Autologous Peripheral Blood Mononuclear Cells in Diabetic Foot Patients With No-option Critical Limb Ischemia

January 31, 2020 updated by: Alessia Scatena, Ospedale San Donato

Autologous Peripheral Blood Mononuclear Cells for Limb Salvage in Diabetic Foot Patients With No-option Critical Limb Ischemia

The objective of this trial is to determine whether PBMNCs in diabetic patients with critical, non revascularizable limb ischemia can prevent major amputation and affect mortality and healing.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

This is an interventional study with historical control group carried out to assess as primary outcome major amputations, overall mortality, number of healed patients in group of patients who received repetitive intra-muscular implant of PBMNCs (3 times; 4-week interval) in comparison to a historical internal control group with a 1:1 case-control ratio. Secondary outcomes are TCPO2, healing time and rest pain.

No-option critical limb ischaemia is defined by evidence of no run-off pedal vessels, failure after several percutaneous intervention and no longer possible re-intervention, failure after infra-genicular bypass grafting, no-walking capacity with severe comorbidities unfit for surgical or endovascular procedures.

Inclusion criteria are: a) ulcers with inadequate perfusion, as indicated by a transcutaneous oxygen pressure value (TcpO2) <30 mmHg; b) ulcers with grade I or II or III and stage C as defined by the Texas University Classification System or W1,2,3 - I 3 - FI 0,1 as defined by the WiFI Classification System c) not eligible for angioplasty or vascular surgery or following failed revascularization; d) possibility to save foot support.

Exclusion criteria are: a) lesion site above the tibial-tarsal joint; b) moderate or severe infection according by the WiFI classification system; c) NYHA class IV; d) Anemia (Hb<8g/dl); e) coagulation disorder/thrombocytopenia (PLT< 50,000 per microliter); f) active cancer/leukemia or lymphoma hematological disease.

Standard of care in both groups includes: diabetes control maximization by the diabetologist, comprehensive foot assessment by the nurse together with the diabetologist, including determination of vibration perception threshold, 10-g monofilament test and TcpO2 measurement, dressings, off-loading and systemic therapy according to the IWGDF guidelines .

Informed consent for participation in the study during the progress of the clinical trial is obtained from all subjects.

Concentration of PB-MNCs autologous cell therapy is produced by a filtration-based point-of-care device with the intended for use intra-operatively, from 120 mL of anticoagulated blood. All the procedures are performed in operatory room with anaesthesiologic support (propofol and/or peripheral block). Blood withdrawal (120 ml) is collected through a peripheral venous access, than loaded and gravity filtration is allowed in about 10 minutes. During filtration, MNCs are captured in the filter while plasma, platelets (PLTs) and red blood cells (RBCs) are not retained. After appropriate surgical debridement of the wound bed multiple perilesional and intramuscular injections of PBMNC cells suspension (0.2-0.3cc in boluses) are injected along the relevant axis below the knee, at intervals of 1-2 cm and to a mean depth of 1.5-2 cm, using a 21G needle. This procedure is repeated on each patient for three times, at intervals of 30-45 days from each other.

Foot-sparing surgery, the removal of all the unviable tissue and the reconstruction of the foot to allow a functional deambulation,is performed at the same time of the last implant in the patients with increased TcpO2 value above 30 mmHg. Between the implants, diabetologists together with nurses evaluated changing in pain, infection signs, wound size, demarcation of the necrosis, granulation tissue formation, perilesional tissue trophism and TcpO2 value to optimize standard of care. After the first treatment, a two years follow-up is registered, with evaluation at 1-3-6-12-18-24 months.

A baseline assessment is carried out, in order to estimate any differences among cases and controls before the treatment. Statistical evaluation includes non-parametric tests (Mann-Whitney U test for independent samples for continuous variables and Cochrane chi-square test for discrete variables), evaluation of Relative Risk (RR), Absolute Risk Reduction (ARR), Relative Risk Reduction (RRR) and Number Needed to Treat (NNT), multivariate survival analysis (Kaplan-Meier's survival analysis model).

Study Type

Interventional

Enrollment (Actual)

76

Phase

  • Not Applicable

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 90 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • ulcers with inadequate perfusion, as indicated by a transcutaneous oxygen pressure value (TcpO2) <30 mmHg;
  • ulcers with grade I or II or III and stage C as defined by the Texas University Classification System or W1,2,3 - I 3 - FI 0,1 as defined by the WiFI Classification System
  • not eligible for angioplasty or vascular surgery or following failed revascularization;
  • possibility to save foot support.

