title: Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial.
abstract: BACKGROUND
  Hepatic veno-occlusive disease is a leading cause of morbidity and mortality after haemopoietic stem-cell transplantation (HSCT). We aimed to assess whether defibrotide can reduce the incidence of veno-occlusive disease in this setting.
  
  
  METHODS
  In our phase 3 open-label, randomised controlled trial, we enrolled patients at 28 European university hospitals or academic medical centres. Eligible patients were younger than 18 years, had undergone myeloablative conditioning before allogeneic or autologous HSCT, and had one or more risk factor for veno-occlusive disease based on modified Seattle criteria. We centrally assigned eligible participants on the basis of a computer-generated randomisation sequence (1:1), stratified by centre and presence of osteopetrosis, to receive intravenous defibrotide prophylaxis (treatment group) or not (control group). The primary endpoint was incidence of veno-occlusive disease by 30 days after HSCT, adjudicated by a masked, independent review committee, in eligible patients who consented to randomisation (intention-to-treat population), and was assessed with a competing risk approach. Patients in either group who developed veno-occlusive disease received defibrotide for treatment. We assessed adverse events to 180 days after HSCT in all patients who received allocated prophylaxis. This trial is registered with ClinicalTrials.gov, number NCT00272948.
  
  
  RESULTS
  Between Jan 25, 2006, and Jan 29, 2009, we enrolled 356 eligible patients to the intention-to-treat population. 22 (12%) of 180 patients randomly allocated to the defibrotide group had veno-occlusive disease by 30 days after HSCT compared with 35 (20%) of 176 controls (risk difference -7·7%, 95% CI -15·3 to -0·1; Z test for competing risk analysis p=0·0488; log-rank test p=0·0507). 154 (87%) of 177 patients in the defibrotide group had adverse events by day 180 compared with 155 (88%) of 176 controls.
  
  
  CONCLUSIONS
  Defibrotide prophylaxis seems to reduce incidence of veno-occlusive disease and is well tolerated. Thus, such prophylaxis could present a useful clinical option for this serious complication of HSCT.
  
  
  BACKGROUND
  Gentium SpA, European Group for Blood and Marrow Transplantation.
authors.affiliation: University of Regensburg, Regensburg, Germany. selim.corbacioglu@klinik.uni-regensburg.de
authors.forename: Selim
authors.initials: S
authors.lastname: Corbacioglu
authors.forename: Simone
authors.initials: S
authors.lastname: Cesaro
authors.forename: Maura
authors.initials: M
authors.lastname: Faraci
authors.forename: Dominique
authors.initials: D
authors.lastname: Valteau-Couanet
authors.forename: Bernd
authors.initials: B
authors.lastname: Gruhn
authors.forename: Attilio
authors.initials: A
authors.lastname: Rovelli
authors.forename: Jaap J
authors.initials: JJ
authors.lastname: Boelens
authors.forename: Annette
authors.initials: A
authors.lastname: Hewitt
authors.forename: Johanna
authors.initials: J
authors.lastname: Schrum
authors.forename: Ansgar S
authors.initials: AS
authors.lastname: Schulz
authors.forename: Ingo
authors.initials: I
authors.lastname: Müller
authors.forename: Jerry
authors.initials: J
authors.lastname: Stein
authors.forename: Robert
authors.initials: R
authors.lastname: Wynn
authors.forename: Johann
authors.initials: J
authors.lastname: Greil
authors.forename: Karl-Walter
authors.initials: KW
authors.lastname: Sykora
authors.forename: Susanne
authors.initials: S
authors.lastname: Matthes-Martin
authors.forename: Monika
authors.initials: M
authors.lastname: Führer
authors.forename: Anne
authors.initials: A
authors.lastname: O'Meara
authors.forename: Jacek
authors.initials: J
authors.lastname: Toporski
authors.forename: Petr
authors.initials: P
authors.lastname: Sedlacek
authors.forename: Paul G
authors.initials: PG
authors.lastname: Schlegel
authors.forename: Karoline
authors.initials: K
authors.lastname: Ehlert
authors.forename: Anders
authors.initials: A
authors.lastname: Fasth
authors.forename: Jacek
authors.initials: J
authors.lastname: Winiarski
authors.forename: Johan
authors.initials: J
authors.lastname: Arvidson
authors.forename: Christine
authors.initials: C
authors.lastname: Mauz-Körholz
authors.forename: Hulya
authors.initials: H
authors.lastname: Ozsahin
authors.forename: Andre
authors.initials: A
authors.lastname: Schrauder
authors.forename: Peter
authors.initials: P
authors.lastname: Bader
authors.forename: Joseph
authors.initials: J
authors.lastname: Massaro
authors.forename: Ralph
authors.initials: R
authors.lastname: D'Agostino
authors.forename: Margaret
authors.initials: M
authors.lastname: Hoyle
authors.forename: Massimo
authors.initials: M
authors.lastname: Iacobelli
authors.forename: Klaus-Michael
authors.initials: KM
authors.lastname: Debatin
authors.forename: Christina
authors.initials: C
authors.lastname: Peters
authors.forename: Giorgio
authors.initials: G
authors.lastname: Dini
mesh_terms: D000293:Adolescent; D001663:Bilirubin / Q000097:blood; D002648:Child; D002675:Child, Preschool; D005260:Female; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006086:Graft vs Host Disease / Q000453:epidemiology; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006504:Hepatic Veno-Occlusive Disease / Q000188:drug therapy / Q000453:epidemiology / Q000517:prevention & control*; D006801:Humans; D015994:Incidence; D007223:Infant; D007262:Infusions, Intravenous; D008297:Male; D009102:Multiple Organ Failure / Q000453:epidemiology; D011089:Polydeoxyribonucleotides / Q000627:therapeutic use*; D051437:Renal Insufficiency / Q000453:epidemiology
chemical_list: D005343:Fibrinolytic Agents; D011089:Polydeoxyribonucleotides; C036901:defibrotide; D001663:Bilirubin