Letermovir-based Dual Therapy for Treatment of Cytomegalovirus Infections

Inclusion Criteria:

1. Age ≥ 18 years

2. Weight ≥ 30 kg

3. Kidney transplant recipient

4. Have a documented CMV infection or disease, with (i) a screening value of CMV DNA ≥ 3000 IU/mL in whole blood or plasma in 2 consecutive assessments separated by ≥ 1day, as determined by local laboratory quantitative polymerase chain reaction (qPCR). Both samples should be taken within 14 days prior to randomization with thesecond sample obtained within 5 days prior to randomization OR (ii) a screeningvalue of CMV DNA ≥ 30000 IU/mL in whole blood or plasma, as determined by locallaboratory quantitative polymerase chain reaction (qPCR), in 1 sample obtainedwithin 5 days prior to randomization

5. Eligible for treatment with oral valganciclovir, per investigator's judgment

6. For patients of childbearing age (following menarche): negative bHCG and effectivemethod of contraception (sexual abstinence, hormonal contraception containingethinylestradiol and levonorgestrel, intrauterine device or hormone-releasingsystem, cap, diaphragm or sponge with spermicide, condom) until 30 days after theend of relevant systemic exposure (week 13). For male an effective method of contraception (sexual abstinence, condom) until 90days 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 toinadequate adherence to antiviral treatment, to the best knowledge of theinvestigator.

2. Have a CMV infection that is known to be genotypically resistant to valganciclovirand/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 72hours. However, patients experiencing CMV infection while receiving ganciclovir orvalganciclovir prophylaxis (i.e. at prophylactic dosages) or letermovir prophylaxiscan 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 ofnormal (ULN), or serum alanine aminotransferase (ALT) ≥ 5 times the ULN, or totalbilirubin ≥ 3 times the ULN (except for documented Gilbert's syndrome). Note:Subjects with biopsy confirmed CMV hepatitis will not be excluded from studyparticipation 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 ≥ 50copies/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 includingrifampicin, 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, ergotalkaloids, dabigatran, atorvastatine, simvastatine, rosuvastatine, pitavastatine orimipenem-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 theinvestigator's opinion could interfere with the interpretation of study results,contraindicate the administration of the assigned study treatment, or compromise thesafety 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 lessthan 25,000/µl, or haemoglobin less than 8 g/dl