- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01757223
Administration of AdVEGF-All6A+ to Myocardium of Individuals With Diffuse CAD Via Minimally Invasive Surgery
January 24, 2021 updated by: Weill Medical College of Cornell University
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...
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.
Study Overview
Status
Withdrawn
Conditions
Intervention / Treatment
Detailed Description
Coronary artery disease (CAD) is the predominant cause of heart failure, a major cause of death and disability throughout the world.
Although prognosis of patients with CAD has been greatly improved by advances in cardiovascular treatment, it is still the first cause of death in the USA.
Treatment options for CAD include diet, exercise, medication, balloon angioplasty with or without stenting, atherectomy and bypass surgery.
For many patients, however, the disease is diffuse and stenting or bypass surgery is not an option.
A new strategy to treat these patients is to use gene therapy to induce new networks of new blood vessels to bypass the arterial system that is blocked, thus providing circulation to deliver oxygen needed by the tissue.
By administering a gene coding for vascular endothelial growth factor (VEGF) to the myocardium, new networks of blood vessels can be created using the genetic material for VEGF.
In experimental animal studies, VEGF is effective at treating ischemia of organs and is safe.
The most direct method of transferring genes to myocardium is by injection under direct vision during a minimally invasive thoracic surgery.
For the present study, the VEGF gene will be delivered to the myocardium using a modified adenovirus (Ad) as a carrier.
The study is designed to test the safety and efficacy of AdVEGF-All6A+.
Study Type
Interventional
Phase
- Phase 2
- Phase 1
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
18 years to 90 years (Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
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
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Double
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
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.
|
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.
|
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.
|
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.
|
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.
|
AdNull is an adenovirus vector identical to AdVEGF-All6A+, except that it does not encode for a transgene.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Time to 1 mm ST depression during exercise-stress testing
Time Frame: 3 mos (Part A); 6 mos (Part B)
|
Collect the times during the stress-test
|
3 mos (Part A); 6 mos (Part B)
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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
|
To assess segmental wall motion in treated territories
|
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
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
|
measured by the Canadian Cardiovascular Society Functional Classification of Angina Pectoris
|
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
Time Frame: Once pre-vector and repeated at 90 days post vector for Part A, and 180 days post-vector for Part B
|
To assess segmental wall motion and perfusion in treated territories
|
Once pre-vector and repeated at 90 days post vector for Part A, and 180 days post-vector for Part B
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (Anticipated)
December 1, 2020
Primary Completion (Anticipated)
October 1, 2030
Study Completion (Anticipated)
October 1, 2030
Study Registration Dates
First Submitted
October 10, 2012
First Submitted That Met QC Criteria
December 20, 2012
First Posted (Estimate)
December 28, 2012
Study Record Updates
Last Update Posted (Actual)
January 27, 2021
Last Update Submitted That Met QC Criteria
January 24, 2021
Last Verified
January 1, 2021
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 1204012330
- 1201-1145 (Other Identifier: Recombinant DNA Advisory Commitee)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
NO
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Yes
Studies a U.S. FDA-regulated device product
No
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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