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

NCT01757223 | Withdrawn Phase 1 DMC FDA Drug

• 2 other identifiers: 12040123301201-1145
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

Coronary Artery Disease

Keywords

Diffuse Coronary Artery Disease (CAD)

Outcome Measures

Primary Outcomes (1)

• Time to 1 mm ST depression during exercise-stress testing

  Collect the times during the stress-test

  3 mos (Part A); 6 mos (Part B)

Secondary Outcomes (3)

• Exercise-stress echocardiogram

  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

• Angina

  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

• Cardiac MRI +/- adenosine stress

  Once pre-vector and repeated at 90 days post vector for Part A, and 180 days post-vector for Part B

Study Arms (5)

Part A, Group 1 - 10^8 pu

EXPERIMENTAL

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+

Part A, Group 2 - 10^9 pu

EXPERIMENTAL

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+

Part A, Group 3 - 10^10 pu

EXPERIMENTAL

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+

Part B, Group 1 - AdVEGF-All6A+

EXPERIMENTAL

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+

Part B, Group 2 - AdNull placebo

EXPERIMENTAL

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

Interventions

AdVEGF-All6A+ BIOLOGICAL

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.

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+

AdNull BIOLOGICAL

AdNull is an adenovirus vector identical to AdVEGF-All6A+, except that it does not encode for a transgene.

Part B, Group 2 - AdNull placebo

Eligibility Criteria

• Age: 18 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Weill Medical College of Cornell University: lead

MeSH Terms

Conditions

Coronary Artery Disease

Condition Hierarchy (Ancestors)

Coronary Disease; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases

Study Officials

• Ronald G Crystal, MD

  Weill Medical College of Cornell University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 10, 2012
• First Posted: December 28, 2012
• Study Start: December 1, 2020
• Primary Completion (Estimated): October 1, 2030
• Study Completion (Estimated): October 1, 2030
• Last Updated: January 27, 2021

Record last verified: 2021-01

Data Sharing

• IPD Sharing: Will not share