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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

Primary Purpose

Cytomegalovirus (CMV)

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Maribavir
Ganciclovir
Valganciclovir
Foscarnet
Cidofovir
Sponsored by
Shire
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cytomegalovirus (CMV)

Eligibility Criteria

12 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • University of Alabama at Birmingham
  • University of Arizona
  • City of Hope National Medical Center
  • University of Southern California
  • UCLA Medical Center
  • UC Davis Medical Center
  • Stanford University
  • Yale University School of Medicine
  • AdventHealth
  • Emory University Hospital
  • Feinberg School of Medicine Northwestern University
  • Loyola University Medical Center
  • University of Chicago Medical Center
  • University of Kentucky
  • Ochsner Clinic Foundation
  • University of Maryland
  • Johns Hopkins Hospital
  • Massachusetts General Hospital
  • Brigham and Womens Hospital
  • UMass Memorial Medical Center
  • University of Michigan
  • Henry Ford Health System
  • William Beaumont Hospital
  • University of Minnesota
  • Mayo Clinic - PPDS
  • University of Nebraska Medical Center
  • Hackensack University Medical Center
  • Columbia University Medical Center
  • Memorial Sloan Kettering Cancer Center
  • New York Presbyterian Hospital - Weill-Cornell
  • SUNY Upstate Medical Center
  • Duke University Medical Center
  • The Christ Hospital
  • University of Cincinnati
  • Cincinnati Children's Hospital Medical Center - PIN
  • University Hospitals Cleveland Medical Center
  • Nationwide Children's Hospital
  • University of Pennsylvania
  • University of Pittsburgh Medical Center
  • Medical University of South Carolina - PPDS
  • St Jude Children's Research Hospital
  • University of Texas Southwestern Medical Center
  • Baylor All Saints Medical Center
  • Baylor College of Medicine
  • MD Anderson Cancer Center
  • University of Utah Health Sciences Center - PPDS
  • Fred Hutchinson Cancer Research Center
  • Westmead Hospital
  • Monash Health, Monash Medical Centre
  • The Alfred Hospital
  • Royal Melbourne Hospital
  • Sir Charles Gairdner Hospital
  • Princess Alexandra Hospital
  • Tiroler Landeskrankenanstalten GmbH
  • Allgemeines Krankenhaus der Stadt Wien
  • UZ Antwerpen
  • Institut Jules Bordet
  • UZ Gent
  • UZ Leuven
  • AZ Sint-Jan AV
  • ZNA Stuivenberg
  • UZ Brussel
  • Hôpital Erasme
  • University of Alberta
  • Hamilton Health Sciences Corporation
  • St. Joseph's Healthcare Hamilton
  • Princess Margaret Hospital
  • University Health Network
  • Centre Hospitalier Universitaire Sainte-Justine
  • McGill University Health Center
  • University Hospital Center Zagreb
  • Copenhagen University Hospital
  • CHRU Brest - Hospital Cavale Blanche
  • Hôpital de Rangueil
  • Hopital Foch
  • CHRU Rennes
  • CHRU Bretonneau
  • CHRU Nantes
  • Hôpital de La Croix Rousse
  • Centre Hospitalier Lyon Sud
  • Hopital Henri Mondor
  • Hôpital Paul Brousse
  • CHU Amiens Hôpital Sud
  • CHU Amiens Hôpital Sud
  • Hopital Gabriel Montpied
  • CHU de GRENOBLE
  • CHRU Lille
  • CHU Dupuytren
  • Groupement Hospitalier Edouard Herriot
  • Groupe Hospitalier Necker Enfants Malades
  • Hôpital Saint Louis
  • Hôpital Saint Antoine
  • CHRU de Poitiers La Miletrie
  • Institut de Cancerologie de la Loire
  • Hôpital Civil
  • Hopital de Hautepierre
  • University Clinic Heidelberg - PPDS
  • Universitätsklinikum Erlangen
  • Universitätsklinikum Essen
  • Universitätsmedizin der Johannes Gutenberg-Universität Mainz
  • Universitatsklinikum Leipzig
  • Universitätsklinikum Erlangen
  • University Clinic Heidelberg - PPDS
  • LMU Klinikum der Universität München
  • Universitätsklinikum Tübingen
  • Ospedale San Raffaele S.r.l. - PPDS
  • Istituto Europeo Di Oncologia
  • Azienda Ospedaliero Universitaria Ospedali Riuniti di Ancona-Umberto I G.M. Lancisi G. Salesi
  • Azienda Ospedaliero Universitaria di Parma
  • Azienda Ospedaliero Universitaria Pisana
  • Fondazione Policlinico Universitario A Gemelli
  • Azienda Sanitaria Universitaria Integrata di Udine
  • Singapore General Hospital (SGH)
  • Hospital Universitario Germans Trias i Pujol
  • Hospital Universitario de Cruces
  • Fundacio Puigvert
  • Hospital Universitario Vall d'Hebrón - PPDS
  • Hospital de La Santa Creu i Sant Pau
  • Hospital Universitario de Bellvitge
  • Hospital Universitario Puerta de Hierro - Majadahonda
  • Complejo Asistencial Universitario de Salamanca - H. Clinico
  • Hospital Clinico Universitario de Valencia
  • Hospital Universitari i Politecnic La Fe de Valencia
  • Centre Hospitalier Universitaire Vaudois
  • University Hospital Coventry
  • Birmingham Heartlands Hospital
  • Beatson West of Scotland Cancer Centre - PPDS
  • Imperial College Healthcare NHS Trust
  • Wythenshawe Hospital - PPDS
  • Sheffield Childrens Hospital
  • Royal Liverpool and Broadgreen University Hospitals NHS Trust
  • Guy's and St Thomas' NHS Foundation Trust - Guy's Hospital
  • Royal Free Hospital
  • Manchester Royal Infirmary - PPDS
  • Churchill Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Maribavir Treatment

