Letermovir-based Dual Therapy for Treatment of Cytomegalovirus Infections

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.

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.

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 ≥ 1 day, as determined by local laboratory quantitative polymerase chain reaction (qPCR). Both samples should be taken within 14 days prior to randomization with the second sample obtained within 5 days prior to randomization OR (ii) a screening value of CMV DNA ≥ 30000 IU/mL in whole blood or plasma, as determined by local laboratory quantitative polymerase chain reaction (qPCR), in 1 sample obtained within 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 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 < 15 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 (at a daily dose > 20mg, and / or if co-administered with cyclosporin A), pravastatin ( if co-administered with cyclosporin A), 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