Letermovir vs Valganciclovir in CMV R+ Kidney Transplant

The purpose of this study is to evaluate the efficacy and tolerability of letermovir compared to standard-of-care, valganciclovir, for the prevention of clinically significant cytomegalovirus (CMV) infection in CMV moderate risk adult kidney transplant recipients.

A 3:1 match of historical valganciclvoir:letermovir arm

• Matching criteria:

• Induction agent: lymphocyte-depleting (rabbit anti-thymocyte globulin or alemtuzumab) versus non-lymphocyte depleting (basiliximab)
• Delayed graft function (dialysis within one week of kidney transplant)
• MMF dose at de novo discharge (weight-based vs non-weight based)

Study Arms:

• Letermovir Arm:

• Letermovir 480 mg PO daily starting POD 4 through 10 OR
• Letermovir 240 mg PO daily if given concomitantly with cyclosporine, for 90 days
• Will be given with acyclovir 400 mg PO BID (or 200 PO BID if CrCl <25) for 90 days
• Historical Arm:

• Valganciclovir 450 mg PO daily (adjusted for renal function) for 90 days

• CrCl 25-30: valganciclovir 450 mg PO q 48 h
• CrCl <25: Valganciclovir 450 mg PO three times weekly

Outcomes:

• Primary Efficacy Objective:

• Incidence of patients with clinically significant CMV infection at 12 months post kidney transplant in patients who received letermovir versus standard of care valganciclovir

• Clinically Significant CMV Infection: CMV disease or symptomatic viremia requiring therapeutic intervention
• Secondary Objectives:

• Tolerability:

• Proportion of patients with leukopenia or neutropenia (composite) in patients who received letermovir versus standard of care valganciclovir
• Leukopenia: white blood cells < 3500 cells/uL
• Neutropenia: absolute neutrophil count < 1000 cells/uL

• Intolerability or early drug discontinuation
• Proportion of patients who discontinue the study drug prematurely due to adverse events or intolerance

o Efficacy:

• Time-to clinically significant CMV infection (days)
• Breakthrough CMV while on CMV prophylaxis
• CMV Viremia

• Detection of CMV DNA in blood via PCR
• Clinically significant CMV infection

• CMV resistance
• Detection of CMV strains with genotypic or phenotypic resistance to antiviral agents used in prophylaxis or treatment

Inclusion criteria

(both arms):

• ≥18 years old
• Kidney transplant recipient with documented CMV IgG seropositive status (R+) within 90 days prior to transplant

Inclusion criteria

(letermovir arm):

• Males agree to use contraception and refraining from donating sperm for 290 days post-treatment initiation
• Females of child-bearing potential agree to follow contraception guidance for 290 days post-treatment initiation

Exclusion criteria

(both arms):

• Multiorgan organ transplant
• Received previous solid organ transplant or HSCT
• Unable to take oral medications
• Uncontrolled infections at the time of enrollment
• Hemodynamically unstable or on mechanical ventilation at the time of enrollment
• Documented HBsAg or detectable HCV RNA 90 days prior to enrollment or HCV+ donor
• Pregnant or breastfeeding or planning to be pregnant, breastfeeding or donating eggs during study period and 90 days post cessation
• Received any anti-CMV drug treatment within 7 days prior to enrollment
• Current user of recreational or illicit drugs or alcohol dependence
• History of CMV disease prior to enrollment

Exclusion criteria

(letermovir arm):

• Previously participated in a letermovir study or any other study with CMV investigational agents
• On dialysis or plasmapheresis at the time of enrollment
• Known or suspected hypersensitivity to active or inactive ingredients from letermovir or acyclovir formulations
• Child-Pugh Class C severe hepatic insufficiency
• Currently participating or has participated in a study with an unapproved compound of device within 28 days or 5 half-lives of this study
• Contraindications per letermovir or acyclovir package insert: patients on pimozide, ergot alkaloids; or pitavastatin and simvastatin when co-administered with cyclosporine