Safety and Efficacy Study of Autologous Bone Marrow Aspirate Concentrate for No-Option Critical Limb Ischemia

Study Overview
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Brief Summary
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The aim of the presented clinical trial is to evaluate a hypothesis, that BMAC prepared from bone marrow aspirate and injected intramuscularly into ischemic areas of the lower extremity in patients with diabetes mellitus type II., intraarterially into the defect of the limb or with an intravenous application only, has a greater potential to improve the perfusion in the ischemic limbs than standard treatment of NO-CLI. Another aim of the study is to find out differences among three different therapeutic types of BMAC application, to define their effectiveness and safety and to compare the impact of different means of application to the speed of healing of the limb defects and the improvement of perfusion parameters.

Detailed Description
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Secondary hypothesis assumes, that the intravenous application of BMAC in patients with T2DM older than 30 years of age, with a dose of insulin exceeding 0.7 U/kg/day or 50U/day will result in decreasing the insulin dose in the course of 6-month follow-up and in an improvement of the glycHBA1c levels, improvement of the liver and kidney function, decrease of the cholesterol levels and improvement of the immune response parameters, i.e. parameters of lymphocytar blastic transformation, more than in case of patients with intramuscular or intraarterial application of BMAC.

Official Title
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Randomised Clinical Study of Safety and Efficacy of Autologous Bone Marrow Aspirate Concentrate (BMAC) for No-option_critical Limb Ischemia in Type-II Diabetes Mellitus Patients. (DIALEG)

Conditions
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Critical Lower Limb Ischemia, Type-2 Diabetes Mellitus

Intervention / Treatment
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* Biological: Group A: Intramuscular
* Biological: Group B: Intraarterial
* Biological: Group C: Intravenous
* Procedure: Group D: Surgical endovascular treatment with maximum medicamentous treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: type 2 diabetes mellitus diagnosis of critical limb ischemia non-healing defect on the study limb ABI value < 50 mmHg or ABI< 0.4 TBI value < 40 mmHg or TBI < 0.4 TcPO2 < 20 mmHg in supine position no other suitable surgical or re-vascularization procedure age > 18 years signed Informed Consent Exclusion Criteria: non-signing of the Informed Consent anticipated life expectancy < 6 months history of bone-marrow disease renal failure or dialysis dependency known malignant disease health risks excluding the possibility of general anaesthesia or sedation life-threatening ischaemic heart disease vast necrosis of the index limb active infectious disease, or ATB treatment treatment with immunosupressives pregnancy, breastfeeding

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A: Intramuscular<br>Intramuscular BMAC application The study subjects in the Group A will receive a treatment of 35ml BMAC administered intramuscularly into the affected limb, in individual punctures of 1 ml. The punctures will be applied into the crural muscle around the defect, the procedure takes approx. 60 minutes. | Biological: Group A: Intramuscular<br>* Intramuscular BMAC application The study subjects in the Group A will receive a treatment of 35ml BMAC administered intramuscularly into the affected limb, in individual punctures of 1 ml. The punctures will be applied into the crural muscle around the defect, the procedure takes approx. 60 minutes.<br>|
| Experimental: Group B: Intraarterial<br>Intraarterial BMAC application The study subjects in the Group B will receive a treatment of 35ml BMAC administered intraarterially into the affected limb. | Biological: Group B: Intraarterial<br>* Intraarterial BMAC application The study subjects in the Group B will receive a treatment of 35ml BMAC administered intraarterially into the affected limb.<br>|
| Experimental: Group C: Intravenous<br>Group C: Intravenous The study subjects in the Group C will receive a treatment of 35ml BMAC administered intravenously into the affected limb. | Biological: Group C: Intravenous<br>* Group C: Intravenous The study subjects in the Group C will receive a treatment of 35ml BMAC administered intravenously into the affected limb.<br>|
| Other: Group D: Control-standard treatment<br>Group D: Control Group Study subjects in Group D will receive a standard treatment for NO-option CLI. | Procedure: Group D: Surgical endovascular treatment with maximum medicamentous treatment<br>* Group D: Control Group Control Group - no experimental intervention, standard endovascular treatment or bypass surgery or maximum medicamentous treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Amputation-free survival | The data for Primary outcome will be collected throughout the first 18 months of the study. The assessed parameters will include amputation-free survival in order to verify the safety and efficacy of the treatment. | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tissue perfusion parameters | The efficacy of BMAC application will be evaluated throughout the whole course of the clinical trial, with final assessment at the end of the trial. Increase of the monitored parameters of the tissue perfusion measured with LDP-Periflux 5000 (Perimed), i.e. increase of the ABI - ankle-brachial index, TP - toe pressure, TBI- Toe Brachial index and TcpO2- transcutaneous oxygen pressure. Decrease of the SPP perfusion parameter - skin perfusion pressure reflecting an inflammatory activity of the affected limb. | 4 years | 
| Clinical outcome classification | The efficacy of BMAC application will be evaluated throughout the whole course of the clinical trial, with final assessment at the end of the trial. - Improvement of the Rutherford scale of CLI | 4 years | 
| Functional angiogenesis imaging outcome | The efficacy of BMAC application will be evaluated throughout the whole course of the clinical trial, with final assessment at the end of the trial. - Increase of the number and quality of newly created vessels measured according to digital subtraction angiography (DSA) or MR-angiography (in allergic patients) | 4 years | 
| Quality of life outcome | The efficacy of BMAC application will be evaluated throughout the whole course of the clinical trial, with final assessment at the end of the trial. Measurable decrease of pain measured on the scale and QOL questionnaire (RAND-36). Healing of the defect or gangrene (size and state of the wound) | 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ischemia, diabetes mellitus, bone marrow aspirate concentrate (BMAC)