Clinical trial NCT04129398: MK-8228 (Letermovir) in the Prevention of Human Cytomegalovirus (CMV) Infection and Disease in Adult Japanese Kidney Transplant Recipients (MK-8228-042)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Cytomegalovirus Infection
Cytomegalovirus Disease
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2019-10-16
Enrollment: 22
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Percentage of Participants With Adverse Events (AEs)
timeFrame: Up to week 52 post-transplant
measure: Percentage of Participants Who Discontinued From Study Drug Due to an AE
timeFrame: Up to week 28 post-transplant
Secondary outcomes:
measure: Percentage of Participants With Adjudicated CMV Disease or Undergone Anti-CMV Treatment
timeFrame: Up to Week 52 post-transplant
measure: Percentage of Participants With Adjudicated CMV Disease
timeFrame: Up to Week 52 post-transplant
measure: Percentage of Participants With Quantifiable CMV DNAemia
timeFrame: Up to Week 52 post-transplant
measure: Area Under the Concentration-time Curve During a Dosing Interval (AUCtau) of Plasma Letermovir-oral Treatment
timeFrame: Any day between Days 6-10: pre-dose, 1, 2.5, 5, 8 and 24 hrs post-dose
measure: Trough Concentration (Ctrough) of Plasma Letermovir - Oral Treatment
timeFrame: Any day between Days 6-10: 24hrs post-dose
measure: Maximum Concentration (Cmax) of Plasma Letermovir - Oral Treatment
timeFrame: Any day between Days 6-10: pre-dose, 1, 2.5, 5, 8 and 24 hrs post-dose
measure: Time to Reach Cmax (Tmax) of Plasma Letermovir - Oral Treatment
timeFrame: Any day between Days 6-10: pre-dose, 1, 2.5, 5, 8 and 24 hrs post-dose
measure: Apparent Clearance at Steady State (CLss/F) of Plasma Letermovir - Oral Treatment
timeFrame: Any day between Days 6-10: pre-dose, 1, 2.5, 5, 8 and 24 hrs post-dose
measure: Area Under the Concentration-time Curve During a Dosing Interval (AUCtau) of Plasma Letermovir - IV Treatment
timeFrame: Any day between Days 6-10: pre-dose, 1, 2.5, 5, 8 and 24 hrs post-dose
measure: Trough Concentration (Ctrough) of Plasma Letermovir - IV Treatment
timeFrame: Pre-dose on Weeks 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 and 28
measure: Concentration at the End of Infusion (Ceoi) of Plasma Letermovir - IV Treatment
timeFrame: Any day between Days 6-10: at end of infusion (1 hours post dose)
measure: Clearance at Steady State (CLss) of Plasma Letermovir - IV Treatment
timeFrame: Any day between Days 6-10: pre-dose, 1, 2.5, 5, 8 and 24 hrs post-dose
Other outcomes:
Locations:
city: Nagoya
country: Japan
facility: Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital ( Site 0002)
state: Aichi
city: Sapporo
country: Japan
facility: Sapporo City General Hospital ( Site 0004)
state: Hokkaido
city: Suita
country: Japan
facility: Osaka University Hospital ( Site 0003)
state: Osaka
city: Tokyo
country: Japan
facility: Tokyo Women's Medical University Hospital ( Site 0001)
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.