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.
Bibliographical noteFunding Information:
SAV and HC are employees of ViroPharma Incorporated. All other authors received research funding from ViroPharma Incorporated in association with this clinical trial. FMM, PJ, GAP, DJW, RFC, JM, MS, HE, and MB have served as paid consultants for ViroPharma Incorporated. FMM has received research funding from Chimerix and Vical, and has served as a paid consultant for AiCuris and Cubist. PL has received research funding from Pfizer, Merck, and Genzyme, has served in the data safety monitoring board for studies sponsored by AiCuris and Opal, and has served as a paid consultant for Vical and GlaxoSmithKline. GAP has received research funding from Pfizer and Enzon, and has served as a paid consultant for Astellas, Schering-Plough, and Pfizer. DJW has received research funding from Chimerix. RFC has received research funding from AiCuris. JHY has received research funding from AiCuris and Chimerix. MB has received research funding from Roche, Chimerix, and Vical, and has served as a paid consultant for Chimerix, Vical, Genentech, Boehringer Ingelheim, Astellas Pharma Inc, Theraclone Sciences, and Novartis.