title: Randomized placebo controlled phase I/II trial of alpha-galactosylceramide for the treatment of chronic hepatitis C.
abstract: OBJECTIVE
  The glycosphingolipid alpha-galactosylceramide has been shown to activate invariant natural killer T cells when presented in the context of CD1d and induces powerful antiviral immune responses via the production of inflammatory cytokines. The aim of this study was to investigate the safety and the antiviral activity of alpha-galactosylceramide as a novel class of treatment for chronic hepatitis C patients.
  
  
  METHODS
  International multicenter dose-escalating randomized placebo-controlled phase I/II trial.
  
  
  RESULTS
  Forty patients were allocated to a dose of 0.1 microg/kg (n=9), 1 microg/kg (n=9), 10 microg/kg (n=11) or to placebo (n=11). alpha-Galactosylceramide was well tolerated and no patients were withdrawn due to side effects. Although most patients showed a decrease in invariant natural killer T cells after administration, no clinically relevant suppression of viral replication was observed. Only one patient, a previous non-responder to peginterferon and ribavirin with high baseline invariant natural killer T cell levels, showed profound signs of immune activation, accompanied by a transient 1.3 log decrease in HCV-RNA and a concomitant increase in ALT after the first administration.
  
  
  CONCLUSIONS
  alpha-Galactosylceramide used as monotherapy for interferon-refractory patients in doses of 0.1-10 microg/kg is safe and it exerts moderate immunomodulatory effects. However, in its current form it has no significant effect on HCV-RNA levels.
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Room Ca 326a, PO Box 2040, 3000 CA Rotterdam, The Netherlands. b.veldt@erasmusmc.nl
authors.forename: Bart J
authors.initials: BJ
authors.lastname: Veldt
authors.forename: Hans J J
authors.initials: HJ
authors.lastname: van der Vliet
authors.forename: B Mary E
authors.initials: BM
authors.lastname: von Blomberg
authors.forename: Hans
authors.initials: H
authors.lastname: van Vlierberghe
authors.forename: Guido
authors.initials: G
authors.lastname: Gerken
authors.forename: Nobusuke
authors.initials: N
authors.lastname: Nishi
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Hayashi
authors.forename: Rik J
authors.initials: RJ
authors.lastname: Scheper
authors.forename: Robert J
authors.initials: RJ
authors.lastname: de Knegt
authors.forename: Alfons J M
authors.initials: AJ
authors.lastname: van den Eertwegh
authors.forename: Harry L A
authors.initials: HL
authors.lastname: Janssen
authors.forename: Carin M J
authors.initials: CM
authors.lastname: van Nieuwkerk
mesh_terms: D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001773:Blood Cells / Q000473:pathology; D016207:Cytokines / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D005699:Galactosylceramides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016174:Hepacivirus / Q000235:genetics / Q000502:physiology; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology / Q000821:virology; D006801:Humans; D007107:Immune System / Q000187:drug effects / Q000503:physiopathology; D007694:Killer Cells, Natural / Q000473:pathology; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000097:blood; D013601:T-Lymphocytes / Q000473:pathology; D016896:Treatment Outcome; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D016207:Cytokines; D005699:Galactosylceramides; D012367:RNA, Viral; C493154:alpha-galactosylceramide; D000410:Alanine Transaminase