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

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

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.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus; Chronic Limb-threatening Ischemia
• Intervention / Treatment: Biological: Cell-based therapy

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Colombia
  • Bucaramanga, Colombia
    • Fundación Oftalmológica de Santander (FOSCAL)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo group; 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; 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.
Experimental: Auto-BM-MNC; 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; 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.
Experimental: Allo-WJ-MSCs; 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; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Fundación Oftalmológica de Santander Clínica Carlos Ardila Lulle
• Investigators: Principal Investigator: Martha L Arango, PhD, Fundación Oftalmológica de Santander Clínica Carlos Ardila Lulle

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2019
• Primary Completion (Actual): September 30, 2020
• Study Completion (Actual): October 28, 2022

Study Registration Dates

• First Submitted: October 30, 2022
• First Submitted That Met QC Criteria: November 20, 2022
• First Posted (Actual): November 30, 2022

Study Record Updates

• Last Update Posted (Actual): November 30, 2022
• Last Update Submitted That Met QC Criteria: November 20, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Mesenchymal stem cells; Bone marrow mononuclear cells
• Additional Relevant MeSH Terms: Pathologic Processes; Ischemia
• Other Study ID Numbers: CLTI 01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No