Open Label Trial of Oral Letermovir for CMV Prophylaxis in Thoracic Transplant Recipients

Inclusion Criteria:

• Heart or Lung transplant recipient
• Donor and/or Recipient CMV seropositive (defined by positive IgG) within 1 year priorto transplantation
• Able to start oral CMV prophylaxis within 14 days of transplantation
• Males at birth agree to use contraception during the treatment period, and for atleast 90 days after the last dose of study treatment, and refrain from donating spermduring this period
• Female at birth is not pregnant or breastfeeding. If of childbearing potential, agreesto follow the contraception guidance during the treatment period and for at least 90days after the last dose of study treatment
• A male or female subject who is of reproductive potential agrees to true abstinence orto use (or have their partner use) 1 acceptable method of birth control starting fromthe time of consent through 90 days after the last dose of study therapy. Trueabstinence is defined as abstinence in line with the preferred and usual lifestyle ofthe subject. Periodic abstinence (e.g., abstinence only on certain calendar days,abstinence only during ovulation period, use of symptothermal method, use ofpost-ovulation methods) and withdrawal are not acceptable methods of contraception.Acceptable methods of birth control are: intrauterine device (IUD), diaphragm withspermicide, contraceptive sponge, condom, and vasectomy OR use of appropriate doublebarrier contraception as per local regulations or guidelines. Hormonal contraceptives (e.g., birth control pills, transdermal patch, or injectables) are unacceptablemethods of birth control for use in this study because it is not known whether thesemethods are affected by co-administration of letermovir.

Exclusion Criteria:

• Any prior solid organ transplant
• Dual organ transplantation
• Prior treated CMV infection
• Unknown CMV serostatus of the donor or recipient
• Suspected or known hypersensitivity to active or inactive ingredients of letermovirformulations and/or acyclovir formulations
• CrCl <10 mL/minute, using Cockcroft-Gault equation, or renal replacement therapy atthe time of enrollment
• Child-Pugh Class C severe hepatic insufficiency at enrollment
• Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5 x theupper limit of normal (ULN) or serum total bilirubin > 2.5 x ULN. Note: Subjects whomeet this exclusion criterion may, at the discretion of the investigator, have onerepeat set of relevant labs done. If the repeat value does not meet this criterion,they may continue in the enrollment process
• Both moderate hepatic insufficiency AND moderate renal insufficiency. Note: Moderatehepatic insufficiency is defined as Child Pugh Class B; moderate renal insufficiencyis defined as a creatinine clearance less than 50 mL/min, as calculated by theCockcroft-Gault equation
• Neutropenia, defined as absolute neutrophil count <1,500/microliter, at the time ofenrollment
• Severe thrombocytopenia, defined as platelets <50,000/microliter, at the time ofenrollment
• Any uncontrolled infection on the day of enrollment
• Documented positive results for human immunodeficiency virus antibody (HIV-Ab) test atany time prior to enrollment, or for hepatitis C virus antibody (HCV-Ab) and withdetectable HCV ribonucleic acid (RNA) within 90 days prior to enrollment, or hepatitisB surface antigen (HBsAg) within 90 days prior to enrollment.
• History of malignancy ≤5 years prior to signing informed consent, with the exceptionof localized basal cell or squamous cell skin cancer
• Pregnant or expecting to conceive, is breastfeeding, or plans to breastfeed from thetime of consent through at least 90 days following cessation of study therapy.
• Expecting to donate eggs or sperm starting from the time of consent through at least 90 days following cessation of study therapy.
• Received within 30 days prior to enrollment or plans to receive during the study anyof the following anti-CMV IgG antibody treatment or anti-CMV drug therapy includingthe following: Cidofovir, CMV hyper-immune globulin, any investigational CMV antiviralagent/biologic therapy.
• Received >14 days of IV ganciclovir prior to initiation of study drug or plans toreceive during the study any of the following anti-CMV drug therapy: ganciclovir,valganciclovir, foscarnet, acyclovir, valacyclovir, famciclovir.
• Currently participating or has participated in a study with an unapprovedinvestigational compound within 28 days, or 5× half-life of the investigationalcompound whichever is longer, of initial dosing on this study
• Previously participated in this study or any other study involving letermovir
• Previously participated or is currently participating in any study involvingadministration of a CMV vaccine or another CMV investigational agent, or is planningto participate in a study of a CMV vaccine or another CMV investigational agent duringthe course of this study.
• For unexposed subjects, any letermovir exposure
• Are unable to take medications orally by day 14 post-transplant