title: Maribavir prophylaxis for prevention of cytomegalovirus disease in recipients of allogeneic stem-cell transplants: a phase 3, double-blind, placebo-controlled, randomised trial.
abstract: BACKGROUND
  Available drugs against cytomegalovirus have adverse effects that compromise their prophylactic use in recipients of allogeneic stem-cell transplants. We assessed the safety, tolerability, and antiviral activity of oral maribavir in such patients.
  
  
  METHODS
  In this placebo-controlled, randomised, double-blind, multicentre phase 3 study, we enrolled adult patients recipient-seropositive or donor-seropositive for cytomegalovirus who had undergone allogeneic stem-cell transplantation. Patients were recruited from 90 centres in Canada, Europe, and the USA. After engraftment, patients were stratified by recipient cytomegalovirus serostatus and conditioning regimen (myeloablative or reduced-intensity) and assigned (2:1) by masked computer-generated randomisation sequence to receive maribavir 100 mg twice daily or placebo for up to 12 weeks, with weekly blood cytomegalovirus surveillance. If the virus was detected, administration of study drug was stopped and pre-emptive anticytomegalovirus treatment started. The primary endpoint was cytomegalovirus disease within 6 months of transplantation. Analysis was by intention-to-treat. This study is registered with ClinicalTrials.gov, NCT00411645.
  
  
  RESULTS
  Between December, 2006, and May, 2008, 681 patients were enrolled and assigned to receive maribavir (454) or placebo (227). The incidence of cytomegalovirus disease within 6 months was 20 of 454 (4%) for the maribavir group and 11 of 227 (5%) for the placebo group (OR 0.90; 95% CI 0.42-1.92). During the 100 days following transplantation, cytomegalovirus infection rates as measured by pp65 antigenaemia were lower in the maribavir group (26.4%) than in the placebo group (34.8%; OR 0.67; 0.47-0.95), but not when measured by plasma cytomegalovirus DNA PCR (27.8%vs 30.4%; OR 0·88; 0.62-1.25), nor by initiation of treatment against cytomegalovirus (30.6%vs 37.4%; OR 0.73, 0.52-1.03). Maribavir was well tolerated: most adverse events, including incident acute graft-versus-host disease and neutropenia, affected both groups equally, except for taste disturbance (15% maribavir, 6% placebo).
  
  
  CONCLUSIONS
  Compared with placebo, maribavir prophylaxis did not prevent cytomegalovirus disease when started after engraftment. Cytomegalovirus disease as a primary endpoint might not be sufficient to show improvements in cytomegalovirus prevention in recipients of allogeneic stem-cell transplants in the setting of pre-emptive antiviral treatment. Clinical and virological composite endpoints should be used in future trials.
  
  
  BACKGROUND
  ViroPharma Incorporated.
authors.affiliation: Brigham & Women's Hospital and Dana-Farber Cancer Institute, Boston, MA 02115, USA. fmarty@partners.org
authors.forename: Francisco M
authors.initials: FM
authors.lastname: Marty
authors.forename: Per
authors.initials: P
authors.lastname: Ljungman
authors.forename: Genovefa A
authors.initials: GA
authors.lastname: Papanicolaou
authors.forename: Drew J
authors.initials: DJ
authors.lastname: Winston
authors.forename: Roy F
authors.initials: RF
authors.lastname: Chemaly
authors.forename: Lynne
authors.initials: L
authors.lastname: Strasfeld
authors.forename: Jo-Anne H
authors.initials: JA
authors.lastname: Young
authors.forename: Tulio
authors.initials: T
authors.lastname: Rodriguez
authors.forename: Johan
authors.initials: J
authors.lastname: Maertens
authors.forename: Michael
authors.initials: M
authors.lastname: Schmitt
authors.forename: Hermann
authors.initials: H
authors.lastname: Einsele
authors.forename: Augustin
authors.initials: A
authors.lastname: Ferrant
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Lipton
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Villano
authors.forename: Hongzi
authors.initials: H
authors.lastname: Chen
authors.forename: Michael
authors.initials: M
authors.lastname: Boeckh
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000009:adverse effects; D002170:Canada; D018890:Chemoprevention / Q000379:methods*; D003586:Cytomegalovirus Infections / Q000517:prevention & control*; D004311:Double-Blind Method; D005060:Europe; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010919:Placebos / Q000008:administration & dosage*; D012263:Ribonucleosides / Q000008:administration & dosage* / Q000009:adverse effects; D033581:Stem Cell Transplantation; D014180:Transplantation; D016896:Treatment Outcome; D014481:United States; D055815:Young Adult; D004004:Dichlororibofuranosylbenzimidazole / Q000031:analogs & derivatives
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D010919:Placebos; D012263:Ribonucleosides; C400401:maribavir; D004004:Dichlororibofuranosylbenzimidazole