Letermovir Treatment in Pediatric Participants Following Allogeneic Haematopoietic Stem Cell Transplantation (HSCT) (MK-8228-030)

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the pharmacokinetics (PK) of letermovir (LET) in pediatric participants. Participants will be enrolled in the following 3 age groups: Age Group 1: From 12 to <18 years of age (adolescents); Age Group 2: From 2 to <12 years of age (children); and Age Group 3: From birth to <2 years of age (neonates, infants and toddlers). All participants will receive open label LET for 14 weeks ( 100 days) post-transplant, with doses based on body weight and age.

Official Title
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A Phase 2b Open-label, Single-arm Study to Evaluate Pharmacokinetics, Efficacy, Safety and Tolerability of Letermovir in Pediatric Participants From Birth to Less Than 18 Years of Age at Risk of Developing CMV Infection and/or Disease Following Allogeneic Haematopoietic Stem Cell Transplantation (HSCT)

Conditions
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Cytomegalovirus (CMV) Infection

Intervention / Treatment
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* Drug: Letermovir oral granules
* Drug: Letermovir tablet
* Drug: Letermovir intravenous


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All participants 12 to <18 years old must have documented positive CMV serostatus (CMV IgG seropositive) for the recipient (R+) within 90 days prior to enrollment. Participants from birth to <12 years old must have documented positive CMV serostatus (CMV IgG seropositive) for the recipient (R+) within 90 days prior to enrollment and/or the donor (D+); the donor serostatus should be documented within 1 year prior to enrollment. Is the recipient of a first allogeneic HSCT (bone marrow, peripheral blood stem cell, or cord blood transplant). Has undetectable CMV DNA from a plasma or whole blood sample collected within 5 days prior to enrollment. Is within 28 days post-HSCT at the time of enrollment. Females are not pregnant, not breastfeeding,and is not a woman of childbearing potential (WOCBP); or is a WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 28 days after the last dose of study intervention. Participants from 2 to <18 years of age must not be on concomitant Cyclosporin A (CsA), and must be able to take LET tablets or the oral granules (either by mouth or via G tube/NG tube), provided the participant does not have a condition that may interfere with the absorption of oral medication (e.g. vomiting, diarrhea, or a malabsorptive condition) from the day of enrollment until the intensive PK sampling is completed in these participants. For participants 2 <12 years old their weight should be at least 10 kg; for participants from birth to <2 years old their weight should be at least 2.5 kg and less than or equal to 15 kg at the time of enrollment. Exclusion Criteria: Has received a previous allogeneic HSCT (Note: receipt of a previous autologous HSCT is acceptable). Has a history of CMV end-organ disease within 6 months prior to enrollment. Has evidence of CMV viremia at any time from either signing of the ICF or the HSCT procedure, whichever is earlier, until the time of enrollment. Has suspected or known hypersensitivity to active or inactive ingredients of LET formulations. Has severe hepatic insufficiency within 5 days prior to enrollment. Is a) on renal replacement therapy (eg, hemodialysis, peritoneal dialysis) OR b) has end-stage renal impairment. Has both moderate hepatic insufficiency and moderate-to-severe renal insufficiency. Has an uncontrolled infection on the day of enrollment. Requires mechanical ventilation or is hemodynamically unstable at the time of enrollment. Has a documented positive result for a human immunodeficiency virus antibody (HIVAb) test at any time prior to enrollment, or for hepatitis C virus antibody (HCV-Ab) with detectable HCV RNA, or hepatitis B surface antigen (HBsAg) within 90 days prior to enrollment. Has active solid tumor malignancies with the exception of localized basal cell or squamous cell skin cancer or the condition under treatment (e.g. lymphomas). Has a preexisting cardiac condition a) for which the patient is currently being treated or b) which required hospitalization within the last 6 months or c) that may be expected to recur during the course of the trial. Has received within 7 days prior to screening any of the following: ganciclovir; valganciclovir; foscarnet; acyclovir; valacyclovir; famciclovir. Has received within 30 days prior to screening of any of the following: cidofovir; CMV immunoglobulin; any investigational CMV antiviral agent/biologic therapy; Rifampin and other strong inducers (such as phenytoin, carbamazepine, St John's wort (Hypericum perforatum), rifabutin and phenobarbital) and moderate inducers such as nafcillin, thioridazine, modafinil and bosentan. Has received LET at any time prior to enrollment in this study. Is currently participating or has participated in a study with an unapproved investigational compound or device within 28 days, or 5X half-life of the investigational compound (excluding monoclonal antibodies), whichever is longer, of initial dosing in this study. Has previously participated in this study or any other study involving LET. Has previously participated or is currently participating in any study involving administration of a CMV vaccine or another CMV investigational agent, or is planning to participate in a study of a CMV vaccine or another CMV investigational agent during the course of this study. Is pregnant or expecting to conceive, is breastfeeding, or plans to breastfeed from the time of consent through 28 days after the last dose of study intervention. Is expecting to donate eggs starting from the time of consent through 28 days after the last dose of study intervention. Has clinically relevant drug or alcohol abuse within 12 months of screening that may interfere with participant treatment, assessment, or compliance with the protocol, as assessed by the investigator.

