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

Research output: Contribution to journalArticle

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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. 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.

Original languageEnglish (US)
Pages (from-to)284-292
Number of pages9
JournalThe Lancet Infectious Diseases
Volume11
Issue number4
DOIs
StatePublished - Apr 2011

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Cytomegalovirus
Stem Cells
Randomized Controlled Trials
Placebos
Transplants
Antiviral Agents
maribavir
Transplantation
Intention to Treat Analysis
Cytomegalovirus Infections
Stem Cell Transplantation
Graft vs Host Disease
Random Allocation
Neutropenia
Pharmaceutical Preparations
Canada
Therapeutics
Tissue Donors
Viruses
Safety

ASJC Scopus subject areas

  • Infectious Diseases

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Maribavir prophylaxis for prevention of cytomegalovirus disease in recipients of allogeneic stem-cell transplants : A phase 3, double-blind, placebo-controlled, randomised trial. / Marty, Francisco M.; Ljungman, Per; Papanicolaou, Genovefa A.; Winston, Drew J.; Chemaly, Roy F.; Strasfeld, Lynne; Young, Jo Anne H; Rodriguez, Tulio; Maertens, Johan; Schmitt, Michael; Einsele, Hermann; Ferrant, Augustin; Lipton, Jeffrey H.; Villano, Stephen A.; Chen, Hongzi; Boeckh, Michael.

In: The Lancet Infectious Diseases, Vol. 11, No. 4, 04.2011, p. 284-292.

Research output: Contribution to journalArticle

Marty, FM, Ljungman, P, Papanicolaou, GA, Winston, DJ, Chemaly, RF, Strasfeld, L, Young, JAH, Rodriguez, T, Maertens, J, Schmitt, M, Einsele, H, Ferrant, A, Lipton, JH, Villano, SA, Chen, H & Boeckh, M 2011, 'Maribavir prophylaxis for prevention of cytomegalovirus disease in recipients of allogeneic stem-cell transplants: A phase 3, double-blind, placebo-controlled, randomised trial', The Lancet Infectious Diseases, vol. 11, no. 4, pp. 284-292. https://doi.org/10.1016/S1473-3099(11)70024-X
Marty, Francisco M. ; Ljungman, Per ; Papanicolaou, Genovefa A. ; Winston, Drew J. ; Chemaly, Roy F. ; Strasfeld, Lynne ; Young, Jo Anne H ; Rodriguez, Tulio ; Maertens, Johan ; Schmitt, Michael ; Einsele, Hermann ; Ferrant, Augustin ; Lipton, Jeffrey H. ; Villano, Stephen A. ; Chen, Hongzi ; Boeckh, Michael. / Maribavir prophylaxis for prevention of cytomegalovirus disease in recipients of allogeneic stem-cell transplants : A phase 3, double-blind, placebo-controlled, randomised trial. In: The Lancet Infectious Diseases. 2011 ; Vol. 11, No. 4. pp. 284-292.
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T1 - Maribavir prophylaxis for prevention of cytomegalovirus disease in recipients of allogeneic stem-cell transplants

T2 - A phase 3, double-blind, placebo-controlled, randomised trial

AU - Marty, Francisco M.

AU - Ljungman, Per

AU - Papanicolaou, Genovefa A.

AU - Winston, Drew J.

AU - Chemaly, Roy F.

AU - Strasfeld, Lynne

AU - Young, Jo Anne H

AU - Rodriguez, Tulio

AU - Maertens, Johan

AU - Schmitt, Michael

AU - Einsele, Hermann

AU - Ferrant, Augustin

AU - Lipton, Jeffrey H.

AU - Villano, Stephen A.

AU - Chen, Hongzi

AU - Boeckh, Michael

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N2 - 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.

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