Prenatal Treatment of Congenital Cytomegalovirus Infection With Letermovir Versus Valaciclovir (CYMEVAL3-step2)
Primary Purpose
Pregnant Women, CMV Infected Fetuses
Status
Not yet recruiting
Phase
Phase 3
Locations
France
Study Type
Interventional
Intervention
Letermovir
Valacyclovir
Sponsored by
About this trial
This is an interventional prevention trial for Pregnant Women focused on measuring cytomegalovirus, pregnant women
Eligibility Criteria
Inclusion Criteria:
- 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, lissencephaly, corpus callosum dysgenesis, cystic leukomalacia)
- 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
- Maternal CMV infection after 15 weeks'
- Creatinine clearance <50 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 Valaciclovir listed in the SmPC of Prevymis® and Zelitrex®
- Women with hypersensitivity to aciclovir
- Concomitant administration of St John's wort
- Woman treated by pimozide, ergot alkaloids, dabigatran, atorvastatin, simvastatin, rosuvastatin, pitavastatin or cyclosporin.
- Woman with hereditary intolerance to galactose, with lactose lapp deficiency, glucose or galactose malabsorption syndrome
Sites / Locations
- Hopital Necker - Enfants malades
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Letermovir
Valaciclovir
Arm Description
Maternal daily administration of letermovir + placebo of valaciclovir
Maternal daily administration of valaciclovir + placebo of letermovir
Outcomes
Primary Outcome Measures
CMV PCR in neonatal blood collected
Negative CMV PCR (<500 IU/ml) in neonatal blood
CMV PCR in neonatal blood collected
Negative CMV PCR (<500 IU/ml) in cord blood
Secondary Outcome Measures
Number of asymptomatic neonates
Birthweight
placental weight
number of long-term sequelae
type of long-term sequelae
maternal full blood count
during pregnancy
maternal renal function
during pregnancy
maternal liver function
measurements of liver enzyme (ALAT ASAT GCT PAL) and bilirubin during pregnancy
gestational age at delivery
neonatal defects non related to infection
neonatal full blood count
neonatal renal function
neonatal liver function
compliance
pill count during pregnancy every 2 weeks and at the end of the trial
compliance
valaciclovir or letermovir concentrations in maternal blood during pregnancy every 2 weeks and at the end of the trial
changes in ultrasound features
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 during pregnancy and at birth or the end of trial
changes in placental features on MRI
changes in placental features on MRI, measuring placental T2 relaxation time, diffusion parameters and IVIM during pregnancy and at birth or the end of trial
brain biometrics during pregnancy
fetal assessment
gyration disorders during pregnancy
fetal assessment
white matter abnormalities during pregnancy
fetal assessment
ventriculomegaly during pregnancy
fetal assessment
parenchymal abnormalities during pregnancy
fetal assessment
hepatomegaly during pregnancy
fetal assessment
splenomegaly during pregnancy
fetal assessment
intestinal abnormalities during pregnancy
fetal assessment
abnormal amniotic fluid volume during pregnancy
fetal assessment
fetal assessment
Classification after pathological cerebral examination in severe and non-severe cases during pregnancy
CMV DNA load in fetal blood
in fetal blood by quantitative PCR in IU/mL
CMV DNA load in cord blood
cord blood by quantitative PCR in IU/mL
CMV DNA load in neonatal blood
neonatal blood by quantitative PCR in IU/mL
CMV DNA load in amniotic fluid
amniotic fluid by quantitative PCR in IU/mL
CMV DNA load in saliva
saliva by quantitative PCR in IU/mL during pregnancy and first days of life
CMV DNA load in urine
urine by quantitative PCR in IU/mL during pregnancy and first days of life
Letermovir concentration in cord blood
in cord blood
Letermovir concentration in amniotic fluid
in amniotic fluid
Letermovir concentration in placenta
in placenta
Letermovir concentration in neonatal blood
in neonatal blood
Sequencing of CMV UL56 and UL89 genes
Sequencing of CMV UL56 and UL89 genes in positive neonates for CMV PCR
Full Information
NCT ID
NCT05446571
First Posted
June 7, 2022
Last Updated
February 10, 2023
Sponsor
Assistance Publique - Hôpitaux de Paris
1. Study Identification
Unique Protocol Identification Number
NCT05446571
Brief Title
Prenatal Treatment of Congenital Cytomegalovirus Infection With Letermovir Versus Valaciclovir
Acronym
CYMEVAL3-step2
Official Title
Prenatal Treatment of Congenital Cytomegalovirus Infection With Letermovir Randomized Against Valaciclovir (Step 2)
Study Type
Interventional
2. Study Status
Record Verification Date
February 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
April 2023 (Anticipated)
Primary Completion Date
February 2029 (Anticipated)
Study Completion Date
February 2029 (Anticipated)
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
The investigators' hypothesis is that maternal treatment with Letermovir will inhibit fetal CMV replication better than Valaciclovir in infected fetuses and lead to a higher proportion of negative CMV PCR at birth in cord blood.
