Cytomegalovirus Infections
Conditions
Keywords
prevention, prophylaxis, Cytomegalovirus, CMV, allogeneic stem cell transplant, SCT
Brief summary
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.
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.
Interventions
DRUGmaribavir
100 mg twice daily for up to 12 weeks
OTHERplacebo
twice daily for up to 12 weeks
Sponsors
Shire
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Endpoint Committee (EC)-Confirmed Cytomegalovirus (CMV) Disease Within 6 Months Post-Transplantation | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Onset of CMV Infection or EC-confirmed CMV Disease Within 6 Months Post- Transplantation | 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 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. |
| Number of Participants With Investigator-determined CMV Disease | Through 12 months post-transplant (Day 1 to 100 days, 6 months, and 12 months post-transplant) | 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. |
| Number of Participants With CMV Infection or EC-confirmed CMV Disease Within 100 Days Post-Transplantation | 100 days 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. |
| Number of Participants With EC-confirmed CMV Disease Within 12 Months Post-Transplantation | 12 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. |
| Number of Participants With CMV Infection or EC-confirmed CMV Disease Within 6 Months Post-transplant | 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. |
| Percent of Participants With Chronic Graft-Versus-Host Disease (GVHD) | Through 6 months post-transplant (Days 1 to 100 and 6 months post-transplant) | 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. |
| 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 | 12 hours post-dose after 1 and 4 weeks of 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. |
| Plasma Concentration of Maribavir Metabolite VP 44469 During Treatment | 12 hours post-dose after 1 and 4 weeks of 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. |
| Percent of Participants With Acute Graft-Versus-Host Disease (GVHD) | Through 6 months post-transplant (Days 1 to 100 and 6 months post-transplant) | 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. |
Countries
Belgium, Canada, France, Germany, Italy, Spain, Sweden, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo twice daily (BID) for up to 12 weeks. | 227 |
| Maribavir 100 mg BID Participants received maribavir 100 mg twice daily (BID) for up to 12 weeks. | 454 |
| Total | 681 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Consent Withdrawn | 13 | 22 |
| Overall Study | Death | 56 | 135 |
| Overall Study | Investigator/Sponsor Decision | 10 | 7 |
| Overall Study | Lost to Follow-up | 2 | 0 |
Baseline characteristics
| Characteristic | Placebo | Maribavir 100 mg BID | Total |
|---|---|---|---|
| Age, Continuous | 49 years STANDARD_DEVIATION 13.1 | 49 years STANDARD_DEVIATION 12.5 | 49 years STANDARD_DEVIATION 12.7 |
| Age, Customized 18 to 44 years | 74 Participants | 136 Participants | 210 Participants |
| Age, Customized 45 to 64 years | 134 Participants | 286 Participants | 420 Participants |
| Age, Customized 65 to 75 years | 18 Participants | 32 Participants | 50 Participants |
| Age, Customized > 75 years | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Female | 98 Participants | 189 Participants | 287 Participants |
| Sex: Female, Male Male | 129 Participants | 265 Participants | 394 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 192 / 223 | 408 / 451 |
| serious Total, serious adverse events | 98 / 223 | 197 / 451 |
Outcome results
Primary
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.
