Cytomegalovirus (CMV)
Conditions
Brief summary
The purpose of this study is to compare the efficacy of maribavir to investigator-assigned anti-Cytomegalovirus (CMV) therapy in CMV viremia clearance in transplant recipients who are refractory or resistant to prior anti-CMV treatment.
Interventions
DRUGMaribavir
Maribavir 400 milligrams (mg) (2x200 mg tablets) will be administered twice daily for 8 weeks.
DRUGGanciclovir
Ganciclovir as per the investigator's prescribed dosing regimen will be administered for 8 weeks.
DRUGValganciclovir
Valganciclovir as per the investigator's prescribed dosing regimen will be administered for 8 weeks.
DRUGFoscarnet
Foscarnet as per the investigator's prescribed dosing regimen will be administered for 8 weeks.
DRUGCidofovir
Cidofovir as per the investigator's prescribed dosing regimen will be administered for 8 weeks.
Sponsors
Shire
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. The participant must be able to provide written, personally signed, and dated informed consent to participate in the study before completing any study-related procedures. As applicable, a parent/both parents or legally authorized representative (LAR) must provide signature of informed consent and there must be documentation of assent by the participant before completing any study-related procedures. 2. The participant must be a recipient of hematopoietic stem cell or solid organ transplant. 3. The participant must have a documented CMV infection in whole blood or plasma, with a screening value of greater than or equal to (\>=) 2730 international units per milliliter (IU/mL) in whole blood or \>= 910 IU/mL in plasma in 2 consecutive assessments, separated by at least 1 day, as determined by local or central specialty laboratory quantitative polymerase chain reaction (qPCR) or comparable quantitative CMV DNA results. Both samples should be taken within 14 days prior to randomization with second sample obtained within 5 days prior to randomization. The same laboratory and same sample type (whole blood or plasma) must be used for these assessments. 4. The participant must have a current CMV infection that is refractory to the most recently administered of the four anti-CMV treatment agents. Refractory is defined as documented failure to achieve greater than (\>) 1 log10 (common logarithm to base 10) decrease in CMV DNA level in whole blood or plasma after a 14 day or longer treatment period with intravenous (IV) ganciclovir/oral valganciclovir, IV foscarnet, or IV cidofovir. a. Participants with documentation of 1 or more CMV genetic mutations associated with resistance to ganciclovir/valganciclovir, foscarnet, and/or cidofovir must also meet the definition of refractory CMV infection. 5. The Investigator must be willing to treat the participant with at least one of the available anti-CMV drugs (ganciclovir, valganciclovir, foscarnet, or cidofovir). Note: Combination therapy with foscarnet and cidofovir is not permitted in the investigator-assigned anti-CMV treatment (IAT) arm due to the potential for serious nephrotoxicity. 6. The participant must be \>= 12 years of age at the time of consent. 7. The participant must weigh \>= 35 kilogram (kg). 8. The participant must have all of the following results as part of screening laboratory assessments (results from either the central laboratory or a local laboratory can be used for qualification): 1. Absolute neutrophil count (ANC) \>= 1000/ millimeter cube (mm\^3) (1.0 x 10\^9/liter \[L\]) 2. Platelet count \>= 25,000/mm\^3 \[25 x 10\^9/L\], 3. Hemoglobin \>= 8 grams per deciliter (g/dL). 4. Estimated glomerular filtration rate (eGFR) \> 30 (milliliters per minute (mL/min) /1.73 square meter (m\^2) as assessed by Modification of Diet in Renal Disease (MDRD) formula for participants \>= 18 years of age or Schwartz formula for participants less than (\<) 18 years of age. 9. The participant must have a negative serum beta-human chorionic gonadotropin (beta-HCG) pregnancy test at screening, if a female of child bearing potential. Additional urine pregnancy tests may be done per institutional requirements. Sexually active females of child bearing potential must agree to comply with any applicable contraceptive requirements of the protocol. If male, must agree to use an acceptable method of birth control, as defined in the protocol, during the study treatment administration period and for 90 days afterward if treated with maribavir, ganciclovir, valganciclovir, or cidofovir and for 180 days afterward if treated with foscarnet. 10. The participant must be able to swallow tablets, or receive tablets crushed and/or dispensed in water via nasogastric or orogastric tube. 11. The participant must be willing and have an understanding and ability to fully comply with study procedures and restrictions defined in the protocol. 12. The participant must be willing to provide necessary samples (example \[e.g,\] biopsy) for the diagnosis of tissue invasive CMV disease at baseline as determined by the Investigator. 13. The participant must have a life expectancy of \>= 8 weeks.
Exclusion criteria
1. Have a current CMV infection that is considered refractory or resistant due to inadequate adherence to prior anti-CMV treatment, to the best knowledge of the Investigator. 2. Require ganciclovir, valganciclovir, foscarnet, or cidofovir administration for conditions other than CMV when study treatment is initiated (example: herpes simplex virus (HSV) coinfection requiring use of any of these agents after the randomization) or would need a coadministration with maribavir for CMV infection. NOTE: A participant who is not continuing with the same anti-CMV drug(s) (ganciclovir, valganciclovir or foscarnet) for the study treatment (if randomized to the investigator assigned anti-CMV treatment arm), must discontinue their use before the first dose of study drug. If participant is currently being treated with cidofovir and is assigned another anti-CMV therapy by the investigator, the participant must discontinue its use at least 14 days prior to randomization at Visit 2/Day 0 and the first dose of study treatment. 3. Be receiving leflunomide, letermovir, or artesunate when study treatment is initiated. NOTE: Participants receiving leflunomide must discontinue the use at least 14 days prior to randomization at Visit 2/Day 0 and the first dose of study treatment. Participants receiving letermovir must discontinue use at least 3 days prior to the first dose of study treatment. Participants receiving artesunate must discontinue the use prior to the first dose of study treatment. 4. Have severe vomiting, diarrhea, or other severe gastrointestinal illness within 24 hours prior to the first dose of study treatment that would preclude administration of oral/enteral medication. 5. Have known hypersensitivity to the active substance or to an excipient for a study treatment. 6. Have tissue invasive CMV disease with central nervous system involvement including the retina (example, CMV retinitis). 7. Have serum aspartate aminotransferase (AST) \> 5 times upper limit of normal (ULN) at screening, or serum alanine aminotransferase (ALT) \> 5 times ULN at screening, or total bilirubin \>= 3.0 x ULN at screening (except for documented Gilbert's syndrome), by local or central lab. Participants with biopsy confirmed CMV hepatitis will not be excluded from study participation despite AST or ALT \> 5 times ULN at screening. 8. Have known positive results for human immunodeficiency virus (HIV). Participants must have a confirmed negative HIV test result within 3 months of study entry or, if unavailable, be tested by a local laboratory during the screening period. 9. Require mechanical ventilation or vasopressors for hemodynamic support at the time of enrollment. 10. Be female and pregnant or breast feeding. 11. Have previously received maribavir. 12. Have received any investigational agent with known anti-CMV activity within 30 days before initiation of study treatment or investigational CMV vaccine at any time. 13. Have received any unapproved agent or device within 30 days before initiation of study treatment. 14. Have active malignancy with the exception of nonmelanoma skin cancer. Participants who have had a hematopoietic stem cell transplant (HSCT) and who experience relapse or progression of the malignancy as per investigator's opinion are not to be enrolled. 15. Be undergoing treatment for acute or chronic hepatitis C. 16. Have any clinically significant medical or surgical condition that, in the investigator's opinion, could interfere with the interpretation of study results, contraindicate the administration of the assigned study treatment, or compromise the safety or well-being of the participant.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieved Confirmed Clearance of Plasma Cytomegalovirus (CMV) Deoxyribonucleic Acid (DNA) (CMV Viremia Clearance) at End of Week 8 | Week 8 | Confirmed CMV viremia clearance was defined as plasma CMV DNA concentration less than (\<) lower limit of quantification (LLOQ) that is, \<137 International Units per milliliter (IU/mL) when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV Test in 2 consecutive postbaseline samples, separated by at least 5 days. Percentage of participants with confirmed CMV viremia clearance at end of study Week 8 regardless of whether either study-assigned treatment was discontinued before the end of the stipulated 8 weeks of therapy, and could not have received alternative anti-CMV treatment were reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieved Confirmed CMV Viremia Clearance and CMV Infection Symptom Control at End of Week 8, Followed by Maintenance of Treatment Effect at Week 16 | Up to Week 16 | Confirmed CMV viremia clearance was defined as plasma CMV DNA concentration \<LLOQ that is, \<137 IU/mL when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test in 2 consecutive postbaseline samples, separated by at least 5 days. CMV infection symptom control was defined as resolution or improvement of tissue invasive CMV disease or CMV syndrome for participants symptomatic at baseline, or maintaining no symptoms of tissue invasive CMV disease or CMV syndrome for participants asymptomatic at baseline. Percentage of participants who achieved CMV viremia clearance and CMV infection symptom control at end of Week 8 through Week 16 were reported. |
| Percentage of Participants Who Achieved Confirmed CMV Viremia Clearance After Receiving 8 Weeks of Study-assigned Treatment | At Week 8 through Weeks 12, 16 and 20 | Confirmed CMV viremia clearance was defined as plasma CMV DNA concentration \<LLOQ that is, \<137IU/mL when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test in 2 consecutive postbaseline samples, separated by at least 5 days. Percentage of participants who achieved confirmed CMV viremia clearance after receiving 8 weeks study-assigned treatment at end of Week 8, and maintained this effect through 12, 16 and 20 were reported. |
| Percentage of Participants Who Achieved Confirmed CMV Viremia Clearance and CMV Infection Symptom Control After Receiving 8 Weeks of Study-assigned Treatment Through Weeks 12, 16 and 20 | At Week 8 through Weeks 12, 16 and 20 | Confirmed CMV viremia clearance was defined as plasma CMV DNA concentration \<LLOQ that is, \<137IU/mL when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test in 2 consecutive postbaseline samples, separated by at least 5 days. CMV infection symptom control was defined as resolution or improvement of tissue invasive CMV disease or CMV syndrome for participants symptomatic at baseline, or maintaining no symptoms of tissue invasive CMV disease or CMV syndrome for participants asymptomatic at baseline. Percentage of participants who achieved confirmed CMV viremia clearance and CMV infection control after receiving 8 weeks study-assigned treatment at end of Week 8, and maintained this effect through 12, 16 and 20 were reported. |
| Time to All Cause Mortality | From enrollment to last serious adverse event (SAE) follow-up (approximately Week 28) | The time to all-cause mortality by the end of the study participation in days was calculated. Participants who were alive at the last study follow-up (regardless of use of rescue or alternative anti-CMV treatment), withdrew from study or were lost to follow-up were censored at the date of last contact. |
| Percentage of Participants Who Maintained CMV Viremia Clearance and CMV Infection Symptom Control at the End of Study Week 8 Through Weeks 12 and 20 Regardless of Whether Either Study-assigned Treatment Was Discontinued Before 8 Weeks of Therapy | At Week 8 through Weeks 12 and 20 | Confirmed CMV viremia clearance was defined as plasma CMV DNA concentration \<LLOQ that is, \<137IU/mL when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test in 2 consecutive postbaseline samples, separated by at least 5 days. CMV infection symptom control was defined as resolution or improvement of tissue invasive CMV disease or CMV syndrome for participants symptomatic at baseline or maintaining no symptoms of tissue invasive CMV disease or CMV syndrome for participants asymptomatic at baseline. Percentage of participants who maintained CMV viremia clearance and CMV infection symptom control at the end of study Week 8 through Weeks 12 and 20 regardless of whether either study-assigned treatment was discontinued before 8 weeks of therapy were reported. |
| Percentage of Participants With Recurrence of CMV Viremia During the First 8 Weeks of Study Regardless of Whether Study-assigned Treatment Was Discontinued Before 8 Weeks of Therapy | At Week 8 | Recurrence of CMV viremia was defined as plasma CMV DNA concentration greater than or equal to (\>=) LLOQ when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test in 2 consecutive plasma samples at least 5 days apart, after achieving confirmed viremia clearance, regardless of whether either study-assigned treatment was discontinued before the end of the stipulated 8 weeks of therapy. Percentage of participants with recurrence of CMV viremia during the first 8 weeks of study regardless of whether study-assigned treatment was discontinued before 8 weeks of therapy were reported. |
| Percentage of Participants With Recurrence of CMV Viremia During the 12 Weeks Follow-up Period Regardless of Whether Study-assigned Treatment Was Discontinued Before 8 Weeks of Therapy | End of Week 8 up to Week 20 (12 weeks follow-up period) | Recurrence of CMV viremia was defined as plasma CMV DNA concentration \>=LLOQ when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test in 2 consecutive plasma samples at least 5 days apart, after achieving confirmed viremia clearance, regardless of whether either study-assigned treatment was discontinued before the end of the stipulated 8 weeks of therapy. Percentage of participants with recurrence of CMV viremia during the 12 weeks follow-up period regardless of whether study-assigned treatment was discontinued before 8 weeks of therapy were reported. |
| Percentage of Participants With Recurrence of CMV Viremia at Any Time on Study Regardless of Whether Study-assigned Treatment Was Discontinued Before 8 Weeks of Therapy | Baseline up to Week 20 | Recurrence of CMV viremia was defined as plasma CMV DNA concentration \>=LLOQ when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test in 2 consecutive plasma samples at least 5 days apart, after achieving confirmed viremia clearance, regardless of whether either study-assigned treatment was discontinued before the end of the stipulated 8 weeks of therapy. Percentage of participants with recurrence of CMV viremia during at any time on study regardless of whether study-assigned treatment was discontinued before 8 weeks of therapy were reported. |
| Percentage of Participants Who Completed 8 Weeks of Study-assigned Treatment With Recurrence of CMV Viremia During the First 8 Weeks of the Treatment | Baseline up to Week 8 | Recurrence of CMV viremia was defined as plasma CMV DNA concentration \>=LLOQ when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test in 2 consecutive plasma samples at least 5 days apart, after achieving confirmed viremia clearance. Percentage of participants with recurrence of CMV viremia during the first 8 Weeks of the treatment who completed 8 weeks of study-assigned treatment were reported. |
