Clinical trial NCT02927067: A Study of Maribavir Compared to Valganciclovir to Treat Cytomegalovirus Infections in People Who Have Received Stem Cell Transplants
Official title: A Phase 3, Multicenter, Randomized, Double-blind, Double-dummy, Active-controlled Study to Assess the Efficacy and Safety of Maribavir Compared to Valganciclovir for the Treatment of Cytomegalovirus (CMV) Infection in Hematopoietic Stem Cell Transplant Recipients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Cytomegalovirus (CMV)
Lead sponsor: Takeda
Sponsor class: INDUSTRY
Collaborators: name: Takeda Development Center Americas, Inc.
First posted: 2016-10-06
Enrollment: 553
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study is about treatment options for cytomegalovirus infections in people who have received stem cell transplants. The main aim of the study is to check if the cytomegalovirus infection can no longer be detected after treatment with marivabir or valganciclovir.

Participants will take 2 tablets of marivabir or valganciclovir and 2 tablets of placebo twice a day for 8 weeks. A placebo will look like marivabir or valganciclovir but will not have any medicine in it.

After treatment, each participant will be followed up for up to 12 weeks.

Participants will visit their study clinic up to 18 times during the study.


Eligibility criteria: Inclusion Criteria:

* 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 participants before completing any study-related procedures. During the COVID-19 public health emergency, informed consent from a potential or current trial participant may, if permitted by local laws and regulations, be obtained via electronic informed consent (eIC) capabilities or an electronic face-to-face consent interview when these individuals are unable to travel to the site (FDA COVID-19 Guidance, 27 January 2021, Q11).
* Be greater than or equal to (\>=) 16 years of age at the time of consent.
* Be a recipient of hematopoietic stem cell transplant.
* Have a documented asymptomatic CMV infection, with a screening value of CMV DNA \>=1365 International Units per millilitre (IU/mL) to less than or equal to (\<=) 273000 IU/mL in whole blood or \>=455 IU/mL to \<=91000 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. Same laboratory and same sample type (whole blood or plasma) should be used for these assessments. Asymptomatic CMV infection is defined as an infection that does not present with tissue invasive CMV disease, as assessed by the investigator. Participants with CMV DNA less than (\<) 910 and \>=455 IU/mL in plasma or \<2730 and \>=1365 IU/mL in whole blood will also need to meet at least 1 of the following criteria for high-risk CMV infection to be eligible:

  1. Human leukocyte antigen (HLA)-related (sibling) donor with at least 1 mismatch at 1 of the following 3 HLA-gene loci: HLA-A, -B or -DR,
  2. Haploidentical donor
  3. Unrelated donor with at least 1 mismatch at 1 of the following 4 HLA -gene loci: HLA-A, -B, -C and -DRB1,
  4. Use of umbilical cord blood as stem cell source,
  5. Use of ex vivo T-cell-depleted grafts,
  6. Grade 2 or greater graft-versus-host-disease (GVHD), requiring the use of systemic corticosteroids (defined as the use of \>=1 milligram per kilogram per day (mg/kg/day) of prednisone or equivalent dose of another corticosteroid).
* Have the current CMV infection as the first episode of CMV viremia after HSCT, either primary or reactivation, which in the investigator's opinion requires treatment.
* Per investigator's judgment, be eligible for treatment with valganciclovir.
* 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 to \>=1000 per cubic millimeter (/mm\^3) \[1.0\*10\^9/L\].
  2. Platelet count \>=25,000/mm\^3 \[25\*10\^9/L\].
  3. Hemoglobin \>=8 grams per deciliter (g/dL).
  4. Estimated creatinine clearance \>=30 milliliters per minute (mL/min).
* Have a negative serum beta human chorionic gonadotropin (beta-HCG) pregnancy test at screening, if a female of child bearing potential. Urine pregnancy tests may be done per institutional requirements; however they are not sufficient for eligibility determination. 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 the last dose of study treatment.
* Be able to swallow tablets.
* Have life expectancy of \>=8 weeks.
* Weigh \>=40 kilograms (kg).
* Be willing and have an understanding and ability to fully comply with study procedures and restrictions defined in the protocol.

