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

Primary Purpose

Critical Lower Limb Ischemia, Type-2 Diabetes Mellitus

Status
Completed
Phase
Phase 2
Locations
Czechia
Study Type
Interventional
Intervention
Group A: Intramuscular
Group B: Intraarterial
Group C: Intravenous
Group D: Surgical endovascular treatment with maximum medicamentous treatment
Sponsored by
University Hospital Ostrava
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Critical Lower Limb Ischemia focused on measuring ischemia, diabetes mellitus, bone marrow aspirate concentrate (BMAC)

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University Hospital Ostrava

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Other

Arm Label

Group A: Intramuscular

Group B: Intraarterial

Group C: Intravenous

Group D: Control-standard treatment

Arm Description

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.

Intraarterial BMAC application The study subjects in the Group B will receive a treatment of 35ml BMAC administered intraarterially into the affected limb.

Group C: Intravenous The study subjects in the Group C will receive a treatment of 35ml BMAC administered intravenously into the affected limb.

Group D: Control Group Study subjects in Group D will receive a standard treatment for NO-option CLI.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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
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)
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)

Full Information

First Posted
September 27, 2012
Last Updated
September 29, 2021
Sponsor
University Hospital Ostrava
Collaborators
Ministry of Health, Czech Republic, Regional Council of the Moravian-Silesian region, KU MSK
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1. Study Identification

Unique Protocol Identification Number
NCT01818310
Brief Title
Safety and Efficacy Study of Autologous Bone Marrow Aspirate Concentrate for No-Option Critical Limb Ischemia
Acronym
DIALEG
Official Title
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)
Study Type
Interventional

2. Study Status

Record Verification Date
September 2021
Overall Recruitment Status
Completed
Study Start Date
September 2012 (Actual)
Primary Completion Date
September 2018 (Actual)
Study Completion Date
October 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital Ostrava
Collaborators
Ministry of Health, Czech Republic, Regional Council of the Moravian-Silesian region, KU MSK

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Critical Lower Limb Ischemia, Type-2 Diabetes Mellitus
Keywords
ischemia, diabetes mellitus, bone marrow aspirate concentrate (BMAC)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
80 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Group A: Intramuscular
Arm Type
Experimental
Arm Description
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.
Arm Title
Group B: Intraarterial
Arm Type
Experimental
Arm Description
Intraarterial BMAC application The study subjects in the Group B will receive a treatment of 35ml BMAC administered intraarterially into the affected limb.
Arm Title
Group C: Intravenous
Arm Type
Experimental
Arm Description
Group C: Intravenous The study subjects in the Group C will receive a treatment of 35ml BMAC administered intravenously into the affected limb.
Arm Title
Group D: Control-standard treatment
Arm Type
Other
Arm Description
Group D: Control Group Study subjects in Group D will receive a standard treatment for NO-option CLI.
Intervention Type
Biological
Intervention Name(s)
Group A: Intramuscular
Intervention Description
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.
Intervention Type
Biological
Intervention Name(s)
Group B: Intraarterial
Intervention Description
Intraarterial BMAC application The study subjects in the Group B will receive a treatment of 35ml BMAC administered intraarterially into the affected limb.
Intervention Type
Biological
Intervention Name(s)
Group C: Intravenous
Intervention Description
Group C: Intravenous The study subjects in the Group C will receive a treatment of 35ml BMAC administered intravenously into the affected limb.
Intervention Type
Procedure
Intervention Name(s)
Group D: Surgical endovascular treatment with maximum medicamentous treatment
Intervention Description
Group D: Control Group Control Group - no experimental intervention, standard endovascular treatment or bypass surgery or maximum medicamentous treatment
Primary Outcome Measure Information:
Title
Amputation-free survival
Description
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.
Time Frame
18 months
Secondary Outcome Measure Information:
Title
Tissue perfusion parameters
Description
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.
Time Frame
4 years
Title
Clinical outcome classification
Description
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
Time Frame
4 years
Title
Functional angiogenesis imaging outcome
Description
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)
Time Frame
4 years
Title
Quality of life outcome
Description
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)
Time Frame
4 years
Other Pre-specified Outcome Measures:
Title
Changes in lymphocyte subsets and levels of inflammatory and antiinflammatory cytokines in each of the groups.
Description
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)
Time Frame
24 months
Title
Metabolic response
Description
The following laboratory parameters throughout the clinical trial: liver and kidney function lipid spectra
Time Frame
24 months
Title
Blood glucose and pancreatic function response
Description
The following parameters will be monitored in the study subjects: glycHBA1c levels C-peptide
Time Frame
24 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Vaclav Prochazka, MD, PhD, MSc
Organizational Affiliation
University Hospital Ostrava
Official's Role
Principal Investigator
Facility Information:
Facility Name
University Hospital Ostrava
City
Ostrava
ZIP/Postal Code
708 52
Country
Czechia

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
10777239
Citation
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.
Results Reference
background
PubMed Identifier
15714369
Citation
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.
Results Reference
background

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

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