Investigator-Assigned Treatment

Arm Description

Participants will receive 400 milligrams (mg) (2x200 mg tablets) maribavir twice daily orally (doses separated by a minimum of 8 hours) for 8 weeks.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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 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.
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.
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.
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.
Predose Concentration (Cmin) of Maribavir
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
AUC0-tau of maribavir for adolescent participants was planned to be reported.
Maximum Plasma Concentration (Cmax) of Maribavir for Adolescent Participants
Cmax of maribavir for adolescent participants was planned to be reported.
Time When Maximum Concentration is Observed (Tmax) of Maribavir for Adolescent Participants
Tmax of maribavir for adolescent participants was planned to be reported.
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.
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.

Full Information

First Posted
September 29, 2016
Last Updated
October 29, 2021
Sponsor
Shire
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1. Study Identification

Unique Protocol Identification Number
NCT02931539
Brief Title
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
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
Study Type
Interventional

2. Study Status

Record Verification Date
September 2021
Overall Recruitment Status
Completed
Study Start Date
December 22, 2016 (Actual)
Primary Completion Date
August 17, 2020 (Actual)
Study Completion Date
August 17, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Shire

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cytomegalovirus (CMV)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
352 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Maribavir Treatment
Arm Type
Experimental
Arm Description
Participants will receive 400 milligrams (mg) (2x200 mg tablets) maribavir twice daily orally (doses separated by a minimum of 8 hours) for 8 weeks.
Arm Title
Investigator-Assigned Treatment
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Maribavir
Other Intervention Name(s)
SHP620
Intervention Description
Maribavir 400 milligrams (mg) (2x200 mg tablets) will be administered twice daily for 8 weeks.
Intervention Type
Drug
Intervention Name(s)
Ganciclovir
Intervention Description
Ganciclovir as per the investigator's prescribed dosing regimen will be administered for 8 weeks.
Intervention Type
Drug
Intervention Name(s)
Valganciclovir
Intervention Description
Valganciclovir as per the investigator's prescribed dosing regimen will be administered for 8 weeks.
Intervention Type
Drug
Intervention Name(s)
Foscarnet
Intervention Description
Foscarnet as per the investigator's prescribed dosing regimen will be administered for 8 weeks.
Intervention Type
Drug
Intervention Name(s)
Cidofovir
Intervention Description
Cidofovir as per the investigator's prescribed dosing regimen will be administered for 8 weeks.
Primary Outcome Measure Information:
Title
Percentage of Participants Who Achieved Confirmed Clearance of Plasma Cytomegalovirus (CMV) Deoxyribonucleic Acid (DNA) (CMV Viremia Clearance) at End of Week 8
Description
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
Secondary Outcome Measure Information:
Title
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
Description
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
Title
Percentage of Participants Who Achieved Confirmed CMV Viremia Clearance After Receiving 8 Weeks of Study-assigned Treatment
Description
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
Title
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
Description
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
Title
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
Description
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
Title
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
Description
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
Title
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
Description
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)
Title
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
Description
