Prenatal Treatment of Congenital Cytomegalovirus Infection With Letermovir Versus Valaciclovir

Pregnant Women Clinical Trial

— CYMEVAL3-step2  

Official title:

Prenatal Treatment of Congenital Cytomegalovirus Infection With Letermovir Randomized Against Valaciclovir (Step 2)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05446571
• Other study ID #: APHP180592_step2
• Secondary ID: 2020-002924-35
• Status: Recruiting
• Phase: Phase 3
• Start date: October 20, 2023
• Est. completion date: August 2029

Study information

• Verified date: January 2024
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: Yves VILLE, MD, PhD
• Phone: +33 1 71 19 63 32
• Email: ville.yves[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 46
• Est. completion date: August 2029
• Est. primary completion date: August 2029
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Cytomegalovirus Infections
• Pregnant Women

Intervention

Drug:
• Letermovir
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
• Valacyclovir
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

Locations

Country	Name	City	State
France	Hopital Necker - Enfants malades	Paris

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	CMV PCR in neonatal blood collected	Negative CMV PCR (<500 IU/ml) in neonatal blood	up to 3 days of life
Primary	CMV PCR in neonatal blood collected	Negative CMV PCR (<500 IU/ml) in cord blood	At Termination of pregnancy
Secondary	Number of asymptomatic neonates		in the first day of life
Secondary	Birthweight		at birth
Secondary	placental weight		at birth
Secondary	number of long-term sequelae		at 2 years of life
Secondary	type of long-term sequelae		at 2 years of life
Secondary	maternal full blood count	during pregnancy	up to 39 weeks
Secondary	maternal renal function	during pregnancy	up to 39 weeks
Secondary	maternal liver function	measurements of liver enzyme (ALAT ASAT GCT PAL) and bilirubin during pregnancy	up to 39 weeks
Secondary	gestational age at delivery		at birth
Secondary	neonatal defects non related to infection		in the first day of life
Secondary	neonatal full blood count		up to 3 days of life
Secondary	neonatal renal function		up to 3 days of life
Secondary	neonatal liver function		up to 3 days of life
Secondary	compliance	pill count during pregnancy every 2 weeks and at the end of the trial	up to 39 weeks
Secondary	compliance	valaciclovir or letermovir concentrations in maternal blood during pregnancy every 2 weeks and at the end of the trial	up to 39 weeks
Secondary	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	up to 39 weeks
Secondary	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	up to 39 weeks
Secondary	brain biometrics during pregnancy	fetal assessment	up to 39 weeks
Secondary	gyration disorders during pregnancy	fetal assessment	up to 39 weeks
Secondary	white matter abnormalities during pregnancy	fetal assessment	up to 39 weeks
Secondary	ventriculomegaly during pregnancy	fetal assessment	up to 39 weeks
Secondary	parenchymal abnormalities during pregnancy	fetal assessment	up to 39 weeks
Secondary	hepatomegaly during pregnancy	fetal assessment	up to 39 weeks
Secondary	splenomegaly during pregnancy	fetal assessment	up to 39 weeks
Secondary	intestinal abnormalities during pregnancy	fetal assessment	up to 39 weeks
Secondary	abnormal amniotic fluid volume during pregnancy	fetal assessment	up to 39 weeks
Secondary	fetal assessment	Classification after pathological cerebral examination in severe and non-severe cases during pregnancy	up to 39 weeks
Secondary	CMV DNA load in fetal blood	in fetal blood by quantitative PCR in IU/mL	up to 39 weeks
Secondary	CMV DNA load in cord blood	cord blood by quantitative PCR in IU/mL	up to 39 weeks
Secondary	CMV DNA load in neonatal blood	neonatal blood by quantitative PCR in IU/mL	up to 3 days of life
Secondary	CMV DNA load in amniotic fluid	amniotic fluid by quantitative PCR in IU/mL	up to 39 weeks
Secondary	CMV DNA load in saliva	saliva by quantitative PCR in IU/mL during pregnancy and first days of life	up to 3 days of life
Secondary	CMV DNA load in urine	urine by quantitative PCR in IU/mL during pregnancy and first days of life	up to 3 days of life
Secondary	Letermovir concentration in cord blood	in cord blood	at birth or TOP
Secondary	Letermovir concentration in amniotic fluid	in amniotic fluid	at birth or TOP
Secondary	Letermovir concentration in placenta	in placenta	at birth or TOP
Secondary	Letermovir concentration in neonatal blood	in neonatal blood	up to 3 days of life
Secondary	Sequencing of CMV UL56 and UL89 genes	Sequencing of CMV UL56 and UL89 genes in positive neonates for CMV PCR	up to 3 days of life