Clinical trial NCT04448392
Conditions: Neonatal Herpes Simplex Infection
Keywords: valacyclovir
Sponsor: University of Alabama at Birmingham
Start date: 2021-07-01; Completion date: 2024-07-24
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open-label, single center, pharmacokinetic (PK) study to assess valacyclovir pharmacokinetics and pharmacodynamics in neonates and compare to the pharmacokinetics and pharmacodynamics of the standard of care treatment dose of intravenous acyclovir. 6 (up to 10 infants) with virologically confirmed neonatal herpes simplex virus (HSV) disease who meet all inclusion/exclusion criteria will be enrolled in the study. Study duration is 5 years. Primary objective is to define the pharmacokinetics of valacyclovir and assess its safety in neonates 2-12 weeks of age who are ≥ 34 weeks gestation.

Detailed description:
This is an open-label, single center, PK study to assess valacyclovir pharmacokinetics and pharmacodynamics in neonates and compare to the pharmacokinetics and pharmacodynamics of the standard of care treatment dose of intravenous acyclovir. Only those babies with virologically confirmed neonatal HSV disease will be enrolled in the study. The decision to initiate valacyclovir for 2 (up to 7) days will be made by a physician based on inclusion/exclusion criteria, and those who meet entry criteria will be eligible for the study. Those enrolled in the study will have daily random parenteral acyclovir PK levels drawn during the first week of treatment (drawn only at times of other lab draws). These infants will also have a pharmacokinetic sampling profile obtained on or after dose 22 and before dose 42 of intravenous acyclovir. The PK samples for the sampling profile will be collected just prior to the next dose of intravenous acyclovir (within 30 minutes prior to the start of the infusion), within 15 minutes of completion of the infusion, and 3-4 hours after infusion. Upon completion of the recommended treatment course duration with intravenous acyclovir determined by disease classification (skin, eye, and mouth; central nervous system; or disseminated disease), the infant will be started on enteral valacyclovir 20 mg/kg every 8 hours.

On day 2 and no more than day 7 of valacyclovir 20 mg/kg every 8 hours, a pharmacokinetic sampling profile will be obtained. The PK samples will be collected just prior to the enteral dose of valacyclovir (hour 0; 8 hours after previous dose and immediately before next dose), 1-2 hours after dose, and 3-5 hours after dose. Primary objective is to define the pharmacokinetics of valacyclovir and assess its safety in neonates 2-12 weeks of age who are ≥ 34 weeks gestation. Secondary objectives are to: 1) assess the pharmacokinetics of high-dose parenteral acyclovir in neonates ≥ 34 weeks gestation with virologically confirmed neonatal HSV disease who are receiving acyclovir as standard of care, 2) compare the pharmacokinetics of high-dose parenteral acyclovir to the pharmacokinetics of the proposed study dose of valacyclovir (20 mg/kg every 8 hours).

Arms: arm 1: All subjects enrolled in the study will receive 2 (up to 7) days of valacyclovir 20 mg/kg every 8 hours after completion of standard of care treatment course with acyclovir.
Interventions: intervention 1: Valacyclovir
Intervention descriptions: intervention 1: Upon completion of standard of care acyclovir for treatment of neonatal HSV disease, valacyclovir oral suspension (per ASHP recipe), 20 mg/kg every 8 hours, to be given for 2 (up to 7) days

Protocol documents:
Prot_SAP_000.pdf: 
 
 EVALUATION OF THE PHARMACOKINETICS AND 
PHARMACODYNAMICS OF VALACYCLOVIR IN NEONATES 
WITH NEONATAL HERPES SIMPLEX VIRUS DISEASE WHO 
HAVE COMPLETED STANDARD OF CARE TREATMENT WITH 
ACYCLOVIR 
NCT: 04448392 
Principal Investigator: Nicole Samies, D.O. 
Version Number:  1.0 
2 June 2020  
 
 


 
 
 
 
 
 ____________________________________________________________________________________________ 
ii 
 
STATEMENT OF COMPLIANCE 
 
 
Each investigator must adhere to the protocol as detailed in this document.  Each 
investigator will be responsible for enrolling only those study participants who have met 
protocol eligibility criteria.  This trial will be conducted in compliance with the protocol, 
International Conference on Harmonization Good Clinical Practice guidelines (ICH-E6), 
and the applicable regulatory requirements, including: 
• U.S. Code of Federal Regulations applicable to clinical studies (45 CFR 46 and 21 
CFR including parts 50 and 56 concerning informed consent and IRB regulations, if 
under IND, 21 CFR 312). 
• Completion of Human Subjects Protection Training.  Refer to 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-061.html; 
http://cme.cancer.gov/clinicaltrials/learning/humanparticipant-protections.asp  


 
 
 
 
 
 ____________________________________________________________________________________________ 
iii 
SIGNATURE PAGE 
The signature below constitutes the approval of this protocol “Evaluation of the 
Pharmacokinetics and Pharmacodynamics of Valacyclovir in 
Neonates with Neonatal Herpes Simplex Virus Disease who have 
Completed Standard of Care Treatment with Acyclovir” and attachments 
and provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable U.S. federal 
regulations and ICH guidelines.  It is understood that no deviations from the protocol 
may be made without permission of the IRB.   
 
Site Investigator: 
 
Signed: 
 
Date: 
 
 
Name 
 
 
 
 
 
Title 
 
 
Signature 
  
  
 
 
 


 
 
 
 
 
 ____________________________________________________________________________________________ 
iv 
TABLE OF CONTENTS  
Page 
Statement of Compliance………………………………………………………………………………... ii 
Signature Page……………………………………………………………………………………………iii 
Table of Contents………………………………………………………………………………………... iv 
List of Abbreviations…………………………………………………………………………………….. vii 
Protocol Summary……………………………………………………………………………………… viii 
1 
Key Roles…………………………………………………………………………………………... 1 
2 
Background Information and Scientific Rationale……………………………………………… 3 
2.1 
Background Information .......................................................................................... 3 
2.2 
Rationale ................................................................................................................ 5 
2.3 
Potential Risks and Benefits ................................................................................... 6 
2.3.1 
Potential Risks ............................................................................................ 6 
2.3.2 
Known Potential Benefits............................................................................. 6 
3 
Objectives…………………………………………………………………………………………... 7 
3.1 
Study Objectives ..................................................................................................... 7 
3.2 
Study Outcome Measures ...................................................................................... 7 
3.2.1 
Primary Outcome Measures ........................................................................ 7 
3.2.2 
Secondary Outcome Measures ................................................................... 7 
4 
Study Design……………………………………………………………………………………… 8 
5 
Study Enrollment and Withdrawal……………………………………………………………… 10 
5.1 
Subject Inclusion Criteria ...................................................................................... 10 
5.2 
Subject Exclusion Criteria ..................................................................................... 10 
5.3 
Treatment Assignment Procedures ....................................................................... 10 
5.3.1 
Randomization Procedures ....................................................................... 10 
5.3.2 
Reasons for Delaying Study-Related Procedures ...................................... 11 
5.3.3 
Reasons for Withdrawal ............................................................................ 11 
5.3.4 
Handling of Withdrawals ............................................................................ 11 
5.3.5 
Termination of Study ................................................................................. 11 
6 
Study Intervention/Investigational Product……………………………………………………. 12 
6.1 
Subject Product Description ................................................................................ 102 
6.1.1 
Acquistion ............................................................................................... 102 
6.1.2 
Formulation, Packaging, Labeling ........................................................... 112 
6.1.3 
Product Sotare and Stability .................................................................... 112 
6.2 
Dosage, Preparation, and Administration of Study Investigational Product ......... 103 
6.2.1 
Preparation of Study Drug ....................................................................... 103 
6.2.2 
Administration of Study Drug ................................................................... 113 
6.3 
Drug Accountability ............................................................................................. 103 
6.4 
Concomitant Medication ..................................................................................... 104 
6.5 
Prohibited Medications ........................................................................................ 103 
7 
Study Schedule……………………………………………………………………………………125 


 
 
 
 
 
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v 
7.1 
Screening ........................................................................................................... 105 
7.2 
Enrollment/Baseline ............................................................................................ 105 
7.2.1 
Baseline Assessment .............................................................................. 105 
7.3 
Study Follow-up .................................................................................................. 105 
7.3.1 
Period 1 ................................................................................................... 105 
7.3.2 
Period 2 ................................................................................................... 116 
7.3.3 
Period 3 ................................................................................................... 117 
7.4 
Early Termination Visit ........................................................................................ 107 
7.5 
Unscheduled Visit ............................................................................................... 107 
8 
Study Procedures/Evaluations…………………………………………………………………..188 
8.1 
Clinical Evaluations ............................................................................................. 188 
8.1.1. Baseline Demographics ............................................................................ 188 
8.2 
Laboratory Evaluations ....................................................................................... 188 
8.2.1 
Special Assays or Procedures ................................................................. 188 
8.2.2 
Specimen Preparation, Handling,and Shipping ....................................... 189 
9 
Assessment of Safety…………………………………………………………………………….200 
9.1 
Safety Reporting:  Adverse Events of Special Interest (AESI) ............................. 200 
9.2 
Type and Duration of Follow-up of Subjects after Adverse Events ...................... 200 
9.3 
Halting Rules ...................................................................................................... 200 
9.3.1 
Discontinue of Study participation for individual subject. ......................... 200 
9.4 
FDA MedWatch Adverse Event Reporting Program ............................................ 211 
10 
Clinical Monitoring………………………………………………………………………………...222 
10.1 
Monitoring Plan ................................................................................................... 222 
11 
Statistical Considerations………………………………………………………………………..233 
11.1 
Study Hypotheses ............................................................................................... 233 
11.2 
Sample Size Considerations ............................................................................... 233 
11.3 
Planned Interim Analyses (if applicable) ............................................................. 233 
11.4 
Final Analysis Plan ............................................................................................. 233 
12 
Source Documents and Access to Source Data/Documents……………………………... 244 
13 
Quality Control and Quality Assurance…………………………………………………………255 
14 
Ethics/Protection of Human Subjects………………………………………………………... 266 
14.1 
Ethical Standard ................................................................................................. 266 
14.2 
Institutional Review Board .................................................................................. 266 
14.3 
Informed Consent Process ................................................................................. 266 
14.3.1 Informed Consent/Assent Process (in Case of a Minor) .......................... 277 
14.4 
Exclusion of Women, Minorities, and Children (Special Populations) .................. 277 
14.5 
Subject Confidentiality ........................................................................................ 277 
14.6 
Study Discontinuation ......................................................................................... 288 
14.7 
Future Use of Stored Specimens ........................................................................ 288 
15 
Data Handling and Record Keeping……………………………………………………………300 
15.1 
Data Management Responsibilities ..................................................................... 300 
15.2 
Data Capture Methods ........................................................................................ 300 
15.3 
Types of Data ..................................................................................................... 311 


 
 
 
 
 
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vi 
15.4 
Timing/Reports ................................................................................................... 311 
15.5 
Study Records Retention .................................................................................... 311 
15.6 
Protocol Deviations ............................................................................................. 311 
16 
Publication Policy…………………………………………………………………………………333 
17 
Literature References…………………………………………………………………………….344 
Supplements/Appendices………………………………………………………………………………366 
Appendix A: Schedule of Events (following Acquisition of Informed Consent)…………………...366 
 
 


 
 
 
 
 
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vii 
LIST OF ABBREVIATIONS  
 
 
 
 
AE 
Adverse Event/Adverse Experience 
AESI 
Adverse Event Special Interest 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AUC 
Area Under the Curve 
CFR 
Code of Federal Regulations 
CHRU 
Child Health Research Unit 
CL 
Clearance 
Cmax 
Maximum serum concentration  
CNS 
Central Nervous System 
CRF 
Case Report Form 
CSF 
Cerebrospinal fluid 
eCRF 
Electronic Case Report Form 
EU 
European Union 
FDA 
Food and Drug Administration 
FWA 
Federalwide Assurance 
GCP 
Good Clinical Practice 
HSV 
Herpes Simplex Virus 
ICH 
International Conference on Harmonisation 
IEC 
Independent or Institutional Ethics Committee 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
IV 
Intravenous 
KG 
Kilogram 
MG 
Milligram 
mL 
Milliliter 
NIH 
National Institutes of Health 
OHRP 
Office for Human Research Protections 
PCR 
Polymerase Chain Reaction 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SEM 
Skin, Eye, and Mouth Disease 
 
 
Vd 
Volume of distribution  
US 
United States 
WBC 
White Blood Cell Count 


 
 
 
 
 
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viii 
PROTOCOL SUMMARY 
 
Title: 
Evaluation of the Pharmacokinetics and Pharmacodynamics of 
Valacyclovir in Neonates with neonatal HSV disease who have 
completed standard of care treatment with acyclovir 
Phase: 
IB  
Population: 
Male and female term infants ≥ 34 weeks gestation who have 
been diagnosed with virologically confirmed neonatal HSV 
disease via culture or polymerase chain reaction (PCR)  
Sample Size: 
6 - 10 
Number of Sites: 
1 
Study Duration: 
5 years 
Subject Participation 
Duration: 
up to 26 days 
Description of Agent or 
Intervention: 
Administration of valacyclovir for 2 to no more than 7 days in 
infants who have completed standard of care treatment course 
for neonatal HSV disease with high-dose parenteral acyclovir to 
obtain pharmacokinetic data. After 2 to no more than 7 days, the 
infant will be switched to the standard-of-care, oral acyclovir, to 
complete the standard 6 months of suppressive therapy.  
Objectives: 
 
 
Primary: 
• 
To define the pharmacokinetics of valacyclovir in neonates 
2-12 weeks of age who are ≥ 34 weeks gestation 
• 
To assess the safety of valacyclovir in treated infants 
 
Secondary: 
• 
To assess the pharmacokinetics of high-dose parenteral 
acyclovir in neonates ≥ 34 weeks gestation with virologically 
confirmed neonatal HSV disease who are receiving acyclovir 
as standard of care  
 
• 
To compare the pharmacokinetics of high-dose parenteral 
acyclovir to the pharmacokinetics of the proposed study 
dose of valacyclovir (20 mg/kg every 8 hours) 
 


 
 
 
 
 
 ____________________________________________________________________________________________ 
ix 
 
Outcome Measures 
 
 
 
Primary Endpoint: 
• 
Plasma pharmacokinetics parameters for valacyclovir 
AUC8 
• 
Cumulative incidence of Grade 3 or higher unsolicited 
adverse events, serious adverse events, or any 
adverse event that is not recovered / not resolved 
Secondary Endpoints: 
• 
Plasma pharmacokinetic parameters for parenteral 
acyclovir AUC8 
• 
Comparison of AUC8 of 20 mg/kg IV acyclovir to the 
AUC8 of 20 mg/kg PO valacyclovir  
Description of Study 
Design: 
 
This is an open-label, single center, PK study to assess 
valacyclovir pharmacokinetics and pharmacodynamics in 
neonates and compare to the pharmacokinetics and 
pharmacodynamics of the standard of care treatment dose of 
intravenous acyclovir. Only those babies with virologically 
confirmed neonatal HSV disease will be enrolled in the study. 
The decision to initiate valacyclovir for 2 (up to 7) days will be 
made by a physician based on inclusion/exclusion criteria, and 
those who meet entry criteria will be eligible for the study. Those 
enrolled in the study will have daily random parenteral acyclovir 
PK levels drawn during the first week of treatment (drawn only 
at times of other lab draws). These infants will also have a 
pharmacokinetic sampling profile obtained on or after dose 22 
and before dose 42 of intravenous acyclovir. The PK samples 
for the sampling profile will be collected just prior to the next 
dose of intravenous acyclovir (within 30 minutes prior to the start 
of the infusion), within 15 minutes of completion of the infusion, 
and 3-4 hours after infusion. Upon completion of the 
recommended treatment course duration with intravenous 
acyclovir determined by disease classification (SEM, CNS, or 
disseminated disease), the infant will be started on enteral 
valacyclovir 20 mg/kg every 8 hours. 
On day 2 and no more than day 7 of valacyclovir 20 mg/kg 
every 8 hours, a pharmacokinetic sampling profile will be 
obtained. The PK samples will be collected just prior to the 


 
 
 
 
 
 ____________________________________________________________________________________________ 
x 
enteral dose of valacyclovir hour 0 (8 hours after previous dose 
and immediately before next dose), 1-2 hours after dose, and 3-
5 hours after dose. 
Subjects with inadequate pharmacokinetic data for analysis 
(e.g., due to dropping out of the study before PK assessments 
are performed, or blood sampling obtained but is inadequate for 
analysis) may be replaced and will not count toward the total of 
6 (and up to 10) subjects.   
 
Estimated Time to 
Complete Enrollment: 
4.5 years from enrollment of the first study subject 


 
 
 
 
 
 ____________________________________________________________________________________________ 
xi 
*Schematic of Study Design: 
 
Initiation of parenteral acyclovir for virologically confirmed 
 neonatal HSV disease per standard of care 
Initiation of valacyclovir 20 
mg/kg every 8 hours for 
research purposes 
Obtain one pharmacokinetic 
sampling profile on or after dose 
22 and before dose 42 of IV 
acyclovir for research purposes 
Second week 
of parenteral 
acyclovir 
Completion of 
parenteral 
acyclovir  
Obtain pharmacokinetic sampling 
for valacyclovir for research 
purposes, and then switch to 
standard of care, oral acyclovir, 
to complete 6 months of 
suppressive therapy as per 
standard of care 
Day 2  
(up to day 7) 
 of valacyclovir 
Daily IV acyclovir PK levels  
(obtained at random times for 
research purposes) 
First week of 
parenteral 
acyclovir  


 
 
 
 
 
1 
1 
KEY ROLES  
Individuals: 
 
 
Co-Principal Investigator: 
Nicole Samies, DO 
Protocol Chair 
Pediatric Infectious Disease Fellow 
The University of Alabama at Birmingham 
1600 Sixth Avenue South, CHB 308 
Birmingham, AL  35233 
Phone: 205-996-6418 
Fax: 
205-975-6549 
e-mail: nsamies@uabmc.edu  
 
Co-Principal Investigator: 
David Kimberlin, MD 
Co-Principal Investigator, Collaborative Antiviral Study Group 
Professor of Pediatrics 
Sergio Stagno Endowed Chair in Pediatric Infectious Diseases 
The University of Alabama at Birmingham 
1600 Seventh Avenue South, CHB 303 
Birmingham, AL 35233 
Phone: 205-934-5316 
Fax: 205-975-9972 
e-mail: dkimberlin@peds.uab.edu 
 
Co-Principal Investigator: 
Richard Whitley, MD 
Co-Principal Investigator, Collaborative Antiviral Study Group 
Professor of Pediatrics 
Pediatric Infectious Disease Fellow 
The University of Alabama at Birmingham 
1600 Seventh Avenue South, CHB 303 
Birmingham, AL 35233 
Phone: 205-996-7878 
Fax: 
205-975-9972 
e-mail: rwhitley@peds.uab.edu 
 
 
 
Institutions: 
 
  
University of Alabama at Birmingham   
Nicole Samies, DO 


 
 
 
 
 
2 
Department of Pediatrics, Division of Infectious Diseases  
1600 6th Avenue South, CHB 308  Birmingham, AL 35233  
Phone: 205-996-6418 
Fax: 205-975-6549 
Email: nsamies@uabmc.edu 
Optional: 
 
Statistician: 
Inmaculada "Chichi" Aban, PhD 
Associate Professor 
Department of Biostatistics 
School of Public Health 
The University of Alabama at Birmingham 
RPHB 327 
Phone: (205) 934-2732 
Fax: 
(205) 975-2541 
e-mail: CAban@ms.soph.uab.edu 
 
UAB Antiviral Pharmacology Laboratory: 
Edward P. Acosta, Pharm.D. 
Professor and Director, Division of Clinical Pharmacology 
University of Alabama at Birmingham 
School of Medicine 
1670 University Blvd, Volker Hall, Room 258 
Birmingham, AL 35294-0019 
Phone: 205-934-2655 
Fax:      205-934-6201 
e-mail:  eacosta@uab.edu 
 
