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

NCT03443869 | Completed Phase 3 Results DMC FDA Drug

• 3 other identifiers: 8228-002MK-8228-0022017-001055-30
• Study Type: interventional
• Target: 601
• Locations: 15 countries
• Sites: 92

Brief Summary

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.

Conditions

CMV Disease

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (4)

• Percentage of Participants With Adjudicated CMV Disease Through 28 Weeks Post-transplant

  Up to 28 weeks

• Time to Onset of Adjudicated CMV Disease Through 52 Weeks Post-transplant

  Up to 52 weeks

• Percentage of Participants With Any AE

  Up to 52 weeks

• Percentage of Participants With Any Drug-related Serious Adverse Event (SAE)

  Up to 52 weeks

Study Arms (2)

Letermovir

EXPERIMENTAL

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; Drug: Acyclovir (ACV); Drug: Placebo to VGCV

Valganciclovir

ACTIVE COMPARATOR

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; Drug: Placebo to ACV; Drug: Placebo to LET

Interventions

Letermovir DRUG

LET 480mg (or 240 mg when administered concomitantly with cyclosporin A) once daily for 28 weeks

Letermovir

Valganciclovir DRUG

900 mg VGCV tablet orally, once daily for 28 weeks

Valganciclovir

Acyclovir (ACV) DRUG

400 mg over-encapsulated ACV tablet orally, every 12 hours for 28 weeks

Letermovir

Placebo to ACV DRUG

Over-encapsulated placebo tablet orally, every 12 hours for 28 weeks

Valganciclovir

Placebo to LET DRUG

Placebo to LET tablet orally, once daily for 28 weeks

Valganciclovir

Placebo to VGCV DRUG

Placebo to VGCV tablet orally, once daily for 28 weeks

Letermovir

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Study Sites (94)

UAB ( Site 0269)

Birmingham, Alabama, 35233, United States

Location

UCLA Medical Center ( Site 0266)

Los Angeles, California, 90095, United States

Location

UC Davis Medical Center ( Site 0271)

Sacramento, California, 95817, United States

Location

University of California-San Francisco ( Site 0236)

San Francisco, California, 94143, United States

Location

Stanford Health Care ( Site 0235)

Stanford, California, 94305, United States

Location

The Emory Clinic ( Site 0247)

Atlanta, Georgia, 30322, United States

Location

University of Chicago ( Site 0251)

Chicago, Illinois, 60637, United States

Location

Indiana University ( Site 0261)

Indianapolis, Indiana, 46202, United States

Location

Ochsner Clinic Foundation ( Site 0238)

New Orleans, Louisiana, 70121, United States

Location

University of Maryland Medical Center ( Site 0234)

Baltimore, Maryland, 21201, United States

Location

Johns Hopkins Hospital ( Site 0232)

Baltimore, Maryland, 21287, United States

Location

Brigham & Women's Hospital ( Site 0244)

Boston, Massachusetts, 02115, United States

Location

Henry Ford Hospital ( Site 0242)

Detroit, Michigan, 48202, United States

Location

University of Nebraska Medical Center ( Site 0272)

Omaha, Nebraska, 68198, United States

Location

Saint Barnabas Medical Center ( Site 0250)

Livingston, New Jersey, 07039, United States

Location

Icahn School of Medicine at Mount Sinai ( Site 0256)

New York, New York, 10029, United States

Location

Columbia University Medical Center ( Site 0255)

New York, New York, 10032, United States

Location

New York Presbyterian Hospital - Weill Cornell Medical Center ( Site 0276)

New York, New York, 10065, United States

Location

Duke University Medical Center ( Site 0243)

Durham, North Carolina, 27710, United States

Location

Wake Forest University Baptist Medical Center ( Site 0260)

Winston-Salem, North Carolina, 27157, United States

Location

The Ohio State University Wexner Medical Center ( Site 0264)

Columbus, Ohio, 43210, United States

Location

University of Pennsylvania ( Site 0270)

Philadelphia, Pennsylvania, 19104, United States

Location

University of Pittsburgh ( Site 0252)

Pittsburgh, Pennsylvania, 15213, United States

Location

Medical University of South Carolina ( Site 0257)

Charleston, South Carolina, 29425, United States

Location

Vanderbilt University Medical Center ( Site 0275)

Nashville, Tennessee, 37232, United States

Location

Virginia Commonwealth University ( Site 0245)

Richmond, Virginia, 23298, United States

Location

University of Washington Medical Center ( Site 0246)

Seattle, Washington, 98195, United States

Location

Hospital El Cruce Nestor Carlos Kirchner ( Site 0351)

San Juan Bautista, Buenos Aires, B1073ABA, Argentina

Location

CEMIC ( Site 0352)

Buenos Aires, Buenos Aires F.D., C1431FWO, Argentina

Location

Instituto de Nefrologia Nephrology S.A. ( Site 0182)

Buenos Aires, C1425APQ, Argentina

Location

Hospital Italiano de Buenos Aires ( Site 0188)

CABA, C1199ABD, Argentina

Location

Instituto de Cardiología de Corrientes Juana F. Cabral ( Site 0181)

Corrientes, W3400AMZ, Argentina

Location

Clinica de nefrologia urologia y enfermedades cardiovasculares ( Site 0354)

Santa Fe, S3000BPJ, Argentina

Location

Royal Prince Alfred Hospital ( Site 0005)

Camperdown, New South Wales, 2050, Australia

Location

Westmead Hospital ( Site 0006)

Westmead, New South Wales, 2145, Australia

Location

Princess Alexandra Hospital ( Site 0004)

Woolloongabba, Queensland, 4102, Australia

Location

Royal Adelaide Hospital ( Site 0003)

Adelaide, South Australia, 5000, Australia

Location

Monash Health-Monash Medical Centre ( Site 0008)

Clayton, Victoria, 3168, Australia

Location

Royal Melbourne Hospital ( Site 0007)

Parkville, Victoria, 3050, Australia

Location

Medizinische Universitat Innsbruck ( Site 0033)

Innsbruck, Tyrol, 6020, Austria

Location

Allgemeines Krankenhaus Universitaetskliniken Wien ( Site 0032)

Vienna, 1090, Austria

Location

Universitair Ziekenhuis Antwerpen ( Site 0041)

Edegem, Antwerpen, 2650, Belgium

Location

Cliniques Universitaires de Bruxelles - CUB - Hopital Erasme ( Site 0042)

Brussels, Bruxelles-Capitale, Region de, 1070, Belgium

Location

UZ Leuven - Campus Gasthuisberg ( Site 0044)

Leuven, Vlaams-Brabant, 3000, Belgium

Location

University of Alberta Hospital ( Site 0221)

Edmonton, Alberta, T6G 2B7, Canada

Location

Vancouver General Hospital ( Site 0224)

Vancouver, British Columbia, V5Z 1M9, Canada

Location

St. Paul's Hospital ( Site 0225)

Vancouver, British Columbia, V6Z 1Y6, Canada

Location

Toronto General Hospital ( Site 0222)

Toronto, Ontario, M5G 2N2, Canada

Location

Hopital Maisonneuve-Rosemont CIUSSS de l Est de L Ile de Montreal ( Site 0226)

Montreal, Quebec, H1T 2M4, Canada

Location

Hospital San Vicente Fundación - Rionegro ( Site 0205)

Rionegro, Antioquia, 054047, Colombia

Location

Clinica del Country ( Site 0208)

Bogotá, Bogota D.C., 110221, Colombia

Location

Clinica Colsanitas S.A. Sede Clinica Universitaria Colombia ( Site 0209)

Bogotá, Bogota D.C., 110311, Colombia

Location

Hospital Universitario Mayor Mederi CIMED ( Site 0206)

Bogotá, Bogota D.C., 110911, Colombia

Location

Sociedad de Cirugia de Bogota Hospital de San Jose ( Site 0203)

Bogotá, Bogota D.C., 111411, Colombia

Location

Fundacion Cardiovascular de Colombia ( Site 0210)

Bucaramanca, Santander Department, 680003, Colombia

Location

Fundacion Valle del Lili ( Site 0285)

Cali, Valle del Cauca Department, 760032, Colombia

Location

Centro Medico Imbanaco de Cali S.A ( Site 0201)

Cali, Valle del Cauca Department, 760042, Colombia

Location

Hopital Pasteur ( Site 0053)

Nice, Alpes-Maritimes, 51069, France

Location

CHU de Bordeaux. Hopital Pellegrin ( Site 0055)

Bordeaux, Gironde, 33076, France

Location

CHU Rangueil ( Site 0054)

Toulouse, Haute-Garonne, 31059, France

Location

C.H.R.U Bretonneau ( Site 0051)

Tours, Indre-et-Loire, 44093, France

Location

Hopital Henri Mondor du Creteil ( Site 0063)

Créteil, Val-de-Marne, 94000, France

Location

CHU - Hopital de Bicetre ( Site 0060)

Le Kremlin-Bicêtre, Val-de-Marne, 94270, France

Location

Hopital Tenon ( Site 0061)

Paris, 75020, France

Location

Medizinische Hochschule Hannover ( Site 0073)

Hanover, Lower Saxony, 30625, Germany

Location

Universitaetsklinikum Essen ( Site 0074)

Essen, North Rhine-Westphalia, 45147, Germany

Location

Charite Universitaetsmedizin Berlin ( Site 0071)

Berlin, 10117, Germany

Location

Pecsi Tudomanyegyetem AOK ( Site 0282)

Pécs, Baranya, 7624, Hungary

Location

Szegedi Tudomanyegyetem ( Site 0284)