| Percentage of Participants Who Completed 8 Weeks of Study-assigned Treatment With Recurrence of CMV Viremia During the 12 Weeks of Follow-up Period | End of Week 8 up to Week 20 (12 weeks follow-up period) | Recurrence of CMV viremia was defined as plasma CMV DNA concentration \>=LLOQ when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test in 2 consecutive plasma samples at least 5 days apart, after achieving confirmed viremia clearance. Percentage of participants who completed 8 weeks of study-assigned treatment with recurrence of CMV viremia during the 12 weeks of follow-up period were reported. |
| Percentage of Participants Who Completed 8 Weeks of Study-assigned Treatment With Recurrence of CMV Viremia During the 20 Weeks of Study | Baseline up to Week 20 | Recurrence of CMV viremia was defined as plasma CMV DNA concentration \>=LLOQ when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test in 2 consecutive plasma samples at least 5 days apart, after achieving confirmed viremia clearance. Percentage of participants with Recurrence of CMV viremia was defined as plasma CMV DNA concentration \>=LLOQ when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test in 2 consecutive plasma samples at least 5 days apart, after achieving confirmed viremia clearance. Percentage of participants who completed 8 weeks of study-assigned treatment with recurrence of CMV viremia during the 20 weeks of study were reported. |
| Percentage of Participants With Recurrence of CMV Viremia While on Study-assigned Treatment | Baseline up to termination of study treatment (up to Week 8) | Recurrence of CMV viremia was defined as plasma CMV DNA concentration \>=LLOQ when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test in 2 consecutive plasma samples at least 5 days apart, after achieving confirmed viremia clearance. Percentage of participants with recurrence of CMV viremia while on study-assigned treatment period were reported. |
| Number of Participants With All-cause Mortality by the End of the Study | From enrollment up to end of study (approximately 44 months) | All-cause mortality was analyzed by the end of study regardless of the use of rescue treatment or alternative anti-CMV treatment. Number of participants who died during the entire study period were reported. |
| Number of Participants Who Had Maribavir CMV Resistance at Baseline | At Baseline | Resistance-associated amino acid substitutions (RASs) to maribavir are known to generally map to the pUL97 and pUL27 genes. Genotyping was performed to identify RASs mapping to the pUL97 and pUL27 genes. Number of participants who had maribavir CMV resistance at baseline were reported. |
| Number of Participants Who Had Post-baseline Resistance to Maribavir | After first dose of study drug up to Week 20 | Resistance-associated amino acid substitutions (RASs) to maribavir are known to generally map to the pUL97 and pUL27 genes. Genotyping was performed to identify RASs mapping to the pUL97 and pUL27 genes. Number of participants who had post-baseline resistance to maribavir were reported. |
| Percentage of Participants Who Achieved Confirmed Clearance of Plasma CMV DNA (CMV Viremia Clearance) at End of Week 8 After Starting Maribavir Rescue Treatment | From start of maribavir rescue treatment through 8 weeks | Confirmed CMV viremia clearance was defined as plasma CMV DNA concentration \<LLOQ that is, \<137 IU/mL when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV Test in 2 consecutive postbaseline samples, separated by at least 5 days, regardless of whether the rescue treatment was discontinued before the end of the stipulated 8 weeks of therapy. Percentage of participants who achieved confirmed CMV viremia clearance at end of Week 8 after starting maribavir rescue treatment were reported. |
| Percentage of Participants Receiving Maribavir Rescue Treatment Who Achieved Confirmed CMV Viremia Clearance and CMV Infection Symptom Control at Week 8 With Maintenance of Effect Through Week 16 | Up to Week 16 | Confirmed CMV viremia clearance was defined as plasma CMV DNA concentration \<LLOQ that is, \<137 IU/mL when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test in 2 consecutive postbaseline samples, separated by at least 5 days. CMV infection symptom control was defined as resolution or improvement of tissue invasive CMV disease or CMV syndrome for participants symptomatic at baseline, or maintaining no symptoms of tissue invasive CMV disease or CMV syndrome for participants asymptomatic at baseline. Percentage of participants receiving maribavir rescue treatment who achieved confirmed CMV viremia clearance and CMV infection symptom control at Week 8 with maintenance of effect through Week 16 were reported. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs During the On-treatment Observation Period | Baseline up to 7 days or 21 days (if cidofovir used) after the last dose of study treatment (up to Week 8) | An adverse event (AE) is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. Serious AE was any untoward medical occurrence (whether considered to be related to study-assigned treatment or not) that at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, resulted in a congenital abnormality/birth defect, or was an important medical event. TEAEs was defined as any adverse events (classified by preferred term) that had a start date on or after the first dose of study treatment or that had a start date before the date of first dose of study treatment, but increased in severity after the first dose of study treatment. |
| Predose Concentration (Cmin) of Maribavir | Predose at Week 1, 4 and 8 | Cmin of maribavir was reported. |
| Area Under the Concentration Time Curve Over the 12-hour Dosing Interval at Steady State (AUC0-tau) of Marivabir for Adolescent Participants | Week 1: Pre-morning dose and 1, 2, 3, 4, 6, 8 and 12 hours post morning dose, Week 4: Pre-morning dose, and Week 8: Pre-morning dose and 2-4 hour post morning dose | AUC0-tau of maribavir for adolescent participants was planned to be reported. |
| Maximum Plasma Concentration (Cmax) of Maribavir for Adolescent Participants | Week 1: Pre-morning dose and 1, 2, 3, 4, 6, 8 and 12 hours post morning dose | Cmax of maribavir for adolescent participants was planned to be reported. |
| Time When Maximum Concentration is Observed (Tmax) of Maribavir for Adolescent Participants | Week 1: Pre-morning dose and 1, 2, 3, 4, 6, 8 and 12 hours post morning dose | Tmax of maribavir for adolescent participants was planned to be reported. |
| Apparent Oral Clearance (CL/F) of Maribavir for Adolescent Participants | Week 1: Pre-morning dose and 1, 2, 3, 4, 6, 8 and 12 hours post morning dose | Apparent oral clearance (CL/F) of maribavir for adolescent participants was planned to be reported. |
| Apparent Volume of Distribution (Vz/F) of Maribavir for Adolescent Participants | Week 1: Pre-morning dose and 1, 2, 3, 4, 6, 8 and 12 hours post morning dose | Apparent volume of distribution (Vz/F) of maribavir for adolescent participants was planned to be reported. |
| Percentage of Participants With Recurrence of CMV Viremia While Off Study-assigned Treatment During Follow-up Period | Termination of study treatment (Week 8) up to the End of the Study (Week 20) | Recurrence of CMV viremia was defined as plasma CMV DNA concentration \>=LLOQ when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test in 2 consecutive plasma samples at least 5 days apart, after achieving confirmed viremia clearance. Percentage of participants with recurrence of CMV viremia while off study-assigned treatment during follow-up period were reported. |
Countries
Australia, Austria, Belgium, Canada, Croatia, Denmark, France, Germany, Italy, Singapore, Spain, Switzerland, United Kingdom, United States
Participant flow
Recruitment details
This study was conducted at 94 sites in North America, Europe, and Asia Pacific between 22 December 2016 (first participant first visit) and 17 August 2020 (last participant last visit).
Pre-assignment details
Participants with cytomegalovirus (CMV) infections were enrolled and randomized into two treatment groups: IAT (control), and Maribavir 400 mg. Participants randomized to IAT treatment arm, if met the stringent criteria for lack of improvement/worsening of CMV infection, considered eligible for entry into Maribavir rescue arm at Week 3 based on medical monitor review. As planned, combined data has been reported for IAT control group.
