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Efficacy and Safety Study of Maribavir Treatment Compared to Investigator-assigned Treatment in Transplant Recipients With Cytomegalovirus (CMV) Infections That Are Refractory or Resistant to Treatment With Ganciclovir, Valganciclovir, Foscarnet, or Cidofovir

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ClinicalTrials.gov Identifier: NCT02931539
Recruitment Status : Completed
First Posted : October 13, 2016
Results First Posted : September 23, 2021
Last Update Posted : November 3, 2021
Sponsor:
Information provided by (Responsible Party):
Takeda ( Shire )

Tracking Information
First Submitted Date  ICMJE September 29, 2016
First Posted Date  ICMJE October 13, 2016
Results First Submitted Date  ICMJE August 9, 2021
Results First Posted Date  ICMJE September 23, 2021
Last Update Posted Date November 3, 2021
Actual Study Start Date  ICMJE December 22, 2016
Actual Primary Completion Date August 17, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 22, 2021)
Percentage of Participants Who Achieved Confirmed Clearance of Plasma Cytomegalovirus (CMV) Deoxyribonucleic Acid (DNA) (CMV Viremia Clearance) at End of Week 8 [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: October 10, 2016)
To compare the efficacy of maribavir to investigator-assigned anti-CMV therapy in CMV viremia clearance as measured by plasma CMV DNA concentration, at the end of the study treatment period [ Time Frame: Week 0 to week 8 ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 22, 2021)
  • 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.
  • 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.
  • Percentage of Participants With Recurrence of CMV Viremia While Off Study-assigned Treatment During Follow-up Period [ Time Frame: 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.
  • Number of Participants Who Had Maribavir CMV Resistance at Baseline [ Time Frame: 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 [ Time Frame: 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.
  • Number of Participants With All-cause Mortality by the End of the Study [ Time Frame: 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.
  • Time to All Cause Mortality [ Time Frame: 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 Achieved Confirmed Clearance of Plasma CMV DNA (CMV Viremia Clearance) at End of Week 8 After Starting Maribavir Rescue Treatment [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ 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 ]
    AUC0-tau of maribavir for adolescent participants was planned to be reported.
  • Maximum Plasma Concentration (Cmax) of Maribavir for Adolescent Participants [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: October 10, 2016)
  • CMV viremia clearance, resolution/improvement of tissue invasive CMV disease if present at baseline and no new onset of tissue invasive CMV disease in patients asymptomatic at baseline, at the end of the study treatment and the follow up [ Time Frame: Week 0 to week 8 and then to 16 ]
  • Assess the maintenance of CMV viremia clearance reached at the end of study treatment, in study treatment arms [ Time Frame: Week 8 to week 12, 16 or 20 ]
  • Assess the maintenance of first achieved viremia clearance, irrespective of the duration of the study treatment [ Time Frame: Week 0 to week 8 ]
  • Maintenance of CMV viremia clearance and resolution/improvement of tissue invasive CMV disease if present at baseline, and no new onset of tissue invasive CMV disease in patients asymptomatic at baseline, off treatment [ Time Frame: Week 8 to week 12 or 20 ]
  • Participant incidence of recurrence of CMV viremia in the two study treatment arms while on study treatment (on treatment) [ Time Frame: Week 0 to week 8 ]
  • Participant incidence of recurrence of CMV viremia in the two study treatment arms in the period after the end of study treatment (off treatment) [ Time Frame: Week 8 to Week 20 ]
  • Profile of mutations in the CMV genes conferring resistance to maribavir [ Time Frame: Week 0 to week 20 ]
  • Participant all-cause mortality [ Time Frame: Week 0 to week 20 ]
  • Assess the efficacy of maribavir administered as the rescue treatment on CMV viremia clearance as measured by plasma CMV DNA concentration, at the end of the study treatment period [ Time Frame: Throughout 8 weeks from the entry into maribavir rescue arm ]
