Clinical trial NCT05319353: A Study to Evaluate the Safety and Tolerability, Pharmacokinetics, and Antiviral Activity of Maribavir for the Treatment of Cytomegalovirus (CMV) Infection in Children and Adolescents Who Have Received a Hematopoietic Stem Cell Transplant (HSCT) or a Solid Organ Transplant (SOT)
Official title: A Phase 3, Open-label, Single-arm, Repeated-dose Study to Evaluate the Safety and Tolerability, Pharmacokinetics, and Antiviral Activity of Maribavir for the Treatment of Cytomegalovirus (CMV) Infection in Children and Adolescents Who Have Received a Hematopoietic Stem Cell Transplant (HSCT) or a Solid Organ Transplant (SOT)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Cytomegalovirus (CMV)
Lead sponsor: Takeda
Sponsor class: INDUSTRY
Collaborators: name: Takeda Development Center Americas, Inc.
First posted: 2022-04-08
Enrollment: 80
Sex: ALL
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Intervention model description: Three dosing cohorts based on participant's age.
Primary purpose: TREATMENT

Brief summary: The main aim of this study is to find out the safety, tolerability and pharmacokinetics (PK) of maribavir for the treatment of CMV infection in children and teenagers after HSCT or SOT and to identify the optimal dose of maribavir using a 200 milligrams (mg) tablet formulation or powder for oral suspension.

The participants will be treated with maribavir for 8 weeks.

Participants need to visit their doctor during 12-week follow-up period.


Eligibility criteria: Inclusion Criteria:

* Parent/both parents or legally authorized representative (LAR) must provide signature of informed consent and there must be documentation of assent by the participant, as age appropriate, before completing any study-related procedures.
* Be a male or female child or adolescent \< 18 years of age at the time of consent. For participants in Cohort 3 only (0 to \<6 years) must have a gestational age of at least 39 weeks and a minimum weight of 5 kg.
* Be a recipient of an SOT or an HSCT that is functioning at the time of screening.
* Have a documented CMV infection which may be a first episode of post-transplant CMV viremia (primary or reactivation) or refractory to other anti-CMV treatments, with a CMV DNA screening value of \>= 1365 International Units per milliliter (IU/mL) in whole blood or \>= 455 IU/mL in plasma in 2 consecutive assessments separated by at least 1 day, as determined by local laboratory quantitative polymerase chain reaction (qPCR) or comparable quantitative nucleic acid amplification test (qNAAT) results. Quantitative assays must be standardized to the World Health Organization (WHO) CMV International Standard. Both samples must be taken within 14 days of first dose of study drug, with the second sample obtained within 5 days prior to first dose of study drug. The same laboratory and same sample type (whole blood or plasma) must be used for both assessments. If documented and verified values are available in medical history that fulfill this criterion entirely, they may be used instead.
* Have all the following results as part of screening laboratory assessments:
* Absolute neutrophil count \>= 500 per cubic millimeter (/mm\^3) (0.5 × 10\^9 per liter \[/L\])
* Platelet count \>= 15,000/mm\^3 (15 × 10\^9/L)
* Hemoglobin \>= 8 grams per deciliter (g/dL) (\>=80 grams per liter \[g/L\]).
* Have an estimated glomerular filtration rate (creatinine-based Bedside Schwartz equation) \>= 30 milliliters per minute (mL/min) /1.73 meter square (m\^2).
* Be a female of nonchildbearing potential. If a female of childbearing potential, have a negative serum human chorionic gonadotropin (hCG) or beta-human chorionic gonadotropin (β-hCG) pregnancy test at screening. Males, or nonpregnant, nonlactating females who are sexually active must agree to comply with the applicable contraceptive requirements of this protocol during the study treatment administration period and for 90 days after the last dose of study treatment.
* Have life expectancy of \>= 8 weeks.
* Be willing and have an understanding and ability to fully comply with the study procedures and restrictions defined in the protocol. For younger children, the parent/both parents or LAR must meet this criterion.
* Participants must have a confirmed negative human immunodeficiency virus (HIV) test result within 3 months of first dose of study drug or, if unavailable, be tested by a local laboratory during the screening period.

Exclusion Criteria:

* Have CMV tissue invasive disease involving the central nervous system (CNS) or retina as assessed by the investigator at the time of screening.
* Have uncontrolled other type of infection as assessed by the investigator on the date of enrollment.
* Have a history of clinically relevant alcohol or drug abuse that may interfere with treatment compliance or assessments with the protocol as determined by the investigator.
* Be receiving valganciclovir, ganciclovir, cidofovir, foscarnet, leflunomide, letermovir, or artesunate when study treatment is initiated, or anticipated to require one of these agents during the 8-week treatment period.
* Have a known hypersensitivity to maribavir or to any excipients.
* Have severe vomiting, diarrhea, or other severe gastrointestinal (GI) illness within 24 hours prior to the first dose of study treatment or a GI absorption abnormality that would preclude administration of oral medication.
* Require mechanical ventilation or vasopressors for hemodynamic support at baseline (Visit 2/Day 1/Week 0).
* Be pregnant (or expecting to conceive) or nursing.
* Have previously completed, discontinued, or have been withdrawn from this study.
* Have received any investigational agent or device within 30 days before initiation of study treatment (includes CMV specific T-cells) or plan to receive an investigational agent or device during the study.

