Clinical trial NCT00534703: Investigation of the Safety and Feasibility of AAV1/SERCA2a Gene Transfer in Patients With Chronic Heart Failure
Official title: Investigation of the Safety and Feasibility of AAV1/SERCA2a Gene Transfer in Patients With Chronic Heart Failure and a Left Ventricular Assist Device
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Chronic Heart Failure
Patients That Have Received a Left Ventricular Assist Device
Keywords: Chronic Heart Failure
Lead sponsor: Imperial College London
Sponsor class: OTHER
Collaborators: name: British Heart Foundation
name: Leducq Foundation
name: Celladon Corporation
First posted: 2007-09-26
Enrollment: 5
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Overall Safety and Feasibility of Administering AAV1/SERCA2a to LVAD Patients
timeFrame: 6 months
Secondary outcomes:
measure: Number of Participants With Exogenous Viral Vector Genome in the Myocardium Measured by qPCR for the Viral DNA
timeFrame: 6 months
measure: Left Ventricular Function (LVEF)
timeFrame: 6 months
measure: Levels of SERCA2a Protein
timeFrame: 6 months
measure: Other Relevant Proteins e.g. Phospholamban, the Sarcoplasmic Reticulum Calcium Release Channel, the Na+/Ca2+-Exchanger.
timeFrame: 6 months
measure: Function of Isolated Myocytes
timeFrame: 6 months
Other outcomes:
Locations:
city: Cambridge
country: United Kingdom
facility: Papworth Hospital
city: Middlesex
country: United Kingdom
facility: Harefield Hospital, Royal Brompton and Harefiled NHS Trust
Study officials:
affiliation: Imperial College London
name: Sian Harding
role: PRINCIPAL_INVESTIGATOR
affiliation: Imperial College London
name: Alexander Lyon
role: PRINCIPAL_INVESTIGATOR
References: