Letermovir/valganciclovir combination versus valganciclovir monotherapy for treatment of cytomegalovirus (CMV) infections in kidney transplant recipients.

INTERVENTION: Product Code: SCP47385062,Pharmaceutical Form: ,Other descriptive name: ,Product Name: PREVYMIS 240 mg film‐coated tablets,Product Code: PRD5769611,Pharmaceutical Form: FILM‐COATED TABLET,Other descriptive name: ,Strength: Letermovir 240mg,Product Name: Placebo of prevymis 240 mg tablets (letermovir),Product Code: N/A,Pharmaceutical Form: N/A,Other descriptive name: N/A,Strength: N/A,Pharmaceutical form of the placebo: N/A CONDITION: CytoMegaloVirus infections,Kidney transplant ; MedDRA version: 20.1Level: PTClassification code: 10011831Term: Cytomegalovirus infectionSystem Organ Class: 100000004862 MedDRA version: 20.1Level: PTClassification code: 10011831Term: Cytomegalovirus infectionSystem Organ Class: 100000004862 Therapeutic area: Diseases [C] ‐ Virus Diseases [C02] SECONDARY OUTCOME: Secondary end point(s):Absence of CMV‐related symptoms at baseline and each visit. Secondary end point(s):Clinical side effects, neutrophil, platelet, hemoglobin, creatinine, liver enzymes, bilirubin, urea tested every week until interruption of antiviral treatment (or at the latest until Week‐12) Secondary end point(s):Eradication of CMV DNAemia (< 200 IU/ml) before Week‐12, detected in whole blood by quantitative CMV PCR every week until interruption of antiviral treatment, or at the latest until Week‐12 Secondary end point(s):Measurement of ganciclovir (in both groups) and letermovir (in the bitherapy arm) trough plasma concentration (Cmin) at Week‐1, Cmin and Cma Xat Week‐2, Cmin in case of premature termination of treatment for any reason or premature exit from the study at any time and for any reason (at the end of the trial). Secondary end point(s):Measurement of the CMV specific T‐cell immunity (by ELISpot‐CMV) at baseline, Week‐3, Week‐6, Week‐9 and Week‐12. Secondary end point(s):Number of days between baseline and first measure of CMV DNAemia < 200 IU/mL in whole blood. Secondary end point(s):Sequencing of UL97, UL54, UL56, UL89 and UL51 genes 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. Secondary end point(s):Sequencing of whole UL97, UL54, UL56, UL89 and UL51 genes in blood samples at baseline Secondary end point(s):Tablet count at each visit PRIMARY OUTCOME: Main Objective:To demonstrate that, compared to valganciclovir monotherapy, a letermovir + valganciclovir combination administered to kidney transplant recipients with CMV infection increases the proportion of patients reaching a virological response on Week‐3 (defined as a = 2 log10 decrease of CMV DNAemia from baseline or an undetectable CMV DNAemia (< 200 IU/mL) on Week 3). Primary end point(s):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 Secondary Objective:To compare the proportion of patients achieving eradication of CMV DNAemia (< 200 IU/mL) before Week‐12 between the 2 arms.,To compare the time to reach eradication of CMV DNAemia (< 200 IU/mL) between the 2 arms.,To compare, among patients with CMV disease at baseline, the percentage of those with resolution of symptoms before Week‐12 between the 2 arms.,To compare the tolerance between the 2 arms.,To compare adherence to treatment between the 2 arms.,To compare the impact of mutation(s) in CMV genes associated with ganciclovir (UL97 and UL54) and letermovir resistance (UL56, UL89 and UL51) at baseline on the response to treatment (virological response on Week‐3 and eradication of CMV DNAemia on Week‐12) in the 2 arms.,To investigate the presence of mutation(s) on CMV genes associated with ganciclovir (UL97 and UL54) and letermovir resistance (UL56, UL89 and UL51) selected at Week‐3 or Week‐12 (in patients achieving criteria defining “treatment failure”) and at any visit in case of viral rebound of CMV DNAemia.,To investigate the relationship between plasma ganciclovir (in the 2 arms) and letermovir (in the dual therapy arm) concentrations at Week‐1 and Week‐2 and the response (virological response on Week‐3 and eradication of CMV DNAemia on Week‐12) and tolerance to antiviral treatment.,To investigate the relationship between CMV specific T‐cell immunity (CMV‐ELISpot) at baseline, Week‐3, Week‐6, Week‐9 and Week‐12, and the response to treatment (virological response on Week‐3 and eradication of CMV DNAemia on Week‐12). INCLUSION CRITERIA: Age = 18 years,Informed consent and signed,Weight = 30 kg,Kidney transplant recipient,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). Both samples should be taken within 14 days prior to randomization with the second sample obtained within 5 days prior to randomization.,Eligible for treatment with oral valganciclovir, per investigator's judgment,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,