Exclusion Criteria:

* Have CMV tissue invasive disease as assessed by the investigator at the time of screening and randomization at Visit 2/Day 0.
* Have a CMV infection that is known to be genotypically resistant to ganciclovir, valganciclovir, foscarnet, or cidofovir based on documented evidence.
* Be presenting with recurrent CMV infection (defined as a new detection of CMV infection in a participants who had at least one previously documented episode of CMV infection post-transplant, and who has had at least 2 weeks of undetectable CMV DNA between the episodes during active surveillance, based on same local laboratory and same sample type). The Participants must also have been off any anti-CMV treatment between the current and prior infection. Otherwise, the current infection may be considered continuation of the prior infection.
* Require ganciclovir, valganciclovir, foscarnet, or cidofovir administration for conditions other than CMV when study treatment is initiated (example: herpes simplex virus \[HSV\] co-infection requiring use of any of these agents after the randomization) or would need a co-administration with maribavir for CMV infection.
* Be receiving leflunomide, letermovir, or artesunate when study treatment is initiated.

Note: Participants who may be 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 3 days prior to first dose of study treatment. Participants receiving artesunate must discontinue the use prior to the first dose of study treatment.

* Be on treatment with anti-CMV agents (ganciclovir, valganciclovir, foscarnet or letermovir) for the current CMV infection for longer than 72 hours.
* Have known hypersensitivity to the active substance or to an excipient of the study treatments.
* 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 medication.
* Require mechanical ventilation or vasopressors for hemodynamic support at the time of randomization.
* Be female and pregnant or nursing.
* Have previously completed, discontinued, or have been withdrawn from this study.
* Have received any investigational agent with known anti-CMV activity within 30 days before initiation of study treatment or CMV vaccine at any time.
* Have received any unapproved agent or device within 30 days before initiation of study treatment.
* Have any clinically significant medical or surgical condition that, in the investigator's opinion, could interfere with interpretation of study results, contraindicate the administration of the assigned study treatment, or compromise the safety or well-being of the participant.
* Have previously received maribavir.
* Have serum aspartate aminotransferase (AST) greater than (\>) 5 times upper limit of normal (ULN) at screening, or serum alanine aminotransferase (ALT) \>5 times ULN at screening, or total bilirubin \>= 3.0\*ULN at screening (except for documented Gilbert's syndrome), as analyzed by local or central laboratory.
* Have known (previously documented) 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.
* Have active malignancy with the exception of nonmelanoma skin cancer, as determined by the investigator. Participants who experience relapse or progression of their underlying malignancy (for which HSCT was performed), as determined by the investigator, are not to be enrolled.
* Be undergoing treatment for acute or chronic hepatitis C

