Coronary Artery DiseasePhase 1/2NCT00134433
Endothelial Modulation for Angiogenic Therapy
A Phase 1/2 study testing intramyocardial VEGF angiogenesis (at a dose of 2 mg) and oral L-arginine supplementation (at a dose of 6 g/day) in people with Coronary Artery Disease, run by Ottawa Heart Institute Research Corporation at 1 site in Canada.
Trial summary
Coronary artery disease is the single most important killer of Canadians. Despite major advances in therapy, there is still a significant proportion of patients identified with the disease who die of it because current treatment approaches cannot effectively palliate their condition. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Coronary Artery Disease
- What is being tested?
- intramyocardial VEGF angiogenesis (at a dose of 2 mg) and oral L-arginine supplementation (at a dose of 6 g/day)
- Type of treatment
- Pill or oral medicine
- How many people
- 20 participants
- Where
- 1 siteCanada
- Study dates
- Nov 2004to Oct 2007
- 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 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Severe chronic angina
- Multi-vessel coronary artery disease
- Diffusely diseased left anterior descending coronary artery (LAD)
- At least 18 years of age at the time of written informed consent
Who cannot join
- Pregnancy, lactation, or any child-bearing potential
- Patients who are candidates for percutaneous transluminal coronary angioplasty (PTCA) or stenting
- Severe left ventricular dysfunction (ejection fraction < 30%)
- Threatened proximal coronary occlusion or unstable angina
- Recent myocardial infarction (< 1 month)
- Chronic renal failure (serum creatinine > 130 µmol/L)
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- Hepatic insufficiency (Child-Pugh Class C)
- Clinically significant valvular heart disease
- Personal history of neoplasia
- Abnormal serum prostate-specific antigen (PSA), bowel neoplasia screening questionnaire, or updated mammography report (if female) - any test not performed within the last 6 months will be conducted prior to confirmation of eligibility
- Family history of cancer (i.e. ≥ 2 first-degree relatives)
- History of diabetic retinopathy
- Latent herpes infection
- Schizophrenia
- Claustrophobia
Trial locations and contacts
1 site in 1 country.
Canada1 site
Division of Cardiac Surgery, University of Ottawa Heart Institute
Ottawa, Ontario, K1Y 4W7
About this study
Official title: Endothelial Modulation With L-Arginine in Patients Undergoing Angiogenic Therapy (EMAT): A 2x2 Factorial Trial
Coronary artery disease is the single most important killer of Canadians. Despite major advances in therapy, there is still a significant proportion of patients identified with the disease who die of it because current treatment approaches cannot effectively palliate their condition. A new treatment modality called therapeutic angiogenesis has appeared on the clinical research scene during the last five years; this approach recreates the natural processes of new blood vessel formation that is observed during growth and development in every human being. It is an extremely potent and promising modality, but so far the results of clinical trials in patients have been equivocal.
One reason for the limited efficacy observed thus far with therapeutic angiogenesis may rest in that factors produced by the lining of the coronary arteries themselves are essential for angiogenic substances to take effect in the heart muscle of patients with severe coronary artery disease. These same patients, however, virtually all have, as a result of their disease, marked dysfunction of their coronaries and therefore fail to produce these factors in adequate quantities. This hypothesis has been verified with extensive animal data by the investigators of this research, where a swine model of coronary disease was shown to severely inhibit the action of angiogenic growth factors. If one wants angiogenesis to work, a means of improving the function of the coronary lining of patients with severe ischemic heart disease must be identified and its effects evaluated in order to allow for angiogenic substances to exert their action towards successful revascularization of the heart muscle.
An amino acid called L-arginine has repeatedly been shown to markedly improve function of the coronary artery lining in patients with ischemic heart disease when administered regularly over a period of several months. This research will therefore test, in the form of a randomized clinical trial, whether this concomitant approach can make angiogenesis effective in patients with advanced coronary disease, by allowing for the action of growth factors to take place in the heart. If this approach is successful, as is anticipated, angiogenesis will constitute an effective modality for the treatment of coronary artery disease, not only in patients with advanced, severe involvement unamenable to any other form of cardiac therapy such as coronary artery bypass grafting, but even perhaps in all patients with coronary artery disease in need of revascularization. The goal of this investigation towards the making of a new, revolutionary, safe and efficacious modality for the treatment of the number one killer disease of Canadians is in complete agreement with the primary objective of the Heart and Stroke Foundation of Canada.
