Combining letermovir and valganciclovir to treat cytomegalovirus infections in kidney transplant patients

Letermovir/Valganciclovir Combination Versus Valganciclovir Monotherapy for Treatment of Cytomegalovirus (CMV) Infections in Kidney Transplant Recipients

This study is testing if a combination of two medications, letermovir and valganciclovir, can better treat cytomegalovirus infections in kidney transplant patients compared to just using valganciclovir alone.

Quick facts

• Phase: Phase 3
• Study type: Interventional
• Enrollment: 80 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Assistance Publique - Hôpitaux de Paris (Academic / other)
• Locations: 5 sites (Paris and 4 other locations)
• Trial ID: NCT06334497 on ClinicalTrials.gov

What this trial studies

This study evaluates the effectiveness and safety of letermovir in combination with valganciclovir for treating cytomegalovirus (CMV) infections in renal transplant recipients. Participants with documented CMV DNAemia will be randomly assigned to receive either the dual therapy or a placebo alongside valganciclovir. The goal is to determine if this combination can eradicate CMV DNAemia more effectively than valganciclovir alone, while also reducing the risk of drug-resistant infections. Treatment success is defined by the eradication of CMV DNAemia and resolution of clinical symptoms within 12 weeks.

Who should consider this trial

Good fit: Ideal candidates are adult kidney transplant recipients with documented CMV DNAemia requiring valganciclovir treatment.

Not a fit: Patients who do not have a documented CMV infection or those who are not eligible for valganciclovir treatment may not benefit from this study.

Why it matters

Potential benefit: If successful, this approach could provide a more effective treatment option for kidney transplant recipients suffering from CMV infections, potentially reducing complications and improving patient outcomes.

How similar studies have performed: Previous studies have shown promising results with dual antiviral therapies for CMV, suggesting that this approach may be effective, though this specific combination is being tested for the first time.

Eligibility criteria

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

Where this trial is running

Paris and 4 other locations

• Hôpital Necker Enfants Malades — Paris, France (Recruiting)
• Hôpital de la Pitié Salpêtrière, Service de Néphrologie — Paris, Île-de-France Region, France (Recruiting)
• Hôpital Européen Georges Pompidou — Paris, Île-de-France Region, France (Recruiting)
• Hôpital Necker Enfants Malades - SMIT — Paris, Île-de-France Region, France (Recruiting)
• Centre 011-Hôpital Bichat, Service de Néphrologie — Paris, Île-de-France Region, France (Recruiting)

Study contacts

• Principal investigator: Pierre FRANGE, MD, PhD — Assistance Publique Hôpitaux Paris
• Study coordinator: Pierre FRANGE, MD, PhD

Conditions Cytomegalovirus Infection; Cytomegalovirus infection; Cytomegalovirus disease