A Phase I Adaptive, Multiple Dose Pharmacokinetic and Safety Assessment of Valacyclovir in Infants at Risk of Acquiring Neonatal Herpes Simplex Virus Disease
Phase: PHASE1
Conditions: Herpes Simplex
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Protocol 20-0033 
Version 4.0 
Neonatal Phase 1 Valacyclovir Study 
05 March 2024 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 1 of 56 
A PHASE 1 ADAPTIVE, MULTIPLE DOSE PHARMACOKINETIC AND SAFETY 
ASSESSMENT OF VALACYCLOVIR IN INFANTS AT RISK OF ACQUIRING 
NEONATAL HERPES SIMPLEX VIRUS DISEASE 
DMID Protocol Number: 20-0033 
IND Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) Division of 
Microbiology and Infectious Diseases (DMID), and  
National Center for Advancing Translational Sciences 
Congenital and Perinatal Infections Consortium 
Principal Investigator:  David W. Kimberlin, MD 
Version Number:  4.0 
05 March 2024 
NIH Funding Mechanism:  1U54AI150225-01 

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STATEMENT OF COMPLIANCE 
Each institution engaged in this research will hold a current Federalwide Assurance (FWA) 
issued by the Office of Human Research Protection (OHRP) for federally funded research. The 
Institutional Review Board (IRB) or Independent/Institutional Ethics Committee (IEC) must be 
registered with OHRP as applicable to the research.   
 
The study will be carried out in accordance with the following as applicable: 
• United States Code of Federal Regulations (CFR) 45 CFR Part 46: Protection of Human 
Subjects 
• U.S. Food and Drug Administration (FDA) Regulations: 21 CFR Part 50 (Protection of 
Human Subjects), 21 CFR Part 54 (Financial Disclosure by Clinical Investigators), 21 
CFR Part 56 (Institutional Review Boards), 21 CFR Part 11, and 21 CFR Part 312 
(Investigational New Drug Application), and/or 21 CFR 812 (Investigational Device 
Exemptions) 
• The International Council for Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use (ICH) E6(R2) Good Clinical Practice, and the 
Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects 
of Research, Report of the National Commission for the Protection of Human Subjects of 
Biomedical and Behavioral Research 
• The policies and procedures of National Institutes of Health (NIH) Office of Extramural 
Research and DMID 
• The National Institute of Allergy and Infectious Diseases (NIAID) Terms of Award 
• All national and Local Regulations and Guidance applicable at each site 
 
The signature below provides the necessary assurance that this study will be conducted 
according to all stipulations of the protocol including statements regarding confidentiality, and 
according to local legal and regulatory requirements, US federal regulations, and ICH E6(R2) 
Good Clinical Practice (GCP) guidelines. 
 
Site Investigator Signature: 
 
 
Signed: 
 
Date: 
 
 
 
______________________________________________ 
Name 
______________________________________________ 
Title 
 
 
 
 
 

Protocol 20-0033 
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TABLE OF CONTENTS 
1. 
PROTOCOL SUMMARY ...................................................................................................... 7 
1.1 
Synopsis .......................................................................................................................... 7 
1.2 
Schedule of Activities (SoA) ........................................................................................ 12 
2. 
INTRODUCTION ................................................................................................................ 13 
2.1 
Study Rationale ............................................................................................................. 13 
2.2 
Background ................................................................................................................... 14 
2.2.1 
Purpose of Study ................................................................................................... 14 
2.3 
Risk/Benefit Assessment .............................................................................................. 17 
2.3.1 
Known Potential Risks .......................................................................................... 17 
2.3.2 
Known Potential Benefits ..................................................................................... 18 
2.3.3 
Assessment of Potential Risks and Benefits ......................................................... 18 
3. 
OBJECTIVES AND ENDPOINTS ...................................................................................... 19 
4. 
STUDY DESIGN.................................................................................................................. 19 
4.1 
Overall Design .............................................................................................................. 19 
4.2 
Justification for Dose .................................................................................................... 21 
5. 
STUDY POPULATION ....................................................................................................... 22 
5.1 
Inclusion Criteria .......................................................................................................... 22 
5.2 
Exclusion Criteria ......................................................................................................... 22 
5.2.1 
Exclusion of Specific Populations ........................................................................ 22 
5.3 
Inclusion of Vulnerable Participants ............................................................................. 22 
5.4 
Lifestyle Considerations ............................................................................................... 22 
5.5 
Screen Failures .............................................................................................................. 23 
5.6 
Strategies for Recruitment and Retention ..................................................................... 23 
5.6.1 
Recruitment ........................................................................................................... 23 
5.6.2 
Retention ............................................................................................................... 23 
5.6.3 
Compensation Plan for Subjects ........................................................................... 23 
5.6.4 
Costs ...................................................................................................................... 23 
6. 
STUDY PRODUCT.............................................................................................................. 23 
6.1 
Study Product(s) and Administration............................................................................ 23 
6.1.1 
Study Product Description .................................................................................... 23 
6.1.2 
Dosing and Administration ................................................................................... 24 
6.1.3 
Dose Escalation ..................................................................................................... 24 
6.1.4 
Dose Modifications ............................................................................................... 25 
6.2 
Preparation/Handling/Storage/Accountability .............................................................. 25 
6.2.1 
Acquisition and Accountability ............................................................................ 25 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ............................................ 25 
6.2.3 
Product Storage and Stability................................................................................ 26 
6.2.4 
Preparation ............................................................................................................ 26 
6.3 
Measures to Minimize Bias: Randomization and Blinding .......................................... 26 

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6.3.1 
Treatment Assignment Procedures ....................................................................... 26 
6.3.2 
Randomization and Blinding ................................................................................ 26 
6.3.3 
Blinding and Masking Procedures ........................................................................ 26 
6.4 
Study Intervention Compliance .................................................................................... 26 
6.5 
Concomitant Therapy.................................................................................................... 27 
6.5.1 
Rescue Medicine ................................................................................................... 27 
7. 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL..................................................................................... 27 
7.1 
Halting Criteria and Discontinuation of Study Intervention ......................................... 27 
7.1.1 
Study Halting Criteria ........................................................................................... 27 
7.1.2 
Individual Halting Criteria .................................................................................... 27 
7.1.3 
Criteria for Continuation of Dosing and Redosing ............................................... 27 
7.1.4 
Follow up for subjects that discontinue study intervention .................................. 28 
7.2 
Participant Withdrawal from the Study and Replacement ............................................ 28 
7.3 
Lost to Follow-Up ......................................................................................................... 28 
8. 
STUDY ASSESSMENTS AND PROCEDURES ................................................................ 28 
8.1 
Screening Procedures .................................................................................................... 28 
8.2 
Efficacy / Immunogenicity Assessments ...................................................................... 28 
8.2.1 
Efficacy / Immunogenicity Evaluations................................................................ 29 
8.3 
Safety and Other Assessments ...................................................................................... 29 
8.3.1 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings .................................................................................................. 30 
8.4 
Adverse Events and Serious Adverse Events ............................................................... 30 
8.4.1 
Definition of Adverse Events (AE)....................................................................... 30 
8.4.1.1 
Solicited Adverse Events .................................................................................. 31 
8.4.1.2 
Unsolicited Events ............................................................................................ 31 
8.4.1.3 
Special Reporting of Adverse Events ............................................................... 31 
8.4.2 
Definition of Serious Adverse Events................................................................... 31 
8.4.2.1 
Suspected Unexpected Serious Adverse Reactions (SUSAR) .......................... 33 
8.4.3 
Classification of an Adverse Event ....................................................................... 33 
8.4.3.1 
Severity of Event............................................................................................... 33 
8.4.3.2 
Relationship to Study Intervention ................................................................... 34 
8.4.4 
Time Period and Frequency for Event Assessment and Follow-Up ..................... 34 
8.4.5 
Adverse Event Reporting ...................................................................................... 34 
8.4.5.1 
Investigators Reporting of AEs ......................................................................... 34 
8.4.6 
Serious Adverse Event Reporting ......................................................................... 34 
8.4.6.1 
Investigators Reporting of SAEs ...................................................................... 34 
8.4.6.2 
Regulatory Reporting of SAEs ......................................................................... 35 
8.4.7 
Reporting Events to Participants ........................................................................... 35 
8.4.8 
Adverse Events of Special Interest ....................................................................... 35 
8.4.9 
Reporting of Pregnancy ........................................................................................ 35 
8.5 
Unanticipated Problems ................................................................................................ 36 
8.5.1 
Definition of Unanticipated Problems (UP) ......................................................... 36 

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8.5.2 
Unanticipated Problem Reporting......................................................................... 36 
8.5.3 
Reporting Unanticipated Problems to Participants ............................................... 36 
9. 
STATISTICAL CONSIDERATIONS.................................................................................. 36 
9.1 
Statistical Hypotheses ................................................................................................... 36 
9.2 
Sample Size Determination........................................................................................... 36 
9.3 
Populations for Analyses .............................................................................................. 37 
9.4 
Statistical Analyses ....................................................................................................... 37 
9.4.1 
General Approach ................................................................................................. 38 
9.4.2 
Analysis of the Primary Endpoint(s)..................................................................... 38 
9.4.3 
Analysis of the Secondary Endpoint(s)................................................................. 39 
9.4.4 
Safety Analyses ..................................................................................................... 39 
9.4.5 
Baseline Descriptive Statistics .............................................................................. 39 
9.4.6 
Planned Interim and Early Analyses ..................................................................... 40 
9.4.6.1 
Interim Safety Analyses .................................................................................... 40 
9.4.6.2 
Interim Immunogenicity or Efficacy Review ................................................... 40 
9.4.7 
Sub-Group Analyses ............................................................................................. 40 
9.4.8 
Tabulation of Individual Participant Data............................................................. 40 
9.4.9 
Exploratory Analyses ............................................................................................ 40 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ... 41 
10.1 
Regulatory, Ethical, and Study Oversight Considerations............................................ 41 
10.1.1 
Informed Consent Process .................................................................................... 41 
10.1.1.1 
Requirements for Permission by Parents/Guardians and Assent by Children 
(in case of a minor) ........................................................................................................... 42 
10.1.1.2 
Other Informed Consent Procedures ............................................................. 42 
10.1.2 
Study Termination and Closure ............................................................................ 42 
10.1.3 
Confidentiality and Privacy .................................................................................. 43 
10.1.4 
Secondary Use of Stored Specimens and Data ..................................................... 43 
10.1.4.1 
Samples for Secondary Research .................................................................. 43 
10.1.4.2 
Data Sharing for Secondary Research .......................................................... 44 
10.1.5 
Key Roles and Study Governance ........................................................................ 44 
10.1.6 
Safety Oversight.................................................................................................... 44 
10.1.7 
Clinical Monitoring ............................................................................................... 45 
10.1.8 
Quality Assurance and Quality Control ................................................................ 46 
10.1.9 
Data Handling and Record Keeping ..................................................................... 46 
10.1.9.1 
Data Collection and Management Responsibilities ...................................... 46 
10.1.9.2 
Study Record Retention ................................................................................ 47 
10.1.9.3 
Source Records ............................................................................................. 47 
10.1.10 Protocol Deviations ............................................................................................... 47 
10.1.11 Publication and Data Sharing Policy .................................................................... 48 
10.1.12 Human Data Sharing Plan ..................................................................................... 48 
10.1.13 Genomic Data Sharing Plan .................................................................................. 48 
10.1.14 Publication ............................................................................................................ 48 
10.1.15 Conflict of Interest Policy ..................................................................................... 48 

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10.2 
Additional Considerations ............................................................................................ 49 
10.2.1 
Research Related Injuries ..................................................................................... 49 
10.3 
Abbreviations ................................................................................................................ 49 
10.4 
Protocol Amendment History ....................................................................................... 51 
11. 
REFERENCES ................................................................................................................. 52 
12. 
APPENDIX A: (ADAPTED FROM) DIVISION OF AIDS TOXICITY TABLES ........ 55 
 
  
 
LIST OF TABLES 
 
Table 1. Schedule of Activities ..................................................................................................... 12 
Table 2. Objectives and Endpoints ............................................................................................... 19 
Table 3. Dosing and Administration ............................................................................................. 24 
Table 4. Protocol Toxicity Table .................................................................................................. 33 
Table 5. Sample Size Determination ............................................................................................ 37 
Table 6. Abbreviations .................................................................................................................. 49 
Table 7. Protocol Amendment History ......................................................................................... 51 
 
 
 

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1. 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Rationale for Proposed Clinical Study 
Herpes simplex virus (HSV) is a rare cause of disease in neonates, but when it occurs, the 
sequelae frequently are devastating.  Neonatal HSV cases are classified as disease localized to 
the skin, eyes, and/or mouth (SEM disease), central nervous system disease (CNS disease), or 
disseminated infection involving multiple organs (disseminated disease).  Neonates with 
disseminated or SEM disease generally present to medical attention at 10-12 days of life, while 
those with CNS disease on average present somewhat later at 16-19 days of life (1).  
Approximately 30% of neonates with disseminated neonatal HSV disease die despite 21 days of 
parenteral antiviral therapy with acyclovir followed by 6 months of oral acyclovir suppression, 
and approximately 20% of surviving babies will have lifelong neurodevelopmental sequelae (2, 
3).  For babies with the CNS classification of neonatal HSV disease receiving the same 
parenteral and suppressive therapy, approximately 5% will die but one-third of survivors will 
have neurodevelopmental sequelae (2, 3).   
 
Approximately 85% of neonatal HSV cases acquire the infection in the peripartum period, as 
they pass through an infected birth canal (4).  Maternal shedding of virus in the genital tract can 
be symptomatic (visible lesions) or asymptomatic (no visible evidence of HSV infection), and 
either can result in peripartum transmission.  Women with active lesions at the time of labor are 
delivered by cesarean section (5), and their neonates are managed with preemptive testing and 
possibly antiviral therapy (6).  However, women with a history of genital HSV but no lesions at 
delivery have no specific management requirements, and the standard of care for management of 
their neonates is to educate the parents on manifestations of neonatal HSV disease, to not test the 
babies for the virus, and to not provide antiviral therapy until evidence of disease manifests (6). 
 
Detection of asymptomatic maternal shedding of HSV at delivery could allow for preemptive 
antiviral treatment of the exposed neonate, thereby blocking perinatal exposure from progressing 
to neonatal infection and disease.  To accomplish this, a reliable and rapid means of detecting 
vaginal shedding at delivery is required, and an appropriate antiviral treatment for the at-risk-but-
not-yet-sick neonate must be characterized.  The former has been accomplished in a recently 
completed study of a novel point-of-care polymerase chain reaction (PCR) assay for the 
detection of HSV DNA in vaginal swabs of pregnant women at delivery 
(BAA#HHSN272201100034C; DMID Protocol Number 11-0070; ClinicalTrials.gov Identifier 
NCT01878383).  The purpose of the current study is to address the second part of what is needed 
by determining the dose of oral valacyclovir that produces reliable acyclovir exposure in 
neonates. 
 
Assessment of Potential Risks and Benefits 
Valacyclovir is the prodrug of acyclovir and is a marketed antiviral medication with a well-
established safety profile.  In young infants, the primary toxicities of parenteral acyclovir are: 1) 
neutropenia, which is reversible with cessation of the drug; and 2) creatinine elevation from 
crystal formation in the collecting tubules of the kidneys (7).  Neither of these complications 
have been seen in studies of oral valacyclovir in infants and children one month of age and older 

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(8).  In order to minimize the likelihood of neutropenia or elevated creatinine in the study 
population, the starting valacyclovir dose regimen in this study will be 10 mg/kg/dose 
administered two time per day, which is one-third of the FDA-approved dose for children 2 years 
of age and older of 20 mg/kg/dose administered three times per day.  Each subject will be 
carefully monitored for bone marrow toxicity (e.g., neutropenia) and nephrotoxicity (e.g., 
elevated creatinine), and the drug will be stopped if significant toxicities are encountered in a 
given subject. 
 
