Safety Study of Gene Therapy for Ischemic Heart Disease in Korea

Phase 1

Completed

Conditions: Ischemic Heart Disease

Interventions: Biological: VM202-0.5 mg
Biological: VM202-1.0 mg
Biological: VM202-2.0 mg

Registration Number: NCT01422772

Lead Sponsor: Helixmith Co., Ltd.

Brief Summary: The purpose of this study is to evaluate the safety of VM202 (Engensis) direct injection into the cardiac muscles of the coronary artery territory where complete revascularization could not be done even through Coronary Artery Bypass Graft (CABG).

Detailed Description: All the patients expected to undergo Coronary Artery Bypass Graft (CABG) will screen for the participation in the clinical study. Subjects who signed the informed consent will receive all the screening tests within 21 days before surgery (Day 0). VM202 (Engensis) will be injected into 4 sites or 8 sites on the coronary artery where complete revascularization was not done since vascular anastomosis could not be performed due to the bad vascular condition during surgery. VM202 (Engensis) will be administered to Group1 (0.5 mg), Group 2 (1 mg) and Group 3 (2 mg) at different concentrations. Subjects will be scheduled to get inpatient treatment during the gene therapy period (7 days) and follow-up tests at Week 2, 4, 8, 12 and 24 based on surgery day (Day 0). Adverse events and concomitant drugs will be checked.

Safety: Evaluated for 6 months after the administration of VM202 (Engensis).

1. Dose-Limiting Toxicity (DLT)

2. Tolerated Dose (TD)

3. Adverse events, vital signs, physical examination and laboratory test values

4. Major Adverse Cardiac Event (MACE) - cardiac death, myocardial infarction, ventricular arrhythmia requiring treatment, or hospitalization for revascularization of target blood vessels)

5. Safety of VM202 intramyocardial injection: persistent hemorrhage, arrhythmia and other complications

Secondary endpoints

\- Efficacy

1. Changes in cardiac function: Left ventricular ejection fraction and cardiac function in the local region by cardiac MRI (Magnetic Resonance Imaging), myocardial SPECT (99 mTc Sestamibi Methoxyl Isobutyl Isonitrile Single Photon Emission Computed Tomography) and Trans Thoracic echocardiography (TTE)

2. Size of viable myocardium: By cardiac MRI (myocardial thickness of intramyocardial gene injection site, gadolinium late contrast enhancement range and the exercise intensity of the local region)

3. Changes in myocardial ischemic area: By myocardial SPECT (blood flow changes at intramyocardial gene injection site from resting to stress condition)

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 9

Inclusion Criteria

Patients aged ≥ 19 and ≤ 75 years
Patients in whom decrease of myocardial perfusion in coronary artery territories (rest perfusion - stress perfusion: ≥ 7%) was observed by myocardial SPECT
Patients judged to have possibly incomplete revascularization based on the observation of the coronary artery's internal diameter of ≤ 1 mm, diffuse atherosclerosis or severe calcification on coronary angiography, or patients judged to have some myocardial perfusion territories that could not be performed Coronary Artery Bypass Graft
Patients who or whose legal representative can write the informed consent before the initiation of the clinical study and comply with the requirements

Exclusion Criteria

Patients with progressive or present heart failure
Patients with uncontrolled ventricular arrhythmia on electrocardiogram, or who have been treated for ventricular arrhythmia
Patients with current or history of malignant tumor
Patients with severe infectious disease
Patients with uncontrolled hematologic disorders
Patients requiring surgery for the accompanying valve diseases or left ventricular volume reduction surgery
Patients with current or history of proliferative retinopathy
Patients with remaining life of less than 1 year and severe accompanying diseases enough to die during the clinical follow-up period
Patients with history of drug or alcohol abuse within the recent 3 months
Women who are pregnant or breast feeding or postmenopausal women of childbearing age. However, women who underwent surgical sterilization including hysterectomy or bilateral tubal ligation can participate in this clinical trial. Even though they consent to the contraception, they cannot be enrolled.
Patients in inappropriate condition judged by investigators
Patients with cerebrovascular diseases (cerebral infarction, cerebral bleeding or transient ischemic attack that are currently occurring or occurred within 6 months)
Patients with idiopathic hypertension who are not controlled with drugs
Patients with severe hepatic disorders
Patients with severe renal disorders
Patients who underwent Coronary Artery Bypass Graft
Patients who underwent angioplasty within 1 year before their enrollment in the study

