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

Start 14 Aug 2024 · Status Ongoing, recruiting · 1 EU/EEA countries · 12 sites · Protocol APHP220791

Overview

Sponsor-declared trial summary

Phase Therapeutic confirmatory (Phase III)

Status Ongoing, recruiting

Participants planned 80

Countries 1

Sites 12

CytoMegaloVirus infections

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 undete…

Key facts

Sponsor: Assistance Publique Hopitaux De Paris
Participant type: Patients
Age range: 18-64 years, 65+ years
Gender: Male and Female
Therapeutic area: Diseases [C] - Virus Diseases [C02]
Trial duration: 14 Aug 2024 → ongoing
Decision date (initial): 2023-11-21
Transition trial: No
Low-intervention: No
Rare-disease indication: No
Vulnerable population: No
Funding sources: Ministry of Health - PHRC

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

Secondary objectives 9

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).

Conditions and MedDRA coding

CytoMegaloVirus infections

Version	Level	Code	Term	System organ class
20.1	PT	10011831	Cytomegalovirus infection	100000004862

Study design 1 period

#	Title	Allocation	Blinding	Roles blinded	Arms
1	LUCY-1 Phase III study, randomised double blind controlled superiority trial, multicenter	Randomised Controlled	Double	[{"id":131052,"code":1,"name":"Subject"},{"id":131051,"code":2,"name":"Investigator"}]	Experimental group: valganciclovir + letermovir: Daily administration : - of valganciclovir (900 mg (2x450 mg-tablets) twice a day in case of estimated Glomerular Filtration Rate (eGFR) ≥ 60 ml/min/1.73m²; reduced doses in case of impaired renal function) and letermovir (480 mg (2x240 mg-tablets) once daily; reduced doses to 240 mg (1x240 mg-tablets) daily if co-administration with cyclosporine A) - up to 12 weeks, until achieving criteria defining “treatment success” or “treatment failure” Control group: valganciclovir + placebo of letermovir: Daily administration : - of valganciclovir (900 mg (2x450 mg-tablets) twice a day in case of eGFR ≥ 60 ml/min/1.73m²; reduced doses in case of impaired renal function) and placebo of letermovir (two tablets once daily; reduced doses to one tablet daily if co-administration with cyclosporine A) - up to 12 weeks, until achieving criteria defining “treatment success” or “treatment failure”

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

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 18

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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

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 endpoints 9

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
Number of days between baseline and first measure of CMV DNAemia < 200 IU/mL in whole blood.
Absence of CMV-related symptoms at baseline and each visit.
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)
Tablet count at each visit
Sequencing of whole UL97, UL54, UL56, UL89 and UL51 genes in blood samples at baseline
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.
Measurement of ganciclovir (in both groups) and letermovir (in the bitherapy arm) trough plasma concentration (Cmin) at Week-1, Cmin and Cmax at Week-2
Measurement of the CMV specific T-cell immunity (by ELISpot-CMV) at baseline, Week-3, Week-6, Week-9 and Week-12.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

PREVYMIS 240 mg film-coated tablets

PRD5769611 · Product

Active substance: Letermovir
Pharmaceutical form: FILM-COATED TABLET
Route of administration: ORAL USE
Max daily dose: 480 mg milligram(s)
Max total dose: 40320 mg milligram(s)
Max treatment duration: 12 Week(s)
Authorisation status: Authorised
ATC code: J05AX18 — -
Marketing authorisation: EU/1/17/1245/001
MA holder: MERCK SHARP & DOHME BV
MA country: EU
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: Yes
Modification description: Therapeutic Indications and duration of the treatment

Comparator 1

Valganciclovir

SCP47385062 · ATC

Active substance: Valganciclovir
Route of administration: ORAL USE
Max daily dose: 1800 mg milligram(s)
Max total dose: 151200 mg milligram(s)
Max treatment duration: 12 Week(s)
Authorisation status: Authorised
ATC code: J05AB14 — VALGANCICLOVIR
Marketing authorisation: -
Paediatric formulation: No
Orphan designation: No
Modified vs. Marketing Authorisation: Yes
Modification description: Therapeutic Indications and duration of the treatment

Placebo 1

Placebo of prevymis 240 mg tablets (letermovir)

N/A · Product

Other product name: N/A
Pharmaceutical form: N/A
ATC code: N/A — N/A
Marketing authorisation: N/A
MA holder: N/A
MA country: Iceland
Paediatric formulation: No

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation: Assistance Publique Hopitaux De Paris
Address: Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux
City: Paris Cedex 10
Postcode: 75475
Country: France

Scientific contact point

Organisation: Assistance Publique Hopitaux De Paris
Contact name: Pierre FRANGE (Coordinating investigator)

Public contact point

Organisation: Assistance Publique Hopitaux De Paris
Contact name: Pierre FRANGE (Coordinating investigator)

Locations

1 EU/EEA country · 12 investigational sites

By country

Country	MS status	Planned subjects	Sites
France	Ongoing, recruiting	80	12
Rest of world	—	0	—