Severe Lower Limb IschemiaPhase 4NCT06473740
The Endovascular Plus GENe Therapy Versus Only EndoVascular Therapy for Severe Limb ischaemiA Trial
A Phase 4 study testing Deoxyribonucleic acid supercoiled plasmid pCMV-VEGF165 (Neovasculgen) in people with Severe Lower Limb Ischemia, run by Amur State Medical Academy at 1 site in Russia.
Trial summary
GENEVA is the world's first multicenter, randomized, prospective, controlled trial of the clinical effectiveness of best endovascular treatment versus best endovascular treatment combined with gene therapy for severe lower limb ischemia (Rutherford categories 4 and 5). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Severe Lower Limb Ischemia
- What is being tested?
- Deoxyribonucleic acid supercoiled plasmid pCMV-VEGF165 (Neovasculgen)
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 386 participants
- Where
- 1 siteRussia
- Study dates
- 20 Jun 2024to 19 May 2029
- Phase
- Phase 4
- Are there results?
- Not yet: the study is under way
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
- Men and women 18 years of age and older;
- Atherosclerotic infrainguinal disease of the peripheral arteries (occlusive-stenotic lesion below the inguinal fold);
- Severe ischemia of the lower extremity, characterized by pain at rest or a non-healing ischemic ulcer, which corresponds to Rutherford categories 4-5 and Fontaine grades III-IV;
- Without any previous surgical intervention of the ipsilateral n/a below the inguinal fold;
- Suitable for endovascular treatment according to researchers;
- Adequate inflow through the aorto-iliac segment;
Show all 23Show fewer
- Willingness to comply with the study protocol, attend follow-up examinations, comply with all instructions and provide written informed consent.
- Non-inclusion criteria:
- Infrainguinal disease of peripheral arteries of non-atherosclerotic origin (aortoarteritis, thromboangiitis, congenital anomalies, vascular injuries, etc.) or acute ischemia;
- Severe ischemia of the lower limb, characterized by gangrene (Rutherford category 6);
- The presence of a popliteal aneurysm (>2.0 cm) on the area of interest;
- Life expectancy <2 years, for reasons not related to occlusive-stenotic disease of the arteries of the n/c;
- Planned high amputation on the ipsilateral lower extremity within 4 weeks after the planned endovascular procedure;
- Hypersensitivity to any components included in the study drug;
- Previous surgical intervention below the inguinal fold (open vascular, endovascular or hybrid treatment);
- Open treatment of the inflow tract of the ipsilateral lower limb within 6 weeks before enrollment in the study (aortofemoral, iliofemoral, axillofemoral, femorofemoral bypass);
- Current chemotherapy or radiation therapy;
- Pregnancy or lactation;
- Cases of AMI, CABG or stroke within 6 weeks before enrollment in the study;
- An absolute contraindication to the use of iodinated contrast agent due to a previous severe allergic reaction (laryngospasm, bronchospasm, cardiorespiratory shock or their equivalent);
- Participation in another clinical trial within the previous 30 days;
- The patient's inability to understand the essence of the study;
- Refusal of the patient to sign informed consent.
Who cannot join
- Refusal of the patient to further participate in the study;
- Use of drugs from the list of prohibited concomitant therapy;
- The use of any other concomitant therapy that, in the opinion of the investigator, may interfere with the assessment of the effectiveness and safety of the investigational medicinal product and/or distort the results of the study;
- Onset of pregnancy;
- Injuries and damage to the ipsilateral lower limb, which, in the opinion of the investigator, may interfere with the assessment of the effectiveness and safety of the study drug and/or distort the results of the study;
- The presence of an adverse event that, in the opinion of the investigator, indicates that continued participation in the study poses an unacceptable risk for the patient.
