Administration of AdVEGF-All6A+ to Myocardium of Individuals With Diffuse CAD Via Minimally Invasive Surgery - Full Text View

Purpose

The proposed Phase I/II clinical trial will be used to determine the safety and toxicity of direct administration of the vector AdVEGF-All6A+ to the ischemic myocardium and to generate preliminary evidence regarding whether direct administration of AdVEGF-All6A+ to the ischemic myocardium will induce growth of collateral blood vessels and improve cardiac function. This is a three-part, multinational/multi-center, placebo controlled study.

Condition	Intervention	Phase
Coronary Artery Disease	Biological: AdVEGF-All6A+ Biological: AdNull	Phase 1 Phase 2

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Investigator) Primary Purpose: Treatment
Official Title:	Phase I/II Study, Administration of AdVEGF-All6A+, a Replication Deficient Adenovirus Vector Expressing a cDNA/Genomic Hybrid of Human Vascular Endothelial Growth Factor to the Ischemic Myocardium of Individuals With Diffuse Coronary Artery Disease Via Minimally Invasive Surgery

Resource links provided by NLM:

MedlinePlus related topics: Coronary Artery Disease Exercise and Physical Fitness

U.S. FDA Resources

Further study details as provided by Weill Medical College of Cornell University:

Primary Outcome Measures:

Time to 1 mm ST depression during exercise-stress testing [ Time Frame: 3 mos (Part A); 6 mos (Part B) ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Exercise-stress echocardiogram [ Time Frame: Twice before vector administration at -30 days and -15 days (± 5 days), and will be repeated at day 90 post-vector for Part A and day 90 and 180 post-vector for Part B ] [ Designated as safety issue: No ]
To assess segmental wall motion in treated territories
Angina, as measured by the Canadian Cardiovascular Society Functional Classification of Angina Pectoris [ Time Frame: Twice pre-vector administration at -30 days and -15 days, and repeated at 30 and 90 days post-vector for Part A and at 30, 90 and 180 days post-vector for Part B ] [ Designated as safety issue: No ]
Cardiac MRI +/- adenosine stress [ Time Frame: Once pre-vector and repeated at 90 days post vector for Part A, and 180 days post-vector for Part B ] [ Designated as safety issue: No ]
To assess segmental wall motion and perfusion in treated territories

Estimated Enrollment:	41
Study Start Date:	January 2013
Estimated Study Completion Date:	January 2028
Estimated Primary Completion Date:	July 2013 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Part A, Group 1 - 10^8 pu 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.	Biological: AdVEGF-All6A+ We will administer AdVEGF-All6A+, an adenovirus vector carrying the genetic material for human vascular endothelial growth factor to the ischemic myocardium of individuals with diffuse coronary artery disease.
Experimental: Part A, Group 2 - 10^9 pu 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.	Biological: AdVEGF-All6A+ We will administer AdVEGF-All6A+, an adenovirus vector carrying the genetic material for human vascular endothelial growth factor to the ischemic myocardium of individuals with diffuse coronary artery disease.
Experimental: Part A, Group 3 - 10^10 pu 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.	Biological: AdVEGF-All6A+ We will administer AdVEGF-All6A+, an adenovirus vector carrying the genetic material for human vascular endothelial growth factor to the ischemic myocardium of individuals with diffuse coronary artery disease.
Experimental: Part B, Group 1 - AdVEGF-All6A+ 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.	Biological: AdVEGF-All6A+ We will administer AdVEGF-All6A+, an adenovirus vector carrying the genetic material for human vascular endothelial growth factor to the ischemic myocardium of individuals with diffuse coronary artery disease.
Experimental: Part B, Group 2 - AdNull placebo 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.	Biological: AdNull AdNull is an adenovirus vector identical to AdVEGF-All6A+, except that it does not encode for a transgene.

Eligibility

Ages Eligible for Study:	18 Years to 90 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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 echocardiogram 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 III-IV
Individuals who 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 8 min on an Asymptomatic Cardiac Ischemia Pilot protocol exercise treadmill test (Stone, PH et al. Am. J. Cardiol. 1997; 80: 1395-1401) 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 relevant to the protocol as assessed by protocol physicians
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 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
Severe chronic obstructive pulmonary disease as demonstrated by either room air arterial PO2 <60 mm Hg or PCO2 >50 mm Hg, or abnormal pulmonary function tests (FEV1 <1 L/sec)
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%
Pregnancy or currently lactating
Prior participation in cardiac gene and/or cell therapy

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01757223

Contacts

Contact: Charleen Hollmann, RN, BSN, MPA, PhD, CCRP	646-962-2672	chollman@med.cornell.edu
Contact: Mary E. Yeotsas, CCRC	646-962-4563	mey2003@med.cornell.edu

Sponsors and Collaborators

Weill Medical College of Cornell University

Investigators

Principal Investigator:

Ronald Crystal, MD

Weill Medical College of Cornell University

More Information

No publications provided

Responsible Party:	Weill Medical College of Cornell University
ClinicalTrials.gov Identifier:	NCT01757223 History of Changes
Other Study ID Numbers:	1204012330, 1201-1145
Study First Received:	October 10, 2012
Last Updated:	December 20, 2012
Health Authority:	United States: Food and Drug Administration United States: Recombinant DNA Advisory Committee United States: Data Safety Monitoring Board United States: Clinical & Translational Science Center United States: Institutional Biosafety Committee United States: Institutional Review Board

Keywords provided by Weill Medical College of Cornell University:

Diffuse Coronary Artery Disease (CAD)

Additional relevant MeSH terms:

Coronary Artery Disease
Myocardial Ischemia
Coronary Disease
Heart Diseases
Cardiovascular Diseases
Arteriosclerosis

Arterial Occlusive Diseases
Vascular Diseases
Endothelial Growth Factors
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on May 23, 2013