Evaluation of Maribavir for Cytomegalovirus Infection in Pediatric Hematopoietic Stem Cell and Solid Organ Transplant Recipients
- Trial ID
- 2023-508988-73-00
- Protocol
- TAK-620-2004
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to characterize the **pharmacokinetics** of maribavir and identify appropriate dosing regimens for the treatment of **cytomegalovirus (CMV) infection** in pediatric patients who have undergone hematopoietic stem cell transplant (HSCT) or solid organ transplant (SOT). Additionally, the study aims to assess the safety and tolerability of maribavir in children and adolescents. Understanding the pharmacokinetics is crucial for optimizing dosing strategies, ensuring efficacy, and minimizing potential adverse effects in this vulnerable population.
Secondary objectives include:
- Evaluating the antiviral activity of maribavir in CMV viremia clearance at the end of Week 8, regardless of the length of study treatment.
- Assessing the maintenance of CMV viremia clearance and symptom control achieved at Week 8, through Week 12, Week 16, and Week 20.
- Evaluating the recurrence of CMV viremia while on study treatment and off study treatment.
- Evaluating the time to first confirmed viremia clearance.
- Evaluating the recurrence of CMV viremia requiring treatment during the 12-week follow-up period in subjects with confirmed viremia clearance at Week 8.
- Assessing the time course of changes in plasma CMV deoxyribonucleic acid (DNA) load from baseline.
- Assessing the profile of mutations in the CMV genes conferring resistance to maribavir.
- Assessing the acceptability and palatability of maribavir.
Participants
The clinical trial involves a total of **46 participants** who are children and adolescents under the age of 18, with a specific focus on those who have received a hematopoietic stem cell transplant (HSCT) or a solid organ transplant (SOT). The study population includes both **male and female** subjects, and it is noted that the participants are considered a vulnerable population due to their medical conditions. The trial targets individuals with a documented **Cytomegalovirus (CMV) infection**, characterized by specific CMV DNA levels in blood or plasma. Participants were selected based on their transplant status and CMV infection criteria, ensuring they meet certain health parameters such as adequate neutrophil and platelet counts, hemoglobin levels, and kidney function. Lifestyle considerations such as diet and physical activity are not specified, but participants must be able to swallow a whole tablet and have a life expectancy of at least eight weeks. The trial aims to assess the pharmacokinetics, safety, and tolerability of maribavir in this pediatric population.
Plans and Procedures
The clinical trial is a **Phase 3**, open-label, single-arm study designed to evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of **maribavir** in the treatment of **cytomegalovirus (CMV) infection** in pediatric patients who have undergone a hematopoietic stem cell transplant (HSCT) or a solid organ transplant (SOT). The trial will involve repeated dosing of maribavir, administered orally in tablet form, with a maximum daily dose of 800 mg and a total treatment period of up to 8 weeks. The study aims to identify appropriate dosing regimens for children and adolescents under 18 years of age, while also assessing the safety profile of the drug.
Participants will be involved in the study for a period that includes the treatment phase and a follow-up period, with the overall trial expected to conclude by March 31, 2027. The trial will commence recruitment on November 13, 2023. The sequence of study visits includes an initial screening visit to confirm eligibility, followed by regular visits during the treatment phase to monitor pharmacokinetics and safety parameters. Key assessments will be conducted at Week 1, Week 4, and Week 8, with additional follow-up visits at Weeks 12, 16, and 20 to evaluate the maintenance of CMV viremia clearance and symptom control.
Inclusion criteria require participants to be under 18 years of age, have a documented CMV infection, and meet specific laboratory and health criteria. Exclusion criteria are not explicitly detailed in the provided data. Participants may be withdrawn from the study if they experience serious adverse events, fail to comply with study procedures, or if the investigator deems it necessary for safety reasons. The primary endpoints include pharmacokinetic measurements at steady state and safety assessments, while secondary endpoints focus on the achievement and maintenance of CMV viremia clearance and the evaluation of maribavir's resistance profile.
Treatment
The clinical trial involves the administration of **maribavir**, an investigational antiviral medication, for the treatment of cytomegalovirus (CMV) infection in pediatric patients who have undergone hematopoietic stem cell transplant (HSCT) or solid organ transplant (SOT). The experimental medication is provided in the form of a **tablet** and is administered orally. The maximum daily dose of maribavir is 800 mg, with a total maximum dose of 44,800 mg over a treatment period of up to 8 weeks. The pharmaceutical form of maribavir is a standard tablet, and it is not a pediatric-specific formulation. The medication is of chemical origin and is identified by the sponsor product code TAK-620. The product is manufactured by SHIRE VIROPHARMA, INC.
Additionally, the trial includes the use of LIVTENCITY 200 mg film-coated tablets, which also contain the active substance **maribavir**. These tablets are similarly administered orally, with a maximum daily dose of 800 mg and a total maximum dose of 44,800 mg over the same treatment period of up to 8 weeks. LIVTENCITY is a film-coated tablet, and like the standard maribavir tablet, it is not formulated specifically for pediatric use. The product is of chemical origin and is produced by TAKEDA PHARMACEUTICALS INTERNATIONAL AG IRELAND BRANCH. The study-specific labeling is applied to this product, and it is identified by the marketing authorization number EU/1/22/1672/001.
