Extension of Letermovir (LET) From Day 100 to Day 200 Post-transplant for the Prevention of Cytomegalovirus (CMV) Infection in Hematopoietic Stem Cell Transplant (HSCT) Participants (MK-8228-040)

NCT ID: NCT03930615

Last Updated: 2024-08-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 220 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-06-21
• Study Completion Date: 2022-03-16

Brief Summary

The purpose of this study was to evaluate the safety and efficacy of letermovir (LET) versus placebo when cytomegalovirus (CMV) prophylaxis was extended from 100 days to 200 days post-transplant in CMV seropositive participants who received an allogenic hematopoietic stem cell transplant (HSCT). It was hypothesized that LET is superior to placebo in the prevention of clinically-significant CMV infection when LET prophylaxis is extended from 100 to 200 days.

Conditions

Cytomegalovirus Infection

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

Letermovir

Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of LET (480 mg once daily alone or 240 mg once daily for participants on cyclosporin A) treatment.

Group Type: EXPERIMENTAL

Letermovir

Intervention Type: DRUG

LET tablet or intravenous infusion at a total daily dose of 240 mg (when given with cyclosporin A) or 480 mg (when given alone).

Placebo

Participants who received HSCT transplant and 100 days of LET prophylaxis were randomized to an additional 100 days of placebo treatment.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo was administered as tablets matched to LET or as inactive (saline or dextrose) intravenous infusion.

Interventions

Letermovir

LET tablet or intravenous infusion at a total daily dose of 240 mg (when given with cyclosporin A) or 480 mg (when given alone).

Intervention Type: DRUG

Placebo

Placebo was administered as tablets matched to LET or as inactive (saline or dextrose) intravenous infusion.

Intervention Type: DRUG

Other Intervention Names

PREVYMIS™, MK-8228

Eligibility Criteria

Inclusion Criteria

• have documented positive CMV serostatus (CMV immunoglobulin G [IgG] seropositive) for recipient (R+) at the time of transplant
• has a history of allogeneic HSCT (bone marrow, peripheral blood stem cell, or cord blood transplant) within ~100 days prior to randomization
• has undetectable CMV deoxyribonucleic acid (DNA) or detectable/not quantifiable CMV DNA from a plasma sample collected within 14 days prior to randomization
• has received LET as primary prophylaxis that started within 28 days of HSCT and continued through Week 14 post-transplant (± 1 week) prior to randomization
• is at high risk of CMV disease, defined as meeting one or more of the following criteria:
• has a related donor with at least 1 mismatch at 1 of the specified 3 human leukocyte antigen (HLA) gene loci (HLA-A, B, or DR)
• has an unrelated donor with at least one mismatch at one of the specified four HLA gene loci (HLA-A, B, C, and DRB1)
• has a haploidentical donor
• has umbilical cord blood as the stem-cell source
• has ex-vivo T-cell-depleted grafts
• has received anti-thymocyte globulin
• has received alemtuzumab
• has graft versus host disease (GVHD) or other conditions, requiring the use of systemic prednisone (or equivalent) at a dose of ≥1 mg/kg of body weight per day within 6 weeks of randomization
• for female participants, is not pregnant or breastfeeding, and is either not a woman of childbearing potential (WOCBP) or is a WOBCP who agrees to use acceptable contraception during the treatment period and for ≥28 days after the last dose of study drug.

Exclusion Criteria

• has a history of CMV end-organ disease or preemptive treatment therapy for CMV after HSCT prior to randomization
• has a history of >14 days total of LET interruption during the first 100 days post-transplant prior to randomization
• has suspected or known hypersensitivity to active or inactive ingredients of LET formulations
• has severe hepatic insufficiency defined as Child-Pugh Class C within 14 days prior to randomization.
• has serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5× the upper limit of normal (ULN) within 14 days prior to randomization
• has end-stage renal impairment with a creatinine clearance less than 10 mL/min, as calculated by the Cockcroft-Gault equation using serum creatinine within 14 days prior to randomization
• has both moderate hepatic insufficiency AND moderate-to-severe renal insufficiency
• has an uncontrolled infection on the day of enrollment
• requires mechanical ventilation or is hemodynamically unstable at the time of enrollment
• has a documented positive result for a human immunodeficiency virus antibody (HIV-Ab) test at any time prior to screening, or for hepatitis C virus antibody (HCV-Ab) with detectable HCV ribonucleic acid (RNA), or hepatitis B surface antigen (HBsAg) within 6 months prior to screening.
• has active solid tumor malignancies with the exception of localized basal cell or squamous cell skin cancer or the condition under treatment (eg, lymphomas)
• has received cidofovir or CMV immunoglobulin with 30 days prior to screening
• is currently participating or has participated in a study with an unapproved investigational compound, monoclonal antibody, or device within 28 days or 5× half-life of the investigational compound or monoclonal antibody, whichever is longer, of initial dosing in this study
• has previously participated in this study or any other study involving LET, 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 28 days after the last dose of study therapy
• is expecting to donate eggs starting from the time of consent through 28 days after the last dose of study therapy
• has clinically relevant drug or alcohol abuse within 12 months of screening that may interfere with participant treatment, assessment, or compliance with the protocol as assessed by the investigator
• has a history or current evidence of any condition, therapy, lab abnormality, or other circumstance that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or would be put at undue risk as judged by the investigator, such that it is not in the best interest of the participant to participate in this study

