Investigation of the Safety and Feasibility of AAV1/SERCA2a Gene Transfer in Patients With Chronic Heart Failure (SERCA-LVAD)

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

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.

Study Overview

• Status: Terminated
• Conditions: Chronic Heart Failure; Patients That Have Received a Left Ventricular Assist Device
• Intervention / Treatment: Genetic: AAV1/SERCA2a; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Cambridge, United Kingdom, CB23 3RE
    • Papworth Hospital
  • Middlesex, United Kingdom, UB9 6JH
    • Harefield Hospital, Royal Brompton and Harefiled NHS Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: AAV1/SERCA2A; SERCA gene therapy	Genetic: AAV1/SERCA2a; AAV1/SERCA2a will be delivered by a percutaneous method in the catheter laboratory. Dose: 1x 10^13 DRP (DNase resistant particles); Other Names: MYDICAR (R)
PLACEBO_COMPARATOR: Placebo; Placebo (saline solution)	Drug: Placebo; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Imperial College London
• Collaborators: British Heart Foundation; Leducq Foundation; Celladon Corporation

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 1, 2014
• Primary Completion (ACTUAL): September 1, 2015
• Study Completion (ACTUAL): September 1, 2015

Study Registration Dates

• First Submitted: September 24, 2007
• First Submitted That Met QC Criteria: September 24, 2007
• First Posted (ESTIMATE): September 26, 2007

Study Record Updates

• Last Update Posted (ACTUAL): February 8, 2023
• Last Update Submitted That Met QC Criteria: January 6, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Chronic Heart Failure
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure
• Other Study ID Numbers: CRO782; 2007-002809-48 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No