- The occurrence or identification of concomitant diseases that prevent the patient's further participation in the clinical trial, in the opinion of the investigator.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Russia1 site, 1 recruiting
- Recruiting
Amur State Medical Academy
Blagoveshchensk, Amur Oblast, 675001
Alexander Korotkikh, PhD, +7 (922) 079-06-22, dr.alex.korotkikh@gmail.com
Sergey Radaev, +7 (969) 255-14-30, radaev@nextgene.ru
About this study
Official title: Multicenter Randomized Prospective Controlled Trial of the Clinical Effectiveness of a Best Endovascular Treatment Versus a Best Endovascular Treatment in Combination With Gene Therapy for Severe Limb Ischemia
GENEVA is the world's first multicenter, randomized, prospective, controlled trial of the clinical effectiveness of best endovascular treatment versus best endovascular treatment combined with gene therapy for severe lower limb ischemia (Rutherford categories 4 and 5). The researchers hypothesized that the combination treatment would significantly reduce the number of re-interventions on the operated segment and high amputations, and also significantly increase the time interval between re-interventions.
Read the detailed description
Objective - To prove the effectiveness and safety of combined endovascular treatment and gene therapy for Fontaine grades III and IV CI (Rutherford grades 4 and 5) in comparison with isolated endovascular treatment by comparing the immediate and long-term results of the two techniques, assessed using clinical and instrumental methods.
Null hypothesis (Н0) - After endovascular treatment in combination with gene therapy with supercoiled plasmid deoxyribonucleic acid pCMV-VEGF165 in patients with critical ischemia of the lower limb III and IV degrees according to Fontaine (categories 4 and 5 according to Rutherford), the number of re-interventions on the operated segment and the number high amputations will be the same as after isolated endovascular treatment.
The frequency of re-interventions on the operated segment during endovascular interventions in the long-term period according to the main randomized clinical trials (BASIL 1, BASIL 2, BEST-CLI) is 25.9%, 19.0%, 23.5%, and the number of high amputations (BASIL 1, BASIL 2) - 19.1% and 18.0% respectively. High amputations lead to disability and loss of performance, incl. and working population. Within 5 years after major amputation, more than half of patients die from concomitant diseases. Each repeat revascularization is significantly more difficult and longer than the previous intervention, reducing the potential for future interventions.
In this regard, the search for new modern minimally invasive methods for the treatment of critical ischemia of the lower extremities, which will help to significantly reduce the number of high amputations and repeated interventions, as well as increase the intervals between repeated interventions, is an extremely important medical and economic problem.
- Conditions
- Severe Lower Limb Ischemia
- Being tested
- Deoxyribonucleic acid supercoiled plasmid pCMV-VEGF165 (Neovasculgen)
- Keywords
- gene therapy, amputation, severe lower limb ischemia, endovascular treatment, stenting, balloon angioplasty
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Deoxyribonucleic acid supercoiled plasmid pCMV-VEGF165 (Neovasculgen)Drug
The drug "Neovasculgen" is a highly purified supercoiled form of the pCMV-VEGF165 plasmid, encoding the Vascular endothelial growth factor (VEGF) under the control of a promoter (DNA control region). Recombinant plasmid DNA consists of the following components: a fragment of the regulatory region (22 nucleotide pairs), which determines the transcription of the gene, the VEGF minigene, upon expression of which the VEGF isoform is synthesized, consisting of 165 amino acids, a splicing signal, a polyadenylation signal and the SV40 transcription terminator, ensuring the synthesis of the mature RNA gene and auxiliary regions required for efficient biosynthesis of plasmid DNA in the cells of the producer strain of Escherichia coli. When molecules of this plasmid penetrate into mammalian cells, VEGF is produced, which stimulates endothelial cells, which leads to the growth of blood vessels (vascularization) in the area of injection.
| Study group | Role | What they receive |
|---|---|---|
| Observation group | Experimental | Best endovascular treatment + Introduction Neovasculgen (International nonproprietary or group name: deoxyribonucleic acid plasmid supercoiled pCMV-VEGF165). Dosage form: Lyophilisate for the preparation of a solution for intramuscular administration in the form of a white powder. Composition for 1 bottle: Active ingredient: supercoiled plasmid deoxyribonucleic acid pCMV-VEGF165 1.2 mg. Excipients: dextrose monohydrate - 60.0 mg, sodium hydrogen phosphate dodecahydrate - 3.94 mg, sodium dihydrogen phosphate dihydrate - 0.16 mg. Description: White lyophilisate. Administer 1 bottle diluted in 20-50 ml of saline on days 7 and 21 after endovascular intervention intramuscularly along the affected vessel. Receives: Drug: Deoxyribonucleic acid supercoiled plasmid pCMV-VEGF165 (Neovasculgen) |
| Standart of Care | No intervention | Arterial stenting with stent grafts or balloon angioplasty |
What is being measured
The primary outcome is the main question the study is designed to answer.
Numper of participants with freedom from repeated interventions on the operated segment
the need for re-intervention on the operated segment will be determined based on the clinical data (return of severe ischemia of the operated limb) together with ultrasound and/or computed tomography data; counting the number of re-interventions in the study group
Measured: within 2 years after the intervention
Numper of participants with freedom from high amputations
amputations will be performed in patients with the development of gangrene of the lower limb; counting the number of high amputations in each study group
Measured: within 2 years after the intervention
Secondary outcomes (11)
amputation-free survival
database data
Measured: within 2 years after the intervention
overall survival
database data
Measured: within 2 years after the intervention
time to major amputation
database data
Measured: within 2 years after the intervention
time to MALE (Major adverse limb event )
database data
Measured: within 2 years after the intervention
time to MACE (Major adverse cardiovascular event )
database data
Measured: within 2 years after the intervention
change time in pain-free walking distance
database data
Measured: within 2 years after the intervention
safety assessment - monitoring for serious adverse events throughout the study after the first drug administration
according to the researchers and the monitor
Measured: within 2 years after the intervention
Number of participants with mortality
database data
Measured: within 30 days after the first revascularization
VAS(Visual Pain System) pain reduction from 0 to 10, where 0 - no pain and 10 - very strong pain
database data
Measured: within 2 years after the intervention
Dynamics of ulcerchealing in diabetic foot syndrome according to the PEDIS classification (Perfusion, Extent, Depth, Infection, Sensation)
database data
Measured: within 2 years after the intervention
Hemodynamic measurements (ankle brachial index changes)
database data
Measured: within 2 years after the intervention
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Jun 2024
- Study start20 Jun 2024
- Primary completion19 May 2027 (estimated)
- Study completion19 May 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Severe Lower Limb IschemiaStudies 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 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 386 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Amur State Medical Academy
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Alrxander Korotkikh, PhD, Principal investigator, Amur State Medical Academy
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06473740
- Sponsor's protocol ID
- GENEVA
- Status last verified
- Jun 2024
- First submitted
- 29 Feb 2024
- Last updated
- 5 Aug 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes
Publications
Vasil'ev AP, Strel'tsova NN, Bessonov IS, Korotkikh AV. [State of microcirculation in patients with atherosclerosis and diabetes mellitus after limb revascularization]. Angiol Sosud Khir. 2020;26(1):22-29. doi: 10.33529/ANGIO2020112. Russian.
PubMed 32240132
Study at a glance
From the registry record, last updated by the sponsor on 5 Aug 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Multicenter Randomized Prospective Controlled Trial of the Clinical Effectiveness of a Best Endovascular Treatment Versus a Best Endovascular Treatment in Combination With Gene Therapy for Severe Limb Ischemia
- ClinicalTrials.gov ID
- NCT06473740
- Acronym / sponsor ID
- GENEVA
- Conditions
- Severe Lower Limb Ischemia
- Keywords
- gene therapy, amputation, severe lower limb ischemia, endovascular treatment, stenting, balloon angioplasty
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 386 participants (estimated)
- Lead sponsor
- Amur State Medical AcademyUniversity, hospital or other
- Study start
- 20 Jun 2024 (actual)
- Primary completion
- 19 May 2027 (estimated)
- Study completion
- 19 May 2029 (estimated)
- First posted
- 25 Jun 2024 (actual)
- 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.