Time frame: 6 months post-transplant
Population: The Intent-to-Treat (ITT) population, defined as all participants who were randomized to one of the therapy groups, regardless of whether the participant received study drug or had any post-baseline evaluations.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants With Endpoint Committee (EC)-Confirmed Cytomegalovirus (CMV) Disease Within 6 Months Post-Transplantation | 11 participants |
| Maribavir 100 mg BID | Number of Participants With Endpoint Committee (EC)-Confirmed Cytomegalovirus (CMV) Disease Within 6 Months Post-Transplantation | 20 participants |
p-value: 0.78995% CI: [0.424, 1.92]Cochran-Mantel-Haenszel
Secondary
Number of Participants Who Died Within 12 Months Post-Transplantation
Time frame: Through 12 months post-transplant (Days 1 to 100, 6 months, and 12 months post-transplant)
Population: The ITT-S population, defined as participants in the ITT population who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants Who Died Within 12 Months Post-Transplantation | 100 days post-transplant | 19 participants |
| Placebo | Number of Participants Who Died Within 12 Months Post-Transplantation | 6 months post-transplant | 37 participants |
| Placebo | Number of Participants Who Died Within 12 Months Post-Transplantation | 12 months post-transplant | 59 participants |
| Maribavir 100 mg BID | Number of Participants Who Died Within 12 Months Post-Transplantation | 100 days post-transplant | 30 participants |
| Maribavir 100 mg BID | Number of Participants Who Died Within 12 Months Post-Transplantation | 6 months post-transplant | 88 participants |
| Maribavir 100 mg BID | Number of Participants Who Died Within 12 Months Post-Transplantation | 12 months post-transplant | 139 participants |
Secondary
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.
Time frame: 100 days post-transplant
Population: The ITT population, defined as all participants who were randomized to one of the therapy groups, regardless of whether the participant received study drug or had any post-baseline evaluations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With CMV Infection or EC-confirmed CMV Disease Within 100 Days Post-Transplantation | pp65 antigenemia assay | 79 participants |
| Placebo | Number of Participants With CMV Infection or EC-confirmed CMV Disease Within 100 Days Post-Transplantation | EC-confirmed disease | 6 participants |
| Placebo | Number of Participants With CMV Infection or EC-confirmed CMV Disease Within 100 Days Post-Transplantation | CMV DNA PCR assay | 69 participants |
| Placebo | Number of Participants With CMV Infection or EC-confirmed CMV Disease Within 100 Days Post-Transplantation | pp65 antigenemia assay or CMV DNA PCR assay | 92 participants |
| Placebo | Number of Participants With CMV Infection or EC-confirmed CMV Disease Within 100 Days Post-Transplantation | Initiation of anti-CMV therapy | 85 participants |
| Maribavir 100 mg BID | Number of Participants With CMV Infection or EC-confirmed CMV Disease Within 100 Days Post-Transplantation | EC-confirmed disease | 11 participants |
| Maribavir 100 mg BID | Number of Participants With CMV Infection or EC-confirmed CMV Disease Within 100 Days Post-Transplantation | pp65 antigenemia assay | 120 participants |
| Maribavir 100 mg BID | Number of Participants With CMV Infection or EC-confirmed CMV Disease Within 100 Days Post-Transplantation | CMV DNA PCR assay | 126 participants |
| Maribavir 100 mg BID | Number of Participants With CMV Infection or EC-confirmed CMV Disease Within 100 Days Post-Transplantation | pp65 antigenemia assay or CMV DNA PCR assay | 157 participants |
| Maribavir 100 mg BID | Number of Participants With CMV Infection or EC-confirmed CMV Disease Within 100 Days Post-Transplantation | Initiation of anti-CMV therapy | 139 participants |
Comparison: Analysis of pp65 antigenemia assayp-value: 0.02295% CI: [0.474, 0.946]Cochran-Mantel-Haenszel
Comparison: Analysis of CMV DNA PCR assayp-value: 0.46895% CI: [0.617, 1.247]Cochran-Mantel-Haenszel
Comparison: Analysis of pp65 antigenemia assay or CMV DNA PCR assayp-value: 0.12595% CI: [0.555, 1.075]Cochran-Mantel-Haenszel
Comparison: Analysis of initiation of anti-CMV therapyp-value: 0.06995% CI: [0.521, 1.026]Cochran-Mantel-Haenszel
Comparison: Analysis of EC-confirmed diseasep-value: 0.8695% CI: [0.332, 2.508]Cochran-Mantel-Haenszel
Secondary
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.
