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

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

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.

Study Overview

• Status: Completed
• Conditions: CMV Disease
• Intervention / Treatment: Drug: Acyclovir (ACV); Drug: Placebo to VGCV; Drug: Valganciclovir; Drug: Placebo to ACV; Drug: Placebo to LET; Drug: Letermovir

• Study Type: Interventional
• Enrollment (Actual): 601
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1425APQ
    • Instituto de Nefrologia Nephrology S.A. ( Site 0182)
  • Caba, Argentina, C1199ABD
    • Hospital Italiano de Buenos Aires ( Site 0188)
  • Corrientes, Argentina, W3400AMZ
    • Instituto de Cardiología de Corrientes Juana F. Cabral ( Site 0181)
  • Santa Fe, Argentina, S3000BPJ
    • Clinica de nefrologia urologia y enfermedades cardiovasculares ( Site 0354)
  • Buenos Aires
    • Florencio Varela, Buenos Aires, Argentina, B1073ABA
      • Hospital El Cruce Nestor Carlos Kirchner ( Site 0351)
  • Caba
    • Buenos Aires, Caba, Argentina, C1431FWO
      • CEMIC ( Site 0352)
• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Royal Prince Alfred Hospital ( Site 0005)
    • Westmead, New South Wales, Australia, 2145
      • Westmead Hospital ( Site 0006)
  • Queensland
    • Woolloongabba, Queensland, Australia, 4102
      • Princess Alexandra Hospital ( Site 0004)
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital ( Site 0003)
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Monash Health-Monash Medical Centre ( Site 0008)
    • Parkville, Victoria, Australia, 3050
      • Royal Melbourne Hospital ( Site 0007)
• Austria
  • Wien, Austria, 1090
    • Allgemeines Krankenhaus Universitaetskliniken Wien ( Site 0032)
  • Tirol
    • Innsbruck, Tirol, Austria, 6020
      • Medizinische Universitat Innsbruck ( Site 0033)
• Belgium
  • Antwerpen
    • Edegem, Antwerpen, Belgium, 2650
      • Universitair Ziekenhuis Antwerpen ( Site 0041)
  • Bruxelles-Capitale, Region De
    • Bruxelles, Bruxelles-Capitale, Region De, Belgium, 1070
      • Cliniques Universitaires de Bruxelles - CUB - Hopital Erasme ( Site 0042)
  • Vlaams-Brabant
    • Leuven, Vlaams-Brabant, Belgium, 3000
      • UZ Leuven - Campus Gasthuisberg ( Site 0044)
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2B7
      • University of Alberta Hospital ( Site 0221)
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • Vancouver General Hospital ( Site 0224)
    • Vancouver, British Columbia, Canada, V6Z 1Y6
      • St. Paul's Hospital ( Site 0225)
  • Ontario
    • Toronto, Ontario, Canada, M5G 2N2
      • Toronto General Hospital ( Site 0222)
  • Quebec
    • Montreal, Quebec, Canada, H1T 2M4
      • Hopital Maisonneuve-Rosemont CIUSSS de l Est de L Ile de Montreal ( Site 0226)
• Colombia
  • Antioquia
    • Rionegro, Antioquia, Colombia, 054047
      • Hospital San Vicente Fundación - Rionegro ( Site 0205)
  • Distrito Capital De Bogota
    • Bogota, Distrito Capital De Bogota, Colombia, 110221
      • Clinica del Country ( Site 0208)
    • Bogota, Distrito Capital De Bogota, Colombia, 110311
      • Clinica Colsanitas S.A. Sede Clinica Universitaria Colombia ( Site 0209)
    • Bogota, Distrito Capital De Bogota, Colombia, 110911
      • Hospital Universitario Mayor Mederi CIMED ( Site 0206)
    • Bogota, Distrito Capital De Bogota, Colombia, 111411
      • Sociedad de Cirugia de Bogota Hospital de San Jose ( Site 0203)
  • Santander
    • Bucaramanca, Santander, Colombia, 680003
      • Fundacion Cardiovascular de Colombia ( Site 0210)
  • Valle Del Cauca
    • Cali, Valle Del Cauca, Colombia, 760032
      • Fundacion Valle del Lili ( Site 0285)
    • Cali, Valle Del Cauca, Colombia, 760042
      • Centro Medico Imbanaco de Cali S.A ( Site 0201)
• France
  • Paris, France, 75020
    • Hopital Tenon ( Site 0061)
  • Alpes-Maritimes
    • Nice, Alpes-Maritimes, France, 51069
      • Hopital Pasteur ( Site 0053)
  • Gironde
    • Bordeaux, Gironde, France, 33076
      • CHU de Bordeaux. Hopital Pellegrin ( Site 0055)
  • Haute-Garonne
    • Toulouse, Haute-Garonne, France, 31059
      • CHU Rangueil ( Site 0054)
  • Indre-et-Loire
    • Tours, Indre-et-Loire, France, 44093
      • C.H.R.U Bretonneau ( Site 0051)
  • Val-de-Marne
    • Creteil, Val-de-Marne, France, 94000
      • Hopital Henri Mondor du Creteil ( Site 0063)
    • Le kremlin bicetre, Val-de-Marne, France, 94270
      • CHU - Hopital de Bicetre ( Site 0060)
• Germany
  • Berlin, Germany, 10117
    • Charite Universitaetsmedizin Berlin ( Site 0071)
  • Niedersachsen
    • Hannover, Niedersachsen, Germany, 30625
      • Medizinische Hochschule Hannover ( Site 0073)
  • Nordrhein-Westfalen
    • Essen, Nordrhein-Westfalen, Germany, 45147
      • Universitaetsklinikum Essen ( Site 0074)
• Hungary
  • Budapest, Hungary, 1082
    • Semmelweis Egyetem ( Site 0281)
  • Debrecen, Hungary, 4032
    • Debreceni Egyetem. ( Site 0283)
  • Baranya
    • Pecs, Baranya, Hungary, 7624
      • Pecsi Tudomanyegyetem AOK ( Site 0282)
  • Csongrad
    • Szeged, Csongrad, Hungary, 6725
      • Szegedi Tudomanyegyetem ( Site 0284)
• Italy
  • Milano, Italy, 20132
    • IRCCS Ospedale San Raffaele di Milano ( Site 0098)
  • Roma, Italy, 00168
    • Policlinico Gemelli Instituto di Clinica Chirurgica ( Site 0093)
  • Piemonte
    • Torino, Piemonte, Italy, 10126
      • A.O.U. Citta della Salute e della Scienza di Torino ( Site 0096)
  • Veneto
    • Padova, Veneto, Italy, 35128
      • Azienda Ospedaliera di Padova U.O.C. Trapianti Rene e Pancreas ( Site 0091)
• Mexico
  • Aguascalientes, Mexico, 20259
    • Centenario Hospital Miguel Hidalgo ( Site 0215)
  • Ciudad de Mexico, Mexico, 14080
    • Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran ( Site 0214)
  • Mexico City, Mexico, 14080
    • Instituto Nacional de Cardiologia Ignacio Chavez ( Site 0213)
  • Veracruz, Mexico, 91900
    • Faicic S de RL de CV ( Site 0211)
  • Morelos
    • Cuernavaca, Morelos, Mexico, 62448
      • Instituto Mexicano de Trasplantes S C ( Site 0212)
• New Zealand
  • Auckland, New Zealand, 1142
    • Auckland City Hospital ( Site 0002)
• Poland
  • Dolnoslaskie
    • Wroclaw, Dolnoslaskie, Poland, 50-556
      • Uniwersytecki Szpital Kliniczny im. Jana Mikulicza-Radeckiego ( Site 0162)
  • Mazowieckie
    • Warszawa, Mazowieckie, Poland, 02-006
      • Szpital Kliniczny Dzieciatka Jezus ( Site 0165)
  • Pomorskie
    • Gdansk, Pomorskie, Poland, 80-952
      • Uniwersyteckie Centrum Kliniczne ( Site 0170)
  • Wielkopolskie
    • Poznan, Wielkopolskie, Poland, 60-479
      • Szpital Wojewodzki w Poznaniu ( Site 0168)
  • Zachodniopomorskie
    • Szczecin, Zachodniopomorskie, Poland, 70-111
      • Pomorski Uniwersytet Medyczny ( Site 0167)
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall de Hebron ( Site 0112)
  • Barcelona, Spain, 08036
    • Hospital Clinic i Provincial de Barcelona ( Site 0113)
  • Madrid, Spain, 28041
    • Hospital Doce de Octubre ( Site 0116)
  • Zaragoza, Spain, 50009
    • Hospital Universitario Miguel Servet ( Site 0118)
  • La Coruna
    • Barcelona, La Coruna, Spain, 08003
      • Hospital del Mar ( Site 0121)
    • L Hospitalet De Llobregat, La Coruna, Spain, 08907
      • Hospital Universitari de Bellvitge IDIBELL ( Site 0114)
• United Kingdom
  • Birmingham, United Kingdom, B15 2GW
    • Queen Elizabeth Hospital ( Site 0356)