Primary outcomes:
measure: Number of Participants Who Achieved Confirmed Clearance of Plasma Cytomegalovirus (CMV) Deoxyribose Nucleic Acid (DNA) at the End of Study Week 8
timeFrame: Week 8
Secondary outcomes:
measure: Number of Participants Who Achieved Confirmed CMV Viremia Clearance and CMV Infection Symptom Control at the End of Week 8, Followed by Maintenance of Treatment Effect at Week 16
timeFrame: Week 8 up to Week 16
measure: Number of Participants Who Achieved Confirmed Clearance of Plasma CMV DNA (CMV Viremia Clearance) at Week 8 After Receiving 8 Weeks of Study Assigned Treatment
timeFrame: Week 8
measure: Number of Participants Who Achieved Confirmed CMV Viremia Clearance After Receiving 8 Weeks of Study-assigned Treatment Through Weeks 12, 16 and 20
timeFrame: Week 8 through Weeks 12, 16 and 20
measure: Number of Participants Who Maintained Confirmed CMV Viremia Clearance at Week 8 After Receiving Study-Assigned Treatment Through Study Weeks 12 and 20 Regardless of Whether Study Assigned Treatment Was Completed
timeFrame: Week 8 through Weeks 12 and 20
measure: Number of Participants With Confirmed Recurrence of Viremia During First 8 Weeks of the Study
timeFrame: Up to Week 8
measure: Number of Participants With Confirmed Recurrence of Viremia During the Follow-up Period
timeFrame: From Week 9 up to Week 20
measure: Number of Participants With Confirmed Recurrence of Viremia at Any Time During the Study
timeFrame: Up to Week 20
measure: Number of Participants With Confirmed Recurrence of Viremia While on Study Treatment and Off Treatment
timeFrame: Baseline up to Week 20
measure: Number of Participants With Grade 3 or 4 (Shift From Baseline Grade <3) and Grade 4 Neutropenia (Shift From Baseline Grade <4) While on Study Treatment
timeFrame: From start of study drug to end of study drug + 1 day (up to approximately Week 8)
measure: Number of Participants With Treatment-Emergent Adverse Events During the On-Treatment Period
timeFrame: From the start of the study treatment to 7 days after the last dose of study treatment (up to approximately Week 9)
measure: Predose Concentration (Cmin) of Maribavir
timeFrame: Weeks 1, 4, and 8: pre-morning dose
measure: Area Under the Concentration-Time Curve Over the 12-Hour Dosing Interval at Steady State AUC(0-tau) of Maribavir for Adolescent Participants Only
timeFrame: Pre-morning dose, 1, 2, 3, 4, 6, 8, and 12 hours post-morning dose of Week 1
measure: Maximum Observed Plasma Concentration (Cmax) of Maribavir for Adolescent Participants Only
timeFrame: Pre-morning dose, 1, 2, 3, 4, 6, 8, and 12 hours post-morning dose of Week 1
measure: Time When Maximum Concentration is Observed (Tmax) of Maribavir for Adolescent Participants Only
timeFrame: Pre-morning dose, 1, 2, 3, 4, 6, 8, and 12 hours post-morning dose of Week 1
measure: Apparent Oral Clearance (CL/F) of Maribavir for Adolescent Participants Only
timeFrame: Pre-morning dose, 1, 2, 3, 4, 6, 8, and 12 hours post-morning dose of Week 1
measure: Apparent Volume of Distribution (Vz/F) of Maribavir for Adolescent Participants Only
timeFrame: Pre-morning dose, 1, 2, 3, 4, 6, 8, and 12 hours post-morning dose of Week 1
Other outcomes:
measure: Number of Participants Developing Resistance
timeFrame: From start of study drug up to end of the study (up to Week 20)
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Los Angeles
country: United States
facility: UCLA Medical Center
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
city: Denver
country: United States
facility: Colorado Blood Cancer Institute - PPDS
state: Colorado
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Maywood
country: United States
facility: Loyola University Medical Center
state: Illinois
city: Baltimore
country: United States
facility: University of Maryland School of Medicine
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Womens Hospital
state: Massachusetts
city: Worcester
country: United States
facility: UMass Memorial Medical Center
state: Massachusetts
city: Detroit
country: United States
facility: Harper University Hospital
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic - PIN
state: Minnesota
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: New York
country: United States
facility: Joan and sandford I. Weill Medical College of Cornell University Clinic
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Nashville
country: United States
facility: TriStar Centennial Medical Center
