The Endovascular Plus GENe Therapy Versus Only EndoVascular Therapy for Severe Limb ischaemiA Trial

Официальное название

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

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат 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 po

Первичные конечные точки

• Numper of participants with freedom from repeated interventions on the operated segment [Срок оценки: within 2 years after the intervention]
• Numper of participants with freedom from high amputations [Срок оценки: within 2 years after the intervention]

Вторичные конечные точки (11)

• amputation-free survival [Срок оценки: within 2 years after the intervention]
• overall survival [Срок оценки: within 2 years after the intervention]
• time to major amputation [Срок оценки: within 2 years after the intervention]
• time to MALE (Major adverse limb event ) [Срок оценки: within 2 years after the intervention]
• time to MACE (Major adverse cardiovascular event ) [Срок оценки: within 2 years after the intervention]
• change time in pain-free walking distance [Срок оценки: within 2 years after the intervention]
• safety assessment - monitoring for serious adverse events throughout the study after the first drug administration [Срок оценки: within 2 years after the intervention]
• Number of participants with mortality [Срок оценки: 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 [Срок оценки: within 2 years after the intervention]
• Dynamics of ulcerchealing in diabetic foot syndrome according to the PEDIS classification (Perfusion, Extent, Depth, Infection, Sensation) [Срок оценки: within 2 years after the intervention]
• Hemodynamic measurements (ankle brachial index changes) [Срок оценки: within 2 years after the intervention]

Критерии участия

Критерии включения

• 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;
• 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.

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Россия · 1 центр

• Amur State Medical Academy — Blagoveshchensk

Публикации

• 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. PMID 32240132

Идентификаторы

NCT: NCT06473740 · GENEVA

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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