- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02454231
Monocentric Trial: Stem Cell Emergency Life Threatening Limbs Arteriopathy (SCELTA) (SCELTA)
Monocentric Randomized Study for the Therapy of Critic Limb Ischemia With Bone Marrow- or Peripheral Blood-derived Stem Cells
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Peripheral arterial disease comprises a clinical spectrum that extends from no symptoms to presentation with critical limb ischemia (CLI), which is a very invalidating condition characterized by rest pain, march inability, trophic lesions and unavoidable progression to major amputations, which are burdened by a high mortality in the first year. The pathophysiology of CLI often associates with a defect in the development of collateral vessels and angiogenesis, a process which refers to the formation of new blood vessels into tissue, due to circulating endothelial progenitor cells (EPCs) and vascular progenitor cells. In the last few years, significant improvement of this condition has been reported following bone marrow (BM) autotransplant or autotransplant of peripheral EPCs mobilized from BM through the injection of granulocyte-colony stimulatory factor (G-CSF). In a previous study, the investigators found that individually variable proportions of circulating CD14+ cells expressed low levels of CD34 (CD14+CD34low) and revealed the functional phenotype of EPCs. The investigators therefore designed a monocentric randomized clinical trial to compare the therapeutic efficacy of BM autotransplant with the autotransplant of a population of circulating CD34+ and CD14+CD34low enriched by a closed sterile immunomagnetic system (enriched circulating EPCs or ECEPCs), without a previous EPC mobilization from BM.
Patients will be evaluated for clinical parameters and ABI, TBI, TCp02 before autotransplant and at three follow-up times after the autotransplant (4, 24 and 52 weeks); also angio-TAC of legs, capillaroscopy, and photoplethysmography will be evaluated at 4, and even at 52 weeks.
Study Type
Enrollment (Actual)
Phase
- Phase 2
- Phase 3
Contacts and Locations
Study Locations
-
-
Tuscany
-
Florence, Tuscany, Italy, 50134
- Azienda Ospedaliero-Universitaria Careggi
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Eligible patients were men and women aged more than 40 years with a diagnosis of CLI due to atherosclerosis of the lower extremities, as defined by the presence of persistent rest pain requiring systemic and continued analgesic treatment in the last 15 days and/or the presence of trophic lesions imputable to the occluding arteriopathy, an ankle-brachial Index (ABI) < 0.40 (with systolic ankle pressure < 50-70 Hg mm), a toe/brachial index (TBI) < 0.40 (with big toe systolic pressure < 30-50 Hg mm), and a transcutaneous oxygen pressure (TC pO2) < 30 Hg mm.
- The patient was considered as eligible for the treatment and enrolled only after the demonstration that intravascular or surgical re-vascularization was not possible, as revealed by ecography and angio-CAT, or when the patient refused to undergo surgical treatments and after having obtained his/her written informed consensus.
Exclusion Criteria:
- Exclusion criteria were: age < 40;
- not atherosclerotic CLI,
- myocardial infarction occurrence in the 6 months;
- cardiac failure of III-IV class NYHA;
- ejection fraction lower than 40%;
- arterial hypertension (>160/100 Hg mm) uncontrolled despite the usage of two anti-hypertensive drugs;
- presence of current or chronic severe infectious diseases;
- osteomyelitis;
- diabetes with glycate hemoglobin > 7.5;
- proliferative diabetic retinopathy;
- hemorrhagic disorders;
- non-atherosclerotic arteriopathy;
- chronic airway insufficiency (p02 <65 Hg mm, pCO2 > 0.50 Hg mm);
- renal failure (creatinine > 2mg/dl);
- contraindications or intolerance to contrast media for radiologic imaging
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: peripheral blood EPC injection
|
intramuscular injection of circulating EPC at leg level
|
Active Comparator: bone marrow MNC injection
|
intramuscular injection of BM MNC at leg level
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Safety as measured by evaluation of any adverse event temporary correlated with the treatment
Time Frame: 52 weeks of follow-up
|
Evaluation of any adverse event temporary correlated with the treatment
|
52 weeks of follow-up
|
Changes in ischemic leg perfusion from baseline
Time Frame: 4, 22, 52 weeks of follow-up
|
Improvement of leg perfusion as assessed by values of Time to Pick (TTP) evaluated by ultrasound tools
|
4, 22, 52 weeks of follow-up
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Improvement of Mean values of the transcutaneous partial oxygen pressure (TCP02)
Time Frame: 4, 22, 52 weeks of follow-up
|
Improvement of mean values of the transcutaneous partial oxygen pressure of at least 20%
|
4, 22, 52 weeks of follow-up
|
Improvement of mean values of ankle brachial pressure index (ABI)
Time Frame: 4, 22, 52 weeks of follow-up
|
improvement (at least 25% increase) of Mean values of ankle brachial pressure index
|
4, 22, 52 weeks of follow-up
|
Improvement of vessel anatomical status
Time Frame: 4, 22, 52 weeks of follow-up
|
Improvement of leg vascularization as assessed by color Doppler ultrasound
|
4, 22, 52 weeks of follow-up
|
Improvement of leg perfusion
Time Frame: 4, 22, 52 weeks of follow-up
|
Improvement of leg perfusion as assessed by plethysmography characterization
|
4, 22, 52 weeks of follow-up
|
Improvement of vessel anatomical status
Time Frame: 4, 22, 52 weeks of follow-up
|
Improvement of leg vascularization as assessed by Angio-CT, defined as presence of new vessels
|
4, 22, 52 weeks of follow-up
|
Quality of life Improvement
Time Frame: -28, 0, 28 weeks of follow-up
|
Quality of life, as assessed by the disease-specific ST22 and SF36 questionaries
|
-28, 0, 28 weeks of follow-up
|
improvement of rest pain
Time Frame: 4, 22, 52 weeks of follow-up
|
Rest pain as evaluated by visual analogue pain scale (VAS)
|
4, 22, 52 weeks of follow-up
|
Improvement of trophic limb lesions
Time Frame: 4, 22, 52 weeks of follow-up
|
Mean score of trophic limb lesions, as evaluated according to Wagner international grade
|
4, 22, 52 weeks of follow-up
|
Reduction of numbers of major amputation (amputation free survival )
Time Frame: 4, 22, 52 weeks of follow-up
|
Reduction of numbers of major amputation compared with untreated patients
|
4, 22, 52 weeks of follow-up
|
improvement of microvascular anatomy
Time Frame: 4, 22, 52 weeks of follow-up
|
evaluation of microvascular anatomy as assessed by capillaroscopy
|
4, 22, 52 weeks of follow-up
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Enrico Maggi, professor, University of Florence
Publications and helpful links
General Publications
- Kalka C, Masuda H, Takahashi T, Kalka-Moll WM, Silver M, Kearney M, Li T, Isner JM, Asahara T. Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3422-7. doi: 10.1073/pnas.97.7.3422.
- Curb JD, Masaki K, Rodriguez BL, Abbott RD, Burchfiel CM, Chen R, Petrovitch H, Sharp D, Yano K. Peripheral artery disease and cardiovascular risk factors in the elderly. The Honolulu Heart Program. Arterioscler Thromb Vasc Biol. 1996 Dec;16(12):1495-500. doi: 10.1161/01.atv.16.12.1495.
- Gregg EW, Sorlie P, Paulose-Ram R, Gu Q, Eberhardt MS, Wolz M, Burt V, Curtin L, Engelgau M, Geiss L; 1999-2000 national health and nutrition examination survey. Prevalence of lower-extremity disease in the US adult population >=40 years of age with and without diabetes: 1999-2000 national health and nutrition examination survey. Diabetes Care. 2004 Jul;27(7):1591-7. doi: 10.2337/diacare.27.7.1591.
- Tateishi-Yuyama E, Matsubara H, Murohara T, Ikeda U, Shintani S, Masaki H, Amano K, Kishimoto Y, Yoshimoto K, Akashi H, Shimada K, Iwasaka T, Imaizumi T; Therapeutic Angiogenesis using Cell Transplantation (TACT) Study Investigators. Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial. Lancet. 2002 Aug 10;360(9331):427-35. doi: 10.1016/S0140-6736(02)09670-8.
- Weitz JI, Byrne J, Clagett GP, Farkouh ME, Porter JM, Sackett DL, Strandness DE Jr, Taylor LM. Diagnosis and treatment of chronic arterial insufficiency of the lower extremities: a critical review. Circulation. 1996 Dec 1;94(11):3026-49. doi: 10.1161/01.cir.94.11.3026. No abstract available. Erratum In: Circulation 2000 Aug 29;102(9):1074.
- Meijer WT, Grobbee DE, Hunink MG, Hofman A, Hoes AW. Determinants of peripheral arterial disease in the elderly: the Rotterdam study. Arch Intern Med. 2000 Oct 23;160(19):2934-8. doi: 10.1001/archinte.160.19.2934.
