Prenatal Treatment of Congenital Cytomegalovirus Infection With Letermovir Randomized Against Valaciclovir - STEP 1 (CYMEVAL3-STEP1) (CYMEVAL3-STEP1)
Primary Purpose
Pregnant Women Undergoing TOP, TOP - Failed Attempted Termination of Pregnancy
Status
Completed
Phase
Not Applicable
Locations
France
Study Type
Interventional
Intervention
Letermovir
Sponsored by
About this trial
This is an interventional other trial for Pregnant Women Undergoing TOP focused on measuring Cytomegalovirus, Pregnant women
Eligibility Criteria
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/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
Sites / Locations
- Hôpital Necker - Enfants malades
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
letermovir
Arm Description
Maternal administration of 1 tablet of Letermovir (240 mg or 480 mg /day) during 3 days before TOP
Outcomes
Primary Outcome Measures
Concentrations reached in fetal blood relative to EC50 of letermovir.
Secondary Outcome Measures
Full Information
NCT ID
NCT04732260
First Posted
January 24, 2021
Last Updated
February 28, 2022
Sponsor
Assistance Publique - Hôpitaux de Paris
1. Study Identification
Unique Protocol Identification Number
NCT04732260
Brief Title
Prenatal Treatment of Congenital Cytomegalovirus Infection With Letermovir Randomized Against Valaciclovir - STEP 1 (CYMEVAL3-STEP1)
Acronym
CYMEVAL3-STEP1
Official Title
Prenatal Treatment of Congenital Cytomegalovirus Infection With Letermovir Randomized Against Valaciclovir - STEP 1
Study Type
Interventional
2. Study Status
Record Verification Date
February 2022
Overall Recruitment Status
Completed
Study Start Date
June 11, 2021 (Actual)
Primary Completion Date
November 5, 2021 (Actual)
Study Completion Date
November 12, 2021 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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.
Detailed Description
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. 5 women will receive 240 mg. In order to have variation in the time elapsed between administration and sampling, it will be asked to 3 women to take the drug every morning and to 2 patients to take the drug every evening. 5 women will receive 480 mg. This time, it will be asked to 2 women to take the drug every morning and to 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:
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
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
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 9 months.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pregnant Women Undergoing TOP, TOP - Failed Attempted Termination of Pregnancy
Keywords
Cytomegalovirus, Pregnant women
7. Study Design
Primary Purpose
Other
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
7 (Actual)
8. Arms, Groups, and Interventions
Arm Title
letermovir
Arm Type
Experimental
Arm Description
Maternal administration of 1 tablet of Letermovir (240 mg or 480 mg /day) during 3 days before TOP
Intervention Type
Drug
Intervention Name(s)
Letermovir
Intervention Description
Each patient will receive 1 tablet of Letermovir (240 mg or 480 mg /day) during 3 days before TOP.
5 women will receive 240 mg. 5 women will receive 480 mg.
Primary Outcome Measure Information:
Title
Concentrations reached in fetal blood relative to EC50 of letermovir.
Time Frame
At termination of pregnancy, on average 3 days after inclusion
10. Eligibility
Sex
Female
Gender Based
Yes
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
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/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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Marianne LERUEZ-VILLE, PhD & MD
Organizational Affiliation
Virology laboratory- reference national Lab for CMV infection -Hôpital Necker-Enfants malades, Paris
Official's Role
Study Chair
Facility Information:
Facility Name
Hôpital Necker - Enfants malades
City
Paris
ZIP/Postal Code
75015
Country
France
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
32353010
Citation
Faure Bardon V, Peytavin G, Le MP, Guilleminot T, Elefant E, Stirnemann J, Leruez-Ville M, Ville Y. Placental transfer of Letermovir & Maribavir in the ex vivo human cotyledon perfusion model. New perspectives for in utero treatment of congenital cytomegalovirus infection. PLoS One. 2020 Apr 30;15(4):e0232140. doi: 10.1371/journal.pone.0232140. eCollection 2020.
Results Reference
background
Learn more about this trial
Prenatal Treatment of Congenital Cytomegalovirus Infection With Letermovir Randomized Against Valaciclovir - STEP 1 (CYMEVAL3-STEP1)
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