Time frame: 6 months post-transplant
Population: The ITT population, defined as all participants who were randomized to one of the therapy groups, regardless of whether the participant received study drug or had any post-baseline evaluations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With CMV Infection or EC-confirmed CMV Disease Within 6 Months Post-transplant | pp65 antigenemia assay | 88 participants |
| Placebo | Number of Participants With CMV Infection or EC-confirmed CMV Disease Within 6 Months Post-transplant | pp65 antigenemia or CMV DNA PCR assay | 101 participants |
| Placebo | Number of Participants With CMV Infection or EC-confirmed CMV Disease Within 6 Months Post-transplant | CMV DNA PCR assay | 77 participants |
| Placebo | Number of Participants With CMV Infection or EC-confirmed CMV Disease Within 6 Months Post-transplant | Initiation of anti-CMV therapy | 92 participants |
| Maribavir 100 mg BID | Number of Participants With CMV Infection or EC-confirmed CMV Disease Within 6 Months Post-transplant | Initiation of anti-CMV therapy | 172 participants |
| Maribavir 100 mg BID | Number of Participants With CMV Infection or EC-confirmed CMV Disease Within 6 Months Post-transplant | CMV DNA PCR assay | 152 participants |
| Maribavir 100 mg BID | Number of Participants With CMV Infection or EC-confirmed CMV Disease Within 6 Months Post-transplant | pp65 antigenemia assay | 143 participants |
| Maribavir 100 mg BID | Number of Participants With CMV Infection or EC-confirmed CMV Disease Within 6 Months Post-transplant | pp65 antigenemia or CMV DNA PCR assay | 183 participants |
Comparison: Analysis of pp65 antigenemia assayp-value: 0.05695% CI: [0.515, 1.008]Cochran-Mantel-Haenszel
Comparison: Analysis of CMV DNA PCR assayp-value: 0.90495% CI: [0.697, 1.375]Cochran-Mantel-Haenszel
Comparison: Analysis of pp65 antigenemia or CMV DNA PCR assayp-value: 0.28995% CI: [0.606, 1.161]Cochran-Mantel-Haenszel
Comparison: Analysis of initiation of anti-CMV therapyp-value: 0.49395% CI: [0.64, 1.239]Cochran-Mantel-Haenszel
Secondary
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.
Time frame: 12 months post-transplant
Population: The ITT population, defined as all participants who were randomized to one of the therapy groups, regardless of whether the participant received study drug or had any post-baseline evaluations.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants With EC-confirmed CMV Disease Within 12 Months Post-Transplantation | 13 participants |
| Maribavir 100 mg BID | Number of Participants With EC-confirmed CMV Disease Within 12 Months Post-Transplantation | 22 participants |
Comparison: Analysis of 12 months post-transplantp-value: 0.61795% CI: [0.411, 1.693]Cochran-Mantel-Haenszel
Secondary
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.
Time frame: Through 12 months post-transplant (Day 1 to 100 days, 6 months, and 12 months post-transplant)
Population: The ITT population, defined as all participants who were randomized to one of the therapy groups, regardless of whether the participant received study drug or had any post-baseline evaluations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Investigator-determined CMV Disease | 100 days post-tranplant | 6 participants |
| Placebo | Number of Participants With Investigator-determined CMV Disease | 6 months post-transplant | 11 participants |
| Placebo | Number of Participants With Investigator-determined CMV Disease | 12 months post-transplant | 13 participants |
| Maribavir 100 mg BID | Number of Participants With Investigator-determined CMV Disease | 100 days post-tranplant | 16 participants |
| Maribavir 100 mg BID | Number of Participants With Investigator-determined CMV Disease | 6 months post-transplant | 26 participants |
| Maribavir 100 mg BID | Number of Participants With Investigator-determined CMV Disease | 12 months post-transplant | 28 participants |
Comparison: Analysis of 100 days post-transplantp-value: 0.542Cochran-Mantel-Haenszel
Comparison: Analysis of 6 months post-transplantp-value: 0.637Cochran-Mantel-Haenszel
Comparison: Analysis of 12 months post-transplantp-value: 0.825Cochran-Mantel-Haenszel
Secondary
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.