GENEVA is the world's first multicenter, randomized, prospective, controlled trial of the clinical effectiveness of best endovascular treatment versus best endovascular treatment combined with gene therapy for severe lower limb ischemia (Rutherford categories 4 and 5). The researchers hypothesized that the combination treatment would significantly reduce the number of re-interventions on the operated segment and high amputations, and also significantly increase the time interval between re-interventions.
Detailed description
Objective - To prove the effectiveness and safety of combined endovascular treatment and gene therapy for Fontaine grades III and IV CI (Rutherford grades 4 and 5) in comparison with isolated endovascular treatment by comparing the immediate and long-term results of the two techniques, assessed using clinical and instrumental methods.
Null hypothesis (Н0) - After endovascular treatment in combination with gene therapy with supercoiled plasmid deoxyribonucleic acid pCMV-VEGF165 in patients with critical ischemia of the lower limb III and IV degrees according to Fontaine (categories 4 and 5 according to Rutherford), the number of re-interventions on the operated segment and the number high amputations will be the same as after isolated endovascular treatment.
The frequency of re-interventions on the operated segment during endovascular interventions in the long-term period according to the main randomized clinical trials (BASIL 1, BASIL 2, BEST-CLI) is 25.9%, 19.0%, 23.5%, and the number of high amputations (BASIL 1, BASIL 2) - 19.1% and 18.0% respectively. High amputations lead to disability and loss of performance, incl. and working population. Within 5 years after major amputation, more than half of patients die from concomitant diseases. Each repeat revascularization is significantly more difficult and longer than the previous intervention, reducing the potential for future interventions.
In this regard, the search for new modern minimally invasive methods for the treatment of critical ischemia of the lower extremities, which will help to significantly reduce the number of high amputations and repeated interventions, as well as increase the intervals between repeated interventions, is an extremely important medical and economic problem.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Observation group | Experimental | Drug: Deoxyribonucleic acid supercoiled plasmid pCMV-VEGF165 (Neovasculgen)Best endovascular treatment + Introduction Neovasculgen (International nonproprietary or group name: deoxyribonucleic acid plasmid supercoiled pCMV-VEGF165). Dosage form: Lyophilisate for the preparation of a solution for intramuscular administration in the form of a white powder. Composition for 1 bottle: Active ingredient: supercoiled plasmid deoxyribonucleic acid pCMV-VEGF165 1.2 mg. Excipients: dextrose monohydrate - 60.0 mg, sodium hydrogen phosphate dodecahydrate - 3.94 mg, sodium dihydrogen phosphate dihydrate - 0.16 mg. Description: White lyophilisate. Administer 1 bottle diluted in 20-50 ml of saline on days 7 and 21 after endovascular intervention intramuscularly along the affected vessel. |
| Standart of Care | No intervention | –Arterial stenting with stent grafts or balloon angioplasty |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (23 listed)
- Men and women 18 years of age and older;
- Atherosclerotic infrainguinal disease of the peripheral arteries (occlusive-stenotic lesion below the inguinal fold);
- Severe ischemia of the lower extremity, characterized by pain at rest or a non-healing ischemic ulcer, which corresponds to Rutherford categories 4-5 and Fontaine grades III-IV;
- Without any previous surgical intervention of the ipsilateral n/a below the inguinal fold;
- Suitable for endovascular treatment according to researchers;
Key exclusion criteria (7 listed)
- Refusal of the patient to further participate in the study;
- Use of drugs from the list of prohibited concomitant therapy;
- The use of any other concomitant therapy that, in the opinion of the investigator, may interfere with the assessment of the effectiveness and safety of the investigational medicinal product and/or distort the results of the study;
- Onset of pregnancy;
- Injuries and damage to the ipsilateral lower limb, which, in the opinion of the investigator, may interfere with the assessment of the effectiveness and safety of the study drug and/or distort the results of the study;
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 |
|---|---|---|
