Letermovir Versus Valganciclovir to Prevent Human Cytomegalovirus Disease in Kidney Transplant Recipients (MK-8228-002)

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the efficacy of letermovir (LET) versus valganciclovir (VGCV) in preventing CMV disease in adult kidney transplant recipients. The primary hypotheses are that LET is non-inferior to VGCV; and if non-inferiority is demonstrated, that LET is superior to VGCV, in preventing CMV disease through 52 weeks post-transplant.

Official Title
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A Phase III, Randomized, Double-Blind, Active Comparator-Controlled Study to Evaluate the Efficacy and Safety of MK-8228 (Letermovir) Versus Valganciclovir for the Prevention of Human Cytomegalovirus (CMV) Disease in Adult Kidney Transplant Recipients

Conditions
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CMV Disease

Intervention / Treatment
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* Drug: Letermovir
* Drug: Valganciclovir
* Drug: Acyclovir (ACV)
* Drug: Placebo to ACV
* Drug: Placebo to LET
* Drug: Placebo to VGCV


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have a documented negative serostatus for CMV within 180 days prior to randomization. Anticipate receiving a primary or secondary allograft kidney from a CMV IgG seropositive (D+) donor at the time of screening AND have received a primary or secondary allograft kidney from a documented D+ donor at the time of randomization. Be within 0 (i.e. day of transplantation) to 7 days (inclusive) post-kidney transplant at the time of randomization. Males agree to use contraception during the treatment period, and for at least 90 days after the last dose of study treatment, and refrain from donating sperm during this period. Female is not pregnant, not breastfeeding, and is not a woman of childbearing potential (WOCBP), OR if a WOCBP, agrees to follow the contraception guidance during the treatment period and for at least 90 days after the last dose of study treatment. Exclusion Criteria: Has received a previous solid organ transplant or hematopoietic stem cell transplant (HSCT). Note: Participants who have received a prior primary allograft kidney may be enrolled, provided that all other inclusion/exclusion criteria are met. Is a multi-organ transplant recipient (e.g. kidney-pancreas). Double kidney transplant recipients (i.e. transplant of two kidneys from the same donor to the same recipient simultaneously) will be excluded. Has a history of CMV disease or suspected CMV disease within 6 months prior to randomization. Has suspected or known hypersensitivity to active or inactive ingredients of LET formulations, VGCV, GCV, and/or ACV formulations. Is on dialysis or plasmapheresis at the time of randomization. Dialysis includes hemofiltration. Has Child-Pugh Class C severe hepatic insufficiency at screening. Has both moderate hepatic insufficiency AND moderate-to-severe renal insufficiency at screening. Has any uncontrolled infection on the day of randomization. Has documented positive results for human immunodeficiency virus antibody (HIV-Ab) test at any time prior to randomization, or for hepatitis C virus antibody (HCV-Ab) and with detectable HCV ribonucleic acid (RNA) within 90 days prior to randomization, or hepatitis B surface antigen (HBsAg) within 90 days prior to randomization. Requires mechanical ventilation, or is hemodynamically unstable, at the time of randomization. Has a history of malignancy ≤5 years prior to signing informed consent. Is pregnant or expecting to conceive, is breastfeeding, or plans to breastfeed from the time of consent through at least 90 days following cessation of study therapy. Is expecting to donate eggs or sperm starting from the time of consent through at least 90 days following cessation of study therapy. Has received within 30 days prior to randomization or plans to receive during the study any of the following anti-CMV IgG antibody treatment or anti-CMV drug therapy including the following: Cidofovir, CMV hyper-immune globulin, Any investigational CMV antiviral agent/biologic therapy. Has received within 7 days prior to randomization or plans to receive during the study any of the following anti-CMV drug therapy: LET, GCV, VGCV, Foscarnet, ACV, Valacyclovir, Famciclovir. 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 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 whichever is longer, of initial dosing on 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.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Letermovir<br>LET 480mg (or 240 mg when administered concomitantly with cyclosporin A) tablet orally; placebo to VGCV tablet orally once daily; and 400 mg capsule of acyclovir (ACV) orally every 12 hours for 28 weeks | Drug: Letermovir<br>* LET 480mg (or 240 mg when administered concomitantly with cyclosporin A) once daily for 28 weeks<br>Drug: Acyclovir (ACV)<br>* 400 mg over-encapsulated ACV tablet orally, every 12 hours for 28 weeks<br>Drug: Placebo to VGCV<br>* Placebo to VGCV tablet orally, once daily for 28 weeks<br>|
| Active Comparator: Valganciclovir<br>900 mg VGCV tablet orally, once daily; placebo to LET tablet orally once daily; and placebo to ACV orally every 12 hours for 28 weeks | Drug: Valganciclovir<br>* 900 mg VGCV tablet orally, once daily for 28 weeks<br>Drug: Placebo to ACV<br>* Over-encapsulated placebo tablet orally, every 12 hours for 28 weeks<br>Drug: Placebo to LET<br>* Placebo to LET tablet orally, once daily for 28 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Adjudicated Cytomegalovirus (CMV) Disease Through 52 Weeks Post-transplant | 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 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Adjudicated CMV Disease Through 28 Weeks Post-transplant | CMV disease was defined as the presence of either CMV end-organ disease or CMV syndrome and was confirmed by an independent, blinded 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 28 weeks | 
| Time to Onset of Adjudicated CMV Disease Through 52 Weeks Post-transplant | The time to onset of adjudicated CMV disease was calculated in days, from the day of randomization to the day of onset of CMV disease as determined by the CAC. | Up to 52 weeks | 
| Percentage of Participants With Any AE | An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product, was also an AE. | Up to 52 weeks | 
| Percentage of Participants With Any Drug-related Serious Adverse Event (SAE) | An SAE was an AE that resulted in death, was life threatening, resulted in persistent or significant disability/incapacity, resulted in or prolonged an existing inpatient hospitalization, was a congenital anomaly/birth defect, was a cancer, was associated with an overdose, was another important medical event. SAEs that the investigator determined the relationship of the AE to the treatment as at least possibly related were reported. | Up to 52 weeks |