Efficacy and safety of intramuscular administration of allogeneic adipose tissue derived and expanded mesenchymal stromal cells in diabetic patients with critical limb ischemia with no possibility of revascularization: study protocol for a randomized controlled double-blind phase II clinical trial (The NOMA Trial)

Abstract Background Chronic lower limb ischemia develops earlier and more frequently in patients with type 2 diabetes mellitus. Diabetes remains the main cause of lower-extremity non-traumatic amputations. Current medical treatment, based on antiplatelet therapy and statins, has demonstrated deficient improvement of the disease. In recent years, research has shown that it is possible to improve tissue perfusion through therapeutic angiogenesis. Both in animal models and humans, it has been shown that cell therapy can induce therapeutic angiogenesis, making mesenchymal stromal cell-based therapy one of the most promising therapeutic alternatives. The aim of this study is to evaluate the feasibility, safety, and efficacy of cell therapy based on mesenchymal stromal cells derived from adipose tissue intramuscular administration to patients with type 2 diabetes mellitus with critical limb ischemia and without possibility of revascularization. Methods A multicenter, randomized double-blind, placebo-controlled trial has been designed. Ninety eligible patients will be randomly assigned at a ratio 1:1:1 to one of the following: control group (n = 30), low-cell dose treatment group (n = 30), and high-cell dose treatment group (n = 30). Treatment will be administered in a single-dose way and patients will be followed for 12 months. Primary outcome (safety) will be evaluated by measuring the rate of adverse events within the study period. Secondary outcomes (efficacy) will be measured by assessing clinical, analytical, and imaging-test parameters. Tertiary outcome (quality of life) will be evaluated with SF-12 and VascuQol-6 scales. Discussion Chronic lower limb ischemia has limited therapeutic options and constitutes a public health problem in both developed and underdeveloped countries. Given that the current treatment is not established in daily clinical practice, it is essential to provide evidence-based data that allow taking a step forward in its clinical development. Also, the multidisciplinary coordination exercise needed to develop this clinical trial protocol will undoubtfully be useful to conduct academic clinical trials in the field of cell therapy in the near future. Trial registration ClinicalTrials.govNCT04466007. Registered on January 07, 2020. All items from the World Health Organization Trial Registration Data Set are included within the body of the protocol.

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Efficacy and safety of intramuscular administration of allogeneic adipose tissue derived and expanded mesenchymal stromal cells in patients with critical limb ischemia and type 2 diabetes with no possibility of revascularization: Study protocol for a randomized controlled double-blind phase II clinical trial (The NOMA Trial).

10.21203/rs.3.rs-321347/v1 ◽

2021 ◽

Author(s):

Barbara Soria-Juan ◽

Mariano Garcia-Arranz ◽

Lucía Llanos ◽

César Aparicio ◽

Alejandro Gonzalez ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Cell Therapy ◽

Stromal Cells ◽

Lower Limb ◽

Limb Ischemia ◽

Therapeutic Angiogenesis ◽

Double Blind ◽

Lower Limb Ischemia

Abstract Background: Chronic lower limb ischemia develops earlier and more frequently in patients with type 2 diabetes mellitus. Diabetes remains the main cause of lower-extremity non-traumatic amputations. Current medical treatment, based on antiplatelet therapy and statins, has demonstrated deficient improvement of the disease. In recent years, research has shown that it is possible to improve tissue perfusion through therapeutic angiogenesis. Both in animal models and humans, it has been shown that cell therapy can induce therapeutic angiogenesis, making mesenchymal stromal cell-based therapy one of the most promising therapeutic alternatives. The aim of this study is to evaluate the feasibility, safety and efficacy of cell therapy based on mesenchymal stromal cells derived from adipose tissue intramuscular administration to patients with type 2 diabetes mellitus with critical limb ischemia and without possibility of revascularization. Methods: A multicenter, randomized double-blind, placebo-controlled trial has been designed. 90 eligible patients will be randomly assigned at a ratio 1:1:1 to one of the following: the control group (n=30), low cell dose treatment group (n=30), and high cell dose treatment group (n=30). Treatment will be administered in a single-dose way and patients will be followed for 12 months. Primary outcome (safety) will be evaluated by measuring the rate of adverse events within the study period. Secondary outcomes (efficacy) will be measured by assessing clinical, analytical and imaging-test parameters. Tertiary outcome (quality of life) will be evaluated with SF-12 and VascuQol-6 scales. Discussion: Chronic lower limb ischemia has limited therapeutic options and constitutes a public health problem in both developed and underdeveloped countries. Given that the current treatment is not established in daily clinical practice, it is essential to provide evidence-based data that allow taking a step forward in its clinical development. Also, the multidisciplinary coordination exercise needed to develop this clinical trial protocol will undoubtfully be useful to conduct academic clinical trials in the field of cell therapy in the near future.Trial registration: ClinicalTrials.gov NCT04466007. Registered on January 07, 2020.

