Combination Letermovir and Standard of Care Antiviral for Enhanced Antiviral Response in Cytomegalovirus Infection in Lung Transplant Recipients

NCT ID: NCT07235683

Last Updated: 2025-11-19

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 40 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-11-30
• Study Completion Date: 2027-08-31

Brief Summary

The primary objective of the CLEAR-CMV trial is to evaluate the efficacy of letermovir therapy plus standard of care (SOC) antiviral compared to SOC plus placebo in achieving clearance of CMV viremia by week 3 in lung transplant recipients with active CMV infection.

Detailed Description

Lung transplant recipients are particularly susceptible to CMV infection due to intensive immunosuppressive regimens required to prevent graft rejection. CMV viremia is associated with increased morbidity, including CMV pneumonitis, and may contribute to chronic lung allograft dysfunction (CLAD).Approximately 30-50% of lung transplant recipients develop CMV infection within the first year post-transplant, with higher rates in CMV-seronegative recipients receiving organs from seropositive donors (D+/R-).

Current standard treatment for CMV infection in transplant recipients involves ganciclovir or its oral prodrug, valganciclovir, which inhibit CMV DNA polymerase. While effective, prolonged use is associated with toxicities, including myelosuppression, and the emergence of resistant strains in some cases. Letermovir, a novel antiviral targeting the CMV terminase complex, has shown efficacy in CMV prophylaxis in hematopoietic stem cell transplant recipients, and in kidney transplant recipients. It has now been extensively studied for use in prophylaxis but there are limited data in treatment. It is an attractive drug in transplant recipients because it has an excellent safety profile and requires no dose adjustment for renal dysfunction. However, data on the use of letermovir for treatment (as opposed to prophylaxis) are more limited. A multicenter study of letermovir use for treatment showed reasonable response rates especially in patients with low viral loads. The use of combination therapy for CMV treatment represents an attractive option, as there is extensive experience with other viruses (e.g. HIV , HCV) to show that this strategy leads to improved response rates and lessens the emergence of antiviral resistance. The use of ganciclovir plus letermovir is attractive because they target two different viral enzymes and both have oral options facilitating outpatient treatment. The most recently published international CMV consensus guidelines reports that the use of combination antiviral therapy is a key research need.

The investigators plan to conduct a pilot trial to determine the efficacy of letermovir plus standard of care (SOC) antiviral therapy in clearing CMV infection. The trial will be conducted in compliance with the protocol, Good Clinical Practices (GCP) and the applicable regulatory requirements.

Conditions

CMV; Lung Transplant Recipient

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

SOC antiviral plus placebo

Patients will receive the standard of care (SOC) antiviral therapy along with a placebo drug. The placebo drug will be administered for three weeks, while the SOC antiviral duration and dosage will be at the discretion of the treating physician.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo will be dosed the same as letermovir: one tablet every 12 hours for the first 24 hours, then one tablet per day for total treatment duration of 21 days.

Valganciclovir/Ganciclovir

Intervention Type: DRUG

Ganciclovir or its oral prodrug, valganciclovir will be administered as the standard of care antiviral therapy. Its duration will be at the discretion of the treatment physician but is typically given until clearance of viremia. The clinical definition of viral clearance is one negative viral load or two viral loads one week apart that are \<200 IU/mL

SOC antiviral plus letermovir active drug

Patients will receive the standard of care (SOC) antiviral therapy in combination with letermovir. The letermovir active drug will be administered for three weeks, while the SOC antiviral treatment duration and dosage will be at the discretion of the treating physician.

Group Type: EXPERIMENTAL

Letermovir

Intervention Type: DRUG

Letermovir (480mg) will be given orally as a loading dose every 12 hours for the first 24 hours, then one tablet per day for a total treatment duration of 21 days. Letermovir treatment will be started within 72 hours of starting SOC antiviral treatment as per the decision of the treating physician.

Valganciclovir/Ganciclovir

Intervention Type: DRUG

Ganciclovir or its oral prodrug, valganciclovir will be administered as the standard of care antiviral therapy. Its duration will be at the discretion of the treatment physician but is typically given until clearance of viremia. The clinical definition of viral clearance is one negative viral load or two viral loads one week apart that are \<200 IU/mL

Interventions

Letermovir

Letermovir (480mg) will be given orally as a loading dose every 12 hours for the first 24 hours, then one tablet per day for a total treatment duration of 21 days. Letermovir treatment will be started within 72 hours of starting SOC antiviral treatment as per the decision of the treating physician.

Intervention Type: DRUG

Placebo

Placebo will be dosed the same as letermovir: one tablet every 12 hours for the first 24 hours, then one tablet per day for total treatment duration of 21 days.

Intervention Type: DRUG

Valganciclovir/Ganciclovir

Ganciclovir or its oral prodrug, valganciclovir will be administered as the standard of care antiviral therapy. Its duration will be at the discretion of the treatment physician but is typically given until clearance of viremia. The clinical definition of viral clearance is one negative viral load or two viral loads one week apart that are \<200 IU/mL

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Recipient of a lung transplant.
• Has confirmed CMV viremia with a viral load ≥ 1000 IU/mL and will receive or has just started SOC antiviral treatment in the past 72h as per the decision of the treating physician.

Exclusion Criteria

• Renal failure with Creatinine clearance <15 mL/min or requiring dialysis
• Severe hepatic impairment (Child-Pugh Class C)
• Participating in another interventional clinical trial
• Combined transplant (e.g heart-lung, lung-liver)
• Known allergy or contraindication to any of the antiviral medications
• Known antiviral resistance.
• Patient receiving cyclosporin, pimozide or ergot alkaloids (due to significant drug interaction with letermovir).
• Patient receiving or expected to receive CMV immunoglobulin or IVIG during the initial three week treatment phase

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University Health Network, Toronto

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

University Health Network, Toronto General Hospital

Toronto, Ontario, Canada

Countries

Canada

Central Contacts

Atul Humar, MD, FRCPC

Role: CONTACT

atul.humar@uhn.ca

416-340-4241

Facility Contacts

Ilona Bahinskaya, MSc, CCRP

Role: primary

Ilona.Bahinskaya@uhn.ca

416-340-4800 ext. 4328

Other Identifiers

25-5760

Identifier Type: -

Identifier Source: org_study_id