Time frame: Through 6 months post-transplant (Days 1 to 100 and 6 months post-transplant)
Population: The ITT Safety (ITT-S) population, defined as participants in the ITT population who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percent of Participants With Acute Graft-Versus-Host Disease (GVHD) | 100 days post-transplant | 39 percentage of participants |
| Placebo | Percent of Participants With Acute Graft-Versus-Host Disease (GVHD) | 6 months post-transplant | 43 percentage of participants |
| Maribavir 100 mg BID | Percent of Participants With Acute Graft-Versus-Host Disease (GVHD) | 100 days post-transplant | 40 percentage of participants |
| Maribavir 100 mg BID | Percent of Participants With Acute Graft-Versus-Host Disease (GVHD) | 6 months post-transplant | 44 percentage of participants |
Comparison: Analysis of 100 days post-transplantp-value: 0.780895% CI: [0.754, 1.457]Cochran-Mantel-Haenszel
Comparison: Analysis of 6 months post-transplantp-value: 0.694695% CI: [0.771, 1.479]Cochran-Mantel-Haenszel
Secondary
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.
Time frame: Through 6 months post-transplant (Days 1 to 100 and 6 months post-transplant)
Population: The ITT-S population, defined as participants in the ITT population who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percent of Participants With Chronic Graft-Versus-Host Disease (GVHD) | 100 days post-transplant | 5 percentage of participants |
| Placebo | Percent of Participants With Chronic Graft-Versus-Host Disease (GVHD) | 6 months post-transplant | 25 percentage of participants |
| Maribavir 100 mg BID | Percent of Participants With Chronic Graft-Versus-Host Disease (GVHD) | 100 days post-transplant | 6 percentage of participants |
| Maribavir 100 mg BID | Percent of Participants With Chronic Graft-Versus-Host Disease (GVHD) | 6 months post-transplant | 19 percentage of participants |
Comparison: Analysis of 100 days post-transplantp-value: 0.630495% CI: [0.592, 2.375]Cochran-Mantel-Haenszel
Comparison: Analysis of 6 months post-transplantp-value: 0.101995% CI: [0.495, 1.066]Cochran-Mantel-Haenszel
Secondary
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.
Time frame: 12 hours post-dose after 1 and 4 weeks of treatment
Population: The pharmacokinetic (PK) population, defined as those participants in the ITT population from whom plasma samples were drawn, tested for maribavir concentrations, and complete, evaluable PK data were available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Plasma Concentration of Maribavir During Treatment | 1 week post-dose, n=63 | 2.11 μg/mL | Standard Deviation 2.1 |
| Placebo | Plasma Concentration of Maribavir During Treatment | 4 weeks post-dose, n=48 | 2.19 μg/mL | Standard Deviation 1.99 |
Secondary
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.
Time frame: 12 hours post-dose after 1 and 4 weeks of treatment
Population: The PK population, defined as those participants in the ITT population from whom plasma samples were drawn, tested for maribavir concentrations, and complete, evaluable PK data were available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Plasma Concentration of Maribavir Metabolite VP 44469 During Treatment | 1 week post-dose, n=63 | 0.56 μg/mL | Standard Deviation 0.36 |
| Placebo | Plasma Concentration of Maribavir Metabolite VP 44469 During Treatment | 4 weeks post-dose, n=48 | 0.65 μg/mL | Standard Deviation 0.47 |
Secondary
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.
Time frame: 6 months post-transplant
Population: The ITT population, defined as all participants who were randomized to one of the therapy groups, regardless of whether the participant received study drug or had any post-baseline evaluations.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to Onset of CMV Infection or EC-confirmed CMV Disease Within 6 Months Post- Transplantation | 21 days |
| Maribavir 100 mg BID | Time to Onset of CMV Infection or EC-confirmed CMV Disease Within 6 Months Post- Transplantation | 22 days |
p-value: 0.129Log Rank
p-value: 0.1395% CI: [0.65, 1.06]Wald Chi-squared