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Director

Role: STUDY_DIRECTOR

Merck Sharp & Dohme LLC

Locations

City of Hope National Medical Center ( Site 0158)

Duarte, California, United States

University of California Davis Medical Center ( Site 0156)

Sacramento, California, United States

University of Miami, Sylvester Comprehensive Cancer Center ( Site 0160)

Miami, Florida, United States

Indiana Blood and Marrow Transplantation ( Site 0175)

Indianapolis, Indiana, United States

Brigham & Women's Hospital ( Site 0161)

Boston, Massachusetts, United States

John Theurer Cancer Center at Hackensack University Med Ctr ( Site 0174)

Hackensack, New Jersey, United States

Memorial Sloan Kettering Cancer Center ( Site 0164)

New York, New York, United States

Duke University Medical Center ( Site 0169)

Durham, North Carolina, United States

The University of Texas MD Anderson Cancer Center ( Site 0154)

Houston, Texas, United States

Fred Hutchinson Cancer Research Center ( Site 0152)

Seattle, Washington, United States

Centre Hospitalier Universitaire Dupuytren ( Site 0182)

Limoges, Haute-Vienne, France

Hopital Saint Eloi ( Site 0031)

Montpellier, Herault, France

Centre Hopitalier Lyon Sud ( Site 0039)

Pierre-Bénite, Rhone, France

CHU Henri Mondor ( Site 0032)

Créteil, Val-de-Marne, France

Institut Gustave Roussy ( Site 0038)

Villejuif, Val-de-Marne, France

CHU Hopital Saint Antoine ( Site 0036)

Paris, , France

Universitaetsklinikum Heidelberg-Medizinische Klinik V ( Site 0042)

Heidelberg, Baden-Wurttemberg, Germany

Universitaetsklinik Koeln ( Site 0041)

Cologne, North Rhine-Westphalia, Germany

Universitaetsklinikum Muenster ( Site 0043)

Münster, North Rhine-Westphalia, Germany

ASST Spedali Civili di Brescia ( Site 0052)

Brescia, Lombardy, Italy

IRCCS Ospedale San Raffaele ( Site 0051)

Milan, , Italy

Fondazione PTV Policlinico Tor Vergata ( Site 0054)

Roma, , Italy

Policlinico Umberto I ( Site 0056)

Roma, , Italy

Policlinico Universitario Agostino Gemelli ( Site 0055)

Roma, , Italy

Jichi Medical University Hospital ( Site 0123)

Shimotsuke, Tochigi, Japan

Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital ( Site 0121)

Hiroshima, , Japan

National Hospital Organization Kumamoto Medical Center ( Site 0122)

Kumamoto, , Japan

Queen Elizabeth University Hospital [Glasgow, UK] ( Site 0096)

Glasgow, Glasgow City, United Kingdom

1Kings College Hospital ( Site 0091)

London, London, City of, United Kingdom

UCL Cancer Institute ( Site 0093)

London, London, City of, United Kingdom

Manchester Royal Infirmary ( Site 0097)

Manchester, , United Kingdom

Freeman Hospital Newcastle upon Tyne Foundation NHS Trust ( Site 0092)

Newcastle upon Tyne, , United Kingdom

Countries

United States; France; Germany; Italy; Japan; United Kingdom

References

Russo D, Schmitt M, Pilorge S, Stelljes M, Kawakita T, Teal VL, Haber B, Bopp C, Dadwal SS, Badshah C. Efficacy and safety of extended duration letermovir prophylaxis in recipients of haematopoietic stem-cell transplantation at risk of cytomegalovirus infection: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Haematol. 2024 Feb;11(2):e127-e135. doi: 10.1016/S2352-3026(23)00344-7. Epub 2023 Dec 21.

Reference Type: RESULT

PMID: 38142695 (View on PubMed)

Dwabe S, Hsiao M, Ali A, Rodman J, Savitala-Damerla L, Nazaretyan S, Kimberly Schiff NP, Tam E, Ladha A, Woan K, Chaudhary P, Yaghmour G. Real world experience: Examining outcomes using letermovir for CMV prophylaxis in high-risk allogeneic hematopoietic stem cell patients in the setting of using T-cell depletion as GVHD prophylaxis. Transpl Immunol. 2023 Feb;76:101769. doi: 10.1016/j.trim.2022.101769. Epub 2022 Dec 2.

Reference Type: DERIVED

PMID: 36464218 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

MK-8228-040

Identifier Type: OTHER

Identifier Source: secondary_id

194797

Identifier Type: REGISTRY

Identifier Source: secondary_id

2018-001038-17

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

8228-040

Identifier Type: -

Identifier Source: org_study_id