Efficacy and Safety of Leymovir Versus Valganciclovir in Prevention of Cytomegalovirus Infection and Cytomegalovirus Disease in Chinese Kidney Transplant Recipients

Efficacy and Safety of Leymovir Versus Valganciclovir in Prevention of Cytomegalovirus Infection and Cytomegalovirus Disease in Chinese Kidney Transplant Recipients

the existing anti-CMV drugs mainly include valganciclovir, ganciclovir and foscarnet sodium, all of which act on DNA polymerase (pUL54), making them prone to cross resistance. DNA synthesis in normal cell is also catalyzed by DNA polymerase, which can also inhibit normal cell production, especially in metabolically active bone marrow cells, leading to bone marrow suppression. In addition, these drugs are mainly metabolized by the kidneys, causing damage to proximal renal tubular cells. Therefore, it is necessary to closely monitor the patient's renal function and adjust the dosage. Overall, the medical demand for effective and well-tolerated treatment methods for CMV infection management in kidney transplant recipients remains unmet, and safer anti-CMV drugs are urgently needed.

The target of letemovir is the CMV DNA terminal enzyme complex, which is different from the target of existing anti-CMV drugs, and does not exhibit cross resistance. Moreover, this target does not have a corresponding substance in mammalian cells and does not exhibit toxicity similar to DNA polymerase targets. In addition, letemovir is mainly metabolized by the liver, and urinary excretion can be ignored (<2% dose), so there is no need to adjust the dose according to renal function. Phase III registered clinical studies abroad have shown that letemovir is not inferior to valganciclovir in preventing CMV disease in kidney transplant recipients. Additionally, letemovir is safer and has a lower incidence of adverse reactions, especially leukopenia or granulocytopenia. However, there is still a lack of data on the use of kidney transplantation in Chinese population.

The aim of this study was to evaluate the efficacy and safety of letamovir in preventing CMV infection and CMV disease in kidney transplant recipients in China.

the existing anti-CMV drugs mainly include valganciclovir, ganciclovir and foscarnet sodium, all of which act on DNA polymerase (pUL54), making them prone to cross resistance. DNA synthesis in normal cell is also catalyzed by DNA polymerase, which can also inhibit normal cell production, especially in metabolically active bone marrow cells, leading to bone marrow suppression. In addition, these drugs are mainly metabolized by the kidneys, causing damage to proximal renal tubular cells. Therefore, it is necessary to closely monitor the patient's renal function and adjust the dosage. Overall, the medical demand for effective and well-tolerated treatment methods for CMV infection management in kidney transplant recipients remains unmet, and safer anti-CMV drugs are urgently needed.

The target of letemovir is the CMV DNA terminal enzyme complex, which is different from the target of existing anti-CMV drugs, and does not exhibit cross resistance. Moreover, this target does not have a corresponding substance in mammalian cells and does not exhibit toxicity similar to DNA polymerase targets. In addition, letemovir is mainly metabolized by the liver, and urinary excretion can be ignored (<2% dose), so there is no need to adjust the dose according to renal function. Phase III registered clinical studies abroad have shown that letemovir is not inferior to valganciclovir in preventing CMV disease in kidney transplant recipients. Additionally, letemovir is safer and has a lower incidence of adverse reactions, especially leukopenia or granulocytopenia. However, there is still a lack of data on the use of kidney transplantation in Chinese population.

The aim of this study was to evaluate the efficacy and safety of letamovir in preventing CMV infection and CMV disease in kidney transplant recipients in China.

Inclusion Criteria:

- 1) Age ≥18 years old, gender unlimited. 2) Receiving the first kidney transplant. 3) Be within 0 (ie, day of transplantation) to 7 days (inclusive) post-kidney transplant at the time of randomization.

4) Obtain informed consent signed .

Exclusion Criteria:

• 1)Received a previous solid organ transplant or HSCT. 2)Is a multi-organ transplant recipient (eg, kidney-pancreas). Note: Double kidney transplant recipients (ie, transplant of two kidneys from the same donor to the same recipient simultaneously) will be excluded.

