Neonatal Phase 1 Valacyclovir Study

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID) (NIH)

Overall Status

Not yet recruiting

CT.gov ID

NCT05468619

Collaborator

(none)

Enrollment

Locations

Arms

18.9

Anticipated Duration (Months)

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Herpes Simplex	Drug: Valacyclovir	Phase 1

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

16 participants

Allocation:

Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Prevention

Official Title:

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

Anticipated Study Start Date :

Sep 9, 2022

Anticipated Primary Completion Date :

Apr 5, 2024

Anticipated Study Completion Date :

Apr 5, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1 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 Valacyclovir is a L-valyl ester of acyclovir.
Experimental: Cohort 2 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 Valacyclovir is a L-valyl ester of acyclovir.

Arm

Intervention/Treatment

Experimental: Cohort 1

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

Valacyclovir is a L-valyl ester of acyclovir.

Experimental: Cohort 2

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

Valacyclovir is a L-valyl ester of acyclovir.

Outcome Measures

Primary Outcome Measures

Neonatal plasma acyclovir mean AUC12 concentrations [Days 1 - 5]
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.

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Day to 2 Days

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama - Children's of Alabama - Clinical Virology	Birmingham	Alabama	United States	35233-1711
2	University of Louisville School of Medicine - Norton Children's Hospital - Infectious Diseases	Louisville	Kentucky	United States	40202
3	M Health Fairview Masonic Children's Hospital	Minneapolis	Minnesota	United States	55454
4	University of Nebraska Medical Center - Children's Hospital and Medical Center - Infectious Diseases	Omaha	Nebraska	United States	68114-4108
5	Steven and Alexandra Cohen Childrens Medical Center of New York - New Hyde Park - Infectious Disease	Queens	New York	United States	11040
6	University of Pennsylvania Perelman School of Medicine - Penn Institute for Immunology	Philadelphia	Pennsylvania	United States	19104-4863
7	University of Texas Southwestern Medical Center - Pediatrics	Dallas	Texas	United States	75235-7701
8	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226-3522