Clinical trial for the treatment of severe limb ischaemia by implantation of cultured immature red cells developed from small amount of bone marrow of the patient

ISRCTN ISRCTN66803682
DOI https://doi.org/10.1186/ISRCTN66803682
Secondary identifying numbers NH18-004
Submission date
28/11/2007
Registration date
18/12/2007
Last edited
12/04/2021
Recruitment status
No longer recruiting
Overall study status
Completed
Condition category
Circulatory System
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data

Plain English summary of protocol

Not provided at time of registration

Contact information

Dr Ken Toba
Scientific

First Department of Internal Medicine
Niigata University Medical and Dental Hospital
Asahimachi 1-754
Niigata
951-8510
Japan

Phone +81 (0)25 227 2185
Email tobaken@med.niigata-u.ac.jp

Study information

Study designPhase I/II study, open-labelled, non-randomised, single arm, single-centre trial
Primary study designInterventional
Secondary study designRandomised controlled trial
Study setting(s)Hospital
Study typeTreatment
Scientific titlePhase I/II clinical study of angiogenesis by Ex-Vivo Expanded Erythroblast Transplantation (Autologous) (EVEETA) for the treatment of patients with chronic severe limb ischaemia
Study acronymEVEETA study
Study objectivesBone Marrow cell Implantation (BMI) has been utilised to treat patients with limb and heart ischaemia. However the angiogenic mechanism was not known. We have found that immature erythroid and monocytic cells included in the implanted bone marrow cooperatively induce angiogenesis via cell-cell interaction and the production of angiogenic growth factors. We then developed culture system of hematopoietic stem cells to expand ex vivo of immature erythroid and monocytic cells in human as well as mouse. Implantation of the ex vivo expanded cells from mouse bone marrow strikingly induced angiogenesis in ischemic lower limb of mice.

The present project has been planned to treat patients with severe limb ischemia by implantation of ex vivo expanded autologous bone marrow cells. Collection of 500 to 1,000 ml of bone marrow from a patient has been required for BMI, while 20 ml of bone marrow is enough for EVEETA.
Ethics approval(s)EVEETA Study, Version 1 was approved by:
1. Ethics Committee of Niigata University Medical School on the 24th May 2006 (ref: 448)
2. Institutional Review Board (IRB) for the Clinical Trials of Pharmaceutical Agents and Medical Instruments, Niigata University Medical and Dental Hospital on the 2nd August 2006 (ref: NH18-004)

EVEETA Study, Version 2 was approved by the Institutional Review Board (IRB) for the Clinical Trials of Pharmaceutical Agents and Medical Instruments, Niigata University Medical and Dental Hospital on the 27th November 2007 (ref: NH18-004)
Health condition(s) or problem(s) studiedSevere peripheral arterial disease including arteriosclerosis obliterans, Buerger disease and arteritis
Intervention1. Autologous Bone Marrow Collection:
20 ml of bone marrow is collected from iliac crest under local anaesthesia 14 days before the implantation.

2. Ex Vivo Expansion Culture:
All procedures are enforced by exclusive technical exparts along the approved protocols in GMP-grade Cell Processing Room established in Bioscience Medical Research Center, Niigata University Medical and Dental Hospital. Mononuclear cells separated from the bone marrow are incubated in a suspension culture in the presence of rh Flt-ligand, rh SCF, rh Thrombopoietin, and culture supplements for 7 days to expand myeloid progenitors.

Harvested and washed cells are further cultured in the presence of rh SCF, rh IGF-I, rh Erythropoietin, and culture supplements for additional 7 days to expand immature erythroblasts and macrophages.

3. Preparation for implant:
Cultured cells are harvested and washed. The cells are resuspended in 50 ml of platelet concentrate supplemented with 6,000 IU of erythropoietin.

4. Treatment:
Aliquots of the 50 ml of cell suspension are intramuscularly injected in 100 points of the ischaemic limb. Daily intramuscular injection of rh erythropoietin in the same loci follows from the next day for consecutive 4 days.
Intervention typeOther
Primary outcome measureEfficacy evaluation: improvement in:
1. Ankle-Brachial Index (ABI) (1 month of implantation)
2. Transcutaneous Oxygen pressure (TcO2) (1 month)
3. Rest pain

Safety evaluation:
1. Adverse effects caused by the implanted cells including teratoma, ossification, etc.
2. Adverse effects caysed by erythropoietin including polycythemia, hypertension, pure red cell aplasia, thrombosis in heart/lung/brain, etc.
3. Adverse effects caused by possible residual components used as supplements for cell culture including allergy, serum sickness, infections, etc.
4. Common adverse effects caused by drug administration stated in National Cancer Institute Common Toxicity Criteria (NCI-CTC)
Secondary outcome measures1. Improvement in ABI (6, 12, 18 and 24 month of implantation) and Transcutaneous Oxygen pressure (TcO2) (6, 12, 18 and 24 months)
2. Improvement in subjective symptoms: Visual Analogue Scale (VAS) in 1, 6, 12, 18 and 24 months of implantation
3. Improvement in limb ulceration in 1, 6, 12, 18 and 24 months of implantation
4. Elongation in range of pain-free walking in 1, 6, 12, 18 and 24 months of implantation
5. The requirement of analgesic in 1, 6, 12, 18 and 24 months of implantation
6. Manifestation of new collaterals evaluated by angiography in 1 month of implantation
Overall study start date28/11/2007
Completion date30/11/2011

Eligibility

Participant type(s)Patient
Age groupAdult
SexBoth
Target number of participants20 participants
Key inclusion criteria1. Peripheral Arterial Disease (PAD) including Arteriosclerosis Obliterans (ASO), Buerger disease, and arteritis associated with collagen diseases
2. Fontaines stage: IIb, III, and IV
3. Chronic limb ischaemia, including rest pain, non-healing ischaemic ulcers, or both, and were not candidates for non-surgical or surgical revascularisation
4. Age: greater than 20 or less than 80 years
5. World Health Organization (WHO) performance status: 0 to 3
Key exclusion criteria1. Patients with the expected rest of their life less than 1 year
2. Patients with drug dependence during the past 3 months
3. Patients with malignant evidence of malignant disorder during the past 5 years
4. Patients with poorly controlled diabetes mellitus accompanied with proliferative retinopathy
5. Patients with significant coronary stenosis
6. Pregnant or possibly pregnant females
7. Patients with acute myocardial infarction, unstable angina, myocarditis, or cerebral infarction during the past 1 month
8. Patients with active infection including Treponema pallidum
9. Patients with positive test for Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV)
10. Patients with history of allergy for antibiotics or iodo
Date of first enrolment28/11/2007
Date of final enrolment30/11/2011

Locations

Countries of recruitment

  • Japan

Study participating centre

First Department of Internal Medicine
Niigata
951-8510
Japan

Sponsor information

Niigata University Medical and Dental Hospital (Japan)
Hospital/treatment centre

Institutional Review Board for the Clinical Trials of Pharmaceutical Agents and Medical Instruments
Asahimachi 1-754
Niigata
951-8510
Japan

Phone +81 (0)25 227 2782
Email hnmrsato@med.niigata-u.ac.jp
Website http://www.bmrc.jp/
ROR logo "ROR" https://ror.org/03b0x6j22

Funders

Funder type

Government

Niigata University Medical and Dental Hospital (Japan) - Fund for Clinical Studies

No information available

Trial also supported in part by:

No information available

Ministry of Education, Culture, Sports and Technology (Japan) - Grants for Scientific Studies entitled:

No information available

Basic study and clinical trial of angiogenesis by ex-vivo expanded erythroblasts (ref: 17590714, April 2005 - March 2007)

No information available

Ex-vivo expanded erythroblasts transplantation' for the treatment of patients with severe chronic lower limb ischemia (ref: 19590856, April 2007 - March 2009)

No information available

Results and Publications

Intention to publish date
Individual participant data (IPD) Intention to shareNo
IPD sharing plan summaryNot provided at time of registration
Publication and dissemination planNot provided at time of registration
IPD sharing plan

Study outputs

Output type Details Date created Date added Peer reviewed? Patient-facing?
Abstract results 23/03/2018 12/04/2021 No No

Editorial Notes

12/04/2021: Publication reference added.