Letermovir-based Dual Therapy for Treatment of Cytomegalovirus Infections (LUCY-1)

Letermovir/Valganciclovir Combination Versus Valganciclovir Monotherapy for Treatment of Cytomegalovirus (CMV) Infections in Kidney Transplant Recipients

The purpose of this study is to evaluate the efficacy and the tolerance of letermovir as part of dual antiviral therapy (in association with valganciclovir) in renal transplant recipients with CMV DNAemia, requiring valganciclovir treatment per investigator's judgment.

Study Overview

• Status: Not yet recruiting
• Conditions: Cytomegalovirus Infection
• Intervention / Treatment: Drug: Letermovir; Drug: Valganciclovir; Drug: Letermovir placebo

Detailed Description

Ganciclovir and valganciclovir are the drugs of choice to treat CMV infections and diseases in immunocompromised patients. However, (val)ganciclovir does not seem to be a panacea and its modest efficacy and dose-limiting toxicities limit effectiveness. More, (val)ganciclovir use may drive development of drug-resistant infections, particularly in immunocompromised patients.

An in vitro study suggested additive effects for the combination of letermovir with all approved drugs for treatment or prevention of CMV infections. Investigator's hypothesis is that letermovir plus valganciclovir dual therapy will inhibit CMV replication faster than valganciclovir monotherapy. More, the use of antiviral dual therapy aims to decrease the risk of drug resistance mutations' selection, as previously demonstrated in several other viral infections.

In this study, renal transplant recipients with CMV DNAemia requiring valganciclovir will be randomized to receive either letermovir plus valganciclovir or letermovir placebo plus valganciclovir, until reaching the "treatment success" or the "treatment failure" criteria, up to 12 weeks.

Treatment success will be defined as, from Week-3:

• eradication of CMV DNAemia, defined as CMV DNAemia in whole blood below lower limit of quantification (LLOQ) < 200 IU/mL on 1 blood sample.
• AND resolution of clinical symptoms of CMV disease (if appropriate)

Treatment failure will be defined as fulfilling at least one criterion among:

• failure to achieve a decrease of CMV DNAemia ≥ 1 log10 IU/mL at Week-3 compared to the baseline CMV DNAemia
• persistence of CMV DNAemia ≥ LLOQ (200 IU/ml) at Week-12
• absence of improved CMV disease at Week-3.

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Pierre FRANGE, MD, PhD; Phone Number: +33 1.44.49.49.61; Email: pierre.frange@aphp.fr
• Study Contact Backup: Name: Aminata TRAORE; Phone Number: +33 1.42.19.27.34; Email: aminata.traore@aphp.fr

Study Locations

• France
  • Paris, France, 75015
    • Hôpital Necker Enfants Malades
    • Contact: Laurence BUSSIERES, PhD; Phone Number: +33 6 62 08 19 58; Email: laurence.bussieres@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥ 18 years
2. Weight ≥ 30 kg
3. Kidney transplant recipient
4. Have a documented CMV infection or disease, with a screening value of CMV DNA ≥ 3000 IU/mL in whole blood or plasma in 2 consecutive assessments separated by ≥ 1 day, as determined by local laboratory quantitative polymerase chain reaction (qPCR).
5. Eligible for treatment with oral valganciclovir, per investigator's judgment

6. For patients of childbearing age (following menarche): negative bHCG and effective method of contraception (sexual abstinence, hormonal contraception containing ethinylestradiol and levonorgestrel, intrauterine device or hormone-releasing system, cap, diaphragm or sponge with spermicide, condom) until 30 days after the end of relevant systemic exposure (week 13).

   For male an effective method of contraception (sexual abstinence, condom) until 90 days after the end of relevant systemic exposure (week 13).

7. Have life expectancy of ≥ 8 weeks
8. French speaking
9. Affiliated to social security regime or an equivalent system
10. Informed consent and signed

Exclusion Criteria:

