Prophylactic Use of Maribavir for the Prevention of Cytomegalovirus (CMV) Disease in Stem Cell Transplant Recipients

A Randomized, Double-blind, Placebo-controlled Study to Assess the Efficacy and Safety of Prophylactic Use of Maribavir for the Prevention of Cytomegalovirus Disease in Recipients of Allogeneic Stem Cell Transplants.

The purpose of this research study is to investigate whether or not maribavir is safe and effective for preventing CMV disease when taken by mouth for up to 12 weeks in patients who have had a stem cell transplant.

Study Overview

• Status: Completed
• Conditions: Cytomegalovirus Infections
• Intervention / Treatment: Drug: maribavir; Other: placebo

Detailed Description

Cytomegalovirus (CMV) infections remain a significant problem following various types of transplants that are associated with strong immunosuppressive therapy. Maribavir is a new oral anti-CMV drug with a novel mechanism of action compared to currently available anti-CMV drugs. This study will test the safety and efficacy of maribavir for the prevention of CMV disease when given as prophylaxis for up to 12 weeks following allogeneic stem cell transplant.

• Study Type: Interventional
• Enrollment (Actual): 681
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Antwerp, Belgium, 2060
    • ZNA Stuivenberg
  • Brugge, Belgium, 8000
    • AZ Sint Jan, Department of Hematology
  • Brussels, Belgium, 1200
    • Cliniques Universitaires St,Luc Dept Hematology
  • Leuven, Belgium, 3000
    • UZ Gasthuisberg
  • Liege, Belgium, 4000
    • CHU Sart -Tilman Department of Medicine, Hematology
• Canada
  • Quebec, Canada, G1J 1Z4
    • Hopital l'Enfant Jesus
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H2Y9
      • QEII Health Sciences Center
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • McMaster University Medical Center
    • London, Ontario, Canada, N6A 4G5
      • London Health Sciences Centre
    • Ottawa,, Ontario, Canada, K1H 8L6
      • Ottawa General Campus
• France
  • Créteil, France, 94010
    • Hopital Henri Mondor
  • Lyon, Cedex 03, France, 69437
    • Edouard Herriot Hopital
  • Marseille Cedex 9, France, 13273
    • Institut Paoli Calmettes
  • Nantes, Cedex 1, France, 44093
    • Hôpital Hôtel Dieu
  • Paris Cedex 10, France, 75475
    • Hopital St. Louis
  • Pessac, France, 33600
    • Hôpital Haut-Lévêque
• Germany
  • Dresden, Germany, 01307
    • Univ. Clinic Dresden
  • Dresden, Germany, 01307
    • University Clinic of Dresden
  • Essen, Germany, 45122
    • University of Essen
  • Freiburg, Germany, 79106
    • University of Freiburg
  • Hamburg, Germany, 20246
    • University of Hamburg-Eppendorf
  • Hannover, Germany, 30625
    • Hannover, Medizinische Hochschule
  • Heidelberg, Germany, 69120
    • University of Heidelberg
  • Koeln, Germany, 50937
    • Universitaetsklinikum Koeln, Clinic I for internal Medicine
  • Mainz, Germany, 55131
    • Johannes-Gutenberg University
  • Ulm, Germany, 89081
    • University Clinic of Ulm
• Italy
  • Firenze, Italy, 50134
    • Careggi University Hospital
  • Genova, Italy, 16132
    • University of San Martino Hospital
  • Milano, Italy, 20132
    • San Raffaele del Monte Tabor
  • Pescara, Italy, 65123
    • Pescara hospital
  • Reggio Calabria, Italy, 89100
    • Bianchi-Melacrino-Morelli Hospital
• Spain
  • Barcelona, Spain, 08036
    • Barcelona Hospital
  • Barcelona, Spain, 08907
    • Duran i Reynals Hospital
  • Salamanca, Spain, E-37007
    • University of Salamanca
• Sweden
  • Goteborg, Sweden, S-413 45
    • Sahlgrenska University Hospital
  • Stockholm, Sweden, 141 86
    • Karolinska University Hospital,Huddinge
  • Uppsala, Sweden, 751 85
    • Akademiska Sjukhuset, Dept Hematology
  • Stockholm
    • Huddinge, Stockholm, Sweden, 14186
      • Karolinska University Hospital
• United Kingdom
  • London, United Kingdom, Nw3 2QG
    • Royal Free Hospital
  • London, United Kingdom, NW1 2BU
    • University College Hospital
  • London, United Kingdom, W12 OHS
    • Hammersmith Hospital
• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas Myeloma Institute
  • California
    • Duarte, California, United States, 91010
      • City of Hope Medical Center
    • La Jolla, California, United States, 92037
      • Scripps Green Hospital
    • La Jolla, California, United States, 92093-0960
      • UCSD Moores Center
    • Los Angeles, California, United States, 90095-1678
      • UCLA Medical Center
    • San Francisco, California, United States, 94143
      • University of California, San Francisco
    • Stanford, California, United States, 94305
      • Stanford University Medical Center
  • Colorado
    • Denver, Colorado, United States, 80218
      • Rocky Mountain Cancer Center
  • Florida
    • Gainesville, Florida, United States, 32610
      • Shands Hospital
    • Tampa, Florida, United States, 33612
      • H. Lee Moffitt Cancer Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
    • Chicago, Illinois, United States, 60611
      • Northwestern University Medical Center
    • Maywood, Illinois, United States, 60153
      • Loyola University
  • Indiana
    • Beech Grove, Indiana, United States, 46107
      • St Francis Hospital
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky Chandler Medical Center
    • Louisville, Kentucky, United States, 40202
      • University Medical Center University of Louisville Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21201-1595
      • Greenbaum Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02114
      • Massachusettes General
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0914
      • University of Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
    • Detroit, Michigan, United States, 48201
      • Wayne State Medical Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic College of Medicine
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • New York, New York, United States, 10021
      • Memorial Sloan-Kettering Cancer Center
    • New York, New York, United States, 10029
      • Mount Sinai Hospital
    • New York, New York, United States, 10021
      • New York Presbyterian Hospital,Weill Cornell Medical Center
    • Rochester, New York, United States, 14642
      • University of Rochester Medical Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina Hospital
    • Durham, North Carolina, United States, 27710
      • Duke Medical Center
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45236
      • The Jewish Hospital
    • Cleveland, Ohio, United States, 44106
      • Ireland Cancer Center Case Western Reserve University
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma
  • Oregon
    • Portland, Oregon, United States, 97239-3098
      • Oregon Health and Sciences University
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Milton S. Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson
    • Philadelphia, Pennsylvania, United States, 19111
      • Jeanes Hospital - Temple
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh Cancer Institute
    • Pittsburgh, Pennsylvania, United States, 15224
      • Western Pennsylvania Cancer Institute
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt Medical Center
  • Texas
    • Dallas, Texas, United States, 75246
      • Baylor University Medical Center
    • Houston, Texas, United States, 77030
      • Methodist Hospital
    • Houston, Texas, United States, 77030-4009
      • MD Anderson Cancer Center
    • San Antonio, Texas, United States, 78229
      • Texas Transplant Institute
  • Utah
    • Salt Lake City, Utah, United States, 84103
      • Latter Day Saints Hospital
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Medical College of Virginia
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Research Center
    • Seattle, Washington, United States, 98108
      • VA Puget Sound Health Center
  • West Virginia
    • Morgantown, West Virginia, United States, 26506-9162
      • West Virginia University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Allogeneic stem cell transplant recipient
• Recipient or donor CMV seropositive
• Have transplant engraftment
• Able to swallow tablets

Exclusion Criteria:

• CMV organ disease
• HIV infection
• Use of other anti-CMV therapy post-transplant

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: A	Drug: maribavir; 100 mg twice daily for up to 12 weeks
Placebo Comparator: B	Other: placebo; twice daily for up to 12 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Endpoint Committee (EC)-Confirmed Cytomegalovirus (CMV) Disease Within 6 Months Post-Transplantation	All investigator-determined cases of CMV disease (i.e., CMV infection or CMV organ disease), were adjudicated by an independent, blinded EC. CMV infection was assessed by (1) pp65 antigenemia assay; (2) CMV DNA polymerase chain reaction (PCR); (3) either assay (pp65 antigenemia or CMV DNA PCR); or (4) initiation of anti-CMV therapy. CMV infection was defined as: CMV infection detected by a positive result from a CMV laboratory assay from at least one central laboratory assay (pp65 antigenemia or CMV DNA PCR assay in plasma) and fever >/=38 °C on >/=2 occasions >/=24 hours apart within a 7-day period and at least one of the following: new or increased malaise, two successive measurements of leucopenia (white blood cell [WBC] count <3500/mm3 or a WBC count decrease of 20% if the cell count prior to onset of clinical symptoms was >4000/mm3) >/=24 hours apart, atypical lymphocytosis >/=5%, and thrombocytopenia. CMV organ disease was defined as described by Ljungman et al., 2002.	6 months post-transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With CMV Infection or EC-confirmed CMV Disease Within 6 Months Post-transplant	All investigator-determined cases of CMV disease (i.e., CMV infection or CMV organ disease), were adjudicated by an independent, blinded EC. CMV infection was assessed by (1) pp65 antigenemia assay; (2) CMV DNA polymerase chain reaction (PCR); (3) either assay (pp65 antigenemia or CMV DNA PCR); or (4) initiation of anti-CMV therapy. CMV infection was defined as: CMV infection detected by a positive result from a CMV laboratory assay from at least one central laboratory assay (pp65 antigenemia or CMV DNA PCR assay in plasma) and fever >/=38 °C on >/=2 occasions >/=24 hours apart within a 7-day period and at least one of the following: new or increased malaise, two successive measurements of leucopenia (white blood cell [WBC] count <3500/mm3 or a WBC count decrease of 20% if the cell count prior to onset of clinical symptoms was >4000/mm3) >/=24 hours apart, atypical lymphocytosis >/=5%, and thrombocytopenia. CMV organ disease was defined as described by Ljungman et al., 2002.	6 months post-transplant
Time to Onset of CMV Infection or EC-confirmed CMV Disease Within 6 Months Post- Transplantation	All investigator-determined cases of CMV disease (i.e., CMV infection or CMV organ disease) were adjudicated by an independent, blinded EC. CMV infection was assessed by (1) pp65 antigenemia assay or (2) CMV DNA polymerase chain reaction (PCR). CMV infection was defined as: CMV infection detected by a positive result from a CMV laboratory assay from at least one central laboratory assay (pp65 antigenemia or CMV DNA PCR assay in plasma) and fever >/=38 °C on >/=2 occasions >/=24 hours apart within a 7-day period and at least one of the following: new or increased malaise, two successive measurements of leucopenia (white blood cell [WBC] count <3500/mm3 or a WBC count decrease of 20% if the cell count prior to onset of clinical symptoms was >4000/mm3) >/=24 hours apart, atypical lymphocytosis >/=5%, and thrombocytopenia. CMV organ disease was defined as described by Ljungman et al., 2002.	6 months post-transplant
Number of Participants With Investigator-determined CMV Disease	CMV infection was assessed by (1) pp65 antigenemia assay; (2) CMV DNA polymerase chain reaction (PCR); (3) either assay (pp65 antigenemia or CMV DNA PCR); or (4) initiation of anti-CMV therapy. CMV infection was defined as: CMV infection detected by a positive result from a CMV laboratory assay from at least one central laboratory assay (pp65 antigenemia or CMV DNA PCR assay in plasma) and fever >/=38 °C on >/=2 occasions >/=24 hours apart within a 7-day period and at least one of the following: new or increased malaise, two successive measurements of leucopenia (white blood cell [WBC] count <3500/mm3 or a WBC count decrease of 20% if the cell count prior to onset of clinical symptoms was >4000/mm3) >/=24 hours apart, atypical lymphocytosis >/=5%, and thrombocytopenia. CMV organ disease was defined as described by Ljungman et al., 2002.	Through 12 months post-transplant (Day 1 to 100 days, 6 months, and 12 months post-transplant)