 
 


 
 
 
 
 
3 
2 
BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
2.1 
Background Information 
Neonatal HSV is an uncommon disease that affects about 1500 infants yearly in the US (1-3)  
with recent studies indicating an increasing incidence over the last several years (4). Although 
uncommon, the disease can have devastating outcomes if not detected and treated early. The 
disease is divided into three classifications: skin, eye, and mouth (SEM), central nervous system 
(CNS), and disseminated. The classification is predictive of mortality and morbidity, with worse 
outcomes noted in the CNS and disseminated groups (5). SEM disease accounts for the 
majority of neonatal HSV disease cases (45%), followed by CNS disease (30%), and then 
disseminated disease (25%) (6). 
Vidarabine was the first antiviral drug recommended for treatment of neonatal HSV disease in 
the 1970s. Although other antiviral agents were studied prior to vidarabine, they were not 
recommended for treatment of neonatal HSV disease as a result of their toxic side effects. 
Vidarabine was later replaced in the 1980s by acyclovir, an acyclic guanine analogue that 
inhibits viral replication by interfering with viral DNA polymerase (7-10). Although low dose 
acyclovir (30 mg/kg/day) was equally efficacious and demonstrated no reduction in mortality 
when compared to vidarabine (5, 6, 11), it was more favorable because of its less toxic profile 
and easier administration (6). A later study performed by the National Institute of Allergy and 
Infectious Diseases Collaborative Antiviral Study Group (CASG) evaluated intermediate dose 
acyclovir (45 mg/kg/day) and high dose acyclovir (60 mg/kg/day) to determine if outcome could 
be improved. High dose acyclovir demonstrated the greatest reduction in mortality rate from 
14% in CNS disease and 54% in disseminated disease to 4% and 30% respectively (12). Thus, 
high dose acyclovir became the new standard of treatment for neonatal HSV disease, although 
the pharmacokinetics of high dose intravenous acyclovir dose were only assessed in two 
subjects (6, 12).  
Currently the standard of care requires that infants diagnosed with neonatal HSV disease are 
treated with high dose intravenous acyclovir for 14-21 days depending on classification of 
the disease (6, 13); infants with SEM disease are recommended to receive 14 days of 
intravenous acyclovir whereas infants with CNS and disseminated disease are recommended to 
receive at least 21 days of intravenous therapy. Those with CNS disease could potentially 
require longer than 21 days of therapy as duration of therapy is determined on clearance of viral 
DNA from the CSF via repeat lumbar puncture performed near the end of the 21 days of 
therapy(14). If the viral DNA is still detected, intravenous acyclovir is continued for an additional 
week and another lumbar puncture is performed. Infants remain hospitalized for the entire 
duration of treatment in order to closely monitor for the potential risk of renal toxicity, a common 
reversible side effect of intravenous acyclovir.  Once the infant has completed the treatment 


 
 
 
 
 
4 
course of intravenous acyclovir, they are transitioned to oral acyclovir (300 mg/m2/dose three 
times a day) and discharged home to complete a total of 6 months of suppressive therapy to 
prevent further neurologic injury by subclinical viral replication (13, 15). Suppressive therapy has 
significantly improved neurologic outcome (higher neurodevelopmental scores) in those 
infants with CNS disease and decreased the number of skin recurrences when started 
immediately after completion of treatment with IV acyclovir (15, 16).  
Although vast advancements have been made in the treatment of neonatal HSV disease to 
reduce mortality and morbidity, there remains a high emotional burden and demand on families 
as a result of guilt, lengthy hospitalizations, and frequent administration of medications for a 
prolonged period of time. There is also a large financial burden on healthcare systems; the 
estimated costs for treatment of neonatal HSV disease accounting for admission and 6 months 
of follow up in a cohort of 900 infants from 2009-2015 was more than 60 million dollars (4), 
which will continue to increase as the incidence of the disease increases. Preventing neonatal 
HSV disease would be ideal to reduce the emotional stress and demand on families and 
financial burden on healthcare systems, but until that time, other means of reducing these 
stressors should be evaluated.  
One way to potentially reduce the emotional stress and demands on families would be to 
decrease the length of hospital stay. Unfortunately, due to oral acyclovir’s poor bioavailability of 
15-30% (8-10, 17, 18), infant’s require intravenous acyclovir for treatment in order to achieve 
the desired acyclovir plasma concentration. Valacyclovir, on the other hand, offers the possibility 
of use in infants for a portion of the treatment course as it can achieve similar concentrations to 
IV acyclovir because of its improved bioavailability of 50-54% (7, 8). Valacyclovir is an enteral 
prodrug of acyclovir synthesized by the addition of L-valine to acyclovir, and it is commonly used 
in the treatment and/or suppression of genital herpes in adolescents, adults, and pregnant 
women (9, 17, 19). Yet, only limited data exists on its use in children. One study performed by 
Kimberlin et al evaluated the pharmacokinetics of valacyclovir in children ranging from 1 month 
to 11 years of age. The study was able to recommend a valacyclovir dose of 20 mg/kg two to 
three times a day in children 3 months of age and older but was unable to recommend a dose 
for those younger than 3 months of age. This is because only one dose (25 mg/kg) was 
evaluated in those 1-2 months of age, and the 1-2 month old infants had a significantly higher 
AUC and Cmax with a 25 mg/kg/dose of valacyclovir when compared to older infants due to 
decreased clearance (20). Thus, the pharmacokinetics of valacyclovir 20 mg/kg in infants less 
than 3 months of age needs to be evaluated in order to determine if valacyclovir can safely be 
recommended for use in the treatment of neonatal HSV disease. The dose recommended must 
approximate the plasma serum concentrations achieved with 20 mg/kg/dose of intravenous 
acyclovir.  
 
UAB has contributed to and led many multi-center pharmacokinetic and pharmacodynamic 
studies including the study that evaluated the use of valacyclovir in children from 1 month to 11 
years of age. Their experience will be extremely helpful in determining the PK data of 
valacyclovir and its potential use in the treatment course of neonatal HSV disease (specifically 


 
 
 
 
 
5 
with SEM disease). Due to biochemical properties, a liquid suspension of valacyclovir has not 
been produced, but the American Society of Health-System Pharmacists provides instructions 
on how to make an extemporaneously suspension that shows stability for at least 21 days (21). 
2.2 
Rationale 
Valacyclovir is frequently used in adolescents and adults for the treatment and suppression of 
genital herpes; it is also recommended for use in pregnant women beginning around 36 weeks 
gestation with a history of genital herpes for suppressive therapy to decrease the risk of 
developing active lesions at time of delivery (19). In 2010, CASG performed a valacyclovir 
pharmacokinetic study in children one month to eleven years of age, and the study provided the 
first recommendations for valacyclovir dosing in children 3 months of age and older. The dose 
recommended was 20 mg/kg two to three times a day. Unfortunately, dosing recommendations 
could not be provided for those 1-2 months of age as only the 25 mg/kg dose was studied (20).  
Therefore, determining if 20 mg/kg every 8 hours is an appropriate dose of valacyclovir in 
infants less than 3 months of age is necessary before it can be recommended for use in the 
treatment of neonatal HSV disease. In order to determine if the dose is appropriate, 
pharmacokinetic data will need to be obtained for valacyclovir and compared to intravenous 
acyclovir pharmacokinetic data. Since pharmacokinetic data on intravenous high-dose acyclovir 
is limited to only two patients, this too will need to be evaluated for comparison purposes.  
 
The proposed study is a PK study evaluating the pharmacokinetics of valacyclovir in infants 2-
12 weeks of age. Only infants ≤ 42 days of age who have been diagnosed with neonatal HSV 
disease on intravenous acyclovir per standard of care guidelines will be eligible for participation. 
The recommended dose of valacyclovir in children 3 months of age and older is 20 mg/kg two to 
three times a day, and thus, the dose to be studied will be 20 mg/kg/dose every 8 hours. 
Valacyclovir will be given anywhere from 2 days up to 7 days depending on when the 
pharmacokinetic data can be obtained. Data will only be obtained during weekday hours in the 
Child Health Research Unit (CHRU) at the University of Alabama at Birmingham. After 
pharmacokinetic data has been obtained, the infant will be switched to oral acyclovir per 
standard of care guidelines to complete 6 months of suppressive therapy. At the completion of 
the study, the pharmacokinetic data for valacyclovir 20 mg/kg every 8 hours in infants 2-12 
weeks of age will be defined and will be evaluated to determine if the recommended dose is 
comparable to the currently recommended IV acyclovir dose. Results from this research will lay 
the foundation for future studies evaluating the use of valacyclovir in a portion of the treatment 
course for neonatal HSV disease - specifically SEM disease - to reduce the number of days an 
infant requires hospitalization and subsequently decrease the cost of admission. Additional 
studies will need to be performed to determine the CNS penetration of valacyclovir in order to 
determine its potential use in infants with CNS disease. All pharmacokinetic assays will be 
performed in the UAB Antiviral Pharmacology Laboratory, which has developed the 
methodology to process microspecimens of blood for several different drug concentration 
studies.   
 


 
 
 
 
 
6 
2.3 
Potential Risks and Benefits 
2.3.1 Potential Risks 
One potential risk relates to the blood draws (e.g., bruising at the site, discomfort, infection) 
required to obtain the pharmacokinetic samples. All infants should have a long-term indwelling 
intravenous catheter (e.g. PICC) during hospitalization for administration of IV acyclovir through 
which blood can be withdrawn without risk of discomfort from a needle stick or bruising at the 
site during or after the blood drawing and rarely infection. However, once the infant is 
discharged from the hospital the indwelling intravenous catheter will need to be removed to 
prevent more harm to the infant as the risk of infection is greater when an indwelling catheter is 
not being used. Thus, valacyclovir pharmacokinetic samples will need to be obtained via a heel 
or venous stick on day 2 up to day 7 of valacyclovir therapy. Heel warmers or socks can be 
used prior to the blood draw to increase blood flow to the heel and reduce the amount of 
discomfort experienced with squeezing of the infant’s heel in order to obtain the amount of blood 
necessary. The weight-based volumes required for the study-specific procedures are less than 
the limits of the Institutional Review Board and the NIH.   
Additionally, daily random pharmacokinetic samples obtained during the first week of IV 
acyclovir will be obtained only at the time of clinical blood draws (creatinine and/or CBC/diff) to 
prevent additional venipuncture procedures solely for study purposes. The weight-based 
volumes required for the study-specific procedures are less than the limits of the Institutional 
Review Board and the NIH.  
Potential risks associated with the use of valacyclovir are comparable to the risks associated 
with long term use of the current standard of care, oral acyclovir. Therefore, monitoring for 
adverse events is not necessary for short term use (2 and up to 7 days) of valacyclovir.  
2.3.2 Known Potential Benefits 
Knowledge of the pharmacokinetic profile will aid in determining if 20 mg/kg/dose every 8 hours 
is the most appropriate dose of valacyclovir to be used in infants (≤ 84 days of age) for 
treatment of neonatal SEM HSV disease. It will also provide further baseline information for 
future studies to evaluate the use of valacyclovir in infants with neonatal HSV CNS disease. 
This information can aid in decreasing the length of hospitalization, emotional burden on 
families, and ultimately health care costs. Participants will not directly benefit themselves from 
participating, though.  


 
 
 
 
 
7 
3 
OBJECTIVES 
3.1 
Study Objectives 
Primary: 
• 
To define the pharmacokinetics of valacyclovir in neonates (≥ 34 weeks gestational age at 
birth and ≥ 2000 g)  
• 
To assess safety of valacyclovir administration 
Secondary: 
• 
To assess the pharmacokinetics of high-dose parenteral acyclovir in neonates ≥ 34 weeks 
gestation with virologically confirmed neonatal HSV disease who are receiving acyclovir as 
standard of care  
• 
To compare the pharmacokinetics of high-dose parenteral acyclovir to the pharmacokinetics 
of the proposed study dose of valacyclovir (20 mg/kg every 8 hours) 
 
3.2 
Study Outcome Measures 
3.2.1 Primary Outcome Measures 
Primary Endpoint: 
Primary Endpoint: 
 
• 
Plasma pharmacokinetic parameters for valacyclovir AUC8  
• 
Cumulative incidence of Grade 3 or higher unsolicited adverse events, serious adverse 
events, or any adverse event that is not recovered / not resolved 
3.2.2 Secondary Outcome Measures 
Secondary Endpoints: 
• 
Plasma pharmacokinetic parameters for parenteral acyclovir AUC8 
• 
Comparison of AUC8 of 20 mg/kg IV acyclovir to the AUC8 of 20 mg/kg PO valacyclovir 
 


 
 
 
 
 
8 
4 
STUDY DESIGN 
This study is an open-label, single-center, pharmacokinetic study of valacyclovir 
pharmacokinetics in male and female infants ≥ 34 weeks gestation, ≤ 42 days of age at initiation 
of intravenous acyclovir, and ≥ 2000 g who have been diagnosed with virologically confirmed 
neonatal HSV disease via culture or polymerase chain reaction (PCR). Infants who meet the 
inclusion criteria will be eligible for the study, and informed consent will be obtained by the 
infant’s parent(s) or legal guardian(s).  
 
Subjects meeting enrollment criteria will be enrolled in this clinical trial. The total sample size will 
be 6 and up to 10 infants diagnosed with any of the 3 disease classifications of neonatal HSV 
disease. Following enrollment, infants during the first week of treatment with intravenous 
acyclovir as per standard of care will have daily random pharmacokinetic levels (population 
based pharmacokinetics) obtained at the same time of clinical blood draws (e.g. creatinine 
and/or CBC/diff), namely using remnant specimens. During the second week of treatment with 
IV acyclovir (between dose 22 and 42) infants will have one pharmacokinetic sampling profile 
obtained. The plasma specimens for the pharmacokinetic sampling profile will be drawn 
immediately prior to next dose (within 30 minutes prior to the start of infusion and 8 hours after 
previous dose) for an 8 hour trough, a post-infusion peak obtained within 15 minutes following 
completion of infusion, and 3-4 hours after infusion. Once these samples are obtained, the 
infant will complete the course of IV acyclovir per the standard of care guidelines.  
 
Upon completion of the intravenous acyclovir per standard of care, the infant will be switched to 
valacyclovir 20 mg/kg every 8 hours for 2 and up to 7 days depending upon availability of the 
CHRU. The first dose of valacyclovir is to be given 8 hours after completion of the last dose of 
IV acyclovir. On day 2 (up to 7), the infant will return to UAB’s CHRU for a PK profile to be 
obtained. The plasma specimens for the pharmacokinetic profile will be drawn at hour 0 (just 
prior to the scheduled valacyclovir dose and 8 hours after the last dose), at 1-2 hours after dose 
for a peak level, and 3-5 hours after dose. Once the infant completes the pharmacokinetic 
sampling, the infant will have completed the study and will be switched to oral acyclovir per 
standard of care guidelines to complete 6 months of oral suppressive therapy for neonatal HSV 
disease. The parent(s) or guardian will be instructed to have the infant follow with an infectious 
disease specialist for appropriate follow up of neonatal HSV disease while on suppressive 
therapy.  
 
All participants will receive the standard of care treatment with 14 to 21 days of IV acyclovir 
(depending on disease classification) followed by 6 months of oral antiviral suppression. The 
only change is that the first few days or oral suppression with be with valacyclovir instead of 
acyclovir. Subjects with inadequate pharmacokinetic data for analysis (e.g., due to dropping out 
of the study before PK assessments are performed or blood sampling obtained but is 


 
 
 
 
 
9 
inadequate for analysis) may be replaced and will not count toward the total of 6 and up to 10 
subjects.   
 
Treatment Day 1 is the calendar day when the first dose of parenteral acyclovir was 
administered to the study subject for clinical purposes and will be the date against which follow-
up visits will be defined. Treatment Dose 1 corresponds to the first dose of parenteral acyclovir 
given to the study subject for clinical purposes. The study enrollment day is unlikely to be the 
same day as Treatment day 1 as individuals will need confirmation of neonatal HSV infection in 
order to be enrolled. Participants can enroll on or before treatment day 14. Study Assessment 
Day 1 is the calendar day when the participant is enrolled in the study.  
 
The study will be divided up into 3 periods: Period 1 will consist of Treatment Day 1 through 
Treatment Day 7, Period 2 will consist of Treatment Day 8 through Treatment Day 14 (or 21 
if being treated for CNS or disseminated infection), and Period 3 will be from the initiation of 
valacyclovir (started after completion of IV acyclovir) until the collection of PK valacyclovir 
specimens. Although it is anticipated, but not required, that patients are enrolled in the study 
prior to treatment day 7 in order to participate in all 3 periods, all patients will be enrolled on or 
before treatment day 14 and will included in all eligible periods based on pre-determined 
classification.  
 
During Period 1, daily pharmacokinetic specimens will be obtained randomly but only at times 
of other clinical blood draws. The acyclovir dose, time of last acyclovir infusion prior to blood 
draw, and time of blood draw will be recorded. During Period 2, only one pharmacokinetic 
sampling profile will be obtained between Treatment Dose 22 and Treatment Dose 42. The 
pharmacokinetic specimens for the profile will be obtained at hour 0 (within 30 minutes of the 
next parenteral acyclovir dose), within 15 minutes of completion of parenteral acyclovir infusion, 
and 3-4 hours after infusion.  
 
During Period 3, a pharmacokinetic sampling profile will be obtained while the infant is on 
valacyclovir. Pharmacokinetic specimens will be obtained at hour 0 (immediately prior to next 
valacyclovir dose; window: -15 min), 1-2 hours post dose, and 3-5 hours post dose. Valacyclovir 
dose, date, time of last valacyclovir dose, and time of blood draw will be recorded.  
 
All pharmacokinetic specimens will be taken to the UAB Antiviral Pharmacology Laboratory for 
processing. No additional blood samples will be required for research purposes.  
 
 


 
 
 
 
 
10 
5 
STUDY ENROLLMENT AND WITHDRAWAL 
Male and female infants ≥ 34 weeks gestation of any ethnicity with virologically confirmed 
neonatal HSV disease via culture- or polymerase chain reaction (PCR). The study population 
will be drawn from the in-hospital setting.  Potential subjects will be identified by the site 
investigators and the study coordinators.  Patients meeting study eligibility criteria will be offered 
enrollment into the trial.  Informed consent signed by study subject’s parent(s) or guardian(s) 
must be obtained prior to study enrollment.  Site investigators are all clinicians who have direct 
access to the study population.   
5.1 
Subject Inclusion Criteria 
1. Signed informed consent from parent(s) or legal guardian(s) 
2. Confirmation of HSV infection from surface culture/PCR, skin lesion culture/PCR, blood 
PCR, or CSF PCR (performed at UAB Virology lab) 
3. ≥ 34 weeks gestational age at birth 
4. Weight at study enrollment is ≥ 2000 grams  
5. Receiving intravenous acyclovir, prescribed by the patient’s physician for ≤ 14 days 
6. ≤ 42 days of age at initiation of parenteral acyclovir 
7. Creatinine ≤ 1.2 
5.2 
Subject Exclusion Criteria 
1. Imminent demise 
2. Current receipt of other investigational drugs 
3. Major congenital anomaly that in the site investigator’s opinion may impact drug metabolism or the 
patient’s volume of distribution 
4. Creatinine of > 1.2 prior to initiation of valacyclovir 
5. Evidence of immunosuppression (HIV infected, immune deficiencies, etc.) 
6. Any condition that, in the opinion of the investigator, would place the subject at an unacceptable 
injury risk or that may interfere with successful study completion  
7. > 42 days of age at initiation of parenteral acyclovir  
8. Concern for parental/guardian compliance 
5.3 
Treatment Assignment Procedures 
5.3.1 Randomization Procedures 
Since this is a pharmacokinetic sampling study evaluating valacyclovir with no therapeutic 
intervention or investigation, no randomization procedures are required.   