state: Tennessee
city: Austin
country: United States
facility: Saint Davids South Austin Medical Center
state: Texas
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: Texas Transplant Institute
state: Texas
city: Seattle
country: United States
facility: VA Puget Sound Health Care System - NAVREF - PPDS
state: Washington
city: Milwaukee
country: United States
facility: The Medical College of Wisconsin, Inc.
state: Wisconsin
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Parkville
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Vienna
country: Austria
facility: Medizinische Universitat Wien (Medical University of Vienna)
state: Wien
city: Linz
country: Austria
facility: Elisabethinen Hospital Linz
city: Edegem
country: Belgium
facility: UZ Antwerpen
state: Antwerpen
city: Bruxelles
country: Belgium
facility: Institute Jules Bordet
state: Brussels
city: Bruxelles
country: Belgium
facility: Cliniques Universitaires Saint-Luc
state: Brussels
city: Jette
country: Belgium
facility: Universitair Ziekenhuis Brussel - PIN
state: Brussels
city: Gent
country: Belgium
facility: University Hospital Gent
state: Oost-Vlaanderen
city: Leuven
country: Belgium
facility: UZ Leuven
state: Vlaams Brabant
city: Brugge
country: Belgium
facility: AZ Sint-Jan AV
state: West-Vlaanderen
city: Liège
country: Belgium
facility: CHU de Liège
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: Halifax
country: Canada
facility: Queen Elizabeth II Health Sciences Center
state: Nova Scotia
city: Hamilton
country: Canada
facility: Hamilton Health Sciences Corporation
state: Ontario
city: Beijing
country: China
facility: Peking University First Hospital
state: Beijing
city: Beijing
country: China
facility: Peking University People's Hospital
state: Beijing
city: Guangzhou
country: China
facility: Nanfang Hospital Southern Medical University
state: Guangdong
city: Suzhou
country: China
facility: The First Affiliated Hospital of Soochow University
state: Jiangsu
city: Changsha
country: China
facility: Xiangya Hospital Central South University
city: Guangzhou
country: China
facility: Guangzhou First People's Hospital
city: Hangzhou Zhejiang
country: China
facility: The First Affiliated Hospital, College of Medicine, Zhejiang University
city: Zhengzhou
country: China
facility: Henan Cancer Hospital
city: Zagreb
country: Croatia
facility: University Hospital Center Zagreb
city: Prague
country: Czechia
facility: Fakultni nemocnice v Motole
state: Praha, Hlavní Mesto
city: Praha
country: Czechia
facility: Ustav hematologie a krevni transfuze
city: Strasbourg Cedex
country: France
facility: Institut de Cancérologie Strasbourg Europe
state: Bas-Rhin
city: Strasbourg Cedex
country: France
facility: Hopital de Hautepierre
state: Bas-Rhin
city: Pessac
country: France
facility: CHU de Bordeaux
state: Gironde
city: Limoges
country: France
facility: Hôpital Universitaire Dupuytren
state: Haute-Vienne
city: GRENOBLE Cedex 9
country: France
facility: CHU de GRENOBLE
state: Isère
city: Nantes
country: France
facility: Hôtel Dieu
state: Loire-Atlantique
city: Angers Cedex 9
country: France
facility: CHU Angers
state: Maine-et-Loire
city: Créteil
country: France
facility: Hopital Henri Mondor
state: Val-de-Marne
city: Besnçon
country: France
facility: Hopital Jean Minjoz
city: Nice
country: France
facility: Institut Paoli Calmettes
city: Paris
country: France
facility: Hôpital Saint Antoine
city: Paris
country: France
facility: Hôpital Saint Louis
city: Toulouse cedex 9
country: France
facility: EDOG - Institut Claudius Regaud - PPDS
city: Muenster
country: Germany
facility: Universitätsklinikum Münster
state: Nordrhein-Westfalen
city: Mainz
country: Germany
facility: Universitätsmedizin der Johannes Gutenberg-Universität Mainz
state: Rheinland-Pfalz
city: Homburg
country: Germany
facility: Universität des Saarlandes
state: Saarland
city: Leipzig
country: Germany
facility: Universitatsklinikum Leipzig
state: Sachsen
city: Augsburg
country: Germany
facility: Universitätsklinikum Augsburg
city: Berlin
country: Germany
facility: Helios Klinikum Berlin-Buch
city: Halle
country: Germany
facility: Martin Luther Universitat Halle Wittenberg
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg Eppendorf
city: Rostock
country: Germany
facility: Universitätsklinik Rostock
city: Stuttgart
country: Germany
facility: Robert Bosch Krankenhaus
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen
city: Athina
country: Greece
