Clinical trial NCT06473740: The Endovascular Plus GENe Therapy Versus Only EndoVascular Therapy for Severe Limb ischaemiA Trial
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Severe Lower Limb Ischemia
Keywords: gene therapy
amputation
severe lower limb ischemia
endovascular treatment
stenting
balloon angioplasty
Lead sponsor: Amur State Medical Academy
Sponsor class: OTHER
First posted: 2024-06-25
Enrollment: 386
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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). 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.

Eligibility criteria: Inclusion Criteria:

1. Men and women 18 years of age and older;
2. Atherosclerotic infrainguinal disease of the peripheral arteries (occlusive-stenotic lesion below the inguinal fold);
3. 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;
4. Without any previous surgical intervention of the ipsilateral n/a below the inguinal fold;
5. Suitable for endovascular treatment according to researchers;
6. Adequate inflow through the aorto-iliac segment;
7. Willingness to comply with the study protocol, attend follow-up examinations, comply with all instructions and provide written informed consent.

Non-inclusion criteria:

1. Infrainguinal disease of peripheral arteries of non-atherosclerotic origin (aortoarteritis, thromboangiitis, congenital anomalies, vascular injuries, etc.) or acute ischemia;
2. Severe ischemia of the lower limb, characterized by gangrene (Rutherford category 6);
3. The presence of a popliteal aneurysm (\>2.0 cm) on the area of interest;
4. Life expectancy \<2 years, for reasons not related to occlusive-stenotic disease of the arteries of the n/c;
5. Planned high amputation on the ipsilateral lower extremity within 4 weeks after the planned endovascular procedure;
6. Hypersensitivity to any components included in the study drug;
7. Previous surgical intervention below the inguinal fold (open vascular, endovascular or hybrid treatment);
8. Open treatment of the inflow tract of the ipsilateral lower limb within 6 weeks before enrollment in the study (aortofemoral, iliofemoral, axillofemoral, femorofemoral bypass);
9. Current chemotherapy or radiation therapy;
10. Pregnancy or lactation;
11. Cases of AMI, CABG or stroke within 6 weeks before enrollment in the study;
12. An absolute contraindication to the use of iodinated contrast agent due to a previous severe allergic reaction (laryngospasm, bronchospasm, cardiorespiratory shock or their equivalent);
13. Participation in another clinical trial within the previous 30 days;
14. The patient's inability to understand the essence of the study;
15. Refusal of the patient to sign informed consent.

Exclusion Criteria:

1. Refusal of the patient to further participate in the study;
2. Use of drugs from the list of prohibited concomitant therapy;
3. 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;
4. Onset of pregnancy;
5. 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;
6. 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.
7. The occurrence or identification of concomitant diseases that prevent the patient's further participation in the clinical trial, in the opinion of the investigator.

Primary outcomes:
measure: Numper of participants with freedom from repeated interventions on the operated segment
timeFrame: within 2 years after the intervention
measure: Numper of participants with freedom from high amputations
timeFrame: within 2 years after the intervention
Secondary outcomes:
measure: amputation-free survival
timeFrame: within 2 years after the intervention
measure: overall survival
timeFrame: within 2 years after the intervention
measure: time to major amputation
timeFrame: within 2 years after the intervention
measure: time to MALE (Major adverse limb event )
timeFrame: within 2 years after the intervention
measure: time to MACE (Major adverse cardiovascular event )
timeFrame: within 2 years after the intervention
measure: change time in pain-free walking distance
timeFrame: within 2 years after the intervention
measure: safety assessment - monitoring for serious adverse events throughout the study after the first drug administration
timeFrame: within 2 years after the intervention
measure: Number of participants with mortality
timeFrame: within 30 days after the first revascularization
measure: VAS(Visual Pain System) pain reduction from 0 to 10, where 0 - no pain and 10 - very strong pain
timeFrame: within 2 years after the intervention
measure: Dynamics of ulcerchealing in diabetic foot syndrome according to the PEDIS classification (Perfusion, Extent, Depth, Infection, Sensation)
timeFrame: within 2 years after the intervention
measure: Hemodynamic measurements (ankle brachial index changes)
timeFrame: within 2 years after the intervention
Other outcomes:
Locations:
city: Blagoveshchensk
country: Russian Federation
facility: Amur State Medical Academy
state: Amur
Study officials:
affiliation: Amur State Medical Academy
name: Alrxander Korotkikh, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.