- Melillo E, Nuti M, Bongiorni L, Golgini E, Balbarini A. [Major and minor amputation rates and lower critical limb ischemia: the epidemiological data of western Tuscany]. Ital Heart J Suppl. 2004 Oct;5(10):794-805. Italian.
- Inglese L, Graziani L, Tarricone R. [Percutaneous treatment of peripheral obstructive arteriopathy: the reasons for a choice]. Ital Heart J Suppl. 2000 Sep;1(9):1138-47. Italian.
- Dzau VJ, Gnecchi M, Pachori AS, Morello F, Melo LG. Therapeutic potential of endothelial progenitor cells in cardiovascular diseases. Hypertension. 2005 Jul;46(1):7-18. doi: 10.1161/01.HYP.0000168923.92885.f7. Epub 2005 Jun 13.
- Ikenaga S, Hamano K, Nishida M, Kobayashi T, Li TS, Kobayashi S, Matsuzaki M, Zempo N, Esato K. Autologous bone marrow implantation induced angiogenesis and improved deteriorated exercise capacity in a rat ischemic hindlimb model. J Surg Res. 2001 Apr;96(2):277-83. doi: 10.1006/jsre.2000.6080.
- Iwaguro H, Yamaguchi J, Kalka C, Murasawa S, Masuda H, Hayashi S, Silver M, Li T, Isner JM, Asahara T. Endothelial progenitor cell vascular endothelial growth factor gene transfer for vascular regeneration. Circulation. 2002 Feb 12;105(6):732-8. doi: 10.1161/hc0602.103673.
- Iba O, Matsubara H, Nozawa Y, Fujiyama S, Amano K, Mori Y, Kojima H, Iwasaka T. Angiogenesis by implantation of peripheral blood mononuclear cells and platelets into ischemic limbs. Circulation. 2002 Oct 8;106(15):2019-25. doi: 10.1161/01.cir.0000031332.45480.79.
- Masuda H, Asahara T. Post-natal endothelial progenitor cells for neovascularization in tissue regeneration. Cardiovasc Res. 2003 May 1;58(2):390-8. doi: 10.1016/s0008-6363(02)00785-x.
- Romagnani P, Annunziato F, Liotta F, Lazzeri E, Mazzinghi B, Frosali F, Cosmi L, Maggi L, Lasagni L, Scheffold A, Kruger M, Dimmeler S, Marra F, Gensini G, Maggi E, Romagnani S. CD14+CD34low cells with stem cell phenotypic and functional features are the major source of circulating endothelial progenitors. Circ Res. 2005 Aug 19;97(4):314-22. doi: 10.1161/01.RES.0000177670.72216.9b. Epub 2005 Jul 14.
- Chambers I, Colby D, Robertson M, Nichols J, Lee S, Tweedie S, Smith A. Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell. 2003 May 30;113(5):643-55. doi: 10.1016/s0092-8674(03)00392-1.
- Mitsui K, Tokuzawa Y, Itoh H, Segawa K, Murakami M, Takahashi K, Maruyama M, Maeda M, Yamanaka S. The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell. 2003 May 30;113(5):631-42. doi: 10.1016/s0092-8674(03)00393-3.
- Pesce M, Scholer HR. Oct-4: gatekeeper in the beginnings of mammalian development. Stem Cells. 2001;19(4):271-8. doi: 10.1634/stemcells.19-4-271.
- Iwama A, Oguro H, Negishi M, Kato Y, Morita Y, Tsukui H, Ema H, Kamijo T, Katoh-Fukui Y, Koseki H, van Lohuizen M, Nakauchi H. Enhanced self-renewal of hematopoietic stem cells mediated by the polycomb gene product Bmi-1. Immunity. 2004 Dec;21(6):843-51. doi: 10.1016/j.immuni.2004.11.004.
- Melillo E, Ferrari M, Balbarini A, Pedrinelli R. Transcutaneous gases determination in diabetic critical limb ischemia. Diabetes Care. 2005 Aug;28(8):2081-2. doi: 10.2337/diacare.28.8.2081. No abstract available.
- Becker F, Gabrielle F, Raoux MH, Brenot R, David M. [Value of measuring transcutaneous oxygen pressure in arterial disease of the legs]. Ann Cardiol Angeiol (Paris). 1989 Oct;38(8):465-72. French.
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- UFlorence
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