The main objective is 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.
In each group , the proportion of asymptomatic neonates and the number and type of long-term sequelae at 2 years will also be assessed and compared.
Detailed Description
15-20% of CMV infected fetuses are symptomatic and up-to 60% of those symptomatic fetuses have postnatal sequelae. Long-term sequelae are essentially neurological deficiencies and hearing loss. Long-term sequelae are mainly seen in fetuses infected following a maternal infection in the first trimester. The physiopathology of brain and inner ear lesions is not completely elucidated but the viral lesions and viral replication play a major role in this altered neurodevelopment. Fetuses with the most severe brain lesions are also those presenting with high CMV replication in the brain and in all other organs. Moreover, placenta infection affects fetal growth causing growth restriction and therefore affects fetal development in that way. Finally, infected fetuses with high blood viral load at diagnosis (around 22 weeks) are more likely to be symptomatic at birth (OR=5.7 IC95% 2.02-16.53). This correlation between symptoms and high levels of viral replication suggests that an antiviral treatment that could efficiently inhibit viral replication could be beneficial.
Neonatal antiviral treatment with Ganciclovir or Valganciclovir has been used for more than 20 years and is recommended for infected neonates that are symptomatic. Two randomized studies demonstrated that this treatment improves hearing and intellectual capacities of symptomatic neonates with central nervous system involvement. However, this improvement is only modest. This modest benefit can probably be explained by the fact that cerebral lesions developed in utero are already fixed in the neonatal period. The investigators' hypothesis is that early prenatal antiviral therapy for infected fetuses at high risk of cerebral lesions will be more efficient to alleviate long-term sequelae than neonatal treatment. The prognosis of fetal infection can now be established upon fetal imaging by ultrasound (US) and MRI, combined with fetal laboratory tests (fetal platelets count and viral load). The prognosis is poor for severe brain lesions and good when imaging and laboratory parameters are normal. In between these extremes, symptomatic fetuses with extra-cerebral or mild cerebral features are an appropriate target for antiviral therapy with the aim to prevent the development of irreversible cerebral injury.
The 3 antiviral drugs (Ganciclovir, Foscarnet and Cidofovir) that are licensed to treat CMV infection and disease in immunosuppressed patients are nucleotide inhibitors and because of their potential carcinogenicity and teratogenicity, they should be avoided in pregnancy. Valaciclovir is efficient to prevent CMV infection in transplanted patients, is safe in pregnancy and crosses the placenta efficiently. The investigators carried a phase II, not randomized, open label clinical trial to test the efficacy of Valaciclovir in infected fetuses. Valaciclovir was given to women carrying a fetus with at least 1 non-severe ultrasound feature from prenatal diagnosis up until delivery. This led to 79% asymptomatic neonates compared to 43% following natural history of the disease. However, the efficacy of Valaciclovir seemed only partial. First, the antiviral effect was partial: although fetal blood viral load decreased with treatment, 90% of treated fetuses still had detectable CMV DNA in cord blood at birth and all had detectable CMV DNA in neonatal saliva and urine. And second, the clinical efficacy was not optimal since only 57% of fetuses with more than 1 ultrasound feature were born asymptomatic, suggestive of Valaciclovir lower efficacy in such cases.
The investigators therefore looked at new anti CMV drugs. Among them only Letermovir has been licensed to prevent CMV disease in transplanted patients in 2018 and will be available in 2019. Letermovir is not a nucleotide inhibitor and has specific anti-CMV activity. In preclinical toxicity studies it was not genotoxic, not teratogenic and did not impair fertility at the recommended human doses. Besides, no specific concern arises from its safety profile in humans. It controls CMV infection and disease in bone marrow transplant patients by achieving blood viral load clearance in 50-80% of cases.
