Safety and Efficacy Study of Autologous BM-MNC Processed by Two Methods for Treating Patients With Chronic Limb Ischemia

Transplantation of Autologous BM-MNC Processed by ResQ Separator and Conventional Manual Method for Patients With Chronic Limb Ischemia: a Multi-center Randomized Controlled Trial

Using autologous bone marrow mononuclear cells (BM-MNC) to treat patients with chronic limb ischemia has been proved safe and effective. However, processing bone marrow by Ficoll density gradient centrifugation is not only time consuming but also expensive. Manually processing of bone marrow also results in large variation in therapeutic cell quantity and quality which directly leads deviation of safety and efficacy of the cell therapy. This study is aiming to compare an automated bone marrow processing system with a conventional manual method in term of safety and efficacy.

Study Overview

• Status: Unknown
• Conditions: Peripheral Arterial Disease; Critical Limb Ischemia; Buerger's Disease
• Intervention / Treatment: Device: ResQ processed bone marrow sample; Device: Ficoll conventional cell processing method

Detailed Description

Using autologous bone marrow mononuclear cells (BM-MNC) to treat patients with chronic limb ischemia has been proved safe and effective. However, processing bone marrow by Ficoll density gradient centrifugation is not only time consuming but also expensive. Manually processing of bone marrow also results in large variation in therapeutic cell quantity and quality which directly lead deviation of safety and efficacy of the cell therapy. This study is aiming to compare an automated bone marrow processing system with a conventional manual method in term of safety and efficacy.

ResQ system developed by Thermogenesis in USA provides an automatic cell processing system for bone marrow. The system takes less than 30 minutes to concentrate the therapeutic mononuclear cells including stem cells in a closed system without adding any additive such as separation reagent (Ficoll). The system also be able to be operated at point of care.

The study is designed to prove no inferior of safety and efficacy of bone marrow cells processed by ResQ to those of cells using conventional manual method. The conventional manual method is involved Ficoll density gradient centrifugation and cell washing stems in an open system. Each of test arms (ResQ vs manual method) consists of 25 patients. The primary outcome is safety which is measured by cell treatment-related adverse events. The secondary endpoints include resting ankle-brachial pressure index (ABI)and toe brachial pressure index (TBI) , transcutaneous oxygen pressure (TcPO2), claudication distance, rest pain scale evaluation, collateral vessel scale, etc.

• Study Type: Interventional
• Enrollment (Anticipated): 50
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Yongquan Gu, MD; Phone Number: 13910002909; Email: gu-yq@263.net

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China
      • Xuan Wu Hospital
      • Contact: Yongquan Gu, MD; Phone Number: 13910002909; Email: gu-yq@263.net
      • Principal Investigator: Yongquan Gu, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 78 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. fontaine's stage 2-4 or resting ABI <0.7
2. age between 20 and 80 years old
3. sign informed consent, voluntary subjects
4. diagnosis of lower extremity arterial occlusive disease, or diabetic lower limb ischemia, or Buerger's disease

Exclusion Criteria:

1. poorly controlled diabetes (HBA1c> 7.0%) and proliferative retinopathy (III-IV stage)
2. malignancy history in the past five years or serum level of tumor markers elevated more than doubled
3. severe heart, liver, kidney, respiratory failure or poor general condition can not tolerate BM-MNC transplantation
4. serious infections (such as cellulitis, osteomyelitis, etc.)or gangrene that a major amputation cannot be avoided
5. aortic or iliac or common femoral artery occlusion
6. pregnant female, or reproductive age female who wants to give birth throughout the course of the study
7. life expectancy less than a year

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ResQ process group; Autologous BM-MNC is enriched with ResQ process(an automatic cell separator). Then the cell product is transplanted into the ischemia limbs of a patient.	Device: ResQ processed bone marrow sample; Autologous bone marrow is processed with ResQ at point of care, prior to the transplantation
Active Comparator: Ficoll-based conventional method; A conventional method based on Ficoll cell separation is used to process bone marrow.	Device: Ficoll conventional cell processing method; Comparison of different cell processing methods

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cell treatment-related adverse event	Temperature,Pulse,Respiration,Blood Pressure; Routine analysis of blood and urine,; Liver function(ALT：alanine aminotransferase,AST：aspartate transferase), Renal function(Blood urea nitrogen,Creatinine;) Function of coagulation(APTT,PT,Fib,TT）; ECG（Electrocardiography）; local inflammatory response; Cell-treatment related death; Cell-treatment related unexpected amputation.	2-wk after bone marrow transplantation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ulcer size	Measuring ulcer area (cm2) and depth (mm)of limb : For each ulcer , photographically record the area and depth with a ruler in order to calculate the ulcer area in square millimeters.	Post bone marrow transplantation: 1, 3, 6, 12 months
rest pain score.	Scoring the rest pain based on the degree of pain as following five scales): 0 level-0 point: no pain; level-1 point: occasional pain which can be recalled;; level-2 points: the pain often but can be tolerated, without or with a little analgesics;; level-3 points: often with need of general analgesics;; level -4 points: affect sleeping due to the pain, general pain medication being difficult to alleviate. Before transplantation: points; after transplantation: points.	Post bone marrow transplantation: 1，3, 6, 12 months
cold sensation score	based on a sense of cold as following five scales: 0 level-0 point: no cold sensation; level-1 point, or : Accasionally cold feeling;; level-2 points: Often with cold feeling;; level-3 points: significantly cold feeling. and can be significantly improved when using a local insulation.; level-4 points: significantly cold feeling，and can not be significantly improved when using a local insulation.	Post bone marrow transplantation:,1，3, 6, 12 months
claudication distance (m)	Measurement of claudication distance (m)： For patients with intermittent claudication, treadmill exercise test (no tilt, speed 3km/hr) is employed to measure claudication distance.	Post bone marrow transplantation:1, 3, 6, 12 months
Resting ABI	Measurement of ABI(ankle brachial index, ABI): Measure arterial pressure with a laser Doppler, and then calculate the ankle-brachial index, that is a ratio of ankle arterial blood pressure to brachial arterial blood pressure at rest.	Post bone marrow transplantation: 1,3, 6, 12 months
Resting TcPO2 (mmHg)	Transcutaneous oxygen pressure(TcPO2) should be measured at the same site in the ischemic limb at rest.	Post bone marrow transplantation:1, 3, 6, 12 months
Collateral vessel score	Collateral vessel score: Using DSA(Digital subtraction angiography)or CTA(computed tomographic angiography) to score the collateral vessel formation. A mean score is obtained for each ischemic limb by 3 independent interventionists based on the following 4 level score: 0 (no new collateral vessels); 1 (A little new collateral vessels); 2 (moderate new collateral blood vessels); 3 (Rich new collateral vessels)	Post bone marrow transplantation: 1,3, 6, 12 months
Amputation rate	Amputation rate and level is recorded.	Post bone marrow transplantation:1, 3, 6, 12 months
Skin microcirculation measurement	using PeriMed "laser-Doppler flowmetry" measure the skin microcirculation on the same site in the ischemic limb at rest.	1,3,6,12 months post transplantation
Resting TBI	Measurement of TBI（Toe Brachial Index): Measure arterial pressure with a laser Doppler, and then calculate Toe Brachial Index, that is a ratio of toe arterial blood pressure to brachial arterial blood pressure.	Post bone marrow transplantation: 1,3, 6, 12 months

Collaborators and Investigators

• Sponsor: Xuanwu Hospital, Beijing
• Collaborators: Hebei Medical University; Thermogenesis Corp.
• Investigators: Principal Investigator: Yong-Quan Gu, Dr., Xuanwu Hospital, Beijing

Study record dates

Study Major Dates

• Study Start: October 1, 2011
• Primary Completion (Anticipated): April 1, 2012
• Study Completion (Anticipated): April 1, 2013

Study Registration Dates

• First Submitted: September 23, 2011
• First Submitted That Met QC Criteria: October 2, 2011
• First Posted (Estimate): October 4, 2011

Study Record Updates

• Last Update Posted (Estimate): October 12, 2011
• Last Update Submitted That Met QC Criteria: October 8, 2011
• Last Verified: October 1, 2011

More Information

Terms related to this study

• Keywords: Peripheral arterial disease; Buerger's disease; atherosclerotic arterial occlusion; bone marrow mononuclear cell; chronic limb ischemia
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Atherosclerosis; Vasculitis; Ischemia; Peripheral Arterial Disease; Peripheral Vascular Diseases; Thromboangiitis Obliterans
• Other Study ID Numbers: TGResQ082011