Evaluation of Letermovir and Valganciclovir Combination Therapy Versus Valganciclovir Monotherapy in Cytomegalovirus Infections in Kidney Transplant Recipients
- Trial ID
- 2023-506216-40-00
- Protocol
- APHP220791
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to demonstrate that a combination of **letermovir** and valganciclovir, when administered to kidney transplant recipients with **cytomegalovirus** (CMV) infection, increases the proportion of patients achieving a virological response by Week-3. This response is defined as a ≥ 2 log10 decrease in CMV DNAemia from baseline or an undetectable CMV DNAemia (< 200 IU/mL) at Week-3. This objective is clinically relevant as it aims to improve early virological response, which is crucial in managing CMV infections in immunocompromised patients, such as those who have undergone kidney transplantation.
Secondary objectives include:
- Comparing the proportion of patients achieving eradication of CMV DNAemia (< 200 IU/mL) before Week-12 between the two treatment arms.
- Comparing the time to reach eradication of CMV DNAemia between the two arms.
- Comparing the percentage of patients with resolution of CMV disease symptoms before Week-12 among those with CMV disease at baseline between the two arms.
- Comparing tolerance and adherence to treatment between the two arms.
- Assessing the impact of mutations in CMV genes associated with resistance to ganciclovir and letermovir on treatment response.
- Investigating the presence of mutations in CMV genes associated with resistance in cases of treatment failure or viral rebound.
- Exploring the relationship between plasma concentrations of ganciclovir and letermovir and the response and tolerance to antiviral treatment.
- Investigating the relationship between CMV-specific T-cell immunity and treatment response.
Participants
The clinical trial involves participants who are **kidney transplant** recipients with **Cytomegalovirus (CMV) infections**. The study population includes both male and female subjects aged 18 years and older, with a minimum weight of 30 kg. Participants are required to have a documented CMV infection or disease, confirmed by specific laboratory criteria. The trial does not include a vulnerable population. Participants must be eligible for treatment with oral valganciclovir, as determined by the investigator. Lifestyle considerations such as effective contraception methods are required for participants of childbearing potential and males, to be maintained for a specified period after the trial. The sponsor has not provided information regarding the total number of participants in the study.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of a combination therapy of **letermovir** and **valganciclovir** compared to **valganciclovir** monotherapy in treating **cytomegalovirus** (CMV) infections in kidney transplant recipients. This is a randomized, double-blind, controlled trial with a primary objective to increase the proportion of patients achieving a virological response by Week 3. The trial is expected to last until March 2027, with recruitment starting in December 2023. Participants will be randomly assigned to receive either the combination therapy or monotherapy, with a placebo group included for comparison.
The study involves several key visits: an initial screening visit, regular follow-up visits, and an end-of-study visit. During the screening visit, eligibility criteria such as age, weight, and documented CMV infection will be assessed. Participants must have a CMV DNA level of at least 3000 IU/mL in two consecutive assessments. Follow-up visits will occur weekly to monitor virological response, clinical side effects, and other health parameters. The end-of-study visit will evaluate the overall treatment efficacy and safety.
Participant involvement is expected to last up to 12 weeks, with conditions for early termination including significant adverse effects or withdrawal of consent. The primary endpoint is a virological response at Week 3, defined as a ≥ 2 log10 decrease in CMV DNAemia or undetectable levels. Secondary endpoints include eradication of CMV DNAemia by Week 12, absence of CMV-related symptoms, and monitoring of clinical side effects. The trial will also assess the pharmacokinetics of the drugs and CMV-specific T-cell immunity at various intervals.
Treatment
The clinical trial involves the administration of **PREVYMIS** 240 mg film-coated tablets, which contain the active substance **letermovir**. This medication is provided in the form of film-coated tablets and is intended for **oral use**. The maximum daily dose is 480 mg, with a total maximum dose of 40,320 mg over a treatment period of up to 12 weeks. Letermovir is a chemical compound, and its role in the trial is as a test medication. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen.
In addition to the experimental treatment, the trial includes the use of **VALGANCICLOVIR**, which serves as a comparator treatment. Valganciclovir is also a chemical compound and is administered orally. The maximum daily dose for valganciclovir is 1800 mg, with a total maximum dose of 151,200 mg over a 12-week period. The pharmaceutical form of valganciclovir is denoted as PHF00169MIG. The administration of valganciclovir is monitored to ensure compliance with the prescribed dosing schedule.
A placebo is also utilized in this study, specifically a placebo of PREVYMIS 240 mg tablets. The placebo is designed to match the appearance of the letermovir tablets but does not contain any active substance. The placebo is used to maintain blinding in the trial and is administered orally. The use of the placebo allows for the assessment of the efficacy and safety of the experimental treatment in comparison to a non-active control.
Efficacy
Efficacy in the clinical trial titled "LUCY-1 - Letermovir/valganciclovir combination versus valganciclovir monotherapy for treatment of cytomegalovirus (CMV) infections in kidney transplant recipients" will be assessed using both primary and secondary endpoints. The primary endpoint is the **virological response** to treatment at 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 endpoints include the eradication of CMV DNAemia (< 200 IU/mL) before Week-12, detected in whole blood by quantitative CMV PCR every week until the interruption of antiviral treatment or at the latest until Week-12, and the number of days between baseline and the first measure of CMV DNAemia < 200 IU/mL in whole blood.
Additional secondary endpoints involve the absence of CMV-related symptoms at baseline and each visit, clinical side effects, and laboratory tests for neutrophil, platelet, hemoglobin, creatinine, liver enzymes, bilirubin, and urea every week until the interruption of antiviral treatment or at the latest until Week-12. Tablet count at each visit will also be recorded. Sequencing of whole UL97, UL54, UL56, UL89, and UL51 genes in blood samples will be conducted at baseline, and sequencing of these genes will be repeated at Week-3 or Week-12 in patients meeting criteria for "treatment failure" and at any visit in patients with a rebound of CMV DNAemia. Measurement of ganciclovir (in both groups) and letermovir (in the bitherapy arm) trough plasma concentration (Cmin) at Week-1, and both Cmin and Cmax at Week-2, will be performed. Additionally, the CMV-specific T-cell immunity will be measured using ELISpot-CMV at baseline, Week-3, Week-6, Week-9, and Week-12.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age ≥ 18 years
- 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, condom) until 90 days after the end of relevant systemic exposure (week 13).
- Have life expectancy of ≥ 8 weeks
- French speaking
- Affiliated to social security regime or an equivalent system
- Informed consent and signed
Exclusion Criteria
- 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.
- Have received anti-CMV vaccine at any time.
- Be receiving leflunomide or artesunate when study treatment is initiated.
- 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.
- 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.
- Have known hereditary intolerance to galactose, with lactose Lapp deficiency, glucose or galactose malabsorption syndrome.
- Have known hypersensitivity to letermovir or to an excipient for a study treatment.
- 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.
- Participation to another clinical trial on medicinal products for human use
- Have a CMV infection that is known to be genotypically resistant to valganciclovir and/or letermovir on documented evidence.
- 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.
- Have an eGFR < 15 mL/min/1.73m² (using the CKD-EPI Creatinine Equation (2009)).
- 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
- Have a severe chronic liver disease (Child-Pugh Class C)
- Have a known human immunodeficiency virus (HIV) infection with plasma HIV RNA ≥ 50 copies/mL within the 3 months before inclusion.
- Require mechanical ventilation or vasopressors for hemodynamic support.
- Be pregnant or breastfeeding.
- 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
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 01 Dec 2023 | 80 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
PREVYMIS 240 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 480 | 12 | PRD5769611 |
Placebo of prevymis 240 mg tabletsletermovir | Placebo | N/A | — | — | — | N/A |
VALGANCICLOVIR | Comparator | PHF00169MIG | ORAL USE | 1800 | 12 | SCP47385062 |