 
 
 
 
 
11 
5.3.2 Reasons for Delaying Study-Related Procedures 
Study related laboratory draws will be delayed or deferred if the investigator believes that 
obtaining them might increase subject risk. If a study related laboratory draw is delayed or 
deferred, study staff will document this on a source document. 
5.3.3 Reasons for Withdrawal 
The criteria for discontinuations during the study include:  
• 
Study subject (parent/legal guardian) wishes to withdraw 
• 
An alternate cause of disease (bacterial or other viral) is identified and acyclovir is 
discontinued 
• 
Non-compliance with study procedures 
• 
Trial termination (by UAB, or agreement of all investigators) 
• 
Any other reason which, in the opinion of the investigator, precludes the study subject's 
participation in the study.  The principal investigator must call the Protocol Chair prior to 
discontinuing a study subject for this reason. 
5.3.4 Handling of Withdrawals 
Study subjects may withdraw voluntarily from participation in the study at any time.  If a study 
subject withdraws or is discontinued from the study at any time prior to completion of the study, 
the reason for this decision will be recorded on the eCRFs.  If subject withdraws before 
collection of the pharmacokinetic collection, this subject may be replaced (see Section 4).  
5.3.5 Termination of Study  
The PI and study team have the right to terminate this study at any time.  Reasons for 
terminating the study may include, but are not limited to, the following: 
• 
Study subject enrollment is unsatisfactory 
• 
Data recording is inaccurate or incomplete 
• 
Investigators do not adhere to the protocol or applicable regulatory guidelines in conducting 
the study. 


 
 
 
 
 
12 
6 
STUDY INTERVENTION/INVESTIGATIONAL PRODUCT 
Although valacyclovir does not currently have a recommended dose for infants 2 months and 
younger, this study is mainly a pharmacokinetic sampling study of valacyclovir in infants 2 
months and younger and is not being used for a therapeutic intervention. Currently intravenous 
acyclovir is recommended for treatment of neonatal HSV disease, which these infants will 
receive per standard of care guidelines. The infants will only receive a short course of 
valacyclovir (2 and up to 7 days) in order to obtain the pharmacokinetic profile and then will be 
switched to the standard of care oral acyclovir to complete 6 months of suppressive therapy. 
The only change is that the first few days or oral suppression with be with valacyclovir instead of 
acyclovir. 
6.1 
6.1.  Study Product Description 
6.1.1 Acquisition 
Valacyclovir will be resourced from COA’s wholesaler. 
6.1.2.  Formulation, Packaging, and Labeling 
A pharmaceutically-manufactured liquid formulation of valacyclovir does not exist 
at this time, but the American Society of Health-System Pharmacists provides 
instructions on how to make an extemporaneous preparation of oral suspension 
from 500 mg caplets. COA’s Investigational Drug Pharmacy will prepare, 
package, and label the study medication. Valacyclovir is supplied in amber glass 
medicine bottles. It will be labeled as an investigational product.   
6.1.3.  Product Storage and Stability 
The valacyclovir caplets should be stored at 15° – 25° C (59° – 77° F).  
Adherence to the USP Controlled Room Temperature is required. After 
constituting the study drug, it can be used within 21 days of preparation.  The 
constituted study drug should be stored under refrigeration (2° – 8° C or 36° – 
46° F) in a refrigerator.  The constituted study drug must not be frozen. 


 
 
 
 
 
13 
6.2 
6.2.  Dosage, Preparation and Administration of Study 
Investigational Product 
The dose of valacyclovir to be evaluated is 20 mg/kg every 8 hours to correlate with 20 
mg/kg every 8 hours of intravenous acyclovir that is already used as standard of care 
for treatment of neonatal HSV disease. The subject enrolled in the study will receive 
anywhere from 2 up to 7 days (6-21 doses) of valacyclovir depending upon availability 
of the CHRU.  
 
6.2.1.  Preparation of Study Drug 
Valacyclovir extemporaneously oral suspension will be reconstituted by COA’s 
research or designated pharmacist. The extemporaneous suspension will be 
prepared following the instructions from the American Society of Health-System 
Pharmacists. 
 
6.2.2.  Administration of Study Drug 
Valacyclovir may be given with or without food. The route of administration of 
study drug will be recorded (orally, nasogastric tube, orogastric tube, etc.). 
6.3 
6.3.  Drug Accountability 
After receipt of the investigational drug, the pharmacist will be responsible for and 
maintain logs of receipt, dispensation, storage conditions, and disposal of study drug.  
All original documents will be provided to the PI and will be maintained in a secure and 
accessible location. 
Used and unused study product will not be disposed of or returned until the study 
monitor reviews and confirms the drug accountability. 
• Used or partially used study product will be disposed of by the local site 
pharmacy in accordance with local regulations after completion of drug 
accountability by the study monitor. 
6.4 
6.4.  Concomitant Medications 
Concomitant medications not be recorded as this is only a PK sampling study.  


 
 
 
 
 
14 
6.5 
6.5.  Prohibited Medications 
No drugs are prohibited while taking valacyclovir as there are no clinically significant 
drug-drug interactions.  
 


 
 
 
 
 
15 
7 
STUDY SCHEDULE 
7.1 
Screening  
Potential subjects will be identified by the site investigators and the study coordinators.  
Informed consent signed by study subject’s parent(s) or guardian(s) must be obtained prior to 
study enrollment. 
7.2 
Enrollment/Baseline 
7.2.1. Baseline Assessment (Window: Treatment Day 1 through Treatment 
day 14) 
• 
Confirm that informed consent has been obtained from parent or legally authorized 
representative 
• 
Document baseline demographics  
o Gestational age at delivery 
o Date of birth 
o Day of life at initiation of IV acyclovir therapy 
o Gender 
o Race 
o Ethnicity 
o Birth weight 
o Weight at enrollment 
o Length in centimeters at enrollment 
o Type of neonatal HSV 
o HSV diagnostic results (surface culture and/or PCR, HSV CSF PCR, HSV blood 
PCR, and/or lesion culture and/or PCR) 
• 
Hematology labs  
o WBC with differential drawn for clinical purposes will be recorded  
• 
Chemistry labs  
o All creatinine and alanine aminotransferase (ALT) values obtained for clinical 
purposes will be recorded  
7.3 
Study Follow-up  
7.3.1. Period 1 (Treatment Day 1 through Treatment Day 7)  
• 
Hematology labs  


 
 
 
 
 
16 
o WBC with differential will be recorded if being drawn for clinical reasons (any 
laboratory value obtained during the window will suffice, with an effort being 
made to capture the most abnormal value) 
• 
Chemistry labs  
o Creatinine and alanine aminotransferase (ALT) values will be recorded if being 
drawn for clinical reasons   
• 
Acyclovir pharmacokinetics  
o A single blood sample for PK determination will be obtained daily at random time 
intervals as able 
o Timepoints for pharmacokinetic draws will occur at random time intervals 
o Date and time of lab draw for PK specimen will be recorded 
o Date and time of last acyclovir infusion prior to PK lab draw will be 
recorded 
o Most recent patient weight, acyclovir dose received, and serum creatinine 
value will be recorded 
o Required amount of whole blood for plasma acyclovir determination at each 
timepoint is 200 L (0.2 mL) 
Note: blood for PK assessments will be obtained at the time that a clinical blood draw 
is being performed, or through the indwelling intravenous catheter, so that no 
additional venipuncture procedures solely for study purposes will be required 
7.3.2. Period 2 (Treatment Day 8 through Treatment Day 14 for SEM disease 
and Treatment Day 21 for CNS and disseminated disease) 
• 
Hematology labs  
o WBC with differential will be recorded if being drawn for clinical reasons (any 
laboratory value obtained during the window will suffice, with an effort being 
made to capture the most abnormal value) 
• 
Chemistry labs  
o Creatinine and alanine aminotransferase (ALT) values will be recorded if being 
drawn for clinical reasons   
• 
Acyclovir pharmacokinetics  
o One acyclovir PK sampling profile will be performed after dose 22 and before 
dose 42 
o Acyclovir concentrations will be obtained at specified timepoints 
o Timepoints for pharmacokinetic draws:  0h (within 30 minutes prior to the start of 
the infusion of acyclovir), within 15 minutes after completion of the infusion, and 
3-4 hours after infusion 
o Most recent patient weight, acyclovir dose received, and serum creatinine value 
will be recorded 
o Required amount of whole blood for plasma acyclovir determination at each 
timepoint is 200 L (0.2 mL) 


 
 
 
 
 
17 
Note: blood for PK assessments will be obtained at the time that a clinical blood draw 
is being performed, or through the indwelling intravenous catheter, so that no 
additional venipuncture procedures solely for study purposes will be required 
7.3.3. Period 3 (Day 2 and up to 7 of valacyclovir)  
• 
Valacyclovir pharmacokinetics  
o One valacyclovir PK sampling profile will be performed on Day 2 (and up to day 
7) of valacyclovir 
o Acyclovir concentrations will be obtained at specified timepoints 
o Timepoints for pharmacokinetic draws:  0h (immediately prior to valacyclovir 
dose; window: -15 min), 1-2 hours after dose, and 3-5 hours after dose 
o Date and time of last valacyclovir dose prior to PK lab draw will be recorded 
o Date and time of valacyclovir dose given in the CHRU will be recorded 
o Required amount of whole blood for plasma acyclovir determination at each 
timepoint is 200 L (0.2 mL) 
Note: blood for PK assessments will be obtained either via venous/heel stick; will 
attempt to reduce discomfort experienced with heel sticks by using a heel warmer 
prior to blood draw   
• 
Initiation of oral acyclovir per standard of care guidelines to complete 6-month course 
of oral suppressive therapy at recommended dose of 300 mg/m2/dose every 8 hours) 
after last PK lab is drawn. Prescription for oral acyclovir to be written and prescription 
filled by outpatient pharmacy and billed to patient’s insurance prior to leaving the 
hospital 
7.4 
Early Termination Visit  
Study subjects may withdraw voluntarily from participation in the study at any time.  If a study 
subject withdraws or is discontinued from the study at any time prior to completion of the study, 
the reason for this decision will be recorded on the eCRFs. SAEs and AEs will be followed 
according to guidelines in Section 9. Upon withdrawal from the study, the infant should follow 
the standard of care guidelines for neonatal HSV disease.  
7.5 
Unscheduled Visit  
Should an unscheduled visit occur, the study subject will be assessed as standard of care.  
 


 
 
 
 
 
18 
8 
STUDY PROCEDURES/EVALUATIONS 
The study procedures and evaluations are summarized in Appendix A: Schedule of Events.  In 
the conduct of this study, hospital staff may perform research activities (e.g., pharmacokinetic 
blood draw collection) under the direction of the Principal Investigator or designee. 
8.1 
Clinical Evaluations 
8.1.1. Baseline Demographics 
To characterize the study subjects, information will be recorded at the baseline study visit 
following the obtaining of informed consent.  Data collected will include basic demographics and 
birth history (date of birth; gestational age at delivery; gender; race; ethnicity; birth weight; 
weight at enrollment; length in centimeters at enrollment; all HSV diagnostic tests, CSF indices 
from lumbar puncture(s); classification of neonatal HSV disease, age at diagnosis; day of life at 
initiation of IV acyclovir therapy; acyclovir dose and dosing frequency). 
8.2 
Laboratory Evaluations 
All chemistry labs (serum creatinine, ALT) will be recorded on eCRFs if they have been drawn 
for clinical reasons; only the most abnormal value for hematology labs (WBC with differential) 
will be recorded on eCRFs if they have been drawn for clinical reasons 
8.2.1 Special Assays or Procedures 
Research assays (Pharmacokinetics will be conducted at the respective UAB lab). 
8.2.1.1.  Acyclovir Pharmacokinetics 
Assessment of acyclovir plasma concentrations will be conducted at the UAB  
Pharmacokinetic Laboratory. Acyclovir concentrations will be obtained on a daily 
basis at random time intervals during Period 1 (Treatment Day 1 through 
Treatment Day 7). One PK sampling profile will then be completed during Period 
2 (between Treatment Day 8 and Treatment Day 14). Timepoints for 
pharmacokinetic draws for Period 2 are as follows: 0 hours (within 30 minutes 
prior to the start of the infusion), within 15 minutes after completion of the 
infusion, and 3-4 hours after infusion.  
Pharmacokinetic specimens will also be obtained during Period 3 (Day 2 up to 
Day 7 of valacyclovir). The timepoints for the lab draws for Period 3 are as 
follows: 0 hours (just prior to the enteral dose of valacyclovir and approximately 8 


 
 
 
 
 
19 
hours after previous dose), 1-2 hours after dose, and 3-5 hours after dose. The 
required amount of whole blood for plasma acyclovir determination at each time 
point is 200L (0.2 mL). Specimens will be processed to separate the plasma, 
and then will be transported to the UAB Pharmacokinetic Laboratory. Most recent 
patient weight, valacyclovir dose received, timing of dose, sample collection time, 
WBC, percentage neutrophils, ANC, ALT, and serum creatinine value will be 
recorded.  
 


 
 
 
 
 
20 
9 
ASSESSMENT OF SAFETY 
Regulatory requirements including the Food and Drug Administration (FDA) regulations, 
International Conference on Harmonisation (ICH) Guidelines for Good Clinical Practice (GCP), 
and European Union (EU) Clinical Trials Directive set forth safety monitoring and reporting 
responsibilities of sponsors and investigators to ensure the safety and protection of human 
subjects participating in clinical trials.  
Any other adverse events that meet the reporting requirements of the Institutional Review Board 
will be documented and reported to Protocol Chair. 
9.1 
Safety Reporting:  Adverse Events of Special Interest (AESI) 
The investigator must also report the following AESI on the AESI case report form: 
o AEs associated with blood draws 
o All adverse events that meet the reporting requirements of the Institutional Review Board 
(which will also be reported to Protocol Chair). 
 
The risks associated with participation in the clinical trial are associated with blood draws 
and potential side effects to valacyclovir. However, the potential drug risks for valacyclovir are 
comparable to the risks associated with long term use of the current standard of care, oral 
acyclovir. Therefore, monitoring for adverse events is not necessary for short term use (2 and 
up to 7 days) of valacyclovir. In an effort to document only untoward medical events that have a 
greater likelihood of being study-related, only adverse events associated with blood draws will 
be considered adverse events for the purposes of this protocol.   
 
 
9.2 
Type and Duration of Follow-up of Subjects after Adverse 
Events 
All AEs as described above will be followed until resolved or considered stable. 
9.3 Halting Rules 
9.3.1 Discontinue of Study participation for individual subject 
Subjects who experience significant problems with blood draws may be withdrawn from any 
future sampling.  
 
 


 
 
 
 
 
21 
9.4 FDA MedWatch Adverse Event Reporting Program 
Reporting of adverse events related to drug administration is not part of the protocol.  The 
reporting is in support of the FDA post-marketing safety surveillance program and is 
encouraged. 
The FDA MedWatch adverse event reporting program allows health care professionals to 
voluntarily report a serious adverse event, product quality problem or product use error that is 
suspected to be associated with the use of an FDA-regulated drug, biologic, medical device or 
dietary supplement.  This system is for the reporting of adverse events noted spontaneously in 
the course of clinical care, and not for events that occur during clinical trials under an 
Investigational New Drug (IND) application.   
The MedWatch Website, http://www.fda.gov/Safety/MedWatch/HowToReport/ucm085568.htm 
can be used to voluntarily report a serious adverse event, product quality problem or product 
use error that is suspected to be associated with the use of an FDA-regulated drug, biologic, 
medical device, dietary supplement or cosmetic.  FDA uses these data to maintain safety 
surveillance of all FDA-regulated products.  A health care professional report may be the critical 
action that prompts a modification in use or design of the product, improves the safety profile of 
the drug or device and leads to increased patient safety. 


 
 
 
 
 
22 
10 
CLINICAL MONITORING 
10.1 Monitoring Plan 
Monitoring of study will be conducted to ensure that human subject protection, study 
procedures, laboratory procedures, study intervention administration, and data collection 
processes are of high quality and meet regulatory guidelines, and that the study is conducted in 
accordance with the protocol and study manuals.  A Clinical Monitoring Plan will not be 
developed. 
If conducted, monitoring visits will include but are not limited to review of regulatory files, case 
report forms, informed consent forms, medical and laboratory reports, and protocol compliance.  
COA research nurses will meet with investigators to discuss any problems and actions to be 
taken and document visit findings and discussions. 
Every effort will be made to maintain the anonymity and confidentiality of subjects during this 
study.  


 
 
 
 
 
23 
11 
STATISTICAL CONSIDERATIONS 
11.1 Study Hypotheses 
Our primary hypothesis is that valacyclovir at 20 mg/kg every 8 hours when administered to very 
young infants will provide adequate exposure to the active metabolite, acyclovir, and be 
comparable to intravenous acyclovir 20 mg/kg every 8 hours.  
11.2 Sample Size Considerations  
The primary endpoint for this study is to determine if 20 mg/kg of valacyclovir every 8 hours is 
comparable to 20 mg/kg of intravenous acyclovir every 8 hours. Thus, based on investigator 
experience, feasibility, and low kinetic variability secondary to renal excretion, a sample size of 
6 and up to 10 subjects will be enrolled. Data will be collected on standardized case report 
forms. Standard non-compartmental techniques will be used initially to estimate 
pharmacokinetic parameters derived from the acyclovir concentration time data. The resource 
utilized for pharmacokinetic analysis is WinNonlin version 5.3, Pharsight Corporation, Mountain 
View, CA. 
11.3 Planned Interim Analyses (if applicable) 
There are no planned interim analyses for this trial. 
11.4 Final Analysis Plan  
Descriptive statistics will be represented by means, standard deviations, and confidence 
intervals for continuous variables and counts and proportions for categorical variables. 
Primary analysis: Acyclovir and valacyclovir pharmacokinetic parameters will initially be 
determined using non-compartmental analysis (WinNonlin v5.3) for each individual subject.  The 
parameters (AUC8, CL, Vd, etc.) will be summarized and further used for exploratory 
pharmacodynamic analysis.   
To compare how the valacyclovir PK as measured by AUC8 in infants diagnosed with neonatal 
HSV disease differ from acyclovir PK as measured by AUC8 in the same subset of patients, we 
will construct 95% confidence intervals around the mean AUC8 and compare these means 
across the subset of patients. Additional pharmacokinetic parameters that compose analyses for 
secondary endpoints include Cmax, T1/2,CL, and Vd. 


 
 
 
 
 
24 
12 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
The PI is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported. The site will maintain appropriate medical and research records for this trial, in 
compliance with ICH E6, Section 4.9 and regulatory and institutional requirements for the 
protection of confidentiality of subjects. Data reported in the eCRF derived from the data 
collection forms should be consistent with the source documents or the discrepancies should be 
explained. 
Documentation of source data is necessary for the reconstruction, evaluation, and validation of 
clinical findings, observations, and other activities during a clinical trial. Source data are all 
information, original records of clinical findings, observations, or other activities in a clinical trial 
necessary for the reconstruction and evaluation of the trial. Examples of these original 
documents and data records include, but are not limited to, Source Document Worksheets, 
hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial.  Source documentation serves to substantiate the integrity of trial data, confirms 
observations that are recorded, and confirm the existence of study participants.  This standard 
also serves to ensure data quality by creating audit trails and enabling verification that data are 
present, complete, and accurate.  


 
 
 
 
 
25 
13 
QUALITY CONTROL AND QUALITY ASSURANCE 
The study site will implement a quality management plan. The quality management procedures 
are described herein.  Data will be evaluated for compliance with the protocol and accuracy in 
relation to source documents.  The study will be conducted in accordance with procedures 
identified in the protocol.  Items to be reviewed include, but are not limited to: eligibility 
(including informed consent), AE reporting, study/clinical endpoints, follow-up visits, regulatory 
documents, missed visits, and review of clinical records.  Data that will be reviewed, who is 
responsible for implementation, and the schedule for internal reviews will be specified or 
referenced in the quality management plan.   
 
