title: 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.
abstract: BACKGROUND
  Peripheral vascular disease of the lower extremities comprises a clinical spectrum that extends from no symptoms to presentation with critical limb ischemia (CLI). Bone marrow derived Mesenchymal Stem Cells (BM- MSCs) may ameliorate the consequences of CLI due to their combinatorial potential for inducing angiogenesis and immunomodulatory environment in situ. The primary objective was to determine the safety of BM- MSCs in patients with CLI.
  
  
  METHODS
  Prospective, double blind randomized placebo controlled multi-center study was conducted in patients with established CLI as per Rutherford classification in category II-4, III-5, or III-6 with infra-inguinal arterial occlusive disease and were not suitable for or had failed revascularization treatment. The primary end point was incidence of treatment - related adverse events (AE). Exploratory efficacy end points were improvement in rest pain, increase in Ankle Brachial Pressure Index (ABPI), ankle pressure, healing of ulcers, and amputation rates. Twenty patients (BM-MSC: Placebo = 1:1) were administered with allogeneic BM-MSCs at a dose of 2 million cells/kg or placebo (PlasmaLyte A) at the gastrocnemius muscle of the ischemic limb.
  
  
  RESULTS
  Improvement was observed in the rest pain scores in both the arms. Significant increase in ABPI and ankle pressure was seen in BM-MSC arm compared to the placebo group. Incidence of AEs in the BM-MSC arm was 13 vs. 45 in the placebo arm where as serious adverse events (SAE) were similar in both the arms (5 in BM-MSC and 4 in the placebo group). SAEs resulted in death, infected gangrene, amputations in these patients. It was observed that the SAEs were related to disease progression and not related to stem cells.
  
  
  CONCLUSIONS
  BM-MSCs are safe when injected IM at a dose of 2 million cells/kg body weight. Few efficacy parameters such as ABPI and ankle pressure showed positive trend warranting further studies.
  
  
  BACKGROUND
  NIH website (http://www.clinicaltrials.gov/ct2/show/NCT00883870).
authors.affiliation: Stempeutics Research Pvt Ltd, Akshay Tech Park, No, 72 & 73, 2nd Floor, EPIP Zone, Phase I-Area, Whitefield, Bangalore 560066, India. pawan.gupta@stempeutics.com
authors.forename: Pawan K
authors.initials: PK
authors.lastname: Gupta
authors.forename: Anoop
authors.initials: A
authors.lastname: Chullikana
authors.forename: Rajiv
authors.initials: R
authors.lastname: Parakh
authors.forename: Sanjay
authors.initials: S
authors.lastname: Desai
authors.forename: Anjan
authors.initials: A
authors.lastname: Das
authors.forename: Sanjay
authors.initials: S
authors.lastname: Gottipamula
authors.forename: Sagar
authors.initials: S
authors.lastname: Krishnamurthy
authors.forename: Naveen
authors.initials: N
authors.lastname: Anthony
authors.forename: Arun
authors.initials: A
authors.lastname: Pherwani
authors.forename: Anish S
authors.initials: AS
authors.lastname: Majumdar
mesh_terms: D000328:Adult; D055109:Ankle Brachial Index; D001854:Bone Marrow Cells / Q000166:cytology; D016026:Bone Marrow Transplantation / Q000379:methods*; D018450:Disease Progression; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007511:Ischemia / Q000473:pathology*; D007866:Leg / Q000473:pathology*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D008875:Middle Aged; D018919:Neovascularization, Physiologic; D016491:Peripheral Vascular Diseases / Q000628:therapy*; D014184:Transplantation, Homologous