Clinical trial NCT01966887: AAV1-CMV-Serca2a GENe Therapy Trial in Heart Failure
Official title: Phase 2 Study of SERCA2a Gene Transfer in Patients With Severe Heart Failure
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Heart Failure Congestive
Ischemic Cardiomyopathy
Non-ischemic Cardiomyopathy
Keywords: Heart failure
Gene therapy
Serca2a
Cardiomyopathy
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Celladon Corporation
First posted: 2013-10-22
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: left ventricular end-systolic volume measured by CT-Scan
timeFrame: at 6 months
Secondary outcomes:
measure: CT-scan other measurments: left ventricular end-diastolic volume
timeFrame: at 6 and 12 months
measure: Cardiac volumes and function
timeFrame: at 6 and 12 months
measure: Cardiac hemodynamic parameters
timeFrame: at 6 months
measure: VO2 max
timeFrame: at 6 and 12 months
measure: Cardiac function assessed by echocardiography
timeFrame: at 6 and12 months
measure: Quality of Life (Kansas city score)
timeFrame: at 3,6,9,12 months
measure: NT-ProBNP
timeFrame: at 6 and12 months
measure: Time to cardiovascular event
timeFrame: at 6 and 12 months
measure: Number of hospitalized patients for worsening heart failure
timeFrame: at 6 and 12 months
measure: Cardiac volumes assessed by echocardiography
timeFrame: at 6 and12 months
measure: CT-scan other measurments: left ventricular end-systolic volume
timeFrame: 12 months
Other outcomes:
Locations:
city: Paris
country: France
facility: CHU Pitié-Salpêtrière
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Jean-Sébastien HULOT, MDPhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hulot JS, Salem JE, Redheuil A, Collet JP, Varnous S, Jourdain P, Logeart D, Gandjbakhch E, Bernard C, Hatem SN, Isnard R, Cluzel P, Le Feuvre C, Leprince P, Hammoudi N, Lemoine FM, Klatzmann D, Vicaut E, Komajda M, Montalescot G, Lompre AM, Hajjar RJ; AGENT-HF Investigators. Effect of intracoronary administration of AAV1/SERCA2a on ventricular remodelling in patients with advanced systolic heart failure: results from the AGENT-HF randomized phase 2 trial. Eur J Heart Fail. 2017 Nov;19(11):1534-1541. doi: 10.1002/ejhf.826. Epub 2017 Apr 10.