Administration of AdVEGF-All6A+ to Myocardium of Individuals With Diffuse CAD Via Minimally Invasive Surgery
Coronary Artery Disease
About this trial
This is an interventional treatment trial for Coronary Artery Disease focused on measuring Diffuse Coronary Artery Disease (CAD)
Eligibility Criteria
Inclusion Criteria:
- Males and females, age 18 to 90
- Demonstrable reversible left ventricular ischemia in viable myocardium as assessed by ST segment/T wave abnormalities detected by exercise testing with 99mTc-sestamibi single-photon emission computed tomography (SPECT) prior to and following the exercise test
- Individuals who have coronary artery disease (CAD) but have angina refractory to medical therapy
- Individuals who experience angina class II-IV as defined by the Canadian Cardiovascular Society
- Individuals who have had a coronary angiogram in the prior 6 months demonstrating diffuse coronary artery disease and are not considered to be eligible for coronary artery bypass surgery, stents, or angioplasty, because of the lack of suitable target lesions
- Individuals must be medically capable of undergoing open thoracotomy
- Individuals must have neutralizing anti-adenovirus serotype 5 titer ≤160; this criteria is based on the knowledge that some individuals have high anti Ad5 neutralizing antibody titer which may limit efficacy
- Hematocrit >30%
- WBC <10,000
- Normal prothrombin, partial thromboplastin time (excluding IV heparin therapy)
- Normal liver-related serum parameters
- Glomerular filtration rate (GFR) > 30 ml/min
- No evidence of active infection of any types, including adenovirus, hepatitis virus (A, B or C) or human immunodeficiency virus
- No evidence of central nervous system, major psychiatric, musculoskeletal or immune disorder
- No allergy to the vehicle used to suspend the virus or contrast materials used in radiographic procedures
- Fertile or infertile individuals; it will be recommended that fertile individuals utilize barrier birth control measures to prevent pregnancy during and for 2 months following the administration of the vector
- Individuals not receiving experimental medications or participating in another experimental protocol for at least 4 weeks prior to entry to the study.
- Individuals must be able to exercise for at least 90 seconds but no more than 15 min on a modified Bruce protocol exercise treadmill test while exhibiting angina with concurrent 1 mm horizontal or downsloping ST-segment depression
- The study individual must be able to undergo the procedures in the protocol
- Willingness to participate in the study
- Capable of providing informed consent
Exclusion Criteria:
- Individuals who do not meet the inclusion criteria will be unable to participate in the protocol
- Individuals in whom participation in the study would compromise the normal care and expected progression of their disease
- Individuals receiving corticosteroids or other immunosuppressive medications
- Individuals with uncontrolled diabetes
- Diabetic individuals with significantly abnormal ophthalmologic exam (moderate or greater disease severity)
- Individuals with hypercholesterolemia (LDL above 190 mg/dl or total cholesterol above 240 mg/dl)
- Body mass index >35
- Recent (<6 wk) cerebral vascular accident
- Recent (<6 wk) transmural myocardial infarction
- Evidence of infection defined by elevated white blood cell (WBC) count, temperature >38.5ºC, infiltrate on chest x-ray
- Unable to undergo cardiac MRI with gadolinium contrast
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values 2.5 greater than normal limits
- Prior cardiac transplantation
- Electrocardiograph abnormalities that would interfere with ST-segment analysis
- Untreated malignant ventricular arrhythmia
- Valvular heart disease requiring surgical intervention
- Preoperative congestive heart failure (New York Heart Association Function Class III or IV or ejection fraction (EF) <25%
- Uncontrollable asthma or chronic obstructive pulmonary disease (COPD)
- Greater than first degree heart block or sinus node dysfunction without a functional pacemaker
- Systolic blood pressure less than 90 mmHg
- Known hypersensitivity to adenosine
- Pregnancy or currently lactating
- Prior participation in cardiac gene and/or cardiac cell therapy
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Experimental
Experimental
Experimental
Experimental
Experimental
Part A, Group 1 - 10^8 pu
Part A, Group 2 - 10^9 pu
Part A, Group 3 - 10^10 pu
Part B, Group 1 - AdVEGF-All6A+
Part B, Group 2 - AdNull placebo
Part A is a dose-escalation, open-label study, administering 3 doses of AdVEGF-All6A+ to n=9 individuals, with n=3 each at 10^8, 10^9, and 10^10 particle units. The purpose of Part A is to determine the highest tolerable dose. Group 1 will receive 10^8 particle units.
Part A is a dose-escalation, open-label study, administering 3 doses of AdVEGF-All6A+ to n=9 individuals, with n=3 each at 10^8, 10^9, and 10^10 particle units. The purpose of Part A is to determine the highest tolerable dose. Group 1 will receive 10^9 particle units.
Part A is a dose-escalation, open-label study, administering 3 doses of AdVEGF-All6A+ to n=9 individuals, with n=3 each at 10^8, 10^9, and 10^10 particle units. The purpose of Part A is to determine the highest tolerable dose. Group 1 will receive 10^10 particle units.
Part B (n=32 subjects) is a randomized, double blind, placebo-controlled study that will compare the AdVEGF-All6A+ vector (n=24) to a placebo, AdNull (n=8). Group 1 will receive AdVEGF-All6A+ at the highest tolerable dose determined in Part A.
Part B (n=32 subjects) is a randomized, double blind, placebo-controlled study that will compare the AdVEGF-All6A+ vector (n=24) to a placebo, AdNull (n=8). Group 2 will receive AdNull, the placebo vector.