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
Title
Percentage of Participants Who Completed 8 Weeks of Study-assigned Treatment With Recurrence of CMV Viremia During the First 8 Weeks of the Treatment
Description
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
Title
Percentage of Participants Who Completed 8 Weeks of Study-assigned Treatment With Recurrence of CMV Viremia During the 12 Weeks of Follow-up Period
Description
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)
Title
Percentage of Participants Who Completed 8 Weeks of Study-assigned Treatment With Recurrence of CMV Viremia During the 20 Weeks of Study
Description
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
Title
Percentage of Participants With Recurrence of CMV Viremia While on Study-assigned Treatment
Description
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)
Title
Percentage of Participants With Recurrence of CMV Viremia While Off Study-assigned Treatment During Follow-up Period
Description
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)
Title
Number of Participants Who Had Maribavir CMV Resistance at Baseline
Description
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
Title
Number of Participants Who Had Post-baseline Resistance to Maribavir
Description
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
Title
Number of Participants With All-cause Mortality by the End of the Study
Description
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)
Title
Time to All Cause Mortality
Description
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)
Title
Percentage of Participants Who Achieved Confirmed Clearance of Plasma CMV DNA (CMV Viremia Clearance) at End of Week 8 After Starting Maribavir Rescue Treatment
Description
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
Title
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
Description
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
Title
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs During the On-treatment Observation Period
Description
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)
Title
Predose Concentration (Cmin) of Maribavir
Description
Cmin of maribavir was reported.
Time Frame
Predose at Week 1, 4 and 8
Title
Area Under the Concentration Time Curve Over the 12-hour Dosing Interval at Steady State (AUC0-tau) of Marivabir for Adolescent Participants
Description
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
Title
Maximum Plasma Concentration (Cmax) of Maribavir for Adolescent Participants
Description
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
Title
Time When Maximum Concentration is Observed (Tmax) of Maribavir for Adolescent Participants
Description
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
Title
Apparent Oral Clearance (CL/F) of Maribavir for Adolescent Participants
Description
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
Title
Apparent Volume of Distribution (Vz/F) of Maribavir for Adolescent Participants
Description
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
12 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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. The participant must be a recipient of hematopoietic stem cell or solid organ transplant. 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. 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. 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. The participant must be >= 12 years of age at the time of consent. The participant must weigh >= 35 kilogram (kg). 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): Absolute neutrophil count (ANC) >= 1000/ millimeter cube (mm^3) (1.0 x 10^9/liter [L]) Platelet count >= 25,000/mm^3 [25 x 10^9/L], Hemoglobin >= 8 grams per deciliter (g/dL). 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. 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. The participant must be able to swallow tablets, or receive tablets crushed and/or dispensed in water via nasogastric or orogastric tube. The participant must be willing and have an understanding and ability to fully comply with study procedures and restrictions defined in the protocol. 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. The participant must have a life expectancy of >= 8 weeks. Exclusion Criteria: 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. 