Previously approved agents under investigation for additional indications are not exclusionary.

* Have previously received maribavir or CMV vaccine at any time.
* 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 study treatment, or compromise the safety or well-being of the participant.
* Have severe liver disease (Child-Pugh score of \>= 10).
* Have serum aspartate aminotransferase greater than (\>) 5 times upper limit of normal (ULN) at screening, or serum alanine aminotransferase \> 5 times ULN at screening, or total bilirubin \>= 3.0 times ULN at screening (except for documented Gilbert's syndrome), as analyzed by local laboratory.
* Have positive results for HIV.
* 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 or SOT was performed), as determined by the investigator, are not to be enrolled.
* Be undergoing treatment for acute or chronic hepatitis B or hepatitis C.
* Requiring ongoing treatment with or an anticipated need for treatment with a strong cytochrome P450 3A (CYP3A) inducer.
* Have a low body weight where total blood volume (TBV) required during study participation will exceed 1 percent (%) TBV per study visit or 3% TBV over a 4-week period.

Primary outcomes:
measure: Maximum Observed Plasma Concentration (Cmax) of Maribavir
timeFrame: Pre-dose; 0.5, 1.5, 3, 4, 6, and 8 hours post-dose on Day 7 (Week 1)
measure: Time to Maximum Observed Concentration (Tmax) of Maribavir
timeFrame: Pre-dose; 0.5, 1.5, 3, 4, 6, and 8 hours post-dose on Day 7 (Week 1)
measure: Minimum Plasma Concentration (Cmin) of Maribavir
timeFrame: Pre-dose; (0.5, 1.5, 3, 4, 6, and 8 hours post-dose) on Day 7 (Week 1); Pre-dose on Day 28 (Week 4); Pre-dose; (2 to 4 hours post-dose) on Day 56 (Week 8)
measure: Area Under the Plasma Concentration-Time Curve Over the 1 Dosing Interval of 12 Hours at Steady State (AUC0-tau) of Maribavir
timeFrame: Pre-dose; 0.5, 1.5, 3, 4, 6, and 8 hours post-dose on Day 7 (Week 1)
measure: Half-Life (t1/2) of Maribavir
timeFrame: Pre-dose; 0.5, 1.5, 3, 4, 6, and 8 hours post-dose on Day 7 (Week 1)
measure: Terminal Elimination Rate Constant (lambdaz) of Maribavir
timeFrame: Pre-dose; 0.5, 1.5, 3, 4, 6, and 8 hours post-dose on Day 7 (Week 1)
measure: Apparent Volume of Distribution (Vz/F) of Maribavir
timeFrame: Pre-dose; 0.5, 1.5, 3, 4, 6, and 8 hours post-dose on Day 7 (Week 1)
measure: Apparent Oral Clearance (CL/F) of Maribavir
timeFrame: Pre-dose; 0.5, 1.5, 3, 4, 6, and 8 hours post-dose on Day 7 (Week 1)
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: From start of study drug administration up to follow-up (Week 20)
Secondary outcomes:
measure: Percentage of Participants With Confirmed CMV viremia Clearance at Week 8
timeFrame: At Week 8
measure: Percentage of Participants who Achieve Maintenance of Confirmed CMV Viremia Clearance and Symptom Control at Week 8 Through Weeks 12, 16 and 20
timeFrame: At Week 8 through Weeks 12, 16, and 20
measure: Percentage of Participants With Confirmed Recurrence of CMV Viremia on Study Treatment and Off Study Treatment
timeFrame: Up to Week 20
measure: Time to First Confirmed Viremia Clearance
timeFrame: Up to Week 20
measure: Percentage of Participants With Confirmed Recurrence of CMV Viremia Treated With Alternative Anti-CMV Treatment During 12-Week Follow-up Period in Participants With Confirmed Viremia Clearance at Week 8
timeFrame: From Week 8 through Week 20
measure: Change From Baseline in Log10 Plasma CMV Deoxyribonucleic Acid (DNA) Load
timeFrame: Baseline up to Week 20
measure: Number of Participants who Develop CMV Resistance to Maribavir
timeFrame: Up to Week 12
measure: Summary Scores for Palatability Assessment of Maribavir
timeFrame: At Weeks 1, 4, and 8
Other outcomes:
Locations:
city: Omaha
country: United States
facility: University of Nebraska Medical Center -985400 Nebraska Medical Center
state: Nebraska
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center - PIN
state: Ohio
city: Fort Worth
country: United States
facility: Cook Children's Health Care System
state: Texas
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center - 1515 Holcombe Blvd
state: Texas
city: Randwick