There are no alternative therapies used in neonates potentially exposed to HSV at delivery 
(because they are born to women with a history of genital HSV and therefore who could be 
shedding virus in their genital tract) but without known exposure (no active maternal lesions at 
delivery).  Standard of care at the current time in these potential exposures is simply to follow 
the baby clinically to see if they develop disease.  Therefore, participating in this study will not 
deprive the subjects of any established therapy, and potentially could provide the benefit of 
preemptive valacyclovir treatment if perinatal exposure had occurred. 
 
Study Design 
This is 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.  The mothers can have no visible evidence of HSV lesions at the time of 
delivery, and the neonates will have no signs or symptoms of neonatal HSV disease.  Neonates 
born to women with active herpetic lesions will be excluded from the study because their 
management is determined by the American Academy of Pediatrics algorithm published in 2013 
(10) and in the 2015, 2018, and 2021 Red Books (6, 11, 12).  Likewise, any baby with signs or 
symptoms suggestive of neonatal HSV disease will be excluded from this study and instead 
managed per standard of care. 
 
The starting dose regimen of oral valacyclovir assessed will be 10 mg/kg administered two times 
daily for 5 days (Cohort 1).  This dosage has been studied in patients 1 year through 11 years of 
age, who received twice-daily dosing for 3-5 days, while a single dose of 25 mg/kg has been 
studied down to 1 month of age (8).  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.  Study Day 1 is the day that 
the first dose of oral valacyclovir is administered.  Following signing of informed consent but 
prior to administration of the first dose of valacyclovir, hematology and chemistry safety labs 
(white blood cell count and differential for absolute neutrophil count, hemoglobin, platelet count, 
alanine aminotransferase, and creatinine) will be obtained and values checked; if no baseline 
hematology or chemistry values are Grade 1 toxicity or higher then dosing of valacyclovir will 
proceed; if any value is Grade 1 toxicity or higher, the subject will be withdrawn from the study 

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prior to receiving any doses of study medication.  In addition, the subject must have had a first 
void before receiving a first dose of study medication.  A single plasma sample will also be 
obtained for a baseline acyclovir concentration, since the mothers of enrolled subjects will have 
been taking antiviral medication prior to delivery.  Dropouts and withdrawn subjects may be 
replaced to reach the target sample size of eight subjects.  Subjects will return to the study site on 
Study Day 5 (window: Study Day 4 through Study Day 5), and also will be assessed for adverse 
events and concomitant medications on Study Day 10 (window: Study Day 7 through Study Day 
13) and on Study Day 42 (window: Study Day 35 through Study Day 49), although the Study 
Day 10 and 42 assessments may occur via either telephone or in-person study visits.  On the 
Study Day 5 (window: Study Day 4 through Study Day 5) visit, plasma samples for PK 
assessments will be obtained around dose 7, 8, 9, or 10 of study drug at 0 hour minus 15 minutes 
(pre-dose), and then 1-2 hours, 4-6 hours, and 8-10 hours following administration of the 
valacyclovir dose (full PK profile).  Safety laboratory assessments (white blood cell count with 
differential, hemoglobin, platelet count, alanine aminotransferase, and creatinine) will be 
obtained at the Study Day 1 (baseline) and Study Day 5 visits.  Safety laboratory values will be 
classified using the Division of AIDS Toxicity Tables (Appendix A).  Study drug will be stopped 
following the obtaining of the PK samples on Study Day 5 (window: Study Day 4 through Study 
Day 5).  Criteria for AEs or SAEs leading to halting of the study are detailed in Section 7.1.1. 
 
Upon full accrual of Cohort 1, the PK and safety data will be reviewed.  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.  Specifically, the target range of acyclovir exposure 
following dosing with oral valacyclovir study drug is from 24,000 ngxhr/mL to 48,000 ngxhr/mL.  
If the mean of observed acyclovir exposures of subjects in Cohort 1 are below 24,000 ngxhr/mL, 
AND if no Grade 3 or Grade 4 AEs or SAEs are detected in any of the study subjects, then the 8 
subjects enrolled in Cohort 2 will receive oral valacyclovir at a dose of 20 mg/kg administered 
two times daily for 5 days.  Alternatively, if the mean of observed acyclovir exposures of 
subjects in Cohort 1 are above 48,000 ngxhr/mL AND if no Grade 3 or Grade 4 AEs or SAEs are 
detected in any of the study subjects, then the 8 subjects enrolled in Cohort 2 will receive oral 
valacyclovir at a dose that has been linearly adjusted downward to target 36,000 ngxh/mL area-
under-the-concentration-time curve from 0 to 12 hours (AUC12).  The study schedule for subjects 
in Cohort 2 will be identical to those in Cohort 1, as described above and in the Schedule of 
Activities table (see Section 1.2).  If the mean of observed acyclovir exposures of subjects in 
Cohort 1 are within the target range of 24,000 ngxhr/mL to 48,000 ngxhr/mL, Cohort 2 will not 
be opened for enrollment unless suggested by the Safety Monitoring Committee (SMC) (see 
Section 9.4.6). 
 
If the targeted exposure is not achieved in Cohorts 1 and 2 and the safety data are acceptable, it is 
possible that additional dosing cohorts could be recommended based upon the results of subjects 
in the first two cohorts.  If such a recommendation is made, dose selection and subject enrollment 
and assessment will follow the approach used for Cohort 2. 
 
 
 

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Study Objectives  
• Primary 
o  To establish the dose of valacyclovir in neonates that reliably achieves systemic 
acyclovir exposures comparable to 10 mg/kg of parenterally administered acyclovir  
 
• Secondary 
o To define the pharmacokinetic profile of acyclovir in neonates receiving oral valacyclovir 
o To assess and describe the safety profile of valacyclovir among treated neonates 
 
Study Endpoints 
• Primary 
o Neonatal plasma acyclovir mean AUC12 concentrations between 24,000 ngxhr/mL and 
48,000 ngxhr/mL 
 
• Secondary 
o Plasma acyclovir PK parameters including maximum plasma concentration (Cmax), time 
to the maximum concentration (Tmax), half-life (t½), oral clearance (CL/F), and volume of 
distribution (V/F) 
o Grade 3 Adverse Events (AEs) 
o Grade 4 Adverse Events and Serious Adverse Events 
 
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 
 
Study Phase (if applicable) 
Phase 1 
 

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Study Population 
Male and female neonates without signs or symptoms of neonatal herpes simplex virus (HSV) 
disease and ≤ 2 days of age, and born to women who received anti-herpesviral suppressive 
therapy due to a history of genital HSV infection will be enrolled.  The study plans to enroll a 
total of 16 neonatal subjects in 2 cohorts, with 8 subjects per cohort.  Decision of enrolling 
Cohort 2 will depend on the safety and PK results of Cohort 1. 
 
Sites 
Approximately 10 sites in the United States 
 
Study Intervention: 
Study Product Description 
Valacyclovir (Valtrex) hydrochloride is a white to off-white powder (from tablets) of the  
hydrochloride salt of the L-valyl ester of acyclovir with the molecular formula C13H20N6O4•HCl 
and a molecular weight of 360.80.  Each 500 mg tablet (blue, film-coated, capsule-shaped 
tablets) contains valacyclovir hydrochloride equivalent to 500 mg  valacyclovir and the inactive 
ingredients carnauba wax, colloidal silicon dioxide, crospovidone, FD&C Blue No. 2 Lake, 
hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 
80, povidone, and titanium dioxide.  SyrPalta has been studied as a vehicle for extemporaneously 
prepared valacyclovir (13), and will be used as the oral liquid vehicle to create the valacyclovir 
formulation for subjects in this study.  SyrPalta contains sucrose 83% w/v; Purified Water; 
Glycerin; Artificial Flavors; 0.2% Alcohol; 0.1% Sodium Benzoate; 0.001% Benzalkonium 
Chloride as a Preservative.  It is the recommended oral liquid vehicle for valacyclovir suspension 
from the extemporaneous compounding references supported by the FDA Safe Use Initiative: the 
Michigan Pediatric Safety Collaboration (https://www.mipedscompounds.org/), and the 
American Society of Health System Pharmacists (ASHP) Standardize 4 Safety Initiative 
(https://www.ashp.org/-/media/assets/pharmacy-practice/s4s/docs/Compound-Oral-Liquid.ashx).  
The shelf life following preparation is 28 days.  Study product will be administered by the 
parent/guardian if subjects are at home, or by the hospital staff if subjects are in the hospital.  
Study Cohort 1 will receive valacyclovir at a dose of 10 mg/kg body weight administered two 
times daily for 5 days, while the dose evaluated in Cohort 2 will be  predicated upon the 
exposure levels of subjects enrolled in Cohort 1.  Specific dosing volumes will be provided for 
each subject based on body weight and valacyclovir oral suspension concentration.  Valacyclovir 
Oral Suspension will be administered into the subject’s mouth via an oral dosing syringe.  The 
parent/guardian will be provided with specific dosing, storage, and administration instructions.  
If the subject vomits or spits up following the dosing, re-dosing for that dose is not allowed. 
 
Study Duration 
The estimated timeframe from study activation to the last subject’s last study day (defined as the 
time point the final subject will be contacted by the study site) is 18 months. 
 
Participant Duration 
42 days 
 
 

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Safety 
The trial will be overseen by a Safety Monitoring Committee (SMC).  
 
1.2 
Schedule of Activities (SoA) 
The study procedures and evaluations are summarized below in the Schedule of Activities table.  
 
Table 1. Schedule of Activities 
 
Study Day (window) 
 
1 
5 (- 1 day) 
10 (± 3 days) 
42 (± 7 days) 
Informed consent 
X 
 
 
 
Baseline 
demographicsa 
X 
 
 
 
Hematology safety 
labsb 
X 
X 
 
 
Chemistry safety 
labsc 
X 
X 
 
 
Adverse Event 
assessment 
Xd 
X 
Xe 
Xe 
Concomitant 
medications 
X 
X 
Xe 
Xe 
Oral valacyclovir 
administration 
BIDf,g 
 
 
 
PK assessmenth 
Xi 
Xj 
 
 
Total volume of 
blood required for 
study 
1.7 mL 
2.3 mL 
0.0 mL 
0.0 mL 
a) Gestational age at delivery, date of birth, gender, race, ethnicity, birth weight, weight at 
enrollment, length in centimeters at enrollment, and baseline conditions prior to study 
enrollment, by body system. 
b) WBC with differential, Hemoglobin, Platelets (approximate total blood needed for these tests 
is 0.5 mL). 
c) Alanine aminotransferase (ALT) and creatinine (approximate total blood needed for these 
tests is 1.0 mL). 
d) Adverse events that occur following the first dose of study medication. 
e) This assessment may occur via telephone or an in-person study visit. 
f) Oral valacyclovir will be administered as 10 mg/kg/dose two times per day (Cohort 1) or as 
20 mg/kg/dose two times per day (or an adjusted dose, as detailed above in Study Design) 
(Cohort 2).  Hematology and chemistry safety labs will be confirmed to have no ≥ Grade 1 
values utilizing the DAIDS Toxicity Tables (Appendix A) prior to the first oral dose of 
valacyclovir being administered on Study Day 1; if any value is Grade 1 toxicity or higher, 
the subject will be withdrawn from the study and will not receive study medication.  In 
addition, the subject must have had a first void before receiving a first dose of study 

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medication.  Total number of study days of study drug administration will be 4 or 5 
(depending on where in the window the Study Day 5 visit is conducted), although the total 
number of doses can be 7, 8, 9, or 10 depending upon when the study drug was started on 
Study Day 1 and whether the PK blood draws on Study Day 5 (window: Study Day 4 
through Study Day 5) are around the first or second dose that day.  Study drug will be 
stopped following the obtaining of the PK samples on Study Day 5 (window: Study Day 4 
through Study Day 5). 
g) Assessment of compliance with administration of study medication throughout the 5-day 
treatment period will be achieved by utilization of a medication diary.  The parent(s) or legal 
guardian(s) will complete this diary daily, indicating the time of drug administration and 
whether the subject vomited following the dose.  The diary will be collected at the Study Day 
5 visit. 
h) A minimum of 200 µL (0.2 mL) of whole blood is required for collection at each time point 
for plasma acyclovir concentration determination. 
i) A single 0.2 mL whole blood sample for PK assessment will be obtained from study subjects 
with the Study Day 1 hematology and chemistry safety labs. 
j) Plasma samples for PK assessments will be obtained from study subjects around dose 7, 8, 9, 
or 10 of study drug at 0 hour -15 minutes (pre-dose), and then 1-2 hours, 4-6 hours, and 8-10 
hours following administration of the dose.  This will be a total blood volume of 0.8 ml if all 
four PK time points are collected. 
 
2. 
INTRODUCTION 
2.1 
Study Rationale 
Approximately 85% of neonatal HSV cases acquire the infection in the peripartum period, as 
they pass through an infected birth canal (4).  Maternal shedding of virus in the genital tract can 
be symptomatic (visible lesions) or asymptomatic (no visible evidence of HSV infection), and 
either can result in peripartum transmission.  Women with active lesions at the time of labor are 
delivered by cesarean section (5), and their neonates are managed with preemptive testing and 
possibly antiviral therapy (6).  However, women with a history of genital HSV but no lesions at 
delivery have no specific management requirements, and the standard of care for management of 
their neonates is to educate the parents on manifestations of neonatal HSV disease, to not test the 
babies for the virus, and to not provide antiviral therapy until evidence of disease manifests (6). 
 
Detection of asymptomatic maternal shedding of HSV at delivery could allow for preemptive 
antiviral treatment of the exposed neonate, thereby blocking perinatal exposure from progressing 
to neonatal infection and disease.  To accomplish this, a reliable and rapid means of detecting 
vaginal shedding at delivery is required, and an appropriate antiviral treatment for the at-risk-but-
not-yet-sick neonate must be characterized.  The former has been accomplished in a recently 
completed study of a novel point-of-care polymerase chain reaction (PCR) assay for the 
detection of HSV DNA in vaginal swabs of pregnant women at delivery 
(BAA#HHSN272201100034C; DMID Protocol Number 11-0070; ClinicalTrials.gov Identifier 
NCT01878383).  The purpose of the current study is to address the second part of what is needed 

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by determining the dose of oral valacyclovir that produces reliable acyclovir exposure in 
neonates. 
 
Since the early 1980s, parenteral acyclovir has been the antiviral therapy for neonatal HSV 
disease (2, 14).  While appropriate for the treatment of neonates who already have HSV disease, 
parenteral acyclovir would not be ideal as preemptive therapy in an exposed neonate because of 
the risks associated with intravenous access at this very young age.  The prodrug valacyclovir is 
the L-valyl ester of acyclovir that is rapidly converted to acyclovir after oral administration by 
first-pass metabolism in the liver (15).  Its mechanism of action is the same as that of its parent 
drug, acyclovir.  While only 15% to 30% of the oral formulation of acyclovir is absorbed, the 
bioavailability of valacyclovir in adults exceeds 50% (16).  After oral administration of 
valacyclovir, though, rapid and complete conversion to acyclovir occurs with first-pass intestinal 
and hepatic metabolism.  Peak serum concentrations, attained about 1.5 hours after a dose has 
been given, are proportional to the amount of drug administered; they range from 0.8 to 8.5 
μg/mL for doses of 100 to 2000 mg (17).  The area-under-the-concentration-time curve (AUC) 
approximates that seen after IV acyclovir.  All other PK characteristics of oral valacyclovir are 
similar to those of IV acyclovir.  
 
Valacyclovir oral suspension has been evaluated in GlaxoSmithKline-sponsored studies in 
children 1 month to 12 years of age (8).  Bioavailability was estimated to be 45% to 51% in all 
age groups except those 3 months through 5 months of age, in whom the bioavailability is lower 
at 22%.  Approximate dose proportionality in Cmax and AUC was seen across the 10 mg/kg to 25 
mg/kg dose range (i.e., dose normalized differences generally within ≤ ~30%) with the exception 
of children 2 years through 5 years of age, for whom a near doubling in Cmax and AUC was noted 
with only a modest increase in dose from 20 to 25 mg/kg (8).  Valacyclovir has not been studied 
in neonates (infants under 1 month of age).  In the U.S., valacyclovir is licensed for the treatment 
of pediatric patients with orolabial HSV recurrences (12 years and older) and chickenpox (2 
years through 17 years of age).  Pediatric valacyclovir dosing is 20 mg/kg per dose (dose not to 
exceed 1 gram) administered either three times a day (for VZV) or twice a day (for HSV) (8, 18).  
Valacyclovir has demonstrated an excellent safety profile over the 20 years since its initial 
approval in the U.S. 
 