The investigators' hypothesis is that maternal treatment with Letermovir will inhibit fetal CMV replication better than Valaciclovir in symptomatic infected fetuses and lead to a higher proportion of negative CMV PCR at birth in cord blood. Since severity is largely related to viral replication, clearance of viral replication is a valid surrogate endpoint for clinical outcome in such rare and phenotypically variable cases
The investigators' main objective is 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. The primary endpoint is the proportion of negative CMV PCR (<500 IU/ml) in neonatal blood collected in the first day of life or in cord blood at termination of pregnancy
The following will also to be compared between the 2 arms : the proportion of asymptomatic neonates, the overall growth, the proportion of long-term sequelae at 2 years of age, the tolerance of treatment for mothers, fetuses and neonates, the maternal adherence to treatment, the evolution of ultrasound features between Day0 and Week 2, Week 4, and Week 6 of treatment, the changes in cerebral and placental features between Day 0 and Week 6 of treatment, using magnetic resonance imaging (MRI), the post-mortem examination in cases with medical termination of pregnancy (TOP).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pregnant Women, CMV Infected Fetuses
Keywords
cytomegalovirus, pregnant women
7. Study Design
Primary Purpose
Prevention
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
46 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Letermovir
Arm Type
Experimental
Arm Description
Maternal daily administration of letermovir + placebo of valaciclovir
Arm Title
Valaciclovir
Arm Type
Active Comparator
Arm Description
Maternal daily administration of valaciclovir + placebo of letermovir
Intervention Type
Drug
Intervention Name(s)
Letermovir
Intervention Description
Maternal daily administration of 240 milligrams of letermovir (1x240 mg-tablets) up-until delivery or TOP Placebo of Valaciclovir ; daily administration of 8 grams of valaciclovir (2 g (4 x500 mg-tablets) every 6 hours) up-until delivery or TOP
Intervention Type
Drug
Intervention Name(s)
Valacyclovir
Intervention Description
Maternal daily administration of 8 grams of valaciclovir (2 g (4 x500 mg-tablets) every 6 hours) up-until delivery or TOP Placebo of letermovir : (1x240 mg-tablets) up-until delivery or TOP
Primary Outcome Measure Information:
Title
CMV PCR in neonatal blood collected
Description
Negative CMV PCR (<500 IU/ml) in neonatal blood
Time Frame
up to 3 days of life
Title
CMV PCR in neonatal blood collected
Description
Negative CMV PCR (<500 IU/ml) in cord blood
Time Frame
At Termination of pregnancy
Secondary Outcome Measure Information:
Title
Number of asymptomatic neonates
Time Frame
in the first day of life
Title
Birthweight
Time Frame
at birth
Title
placental weight
Time Frame
at birth
Title
number of long-term sequelae
Time Frame
at 2 years of life
Title
type of long-term sequelae
Time Frame
at 2 years of life
Title
maternal full blood count
Description
during pregnancy
Time Frame
up to 39 weeks
Title
maternal renal function
Description
during pregnancy
Time Frame
up to 39 weeks
Title
maternal liver function
Description
measurements of liver enzyme (ALAT ASAT GCT PAL) and bilirubin during pregnancy
Time Frame
up to 39 weeks
Title
gestational age at delivery
Time Frame
at birth
Title
neonatal defects non related to infection
Time Frame
in the first day of life
Title
neonatal full blood count
Time Frame
up to 3 days of life
Title
neonatal renal function
Time Frame
up to 3 days of life
Title
neonatal liver function
Time Frame
up to 3 days of life
Title
compliance
Description
pill count during pregnancy every 2 weeks and at the end of the trial
Time Frame
up to 39 weeks
Title
compliance
Description
valaciclovir or letermovir concentrations in maternal blood during pregnancy every 2 weeks and at the end of the trial
Time Frame
up to 39 weeks
Title
changes in ultrasound features
Description
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 during pregnancy and at birth or the end of trial
Time Frame
up to 39 weeks
Title
changes in placental features on MRI
Description
