Peripheral Vascular DiseasesPhase 1/2NCT00533104
Cell Therapy in Chronic Limb Ischemia
A Phase 1/2 study testing BM-MNC preparation and PB-MNC preparation in people with Peripheral Vascular Diseases, run by CHU de Reims at 1 site in France.
Trial summary
The primary focus of the trial is safety and efficacy of the intra-muscular implantation of either bone-marrow, or peripheral blood mononuclear cells, in critical limb ischemia, as judged by the proportion of patients which are alive without major amputation 6 months after inclusion. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Peripheral Vascular Diseases
- What is being tested?
- BM-MNC preparation and PB-MNC preparation
- Type of treatment
- Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 40 participants
- Where
- 1 siteFrance
- Study dates
- Oct 2004to Feb 2009
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients with unilateral critical chronic limb ischemia but not suitable candidates for non-surgical or surgical revascularization
- Before being included, the patient must be screened for human immunodeficiency virus, hepatitis B virus, hepatitis C virus, treponema pallidum
Who cannot join
- Buerger disease
- Ischemic ulcers with infectious symptoms
- Diabetes mellitus with HbA1c > 7,5% or with proliferative retinopathy
- Past or current malignancy
- Contra-indication to general anaesthesia
- Chronic haemodialysis
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- Prothrombin Time < 60%,
- Recent onset (within 3 months) of myocardial infarction or brain infarction
- Coronary angioplasty within 1 year
- Atrial fibrillation, mechanical mitral prosthetic valve
- Unexplained hematological abnormality.
- Expected life span less than six months
- Patient not competent to give informed consent
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Critical Limb Ischemia Treatment by Local Intra-Muscular Injection of Autologous Mononuclear Cells
The primary focus of the trial is safety and efficacy of the intra-muscular implantation of either bone-marrow, or peripheral blood mononuclear cells, in critical limb ischemia, as judged by the proportion of patients which are alive without major amputation 6 months after inclusion.
Read the detailed description
Critical limb ischemia is a frequent situation whose incidence can be evaluated to 500 to 1,000 per million per year. Limb salvage is the main goal of therapy and is usually attempted by surgical or percutaneous vascularization procedures. However approximately 25 % of patients are not suitable for such procedures and it was estimated that less than half of these patients were alive without any major amputation after 6 months. In this setting cell therapy has been proposed to stimulate angiogenesis. The first significant experience in humans was reported by TATEISHI-YUYAMA et al who showed that autologous implantation of bone marrow mononuclear cells (BM-MNC) was safe and increased blood flow in ischemic limbs resulting in clinical improvement. The same authors did not observe any efficacy of peripheral blood mononuclear cells (PB-MNC). Subsequently other publications reported positive effects of PB-MNC which were harvested after previous treatment with haematopoietic growth factor to induce a mobilization of stem cells. However such a treatment could have deleterious effects in patients presenting with advanced arterial disease. In this context we propose a prospective bi-centric trial to evaluate the safety and efficacy of autologous implantation of either BM-MNC or PB-MNC without previous mobilization with hematopoïetic factor, in patients with critical limb ischemia.
The trial is designed in two steps : a first series of eight patients are treated with BM-MNC and the following eight will receive PB-MNC. An interim analysis is planned after these first sixteen cases. Based on this analysis, it will be decided to include 12 further patients with each type of cells.Patients are consecutively included as soon as they present with appropriate criteria and are not selected to receive one or another type of cells.
Before implantation, MNC counts, differential and viability are determined. CD34+, CD34+/CD133+ and CD34+/CD133+/flk-1+ cells are counted by flow-cytometry.
Clinical symptoms and TcPO2 are monitored 1, 2, 7 and 14 days, 1, 3, and 6 months after cell implantation. Blood cell count, C-reactive protein, Interleukin-6, tumor necrosis factor-α, myoglobin, and creatinin-kinase are determined at day 0, 1, 3 and 7 ; blood vascular-endothelial-growth-factor (VEGF) level and CD34+, CD34+/CD133+ blood cells are measured before and 72 hours after implantation
- Conditions
- Peripheral Vascular Diseases
- Being tested
- BM-MNC preparation, PB-MNC preparation
- Keywords
- Limb ischemia, Cell Therapy
- Medical subject headings
- Peripheral Vascular Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
BM-MNC preparationProcedure or surgery
For autologous bone marrow - mononuclear cells preparation, 500ml of bone marrow are collected under general anaesthesia; mononuclear cells are separated using a blood-cells separator (COBE SPECTRA, GAMBRO BCT) and concentrated to produce a final volume of 40ml.
Cells are implanted 1 to 3 hours after preparation by multiple intramuscular injections into the gastrocnemius of the ischemic leg.(30 injection sites, 1 to 1.5 cm deep, spaced 1 cm apart,1 ml per injection).
