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

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

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

Study Overview

• Status: Terminated
• Conditions: Ischemic Cardiomyopathy; Non-ischemic Cardiomyopathy; Heart Failure Congestive
• Intervention / Treatment: Genetic: MYDICAR-single intracoronary infusion; Genetic: Placebo; single intracoronary infusion

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.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Paris, France, 75013
    • CHU Pitié-Salpêtrière

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: MYDICAR-single intracoronary infusion; Genetic / AAV1 Serca2a (MYDICAR)	Genetic: MYDICAR-single intracoronary infusion; AAV1/Serca2a; Other Names: 1x10e13 DRP; single intracoronary infusion
PLACEBO_COMPARATOR: Placebo; single intracoronary infusion; Placebo comparator	Genetic: Placebo; single intracoronary infusion; single intracoronary infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
Cardiac volumes and function	Cardiac volumes and function / changes from baseline to 6 months & 12 months	at 6 and 12 months
Cardiac hemodynamic parameters	Cardiac hemodynamic parameters; changes from baseline to 6 months	at 6 months
VO2 max	VO2 max; changes from baseline to 6 months and 12 months	at 6 and 12 months
Cardiac function assessed by echocardiography	Changes from baseline to 6 and12 months in:Echocardiographic assessments	at 6 and12 months
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
NT-ProBNP	Changes from baseline to 6 and12 months in:NT-ProBNP	at 6 and12 months
Time to cardiovascular event	Time to cardiovascular event (all-cause death, heart transplant, LVAD implantation) - administration to 12 months	at 6 and 12 months
Number of hospitalized patients for worsening heart failure		at 6 and 12 months
Cardiac volumes assessed by echocardiography	Changes from baseline to 6 and12 months in:Echocardiographic assessments	at 6 and12 months
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

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Celladon Corporation
• Investigators: Principal Investigator: Jean-Sébastien HULOT, MDPhD, Assistance Publique - Hôpitaux de Paris

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: December 1, 2013
• Primary Completion (ACTUAL): September 1, 2015
• Study Completion (ACTUAL): February 1, 2016

Study Registration Dates

• First Submitted: September 26, 2013
• First Submitted That Met QC Criteria: October 17, 2013
• First Posted (ESTIMATE): October 22, 2013

Study Record Updates

• Last Update Posted (ACTUAL): August 29, 2017
• Last Update Submitted That Met QC Criteria: August 28, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: Heart failure; Cardiomyopathy; Gene therapy; Serca2a
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Cardiomyopathies
• Other Study ID Numbers: P081252