Condition category
Circulatory System
Date applied
28/11/2007
Date assigned
18/12/2007
Last edited
18/12/2007
Prospective/Retrospective
Retrospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Not provided at time of registration

Trial website

Contact information

Type

Scientific

Primary contact

Dr Ken Toba

ORCID ID

Contact details

First Department of Internal Medicine
Niigata University Medical and Dental Hospital
Asahimachi 1-754
Niigata
951-8510
Japan
+81 (0)25 227 2185
tobaken@med.niigata-u.ac.jp

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

NH18-004

Study information

Scientific title

Phase I/II clinical study of angiogenesis by Ex-Vivo Expanded Erythroblast Transplantation (Autologous) (EVEETA) for the treatment of patients with chronic severe limb ischaemia

Acronym

EVEETA study

Study hypothesis

Bone 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

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)

Study design

Phase I/II study, open-labelled, non-randomised, single arm, single-centre trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Condition

Severe peripheral arterial disease including arteriosclerosis obliterans, Buerger disease and arteritis

Intervention

1. 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 type

Other

Phase

Phase I/II

Drug names

Primary outcome measures

Efficacy 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 measures

1. 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 trial start date

28/11/2007

Overall trial end date

30/11/2011

Reason abandoned

Eligibility

Participant inclusion criteria

1. 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

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

20 participants

Participant exclusion criteria

1. 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

Recruitment start date

28/11/2007

Recruitment end date

30/11/2011

Locations

Countries of recruitment

Japan

Trial participating centre

First Department of Internal Medicine
Niigata
951-8510
Japan

Sponsor information

Organisation

Niigata University Medical and Dental Hospital (Japan)

Sponsor details

Institutional Review Board for the Clinical Trials of Pharmaceutical Agents and Medical Instruments
Asahimachi 1-754
Niigata
951-8510
Japan
+81 (0)25 227 2782
hnmrsato@med.niigata-u.ac.jp

Sponsor type

Hospital/treatment centre

Website

http://www.bmrc.jp/

Funders

Funder type

Government

Funder name

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

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

Trial also supported in part by:

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

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

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

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

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

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

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes