A study to test the safety, dosage and effectiveness of maribavir for the treatment of cytomegalovirus (CMV) infection in children and adolescents who have received transplant

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Takeda Development Center Americas Inc.

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Virus Diseases [C02]

Trial duration

29 Oct 2025 → ongoing

Decision date (initial)

2024-04-22

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Takeda Development Center Americas, Inc.

External identifiers

EU CT number

2023-508988-73-00

EudraCT number

2021-004279-15

ClinicalTrials.gov

NCT05319353

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others, Dose response, Pharmacogenomic, Pharmacogenetic, Safety, Pharmacodynamic, Therapy, Pharmacokinetic, Efficacy

"1. To characterize the pharmacokinetics (PK) of maribavir and identify dosing regimens for CMV infection treatment in pediatric HSCT and SOT subjects from 0 years to <18years of age.
2. To assess the safety and tolerability of maribavir in children and adolescents."

Secondary objectives 8

1. 1. To evaluate the antiviral activity of maribavir in CMV viremia clearance at the end of Week8 regardless of the length of study treatment
2. 2. To assess the maintenance of CMV viremia clearance and symptom control achieved at Week8, through Week12 (4weeks post-treatment), Week16 (8weeks post-treatment), and Week20 (12weeks posttreatment)
3. 3.To evaluate the recurrence of CMV viremia while on study treatment and off study treatment
4. 4.To evaluate the time to first confirmed viremia clearance
5. 5. To evaluate the recurrence of CMV viremia requiring treatment during the 12-week follow-up period in subjects with confirmed viremia clearance at Week 8
6. 6. To assess the time course of changes in plasma CMV deoxyribonucleic acid (DNA) load from baseline(Visit 2/Day 1/Week 0)
7. 7. To assess the profile of mutations in the CMV genes conferring resistance to maribavir
8. 8. To assess the acceptability and palatability of maribavir

Conditions and MedDRA coding

Cytomegalovirus (CMV) infection in children and adolescents who have received a hematopoietic stem cell transplant (HSCT) or a solid organ transplant (SOT)

Study design 3 periods

Regulatory references

Scientific advice from competent authorities

Federal Agency For Medicines And Health Products, European Medicines Agency, Swedish Medical Products Agency, Food And Drug Administration, National Agency For The Safety Of Medicine And Health Products

EMA paediatric investigation plan (PIP)

EMEA-000018-PIP26-07

Plan to share IPD

Yes

IPD 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  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

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. 1. 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.
2. "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. "
3. 2. 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.
4. "3. Be a recipient of an SOT or an HSCT that is functioning at the time of screening."
5. 4. 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.
6. 5. 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).
7. 6. Have an estimated glomerular filtration rate (creatinine based Bedside Schwartz equation) ≥30 mL/min/1.73 m^2.
8. "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."
9. 8. 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.
10. "9. Have life expectancy of ≥8 weeks. "
11. 11.      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 19

1. "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. 2.Have uncontrolled other type of infection as assessed by the investigator on the date of enrollment.
3. 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. 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. 5.Have a known hypersensitivity to maribavir or to any excipients.
6. 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. 7.Require mechanical ventilation or vasopressors for hemodynamic support at baseline(Visit2/Day1/Week0).
8. 8.Be pregnant (or expecting to conceive) or nursing.
9. 9.Have previously completed, discontinued, or have been withdrawn from this study.
10. 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. "11.Have previously received maribavir or CMV vaccine at any time. "
12. "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. 13.Have severe liver disease (Child-Pugh score of ≥10).
14. 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. 15.Have positive results for human immunodeficiency virus (HIV).
16. 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. 17.Be undergoing treatment for acute or chronic hepatitis B or hepatitis C.
18. 18. Requiring ongoing treatment with or an anticipated need for treatment with a strong CYP3A inducer.
19. 19. 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).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. PK at steady state 1 including max observed plasma concentration (Cmax), time when Cmaxis observed (Tmax), maribavir min concentration predose (Cmin),under plasma concentration-time curve over 1 dosing interval of 12hrs at steady state (AUC0-tau), half-life (t1/2), terminal elimination rate constant (λz), apparent vol of distribution (Vz/F), and apparent oral clearance (CL/F) based on PK samples collected Week1. Cminat Week4 (predose) and Week 8 (predose 2 to 4 hrs after the AM dose).
2. 2. Safety and tolerability assessments: serious adverse events (SAEs), adverse events (AEs) (including instances of CMV disease), vital signs, clinical laboratory evaluations at specified visits, ECGs, and discontinuations from the study drug/study.