Read the detailed description
The EMAT trial tests the hypothesis that the concomitant treatment of chronic endothelial dysfunction in patients undergoing angiogenic therapy can make angiogenesis clinically effective. This is achieved with a 2x2 factorial, double-blind, placebo-controlled randomized trial of intramyocardial vascular endothelial growth factor (VEGF) angiogenesis at a dose of 2 mg and of adjunct endothelial modulation therapy using oral L-arginine supplementation at a dose of 6 g/day in patients undergoing surgical perivascular angiogenic therapy. The study involves surgical angiogenesis techniques similar to those previously used and reported to be clinically safe by the principal investigator and collaborators. Patients with a diffusely disease left anterior descending (LAD) coronary artery have this artery grafted with an internal thoracic artery in either its proximal or distal portion (according to what is felt by the surgeon to be most optimal as per usual practice). The segment of the LAD that is not directly bypassed (i.e. either the proximal portion if a distal bypass is performed by the surgeon or the distal portion if a proximal bypass is performed) is treated by the surgeon with VEGF angiogenesis or placebo injections. Other coronary arteries in need of bypass grafting are grafted as per usual practice, using arterial grafts. Patients are therefore randomized to one of four groups at the time of coronary artery bypass grafting:
- growth factor (VEGF) angiogenesis along the diffusely diseased, non-directly bypassed LAD segment + L-arginine oral supplementation;
- placebo "angiogenesis" along the diffusely diseased, non-directly bypassed LAD segment + L-arginine oral supplementation;
- growth factor (VEGF) angiogenesis along the diffusely diseased, non-directly bypassed LAD segment + placebo oral supplementation; and
- placebo "angiogenesis" along the diffusely diseased, non-directly bypassed LAD segment + placebo oral supplementation.
The angiogenesis treatment consists either of the injection of 2 mg (divided in 10 injections of 200 μg each) of plasmid DNA encoding for the VEGF165 gene or of 10 x 1 ml injections of a sterile physiologic saline solution in the myocardial territory and septum along the diffusely diseased, non-directly bypassed LAD segment. Other myocardial territories are concomitantly revascularized with arterial coronary bypass grafts.
The EMAT trial's primary end-points relate to objective myocardial perfusion indices and contractility of the intervened anterior myocardial portion, respectively measured with cardiac positron-emission tomography (PET) by using the investigational radioisotope 13-N ammonia, and by RNA or echocardiography. Using 13-N PET, collateral-dependent blood flow and ischemic zone size are measured in a double-blind fashion by a single observer at baseline and at 3 months. To better delineate the actual effects of angiogenic therapy, baseline perfusion scans are obtained 3 to 5 days after the operative procedure in order to account for the potentially confounding effect of CABG on myocardial perfusion to the proximal and distal anterior and septal territories. The functional, secondary end-points of the EMAT trial consist of clinical outcomes including major adverse cardiac events (MACE), freedom from angina, and angina class.
- Conditions
- Coronary Artery Disease
- Being tested
- intramyocardial VEGF angiogenesis (at a dose of 2 mg), oral L-arginine supplementation (at a dose of 6 g/day)
- Keywords
- Coronary Artery Disease, Diffuse, Coronary Artery Disease, Deemed Inoperable
- 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.
intramyocardial VEGF angiogenesis (at a dose of 2 mg)Genetic
oral L-arginine supplementation (at a dose of 6 g/day)Drug
What is being measured
The primary outcome is the main question the study is designed to answer.
Blood flow to ischemic zone at 6 months compared to baseline: Persantine Ammonia Perfusion PET done at baseline prior to discharge from hospital and repeated at 3 months post intervention
Echocardiogram done at baseline prior to discharge from hospital and repeated at 3 months post intervention
Freedom from angina recurrence: Study participant interview and Seattle Angina Questionnaire administered (3 months, 6 months, 1 year). Results compared from preoperative baseline.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Aug 2005 (estimated)
- Study startNov 2004
- Primary completionMar 2007
- Study completionOct 2007
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.
- 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
- Factorial
- Masking
- Double blind
- Enrolment
- 20 participants (actual)
Sponsor and investigators
- Lead sponsor
- Ottawa Heart Institute Research Corporation
- Sponsor type
- University, hospital or other
- Collaborators
- Heart and Stroke Foundation of Ontario
- Responsible party
- Principal investigator, Marc Ruel MD MPH FRCSC, Ottawa Heart Institute Research Corporation
- Investigators
- Marc Ruel, MD MPH FRCSC, Principal investigator, Ottawa Heart Institute Research Corporation
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00134433
- Sponsor's protocol ID
- NA5163
- Status last verified
- Jun 2012
- First submitted
- 22 Aug 2005
- Last updated
- 21 Jun 2012
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 21 Jun 2012. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Endothelial Modulation With L-Arginine in Patients Undergoing Angiogenic Therapy (EMAT): A 2x2 Factorial Trial
- ClinicalTrials.gov ID
- NCT00134433
- Acronym / sponsor ID
- NA5163
- Conditions
- Coronary Artery Disease
- Keywords
- Coronary Artery Disease, Diffuse, Coronary Artery Disease, Deemed Inoperable
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 20 participants (actual)
- Lead sponsor
- Ottawa Heart Institute Research CorporationUniversity, hospital or other
- Collaborators
- Heart and Stroke Foundation of Ontario
- Study start
- Nov 2004
- Primary completion
- Mar 2007 (actual)
- Study completion
- Oct 2007 (actual)
- First posted
- 24 Aug 2005 (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.
Coronary artery disease is the single most important killer of Canadians. Despite major advances in therapy, there is still a significant proportion of patients identified with the disease who die of it because current treatment approaches cannot effectively palliate their condition. A new treatment modality called therapeutic angiogenesis has appeared on the clinical research scene during the last five years; this approach recreates the natural processes of new blood vessel formation that is observed during growth and development in every human being. It is an extremely potent and promising modality, but so far the results of clinical trials in patients have been equivocal.
One reason for the limited efficacy observed thus far with therapeutic angiogenesis may rest in that factors produced by the lining of the coronary arteries themselves are essential for angiogenic substances to take effect in the heart muscle of patients with severe coronary artery disease. These same patients, however, virtually all have, as a result of their disease, marked dysfunction of their coronaries and therefore fail to produce these factors in adequate quantities. This hypothesis has been verified with extensive animal data by the investigators of this research, where a swine model of coronary disease was shown to severely inhibit the action of angiogenic growth factors. If one wants angiogenesis to work, a means of improving the function of the coronary lining of patients with severe ischemic heart disease must be identified and its effects evaluated in order to allow for angiogenic substances to exert their action towards successful revascularization of the heart muscle.
An amino acid called L-arginine has repeatedly been shown to markedly improve function of the coronary artery lining in patients with ischemic heart disease when administered regularly over a period of several months. This research will therefore test, in the form of a randomized clinical trial, whether this concomitant approach can make angiogenesis effective in patients with advanced coronary disease, by allowing for the action of growth factors to take place in the heart. If this approach is successful, as is anticipated, angiogenesis will constitute an effective modality for the treatment of coronary artery disease, not only in patients with advanced, severe involvement unamenable to any other form of cardiac therapy such as coronary artery bypass grafting, but even perhaps in all patients with coronary artery disease in need of revascularization. The goal of this investigation towards the making of a new, revolutionary, safe and efficacious modality for the treatment of the number one killer disease of Canadians is in complete agreement with the primary objective of the Heart and Stroke Foundation of Canada.
