The Enhanced Angiogenic Cell Therapy - Acute Myocardial Infarction Trial (ENACT-AMI)

A Phase IIb, Randomized, Double-blind, Placebo Controlled Study Using Transplantation of Autologous Early Endothelial Progenitor Cells(EPCs) for Patients Who Have Suffered Acute Myocardial Infarction

This will be the first clinical trial to include a strategy designed to enhance the function of autologous progenitor cells by overexpressing eNOS, and the first to use combination gene and cell therapy for the treatment of cardiac disease.

Study Overview

• Status: Active, not recruiting
• Conditions: Anterior Wall Myocardial Infarction
• Intervention / Treatment: Biological: Plasma-Lyte A and 25% Autologous Plasma; Biological: Autologous EPCs; Biological: Autologous EPCs Transfected with human eNOS

Detailed Description

Introduction:

• Despite the widespread use of pharmacological and/or interventional reperfusion therapies, recovery of cardiac function in myocardial infarction patients is often modest or in some cases absent. Unlike classical re-perfusion therapies, which must be delivered before irreversible cardiac damage has occurred, the use of progenitor cells could potentially restore functional tissue in regions that otherwise would form only scar. A number of clinical trials have been performed, mainly using autologous bone marrow cells, and these suggest a significant albeit modest improvement in cardiac function post MI. However, a major limitation of autologous cell therapy in patients with cardiovascular disease is the deleterious influence of age and other cardiac risk factors on progenitor cell activity, which may limit greatly the potential efficacy of this promising approach.

Trial Design:

• The Enhanced Angiogenic Cell Therapy - Acute Myocardial Infarction (ENACT-AMI) trial is a Canadian, 5-center, phase IIb, double-blind, parallel, randomized placebo controlled trial assessing the safety and efficacy of cell and gene therapy for patients with moderate to large anterior STEMI and who have undergone re-vascularization with stent implantation to the infarct related artery (IRA). The anticipated recruitment target is 100 patients over a two-year period.
• Consenting participants who qualify during the screening process, will undergo apheresis. Randomization, through a web-based system will take place immediately after successful apheresis. The cell collection samples will be sent to a cell manufacturing facility for manufacturing according to the treatment allocation of: a)Placebo (Plasma-Lyte A & 25% autologous plasma), b)EPCs or c)EPCs transfected with human endothelial nitric oxide synthase (eNOS).
• Approximately 5-7 days later, the patient will receive the randomized treatment allocation via intracoronary injection into the IRA. Participants will remain in hospital overnight for continuous cardiac monitoring. The first post-delivery visit will take place the following morning before hospital discharge. Subsequent study visits will be clinic visits at 1 week, 1, 3 and 6 months after study treatment. Subsequently, a registry to collect long-term safety information from telephone contacts will continue annually for 10 years. During the registry period, participants will be allowed to volunteer for enrolment in other clinical trials.

• Study Type: Interventional
• Enrollment (Actual): 47
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Québec, Canada, G1V 4G5
    • Institut Universitaire de Cardiologie et de Pneumonologie de Québec - Université Laval
  • Ontario
    • Ottawa, Ontario, Canada, K1Y 4W7
      • University of Ottawa Heart Institute
    • Toronto, Ontario, Canada, M5B 1W8
      • St. Michael's Hospital
  • Quebec
    • Montreal, Quebec, Canada, H1T 1C8
      • L'Institut de Cardiologie de Montréal

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:

• Male or female 18-80 years of age
• Clinical diagnosis of anterior ST-elevation myocardial infarction within the last 30 days, with any one of the following 12-lead electrocardiographic changes:
• a) Greater than or equal to 1 mm ST elevation or new Q waves in 2 adjacent electrocardiographic precordial leads
• b) A new left bundle branch block AND and for patients presenting within 3 days of onset of chest pain an increase in cardiospecific enzymes (>3x CK with, EITHER positive MB fraction or increase in troponin compared to institution laboratory normal ranges)
• Successful PCI with stent implantation to infarct-related artery within the last 30 days; defined as residual stenosis no greater than 30%, TIMI flow of at least 2 or greater and a reference diameter of at least > 2mm
• Is considered hemodynamically stable at time of enrollment and immediately prior to cell delivery
• Screening LVEF must be no greater than 45% by echocardiography (determined by Simpson's method) performed at least 4 days after revascularization procedure. (All screening echos done within the first 4 days post-PCI must be repeated either by echocardiography or MRI prior to cell delivery to ensure that the variability does not exceed 10%)
• In the case of a previous myocardial infarction, documented LVEF must be 55% or greater
• Female participants MUST be surgically sterile, post-menopausal, have documented infertility, or are of child-bearing potential wih laboratory confirmation of non-pregnant state
• Provided written informed consent and is willing to comply with study follow-up visits