Secondary endpoints 13

1. 1. Achievement of the confirmed clearance of plasma CMV DNA (ie, 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.
2. 2. Maintenance of CMV viremia clearance and symptom control achieved at Week8 through Week 12 (4 weeks post-treatment period), Week16 (8 weeks post-treatment period), and Week20 (12weeks post-treatment period).
3. 3. Recurrence of CMV viremia while on study treatment and off study treatment.The proportion of subjects with confirmed recurrence of viremia while on study treatment and in the follow-up period after the subject is discontinued from study treatment, and the corresponding 95% CI will be calculated.
4. 4. Time to first confirmed viremia clearance at any time during the study. – The time to first confirmed viremia clearance at any time during the study will be summarized using the Kaplan-Meier method.
5. 5. Recurrence treated with alternative anti-CMV treatment in the 12- week follow-up period in subjects with confirmed viremia clearance at Week 8. – The proportion of subjects with confirmed recurrence of CMV viremia treated with alternative anti-CMV treatment in the 12-week follow-up period in subjects with confirmed viremia clearance at Week 8, and the corresponding 95% CI, will be calculated.
6. 6. Changes in plasma CMV DNA load from baseline(Visit 2/Day0/Week0)by study week. –Change from baseline (Visit 2/Day 1/Week 0) in log10 plasma CMV DNA on study after receiving study treatment will be summarized descriptively."
7. 7. Maribavir CMV resistance profile. Details of the analysis will be specified in the resistance analysis plan.
8. 8. Acceptability and palatability assessment of maribavir at Weeks 1, 4, and 8 (or end of treatment). – Palatability data will be summarized descriptively for each age cohort and overall at Weeks 1, 4, and 8 (or end of treatment).
9. continuation point 1. The proportion of subjects with confirmed CMV viremia clearance, at the end of Week 8, regardless of whether study treatment was discontinued early and the corresponding 95% CIs will be calculated for each age cohort and overall. Subjects who take alternative anti-CMV treatment before Week 8 or have missing data at Week 8 due to early discontinuation or any other reasons will be considered as nonresponders.
10. continuation point 1 French translation
11. continuation point 2 part 1. The proportion of subjects who achieve maintenance of confirmed CMV viremia clearance and symptom control achieved at the end of Week 8 through to Week 12, Week 16, and Week 20 with the corresponding 95% CIs will be calculated for each age cohort and overall.
12. continuation point 2 part 2. For clearance of CMV viremia achieved at the end of Week 8, regardless of whether study treatment was discontinued before the end of the stipulated 8 weeks of therapy, and maintenance of such effect through Week 12, Week 16, and Week 20, the subject must have received study treatment exclusively and must also have symptom control. Cytomegalovirus infection symptom control includes:
13. continuation point 2 part 3. - • Resolution or improvement of tissue invasive disease or CMV syndrome for symptomatic subjects at baseline (Visit 2/Day 1/Week 0) • No new symptoms for asymptomatic subjects at baseline (Visit 2/Day 1/Week 0)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Takeda Development Center Americas Inc.

Sponsor organisation

Takeda Development Center Americas Inc.

Address

95 Hayden Avenue

City

Lexington

Postcode

02421-7942

Country

United States

Scientific contact point

Organisation

Takeda Development Center Americas Inc.

Contact name

Xuejun Peng

Public contact point

Organisation

Takeda Development Center Americas Inc.

Contact name

Takeda

Third parties 13

Locations

4 EU/EEA countries · 17 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 4 · Art. 38 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 79 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications