Intraarterial Infusion of Autologous Bone Marrow in Diabetic Patients With Chronic Ischemia of Lower Limbs (CLI) no Revascularization

Phase II Clinical Trial of Therapeutic Angiogenesis With Mononuclear Cells Autologous Bone Marrow in Patients With Chronic Ischemia Diabetics Critical Limb (CLI) no Revascularization.

The aim of the study is to evaluate the safety and feasibility of autologous bone marrow mononuclear cells autologous administered intra-arterially in the affected limb of diabetic patients with chronic critical ischemia of the lower limbs (CLI) without possibility of revascularization or other therapeutic alternatives.

The trial hypothesis we propose consists of mononuclear cells of bone marrow providing progenitor cells with regenerative capacity and secrete also several angiogenic factors, and their implantation into ischemic tissues with both elements should contribute to angiogenesis and tissue regeneration with recovery of the circulation in the affected limb

Study Overview

• Status: Completed
• Conditions: Diabetic Foot; Critical Limb Ischemia (CLI)
• Intervention / Treatment: Other: Intraarterial infusion of autologous bone marrow cells

Detailed Description

Phase II Clinical Trial, a prospective, multicenter, open, randomized, parallel-group controlled with three dose levels.

The study population will consist of a total of 60 diabetic patients with chronic critical ischemia of one leg (CLI) and no possibility of revascularization. In the experimental group will include a total of 45 patients divided into three dose levels, 15 patients in each level (increasing doses of mononuclear cells of bone marrow evenly) and 15 patients in control group (no cell therapy). Patients will be randomly assigned to either the control group or to any of the three experimental groups in which the dose of mononuclear cells of bone marrowo will be:

• Group 1(15 patients): no cell therapy.
• Group 2(15 patients): 1x108 mononuclear cells of bone marrow
• Gropu 3(15 patients): 5x108 mononuclear cells of bone marrow
• Group 4(15 patients): 1x109 mononuclear cells of bone marrow The cell therapy medicinal product shall be administered in all cases intraarterially.

Patients were evaluated by clinical, radiological and angiologist methods. This is a randomized controlled trial in which the safety and feasibility of cell therapy medicinal product shall be measured by comparing the response variables after treatment compared to baseline prior to implementation. Secondarily the results obtained are compared with each of the dose groups.

Patients will receive in a concomitant way the drug treatment established by the good practice, so it would certainly be possible that some improvement occurs due to drug treatment.

The primary variable is the improvement in the vascularización of the treated limb determined by clinical, angiologic and angiographic parameters.

It is estimated that the inclusion period lasts between twelve and eighteen months with twelve months follow-up. Therefore the total study duration range between twenty-four and thirty months from the inclusion of the first patient to the end of the follow-up of the last patient included.

Objectives of the study:

- Main objective: To evaluate the safety and feasibility of mononuclear cells of autologous bone marrow administered intra-arterially in the affected limb of diabetic patients with chronic critical ischemia of the lower limbs without possibility of revascularization or other therapeutic alternatives.

Secondary objectives:

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Spain
  • Cordoba, Spain, 14004
    • Hospital Universitario Reina Sofía
  • Granada, Spain, 18012
    • Hospital Universitario San Cecilio
  • Granada, Spain, 18014
    • Hospital Universitario Virgen de la Nieves
  • Murcia, Spain, 30008
    • Hospital Universitario Morales Meseguer
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen del Rocío

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Type 1 or 2 diabetes mellitus
2. Grade II-III Rutherford-Becker peripheral vascular disease affecting at least one limb
3. Arterial obstruction(s) located at infrapopliteal level
4. No options of endoarterial or surgical revascularization
5. Life expectancy more than 2 years
6. Unlikelihood of major amputation of the leg during the next 12 months
7. Normal analytical parameters in blood: leucocytes>3000/micoL, neutrophils>1500 microL, Hb>10mg/dl, platelets>100000 microL,AST and ALT<2.5 standard value, creatinin<2.5 mg/dl
8. Written informed consent
9. Negative pregnancy test when applicable

Exclusion Criteria:

