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)
- Registration Number
- NCT05319353
- Lead Sponsor
- Takeda
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 80
- 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.
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Cohort 3: Maribavir 400, 200, 100 or 50 mg Maribavir Participants with 0 to \< 6 years of age will receive maribavir 400 mg (2\*200 mg tablets or powder for oral suspension) BID based on body weight \>= 25 kg; or 200 mg tablet or powder for oral suspension BID based on body weight 14 to \< 25 kg; or 100 mg powder for oral suspension BID based on body weight 10 to \< 14 kg; or 50 mg powder for oral suspension BID based on body weight 7 to \< 10 kg; or 50 mg powder for oral suspension once daily (QD) based on body weight 5 to \<7 kg for up to 8 weeks treatment period (Day 1/Week 0 to Day 56/Week 8). Cohort 1: Maribavir 400, 200 or 100 mg Maribavir Participants with greater than or equal to (\>=) 12 to less than (\<) 18 years of age will receive maribavir 400 milligrams (mg) (2\*200 mg tablets or powder for oral suspension) twice daily (BID) based on body weight \>= 25 kilogram (kg); or 200 mg tablet or powder for oral suspension BID based on body weight 14 to \< 25 kg; or 100 mg powder for oral suspension BID based on body weight 10 to \< 14 kg for up to 8 weeks treatment period (Day 1/Week 0 to Day 56/Week 8). Cohort 2: Maribavir 400, 200 or 100 mg Maribavir Participants with \>= 6 to \< 12 years of age will receive maribavir 400 mg (2\*200 mg tablets or powder for oral suspension) BID based on body weight \>= 25 kg; or 200 mg tablet or powder for oral suspension BID based on body weight 14 to \< 25 kg; or 100 mg powder for oral suspension BID based on body weight 10 to \< 14 kg orally for up to 8 weeks treatment period (Day 1/Week 0 to Day 56/Week 8).
- Primary Outcome Measures
Name Time Method Maximum Observed Plasma Concentration (Cmax) of Maribavir Pre-dose; 0.5, 1.5, 3, 4, 6, and 8 hours post-dose on Day 7 (Week 1) Cmax of maribavir will be evaluated.
Time to Maximum Observed Concentration (Tmax) of Maribavir Pre-dose; 0.5, 1.5, 3, 4, 6, and 8 hours post-dose on Day 7 (Week 1) Tmax of maribavir will be evaluated.
Minimum Plasma Concentration (Cmin) of Maribavir 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) Cmin of maribavir will be evaluated.
Apparent Oral Clearance (CL/F) of Maribavir Pre-dose; 0.5, 1.5, 3, 4, 6, and 8 hours post-dose on Day 7 (Week 1) CL/F of maribavir will be evaluated.
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) From start of study drug administration up to follow-up (Week 20) An AE is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily be considered related to investigational product. SAE is any untoward medical occurrence (whether considered related to investigational product or not) that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital abnormality or birth defect, or is an important medical event.
Area Under the Plasma Concentration-Time Curve Over the 1 Dosing Interval of 12 Hours at Steady State (AUC0-tau) of Maribavir Pre-dose; 0.5, 1.5, 3, 4, 6, and 8 hours post-dose on Day 7 (Week 1) AUC0-tau of maribavir will be evaluated.
Half-Life (t1/2) of Maribavir Pre-dose; 0.5, 1.5, 3, 4, 6, and 8 hours post-dose on Day 7 (Week 1) t1/2 of maribavir will be evaluated.
Terminal Elimination Rate Constant (lambdaz) of Maribavir Pre-dose; 0.5, 1.5, 3, 4, 6, and 8 hours post-dose on Day 7 (Week 1) Lambdaz of maribavir will be evaluated.
Apparent Volume of Distribution (Vz/F) of Maribavir Pre-dose; 0.5, 1.5, 3, 4, 6, and 8 hours post-dose on Day 7 (Week 1) Vz/F of maribavir will be evaluated.