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Erosive and ulcerative lesions of the gastrointestinal tract and bleeding in patients with critical lower limb ischemia and diabetes mellitus underwent endovascular interventions

Grekov s Bulletin of Surgery ◽

10.24884/0042-4625-2021-180-1-65-72 ◽

2021 ◽

Vol 180 (1) ◽

pp. 65-72

Author(s):

A. A. Poliantsev ◽

D. V. Frolov ◽

A. M. Linchenko ◽

S. N. Karpenko ◽

A. A. Chernovolenko ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Lower Limb ◽

Limb Ischemia ◽

Lower Limb Ischemia ◽

Endovascular Interventions ◽

Ulcerative Lesions ◽

The Relationship

The objective was to study the prevalence of erosive and ulcerative gastroduodenal lesions, bleedings of this localization and the relationship with factors predisposing to them in patients with critical lower limb ischemia and type 2 diabetes mellitus who underwent endovascular intervention for limb revascularization.Methods and materials. The study included 81 patients aged 67.5±6.8 years, hospitalized in the department of vascular surgery with critical lower limb ischemia of atherosclerotic genesis and type 2 diabetes mellitus to perform revascularization by means of transluminal balloon angioplasty with stenting when indicated. In the preoperative period, all patients underwent fibrogastroduodenoscopy, according to the results of which a scoring assessment of the lesion of the gastric mucosa and duodenum was presented.Results. All patients participating in the study were diagnosed with pathology of the gastroduodenal zone: in 95.1 % of the inflammatory nature, in 4.9 % of the ulcer. The relationship between the duration of rest pain, the fact of damage to the mucous membrane of the upper gastrointestinal tract and its severity was not revealed, but the relationship of erosive and ulcerative lesions of the stomach and duodenum with the number of taken pain pills was determined. In patients with repeated endovascular intervention and / or amputation, gastrointestinal bleedings were more often recorded compared with study participants who underwent a single revascularization – 11.1 and 1.6 % of patients, respectively.Conclusion. Erosive and ulcerative lesions of varying severity are present in all patients with critical lower limb ischemia on the background of diabetes mellitus. At the same time, patients with repeated endovascular interventions and / or amputations are more susceptible to bleeding. For the prevention of pathology of the stomach and duodenum, an in-depth diagnosis and a differentiated approach are required.

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Hyperfibrinogenemia in Peripheral Arterial Disease: Coexistent and Independent Risk Factor (A Report of Two Cases and Review of Literature)

PRILOZI ◽

10.2478/prilozi-2018-0046 ◽

2018 ◽

Vol 39 (2-3) ◽

pp. 93-96

Author(s):

Marijan Bosevski ◽

Gorjan Krstevski ◽

Irena Mitevska ◽

Emilija Antova ◽

Golubinka Bosevska

Keyword(s):

Diabetes Mellitus ◽

Risk Factor ◽

Lower Limb ◽

Case Reports ◽

Limb Ischemia ◽

Arterial Disease ◽

Lower Limb Ischemia ◽

Left Limb ◽

Peripheral Arterial

Abstract These case reports aim to show that hyperfibrinogenemia is a risk factor for the progression and prognosis of peripheral arterial disease (PAD), in patients with and without diabetes mellitus type 2. We present a patient with PAD who has type 2 diabetes mellitus, who has previously been repeatedly treated for lower limb ischemia with multiple vascular surgeries performed. A few weeks before admission the patient developed critical lower limb ischemia, which was treated with an iliaco-popliteal and femorofemoral bypass. The patient had elevated serum fibrinogen values. In the current admission, renewed left limb ischemia was diagnosed, and surgically evaluated with a recommendation for amputation of the left limb as a surgical recommendation. Our second patient had a stable intermittent claudication, dyslipidemia and hyperfibrinogenemia. He was successfully treated for those risk factors. Regular monitoring of the patient showed improved claudication distance and quality of life Our case reports, supported by a literature review, demonstrate that hyperfibrinogenemia is a possible risk factor for progression and the prognosis of PAD.

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