facility: Attikon University General Hospital
state: Attiki
city: Thessaloniki
country: Greece
facility: Georgios Papanikolaou General Hospital of Thessaloniki
city: Budapest
country: Hungary
facility: Del-pesti Centrumkorhaz- Orszagos Hematologiai és Infektologiai Intezet
city: Ramat Gan
country: Israel
facility: Sheba Medical Center - PPDS
state: HaMerkaz
city: Jerusalem
country: Israel
facility: Hadassah Medical Center - PPDS
state: Yerushalayim
city: Haifa
country: Israel
facility: Rambam Medical Center - PPDS
city: Tel-Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center PPDS
city: Brescia
country: Italy
facility: Ospedale Dell'Angelo
state: Lombardia
city: Torino
country: Italy
facility: Ospedale Infantile Regina Margherita - INCIPIT - PIN
state: Piemonte
city: Verona
country: Italy
facility: Azienda Ospedaliera Universitaria Integrata Di Verona
state: Veneto
city: Firenze
country: Italy
facility: Azienda Ospedaliera Universitaria Careggi
city: Milano
country: Italy
facility: Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario A Gemelli
city: Torino
country: Italy
facility: Azienda Ospedaliera Città della Salute e della Scienza di Torino
city: Busan
country: Korea, Republic of
facility: Dong-A University Hospital
city: Daegu
country: Korea, Republic of
facility: Keimyung University Dongsan Hospital
city: Grafton
country: New Zealand
facility: Auckland City Hospital
state: Auckland
city: Christchurch
country: New Zealand
facility: Canterbury Health Laboratories
state: South Island
city: Wroclaw
country: Poland
facility: Uniwersytecki Szpital Kliniczny im. Jana Mikulicza Radeckiego we Wroclawiu
state: Dolnoslaskie
city: Warszawa
country: Poland
facility: MTZ Clinical Research Sp z o o - PRATIA - PPDS
state: Mazowieckie
city: Gdansk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne
city: Saint Petersburg
country: Russian Federation
facility: First St. Petersburg State Medical University n.a. I.P Pavlov
state: Sankt-Peterburg
city: Irkutsk
country: Russian Federation
facility: Regional Oncology Center
city: Kirov
country: Russian Federation
facility: Kirov Research Institute of Haematology and Blood Transfusion
city: Singapore
country: Singapore
facility: National University Hospital
city: Singapore
country: Singapore
facility: Singapore General Hospital (SGH)
city: Badalona
country: Spain
facility: Hospital Universitario Germans Trias i Pujol
state: Barcelona
city: Santander
country: Spain
facility: Hospital Universitario Marques de Valdecilla
state: Cantabria
city: Salamanca
country: Spain
facility: Complejo Asistencial Universitario de Salamanca - H. Clinico
state: Castilla Y León
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebrón - PPDS
city: Barcelona
country: Spain
facility: ICO l'Hospitalet Hospital Duran i Reynals
city: Cordoba
country: Spain
facility: C.H. Regional Reina Sofia - PPDS
city: Granada
country: Spain
facility: Hospital Universitario Virgen de Las Nieves
city: Madrid
country: Spain
facility: Hospital Universitario de La Princesa
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal
city: Madrid
country: Spain
facility: Hospital Universitario Puerta de Hierro - Majadahonda
city: Málaga
country: Spain
facility: Hospital Regional Universitario de Malaga - Hospital General
city: San Sebastian Gipuzkoa
country: Spain
facility: Hospital Universitario de Donostia
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic La Fe de Valencia
city: Zurich
country: Switzerland
facility: Universitätsspital Zürich
city: Adana
country: Turkey
facility: Baskent University Medical Faculty Adana Practice and Research Center
city: Ankara
country: Turkey
facility: Ankara University Medica Faculty Hematology Department Clinical Research Area PPDS
city: West Midlands
country: United Kingdom
facility: Birmingham Heartlands Hospital
state: Birmingham
city: London
country: United Kingdom
facility: Hammersmith Hospital
state: London, City Of
city: London
country: United Kingdom
facility: University College London
state: London, City Of
city: Tooting
country: United Kingdom
facility: St George's Hospital
state: London
city: Liverpool
country: United Kingdom
facility: Clatterbridge Cancer Centre Liverpool
state: Merseyside
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust - PPDS
city: Southampton
country: United Kingdom
facility: Southampton University Hospitals NHS Trust
Study officials:
affiliation: Shire
name: Study Director
role: STUDY_DIRECTOR
References: