Maribavir Versus Oral Ganciclovir For The Prevention of Cytomegalovirus (CMV) Disease in Liver Transplant Recipients

Study Description

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Brief Summary:

The purpose of this research study is to investigate whether or not oral maribavir is safe and effective compared to oral ganciclovir for preventing CMV disease when administered for up to 14 weeks in patients who have had a liver transplant.

Condition or disease	Intervention/treatment	Phase
Cytomegalovirus Infections	Drug: maribavir; Drug: ganciclovir	Phase 3

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 14 weeks following orthotopic liver transplantation.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	307 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Triple (Participant, Care Provider, Investigator)
Primary Purpose:	Prevention
Official Title:	A Randomized, Double-blind Study To Assess The Efficacy And Safety Of Prophylactic Use Of Maribavir Versus Oral Ganciclovir For The Prevention Of Cytomegalovirus Disease In Recipients Of Orthotopic Liver Transplants
Study Start Date :	July 2007
Actual Primary Completion Date :	May 2009
Actual Study Completion Date :	September 2009

Arms and Interventions

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Arm	Intervention/treatment
Experimental: 1	Drug: maribavir; 100mg twice a day for 14 weeks.
Active Comparator: 2	Drug: ganciclovir; 1000mg three times per day for 14 weeks.

Outcome Measures

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Primary Outcome Measures :

1. Number of Participants With Endpoint Committee (EC)-Confirmed Cytomegalovirus (CMV) Disease Within 6 Months Post-Transplantation [ Time Frame: 6 months post-transplant ]
   All investigator-determined (protocol-defined) cases of CMV disease (i.e., symptomatic CMV infection or CMV organ disease), were adjudicated by an independent, blinded EC. Symptomatic 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 polymerase chain reaction [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.

Secondary Outcome Measures :