2.2 
Background 
2.2.1 
Purpose of Study 
Background of Neonatal Herpes Simplex Virus Disease 
Herpes simplex virus (HSV) is a rare cause of disease in neonates, but when it occurs the 
sequelae frequently are devastating.  We recently documented that neonatal HSV disease 
incidence was approximately 1 in 3,000 deliveries in 2000, but by 2012 had increased by almost 
60% to 1 in 1,900 live births (19).  With an annual national birth cohort of 3.8 million, this 
equates to 2,000 babies delivered each year who develop neonatal HSV disease.  Neonatal HSV 
cases are classified as disease localized to the skin, eyes, and/or mouth (SEM disease), central 
nervous system disease (CNS disease), or disseminated infection involving multiple organs 
(disseminated disease).  Neonates with disseminated or SEM disease generally present to 

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medical attention at 10-12 days of life, while those with CNS disease on average present 
somewhat later at 16-19 days of life (1).  Approximately 30% of neonates with disseminated 
neonatal HSV disease die despite 21 days of parenteral antiviral therapy with acyclovir followed 
by 6 months of oral acyclovir suppression, and approximately 20% of surviving babies will have 
lifelong neurodevelopmental sequelae (2, 3).  For babies with the CNS classification of neonatal 
HSV disease receiving the same parenteral and suppressive therapy, approximately 5% will die 
but one-third of survivors will have neurodevelopmental sequelae (2, 3).   
 
Timing of Transmission from Mother to Neonate 
The overwhelming majority (85%) of babies with neonatal HSV disease acquire the virus from 
their mothers during the birth process (4).  The mothers of these babies are usually 
asymptomatically shedding HSV in their genital tract (20-22).  Neonates acquiring the virus then 
present with signs and symptoms of disease at 10 to 19 days of life, as discussed above.  While 
maternal antiviral suppression with oral valacyclovir, the prodrug of acyclovir, is routinely 
provided near the end of pregnancy to women with a history of genital herpes (9, 23-26), it is 
ineffective in completely suppressing viral shedding at delivery (25-28) and babies born to 
women on antiviral suppression can still develop neonatal HSV disease (29). 
 
Definitions Related to HSV Acquisition by Neonate 
Since neonatal HSV is acquired perinatally (during the birth process), it is important to use 
standardized language relating to transmission.  Following neonatal exposure to HSV during 
the time of delivery, neonatal infection occurs as viral replication occurs over the first several 
days of life on the neonate’s skin and mucous membranes.  Neonatal infection then progresses to 
neonatal disease at generally 10 to 19 days of life, as discussed above.  
 
Public Health Impact and Current Standard of Care for Treatment/Prevention of 
Neonatal HSV Disease 
From a study of Medicaid-enrolled children from 2009-2015, costs for care of infants with 
neonatal HSV over the first six months of life exceeded $60M (19).  This large number is only 
part of the overall public health impact of neonatal HSV, though.  Up to 20% of women of 
reproductive age are infected with HSV type 2 (HSV-2), which virtually exclusively causes 
genital infection (30).  Furthermore, over the past decade 60% to 80% of genital herpes 
infections are caused by HSV type 1 (HSV-1), which more commonly causes orolabial HSV 
infection (31, 32).  It therefore is estimated that approximately one-third of women of 
childbearing age have a genital HSV infection, and therefore are at risk of transmitting the virus 
to their newborn at the time of delivery to cause neonatal HSV disease (4).  Knowledge of this 
can drive pediatric decision-making when neonates are admitted at 2 to 3 weeks of life with 
fever and undergo a sepsis evaluation, with additional costs incurred in the workup of these 
babies even if they do not have neonatal HSV disease and therefore are not captured in the costs 
above. 
 
Acyclovir is the mainstay for the treatment of HSV, both in adults and in neonates.  From the 
1980s through the 2000s, the precursor of the Congenital and Perinatal Infections Consortium 
(CPIC), which was known then as the Collaborative Antiviral Study Group (CASG), established 
the standard of care for the treatment of neonatal HSV disease in a series of studies.  The first 

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established the superiority of a lower dose of parenteral acyclovir (30 mg/kg/day) over an older 
antiviral drug, vidarabine (14), and the second established the superiority of higher dose 
parenteral acyclovir (60 mg/kg/day) for a longer duration of treatment (21 days for CNS and 
disseminated neonatal HSV) (2).  The CASG then conducted a placebo-controlled study of oral 
acyclovir suppressive therapy following treatment of acute neonatal disease (3), in which we 
determined that babies with neonatal HSV CNS disease had significantly improved 
neurodevelopmental outcomes when immediately started on active antiviral suppression 
following parenteral acyclovir therapy of acute disease, compared with babies in whom oral 
antiviral suppression was deferred until after skin lesions recurred or who only received placebo.  
Even with use of higher dose parenteral acyclovir followed by immediate antiviral suppression, 
each year in the United States over 100 babies die from neonatal herpes, and 250 survivors are 
left with significant neurologic damage (2-4, 20, 33).  Approximately 1,000 more survive 
without neurologic impairment, yet still require two to three weeks of hospitalization for IV 
therapy of acute disease, which puts significant emotional stress on their families – especially 
given the fact that this involves a sexually transmitted infection that the mother passed to her 
newborn (2, 3, 33). 
 
Role of Study in Clinical Development 
No new antiviral drugs active against HSV are in advanced stages of development, and use of 
existing therapies (parenteral acyclovir for treatment of acute neonatal HSV disease followed by 
oral acyclovir suppression) has been maximized already.  Therefore, our strategy to decrease the 
deaths and neurologic morbidity caused by HSV in the neonatal population has shifted to 
preventing neonatal exposure to HSV in the maternal genital tract at the time of delivery from 
progressing to neonatal infection and subsequently to neonatal disease at 10-19 days of life.  
The current study will provide critical data needed in this prevention strategy by determining the 
appropriate dose of oral antiviral medication that can be expected to halt viral replication on the 
skin or mucous membranes of newborns exposed to HSV at delivery, thereby preventing the 
HSV exposure from ever progressing to infection or neonatal HSV disease. 
 
Description of Study Product 
Oral valacyclovir has a much more favorable bioavailability than oral acyclovir in all age groups 
studied to date.  Only 15% to 30% of oral acyclovir is absorbed (34, 35).  In contrast, the oral 
bioavailability of valacyclovir in adults exceeds 50% (16), and in young infants 1-2 months of 
age is 45% (8).  Valacyclovir is the L-valyl ester prodrug of acyclovir, and following absorption 
in the gastrointestinal tract is rapidly converted to acyclovir by first-pass metabolism in the liver 
(15).  Thus, oral valacyclovir is a more efficient way to deliver acyclovir systemically compared 
with oral acyclovir.  The active metabolite of valacyclovir is a deoxyguanosine analogue with an 
acyclic side chain that lacks the 3′-hydoxyl group of natural nucleosides (34).  Following 
preferential uptake by infected cells, acyclovir is monophosphorylated by HSV-encoded 
thymidine kinase.  Subsequent diphosphorylation and triphosphorylation are catalyzed by host 
cell enzymes, resulting in acyclovir triphosphate concentrations that are 40 to 100 times higher 
in HSV-infected cells than in noninfected cells (36).  Acyclovir triphosphate prevents viral DNA 
synthesis by inhibiting the viral DNA polymerase.  In vitro, acyclovir triphosphate competes 
with deoxyguanosine triphosphate as a substrate for viral DNA polymerase.  Because acyclovir 
triphosphate lacks the 3′-hydroxyl group required for elongation of the DNA chain, the growing 

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chain of DNA is terminated.  In the presence of the deoxynucleoside triphosphate 
complementary to the next template position, the viral DNA polymerase is functionally 
inactivated (37).  In addition, acyclovir triphosphate is a much better substrate for the viral 
polymerase than for cellular DNA polymerase, resulting in little incorporation of acyclovir into 
host cellular DNA.  The higher concentration of the active triphosphate anabolite in infected 
cells plus the affinity for viral polymerases result in the very low toxicity of acyclovir in 
noninfected host cells. 
 
Prior Studies of the Study Product 
In the United States, valacyclovir is licensed for the treatment of pediatric patients with orolabial 
HSV recurrences (12 years and older) and chickenpox (2 years through 17 years of age).  
Pediatric valacyclovir dosing is 20 mg/kg per dose (dose not to exceed 1 gram) administered 
either three times a day (for VZV) or twice a day (for HSV) (8).  Valacyclovir oral suspension 
has been evaluated in company-sponsored studies in 112 children 1 month through 11 years of 
age (8, 18).  Dosing regimens evaluated were 25 mg/kg as a single dose in 1 month old through 
23 month old subjects, 10 mg/kg as a twice-daily dose for 3–5 days in 1 year old through 11 year 
old subjects, and 20 mg/kg as a 3-times-daily dose for 5 days in 1 year old through 11 year old 
subjects (8).  Bioavailability was estimated to be 45% to 51% in all age groups except those 3 
months through 5 months of age, in whom the bioavailability is lower at 22%.  Approximate 
dose proportionality in Cmax and area-under-the-curve (AUC) was seen across the 10 mg/kg to 25 
mg/kg dose range (i.e., dose normalized differences generally within ≤ ~30%) with the exception 
of children 2 years through 5 years of age, for whom a near doubling in Cmax and AUC was noted 
with only a modest increase in dose from 20 to 25 mg/kg (8).  Valacyclovir has not been studied 
in neonates (infants under 1 month of age), which is the purpose of this study.  GlaxoSmithKline 
has provided to us the patient-level data from their prior pediatric PK studies of valacyclovir in 
children 1 month through 11 years of age (8), which we have utilized along with our prior data on 
the pharmacokinetics of parenteral acyclovir in neonates (2) to identify the doses of valacyclovir 
being evaluated in this study. 
 
2.3 
Risk/Benefit Assessment 
2.3.1 
Known Potential Risks 
Valacyclovir is the prodrug of acyclovir and is a marketed antiviral medication with a well-
established safety profile.  In young infants, the primary toxicities of parenteral acyclovir are: 1) 
neutropenia, which is reversable with cessation of the drug; and 2) creatinine elevation from 
crystal formation in the collecting tubules of the kidneys (7).  Neither of these complications 
have been seen in studies of oral valacyclovir in infants and children one month of age and older 
(8).  In order to minimize the likelihood of neutropenia or elevated creatinine in the study 
population, the starting valacyclovir dose regimen in this study will be 10 mg/kg/dose 
administered two times per day, which is one-third of the FDA-approved dose for children 2 
years of age and older of 20 mg/kg/dose administered three times per day.  Each subject will be 
carefully monitored for bone marrow toxicity (e.g., neutropenia) and nephrotoxicity (e.g., 
elevated creatinine) and the drug will be stopped if significant toxicities are encountered in a 
given subject. 

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There are no alternative therapies used in neonates potentially exposed to HSV at delivery 
(because they are born to women with a history of genital HSV and therefore who could be 
shedding virus in their genital tract) but without known exposure (no active maternal lesions at 
delivery).  Standard of care at the current time in these potential exposures is simply to follow 
the baby clinically to see if they develop disease.  Therefore, participating in this study will not 
deprive the subjects of any established therapy. 
 
Risks to Privacy:  Subjects will be asked to provide personal health information (PHI).  All 
attempts will be made to keep this PHI confidential within the limits of the law.  However, there 
is a chance that unauthorized persons will see the subject’s PHI.  All study records will be kept 
in a locked file cabinet or maintained in a locked room at each participating clinical site.  
Electronic files will be password protected.  Only people who are involved in the conduct, 
oversight, monitoring, or auditing of this trial will be allowed access to the PHI that is collected.  
Any publications from this trial will not use information that will identify subjects by name.  
Organizations that may inspect and/or copy research records maintained at the participating site 
for quality assurance and data analysis include groups such as the IRB, NIAID, and the FDA. 
 
2.3.2 
Known Potential Benefits 
There may be no direct benefit from the experimental treatment to the neonates potentially 
exposed to HSV at the time of delivery.  This trial will determine what dose of oral valacyclovir 
provides the desired acyclovir systemic concentrations to effectively prevent infection from 
developing following an exposure to the virus at birth.  Subjects who participate will contribute 
to the knowledge about the safety and pharmacokinetics of valacyclovir in neonates.  We have 
selected the study population for this Phase 1 study carefully and deliberately, to include only 
those neonates whose mothers have a history of genital HSV and are on oral antiviral 
suppressive therapy for the last several weeks of pregnancy, as is recommended by the American 
College of Obstetricians and Gynecologists (ACOG) (9).  However, women with a history of 
genital HSV infection may still shed HSV asymptomatically at delivery even when receiving 
antiviral suppression (25-28, 38).  Babies born to these women can develop neonatal HSV 
disease (29), which documents that they remain at risk of acquiring neonatal HSV even when the 
mothers do not have active lesions at delivery.  By requiring that subjects enrolled on this study 
be delivered to women on oral antiviral suppressive therapy, we have deliberately selected a 
population that could potentially benefit from participation on the study if they are exposed to 
HSV at delivery and if the oral valacyclovir study drug that they will receive in the study 
provides benefit in preventing that exposure from progressing to neonatal infection and disease 
 
2.3.3 
Assessment of Potential Risks and Benefits 
Participation in this study will not adversely increase the risk that newborns face when exposed 
to HSV at the time of delivery without treatment. This study will lead to the knowledge that can 
be used to determine the correct dosage of valacyclovir that is needed to effectively preemptively 
treat HSV-exposed neonates at the time of delivery. Known exposure to HSV at delivery is an 
exclusion criterion for study enrollment. 
 
 

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3. 
OBJECTIVES AND ENDPOINTS 
 
Table 2. Objectives and Endpoints 
OBJECTIVES 
ENDPOINTS  
(OUTCOME MEASURES) 
Primary 
 
• To establish the dose of valacyclovir in 
neonates that reliably achieves systemic 
acyclovir exposures comparable to 10 
mg/kg of parenterally administered 
acyclovir 
• Neonatal plasma acyclovir mean AUC12 
concentrations between 24,000 ngxhr/mL 
and 48,000 ngxhr/mL 
Secondary 
 
• 
To define the pharmacokinetic profile of 
acyclovir in neonates receiving oral 
valacyclovir 
• Plasma acyclovir PK parameters including 
maximum serum concentration (Cmax), 
time to the maximum concentration 
(Tmax), half-life (t1/2), oral clearance 
(CL/F), and volume of distribution (V/F) 
• To assess and describe the safety profile 
of valacyclovir among treated neonates 
• Grade 3 Adverse Events (AEs) 
• Grade 4 Adverse Events and Serious 
Adverse Events 
4. 
STUDY DESIGN 
4.1 
Overall Design 
This is a Phase 1, open label multicenter trial to assess the safety and pharmacokinetics 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 are receiving 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.  The mothers can have no visible evidence of HSV lesions at the time of 
delivery, and the neonates will have no signs or symptoms of neonatal HSV disease.  Neonates 
born to women with active herpetic lesions will be excluded from the study because their 
management is determined by the American Academy of Pediatrics algorithm published in 2013 
(10) and in the 2015, 2018, and 2021 Red Books (6, 11, 12).  Likewise, any baby with signs or 
symptoms suggestive of neonatal HSV disease will be excluded from this study and instead 
managed per standard of care. 
 