| Deoxyribonucleic acid supercoiled plasmid pCMV-VEGF165 (Neovasculgen)The drug "Neovasculgen" is a highly purified supercoiled form of the pCMV-VEGF165 plasmid, encoding the Vascular endothelial growth factor (VEGF) under the control of a promoter (DNA control region). Recombinant plasmid DNA consists of the following components: a fragment of the regulatory region (22 nucleotide pairs), which determines the transcription of the gene, the VEGF minigene, upon expression of which the VEGF isoform is synthesized, consisting of 165 amino acids, a splicing signal, a polyadenylation signal and the SV40 transcription terminator, ensuring the synthesis of the mature RNA gene and auxiliary regions required for efficient biosynthesis of plasmid DNA in the cells of the producer strain of Escherichia coli. When molecules of this plasmid penetrate into mammalian cells, VEGF is produced, which stimulates endothelial cells, which leads to the growth of blood vessels (vascularization) in the area of injection. | Drug | Observation group |
Primary outcome
Numper of participants with freedom from repeated interventions on the operated segment
Time frame: within 2 years after the intervention
the need for re-intervention on the operated segment will be determined based on the clinical data (return of severe ischemia of the operated limb) together with ultrasound and/or computed tomography data; counting the number of re-interventions in the study group
Numper of participants with freedom from high amputations
Time frame: within 2 years after the intervention
amputations will be performed in patients with the development of gangrene of the lower limb; counting the number of high amputations in each study group
11 secondary outcomes
amputation-free survival
Time frame: within 2 years after the intervention
overall survival
Time frame: within 2 years after the intervention
time to major amputation
Time frame: within 2 years after the intervention
time to MALE (Major adverse limb event )
Time frame: within 2 years after the intervention
time to MACE (Major adverse cardiovascular event )
Time frame: within 2 years after the intervention
change time in pain-free walking distance
Time frame: within 2 years after the intervention
safety assessment - monitoring for serious adverse events throughout the study after the first drug administration
Time frame: within 2 years after the intervention
Number of participants with mortality
Time frame: within 30 days after the first revascularization
VAS(Visual Pain System) pain reduction from 0 to 10, where 0 - no pain and 10 - very strong pain
Time frame: within 2 years after the intervention
Dynamics of ulcerchealing in diabetic foot syndrome according to the PEDIS classification (Perfusion, Extent, Depth, Infection, Sensation)
Time frame: within 2 years after the intervention
Hemodynamic measurements (ankle brachial index changes)
Time frame: within 2 years after the intervention
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Aug 2024.
- Background: PubMed 32240132Vasil'ev AP, Strel'tsova NN, Bessonov IS, Korotkikh AV. [State of microcirculation in patients with atherosclerosis and diabetes mellitus after limb revascularization]. Angiol Sosud Khir. 2020;26(1):22-29. doi: 10.33529/ANGIO2020112. Russian.
- Individual participant dataSharing planned: Yes
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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.
Alrxander Korotkikh, PhD principal investigator
Amur State Medical Academy
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Deoxyribonucleic acid supercoiled plasmid pCMV-VEGF165 (Neovasculgen) in people with Severe Lower Limb Ischemia, run by Amur State Medical Academy at 1 site in Russia.
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 23 inclusion and 7 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: looking for participants now, as of the sponsor's last update on 5 Aug 2024. 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 Russia. 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 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Alrxander Korotkikh, PhD (+7 (922) 079-06-22, dr.alex.korotkikh@gmail.cpm), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Numper of participants with freedom from repeated interventions on the operated segment (time frame: within 2 years after the intervention). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06473740, which also lists 1 linked publication.
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 5 Aug 2024.