title: Human placenta-derived cells (PDA-001) for the treatment of adults with multiple sclerosis: a randomized, placebo-controlled, multiple-dose study.
abstract: BACKGROUND
  Infusion of PDA-001, a preparation of mesenchymal-like cells derived from full-term human placenta, is a new approach in the treatment of patients with multiple sclerosis.
  
  
  OBJECTIVE
  This safety study aimed to rule out the possibility of paradoxical exacerbation of disease activity by PDA-001 in patients with multiple sclerosis.
  
  
  METHODS
  This was a phase 1b, multicenter, randomized, double-blind, placebo-controlled, 2-dose ranging study including patients with relapsing-remitting multiple sclerosis or secondary progressive multiple sclerosis. The study was conducted at 6 sites in the United States and 2 sites in Canada. Patients were randomized 3:1 to receive 2 low-dose infusions of PDA-001 (150×10(6) cells) or placebo, given 1 week apart. After completing this cohort, subsequent patients received high-dose PDA-001 (600×10(6) cells) or placebo. Monthly brain magnetic resonance imaging scans were performed. The primary end point was ruling out the possibility of paradoxical worsening of MS disease activity. This was monitored using Cutter׳s rule (≥5 new gadolinium lesions on 2 consecutive scans) by brain magnetic resonance imaging on a monthly basis for six months and also the frequency of multiple sclerosis relapse.
  
  
  RESULTS
  Ten patients with relapsing-remitting multiple sclerosis and 6 with secondary progressive multiple sclerosis were randomly assigned to treatment: 6 to low-dose PDA-001, 6 to high-dose PDA-001, and 4 to placebo. No patient met Cutter׳s rule. One patient receiving high-dose PDA-001 had an increase in T2 and gadolinium lesions and in Expanded Disability Status Scale score during a multiple sclerosis flare 5 months after receiving PDA-001. No other patient had an increase in Expanded Disability Status Scale score>0.5, and most had stable or decreasing Expanded Disability Status Scale scores. With high-dose PDA-001, 1 patient experienced a grade 1 anaphylactoid reaction and 1 had grade 2 superficial thrombophlebitis. Other adverse events were mild to moderate and included headache, fatigue, infusion site reactions, and urinary tract infection.
  
  
  CONCLUSIONS
  PDA-001 infusions were safe and well tolerated in relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis patients. No paradoxical worsening of lesion counts was noted with either dose.
authors.affiliation: Icahn School of Medicine at Mount Sinai, 5 East 98th Street, Box 1138, New York, NY 10029, United States. Electronic address: fred.lublin@mssm.edu.
authors.forename: Fred D
authors.initials: FD
authors.lastname: Lublin
authors.affiliation: Swedish Neuroscience Institute, 1600 East Jefferson, Suite 205, Seattle, WA 98122, United States. Electronic address: James.Bowen@swedish.org.
authors.forename: James D
authors.initials: JD
authors.lastname: Bowen
authors.affiliation: MultiCare Health System-Neuroscience Center of Washington, 915 6th Avenue, Suite 101 and 200, Tacoma, WA 98405, United States. Electronic address: John.Huddlestone@multicare.org.
authors.forename: John
authors.initials: J
authors.lastname: Huddlestone
authors.affiliation: London Health Sciences Centre, University Hospital, Multiple Sclerosis Clinic, 7th Floor, 339 Windermere Road, PO Box 5339, London, ON, Canada N6A 5A5. Electronic address: Marcelo.Kremenchutzky@lhsc.on.ca.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Kremenchutzky
authors.affiliation: University of Minnesota, Clinical Neuroscience Research Unit, 717 Delaware Street SE, Suite 246, Minneapolis, MN 55414, United States. Electronic address: carpe004@umn.edu.
authors.forename: Adam
authors.initials: A
authors.lastname: Carpenter
authors.affiliation: University of Colorado Denver, 12631 E. 17th Avenue, Mail Stop B185, Room 5506, Aurora, CO 80045, United States. Electronic address: John.Corboy@ucdenver.edu.
authors.forename: John R
authors.initials: JR
authors.lastname: Corboy
authors.affiliation: The Ottawa Hospital Multiple Sclerosis Clinic, 501 Smyth Road, Box 607, Ottawa, Ontario, Canada K1H 8L6. Electronic address: mfreedman@ottawahospital.on.ca.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Freedman
authors.affiliation: MS Comprehensive Care Center, MSC T12-020 SUNY, Stony Brook, NY 11794, United States. Electronic address: Lauren.Krupp@stonybrook.edu.
authors.forename: Lauren
authors.initials: L
authors.lastname: Krupp
authors.affiliation: Celgene Cellular Therapeutics, 7 Powderhorn Road, Warren, NJ 07059, United States. Electronic address: cpaulo@celgene.com.
authors.forename: Corri
authors.initials: C
authors.lastname: Paulo
authors.affiliation: Celgene Cellular Therapeutics, 7 Powderhorn Road, Warren, NJ 07059, United States. Electronic address: rhariri@celgene.com.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Hariri
authors.affiliation: Celgene Cellular Therapeutics, 7 Powderhorn Road, Warren, NJ 07059, United States. Electronic address: sfischkoff@celgene.com.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Fischkoff
mesh_terms: D000328:Adult; D001921:Brain / Q000473:pathology; D002170:Canada; D003287:Contrast Media; D004185:Disability Evaluation; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D005682:Gadolinium; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D008875:Middle Aged; D020528:Multiple Sclerosis, Chronic Progressive / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D012008:Recurrence; D012720:Severity of Illness Index; D016896:Treatment Outcome; D014481:United States
chemical_list: D003287:Contrast Media; D005682:Gadolinium
keywords: Cell therapy; Clinical trial; Immunomodulators; Mesenchymal stromal cells; Multiple sclerosis