The starting dose regimen of oral valacyclovir assessed will be 10 mg/kg administered two times 
daily for 5 days (Cohort 1).  This dosage has been studied in patients 1 year through 11 years of 
age, who received twice-daily dosing for 3-5 days, while a single dose of 25 mg/kg has been 
studied down to 1 month of age (8).  Cohort 1 will be comprised of eight subjects.  Following 

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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.  Study Day 1 is the day that 
the first dose of oral valacyclovir is administered.  Following signing of informed consent but 
prior to administration of the first dose of valacyclovir, hematology and chemistry safety labs 
(white blood cell count and differential for absolute neutrophil count, hemoglobin, platelet count, 
alanine aminotransferase, and creatinine) will be obtained and values checked; if no baseline 
hematology or chemistry values are Grade 1 toxicity or higher then dosing of valacyclovir will 
proceed; if any value is Grade 1 toxicity or higher, the subject will be withdrawn from the study 
prior to receiving any doses of study medication.  In addition, the subject must have had a first 
void before receiving a first dose of study medication.  A single plasma sample will also be 
obtained for a baseline acyclovir concentration, since the mothers of enrolled subjects will have 
been taking antiviral medication prior to delivery.  Dropouts and withdrawn subjects may be 
replaced to reach the target sample size of eight subjects.  Subjects will return to the study site on 
Study Day 5 (window: Study Day 4 through Study Day 5), and also will be assessed for adverse 
events and concomitant medications on Study Day 10 (window: Study Day 7 through Study Day 
13) and on Study Day 42 (window: Study Day 35 through Study Day 49), although the Study 
Day 10 and 42 assessments may occur via telephone or in-person study visits.  On the Study Day 
5 (window: Study Day 4 through Study Day 5) visit, plasma samples for PK assessments will be 
obtained around dose 7, 8, 9, or 10 of study drug at 0 hour minus 15 minutes (pre-dose), and then 
1-2 hours, 4-6 hours, and 8-10 hours following administration of the valacyclovir dose (full PK 
profile).  Safety laboratory assessments (white blood cell count with differential, hemoglobin, 
platelet count, alanine aminotransferase, and creatinine) will be obtained at the Study Day 1 
(baseline) and Study Day 5 visits.  Safety laboratory values will be classified using the Division of 
AIDS Toxicity Tables (Appendix A).  Study drug will be stopped following the obtaining of the 
PK samples on Study Day 5 (window: Study Day 4 through Study Day 5).  Criteria for AEs or 
SAEs leading to halting of the study are detailed in Section 7.1.1.  The total number of study 
days of study drug administration will be 4 or 5 (depending on where in the window the Study 
Day 5 visit is conducted), although the total number of doses can be 7, 8, 9, or 10 depending 
upon when the study drug was started on Study Day 1 and whether the PK blood draws on Study 
Day 5 (window: Study Day 4 through Study Day 5) are around the first or second dose that day.   
 
The target concentration of acyclovir following oral valacyclovir dosing is 24,000 ngxhr/mL to 
48,000 ngxhr/mL.  This range was selected because a normalized dose of 10 mg/kg of parenteral 
acyclovir produces a mean (± SD) AUC∞ of 36,000 (± 12,000) ngxhr/mL in infants 1-2 months of 
age (8).  This 10 mg/kg parenteral acyclovir dose was the accepted treatment dose for neonatal 
disease in the 1980s and 1990s (14), and successfully prevents neonatal HSV SEM disease from 
progressing to disseminated disease (20).  In the current study, antiviral therapy is being used to 
prevent neonatal exposure from progressing to neonatal infection (and thus to neonatal 
disease).  The drug exposure that prevented less severe disease (SEM disease) from progressing 
to more severe disease (disseminated disease) has therefore been selected as the target range.  
Although a 20 mg/kg parenteral acyclovir treatment dose for neonatal disease improves survival 
in neonatal disease (2), the current study is not proposing to treat disseminated disease but rather 
to prevent neonatal disease from developing in the first place.  Additionally, the amount of virus 
present on the skin and mucous membranes in exposed neonates will be lower than in 10-19 day 

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old infants who already have neonatal HSV disease, suggesting that lower drug exposure will be 
sufficient.  Finally, this lower exposure has also been selected to minimize likelihood of drug 
toxicity.  
 
Upon full accrual of Cohort 1, the PK and safety data will be reviewed.  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.  If the mean of observed acyclovir exposures of subjects in 
Cohort 1 are below 24,000 ngxhr/mL, AND if no Grade 3 or Grade 4 AEs or SAEs are detected in 
any of the study subjects, then the 8 subjects enrolled in Cohort 2 will receive oral valacyclovir at 
a dose of 20 mg/kg administered two times daily for 5 days.  Alternatively, if the mean of 
observed acyclovir exposures of subjects in Cohort 1 are above 48,000 ngxhr/mL AND if no 
Grade 3 or Grade 4 AEs or SAEs are detected in any of the study subjects, then the 8 subjects 
enrolled in Cohort 2 will receive oral valacyclovir at a dose that has been linearly adjusted 
downward to target 36,000 ngxh/mL area-under-the-concentration-time curve from 0 to 12 hours 
(AUC12).  The study schedule for subjects in Cohort 2 will be identical to those in Cohort 1, as 
described above and in the Schedule of Activities table (see Section 1.2).  If the mean of 
observed acyclovir exposures of subjects in Cohort 1 are within the target range of 24,000 
ngxhr/mL to 48,000 ngxhr/mL, Cohort 2 will not be opened for enrollment unless suggested by 
the Safety Monitoring Committee (SMC) (see Section 9.4.6). 
 
If the targeted exposure is not achieved in Cohorts 1 and 2 and the safety data are acceptable, it is 
possible, but not anticipated, that additional dosing cohorts could be recommended based upon 
the results of subjects in the first two cohorts.  If such a recommendation is made, dose selection 
and subject enrollment and assessment will follow the approach used for Cohort 2. 
 
Schedule of assessments can be found in Section 1.2, Schedule of Activities.  Dose escalation or 
dose-ranging details are found in Section 6.1.2, Dosing and Administration.  Full details of 
interim analysis are found in Section 9.4.6, Planned Interim Analysis 
 
4.2 
Justification for Dose 
Valacyclovir oral suspension has been evaluated in GlaxoSmithKline-sponsored studies in 
children 1 month to 12 years of age (8), but not in neonates (infants under 1 month of age).  In 
the U.S., valacyclovir is licensed for the treatment of pediatric patients with orolabial HSV 
recurrences (12 years and older) and chickenpox (2 years through 17 years of age).  Pediatric 
valacyclovir dosing is 20 mg/kg per dose (dose not to exceed 1 gram) administered either three 
times a day (for VZV) or twice a day (for HSV) (8).  Valacyclovir has demonstrated an excellent 
safety profile over the 20 years since its initial approval in the U.S.  In order to minimize the 
likelihood of neutropenia or elevated creatinine in the study population, the starting valacyclovir 
dose regimen in this study will be 10 mg/kg/dose, which is one-third of the FDA-approved dose 
for children 2 years of age and older of 20 mg/kg/dose administered three times per day.  Each 
subject will be carefully monitored for bone marrow toxicity (e.g., neutropenia) and 
nephrotoxicity (e.g., elevated creatinine) and the drug will be stopped if significant toxicities are 
encountered in a given subject. 

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5. 
STUDY POPULATION 
Neonates delivered to mothers receiving oral valacyclovir therapy (or equivalent antiviral drug) 
for suppression of genital HSV recurrences at the end of pregnancy will be enrolled within the 
first two days of life. 
5.1 
Inclusion Criteria 
To be eligible to participate in this study, an individual must meet all of the following criteria: 
• Signed informed consent from parent(s) or legal guardian(s) 
• Maternal history of genital HSV infection 
• Maternal receipt of oral acyclovir, valacyclovir, or famciclovir suppressive therapy for ≥ 7 
days prior to delivery 
• Gestational age ≥ 38 weeks at birth 
• ≤ 2 days of age at study enrollment* 
• Weight at study enrollment ≥ 2,000 grams 
 
* For purposes of this study, the calendar day of birth is Day of Life 0 
5.2 
Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
• Evidence of neonatal HSV infection 
• Evidence of sepsis 
• Known renal anomalies or dysfunction 
• Maternal genital lesions suspicious for HSV at the time of delivery 
• Infants known to be born to women who are HIV positive (but HIV testing is not required for 
study entry) 
• Current receipt in the neonate of acyclovir, ganciclovir, famciclovir, or any investigational 
drugs 
 
5.2.1 
Exclusion of Specific Populations 
This pediatric study will not exclude young children, females, or minorities.  This study will be 
inclusive of all children who meet the inclusion/exclusion criteria, regardless of religion, gender, 
or ethnic background. 
 
5.3 
Inclusion of Vulnerable Participants 
Not applicable 
 
5.4 
Lifestyle Considerations 
Not applicable 
 
 

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5.5 
Screen Failures 
The investigator or designee is to review the inclusion/exclusion criteria and determine the 
subject’s eligibility for study participation.  Only the following information will be collected on 
screen failures: demographics (age, screen number, sex, ethnicity, and race) and reason for 
ineligibility. The parent(s)/guardian(s) of subjects who are found to be ineligible will be told the 
reason for ineligibility. 
5.6 
Strategies for Recruitment and Retention 
5.6.1 
Recruitment 
Each site participating in this study will develop an individual recruitment plan that is specific to 
their region and facility requirements.  Recruitment materials may be delivered in prenatal and 
postnatal settings.  
 
5.6.2 
Retention 
Enrolled subjects will be followed for only 42 days.  Challenges with subject retention are 
therefore not anticipated. 
 
5.6.3 
Compensation Plan for Subjects  
Study subject compensation, if any, will be determined by the individual sites. The compensation 
plan will be in accordance with local IRB requirements and subject to local IRB approval.  
 
5.6.4 
Costs 
There is no cost to subjects for the research tests, procedures, and study product while taking part 
in this trial.  Procedures and treatment for clinical care may be billed to the subject, subject’s 
insurance or third party.   
 
6. 
STUDY PRODUCT 
6.1 
Study Product(s) and Administration 
6.1.1 
Study Product Description 
Valacyclovir hydrochloride (Valtrex) is a white to off-white powder (from tablets) of the 
hydrochloride salt of the L-valyl ester of acyclovir with the molecular formula C13H20N6O4•HCl 
and a molecular weight of 360.80.  Each 500 mg tablet (blue, film-coated) contains valacyclovir 
hydrochloride equivalent to 500 mg valacyclovir and the inactive ingredients carnauba wax, 
colloidal silicon dioxide, crospovidone, FD&C Blue No. 2 Lake, hypromellose, magnesium 
stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, povidone, and titanium 
dioxide (18).  Valacyclovir tablets will be extemporaneously compounded as an oral suspension 
using SyrPalta as the oral liquid vehicle (13).  SyrPalta syrup vehicle contains sucrose 83% w/v; 
Purified Water; Glycerin; Artificial Flavors; 0.2% Alcohol; 0.1% Sodium Benzoate; 0.001% 
Benzalkonium Chloride as a Preservative.  It is the recommended oral liquid vehicle for 

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valacyclovir suspension from the extemporaneous compounding references supported by the 
FDA Safe Use Initiative:  the Michigan Pediatric Safety 
Collaboration (https://www.mipedscompounds.org/), and the American Society of Health 
System Pharmacists (ASHP) Standardize 4 Safety Initiative (https://www.ashp.org/-
/media/assets/pharmacy-practice/s4s/docs/Compound-Oral-Liquid.ashx).  
 
6.1.2 
Dosing and Administration 
The shelf-life of valacyclovir oral suspension following preparation is 28 days in the refrigerator 
between 2ºC to 8ºC (36ºF to 46ºF).  Study product will be administered by the parent/guardian if 
subjects are at home, or by the hospital staff if subjects are in the hospital.  Study Cohort 1 will 
receive valacyclovir at a dose of 10 mg/kg body weight administered two times daily for 5 days, 
while the dose evaluated in Cohort 2 will be predicated upon the exposure levels of subjects 
enrolled in Cohort 1.  Specific dosing volumes will be provided for each subject based on body 
weight and valacyclovir oral suspension concentration.  Valacyclovir Oral Suspension will be 
administered into the subject’s mouth via an oral dosing syringe.  The parent/guardian will be 
provided with specific dosing, storage, and administration instructions.  If the subject vomits or 
spits up following the dosing, re-dosing for that dose is not allowed. 
Table 3. Dosing and Administration 
Cohort 
Product Name 
Dose 
Route 
Frequency of 
Administration 
Duration of Therapy 
1 
Valacyclovir 
10 mg/kg 
Oral 
bid 
5 days 
2 
Valacyclovir 
TBD 
Oral 
bid 
5 days 
 
6.1.3 
Dose Escalation 
Dose selection for Cohort 2 will be predicated upon the pharmacokinetic data from Cohort 1.  
Specifically, the target range of acyclovir exposure is between 24,000 ngxhr/mL and 48,000 
ngxhr/mL.  If the mean of observed acyclovir exposures of subjects in Cohort 1 are below 24,000 
ngxhr/mL, AND if no Grade 3 or Grade 4 AEs or SAEs are detected in any of the study subjects, 
then the 8 subjects enrolled in Cohort 2 will receive oral valacyclovir at a dose of 20 mg/kg 
administered two times daily for 5 days.  Alternatively, if the mean of observed acyclovir 
exposures of subjects in Cohort 1 are above 48,000 ngxhr/mL AND if no Grade 3 or Grade 4 
AEs or SAEs are detected in any of the study subjects, then the 8 subjects enrolled in Cohort 2 
will receive oral valacyclovir at a dose that has been linearly adjusted downward to target 36,000 
ngxh/mL area-under-the-concentration-time curve from 0 to 12 hours (AUC12).    If the mean of 
observed acyclovir exposures of subjects in Cohort 1 are within the target range of 24,000 
ngxhr/mL to 48,000 ngxhr/mL, Cohort 2 will not be opened for enrollment unless suggested by 
the Safety Monitoring Committee (SMC) (see Section 9.4.6). 
 
If the targeted exposure is not achieved in Cohorts 1 and 2 and the safety data are acceptable, it is 
possible, but not anticipated, that additional dosing cohorts could be recommended based upon 
the results of subjects in the first two cohorts.  If such a recommendation is made, dose selection 
and subject enrollment and assessment will follow the approach used for Cohort 2. 
 

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6.1.4 
Dose Modifications 
Valacyclovir will be dosed according to the study cohort into which the subject enrolls.  Study 
Cohort 1 will receive 10 mg/kg body weight administered two times daily for 5 days, while the 
dose for Cohort 2 will be predicated upon the pharmacokinetic results of subjects enrolled in 
Cohort 1, as detailed in Section 4. 
 
6.2 
Preparation/Handling/Storage/Accountability 
6.2.1 
Acquisition and Accountability 
Acquisition: 
Commercial brand name (Valtrex) valacyclovir (500 mg tablets) and SyrPalta syrup vehicle will 
be shipped to the participating sites from the DMID Clinical Material Services (CMS).  Ancillary 
supplies for oral administration, such as amber bottles and oral dosing syringes, will be provided 
by the clinical research site.  Multiple lots may be provided.  The study products will be open 
label and not kit specific.  Extemporaneous preparation of the suspension formulation will be 
performed by the site’s research pharmacist following enrollment of a subject (13). 
 
Accountability: 
After receipt of the study product, the site principal investigator (PI) is responsible for study 
product distribution and disposition and has ultimate responsibility for study product 
accountability.  The Site PI will delegate to the site Research Pharmacist the responsibility for 
study product accountability.  Each pharmacist will be responsible for and will maintain logs of 
receipt, accountability, dispensation, storage conditions, and disposal of study drug.  All study 
product, whether administered or not, must be documented on the appropriate study product 
accountability record or dispensing log.  Parents/guardians will be instructed to return the used 
bottle and medication diary to the PI at Study Day 5. 
 
Unused (e.g., returned) study product will be retained at the site until further instruction from the 
Sponsor or its designee.  Upon study completion, or termination and final monitoring visit, the 
Sponsor or its designee will provide instructions for the return of any remaining unused study 
product to the repository or destroyed according to site procedures with a second staff member 
observing and verifying the destruction.  Used study product will be destroyed at the site in 
accordance with standard site procedures following monitoring and release for destruction, 
unless the site’s local storage policy prohibits retention of used IP.  In that event, used study 
product may be destroyed on-site following applicable site procedures with a second staff 
member observing and verifying the destruction. 
 
At study completion, the sites will be required to return the drug accountability log to the UAB 
Central Unit (CU) upon request, retaining a copy of the drug accountability form in their study 
files. 
 
