Coronary Artery DiseasePhase 1/2NCT01757223
Administration of AdVEGF-All6A+ to Myocardium of Individuals With Diffuse CAD Via Minimally Invasive Surgery
A Phase 1/2 study testing AdVEGF-All6A+ and AdNull in people with Coronary Artery Disease, run by Weill Medical College of Cornell University.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 90 years
- Conditions the study is for
- Coronary Artery Disease
- What is being tested?
- AdVEGF-All6A+ and AdNull
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- No sites listed yet
- Study dates
- Dec 2020to Oct 2030
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 90 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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
Who cannot join
- 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)
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- 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
About this study
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...
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.
Read the 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+.
- Conditions
- Coronary Artery Disease
- Being tested
- AdVEGF-All6A+, AdNull
- Keywords
- Diffuse Coronary Artery Disease (CAD)
- Medical subject headings
- Coronary Artery Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
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.
AdNullBiological
AdNull is an adenovirus vector identical to AdVEGF-All6A+, except that it does not encode for a transgene.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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. Receives: 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. Receives: 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. Receives: Biological: AdNull |
What is being measured
The primary outcome is the main question the study is designed to answer.
Time to 1 mm ST depression during exercise-stress testing
Collect the times during the stress-test
Measured: 3 mos (Part A); 6 mos (Part B)
Secondary outcomes (3)
Exercise-stress echocardiogram
To assess segmental wall motion in treated territories
Measured: 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
measured by the Canadian Cardiovascular Society Functional Classification of Angina Pectoris
Measured: 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
To assess segmental wall motion and perfusion in treated territories
Measured: Once pre-vector and repeated at 90 days post vector for Part A, and 180 days post-vector for Part B
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Dec 2012 (estimated)
- Study startDec 2020 (estimated)
- Primary completionOct 2030 (estimated)
- Study completionOct 2030 (estimated)
Why it stopped: Closure due to lack of funding.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Coronary Artery DiseaseStudies of the same condition, open and under way.
- More trials run by Weill Medical College of Cornell UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Weill Medical College of Cornell University
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Ronald G Crystal, MD, Principal investigator, Weill Medical College of Cornell University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01757223
- Sponsor's protocol ID
- 1204012330
- Other IDs
- 1201-1145
- Status last verified
- Jan 2021
- First submitted
- 10 Oct 2012
- Last updated
- 27 Jan 2021
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 27 Jan 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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...
- ClinicalTrials.gov ID
- NCT01757223
- Acronym / sponsor ID
- 1204012330
- Conditions
- Coronary Artery Disease
- Keywords
- Diffuse Coronary Artery Disease (CAD)
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: Closure due to lack of funding.
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Weill Medical College of Cornell UniversityUniversity, hospital or other
- Study start
- Dec 2020 (estimated)
- Primary completion
- Oct 2030 (estimated)
- Study completion
- Oct 2030 (estimated)
- First posted
- 28 Dec 2012 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 5
| Arm | Type | Receives |
|---|---|---|
| Part A, Group 1 - 10^8 pu | Experimental | Biological: AdVEGF-All6A+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, Group 2 - 10^9 pu | Experimental | Biological: AdVEGF-All6A+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, Group 3 - 10^10 pu | Experimental | Biological: AdVEGF-All6A+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, Group 1 - AdVEGF-All6A+ | Experimental | Biological: 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. |
| Part B, Group 2 - AdNull placebo | Experimental | Biological: AdNullPart 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. |
Who may qualify
- Ages
- 18 to 90 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (21 listed)
- 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
Key exclusion criteria (23 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| 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. | Biological | 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+ |
| AdNullAdNull is an adenovirus vector identical to AdVEGF-All6A+, except that it does not encode for a transgene. | Biological | Part B, Group 2 - AdNull placebo |
Primary outcome
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 secondary outcomes
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
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
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
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Jan 2021.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ronald G Crystal, MD principal investigator
Weill Medical College of Cornell University
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing AdVEGF-All6A+ and AdNull in people with Coronary Artery Disease, run by Weill Medical College of Cornell University.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 21 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 27 Jan 2021. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Time to 1 mm ST depression during exercise-stress testing (time frame: 3 mos (Part A); 6 mos (Part B)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Jan 2021.