1. Number of Participants With CMV Infection or EC-confirmed CMV Disease Within 6 Months Post-Transplantation [ Time Frame: 6 months post-transplant ]
   Incidence of CMV infection or EC-confirmed CMV disease within the 6-month post-transplant period included in this section were defined (1) with infection assessed by pp65 antigenemia assay; (2) with infection assessed by CMV DNA PCR; (3) with infection assessed by either assay (pp65 antigenemia or CMV DNA PCR); and (4) with infection assessed by initiation of anti-CMV therapy.
2. Time to Onset of CMV Infection or EC-confirmed CMV Disease Within 6 Months Post-Transplantation [ Time Frame: 6 months post-transplant ]
   All investigator-determined (protocol-defined) cases of CMV disease (i.e., symptomatic CMV infection or CMV organ disease) were adjudicated by an independent, blinded EC. CMV infection was assessed by pp65 Antigenemia or CMV DNA PCR from a central or local lab. CMV organ disease was defined as described by Ljungman et al., 2002.
3. Number of Participants With Investigator-determined CMV Disease [ Time Frame: Through 6 months post-transplant (Day 1 to 100 days and 6 months post-transplant) ]
   Symptomatic 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 polymerase chain reaction [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.
4. Number of Participants With EC-confirmed CMV Disease Within 100 Days Post-Transplantation [ Time Frame: 100 days post-transplant ]
   All investigator-determined (protocol-defined) cases of CMV disease (i.e., symptomatic CMV infection or CMV organ disease), were adjudicated by an independent, blinded EC. Symptomatic 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 polymerase chain reaction [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.
5. Number of Participants With CMV Infection or EC-confirmed CMV Disease Within 100 Days Post-Transplantation [ Time Frame: 100 days post-transplant ]
   Incidence of CMV infection or EC-confirmed CMV disease within the 6-month post-transplant period included in this section were defined (1) with infection assessed by pp65 antigenemia assay; (2) with infection assessed by CMV DNA PCR; (3) with infection assessed by either assay (pp65 antigenemia or CMV DNA PCR); and (4) with infection assessed by initiation of anti-CMV therapy.
6. Number of Participants With Retransplantation [ Time Frame: Through 6 months post-transplant (From Day 1 to 100 days and 6 months post-transplant) ]
7. Number of Participants With Graft Failure Related Death [ Time Frame: Through 6 months post-transplant (From Day 1 to 100 days and 6 months post-transplant) ]
8. Number of Participants With Acute Graft Rejection [ Time Frame: 26 weeks post-transplant ]
   Rejection was assessed by examining a liver biopsy sample. Diagnosis of graft rejection included a global assessment grade and a rejection activity index score.
9. Number of Participants Who Died Within 6 Months Post-Transplantation [ Time Frame: 6 months post-transplant ]
10. Percent of Participants With Signs of Bone Marrow Suppression [ Time Frame: 15 weeks ]
    Bone marrow suppression was assessed by the occurrence of adverse events (AEs) of investigator-reported leukopenia, neutropenia, thrombocytopenia, and pancytopenia; absolute neutrophil count (ANC) <1000/mm3; white blood cell (WBC) count toxicity grade shifts from 0-2 at baseline to a maximum of 3-4 post-baseline; and use of hematopoietic growth factors during the 6 month post-transplant period.
11. Plasma Concentration of Maribavir During Treatment [ Time Frame: 12 hours post-dose after 2, 6, and 10 weeks of treatment ]
    For the first 16 subjects to have PK profiling performed, PK sampling was collected at Weeks 2, 6 and 10. For subsequent subjects that have PK profiling performed, PK sampling was collected at Weeks 2 and 6. Samples were collected 12 hours after the morning dose of maribavir. Permissible assessment windows for pharmacokinetic profile sampling purposes were +/- 5 days for each sampling day. Samples for determination of maribavir concentration were analyzed by a validated liquid chromatography tandem mass spectrometry (LC/MS/MS) method. For plasma, the minimum detectable concentration for maribavir was 0.2 μg/mL.
12. Plasma Concentration of Maribavir Metabolite VP 44469 During Treatment [ Time Frame: 12 hours post-dose after 2, 6, and 10 weeks of treatment ]
    For the first 16 subjects to have PK profiling performed, PK sampling was collected at Weeks 2, 6 and 10. For subsequent subjects that have PK profiling performed, PK sampling was collected at Weeks 2 and 6. Samples were collected 12 hours after the morning dose of maribavir. Permissible assessment windows for pharmacokinetic profile sampling purposes were +/- 5 days for each sampling day. Samples for determination of VP 44469 (a metabolite of maribavir) concentration were analyzed by a validated liquid chromatography tandem mass spectrometry (LC/MS/MS) method. For plasma, the minimum detectable concentration for VP 44469 was 0.2 μg/mL.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Orthotopic liver transplant recipient
• Donor CMV seropositive / Recipient CMV seronegative
• Enrolled within 10 days after liver transplant
• Able to swallow tablets

Exclusion Criteria:

• Multiple organ transplant
• HIV infection
• CMV disease
• Use of other anti-CMV therapy at time of enrollment

Contacts and Locations

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Sponsors and Collaborators

Shire

Investigators

Study Director:	Stephen A Villano, MD	ViroPharma

More Information

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Responsible Party:	Shire
ClinicalTrials.gov Identifier:	NCT00497796 History of Changes
Other Study ID Numbers:	1263-301; 2007-004729-16 ( EudraCT Number ); SHP620-301 ( Other Identifier: Shire )
First Posted:	July 9, 2007
Results First Posted:	June 4, 2015
Last Update Posted:	June 4, 2015
Last Verified:	March 2014

Keywords provided by Shire:

cytomegalovirus; CMV; prophylaxis; liver; liver transplant

Additional relevant MeSH terms:

Cytomegalovirus Infections; Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Ganciclovir; Ganciclovir triphosphate	Antiviral Agents; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action