Participants by arm
| Arm | Count |
|---|---|
| Investigator-assigned Anti-CMV Treatment (IAT) Participants received 1 or 2 of the 4 anti-CMV agents from the following: ganciclovir, valganciclovir, foscarnet, or cidofovir based on the investigator's discretion for the 8 week treatment period. | 117 |
| Maribavir 400 mg Participants received maribavir 400 mg (2\*200 mg tablets), orally, twice daily for the 8 week treatment period. | 235 |
| Total | 352 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Period 1: Treatment Phase | Adverse Event | 5 | 1 | 0 |
| Period 1: Treatment Phase | Death | 8 | 24 | 0 |
| Period 1: Treatment Phase | Investigator discretion | 1 | 1 | 0 |
| Period 1: Treatment Phase | Lost to Follow-up | 1 | 2 | 0 |
| Period 1: Treatment Phase | Participants transitioned into maribavir rescue arm | 22 | 0 | 0 |
| Period 1: Treatment Phase | Protocol Violation | 6 | 0 | 0 |
| Period 1: Treatment Phase | Withdrawal by Subject | 16 | 8 | 0 |
| Period 2: Maribavir Rescue Therapy | Sponsor decision | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Maribavir 400 mg | Total | Investigator-assigned Anti-CMV Treatment (IAT) |
|---|---|---|---|
| Age, Continuous | 53.8 years STANDARD_DEVIATION 13.39 | 53.0 years STANDARD_DEVIATION 13.22 | 51.5 years STANDARD_DEVIATION 12.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 14 Participants | 21 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 198 Participants | 293 Participants | 95 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 23 Participants | 38 Participants | 15 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 9 Participants | 16 Participants | 7 Participants |
| Race (NIH/OMB) Black or African American | 29 Participants | 47 Participants | 18 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 18 Participants | 23 Participants | 5 Participants |
| Race (NIH/OMB) White | 179 Participants | 266 Participants | 87 Participants |
| Sex: Female, Male Female | 87 Participants | 139 Participants | 52 Participants |
| Sex: Female, Male Male | 148 Participants | 213 Participants | 65 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 6 / 56 | 7 / 47 | 0 / 6 | 0 / 7 | 27 / 234 | 0 / 22 |
| other Total, other adverse events | 54 / 56 | 43 / 47 | 5 / 6 | 7 / 7 | 229 / 234 | 22 / 22 |
| serious Total, serious adverse events | 33 / 56 | 26 / 47 | 3 / 6 | 1 / 7 | 131 / 234 | 14 / 22 |
Outcome results
Primary
Percentage of Participants Who Achieved Confirmed Clearance of Plasma Cytomegalovirus (CMV) Deoxyribonucleic Acid (DNA) (CMV Viremia Clearance) at End of Week 8
Confirmed CMV viremia clearance was defined as plasma CMV DNA concentration less than (\<) lower limit of quantification (LLOQ) that is, \<137 International Units per milliliter (IU/mL) when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV Test in 2 consecutive postbaseline samples, separated by at least 5 days. Percentage of participants with confirmed CMV viremia clearance at end of study Week 8 regardless of whether either study-assigned treatment was discontinued before the end of the stipulated 8 weeks of therapy, and could not have received alternative anti-CMV treatment were reported.
Time frame: Week 8
Population: The randomized set consisted of all participants who had signed informed consent and had begun some study procedures and were randomized to the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Investigator-assigned Anti-CMV Treatment (IAT) | Percentage of Participants Who Achieved Confirmed Clearance of Plasma Cytomegalovirus (CMV) Deoxyribonucleic Acid (DNA) (CMV Viremia Clearance) at End of Week 8 | 23.9 percentage of participants |
| Maribavir 400 mg | Percentage of Participants Who Achieved Confirmed Clearance of Plasma Cytomegalovirus (CMV) Deoxyribonucleic Acid (DNA) (CMV Viremia Clearance) at End of Week 8 | 55.7 percentage of participants |
p-value: <0.00195% CI: [22.8, 42.74]Cochran-Mantel-Haenszel
Secondary
Apparent Oral Clearance (CL/F) of Maribavir for Adolescent Participants
Apparent oral clearance (CL/F) of maribavir for adolescent participants was planned to be reported.
Time frame: Week 1: Pre-morning dose and 1, 2, 3, 4, 6, 8 and 12 hours post morning dose
Population: The pharmacokinetic set consisted of all participants who had taken any dose of study treatment and who had plasma samples drawn and tested for maribavir concentrations. This OM was planned to be analyzed only in adolescent participants. Data was not collected and analyzed as adolescent participants were not enrolled in this study. Here overall number of participants analyzed were participants who were evaluable for this outcome measure.
Secondary
Apparent Volume of Distribution (Vz/F) of Maribavir for Adolescent Participants
Apparent volume of distribution (Vz/F) of maribavir for adolescent participants was planned to be reported.
Time frame: Week 1: Pre-morning dose and 1, 2, 3, 4, 6, 8 and 12 hours post morning dose
Population: The pharmacokinetic set consisted of all participants who had taken any dose of study treatment and who had plasma samples drawn and tested for maribavir concentrations. This OM was planned to be analyzed only in adolescent participants. Data was not collected and analyzed as adolescent participants were not enrolled in this study. Here overall number of participants analyzed were participants who were evaluable for this outcome measure.
Secondary
Area Under the Concentration Time Curve Over the 12-hour Dosing Interval at Steady State (AUC0-tau) of Marivabir for Adolescent Participants
AUC0-tau of maribavir for adolescent participants was planned to be reported.
Time frame: Week 1: Pre-morning dose and 1, 2, 3, 4, 6, 8 and 12 hours post morning dose, Week 4: Pre-morning dose, and Week 8: Pre-morning dose and 2-4 hour post morning dose
Population: The pharmacokinetic set consisted of all participants who had taken any dose of study treatment and who had plasma samples drawn and tested for maribavir concentrations. This OM was planned to be analyzed only in adolescent participants. Data was not collected and analyzed as adolescent participants were not enrolled in this study. Here overall number of participants analyzed were participants who were evaluable for this outcome measure.
Secondary
Maximum Plasma Concentration (Cmax) of Maribavir for Adolescent Participants
Cmax of maribavir for adolescent participants was planned to be reported.
Time frame: Week 1: Pre-morning dose and 1, 2, 3, 4, 6, 8 and 12 hours post morning dose
Population: The pharmacokinetic set consisted of all participants who had taken any dose of study treatment and who had plasma samples drawn and tested for maribavir concentrations. This OM was planned to be analyzed only in adolescent participants. Data was not collected and analyzed as adolescent participants were not enrolled in this study. Here overall number of participants analyzed were participants who were evaluable for this outcome measure.
Secondary
Number of Participants Who Had Maribavir CMV Resistance at Baseline
Resistance-associated amino acid substitutions (RASs) to maribavir are known to generally map to the pUL97 and pUL27 genes. Genotyping was performed to identify RASs mapping to the pUL97 and pUL27 genes. Number of participants who had maribavir CMV resistance at baseline were reported.
Time frame: At Baseline
Population: The combination of maribavir resistance set (MRS) and non-MRS set (MRS+non-MRS) included all participants in modified randomized set who had been randomized in the study and who had taken any dose of study-assigned treatment with evaluable CMV genotypic data at baseline with or without pre-existing known maribavir RASs in pUL97 and/or pUL27. Here overall number of participants analyzed were participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Investigator-assigned Anti-CMV Treatment (IAT) | Number of Participants Who Had Maribavir CMV Resistance at Baseline | RASs associated with pUL27 only | 0 Participants |
| Investigator-assigned Anti-CMV Treatment (IAT) | Number of Participants Who Had Maribavir CMV Resistance at Baseline | RASs associated with pUL97 only | 3 Participants |
| Investigator-assigned Anti-CMV Treatment (IAT) | Number of Participants Who Had Maribavir CMV Resistance at Baseline | RASs associated with pUL97 and pUL27 | 0 Participants |
| Maribavir 400 mg | Number of Participants Who Had Maribavir CMV Resistance at Baseline | RASs associated with pUL27 only | 0 Participants |
| Maribavir 400 mg | Number of Participants Who Had Maribavir CMV Resistance at Baseline | RASs associated with pUL97 only | 1 Participants |
| Maribavir 400 mg | Number of Participants Who Had Maribavir CMV Resistance at Baseline | RASs associated with pUL97 and pUL27 | 0 Participants |
| Maribavir 400 mg | Number of Participants Who Had Maribavir CMV Resistance at Baseline | RASs associated with pUL97 only | 0 Participants |
| Maribavir 400 mg | Number of Participants Who Had Maribavir CMV Resistance at Baseline | RASs associated with pUL97 and pUL27 | 0 Participants |
| Maribavir 400 mg | Number of Participants Who Had Maribavir CMV Resistance at Baseline | RASs associated with pUL27 only | 1 Participants |
Secondary
Number of Participants Who Had Post-baseline Resistance to Maribavir
Resistance-associated amino acid substitutions (RASs) to maribavir are known to generally map to the pUL97 and pUL27 genes. Genotyping was performed to identify RASs mapping to the pUL97 and pUL27 genes. Number of participants who had post-baseline resistance to maribavir were reported.
