Intermittent ClaudicationPhase 1NCT00080392
EW-A-401 to Treat Intermittent Claudication
A Phase 1 study testing DNA Plasmid Vector and EW-A-401 DNA Plasmid Vector in people with Intermittent Claudication and Arteriosclerosis, run by National Heart, Lung, and Blood Institute (NHLBI) at 3 sites in United States.
Trial summary
This study will test the safety of a drug called EW-A-401 in patients with intermittent claudication - pain and discomfort in the legs due to blockages of the arteries. The study will also evaluate whether EW-A-401 improves blood flow to the legs. Read more about this study
- Who is it for?
- Ages 21 years and older
- Conditions the study is for
- Intermittent Claudication, Arteriosclerosis
- What is being tested?
- DNA Plasmid Vector and EW-A-401 DNA Plasmid Vector
- How many people
- 10 participants
- Where
- 3 sitesUnited States
- Study dates
- 27 Mar 2004to 29 Dec 2011
- Phase
- Phase 1
- 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 21 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Adults greater than or equal to 21 years.
- Limiting lower limb intermittent claudication due to infra-inguinal obstructive atherosclerosis, not optimal for catheter-based treatment.
- Patient femoral artery inflow by radio contrast or magnetic resonance angiography within the previous 12 months.
- Stable symptoms for at least 4 months.
- Peak walking time (PWT) on standardized Gardner Exercise Treadmill Exam between 1 and 12 minutes.
- Resting ankle-brachial systolic blood pressure index (ABI) less than 0.9 in the more-affected limb.
Show all 11Show fewer
- Bilateral PAD for subjects enrolled into Strata C-F with the less-affected limb having any of the following:
- Resting or post-exercise ABI less than or equal to 0.9.
- Typical intermittent claudication.
- Infrainguinal obstructive atherosclerosis in a femoropopliteal and/or tibial artery greater than or equal to 70%.
- Subjects enrolled into Strata A and B may have both unilateral or bilateral peripheral atherosclerotic disease.
Who cannot join
- Any history of malignancy or a known genetic predisposition for developing cancer except for curatively resected basal cell carcinoma of skin, squamous cell carcinoma of skin, cervical carcinoma in situ, or resected benign colonic polyps.
- Non-compressible arteries (resting ankle-brachial systolic blood pressure index (ABI) greater than 1.3 in the more-affected limb).
- Evidence of malignancy after screening according to modified American Cancer Society Guidelines in the following organ systems (screening procedures in addition to history and physical exam are noted):
- -Prostate: subjects with the following PSA levels above the recommended age-specific cut-points will be excluded
- Age 50-59 greater than or equal to 3.7
- Age 60-69 greater than or equal to 5.1
Show all 48Show fewer
- Age 70-79 greater than or equal to 7.0
- Age 80 plus-greater than or equal to 7.2
- Subjects with PSA values above the age-specific cut-points are eligible if a prostate biopsy, within 12 months, shows neither prostate cancer nor high-grade prostatic intraepithelial neoplasia (PIN).
- Breast: mammogram
- Cervix: Pap smear
- Colon: Colonoscopy
- Skin
- Lung: contrast chest CT scan
- Proliferative retinopathy, severe non-proliferative retinopathy, advanced age-related macular degeneration, especially subjects with chorodial neovascularization, diabetic retinopathy, macular edema, or intraocular surgery within 3 months.
- Limiting symptom on Gardner Exercise Treadmill Examination other than intermittent claudication.
- Co-morbid conditions that limit exercise capacity:
- Severe arthritis affecting lower extremities
- Severe chronic obstructive pulmonary disease
- Angina pectoris greater than Canadian Angina Class 2
- Dyspnea greater than New York Heart Association Class II
- Cardiovascular surgery or percutaneous revascularization within 4 months.
- Inclusion is permitted two or more months after successful iliac stenting in the presence of significant infra-inguinal atherosclerotic obstruction.
- Inclusion is permitted immediately after unsuccessful attempts at percutaneous recanalization of total occlusions of infra-inguinal arteries.
- Coagulopathy:
- aPTT greater than 1.4 x mean laboratory normal reference range
- International Normalized Ration of Prothrombin Time greater than 1.5
- Patients on anticoagulation therapy are eligible to participate, with reversal of coagulopathy in accordance with ACC/AHA guidelines, except patients with: Recent arterial (0-1 month) thromboemboism; Recent venous (0-3 months) thromboembolism; Recurrent venous thromboembolism; Non-valvular atrial fibrillation and previous thromboembolism; Mechanical prosthetic valve.
- Women of childbearing potential.
- Subjects unwilling to use barrier contraception during the study.
- Subjects unsuitable for unilateral investigational thigh compression for perfusion measurements due to:
- Patent femoropopliteal or femorotibial bypass graft or patent femoropopliteal stent on both limbs.
- Subjects with one of the above features who are amenable to contralateral thigh compression are eligible for enrollment.
- Immune compromise including chronic HIV, HBV, and HCV infection.
- Contraindication to Magnetic Resonance Imaging:
- Allergy to Gadolinium MRI contrast agents.
- Implanted cardiac pacemaker or defibrillator.
- Central nervous system aneurysm clips.
- Implanted neural stimulator.
- Cochlear implant.
- Ocular foreign body (e.g. metal shavings).
- Insulin Pump.
- Metal shrapnel or bullet.
- Note: When subjects can provide evidence that their implanted device is labeled compatible with MRI, exceptions to the above exclusions can be made and recorded in the note.
- Creatinine clearance less than or equal to 20 mL per minute. Creatinine clearance (CLcr) will be estimated using the Cockcroft-Gault formula.
- Current alcohol, drug abuse, severe medical, psychiatric, behavioral, or emotional disorder of any other condition that may preclude a subject from complying with all requirement of the protocol.
- Subjects receiving experimental medication or participating in another study receiving an experimental drug or procedure within 30 days prior to enrollment.
- Unable or unwilling to provide written informed consent.
Trial locations and contacts
3 sites in 1 country.
United States3 sites
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
Baptist Health System, Inc.
Birmingham, Alabama, 35213
University of Wisconsin
Madison, Wisconsin, 53792
About this study
Official title: Modulation of Vascular Endothelial Growth Factor (VEGF) Using an Engineered Zinc-Finger Transcription Factor to Treat Lower Limb Intermittent Claudication
This study will test the safety of a drug called EW-A-401 in patients with intermittent claudication - pain and discomfort in the legs due to blockages of the arteries. The study will also evaluate whether EW-A-401 improves blood flow to the legs. EW-A-401 contains genetic material (DNA) that instructs the body to produce specific proteins that promote the growth of new blood vessels and may, therefore, improve blood flow to the legs.
Patients 21 years of age and older with pain or discomfort of one or both legs due to blockages of the arteries below the groin may be eligible for this study. Candidates are screened with a medical history, physical examination, blood and urine tests, eye examination, chest x-ray and CT scan of the chest, and treadmill tests. Patients who are able to exercise more than 12 minutes on the treadmill may not enroll in the study.
Read more
Participants undergo the following procedures:
- Muscle biopsy: On the first day of the study, patients have a muscle biopsy. This procedure is done under local anesthesia with mild sedation. A 1-inch incision is cut into the skin over a calf muscle and a small amount of muscle tissue is removed for examination by a pathologist.
- Drug treatment and tests: About 10 to 13 days after the biopsy, patients are admitted to the NIH Clinical Center for 3 to 5 days for drug treatment and tests. They receive 10 injections of either the study drug (EW-A-401) or placebo (an inactive substance) in each leg during a single session lasting about 1 hour. In addition, they have blood and urine tests, complete questionnaires about their symptoms, and undergo magnetic resonance imaging (MRI), a test that a magnetic field and radio waves to produce detailed images of body tissues and organs. For this procedure, the patient lies on a table that slides into the scanner (a large hollow tube) for imaging of the blood vessels in the legs. Patients wear headphones to muffle loud knocking and thumping sounds that occur during the scanning process.
- 30-day follow-up: Patients return to the Clinical Center three times over 30 days following the hospital stay for a medical history, physical examination, and blood and urine tests to assess the safety of EW-A-401.
- Extended follow-up: Patients return to the Clinical Center at 3, 6, and 12 months after hospitalization for a medical history and physical examination, blood and urine tests, two treadmill tests, questionnaires about symptoms, and MRI studies, including imaging for blood flow measurement. Blood flow to the legs is measured during MRI using large blood pressure cuffs inflated around the legs during the scanning. The cuffs are inflated very tightly for 5 minutes, and then a dye is injected into an arm vein to brighten the images. Additional pictures are taken over the next 5 to 10 minutes. At two of these follow-up visits, patients also have an eye examination, and at the 3- or 6-month visit they have a repeat muscle biopsy of the calf.
The study lasts 12 months. After 6 months, patients will be told whether they received EW-A-401 or placebo. Because EW-A-401 is so new, patients will continue to be contacted every year after the study is completed.
Read the detailed description
Lower limb intermittent claudication, muscular pain with exercise relieved promptly by rest, is a disabling syndrome affecting over 10 million patients in the United States. Intermittent claudication is caused by peripheral artery atherosclerosis, the same disease causing heart attack. Peripheral artery atherosclerosis impairs blood flow to skeletal muscles in the lower limbs. Growth factors, such as vascular endothelial growth factor (VEGF-A), have been shown in animal studies to improve blood flow the lower limbs by promoting the growth of new blood vessels.
This clinical study tests the safety and feasibility of gene transfer of an agent (EW-A-401) intended to improve blood flow in the skeletal muscle of subjects with intermittent claudication. The investigational agent is a circle of genetic material (plasmid DNA) that instructs the body to produce a genetically-engineered transcription factor, a protein that regulates expression of genes. This specific transcription factor has been shown in animal studies to increase expression of the VEGF-A gene, and to promote the growth of new blood vessels. The study agent will be delivered by injection into leg muscle during a single session. This is the first human experience using this transcription factor.
This study has a randomized, double-blind, dose-escalation, placebo-controlled design. The primary outcome measure will be safety and toxicity. In addition, we will collect exploratory effectiveness information including blood flow, walking capacity, quality of life, and inspection of blood vessels on samples of leg muscle.
- Conditions
- Intermittent Claudication, Arteriosclerosis
- Being tested
- DNA Plasmid Vector, EW-A-401 DNA Plasmid Vector
- Keywords
- Gene Transfer, Therapeutic Angiogenesis, Peripheral Arterial Disease, Perfusion, Magnetic Resonance Imaging, Peripheral Vascular Disease, Claudication, PAD, Leg Claudication, Intermittent Claudication
- Medical subject headings
- Intermittent Claudication, Arteriosclerosis, Peripheral Arterial Disease, Peripheral Vascular Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DNA Plasmid VectorDrug
EW-A-401 DNA Plasmid VectorDrug
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Mar 2004 (estimated)
- Study start27 Mar 2004
- Study completion29 Dec 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Intermittent ClaudicationStudies of the same condition, open and under way.
- More trials run by National Heart, Lung, and Blood Institute (NHLBI)The 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
- Primary purpose
- Treatment
- Enrolment
- 10 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00080392
- Sponsor's protocol ID
- 040143
- Other IDs
- 04-H-0143
- Status last verified
- 29 Dec 2011
- First submitted
- 30 Mar 2004
- Last updated
- 12 Dec 2019
- Results posted
- No
Publications
Anderson WF. What about those monkeys that got T-cell lymphoma? Hum Gene Ther. 1993 Feb;4(1):1-2. doi: 10.1089/hum.1993.4.1-1. No abstract available.
