AAV1-CMV-Serca2a GENe Therapy Trial in Heart Failure

Ischemic Cardiomyopathy Clinical Trial

— AGENT-HF  

Official title:

Phase 2 Study of SERCA2a Gene Transfer in Patients With Severe Heart Failure

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01966887
• Other study ID #: P081252
• Status: Terminated
• Phase: Phase 2
• First received: September 26, 2013
• Last updated: August 28, 2017
• Start date: December 2013
• Est. completion date: February 2016

Study information

• Verified date: August 2017
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 10
• Est. completion date: February 2016
• Est. primary completion date: September 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Cardiomyopathies
• Heart Failure
• Heart Failure Congestive
• Ischemic Cardiomyopathy
• Non-ischemic Cardiomyopathy

Intervention

Genetic:
• MYDICAR-single intracoronary infusion
AAV1/Serca2a
• Placebo; single intracoronary infusion
single intracoronary infusion

Locations

Country	Name	City	State
France	CHU Pitié-Salpêtrière	Paris

Sponsors (2)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris	Celladon Corporation

Country where clinical trial is conducted

France, 

References & Publications (1)

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, Lompré AM, Hajjar RJ; AG — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	left ventricular end-systolic volume measured by CT-Scan	left ventricular end-systolic volume measured by CT-Scan / changes from baseline to 6 months	at 6 months
Secondary	CT-scan other measurments: left ventricular end-diastolic volume	CT-scan other measurments: left ventricular end-diastolic volume / changes from baseline to 6 and 12 months	at 6 and 12 months
Secondary	Cardiac volumes and function	Cardiac volumes and function / changes from baseline to 6 months & 12 months	at 6 and 12 months
Secondary	Cardiac hemodynamic parameters	Cardiac hemodynamic parameters; changes from baseline to 6 months	at 6 months
Secondary	VO2 max	VO2 max; changes from baseline to 6 months and 12 months	at 6 and 12 months
Secondary	Cardiac function assessed by echocardiography	Changes from baseline to 6 and12 months in:Echocardiographic assessments	at 6 and12 months
Secondary	Quality of Life (Kansas city score)	Changes from baseline to 3,6,9,12 months in:Quality of Life	at 3,6,9,12 months
Secondary	NT-ProBNP	Changes from baseline to 6 and12 months in:NT-ProBNP	at 6 and12 months
Secondary	Time to cardiovascular event	Time to cardiovascular event (all-cause death, heart transplant, LVAD implantation) - administration to 12 months	at 6 and 12 months
Secondary	Number of hospitalized patients for worsening heart failure		at 6 and 12 months
Secondary	Cardiac volumes assessed by echocardiography	Changes from baseline to 6 and12 months in:Echocardiographic assessments	at 6 and12 months
Secondary	CT-scan other measurments: left ventricular end-systolic volume	CT-scan other measurments: left ventricular end-systolic volume / changes from baseline to 12 months	12 months