Time frame: After first dose of study drug up to Week 20
Population: The combination of maribavir resistance set (MRS) and non-MRS set (MRS+non-MRS) included all participants in modified randomized set who had been randomized in the study and who had taken any dose of study-assigned treatment with evaluable CMV genotypic data at baseline with or without pre-existing known maribavir RASs in pUL97 and/or pUL27.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Investigator-assigned Anti-CMV Treatment (IAT) | Number of Participants Who Had Post-baseline Resistance to Maribavir | RASs associated with pUL27 only | 0 Participants |
| Investigator-assigned Anti-CMV Treatment (IAT) | Number of Participants Who Had Post-baseline Resistance to Maribavir | RASs associated with pUL97 only | 0 Participants |
| Investigator-assigned Anti-CMV Treatment (IAT) | Number of Participants Who Had Post-baseline Resistance to Maribavir | RASs associated with pUL97 and pUL27 | 0 Participants |
| Maribavir 400 mg | Number of Participants Who Had Post-baseline Resistance to Maribavir | RASs associated with pUL27 only | 0 Participants |
| Maribavir 400 mg | Number of Participants Who Had Post-baseline Resistance to Maribavir | RASs associated with pUL97 only | 4 Participants |
| Maribavir 400 mg | Number of Participants Who Had Post-baseline Resistance to Maribavir | RASs associated with pUL97 and pUL27 | 0 Participants |
| Maribavir 400 mg | Number of Participants Who Had Post-baseline Resistance to Maribavir | RASs associated with pUL97 only | 45 Participants |
| Maribavir 400 mg | Number of Participants Who Had Post-baseline Resistance to Maribavir | RASs associated with pUL97 and pUL27 | 0 Participants |
| Maribavir 400 mg | Number of Participants Who Had Post-baseline Resistance to Maribavir | RASs associated with pUL27 only | 0 Participants |
Secondary
Number of Participants With All-cause Mortality by the End of the Study
All-cause mortality was analyzed by the end of study regardless of the use of rescue treatment or alternative anti-CMV treatment. Number of participants who died during the entire study period were reported.
Time frame: From enrollment up to end of study (approximately 44 months)
Population: The randomized set consisted of all participants who had signed informed consent and had begun some study procedures and were randomized to the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Investigator-assigned Anti-CMV Treatment (IAT) | Number of Participants With All-cause Mortality by the End of the Study | 13 Participants |
| Maribavir 400 mg | Number of Participants With All-cause Mortality by the End of the Study | 27 Participants |
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs During the On-treatment Observation Period
An adverse event (AE) is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. Serious AE was any untoward medical occurrence (whether considered to be related to study-assigned treatment or not) that at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, resulted in a congenital abnormality/birth defect, or was an important medical event. TEAEs was defined as any adverse events (classified by preferred term) that had a start date on or after the first dose of study treatment or that had a start date before the date of first dose of study treatment, but increased in severity after the first dose of study treatment.
Time frame: Baseline up to 7 days or 21 days (if cidofovir used) after the last dose of study treatment (up to Week 8)
Population: The safety set consisted of all participants who had taken any dose of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Investigator-assigned Anti-CMV Treatment (IAT) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs During the On-treatment Observation Period | TEAEs | 106 Participants |
| Investigator-assigned Anti-CMV Treatment (IAT) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs During the On-treatment Observation Period | Serious TEAEs | 43 Participants |
| Maribavir 400 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs During the On-treatment Observation Period | TEAEs | 22 Participants |
| Maribavir 400 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs During the On-treatment Observation Period | Serious TEAEs | 11 Participants |
| Maribavir 400 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs During the On-treatment Observation Period | TEAEs | 228 Participants |
| Maribavir 400 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs During the On-treatment Observation Period | Serious TEAEs | 90 Participants |
Secondary
Percentage of Participants Receiving Maribavir Rescue Treatment Who Achieved Confirmed CMV Viremia Clearance and CMV Infection Symptom Control at Week 8 With Maintenance of Effect Through Week 16
Confirmed CMV viremia clearance was defined as plasma CMV DNA concentration \<LLOQ that is, \<137 IU/mL when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test in 2 consecutive postbaseline samples, separated by at least 5 days. CMV infection symptom control was defined as resolution or improvement of tissue invasive CMV disease or CMV syndrome for participants symptomatic at baseline, or maintaining no symptoms of tissue invasive CMV disease or CMV syndrome for participants asymptomatic at baseline. Percentage of participants receiving maribavir rescue treatment who achieved confirmed CMV viremia clearance and CMV infection symptom control at Week 8 with maintenance of effect through Week 16 were reported.
Time frame: Up to Week 16
Population: The rescue set consisted of all participants who entered the rescue arm and received any dose of maribavir as rescue therapy. As planned, this OM was assessed only in maribavir rescue arm.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Investigator-assigned Anti-CMV Treatment (IAT) | Percentage of Participants Receiving Maribavir Rescue Treatment Who Achieved Confirmed CMV Viremia Clearance and CMV Infection Symptom Control at Week 8 With Maintenance of Effect Through Week 16 | 27.3 percentage of participants |
Secondary
Percentage of Participants Who Achieved Confirmed Clearance of Plasma CMV DNA (CMV Viremia Clearance) at End of Week 8 After Starting Maribavir Rescue Treatment
Confirmed CMV viremia clearance was defined as plasma CMV DNA concentration \<LLOQ that is, \<137 IU/mL when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV Test in 2 consecutive postbaseline samples, separated by at least 5 days, regardless of whether the rescue treatment was discontinued before the end of the stipulated 8 weeks of therapy. Percentage of participants who achieved confirmed CMV viremia clearance at end of Week 8 after starting maribavir rescue treatment were reported.
Time frame: From start of maribavir rescue treatment through 8 weeks
Population: The rescue set consisted of all participants who entered the rescue arm and received any dose of maribavir as rescue therapy. As planned, this OM was assessed only in maribavir rescue arm.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Investigator-assigned Anti-CMV Treatment (IAT) | Percentage of Participants Who Achieved Confirmed Clearance of Plasma CMV DNA (CMV Viremia Clearance) at End of Week 8 After Starting Maribavir Rescue Treatment | 50.0 percentage of participants |
Secondary
Percentage of Participants Who Achieved Confirmed CMV Viremia Clearance After Receiving 8 Weeks of Study-assigned Treatment
Confirmed CMV viremia clearance was defined as plasma CMV DNA concentration \<LLOQ that is, \<137IU/mL when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test in 2 consecutive postbaseline samples, separated by at least 5 days. Percentage of participants who achieved confirmed CMV viremia clearance after receiving 8 weeks study-assigned treatment at end of Week 8, and maintained this effect through 12, 16 and 20 were reported.