Exclusion Criteria:

• Significant unprotected left main disease (stenosis of 50% or greater on diagnostic angiography)
• An increase in LVEF by greater that 10% from initial LVEF evaluation for repeat assessments
• The presence of significant coronary lesions, other than the index lesion of the IRA
• A history of significant ventricular arrhythmia NOT related to index STEMI
• A history of cerebro-vascular accident or transient ischemic attack within 6 months of enrollment
• Meets at least one exclusion criterion for MRI (NB: Recent stent implantation is not an exclusion)
• Inability to undergo apheresis procedure (i.e.: poor venous access, laboratory abnormalities)
• A history of uncorrected significant valvular heart disease
• A history of left ventricular dysfunction prior to index STEMI
• A history of human immunodeficiency virus (HIV) or hepatitis B or C infection
• A history of malignancy within 5 years (Except for low-grade and fully resolved non-melanoma skin cancer)
• A history of allergy to gentamycin or amphotericin
• A history of Heparin-Induced Thrombocytopenia (HIT)
• A history of non-compliance
• Active inflammatory autoimmune disease requiring chronic immunosuppressive therapy
• Creatinine clearance <60 by Cockcroft-Gault Calculator
• Confirmed pregnant or lactating
• Is enrolled in a current investigational drug or device trial
• Participant has received cell or gene therapy in past
• The presence of any significant co-morbidities that, in the investigator's opinion, would preclude the participant from taking part in the trial
• Inability to provide informed consent and comply with the follow-up visit schedule

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Plasma-Lyte A and 25% autologous plasma	Biological: Plasma-Lyte A and 25% Autologous Plasma; Single dose of 8 mls given by investigator via intracoronary injection into stent of infarct-related artery
Experimental: Autologous EPCs	Biological: Autologous EPCs; Single dose of 20 million cells in 8 mls given by investigator via intracoronary injection into stent of infarct-related artery; Other Names: Non-applicable
Experimental: Autologous EPCs Transfected with human eNOS	Biological: Autologous EPCs Transfected with human eNOS; Single dose of 20 million cells in 8 mls given by investigator via intracoronary injection into stent of infarct-related artery; Other Names: Non-applicable

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessment of Global LVEF	A change in global left ventricular ejection fraction by cardiac MRI between those treated with cell/gene enriched EPCs versus placebo; Change in global left ventricular ejection fraction by cardiac MRI between those treated with non-transfected autologous EPCs versus eNOS transfected EPCs.	Baseline to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessment of: Cardiac wall motion and volumes	Change in regional wall motion and regional wall thickening by cardiac MRI between the above patient groups; Change in echocardiographic assessment of LVEF, infarct size and ventricular volumes between the above patient groups	Baseline to 6 months
Time To Clinical Worsening (TTCW)	Quality of Life Measures: Participants will complete SF-36 and DASI questionnaires at baseline, 3 and 6 months.	Baseline to 6 months
Safety Measurements	Clinically significant changes in CK and troponin more than 24 hours post delivery; Clinically significant changes in ECG; Assessment of major acute cardiac events; Evidence of any systemic embolization during the hospitalization period; Need for revacularization procedures	Baseline to 6 months

Collaborators and Investigators

• Sponsor: Ottawa Hospital Research Institute
• Collaborators: Canadian Institutes of Health Research (CIHR); Stem Cell Network
• Investigators: Principal Investigator: Duncan Stewart, MD, FRCP C, Ottawa Hospital Research Institute

Study record dates

Study Major Dates

• Study Start (Actual): July 19, 2013
• Primary Completion (Actual): March 5, 2020
• Study Completion (Anticipated): September 1, 2030

Study Registration Dates

• First Submitted: July 7, 2009
• First Submitted That Met QC Criteria: July 8, 2009
• First Posted (Estimate): July 10, 2009

Study Record Updates

• Last Update Posted (Actual): December 2, 2020
• Last Update Submitted That Met QC Criteria: December 1, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Keywords: MRI; Stent; myocardial infarction; nitric oxide; endothelial progenitor cells
• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Myocardial Infarction; Infarction; Anterior Wall Myocardial Infarction; Pharmaceutical Solutions; Ophthalmic Solutions; Plasma-lyte 148
• Other Study ID Numbers: 2008-872; ISRCTN47943321 (Registry Identifier: controlled-trials.com)