6.2.2 
Formulation, Appearance, Packaging, and Labeling 
Commercial valacyclovir tablets 500 mg (Valtrex) will be supplied for extemporaneous 
preparation of the suspension formulation by the Research Pharmacist.  Valacyclovir 

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hydrochloride is a white to off-white powder (from tablets) of the hydrochloride salt of the L-
valyl ester of acyclovir.  The blue, film-coated tablets are printed with edible white ink.  
Commercial SyrPalta will be supplied as the vehicle for the valacyclovir suspension and is a 
clear liquid (13).  Valacyclovir oral suspension will be stored in an amber medicine bottle with a 
child-resistant closure.  The final prepared oral suspension will be labeled with the FDA-required 
cautionary statement “Caution: New Drug Limited by Federal Law to Investigational Use”. 
 
6.2.3 
Product Storage and Stability 
Valacyclovir tablets will be stored at 15°C to 25°C (59°F to 77°F).  SryPalta syrup vehicle will 
be stored between 13°C to 29°C (56°F to 85°F).  The final prepared valacyclovir oral suspension 
will be stored refrigerated between 2°C and 8° C (36° to 46°F) in the pharmacy and subject’s 
home.  Shake well before using.  Discard after 28 days. 
 
6.2.4 
Preparation 
Valacyclovir Oral Suspension will be extemporaneously prepared by the site Research 
Pharmacist following the instructions in the Manual of Procedures for dispensing to the study 
subject.  One bottle will be compounded and dispensed at study enrollment and will suffice for 
the full 5-day treatment period.  Resupply will only be provided in the event of loss of the 
product by the family.  Additional details regarding preparation and procedures for dispensing or 
administration of study product will be described in the protocol-specific Manual of Procedures. 
 
6.3 
Measures to Minimize Bias: Randomization and Blinding 
6.3.1 
Treatment Assignment Procedures 
Not applicable.  All subjects will receive study product. 
6.3.2 
Randomization and Blinding 
Not Applicable 
6.3.3 
Blinding and Masking Procedures 
Not applicable.  No masking procedures will be done. 
 
6.4 
Study Intervention Compliance 
Assessment of compliance with administration of study medication throughout the 5-day 
treatment period will be achieved by utilization of a medication diary.  The parent(s) or legal 
guardian(s) will complete this diary daily, indicating the time of drug administration and whether 
the subject vomited following the dose.  The diary will also note the storage conditions of the 
product (e.g. refrigerated).  The diary will be collected at the Study Day 5 visit. 
 
 
 
 

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6.5 
Concomitant Therapy 
Concomitant medications will be recorded on the specified CRF at Study Visit Days 1, 5, 10, and 
42. 
 
6.5.1 
Rescue Medicine 
Not applicable   
 
7. 
STUDY INTERVENTION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
Halting Criteria and Discontinuation of Study Intervention 
7.1.1 
Study Halting Criteria 
Enrollment and study product administration will be halted for SMC review/recommendation if 
any of the following is reported: 
• Any subject experiences an SAE after study product administration that is considered related 
to the study product. 
• Two subjects experience an AE Grade 2 or higher from the same organ class, deemed to be a 
study product-related unsolicited AE. 
• Two subjects experience the same Grade 2 or higher study product-related safety laboratory 
AE.  
 
Additionally, DMID and the Central Unit may interrupt study dosing and/or study entry at any 
time if medically indicated.  To minimize risk, the medical monitor will review real-time safety 
data and the SMC will review cumulative safety data.  If enrollment is halted based upon the 
study halting criteria above or the review of the safety data, upon completion of the review and 
receipt of advice of the SMC, DMID and the Central Unit Administration will determine if study 
entry or study dosing may continue according to the protocol. 
 
7.1.2 
Individual Halting Criteria 
Subjects with any initial (pre-dosing) hematology or chemistry safety lab that is ≥ Grade 1 in 
value utilizing the DAIDS Toxicity Tables (Appendix A) will be withdrawn from the study and 
will not receive study medication.  During the 5 days of study product dosing, a Grade 2 or 
higher AE, including a laboratory AE, will result in halting of study product administration for 
the subject.  If a subject develops signs/symptoms of HSV infection, study medication will be 
stopped and standard antiviral therapy will be administered. 
 
7.1.3 
Criteria for Continuation of Dosing and Redosing 
In the event a halting rule is met: 

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• An unscheduled safety analysis by the SMC will be required for approval of further 
enrollment, and 
• Further administration of the study product is suspended for ALL subjects until an 
assessment by the SMC takes place. 
 
7.1.4 
Follow up for subjects that discontinue study intervention 
Study subjects that discontinue study drug will be offered an opportunity to complete the follow-
up study visits through study day 42.  They will complete all follow-up visits as outlined in the 
study Schedule of Activities in Section 1.2. 
 
7.2 
Participant Withdrawal from the Study and Replacement 
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.  Should a study subject’s therapy be 
discontinued prematurely, all clinical and laboratory evaluations scheduled during the next study 
visit will be completed on the day the study subject is discontinued, if possible.  Dropouts and 
withdrawn subjects may be replaced to reach the target of sample size. 
7.3 
Lost to Follow-Up 
A participant will be considered lost to follow-up if he or she fails to return for more than one 
scheduled visit and is unable to be contacted by the study site staff.  These efforts will be 
documented in the subject’s study record. 
 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
The study procedures and evaluations are summarized in the Schedule of Activities in Section 
1.2. 
 
8.1 
Screening Procedures 
It is anticipated that screening will occur either in the final weeks of pregnancy or at the time of 
delivery by identifying pregnant women who are receiving antiviral suppressive therapy for 
genital HSV infections.  Each site will determine the manner by which patients who could be 
eligible for study enrollment are identified and their mothers approached for discussion of 
participating in the study. 
 
8.2 
Efficacy / Immunogenicity Assessments 
Not applicable 
 
 

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8.2.1 
Efficacy / Immunogenicity Evaluations 
Not applicable 
8.3 
Safety and Other Assessments 
Baseline Demographics 
The following information will be collected from the subject’s medical records to the extent the 
information is available, or by direct assessment of the subject and questioning of the parent(s) or 
legal guardian(s):  Gestational age at delivery, date of birth, gender, race, ethnicity, birth weight, 
weight at enrollment, length in centimeters at enrollment, and baseline conditions prior to study 
enrollment, by body system. 
 
Adverse Event Assessment 
At each study visit following the receipt of first dose of study drug and continuing through four 
weeks following the final dose of study drug, the study subject will be assessed for any adverse 
events. 
 
Concomitant Medications Assessment 
At each study visit from the receipt of first dose of study drug and continuing through four weeks 
following the final dose of study drug, concomitant medications that are being administered to 
the subject will be recorded. 
 
Laboratory Evaluations 
Blood for study-specified laboratory evaluations may be obtained by methods such as the 
following:  venipuncture, heel stick, indwelling intravenous catheter, etc.  As detailed below, 
blood will be obtained for assessment of hematology safety labs, chemistry safety labs, and 
acyclovir concentrations; blood draws will be attempted a second time if the first attempt is 
unsuccessful.  If an insufficient volume of blood is obtained for all of the tests at any given study 
visit, the following prioritization as to which tests to send will apply (most important to least 
important):  1) pharmacokinetic samples for acyclovir plasma concentrations (most important); 
2) hematology safety labs (second most important); and 3) chemistry safety labs (third most 
important).  With the exception of the pharmacokinetic samples and the white blood cell count 
with differential, those lab tests that are unable to be obtained due to lack of sufficient blood or 
parental refusal at a given study visit will be noted but will not be reported as protocol 
deviations.  As far as possible, research specimens should be taken to coincide with clinical care. 
 
Clinical Laboratory Evaluations 
The breakdowns of the amount of blood for individual tests are provided in the Schedule of 
Activities in Section 1.2.  Clinical laboratory results can be used for chemistry and hematology 
safety labs if collected within the required study window.  If labs drawn for the study-required 
assessments are not evaluable, blood draws will not be repeated. 
 
Hematology Safety Labs 
All hematology safety laboratory assessments will be conducted at the PI’s local lab.  They will 
be obtained on Study Days 1 and 5.  The following will be tested:  white blood cell count (WBC) 

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with differential, hemoglobin, and platelet count.  From the WBC count and differential, the 
absolute neutrophil count (ANC) will be calculated (39). 
 
Chemistry Safety Labs 
All chemistry safety laboratory assessments will be conducted at the PI’s local lab.  They will be 
obtained on Study Days 1 and 5.  The following will be tested:  alanine aminotransferase (ALT) 
and creatinine. 
 
Special Assays or Procedures: Pharmacokinetic Testing 
Assessment of acyclovir plasma concentrations will be conducted at the UAB Central 
Pharmacokinetic Laboratory.  On Study Day 1, a blood sample will be obtained at the same time 
as the Study Day 1 hematology and chemistry safety labs.  On Study Day 5 (window: Study Day 
4 through Study Day 5), blood will be obtained around dose 7, 8, 9, or 10 of study drug at 15 
minutes before the dose (pre-dose), and then 1-2 hours, 4-6 hours, and 8-10 hours following 
administration of the dose.  Specific instructions for shipping PK samples are found in the MOP. 
 
8.3.1 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings 
If a physical parameter or laboratory value is outside of the protocol specified range, then the 
measurement may be repeated if there is a technical problem with the measurement cause by a 
laboratory error or a malfunctioning or inappropriate device.  Laboratory parameters other than 
those specified in hematology safety labs and chemistry safety labs as part of the CBC and 
complete metabolic panel need to be evaluated by the site physician, recorded in the source 
document, and reported as laboratory AEs if clinically significant. 
 
8.4 
Adverse Events and Serious Adverse Events 
8.4.1 
Definition of Adverse Events (AE) 
An Adverse Event is any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of medicinal (investigational) 
product whether or not considered drug related. The occurrence of an AE may come to the 
attention of study personnel during study visits and interviews of a study recipient presenting for 
medical care, or upon review by a study monitor. 
 
Investigators participating in this clinical trial are responsible for and will: 
• Evaluate subject safety including assessment of adverse events (AEs) for seriousness, 
severity, and causality; 
• Notify the Central Unit, CROMS PVG, and EMMES of protocol-defined serious adverse 
events (SAEs) within 24 hours; (details provided in the MOP) 
• Provide detailed written reports, including necessary documentation requested by the sponsor 
or institutional review board (IRB)/independent ethics committee (IEC), promptly following 
immediate initial reports; and 
• Inform the IRB/IEC of AEs as required by applicable regulatory requirements. 

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Information to be collected on reportable AEs includes event description, time of onset, 
clinician’s assessment of severity, relationship to study product (assessed only by those with the 
training and authority to make a diagnosis, which would include MD or DO), and time of 
resolution/stabilization of the event. All AEs occurring from Study Day 1 through four weeks 
following the last dose of study drug must be documented appropriately regardless of 
relationship. All AEs will be followed to adequate resolution.  
Any medical condition that is present at the time that the patient is enrolled should be considered 
as a baseline condition and not reported as an AE. However, if the event meets the criteria and 
the grade of the event worsens at any time during the study, it should be recorded as an AE. 
 
The determination of seriousness, severity, and causality will be made by an on-site investigator 
who is qualified (licensed) to diagnose AE information, provide a medical evaluation of AEs, 
and classify AEs based upon medical judgment. This includes MD or DO.  Events will be 
identified by assessing the subject at each visit.  If a subject is hospitalized, the medical record 
should be reviewed to identify AEs.  The PI is responsible for identifying and reporting AEs 
according to protocol guidelines. 
 
8.4.1.1 
Solicited Adverse Events 
Solicited adverse events are anticipated local and systemic adverse events for which consistent 
collection of information is desired. This may include: 
• Common and expected according to the available knowledge about the product, or 
• Specific events of concern that should be ascertained on every participant. 
 
8.4.1.2 
Unsolicited Events 
All AEs spontaneously reported by the subject and/or in response to an open question from study 
personnel or revealed by observation, physical examination or other diagnostic procedures 
must be recorded in the source document and on the appropriate page of the case report form. 
All reported unsolicited AEs are graded in accordance with the protocol toxicity tables. 
 
8.4.1.3 
Special Reporting of Adverse Events 
Not applicable 
 
8.4.2 
Definition of Serious Adverse Events  
An SAE is defined as an adverse event or suspected adverse reaction is considered “serious” if, 
in the view of either the investigator or sponsor, it results in any of the following outcomes:  
• Death, 
• A life-threatening adverse event*;  
• Inpatient hospitalization or prolongation of existing hospitalization;  
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions; or  
• A congenital anomaly/birth defect.   

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* Life-threatening adverse event. An adverse event is considered “life-threatening” if, in the 
view of either the investigator or sponsor, its occurrence places the patient or subject at 
immediate risk of death.  It does not include an adverse event that, had it occurred in a more 
severe form, might have caused death.  It does not necessarily include all grade 4 AEs according 
to the toxicity tables in Appendix A. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalizations may be considered serious when, based upon appropriate medical judgment they 
may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
 
All SAEs will be: 
• Recorded on the appropriate SAE eCRF; 
• Followed through resolution or stabilization by a licensed study physician (listed on the Form 
1572 as the site PI or Sub-Investigator); 
• Reviewed and evaluated by DMID, and will be sent to the SMC (for periodic review) and the 
IRB. 
 
Relationship to Study Products:  The physician’s assessment of an AE's relationship to 
valganciclovir study drug is part of the documentation process, but it is not a factor in 
determining what is or is not reported in the study.  If there is any doubt as to whether a clinical 
observation is an AE, the event should be reported. All AEs must have their relationship to study 
product assessed using the terms “related” or “not related,” and should be followed through 
resolution or stabilization. In a clinical trial, the study product must always be suspect.  
 
The investigator must provide an assessment of relationship of AEs to the study product based 
on: 
• Temporal relationship of the event to the administration of study product; 
• Whether an alternative etiology has been identified; 
• Biological plausibility; and 
• Existing therapy, and/or concomitant medications.  
 
To help assess, the following guidelines are used: 
• Related– There is a reasonable possibility that the study product caused the adverse event. 
Reasonable possibility means that there is evidence to suggest a causal relationship between 
the study product and the adverse event. 
• Not Related– There is not a reasonable possibility that the administration of the study 
product caused the event. 
 

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8.4.2.1 
Suspected Unexpected Serious Adverse Reactions (SUSAR) 
A SUSAR is any SAE where a causal relationship with the study product is at least a reasonably 
possible but is not listed in the Investigator Brochure, Package Insert, and/or Summary of 
Product Characteristics. 
 
8.4.3 
Classification of an Adverse Event 
The determination of seriousness, severity, and causality will be made by an on-site investigator 
who is qualified (licensed) to diagnose AE information, provide a medical evaluation of AEs, 
and classify AEs based upon medical judgment. This includes but is not limited to physicians, 
physician assistants, and nurse practitioners.  
 
8.4.3.1 
Severity of Event 
All reportable AEs will be graded by the investigator according to the protocol toxicity tables 
(Appendix A) using a four-grade system (Table 1).  For safety laboratory results with an absolute 
number in the toxicity tables (e.g., hemoglobin), grading of the AEs will be according to the 
toxicity tables and not according to the local laboratory reference range.  For safety laboratory 
results with a reference to the Upper Limit Normal (ULN) in the toxicity tables (e.g., ALT or 
SGPT), grading of the AEs will utilize the ULN of the local laboratory reference range in 
determining grading of the event per the toxicity tables. Grade 4 AEs will be only reported as 
SAE if the event meets one of the regulatory definitions of SAE described below based on the 
study site physician judgment.  The functional table below should be used to grade the severity 
of an AE that is not specifically identified in the grading table.  In addition, all deaths related to 
an AE are to be classified as grade 5. 
 