PB-MNC preparationProcedure or surgery
Peripheral blood - mononuclear cells are collected through cytapheresis with the same blood-cells separator which is adjusted to obtain a 40 mL cell product. No previous mobilization with hematopoïetic growth-factor is administered.
Cells are implanted 1 to 3 hours after preparation by multiple intramuscular injections into the gastrocnemius of the ischemic leg.(30 injection sites, 1 to 1.5 cm deep, spaced 1 cm apart,1 ml per injection).
| Study group | Role | What they receive |
|---|---|---|
| BM-MNC | Experimental | Patients are implanted with bone marrow - mononuclear cells Receives: Procedure: BM-MNC preparation |
| PB-MNC | Experimental | Patients are implanted with peripheral blood - mononuclear cells Receives: Procedure: PB-MNC preparation |
What is being measured
The primary outcome is the main question the study is designed to answer.
Survival without major amputation
Measured: 6 months after implantation
Secondary outcomes (1)
clinical symptoms and haemodynamic parameters
Measured: Within 6 months after implantation
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Sep 2007 (estimated)
- Study startOct 2004
- Primary completionFeb 2009
- Study completionFeb 2009
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Peripheral Vascular DiseasesStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 40 participants (actual)
Sponsor and investigators
- Lead sponsor
- CHU de Reims
- Sponsor type
- University, hospital or other
- Investigators
- Bernard PIGNON, MD, Study director, University Hospital REIMS FRANCEMarie-Antoinette SEVESTRE, MD, Principal investigator, University Hospital AMIENS FRANCE
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00533104
- Sponsor's protocol ID
- PHRC Région 2003 / R11-05 / 95
- Status last verified
- Feb 2009
- First submitted
- 19 Sep 2007
- Last updated
- 6 Feb 2009
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Pignon B, Sevestre MA, Chatelain D, Albertini JN, Sevestre H. Histological changes after implantation of autologous bone marrow mononuclear cells for chronic critical limb ischemia. Bone Marrow Transplant. 2007 May;39(10):647-8. doi: 10.1038/sj.bmt.1705656. Epub 2007 Mar 26. No abstract available.
PubMed 17384655Al-Rifai R, Nguyen P, Bouland N, Terryn C, Kanagaratnam L, Poitevin G, Francois C, Boisson-Vidal C, Sevestre MA, Tournois C. In vivo efficacy of endothelial growth medium stimulated mesenchymal stem cells derived from patients with critical limb ischemia. J Transl Med. 2019 Aug 9;17(1):261. doi: 10.1186/s12967-019-2003-3.
PubMed 31399109Capiod JC, Tournois C, Vitry F, Sevestre MA, Daliphard S, Reix T, Nguyen P, Lefrere JJ, Pignon B. Characterization and comparison of bone marrow and peripheral blood mononuclear cells used for cellular therapy in critical leg ischaemia: towards a new cellular product. Vox Sang. 2009 Apr;96(3):256-65. doi: 10.1111/j.1423-0410.2008.01138.x. Epub 2008 Dec 15.
PubMed 19207166
Study at a glance
From the registry record, last updated by the sponsor on 6 Feb 2009. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Critical Limb Ischemia Treatment by Local Intra-Muscular Injection of Autologous Mononuclear Cells
- ClinicalTrials.gov ID
- NCT00533104
- Acronym / sponsor ID
- PHRC Région 2003 / R11-05 / 95
- Conditions
- Peripheral Vascular Diseases
- Keywords
- Limb ischemia, Cell Therapy
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 40 participants (actual)
- Lead sponsor
- CHU de ReimsUniversity, hospital or other
- Study start
- Oct 2004
- Primary completion
- Feb 2009 (actual)
- Study completion
- Feb 2009 (actual)
- First posted
- 21 Sep 2007 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The primary focus of the trial is safety and efficacy of the intra-muscular implantation of either bone-marrow, or peripheral blood mononuclear cells, in critical limb ischemia, as judged by the proportion of patients which are alive without major amputation 6 months after inclusion.
Detailed description
Critical limb ischemia is a frequent situation whose incidence can be evaluated to 500 to 1,000 per million per year. Limb salvage is the main goal of therapy and is usually attempted by surgical or percutaneous vascularization procedures. However approximately 25 % of patients are not suitable for such procedures and it was estimated that less than half of these patients were alive without any major amputation after 6 months. In this setting cell therapy has been proposed to stimulate angiogenesis. The first significant experience in humans was reported by TATEISHI-YUYAMA et al who showed that autologous implantation of bone marrow mononuclear cells (BM-MNC) was safe and increased blood flow in ischemic limbs resulting in clinical improvement. The same authors did not observe any efficacy of peripheral blood mononuclear cells (PB-MNC). Subsequently other publications reported positive effects of PB-MNC which were harvested after previous treatment with haematopoietic growth factor to induce a mobilization of stem cells. However such a treatment could have deleterious effects in patients presenting with advanced arterial disease. In this context we propose a prospective bi-centric trial to evaluate the safety and efficacy of autologous implantation of either BM-MNC or PB-MNC without previous mobilization with hematopoïetic factor, in patients with critical limb ischemia.