Detailed description
The EMAT trial tests the hypothesis that the concomitant treatment of chronic endothelial dysfunction in patients undergoing angiogenic therapy can make angiogenesis clinically effective. This is achieved with a 2x2 factorial, double-blind, placebo-controlled randomized trial of intramyocardial vascular endothelial growth factor (VEGF) angiogenesis at a dose of 2 mg and of adjunct endothelial modulation therapy using oral L-arginine supplementation at a dose of 6 g/day in patients undergoing surgical perivascular angiogenic therapy. The study involves surgical angiogenesis techniques similar to those previously used and reported to be clinically safe by the principal investigator and collaborators. Patients with a diffusely disease left anterior descending (LAD) coronary artery have this artery grafted with an internal thoracic artery in either its proximal or distal portion (according to what is felt by the surgeon to be most optimal as per usual practice). The segment of the LAD that is not directly bypassed (i.e. either the proximal portion if a distal bypass is performed by the surgeon or the distal portion if a proximal bypass is performed) is treated by the surgeon with VEGF angiogenesis or placebo injections. Other coronary arteries in need of bypass grafting are grafted as per usual practice, using arterial grafts. Patients are therefore randomized to one of four groups at the time of coronary artery bypass grafting:
- growth factor (VEGF) angiogenesis along the diffusely diseased, non-directly bypassed LAD segment + L-arginine oral supplementation;
- placebo "angiogenesis" along the diffusely diseased, non-directly bypassed LAD segment + L-arginine oral supplementation;
- growth factor (VEGF) angiogenesis along the diffusely diseased, non-directly bypassed LAD segment + placebo oral supplementation; and
- placebo "angiogenesis" along the diffusely diseased, non-directly bypassed LAD segment + placebo oral supplementation.
The angiogenesis treatment consists either of the injection of 2 mg (divided in 10 injections of 200 μg each) of plasmid DNA encoding for the VEGF165 gene or of 10 x 1 ml injections of a sterile physiologic saline solution in the myocardial territory and septum along the diffusely diseased, non-directly bypassed LAD segment. Other myocardial territories are concomitantly revascularized with arterial coronary bypass grafts.
The EMAT trial's primary end-points relate to objective myocardial perfusion indices and contractility of the intervened anterior myocardial portion, respectively measured with cardiac positron-emission tomography (PET) by using the investigational radioisotope 13-N ammonia, and by RNA or echocardiography. Using 13-N PET, collateral-dependent blood flow and ischemic zone size are measured in a double-blind fashion by a single observer at baseline and at 3 months. To better delineate the actual effects of angiogenic therapy, baseline perfusion scans are obtained 3 to 5 days after the operative procedure in order to account for the potentially confounding effect of CABG on myocardial perfusion to the proximal and distal anterior and septal territories. The functional, secondary end-points of the EMAT trial consist of clinical outcomes including major adverse cardiac events (MACE), freedom from angina, and angina class.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Factorial
- Masking
- Double blind
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Severe chronic angina
- Multi-vessel coronary artery disease
- Diffusely diseased left anterior descending coronary artery (LAD)
- At least 18 years of age at the time of written informed consent
Key exclusion criteria (15 listed)
- Pregnancy, lactation, or any child-bearing potential
- Patients who are candidates for percutaneous transluminal coronary angioplasty (PTCA) or stenting
- Severe left ventricular dysfunction (ejection fraction < 30%)
- Threatened proximal coronary occlusion or unstable angina
- Recent myocardial infarction (< 1 month)
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 |
|---|---|---|
| intramyocardial VEGF angiogenesis (at a dose of 2 mg) | Genetic | – |
| oral L-arginine supplementation (at a dose of 6 g/day) | Drug | – |
Primary outcome
Blood flow to ischemic zone at 6 months compared to baseline: Persantine Ammonia Perfusion PET done at baseline prior to discharge from hospital and repeated at 3 months post intervention
Echocardiogram done at baseline prior to discharge from hospital and repeated at 3 months post intervention
Freedom from angina recurrence: Study participant interview and Seattle Angina Questionnaire administered (3 months, 6 months, 1 year). Results compared from preoperative baseline.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Jun 2012.
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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.
Marc Ruel, MD MPH FRCSC principal investigator
Ottawa Heart Institute Research Corporation
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing intramyocardial VEGF angiogenesis (at a dose of 2 mg) and oral L-arginine supplementation (at a dose of 6 g/day) in people with Coronary Artery Disease, run by Ottawa Heart Institute Research Corporation at 1 site in Canada.
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 4 inclusion and 15 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: finished, as of the sponsor's last update on 21 Jun 2012. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
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 is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
Blood flow to ischemic zone at 6 months compared to baseline: Persantine Ammonia Perfusion PET done at baseline prior to discharge from hospital and repeated at 3 months post intervention. The study lists 3 primary outcomes in all. 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 21 Jun 2012.