284 www.thelancet.com/infection Vol 11 April 2011 Articles Lancet Infect Dis 2011; 11: 284–92 Published Online March 16, 2011 DOI:10.1016/S1473- 3099(11)70024-X This paper has been corrected. The corrected version first appeared at thelancet.com/infection on March 18, 2011 See Comment page 255 *The investigators and institutions that participated in the Maribavir 1263–300 study are listed in p 1 of the webappendix Presented in abstract form at the 2009 Annual Meeting of the European Group for Blood and Marrow Transplantation, Göteborg, Sweden, on March 31, 2009 Brigham & Women’s Hospital and Dana-Farber Cancer Institute, Boston, MA, USA (F M Marty MD); Karolinska Institutet, Stockholm, Sweden (Prof P Ljungman MD); Memorial Sloan-Kettering Cancer Center, New York, NY, USA (G A Papanicolaou MD); University of California Los Angeles Medical Center, Los Angeles, CA, USA (D J Winston MD); University of Texas MD Anderson Cancer Center, Houston, TX, USA (R F Chemaly MD); Oregon Health & Science University, Portland, OR, USA (L Strasfeld MD); University of Minnesota Medical Center, Minneapolis, MN, USA (J-A H Young MD); Loyola University Medical Center, Maywood, IL, USA (T Rodriguez MD); University Hospital Gasthuisberg, Leuven, Belgium (Prof J Maertens MD); University of Ulm, Ulm, Germany (M Schmitt MD); University of Würzburg, Würzberg, Germany Maribavir prophylaxis for prevention of cytomegalovirus disease in recipients of allogeneic stem-cell transplants: a phase 3, double-blind, placebo-controlled, randomised trial Francisco M Marty, Per Ljungman, Genovefa A Papanicolaou, Drew J Winston, Roy F Chemaly, Lynne Strasfeld, Jo-Anne H Young, Tulio Rodriguez, Johan Maertens, Michael Schmitt, Hermann Einsele, Augustin Ferrant, Jeffrey H Lipton, Stephen A Villano, Hongzi Chen, Michael Boeckh, for the Maribavir 1263–300 Clinical Study Group* Summary 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. Findings 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). Interpretation 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. Funding ViroPharma Incorporated. Introduction Before the availability of effective antiviral strategies, cytomegalovirus disease was a common cause of morbidity and mortality after allogeneic stem-cell transplantation. 1 Currently, this disease can be prevented in most recipients of allogeneic stem-cell transplant either by pre-emptive treatment based on cytomegalovirus detection in blood by antigenaemia 2 or PCR, 3 or by universal prophylaxis initiated in at-risk patients at engraftment and continued until 100 days after transplantation. 4,5 Although these strategies reduce cytomegalovirus disease, they are limited by neutropenia caused by ganciclovir or valganciclovir. Second-line antiviral drugs foscarnet 6 and cidofovir 7 cause renal toxic effects and other adverse events. Finally, even in the pre-emptive therapy era, 8 recipient patients seropositive for cytomegalovirus continue to have a higher mortality than do seronegative recipients. 9 Thus, more effective and safer antiviral drugs that can be given prophylactically to recipients of allogeneic stem-cell transplant are clearly needed. Maribavir (ViroPharma Incorporated) is an orally available antiviral drug that binds to the human cytomegalovirus protein kinase UL97 and causes inhibition of viral encapsidation and nuclear egress of viral particles from infected cells. 10,11 In vitro, maribavir is more potent than is ganciclovir against cytomegalovirus, and is active against ganciclovir-resistant cytomegalo- virus strains. 12 In a phase 2 study of recipients of allogeneic stem-cell transplant, 13 maribavir prevented cytomegalovirus infection significantly better than did