  • London, City Of
    • London, London, City Of, United Kingdom, SW17 0QT
      • St Georges University Hospitals NHS Foundation Trust. ( Site 0136)
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • UAB ( Site 0269)
  • California
    • Los Angeles, California, United States, 90095
      • UCLA Medical Center ( Site 0266)
    • Sacramento, California, United States, 95817
      • UC Davis Medical Center ( Site 0271)
    • San Francisco, California, United States, 94143
      • University of California-San Francisco ( Site 0236)
    • Stanford, California, United States, 94305
      • Stanford Health Care ( Site 0235)
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • The Emory Clinic ( Site 0247)
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago ( Site 0251)
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University ( Site 0261)
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Clinic Foundation ( Site 0238)
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Medical Center ( Site 0234)
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Hospital ( Site 0232)
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham & Women's Hospital ( Site 0244)
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital ( Site 0242)
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center ( Site 0272)
  • New Jersey
    • Livingston, New Jersey, United States, 07039
      • Saint Barnabas Medical Center ( Site 0250)
  • New York
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai ( Site 0256)
    • New York, New York, United States, 10032
      • Columbia University Medical Center ( Site 0255)
    • New York, New York, United States, 10065
      • New York Presbyterian Hospital - Weill Cornell Medical Center ( Site 0276)
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center ( Site 0243)
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Baptist Medical Center ( Site 0260)
  • Ohio
    • Columbus, Ohio, United States, 43210
      • The Ohio State University Wexner Medical Center ( Site 0264)
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania ( Site 0270)
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh ( Site 0252)
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina ( Site 0257)
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center ( Site 0275)
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University ( Site 0245)
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington Medical Center ( Site 0246)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Limaye AP, Budde K, Humar A, Vincenti F, Kuypers DRJ, Carroll RP, Stauffer N, Murata Y, Strizki JM, Teal VL, Gilbert CL, Haber BA. Letermovir vs Valganciclovir for Prophylaxis of Cytomegalovirus in High-Risk Kidney Transplant Recipients: A Randomized Clinical Trial. JAMA. 2023 Jul 3;330(1):33-42. doi: 10.1001/jama.2023.9106.

Helpful Links

• Merck Clinical Trial Information

Study record dates

Study Major Dates

• Study Start (Actual): May 3, 2018
• Primary Completion (Actual): April 5, 2022
• Study Completion (Actual): April 5, 2022

Study Registration Dates

• First Submitted: February 19, 2018
• First Submitted That Met QC Criteria: February 19, 2018
• First Posted (Actual): February 23, 2018

Study Record Updates

• Last Update Posted (Actual): July 28, 2023
• Last Update Submitted That Met QC Criteria: July 26, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antineoplastic Agents; Poly(ADP-ribose) Polymerase Inhibitors; Valganciclovir; Letermovir; Acyclovir
• Other Study ID Numbers: 8228-002; MK-8228-002 (Other Identifier: Merck); 2017-001055-30 (EudraCT Number)

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