The CASG research nurses will verify that the clinical trial is conducted and data are generated, 
documented, and reported in compliance with the protocol, ICH E6(R1), and the applicable 
regulatory requirements. 
 


 
 
 
 
 
26 
14 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
14.1 Ethical Standard 
The investigator will ensure that this study is conducted in full conformity with the principles set 
forth in The Belmont Report: Ethical Principles and Guidelines for the Protection of Human 
Subjects of Research of the US National Commission for the Protection of Human Subjects of 
Biomedical and Behavioral Research (April 18, 1979) and codified in 45 CFR Part 46 and/or the 
ICH E6; 62 Federal Regulations 25691 (1997). 
14.2 Institutional Review Board 
Reviewing IRBs must be registered with the OHRP to conduct studies. In the United States and 
in other countries, institutions are required to hold a current US Federal wide Assurance (FWA) 
issued by OHRP. 
 
This protocol, informed consent documents, relevant supporting information, and all volunteer 
recruitment or advertisement information will be submitted to the Institutional Review Board 
(IRB) for review and must be approved before the study is initiated.  Any amendments to the 
protocol must also be approved by the IRB prior to implementing changes in the study.  
 
The investigator is responsible for keeping the IRB apprised of the progress of the study and of 
any changes made to the protocol as deemed appropriate, but in any case at least once per 
year.  The investigator must also keep the IRB informed of any significant AEs. 
All IRB approved documents as well as relevant study correspondence should be copied and 
sent to the UAB Central Unit. 
14.3 Informed Consent Process 
The process of obtaining informed consent must be documented in the medical records, clinic 
chart, and/or research chart.  The consent form must be signed and dated by the subject’s 
parent(s)/legal guardian(s) before participation in the study.  A copy of the signed consent form 
must be provided to the subject’s parent(s)/legal guardian(s).  Signed consent forms must 
remain in each study participants study file and must be available for verification by COA 
research nurses  at any time.  
 
The investigational nature and research objectives of this trial, the procedure, and its attendant 
risks and discomforts will be carefully explained to the subject’s parent(s)/legal guardian(s).  A 
signed informed consent document will be obtained from each subject’s parent(s)/legal 
guardian(s) prior to entry into this study.  At any time during participation in the protocol, if new 
information becomes available relating to risks, AEs, or toxicities, this information will be 
provided orally or in writing to all enrolled or prospective subject’s parent(s)/legal guardian(s). 


 
 
 
 
 
27 
Documentation will be provided to the IRB and, if necessary, the informed consent will be 
amended to reflect any relevant information. 
An investigator shall seek such consent only under circumstances that provide the subject’s 
parent(s)/legal guardian(s) sufficient opportunity to consider whether or not to participate and 
that minimize the possibility of coercion or undue influence. The information that is given to the 
subject’s parent(s)/legal guardian(s) shall be in language understandable to the subject’s 
parent(s)/legal guardian(s). 
Subject’s parent(s)/legal guardian(s) will sign the informed consent document prior to any 
procedures being done specifically for the study.  Subject’s parent(s)/legal guardian(s) should 
have the opportunity to discuss the study with their family, friends or personal physician, or think 
about it prior to agreeing to participate. Subject’s parent(s)/legal guardian(s) may withdraw 
consent at any time throughout the course of the trial.  A copy of the informed consent 
document will be given to the subject’s parent(s)/legal guardian(s) for their records.  The rights 
and welfare of the subjects will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study. 
14.3.1 Informed Consent/Assent Process (in Case of a Minor) 
If required by the site’s IRB, the parent or legal guardian will sign a waiver of assent for the 
minor due to the study participant’s age.  Assent age will be determined by the local IRB.  
Appropriate documentation will be required for subjects who are the age of assent, whether 
mature enough to read and capable of providing signed assent, or whether too young to read 
but capable of providing verbal assent, as determined by the local IRB in compliance with 
45CFR46.  Local IRBs will review and assign the risk level. 
14.4 Exclusion of Women, Minorities, and Children (Special 
Populations) 
This study will be conducted solely in infants.  The study will not exclude young children, 
females, or minorities. 
14.5 Subject Confidentiality 
The information obtained during the conduct of this clinical study is confidential, and disclosure 
to third parties other than those noted below is prohibited.  The results of the research study 
may be published, but study participant’s names or identities will not be revealed.  Records will 
remain confidential.  To maintain confidentiality, the principal investigators will keep records in 
locked cabinets or locked rooms and the results of tests will be coded to prevent association 
with volunteers’ names.  Data entered into computerized files will be accessible only by 
authorized personnel directly involved with the study and will be encoded.  
 


 
 
 
 
 
28 
The study investigator is obliged to provide complete test results and all data developed in this 
study.  The PI/study investigators may disclose this information to appropriate regulatory 
authorities or clinical practice management groups (such as Pediatric Infectious Disease 
Society) as deemed necessary.   
  
Subject-specific information may be provided to other appropriate medical personnel only with 
the study participant’s parent/legal guardian permission.  To ensure compliance with current 
ICH guidelines, data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, UAB personnel, and the IRB/IEC for the 
study site. 
14.6 Study Discontinuation 
Infants enrolled in the study will follow the standard of care guidelines for treatment of neonatal 
HSV disease, and upon completion of treatment with IV acyclovir, will be switched to 
valacyclovir for 2 days (and up to 7 days) prior to initiating oral acyclovir for suppressive therapy 
as per the standard of care. Therefore, if the study is discontinued, infants must follow the 
standard of care guidelines for both treatment and suppressive therapy of neonatal HSV 
disease.  
14.7 Future Use of Stored Specimens  
Remnant specimens will be held in case assays need to be repeated, and some of the 
specimens obtained from study participants during this study will be stored indefinitely in the 
UAB Central Laboratory at the University of Alabama at Birmingham and may be used in future 
virology research.  These specimens will be labeled with a code number and not with the study 
participant’s name.  At the time of consent for study participation, study participant’s parent/legal 
guardian will have the opportunity to either agree to have their specimens used in future virology 
research or decline to have their specimens used in future virology research. The study 
participant’s parent/legal guardian will indicate his/her preference by initialing the appropriate 
line or checking the appropriate box of the Consent Form in the section entitled, “Future Use of 
Specimens”.  Non-protocol designated, future testing of samples will be performed only on 
samples from study participants who have consented for future testing of samples.  Residual 
specimens from subject who decline future use will be destroyed after the study, final analysis 
and report writing is complete. 
A repository for residual samples will be established according to OHRP guidelines ensuring 
that codes or other personally identifying links will not be distributed to future researchers. 
The specimens will be stored indefinitely in the UAB Central Laboratory at the University of 
Alabama at Birmingham.  HSV specimens from study participants will be labeled and coded 
without study participant’s identifiers.  If the study participant’s parent/legal guardian has 
indicated in the signed consent form that he/she does not agree to allow the future use of 


 
 
 
 
 
29 
specimens for future virology research, then his/her child’s specimens will be destroyed at the 
completion of the study. 


 
 
 
 
 
30 
15 
DATA HANDLING AND RECORD KEEPING 
The investigator is responsible to ensure the accuracy, completeness, legibility, and timeliness 
of the data reported. 
Electronic case report forms (eCRFs) will be developed.  Original data will be recorded on 
source documents (e.g., medical records, research progress notes, Source Document 
Worksheets documenting research related procedures). Source Document Worksheets that 
mirror each data field on the eCRF will be available for use as a tool to record and maintain data 
for each study participant enrolled in the study when other source documents are not used to 
collect original data.  All source documents should be completed in a neat, legible manner to 
ensure accurate interpretation of data.  When making a change or correction, cross out the 
original entry with a single line and initial and date the change. Do not erase, overwrite, or use 
correction fluid or tape on the original.  
Data recorded on the eCRF that differ from source documents must be explained on the 
Comments eCRF and in the subject’s source documents. 
15.1 Data Management Responsibilities 
All eCRFS must be reviewed by the investigator’s research team, under the supervision of the 
investigator, who will ensure that they are accurate and complete.  All data must be supported 
by source documents, which will remain available for review by regulatory personnel and 
monitors.  Adverse events must be graded, assessed for intensity and causality, and reviewed 
by the site investigator or designee.      
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site PI.  During the study, the investigator must maintain complete and accurate 
documentation for the study. 
The PI with the help of the statisticians  will be responsible for analysis of the study data and 
writing of the clinical study report.   
15.2 Data Capture Methods 
Clinical and laboratory data will be entered into a 21 CRF Part 11 compliant electronic Data 
Entry System (eDES).  The data system includes password protection and internal quality 
checks, such as automated range checks, to identify data that appear to be inconsistent, 
incomplete, or inaccurate. Clinical data will be entered directly from the source documents. 


 
 
 
 
 
31 
15.3 Types of Data 
Data for this study will include clinical laboratory, pharmacokinetic, virologic results, and clinical 
and outcome measures (e.g., PK, weight, and virology). 
15.4 Timing/Reports 
There are no planned interim analyses or safety reviews for this trial.  
15.5 Study Records Retention 
Records and documents pertaining to the conduct of this study, including source documents, 
consent forms, laboratory test results, and medication inventory records, must be retained by 
the investigator for at least 2 years following completion of the study.  No study records shall be 
destroyed without prior authorization.  These documents should be retained for a longer period, 
however, if required by local regulations. 
15.6 Protocol Deviations 
Each investigator must adhere to the protocol as detailed in this document and agree that any 
changes to the protocol must be approved by the PI prior to seeking approval from the IRB/IEC.  
Each investigator will be responsible for enrolling only those study participants who have met 
protocol eligibility criteria. 
A protocol deviation is any noncompliance with the clinical trial protocol.  The noncompliance 
may be either on the part of the study participant, the investigator, or the study site staff.  As a 
result of deviations, corrective actions are to be developed by the site and implemented 
promptly.  
These practices are consistent with ICH E6 GCP sections: 
4.5 
Compliance with Protocol, Sections 4.5.1, 4.5.2, and 4.5.3 
5.1 
Quality Assurance and Quality Control, Section 5.1.1 
5.20 
Noncompliance, Sections 5.20.1 and 5.20.2. 
It is the responsibility of the site to use continuous vigilance to identify and report deviations 
within 1 business day of identification of the protocol deviation that increases subject risk.  
Deviations that do not increase subject risk can be reported within 5 business days of 
knowledge of the event.  All deviations must be promptly reported to the PI.  