PubMed 84613792nd Euregenethy Multidisciplinary Forum on Regulatory and Safety Issues in Gene Therapy. June 9-11, 2000. Paris, France. Abstracts. J Gene Med. 2000;2(4 Suppl):1-47. No abstract available.
PubMed 10979487Adam E, Nasz I. [Adenovirus vectors and their clinical application in gene therapy]. Orv Hetil. 2001 Sep 23;142(38):2061-70. Hungarian.
PubMed 11697063
Study at a glance
From the registry record, last updated by the sponsor on 12 Dec 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Modulation of Vascular Endothelial Growth Factor (VEGF) Using an Engineered Zinc-Finger Transcription Factor to Treat Lower Limb Intermittent Claudication
- ClinicalTrials.gov ID
- NCT00080392
- Acronym / sponsor ID
- 040143
- Conditions
- Intermittent Claudication, Arteriosclerosis
- Keywords
- Gene Transfer, Therapeutic Angiogenesis, Peripheral Arterial Disease, Perfusion, Magnetic Resonance Imaging, Peripheral Vascular Disease, Claudication, PAD
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 10 participants (actual)
- Lead sponsor
- National Heart, Lung, and Blood Institute (NHLBI)US National Institutes of Health
- Study start
- 27 Mar 2004
- Study completion
- 29 Dec 2011 (actual)
- First posted
- 30 Mar 2004 (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.
This study will test the safety of a drug called EW-A-401 in patients with intermittent claudication - pain and discomfort in the legs due to blockages of the arteries. The study will also evaluate whether EW-A-401 improves blood flow to the legs. EW-A-401 contains genetic material (DNA) that instructs the body to produce specific proteins that promote the growth of new blood vessels and may, therefore, improve blood flow to the legs.
Patients 21 years of age and older with pain or discomfort of one or both legs due to blockages of the arteries below the groin may be eligible for this study. Candidates are screened with a medical history, physical examination, blood and urine tests, eye examination, chest x-ray and CT scan of the chest, and treadmill tests. Patients who are able to exercise more than 12 minutes on the treadmill may not enroll in the study.
Participants undergo the following procedures:
- Muscle biopsy: On the first day of the study, patients have a muscle biopsy. This procedure is done under local anesthesia with mild sedation. A 1-inch incision is cut into the skin over a calf muscle and a small amount of muscle tissue is removed for examination by a pathologist.
- Drug treatment and tests: About 10 to 13 days after the biopsy, patients are admitted to the NIH Clinical Center for 3 to 5 days for drug treatment and tests. They receive 10 injections of either the study drug (EW-A-401) or placebo (an inactive substance) in each leg during a single session lasting about 1 hour. In addition, they have blood and urine tests, complete questionnaires about their symptoms, and undergo magnetic resonance imaging (MRI), a test that a magnetic field and radio waves to produce detailed images of body tissues and organs. For this procedure, the patient lies on a table that slides into the scanner (a large hollow tube) for imaging of the blood vessels in the legs. Patients wear headphones to muffle loud knocking and thumping sounds that occur during the scanning process.
- 30-day follow-up: Patients return to the Clinical Center three times over 30 days following the hospital stay for a medical history, physical examination, and blood and urine tests to assess the safety of EW-A-401.
- Extended follow-up: Patients return to the Clinical Center at 3, 6, and 12 months after hospitalization for a medical history and physical examination, blood and urine tests, two treadmill tests, questionnaires about symptoms, and MRI studies, including imaging for blood flow measurement. Blood flow to the legs is measured during MRI using large blood pressure cuffs inflated around the legs during the scanning. The cuffs are inflated very tightly for 5 minutes, and then a dye is injected into an arm vein to brighten the images. Additional pictures are taken over the next 5 to 10 minutes. At two of these follow-up visits, patients also have an eye examination, and at the 3- or 6-month visit they have a repeat muscle biopsy of the calf.
