MK-8228 (Letermovir) in the Prevention of Human Cytomegalovirus (CMV) Infection and Disease in Adult Japanese Kidney Transplant Recipients (MK-8228-042)

Study Overview
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Brief Summary
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This study aims to evaluate the safety, efficacy and pharmacokinetics (PK) of Letermovir (LET) administered as prevention of cytomegalovirus (CMV) infection and disease in adult Japanese kidney transplant recipients.

Official Title
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A Phase 3, Open-Label, Single-Arm Clinical Study to Evaluate the Safety, Efficacy and Pharmacokinetics of MK-8228 (Letermovir) for the Prevention of Human Cytomegalovirus (CMV) Infection and Disease in Adult Japanese Kidney Transplant Recipients

Conditions
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Cytomegalovirus Infection, Cytomegalovirus Disease

Intervention / Treatment
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* Drug: Letermovir tablet
* Drug: Letermovir IV


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Meets recipient and/or donor CMV Immunoglobulin G (IgG) serostatus. Anticipates receiving a primary or secondary allograft kidney at the time of screening and have received a primary or secondary allograft kidney at the time of allocation. Is within 0 (i.e., day of transplantation) to 7 days (inclusive) post-kidney transplant at the time of allocation. Is a Japanese male or female from 18 years to any years of age inclusive, at the time of signing the informed consent. Female is not pregnant or breastfeeding, and is not a woman of childbearing potential (WOCBP); but if a WOCBP, she is using an acceptable contraceptive method, or is abstinent from heterosexual intercourse, and must have a negative highly sensitive pregnancy test within 72 hours before the first dose of study intervention. Exclusion Criteria: Has received a previous solid organ transplant or hematopoietic stem cell transplant (HSCT). Is a multi-organ transplant recipient (e.g., kidney-pancreas). Has a history of CMV disease or suspected CMV disease within 6 months prior to allocation. Has positive results on CMV assay and/or CMV antigen test at any time between the completion of the transplant surgery and time of allocation. Has suspected or known hypersensitivity to active or inactive ingredients of LET formulations. Is on dialysis (for the purposes of this protocol dialysis includes hemofiltration) or plasmapheresis at the time of allocation. Has Child-Pugh Class C severe hepatic insufficiency at screening. Has post-transplant renal function of creatinine clearance (CrCl) ≤10 mL/min at allocation (measured locally). Has both moderate hepatic insufficiency AND moderate-to-severe renal insufficiency at screening. Has any uncontrolled infection on the day of allocation. Has documented positive results for human immunodeficiency virus antibody (HIV-Ab) test at any time prior to allocation, or for hepatitis C virus antibody (HCV-Ab) and with detectable HCV RNA within 90 days prior to allocation or hepatitis B surface antigen (HBsAg) within 90 days prior to allocation. Requires mechanical ventilation, or is hemodynamically unstable, at the time of allocation. Has a history of malignancy ≤5 years prior to signing informed consent. Has received within 30 days prior to allocation or plans to receive during the study any of the following: CMV immune globulin; any investigational CMV antiviral agent/biologic therapy. Has received any dose of LET prior to allocation. Has received within 7 days prior to allocation or plans to receive during the study any anti-CMV drug therapy. Is a user of recreational or illicit drugs or has had a recent history (within the last year) of drug or alcohol abuse or dependence. Is taking or plans to take any of the prohibited medications listed in the protocol. Is currently participating or has participated in a study with an unapproved investigational compound or device within 28 days, or 5× half-life of the investigational compound. 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 at least 28 days following cessation of study therapy. Is expecting to donate eggs starting from the time of consent through at least 28 days following cessation of study therapy.

Ages Eligible for Study
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Minimum Age: 18 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 oral or intravenous (IV) formulation will be administered once daily for up to 28 weeks, beginning up to 7 days post-transplant. The dose will be 240 mg once daily for participants receiving concomitant cyclosporin A (CsA) and 480 mg once daily for participants not receiving CsA. IV infusion will be administered only to participants who are unable to swallow tablets or who have a condition that may interfere with absorption of the tablets. | Drug: Letermovir tablet<br>* A single 240 mg tablet or two 240 mg tablets letermovir administered orally, once daily for 28 weeks<br>* Other names: PREVYMIS™;Drug: Letermovir IV<br>* IV solution of 240 mg (one vial) or 480 mg (2 vials) letermovir in 250 mL infused over 60 minutes, once daily for 28 weeks<br>* Other names: PREVYMIS™;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants with Adverse Events (AEs) | Percentage of participants with one or more adverse events (AEs) | Up to week 52 post-transplant | 
| Percentage of participants who discontinued from study drug | Percentage of participants who discontinued from study drug due to an AE | Up to week 28 post-transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants with adjudicated CMV disease or undergone anti-CMV treatment | Percentage of participants with adjudicated CMV disease or undergone anti-CMV treatment | Up to Week 52 post-transplant | 
| Percentage of participants with adjudicated CMV disease | Percentage of participants with adjudicated CMV disease | Up to Week 52 post-transplant | 
| Percentage of participants with quantifiable CMV DNAemia | Percentage of participants with quantifiable CMV DNAemia | Up to Week 52 post-transplant | 
| Area under the concentration-time curve (AUC) of plasma Letermovir - oral treatment | Area under the concentration-time curve to the end of the dosing period (AUCtau) of plasma LET - oral treatment | Any day between Days 6-10: pre-dose, 1, 2.5, 5, 8 and 24 hrs post-dose | 
| Trough concentration (Ctrough) of plasma Letermovir - oral treatment | Trough concentration (Ctrough) of plasma LET - oral treatment | Pre-dose on Weeks 1, 2,4, 6, 8, 10, 12, 16, 20, 24 and 28 | 
| Maximum concentration (Cmax) of plasma Letermovir - oral treatment | Maximum concentration (Cmax) of plasma LET - oral treatment | Any day between Days 6-10: pre-dose, 1, 2.5, 5, 8 and 24 hrs post-dose | 
| Time to Cmax (Tmax) of plasma Letermovir - oral treatment | Time to Cmax (Tmax) of plasma LET - oral treatment | Any day between Days 6-10: pre-dose, 1, 2.5, 5, 8 and 24 hrs post-dose | 
| Apparent clearance at steady state (CLss/F) of plasma Letermovir - oral treatment | Apparent clearance at steady state (CLss/F) of plasma LET - oral treatment | Any day between Days 6-10: pre-dose, 1, 2.5, 5, 8 and 24 hrs post-dose | 
| Area under the concentration-time curve (AUC) of plasma Letermovir - IV treatment | Area under the concentration-time curve to the end of the dosing period (AUCtau) of plasma LET - IV treatment | Any day between Days 6-10: pre-dose, 1, 2.5, 5, 8 and 24 hrs post-dose | 
| Trough concentration (Ctrough) of plasma Letermovir - IV treatment | Trough concentration (Ctrough) of plasma LET - IV treatment | Pre-dose on Weeks 2,4, 6, 8, 10, 12, 16, 20, 24 and 28 | 
| Concentration at the end of infusion (Ceoi) of plasma Letermovir - IV treatment | Concentration at the end of infusion (Ceoi) of plasma LET - IV treatment | Any day between Days 6-10: at end of infusion (up to 1 hour) | 
| Clearance at steady state (CLss) of plasma Letermovir - IV treatment | Clearance at steady state (CLss) of plasma LET - IV treatment | Any day between Days 6-10: pre-dose, 1, 2.5, 5, 8 and 24 hrs post-dose |