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. 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. 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. Have known hypersensitivity to the active substance or to an excipient for a study treatment. Have tissue invasive CMV disease with central nervous system involvement including the retina (example, CMV retinitis). 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. 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. Require mechanical ventilation or vasopressors for hemodynamic support at the time of enrollment. Be female and pregnant or breast feeding. Have previously received maribavir. 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. Have received any unapproved agent or device within 30 days before initiation of study treatment. 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. Be undergoing treatment for acute or chronic hepatitis C. 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Study Director
Organizational Affiliation
Shire
Official's Role
Study Director
Facility Information:
Facility Name
University of Alabama at Birmingham
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35294-0006
Country
United States
Facility Name
University of Arizona
City
Tucson
State/Province
Arizona
ZIP/Postal Code
85724
Country
United States
Facility Name
City of Hope National Medical Center
City
Duarte
State/Province
California
ZIP/Postal Code
91010
Country
United States
Facility Name
University of Southern California
City
Los Angeles
State/Province
California
ZIP/Postal Code
90033
Country
United States
Facility Name
UCLA Medical Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
UC Davis Medical Center
City
Sacramento
State/Province
California
ZIP/Postal Code
95817
Country
United States
Facility Name
Stanford University
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States
Facility Name
Yale University School of Medicine
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06520
Country
United States
Facility Name
AdventHealth
City
Orlando
State/Province
Florida
ZIP/Postal Code
32804
Country
United States
Facility Name
Emory University Hospital
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Feinberg School of Medicine Northwestern University
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
Loyola University Medical Center
City
Maywood
State/Province
Illinois
ZIP/Postal Code
60153
Country
United States
Facility Name
University of Chicago Medical Center
City
Maywood
State/Province
Illinois
ZIP/Postal Code
60153
Country
United States
Facility Name
University of Kentucky
City
Lexington
State/Province
Kentucky
ZIP/Postal Code
40536
Country
United States
Facility Name
Ochsner Clinic Foundation
City
New Orleans
State/Province
Louisiana
ZIP/Postal Code
70121
Country
United States
Facility Name
University of Maryland
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21201
Country
United States
Facility Name
Johns Hopkins Hospital
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Brigham and Womens Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
UMass Memorial Medical Center
City
Worcester
State/Province
Massachusetts
ZIP/Postal Code
01655
Country
United States
Facility Name
University of Michigan
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
Henry Ford Health System
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48202
Country
United States
Facility Name
William Beaumont Hospital
City
Royal Oak
State/Province
Michigan
ZIP/Postal Code
48073
Country
United States
Facility Name
University of Minnesota
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55454
Country
United States
Facility Name
Mayo Clinic - PPDS
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
59905
Country
United States
Facility Name
University of Nebraska Medical Center
City
Omaha
State/Province
Nebraska
ZIP/Postal Code
68198-5400
Country
United States
Facility Name
Hackensack University Medical Center
City
Hackensack
State/Province
New Jersey
ZIP/Postal Code
07601
Country
United States
Facility Name
Columbia University Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
Memorial Sloan Kettering Cancer Center
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
New York Presbyterian Hospital - Weill-Cornell
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
