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)
Condition: Cytomegalovirus Infection
MeSH terms: Infections; Cytomegalovirus Infections
Intervention: Letermovir; Placebo
Intervention description: 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 was administered as tablets matched to LET or as inactive (saline or dextrose) intravenous infusion.
Intervention MeSH terms: Letermovir
Phase: Phase 3
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 220.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

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