AAV1-CMV-Serca2a GENe Therapy Trial in Heart Failure (AGENT-HF)

Assistance Publique - Hôpitaux de Paris

Status and phase

Terminated

Phase 2

Conditions

Heart Failure Congestive

Non-ischemic Cardiomyopathy

Ischemic Cardiomyopathy

Treatments

Genetic: MYDICAR-single intracoronary infusion

Genetic: Placebo; single intracoronary infusion

Study type

Interventional

Funder types

Other

Industry

Identifiers

NCT01966887

P081252

Details and patient eligibility

About

The purpose of this study is to determine the effect of intracoronary SERCA2a Gene transfer on cardiac volumes and function using multimodality cardiac imaging.

Full description

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 left ventricular function and remodeling. The aim of the study is to investigate the effect of an adeno-associated viral vector expressing the sarcoplasmic reticulum calcium ATPase (SERCA2a), driven by the CMV promoter (AAV1-CMV-SERCA2a), on the ventricular remodeling of patients with severe heart failure using multimodality cardiac imaging. This is a Phase 2 monocenter double blind randomized placebo-controled, parallel study. The study will enroll 44 symptomatic heart failure patients with NYHA IIIb/IV, with left-ventricular ejection fraction of 35% or less receiving an optimal standard medical therapy. The absence of neutralizing antibodies against AAV1 will be primarily checked. Seronegative patients will be randomized to receive either 1x10e13 AAV1-CMV-Serca2a or a placebo as a single intracoronary infusion. Evolution during the next 6 months of the left ventricular end-systolic volume (measured with a 256-slices CT-scan before injection and 6 months later) will be the primary endpoint. Secondary endpoints will include changes in the LVEF, diastolic volumes, VO2max, Echocardiographic remodeling, BNP, cardiac hemodynamics and biological safety profile.

Enrollment

10 patients

Sex

All

Ages

18 to 80 years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Patients with NYHA class III / IV severe heart failure ≥ 3 months
Ischemic or non-ischemic origin
Left ventricular ejection fraction ≤35%
Patients must be receiving optimal (maximum tolerated doses) medical treatment (diuretics, renin-angiotensin-aldosterone system blockers, beta blockers, ±Ivabradine) for at least 1 month (with the exception of diuretic dose titration) and must be stable.
No decompensated congestive heart failure within the past month
With or without an ICD if the ICD was implanted over 3 months ago, with or without biventricular pacing if the RCT was implanted over 6 months ago
All women of childbearing potential must have a negative urine pregnancy test prior to administration of investigational medicinal product
Patient must have given written informed consent to participate in this study

Exclusion criteria

<18 or >80 years old
AAV1 seropositivity (titer <1:2) in the last 3 months
Atrial fibrillation in the absence of permanent ventricular pacing
Coronary revascularization or heart surgery or pacemaker implantation < 3 months
Ischemic heart disease without at least one coronary artery with a TIMI-3 flow
Restrictive cardiomyopathy, hypertrophic obstructive cardiomyopathy, pericardial disease, cardiac amyloidosis
Heart transplant, an already implanted or needing to urgently implant external ventricular assist device
Myocardial infarction (STEMI or NSTEMI) < 3 months
Treatment with intravenous positive inotropic agents or diuretics in the past 28 days
Pregnant or nursing patient
Female patient of childbearing age with no effective means of contraception
Severe renal failure defined by a creatinine clearance of < 30 mL/min (last bloodwork done less than 6 months)
Liver failure, chronic liver disease or laboratory tests > 3 x N (AST, ALT, ALP))(last bloodwork done less than 6 months)
Thrombocytopenia (<50,000/mm3
Patient treated with immunosuppressants, has an immunodeficiency or whose neutrophil count < 1000 mm3
Recent sepsis (< 3 months)
Active neoplasia or treated < 5 years
No medical insurance
Patient is enrolled in another randomized study
Patient does not understand the protocol procedures sponsor suspects poor compliance with the protocol