Clinical trial NCT03930615: 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)
Official title: A Phase 3 Randomized, Double-blind, Placebo-controlled Clinical Trial to Evaluate the Safety and Efficacy of Letermovir (LET) Prophylaxis When Extended From 100 Days to 200 Days Post-transplant in Cytomegalovirus (CMV) Seropositive Recipients (R+) of an Allogenic Hematopoietic Stem Cell Transplant (HSCT)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Cytomegalovirus Infection
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2019-04-29
Enrollment: 220
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.


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

Primary outcomes:
measure: Percentage of Participants With Clinically Significant CMV Infection From Week 14 (~100 Days) Post-transplant Through Week 28 (~200 Days) Post-transplant
timeFrame: From Week 14 post-transplant to Week 28 post-transplant (approximately 14 weeks)
Secondary outcomes:
measure: Percentage of Participants Experiencing ≥1 Adverse Events (AEs) From Week 14 (~100 Days) Post-transplant Through Week 28 (~200 Days) Post-transplant
timeFrame: From Week 14 post-transplant to Week 28 post-transplant (approximately 14 weeks)
measure: Percentage of Participants Withdrawing From Study Drug Due to an AE From Week 14 (~100 Days) Post-transplant Through Week 28 (~200 Days) Post-transplant
timeFrame: From Week 14 post-transplant to Week 28 post-transplant (approximately 14 weeks)
measure: Percentage of Participants With Clinically Significant CMV Infection From Week 14 Post-transplant Through Week 38 Post-transplant
timeFrame: From Week 14 post-transplant to Week 38 post-transplant (approximately 24 weeks)
measure: Percentage of Participants With Clinically Significant CMV Infection From Week 14 Post-transplant Through Week 48 Post-transplant
timeFrame: From Week 14 post-transplant to Week 48 post-transplant (approximately 34 weeks)
measure: Time to Onset of Clinically Significant CMV Infection From Week 14 Post-transplant to Week 28 Post-transplant
timeFrame: From Week 14 post-transplant to Week 28 post-transplant (approximately 14 weeks)
measure: Time to Onset of Clinically Significant CMV Infection From Week 14 Post-transplant to Week 48 Post-transplant
timeFrame: From Week 14 post-transplant to Week 48 post-transplant (approximately 34 weeks)
measure: Percentage of Participants With CMV Viremia Who Started PET From Week 14 Post-transplant to Week 28 Post-transplant
timeFrame: From Week 14 post-transplant to Week 28 post-transplant (approximately 14 weeks)
measure: Percentage of Participants With CMV Viremia Who Started PET From Week 14 Post-transplant to Week 48 Post-transplant
timeFrame: From Week 14 post-transplant to Week 48 post-transplant (approximately 34 weeks)
measure: Percentage of Participants With All-cause Mortality From Week 14 Post-transplant to Week 28 Post-transplant
timeFrame: From Week 14 post-transplant to Week 28 post-transplant (approximately 14 weeks)
measure: Percentage of Participants With All-cause Mortality From Week 14 Post-transplant to Week 48 Post-transplant
timeFrame: From Week 14 post-transplant to Week 48 post-transplant (approximately 34 weeks)
measure: Time to All-cause Mortality From Week 14 Post-transplant to Week 28 Post-transplant
timeFrame: From Week 14 post-transplant to Week 28 post-transplant (approximately 14 weeks)
measure: Time to All-cause Mortality From Week 14 Post-transplant to Week 48 Post-transplant
timeFrame: From Week 14 post-transplant to Week 48 post-transplant (approximately 34 weeks)
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope National Medical Center ( Site 0158)
state: California
city: Sacramento
country: United States
facility: University of California Davis Medical Center ( Site 0156)
state: California
city: Miami
country: United States
facility: University of Miami, Sylvester Comprehensive Cancer Center ( Site 0160)
state: Florida
city: Indianapolis
country: United States
facility: Indiana Blood and Marrow Transplantation ( Site 0175)
state: Indiana
city: Boston
country: United States
facility: Brigham & Women's Hospital ( Site 0161)
state: Massachusetts
city: Hackensack
country: United States
facility: John Theurer Cancer Center at Hackensack University Med Ctr ( Site 0174)
state: New Jersey
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center ( Site 0164)
state: New York
city: Durham
country: United States
facility: Duke University Medical Center ( Site 0169)
state: North Carolina
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center ( Site 0154)
state: Texas
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center ( Site 0152)
state: Washington
city: Limoges
country: France
facility: Centre Hospitalier Universitaire Dupuytren ( Site 0182)
state: Haute-Vienne
city: Montpellier
country: France
facility: Hopital Saint Eloi ( Site 0031)
state: Herault
city: Pierre Benite
country: France
facility: Centre Hopitalier Lyon Sud ( Site 0039)
state: Rhone
city: Creteil
country: France
facility: CHU Henri Mondor ( Site 0032)
state: Val-de-Marne
city: Villejuif
country: France
facility: Institut Gustave Roussy ( Site 0038)
state: Val-de-Marne
city: Paris
country: France
facility: CHU Hopital Saint Antoine ( Site 0036)
city: Heidelberg
country: Germany
facility: Universitaetsklinikum Heidelberg-Medizinische Klinik V ( Site 0042)
state: Baden-Wurttemberg
city: Koeln
country: Germany
facility: Universitaetsklinik Koeln ( Site 0041)
state: Nordrhein-Westfalen
city: Muenster
country: Germany
facility: Universitaetsklinikum Muenster ( Site 0043)
state: Nordrhein-Westfalen
city: Brescia
country: Italy
facility: ASST Spedali Civili di Brescia ( Site 0052)
state: Lombardia
city: Milano
country: Italy
facility: IRCCS Ospedale San Raffaele ( Site 0051)
city: Roma
country: Italy
facility: Fondazione PTV Policlinico Tor Vergata ( Site 0054)
city: Roma
country: Italy
facility: Policlinico Umberto I ( Site 0056)
city: Roma
country: Italy
facility: Policlinico Universitario Agostino Gemelli ( Site 0055)
city: Shimotsuke
country: Japan
facility: Jichi Medical University Hospital ( Site 0123)
state: Tochigi
city: Hiroshima
country: Japan
facility: Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital ( Site 0121)
city: Kumamoto
country: Japan
facility: National Hospital Organization Kumamoto Medical Center ( Site 0122)
city: Glasgow
country: United Kingdom
facility: Queen Elizabeth University Hospital [Glasgow, UK] ( Site 0096)
state: Glasgow City
city: London
country: United Kingdom
facility: 1Kings College Hospital ( Site 0091)
state: London, City Of
city: London
country: United Kingdom
facility: UCL Cancer Institute ( Site 0093)
state: London, City Of
city: Manchester
country: United Kingdom
facility: Manchester Royal Infirmary ( Site 0097)
city: Newcastle upon Tyne
country: United Kingdom
facility: Freeman Hospital Newcastle upon Tyne Foundation NHS Trust ( Site 0092)
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.