- Secondary Outcome Measures
Name Time Method Percentage of Participants With Confirmed Recurrence of CMV Viremia on Study Treatment and Off Study Treatment Up to Week 20 Confirmed recurrence of CMV viremia is defined as plasma CMV DNA concentration greater than or equal to (\>=) LLOQ when assessed in 2 consecutive plasma samples at least 5 days apart, after achieving confirmed viremia clearance. Percentage of participants with confirmed recurrence of viremia on study treatment and off study treatment will be reported.
Change From Baseline in Log10 Plasma CMV Deoxyribonucleic Acid (DNA) Load Baseline up to Week 20 Change from baseline in log10 plasma CMV DNA on study after receiving study treatment by study week will be reported.
Percentage of Participants With Confirmed CMV viremia Clearance at Week 8 At Week 8 Confirmed CMV viremia clearance is defined as plasma CMV DNA concentration below the lower limit of quantification (LLOQ) at a central specialty laboratory, in 2 consecutive postbaseline samples, separated by at least 5 days at Week 8 regardless of the length of study treatment. Percentage of participants with confirmed CMV viremia clearance at Week 8 will be reported.
Percentage of Participants who Achieve Maintenance of Confirmed CMV Viremia Clearance and Symptom Control at Week 8 Through Weeks 12, 16 and 20 At Week 8 through Weeks 12, 16, and 20 Confirmed CMV viremia clearance is defined as plasma CMV DNA concentration below the lower LLOQ at a central specialty laboratory, in 2 consecutive postbaseline samples, separated by at least 5 days regardless of the length of study treatment. CMV infection symptom control is defined as resolution or improvement of tissue invasive disease or CMV syndrome for symptomatic participants at baseline, or no new symptoms for asymptomatic participants at baseline. Percentage of participants who achieve maintenance of confirmed CMV viremia clearance and symptom control at Week 8 through Weeks 12, 16 and 20 will be reported.
Time to First Confirmed Viremia Clearance Up to Week 20 Confirmed CMV viremia clearance is defined as plasma CMV DNA concentration below the lower LLOQ when assessed at a central specialty laboratory, in 2 consecutive postbaseline samples, separated by at least 5 days. Time to first confirmed viremia clearance at any time during the study will be summarized using the Kaplan-Meier method.
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 From Week 8 through Week 20 Confirmed recurrence of CMV viremia is defined as plasma CMV DNA concentration \>= LLOQ when assessed in 2 consecutive plasma samples at least 5 days apart, after achieving confirmed viremia clearance. Percentage of participants with confirmed recurrence of CMV viremia treated with alternative anti-CMV treatment in the 12-Week follow-up period in participants with confirmed viremia clearance at Week 8 will be reported.
Number of Participants who Develop CMV Resistance to Maribavir Up to Week 12 CMV DNA genotyping will be performed for the UL97, UL54, UL56, and UL27 genes known to confer resistance to conventional anti-CMV therapies or Maribavir. Number of participants who developed post-baseline CMV resistance to maribavir up to Week 12 will be reported.
Summary Scores for Palatability Assessment of Maribavir At Weeks 1, 4, and 8 Palatability (taste, feel, smell, ease of swallowing and after-taste) is being measured using a 5-point facial hedonic scale correlated with a 100-point linear visual analogue scale (VAS) ranges from 0: very bad to 100: very good. Scores will be summarized descriptively at Weeks 1, 4 and 8.
