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

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

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.

Study Overview

• Status: Completed
• Conditions: Cytomegalovirus Infection; Cytomegalovirus Disease
• Intervention / Treatment: Drug: Letermovir tablet; Drug: Letermovir IV

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 3

Contacts and Locations

Study Locations

• Japan
  • Tokyo, Japan, 162-8666
    • Tokyo Women's Medical University Hospital ( Site 0001)
  • Aichi
    • Nagoya, Aichi, Japan, 466-8650
      • Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital ( Site 0002)
  • Hokkaido
    • Sapporo, Hokkaido, Japan, 060-8604
      • Sapporo City General Hospital ( Site 0004)
  • Osaka
    • Suita, Osaka, Japan, 565-0871
      • Osaka University Hospital ( Site 0003)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Letermovir; 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; A single 240 mg tablet or two 240 mg tablets letermovir administered orally, once daily for 28 weeks; Other Names: MK-8228; PREVYMIS®; Drug: Letermovir IV; 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; Other Names: MK-8228; PREVYMIS®

What is the study measuring?

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 Due to an AE	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	CMV disease was defined as the presence of either CMV end-organ disease or CMV syndrome and was confirmed by an independent, blinded Clinical Adjudication Committee (CAC). Only CAC-confirmed ("adjudicated") cases were included in percentage of participants who met the endpoint. Investigator-assessed cases which were not confirmed by the CAC were not included. Participants who have undergone anti-CMV treatment was defined as initiation of approved anti-CMV agents based on at least one positive cell on CMV antigenemia and/or quantifiable CMV DNA PCR assay performed locally.	Up to Week 52 post-transplant
Percentage of Participants With Adjudicated CMV Disease	CMV disease was defined as the presence of either CMV end-organ disease or CMV syndrome and was confirmed by an independent, blinded Clinical Adjudication Committee (CAC). Only CAC-confirmed ("adjudicated") cases were included in percentage of participants who met the endpoint. Investigator-assessed cases which were not confirmed by the CAC were not included.	Up to Week 52 post-transplant
Percentage of Participants With Quantifiable CMV DNAemia	Quantifiable CMV DNAemia (central) was defined as any case with a numeric value or >910,000,000 (not including reporting of PCR results as "detected, not quantifiable") using the Roche COBAS® AmpliPrep/COBAS TaqMan® (CAP/CTM) assay, which was performed by the central laboratory.	Up to Week 52 post-transplant
Area Under the Concentration-time Curve During a Dosing Interval (AUCtau) of Plasma Letermovir-oral Treatment	AUCtau was defined as a measure of letermovir exposure that was calculated as the product of plasma drug concentration and time following an oral administration of letermovir.	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	Ctrough was defined as the minimum concentration of letermovir that occurred immediately following an oral administration of letermovir.	Any day between Days 6-10: 24hrs post-dose
Maximum Concentration (Cmax) of Plasma Letermovir - Oral Treatment	Cmax was defined as the maximum concentration of letermovir observed in plasma following an oral administration of letermovir.	Any day between Days 6-10: pre-dose, 1, 2.5, 5, 8 and 24 hrs post-dose
Time to Reach Cmax (Tmax) of Plasma Letermovir - Oral Treatment	Tmax was defined as the time required post dosing to reach a maximum plasma concentration of letermovir following an oral administration of letermovir.	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 letermovir following an oral administration of letermovir.	Any day between Days 6-10: pre-dose, 1, 2.5, 5, 8 and 24 hrs post-dose
Area Under the Concentration-time Curve During a Dosing Interval (AUCtau) of Plasma Letermovir - IV Treatment	AUCtau was defined as a measure of letermovir exposure that was calculated as the product of plasma drug concentration and time following an IV administration of letermovir was intended to measure.	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	Ctrough was defined as the minimum concentration of letermovir that occurred immediately following an IV administration of letermovir was intended to measure.	Pre-dose on Weeks 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 and 28
Concentration at the End of Infusion (Ceoi) of Plasma Letermovir - IV Treatment	Ceoi is defined as the amount of letermovir in plasma following an IV administration of letermovir was intended to measure.	Any day between Days 6-10: at end of infusion (1 hours post dose)
Clearance at Steady State (CLss) of Plasma Letermovir - IV Treatment	Clearance at steady state (CLss) of plasma letermovir following an IV administration of letermovir was intended to measure.	Any day between Days 6-10: pre-dose, 1, 2.5, 5, 8 and 24 hrs post-dose

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC
• Investigators: Study Director: Medical Director, Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Ishida H, Goto N, Imamura R, Sasaki H, Unagami K, Futamura K, Murata Y, Oshima N, Eto T, Haber B. Letermovir safety and efficacy for cytomegalovirus prophylaxis in adult Japanese kidney transplant recipients: a multicenter, open-label, noncomparative Phase 3 study. Clin Exp Nephrol. 2024 Aug;28(8):822-831. doi: 10.1007/s10157-024-02471-0. Epub 2024 Apr 13.

Helpful Links

• Merck Clinical Trials Information

Study record dates

Study Major Dates

• Study Start (Actual): December 27, 2019
• Primary Completion (Actual): October 6, 2022
• Study Completion (Actual): October 6, 2022

Study Registration Dates

• First Submitted: October 15, 2019
• First Submitted That Met QC Criteria: October 15, 2019
• First Posted (Actual): October 16, 2019

Study Record Updates

• Last Update Posted (Actual): August 21, 2024
• Last Update Submitted That Met QC Criteria: July 29, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Virus Diseases; Disease Attributes; DNA Virus Infections; Herpesviridae Infections; Infections; Communicable Diseases; Cytomegalovirus Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antineoplastic Agents; Poly(ADP-ribose) Polymerase Inhibitors; Letermovir
• Other Study ID Numbers: 8228-042; MK-8228-042 (Other Identifier: Merck Protocol Number); 195020 (Registry Identifier: JAPIC-CTI)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No