1. Have a current CMV infection that is considered refractory or resistant due to inadequate adherence to antiviral treatment, to the best knowledge of the investigator.
2. Have a CMV infection that is known to be genotypically resistant to valganciclovir and/or letermovir on documented evidence.
3. Be on treatment with anti-CMV agents (ganciclovir, valganciclovir, foscarnet, cidofovir, letermovir or maribavir) for the current CMV infection for longer than 72 hours. However, patients experiencing CMV infection while receiving ganciclovir or valganciclovir prophylaxis (i.e. at prophylactic dosages) or letermovir prophylaxis can be included.
4. Have an eGFR < 30 mL/min/1.73m² (using the CKD-EPI Creatinine Equation (2009)).
5. Have serum aspartate aminotransferase (AST) ≥ 5 times higher than the upper limit of normal (ULN), or serum alanine aminotransferase (ALT) ≥ 5 times the ULN, or total bilirubin ≥ 3 times the ULN (except for documented Gilbert's syndrome). Note: Subjects with biopsy confirmed CMV hepatitis will not be excluded from study participation despite AST or ALT ≥ 5 times ULN
6. Have a severe chronic liver disease (Child-Pugh Class C)
7. Have a known human immunodeficiency virus (HIV) infection with plasma HIV RNA ≥ 50 copies/mL within the 3 months before inclusion.
8. Require mechanical ventilation or vasopressors for hemodynamic support.
9. Be pregnant or breastfeeding.
10. Have received anti-CMV vaccine at any time.
11. Be receiving leflunomide or artesunate when study treatment is initiated.
12. Be receiving strong inhibitors or inducers of hepatic CYP enzymes including rifampicin, phenytoin, clarithromycin, ritonavir, or cobicistat or St. John's wort (Hypericum perforatum) when study treatment is initiated.
13. Be receiving efavirenz, etravirine, nevirapine, lopinavir, pimozine, ergot alkaloids, dabigatran, atorvastatine, simvastatine, rosuvastatine, pitavastatine or imipenem-cilastatine when study treatment is initiated.
14. Have known hereditary intolerance to galactose, with lactose Lapp deficiency, glucose or galactose malabsorption syndrome.
15. Have known hypersensitivity to letermovir or to an excipient for a study treatment.
16. Have any clinically significant medical or surgical condition that in the investigator's opinion could interfere with the interpretation of study results, contraindicate the administration of the assigned study treatment, or compromise the safety or well-being of the subject.
17. Participation to another clinical trial on medicinal products for human use
18. Have an absolute neutrophil count less than 500 cells/µl, or platelet count less than 25,000/µl, or haemoglobin less than 8 g/dl

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Letermovir+Valganciclovir; Daily administration of Letermovir plus Valganciclovir	Drug: Letermovir; 480mg (2X240mg- tablets) of Letermovir given orally once a day until the "treatment success" or the "treatment failure", up to 12 weeks. In case of co-administration with cyclosporine A, the dosage of Letermovir will be reduced.; Drug: Valganciclovir; Valganciclovir 900 mg (2X450 mg-tablets) twice a day until the "treatment success" or the "treatment failure", up to 12 weeks. In case of impaired renal function, the dosage of valganciclovir will be reduced.
Active Comparator: Letermovir Placebo+Valganciclovir; Daily administration of Letermovir placebo plus Valganciclovir	Drug: Valganciclovir; Valganciclovir 900 mg (2X450 mg-tablets) twice a day until the "treatment success" or the "treatment failure", up to 12 weeks. In case of impaired renal function, the dosage of valganciclovir will be reduced.; Drug: Letermovir placebo; 480mg (2X240mg- tablets) of Letermovir placebo given orally once a day until the "treatment success" or the "treatment failure", up to 12 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Virological response to treatment on week-3	defined as a ≥ 2 log10 decrease of CMV DNAemia in whole blood from baseline, or an undetectable CMV DNAemia (< 200 IU/mL) in whole blood	3 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Eradication of CMV DNAemia (< 200 IU/ml) before Week-12	quantitative CMV PCR performed in whole blood every week until interruption of antiviral treatment, or at the latest until Week-12	12 weeks
Number of days between baseline and first measure of CMV DNAemia < 200 IU/mL	Quantitative CMV PCR performed in whole blood every week until interruption of antiviral treatment, or at the latest until Week-12	12 weeks
Absence of CMV-related symptoms at baseline and each visit		12 weeks
Adverse event (AE) occurence	Clinical examination and clinical laboratory assessments performed every week until interruption of antiviral treatment (or at the latest until Week-12)	12 weeks
Sequencing of whole UL97, UL54, UL56, UL89 and UL51 genes	in blood samples at baseline, at Week-3 or Week-12 (in patients achieving criteria defining "treatment failure"), and at any visit in patients presented with rebound of CMV DNAemia	12 weeks
Ganciclovir plasma concentration	at Week-1 and Week-2, in case of premature termination of treatment for any reason or premature exit from the study.	2 weeks
Letermovir plasma concentration	t Week-1 and Week-2, in case of premature termination of treatment for any reason or premature exit from the study.	2 weeks
Measure of the CMV specific T-cell immunity	at baseline, Week-3, Week-6, Week-9 and Week-12.	12 weeks

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Study Chair: Marianne LERUEZ-VILLE, MD, PhD, Virology laboratory- reference national Lab for CMV infection -Hôpital Necker Enfants malades, Paris; Principal Investigator: Pierre FRANGE, MD, PhD, Assistance Publique Hôpitaux Paris

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2024
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): April 1, 2027

Study Registration Dates

• First Submitted: February 15, 2024
• First Submitted That Met QC Criteria: March 25, 2024
• First Posted (Actual): March 28, 2024

Study Record Updates

• Last Update Posted (Actual): March 28, 2024
• Last Update Submitted That Met QC Criteria: March 25, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Cytomegalovirus infection; Cytomegalovirus disease
• Additional Relevant MeSH Terms: Pathologic Processes; Virus Diseases; Disease Attributes; DNA Virus Infections; Herpesviridae Infections; Infections; Communicable Diseases; Cytomegalovirus Infections; 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: APH220791; 2023-506216-40-00 (Other Identifier: EU CT)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No