Table 4. Protocol Toxicity Table 
 (Four-grade system utilized for this trial [see also Appendix A]) 
PARAMETER GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-
THREATENING 
Clinical 
adverse 
event NOT 
identified 
elsewhere in 
the 
grading table 
Mild symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities with 
intervention not 
indicated 
Moderate 
symptoms 
causing greater 
than minimal 
interference with 
usual social & 
functional 
activities with 
intervention 
indicated 
Severe symptoms 
causing inability to 
perform usual 
social & functional 
activities with 
intervention or 
hospitalization 
indicated 
Potentially life-
threatening 
symptoms causing 
inability to perform 
basic self-care functions 
with intervention 
indicated to prevent 
permanent impairment, 
persistent disability, or 
death 
 
 

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8.4.3.2 
Relationship to Study Intervention 
For each reported adverse reaction, the Principal Investigator or designee must assess the 
relationship of the event to the study product using the following guideline: 
• Related – The AE is known to occur with the study intervention, there is a reasonable 
possibility that the study intervention caused the AE, or there is a temporal relationship 
between the study intervention and event. Reasonable possibility means that there is 
evidence to suggest a causal relationship between the study intervention and the AE. 
• Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study 
intervention and event onset, or an alternate etiology has been established. 
 
8.4.4 
Time Period and Frequency for Event Assessment and Follow-Up 
All AEs, including safety laboratory AEs, and all SAEs will be documented from Study Day 1 
through four weeks following the last dose of study drug. 
 
All AEs and SAEs will be followed until resolution, even if this extends beyond the study-
reporting period, which is 4 weeks following the last dose of study product. Resolution of an AE 
is defined as the return to pretreatment status or stabilization of the condition with the 
expectation that it will remain chronic.  
 
At any time after completion of the study, if the investigator becomes aware of an SAE that is 
suspected to be related to study product, the investigator will report the event. 
 
8.4.5 
Adverse Event Reporting 
8.4.5.1 
Investigators Reporting of AEs 
Information on all AEs should be recorded on the eCRF. All clearly related signs, symptoms, and 
results of diagnostic procedures performed because of an AE should be grouped together and 
recorded as a single diagnosis. If the AE is a laboratory abnormality that is part of a clinical 
condition or syndrome, it should be recorded as the syndrome or diagnosis rather than the 
individual laboratory abnormality. Each AE will also be described in terms of duration (start and 
stop date), severity, association with the study product, action(s) taken, and outcome. 
 
8.4.6 
Serious Adverse Event Reporting 
8.4.6.1 
Investigators Reporting of SAEs 
Any AE that meets the protocol defined criterion as an SAE must be submitted immediately 
(within 24 hours of identification) on an SAE form to the DMID Pharmacovigilance Group at the 
following address: 
 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS) 
6500 Rock Spring Dr., Suite 650 
Bethesda, MD 20817, USA 

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SAE Hot Line: 1-800-537-9979 (US) or 1-301-897-1709 (outside US) 
SAE FAX Phone Number: 1-800-275-7619 (US) or 1-301-897-1710 (outside US) 
SAE Email address:  PVG@dmidcroms.com 
 
The DMID Serious Adverse Event form can be found at 
https://www.dmidcroms.com/CRS/PVG/PVG_Public/SAE%20Form_V%204.0.pdf. 
 
The Investigator will call the Clinical Studies Administrator at the Central Unit to notify them 
that an SAE has been identified.  Other supporting documentation of the event may be requested 
by the DMID Pharmacovigilance Group and should be provided as soon as possible.  The DMID 
medical monitor will review and assess the SAE for regulatory reporting and potential impact on 
study subject safety and protocol conduct. At any time after completion of the study, if the 
investigator becomes aware of an SAE that is suspected to be related to study product, the 
investigator will report the event to the DMID Pharmacovigilance Group. 
8.4.6.2 
Regulatory Reporting of SAEs 
Following notification from the site Principal Investigator or appropriate sub-investigator, 
DMID, as the IND sponsor, will report any suspected unexpected serious adverse event 
(SUSAR) as an IND safety report to the FDA and will notify all participating site Principal 
Investigators (i.e., all Principal Investigators to whom the sponsor is providing drug under its 
IND(s) or under any Principal Investigator’s IND(s)of potential serious risks from clinical 
studies or any other source, as soon as possible.  DMID will report to the FDA any unexpected 
fatal or life-threatening suspected adverse reaction as soon as possible, but in no case later than 7 
calendar days after the sponsor’s initial receipt of the information.  If the event is not fatal or life-
threatening the IND safety report will be submitted within 15 calendar days after the sponsor 
determines that the information qualifies for reporting as specified in 21 CFR Part 312.32.  
Relevant follow up information to an IND safety report will be submitted as soon as the 
information is available.  Upon request from FDA, DMID will submit to the FDA any additional 
data or information that the agency deems necessary, as soon as possible, but in no case later 
than 15 calendar days after receiving the request.   
 
SAEs that are not SUSARs will be reported to the FDA at least annually in a summary format 
which includes all SAEs.   
 
8.4.7 
Reporting Events to Participants 
Not applicable 
 
8.4.8 
Adverse Events of Special Interest 
Not applicable 
 
8.4.9 
Reporting of Pregnancy 
Not applicable 
 

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8.5 
Unanticipated Problems 
8.5.1 
Definition of Unanticipated Problems (UP) 
Not applicable  
8.5.2 
Unanticipated Problem Reporting 
Not applicable  
8.5.3 
Reporting Unanticipated Problems to Participants 
Not applicable 
 
9. 
STATISTICAL CONSIDERATIONS 
9.1 
Statistical Hypotheses 
We hypothesize that the pharmacokinetics (PK) of acyclovir in neonates, following 
administration of the prodrug valacyclovir, are definable in an adaptive, dose-escalation study 
with sparse and intensive concentration-time assessments. 
 
9.2 
Sample Size Determination 
The sample size will be characterized by the width of a 95% confidence interval for AUC∞ in 
Cohort 1. As previously noted, in infants 1-2 months of age, the mean (± SD) AUC∞ is 36,000 (± 
12,000) ngxhr/mL for a normalized dose of 10 mg/kg of IV acyclovir (8).  A higher (lower) dose 
for Cohort 2 will be considered when observed acyclovir exposures in Cohort 1 are below the 
mean of 24,000 (above 48,000) ngxhr/mL. Assuming a constant coefficient of variation of 0.3333 
in determining the standard deviation of AUC∞ for a given mean, a sample size of 8 will be 
characterized in terms of the width of a 95% two-sided confidence interval for the mean. If the 
observed mean is 24,000 ngxhr/mL and using a standard deviation of 8,000 ngxhr/mL, a two-
sided 95% confidence for the mean AUC∞ is (17,312-30,688), i.e. the true mean can be as low as 
17,312 ngxhr/mL but no higher than 30,688 ngxhr/mL. If the observed mean is 48,000 ngxhr/mL 
and using a standard deviation of 15,998 ngxhr/mL, a two-sided 95% confidence interval for the 
mean AUC∞ is (34,625-61,375), i.e., the true mean can be as high as 61,375 ngxhr/mL but no 
lower than 34,625 ngxhr/mL. For the confidence intervals for other sample sizes, please see table 
below. 
 
For the 95% upper bound for the proportion experiencing AEs or SAEs when 0 are observed in a 
sample size of n.  For example, if n=8 and no SAEs are observed, then there is 95% confidence 
that the rate is no more than 36.9%.  If n=10, there is 95% confidence that the rate is not more 
than 30.8%.  The larger the n, the tighter (i.e., closer to 0) the upper bound. 
 
 

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Table 5. Sample Size Determination 
N 
95% 
Confidence 
Bound for 
Event 
Rates* 
95% CI for Mean AUC∞  
assuming a sample  
mean of 24,000 and SD=8,000 
95% CI for Mean AUC∞ 
assuming a sample mean of 
48,000 and SD=15,998 
Lower 
Upper 
Lower 
Upper 
5 
0.5218 
14,066.69 
33,933.31 
28,135.86 
67,864.14 
6 
0.4593 
15,604.52 
32,395.49 
31,211.13 
64,788.87 
7 
0.4096 
16,601.23 
31,398.77 
33,204.32 
62,795.68 
8 
0.3694 
17,311.83 
30,688.17 
34,625.34 
61,374.66 
9 
0.3363 
17,850.66 
30,149.34 
35,702.85 
60,297.15 
10 
0.3085 
18,277.15 
29,722.86 
36,555.72 
59,444.28 
11 
0.2849 
18,625.53 
29,374.47 
37,252.40 
58,747.60 
12 
0.2646 
18,917.04 
29,082.96 
37,835.36 
58,164.64 
13 
0.2471 
19,165.65 
28,834.35 
38,332.51 
57,667.49 
14 
0.2316 
19,380.94 
28,619.06 
38,763.03 
57,236.97 
15 
0.2180 
19,569.75 
28,430.25 
39,140.60 
56,859.40 
*when no events are observed 
 
 
 
9.3 
Populations for Analyses 
Intent to Treat Population 
Any child who receives at least one dose of study medication will be included in an intention to 
treat (ITT) analysis of safety. 
Per Protocol Population 
Children who complete the course of study medication will be included in a per protocol (PP) 
analysis of pharmacokinetics. 
 
Safety Population 
The Safety Population will consist of all subjects who have received at least one dose of study 
product and for whom any data on safety are available. 
9.4 
Statistical Analyses 
The primary objective of this study is to describe the acyclovir AUC12 following oral dosing of 
valacyclovir at the proposed starting dose in Cohort 1 and a linearly adjusted dose in Cohort 2 if 
required to achieve the targeted exposure.  As such, only descriptive statistics will be needed to 
summarize the pharmacokinetic data.  This is an observational pharmacokinetic study with no 
comparator arms.  Our goal is to generate preliminary pharmacokinetic data in this population to 
help inform larger dosing/efficacy trials in the future.  The AUC12 will be the primary parameter 
summarized, but secondary objective pharmacokinetic parameters such as CL/F, T1/2, Cmax, 
V/F, and others will also be summarized using descriptive statistics.  These statistics will include 
at least the mean, standard deviation, coefficient of variation, median, range, and mean.  
 

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The low valacyclovir dose that is being assessed is expected to produce exposures well within a 
clinically acceptable range for older neonates receiving IV acyclovir dosing.  Therefore, any AEs 
are expected to be similar in frequency and severity to what is already known about the drug 
within this exposure range.  Any AEs will be summarized by grade and frequency (percent).  
Symptoms and toxicities (e.g., AEs) will be listed and the counts and proportion computed by 
dose cohort.  The Clopper-Pearson method will be used to estimate 95% confidence intervals (or 
upper bound) around the estimates of these proportions and Fisher's exact test to compare the 
proportions between dose cohorts.  Summary statistics for continuous laboratory safety 
parameters will be presented.  The data also will be presented using appropriate graphical tools 
to help compare the different dose cohorts.  The exact Wilcoxon test will be used to compare 
between dose cohorts at a given time point or area under the curve for variables collected over 
time (e.g., laboratory parameters).  For area under the curve, the average will be taken to adjust 
for shortened length of follow-up for dropouts.  Linear mixed model with random intercept may 
be considered to analyze data collected over time to account for correlation of data from the 
same subject.  This method provides another perspective of comparing the treatment cohorts as 
area under the curve due to being a summary statistic may miss important features of the data 
that mixed model may detect.  The generalized linear mixed model can handle continuous, 
binary and count data.  To measure strength of correlation between continuous variables, the 
Pearson correlation (or Spearman rank correlation for variables not distributed normally) will be 
used.  Analyses will be done using SAS version 9.4. 
 
9.4.1 
General Approach 
Data will be summarized using mean, standard deviation, median, minimum and maximum for 
continuous variables and count and percentages for categorical variables.  For laboratory data, 
10th and 90th percentiles will be used instead of minimum and maximum.  Mean plots and 
boxplots will be used to display summary statistics over time for continuous variables.  For 
comparing the demographic and laboratory variables between cohorts at a given time point, exact 
two-tailed Wilcoxon test will be used to compare the two cohorts for continuous variables, due to 
small sample size and indication of nonnormality, and two-tailed Fisher’s exact test for 
categorical variables.  For estimating proportions, Clopper-Pearson method will be utilized.  For 
investigating the change in hematology and chemistry parameters collected over time, 
generalized linear mixed model with random effects may be utilized to compare the cohorts.  
Confidence level will be at least 95% for estimation and significance level will be at most 5% for 
test of hypothesis, respectively.  There will be no adjustments for multiple intervals or testing. 
 
9.4.2 
Analysis of the Primary Endpoint(s) 
Standard noncompartmental techniques will be used to assess pharmacokinetic parameters 
derived from the full PK profile obtained on Study Day 5 (window: Study Day 4 through Study 
Day 5).  The resource utilized for pharmacokinetic analysis is Phoenix WinNonlin v8.3.1 (or 
later), Certara USA, Inc. (Princeton, NJ).  AUC12 is the primary objective, which will be 
determined using the linear-log trapezoidal rule.  In addition, a population PK analysis may be 
conducted at the end of the study.  
 
 

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9.4.3 
Analysis of the Secondary Endpoint(s) 
Secondary objectives include calculation of additional pharmacokinetic parameters other than 
AUC12, including (but not limited to): AUC∞, Cmax, t1/2, Tmax, ke, CL/F, V/F, C12h, and Tlast.  Cmax 
will be taken as the maximum observed concentration.  Tmax is the time at which Cmax occurs.  
Oral clearance (CL/F) will be calculated as dose/AUC12.  The elimination half-life (t1/2) is a 
secondary parameter that will be determined using regression analysis of the terminal elimination 
phase concentration-time points.  This will also be accomplished using Phoenix WinNonlin (see 
section 9.4.2 for additional details).  
 
Grade 3 AEs and 4 AEs and SAEs are also secondary endpoints.  See Section 9.4.4 for details of 
their analyses. 
 
9.4.4 
Safety Analyses 
Safety evaluations will be based on the incidence, severity, and type of AEs.  Safety variables 
will be tabulated and presented for all subjects in the safety population.  All tests will use a 5% 
significance level, i.e., p-values < 0.05 will be considered significant, and for estimation a 95% 
confidence level will be used. 
Symptoms and toxicities will be listed and the counts and proportion computed by dose cohort.  
Clopper-Pearson method will be used to estimate confidence intervals (or upper bound) around 
the estimates of these proportions and Fisher's exact test to compare the proportions between 
dose cohorts.  Summary statistics will be presented for continuous laboratory safety parameters.  
Data will be presented using appropriate graphical tools to help compare the different dose 
cohorts.  The exact Wilcoxon test will be used to compare between dose cohorts at a given time 
point or area under the curve for variables collected over time (e.g., laboratory parameters).  For 
area under the curve, the average will be taken to adjust for shortened length of follow-up for 
dropouts.  Linear mixed model with random intercept may be considered to analyze data 
collected over time to account for correlation of data from the same subject.  This method 
provides another perspective of comparing the treatment cohorts as area under the curve due to 
being a summary statistic may miss important features of the data that mixed model may detect.  
The generalized linear mixed model can handle continuous, binary and count data.  To measure 
strength of correlation between continuous variables, the Pearson correlation (or Spearman rank 
correlation for variables not distributed normally) will be used.  Analyses will be done using 
SAS version 9.4. 
 
9.4.5 
Baseline Descriptive Statistics 
Baseline characteristics will be summarized.  For both continuous and categorical variables, 
appropriate summary statistics will be applied.  For continuous variables, descriptive statistics 
will include the number of non-missing values, mean, standard deviation, median, minimum, and 
maximum.  For categorical variables, descriptive statistics will include counts and percentages 
per category. 
 
 

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9.4.6 
Planned Interim and Early Analyses 
The initial oral valacyclovir dose will be 10 mg/kg administered two times daily for 5 days 
(Cohort 1).  The target exposure for acyclovir following oral valacyclovir dosing is 36,000 
ngxhr/mL with a range of 24,000 ngxhr/mL to 48,000 ngxhr/mL.  Upon full accrual of Cohort 1, 
the PK and safety data will be reviewed.  If the mean of observed acyclovir exposures of subjects 
in Cohort 1 are below 24,000 ngxhr/mL, AND if no Grade 3 or Grade 4 AEs or SAEs are detected 
in any of the study subjects, then the 8 subjects enrolled in Cohort 2 will receive oral valacyclovir 
at a dose of 20 mg/kg administered two times daily for 5 days.  Alternatively, if the mean of 
observed acyclovir exposures of subjects in Cohort 1 are above 48,000 ngxhr/mL AND if no 
Grade 3 or Grade 4 AEs or SAEs are detected in any of the study subjects, then the 8 subjects 
enrolled in Cohort 2 will receive oral valacyclovir at a dose that has been linearly adjusted 
downward to target 36,000 ngxh/mL area-under-the-concentration-time curve from 0 to 12 hours 
(AUC12).  The SMC retains the ability to suggest an alternative dose be studied in Cohort 2 if the 
mean AUC12 from Cohort 1 is within but at or near the lower or upper ranges in order to attain an 
AUC12 closer to the 36,000 ngxhr/mL target. After assessment of drug exposure and safety in 
Cohort 1, eight new subjects will be enrolled in Cohort 2, with the dose that these subjects will 
receive being predicated upon the pharmacokinetic data from Cohort 1.  
 
If the targeted exposure is not achieved in Cohorts 1 and 2 and the safety data are acceptable, it is 
possible, but not anticipated, that additional dosing cohorts could be recommended based upon 
the results of subjects in the first two cohorts.  If such a recommendation is made, dose selection 
and subject enrollment and assessment will follow the approach used for Cohort 2. 
 
9.4.6.1 
Interim Safety Analyses 
See Section 9.4.6. 
9.4.6.2 
Interim Immunogenicity or Efficacy Review 
Not Applicable 
9.4.7 
Sub-Group Analyses 
Not Applicable 
 
9.4.8 
Tabulation of Individual Participant Data 
Individual participant data will be listed by measure of pharmacokinetic parameter, including 
demographic characteristics. 
 
9.4.9 
Exploratory Analyses 
Not applicable 
 
 
 
 

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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 
Regulatory, Ethical, and Study Oversight Considerations 
Ethical Consideration 
 
This trial will be conducted in compliance with the protocol, International Conference on 
Harmonization Good Clinical Practice E6 (ICH-GCP), 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.  
 
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). 
 
Institutional Review Board 
The UAB Central Unit will identify the IRB that will serve as the Single (Central) IRB of record 
for the U.S. sites participating in this study.  Only institutions holding a current US Federalwide 
Assurance (FWA) issued by OHRP will be allowed to participate in this study. 
 
This protocol, informed consent documents, relevant supporting information, and all types of 
volunteer recruitment or advertisement information will be submitted to the Single IRB of record 
for review and must be approved before the study is initiated.  Any amendments to the protocol 
must also be approved by the Single IRB of record prior to implementing changes in the study.  
The UAB Central Unit will inform the Single IRB of record of the progress of the study and of 
any changes made to the protocol as deemed appropriate, but at least once per year. 
 
The site investigator is responsible for keeping their local IRB apprised of the progress of the 
study and of any changes made to the protocol as deemed appropriate, but at least once per year.  
All IRB approved documents as well as relevant study correspondence should be copied and sent 
to the UAB Central Unit. 
 
10.1.1 
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 

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in each study participants study file and must be available for verification by study monitors at 
any time.  
The investigational nature and research objectives of this study, its procedures, 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, this information will be provided orally or in 
writing to all enrolled or prospective subject’s parent(s)/legal guardian(s).  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). 
 
The subject’s parent(s)/legal guardian(s) will sign the informed consent document prior to any 
procedures being done specifically for the study.  The 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.  The subject’s parent(s)/legal guardian(s) may 
withdraw consent at any time throughout the course of the study.  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. 
10.1.1.1 
Requirements for Permission by Parents/Guardians and Assent by Children (in 
case of a minor)  
If required by the IRB, the parent or legal guardian will sign a waiver of assent for the minor due 
to the study participant’s age. 
10.1.1.2 
Other Informed Consent Procedures 
Not applicable  
 
10.1.2 
Study Termination and Closure 
The NIH or study Principal Investigator have the right to terminate this study at any time.  
Reasons for terminating the study may include, but are not limited to, the following: 
• The incidence or severity of adverse events in this or other studies indicates a potential health 
hazard to study participants. 
• Study participant enrollment is unsatisfactory. 
• Data recording is inaccurate or incomplete. 
• Investigators do not adhere to the protocol or applicable regulatory guidelines in conducting 
the study. 
• Regulatory authority action. 
 

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The sponsor will notify regulatory authorities as applicable.   
  
10.1.3 
Confidentiality and Privacy 
Subject confidentiality will be held in trust by the participating investigators, their staff, the 
Sponsor and their agents.  This confidentiality is extended to cover clinical information related to 
subjects, test results of biological samples and all other information generated during this study. 
This research is covered by a Certificate of Confidentiality from the National Institutes of 
Health.  The information obtained during the conduct of this natural history 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 investigator at each 
site 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.  
Data received by DMID will not include subject specific data but only encoded data.  
The study investigator is obliged to provide the UAB Central Unit and NIAID/DMID with 
complete test results and all data developed in this study; no direct identifiers will be shared.  
NIH/NIAID/DMID or UAB may disclose this information to appropriate regulatory authorities 
or clinical practice management groups (e.g., American Academy of Pediatrics, 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, the NIH/NIAID/DMID, UAB Central 
Unit personnel, and the IRB/IEC for each study site. 
Data may be shared within the NIH/NCATS Rare Diseases Clinical Research Network, as 
required by NCATS or posted on NIH datasharing websites.  No direct identifiers will be shared. 
 
10.1.4 
Secondary Use of Stored Specimens and Data  
 
10.1.4.1 
Samples for Secondary Research 
Secondary Human Subject Research is the re-use of identifiable data or identifiable 
biospecimens that were collected from some other “primary” or “initial” activity, such as the 
data and samples collected in this protocol.  Any use of the sample or data for secondary research 
purposes, however, will be presented in a separate protocol and require separate IRB approval.  
Some of the information and specimens obtained from study participants during this study will 
be stored indefinitely in the UAB Central Laboratory at the University of Alabama at 
Birmingham in accordance with OHRP guidelines ensuring that codes or other personally 
identifying links will not be distributed to future researchers and may be used in secondary  
microbial or antiviral research.  The information and specimens will be labeled with a code 
number linking them to the participant but not with the study participant’s name or other 

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identifiers.  At the time of consent for study participation, study participant’s parent/legal 
guardian will have the opportunity to either agree to have their baby’s information and 
specimens be stored and used in future research or decline storing and sharing for future 
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 “Use of Samples or Data in Other Research Studies”.  Future testing of samples will be 
performed only on samples from study participants who have consented for future storage and 
testing of samples.  Residual research specimens from subject who decline future use will be 
destroyed after the study, final analysis and report writing have all been completed. 
 
Samples will be collected with the subjects’ consent in this protocol with the intent to store for 
additional research (i.e. samples collected beyond those needed for primary research) and will be 
used in future studies on microbial or antiviral research. Specimens will be labeled only with a 
barcode and a unique tracking number to protect subject confidentiality.  Secondary research 
with coded samples and data may occur, but subject confidentiality will be maintained as 
described for this protocol.  Any future testing laboratory will not have access to the code, and 
therefore will not be able to identify study participants.  Genetic testing on these samples will not 
be performed.  An IRB review of the secondary research using coded specimens is required. 
 
10.1.4.2 
Data Sharing for Secondary Research 
Data from this study may be used for secondary research.  All the individual participant data 
collected during the trial will be made available after de-identification.  The Statistical Analysis 
Plan and Analytic Code will also be made available.  These data will be available immediately 
following publication, with no end date.  At the end of the trial, the data may be made available 
to researchers who provide a methodologically sound proposal.  The data will be available for 
any purpose outlined in the approved proposal. Proposals should be directed to David Kimberlin, 
MD (Principal Investigator for this study) at dkimberlin@peds.uab.edu.  To gain access, data 
requestors will need to sign a data access agreement.  An investigator may request removal of 
data on individual study subjects from NIH data repositories in the event that a research subject 
withdraws or changes his/her consent.  However, some data that have been distributed for 
approved research use cannot be retrieved. 
10.1.5 
Key Roles and Study Governance 
The study is sponsored by DMID.  Decisions related to the study will be made by the protocol 
team.  All study team members and roles are listed in the Manual of Procedures (MOP). 
 
10.1.6 
Safety Oversight 
The DMID Medical Monitor will be responsible for reviewing SAEs in real time and all safety 
data.  The Lead PI will also review the SAEs and AE listings as needed to ensure the safe 
conduct of this trial. 
 
Safety oversight will be conducted by a Safety Monitoring Committee (SMC) that is an 
independent group of experts that monitors subject safety and advises DMID.  The SMC 

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members will be separate and independent of study personnel participating in this trial and 
should not have scientific, financial or other conflict of interest related to this trial.  The SMC 
will consist of members with appropriate expertise to contribute to the interpretation of the data 
from this trial.  The SMC will operate under the rules of a SMC-approved charter that will be 
written at the organizational meeting of the SMC.  The SMC will review AEs and SAEs on a 
regular and ad hoc basis during the trial.  
 
The SMC will conduct the following reviews: 
• After each cohort of 8 subjects has completed dosing and been followed for 42 days. 
• Ad hoc meeting:  
o When trial-level halting criteria are met 
o At the request of DMID to review a potential safety concern identified by either the lead 
PI, DMID Medical Monitor, or protocol team 
• A final review meeting to review the cumulative safety data for this trial.  
 
The study will not stop enrolled awaiting the regularly scheduled SMC reviews, although the 
SMC may recommend temporary or permanent cessation of enrollment based on their safety 
reviews.  
 
Additional data may be requested by the SMC, and interim statistical reports may be generated 
as deemed necessary and appropriate by SMC.  The SMC may receive data in aggregate and 
presented by treatment arm.  The SMC may also be provided with expected and observed rates 
of the expected AEs.  The SMC will review grouped data in the closed session only.  As an 
outcome of each review/meeting, the SMC will make a recommendation as to the advisability of 
proceeding with study interventions (as applicable), and to continue, modify, or terminate this 
trial. 
 
10.1.7 
Clinical Monitoring 
Clinical site monitoring will be conducted to ensure that the rights and well being of study 
subjects are protected and that the reported trial data are accurate, complete and verifiable.  
Clinical site monitoring also ensures that the conduct of the trial is in compliances with the 
currently approved protocol/amendment(s), ICH, GCP and with applicable regulatory 
requirements(s) and sponsor requirements.  Clinical monitoring will also verify that any critical 
study procedures are completed following specific instructions in the protocol specific MOP.  
DMID, the sponsor of this study, or its designee will conduct site monitoring visits as detailed in 
the clinical monitoring plan (CMP). 
Site visits will be made at standard intervals in accordance with the monitoring plan.  More 
frequent visits may be made if needed.  Monitoring visits will include, but are not limited to, 
review of regulatory files, product accountability records, CRFs, ICFs medical and laboratory 
reports, study site product storage records, and protocol and GCP compliance.  Site monitors will 
have access to each participating site, study personnel, and all study documentation according to 
the DMID-approved site monitoring plan.  Remote or on-site monitoring may be used.  Study 
monitors will meet with the site PIs to discuss any problems and outstanding issues and will 

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document site visit findings and discussions.  The UAB Central Unit will work with the sites to 
address all monitoring findings. 
 
10.1.8 
Quality Assurance and Quality Control 
Each study site will have a quality management plan.  Following a written DMID-accepted site 
quality management plan, the investigational site is responsible for conducting routine quality 
assurance and quality control activities to internally monitor study progress and protocol 
compliance.  The PI will provide direct access to all trial-related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local 
and regulatory authorities.  The PI will ensure all study personnel are appropriately trained and 
applicable documentation is maintained on site. 
The SDCC will implement quality control procedures beginning with the data entry system and 
generate data quality control checks that will be run on the database.  Any missing data or data 
anomalies will be communicated to the site(s) for clarification and resolution. 
 
10.1.9 
Data Handling and Record Keeping 
 
10.1.9.1 
Data Collection and Management Responsibilities 
Data collection is the responsibility of the study personnel at the participating clinical study site 
under the supervision of the site PI.  The site PI must maintain complete and accurate source 
documentation.  At the end of the study, the PI will attest to the accurateness of data collected at 
the study site. 
Clinical data from source documentation (including, but not limited to, AEs/SAEs, concomitant 
medications, medical history, physical assessments, clinical and research laboratory data) will be 
entered into CRFs via a 21 CFR Part 11-compliant Internet Data Entry System (IDES) provided 
by the SDCC.  The data system includes password protection and internal quality checks, such as 
automatic range checks, to identify data that appear inconsistent, incomplete, or inaccurate. AEs 
and concomitant medications will be coded according to the most current versions of MedDRA 
and WhoDrug, respectively.  
The SDCC for this study will be responsible for data management, quality review, analysis and 
reporting of the study data. 
AEs will be coded according to the MedDRA dictionary version 23.0 or higher. A separate study 
specific Study Data Standardization Plan (SDSP) appendix will be developed which describes 
the technical recommendations for the submission of human study data and related information 
in a standardized electronic format throughout product development.  At the end of the study, a 
copy of all datasets including annotated CRFs and data dictionary will be provided to DMID and 
to the lead PI.   
 

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10.1.9.2 
Study Record Retention 
Study related records and documents pertaining to the conduct of this study, including subject 
source documents and electronic records, consent forms, the regulatory file, laboratory test 
results, and study product accountability records, must be retained by the investigator for at least 
2 years following completion of the study.  No study records shall be destroyed without written 
authorization from the UAB Central Unit and NIAID/DMID.  These documents should be 
retained for a longer period, however, if required by local regulations.  Consent forms with 
specimen retention linked to identifiable specimens will be maintained for as long as the 
specimens remain in identifiable format and a minimum of three years after use of the 
identifiable specimens in nonexempt human subject research.  It is the responsibility of the 
sponsor to notify the UAB Central Unit, which will notify the investigators, when these 
documents no longer need to be retained. 
 
10.1.9.3 
Source Records 
Source data are all information in original records (and certified copies of original records) of 
clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source data should be attributable, legible, 
contemporaneous, original, accurate, and complete.  Each participating site will maintain 
appropriate medical and research records for this trial, in compliance with ICH GCP, regulatory, 
and institutional requirements.  Data recorded in the CRF derived from source documents should 
be consistent with the data recorded on the source documents.  Data collection forms used as 
source documents will be derived from the eCRFs and be provided by the SDCC.  
 
10.1.10 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trials protocol, GCP, or Manual of 
Procedures requirements.  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.  All individual protocol deviations will be 
addressed in study subject records. 
It is the responsibility of the site PI and study personnel 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 
Sponsor DMID per the protocol deviation reporting procedures. 
A completed copy of the DMID protocol deviation form must be maintained in the regulatory 
file (Project Notebook or designated location) as well as in the subject’s source documents.  
Protocol deviations must be sent to the Single (Central) IRB and the local IRB per the IRB’s 
guidelines.  The site PI/study staff is responsible for knowing and adhering to their IRB/IEC 
requirements. 
 
 

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10.1.11 
Publication and Data Sharing Policy 
This trial will be registered in the public registry ClinicalTrials.gov per NIH policy.  Results 
from the trial will be published on ClinicalTrials.gov in accordance with the policy and U.S. law 
and will be published in a scientific journal. 
 
10.1.12 
Human Data Sharing Plan 
This study will be conducted in accordance with the following publication and data sharing 
policies and regulations: 
• National Institutes of Health (NIH) Public Access Policy, which ensures that the public has 
access to the published results of NIH funded research. It requires scientists to submit final 
peer-reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed 
Central upon acceptance for publication. 
 
As this study is conducted as part of the National Center for Advancing Translational Science 
(NCATS) Rare Diseases Clinical Research Network (RDCRN), data may be shared with a 
common data repository maintained by NCATS and managed by the Data Management and 
Coordinating Center (DMCC). 
 
10.1.13 
Genomic Data Sharing Plan 
Not applicable 
 
10.1.14 
Publication 
Following completion of this study, the investigators are expected to publish the results in a 
scientific journal.  The study will adhere to the following publication and data sharing policies 
and regulations: 
• This study will comply with the NIH Public Access Policy, which ensures that the public has 
access to the published results of NIH funded research. As such, the final peer reviewed 
journal manuscripts will accessible to the public on PubMed Central no later than 12 months 
after publication.  
 