Time frame: At Week 8 through Weeks 12, 16 and 20
Population: The randomized set consisted of all participants who had signed informed consent and had begun some study procedures and were randomized to the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Investigator-assigned Anti-CMV Treatment (IAT) | Percentage of Participants Who Achieved Confirmed CMV Viremia Clearance After Receiving 8 Weeks of Study-assigned Treatment | At Week 8 | 18.8 percentage of participants |
| Investigator-assigned Anti-CMV Treatment (IAT) | Percentage of Participants Who Achieved Confirmed CMV Viremia Clearance After Receiving 8 Weeks of Study-assigned Treatment | At Week 12 | 5.1 percentage of participants |
| Investigator-assigned Anti-CMV Treatment (IAT) | Percentage of Participants Who Achieved Confirmed CMV Viremia Clearance After Receiving 8 Weeks of Study-assigned Treatment | At Week 16 | 5.1 percentage of participants |
| Investigator-assigned Anti-CMV Treatment (IAT) | Percentage of Participants Who Achieved Confirmed CMV Viremia Clearance After Receiving 8 Weeks of Study-assigned Treatment | At Week 20 | 4.3 percentage of participants |
| Maribavir 400 mg | Percentage of Participants Who Achieved Confirmed CMV Viremia Clearance After Receiving 8 Weeks of Study-assigned Treatment | At Week 20 | 18.3 percentage of participants |
| Maribavir 400 mg | Percentage of Participants Who Achieved Confirmed CMV Viremia Clearance After Receiving 8 Weeks of Study-assigned Treatment | At Week 8 | 54.9 percentage of participants |
| Maribavir 400 mg | Percentage of Participants Who Achieved Confirmed CMV Viremia Clearance After Receiving 8 Weeks of Study-assigned Treatment | At Week 16 | 18.7 percentage of participants |
| Maribavir 400 mg | Percentage of Participants Who Achieved Confirmed CMV Viremia Clearance After Receiving 8 Weeks of Study-assigned Treatment | At Week 12 | 22.6 percentage of participants |
Secondary
Percentage of Participants Who Achieved Confirmed CMV Viremia Clearance and CMV Infection Symptom Control After Receiving 8 Weeks of Study-assigned Treatment Through Weeks 12, 16 and 20
Confirmed CMV viremia clearance was defined as plasma CMV DNA concentration \<LLOQ that is, \<137IU/mL when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test in 2 consecutive postbaseline samples, separated by at least 5 days. CMV infection symptom control was defined as resolution or improvement of tissue invasive CMV disease or CMV syndrome for participants symptomatic at baseline, or maintaining no symptoms of tissue invasive CMV disease or CMV syndrome for participants asymptomatic at baseline. Percentage of participants who achieved confirmed CMV viremia clearance and CMV infection control after receiving 8 weeks study-assigned treatment at end of Week 8, and maintained this effect through 12, 16 and 20 were reported.
Time frame: At Week 8 through Weeks 12, 16 and 20
Population: The randomized set consisted of all participants who had signed informed consent and had begun some study procedures and were randomized to the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Investigator-assigned Anti-CMV Treatment (IAT) | Percentage of Participants Who Achieved Confirmed CMV Viremia Clearance and CMV Infection Symptom Control After Receiving 8 Weeks of Study-assigned Treatment Through Weeks 12, 16 and 20 | At Week 16 | 5.1 percentage of participants |
| Investigator-assigned Anti-CMV Treatment (IAT) | Percentage of Participants Who Achieved Confirmed CMV Viremia Clearance and CMV Infection Symptom Control After Receiving 8 Weeks of Study-assigned Treatment Through Weeks 12, 16 and 20 | At Week 12 | 5.1 percentage of participants |
| Investigator-assigned Anti-CMV Treatment (IAT) | Percentage of Participants Who Achieved Confirmed CMV Viremia Clearance and CMV Infection Symptom Control After Receiving 8 Weeks of Study-assigned Treatment Through Weeks 12, 16 and 20 | At Week 20 | 4.3 percentage of participants |
| Investigator-assigned Anti-CMV Treatment (IAT) | Percentage of Participants Who Achieved Confirmed CMV Viremia Clearance and CMV Infection Symptom Control After Receiving 8 Weeks of Study-assigned Treatment Through Weeks 12, 16 and 20 | At Week 8 | 18.8 percentage of participants |
| Maribavir 400 mg | Percentage of Participants Who Achieved Confirmed CMV Viremia Clearance and CMV Infection Symptom Control After Receiving 8 Weeks of Study-assigned Treatment Through Weeks 12, 16 and 20 | At Week 20 | 18.3 percentage of participants |
| Maribavir 400 mg | Percentage of Participants Who Achieved Confirmed CMV Viremia Clearance and CMV Infection Symptom Control After Receiving 8 Weeks of Study-assigned Treatment Through Weeks 12, 16 and 20 | At Week 8 | 54.9 percentage of participants |
| Maribavir 400 mg | Percentage of Participants Who Achieved Confirmed CMV Viremia Clearance and CMV Infection Symptom Control After Receiving 8 Weeks of Study-assigned Treatment Through Weeks 12, 16 and 20 | At Week 16 | 18.7 percentage of participants |
| Maribavir 400 mg | Percentage of Participants Who Achieved Confirmed CMV Viremia Clearance and CMV Infection Symptom Control After Receiving 8 Weeks of Study-assigned Treatment Through Weeks 12, 16 and 20 | At Week 12 | 22.6 percentage of participants |
Secondary
Percentage of Participants Who Achieved Confirmed CMV Viremia Clearance and CMV Infection Symptom Control at End of Week 8, Followed by Maintenance of Treatment Effect at Week 16
Confirmed CMV viremia clearance was defined as plasma CMV DNA concentration \<LLOQ that is, \<137 IU/mL when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test in 2 consecutive postbaseline samples, separated by at least 5 days. CMV infection symptom control was defined as resolution or improvement of tissue invasive CMV disease or CMV syndrome for participants symptomatic at baseline, or maintaining no symptoms of tissue invasive CMV disease or CMV syndrome for participants asymptomatic at baseline. Percentage of participants who achieved CMV viremia clearance and CMV infection symptom control at end of Week 8 through Week 16 were reported.
Time frame: Up to Week 16
Population: The randomized set consisted of all participants who had signed informed consent and had begun some study procedures and were randomized to the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Investigator-assigned Anti-CMV Treatment (IAT) | Percentage of Participants Who Achieved Confirmed CMV Viremia Clearance and CMV Infection Symptom Control at End of Week 8, Followed by Maintenance of Treatment Effect at Week 16 | 10.3 percentage of participants |
| Maribavir 400 mg | Percentage of Participants Who Achieved Confirmed CMV Viremia Clearance and CMV Infection Symptom Control at End of Week 8, Followed by Maintenance of Treatment Effect at Week 16 | 18.7 percentage of participants |
p-value: 0.01395% CI: [2.02, 16.88]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Who Completed 8 Weeks of Study-assigned Treatment With Recurrence of CMV Viremia During the 12 Weeks of Follow-up Period
Recurrence of CMV viremia was defined as plasma CMV DNA concentration \>=LLOQ when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test in 2 consecutive plasma samples at least 5 days apart, after achieving confirmed viremia clearance. Percentage of participants who completed 8 weeks of study-assigned treatment with recurrence of CMV viremia during the 12 weeks of follow-up period were reported.