Number of Participants With CMV Infection or EC-confirmed CMV Disease Within 100 Days Post-Transplantation	All investigator-determined cases of CMV disease (i.e., CMV infection or CMV organ disease), were adjudicated by an independent, blinded EC. CMV infection was assessed by (1) pp65 antigenemia assay; (2) CMV DNA polymerase chain reaction (PCR); (3) either assay (pp65 antigenemia or CMV DNA PCR); or (4) initiation of anti-CMV therapy. CMV infection was defined as: CMV infection detected by a positive result from a CMV laboratory assay from at least one central laboratory assay (pp65 antigenemia or CMV DNA PCR assay in plasma) and fever >/=38 °C on >/=2 occasions >/=24 hours apart within a 7-day period and at least one of the following: new or increased malaise, two successive measurements of leucopenia (white blood cell [WBC] count <3500/mm3 or a WBC count decrease of 20% if the cell count prior to onset of clinical symptoms was >4000/mm3) >/=24 hours apart, atypical lymphocytosis >/=5%, and thrombocytopenia. CMV organ disease was defined as described by Ljungman et al., 2002.	100 days post-transplant
Number of Participants With EC-confirmed CMV Disease Within 12 Months Post-Transplantation	All investigator-determined cases of CMV disease (i.e., CMV infection or CMV organ disease), were adjudicated by an independent, blinded EC. CMV infection was assessed by (1) pp65 antigenemia assay; (2) CMV DNA polymerase chain reaction (PCR); (3) either assay (pp65 antigenemia or CMV DNA PCR); or (4) initiation of anti-CMV therapy. CMV infection was defined as: CMV infection detected by a positive result from a CMV laboratory assay from at least one central laboratory assay (pp65 antigenemia or CMV DNA PCR assay in plasma) and fever >/=38 °C on >/=2 occasions >/=24 hours apart within a 7-day period and at least one of the following: new or increased malaise, two successive measurements of leucopenia (white blood cell [WBC] count <3500/mm3 or a WBC count decrease of 20% if the cell count prior to onset of clinical symptoms was >4000/mm3) >/=24 hours apart, atypical lymphocytosis >/=5%, and thrombocytopenia. CMV organ disease was defined as described by Ljungman et al., 2002.	12 months post-transplant
Percent of Participants With Acute Graft-Versus-Host Disease (GVHD)	Analysis of acute GVHD was based on reported adverse events that mapped to the relevant MedDRA dictionary terms for acute GVHD. The percentage reported is for the occurrence of any grade of acute GVHD.	Through 6 months post-transplant (Days 1 to 100 and 6 months post-transplant)
Percent of Participants With Chronic Graft-Versus-Host Disease (GVHD)	Analysis of chronic GVHD was based on reported adverse events that mapped to the relevant MedDRA dictionary terms for chronic GVHD. The percentage reported is for the occurrence of any grade of chronic GVHD.	Through 6 months post-transplant (Days 1 to 100 and 6 months post-transplant)
Number of Participants Who Died Within 12 Months Post-Transplantation		Through 12 months post-transplant (Days 1 to 100, 6 months, and 12 months post-transplant)
Plasma Concentration of Maribavir During Treatment	Pharmacokinetic (PK) profile sampling was performed to evaluate plasma concentrations of Maribavir. During the study drug administration period, blood samples for this purpose were collected on Day 7 (Week 1) and at Week 4. Every effort was made to ensure that doses were administered 12 hours apart on the day before and on the day of PK sampling. Permissible assessment windows for PK profile sampling purposes were +/- 3 days and +/- 5 days for the 1- and 4- week samples, respectively. Samples were analyzed by a validated liquid chromatography tandem mass spectrometry (LC/MS/MS) method. The validated lower limit of quantitation (LLOQ) in plasma was 0.2 μg/mL.	12 hours post-dose after 1 and 4 weeks of treatment
Plasma Concentration of Maribavir Metabolite VP 44469 During Treatment	Pharmacokinetic (PK) profile sampling was performed to evaluate plasma concentrations of VP 44469, a metabolite of Maribavir. During the study drug administration period, blood samples for this purpose were collected on Day 7 (Week 1) and at Week 4. Every effort was made to ensure that doses were administered 12 hours apart on the day before and on the day of PK sampling. Permissible assessment windows for PK profile sampling purposes were +/- 3 days and +/- 5 days for the 1- and 4- week samples, respectively. Samples were analyzed by a validated liquid chromatography tandem mass spectrometry (LC/MS/MS) method. The validated lower limit of quantitation (LLOQ) in plasma was 0.2 μg/mL.	12 hours post-dose after 1 and 4 weeks of treatment

