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

Primary Purpose

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

Status
Terminated
Phase
Phase 2
Locations
United Kingdom
Study Type
Interventional
Intervention
AAV1/SERCA2a
Placebo
Sponsored by
Imperial College London
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Heart Failure focused on measuring Chronic Heart Failure

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Papworth Hospital
  • Harefield Hospital, Royal Brompton and Harefiled NHS Trust

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

AAV1/SERCA2A

Placebo

Arm Description

SERCA gene therapy

Placebo (saline solution)

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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 %
Levels of SERCA2a Protein
Other Relevant Proteins e.g. Phospholamban, the Sarcoplasmic Reticulum Calcium Release Channel, the Na+/Ca2+-Exchanger.
Function of Isolated Myocytes

Full Information

First Posted
September 24, 2007
Last Updated
January 6, 2023
Sponsor
Imperial College London
Collaborators
British Heart Foundation, Leducq Foundation, Celladon Corporation
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1. Study Identification

Unique Protocol Identification Number
NCT00534703
Brief Title
Investigation of the Safety and Feasibility of AAV1/SERCA2a Gene Transfer in Patients With Chronic Heart Failure
Acronym
SERCA-LVAD
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

2. Study Status

Record Verification Date
January 2023
Overall Recruitment Status
Terminated
Why Stopped
Early termination following Trial Steering Committee recommendation
Study Start Date
July 2014 (Actual)
Primary Completion Date
September 2015 (Actual)
Study Completion Date
September 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Imperial College London
Collaborators
British Heart Foundation, Leducq Foundation, Celladon Corporation

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Heart Failure, Patients That Have Received a Left Ventricular Assist Device
Keywords
Chronic Heart Failure

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
5 (Actual)

8. Arms, Groups, and Interventions

Arm Title
AAV1/SERCA2A
Arm Type
Active Comparator
Arm Description
SERCA gene therapy
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo (saline solution)
Intervention Type
Genetic
Intervention Name(s)
AAV1/SERCA2a
Other Intervention Name(s)
MYDICAR (R)
Intervention Description
AAV1/SERCA2a will be delivered by a percutaneous method in the catheter laboratory. Dose: 1x 10^13 DRP (DNase resistant particles)
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
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.
Primary Outcome Measure Information:
Title
Overall Safety and Feasibility of Administering AAV1/SERCA2a to LVAD Patients
Description
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
Secondary Outcome Measure Information:
Title
Number of Participants With Exogenous Viral Vector Genome in the Myocardium Measured by qPCR for the Viral DNA
Description
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
Title
Left Ventricular Function (LVEF)
Description
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
Title
Levels of SERCA2a Protein
Time Frame
6 months
Title
Other Relevant Proteins e.g. Phospholamban, the Sarcoplasmic Reticulum Calcium Release Channel, the Na+/Ca2+-Exchanger.
Time Frame
6 months
Title
Function of Isolated Myocytes
Time Frame
6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sian Harding
Organizational Affiliation
Imperial College London
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Alexander Lyon
Organizational Affiliation
Imperial College London
Official's Role
Principal Investigator
Facility Information:
Facility Name
Papworth Hospital
City
Cambridge
ZIP/Postal Code
CB23 3RE
Country
United Kingdom
Facility Name
Harefield Hospital, Royal Brompton and Harefiled NHS Trust
City
Middlesex
ZIP/Postal Code
UB9 6JH
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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

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