Letermovir for CMV Prevention After Lung Transplantation

An Open-label Pilot Protocol to Evaluate the Efficacy of Letermovir for the Prevention of Human Cytomegalovirus (CMV) Infection and Disease in Adult Lung Transplant Recipients With Idiopathic Pulmonary Fibrosis

This is an interventional, open-label, single center, pilot study with historical controls to test the efficacy of letermovir (LET) for the prevention of CMV infection and disease in adult lung transplant recipients (LTRs) with idiopathic pulmonary fibrosis (IPF).

Study Overview

• Status: Recruiting
• Conditions: CMV; Lung Transplant
• Intervention / Treatment: Drug: Letermovir; Drug: Valganciclovir

Detailed Description

Approximately 30 patients with IPF listed for lung transplantation will be enrolled and 15 are expected to undergo lung transplantation during the study period and receive the intervention. Patients who are CMV seropositive will receive letermovir for 6 months, patients who are CMV seronegative and receive lungs from a CMV seropositive donor (CMV D+/R-) will receive letermovir for 12 months. All patients will be followed for 12 weeks after completion of letermovir for the occurrence of CMV infection or disease after prophylaxis.

Historical controls will be LTRs for IPF from 2010-2019 who are CMV R+ or CMV D+/R- (donor positive/recipient negative). CMV prophylaxis in the historical controls was with valganciclovir for 6 months for CMV R+ and for 12 months for CMV D+/R-. Patients will be matched for CMV serostatus, induction immunosuppression, age, and telomere length.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Kailey Hughes Kramer, MPH; Phone Number: 412-648-6453; Email: hugheskl4@upmc.edu
• Study Contact Backup: Name: Fernanda Silveira, MD; Phone Number: 412-648-6512; Email: silvfd@upmc.edu

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Recruiting
      • UPMC
      • Contact: Kailey Hughes Kramer, MPH; Phone Number: 421-648-6453; Email: hugheskl4@upmc.edu
      • Contact: Kelly Friday; Phone Number: 412-648-6377; Email: fridaykc@upmc.edu
      • Principal Investigator: Fernanda Silveira, MD
    • Pittsburgh, Pennsylvania, United States, 15213
      • Not yet recruiting
      • UPMC
      • Contact: Kailey Hughes Kramer, MPH; Phone Number: 412-648-6453; Email: hugheskl4@upmc.edu
      • Contact: Fernanda Silveira, MD; Phone Number: 412-648-6512; Email: silvfd@upmc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥18 years on day of signing informed consent
• Listed for lung transplantation (single or double) due to a diagnosis of IPF or receipt of a lung transplant (single or double) for IPF in the 72 hours prior to enrollment
• Have a documented positive serostatus for CMV (CMV IgG seropositive, R+)
• Have a documented negative serostatus for CMV (CMV IgG seronegative, R-) and anticipate receiving or having received a lung allograft from a CMV IgG positive donor, D+). Only participants who are R+ or who are CMV D+/R- will receive intervention. Participants who are CMV D-/R- will be considered screen failures
• Able to travel to UPMC for routine post-transplant visits for a minimum of 15 months after transplantation
• Able to provide informed consent
• Be willing to use a contraceptive method while receiving LET and for at least 90 days following last dose of LET

Exclusion Criteria:

• Receipt of a previous solid organ transplant or hematopoietic stem cell transplant
• Multi-organ transplant recipient, i.e., heart-lung or lung-liver
• HIV seropositive
• HCV antibody or HCV RNA positive
• Donor HCV NAT positive
• Anticipated need for use of ganciclovir, valganciclovir, foscarnet, or cidofovir at the time of transplant
• Known or suspected hypersensitivity to LET or acyclovir
• CrCl < 10 ml/min or dialysis on day of transplant
• Child-Pugh Class C severe hepatic insufficiency
• Pregnancy or expected to conceive while on LET and through at least 90 days following cessation of LET