SUNY Upstate Medical Center
City
Syracuse
State/Province
New York
ZIP/Postal Code
13210
Country
United States
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710-4000
Country
United States
Facility Name
The Christ Hospital
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45220
Country
United States
Facility Name
University of Cincinnati
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45220
Country
United States
Facility Name
Cincinnati Children's Hospital Medical Center - PIN
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229-3039
Country
United States
Facility Name
University Hospitals Cleveland Medical Center
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44106
Country
United States
Facility Name
Nationwide Children's Hospital
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43205
Country
United States
Facility Name
University of Pennsylvania
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
University of Pittsburgh Medical Center
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15213
Country
United States
Facility Name
Medical University of South Carolina - PPDS
City
Charleston
State/Province
South Carolina
ZIP/Postal Code
29425
Country
United States
Facility Name
St Jude Children's Research Hospital
City
Memphis
State/Province
Tennessee
ZIP/Postal Code
38105
Country
United States
Facility Name
University of Texas Southwestern Medical Center
City
Dallas
State/Province
Texas
ZIP/Postal Code
75390
Country
United States
Facility Name
Baylor All Saints Medical Center
City
Fort Worth
State/Province
Texas
ZIP/Postal Code
76104
Country
United States
Facility Name
Baylor College of Medicine
City
Houston
State/Province
Texas
ZIP/Postal Code
77030-2348
Country
United States
Facility Name
MD Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
University of Utah Health Sciences Center - PPDS
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84132
Country
United States
Facility Name
Fred Hutchinson Cancer Research Center
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States
Facility Name
Westmead Hospital
City
Westmead
State/Province
New South Wales
ZIP/Postal Code
2145
Country
Australia
Facility Name
Monash Health, Monash Medical Centre
City
Clayton
State/Province
Victoria
ZIP/Postal Code
3168
Country
Australia
Facility Name
The Alfred Hospital
City
Melbourne
State/Province
Victoria
ZIP/Postal Code
3004
Country
Australia
Facility Name
Royal Melbourne Hospital
City
Parkville
State/Province
Victoria
ZIP/Postal Code
3050
Country
Australia
Facility Name
Sir Charles Gairdner Hospital
City
Nedlands
State/Province
Washington
ZIP/Postal Code
6009
Country
Australia
Facility Name
Princess Alexandra Hospital
City
Brisbane
ZIP/Postal Code
4102
Country
Australia
Facility Name
Tiroler Landeskrankenanstalten GmbH
City
Innsbruck
ZIP/Postal Code
6020
Country
Austria
Facility Name
Allgemeines Krankenhaus der Stadt Wien
City
Wien
ZIP/Postal Code
1090
Country
Austria
Facility Name
UZ Antwerpen
City
Edegem
State/Province
Antwerpen
ZIP/Postal Code
2650
Country
Belgium
Facility Name
Institut Jules Bordet
City
Bruxelles
State/Province
Brussels
ZIP/Postal Code
1000
Country
Belgium
Facility Name
UZ Gent
City
Gent
State/Province
Oost-Vlaanderen
ZIP/Postal Code
9000
Country
Belgium
Facility Name
UZ Leuven
City
Leuven
State/Province
Vlaams Brabant
ZIP/Postal Code
3000
Country
Belgium
Facility Name
AZ Sint-Jan AV
City
Brugge
State/Province
West-Vlaanderen
ZIP/Postal Code
8000
Country
Belgium
Facility Name
ZNA Stuivenberg
City
Antwerpen
ZIP/Postal Code
2060
Country
Belgium
Facility Name
UZ Brussel
City
Brussels
ZIP/Postal Code
1090
Country
Belgium
Facility Name
Hôpital Erasme
City
Bruxelles
ZIP/Postal Code
1070
Country
Belgium
Facility Name
University of Alberta
City
Edmonton
State/Province
Alberta
ZIP/Postal Code
T6G 2G3
Country
Canada
Facility Name
Hamilton Health Sciences Corporation
City
Hamilton
State/Province
Ontario
ZIP/Postal Code
L8N 3Z5
Country
Canada
Facility Name
St. Joseph's Healthcare Hamilton
City
Hamilton
State/Province
Ontario
ZIP/Postal Code
L8N 4A6
Country
Canada
Facility Name
Princess Margaret Hospital
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 2M9
Country
Canada
Facility Name
University Health Network
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 2N2
Country
Canada
Facility Name
Centre Hospitalier Universitaire Sainte-Justine
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H3T 1C5
Country
Canada
Facility Name
McGill University Health Center
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H4A 3J1
Country
Canada
Facility Name
University Hospital Center Zagreb
City
Zagreb
ZIP/Postal Code
10000
Country
Croatia
Facility Name
Copenhagen University Hospital
City
København Ø
State/Province
Capital
ZIP/Postal Code
2100
Country
Denmark
Facility Name
CHRU Brest - Hospital Cavale Blanche
City
Brest
State/Province
Finistère
ZIP/Postal Code
29609
Country
France
Facility Name
Hôpital de Rangueil
City
Toulouse
State/Province
Haute-Garonne
ZIP/Postal Code
31059
Country
France
Facility Name
Hopital Foch
City
Suresnes
State/Province
Hauts-de-Seine
ZIP/Postal Code
92150
Country
France
Facility Name
CHRU Rennes
City
Rennes
State/Province
Ille-et-Vilaine
ZIP/Postal Code
35033
Country
France
Facility Name
CHRU Bretonneau
City
Tours
State/Province
Indre-et-Loire
ZIP/Postal Code
37044
Country
France
Facility Name
CHRU Nantes
City
Nantes
State/Province
Loire-Atlantique
ZIP/Postal Code
44093
Country
France
Facility Name
Hôpital de La Croix Rousse
City
Lyon
State/Province
Rhône
ZIP/Postal Code
69004
Country
France
Facility Name
Centre Hospitalier Lyon Sud
City
Pierre-bénite
State/Province
Rhône
ZIP/Postal Code
69495
Country
France
Facility Name
Hopital Henri Mondor
City
Créteil
State/Province
Val-de-Marne
ZIP/Postal Code
94010
Country
France
Facility Name
Hôpital Paul Brousse
City
Villejuif
State/Province
Val-de-Marne
ZIP/Postal Code
94800
Country
France
Facility Name
CHU Amiens Hôpital Sud
City
AMIENS Cedex 1
ZIP/Postal Code
80054
Country
France
Facility Name
CHU Amiens Hôpital Sud
City
Amiens
ZIP/Postal Code
80054
Country
France
Facility Name
Hopital Gabriel Montpied
City
Clermont-Ferrand
ZIP/Postal Code
63003
Country
France
Facility Name
CHU de GRENOBLE
City
Grenoble
ZIP/Postal Code
38043
Country
France
Facility Name
CHRU Lille
City
Lille Cedex
ZIP/Postal Code
59037
Country
France
Facility Name
CHU Dupuytren
City
Limoges Cedex
ZIP/Postal Code
87042
Country
France
Facility Name
Groupement Hospitalier Edouard Herriot
City
Lyon
ZIP/Postal Code
69437
Country
France
Facility Name
Groupe Hospitalier Necker Enfants Malades
City
Paris
ZIP/Postal Code
75015
Country
France
Facility Name
Hôpital Saint Louis
City
Paris
ZIP/Postal Code
75475
Country
France
Facility Name
Hôpital Saint Antoine
City
Paris
ZIP/Postal Code
75571
Country
France
Facility Name
CHRU de Poitiers La Miletrie
City
Poitiers
ZIP/Postal Code
86000
Country
France
Facility Name
Institut de Cancerologie de la Loire
City
Saint-Priest en Jarez
ZIP/Postal Code
42271
Country
France
Facility Name
Hôpital Civil
City
STRASBOURG Cedex
ZIP/Postal Code
67091
Country
France
Facility Name
Hopital de Hautepierre
City
Strasbourg
ZIP/Postal Code
67091
Country
France
Facility Name
University Clinic Heidelberg - PPDS
City
Heidelberg
State/Province
Baden-Württemberg
ZIP/Postal Code
69120
Country
Germany
Facility Name
Universitätsklinikum Erlangen
City
Erlangen
State/Province
Bayern
ZIP/Postal Code
91054
Country
Germany
Facility Name
Universitätsklinikum Essen
City
Essen
State/Province
Nordrhein-Westfalen
ZIP/Postal Code
45122
Country
Germany
Facility Name
Universitätsmedizin der Johannes Gutenberg-Universität Mainz
City
Mainz
State/Province
Rheinland-Pfalz
ZIP/Postal Code
55101
Country
Germany
Facility Name
Universitatsklinikum Leipzig
City
Leipzig
State/Province
Sachsen
ZIP/Postal Code
04103
Country
Germany
Facility Name
Universitätsklinikum Erlangen
City
Erlangen
ZIP/Postal Code
91054
Country
Germany
Facility Name
University Clinic Heidelberg - PPDS
City
Heidelberg
ZIP/Postal Code
69120
Country
Germany
Facility Name
LMU Klinikum der Universität München
City
München
ZIP/Postal Code
81377
Country
Germany
Facility Name
Universitätsklinikum Tübingen
City
Tübingen
ZIP/Postal Code
72076
Country
Germany
Facility Name
Ospedale San Raffaele S.r.l. - PPDS
City
Milano
State/Province
Lombardia
ZIP/Postal Code
20132
Country
Italy
Facility Name
Istituto Europeo Di Oncologia
City
Milano
State/Province
Lombardia
ZIP/Postal Code
20141
Country
Italy
Facility Name
Azienda Ospedaliero Universitaria Ospedali Riuniti di Ancona-Umberto I G.M. Lancisi G. Salesi
City
Ancona
State/Province
Marche
ZIP/Postal Code
60126
Country
Italy
Facility Name
Azienda Ospedaliero Universitaria di Parma
City
Parma
ZIP/Postal Code
43126
Country
Italy
Facility Name
Azienda Ospedaliero Universitaria Pisana
City
Pisa
ZIP/Postal Code
56216
Country
Italy
Facility Name
Fondazione Policlinico Universitario A Gemelli
City
Roma
ZIP/Postal Code
00168
Country
Italy
Facility Name
Azienda Sanitaria Universitaria Integrata di Udine
City
Udine
ZIP/Postal Code
12345
Country
Italy
Facility Name
Singapore General Hospital (SGH)
City
Singapore
ZIP/Postal Code
169608
Country
Singapore
Facility Name
Hospital Universitario Germans Trias i Pujol
City
Badalona
State/Province
Barcelona
ZIP/Postal Code
08916
Country
Spain
Facility Name
Hospital Universitario de Cruces
City
Barakaldo
ZIP/Postal Code
48903
Country
Spain
Facility Name
Fundacio Puigvert
City
Barcelona
ZIP/Postal Code
08025
Country
Spain
Facility Name
Hospital Universitario Vall d'Hebrón - PPDS
City
Barcelona
ZIP/Postal Code
08035
Country
Spain
Facility Name
Hospital de La Santa Creu i Sant Pau
City
Barcelona
ZIP/Postal Code
08041
Country
Spain
Facility Name
Hospital Universitario de Bellvitge
City
L'Hospitalet de Llobregat
ZIP/Postal Code
08907
Country
Spain
Facility Name
Hospital Universitario Puerta de Hierro - Majadahonda
City
Madrid
ZIP/Postal Code
28222
Country
Spain
Facility Name
Complejo Asistencial Universitario de Salamanca - H. Clinico
City
Salamanca
ZIP/Postal Code
37007
Country
Spain
Facility Name
Hospital Clinico Universitario de Valencia
City
Valencia
ZIP/Postal Code
46010
Country
Spain
Facility Name
Hospital Universitari i Politecnic La Fe de Valencia
City
Valencia
ZIP/Postal Code
46026
Country
Spain
Facility Name
Centre Hospitalier Universitaire Vaudois
City
Lausanne
State/Province
Vaud (fr)
ZIP/Postal Code
1011
Country
Switzerland
Facility Name
University Hospital Coventry
City
Coventry
State/Province
Birmingham
ZIP/Postal Code
CV2 2DX
Country
United Kingdom
Facility Name
Birmingham Heartlands Hospital
City
West Midlands
State/Province
Birmingham
ZIP/Postal Code
B9 5SS
Country
United Kingdom
Facility Name
Beatson West of Scotland Cancer Centre - PPDS
City
Glasgow
State/Province
Glasgow City
ZIP/Postal Code
G12 0YN
Country
United Kingdom
Facility Name
Imperial College Healthcare NHS Trust
City
London
State/Province
London, City Of
ZIP/Postal Code
W12 0HS
Country
United Kingdom
Facility Name
Wythenshawe Hospital - PPDS
City
Wythenshawe
State/Province
Manchester
ZIP/Postal Code
M23 9LT
Country
United Kingdom
Facility Name
Sheffield Childrens Hospital
City
Sheffield
State/Province
Yorkshire
ZIP/Postal Code
S10 2TH
Country
United Kingdom
Facility Name
Royal Liverpool and Broadgreen University Hospitals NHS Trust
City
Liverpool
ZIP/Postal Code
L7 8XP
Country
United Kingdom
Facility Name
Guy's and St Thomas' NHS Foundation Trust - Guy's Hospital
City
London
ZIP/Postal Code
NW3 2QG
Country
United Kingdom
Facility Name
Royal Free Hospital
City
London
ZIP/Postal Code
NW3 2QG
Country
United Kingdom
Facility Name
Manchester Royal Infirmary - PPDS
City
Manchester
ZIP/Postal Code
M13 9WL
Country
United Kingdom
Facility Name
Churchill Hospital
City
Oxford
ZIP/Postal Code
OX3 7LJ
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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.
IPD Sharing 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.
IPD Sharing URL
https://vivli.org/ourmember/takeda/
Citations:
PubMed Identifier
34864943
Citation
Avery RK, Alain S, Alexander BD, Blumberg EA, Chemaly RF, Cordonnier C, Duarte RF, Florescu DF, Kamar N, Kumar D, Maertens J, Marty FM, Papanicolaou GA, Silveira FP, Witzke O, Wu J, Sundberg AK, Fournier M; SOLSTICE Trial Investigators. Maribavir for Refractory Cytomegalovirus Infections With or Without Resistance Post-Transplant: Results From a Phase 3 Randomized Clinical Trial. Clin Infect Dis. 2022 Sep 10;75(4):690-701. doi: 10.1093/cid/ciab988. Erratum In: Clin Infect Dis. 2023 Feb 8;76(3):560.
Results Reference
derived
PubMed Identifier
33811823
Citation
Del Pozo Martin 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. No abstract available.
Results Reference
derived
Links:
URL
https://clinicaltrials.takeda.com/study-detail/5f6b5fd74db2bf003ab46f3d
Description
To obtain more information on the study, click here/on this link

Learn more about this trial

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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