Monocentric Trial: Stem Cell Emergency Life Threatening Limbs Arteriopathy (SCELTA)

Critical Limb Ischemia Clinical Trial

— SCELTA  

Official title:

Monocentric Randomized Study for the Therapy of Critic Limb Ischemia With Bone Marrow- or Peripheral Blood-derived Stem Cells

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02454231
• Other study ID #: UFlorence
• Status: Completed
• Phase: Phase 2/Phase 3
• First received: May 19, 2015
• Last updated: May 8, 2017
• Start date: September 2009
• Est. completion date: October 2015

Study information

• Verified date: May 2017
• Source: University of Florence
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The investigators designed a randomized clinical trial (stem cell emergency life threatening arteriopathy or SCELTA) to compare the therapeutic efficacy of the auto-transplant of enriched circulating EPCs (ECEPCs) with auto-transplant of BM-MNCs. ECEPCs, obtained by immunoselection of CD14+ and CD34+ cells, or BM-MNCs, were injected intramuscularly in the affected limb of patients with critical limb ischemia (CLI).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 45
• Est. completion date: October 2015
• Est. primary completion date: May 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Critical Limb Ischemia
• Ischemia

Intervention

Biological:
• Transplantation of circulating CD14+CD34+cells
intramuscular injection of circulating EPC at leg level
• Transplantation of BM MNC
intramuscular injection of BM MNC at leg level

Locations

Country	Name	City	State
Italy	Azienda Ospedaliero-Universitaria Careggi	Florence	Tuscany

Sponsors (2)

Lead Sponsor	Collaborator
University of Florence	Tuscany Region

Country where clinical trial is conducted

Italy, 

References & Publications (20)

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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. — View Citation

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. Epub 2005 Jun 13. Review. — View Citation

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. — View Citation

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. Retraction in: Circulation. 2013 Jun 11;127(23):e842. — View Citation

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. — View Citation

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. Review. Italian. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Masuda H, Asahara T. Post-natal endothelial progenitor cells for neovascularization in tissue regeneration. Cardiovasc Res. 2003 May 1;58(2):390-8. Review. — View Citation

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. — View Citation

Melillo E, Ferrari M, Balbarini A, Pedrinelli R. Transcutaneous gases determination in diabetic critical limb ischemia. Diabetes Care. 2005 Aug;28(8):2081-2. — View Citation

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. — View Citation

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. — View Citation

Pesce M, Schöler HR. Oct-4: gatekeeper in the beginnings of mammalian development. Stem Cells. 2001;19(4):271-8. Review. — View Citation

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. Epub 2005 Jul 14. — View Citation

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. — View Citation

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. Review. Erratum in: Circulation 2000 Aug 29;102(9):1074. — View Citation

* Note: There are 20 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety as measured by evaluation of any adverse event temporary correlated with the treatment	Evaluation of any adverse event temporary correlated with the treatment	52 weeks of follow-up
Primary	Changes in ischemic leg perfusion from baseline	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	Improvement of Mean values of the transcutaneous partial oxygen pressure (TCP02)	Improvement of mean values of the transcutaneous partial oxygen pressure of at least 20%	4, 22, 52 weeks of follow-up
Secondary	Improvement of mean values of ankle brachial pressure index (ABI)	improvement (at least 25% increase) of Mean values of ankle brachial pressure index	4, 22, 52 weeks of follow-up
Secondary	Improvement of vessel anatomical status	Improvement of leg vascularization as assessed by color Doppler ultrasound	4, 22, 52 weeks of follow-up
Secondary	Improvement of leg perfusion	Improvement of leg perfusion as assessed by plethysmography characterization	4, 22, 52 weeks of follow-up
Secondary	Improvement of vessel anatomical status	Improvement of leg vascularization as assessed by Angio-CT, defined as presence of new vessels	4, 22, 52 weeks of follow-up
Secondary	Quality of life Improvement	Quality of life, as assessed by the disease-specific ST22 and SF36 questionaries	-28, 0, 28 weeks of follow-up
Secondary	improvement of rest pain	Rest pain as evaluated by visual analogue pain scale (VAS)	4, 22, 52 weeks of follow-up
Secondary	Improvement of trophic limb lesions	Mean score of trophic limb lesions, as evaluated according to Wagner international grade	4, 22, 52 weeks of follow-up
Secondary	Reduction of numbers of major amputation (amputation free survival )	Reduction of numbers of major amputation compared with untreated patients	4, 22, 52 weeks of follow-up
Secondary	improvement of microvascular anatomy	evaluation of microvascular anatomy as assessed by capillaroscopy	4, 22, 52 weeks of follow-up