The study lasts 12 months. After 6 months, patients will be told whether they received EW-A-401 or placebo. Because EW-A-401 is so new, patients will continue to be contacted every year after the study is completed.
Detailed description
Lower limb intermittent claudication, muscular pain with exercise relieved promptly by rest, is a disabling syndrome affecting over 10 million patients in the United States. Intermittent claudication is caused by peripheral artery atherosclerosis, the same disease causing heart attack. Peripheral artery atherosclerosis impairs blood flow to skeletal muscles in the lower limbs. Growth factors, such as vascular endothelial growth factor (VEGF-A), have been shown in animal studies to improve blood flow the lower limbs by promoting the growth of new blood vessels.
This clinical study tests the safety and feasibility of gene transfer of an agent (EW-A-401) intended to improve blood flow in the skeletal muscle of subjects with intermittent claudication. The investigational agent is a circle of genetic material (plasmid DNA) that instructs the body to produce a genetically-engineered transcription factor, a protein that regulates expression of genes. This specific transcription factor has been shown in animal studies to increase expression of the VEGF-A gene, and to promote the growth of new blood vessels. The study agent will be delivered by injection into leg muscle during a single session. This is the first human experience using this transcription factor.
This study has a randomized, double-blind, dose-escalation, placebo-controlled design. The primary outcome measure will be safety and toxicity. In addition, we will collect exploratory effectiveness information including blood flow, walking capacity, quality of life, and inspection of blood vessels on samples of leg muscle.
Study design
- Primary purpose
- Treatment
Who may qualify
- Ages
- 21 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (11 listed)
- Resting or post-exercise ABI less than or equal to 0.9.
- Typical intermittent claudication.
- Infrainguinal obstructive atherosclerosis in a femoropopliteal and/or tibial artery greater than or equal to 70%.
- Subjects enrolled into Strata A and B may have both unilateral or bilateral peripheral atherosclerotic disease.
Key exclusion criteria (48 listed)
- Any history of malignancy or a known genetic predisposition for developing cancer except for curatively resected basal cell carcinoma of skin, squamous cell carcinoma of skin, cervical carcinoma in situ, or resected benign colonic polyps.
- Non-compressible arteries (resting ankle-brachial systolic blood pressure index (ABI) greater than 1.3 in the more-affected limb).
- Evidence of malignancy after screening according to modified American Cancer Society Guidelines in the following organ systems (screening procedures in addition to history and physical exam are noted):
- -Prostate: subjects with the following PSA levels above the recommended age-specific cut-points will be excluded
- Age 50-59 greater than or equal to 3.7
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 |
|---|---|---|
| DNA Plasmid Vector | Drug | – |
| EW-A-401 DNA Plasmid Vector | Drug | – |
Primary outcome
Not reported in the source record.
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 12 Dec 2019.
- Background: PubMed 8461379Anderson WF. What about those monkeys that got T-cell lymphoma? Hum Gene Ther. 1993 Feb;4(1):1-2. doi: 10.1089/hum.1993.4.1-1. No abstract available.
- Background: PubMed 109794872nd Euregenethy Multidisciplinary Forum on Regulatory and Safety Issues in Gene Therapy. June 9-11, 2000. Paris, France. Abstracts. J Gene Med. 2000;2(4 Suppl):1-47. No abstract available.
- Background: PubMed 11697063Adam E, Nasz I. [Adenovirus vectors and their clinical application in gene therapy]. Orv Hetil. 2001 Sep 23;142(38):2061-70. Hungarian.
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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.
The record lists no contact. Use the official record to reach the sponsor.
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing DNA Plasmid Vector and EW-A-401 DNA Plasmid Vector in people with Intermittent Claudication and Arteriosclerosis, run by National Heart, Lung, and Blood Institute (NHLBI) at 3 sites in United States.
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 11 inclusion and 48 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 12 Dec 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in United States. 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 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.
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.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00080392, which also lists 3 linked publications.
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 12 Dec 2019.