  • CMV viremia clearance, resolution/improvement of tissue invasive CMV disease if present at baseline and no new onset of disease in patients asymptomatic at baseline, at the end of the study treatment and the follow up in maribavir rescue arm [ Time Frame: Throughout 8 weeks from the entry into maribavir rescue arm to 8 weeks of follow-up ]
  • Participant safety and tolerability of maribavir measured by treatment-emergent adverse events (TEAEs) and treatment-emergent SAEs, overall study AEs and overall study SAEs [ Time Frame: Week 0 to week 20 ]
  • Pharmacokinetics (PK) of maribavir based on sparse sampling as measured by area under the curve (AUC) [ Time Frame: Week 1 to week 8 ]
  • Participant change from baseline in vital signs [ Time Frame: Baseline to week 20 ]
  • Participant change from baseline in clinical laboratory tests [ Time Frame: Baseline to week 20 ]
  • Participant summary of abnormal findings from physical examination [ Time Frame: Baseline to week 20 ]
  • Participant change from baseline in ECG assessment [ Time Frame: Baseline to week 20 ]
  • Change from baseline in the number of participants that require treatment with hemopoietic growth factors [ Time Frame: Baseline to week 20 ]
  • Change from baseline in the number of participants that require treatment with blood or blood products [ Time Frame: Baseline to week 20 ]
  • Change from baseline in the number of participants that require treatment with invasive bacterial and fungal infections [ Time Frame: Baseline to week 20 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Efficacy and Safety Study of Maribavir Treatment Compared to Investigator-assigned Treatment in Transplant Recipients With Cytomegalovirus (CMV) Infections That Are Refractory or Resistant to Treatment With Ganciclovir, Valganciclovir, Foscarnet, or Cidofovir
Official Title  ICMJE A Phase 3, Multicenter, Randomized, Open-label, Active-controlled Study to Assess the Efficacy and Safety of Maribavir Treatment Compared to Investigator-assigned Treatment in Transplant Recipients With Cytomegalovirus (CMV) Infections That Are Refractory or Resistant to Treatment With Ganciclovir, Valganciclovir, Foscarnet, or Cidofovir
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Cytomegalovirus (CMV)
Intervention  ICMJE
  • Drug: Maribavir
    Maribavir 400 milligrams (mg) (2x200 mg tablets) will be administered twice daily for 8 weeks.
    Other Name: SHP620
  • Drug: Ganciclovir
    Ganciclovir as per the investigator's prescribed dosing regimen will be administered for 8 weeks.
  • Drug: Valganciclovir
    Valganciclovir as per the investigator's prescribed dosing regimen will be administered for 8 weeks.
  • Drug: Foscarnet
    Foscarnet as per the investigator's prescribed dosing regimen will be administered for 8 weeks.
  • Drug: Cidofovir
    Cidofovir as per the investigator's prescribed dosing regimen will be administered for 8 weeks.
Study Arms  ICMJE
  • Experimental: Maribavir Treatment
    Participants will receive 400 milligrams (mg) (2x200 mg tablets) maribavir twice daily orally (doses separated by a minimum of 8 hours) for 8 weeks.
    Intervention: Drug: Maribavir
  • Active Comparator: Investigator-Assigned Treatment
    Participants will receive anti-CMV agent best suited to treat the respective participant as per the investigator's prescribed dosing regimen for 8 weeks. Agents of choice include: ganciclovir, valganciclovir, foscarnet, or cidofovir.
    Interventions:
    • Drug: Ganciclovir
    • Drug: Valganciclovir
    • Drug: Foscarnet
    • Drug: Cidofovir
Publications * Del Pozo Martín Y. 47th Annual Meeting of the EBMT. Lancet Haematol. 2021 May;8(5):e317-e318. doi: 10.1016/S2352-3026(21)00104-6. Epub 2021 Mar 31.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 21, 2020)
352
Original Estimated Enrollment  ICMJE
 (submitted: October 10, 2016)
351
Actual Study Completion Date  ICMJE August 17, 2020
Actual Primary Completion Date August 17, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 12 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Austria,   Belgium,   Canada,   Croatia,   Denmark,   France,   Germany,   Italy,   Singapore,   Spain,   Switzerland,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02931539
Other Study ID Numbers  ICMJE SHP620-303
2015-004725-13 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Supporting Materials: Clinical Study Report (CSR)
Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
URL: https://vivli.org/ourmember/takeda/
Responsible Party Takeda ( Shire )
Study Sponsor  ICMJE Shire
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Study Director Shire
PRS Account Takeda
Verification Date September 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP