Step 1: Maternal administration of 1 tablet of Letermovir (240 mg or 480 mg /day) during 3 days before TOP Step 2: Maternal daily administration of 240 or 480 milligrams of letermovir (1x240 mg-tablets) or (1x480 mg-tablets) (the dose will be choosen depending on the results obtained on step 1) up-until delivery or TOP
Conditions
Interventions
Trade Name: Valaciclovir Arrow 500 mg
Product Name: Valaciclovir Arrow
Pharmaceutical Form: Tablet
INN or Proposed INN: valaciclovir
Other descriptive name: VALACICLOVIR HYDROCHLORIDE HYDRATE
Concentr
Sponsors
ASSISTANCE PUBLIQUE HÔPITAUX DE PARIS
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 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 18 -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=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: Step1: -Participation to another interventional drug trial (category 1) -Subject protected by law under guardianship or curatorship -Woman with creatinine clearance <50 ml/mn -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 <50 ml/mn -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® -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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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 Objective: 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 and at M1 and M4 saliva at day 3 and at M1 urine retrieved in the first 3 days of life saliva sampled at M4, M12,M18 and M24 -Anti-viral Letermovir transfer from mother to fetus -Search for mutation(s) in CMV genes associated with Letermovir resistance (UL56 and UL89) ;Primary end point(s): 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 ;Timepoint(s) of evaluation of this end point: At the end of follow-ups for the last patient | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 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 and at M1 and M4 saliva at day 3 and at M1 urine retrieved in the first 3 days of life saliva sampled at M4, M12,M18 and M24 -Anti-viral Letermovir transfer from mother to fetus -Search for mutation(s) in CMV genes associated with Letermovir resistance (UL56 and UL89) Secondary endpoints: -Number of asymptomatic neonates -Birthweight and placental weight -Number and type of long-term sequelae at 2 years -Maternal: full blood count, renal & liver function -Neonatal: gestational age at birth, defects non related to infection, full blood count, renal & liver function -Pill count every 2 weeks and at the end of the trial and after ending the double blinding: Valaciclovir or Letermovir concentrations in maternal blood (every 2 weeks and at birth or TOP) -Changes in ultrasound features as per 4 groups: 1) stable, 2) disappearance or decrease in symptoms, 3) increase or new non-severe symptoms 4) appearance of severe cerebral symptoms -Changes in placental features on MRI, measuring placental T2 relaxation time, diffusion parameters and IVIM -Fetal assessment: brain biometrics, gyration disorders, white matter abnormalities, ventriculomegaly, parenchymal abnormalities, hepatomegaly, splenomegaly, intestinal abnormalities, abnormal amniotic fluid volume -Class | — |
Countries
France
Contacts
Public Contactshohreh AZIMI
Direction de la Recherche Clinique et de l’Innovation (DRCI)
Outcome results
None listed