
Lancet, 2016, 387 (10024), pp.1178-1186
ISSN
1474-547X
Publisher
Elsevier
Start Page
1178
End Page
1186
Journal / Book Title
Lancet
Volume
387
Issue
10024
Copyright Statement
© 2016, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/
Sponsor
British Heart Foundation
Identifier
PII: S0140-6736(16)00082-9
Grant Number
FS/11/67/28954
Subjects
Science & Technology
Life Sciences & Biomedicine
Medicine, General & Internal
General & Internal Medicine
SARCOPLASMIC-RETICULUM CA2+-ATPASE
HEART-FAILURE
MYOCARDIAL-FUNCTION
DELIVERY
MODEL
EXPRESSION
Aged
Calcium
Dependovirus
Double-Blind Method
Female
Genetic Therapy
Genetic Vectors
Heart Failure
Humans
Kaplan-Meier Estimate
Male
Middle Aged
Recurrence
Sarcoplasmic Reticulum Calcium-Transporting ATPases
Treatment Outcome
Up-Regulation
Humans
Dependovirus
Recurrence
Calcium
Treatment Outcome
Double-Blind Method
Up-Regulation
Genetic Vectors
Aged
Middle Aged
Female
Male
Sarcoplasmic Reticulum Calcium-Transporting ATPases
Heart Failure
Kaplan-Meier Estimate
Genetic Therapy
General & Internal Medicine
11 Medical and Health Sciences
Publication Status
Published
Date Publish Online
2016-01-21