  3)Has a history of CMV disease or suspected CMV disease within 6 months prior to randomization.

  4)Has evidence of CMV viremia at any time from the signing of the ICF or the transplant procedure until the randomization period; 5)Has suspected or known hypersensitivity to active or inactive ingredients of LET formulations, VGCV, GCV, formulations.

  6)Is on dialysis or plasmapheresis at the time of randomization. Note: For the purposes of this protocol, dialysis includes hemofiltration. Participant who: (1) has had dialysis or plasmapheresis within 7 days (inclusive) post-transplant but is not on dialysis or plasmapheresis at the time of randomization; and (2) is expected to remain off dialysis or plasmapheresis may be enrolled, provided that all other inclusion/exclusion criteria are met.

  7)Has post-transplant renal function of CrCI 10 mL/min at randomization (measured) locally). For this exclusion criterion, CrCl will be calculated using the Cockcroft-Gault equation using the most recently obtained and available serum creatinine value collected within 3 calendar days prior to and including the day of randomization and after the conclusion of any clinically warranted (at the discretion of the investigator) post-transplant dialysis or plasmapheresis.

  8)Has Child-Pugh Class C severe hepatic insufficiency at screening. 9)Has both moderate hepatic insufficiency AND moderate-to-severe renal insufficiency at screening.

Note: Moderate hepatic insufficiency is defined as Child-Pugh Class B. moderate-to-severe renal insufficiency is defined as CrCl <50 mL/min, as calculated by the Cockcroft-Gault equation, respectively.

10)Has any uncontrolled infection on the day of randomization. 11)Has documented positive results for human immunodeficiency virus antibody (HIV-Ab) test at any time prior to randomization, or for hepatitis C virus antibody (HCV-Ab) and with detectable HCV ribonucleic acid (RNA) within 90 days prior to randomization or hepatitis B surface antigen (HBsAg) within 90 days prior to randomization.

12)Requires mechanical ventilation, or is hemodynamically unstable, at the time of randomization.

13)Has a history of malignancy 5 years prior to signing informed consent except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer or carcinoma in situ; or is under evaluation for other active or suspected malignancy.

14)Is pregnant or expecting to conceive, is breastfeeding, or plans to breastfeed from the time of consent through at least 90 days following cessation of study therapy.

15)Has a history or current evidence of any condition, therapy, lab abnormality, or other circumstance that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or put the participant at undue risk, as judged by the investigator, such that it is not in the best interest of the participant to participate in this study.

16)laboratory value at screening: hemoglobin <8g/dL; Or neutrophils <1.0*109/L; Or platelet <25*109/L; Serum AST or ALT>5×ULN; Or serum total bilirubin >2.5×ULN; 17)Has received within 30 days prior to randomization or plans to receive during the study any of the following anti-CMV IgG antibody treatment or anti-CMV drug therapy including: Cidofovirb. CMV hyper-immune globulinc. Any investigational CMV antiviral agent/biologic therapy.

18)Has received within 7 days prior to randomization or plans to receive during the study any of the following anti-CMV drug therapy including: LET, GCV, VGCV, Foscarneth, ACV (at doses >3200 mg PO per day or >25 mg/kg IV per day), Valacyclovir (at doses >3 g PO per day), Famciclovir (at doses >1500 mg PO per day).

19)are expected to receive TCM or herbal treatment during study treatment and within 14 days after study administration; 20)Is currently participating or has participated in a study with an unapproved investigational compound or device within 28 days, or 5 x half-life of the investigational compound (excluding monoclonal antibodies), whichever is longer, of initial dosing on this study. Participants previously treated with an investigational monoclonal antibody will be eligible to participate after a 150-day washout period.

21)Has previously participated or is currently participating in any study involving administration of a CMV vaccine or another CMV investigational agent, or is planning to participate in a study of a CMV vaccine or another CMV investigational agent during the course of this study.

22)Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling or child) who is investigational site or sponsor staff directly involved with this study.