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Letermovir; Participants who are CMV seropositive (CMV R+) will receive letermovir prophylaxis for 6 months, and participants who are CMV donor seropositive/recipient seronegative (CMV D+/R-) will receive letermovir prophylaxis for 12 months. Letermovir will be administered at a dose of 480 mg IV or oral once daily. IV administration will occur only for those patients unable to swallow tablets. If letermovir is co-administered with cyclosporine A, the dosage of letermovir will be decreased to 240 mg once daily.	Drug: Letermovir; Participants who are CMV R+ will receive LET prophylaxis for 6 months, and participants who are CMV D+/R- will receive LET prophylaxis for 12 months. The duration of prophylaxis is per current standard of care. LET will be administered at a dose of 480 mg IV or oral once daily. IV administration will occur only for those patients unable to swallow tablets. If LET is co-administered with cyclosporin A (CsA), the dosage of LET should be decreased to 240 mg once daily. All patients will be followed for 12 weeks after completion of LET for the occurrence of CMV infection or disease after prophylaxis. Participants on this protocol will receive acyclovir 400 mg orally BID for the duration of LET therapy for herpes simplex virus and varicella zoster virus prophylaxis.; Other Names: Prevymis
Active Comparator: Valganciclovir; Historical controls will be lung transplant recipients for idiopathic pulmonary fibrosis from 2010-2019 who are CMV R+ or CMV D+/R-. CMV prophylaxis in the historical controls was with valganciclovir for 6 months for CMV R+ and for 12 months for CMV D+/R-.	Drug: Valganciclovir; Historical controls will have received CMV prophylaxis with valganciclovir for 6 months for CMV R+ and for 12 months for CMV D+/R-.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurrence of CMV infection or disease during prophylaxis	Proportion of lung transplant recipients with idiopathic pulmonary fibrosis with CMV infection or disease during letermovir prophylaxis. This will be compared to the proportion of CMV infection or disease in historical lung transplant recipients with idiopathic pulmonary fibrosis who received valganciclovir prophylaxis	6-12 months post-transplant
Occurrence of CMV infection or disease in the 3 months following completion of prophylaxis	Proportion of lung transplant recipients with idiopathic pulmonary fibrosis with CMV infection or disease in the 3 months following completion of prophylaxis with letermovir. This will be compared to the proportion of CMV infection or disease in the 3 months following in historical lung transplant recipients with idiopathic pulmonary fibrosis who received valganciclovir prophylaxis.	12 weeks after completion of letermovir

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Discontinuation events	Discontinuation of letermovir will be compared to discontinuation of valganciclovir in historical controls	6-12 months
Occurrence of leukopenia or neutropenia while on prophylaxis	Proportion of participants who develop any of the following while receiving letermovir: total WBC count ≤ 3,500 cells/mL or absolute neutrophil count ≤ 1,000 cells/mL. This will be compared to the rate of total WBC count ≤ 3,500 cells/mL or absolute neutrophil count ≤ 1,000 cells/mL in historical controls while receiving valganciclovir prophylaxis.	6-12 months

Collaborators and Investigators

• Sponsor: Fernanda P Silveira, MD, MS
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Fernanda Silveira, University of Pittsburgh

Study record dates

Study Major Dates

• Study Start (Actual): December 6, 2021
• Primary Completion (Estimated): July 1, 2025
• Study Completion (Estimated): July 1, 2025

Study Registration Dates

• First Submitted: April 20, 2021
• First Submitted That Met QC Criteria: September 2, 2021
• First Posted (Actual): September 13, 2021

Study Record Updates

• Last Update Posted (Actual): March 5, 2024
• Last Update Submitted That Met QC Criteria: March 1, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Lung transplant; CMV; Letermovir
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antineoplastic Agents; Poly(ADP-ribose) Polymerase Inhibitors; Valganciclovir; Letermovir
• Other Study ID Numbers: STUDY21040074

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: We do not plan to share individual participant data outside of our investigative team. Aggregate data will be shared in publications as appropriate.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No