Trial Locations
- Locations (47)
Irmandade Da Santa Casa de Misericordia de Porto Alegre
🇧🇷Porto Alegre, Rio Grande Do Sul, Brazil
Hospital de Clinicas de Porto Alegre (HCPA) - PPDS
🇧🇷Porto Alegre, Rio Grande Do Sul, Brazil
Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo
🇧🇷Porto Alegre, Rio Grande Do Sul, Brazil
Hospital Do Rim E Hipertensão
🇧🇷São Paulo, Brazil
Children's Hospital Capital Institute of Pediatrics
🇨🇳Beijing, Beijing, China
Beijing Children's Hospital, Capital Medical University - PIN
🇨🇳Beijing, Beijing, China
Shanghai Children's Medical Center
🇨🇳Shanghai, Shanghai, China
Institute of Hematology and Blood Diseases Hospital Chinese Academy of Medical Sciences - PPDS
🇨🇳Tianjin, Tianjin, China
CHU de Rennes - Hôpital Pontchaillou
🇫🇷Rennes, Ille-et-Vilaine, France
CHU de Grenoble Alpes - Hôpital Michallon
🇫🇷La Tronche, Isère, France
CHRU Nantes
🇫🇷Nantes, Loire-Atlantique, France
Hopital Necker
🇫🇷Paris, France
Universitätsklinikum Würzburg
🇩🇪Würzburg, Bayern, Germany
Universitätsklinikum Münster
🇩🇪Münster, Nordrhein-Westfalen, Germany
Universitatsklinikum Jena - Am Klinikum 1-Erlanger Allee 101
🇩🇪Jena, Thüringen, Germany
Universitätsklinikum Hamburg Eppendorf
🇩🇪Hamburg, Germany
Medizinische Hochschule Hannover
🇩🇪Hannover, Germany
The Chaim Sheba Medical Center - PPDS
🇮🇱Ramat Gan, Tel-Aviv, Israel
Tel Aviv Sourasky Medical Center Ichilov - PPDS
🇮🇱Tel Aviv-Yafo, Tel-Aviv, Israel
Rambam Health Care Campus - PPDS
🇮🇱Haifa, Israel
Hadassah Medical Center- Ein Kerem - PPDS
🇮🇱Petah Tiqva, Israel
National Center for Child Health and Development
🇯🇵Nagoya-Shi, Aiti, Japan
Saitama Children's Medical Center
🇯🇵Isehara-Shi, Kanagawa, Japan
Shizuoka Children's Hospital
🇯🇵Aoi-ku, Sizuoka, Japan
Hyogo Prefectural Kobe Children's Hospital
🇯🇵Chiba-Shi, Japan
Osaka Women's and Children's Hospital
🇯🇵Izumi-Shi, Ôsaka, Japan
Hospital Sant Joan de Deu - PIN
🇪🇸Espluges De Llobregat, Barcelona, Spain
Hospital Universitario La Paz - PPDS
🇪🇸Horcajo de la Sierra, Madrid, Spain
Hospital Regional Universitario de Malaga - Hospital Materno-Infantil
🇪🇸Malaga, Málaga, Spain
Hospital Universitario Vall d´Hebron- PPDS
🇪🇸Barcelona, Spain
Hospital Infantil Universitario Niño Jesus - PIN
🇪🇸Madrid, Spain
Nottingham University Hospitals NHS Trust
🇬🇧Nottingham, Nottinghamshire, United Kingdom
Birmingham Women's and Children's NHS Foundation Trust
🇬🇧Birmingham, West Midlands, United Kingdom
King's College Hospital
🇬🇧London, Lambeth, United Kingdom
Royal Manchester Children's Hospital - PIN
🇬🇧Manchester, Lancashire, United Kingdom
Great Ormond Street Hospital
🇬🇧London, United Kingdom
University of Nebraska Medical Center -985400 Nebraska Medical Center
🇺🇸Omaha, Nebraska, United States
Cincinnati Children's Hospital Medical Center - PIN
🇺🇸Cincinnati, Ohio, United States
Cook Children's Health Care System
🇺🇸Fort Worth, Texas, United States
University of Texas MD Anderson Cancer Center - 1515 Holcombe Blvd
🇺🇸Houston, Texas, United States
Sydney Children's Hospital
🇦🇺Randwick, New South Wales, Australia
Queensland Children's Hospital
🇦🇺South Brisbane, Queensland, Australia
Perth Children's Hospital
🇦🇺Nedlands, Western Australia, Australia
Royal Children's Hospital Melbourne - PIN
🇦🇺Parkville, Victoria, Australia
Hôpital Universitaire des Enfants Reine Fabiola (HUDERF)
🇧🇪Bruxelles, Brussels, Belgium
Cliniques Universitaires Saint-Luc
🇧🇪Sint-Lambrechts-Woluwe, Brussels, Belgium
UZ Gent
🇧🇪Gent, Oost-Vlaanderen, Belgium