Time frame: End of Week 8 up to Week 20 (12 weeks follow-up period)
Population: The randomized set consisted of all participants who had signed informed consent and had begun some study procedures and were randomized to the study. Here overall number of participants analyzed were participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Investigator-assigned Anti-CMV Treatment (IAT) | Percentage of Participants Who Completed 8 Weeks of Study-assigned Treatment With Recurrence of CMV Viremia During the 12 Weeks of Follow-up Period | 35.5 percentage of participants |
| Maribavir 400 mg | Percentage of Participants Who Completed 8 Weeks of Study-assigned Treatment With Recurrence of CMV Viremia During the 12 Weeks of Follow-up Period | 40.9 percentage of participants |
Secondary
Percentage of Participants Who Completed 8 Weeks of Study-assigned Treatment With Recurrence of CMV Viremia During the 20 Weeks of Study
Recurrence of CMV viremia was defined as plasma CMV DNA concentration \>=LLOQ when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test in 2 consecutive plasma samples at least 5 days apart, after achieving confirmed viremia clearance. Percentage of participants with Recurrence of CMV viremia was defined as plasma CMV DNA concentration \>=LLOQ when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test in 2 consecutive plasma samples at least 5 days apart, after achieving confirmed viremia clearance. Percentage of participants who completed 8 weeks of study-assigned treatment with recurrence of CMV viremia during the 20 weeks of study were reported.
Time frame: Baseline up to Week 20
Population: The randomized set consisted of all participants who had signed informed consent and had begun some study procedures and were randomized to the study. Here overall number of participants analyzed were participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Investigator-assigned Anti-CMV Treatment (IAT) | Percentage of Participants Who Completed 8 Weeks of Study-assigned Treatment With Recurrence of CMV Viremia During the 20 Weeks of Study | 45.2 percentage of participants |
| Maribavir 400 mg | Percentage of Participants Who Completed 8 Weeks of Study-assigned Treatment With Recurrence of CMV Viremia During the 20 Weeks of Study | 56.1 percentage of participants |
Secondary
Percentage of Participants Who Completed 8 Weeks of Study-assigned Treatment With Recurrence of CMV Viremia During the First 8 Weeks of the Treatment
Recurrence of CMV viremia was defined as plasma CMV DNA concentration \>=LLOQ when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test in 2 consecutive plasma samples at least 5 days apart, after achieving confirmed viremia clearance. Percentage of participants with recurrence of CMV viremia during the first 8 Weeks of the treatment who completed 8 weeks of study-assigned treatment were reported.
Time frame: Baseline up to Week 8
Population: The randomized set consisted of all participants who had signed informed consent and had begun some study procedures and were randomized to the study. Here overall number of participants analyzed were participants who were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Investigator-assigned Anti-CMV Treatment (IAT) | Percentage of Participants Who Completed 8 Weeks of Study-assigned Treatment With Recurrence of CMV Viremia During the First 8 Weeks of the Treatment | 9.7 percentage of participants |
| Maribavir 400 mg | Percentage of Participants Who Completed 8 Weeks of Study-assigned Treatment With Recurrence of CMV Viremia During the First 8 Weeks of the Treatment | 15.2 percentage of participants |
Secondary
Percentage of Participants Who Maintained CMV Viremia Clearance and CMV Infection Symptom Control at the End of Study Week 8 Through Weeks 12 and 20 Regardless of Whether Either Study-assigned Treatment Was Discontinued Before 8 Weeks of Therapy
Confirmed CMV viremia clearance was defined as plasma CMV DNA concentration \<LLOQ that is, \<137IU/mL when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test in 2 consecutive postbaseline samples, separated by at least 5 days. CMV infection symptom control was defined as resolution or improvement of tissue invasive CMV disease or CMV syndrome for participants symptomatic at baseline or maintaining no symptoms of tissue invasive CMV disease or CMV syndrome for participants asymptomatic at baseline. Percentage of participants who maintained CMV viremia clearance and CMV infection symptom control at the end of study Week 8 through Weeks 12 and 20 regardless of whether either study-assigned treatment was discontinued before 8 weeks of therapy were reported.
Time frame: At Week 8 through Weeks 12 and 20
Population: The randomized set consisted of all participants who had signed informed consent and had begun some study procedures and were randomized to the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Investigator-assigned Anti-CMV Treatment (IAT) | Percentage of Participants Who Maintained CMV Viremia Clearance and CMV Infection Symptom Control at the End of Study Week 8 Through Weeks 12 and 20 Regardless of Whether Either Study-assigned Treatment Was Discontinued Before 8 Weeks of Therapy | At Week 8 | 23.9 percentage of participants |
| Investigator-assigned Anti-CMV Treatment (IAT) | Percentage of Participants Who Maintained CMV Viremia Clearance and CMV Infection Symptom Control at the End of Study Week 8 Through Weeks 12 and 20 Regardless of Whether Either Study-assigned Treatment Was Discontinued Before 8 Weeks of Therapy | At Week 12 | 10.3 percentage of participants |
| Investigator-assigned Anti-CMV Treatment (IAT) | Percentage of Participants Who Maintained CMV Viremia Clearance and CMV Infection Symptom Control at the End of Study Week 8 Through Weeks 12 and 20 Regardless of Whether Either Study-assigned Treatment Was Discontinued Before 8 Weeks of Therapy | At Week 20 | 9.4 percentage of participants |
| Maribavir 400 mg | Percentage of Participants Who Maintained CMV Viremia Clearance and CMV Infection Symptom Control at the End of Study Week 8 Through Weeks 12 and 20 Regardless of Whether Either Study-assigned Treatment Was Discontinued Before 8 Weeks of Therapy | At Week 8 | 55.7 percentage of participants |
| Maribavir 400 mg | Percentage of Participants Who Maintained CMV Viremia Clearance and CMV Infection Symptom Control at the End of Study Week 8 Through Weeks 12 and 20 Regardless of Whether Either Study-assigned Treatment Was Discontinued Before 8 Weeks of Therapy | At Week 12 | 22.6 percentage of participants |
| Maribavir 400 mg | Percentage of Participants Who Maintained CMV Viremia Clearance and CMV Infection Symptom Control at the End of Study Week 8 Through Weeks 12 and 20 Regardless of Whether Either Study-assigned Treatment Was Discontinued Before 8 Weeks of Therapy | At Week 20 | 18.3 percentage of participants |
Secondary
Percentage of Participants With Recurrence of CMV Viremia at Any Time on Study Regardless of Whether Study-assigned Treatment Was Discontinued Before 8 Weeks of Therapy
Recurrence of CMV viremia was defined as plasma CMV DNA concentration \>=LLOQ when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test in 2 consecutive plasma samples at least 5 days apart, after achieving confirmed viremia clearance, regardless of whether either study-assigned treatment was discontinued before the end of the stipulated 8 weeks of therapy. Percentage of participants with recurrence of CMV viremia during at any time on study regardless of whether study-assigned treatment was discontinued before 8 weeks of therapy were reported.
Time frame: Baseline up to Week 20
Population: The randomized set consisted of all participants who had signed informed consent and had begun some study procedures and were randomized to the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Investigator-assigned Anti-CMV Treatment (IAT) | Percentage of Participants With Recurrence of CMV Viremia at Any Time on Study Regardless of Whether Study-assigned Treatment Was Discontinued Before 8 Weeks of Therapy | 33.8 percentage of participants |
| Maribavir 400 mg | Percentage of Participants With Recurrence of CMV Viremia at Any Time on Study Regardless of Whether Study-assigned Treatment Was Discontinued Before 8 Weeks of Therapy | 56.5 percentage of participants |
Secondary
Percentage of Participants With Recurrence of CMV Viremia During the 12 Weeks Follow-up Period Regardless of Whether Study-assigned Treatment Was Discontinued Before 8 Weeks of Therapy
Recurrence of CMV viremia was defined as plasma CMV DNA concentration \>=LLOQ when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test in 2 consecutive plasma samples at least 5 days apart, after achieving confirmed viremia clearance, regardless of whether either study-assigned treatment was discontinued before the end of the stipulated 8 weeks of therapy. Percentage of participants with recurrence of CMV viremia during the 12 weeks follow-up period regardless of whether study-assigned treatment was discontinued before 8 weeks of therapy were reported.
