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

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified March 2014 by Imperial College London
Sponsor:
Collaborators:
British Heart Foundation
Leducq Foundation
Celladon Corporation
Information provided by (Responsible Party):
Imperial College London
ClinicalTrials.gov Identifier:
NCT00534703
First received: September 24, 2007
Last updated: March 13, 2014
Last verified: March 2014
  Purpose

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. 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.


Condition Intervention Phase
Chronic Heart Failure
Patients That Have Received a Left Ventricular Assist Device
Genetic: AAV1/SERCA2a
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Investigation of the Safety and Feasibility of SERCA Gene Transfer in the Human Failing Heart Using an Adeno-associated Viral Vector

Resource links provided by NLM:


Further study details as provided by Imperial College London:

Primary Outcome Measures:
  • Overall safety and feasibility of administering AAV1/SERCA2a to LVAD patients. Overall safety and feasibility of administering AAV1/SERCA2a to LVAD patients [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
    Safety is defined as incidence of 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:
  • Presence of exogenous viral vector genome in the myocardium measured by qPCR for the viral DNA [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Left ventricular function assessed by echocardiography and exercise capacity (6MWT, MVO2)during minimal LVAD support (low/no flow settings depending upon device) [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Levels of SERCA2a protein [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Other relevant proteins e.g. phospholamban, the sarcoplasmic reticulum calcium release channel, the Na+/Ca2+-exchanger. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Function of isolated myocytes [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Estimated Enrollment: 24
Study Start Date: May 2014
Estimated Study Completion Date: May 2016
Estimated Primary Completion Date: January 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: AAV1/SERCA2A 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 Name: MYDICAR (R)
Placebo Comparator: Placebo 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.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00534703

Contacts
Contact: Sian Harding 020 7594 3009 sian.harding@imperial.ac.uk
Contact: Alexander Lyon 020 7594 3409 a.lyon@imperial.ac.uk

Locations
United Kingdom
Papworth Hospital Not yet recruiting
Cambridge, United Kingdom, CB23 3RE
Principal Investigator: Steven Tsui         
Harefield Hospital, Royal Brompton and Harefiled NHS Trust Not yet recruiting
Middlesex, United Kingdom, UB9 6JH
Principal Investigator: Nick Banner         
Sponsors and Collaborators
Imperial College London
British Heart Foundation
Leducq Foundation
Celladon Corporation
Investigators
Principal Investigator: Sian Harding Imperial College London
Principal Investigator: Alexandar Lyon Imperial College London
  More Information

No publications provided

Responsible Party: Imperial College London
ClinicalTrials.gov Identifier: NCT00534703     History of Changes
Other Study ID Numbers: CRO782, 2007-002809-48
Study First Received: September 24, 2007
Last Updated: March 13, 2014
Health Authority: United Kingdom: Research Ethics Committee
United Kingdom: Medicines and Healthcare Products Regulatory Agency

Additional relevant MeSH terms:
Heart Failure
Heart Diseases
Cardiovascular Diseases

ClinicalTrials.gov processed this record on July 28, 2014