10.1.15 
Conflict of Interest Policy 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed.  Furthermore, persons who have a perceived conflict of interest will be 
required to have such conflicts managed in a way that is appropriate to their participation in the 
design and conduct of this trial.  DMID has established policies and procedures for all study 
group members to disclose all conflicts of interest and will establish a mechanism for the 
management of all reported dualities of interest. 
 

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10.2 
Additional Considerations 
 
10.2.1 
Research Related Injuries 
For any potential research related injury, the site principal investigator or designee will assess the 
subject.  Study personnel will try to reduce, control, and treat any complications from this study. 
Immediate medical treatment may be provided by the participating study site.  As needed, 
referrals to appropriate health care facilities will be provided to the subject.   
The site principal investigator should then determine if an injury occurred as a direct result of the 
tests or treatments that are done for this trial.  If the site PI determines that the injury occurred to 
a subject as a direct results of the tests or treatments, then immediate medical treatment may be 
provided, such as giving emergency medications to stop allergic reactions.  Referrals to 
appropriate health care facilities will be provided.  No financial compensation will be provided 
by the NIAID, NIH, the federal government, or the participating site to the subject, for any injury 
suffered due to participation in this trial. 
10.3 
Abbreviations 
Table 6. Abbreviations 
ACOG 
American College of Obstetrics and Gynecology 
AE 
Adverse Event 
ALT 
Alanine Transaminase 
ANCOVA 
Analysis of Covariance 
AUC 
Area Under the Curve 
BID 
Twice daily 
CASG 
Collaborative Antiviral Study Group 
CBC 
Complete Blood Count 
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CLIA 
Clinical Laboratory Improvement Amendments 
CMS 
Clinical Material Services 
CNS 
Central Nervous System 
CPIC 
Congenital and Perinatal Infections Consortium 
CRF 
Case Report Form 
CROMS 
Clinical Research Operations and Management Support 
CU 
Central Unit 
DCC 
Data Coordinating Center 
DMID 
Division of Microbiology and Infectious Diseases 
DSMB 
Data Safety Monitoring Board 
eCRF 
Electronic Case Report Forms 
eDES 
Electronic Data Entry System 
FDA 
Food and Drug Administration 
FWA 
Federal Wide Assurance 

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GCP 
Good Clinical Practice 
GCSF 
Granulocyte colony-stimulating factor 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HSV 
Herpes Simplex Virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IEC 
Independent or Institutional Ethics Committee 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intent To Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MedDRAÒ 
Medical Dictionary for Regulatory Activities 
Mg 
Milligram 
MOP 
Manual of Procedures 
N 
Number (typically refers to subjects) 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
OHRP 
Office for Human Research Protections 
PCR 
Polymerase  Chain Reaction 
PI 
Principal Investigator 
PMTCT 
Prevention of mother-to-child transmission 
PK 
Pharmacokinetics 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SDCC 
Statistical and Data Coordinating Center 
SEM 
Skin, Eye, Mouth 
SMA 
Secondary Medical Assessor 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
UAB CU 
University of Alabama at Birmingham Central Unit 
ULN 
Upper limit of normal 
UP 
Unanticipated Problem 
US 
United States 
VZV 
Varicella-zoster virus 
WBC 
White Blood Cell 
 

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10.4 
Protocol Amendment History 
Table 7. Protocol Amendment History 
Version 
Date 
Description of Change  
Brief Rationale 
4.0 
05 March 
2024 
• Clarification of number of 
doses a subject may receive 
• Clarification of dose around 
which PK samples should be 
obtained 
• Clarification that an SMC will 
be overseeing the study rather 
than a DSMB 
• Addition of the web link to the 
DMID Serious Adverse Event 
form 
There were internal 
discrepancies in v3.0 of the 
protocol. These have been 
corrected in v4.0. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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11. 
REFERENCES 
 
1. 
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. 
2. 
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. 
3. 
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. 
4. 
Kimberlin DW. Neonatal herpes simplex infection. Clinical microbiology reviews. 
2004;17(1):1-13. 
5. 
ACOG Practice Bulletin: Clinical Management Guidelines for Obstetrician-
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6. 
American Academy of Pediatrics. Herpes simplex. In: Kimberlin DW, Barnett ED, 
Lynfield R, Sawyer MH, editors. Red Book: 2021 Report of the Committee on Infectious 
Diseases. 32nd ed. Itasca, IL: American Academy of Pediatrics; 2021. p. 407-17. 
7. 
Rao S, Abzug MJ, Carosone-Link P, Peterson T, Child J, Siparksy G, et al. Intravenous 
acyclovir and renal dysfunction in children: a matched case control study. J Pediatr. 
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9. 
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Kimberlin DW, Baley J. Guidance on management of asymptomatic neonates born to 
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American Academy of Pediatrics. Herpes simplex. In: Kimberlin DW, Brady MT, 
Jackson MA, Long SS, editors. Red Book: 2015 Report of the Committee on Infectious 
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12. 
American Academy of Pediatrics. Herpes simplex. In: Kimberlin DW, Brady MT, 
Jackson MA, Long SS, editors. Red Book: 2018 Report of the Committee on Infectious 
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13. 
Fish DN, Vidaurri VA, Deeter RG. Stability of valacyclovir hydrochloride in 
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14. 
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. N Engl J 
Med. 1991;324(7):444-9. 

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15. 
Jacobson MA. Valaciclovir (BW256U87): the L-valyl ester of acyclovir. Journal of 
Medical Virology. 1993;Suppl(1):150-3. 
16. 
Soul-Lawton J, Seaber E, On N, Wootton R, Rolan P, Posner J. Absolute bioavailability 
and metabolic disposition of valaciclovir, the L-valyl ester of acyclovir, following oral 
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17. 
Weller S, Blum MR, Doucette M, Burnette T, Cederberg DM, de Miranda P, et al. 
Pharmacokinetics of the acyclovir pro-drug valaciclovir after escalating single- and 
multiple-dose administration to normal volunteers. Clinical Pharmacology & 
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18. 
Valacyclovir Package Insert. 2008 [Available from: 
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19. 
Mahant S, Hall M, Schondelmeyer AC, Berry JG, Kimberlin DW, Shah SS, et al. 
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20. 
Whitley RJ, Corey L, Arvin A, Lakeman FD, Sumaya CV, Wright PF, et al. Changing 
presentation of herpes simplex virus infection in neonates. J Infect Dis. 1988;158(1):109-
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21. 
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22. 
Yeager AS, Arvin AM. Reasons for the absence of a history of recurrent genital 
infections in mothers of neonates infected with herpes simplex virus. Pediatrics. 
1984;73(2):188-93. 
23. 
Braig S, Luton D, Sibony O, Edlinger C, Boissinot C, Blot P, et al. Acyclovir prophylaxis 
in late pregnancy prevents recurrent genital herpes and viral shedding. Eur J Obstet 
Gynecol Reprod Biol. 2001;96(1):55-8. 
24. 
Scott LL, Sanchez PJ, Jackson GL, Zeray F, Wendel GD, Jr. Acyclovir suppression to 
prevent cesarean delivery after first-episode genital herpes. Obstet Gynecol. 
1996;87(1):69-73. 
25. 
Scott LL, Hollier LM, McIntire D, Sanchez PJ, Jackson GL, Wendel GD, Jr. Acyclovir 
suppression to prevent recurrent genital herpes at delivery. Infectious Diseases in 
Obstetrics & Gynecology. 2002;10(2):71-7. 
26. 
Sheffield JS, Hill JB, Hollier LM, Laibl VR, Roberts SW, Sanchez PJ, et al. Valacyclovir 
Prophylaxis to Prevent Recurrent Herpes at Delivery: A Randomized Clinical Trial. 
Obstet Gynecol. 2006;108(1):141-7. 
27. 
Brocklehurst P, Kinghorn G, Carney O, Helsen K, Ross E, Ellis E, et al. A randomised 
placebo controlled trial of suppressive acyclovir in late pregnancy in women with 
recurrent genital herpes infection. British Journal of Obstetrics & Gynaecology. 
1998;105(3):275-80. 
28. 
Andrews WW, Kimberlin DF, Whitley R, Cliver S, Ramsey PS, Deeter R. Valacyclovir 
therapy to reduce recurrent genital herpes in pregnant women. Am J Obstet Gynecol. 
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29. 
Pinninti SG, Angara R, Feja KN, Kimberlin DW, Leach CT, Conrad DA, et al. Neonatal 
herpes disease following maternal antenatal antiviral suppressive therapy: a multicenter 
case series. J Pediatr. 2012;161(1):134-8 e1-3. 

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30. 
McQuillan G, Kruszon-Moran D, Flagg EW, Paulose-Ram R. Prevalence of Herpes 
Simplex Virus Type 1 and Type 2 in Persons Aged 14-49: United States, 2015-2016. 
NCHS Data Brief. 2018(304):1-8. 
31. 
Kimberlin DW, Rouse DJ. Genital herpes. N Engl J Med. 2004;350(19):1970-7. 
32. 
Kimberlin DW. The Scarlet H. J Infect Dis. 2014;209:315-7. 
33. 
Brown ZA, Wald A, Morrow RA, Selke S, Zeh J, Corey L. Effect of serologic status and 
cesarean delivery on transmission rates of herpes simplex virus from mother to infant. 
JAMA. 2003;289(2):203-9. 
34. 
Wagstaff AJ, Faulds D, Goa KL. Aciclovir. A reappraisal of its antiviral activity, 
pharmacokinetic properties and therapeutic efficacy. Drugs. 1994;47(1):153-205. 
35. 
Morse GD, Shelton MJ, O'Donnell AM. Comparative pharmacokinetics of antiviral 
nucleoside analogues. Clinical Pharmacokinetics. 1993;24(2):101-23. 
36. 
Elion GB. Mechanism of action and selectivity of acyclovir. American Journal of 
Medicine. 1982;73(1A):7-13. 
37. 
Reardon JE, Spector T. Herpes simplex virus type 1 DNA polymerase. Mechanism of 
inhibition by acyclovir triphosphate. Journal of Biological Chemistry. 
1989;264(13):7405-11. 
38. 
Sheffield JS, Wendel GDJ, Laibl VR, Roberts SW, Sanchez PJ, Hollier LM, et al. 
Valacyclovir Prophylaxis to Prevent Recurrent Herpes at Delivery: A Randomized 
Clinical Trial. Obstet Gynecol. 2006;108(6):1550-2. 
39. 
Weinberg GA, D'Angio CT. Laboratory Aids for Diagnosis of Neonatal Sepsis. In: 
Wilson CB, Nizet V, Maldonado YA, Remington JS, Klein JO, editors. Remington and 
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Elsevier Publishing; 2016. p. 1134-6. 
 
 
 

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12. 
APPENDIX A: (ADAPTED FROM) DIVISION OF AIDS 
TOXICITY TABLES 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
ALT or SGPT, High 
Report only one 
1.25  to < 2.5 
x ULN 
2.5 to < 5.0 x ULN 
5.0  to < 10.0 x ULN 
≥ 10.0 x ULN 
Creatinine, High 
1.1 to 1.3 x ULN 
> 1.3 to 1.8 x ULN 
OR Increase of 
> 0.3 mg/dL above 
baseline 
> 1.8  to < 3.5 
x ULN OR Increase 
of 1.5 to < 2.0 x 
above baseline 
≥ 3.5 x ULN OR 
Increase of ≥ 2.0 x above 
baseline 
Absolute Neutrophil 
Count (ANC), Low 
(cells/mm3; cells/L) 
> 7 days of age 
800 to 1,000 
0.800 x 109 to 1.000 x 
109 
600 to 799 
0.600 x 109 to 0.799 x 
109 
400 to 599 
0.400 x 109 to 0.599 x 
109 
< 400 
< 0.400 x 109 
2 to 7 days of age 
1,250 to 1,500 
1.250 x 109 to 1.500 x 
109 
1,000 to 1,249 
1.000 x 109 to 1.249 x 
109 
750 to 999 
0.750 x 109 to 0.999 x 
109 
< 750 
< 0.750 x 109 
≤ 1 day of age 
4,000 to 5,000 
4.000 x 109 to 
5.000 x 109 
3,000 to 3,999 
3.000 x 109 to 3.999 x 
109 
1,500 to 2,999 
1.500 x 109 to 2.999 x 
109 
< 1,500 
< 1.500 x 109 
Hemoglobin, Low 
(g/dL; mmol/L) 
≥ 13 years of age 
(male only) 
10.0 to 10.9 
6.19 to 6.76 
9.0 to < 10.0 
5.57 to < 6.19 
7.0 to < 9.0 
4.34 to < 5.57 
< 7.0 
< 4.34 
≥ 13 years of age 
(female only) 
9.5 to 10.4 
5.88 to 6.48 
8.5 to < 9.5 
5.25 to < 5.88 
6.5 to < 8.5 
4.03 to < 5.25 
< 6.5 
< 4.03 
57 days of age to < 13 
years of age 
(male and female) 
9.5 to 10.4 
5.88 to 6.48 
8.5 to < 9.5 
5.25 to < 5.88 
6.5 to < 8.5 
4.03 to < 5.25 
< 6.5 
< 4.03 
36 to 56 days of age 
(male and female) 
8.5 to 9.6 
5.26 to 5.99 
7.0 to < 8.5 
4.32 to < 5.26 
6.0 to < 7.0 
3.72 to < 4.32 
< 6.0 
< 3.72 
22 to 35 days of age 
(male and female) 
9.5 to 11.0 
5.88 to 6.86 
8.0 to < 9.5 
4.94 to < 5.88 
6.7 to < 8.0 
4.15 to < 4.94 
< 6.7 
< 4.15 
8 to ≤ 21 days of age 
(male and female) 
11.0 to 13.0 
6.81 to 8.10 
9.0 to < 11.0 
5.57 to < 6.81 
8.0 to < 9.0 
4.96 to < 5.57 
< 8.0 
< 4.96 
≤ 7 days of age 
(male and female) 
13.0 to 14.0 
8.05 to 8.72 
10.0 to < 13.0 
6.19 to < 8.05 
9.0 to < 10.0 
5.59 to < 6.19 
< 9.0 
< 5.59 

Protocol 20-0033 
Version 4.0 
Neonatal Phase 1 Valacyclovir Study 
 
05 March 2024 
 
 
DMID/NIAID/NIH 
CONFIDENTIAL 
Page 56 of 56 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Platelets, Decreased 
(cells/mm3; cells/L) 
100,000  to 
< 124,999 
100.000 x 109  to 
< 124.999 x 109 
50,000  to 
< 100,000 
50.000 x 109  to 
< 100.000 x 109 
25,000  to 
< 50,000 
25.000 x 109  to 
< 50.000 x 109 
< 25,000 
< 25.000 x 109 
WBC, Decreased 
(cells/mm3; cells/L) 
> 7 days of age 
2,000 to 2,499 
2.000 x 109 to 2.499 x 
109 
1,500 to 1,999 
1.500 x 109 to 1.999 x 
109 
1,000 to 1,499 
1.000 x 109 to 1.499 x 
109 
< 1,000 
< 1.000 x 109 
≤ 7 days of age 
5,500 to 6,999 
5.500 x 109 to 6.999 x 
109 
4,000 to 5,499 
4.000 x 109 to 5.499 x 
109 
2,500 to 3,999 
2.500 x 109 to 3.999 x 
109 
< 2,500 
< 2.500 x 109 
Diarrhea 
< 1 year of age 
Liquid stools 
(more unformed 
than usual) but 
usual number of 
stools  
 
Liquid stools with 
increased number of 
stools OR Mild 
dehydration  
 
Liquid stools with 
moderate dehydration 
Life-threatening 
consequences (e.g., liquid 
stools resulting in severe 
dehydration, hypotensive 
shock)  
Vomiting 
Transient or 
intermittent 
AND No or 
minimal 
interference 
with oral 
intake  
Frequent episodes with 
no or mild dehydration 
Persistent vomiting 
resulting in orthostatic 
hypotension OR 
Aggressive rehydration 
indicated (e.g., IV 
fluids)  
Life-threatening 
consequences (e.g., 
hypotensive shock)