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: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Letermovir<br>Letermovir administered either orally or intravenously within 28 days post-transplant, once daily through week 14 (approximately 100 days). Dosing will vary based on age, weight, and whether participant takes cyclosporin A as a concomitant medication. | Drug: Letermovir oral granules<br>* Granules administered orally based on age, weight, and whether participant takes cyclosporin A as a concomitant medication.<br>* Other names: AIC001;Drug: Letermovir tablet<br>* Tablet administered orally based on age, weight, and whether participant takes cyclosporin A as a concomitant medication.<br>* Other names: AIC001;Drug: Letermovir intravenous<br>* Letermovir administered intravenously based on age, weight, and whether participant takes cyclosporin A as a concomitant medication.<br>* Other names: AIC001;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the concentration-time curve of plasma letermovir for oral formulation | Area under the curve from time 0 to 24 hours post-dose (AUC0-24) of plasma letermovir during intensive pharmacokinetics (PK), for participants receiving oral formulation. | Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose | 
| Maximal concentration of plasma letermovir for oral formulation | Maximal concentration (Cmax) of plasma letermovir during intensive PK, for participants receiving oral formulation. | Day 7: Pre-dose, 1, 2.5, 8, and 24 hours post-dose | 
| Minimum concentration of plasma letermovir observed before next dose for oral formulation | Minimum concentration of plasma letermovir observed before next dose (Ctrough) during intensive PK, for participants receiving oral formulation. | Day 7: Pre-dose | 
| Area under the concentration-time curve of plasma letermovir for intravenous formulation | Area under the curve from time 0 to 24 hours post-dose (AUC0-24) of plasma letermovir, for participants receiving intravenous (IV) formulation. | After 5 consecutive days of administration of intravenous formulation: Pre-dose, 1, 2.5, 8, and 24 hours post-dose (up to 14 weeks) | 
| Concentration at the end of infusion of plasma letermovir for IV formulation | Concentration of plasma letermovir at the end of infusion (Ceoi), for participants receiving IV formulation. | After 5 consecutive days of administration of IV formulation: 1 hour post-dose (up to 14 weeks) | 
| Minimum concentration of plasma letermovir observed before next dose for IV formulation | Minimum concentration of plasma letermovir observed before next dose (Ctrough) during intensive PK, for participants receiving IV formulation. | After 5 consecutive days of administration of IV formulation: Pre-dose (up to 14 weeks) | 
| Minimum concentration of plasma letermovir observed before next dose during sparse PK for oral formulation | Minimum concentration of plasma letermovir observed before next dose (Ctrough) during sparse PK, for participants receiving oral formulation. | Pre-dose on Weeks 2, 4, 6, 8, 12, 14 | 
| Minimum concentration of plasma letermovir observed before next dose during sparse PK for IV formulation | Minimum concentration of plasma letermovir observed before next dose (Ctrough) during sparse PK, for participants receiving IV formulation. | Pre-dose on Weeks 2, 4, 6, 8, 12, 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants with an adverse event | Percentage of participants with one or more adverse event (AE). | Up to Week 48 post-transplant (up to 52 weeks) | 
| Participants who discontinued study medication | Percentage of participants who discontinued study medication due to an AE. | Up to Week 14 post-transplant (up to 18 weeks) | 
| Participants with clinically significant CMV infection through Week 14 post-transplant | Percentage of participants with clinically significant CMV infection (CS-CMVi) through Week 14 post-transplant | Up to Week 14 post-transplant (up to 18 weeks) | 
| Participants with clinically significant CMV infection through Week 24 post-transplant | Percentage of participants with clinically significant CMV infection (CS-CMVi) through Week 24 post-transplant | Up to Week 24 post-transplant (up to 28 weeks) | 
| Score on a palatability scale for participants receiving oral granules. | Palatability was measured by a facial hedonic scale (FHS), a five point facial expression scale depicting various degrees of pleasure, where a score of 1 indicated disliked very much; ranging to a score of 5 which indicated liked very much. | On the first and eighth day of administration of oral formulation up to Week 14 post-transplant (up to 18 weeks) |