changes in placental features on MRI, measuring placental T2 relaxation time, diffusion parameters and IVIM during pregnancy and at birth or the end of trial
Time Frame
up to 39 weeks
Title
brain biometrics during pregnancy
Description
fetal assessment
Time Frame
up to 39 weeks
Title
gyration disorders during pregnancy
Description
fetal assessment
Time Frame
up to 39 weeks
Title
white matter abnormalities during pregnancy
Description
fetal assessment
Time Frame
up to 39 weeks
Title
ventriculomegaly during pregnancy
Description
fetal assessment
Time Frame
up to 39 weeks
Title
parenchymal abnormalities during pregnancy
Description
fetal assessment
Time Frame
up to 39 weeks
Title
hepatomegaly during pregnancy
Description
fetal assessment
Time Frame
up to 39 weeks
Title
splenomegaly during pregnancy
Description
fetal assessment
Time Frame
up to 39 weeks
Title
intestinal abnormalities during pregnancy
Description
fetal assessment
Time Frame
up to 39 weeks
Title
abnormal amniotic fluid volume during pregnancy
Description
fetal assessment
Time Frame
up to 39 weeks
Title
fetal assessment
Description
Classification after pathological cerebral examination in severe and non-severe cases during pregnancy
Time Frame
up to 39 weeks
Title
CMV DNA load in fetal blood
Description
in fetal blood by quantitative PCR in IU/mL
Time Frame
up to 39 weeks
Title
CMV DNA load in cord blood
Description
cord blood by quantitative PCR in IU/mL
Time Frame
up to 39 weeks
Title
CMV DNA load in neonatal blood
Description
neonatal blood by quantitative PCR in IU/mL
Time Frame
up to 3 days of life
Title
CMV DNA load in amniotic fluid
Description
amniotic fluid by quantitative PCR in IU/mL
Time Frame
up to 39 weeks
Title
CMV DNA load in saliva
Description
saliva by quantitative PCR in IU/mL during pregnancy and first days of life
Time Frame
up to 3 days of life
Title
CMV DNA load in urine
Description
urine by quantitative PCR in IU/mL during pregnancy and first days of life
Time Frame
up to 3 days of life
Title
Letermovir concentration in cord blood
Description
in cord blood
Time Frame
at birth or TOP
Title
Letermovir concentration in amniotic fluid
Description
in amniotic fluid
Time Frame
at birth or TOP
Title
Letermovir concentration in placenta
Description
in placenta
Time Frame
at birth or TOP
Title
Letermovir concentration in neonatal blood
Description
in neonatal blood
Time Frame
up to 3 days of life
Title
Sequencing of CMV UL56 and UL89 genes
Description
Sequencing of CMV UL56 and UL89 genes in positive neonates for CMV PCR
Time Frame
up to 3 days of life
10. Eligibility
Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
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, lissencephaly, corpus callosum dysgenesis, cystic leukomalacia)
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
Maternal CMV infection after 15 weeks'
Creatinine clearance <50 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 Valaciclovir listed in the SmPC of Prevymis® and Zelitrex®
Women with hypersensitivity to aciclovir
Concomitant administration of St John's wort
Woman treated by pimozide, ergot alkaloids, dabigatran, atorvastatin, simvastatin, rosuvastatin, pitavastatin or cyclosporin.
Woman with hereditary intolerance to galactose, with lactose lapp deficiency, glucose or galactose malabsorption syndrome
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Yves VILLE, MD, PhD
Phone
01 71 19 63 32
Email
ville.yves@gmail.com
First Name & Middle Initial & Last Name or Official Title & Degree
Aminata TRAORE
Phone
01 48 19 27 34
Email
aminata.traore6@aphp.fr
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Marianne LERUEZ-VILLE, MD, PhD
Organizational Affiliation
Virology laboratory- reference national Lab for CMV infection -Hôpital Necker-Enfants malades, Paris
Official's Role
Study Chair
Facility Information:
Facility Name
Hopital Necker - Enfants malades
City
Paris
ZIP/Postal Code
75015
Country
France
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Laurence BUSSIERES, PhD
Phone
06 62 08 19 58
Email
laurence.buissieres@aphp.fr
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Prenatal Treatment of Congenital Cytomegalovirus Infection With Letermovir Versus Valaciclovir
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