title: Effect of repetitive intra-arterial infusion of bone marrow mononuclear cells in patients with no-option limb ischemia: the randomized, double-blind, placebo-controlled Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-arterial Supplementation (JUVENTAS) trial.
abstract: BACKGROUND
  Patients with severe limb ischemia may not be eligible for conventional therapeutic interventions. Pioneering clinical trials suggest that bone marrow-derived cell therapy enhances neovascularization, improves tissue perfusion, and prevents amputation. The objective of this trial was to determine whether repetitive intra-arterial infusion of bone marrow mononuclear cells (BMMNCs) in patients with severe, nonrevascularizable limb ischemia can prevent major amputation.
  
  
  RESULTS
  The Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-arterial Supplementation (JUVENTAS) trial is a randomized, double-blind, placebo-controlled clinical trial in 160 patients with severe, nonrevascularizable limb ischemia. Patients were randomly assigned to repetitive (3 times; 3-week interval) intra-arterial infusion of BMMNC or placebo. No significant differences were observed for the primary outcome, ie, major amputation at 6 months, with major amputation rates of 19% in the BMMNC versus 13% in the placebo group (relative risk, 1.46; 95% confidence interval, 0.62-3.42). The safety outcome (all-cause mortality, occurrence of malignancy, or hospitalization due to infection) was not significantly different between the groups (relative risk, 1.46; 95% confidence interval, 0.63-3.38), neither was all-cause mortality at 6 months with 5% versus 6% (relative risk, 0.78; 95% confidence interval, 0.22-2.80). Secondary outcomes quality of life, rest pain, ankle-brachial index, and transcutaneous oxygen pressure improved during follow-up, but there were no significant differences between the groups.
  
  
  CONCLUSIONS
  Repetitive intra-arterial infusion of autologous BMMNCs into the common femoral artery did not reduce major amputation rates in patients with severe, nonrevascularizable limb ischemia in comparison with placebo. The general improvement in secondary outcomes during follow-up in both the BMMNC and the placebo group, as well, underlines the essential role for placebo-controlled design of future trials.
  
