Combination Letermovir and Standard of Care Antiviral for Enhanced Antiviral Response in Cytomegalovirus Infection in Lung Transplant Recipients (CLEAR-CMV)

University Health Network, Toronto

Status and phase: Not yet enrolling; Phase 4

Conditions: CMV; Lung Transplant Recipient

Treatments: Drug: Letermovir; Drug: Valganciclovir/Ganciclovir; Drug: Placebo

Study type: Interventional

Funder types: Other

Identifiers

NCT07235683

25-5760

Details and patient eligibility

About

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.

Full 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.

Enrollment: 40 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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40 participants in 2 patient groups, including a placebo group

SOC antiviral plus placebo

Placebo Comparator group

Description:

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.

Treatment:

Drug: Valganciclovir/Ganciclovir

Drug: Placebo

SOC antiviral plus letermovir active drug

Experimental group

Description:

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.

Treatment:

Drug: Valganciclovir/Ganciclovir

Drug: Letermovir