Throughout the trial, participant compliance with the dosing regimen is monitored to ensure adherence to the prescribed treatment schedule. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. The primary objective of the trial is to evaluate the pharmacokinetics, safety, and tolerability of maribavir in the specified patient population.
Efficacy
Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the pharmacokinetics (PK) of **maribavir** at steady state, which will be evaluated by measuring parameters such as the maximum observed plasma concentration (Cmax), time to reach Cmax (Tmax), minimum concentration before dosing (Cmin), area under the plasma concentration-time curve over a 12-hour dosing interval (AUC0-tau), half-life (t1/2), terminal elimination rate constant (λz), apparent volume of distribution (Vz/F), and apparent oral clearance (CL/F). These PK samples will be collected at Week 1, with additional Cmin measurements at Week 4 and Week 8.
Secondary endpoints focus on the virological response and include the achievement of confirmed clearance of plasma CMV DNA, defined as a concentration below the lower limit of quantification in two consecutive post-baseline samples at Week 8. The maintenance of CMV viremia clearance and symptom control will be monitored through Week 12, Week 16, and Week 20. Other secondary endpoints include the recurrence of CMV viremia, time to first confirmed viremia clearance, recurrence treated with alternative anti-CMV treatment, changes in plasma CMV DNA load from baseline, and the resistance profile of maribavir. Additionally, the acceptability and palatability of maribavir will be assessed at Weeks 1, 4, and 8 or at the end of treatment.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Parent/both parents or LAR must provide signature of informed consent and there must be documentation of assent by the subject, as age appropriate, before completing any study-related procedures.
- "10. 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. "
- Be a male or female child or adolescent <18 years of age at the time of consent; for subjects in Cohort 3 only (0 to <6 years),, must have a minimum gestational age of at least 39 weeks and minimum weight of 5 kg.
- "3. 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 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 qPCR or comparable 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 a documented and verified value is available in medical history that fulfills this criterion entirely, it may be used instead.
- Have all the following results as part of screening laboratory assessments: a. Absolute neutrophil count ≥500/mm3 (0.5 × 10^9/L) b. Platelet count ≥15,000/mm3 (15 × 10^9/L) c. Hemoglobin ≥8 g/dL. (≥80 g/L).
- Have an estimated glomerular filtration rate (creatinine based Bedside Schwartz equation) ≥30 mL/min/1.73 m^2.
- "7. Be a female of nonchildbearing potential. If a female of childbearing potential, have a negative serum human chorionic gonadotropin (hCG) or beta-hCG (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."
- Be able to swallow a whole, intact tablet (unless the subject has a feeding tube, such as a nasogastric [NG] or orogastric [OG] tube, in which case a crushed tablet or the powder-for-oral-suspension formulation can be administered) or be able to swallow an oral suspension.
- "9. Have life expectancy of ≥8 weeks. "
- Subjects must have a confirmed negative 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
- "Subjects must not: 1.Have CMV tissue invasive disease involving the central nervous system or retina as assessed by the investigator at the time of screening."
- 2.Have uncontrolled other type of infection as assessed by the investigator on the date of enrollment.
- 3.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.
- 4.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.
- 5.Have a known hypersensitivity to maribavir or to any excipients.
- 6.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.
- 7.Require mechanical ventilation or vasopressors for hemodynamic support at baseline(Visit2/Day1/Week0).
- 8.Be pregnant (or expecting to conceive) or nursing.
- 9.Have previously completed, discontinued, or have been withdrawn from this study.
- 10.Have received an 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.
- "11.Have previously received maribavir or CMV vaccine at any time. "
- "12.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 subject."
- 13.Have severe liver disease (Child-Pugh score of ≥10).
- 14.Have serum aspartate aminotransferase >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.
- 15.Have positive results for human immunodeficiency virus (HIV).
- 16.Have active malignancy with the exception of nonmelanoma skin cancer, as determined by the investigator. Subjects 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.
- 17.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 CYP3A inducer.
- Have a low body weight where total blood volume (TBV) required during study participation will exceed 1% TBV per study visit or 3% TBV over a 4 week period (see Section 8.2.4.3 and Appendix 3 for blood collection volumes and TBV determination).
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 13 Nov 2023 | 3 |
 France | Not Recruiting | 13 Nov 2023 | 6 |
 Germany | Not Recruiting | 13 Nov 2023 | 6 |
 Spain | Not Recruiting | 13 Nov 2023 | 6 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
maribavir | Test | TABLET | ORAL USE | 800 | 8 | PRD5750009 |
Maribavir | Test | ORAL SUSPENSION | ORAL USE | 800 | 8 | PRD11502067 |
LIVTENCITY 200 mg film-coated tablets. | Test | FILM-COATED TABLETS | ORAL USE | 800 | 8 | PRD10042381 |
Maribavir | Test | ORAL SUSPENSION | ORAL USE | 800 | 8 | PRD11502066 |