1. History of neoplasm or hematological disease
2. Uncontrolled high blood pressure (>180/110)
3. Severe cardiac insufficiency (NYHA IV) or ejection fraction<30%
4. Malignant ventricular arrythmia
5. Deep venous thrombosis during the last 3 months
6. Active bacterial infection
7. Treatment with hyperbaric oxygen, vasoactive drugs, Cox-II inhibitors or antiangiogenic agents
8. Body mass index > 40
9. Alcoholism
10. Proliferative retinopathy
11. HIV, HBV or HCV viral infection
12. Stroke or myocardial infarction during the last 3 months

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low dose (1x10 E8); Dose of 1x10 E8 autologous bone marrow-derived mononuclear cells	Other: Intraarterial infusion of autologous bone marrow cells; Autologous bone marrow-derived mononuclear cells will be infused by an intraarterial catheter into de ischemic limb. The number of infused cells will be 1x10 E8, 5x10E8 and 1x10 E9 in the low,intermediate and high dose arms respectively
Experimental: Intermediate dose (5x10 E8); Dose of 5x10 E8 autologous bone marrow-derived mononuclear cells	Other: Intraarterial infusion of autologous bone marrow cells; Autologous bone marrow-derived mononuclear cells will be infused by an intraarterial catheter into de ischemic limb. The number of infused cells will be 1x10 E8, 5x10E8 and 1x10 E9 in the low,intermediate and high dose arms respectively
Experimental: High dose (1x10 E9); Dose of 1x10 E9 autologous bone marrow-derived mononuclear cells	Other: Intraarterial infusion of autologous bone marrow cells; Autologous bone marrow-derived mononuclear cells will be infused by an intraarterial catheter into de ischemic limb. The number of infused cells will be 1x10 E8, 5x10E8 and 1x10 E9 in the low,intermediate and high dose arms respectively
No Intervention: Control; Conventional treatment established by the good clinical practice

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Number of adverse events	24 h, 1,3 ,6 ,9 and 12 months
AngioRNM and/or AngioTC changes	baseline and 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinically objective improvement in the ischemic limb	(Ankle/brachial index, transcutaneous oxygen pressure, degree of Rutherford-Becker, greater ulcer size and perimeter calf muscle)	1, 3, 6, 9 and 12 months

Collaborators and Investigators

• Sponsor: Andalusian Initiative for Advanced Therapies - Fundación Pública Andaluza Progreso y Salud
• Collaborators: Iniciativa Andaluza en Terapias Avanzadas
• Investigators: Study Chair: Inmaculada Herrera, MD, PhD, Hospital Universitario Reina Sofía de Córdoba; Principal Investigator: Francisco Tadeo Gomez, MD, PhD, Hospital Virgen del Rocío; Principal Investigator: Jose Patricio Linares, MD, PhD, Hospital Universitario San Cecilio; Principal Investigator: Diego Martinez, MD, PhD, Hospital Universitario Morales Messeguer; Principal Investigator: Vicente García, MD,PhD, University Hospital Virgen de las Nieves; Principal Investigator: Antonio Chacon, MD, PhD, Hospital Universitario Reina Sofía

Study record dates

Study Major Dates

• Study Start: July 1, 2009
• Primary Completion (Actual): March 1, 2013
• Study Completion (Actual): March 1, 2013

Study Registration Dates

• First Submitted: September 29, 2009
• First Submitted That Met QC Criteria: September 29, 2009
• First Posted (Estimate): September 30, 2009

Study Record Updates

• Last Update Posted (Estimate): March 16, 2016
• Last Update Submitted That Met QC Criteria: March 15, 2016
• Last Verified: November 1, 2014

More Information

Terms related to this study

• Keywords: cell therapy; diabetic foot; bone marrow derived mononuclear cells; critical limb ischemia (CLI)
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Skin Diseases; Endocrine System Diseases; Diabetic Angiopathies; Leg Ulcer; Skin Ulcer; Diabetes Complications; Diabetes Mellitus; Diabetic Neuropathies; Foot Ulcer; Diabetic Foot; Ischemia
• Other Study ID Numbers: CMMo/ICPD/2008; 2008-004064-39 (EudraCT Number)