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)

Официальное название

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)

Обзор

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.

Вмешательства

• Препарат Maribavir
  Participants will receive maribavir.

Первичные конечные точки

• Maximum Observed Plasma Concentration (Cmax) of Maribavir [Срок оценки: Pre-dose; 0.5, 1.5, 3, 4, 6, and 8 hours post-dose on Day 7 (Week 1)]
• Time to Maximum Observed Concentration (Tmax) of Maribavir [Срок оценки: Pre-dose; 0.5, 1.5, 3, 4, 6, and 8 hours post-dose on Day 7 (Week 1)]
• Minimum Plasma Concentration (Cmin) of Maribavir [Срок оценки: 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)]
• Area Under the Plasma Concentration-Time Curve Over the 1 Dosing Interval of 12 Hours at Steady State (AUC0-tau) of Maribavir [Срок оценки: Pre-dose; 0.5, 1.5, 3, 4, 6, and 8 hours post-dose on Day 7 (Week 1)]
• Half-Life (t1/2) of Maribavir [Срок оценки: Pre-dose; 0.5, 1.5, 3, 4, 6, and 8 hours post-dose on Day 7 (Week 1)]
• Terminal Elimination Rate Constant (lambdaz) of Maribavir [Срок оценки: Pre-dose; 0.5, 1.5, 3, 4, 6, and 8 hours post-dose on Day 7 (Week 1)]
• Apparent Volume of Distribution (Vz/F) of Maribavir [Срок оценки: Pre-dose; 0.5, 1.5, 3, 4, 6, and 8 hours post-dose on Day 7 (Week 1)]
• Apparent Oral Clearance (CL/F) of Maribavir [Срок оценки: Pre-dose; 0.5, 1.5, 3, 4, 6, and 8 hours post-dose on Day 7 (Week 1)]
• Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [Срок оценки: From start of study drug administration up to follow-up (Week 20)]

Вторичные конечные точки (8)

• Percentage of Participants With Confirmed CMV viremia Clearance at Week 8 [Срок оценки: At Week 8]
• Percentage of Participants who Achieve Maintenance of Confirmed CMV Viremia Clearance and Symptom Control at Week 8 Through Weeks 12, 16 and 20 [Срок оценки: At Week 8 through Weeks 12, 16, and 20]
• Percentage of Participants With Confirmed Recurrence of CMV Viremia on Study Treatment and Off Study Treatment [Срок оценки: Up to Week 20]
• Time to First Confirmed Viremia Clearance [Срок оценки: Up to Week 20]
• 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 [Срок оценки: From Week 8 through Week 20]
• Change From Baseline in Log10 Plasma CMV Deoxyribonucleic Acid (DNA) Load [Срок оценки: Baseline up to Week 20]
• Number of Participants who Develop CMV Resistance to Maribavir [Срок оценки: Up to Week 12]
• Summary Scores for Palatability Assessment of Maribavir [Срок оценки: At Weeks 1, 4, and 8]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 8 центров

• Nemours Children's Health - Wilmington - PIN — Wilmington
• Johns Hopkins All Children's Hospital - Main - PIN — St. Petersburg
• Ann and Robert H Lurie Childrens Hospital of Chicago - PIN — Chicago
• University of Nebraska Medical Center -985400 Nebraska Medical Center — Omaha
• Cincinnati Children's Hospital Medical Center - PIN — Cincinnati
• Cook Children's Health Care System — Fort Worth
• University of Texas MD Anderson Cancer Center - 1515 Holcombe Blvd — Houston
• Texas Children's Hospital - Wallace Tower - PIN — Houston

Китай · 6 центров

• Capital Center For Children's Healthy, Capital Medical University — Пекин
• Beijing Children's Hospital, Capital Medical University - PIN — Пекин
• The First Affiliated Hospital, Sun Yat-sen University - Main — Гуанчжоу
• Shenzhen Children's Hospital — Шэньчжэнь
• Shanghai Children's Medical Center - Zhangjiang Campus — Шанхай
• Institute of Hematology and Blood Diseases Hospital Chinese Academy of Medical Sciences - — Тяньцзинь

Германия · 5 центров

• Universitätsklinikum Würzburg — Würzburg
• Universitätsklinikum Münster — Münster
• Universitatsklinikum Jena - Am Klinikum 1-Erlanger Allee 101 — Jena
• Universitätsklinikum Hamburg Eppendorf — Hamburg
• Medizinische Hochschule Hannover — Hanover

Япония · 5 центров

• Saitama Prefectural Children's Medical Center — Saitama-Shi Chuo-Ku
• Shizuoka Children's Hospital — Aoi-ku
• National Center for Child Health and Development — Setagaya-Ku
• Hyogo Prefectural Kobe Children's Hospital — Chiba
• Osaka Women's and Children's Hospital — Izumi-Shi

Испания · 5 центров

• Hospital Sant Joan de Deu - PIN — Espluges de Llobregat
• Hospital Universitario La Paz - PPDS — Horcajo de la Sierra
• Hospital Regional Universitario de Malaga - Hospital Materno-Infantil — Málaga
• Hospital Universitario Vall d´Hebron- PPDS — Barcelona
• Hospital Infantil Universitario Niño Jesus - PIN — Madrid

Великобритания · 5 центров

• King's College Hospital — London
• Royal Manchester Children's Hospital - PIN — Manchester
• Nottingham University Hospitals NHS Trust — Nottingham
• Birmingham Women's and Children's NHS Foundation Trust — Birmingham
• Great Ormond Street Hospital — London

Австралия · 4 центра

• Minderoo Children's Comprehensive Cancer Centre — Randwick
• Queensland Children's Hospital — Woollangabba
• Royal Children's Hospital Melbourne - PIN — Parkville
• Perth Children's Hospital — Nedlands

Бразилия · 4 центра

• Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo — Porto Alegre
• Irmandade Da Santa Casa de Misericordia de Porto Alegre — Porto Alegre
• Hospital de Clinicas de Porto Alegre (HCPA) - PPDS — Porto Alegre
• Hospital Do Rim E Hipertensão — São Paulo

Франция · 4 центра

• CHU de Rennes - Hôpital Pontchaillou — Rennes
• CHU de Grenoble Alpes - Hôpital Michallon — La Tronche
• CHRU Nantes — Nantes
• Hopital Necker — Paris

Израиль · 4 центра

• The Chaim Sheba Medical Center - PPDS — Ramat Gan
• Tel Aviv Sourasky Medical Center Ichilov - PPDS — Tel Aviv
• Rambam Health Care Campus - PPDS — Haifa
• Hadassah Medical Center- Ein Kerem - PPDS — Petah Tikva

Бельгия · 3 центра

• Hôpital Universitaire des Enfants Reine Fabiola (HUDERF) — Brussels
• Cliniques Universitaires Saint-Luc — Woluwe-Saint-Lambert
• UZ Gent — Ghent

Публикации

• Fisher JE, Mulieri K, Finch E, Ericson JE. Use of Maribavir for Multidrug Resistant Cytomegaloviremia in a Pediatric Oncology Patient. J Pediatr Hematol Oncol. 2024 Apr 1;46(3):e244-e247. doi: 10.1097/MPH.0000000000002841. Epub 2024 Mar 1. PMID 38447094

Идентификаторы

NCT: NCT05319353 · TAK-620-2004 · 2021-004279-15 · jRCT2031230753 · 2023-508988-73-00

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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