Efficacy and Safety of Mesenchymal Stem Cell Clusters in Patients with Critical Limb Ischemia

Summary

This clinical trial is designed as a Phase 1/2a clinical trial targeting patients with critical limb ischemia. The trial is composed of Phase 1 to assess the tolerability and safety and Phase 2a to assess the safety and efficacy of the investigational product(A cluster of adipose-derived mesenchymal stem cells (3D-A) (cluster of adipose- derived mesenchymal stem cells)) and proceeds in that order.

Timeline

Start

2020-11-04

Primary completion

2024-04-22

Completion

2024-07-01

Publications

• Background Isner JM, Baumgartner I, Rauh G, Schainfeld R, Blair R, Manor O, Razvi S, Symes JF. Treatment of thromboangiitis obliterans (Buerger's disease) by intramuscular gene transfer of vascular endothelial growth factor: preliminary clinical results. J Vasc Surg. 1998 Dec;28(6):964-73; discussion 73-5. doi: 10.1016/s0741-5214(98)70022-9.
• Background Bura A, Planat-Benard V, Bourin P, Silvestre JS, Gross F, Grolleau JL, Saint-Lebese B, Peyrafitte JA, Fleury S, Gadelorge M, Taurand M, Dupuis-Coronas S, Leobon B, Casteilla L. Phase I trial: the use of autologous cultured adipose-derived stroma/stem cells to treat patients with non-revascularizable critical limb ischemia. Cytotherapy. 2014 Feb;16(2):245-57. doi: 10.1016/j.jcyt.2013.11.011.
• Background Powell RJ, Goodney P, Mendelsohn FO, Moen EK, Annex BH; HGF-0205 Trial Investigators. Safety and efficacy of patient specific intramuscular injection of HGF plasmid gene therapy on limb perfusion and wound healing in patients with ischemic lower extremity ulceration: results of the HGF-0205 trial. J Vasc Surg. 2010 Dec;52(6):1525-30. doi: 10.1016/j.jvs.2010.07.044.
• Background Lee HC, An SG, Lee HW, Park JS, Cha KS, Hong TJ, Park JH, Lee SY, Kim SP, Kim YD, Chung SW, Bae YC, Shin YB, Kim JI, Jung JS. Safety and effect of adipose tissue-derived stem cell implantation in patients with critical limb ischemia: a pilot study. Circ J. 2012;76(7):1750-60. doi: 10.1253/circj.cj-11-1135. Epub 2012 Apr 12.
• Background Murphy MP, Lawson JH, Rapp BM, Dalsing MC, Klein J, Wilson MG, Hutchins GD, March KL. Autologous bone marrow mononuclear cell therapy is safe and promotes amputation-free survival in patients with critical limb ischemia. J Vasc Surg. 2011 Jun;53(6):1565-74.e1. doi: 10.1016/j.jvs.2011.01.074. Epub 2011 Apr 22.
• Background Lasala GP, Silva JA, Minguell JJ. Therapeutic angiogenesis in patients with severe limb ischemia by transplantation of a combination stem cell product. J Thorac Cardiovasc Surg. 2012 Aug;144(2):377-82. doi: 10.1016/j.jtcvs.2011.08.053. Epub 2011 Nov 12.
• Background Kawamoto A, Katayama M, Handa N, Kinoshita M, Takano H, Horii M, Sadamoto K, Yokoyama A, Yamanaka T, Onodera R, Kuroda A, Baba R, Kaneko Y, Tsukie T, Kurimoto Y, Okada Y, Kihara Y, Morioka S, Fukushima M, Asahara T. Intramuscular transplantation of G-CSF-mobilized CD34(+) cells in patients with critical limb ischemia: a phase I/IIa, multicenter, single-blinded, dose-escalation clinical trial. Stem Cells. 2009 Nov;27(11):2857-64. doi: 10.1002/stem.207.
• Background Ruiz-Salmeron R, de la Cuesta-Diaz A, Constantino-Bermejo M, Perez-Camacho I, Marcos-Sanchez F, Hmadcha A, Soria B. Angiographic demonstration of neoangiogenesis after intra-arterial infusion of autologous bone marrow mononuclear cells in diabetic patients with critical limb ischemia. Cell Transplant. 2011;20(10):1629-39. doi: 10.3727/096368910X0177.
• Background Benoit E, O'Donnell TF, Patel AN. Safety and efficacy of autologous cell therapy in critical limb ischemia: a systematic review. Cell Transplant. 2013;22(3):545-62. doi: 10.3727/096368912X636777. Epub 2012 Mar 28.
• Background Cacione DG, do Carmo Novaes F, Moreno DH. Stem cell therapy for treatment of thromboangiitis obliterans (Buerger's disease). Cochrane Database Syst Rev. 2018 Oct 31;10(10):CD012794. doi: 10.1002/14651858.CD012794.pub2.
• Background Criqui MH, Fronek A, Barrett-Connor E, Klauber MR, Gabriel S, Goodman D. The prevalence of peripheral arterial disease in a defined population. Circulation. 1985 Mar;71(3):510-5. doi: 10.1161/01.cir.71.3.510.
• Background Selvin E, Erlinger TP. Prevalence of and risk factors for peripheral arterial disease in the United States: results from the National Health and Nutrition Examination Survey, 1999-2000. Circulation. 2004 Aug 10;110(6):738-43. doi: 10.1161/01.CIR.0000137913.26087.F0. Epub 2004 Jul 19.
• Background Hirsch AT, Criqui MH, Treat-Jacobson D, Regensteiner JG, Creager MA, Olin JW, Krook SH, Hunninghake DB, Comerota AJ, Walsh ME, McDermott MM, Hiatt WR. Peripheral arterial disease detection, awareness, and treatment in primary care. JAMA. 2001 Sep 19;286(11):1317-24. doi: 10.1001/jama.286.11.1317.
• Background Kinlay S. Management of Critical Limb Ischemia. Circ Cardiovasc Interv. 2016 Feb;9(2):e001946. doi: 10.1161/CIRCINTERVENTIONS.115.001946.
• Background Dohmen A, Eder S, Euringer W, Zeller T, Beyersdorf F. Chronic critical limb ischemia. Dtsch Arztebl Int. 2012 Feb;109(6):95-101. doi: 10.3238/arztebl.2012.0095. Epub 2012 Feb 10.
• Background Davies MG. Criticial limb ischemia: epidemiology. Methodist Debakey Cardiovasc J. 2012 Oct-Dec;8(4):10-4. doi: 10.14797/mdcj-8-4-10.
• Background Soder HK, Manninen HI, Jaakkola P, Matsi PJ, Rasanen HT, Kaukanen E, Loponen P, Soimakallio S. Prospective trial of infrapopliteal artery balloon angioplasty for critical limb ischemia: angiographic and clinical results. J Vasc Interv Radiol. 2000 Sep;11(8):1021-31. doi: 10.1016/s1051-0443(07)61332-3.
• Background Nasr MK, McCarthy RJ, Hardman J, Chalmers A, Horrocks M. The increasing role of percutaneous transluminal angioplasty in the primary management of critical limb ischaemia. Eur J Vasc Endovasc Surg. 2002 May;23(5):398-403. doi: 10.1053/ejvs.2002.1615.
• Background Guiducci S, Porta F, Saccardi R, Guidi S, Ibba-Manneschi L, Manetti M, Mazzanti B, Dal Pozzo S, Milia AF, Bellando-Randone S, Miniati I, Fiori G, Fontana R, Amanzi L, Braschi F, Bosi A, Matucci-Cerinic M. Autologous mesenchymal stem cells foster revascularization of ischemic limbs in systemic sclerosis: a case report. Ann Intern Med. 2010 Nov 16;153(10):650-4. doi: 10.7326/0003-4819-153-10-201011160-00007.
• Background Gupta PK, Chullikana A, Parakh R, Desai S, Das A, Gottipamula S, Krishnamurthy S, Anthony N, Pherwani A, Majumdar AS. A double blind randomized placebo controlled phase I/II study assessing the safety and efficacy of allogeneic bone marrow derived mesenchymal stem cell in critical limb ischemia. J Transl Med. 2013 Jun 10;11:143. doi: 10.1186/1479-5876-11-143.
• Background Ito J, Moriyama H, Inokuchi S, Goto N. Human lower limb muscles: an evaluation of weight and fiber size. Okajimas Folia Anat Jpn. 2003 Aug;80(2-3):47-55. doi: 10.2535/ofaj.80.47.
• Background Charles JP, Cappellari O, Spence AJ, Hutchinson JR, Wells DJ. Musculoskeletal Geometry, Muscle Architecture and Functional Specialisations of the Mouse Hindlimb. PLoS One. 2016 Apr 26;11(4):e0147669. doi: 10.1371/journal.pone.0147669. eCollection 2016.
• Background Park IS, Rhie JW, Kim SH. A novel three-dimensional adipose-derived stem cell cluster for vascular regeneration in ischemic tissue. Cytotherapy. 2014 Apr;16(4):508-22. doi: 10.1016/j.jcyt.2013.08.011. Epub 2013 Nov 7.
• Background Park IS, Kang JA, Kang J, Rhie JW, Kim SH. Therapeutic effect of human adipose-derived stromal cells cluster in rat hind-limb ischemia. Anat Rec (Hoboken). 2014 Dec;297(12):2289-98. doi: 10.1002/ar.22961. Epub 2014 Jul 25.
• Background Schroder F, Diehm N, Kareem S, Ames M, Pira A, Zwettler U, Lawall H, Diehm C. A modified calculation of ankle-brachial pressure index is far more sensitive in the detection of peripheral arterial disease. J Vasc Surg. 2006 Sep;44(3):531-6. doi: 10.1016/j.jvs.2006.05.016.
• Background Rutherford RB, Baker JD, Ernst C, Johnston KW, Porter JM, Ahn S, Jones DN. Recommended standards for reports dealing with lower extremity ischemia: revised version. J Vasc Surg. 1997 Sep;26(3):517-38. doi: 10.1016/s0741-5214(97)70045-4.
• Background Heo SH, Park YS, Kang ES, Park KB, Do YS, Kang KS, Kim DI. Early Results of Clinical Application of Autologous Whole Bone Marrow Stem Cell Transplantation for Critical Limb Ischemia with Buerger's Disease. Sci Rep. 2016 Jan 21;6:19690. doi: 10.1038/srep19690.
• Background Kim HJ, Jang SY, Park JI, Byun J, Kim DI, Do YS, Kim JM, Kim S, Kim BM, Kim WB, Kim DK. Vascular endothelial growth factor-induced angiogenic gene therapy in patients with peripheral artery disease. Exp Mol Med. 2004 Aug 31;36(4):336-44. doi: 10.1038/emm.2004.44.
• Background Qadura M, Terenzi DC, Verma S, Al-Omran M, Hess DA. Concise Review: Cell Therapy for Critical Limb Ischemia: An Integrated Review of Preclinical and Clinical Studies. Stem Cells. 2018 Feb;36(2):161-171. doi: 10.1002/stem.2751. Epub 2018 Jan 3.
• Background Greenblatt DJ, Allen MD. Intramuscular injection-site complications. JAMA. 1978 Aug 11;240(6):542-4.
• Background Muller-Vahl H. Adverse reactions after intramuscular injections. Lancet. 1983 May 7;1(8332):1050. doi: 10.1016/s0140-6736(83)92679-x. No abstract available.
• Background Mishra P, Stringer MD. Sciatic nerve injury from intramuscular injection: a persistent and global problem. Int J Clin Pract. 2010 Oct;64(11):1573-1579. doi: 10.1111/j.1742-1241.2009.02177.x.
• Background Rodger MA, King L. Drawing up and administering intramuscular injections: a review of the literature. J Adv Nurs. 2000 Mar;31(3):574-82. doi: 10.1046/j.1365-2648.2000.01312.x.
• Background Cocoman A, Murray J. Intramuscular injections: a review of best practice for mental health nurses. J Psychiatr Ment Health Nurs. 2008 Jun;15(5):424-34. doi: 10.1111/j.1365-2850.2007.01236.x.
• Background Grenon SM, Vittinghoff E, Owens CD, Conte MS, Whooley M, Cohen BE. Peripheral artery disease and risk of cardiovascular events in patients with coronary artery disease: insights from the Heart and Soul Study. Vasc Med. 2013 Aug;18(4):176-84. doi: 10.1177/1358863X13493825. Epub 2013 Jul 8.
• Background Conte MS, Geraghty PJ, Bradbury AW, Hevelone ND, Lipsitz SR, Moneta GL, Nehler MR, Powell RJ, Sidawy AN. Suggested objective performance goals and clinical trial design for evaluating catheter-based treatment of critical limb ischemia. J Vasc Surg. 2009 Dec;50(6):1462-73.e1-3. doi: 10.1016/j.jvs.2009.09.044. Epub 2009 Nov 7.
• Background Shigematsu H, Yasuda K, Iwai T, Sasajima T, Ishimaru S, Ohashi Y, Yamaguchi T, Ogihara T, Morishita R. Randomized, double-blind, placebo-controlled clinical trial of hepatocyte growth factor plasmid for critical limb ischemia. Gene Ther. 2010 Sep;17(9):1152-61. doi: 10.1038/gt.2010.51. Epub 2010 Apr 15.
• Dubsky M, Husakova J, Sojakova D, Fejfarova V, Jude EB. Cell Therapy of Severe Ischemia in People with Diabetic Foot Ulcers-Do We Have Enough Evidence? Mol Diagn Ther. 2023 Nov;27(6):673-683. doi: 10.1007/s40291-023-00667-w. Epub 2023 Sep 22.

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