Neonatal Phase 1 Valacyclovir Study

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

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.

Study Overview

• Status: Recruiting
• Conditions: Herpes Simplex
• Intervention / Treatment: Drug: Valacyclovir

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 Type: Interventional
• Enrollment (Estimated): 16
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: David W. Kimberlin; Phone Number: 12059966097; Email: dkimberlin@peds.uab.edu

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233-0011
      • Recruiting
      • Children's of Alabama Child Health Research Unit (CHRU)
  • Georgia
    • Atlanta, Georgia, United States, 30322-1014
      • Not yet recruiting
      • Emory University School of Medicine
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Recruiting
      • University of Louisville School of Medicine - Norton Children's Hospital - Infectious Diseases
  • Minnesota
    • Minneapolis, Minnesota, United States, 55454
      • Recruiting
      • M Health Fairview Masonic Children's Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63110-1010
      • Recruiting
      • Washington University in St. Louis
  • Nebraska
    • Omaha, Nebraska, United States, 68114-4108
      • Recruiting
      • University of Nebraska Medical Center - Children's Hospital and Medical Center - Infectious Diseases
  • New York
    • Queens, New York, United States, 11040
      • Not yet recruiting
      • Steven and Alexandra Cohen Childrens Medical Center of New York - New Hyde Park - Infectious Disease
    • Rochester, New York, United States, 14642-0001
      • Recruiting
      • University of Rochester Medical Center - Strong Memorial Hospital - Infectious Diseases
    • Syracuse, New York, United States, 13210-2342
      • Recruiting
      • SUNY Upstate Medical University Hospital - Pediatrics
  • North Carolina
    • Charlotte, North Carolina, United States, 28207
      • Recruiting
      • Atrium Health ID Consultants & Infusion Care Specialists
  • Ohio
    • Columbus, Ohio, United States, 43205
      • Not yet recruiting
      • Ohio State University - Wexner Medical Center - Infectious Diseases Clinic
  • Texas
    • Dallas, Texas, United States, 75235-7701
      • Not yet recruiting
      • University of Texas Southwestern Medical Center - Pediatrics
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226-3522
      • Recruiting
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 2 days (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Signed informed consent from parent(s) or legal guardian(s)
2. Maternal history of genital HSV infection
3. Maternal receipt of oral acyclovir, valacyclovir, or famciclovir suppressive therapy for = 7 days prior to delivery
4. Gestational age = 38 weeks at birth
5. = 2 days of age at study enrollment
6. Weight at study enrollment = 2,000 grams

Exclusion Criteria:

1. Evidence of neonatal HSV infection
2. Evidence of sepsis
3. Known renal anomalies or dysfunction
4. Maternal genital lesions suspicious for HSV at the time of delivery
5. Infants known to be born to women who are HIV positive (but HIV testing is not required for study entry)
6. Current receipt in the neonate of acyclovir, ganciclovir, famciclovir, or any investigational drugs

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Study record dates

Study Major Dates

• Study Start (Actual): September 23, 2022
• Primary Completion (Estimated): November 29, 2024
• Study Completion (Estimated): November 29, 2024

Study Registration Dates

• First Submitted: July 19, 2022
• First Submitted That Met QC Criteria: July 19, 2022
• First Posted (Actual): July 21, 2022

Study Record Updates

• Last Update Posted (Actual): April 26, 2024
• Last Update Submitted That Met QC Criteria: April 25, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Phase I; Disease; Neonatal; Herpes Simplex Virus; Valacyclovir
• Additional Relevant MeSH Terms: Skin Diseases; Virus Diseases; Infections; DNA Virus Infections; Skin Diseases, Infectious; Skin Diseases, Viral; Herpesviridae Infections; Herpes Simplex; Anti-Infective Agents; Antiviral Agents; Valacyclovir
• Other Study ID Numbers: 20-0033; 5U54AI150225-04 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No