Prenatal Treatment of Congenital Cytomegalovirus Infection With Letermovir Randomized Against Valaciclovir - STEP 1 (CYMEVAL3-STEP1)
Prenatal Treatment of Congenital Cytomegalovirus Infection With Letermovir Randomized Against Valaciclovir - STEP 1 (CYMEVAL3-STEP1)
In the model of the perfused cotyledon, Letermovir crosses the placenta to reach appropriate
 fetal concentration. The cotyledon model can only be performed in the third trimester
 placenta. Although it is probable that the transplacental passage in the second trimester is
 in the same range than the one found in the 2th trimester, it needs to be confirmed. The
 study will be divided in 2 steps: step 1 will study the Letermovir transplacental transfer in
 the second trimester and step 2 will test the efficacy of letermovir to inhibit replication
 in infected fetuses.

 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.
The eligible population of step 1 will be pregnant women in their second trimester of
 pregnancy and undergoing TOP for any fetal abnormality and no evidence of placental
 dysfunction.

 Letermovir (LTM) is a new anti CMV drug, manufactured by Merck that:

 -  is highly efficient in vitro against CMV (more than ganciclovir the gold standard drug)

 -  is as efficient as valganciclovir to cure CMV infection and highly efficient as a
 prophylaxis to avoid CMV infection and disease in bone marrow transplated patients

 -  is very well tolerated

 -  has no data from the use in pregnant women and animal studies are insufficient with
 respect to fetotoxicity, but no specific concern in pregnant women arises from its
 safety profile

 -  crosses the placenta in the ex vivo model of the human perfused cotyledon to reach
 efficient fetal concentration

 In this STEP 1 study, we elected to test 2 Letermovir dosages:

 -  240 mg given orally once a day. Based on 10% rate of letermovir transplacental passage
 as demonstrated in the cotyledonon model, we calculated that the dosage of 240 mg given
 once a day to the pregnant woman should be suffisent to reach efficient concentration in
 fetal blood.

 -  480 mg /day given orally once a day. 480 mg per day is the recommended dose to prevent
 CMV infection in bone marrow transplanted patients;

 The risks added by the study are those of letermovir: nausea, diarrhea and vomiting
 (frequent), hypersensitivity, loss of appetite, headache, vertigo, abdominal pain, ALT and
 AST increase, muscule spasm, blood creatinine increase, fatigue, peripheral edema (very
 rare). The expected benefit for the women is: none.

 Women and obstetrician investigator will sign the written consent for the trial.

 -  Validation of inclusion and non-inclusion criteria will be assessed by the obstetrician
 investigator as follows:

 -  age, weight, height and medical history will be collected.

 -  Inquiry on maternal concomitant treatment(s)

 -  Blood sampling: (4 ml altogether)

 -  1 Heparinate Lithium tube (2 ml) for measurements of urea, creatinine, creatinine
 clearance, liver enzyme (ALAT ASAT GGT PAL), bilirubine

 -  1 EDTA tube of 2 ml for full blood test count These measurements will be done in the
 biochemistry laboratory of the investigating site.

 When validation of inclusion and non-inclusion criteria is done (all the criteria will be
 available on the day of the baseline visit), the woman receives the tablets of letermovir.
 They will be allocated either 240 mg or 480 mg up until termination of pregnancy. The first 5
 included women will receive 240 mg. In order to have variation in the time elapsed between
 administration and sampling, it will be asked to the first 3 women to take the drug every
 morning and to the following 2 patients to take the drug every evening. The 5 subsequent
 women will receive 480 mg. This time, it will be asked to the first 2 women to take the drug
 every morning and to the following 3 patients to take the drug every evening.

 Hence, the day of TOP, patients who take the drug every evening will have the largest delay
 between the last intake and blood sampling. The patients who take the drug every morning
 should take the last tablet early in the morning the day of TOP and latest 4 hours before the
 blood sampling.

 After the baseline visit, there will be one other visit just before TOP; the obstetrician
 investigator will be in charge of this visit:

 1. Maternal examination will comprise:

 -  Inquiry of potential side effects (nausea, vomiting, diarrhea, rash, cough,
 peripheral edema, headache, abdominal pain, decrease appetite, others)

 -  SAE/AE will be collected

 -  Blood pressure measurement

 -  Blood sampling: (5 ml) with: one Lithium Heparinate tube for letermovir dosage

 -  1 Heparinate Lithium tube (2 ml) for measurements of urea, creatinine, creatinine
 clearance, liver enzyme (ALAT ASAT GGT PAL), bilirubine

 -  Hours of the 3 intakes of pills will be recorded in an individual treatment booklet

 2. At TOP, fetal examination will comprise:

 -  Fetal blood sampling (5 ml in a Lithium Heparinate tube for Letermovir dosage)
 collected at the time of feticide before lethal injection is given in the umbilical
 vein under ultrasound guidance.

 -  Amniotic fluid sampling (5 ml on Lithium heparinate tube for Letermovir dosage)
 collected by the midwife at the time of artificial rupture of the amniotic
 membranes.

 -  Placental biopsies sampling (2 cotyledons for Letermovir dosage) collected after
 delivery.

 -  SAE/AE will be collected

 3. At day 4 after TOP:

 Phone call to collect SAE/AE after TOP

 The duration of participation of each woman including data collection will be a maximum of 7
 days (3 days before the TOP and 4 days after TOP).

 The duration of the study will be 3 months.
Inclusion Criteria:

 -  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

 Exclusion Criteria:

 -  Participation to another interventional drug trial (category 1)

 -  Subject protected by law under guardianship or curatorship

 -  Woman with creatinine clearance <75 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