 
 
 
 
 
32 
All deviations from the protocol must be addressed in the source documents. Protocol 
deviations must be sent to the local IRB per the IRB’s guidelines.  The site PI/study staff is 
responsible for knowing and adhering to their IRB/IEC requirements. 


 
 
 
 
 
33 
16 
PUBLICATION POLICY 
Following completion of this study, the investigators are expected to publish the results in a 
scientific journal.   
 
The International Committee of Medical Journal Editors (ICMJE) member journals have adopted 
a trials-registration policy as a condition for publication.  This policy requires that all clinical trials 
be registered in a public trials registry such as ClinicalTrials.gov, which is sponsored by the 
National Library of Medicine.  Other biomedical journals are considering adopting similar 
policies. 
Unless exempted, this trial will be registered prior to enrollment of study subjects.  It is the 
responsibility of the study’s PI (e.g., Dr. Samies) to register the non-exempted trials and post 
results in compliance with Public Law 110-85, the Food and Drug Administration Amendments 
Act of 2007 (FDAAA). 
 


 
 
 
 
 
34 
17 
LITERATURE REFERENCES 
1. 
Kimberlin D, Powell D, Gruber W, Diaz P, Arvin A, Kumar M, et al. Administration of oral 
acyclovir suppressive therapy after neonatal herpes simplex virus disease limited to the skin, 
eyes and mouth: results of a phase I/II trial. Pediatr Infect Dis J. 1996;15(3):247-54. 
2. 
Kimberlin DW, Baley J, Committee on Infectious D, Committee on F, Newborn. 
Guidance on management of asymptomatic neonates born to women with active genital herpes 
lesions. Pediatrics. 2013;131(2):383-6. 
3. 
Pinninti SG, Kimberlin DW. Neonatal herpes simplex virus infections. Pediatr Clin North 
Am. 2013;60(2):351-65. 
4. 
Mahant S, Hall M, Schondelmeyer AC, Berry JG, Kimberlin DW, Shah SS, et al. 
Neonatal Herpes Simplex Virus Infection Among Medicaid-Enrolled Children: 2009-2015. 
Pediatrics. 2019;143(4). 
5. 
Kimberlin DW, Lin CY, Jacobs RF, Powell DA, Frenkel LM, Gruber WC, et al. Natural 
history of neonatal herpes simplex virus infections in the acyclovir era. Pediatrics. 
2001;108(2):223-9. 
6. 
Kimberlin DW. Neonatal herpes simplex infection. Clin Microbiol Rev. 2004;17(1):1-13. 
7. 
Bodilsen J, Nielsen H, Whitley RJ. Valaciclovir therapy for herpes encephalitis: caution 
advised. J Antimicrob Chemother. 2019;74(6):1467-8. 
8. 
Cunha BA, Baron J. The pharmacokinetic basis of oral valacyclovir treatment of herpes 
simplex virus (HSV) or varicella zoster virus (VZV) meningitis, meningoencephalitis or 
encephalitis in adults. J Chemother. 2017;29(2):122-5. 
9. 
Tyring SK, Baker D, Snowden W. Valacyclovir for herpes simplex virus infection: long-
term safety and sustained efficacy after 20 years' experience with acyclovir. J Infect Dis. 
2002;186 Suppl 1:S40-6. 
10. 
Whitley RJ. Herpes simplex virus infection. Semin Pediatr Infect Dis. 2002;13(1):6-11. 
11. 
Whitley R, Arvin A, Prober C, Burchett S, Corey L, Powell D, et al. A controlled trial 
comparing vidarabine with acyclovir in neonatal herpes simplex virus infection. Infectious 
Diseases Collaborative Antiviral Study Group. N Engl J Med. 1991;324(7):444-9. 
12. 
Kimberlin DW, Lin CY, Jacobs RF, Powell DA, Corey L, Gruber WC, et al. Safety and 
efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus 
infections. Pediatrics. 2001;108(2):230-8. 
13. 
Diseases CoI, Pediatrics AAo. Red Book: 2018-2021 Report of the Committee on 
Infectious Diseases. 31st ed. Itasca, IL: American Academy of Pediatrics; 2018. 
14. 
James SH, Kimberlin DW. Neonatal herpes simplex virus infection: epidemiology and 
treatment. Clin Perinatol. 2015;42(1):47-59, viii. 
15. 
Kimberlin DW, Whitley RJ, Wan W, Powell DA, Storch G, Ahmed A, et al. Oral acyclovir 
suppression and neurodevelopment after neonatal herpes. N Engl J Med. 2011;365(14):1284-
92. 
16. 
Whitley RJ. The use of antiviral drugs during the neonatal period. Clin Perinatol. 
2012;39(1):69-81. 
17. 
Granero GE, Amidon GL. Stability of valacyclovir: implications for its oral bioavailability. 
Int J Pharm. 2006;317(1):14-8. 
18. 
Lycke J, Malmestrom C, Stahle L. Acyclovir levels in serum and cerebrospinal fluid after 
oral administration of valacyclovir. Antimicrob Agents Chemother. 2003;47(8):2438-41. 


 
 
 
 
 
35 
19. 
Bulletins ACoP. ACOG Practice Bulletin. Clinical management guidelines for 
obstetrician-gynecologists. No. 82 June 2007. Management of herpes in pregnancy. Obstet 
Gynecol. 2007;109(6):1489-98. 
20. 
Kimberlin DW, Jacobs RF, Weller S, van der Walt JS, Heitman CK, Man CY, et al. 
Pharmacokinetics and safety of extemporaneously compounded valacyclovir oral suspension in 
pediatric patients from 1 month through 11 years of age. Clin Infect Dis. 2010;50(2):221-8. 
21. 
Fish DN, Vidaurri VA, Deeter RG. Stability of valacyclovir hydrochloride in 
extemporaneously prepared oral liquids. Am J Health Syst Pharm. 1999;56(19):1957-60. 


 
 
 
 
 
 ____________________________________________________________________________________________ 
36 
SUPPLEMENTS/APPENDICES 
APPENDIX A: SCHEDULE OF EVENTS 
(FOLLOWING ACQUISITION OF INFORMED CONSENT) 
Blue font represents tests being obtained for clinical purposes 
Gray boxes represent infants being treated for CNS or disseminated disease (these infants receive 21 
days of therapy vs SEM disease patients who receive 14 days of therapy). No research labs will be 
obtained during this time. 
 
 
Treatment Day 
 
Period 1 
 
Period 2 
 
Period 3 
 
1 
2 
3 
4 
5 
6 
7 
8 - 14 
15 - 21 
Day 2 (up to 7) 
of valacyclovir 
Study Enrollmenta 
X 
 
 
Baseline demographicsb 
X 
 
 
Neonatal HSV disease 
Classificationc 
X 
 
 
Hematology labsd 
X 
X 
 
 
Chemistry labse 
X 
X 
 
 
Acyclovir 
pharmacokineticsf 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg 
Xh 
 
 
Valacyclovir 
pharmacokineticsi 
 
 
 
 
 
 
 
 
 
Xj 
IV acyclovir 
administration 
 
 
 
Oral valacyclovir 
administration every 8 
hours 
 
 
 
 
 
 
 
 
 
 
Total volume of blood 
required for study 
0.2
mL 
0.2
mL 
0.2
mL 
0.2
mL 
0.2
mL 
0.2
mL 
0.2
mL  
0.6 
mL 
 
0.6 mL 
 
a) Participants can enroll in the study on or before treatment day 14, and therefore, data collected for 
each infant will be dependent on date of enrollment.  
b) Gestational age at delivery, postmenstrual age at delivery, date of birth, day of life at initiation of IV 
acyclovir therapy, gender, race, ethnicity, birth weight, weight at enrollment, length in centimeters at 
enrollment, acyclovir dose and frequency 
c) Treating physician’s assessment of Skin-eye-mouth (SEM), central nervous system (CNS), or 
Disseminated neonatal HSV disease, based upon clinical assessments of skin lesions, skin viral 
studies, mucous membrane viral studies, CSF PCR, blood PCR, transaminitis, seizures, pneumonitis, 
coagulopathy, etc. 
d) WBC with differential, hemoglobin, platelet will be recorded if drawn for clinical purposes (any 
laboratory value obtained during the window will suffice, with an effort being made to capture the 
most abnormal value) 


 
 
 
 
 
 ____________________________________________________________________________________________ 
37 
e) All creatinine values will be recorded if drawn for clinical purposes. Any alanine aminotransferase 
(ALT) value obtained during the window will suffice, with an effort being made to capture the most 
abnormal value) 
f) 
A minimum of 200 L (0.2 mL) of whole blood is required for plasma PK analyses for acyclovir 
g) A single plasma sample for PK determination will be obtained at each visit marked on the Schedule of 
Events. These samples will be obtained at random time intervals, but only at the time that a clinical 
blood draw is being performed, or through the indwelling intravenous catheter, so that no additional 
venipuncture solely for study purposes will be required; most recent weight, acyclovir dose received 
(date, time, and mg dose), and serum creatinine value will be recorded. 
h) Acyclovir concentrations will be obtained with one of the Study Assessment Doses between dose 22 
and 42 (Study Day 8 through Study Day 14) at the following time points: 0h (within 30 minutes prior to 
the start of acyclovir infusion), within 15 minutes after completion of the infusion, and 3-4 hours after 
infusion. 
i) 
A minimum of 200 L (0.2 mL) of whole blood is required for plasma PK analyses for acyclovir 
j) 
Acyclovir concentrations will be obtained with one of the valacyclovir Study Assessment Doses (after 
dose 3 of valacyclovir) at the following time points: 0 hr (8 hours after previous dose), 1-2 hours after 
dose, and 3-5 hours after dose.