A Study to Evaluate the Safety and Tolerability, Pharmacokinetics, and Antiviral Activity of Maribavir for the Treatment of Children and Teenage Transplant Recipients With CMV Infection

Study Overview
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Brief Summary
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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) adult tablet formulation or other formulation based on PK modeling. The participants will be treated with maribavir for 8 weeks. Participants need to visit their doctor during 12-week follow-up period.

Official Title
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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)

Conditions
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Cytomegalovirus (CMV)

Intervention / Treatment
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* Drug: Maribavir


Participation Criteria
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Eligibility Criteria
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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. 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 capabilities or an electronic face-to-face consent interview when these individuals are unable to travel to the site. Be a male or female child or adolescent < 18 years of age at the time of consent. For participants in Cohort 3 only, must have a gestational age of at least 38 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, with a CMV deoxyribonucleic acid (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 or central specialty laboratory quantitative polymerase chain reaction (qPCR) or comparable quantitative CMV DNA results. 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. 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) 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. 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 (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). 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 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 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 30-day period.

Ages Eligible for Study
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Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: Three dosing cohorts based on participant's age.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Maribavir 400 or 200 mg<br>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) twice daily (BID) based on body weight >= 25 kilogram (kg) or 200 mg tablet BID based on body weight 10 to < 25 kg orally for up to 8 weeks treatment period (Day 0/Week 0 to Day 56/Week 8). The dosing regimen will be based on the participant's body weight and may be updated over the course of the study based on the internal interim analyses on PK, safety, and tolerability of at least 5 participants in each cohort. | Drug: Maribavir<br>* Participants will receive maribavir.<br>* Other names: TAK-620;|
| Experimental: Cohort 2: Maribavir 400 or 200 mg<br>Participants with >= 6 to < 12 years of age will receive maribavir 400 mg (2*200 mg tablets) BID based on body weight >= 25 kg or 200 mg tablet BID based on body weight 10 to < 25 kg orally for up to 8 weeks treatment period (Day 0/Week 0 to Day 56/Week 8). The dosing regimen will be based on the participant's body weight and may be updated over the course of the study based on the internal interim analyses on PK, safety, and tolerability of at least 5 participants in each cohort. | Drug: Maribavir<br>* Participants will receive maribavir.<br>* Other names: TAK-620;|
| Experimental: Cohort 3: Maribavir<br>Participants with 0 to < 6 years of age will receive maribavir based on PK modeling. | Drug: Maribavir<br>* Participants will receive maribavir.<br>* Other names: TAK-620;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) of Maribavir | Cmax of maribavir will be evaluated. | 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 | Tmax of maribavir will be evaluated. | 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 | Cmin of maribavir will be evaluated. | 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 and 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 | AUC0-tau of maribavir will be evaluated. | 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 | t1/2 of maribavir will be evaluated. | 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 | Lambdaz of maribavir will be evaluated. | 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 | Vz/F of maribavir will be evaluated. | 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 | CL/F of maribavir will be evaluated. | Pre-dose, 0.5, 1.5, 3, 4, 6, and 8 hours post-dose on Day 7 (Week 1) | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | An adverse event (AE) is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. A TEAE is defined as any event emerging or manifesting at or after the initiation of treatment with an investigational product or medicinal product or any existing event that worsens in either intensity or frequency following exposure to the investigational product or medicinal product. An SAE is any untoward medical occurrence (whether considered related to investigational product or not and at any dose) that at any dose results in death, life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital abnormality or birth defect, an important medical event. TEAEs included serious and non-serious AEs. | From start of study drug administration up to follow-up (Week 20) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Confirmed CMV viremia Clearance 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. | 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 | 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. | 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 | 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. | Up to Week 20 | 
| Time to First Confirmed Viremia Clearance | 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. | 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 | 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. | From Week 8 through Week 20 | 
| Change From Baseline in Log10 Plasma CMV Deoxyribonucleic Acid (DNA) Load | Change from baseline in log10 plasma CMV DNA on study after receiving study treatment by study week will be reported. | Baseline up to Week 20 | 
| Number of Participants who Develop CMV Resistance to Maribavir | 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. | Up to Week 12 | 
| Summary Scores for Palatability Assessment of Maribavir | 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. | At Weeks 1, 4, and 8 |