Neonatal Phase 1 Valacyclovir Study

Study Overview
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Brief Summary
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A Phase 1 study that will determine the valacyclovir dose that results in a systemic acyclovir exposure comparable to 10 mg/kg of parenterally administered acyclovir, which is an AUC0-12 of 24,000 ngxhr/mL to 48,000 ngxhr/mL. Neonates at risk of acquiring neonatal HSV will be enrolled in one of 2 cohorts. Cohort 1 will be comprised of eight subjects who will receive an initial dose of 10ml/kg of oral valacyclovir. Samples for PK assessments will be obtained to assess the exposure concentration. If the safety profile and the drug exposure concentrations in Cohort 1 are acceptable, eight new subjects will be enrolled in Cohort 2. The dose that these subjects will receive will be predicated upon the pharmacokinetic data from Cohort 1.

Detailed Description
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A Phase 1, open label multicenter trial to assess the safety and pharmacokinetics (PKs) of oral valacyclovir in neonates who are at risk of acquiring neonatal herpes simplex virus disease. This study will determine the valacyclovir dose that results in a systemic acyclovir exposure comparable to 10 mg/kg of parenterally administered acyclovir, which is an AUC0-12 of 24,000 ngxhr/mL to 48,000 ngxhr/mL. Neonates whose mothers have a history of genital HSV infection and received oral valacyclovir in the last several weeks of pregnancy, as per the recommendations of the American College of Obstetrics and Gynecology (ACOG) (9), will be eligible for enrollment. Cohort 1 will be comprised of eight subjects. Following informed consent, each subject will receive 10 mg/kg of oral valacyclovir, and may start taking oral valacyclovir while still in the birth hospital, with subsequent dosing at home, or may start taking oral valacyclovir following discharge from the birth hospital. If the safety profile and the drug exposure concentrations in Cohort 1 are acceptable, eight new subjects will be enrolled in Cohort 2. The dose that these subjects will receive will be predicated upon the pharmacokinetic data from Cohort 1. The primary study objective is to establish the dose of valacyclovir in neonates that reliably achieves systemic acyclovir exposures comparable to 10 mg/kg of parenterally administered acyclovir. The secondary study objectives are: 1) to define the pharmacokinetic profile of acyclovir in neonates receiving oral valacyclovir and 2) to assess and describe the safety profile of valacyclovir among treated neonates.

Official Title
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A Phase I Adaptive, Multiple Dose Pharmacokinetic and Safety Assessment of Valacyclovir in Infants at Risk of Acquiring Neonatal Herpes Simplex Virus Disease

Conditions
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Herpes Simplex

Intervention / Treatment
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* Drug: Valacyclovir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent from parent(s) or legal guardian(s) Maternal history of genital HSV infection Maternal receipt of oral acyclovir, valacyclovir, or famciclovir suppressive therapy for = 7 days prior to delivery Gestational age = 38 weeks at birth = 2 days of age at study enrollment Weight at study enrollment = 2,000 grams Exclusion Criteria: Evidence of neonatal HSV infection Evidence of sepsis Known renal anomalies or dysfunction Maternal genital lesions suspicious for HSV at the time of delivery Infants known to be born to women who are HIV positive (but HIV testing is not required for study entry) Current receipt in the neonate of acyclovir, ganciclovir, famciclovir, or any investigational drugs

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 2 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>A cohort of neonates who are at risk of acquiring neonatal herpes simplex virus disease will receive 10 mg/kg of valacyclovir will be administered orally two times daily for 5 days. N=8 | Drug: Valacyclovir<br>* Valacyclovir is a L-valyl ester of acyclovir.<br>|
| Experimental: Cohort 2<br>If the safety profile and the drug exposure concentrations in Cohort 1 are acceptable, eight new subjects will be enrolled in Cohort 2. If the mean of observed acyclovir exposures of subjects in Cohort 1 are below 24,000 ngxhr/mL, AND if no Grade 3 or Grade 4 AEs or SAEs are detected in any of the study subjects, then the 8 subjects enrolled in Cohort 2 will receive oral valacyclovir at a dose of 20 mg/kg administered two times daily for 5 days. Alternatively, if the mean of observed acyclovir exposures of subjects in Cohort 1 are above 48,000 ngxhr/mL AND if no Grade 3 or Grade 4 AEs or SAEs are detected in any of the study subjects, then the 8 subjects enrolled in Cohort 2 will receive oral valacyclovir at a dose that has been linearly adjusted downward to target 36,000 ngxh/mL area-under-the-concentration-time curve from 0 to 12 hours (AUC12). | Drug: Valacyclovir<br>* Valacyclovir is a L-valyl ester of acyclovir.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neonatal plasma acyclovir mean AUC12 concentrations | To establish the dose of valacyclovir in neonates that reliably achieves systemic acyclovir exposures comparable to 10 mg/kg of parenterally administered acyclovir. Acyclovir target concentration of following oral valacyclovir dosing is 24,000 ngxhr/mL to 48,000 ngxhr/mL. | Days 1 - 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Half-life (t1/2) of acyclovir | To define the pharmacokinetic profile of acyclovir in neonates receiving oral valacyclovir | Days 1 - 5 | 
| Maximum Serum Concentration (Cmax) of acyclovir | To define the pharmacokinetic profile of acyclovir in neonates receiving oral valacyclovir | Days 1 - 5 | 
| Occurrence of Grade 3 Adverse Events (AEs) | To assess and describe the safety profile of valacyclovir among treated neonates | Days 1 - 42 | 
| Occurrence of Grade 4 Adverse Events and Serious Adverse Events | To assess and describe the safety profile of valacyclovir among treated neonates | Days 1 - 42 | 
| Oral Clearance (CL/F) of acyclovir | To define the pharmacokinetic profile of acyclovir in neonates receiving oral valacyclovir | Days 1 - 5 | 
| Time to the maximum concentration (Tmax) of acyclovir | To define the pharmacokinetic profile of acyclovir in neonates receiving oral valacyclovir | Days 1 - 5 | 
| Volume of distribution (V/F) of acyclovir | To define the pharmacokinetic profile of acyclovir in neonates receiving oral valacyclovir | Days 1 - 5 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Disease, Herpes Simplex Virus, Neonatal, Phase I, Valacyclovir