Bone Marrow Mononuclear Cells vs Mesenchymal Stem Cells in Diabetic Patients With Chronic Limb Ischemia

Study Overview
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Brief Summary
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Patients in the severe stages of Chronic limb-threatening ischemia (CLTI) are prone to amputation and death, leading to poor quality of life and a great socioeconomic burden. There is an urgent need to develop an effective therapeutic strategy to treat this disease. In this context, autologous bone marrow mononuclear cells (BM-MNC) and allogeneic mesenchymal stem cells derived from different sources have emerged as promising therapeutic approaches for this condition.

Detailed Description
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Comparison of the therapeutic potential of BM-MNC vs. allogeneic Wharton jelly-derived mesenchymal stem cells (allo-WJ-MSCs) in diabetic patients with CLTI. Twenty-four type 2 diabetic patients in the most severe stages of the CLTI (category 4 or 5 in Rutherford's classification and transcutaneous oxygen pressure (TcPO2) below 30 mm Hg were enrolled and randomized to receive 15 injections of (i) BM-MNC (7.197x106 ± 2.984 x106 cells/mL each with 2% of autologous serum) (n=7), (ii) allo-WJ-MSCs (1.333 x106 cells/mL each with 5% of human serum albumin serum) (n=7) or (iii) placebo solution (1 mL saline solution with 2% of autologous serum) (n=10), which were administered into the periadventitial arteries. The follow-up visits were at months 1, 3, 6, and 12, to evaluate the following parameters: (i) Rutherford classification (0 to 6) (ii) TcPO2 (mmHg) (iii) Wound closure (area cm2) (iv) pain (visual analogue scale (0-10) (v) pain-free walking distance (m) (vi) revascularization and limb-survival proportion during follow-up (vii) the quality of life (EQ-5D questionnaire).

Official Title
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Comparison of the Therapeutic Potential of Autologous Bone Marrow Mononuclear Cells Versus Allogenic Wharton Jelly-derived Mesenchymal Stem Cells in Diabetic Patients With Chronic Limb-threatening Ischemia

Conditions
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Chronic Limb-threatening Ischemia, Diabetes Mellitus

Intervention / Treatment
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* Biological: Cell-based therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult male or female, 40 years of age or over (until 85 years old) TcPO2 ≤ 30 mmHg. Diagnosis of diabetes. Patients with signs of critical ischemia such as (i) ulcer that does not heal, (ii) necrosis or loss of tissue, (iii) pain at rest, and (iv) intermittent claudication. Basal Rutherford classification stage 3 to 5. Non-revascularizable patients due to comorbidities and/or anatomy. Patients that despite revascularization (vascular surgery), have adequate distal beds to perfuse the limb. Ankle/brachial index less than 0.4. Stenosis or occlusion of the infrapatellar arteries. Exclusion Criteria: Participants that do not sign the informed consent. Presence of osteomyelitis. Hemodynamic instability (MAP<65 mmHg or vasopressor requirement). Any acute systemic infectious disease process. Severe sepsis. Uncontrolled coagulopathy. Condition of cancer. Use of immunosuppressive or cytotoxic drugs Alterations of the bone marrow that do not allow the adequate extraction of the components to be used as: acute leukemia, chronic leukemia, marrow aplasia, myelodysplastic syndrome, and myelophthisis. Contraindication of sedation for bone marrow aspirate. Patients who have suffered in a period < six months of myocardial infarction, disease cerebrovascular or coronary intervention. Patients with liver failure indicated by serum transaminases (aspartate aminotransferase and alanine aminotransferase), with values twice the normal limit. Any acute or chronic contagious disease including hepatitis B, hepatitis C, and HIV. Any other comorbidity that the treating vascular surgeon considers as a contraindication to cell treatments.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 85 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo group<br>Placebo group (n=10), which consisted of 15 injections of 1 mL of vehicle (1 mL saline solution with 2% of autologous serum) on periadventitial arteries in one dose at day 0. | Biological: Cell-based therapy<br>* One dose of auto-BM-MNC, one dose of allo-WJ-MSCs, or one dose of placebo solution (saline solution with 2% of autologous serum), were periadventitial arteries administration in CTLI patients.<br>|
| Experimental: Auto-BM-MNC<br>Auto-BM-MNC (n=7) were obtained from diabetic patients. Fifteen injections of 7.197x106 ± 2.984x106 cells/mL each with 2% of autologous serum were periadventitial arteries administrated in one dose at day 0. | Biological: Cell-based therapy<br>* One dose of auto-BM-MNC, one dose of allo-WJ-MSCs, or one dose of placebo solution (saline solution with 2% of autologous serum), were periadventitial arteries administration in CTLI patients.<br>|
| Experimental: Allo-WJ-MSCs<br>Allo-WJ-MSCs (n=7) were obtained from culturing the WJ from healthy cordon umbilical donors unrelated to the patient. Fifteen injections of 1.333x106 cells/mL each with 5% of human serum albumin serum were periadventitial arteries administrated in one dose at day 0. | Biological: Cell-based therapy<br>* One dose of auto-BM-MNC, one dose of allo-WJ-MSCs, or one dose of placebo solution (saline solution with 2% of autologous serum), were periadventitial arteries administration in CTLI patients.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety profile: (adverse events (AEs) and serious AEs) | AEs: (i) local toxicity, including signs of local inflammation (swelling, warmth, impairment of function), worsening of ulcer, new ulcer, or hematomas after auto-BM-MNC or allo-WJ-MSCs administration. (ii) systemic toxicity as fever, allergies. (iii) maximum grade toxicity for tissue. | 12 months | 
| Safety profile | Serious AEs: hospitalization, malignancy, amputation, persistent or significant disability, or death. | 12 months | 
| Efficacy profile: Rutherford's classification | 0 to 6 | 12 months | 
| TcPO2 | mmHg | 12 months | 
| Efficacy profile: Visual Analogue Scale pain | 0 to10 | 12 months | 
| Efficacy profile: Pain-free walking distance | meters | 12 months | 
| Efficacy profile: Wound closure | cm2 | 12 months | 
| Efficacy profile: Revascularization | Percentage | 12 months | 
| Efficacy profile: Limb survival proportion | Percentage | 12 months | 
| Efficacy profile: Quality of life | EQ-5D questionnaire | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bone marrow mononuclear cells, Mesenchymal stem cells