Szeged, Csongrád megye, 6725, Hungary

Location

Semmelweis Egyetem ( Site 0281)

Budapest, 1082, Hungary

Location

Debreceni Egyetem. ( Site 0283)

Debrecen, 4032, Hungary

Location

A.O.U. Citta della Salute e della Scienza di Torino ( Site 0096)

Turin, Piedmont, 10126, Italy

Location

Azienda Ospedaliera di Padova U.O.C. Trapianti Rene e Pancreas ( Site 0091)

Padua, Veneto, 35128, Italy

Location

IRCCS Ospedale San Raffaele di Milano ( Site 0098)

Milan, 20132, Italy

Location

Policlinico Gemelli Instituto di Clinica Chirurgica ( Site 0093)

Roma, 00168, Italy

Location

Instituto Mexicano de Trasplantes S C ( Site 0212)

Cuernavaca, Morelos, 62448, Mexico

Location

Centenario Hospital Miguel Hidalgo ( Site 0215)

Aguascalientes, 20259, Mexico

Location

Instituto Nacional de Cardiologia Ignacio Chavez ( Site 0213)

Mexico City, 14080, Mexico

Location

Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran ( Site 0214)

Mexico City, 14080, Mexico

Location

Faicic S de RL de CV ( Site 0211)

Veracruz, 91900, Mexico

Location

Auckland City Hospital ( Site 0002)

Auckland, 1142, New Zealand

Location

Szpital Wojewodzki w Poznaniu ( Site 0168)

Poznan, Greater Poland Voivodeship, 60-479, Poland

Location

Uniwersytecki Szpital Kliniczny im. Jana Mikulicza-Radeckiego ( Site 0162)

Wroclaw, Lower Silesian Voivodeship, 50-556, Poland

Location

Szpital Kliniczny Dzieciatka Jezus ( Site 0165)

Warsaw, Masovian Voivodeship, 02-006, Poland

Location

Uniwersyteckie Centrum Kliniczne ( Site 0170)

Gdansk, Pomeranian Voivodeship, 80-952, Poland

Location

Pomorski Uniwersytet Medyczny ( Site 0167)

Szczecin, West Pomeranian Voivodeship, 70-111, Poland

Location

Hospital del Mar ( Site 0121)

Barcelona, La Coruna, 08003, Spain

Location

Hospital Universitari de Bellvitge IDIBELL ( Site 0114)

L'Hospitalet de Llobregat, La Coruna, 08907, Spain

Location

Hospital Universitari Vall de Hebron ( Site 0112)

Barcelona, 08035, Spain

Location

Hospital Clinic i Provincial de Barcelona ( Site 0113)

Barcelona, 08036, Spain

Location

Hospital Doce de Octubre ( Site 0116)

Madrid, 28041, Spain

Location

Hospital Universitario Miguel Servet ( Site 0118)

Zaragoza, 50009, Spain

Location

St Georges University Hospitals NHS Foundation Trust. ( Site 0136)

London, London, City of, SW17 0QT, United Kingdom

Location

Queen Elizabeth Hospital ( Site 0356)

Birmingham, B15 2GW, United Kingdom

Location

Related Publications (3)

• 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.

  PMID: 37279999 RESULT

• Strizki JM, Diamond TL, Teal VL, Gilbert CL, Wang W, Stauffer N, Haber BA. Cytomegalovirus Antiviral Resistance Among Kidney Transplant Recipients in a Phase 3 Trial of Letermovir vs Valganciclovir Prophylaxis. J Infect Dis. 2024 Dec 16;230(6):e1287-e1298. doi: 10.1093/infdis/jiae287.

  PMID: 38853607 DERIVED

• Vernooij RW, Michael M, Ladhani M, Webster AC, Strippoli GF, Craig JC, Hodson EM. Antiviral medications for preventing cytomegalovirus disease in solid organ transplant recipients. Cochrane Database Syst Rev. 2024 May 3;5(5):CD003774. doi: 10.1002/14651858.CD003774.pub5.

  PMID: 38700045 DERIVED

Related Links

• Merck Clinical Trial Information

MeSH Terms

Interventions

letermovir; Valganciclovir; Acyclovir

Intervention Hierarchy (Ancestors)

Ganciclovir; Guanine; Hypoxanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme LLC

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 19, 2018
• First Posted: February 23, 2018
• Study Start: May 3, 2018
• Primary Completion: April 5, 2022
• Study Completion: April 5, 2022
• Last Updated: July 28, 2023
• Results First Posted: April 14, 2023

Record last verified: 2023-07

Data Sharing

• IPD Sharing: Will share

Locations

CA (5); AR (6); BE (3); HU (4); IT (4); AU (6); US (27); GB (2); ES (6); DE (3); NZ (1); FR (7); ME (5); CO (8); PL (5)