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

Study Overview
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Brief Summary
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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
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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.

Official Title
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Investigation of the Safety and Feasibility of AAV1/SERCA2a Gene Transfer in Patients With Chronic Heart Failure and a Left Ventricular Assist Device

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

Intervention / Treatment
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* Genetic: AAV1/SERCA2a
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Patients that have had a left ventricular assist device (LVAD) implanted for chronic heart failure, where chronic heart failure is defined as at least 6 months Patients are clinically stable in the opinion of the clinical team looking after the patient Written informed consent Exclusion criteria <18 or >70 years of age at the time of consent Pregnancy or within 6 months of giving birth Women of child-bearing potential not using an effective method of contraception Men not using an effective method of contraception Suspected or active viral, fungal or parasitic infection within 48 hours prior to administration of IMP, in the opinion of the investigator*. Patients at a high risk of thrombosis in the opinion of the investigator Patients with a previous episode of LVAD thrombosis Patients with persistently raised lactate dehydrogenase (LDH >2.5 ULN) Patients requiring triple anticoagulation i.e. warfarin and dual anti-platelet Patients participating in another clinical trial Patients unable to comply with the protocol mandated procedures for social or other reasons, in the opinion of the investigator and primary care physician Eligible, enrolled and randomised patients who develop an infection will have study treatment delayed until 7 or more days after the time point when infection is no longer clinically evident.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: AAV1/SERCA2A<br>SERCA gene therapy | Genetic: AAV1/SERCA2a<br>* AAV1/SERCA2a will be delivered by a percutaneous method in the catheter laboratory. Dose: 1x 10^13 DRP (DNase resistant particles)<br>* Other names: MYDICAR (R);|
| Placebo Comparator: Placebo<br>Placebo (saline solution) | Drug: Placebo<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 % | 6 months | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Heart Failure