Investigation of the Safety and Feasibility of AAV1/SERCA2a Gene Transfer in Patients With Chronic Heart Failure

Phase 2

Terminated

Conditions: Chronic Heart Failure
Patients That Have Received a Left Ventricular Assist Device

Brief Summary: 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.

Detailed Description: 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.

Recruitment & Eligibility

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Arm && Interventions

Group	Intervention	Description
AAV1/SERCA2A	AAV1/SERCA2a	SERCA gene therapy
Placebo	Placebo	Placebo (saline solution)

Primary Outcome Measures

Name	Time	Method
Overall Safety and Feasibility of Administering AAV1/SERCA2a to LVAD Patients	6 months	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.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Exogenous Viral Vector Genome in the Myocardium Measured by qPCR for the Viral DNA	6 months	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.
Levels of SERCA2a Protein	6 months
Other Relevant Proteins e.g. Phospholamban, the Sarcoplasmic Reticulum Calcium Release Channel, the Na+/Ca2+-Exchanger.	6 months
Function of Isolated Myocytes	6 months
Left Ventricular Function (LVEF)	6 months	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 %

Locations (2): Harefield Hospital, Royal Brompton and Harefiled NHS Trust
🇬🇧
Middlesex, United Kingdom
Papworth Hospital
🇬🇧
Cambridge, United Kingdom