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

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)

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.

Study Overview

• Status: Completed
• Conditions: Critical Lower Limb Ischemia; Type-2 Diabetes Mellitus
• Intervention / Treatment: Biological: Group A: Intramuscular; Biological: Group B: Intraarterial; Biological: Group C: Intravenous; Procedure: Group D: Surgical endovascular treatment with maximum medicamentous treatment

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Czechia
  • Ostrava, Czechia, 708 52
    • University Hospital Ostrava

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group A: Intramuscular; 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; 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.
Experimental: Group B: Intraarterial; 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; Intraarterial BMAC application The study subjects in the Group B will receive a treatment of 35ml BMAC administered intraarterially into the affected limb.
Experimental: Group C: Intravenous; 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; Group C: Intravenous The study subjects in the Group C will receive a treatment of 35ml BMAC administered intravenously into the affected limb.
Other: Group D: Control-standard treatment; 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; Group D: Control Group Control Group - no experimental intervention, standard endovascular treatment or bypass surgery or maximum medicamentous treatment

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in lymphocyte subsets and levels of inflammatory and antiinflammatory cytokines in each of the groups.	The immune response of study subjects will be monitored following the transplantation of stem cells, together with the periphery lymphocyte function (T-cells, B-cells, NK-cells). Immune response parameters, (i.e. parameters of lymphocytar blastic transformation)	24 months
Metabolic response	The following laboratory parameters throughout the clinical trial: liver and kidney function; lipid spectra	24 months
Blood glucose and pancreatic function response	The following parameters will be monitored in the study subjects: glycHBA1c levels; C-peptide	24 months

Collaborators and Investigators

• Sponsor: University Hospital Ostrava
• Collaborators: Ministry of Health, Czech Republic; Regional Council of the Moravian-Silesian region, KU MSK
• Investigators: Principal Investigator: Vaclav Prochazka, MD, PhD, MSc, University Hospital Ostrava

Publications and helpful links

General Publications

• Dormandy J, Heeck L, Vig S. The natural history of claudication: risk to life and limb. Semin Vasc Surg. 1999 Jun;12(2):123-37.
• Clair DG, Dayal R, Faries PL, Bernheim J, Nowygrod R, Lantis JC 2nd, Beavers FP, Kent KC. Tibial angioplasty as an alternative strategy in patients with limb-threatening ischemia. Ann Vasc Surg. 2005 Jan;19(1):63-8. doi: 10.1007/s10016-004-0136-0.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2012
• Primary Completion (Actual): September 1, 2018
• Study Completion (Actual): October 1, 2018

Study Registration Dates

• First Submitted: September 27, 2012
• First Submitted That Met QC Criteria: March 21, 2013
• First Posted (Estimate): March 26, 2013

Study Record Updates

• Last Update Posted (Actual): September 30, 2021
• Last Update Submitted That Met QC Criteria: September 29, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: ischemia; diabetes mellitus; bone marrow aspirate concentrate (BMAC)
• Additional Relevant MeSH Terms: Pathologic Processes; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Ischemia
• Other Study ID Numbers: 2012-T2DM-CLI; 2012-001825-28 (EudraCT Number)

Plan for Individual participant data (IPD)

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