Time frame: End of Week 8 up to Week 20 (12 weeks follow-up period)
Population: The randomized set consisted of all participants who had signed informed consent and had begun some study procedures and were randomized to the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Investigator-assigned Anti-CMV Treatment (IAT) | Percentage of Participants With Recurrence of CMV Viremia During the 12 Weeks Follow-up Period Regardless of Whether Study-assigned Treatment Was Discontinued Before 8 Weeks of Therapy | 21.5 percentage of participants |
| Maribavir 400 mg | Percentage of Participants With Recurrence of CMV Viremia During the 12 Weeks Follow-up Period Regardless of Whether Study-assigned Treatment Was Discontinued Before 8 Weeks of Therapy | 38.6 percentage of participants |
Secondary
Percentage of Participants With Recurrence of CMV Viremia During the First 8 Weeks of Study Regardless of Whether Study-assigned Treatment Was Discontinued Before 8 Weeks of Therapy
Recurrence of CMV viremia was defined as plasma CMV DNA concentration greater than or equal to (\>=) LLOQ when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test in 2 consecutive plasma samples at least 5 days apart, after achieving confirmed viremia clearance, regardless of whether either study-assigned treatment was discontinued before the end of the stipulated 8 weeks of therapy. Percentage of participants with recurrence of CMV viremia during the first 8 weeks of study regardless of whether study-assigned treatment was discontinued before 8 weeks of therapy were reported.
Time frame: At Week 8
Population: The randomized set consisted of all participants who had signed informed consent and had begun some study procedures and were randomized to the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Investigator-assigned Anti-CMV Treatment (IAT) | Percentage of Participants With Recurrence of CMV Viremia During the First 8 Weeks of Study Regardless of Whether Study-assigned Treatment Was Discontinued Before 8 Weeks of Therapy | 12.3 percentage of participants |
| Maribavir 400 mg | Percentage of Participants With Recurrence of CMV Viremia During the First 8 Weeks of Study Regardless of Whether Study-assigned Treatment Was Discontinued Before 8 Weeks of Therapy | 17.9 percentage of participants |
Secondary
Percentage of Participants With Recurrence of CMV Viremia While Off Study-assigned Treatment During Follow-up Period
Recurrence of CMV viremia was defined as plasma CMV DNA concentration \>=LLOQ when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test in 2 consecutive plasma samples at least 5 days apart, after achieving confirmed viremia clearance. Percentage of participants with recurrence of CMV viremia while off study-assigned treatment during follow-up period were reported.
Time frame: Termination of study treatment (Week 8) up to the End of the Study (Week 20)
Population: The randomized set consisted of all participants who had signed informed consent and had begun some study procedures and were randomized to the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Investigator-assigned Anti-CMV Treatment (IAT) | Percentage of Participants With Recurrence of CMV Viremia While Off Study-assigned Treatment During Follow-up Period | 29.2 percentage of participants |
| Maribavir 400 mg | Percentage of Participants With Recurrence of CMV Viremia While Off Study-assigned Treatment During Follow-up Period | 40.8 percentage of participants |
Secondary
Percentage of Participants With Recurrence of CMV Viremia While on Study-assigned Treatment
Recurrence of CMV viremia was defined as plasma CMV DNA concentration \>=LLOQ when assessed by COBAS® AmpliPrep/COBAS® TaqMan® CMV test in 2 consecutive plasma samples at least 5 days apart, after achieving confirmed viremia clearance. Percentage of participants with recurrence of CMV viremia while on study-assigned treatment period were reported.
Time frame: Baseline up to termination of study treatment (up to Week 8)
Population: The randomized set consisted of all participants who had signed informed consent and had begun some study procedures and were randomized to the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Investigator-assigned Anti-CMV Treatment (IAT) | Percentage of Participants With Recurrence of CMV Viremia While on Study-assigned Treatment | 4.6 percentage of participants |
| Maribavir 400 mg | Percentage of Participants With Recurrence of CMV Viremia While on Study-assigned Treatment | 15.8 percentage of participants |
Secondary
Predose Concentration (Cmin) of Maribavir
Cmin of maribavir was reported.
Time frame: Predose at Week 1, 4 and 8
Population: The pharmacokinetic set consisted of all participants who had taken any dose of study treatment and who had plasma samples drawn and tested for maribavir concentrations. Here overall number of participants analyzed were participants who were evaluable for this outcome measure and number analyzed were participants who were evaluable for the outcome measure at given time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Investigator-assigned Anti-CMV Treatment (IAT) | Predose Concentration (Cmin) of Maribavir | Cmin at Week 1 | 8.77 micrograms per milliliter (mcg/mL) | Standard Deviation 7.88 |
| Investigator-assigned Anti-CMV Treatment (IAT) | Predose Concentration (Cmin) of Maribavir | Cmin at Week 4 | 7.59 micrograms per milliliter (mcg/mL) | Standard Deviation 7.05 |
| Investigator-assigned Anti-CMV Treatment (IAT) | Predose Concentration (Cmin) of Maribavir | Cmin at Week 8 | 7.19 micrograms per milliliter (mcg/mL) | Standard Deviation 6.41 |
| Maribavir 400 mg | Predose Concentration (Cmin) of Maribavir | Cmin at Week 8 | 5.65 micrograms per milliliter (mcg/mL) | Standard Deviation 4.47 |
| Maribavir 400 mg | Predose Concentration (Cmin) of Maribavir | Cmin at Week 1 | 8.57 micrograms per milliliter (mcg/mL) | Standard Deviation 6.28 |
| Maribavir 400 mg | Predose Concentration (Cmin) of Maribavir | Cmin at Week 4 | 5.75 micrograms per milliliter (mcg/mL) | Standard Deviation 3.99 |
Secondary
Time to All Cause Mortality
The time to all-cause mortality by the end of the study participation in days was calculated. Participants who were alive at the last study follow-up (regardless of use of rescue or alternative anti-CMV treatment), withdrew from study or were lost to follow-up were censored at the date of last contact.
Time frame: From enrollment to last serious adverse event (SAE) follow-up (approximately Week 28)
Population: The randomized set consisted of all participants who had signed informed consent and had begun some study procedures and were randomized to the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Investigator-assigned Anti-CMV Treatment (IAT) | Time to All Cause Mortality | 73.0 days |
| Maribavir 400 mg | Time to All Cause Mortality | 55.0 days |
p-value: 0.64795% CI: [0.549, 2.357]Log Rank
Secondary
Time When Maximum Concentration is Observed (Tmax) of Maribavir for Adolescent Participants
Tmax of maribavir for adolescent participants was planned to be reported.
Time frame: Week 1: Pre-morning dose and 1, 2, 3, 4, 6, 8 and 12 hours post morning dose
Population: The pharmacokinetic set consisted of all participants who had taken any dose of study treatment and who had plasma samples drawn and tested for maribavir concentrations. This OM was planned to be analyzed only in adolescent participants. Data was not collected and analyzed as adolescent participants were not enrolled in this study. Here overall number of participants analyzed were participants who were evaluable for this outcome measure.