Collaborators and Investigators

• Sponsor: Shire

Publications and helpful links

General Publications

• Marty FM, Ljungman P, Papanicolaou GA, Winston DJ, Chemaly RF, Strasfeld L, Young JA, Rodriguez T, Maertens J, Schmitt M, Einsele H, Ferrant A, Lipton JH, Villano SA, Chen H, Boeckh M; Maribavir 1263-300 Clinical Study Group. Maribavir prophylaxis for prevention of cytomegalovirus disease in recipients of allogeneic stem-cell transplants: a phase 3, double-blind, placebo-controlled, randomised trial. Lancet Infect Dis. 2011 Apr;11(4):284-92. doi: 10.1016/S1473-3099(11)70024-X. Epub 2011 Mar 21. Erratum In: Lancet Infect Dis. 2011 May;11(5):343.

Study record dates

Study Major Dates

• Study Start (Actual): December 13, 2006
• Primary Completion (Actual): November 10, 2008
• Study Completion (Actual): May 23, 2009

Study Registration Dates

• First Submitted: December 12, 2006
• First Submitted That Met QC Criteria: December 12, 2006
• First Posted (Estimate): December 14, 2006

Study Record Updates

• Last Update Posted (Actual): June 11, 2021
• Last Update Submitted That Met QC Criteria: June 2, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: prevention; prophylaxis; Cytomegalovirus; CMV; SCT; allogeneic stem cell transplant
• Additional Relevant MeSH Terms: Virus Diseases; Infections; DNA Virus Infections; Herpesviridae Infections; Cytomegalovirus Infections; Anti-Infective Agents; Antiviral Agents; Maribavir
• Other Study ID Numbers: 1263-300; 2006-005692-18 (EudraCT Number); SHP620-300 (Other Identifier: Shire)