MARIBAVIR for Cytomegalovirus (CMV) infection (post-transplant)

Inclusion criteria

• {"criterion_text":"- 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.\n- \"9. Have life expectancy of ≥8 weeks. \"\n- 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.\n- \"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. \"\n- 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.\n- \"3. Be a recipient of an SOT or an HSCT that is functioning at the time of screening.\"\n- 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.\n- 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).\n- 6. Have an estimated glomerular filtration rate (creatinine based Bedside Schwartz equation) ≥30 mL/min/1.73 m^2.\n- \"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.\"\n- 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."}

Exclusion criteria

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8.Be pregnant (or expecting to conceive) or nursing.\n- 9.Have previously completed, discontinued, or have been withdrawn from this study."}

Primary endpoints

• {"endpoint_text":"- 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).\n- 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.","definition_or_measurement_approach":"PK parameters measured from serial PK samples collected Week 1 with predose Cmin measurements at Week 4 and Week 8 (predose and 2–4 hours after AM dose). Safety and tolerability assessed by collection and review of SAEs, AEs (including CMV disease), vital signs, clinical laboratory evaluations at specified visits, ECGs, and recording of discontinuations."}

Secondary endpoints

• {"endpoint_text":"- 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.","definition_or_measurement_approach":"Clearance defined as plasma CMV DNA below LLOQ at central specialty laboratory in 2 consecutive post-baseline samples separated by ≥5 days, assessed at Week 8."}
• {"endpoint_text":"- 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).","definition_or_measurement_approach":"Assessment of maintenance of clearance and symptom control at Weeks 12, 16, and 20 following Week 8 clearance."}
• {"endpoint_text":"- 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.","definition_or_measurement_approach":"Proportion of subjects with confirmed recurrence during treatment and follow-up; 95% CI calculated."}
• {"endpoint_text":"- 4. Time to first confirmed viremia clearance at any time during the study. –\tThe time to first confirmed viremia clearance at any time during the study will be summarized using the Kaplan-Meier method.","definition_or_measurement_approach":"Time-to-event (first confirmed viremia clearance) summarized using Kaplan–Meier method."}
• {"endpoint_text":"- 5. Recurrence treated with alternative anti-CMV treatment in the 12- week follow-up period in subjects with confirmed viremia clearance at Week 8. –\tThe 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.","definition_or_measurement_approach":"Proportion of subjects with recurrence requiring alternative anti-CMV therapy during 12-week follow-up; 95% CI calculated."}
• {"endpoint_text":"- 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.\"","definition_or_measurement_approach":"Change from baseline in log10 plasma CMV DNA summarized descriptively by study week."}
• {"endpoint_text":"- 7. Maribavir CMV resistance profile. Details of the analysis will be specified in the resistance analysis plan.","definition_or_measurement_approach":"Resistance mutations/profile assessed per resistance analysis plan (genotyping performed for subjects ≥2 years at baseline and as applicable)."}
• {"endpoint_text":"- 8. Acceptability and palatability assessment of maribavir at Weeks 1, 4, and 8 (or end of treatment). –\tPalatability data will be summarized descriptively for each age cohort and overall at Weeks 1, 4, and 8 (or end of treatment).","definition_or_measurement_approach":"Palatability assessed via hedonic scales and summarized descriptively by age cohort at Weeks 1, 4, and 8 (or end of treatment)."}
• {"endpoint_text":"- 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.","definition_or_measurement_approach":"Proportion with confirmed clearance at Week 8 (nonresponders imputed for early alternative treatment or missing Week 8 data); 95% CIs calculated by cohort and overall."}
• {"endpoint_text":"- continuation point 1 French translation","definition_or_measurement_approach":""}
• {"endpoint_text":"- 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.","definition_or_measurement_approach":"Proportion maintaining clearance and symptom control at Weeks 12, 16, 20; 95% CIs calculated by cohort and overall."}
• {"endpoint_text":"- 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:","definition_or_measurement_approach":"Maintenance requires exclusive receipt of study treatment for the clearance and demonstration of symptom control as defined in subsequent text."}
• {"endpoint_text":"- continuation point 2 part 3. - •\tResolution or improvement of tissue invasive disease or CMV syndrome for symptomatic subjects at baseline (Visit 2/Day 1/Week 0) •\tNo new symptoms for asymptomatic subjects at baseline (Visit 2/Day 1/Week 0)","definition_or_measurement_approach":"Symptom control defined as resolution/improvement of tissue-invasive disease or no new symptoms for asymptomatic subjects at baseline."}

France

Earliest CTIS Part Ii Submission Date

03-04-2024

Latest Decision Or Authorization Date

16-09-2025

Processing Time Days

531

Number Of Sites

4

Number Of Participants

6

Belgium

Earliest CTIS Part Ii Submission Date

03-04-2024

Latest Decision Or Authorization Date

15-09-2025

Processing Time Days

530

Number Of Sites

3

Number Of Participants

3

Germany

Earliest CTIS Part Ii Submission Date

03-04-2024

Latest Decision Or Authorization Date

05-05-2026

Processing Time Days

762

Number Of Sites

5

Number Of Participants

6

Spain

Earliest CTIS Part Ii Submission Date

03-04-2024

Latest Decision Or Authorization Date

04-05-2026

Processing Time Days

761

Number Of Sites

5

Number Of Participants

6

Primary sponsor

Full Name

Takeda Development Center Americas Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

Pharmaceutical Product Development LLC

Responsibilities

[codes: 1,10,11,12,6,8,9]

Name

Endpoint

Responsibilities

IVRS30 – treatment randomisation

Third parties

• {"country":"United States","full_name":"Eurofins Viracor Biopharma Services Inc.","duties_or_roles":"Routine clinical pathology testing, Primary/ surrogate endpoint test","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Pharmaceutical Product Development LLC","duties_or_roles":"[codes: 1,10,11,12,6,8,9]","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Signant Health Global LLC","duties_or_roles":"Digital services: eICF, eCOA, Televisits","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Advarra Inc.","duties_or_roles":"[code: 2]","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Unisphere Travel Ltd. Inc.","duties_or_roles":"Patient Travel/Concierge","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Celerion Inc.","duties_or_roles":"Primary/ surrogate endpoint test","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Medidata Solutions Inc.","duties_or_roles":"[code: 7]","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Endpoint","duties_or_roles":"IVRS30 – treatment randomisation","organisation_type":"Industry"}
• {"country":"United States","full_name":"Praxis Communications LLC","duties_or_roles":"[code: 2]","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Marken","duties_or_roles":"Home Health Care, Direct to Patient services","organisation_type":"Industry"}
• {"country":"China","full_name":"Wuxi Apptec Co. Ltd.","duties_or_roles":"Routine clinical pathology testing, Primary/ surrogate endpoint test","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Q2","duties_or_roles":"Clinical haematology, Clinical microbiology, Serology/ endocrinology, Primary/ surrogate endpoint test","organisation_type":"Industry"}
• {"country":"United States","full_name":"Almac","duties_or_roles":"DEPOT, IP SHIPMENTS","organisation_type":"Pharmaceutical company"}