Herpes Simplex
Conditions
Keywords
Disease, Herpes Simplex Virus, Neonatal, Phase I, Valacyclovir
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.
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.
Interventions
DRUGValacyclovir
Valacyclovir is a L-valyl ester of acyclovir.
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Days to 2 Days
Healthy volunteers
No
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 * For purposes of this study, the calendar day of birth is Day of Life 0
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-Time Curve From 0 to 12 Hours (AUC12) of Acyclovir in Plasma | 0 hour minus 15 minutes (pre-dose), 1-2 hours, 4-6 hours, and 8-10 hours post one of the Day 5 doses | Pharmacokinetics (PK) parameters were estimated from the Acyclovir plasma concentration-time data after one of the doses received on Study Day 5 (window: Study Day 4 through Study Day 5 around either dose 7, 8, 9, or 10 of the study drug; samples were only collected after one of these doses) using Phoenix WinNonlin Non-compartmental analysis. The estimate assumes steady state has been achieved. As blood was only collected up to 8-10 hours post dose, log-linear interpolation was used to calculate the AUC12. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Apparent Terminal Elimination Half-life (t1/2) of Acyclovir in Plasma | 0 hour minus 15 minutes (pre-dose), 1-2 hours, 4-6 hours, and 8-10 hours post one of the Day 5 doses | PK parameters were estimated from the Acyclovir plasma concentration-time data after one of the doses received on Study Day 5 (window: Study Day 4 through Study Day 5 around either dose 7, 8, 9, or 10 of the study drug; samples were only collected after one of these doses) using Phoenix WinNonlin Non-compartmental analysis. The estimate assumes steady state has been achieved. |
| Maximum Concentration (Cmax) of Acyclovir in Plasma | 0 hour minus 15 minutes (pre-dose), 1-2 hours, 4-6 hours, and 8-10 hours post one of the Day 5 doses | PK parameters were estimated from the Acyclovir plasma concentration-time data after one of the doses received on Study Day 5 (window: Study Day 4 through Study Day 5 around either dose 7, 8, 9, or 10 of the study drug; samples were only collected after one of these doses) using Phoenix WinNonlin Non-compartmental analysis. The estimate assumes steady state has been achieved. |
| Apparent Oral Clearance (CL/F) of Acyclovir in Plasma | 0 hour minus 15 minutes (pre-dose), 1-2 hours, 4-6 hours, and 8-10 hours post one of the Day 5 doses | PK parameters were estimated from the Acyclovir plasma concentration-time data after one of the doses received on Study Day 5 (window: Study Day 4 through Study Day 5 around either dose 7, 8, 9, or 10 of the study drug; samples were only collected after one of these doses) using Phoenix WinNonlin Non-compartmental analysis. The estimate assumes steady state has been achieved. |
| Time to the Maximum Concentration (Tmax) of Acyclovir in Plasma | 0 hour minus 15 minutes (pre-dose), 1-2 hours, 4-6 hours, and 8-10 hours post one of the Day 5 doses | PK parameters were estimated from the Acyclovir plasma concentration-time data after one of the doses received on Study Day 5 (window: Study Day 4 through Study Day 5 around either dose 7, 8, 9, or 10 of the study drug; samples were only collected after one of these doses) using Phoenix WinNonlin Non-compartmental analysis. The estimate assumes steady state has been achieved. |
| Apparent Volume of Distribution During Terminal Phase (V/F) of Acyclovir in Plasma | 0 hour minus 15 minutes (pre-dose), 1-2 hours, 4-6 hours, and 8-10 hours post one of the Day 5 doses | PK parameters were estimated from the Acyclovir plasma concentration-time data after one of the doses received on Study Day 5 (window: Study Day 4 through Study Day 5 around either dose 7, 8, 9, or 10 of the study drug; samples were only collected after one of these doses) using Phoenix WinNonlin Non-compartmental analysis. The estimate assumes steady state has been achieved. |
| Frequency of Grade 3 Adverse Events (AEs) | Day 1 through Day 42 | The number of participants who experienced at least one Grade 3 AE, including both non-serious AEs and serious adverse events (SAEs). |
| Frequency of Grade 4 AEs | Day 1 through Day 42 | The number of participants who experienced at least one Grade 4 AE, including both non-serious AEs and SAEs. |
Countries
United States
Participant flow
Recruitment details
The study population included neonates delivered to mothers receiving oral valacyclovir therapy (or equivalent antiviral drug) for suppression of genital herpes simplex virus (HSV) recurrences at the end of pregnancy and were within the first two days of life. Participants were enrolled from three sites in the United States between August 7, 2023 and June 4, 2025.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 1.5 days STANDARD_DEVIATION 0.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Gestational Age at Birth | 39.0 weeks STANDARD_DEVIATION 0.5 |
| Length at Enrollment | 50.879 cm STANDARD_DEVIATION 1.363 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 5 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 11 Participants |
| Weight at Birth | 3.247 kg STANDARD_DEVIATION 0.312 |
| Weight at Enrollment | 3.160 kg STANDARD_DEVIATION 0.303 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 2 |
| other Total, other adverse events | 6 / 13 | 0 / 2 |
| serious Total, serious adverse events | 1 / 13 | 0 / 2 |
Outcome results
None listed