The aim of the study is to determine the safety and feasibility of giving an adeno-associated viral vector expressing the sarcoplasmic reticulum calcium ATPase (SERCA2a), driven by the CMV promoter (AAV1-CMV-SERCA2a), to heart failure patients that have received a left ventricular assist device (LVAD) for an accepted clinical indication.
It is a randomised, double-blind study of 24 patients that will be randomised to receive either the study drug (AAV1.SERCA2a) or placebo. The purpose of gene transfer of SERCA2a is to improve systolic and diastolic function of the failing ventricle. Studies show that reduction of SERCA2a in failing ventricle is a key factor in depression of contraction, and that restoration of SERCA2a levels can improve function to near normal levels. The vector will be delivered during a cardiac catheterisation procedure by a 10-minute infusion into the coronary arteries. Myocardial tissue is obtained at the time of LVAD placement, as a routine part of device implantation. Further samples will be obtained when the heart is transplanted or the LVAD removed. Measures of tissue inflammation as well as efficacy of gene transfer will be made by comparing these two samples. Recovery of contractile function of the heart will be assessed during attempts to wean patients from the LVAD using standard protocols. The results will be assessed in conjunction with two companion studies which will start earlier in the US, one performing SERCA2a gene transfer with the same vector, but delivered by direct injection into the myocardium during LVAD insertion, and one using AAV1-CMV-SERCA2a delivered percutaneously in heart failure patients. The latter has both a dose-ranging and placebo-controlled arm.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
5
AAV1/SERCA2a will be delivered by a percutaneous method in the catheter laboratory. Dose: 1x 10\^13 DRP (DNase resistant particles)
Placebo aliquots will be of the same composition as the investigational medicinal product with the absence of the active ingredient and will be visually indistinguishable from the medicinal product. Placebo is prepared and handled exactly as above in a blinded fashion.
Papworth Hospital
Cambridge, United Kingdom
Harefield Hospital, Royal Brompton and Harefiled NHS Trust
Middlesex, United Kingdom
Overall Safety and Feasibility of Administering AAV1/SERCA2a to LVAD Patients
Safety is defined as the incidence of patients experiencing death and major adverse cardiovascular events, and out of range laboratory values. Both AAV1/SERCA2a treated cohorts (NAb+ and NAb-) will be compared to the placebo group.
Time frame: 6 months
Number of Participants With Exogenous Viral Vector Genome in the Myocardium Measured by qPCR for the Viral DNA
The trial was terminated early with only 5 subjects enrolled. As a result full statistical analysis for both primary and secondary outcomes was impossible and a more pragmatic approach was undertaken to assess product safety.
Time frame: 6 months
Left Ventricular Function (LVEF)
Left ventricular function assessed by echocardiography and exercise capacity (6MWT, MVO2) during minimal LVAD support (low/no flow settings depending upon device) LVEF expressed as %
Time frame: 6 months
Levels of SERCA2a Protein
Time frame: 6 months
Other Relevant Proteins e.g. Phospholamban, the Sarcoplasmic Reticulum Calcium Release Channel, the Na+/Ca2+-Exchanger.
Time frame: 6 months
Function of Isolated Myocytes
Time frame: 6 months
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