Exclusion Criteria:

  • lesion site above the tibial-tarsal joint;
  • moderate or severe infection according by the WiFI classification system;
  • NYHA class IV; d) Anemia (Hb<8g/dl);
  • coagulation disorder/thrombocytopenia (PLT< 50,000 per microliter);
  • active cancer/leukemia or lymphoma hematological disease.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Sequential Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: A-PBMNC therapy
Patients in A-PBMNC therapy are treated with wound bed multiple perilesional and intramuscular injections of PBMNC cells suspension (0.2-0.3cc in boluses). This procedure is repeated on each patient for three times, at intervals of 30-45 days from each other.
Device: Pall Celeris System, point of care device for human cell therapy
Concentration of PB-MNCs autologous cell therapy was produced by a filtration-based point-of-care device. All the procedures were performed in operatory room with anaesthesiologic support (propofol and/or peripheral block). Blood withdrawal (120 ml) was collected through a peripheral venous access. Blood was loaded, and gravity filtration was allowed to proceed until the upstream side of the filter had no remaining blood; filtration last about 10 minutes. During filtration, MNCs were captured in the filter while plasma, platelets (PLTs) and red blood cells (RBCs) were not retained. Immediately concentrate solution is injected in the perilesional area and intramuscular in the foot and the leg (0.2-0.3cc in boluses) below the knee, at intervals of 1-2 cm and to a mean depth of 1.5-2 cm, using a 21G needle. This procedure is repeated on each patient for three times, at intervals of 30-45 days from each other.
No Intervention: No A-PBMNC therapy
Patients in No A-PBMNC therapy receive only supportive treatment including wound care and pain killer drug.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Amputation-free survival at 1 month
Time Frame: 1 month
rate of non amputated limb 1 month after the intervention
1 month
Amputation-free survival at 3 months
Time Frame: 3 months
rate of non amputated limb 3 months after the intervention
3 months
Amputation-free survival at 6 months
Time Frame: 6 months
rate of non amputated limb 6 months after the intervention
6 months
Amputation-free survival at 12 months
Time Frame: 12 months
rate of non amputated limb 12 months after the intervention
12 months
Amputation-free survival at 18 months
Time Frame: 18 months
rate of non amputated limb 18 months after the intervention
18 months
Amputation-free survival at 24 months
Time Frame: 24 months
rate of non amputated limb 24 months after the intervention
24 months
risk of death at 1 month
Time Frame: 1 month
rate of dead subjects 1 month after the intervention
1 month
risk of death at 3 months
Time Frame: 3 months
rate of dead subjects 3 months after the intervention
3 months
risk of death at 6 months
Time Frame: 6 months
rate of dead subjects 6 months after the intervention
6 months
risk of death at 12 months
Time Frame: 12 months
rate of dead subjects 12 months after the intervention
12 months
risk of death at 18 months
Time Frame: 18 months
rate of dead subjects 18 months after the intervention
18 months
risk of death at 24 months
Time Frame: 24 months
rate of dead subjects 24 months after the intervention
24 months
probability of healing at 1 month
Time Frame: 1 month
rate of healed subjects 1 month after the intervention
1 month
probability of healing at 3 months
Time Frame: 3 months
rate of healed subjects 3 months after the intervention
3 months
probability of healing at 6 months
Time Frame: 6 months
rate of healed subjects 6 months after the intervention
6 months
probability of healing at 12 months
Time Frame: 12 months
rate of healed subjects 12 months after the intervention
12 months
probability of healing at 18 months
Time Frame: 18 months
rate of healed subjects 18 months after the intervention
18 months
probability of healing at 24 months
Time Frame: 24 months
rate of healed subjects 24 months after the intervention
24 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
transcutaneous oxygen measurement (TcPO2) variation
Time Frame: 0-3 months
comparison of TcPO2 at the second follow up (3 months after intervention) with the baseline measure
0-3 months
Healing time
Time Frame: within 24 months
time to reach complete epithelialization
within 24 months
rest pain
Time Frame: 0-1-3 months
comparison of rest pain measured by a numeric rating scale (NRS) min 0 - max 10, where 10 is the worst pain the patient has felt
0-1-3 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Ospedale San Donato

Investigators

  • Study Chair: Leonardo Ercolini, MD, Vascular Surgery Unit San Donato Hospital Arezzo

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 1, 2014

Primary Completion (Actual)

February 1, 2019

Study Completion (Actual)

December 1, 2019

Study Registration Dates

First Submitted

January 25, 2020

First Submitted That Met QC Criteria

January 31, 2020

First Posted (Actual)

February 5, 2020

Study Record Updates

Last Update Posted (Actual)

February 5, 2020

Last Update Submitted That Met QC Criteria

January 31, 2020

Last Verified

January 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • MONODIAB-19-01

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

IPD Plan Description

data should not be shared before study completion and approvation by all the collaborators. Sharing data before this time would jeopardize the integrity of the clinical trial process and risk the scientific validity of the results.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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