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Cohort I	VM202-0.5 mg	0.5 mg/ 1 mL of VM202 was intramyocardially injected into 4 sites
Cohort II	VM202-1.0 mg	1 mg/ 2 mL of VM202 was intramyocardially injected into 8 sites
Cohort III	VM202-2.0 mg	2 mg/ 4 mL of VM202 was intramyocardially injected into 8 sites

Primary Outcome Measures

Name	Time	Method
The Incidence of Adverse Events - Total Adverse Events (AE)	24 weeks	Subjects who have been administered the investigational drug will be included, regardless of protocol violations or adherence to visit schedules. This clinical trial is designed to evaluate safety over a 6-month period. Assessments Include: Adverse reactions, vital signs, physical exam, laboratory test results
The Severity of Adverse Events - Total Adverse Events by Severity	24 weeks	Subjects who have been administered the investigational drug will be included, regardless of protocol violations or adherence to visit schedules. This clinical trial is designed to evaluate safety over a 6-month period. Assessments Include: Adverse reactions, vital signs, physical exam, laboratory test results

Secondary Outcome Measures

Name	Time	Method
Percentage of Change From Baseline/Screening in Left Ventricular Ejection Fraction Evaluated by Magnetic Resonance Imaging	Day 0, 12 weeks, 24 weeks	Changes in Percentage of Left Ventricular Ejection Fraction by Cardiac Magnetic Resonance Imaging (MRI). Cardiac MRI will be used to monitor for the development of intramyocardial hemangiomas. Analysis will follow the standard cardiac MRI protocols of the Department of Radiology at Seoul National University Hospital, using an appropriate segment model based on the patient's heart size. Parameters evaluated will include left ventricular volume (mL), wall motion index, myocardial thickness (mm), and LVEF (%). Comparisons will be made between baseline/screening and follow-up measurements for each patient, as well as between treatment groups.
Percentage of Change From Baseline/Screening in Cardiac Function Evaluated by Echocardiography	Day 0, Day 7, 12 weeks, 24 weeks	Changes from screening in cardiac function evaluated based on Percentage of Left Ventricular Ejection Fraction by cardiac Trans-thoracic Echocardiography (TTE). From transthoracic echocardiography, left ventricular diameter (mm), ejection fraction (%), and wall thickness (mL) will be measured and compared from Screening/Baseline to follow-up results after surgery. The Wall Motion Score Index will be calculated by dividing the myocardium into 16 segments and assigning a score to each area based on motion: \[1 = normal, 2 = hypokinetic, 3 = akinetic, 4 = dyskinetic\]. The total score for the entire myocardium and the right coronary artery region will be averaged by the number of segments.
Changes in Size of Viable Myocardium - End-Systolic Thickness	Day 0, 12 weeks, 24 weeks	The size of the viable myocardium was evaluated based on the myocardium thickness at the site of intramyocardial gene injection by Magnetic Resonance Imaging - End-Systolic Thickness. Using cardiac MRI, the myocardial thickness at the gene injection site, the extent of late gadolinium enhancement, and local wall motion strength will be evaluated. Differences between groups before and after VM202RY administration will be tested using the Kruskal-Wallis test.
Changes in Size of Viable Myocardium - End-Diastolic Thickness	Day 0, 12 weeks, 24 weeks	The size of the viable myocardium was evaluated based on the myocardium thickness at the site of intramyocardial gene injection by Magnetic Resonance Imaging - End-Diastolic Thickness. Using cardiac MRI, the myocardial thickness at the gene injection site, the extent of late gadolinium enhancement, and local wall motion strength will be evaluated. Differences between groups before and after VM202RY administration will be tested using the Kruskal-Wallis test.
Changes in Myocardial Ischemic Area - Stress Condition	Day 0, 12 weeks, 24 weeks	Changes in Myocardial Ischemic Area evaluated by 99mTc Sestamibi Methoxyl Isobutyl Isonitrile Single Photon Emission Computed Tomography (SPECT) based on Percentage of perfusion volume - Stress Condition
Changes in Myocardial Ischemic Area - Resting Condition	Day 0, 12 weeks, 24 weeks	Changes in Myocardial Ischemic Area evaluated by 99mTc Sestamibi Methoxyl Isobutyl Isonitrile Single Photon Emission Computed Tomography (SPECT) based on Percentage of perfusion volume - Resting Condition