" Prenatal treatment of congenital cytomegalovirus infection with letermovir randomized against valaciclovir (CYMEVAL III)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Patients

Age range

18-64 years

Gender

Female

Therapeutic area

Diseases [C] - Virus Diseases [C02]

Trial duration

22 Jul 2024 → ongoing

Decision date (initial)

2024-07-22

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Ministry of Health

External identifiers

EU CT number

2024-512869-14-00

EudraCT number

2020-002924-35

ClinicalTrials.gov

NCT04732260

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Prophylaxis, Efficacy, Dose response, Therapy, Safety

Step 1:
Main objective To measure the Letermovir transplacental transfer in the second trimester and its accumulation in the amniotic fluid and the
placenta in the second trimester

Primary end point: Concentrations reached in fetal blood relative to EC50 of letermovir.
Step 2:
Main objective:
To demonstrate that Letermovir administered to women carrying a CMV
infected fetus following a maternal infection of the first trimester
increases the proportion of neonates with a negative CMV PCR in
neonatal blood collected in the first day of life or in cord blood in case of
termination of pregnancy (TOP) compared to Valaciclovir

Secondary objectives 1

1. Secondary objectives: (step 2) The following are to be compared between the 2 arms: -Proportion of asymptomatic neonates -Overall growth -Proportion of long-term sequelae at 2 years -Tolerance of treatment for mothers, fetuses and neonates -Adherence to treatment -Evolution of ultrasound features between Day0 and Week 2, Week 4, and Week 6 of treatment -Changes in cerebral and placental features between Day 0 and Week 6 of treatment, using magnetic resonance imaging (MRI). -Post-mortem examination in cases with medical termination of pregnancy (TOP) -CMV DNA levels in amniotic fluid and fetal blood (if done) at diagnosis (inclusion) amniotic fluid and saliva at birth, blood at day 3, saliva at day 3 and at M1 with the doctor discretion, urine retrieved in the first 3 days of life, saliva sampled at M6 (+/-2), M12 (+/-3), M18 (+/-3) and M24 (+/-3) -Anti-viral Letermovir transfer from mother to fetus -Search for mutation(s) in CMV genes associated with Letermovir resistance (UL56 and UL89)

Conditions and MedDRA coding

Diseases [C] - Virus Diseases [C02]

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. Step1: -Pregnant woman ≥ 18 years old - in her second trimester of pregnancy - undergoing TOP for any fetal abnormality - no evidence of placental dysfunction. - - affiliation to a social security regime//health insurance - given consent for the study. - patient must be able and willing to comply with study visits and procedures Step2: -Pregnant woman ≥ 18 years old, - CMV infection in the 1st trimester - with an infected fetus at 15 -28 weeks (positive CMV PCR in the amniotic fluid) With a fetus presenting without any severe cerebral ultrasound feature (ventriculomegaly ≥15 mm, hydrocephalus, periventricular hyperechogenicity, microcephaly<-3SD, vermian hypoplasia, porencephaly, lisencephaly, corpus callosum dysgenesis, cystic leukomalacia, Mega-cisterna magna >10 mm) - affiliation to a social security regime//health insurance - Given consent for the study - Patient must be able and willing to comply with study visits and procedures

Exclusion criteria 1

1. Step1: -Participation to another interventional drug trial (category 1) -Subject protected by law under guardianship or curatorship -Woman with creatinine clearance <75 ml/mn/1,73m² -Woman with liver insufficiency (Child Pugh grade C), AST, ALT 5 x ULN, bilirubin 2 x ULN. -Woman with known allergy to Letermovir -Contraindication for the administration of Letermovir listed in the SmPC of Prevymis® -Woman treated by pimozide, ergot alkaloids, dabigatran, atorvastatin, simvastatin, rosuvastatin, pitavastatine or cyclosporine. -Concomitant administration of millepertuis -Woman with hereditary intolerance to galactose, with lactose lapp deficiency, glucose or galactose malabsorption syndrome Step2: -Participation to another interventional drug trial (category 1) -Subject protected by law under guardianship or curatorship -Maternal CMV infection after 15 weeks -creatinine clearance <75 ml/mn/1,73m² -liver insufficiency (Child Pugh grade C), AST, ALT 5 x ULN, bilirubin 2 x ULN. -Woman with known allergy to Letermovir or Valaciclovir -Contraindication for the administration of Letermovir and valaciclovirlisted in the SmPC of Prevymis® and Zelitrex® - Women with hypersensitivity to aciclovir -Concomitant administration of millepertuis -woman treated by pimozidee, ergot alkaloids, dabigatran, atorvastatin, simvastatin, rosuvastatin, pitavastatine or cyclosporine. -Woman with hereditary intolerance to galactose, with lactose lapp deficiency, glucose or galactose malabsorption syndrome

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Primary endpoint: Negative CMV PCR (<500 IU/ml) in neonatal blood collected in the first day of life or in cord blood at termination of pregnancy

Secondary endpoints 1

1. Secondary objectives: (step 2) The following are to be compared between the 2 arms: -Proportion of asymptomatic neonates -Overall growth -Proportion of long-term sequelae at 2 years -Tolerance of treatment for mothers, fetuses and neonates -Adherence to treatment -Evolution of ultrasound features between Day0 and Week 2, Week 4, and Week 6 of treatment -Changes in cerebral and placental features between Day 1st magnetic resonance imaging (MRI) within the first month of inclusion and 2nd MR

Investigational products

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

Test 1

Comparator 1

Placebo 2

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

Pr Yves VILLE

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Pr Yves VILLE

Locations

1 EU/EEA country · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 9 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications