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

• ClinicalTrials.gov Identifier: NCT05319353
• Recruitment Status: Not yet recruiting
• First Posted: April 8, 2022
• Last Update Posted: October 5, 2022
• Sponsor: Takeda
• Collaborator: Takeda Development Center Americas, Inc.
• Information provided by (Responsible Party): Takeda

Study Description

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) 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.

Condition or disease	Intervention/treatment	Phase
Cytomegalovirus (CMV)	Drug: Maribavir	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 80 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Intervention Model Description: Three dosing cohorts based on participant's age.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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)
• Estimated Study Start Date: March 31, 2023
• Estimated Primary Completion Date: February 17, 2027
• Estimated Study Completion Date: February 17, 2027

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cohort 1: Maribavir 400 or 200 mg; Participants with greater than (>=) 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 < 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; Participants will receive maribavir.; Other Name: TAK-620
Experimental: Cohort 2: Maribavir 400 or 200 mg; 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 10-25 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; Participants will receive maribavir.; Other Name: TAK-620
Experimental: Cohort 3: Maribavir; Participants with 0 to < 6 years of age will receive maribavir based on PK modeling.	Drug: Maribavir; Participants will receive maribavir.; Other Name: TAK-620

Outcome Measures

Primary Outcome Measures :

1. Maximum Observed Plasma Concentration (Cmax) of Maribavir [ Time Frame: 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.
2. Time to Maximum Observed Concentration (Tmax) of Maribavir [ Time Frame: 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.
3. Minimum Plasma Concentration (Cmin) of Maribavir [ Time Frame: 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 on Day 56 (Week 8) ]
   Cmin of maribavir will be evaluated.
4. Area Under the Plasma Concentration-Time Curve Over the 1 Dosing Interval of 12 Hours at Steady State (AUC0-tau) of Maribavir [ Time Frame: 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.
5. Half-Life (t1/2) of Maribavir [ Time Frame: 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.
6. Terminal Elimination Rate Constant (lambdaz) of Maribavir [ Time Frame: 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.
7. Apparent Volume of Distribution (Vz/F) of Maribavir [ Time Frame: 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.
8. Apparent Oral Clearance (CL/F) of Maribavir [ Time Frame: 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.
9. Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs [ Time Frame: From start of study drug administration up to follow-up (Week 20) ]
   An adverse event (AE) is any untoward medical occurrence in a clinical investigation participants 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.

Secondary Outcome Measures :

1. Percentage of Participants With Confirmed CMV viremia Clearance at Week 8 [ Time Frame: 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.
2. Percentage of Participants who Achieve Maintenance of Confirmed CMV Viremia Clearance and Symptom Control at Week 8 Through Weeks 12, 16 and 20 [ Time Frame: 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.
3. Percentage of Participants With Confirmed Recurrence of CMV Viremia on Study Treatment and Follow-up Period [ Time Frame: Up to Week 20 ]
   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 in the follow-up period after the participant is discontinued from study-assigned treatment will be reported.
4. Time to First Confirmed Viremia Clearance [ Time Frame: 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.
5. 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 Virema Clearance at Week 8 [ Time Frame: From Week 8 through Week 20 ]
   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.
6. Change From Baseline in Log10 Plasma CMV Deoxyribonucleic Acid (DNA) Load [ Time Frame: 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.
7. Number of Participants who Develop CMV Resistance Mutations Conferring Resistance to Maribavir [ Time Frame: Baseline up to Week 14 ]
   CMV Resistance Mutations Conferring Resistance are known to generally map to the UL97, UL54, UL56, and UL27 CMV genes. Genotyping analysis will be specified in the resistance analysis plan. Number of participants who develop CMV resistance mutations conferring resistance to maribavir up to Week 14 will be reported.
8. Summary Scores for Palatability Assessment of Maribavir [ Time Frame: 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.

Eligibility Criteria

• Ages Eligible for Study: up to 17 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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. 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 within 14 days of first dose of study drug, separated by at least 1 day, by quantitative polymerase chain reaction (qPCR) or comparable quantitative CMV DNA results.

• 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 >= 7 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 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 0/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 any investigational agent with known anti-CMV activity, and 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 assigned 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 known (previously documented) 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.

Contacts and Locations

Contacts

Contact: Takeda Contact; +1-877-825-3327; medinfoUS@takeda.com

Sponsors and Collaborators

Takeda

Takeda Development Center Americas, Inc.

Investigators

• Study Director: Study Director; Takeda

More Information

Additional Information:

To obtain more information on the study, click here/on this link 

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT05319353
• Other Study ID Numbers: TAK-620-2004; 2021-004279-15 ( EudraCT Number )
• First Posted: April 8, 2022
• Last Update Posted: October 5, 2022
• Last Verified: October 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)
• Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/ For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
• URL: https://vivli.org/ourmember/takeda/

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Additional relevant MeSH terms:

Cytomegalovirus Infections; Infections; Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Maribavir; Antiviral Agents; Anti-Infective Agents