The trial is designed in two steps : a first series of eight patients are treated with BM-MNC and the following eight will receive PB-MNC. An interim analysis is planned after these first sixteen cases. Based on this analysis, it will be decided to include 12 further patients with each type of cells.Patients are consecutively included as soon as they present with appropriate criteria and are not selected to receive one or another type of cells.
Before implantation, MNC counts, differential and viability are determined. CD34+, CD34+/CD133+ and CD34+/CD133+/flk-1+ cells are counted by flow-cytometry.
Clinical symptoms and TcPO2 are monitored 1, 2, 7 and 14 days, 1, 3, and 6 months after cell implantation. Blood cell count, C-reactive protein, Interleukin-6, tumor necrosis factor-α, myoglobin, and creatinin-kinase are determined at day 0, 1, 3 and 7 ; blood vascular-endothelial-growth-factor (VEGF) level and CD34+, CD34+/CD133+ blood cells are measured before and 72 hours after implantation
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| BM-MNC | Experimental | Procedure: BM-MNC preparationPatients are implanted with bone marrow - mononuclear cells |
| PB-MNC | Experimental | Procedure: PB-MNC preparationPatients are implanted with peripheral blood - mononuclear cells |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (2 listed)
- Patients with unilateral critical chronic limb ischemia but not suitable candidates for non-surgical or surgical revascularization
- Before being included, the patient must be screened for human immunodeficiency virus, hepatitis B virus, hepatitis C virus, treponema pallidum
Key exclusion criteria (13 listed)
- Buerger disease
- Ischemic ulcers with infectious symptoms
- Diabetes mellitus with HbA1c > 7,5% or with proliferative retinopathy
- Past or current malignancy
- Contra-indication to general anaesthesia
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| BM-MNC preparationFor autologous bone marrow - mononuclear cells preparation, 500ml of bone marrow are collected under general anaesthesia; mononuclear cells are separated using a blood-cells separator (COBE SPECTRA, GAMBRO BCT) and concentrated to produce a final volume of 40ml. Cells are implanted 1 to 3 hours after preparation by multiple intramuscular injections into the gastrocnemius of the ischemic leg.(30 injection sites, 1 to 1.5 cm deep, spaced 1 cm apart,1 ml per injection). | Procedure or surgery | BM-MNC |
| PB-MNC preparationPeripheral blood - mononuclear cells are collected through cytapheresis with the same blood-cells separator which is adjusted to obtain a 40 mL cell product. No previous mobilization with hematopoïetic growth-factor is administered. Cells are implanted 1 to 3 hours after preparation by multiple intramuscular injections into the gastrocnemius of the ischemic leg.(30 injection sites, 1 to 1.5 cm deep, spaced 1 cm apart,1 ml per injection). | Procedure or surgery | PB-MNC |
Primary outcome
Survival without major amputation
Time frame: 6 months after implantation
1 secondary outcome
clinical symptoms and haemodynamic parameters
Time frame: Within 6 months after implantation
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Feb 2009.
- Results publication: PubMed 17384655Pignon B, Sevestre MA, Chatelain D, Albertini JN, Sevestre H. Histological changes after implantation of autologous bone marrow mononuclear cells for chronic critical limb ischemia. Bone Marrow Transplant. 2007 May;39(10):647-8. doi: 10.1038/sj.bmt.1705656. Epub 2007 Mar 26. No abstract available.
- Derived from this study: PubMed 31399109Al-Rifai R, Nguyen P, Bouland N, Terryn C, Kanagaratnam L, Poitevin G, Francois C, Boisson-Vidal C, Sevestre MA, Tournois C. In vivo efficacy of endothelial growth medium stimulated mesenchymal stem cells derived from patients with critical limb ischemia. J Transl Med. 2019 Aug 9;17(1):261. doi: 10.1186/s12967-019-2003-3.
- Derived from this study: PubMed 19207166Capiod JC, Tournois C, Vitry F, Sevestre MA, Daliphard S, Reix T, Nguyen P, Lefrere JJ, Pignon B. Characterization and comparison of bone marrow and peripheral blood mononuclear cells used for cellular therapy in critical leg ischaemia: towards a new cellular product. Vox Sang. 2009 Apr;96(3):256-65. doi: 10.1111/j.1423-0410.2008.01138.x. Epub 2008 Dec 15.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Bernard PIGNON, MD study director
University Hospital REIMS FRANCE
Marie-Antoinette SEVESTRE, MD principal investigator
University Hospital AMIENS FRANCE
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing BM-MNC preparation and PB-MNC preparation in people with Peripheral Vascular Diseases, run by CHU de Reims at 1 site in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 6 Feb 2009. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Survival without major amputation (time frame: 6 months after implantation). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00533104, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Feb 2009.