  
  BACKGROUND
  http://www.clinicaltrials.gov. Unique identifier: NCT00371371.
authors.affiliation: From Department of Nephrology & Hypertension (M.T., M.C.V.), Department of Vascular Surgery (M.T., F.L.M.), Department of Radiology (R.W.S., W.P.Th.M.M.), Van Creveldkliniek/Department of Hematology (R.E.G.S.), Cell Therapy Facility/ Department of Clinical Pharmacy (I.C.M.S.-C.), Julius Center for Health Sciences and Primary Care (Y.v.d.G., A.A., I.v.d.T.), Brain Center Rudolf Magnus, Department of Neurology and Neurosurgery (A.A.), and Department of Cardiology (P.A.D.), University Medical Center Utrecht, The Netherlands.
authors.forename: Martin
authors.initials: M
authors.lastname: Teraa
authors.affiliation: From Department of Nephrology & Hypertension (M.T., M.C.V.), Department of Vascular Surgery (M.T., F.L.M.), Department of Radiology (R.W.S., W.P.Th.M.M.), Van Creveldkliniek/Department of Hematology (R.E.G.S.), Cell Therapy Facility/ Department of Clinical Pharmacy (I.C.M.S.-C.), Julius Center for Health Sciences and Primary Care (Y.v.d.G., A.A., I.v.d.T.), Brain Center Rudolf Magnus, Department of Neurology and Neurosurgery (A.A.), and Department of Cardiology (P.A.D.), University Medical Center Utrecht, The Netherlands.
authors.forename: Ralf W
authors.initials: RW
authors.lastname: Sprengers
authors.affiliation: From Department of Nephrology & Hypertension (M.T., M.C.V.), Department of Vascular Surgery (M.T., F.L.M.), Department of Radiology (R.W.S., W.P.Th.M.M.), Van Creveldkliniek/Department of Hematology (R.E.G.S.), Cell Therapy Facility/ Department of Clinical Pharmacy (I.C.M.S.-C.), Julius Center for Health Sciences and Primary Care (Y.v.d.G., A.A., I.v.d.T.), Brain Center Rudolf Magnus, Department of Neurology and Neurosurgery (A.A.), and Department of Cardiology (P.A.D.), University Medical Center Utrecht, The Netherlands.
authors.forename: Roger E G
authors.initials: RE
authors.lastname: Schutgens
authors.affiliation: From Department of Nephrology & Hypertension (M.T., M.C.V.), Department of Vascular Surgery (M.T., F.L.M.), Department of Radiology (R.W.S., W.P.Th.M.M.), Van Creveldkliniek/Department of Hematology (R.E.G.S.), Cell Therapy Facility/ Department of Clinical Pharmacy (I.C.M.S.-C.), Julius Center for Health Sciences and Primary Care (Y.v.d.G., A.A., I.v.d.T.), Brain Center Rudolf Magnus, Department of Neurology and Neurosurgery (A.A.), and Department of Cardiology (P.A.D.), University Medical Center Utrecht, The Netherlands.
authors.forename: Ineke C M
authors.initials: IC
authors.lastname: Slaper-Cortenbach
authors.affiliation: From Department of Nephrology & Hypertension (M.T., M.C.V.), Department of Vascular Surgery (M.T., F.L.M.), Department of Radiology (R.W.S., W.P.Th.M.M.), Van Creveldkliniek/Department of Hematology (R.E.G.S.), Cell Therapy Facility/ Department of Clinical Pharmacy (I.C.M.S.-C.), Julius Center for Health Sciences and Primary Care (Y.v.d.G., A.A., I.v.d.T.), Brain Center Rudolf Magnus, Department of Neurology and Neurosurgery (A.A.), and Department of Cardiology (P.A.D.), University Medical Center Utrecht, The Netherlands.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: van der Graaf
authors.affiliation: From Department of Nephrology & Hypertension (M.T., M.C.V.), Department of Vascular Surgery (M.T., F.L.M.), Department of Radiology (R.W.S., W.P.Th.M.M.), Van Creveldkliniek/Department of Hematology (R.E.G.S.), Cell Therapy Facility/ Department of Clinical Pharmacy (I.C.M.S.-C.), Julius Center for Health Sciences and Primary Care (Y.v.d.G., A.A., I.v.d.T.), Brain Center Rudolf Magnus, Department of Neurology and Neurosurgery (A.A.), and Department of Cardiology (P.A.D.), University Medical Center Utrecht, The Netherlands.
authors.forename: Ale
authors.initials: A
authors.lastname: Algra
authors.affiliation: From Department of Nephrology & Hypertension (M.T., M.C.V.), Department of Vascular Surgery (M.T., F.L.M.), Department of Radiology (R.W.S., W.P.Th.M.M.), Van Creveldkliniek/Department of Hematology (R.E.G.S.), Cell Therapy Facility/ Department of Clinical Pharmacy (I.C.M.S.-C.), Julius Center for Health Sciences and Primary Care (Y.v.d.G., A.A., I.v.d.T.), Brain Center Rudolf Magnus, Department of Neurology and Neurosurgery (A.A.), and Department of Cardiology (P.A.D.), University Medical Center Utrecht, The Netherlands.
authors.forename: Ingeborg
authors.initials: I
authors.lastname: van der Tweel
authors.affiliation: From Department of Nephrology & Hypertension (M.T., M.C.V.), Department of Vascular Surgery (M.T., F.L.M.), Department of Radiology (R.W.S., W.P.Th.M.M.), Van Creveldkliniek/Department of Hematology (R.E.G.S.), Cell Therapy Facility/ Department of Clinical Pharmacy (I.C.M.S.-C.), Julius Center for Health Sciences and Primary Care (Y.v.d.G., A.A., I.v.d.T.), Brain Center Rudolf Magnus, Department of Neurology and Neurosurgery (A.A.), and Department of Cardiology (P.A.D.), University Medical Center Utrecht, The Netherlands.
authors.forename: Pieter A
authors.initials: PA
authors.lastname: Doevendans
authors.affiliation: From Department of Nephrology & Hypertension (M.T., M.C.V.), Department of Vascular Surgery (M.T., F.L.M.), Department of Radiology (R.W.S., W.P.Th.M.M.), Van Creveldkliniek/Department of Hematology (R.E.G.S.), Cell Therapy Facility/ Department of Clinical Pharmacy (I.C.M.S.-C.), Julius Center for Health Sciences and Primary Care (Y.v.d.G., A.A., I.v.d.T.), Brain Center Rudolf Magnus, Department of Neurology and Neurosurgery (A.A.), and Department of Cardiology (P.A.D.), University Medical Center Utrecht, The Netherlands.
authors.forename: Willem P Th M
authors.initials: WP
authors.lastname: Mali
authors.affiliation: From Department of Nephrology & Hypertension (M.T., M.C.V.), Department of Vascular Surgery (M.T., F.L.M.), Department of Radiology (R.W.S., W.P.Th.M.M.), Van Creveldkliniek/Department of Hematology (R.E.G.S.), Cell Therapy Facility/ Department of Clinical Pharmacy (I.C.M.S.-C.), Julius Center for Health Sciences and Primary Care (Y.v.d.G., A.A., I.v.d.T.), Brain Center Rudolf Magnus, Department of Neurology and Neurosurgery (A.A.), and Department of Cardiology (P.A.D.), University Medical Center Utrecht, The Netherlands.
authors.forename: Frans L
authors.initials: FL
authors.lastname: Moll
authors.affiliation: From Department of Nephrology & Hypertension (M.T., M.C.V.), Department of Vascular Surgery (M.T., F.L.M.), Department of Radiology (R.W.S., W.P.Th.M.M.), Van Creveldkliniek/Department of Hematology (R.E.G.S.), Cell Therapy Facility/ Department of Clinical Pharmacy (I.C.M.S.-C.), Julius Center for Health Sciences and Primary Care (Y.v.d.G., A.A., I.v.d.T.), Brain Center Rudolf Magnus, Department of Neurology and Neurosurgery (A.A.), and Department of Cardiology (P.A.D.), University Medical Center Utrecht, The Netherlands. m.c.verhaar@umcutrecht.nl.
authors.forename: Marianne C
authors.initials: MC
authors.lastname: Verhaar
mesh_terms: D000368:Aged; D000671:Amputation, Surgical / Q000706:statistics & numerical data; D016026:Bone Marrow Transplantation / Q000379:methods*; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D004311:Double-Blind Method; D005121:Extremities / Q000098:blood supply*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007261:Infusions, Intra-Arterial / Q000379:methods*; D007511:Ischemia / Q000209:etiology* / Q000401:mortality / Q000601:surgery*; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D018919:Neovascularization, Physiologic; D058729:Peripheral Arterial Disease / Q000150:complications* / Q000401:mortality; D011788:Quality of Life; D012307:Risk Factors; D015996:Survival Rate; D016896:Treatment Outcome
keywords: atherosclerosis; cells; peripheral vascular diseases