country: Australia
facility: Sydney Children's Hospital
state: New South Wales
city: South Brisbane
country: Australia
facility: Queensland Children's Hospital
state: Queensland
city: Parkville
country: Australia
facility: Royal Children's Hospital Melbourne - PIN
state: Victoria
city: Nedlands
country: Australia
facility: Perth Children's Hospital
state: Western Australia
city: Bruxelles
country: Belgium
facility: Hôpital Universitaire des Enfants Reine Fabiola (HUDERF)
state: Brussels
city: Sint-Lambrechts-Woluwe
country: Belgium
facility: Cliniques Universitaires Saint-Luc
state: Brussels
city: Gent
country: Belgium
facility: UZ Gent
state: Oost-Vlaanderen
city: Porto Alegre
country: Brazil
facility: Irmandade Da Santa Casa de Misericordia de Porto Alegre
state: Rio Grande Do Sul
city: Porto Alegre
country: Brazil
facility: Hospital de Clinicas de Porto Alegre (HCPA) - PPDS
state: Rio Grande Do Sul
city: Porto Alegre
country: Brazil
facility: Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo
state: Rio Grande Do Sul
city: São Paulo
country: Brazil
facility: Hospital Do Rim E Hipertensão
city: Beijing
country: China
facility: Children's Hospital Capital Institute of Pediatrics
state: Beijing
city: Beijing
country: China
facility: Beijing Children's Hospital, Capital Medical University - PIN
state: Beijing
city: Shanghai
country: China
facility: Shanghai Children's Medical Center
state: Shanghai
city: Tianjin
country: China
facility: Institute of Hematology and Blood Diseases Hospital Chinese Academy of Medical Sciences - PPDS
state: Tianjin
city: Rennes
country: France
facility: CHU de Rennes - Hôpital Pontchaillou
state: Ille-et-Vilaine
city: La Tronche
country: France
facility: CHU de Grenoble Alpes - Hôpital Michallon
state: Isère
city: Nantes
country: France
facility: CHRU Nantes
state: Loire-Atlantique
city: Paris
country: France
facility: Hopital Necker
city: Würzburg
country: Germany
facility: Universitätsklinikum Würzburg
state: Bayern
city: Münster
country: Germany
facility: Universitätsklinikum Münster
state: Nordrhein-Westfalen
city: Jena
country: Germany
facility: Universitatsklinikum Jena - Am Klinikum 1-Erlanger Allee 101
state: Thüringen
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg Eppendorf
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Ramat Gan
country: Israel
facility: The Chaim Sheba Medical Center - PPDS
state: Tel-Aviv
city: Tel Aviv-Yafo
country: Israel
facility: Tel Aviv Sourasky Medical Center Ichilov - PPDS
state: Tel-Aviv
city: Haifa
country: Israel
facility: Rambam Health Care Campus - PPDS
city: Petah Tiqva
country: Israel
facility: Hadassah Medical Center- Ein Kerem - PPDS
city: Nagoya-Shi
country: Japan
facility: National Center for Child Health and Development
state: Aiti
city: Isehara-Shi
country: Japan
facility: Saitama Children's Medical Center
state: Kanagawa
city: Aoi-ku
country: Japan
facility: Shizuoka Children's Hospital
state: Sizuoka
city: Chiba-Shi
country: Japan
facility: Hyogo Prefectural Kobe Children's Hospital
city: Izumi-Shi
country: Japan
facility: Osaka Women's and Children's Hospital
state: Ôsaka
city: Espluges De Llobregat
country: Spain
facility: Hospital Sant Joan de Deu - PIN
state: Barcelona
city: Horcajo de la Sierra
country: Spain
facility: Hospital Universitario La Paz - PPDS
state: Madrid
city: Malaga
country: Spain
facility: Hospital Regional Universitario de Malaga - Hospital Materno-Infantil
state: Málaga
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d´Hebron- PPDS
city: Madrid
country: Spain
facility: Hospital Infantil Universitario Niño Jesus - PIN
city: London
country: United Kingdom
facility: King's College Hospital
state: Lambeth
city: Manchester
country: United Kingdom
facility: Royal Manchester Children's Hospital - PIN
state: Lancashire
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust
state: Nottinghamshire
city: Birmingham
country: United Kingdom
facility: Birmingham Women's and Children's NHS Foundation Trust
state: West Midlands
city: London
country: United Kingdom
facility: Great Ormond Street Hospital
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References: