Evaluation of the Pharmacokinetics and Pharmacodynamics of Ganciclovir in Premature Infants Receiving Treatment for Cytomegalovirus Infection
Conditions: Cytomegalovirus Infections
Sponsor: University of Alabama at Birmingham

 
EVALUATION OF THE PHARMACOKINETICS AND 
PHARMACODYNAMICS OF GANCICLOVIR IN PREMATURE 
INFANTS RECEIVING TREATMENT FOR CYTOMEGALOVIRUS 
INFECTION 
DMID Protocol Number: 11-0067 
 
DMID Funding Mechanism:  HHSN272201100037C 
Sponsor: DMID 
Principal Investigator: David W. Kimberlin, M.D. 
DMID Clinical Project Manager: Walla Dempsey, Ph.D. 
DMID Medical Monitor: Venus Shahamatdar, M.D. 
Version Number:  2.0 
14 August 2015  
 
 

Collaborative Antiviral Study Group                                                    DMID Protocol #11-0067, Version 2.0  
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STATEMENT OF COMPLIANCE 
 
 
Each investigator must adhere to the protocol as detailed in this document.  Each 
investigator will be responsible for enrolling only those study participants who have met 
protocol eligibility criteria.  This trial will be conducted in compliance with the protocol, 
International Conference on Harmonization Good Clinical Practice guidelines (ICH-E6), 
and the applicable regulatory requirements, including: 
 U.S. Code of Federal Regulations applicable to clinical studies (45 CFR 46 and 21 
CFR including parts 50 and 56 concerning informed consent and IRB regulations, if 
under IND, 21 CFR 312). 
 Completion of Human Subjects Protection Training.  Refer to 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-061.html; 
http://cme.cancer.gov/clinicaltrials/learning/humanparticipant-protections.asp  

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SIGNATURE PAGE 
The signature below constitutes the approval of this protocol “Evaluation of the 
Pharmacokinetics and Pharmacodynamics of Ganciclovir in 
Premature Infants Receiving Treatment for Cytomegalovirus Infection” 
and attachments and provides the necessary assurances that this trial will be conducted 
according to all stipulations of the protocol, including all statements regarding 
confidentiality, and according to local legal and regulatory requirements and applicable 
U.S. federal regulations and ICH guidelines.  It is understood that no deviations from the 
protocol may be made without permission of the Sponsor.   
 
Site Investigator: 
 
Signed: 
 
Date: 
 
 
Name 
 
 
 
 
 
Title 
 
 
  
 
 
 

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TABLE OF CONTENTS 
Page 
Statement of Compliance………………………………………………………………………………... ii 
Signature Page……………………………………………………………………………………………iii 
Table of Contents………………………………………………………………………………………... iv 
List of Abbreviations……………………………………………………………………………………...vi 
Protocol Summary……………………………………………………………………………………… viii 
1 
Key Roles…………………………………………………………………………………………... 1 
2 
Background Information and Scientific Rationale……………………………………………… 6 
2.1 
Background Information ........................................................................................... 6 
2.2 
Rationale .................................................................................................................. 7 
2.3 
Potential Risks and Benefits ..................................................................................... 7 
2.3.1 
Potential Risks .............................................................................................. 7 
2.3.2 
Known Potential Benefits .............................................................................. 8 
3 
Objectives…………………………………………………………………………………………...9 
3.1 
Study Objectives ...................................................................................................... 9 
3.2 
Study Outcome Measures ........................................................................................ 9 
3.2.1 
Primary Outcome Measures ......................................................................... 9 
3.2.2 
Secondary Outcome Measures .................................................................... 9 
3.2.3 
Exploratory Outcome Measures ................................................................... 9 
4 
Study Design………………………………………………………………………………………10 
5 
Study Enrollment and Withdrawal……………………………………………………………… 12 
5.1 
Subject Inclusion Criteria ........................................................................................ 12 
5.2 
Subject Exclusion Criteria ...................................................................................... 12 
5.3 
Treatment Assignment Procedures ........................................................................ 12 
5.3.1 
Randomization Procedures ........................................................................ 12 
5.3.2 
Reasons for Delaying Study-Related Procedures ...................................... 12 
5.3.3 
Reasons for Withdrawal ............................................................................. 13 
5.3.4 
Handling of Withdrawals ............................................................................. 13 
5.3.5 
Termination of Study .................................................................................. 13 
6 
Study Intervention/Investigational Product……………………………………………………. 14 
8 
Study Procedures/Evaluations…………………………………………………………………..23 
8.1 
Clinical Evaluations ................................................................................................ 23 
8.1.1. Baseline Demographics ............................................................................... 23 
8.2 
Laboratory Evaluations ........................................................................................... 23 
8.2.1 
Special Assays or Procedures .................................................................... 23 
8.2.2 
Specimen Preparation, Handling, and Shipping ......................................... 26 
8.3 
PRBC Transfusion Assessment ............................................................................. 27 
9 
Assessment of Safety…………………………………………………………………………….28 
9.1 
Safety Reporting:  Adverse Events of Special Interest (AESI) ............................... 28 

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9.2 
Type and Duration of Follow-up of Subjects after Adverse Events ........................ 28 
9.3 
Halting Rules .......................................................................................................... 28 
9.3.1 
Discontinue of Study participation for individual subject. ............................ 28 
9.3.2 
Discontinuation of Study Enrollment Pending Sponsor Review ................. 29 
9.4 
DMID Safety Oversight ........................................................................................... 30 
9.5 
FDA MedWatch Adverse Event Reporting Program .............................................. 31 
10 
Clinical Monitoring………………………………………………………………………………...32 
10.1 
Site Monitoring Plan ............................................................................................... 32 
11 
Statistical Considerations……………………………………………………………………….. 33 
11.1 
Study Hypotheses .................................................................................................. 33 
11.2 
Sample Size Considerations .................................................................................. 33 
11.3 
Planned Interim Analyses (if applicable) ................................................................ 34 
11.4 
Final Analysis Plan ................................................................................................. 34 
12 
Source Documents and Access to Source Data/Documents………………………………...36 
13 
Quality Control and Quality Assurance…………………………………………………………37 
14 
Ethics/Protection of Human Subjects…………………………………………………………...38 
14.1 
Ethical Standard ..................................................................................................... 38 
14.2 
Institutional Review Board ...................................................................................... 38 
14.3 
Informed Consent Process ..................................................................................... 38 
14.3.1  Informed Consent/Assent Process (in Case of a Minor)............................. 39 
14.4 
Exclusion of Women, Minorities, and Children (Special Populations) .................... 39 
14.5 
Subject Confidentiality ............................................................................................ 40 
14.6 
Study Discontinuation ............................................................................................. 40 
14.7 
Future Use of Stored Specimens ........................................................................... 40 
15 
Data Handling and Record Keeping…………………………………………………………… 42 
15.1 
Data Management Responsibilities ........................................................................ 42 
15.2 
Data Capture Methods ........................................................................................... 43 
15.3 
Types of Data ......................................................................................................... 43 
15.4 
Timing/Reports ....................................................................................................... 43 
15.5 
Study Records Retention ....................................................................................... 43 
15.6 
Protocol Deviations ................................................................................................ 43 
16 
Publication Policy………………………………………………………………………………… 45 
17 
Literature References……………………………………………………………………………. 46 
Supplements/Appendices……………………………………………………………………………… 49 
Appendix A: Schedule of Events (following Acquisition of Informed Consent)…………………... 50 
 
 

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LIST OF ABBREVIATIONS 
 
 
 
 
AE 
Adverse Event/Adverse Experience 
AESI 
Adverse Event Special Interest 
AUC 
Area Under the Curve 
CASG 
Collaborative Antiviral Study Group 
CFR 
Code of Federal Regulations 
CMV 
Cytomegalovirus 
CQMP 
Clinical Quality Management Plan 
CRF 
Case Report Form 
CROMS 
Clinical Research Operations and Management Support 
DAIDS 
Division of AIDS 
DHHS 
Department of Health and Human Services 
DMID 
Division of Microbiology and Infectious Diseases, NIAID, NIH, 
DHHS 
eCRF 
Electronic Case Report Form 
FDA 
Food and Drug Administration 
FWA 
Federalwide Assurance 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent or Institutional Ethics Committee 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
KG 
Kilogram 
MG 
Milligram 
mL 
Milliliter 
MOP 
Manual of Procedures 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH, DHHS 
NIH 
National Institutes of Health 
OHRP 
Office for Human Research Protections 
PCR 
Polymerase Chain Reaction 
PD 
Pharmacodynamic 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PK 
Pharmacokinetics 

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PRBC 
Packed Red Blood Cell 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
US 
United States 
 

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PROTOCOL SUMMARY 
 
Title: 
Evaluation of the Pharmacokinetics and Pharmacodynamics of 
Ganciclovir in Premature Infants Receiving Treatment for 
Cytomegalovirus Infection 
Phase: 
Not Applicable (clinical sampling study) 
Population: 
Male and female premature infants < 32 weeks gestation who 
are being treated for medical reasons with intravenous 
ganciclovir for proven [e.g., culture- or polymerase chain 
reaction (PCR)-confirmed] CMV infections.  Subjects will be 
stratified according to age (gestational and chronologic) 
Sample Size: 
32 
Number of Sites: 
15 
Study Duration: 
5 years 
Subject Participation 
Duration: 
Up to 7 weeks  
Description of Agent or 
Intervention: 
None. 
This is not an interventional study.  It is a clinical sampling 
study, and ganciclovir will not be administered as part of the 
protocol. 
 
Objectives: 
 
 
The goals of the study are to determine ganciclovir 
pharmacokinetic and pharmacodynamic parameters in 
premature infants who receive IV ganciclovir as part of medical 
care to treat CMV infections. 
 
Primary: 
 
To define the pharmacokinetics of ganciclovir in premature 
(< 32 weeks gestational age at birth) infants 
 
Secondary: 

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 
To assess changes in quantitative viral DNA in whole blood 
as a function of ganciclovir pharmacokinetics 
 
To assess clearance of CMV in urine as a function of 
ganciclovir pharmacokinetics 
 
Exploratory: 
 
To assess development of neutropenia as a function of 
ganciclovir pharmacokinetics 
 
To determine the potential for the development of resistance 
to ganciclovir as a function of pharmacokinetics, dose, age, 
and duration of therapy 
 
 
Outcome Measures 
 
 
 
Primary Endpoint: 
• 
Plasma pharmacokinetics parameters for ganciclovir 
AUC12  
Secondary Endpoints: 
• 
Plasma pharmacokinetics parameters for ganciclovir, 
including maximum serum concentration (Cmax), half-life 
(T1/2), CL, and Vd 
• 
Correlation of ganciclovir plasma concentrations with 
CMV whole blood viral load 
• 
Correlation of ganciclovir plasma concentrations with 
clearance of CMV in urine  
Exploratory Endpoints: 
• 
Correlation of ganciclovir plasma concentrations with 
neutropenia 
• 
Detection of resistance to ganciclovir 
 
Description of Study 
Design: 
 
This is an open-label, multi-center, clinical sampling study to 
assess ganciclovir pharmacokinetics and pharmacodynamics  in 
premature infants undergoing antiviral therapy for CMV.  Only 
those subjects who receive ganciclovir for clinical reasons will 
be enrolled.  The decision to initiate ganciclovir therapy will be 

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made by the attending physician based upon his/her clinical 
decision to treat virologically-confirmed CMV infection; infants 
receiving such therapy and meeting entry criteria will then be 
eligible for this study.  Therefore, ganciclovir will not be provided 
under this protocol. 
 
Subjects meeting enrollment criteria will be entered into this 
clinical trial.  Following enrollment, subjects will be stratified by 
gestational age and by chronologic age as follows:  1) ≤ 27 
weeks 6 days gestational age at birth and ≤ 30 days chronologic 
age at study enrollment; 2) ≤ 27 weeks 6 days gestational age 
at birth and > 30 days chronologic age at study enrollment; 3) ≥ 
28 weeks 0 days gestational age at birth and ≤ 30 days 
chronologic age at study enrollment; 4) ≥ 28 weeks 0 days 
gestational age at birth and > 30 days chronologic age at study 
enrollment.  The total sample size across these four cohorts is 
32 subjects.  Subjects in each cohort with inadequate 
pharmacokinetic data for analysis (e.g., due to dropping out of 
the study before PK assessments are performed, or blood 
sampling obtained but is inadequate for analysis) may be 
replaced and will not count toward the total of 32 subjects.  
Additionally, enrollment of an additional 2-3 subjects may be 
allowed for operational reasons. 
A full pharmacokinetic profile will be obtained following at least 
one of the ganciclovir doses received after study enrollment. 
The PK samples will be obtained after the subject has received 
study assessment dose 3, 4, 5, 6, 7, or 8 of intravenous 
ganciclovir.  Typically, ganciclovir is administered twice per day 
in these infants for a duration in excess of 10 days.  Specimens 
will be shipped for processing at that time.  The pharmacokinetic 
data will then be provided to the study site, including the AUC 
and CL values for information purposes.     
Dose and duration of intravenous ganciclovir therapy is at the 
discretion of the treating physician and will not be dictated by 
the research protocol.  Both whole blood for CMV PCR and 
urine for CMV detection will be obtained once in each study 
period as long as the subject is receiving intravenous ganciclovir 
therapy.  These specimens will be used to determine viral load 
and ganciclovir resistance.  Since ganciclovir is a renally 

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excreted drug, serum creatinine will be drawn for the research 
protocol on the day that the ganciclovir pharmacokinetic 
specimens are obtained in order to calculate creatinine 
clearance using a method such as the modified Schwartz 
formula, and thus correlate ganciclovir clearance with renal 
function. Otherwise, data from hematology assessments (WBC 
count and differential, hemoglobin, platelet count) and from 
chemistry labs (serum creatinine, AST, and ALT) will be 
recorded on the study case report forms during each study 
period if they are being obtained for clinical reasons, but will not 
be drawn only for the purposes of the study.  Ganciclovir dosing 
information (mg/dose, dosing interval, and subject weight) will 
be recorded on the day of the pharmacokinetic blood draws, and 
weekly from Period 1 through Period 7 as long as the subject is 
receiving intravenous ganciclovir therapy. 
If the subject continues to receive intravenous ganciclovir from 
Study Assessment Day 18 through Study Assessment  Day 24 
(Period 4), a second PK assessment may be performed at the 
request of the treating physician if the subject weighs 575  
grams or more at the time of specimen collection. 
Estimated Time to 
Complete Enrollment: 
4 years from enrollment of the first study subject 

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*Schematic of Study Design: 
 
 
P 
A 
R 
E 
N 
T 
E 
R 
A 
L 
 
G 
A 
N 
C 
I 
C 
L 
O 
V 
I 
R 
 
A 
D 
M 
I 
N 
I 
S 
T 
R 
A 
T 
I 
O 
N 
Period 1 (Study Assessment Day 1 through Study 
Assessment Day 3)  
Ganciclovir PK 
Virologic specimens (once per study period) 
Safety laboratory tests 
Period 2 (Study Assessment Day 4 through Study 
Assessment Day 10) 
Virologic specimens (once per study period) 
Safety laboratory tests 
Period 3 (Study Assessment Day 11 through Study 
Assessment Day 17) 
Virologic specimens (once per study period) 
Safety laboratory tests 
Period 4 (Study Assessment Day 18 through Study 
Assessment Day 24)  
Ganciclovir PK (if requested by treating physician 
and subject’s weight is ≥ to 575 grams on the day 
obtained) 
Virologic specimens (once per study period) 
Safety laboratory tests
Period 5 (Study Assessment Day 25 through Study 
Assessment Day 31)  
Virologic specimens (once per study period) 
Safety laboratory tests 
Period 6 (Study Assessment Day 32 through Study 
Assessment Day 38)  
Virologic specimens (once per study period if 
subject’s weight is ≥ 600 grams on the day obtained) 
Safety laboratory tests 
Period 7 (Study Assessment Day 39 through Study 
Assessment Day 42)  
Virologic specimens (once per study period if 
subject’s weight is ≥ 650 grams on the day obtained) 
Safety laboratory tests 

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1 
KEY ROLES 
Individuals: 
DMID Clinical Project  Manager : 
Walla Dempsey, PhD 
Virology Branch  
Division of Microbiology and Infectious Diseases, NIAID, NIH  
6610 Rockledge Drive, MSC 6603  
Bethesda, MD  20892-6603 (Zip for express mail is 20817) 
Phone: 301-496-7453 
Fax: 
301-480-1594 
wdempsey@niaid.nih.gov  
 
Principal Investigator: 
David W. Kimberlin, M.D. 
Protocol Chair 
Co-Principal Investigator, Collaborative Antiviral Study Group 
Professor of Pediatrics 
Sergio Stagno Endowed Chair in Pediatric Infectious Diseases 
The University of Alabama at Birmingham 
1600 Seventh Avenue South, CHB 303 
Birmingham, AL  35233 
Phone: 205-934-5316 
Fax: 
205-975-9972 
e-mail: dkimberlin@peds.uab.edu  
 
Program Director: 
Penny Jester BSN MPH CCRC 
Collaborative Antiviral Study Group 
The University of Alabama at Birmingham 
1600 Seventh Avenue South, CHB 303 
Birmingham, AL  35233 
Phone: 205-934-5316 
Fax:  205-934-8559 
e-mail: pjester@peds.uab.edu  
Clinical Studies Administrator 
Bari Cotton, RN 
Collaborative Antiviral Study Group 
The University of Alabama at Birmingham 
1600 Seventh Avenue South, CHB 303 
Birmingham, AL  35233 
Phone: 205-934-5316 

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Fax: 
205-934-8559 
e-mail: bcotton@peds.uab.edu   
Medical Monitor:  
Venus Shahamatdar, M.D. 
Office of Clinical Research Affairs 
Division of Microbiology and Infectious Diseases, NIAID, NIH  
5601 Fishers Lane, 7E54, 
Bethesda, MD  20892-9826 
Phone: 240-627-3369   
Email: venus.shahamatdar@nih.gov   
Institutions: 
 
University of Alabama at Birmingham  
David W. Kimberlin, M.D. 
 
Department of Pediatrics, Division of Infectious Diseases  
1600 7th Avenue South, CHB 303 
 
Birmingham, AL 35233 
 
Phone: 205-934-5316  
Fax: 205-975-9972 
 
Email: Dkimberlin@peds.uab.edu  
 
Carolinas Medical Center - Charlotte  
Amina Ahmed, M.D. B.S. 
 
Department of Pediatrics 
 
1000 Blythe Boulevard 
MEB-4th 
 
Charlotte, NC 28203  
Phone: 704-381-6870  
Fax:  704-355-4529 
Email: Amina.ahmed@carolinashealthcare.org  
 
Children's Hospital of Pittsburgh of UPMC 
 
Marian G. Michaels, M.D., M.P.H. 
One Children's Hospital Drive 
4401 Pen Avenue, AOB 3rd Floor 
 
Pittsburgh, PA 15224  
Phone: 412-692-6786/4129158191  
Fax: 412-864-8977 
 
Email: marian.michaels@chp.edu  
 
Children's National Medical Center  
Roberta L. DeBiasi, MD 
 
111 Michigan Avenue, NW 
 
Pediatric Infectious Diseases, West Wing 3.5 
 
Washington, DC 20010 
 
Phone: 202-476-5051  
Fax: 202-476-3850 
 
Email: rdebiasi@cnmc.org 

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Johns Hopkins Medical Institutions  
Ravit Boger, MD 
 
 
Division of Pediatric Infectious Diseases 
 
Rubinstein Child Health Building, 200 North Wolfe Street 
 
Room 3153 
 
Baltimore, MD 21287  
Phone: 410-614-3917  
Fax: 410-614-1491 
 
Email: boger@jhmi.edu  
 
Louisiana State University Health Science Center – Shreveport 
John Vanchiere, MD, PhD 
1501 Kings Highway, #5-303 
Shreveport, LA  71103 
Phone: 318-675-7877  
Fax: 318-675-6059 
 
Email: jvanch@lsuhsc.edu 
 
MetroHealth Medical Center 
Nazha F. Abughali, M.D. 
 
Department of Pediatrics 
2500 MetroHealth Drive 
Old Research Bldg  Rm 350 
Cleveland, OH 44109 
Phone: 216-778-3402 
Fax: 216-778-2435 
Email: nabughali@metrohealth.org  
 
Rhode Island Hospital 
Penelope Dennehy, MD  
Division of Pediatric Infectious Diseases 
 
593 Eddy Street      
PO Box RM 018 
 
Providence, RI 02903  
Phone: 401-444-8360  
Fax: 401-444-5650 
 
Email: pdennehy@lifespan.org  
 
Steven & Alexandra Cohen Children’s Medical Center of New 
York (CCMC) 
Sunil Sood, MD 
 
300 Community Drive  
9 Tower North Shore University Hospital, Room 8  
 
Manhasset, NY 11030 
 
Phone: 516-562-3957  
Fax: 516-562-3958 
 
Email: sood@lij.edu  

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University of Arkansas for Medical Sciences  
Jose Romero, MD 
 
Arkansas Children's Hospital  
800 Marshall Street 
 
Pediatric Infectious Diseases, Slot 512-11 
 
Little Rock, AR 72202  
Phone: 501-364-1416  
Fax: 501-364-3551 
 
Email: RomeroJose@uams.edu  
 
University of Rochester Medical Center 
 
Mary Caserta, M.D. 
 
601 Elmwood Avenue 
Box 690 
 
 
Rochester, NY 14642  
Phone: 585-275-5944  
Fax: 585-273-1104 
 
Email: mary_caserta@urmc.rochester.edu  
 
University of South Florida School of Medicine 
Jorge Lujan-Zilbermann, MD 
17 Davis Blvd, Suite 200 
Division of Infectious Disease 
Tampa, Florida 33606 
Phone: 813-259-8800  
Fax: 813-259-8805 
 
Email: jlujanzi@health.usf.edu 
 
University of Texas – Southwestern 
Pablo Sanchez, MD  
Southwestern Med. Center 
 
Department of Pediatrics 
 
5323 Harry Hines Boulevard, Rm # E3.508  
Dallas, TX 75390-9063 
 
Phone: 214-648-3753  
Fax: 214-648-2481 
 
Email: Pablo.Sanchez@UTSouthwestern.edu  
 
Vanderbilt University Medical Center  
Natasha B. Halasa, MD, MPH 
 
Pediatric Infectious Diseases  
1161 21st Avenue South 
 
D-7235 MCN  
Nashville, TN 37232-2581 
 
Phone: 615-322-3346  
Fax: 615-343-9723 
 
Email: natasha.halasa@vanderbilt.edu  

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Washington University in St Louis School of Medicine  
Gregory Storch, M.D.  
School of Med. at St. Louis Children's Hospital 
 
660 S. Euclid  
Campus Box 8116 
 
St. Louis, MO 63110  
Phone: 314-454-6079  
Fax: 314-747-1404 
 
Email: storch_G@kids.wustl.edu  
Optional: 
 
Statistician: 
Inmaculada "Chichi" Aban, PhD 
Associate Professor 
Department of Biostatistics 
School of Public Health 
The University of Alabama at Birmingham 
RPHB 327 
Phone: (205) 934-2732 
Fax: 
(205) 975-2541 
e-mail: CAban@ms.soph.uab.edu 
 
UAB Antiviral Pharmacology Laboratory: 
Edward P. Acosta, Pharm.D. 
Professor and Director, Division of Clinical Pharmacology 
University of Alabama at Birmingham 
School of Medicine 
1670 University Blvd, Volker Hall, Room 258 
Birmingham, AL 35294-0019 
Phone: 205-934-2655 
Fax:      205-934-6201 
e-mail:  eacosta@uab.edu 
 
 
 

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2 
BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
2.1 
Background Information 
The natural history of congenitally acquired CMV infection is well described.1-7  In contrast, 
outcomes of perinatally and postnatally acquired CMV infections are less well characterized.  It 
is generally agreed that postnatal acquisition of CMV in term infants does not lead to 
symptomatology or disease.8  In preterm infants, initial case reports suggested that peri- and 
postnatally acquired CMV infections could produce severe disease.9-14  Larger series and case-
controlled trials more recently suggest that symptomatic disease in preterm babies is less 
common than asymptomatic infection, and long-term sequelae are rare.15-19  Nevertheless, 
severe disseminated CMV disease can occur in premature infants, including life-threatening 
pneumonitis, hepatitis, and thrombocytopenia.20  Antiviral therapy in such patients is frequently 
used, albeit without either controlled data to demonstrate benefit or knowledge of proper dosing 
regimens.12  In patients with symptomatic congenital CMV disease, six weeks of intravenous 
ganciclovir improves hearing outcomes in early childhood,21 and may benefit 
neurodevelopmental outcomes as well.22  In premature babies with visceral disease from 
postnatally acquired CMV, the goal of antiviral therapy is different; namely, it is to treat the end-
organ disease, which is occurring at that time, rather than to prevent or improve long-term 
sequelae.  Without efficacy data, the duration of treatment is variable, but anecdotal experience 
suggests that it generally is in the range of two to four weeks of total antiviral therapy.  
Approximately two-thirds of treated neonates receiving six weeks of intravenous ganciclovir 
develop Grade 3 or 4 neutropenia (utilizing the DAIDS Toxicity Tables) during therapy.21 
 
The appropriate dose of intravenous ganciclovir for premature babies has not been studied.  
Previous studies of ganciclovir have indicated that the area-under-the-concentration curve 
(AUC) of ganciclovir is most closely related to virologic treatment success.23  Data from an 
National Institute of Allergy and Infectious Diseases (NIAID) CASG Phase II study of 
intravenous ganciclovir (6 mg/kg/dose q 12 hrs) in term neonates with symptomatic congenital 
CMV disease revealed a median AUC12 of 27 μgxh/mL (mean AUC12=32.3+13.7 μgxh/mL, 
range 17.2 to 55.9 μgxh/mL, n=13).24  A more recent CASG investigation of oral valganciclovir 
included comparative pharmacokinetic data following 6 mg/kg/dose every 12 hrs of intravenous 
ganciclovir.  The mean AUC12 in young neonates (median age: 16.5 days) on the second day 
following study enrollment was 38.2 μgxh/mL (median: 25.5 μgxh/mL), but the coefficient of 
variation was large (112).25  In five neonates in whom pharmacokinetic sampling was performed 
on day 4 and day 34 of intravenous ganciclovir therapy, ganciclovir clearance nearly doubled 
and AUC12 reduced by almost half over the 30 day interval,25 suggesting that maturational 
changes may be occurring rapidly in early life which may affect ganciclovir dosing.  No data 
exist on ganciclovir dosing in very premature babies, who are at greatest risk for CMV disease 

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due to the absence of transplacental antibodies.  Notably, acyclovir must be dose-adjusted 
based upon renal function such as that which can occur with prematurity.26 
The CASG and the UAB Central Unit have had significant success in performing multi-center 
pharmacokinetic and pharmacodynamic studies with both ganciclovir and valganciclovir in 
infants during the first month of life.21,22,25,27-30  In this study, this experience will be utilized to 
further define the utility of this drug in very premature children.   
2.2 
Rationale 
Parenteral ganciclovir is used regularly in premature neonates to treat end-organ disease, but 
the appropriate dose to use has never been studied or defined.  This is a clinical sampling 
study, and premature infants who receive intravenous ganciclovir as part of clinical care will be 
eligible for participation.  A prospective treatment trial is not feasible at this time, but this study 
will inform dosing parameters for a subsequent prospective study to evaluate dose and 
effectiveness.  At the completion of the study, appropriate dosing of intravenous ganciclovir in 
premature infants will be defined.  While this will not allow for conclusions to be drawn regarding 
efficacy, these data will help minimize toxicity for future premature babies treated with 
ganciclovir.  Importantly, all pharmacokinetic assays will be performed in the UAB Antiviral 
Pharmacology Laboratory.  Of relevance to this trial, this laboratory has developed the 
methodology to process microspecimens of blood for ganciclovir drug concentrations.  
2.3 
Potential Risks and Benefits 
2.3.1 Potential Risks 
As a sampling study, the potential risks relate to blood draws (e.g., bruising at the site, infection, 
anemia possibly requiring packed red blood cell transfusion).  Requiring a baby to be at least 
500 grams at the time of study enrollment will ensure that blood volumes withdrawn will be 
acceptable by research standards.  Additionally, virtually all of the subjects will have long-term 
intravenous access for clinical care, through which blood can be withdrawn without risk of 
discomfort  from the needle stick or bruising at the site during or after the blood drawing and 
rarely an infection.  Transfusions are expected in hospitalized premature infants.  One study 
reported that extremely premature neonates receive an average of 5.2 ± 4.2 transfusions over a 
six week period.31  Other trials have reported similar numbers of transfusions in this 
population.32,33  It is possible that even higher numbers of transfusions might be experienced in 
the at-risk population in this sampling study since they are receiving the myelosuppressive drug 
ganciclovir as part of clinical care.  Transfusions are not associated with long-term sequelae.33  
Nevertheless, throughout the conduct of this study, transfusion rates will be carefully monitored. 

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2.3.2 Known Potential Benefits 
Knowledge of a given subject’s pharmacokinetic profile may allow for rational clinical 
adjustments in treatment dose, thereby minimizing potential drug toxicity and maximizing 
potential antiviral efficacy. 

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3 
OBJECTIVES 
3.1 
Study Objectives 
Primary: 
 
To define the pharmacokinetics of ganciclovir in premature (< 32 weeks gestational age at 
birth) infants 
Secondary: 
 
To assess changes in quantitative viral DNA in whole blood as a function of ganciclovir 
pharmacokinetics 
 
To assess clearance of CMV in urine as a function of ganciclovir pharmacokinetics 
Exploratory: 
 
To assess development of neutropenia as a function of ganciclovir pharmacokinetics 
 
To determine the potential for the development of resistance to ganciclovir as a function of 
pharmacokinetics, dose, age, and duration of therapy 
3.2 
Study Outcome Measures 
3.2.1 Primary Outcome Measures 
Primary Endpoint: 
Primary Endpoint: 
 
• 
Plasma pharmacokinetics parameters for ganciclovir AUC12  
3.2.2 Secondary Outcome Measures 
Secondary Endpoints: 
• 
Plasma pharmacokinetics parameters for ganciclovir, including maximum serum 
concentration (Cmax), half-life (T1/2), CL, and Vd 
• 
Correlation of ganciclovir plasma concentrations with CMV whole blood viral load 
• 
Correlation of ganciclovir plasma concentrations with clearance of CMV in urine  
3.2.3 Exploratory Outcome Measures 
Exploratory Endpoints: 
• 
Correlation of ganciclovir plasma concentrations with neutropenia 
• 
Detection of resistance to ganciclovir 

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4 
STUDY DESIGN 
This is an open-label, multi-center, clinical sampling study of ganciclovir pharmacokinetics and 
pharmacodynamics of ganciclovir in premature infants undergoing antiviral therapy for CMV.  
Only those subjects who receive ganciclovir for clinical reasons will be enrolled.  The decision to 
initiate ganciclovir therapy will be made by the attending physician based upon his/her clinical 
decision to treat virologically-confirmed CMV infection; infants receiving such therapy and 
meeting entry criteria will then be eligible for this study.  Therefore, ganciclovir will be dispensed 
from the institution’s pharmacy and not provided under this protocol. 
 
Subjects meeting enrollment criteria will be entered into this clinical trial.  Following enrollment, 
subjects will be stratified by gestational age and by chronologic age as follows:  1) ≤ 27 weeks 6 
days gestational age at birth and ≤ 30 days chronologic age at study enrollment; 2) ≤ 27 weeks 
6 days gestational age at birth and > 30 days chronologic age at study enrollment; 3) ≥ 28 
weeks 0 days gestational age at birth and ≤ 30 days chronologic age at study enrollment; 4) ≥ 
28 weeks 0 days gestational age at birth and > 30 days chronologic age at study enrollment.  
The total sample size across these four cohorts is 32 subjects.  Subjects in each cohort with 
inadequate pharmacokinetic data for analysis (e.g., due to dropping out of the study before PK 
assessments are performed, or blood sampling obtained but is inadequate for analysis) may be 
replaced and will not count toward the total of 32 subjects.  Additionally, enrollment of an 
additional 2-3 subjects may be allowed for operational reasons.  
 
Treatment Day 1 is the calendar day when the first dose of intravenous ganciclovir was  
administered to the study subject for clinical care, and Treatment Dose 1 corresponds to 
the first dose of intravenous ganciclovir the patient receives under clinical care.  Study  
Assessment Dose 1 is the first dose of intravenous ganciclovir the subject receives 
following enrollment on the trial, and Study Assessment  Day 1 is the calendar day when 
Study Assessment Dose 1 is administered.  Both Treatment Day 1 and Treatment Dose 1 
can coincide with or precede study enrollment; Study Assessment Day 1 and Study Assessment 
Dose 1 by definition will follow study enrollment, and may or may not equate with Treatment 
Day 1 and Treatment Dose 1.  Typically, ganciclovir is administered twice per day in these 
infants. 
 
With the receipt of one of the Study Assessment Doses (dose 3, 4, 5, 6, 7, or 8) of intravenous 
ganciclovir, pharmacokinetic specimens will be obtained at 0h (immediately prior to IV 
ganciclovir dose; window: -15 min), 1h (immediately after the end of the IV ganciclovir dose; 
window: +15 min), 2-3h, 5-7h, and 10-12h.  This complete set of pharmacokinetic time points 
will allow for the AUC and clearance (CL) to be calculated in each subject.  Specimens will be 
shipped to the UAB Antiviral Pharmacology Laboratory for processing at that time.  The 
pharmacokinetic data will then be provided to the study site, including the AUC and CL values, 

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for information purposes.  The decision of whether or not to adjust the dose will be a clinical one 
to be decided by the treating physician, and will not be dictated by the research protocol.  The 
parameters for AUC and CL from prior CASG ganciclovir27,30 and valganciclovir25,29 studies 
demonstrate that these PK parameters may be useful in guiding dose adjustments.  Duration 
and dose of intravenous ganciclovir therapy is made at the discretion of the treating physician 
and will not be dictated by the research protocol.   
 
Both whole blood for CMV PCR and urine for CMV assessment will be obtained serially through 
Study Assessment Period 7 as long as the subject is receiving intravenous ganciclovir therapy 
(that is, until the ganciclovir is permanently discontinued).  These specimens will be used to 
determine viral load and, as indicated, ganciclovir resistance.  At each sample collection time, 
urine will be split into two aliquots.  These aliquots will be available for CMV detection as 
appropriate, based upon whole blood viral loads.  Specimens will then be available for 
subsequent testing for ganciclovir resistance in the UAB Virology Resistance Laboratory.  Since 
ganciclovir is a renally excreted drug, serum creatinine will be drawn for the research protocol 
on the day that the ganciclovir pharmacokinetic specimens are obtained in order to calculate 
creatinine clearance using a method such as the modified Schwartz formula, and thus correlate 
ganciclovir clearance with renal function.  Otherwise, data from hematology assessments (WBC 
count and differential, hemoglobin, platelet count) and from chemistry labs (serum creatinine, 
ALT, and AST) will be recorded on the study case report forms each study assessment period if 
they are being obtained for clinical reasons, but will not be drawn only for the purposes of the 
study.  Ganciclovir dosing information (mg/dose, dosing interval, and subject weight) will be 
recorded on the day of the pharmacokinetic blood draws.  Once a subject is successfully 
enrolled into the study the ganciclovir dosing information (mg/dose and dosing interval) will be 
recorded from the start of clinical treatment of ganciclovir until date of enrollment.  After 
enrollment ganciclovir dosing information (mg/dose and dosing interval) will be captured from 
Study Assessment Period 1 through the Study Assessment Period 7; as long as the subject is 
receiving intravenous ganciclovir therapy. 
 
If the subject continues to receive intravenous ganciclovir from Study Assessment Day 18 
through Study Assessment Day 24 (Period 4), and at the request of the treating physician, an 
additional set of blood samples will be obtained for PK assessments if the subject is 575 grams 
or more at time of collection.  The additional samples will be analyzed as they are received in 
the UAB Antiviral Pharmacology Laboratory and the results will be provided to the treating 
physician for information purposes.  Specimens would be obtained around one dose 
administered during this window, using the same sampling times as with the first 
pharmacokinetic draws. 

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5 
STUDY ENROLLMENT AND WITHDRAWAL 
Male and female premature infants < 32 weeks gestation of any ethnicity who are being treated 
with intravenous ganciclovir for proven [e.g., culture- or polymerase chain reaction (PCR)-
confirmed] CMV infections are eligible for enrollment.  Participating clinical sites will identify 
potential study subjects.  Patients meeting study eligibility criteria may be offered enrollment into 
the trial.  Informed consent signed by study subject’s parent(s) or guardian(s) must be obtained 
prior to study enrollment.  Site investigators are all clinicians and also care providers for the 
neonatologists at their respective institutions, and therefore have direct access to the study 
population.  The study population will be drawn from the in-hospital setting.  Potential subjects 
will be identified by the site investigators and the study coordinators. 
5.1 
Subject Inclusion Criteria 
1. Signed informed consent from parent(s) or legal guardian(s) 
2. Confirmation of CMV infection from urine, blood, or saliva by culture, shell vial, or PCR tests 
(local lab) 
3. Receiving intravenous ganciclovir, prescribed by the patient’s physician and anticipated to 
receive at least 3 more doses after consenting 
4. < 32 weeks gestational age at birth 
5. ≥ 500 grams at study enrollment 
5.2 
Subject Exclusion Criteria 
1. Imminent demise 
2. Current receipt of valganciclovir or foscarnet 
3. Receiving breast milk from a mother who is being treated with ganciclovir or valganciclovir 
4. Current receipt of other investigational drugs 
5. Major congenital anomaly that in the site investigator’s opinion may impact drug metabolism or the 
patient’s volume of distribution 
5.3 
Treatment Assignment Procedures 
5.3.1 Randomization Procedures 
Since this is a sampling study with no therapeutic intervention or investigation, there are no 
randomization procedures.   
5.3.2 Reasons for Delaying Study-Related Procedures 
Study related laboratory draws will be delayed or deferred if the investigator believes that 
obtaining them might increase subject risk [e.g., at risk of a packed red blood cell (PRBC) 

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transfusion due to the removal of blood for the study; however, if the subject would receive a 
transfusion of packed red blood cells even if the study-related labs were not obtained, then this 
would not be considered a situation of increasing subject risk].  Additionally, a study-related 
laboratory specimen that is unevaluable due to clotting or laboratory related issues will not be 
repeated.  If a study related laboratory draw is delayed or deferred, study staff will document 
this on a source document. 
5.3.3 Reasons for Withdrawal 
The criteria for discontinuations during the study include:  
 
Study subject (parent/legal guardian) wishes to withdraw 
 
Non-compliance with study procedures 
 
Trial termination (by UAB, , FDA, DMID, NIAID, NIH, or agreement of all investigators) 
 
Any other reason which, in the opinion of the investigator, precludes the study subject's 
participation in the study.  The principal investigator must call the Protocol Chair prior to 
discontinuing a study subject for this reason. 
5.3.4 Handling of Withdrawals 
Study subjects may withdraw voluntarily from participation in the study at any time.  If a study 
subject withdraws or is discontinued from the study at any time prior to completion of the study, 
the reason for this decision will be recorded on the eCRFs.  If subject withdraws before 
collection of the pharmacokinetic collection, this subject may be replaced (see Section 4).  
5.3.5 Termination of Study  
The UAB Central Unit and NIH have the right to terminate this study at any time.  Reasons for 
terminating the study may include, but are not limited to, the following: 
 
Study subject enrollment is unsatisfactory 
 
Data recording is inaccurate or incomplete 
 
Investigators do not adhere to the protocol or applicable regulatory guidelines in conducting 
the study. 

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6 
STUDY INTERVENTION/INVESTIGATIONAL PRODUCT 
None. 
This is a sampling study with no therapeutic intervention.  Only subjects who receive 
intravenous ganciclovir as practice of medicine will be eligible to enroll.  Intravenous ganciclovir 
will not be provided under this protocol. 

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7 
STUDY SCHEDULE 
7.1 
Screening  
There are no screening procedures for this study.  Potential subjects will be identified by the site 
investigators and the study coordinators.  Informed consent signed by study subject’s parent(s) 
or guardian(s) must be obtained prior to study enrollment. 
7.2 
Enrollment/Baseline 
7.2.1.  Baseline Assessment (Period 1:  Study Assessment Day 1 through 
Study Assessment Day 3, unless broader window specified) 
 
Confirm that informed consent has been obtained from parent or legally authorized 
representative 
 
Document baseline demographics (see Section 8.1.1; Window: Birth through Study 
Assessment Day 3) 
o Gestational age at delivery 
o Date of birth 
o Day of life at initiation of IV ganciclovir therapy 
o Gender 
o Race 
o Ethnicity 
o Birth weight 
o Weight at enrollment 
o Length in centimeters at enrollment 
o Reason ganciclovir being administered 
o Ganciclovir dose and dosing frequency 
o Manufacturer of the ganciclovir lot utilized at the treating facility 
o Date ganciclovir therapy was initiated 
 
Hematology labs (see Section 8.2; Window: Birth through Study Assessment Day 3) 
o WBC with differential, hemoglobin, and platelet count, if being drawn for clinical 
reasons; any laboratory value obtained during the window will suffice, with an 
effort being made to capture the most abnormal value 
 
Chemistry labs (see Section 8.2; Window: Birth through Study Assessment Day 3) 
o AST and ALT, if being drawn for clinical reasons; any laboratory value obtained 
during the window will suffice, with an effort being made to capture the most 
abnormal value 

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 
Serum Creatinine (see Section 8.2) 
o To be drawn on the calendar day that ganciclovir PKs are being drawn (Window: 
Study Assessment Day 1 through Study Assessment Day 5)  
o Required amount of whole blood for serum creatinine is 0.25 mL 
 
 
Ganciclovir pharmacokinetics (see Section 8.2.2.2.) 
o Ganciclovir concentrations will be obtained with one of the Study Assessment 
Dose 3, 4, 5, 6, 7, or 8 (Window:Study Assessment Day 1 through Study 
Assessment Day 5) 
o Timepoints for pharmacokinetic draws:  0h (immediately prior to IV ganciclovir 
dose; window: -15 min), 1h (immediately after the end of the IV ganciclovir dose; 
window: +15 min), 2-3h, 5-7h, and 10-12h 
o Required amount of whole blood for plasma ganciclovir determination at each 
timepoint is 200 L (0.2 mL) 
 
Virology specimens (see Sections 8.2.2.1.) 
o Blood for CMV quantitative PCR will be obtained (required amount of whole 
blood for CMV PCR is 0.5 mL) 
o If obtainable, urine for CMV detection will be collected non-invasively (e.g., 
bagged, from indwelling foley catheter, excess clinical specimen, etc.) 
 
Clinical treatment ganciclovir dosing information 
o mg/dose 
o Dosing interval 
o Patient weight 
 
PRBC transfusion documentation on eCRF 
 
Study Assessment ganciclovir dosing information 
o mg/dose 
o Dosing interval 
o Subject weight 
7.3 
Follow-up  
7.3.1.  Period 2 (Study Assessment Day 4 through Study Assessment Day 
10)  
Documentation of receipt of PRBC transfusion(s) will be provided on an eCRF.  If the 
study subject has NOT received ≥ 10 PRBC transfusions (see Section 9.3.1), proceed 
with required assessments. 
Required assessments [following confirmation that subject is still receiving ganciclovir 
(e.g., that the ganciclovir has not been permanently discontinued)]:  1) virology blood 

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specimens for CMV viral load (required amount of whole blood for CMV PCR is 0.5 mL); 
2) CMV detection from noninvasive urine specimen (if obtainable); 3) ganciclovir dosing 
information (mg/dose, dosing interval, subject weight). 
Optional assessments (if being drawn for clinical reasons; any laboratory value obtained 
during the window will suffice, with an effort being made to capture the most abnormal 
value):  1) hematology labs (WBC with differential, hemoglobin, platelet count); 2) 
chemistry labs (AST, ALT); 3) serum creatinine. 
 
Study Assessments (as described) 
Optional Assessments* 
Virology blood specimens for CMV viral load 
Hematology labs (WBC with 
differential, hemoglobin, platelet 
count) 
If obtainable, CMV detection from noninvasive urine 
specimen (e.g., bagged, from indwelling foley 
catheter, excess clinical specimen, etc.) 
Chemistry labs (AST, ALT) 
Ganciclovir dosing information (mg/dose, dosing 
interval, subject weight) 
Serum creatinine 
* If being drawn for clinical reasons; any laboratory value obtained during the window will 
suffice, with an effort being made to capture the most abnormal value 
7.3.2.  Period 3 (Study Assessment Day 11 through Study Assessment Day 
17)  
Documentation of receipt of PRBC transfusion(s) will be provided on an eCRF.  If the 
study subject has NOT received ≥ 10 PRBC transfusions (see Section 9.3.1), proceed 
with required assessments. 
Required assessments [following confirmation that subject is still receiving ganciclovir 
(e.g., that the ganciclovir has not been permanently discontinued)]:  1) virology blood 
specimens for CMV viral load (required amount of whole blood for CMV PCR is 0.5 mL); 
2) CMV detection from noninvasive urine specimen (if obtainable); 3) ganciclovir dosing 
information (mg/dose, dosing interval, subject weight). 
Optional assessments (if being drawn for clinical reasons; any laboratory value obtained 
during the window will suffice, with an effort being made to capture the most abnormal 

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value):  1) hematology labs (WBC with differential, hemoglobin, platelet count); 2) 
chemistry labs (AST, ALT); 3) serum creatinine. 
 
Study Assessments (as described) 
Optional Assessments* 
Virology blood specimens for CMV viral load 
Hematology labs (WBC with 
differential, hemoglobin, platelet 
count) 
If obtainable, CMV detection from noninvasive urine 
specimen (e.g., bagged, from indwelling foley 
catheter, excess clinical specimen, etc.) 
Chemistry labs (AST, ALT) 
Ganciclovir dosing information (mg/dose, dosing 
interval, subject weight) 
Serum creatinine 
* If being drawn for clinical reasons; any laboratory value obtained during the window will 
suffice, with an effort being made to capture the most abnormal value 
7.3.3.  Period 4 (Study Assessment Day 18 through Study Assessment Day 
24)  
 
Documentation of receipt of PRBC transfusion(s) will be provided on an eCRF.  If the 
study subject has NOT received ≥ 10 PRBC transfusions (see Section 9.3.1), 
proceed with required assessments. 
 
Confirmation that subject is still receiving ganciclovir (e.g., that the ganciclovir has 
not been permanently discontinued) 
 
Hematology labs (see Section 8.2) 
o WBC with differential, hemoglobin, and platelet count, if being drawn for clinical 
reasons; any laboratory value obtained during the window will suffice, with an 
effort being made to capture the most abnormal value 
 
Chemistry labs (see Section 8.2) 
o AST and ALT, if being drawn for clinical reasons; any laboratory value obtained 
during the window will suffice, with an effort being made to capture the most 
abnormal value 
 
Serum creatinine (see Section 8.2) 
o Obtain if the ganciclovir pharmacokinetics are being obtained during this study 
assessment period 

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o To be drawn on the calendar day that ganciclovir PKs are being drawn 
 
Ganciclovir pharmacokinetics, if desired by the treating physicians and the subject 
weighs ≥ 575 grams at that time (see Section 8.2.2.2.) 
o Ganciclovir concentrations may be obtained around one dose in this assessment 
window (Study Assessment Day 18 through Study Assessment Day 24) 
o Timepoints for pharmacokinetic draws:  0h (immediately prior to IV ganciclovir 
dose; window: -15 min), 1h (immediately after the end of the IV ganciclovir dose; 
window: +15 min), 2-3h, 5-7h, and 10-12h 
o Required amount of whole blood for plasma ganciclovir determination at each 
timepoint is 200 L (0.2 mL) 
o If subject weighs < 575 grams, the second set of PK draws cannot be performed 
 
Virology specimens (see Sections 8.2.2.1.) 
o Blood for CMV quantitative PCR will be obtained (required amount of whole 
blood for CMV PCR is 0.5 mL) 
o If obtainable, urine for CMV detection will be obtained non-invasively (e.g., 
bagged, from indwelling foley catheter, excess clinical specimen, etc.) 
 
Ganciclovir dosing information 
o mg/dose 
o Dosing interval 
o Subject weight 
7.3.4.  Period 5 (Study Assessment Day 25 through Study Assessment Day 
31)  
Documentation of receipt of PRBC transfusion(s) will be provided on an eCRF.  If the 
study subject has NOT received ≥ 10 PRBC transfusions (see Section 9.3.1), proceed 
with required assessments. 
Required assessments [following confirmation that subject is still receiving ganciclovir 
(e.g., that the ganciclovir has not been permanently discontinued)]:  1) virology blood 
specimens for CMV viral load (required amount of whole blood for CMV PCR is 0.5 mL); 
2) CMV detection from noninvasive urine specimen (if obtainable); 3) ganciclovir dosing 
information (mg/dose, dosing interval, subject weight). 
Optional assessments (if being drawn for clinical reasons; any laboratory value obtained 
during the window will suffice, with an effort being made to capture the most abnormal 
value):  1) hematology labs (WBC with differential, hemoglobin, platelet count); 2) 
chemistry labs (AST, ALT); 3) serum creatinine. 
 

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Study Assessments ( as described) 
Optional Assessments* 
Virology blood specimens for CMV viral load 
Hematology labs (WBC with 
differential, hemoglobin, platelet 
count) 
If obtainable, CMV detection from noninvasive urine 
specimen (e.g., bagged, from indwelling foley 
catheter, excess clinical specimen, etc.) 
Chemistry labs (AST, ALT) 
Ganciclovir dosing information (mg/dose, dosing 
interval, subject weight) 
Serum creatinine 
* If being drawn for clinical reasons; any laboratory value obtained during the window will 
suffice, with an effort being made to capture the most abnormal value 
 
 
7.3.5.  Period 6 (Study Assessment Day 32 through Study Assessment Day 
38)  
Documentation of receipt of PRBC transfusion(s) will be provided on an eCRF.  If the 
study subject has NOT received ≥ 10 PRBC transfusions (see Section 9.3.1), proceed 
with required assessments. 
Required assessments [following confirmation that subject is still receiving ganciclovir 
(e.g., that the ganciclovir has not been permanently discontinued)]:  1) virology blood 
specimens for CMV viral load (required amount of whole blood for CMV PCR is 0.5 mL); 
2) CMV detection from noninvasive urine specimen (if obtainable); 3) ganciclovir dosing 
information (mg/dose, dosing interval, subject weight). 
Optional assessments (if being drawn for clinical reasons; any laboratory value obtained 
during the window will suffice, with an effort being made to capture the most abnormal 
value):  1) hematology labs (WBC with differential, hemoglobin, platelet count); 2) 
chemistry labs (AST, ALT); 3) serum creatinine. 

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Study Assessments (as described) 
Optional Assessments* 
Virology blood specimens for CMV viral load (NOTE: 
if subject weighs < 600 grams, this virology specimen 
will not be obtained) 
Hematology labs (WBC with 
differential, hemoglobin, platelet 
count) 
If obtainable, CMV detection from noninvasive urine 
specimen (e.g., bagged, from indwelling foley 
catheter, excess clinical specimen, etc.) 
Chemistry labs (AST, ALT) 
Ganciclovir dosing information (mg/dose, dosing 
interval, subject weight) 
Serum creatinine 
* If being drawn for clinical reasons; any laboratory value obtained during the window will 
suffice, with an effort being made to capture the most abnormal value 
7.4 
Final Study Visit 
7.4.1.  Period 7 (Study Assessment Day 39 through Study Assessment Day 
42) 
Documentation of receipt of PRBC transfusion(s) will be provided on an eCRF.  If the 
study subject has NOT received ≥ 10 PRBC transfusions (see Section 9.3.1), proceed 
with required assessments. 
Required assessments [following confirmation that subject is still receiving ganciclovir 
(e.g., that the ganciclovir has not been permanently discontinued)]:  1) virology blood 
specimens for CMV viral load (required amount of whole blood for CMV PCR is 0.5 mL); 
2) CMV detection from noninvasive urine specimen (if obtainable); 3) ganciclovir dosing 
information (mg/dose, dosing interval, subject weight). 
Optional assessments (if being drawn for clinical reasons; any laboratory value obtained 
during the window will suffice, with an effort being made to capture the most abnormal 
value):  1) hematology labs (WBC with differential, hemoglobin, platelet count); 2) 
chemistry labs (AST, ALT); 3) Serum creatinine. 

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Study Assessments (as described) 
Optional Assessments* 
Virology blood specimens for CMV viral load (NOTE: 
if subject weighs < 650 grams, this virology specimen 
will not be obtained)  
Hematology labs (WBC with 
differential, hemoglobin, platelet 
count) 
If obtainable, CMV detection from noninvasive urine 
specimen (e.g., bagged, from indwelling foley 
catheter, excess clinical specimen, etc.) 
Chemistry labs (AST, ALT) 
Ganciclovir dosing information (mg/dose, dosing 
interval, subject weight) 
Serum creatinine 
* If being drawn for clinical reasons; any laboratory value obtained during the window will 
suffice, with an effort being made to capture the most abnormal value 
7.5 
Early Termination Visit 
Study subjects may withdraw voluntarily from participation in the study at any time.  If a study 
subject withdraws or is discontinued from the study at any time prior to completion of the study, 
the reason for this decision will be recorded on the eCRFs.  The remaining follow-up evaluations 
will be conducted if patient consent is obtained.  SAEs and AEs will be followed according to 
guidelines in Section 9. 
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.  All key endpoints will be evaluated and all randomized study subjects will 
continue to be followed as long as possible and included in the final analysis. 
7.6 
Unscheduled Visit  
All subjects enrolled on the study are hospitalized.  As such, there will not be unscheduled 
visits. 
 
 

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8 
STUDY PROCEDURES/EVALUATIONS 
The study procedures and evaluations are summarized in Appendix A.  In the conduct of this 
study, hospital staff may perform research activities (e.g., pharmacokinetic blood draw 
collection, serum creatinine collection, blood CMV viral load collection, urine collection for 
CMV), under the direction of the site Principal Investigator or designee. 
8.1 
Clinical Evaluations 
8.1.1. Baseline Demographics 
To characterize the study subjects, information will be recorded at the baseline study visit 
(Period 1) following the obtaining of informed consent.  Data collected will include basic 
demographics and birth history (date of birth; gender; race; ethnicity; birth weight; weight at 
enrollment; length in centimeters at enrollment; reason ganciclovir is being administered, 
gestational age at birth; ganciclovir dose and dosing frequency at time of enrollment; detailed 
ganciclovir dose and dosing frequency since ganciclovir therapy was initiated; manufacturer of 
the ganciclovir lot utilized at the treating facility; and date ganciclovir therapy was initiated). 
8.2 
Laboratory Evaluations 
Chemistry labs (serum creatinine) will be drawn on the calendar day that ganciclovir PKs are 
being drawn; required amount of whole blood for serum creatinine is 0.25 mL.  All other 
chemistry labs (serum creatinine, AST, and ALT) and hematology labs (WBC with differential, 
hemoglobin, platelet count) will be recorded on eCRFs if they have been drawn for clinical 
reasons; any laboratory value obtained during the window will suffice, with an effort being made 
to capture the most abnormal value. 
8.2.1 Special Assays or Procedures 
Research assays (CMV viral load/resistance and pharmacokinetics will be conducted at the 
respective UAB Central labs). 
8.2.1.1.  CMV Viral Load/Resistance Testing 
Assessment of CMV viral load in whole blood will be conducted at the UAB 
Central Laboratory.  The required amount of whole blood for CMV PCR is 0.5 
mL.  Whole blood will be collected at each study visit from Period 1 through 
Period 5.  Whole blood will also be collected at the Period 6 study visit if the 

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subject weighs at least 600 grams, and at the Period 7 study visit if the subject 
weighs at least 650 grams. 
Urine collection by noninvasive mechanism (e.g., bagged, indwelling foley 
catheter, excess clinical specimen, etc.) will be attempted at each study visit.  If 
urine is obtainable, it will be frozen and sent to the UAB Central Laboratory for 
processing.  If an attempt to obtain urine for CMV detection is unsuccessful, 
study staff will document the failed attempt on a source document.  All 
specimens collected will be sent to the UAB Central Laboratory. 
 
Viral detection assays will be performed in the UAB Central Laboratory.  These 
assays and tests are in clinical and research use already in the Central 
Laboratory.  The detection of CMV DNA will be performed using the CMV two 
primer Taqman assay already employed regularly in our laboratory.  The 
detection limit of our real-time PCR assay, as determined by the sensitivity 
titration analysis, is 10genomic equivalents per reaction. The results of 10 
different runs on different days are shown in the Table below.  Regression 
analysis shows a very high correlation coefficient (0.9996) for the 6 log 
concentration range (see Figure below). 
 
 
genome 
equivalents log(10) 
# +/10 
ct(mean)
std 
 
 
 
 
 
1000000 
6
10/10
18.362
0.085609 
100000 
5
10/10
21.476
0.155863 
10000 
4
10/10
24.855
0.187157 
1000 
3
10/10
28.321
0.305449 
100 
2
10/10
31.869
0.2283 
10 
1
10/10
35.283
0.606045 
 
 

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The amplification efficiency is calculated to be 1.95 with the theoretical maximum 
of 2.0, which would indicate a doubling with each PCR cycle.  Each assay 
contains a No Target Control and inhibition is monitored using a house-keeping 
gene, human albumin.  This  2 primer set assay has been used for several 
previous  studies and has been utilized in the Children’s Diagnostic Virology 
Laboratory for 2 years, primarily to monitor transplant patients.  The Diagnostic 
Laboratory participates in the College of American Pathologists, CAP, 
quantitative unknowns for CMV, EBV and BK viruses.  Over the last 3 cycles, the 
CMV assay has been within 4 fold of the mean for these unknowns and has 
improved with each group. 
Antiviral resistance will be performed in the UAB Viral Resistance Laboratory.  
Lab testing of viral isolates for ganciclovir resistance will be conducted by a 
standing SOP with a fully characterized  assay.  
8.2.1.2.  Ganciclovir Pharmacokinetics/Adherence 
Assessment of ganciclovir plasma concentrations will be conducted at the UAB  
Central Pharmacokinetic Laboratory.  Ganciclovir concentrations will be obtained 
with one of the Study Assessment Doses 3, 4, 5, 6, 7, or 8 (Window: Study 
Assessment Day 1 through Study Assessment Day 5).  Timepoints for 

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pharmacokinetic draws are as follows:  0h (immediately prior to IV ganciclovir 
dose; window: -15 min), 1h (immediately after the end of the IV ganciclovir dose; 
window: +15 min), 2-3h, 5-7h, and 10-12h.  The required amount of whole blood 
for plasma ganciclovir determination at each timepoint is 200 L (0.2 mL).  
Specimens will be processed to separate the plasma, which will be shipped to 
the UAB  Central Pharmacokinetic Laboratory. 
If desired by the treating physicians and the subject weighs ≥ 575 grams at that 
time, ganciclovir concentrations may be evaluated again around one dose in this 
assessment window (Study Assessment Day 18 through Study Assessment Day 
24).  Timepoints for pharmacokinetic draws are as follows:  0h (immediately prior 
to IV ganciclovir dose; window: -15 min), 1h (immediately after the end of the IV 
ganciclovir dose; window: +15 min), 2-3h, 5-7h, and 10-12h.  The required 
amount of whole blood for plasma ganciclovir determination at each timepoint is 
200 L (0.2 mL).  Specimens will be processed to separate the plasma, which 
will be shipped to the UAB  Central Pharmacokinetic Laboratory.  If subject 
weighs < 575 grams, the second set of PK draws cannot be performed. 
A rapid, sensitive and specific high performance liquid chromatographic (HPLC) 
assay is used for the determination of ganciclovir in 200uL of human plasma.  
The UV detector, set to monitor the 270nm wavelength, provides adequate 
sensitivity with minimal interference from endogenous matrix components.  The 
calibration curves are linear for ganciclovir over the range of 10 to 10,000 ng/mL. 
 
8.2.2 Specimen Preparation, Handling, and Shipping 
8.2.2.1 
Instructions for Specimen Preparation, Handling, and Storage 
Specific instructions on specimen preparation, handling and storage will be provided in the 
Manual of Procedures for this study. 
8.2.2.2 
Specimen Shipment 
Specific instructions on specimen shipping will be provided in the Manual of Procedures for this 
study. 
 

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8.3 
PRBC Transfusion Assessment 
PRBC transfusions are commonly required in the management of critically ill premature babies.  
Because of the fragile nature of these subjects and the concern of risk of increasing the 
frequency of blood transfusions in participants in this sampling study, once during each Study 
Period the study team will record the number of PRBC transfusions received by the study 
subject since enrollment (for the Period 1 documentation) or since the last recording (for 
documentation for Periods 2-7).  A PRBC transfusion is defined as ≥ 10 mL/kg of PRBCs within 
a 24 hour period. 

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9 
ASSESSMENT OF SAFETY 
This is a non-interventional sampling study.  Risk to subjects is limited to risks associated with 
blood draws.  In an effort to document only untoward medical events that have a greater 
likelihood of being study-related, only adverse events associated with blood draws will be 
considered adverse events for the purposes of this protocol.  These events will be reported as 
adverse events of special interest (AESIs).  Information to be collected includes event 
description, time of onset, clinician’s assessment of severity, relationship to blood draw 
(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.  AEs will be followed to 
adequate resolution.  
Any other adverse events that meet the reporting requirements of the Institutional Review Board 
will be documented as AESIs, and reported to Protocol Chair, DMID Medical Officer, Medical 
Monitor and the Clinical Project Manager. 
9.1 
Safety Reporting:  Adverse Events of Special Interest (AESI) 
The investigator must also report the following AESI on the AESI case report form: 
o AEs associated with blood draws 
o All adverse events that meet the reporting requirements of the Institutional Review Board 
(which will also be reported to Protocol Chair, DMID Medical Officer, Medical Monitor and 
the Clinical Project Manager). 
o  
9.2 
Type and Duration of Follow-up of Subjects after Adverse 
Events 
All AEs as described above will be followed until resolved or considered stable. 
9.3 
Halting Rules 
9.3.1 Discontinue of Study participation for individual subject. 
Subjects who experience significant problems with blood draws may be withdrawn from any 
future sampling.  Transfusions are expected in hospitalized premature infants.  One study 
reported that extremely premature neonates receive an average of 5.2 ± 4.2 transfusions over a 
six week period.31  Other trials have reported similar numbers of transfusions in this 
population.32,33  It is possible that even higher numbers of transfusions might be experienced in 

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the at-risk population in this sampling study since they are receiving the myelosuppressive drug 
ganciclovir as part of clinical care.  Transfusions are not associated with long-term sequelae.33  
Nevertheless, if a study subject receives ≥ 10 PRBC transfusions during the course of the study, 
all future study-related blood draws will not be performed. 
9.3.2 Discontinuation of Study Enrollment Pending Sponsor Review 
DMID may interrupt study testing and/or study entry at any time if medically indicated.  To 
minimize risk, the Protocol Chair, DMID Medical Officer, and Medical Monitor will review 
cumulative safety data.   
Study enrollment and dosing will be stopped, and an ad hoc review will be performed if: 
 
X of the first Y subjects enrolled have more than 5 packed red blood cell (PRBC) 
transfusions during their period of time on the study, according to the table below.  For a 
PRBC transfusion to be counted toward this halting rule, it must involve ≥ 10 mL/kg of 
PRBCs administered within a 24 hour period of time. 
 
Number 
enrolled 
(Y) 
Stop/Investigate 
when number 
with events 
equals this 
number (X) 
type I 
error 
power 
when 
mean=7 
4 
4 
0.0218 
0.2391 
5 
5 
0.0084 
0.1672 
6 
5 
0.0341 
0.4186 
7 
6 
0.0151 
0.3279 
8 
6 
0.0406 
0.5500 
9 
7 
0.0196 
0.4609 
10 
7 
0.0438 
0.6477 
11 
8 
0.0225 
0.5675 
12 
8 
0.0450 
0.7218 
13 
9 
0.0242 
0.6522 
14 
9 
0.0450 
0.7787 
15 
10 
0.0251 
0.7195 
16 
10 
0.0442 
0.8230 
17 
11 
0.0254 
0.7732 
18 
11 
0.0429 
0.8578 
19 
12 
0.0253 
0.8162 
20 
12 
0.0414 
0.8853 

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21 
13 
0.0248 
0.8506 
22 
13 
0.0397 
0.9072 
23 
14 
0.0242 
0.8784 
24 
14 
0.0378 
0.9246 
25 
15 
0.0234 
0.9008 
26 
15 
0.0360 
0.9387 
27 
16 
0.0226 
0.9189 
28 
16 
0.0342 
0.9500 
29 
16 
0.0496 
0.9701 
30 
17 
0.0324 
0.9592 
31 
17 
0.0465 
0.9756 
32 
18 
0.0307 
0.9666 
 
This halting rule is supported by an NICHD study that reported that extremely premature 
neonates receive 5.2 ± 4.2 transfusions per patient.31  Other trials have reported similar 
numbers of transfusions in this population.32,33  We therefore will anticipate up to 5 transfusions 
of PRBCs per subject.  Subjects who would qualify for study enrollment are very sick, and 
frequent PRBC transfusions may be related to their underlying illness and not to the study-
related blood draws.  If following the review additional study enrollment is deemed safe, 
enrollment may be allowed to resume.  Assuming the number of transfusions follows a Poisson 
distribution with mean of 5, then the probability of a subject receiving more than 5 PRBC 
transfusions is 0.384 (or 38.4%).  If the halting rule is to stop the study when exactly 4 subjects 
receive more than 5 transfusions, then the probability of halting the study based on the given 
assumptions is 0.001 (or 0.1%) using a Binomial distribution with n=32 and probability of 
success equal to 0.384. 
9.4 
DMID Safety Oversight 
DMID (medical officer, medical monitor and clinical project manager), the Protocol Chair, the 
UAB Central Unit, and an independent safety monitor (ISM) with expertise in pharmacology will: 
 
Monitor ganciclovir systemic exposures achieved with the clinical administration of 
ganciclovir.   
 
Review the safety information when a halting rule is met. 
 
Review AESIs on a regular basis. 
 
 

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

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10 
CLINICAL MONITORING 
10.1 Site Monitoring Plan 
Site Monitoring will be conducted to ensure that human subject protection, study procedures, 
laboratory procedures, study intervention administration, and data collection processes are of 
high quality and meet sponsor, GCP/ICH, and regulatory guidelines, and that the study is 
conducted in accordance with the protocol and study manuals.  NIAID/ DMID, the sponsor of 
this study, or its designee will conduct site monitoring visits as detailed in the monitoring plan.  A 
Clinical Monitoring Plan will be developed to include specifics about the monitoring, including a 
description of the number and type of subjects monitored, frequency of visits, tasks completed 
during the visits, and the different types of visits that will be used during the monitoring.  The 
monitoring plan will be a risk based assessment. 
Site visits typically may be made at standard defined intervals.  More frequent sites visits may 
be made if needed.  Monitoring visits will include, but are not limited to, review of regulatory 
files, case report forms, informed consent forms, medical and laboratory reports, and protocol 
compliance.  Study monitors will meet with investigators to discuss any problems and actions to 
be taken and document visit findings and discussions. 
Every effort will be made to maintain the anonymity and confidentiality of subjects during this 
study. However, because of the experimental nature of this sampling study, the Investigator 
agrees to allow representatives of the sponsor as well as authorized representatives of the Food 
and Drug Administration, or other Regulatory agencies or the UAB Central Unit, to inspect the 
facilities used in this study and to inspect, for purposes of verification, the hospital or clinic 
records of all subjects enrolled into this. 

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11 
STATISTICAL CONSIDERATIONS 
11.1 Study Hypotheses 
Our primary hypothesis is that ganciclovir pharmacokinetics and pharmacodynamics in 
premature infants with postnatally or congenitally acquired CMV infection differ from those in 
term neonates and older infants. 
11.2 Sample Size Considerations 
The primary outcome used for power analysis is the area under the curve for 12 hours (AUC12) 
following 6 mg/kg of ganciclovir.  In a one-way ANOVA design, we would like to compare the 
means of 4 groups (see below) with sample sizes of approximately 8, 8, 8, and 8 (32 total 
subjects enrolled across the four cohorts).  If the means of the AUC12 of the 4 groups are 20, 
20, 30, and 35 assuming a common standard deviation of 10, these mean differences 
(equivalent to an effect size of 0.72) will be detected at 83% power using an F test with 0.05 
level of significance.  In order to look at other possible scenarios, we provide the table below 
that looks at other standard deviation values, its corresponding effect size given the differences 
in means as described above, and the power of detecting such a difference/effect size.  If 
estimating the AUC without regard to the groups, the margin of errors associated with a 95% 
confidence interval assuming different standard deviation values and a sample size of 32 are 
given in the table below. 
 
Standard Deviation 
S=8 
S=9 
S=10 
S=11 
Effect Size 
0.81 
0.72 
0.64 
0.59 
Power 
96% 
91% 
83% 
75% 
Margin of Error 
2.33 
2.62 
2.91 
3.20 
 
The above parameter values were hypothesized based on results from other studies.25,34  It is 
worth noting that there are no PK data in this population and the results are likely to be different 
from other studies due to the maturational changes. 
Following enrollment, subjects will be stratified by gestational age and by chronologic age as 
follows:  1) ≤ 27 weeks 6 days gestational age at birth and ≤ 30 days chronologic age at study 
enrollment; 2) ≤ 27 weeks 6 days gestational age at birth and > 30 days chronologic age at 
study enrollment; 3) ≥ 28 weeks 0 days gestational age at birth and ≤ 30 days chronologic age 
at study enrollment; 4) ≥ 28 weeks 0 days gestational age at birth and > 30 days chronologic 
age at study enrollment.  The total sample size across these four cohorts is 32 subjects.  
Enrollment of an additional 2-3 subjects may be allowed for operational reasons.  If the 32 

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subjects enrolled are not balanced across the 4 groups, we instead will look at the correlation 
between gestational age at birth. With 32 subjects, the margin of errors of a 95% confidence 
interval for estimating the correlation given the observed correlation values are given below. 
 
Correlation 
0.4 
0.5 
0.6 
0.7 
Margin of Error 
0.6 
0.542 
0.47 
0.38 
Data will be collected on standardized case report forms.  Standard non-compartmental 
techniques will be used initially to estimate pharmacokinetic parameters derived from the 
ganciclovir concentration-time data.  The resource utilized for pharmacokinetic analysis is 
WinNonlin version 5.3, Pharsight Corporation, Mountain View, CA. 
11.3 Planned Interim Analyses (if applicable) 
There are no planned interim analyses or safety reviews for this trial. 
11.4 Final Analysis Plan 
Primary analysis: To compare the ganciclovir pharmacokinetics and pharmacodynamics as 
measured by AUC12 in premature infants with postnatally or congenitally acquired CMV 
infection differ from those in term neonates and older infants, we will construct 95% confidence 
intervals around the mean AUC12 for the subjects in this study and compare these means 
across the groups.  If there are not enough subjects in the groups, we will use the actual 
gestational age and correlate it with the AUC12 by computing correlation coefficients and a fitting 
regression model.  Additional pharmacokinetic parameters that compose analyses for 
secondary endpoints include Cmax, T1/2,CL, and VD.  For measures that are repeated over 
time, we will utilize mixed models for repeated measures.  In addition to being able to compare 
these outcomes for the different groups, we can also look into how these measures change over 
time and adjust for covariates.  
Ganciclovir pharmacokinetic parameters will initially be determined using non-compartmental 
analysis (WinNonlin v5.3) for each individual subject.  The parameters (AUC12, CL, Vd, etc.) will 
be summarized and further used for exploratory pharmacodynamic analysis.  We will also apply 
pharmacokinetic models to the concentration-time data, either individually or using a population 
approach.  We may also pool these data with prior CASG 109 PK data in order to have a more 
robust covariate analysis across a wider range of ages. 
The second pharmacokinetic analysis will utilize either population pharmacokinetic or individual 
modeling approaches, depending upon how much data we actually are able to collect and the 
nature of those data.  Concentration-time data will be analyzed using nonlinear mixed-effects in 
ADAPT 5.0.  If a population approach is employed, this will give us the opportunity to explore 

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relationships between ganciclovir exposure and multiple covariates, such as gestational age, 
weight, renal function, etc.  
A 95% confidence interval will be constructed to evaluate the mean changes in the log of the 
viral load between baseline (day 1) and weeks 1, 2, 3, 4, 5, and 6.  Area under the curve will be 
calculated for each subject’s CMV viral load measurement utilizing the trapezoidal rule.  These 
AUCs will be calculated over the entire course of drug administration.  Spearman’s correlations 
will be given for each AUC estimation and also for the AUC after baseline viral load (VL) 
adjustment.  Analysis of variance will be used to investigate whether grouping AUCs into groups 
(undetected, 100-1000, 1000-10000 and ≥ 10000) would indicate any PD relationships.  In 
addition, changes in CMV viral load from baseline over time (weeks 1 through 6) will be 
correlated with PK parameters.  These data will provide the framework for all PD analyses, 
where ganciclovir exposures variables will be correlated with the response variables using linear 
or maximum effect PD models. 
Secondary analyses: To investigate the association of secondary outcomes namely, 
neutropenia, CMV in urine, viral load and resistance to ganciclovir, with plasma concentration, 
we will utilize inference methods based on Generalized Estimating Equations (GEE) which 
models repeated binary data. As in the primary analysis, GEE will enable us to compare groups, 
investigate changes of outcomes over time, and adjust for any covariates. 

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12 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
The site will maintain appropriate medical and research records for this trial, in compliance with 
ICH E6, Section 4.9 and regulatory and institutional requirements for the protection of 
confidentiality of subjects. As part of participating in a DMID-sponsored, DMID-affiliated, or 
manufacturer-sponsored study, the site will permit authorized representatives of the sponsor(s), 
DMID, the UAB Central Unit and regulatory agencies to examine (and when required by 
applicable law, to copy) clinical records for the purposes of quality assurance reviews, audits, 
and evaluation of the study safety and progress. 
Documentation of source data is necessary for the reconstruction, evaluation, and validation of 
clinical findings, observations, and other activities during a clinical trial. Source data are all 
information, original records of clinical findings, observations, or other activities in a clinical trial 
necessary for the reconstruction and evaluation of the trial. Examples of these original 
documents and data records include, but are not limited to, Source Document Worksheets, 
hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial.  Source documentation serves to substantiate the integrity of trial data, confirms 
observations that are recorded, and confirm the existence of study participants.  This standard 
also serves to ensure data quality by creating audit trails and enabling verification that data are 
present, complete, and accurate.  Sites that are participating in this trial should consult the 
MOP, and DMID/NIAID Source Document Standards (most current version) for specific 
instruction and forms. 

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13 
QUALITY CONTROL AND QUALITY ASSURANCE 
The study site will implement a quality management plan.  The quality management procedures 
are described herein, as well as in the Manual of Procedures and the study site quality 
management plan (QMP).  Per the QMP, data will be evaluated for compliance with the protocol 
and accuracy in relation to source documents.  The study will be conducted in accordance with 
procedures identified in the protocol.  Items to be reviewed include, but are not limited to: 
eligibility (including informed consent), AE reporting, study/clinical endpoints, follow-up visits, 
regulatory documents, missed visits, and review of clinical records.  Data that will be reviewed, 
who is responsible for implementation, and the schedule for internal reviews will be specified or 
referenced in the quality management plan.   
 
The  study monitors will verify that the clinical trial is conducted and data are generated, 
documented, and reported in compliance with the protocol, ICH E6(R1), and the applicable 
regulatory requirements.  Reports will be submitted to DMID and UAB on monitoring activities.  
The study site research team 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 their 
designees. 
 
The UAB Statistical and Data Coordinating Center will implement quality control procedures 
beginning with the data entry system and generate data quality control checks that will be run 
on the database within 24 hours of new data entered into the system.  Full documentation of 
these checks will be provided to the UAB Central Unit so that any resulting queries can easily 
be understood and transmitted to the respective site for resolution within a short period of time. 
These processes are validated by a second programmer and also tested with faulty test data.  
All of these procedures and processes are described in detail in the DMID 11-0067 Data 
Management Plan (DMP) specific for this protocol.  The DMP defines and provides instructions 
regarding the conduct of the data management processes, describing in detail the following: the 
work to be performed, the responsible individuals/groups, applicable SOPs and Guidelines, and 
required documentation. 

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14 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
14.1 Ethical Standard 
The investigator will ensure that this study is conducted in full conformity with the principles set 
forth in The Belmont Report: Ethical Principles and Guidelines for the Protection of Human 
Subjects of Research of the US National Commission for the Protection of Human Subjects of 
Biomedical and Behavioral Research (April 18, 1979) and codified in 45 CFR Part 46 and/or the 
ICH E6; 62 Federal Regulations 25691 (1997). 
14.2 Institutional Review Board 
Reviewing IRBs must be registered with the OHRP to conduct FDA-regulated studies.  In the 
United States and in other countries, 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 Institutional Review 
Board (IRB) for review and must be approved before the study is initiated.  Any amendments to 
the protocol must also be approved by the IRB prior to implementing changes in the study.  
 
The investigator is responsible for keeping the IRB apprised of the progress of the study and of 
any changes made to the protocol as deemed appropriate, but in any case at least once per 
year.  The investigator must also keep the IRB informed of any significant AEs. 
 
All IRB approved documents as well as relevant study correspondence should be copied and 
sent to the UAB Central Unit. 
For this study, clinical sites will have the opportunity to participate in a Facilitated Central IRB 
process supported by the UAB Institutional Review Board and the UAB Central Unit.  
Participating sites will be provided with detailed instructions on required responsibilities for 
participating an OHRP compliant Facilitated IRB. 
14.3 Informed Consent Process 
The process of obtaining informed consent must be documented in the medical records, clinic 
chart, and/or research chart.  The consent form must be signed and dated by the subject’s 
parent(s)/legal guardian(s) before participation in the study.  A copy of the signed consent form 
must be provided to the subject’s parent(s)/legal guardian(s).  Signed consent forms must 
remain in each study participants study file and must be available for verification by study 
monitors at any time.  

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The investigational nature and research objectives of this trial, the procedure, and its attendant 
risks and discomforts will be carefully explained to the subject’s parent(s)/legal guardian(s).  A 
signed informed consent document will be obtained from each subject’s parent(s)/legal 
guardian(s) prior to entry into this study.  At any time during participation in the protocol, if new 
information becomes available relating to risks, AEs, or toxicities, this information will be 
provided orally or in writing to all enrolled or prospective subject’s parent(s)/legal guardian(s). 
Documentation will be provided to the IRB and, if necessary, the informed consent will be 
amended to reflect any relevant information. 
An investigator shall seek such consent only under circumstances that provide the subject’s 
parent(s)/legal guardian(s) sufficient opportunity to consider whether or not to participate and 
that minimize the possibility of coercion or undue influence. The information that is given to the 
subject’s parent(s)/legal guardian(s) shall be in language understandable to the subject’s 
parent(s)/legal guardian(s). 
Subject’s parent(s)/legal guardian(s) will sign the informed consent document prior to any 
procedures being done specifically for the study.  Subject’s parent(s)/legal guardian(s) should 
have the opportunity to discuss the study with their family, friends or personal physician, or think 
about it prior to agreeing to participate.  Subject’s parent(s)/legal guardian(s) may withdraw 
consent at any time throughout the course of the trial.  A copy of the informed consent 
document will be given to the subject’s parent(s)/legal guardian(s) for their records.  The rights 
and welfare of the subjects will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study. 
14.3.1 Informed Consent/Assent Process (in Case of a Minor) 
If required by the site’s IRB, the parent or legal guardian will sign a waiver of assent for the 
minor due to the study participant’s age.  Assent age will be determined by the local IRB.  
Appropriate documentation will be required for subjects who are the age of assent, whether 
mature enough to read and capable of providing signed assent, or whether too young to read 
but capable of providing verbal assent, as determined by the local IRB in compliance with 
45CFR46.  Local IRBs will review and assign the risk level. 
14.4 Exclusion of Women, Minorities, and Children (Special 
Populations) 
This study will be conducted solely in premature infants.  The study will not exclude young 
children, females, or minorities. 

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14.5 Subject Confidentiality 
The information obtained during the conduct of this clinical study is confidential, and disclosure 
to third parties other than those noted below is prohibited.  The results of the research study 
may be published, but study participant’s names or identities will not be revealed.  Records will 
remain confidential.  To maintain confidentiality, the principal investigators 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.  However, subject specific 
information will be available to the clinical monitors, to the FDA and to health authorities where 
provided by law. .   
 
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.  The NIAID/DMID or UAB  may 
disclose this information to appropriate regulatory authorities or clinical practice management 
groups (such as Pediatric Infectious Disease Society) as deemed necessary.   
  
Subject-specific information may be provided to other appropriate medical personnel only with 
the study participant’s parent/legal guardian permission.  To ensure compliance with current 
ICH guidelines, data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, the NIAID/DMID, UAB Central Unit 
personnel, and the IRB/IEC for each study site. 
14.6 Study Discontinuation 
Therapy is not being provided by the study in this sampling trial.  Therefore, there is no 
procedure for subjects to continue therapy if the study is discontinued. 
14.7 Future Use of Stored Specimens 
Some of the specimens obtained from study participants during this study will be stored 
indefinitely in the UAB Central Laboratory at the University of Alabama at Birmingham and may 
be used in future CMV research.  These specimens will be labeled with a code number and not 
with the study participant’s name.  At the time of consent for study participation, study 
participant’s parent/legal guardian will have the opportunity to either agree to have their 
specimens used in future CMV research or decline to have their specimens used in future CMV 
research.  The study participant’s parent/legal guardian will indicate his/her preference by 
initialing the appropriate line or checking the appropriate box of the Consent Form in the section 
entitled, “Future Use of Specimens”.  Non-protocol designated, future testing of samples will be 
performed only on samples from study participants who have consented for future testing of 
samples.  These specimens will only be utilized to better understand the natural history of CMV 

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41 
or improve diagnosis.  Residual specimens from subject who decline future use will be 
destroyed after the study, final analysis and report writing is complete. 
A repository for residual samples will be established according to OHRP guidelines ensuring 
that codes or other personally identifying links will not be distributed to future researchers. 
The specimens will be stored indefinitely in the UAB Central Laboratory at the University of 
Alabama at Birmingham.  CMV specimens from study participants will be labeled and coded 
without study participant’s identifiers.  If the study participant’s parent/legal guardian has 
indicated in the signed consent form that he/she does not agree to allow the future use of 
specimens for future CMV research, then his/her child’s specimens will be destroyed at the 
completion of the study. 

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15 
DATA HANDLING AND RECORD KEEPING 
The investigator is responsible to ensure the accuracy, completeness, legibility, and timeliness 
of the data reported. 
Electronic case report forms (eCRFs) will be developed by the UAB Statistical and Data 
Coordinating Center.  The eCRFs will be provided electronically by the UAB Central Unit.  
Original data will be recorded on source documents (e.g., medical records, research progress 
notes, Source Document Worksheets documenting research related procedures).  The DMID 
11-0067 DMP provides a description of how the system will function.  Source Document 
Worksheets that mirror each data field on the eCRF will be available for use by sites as a tool to 
record and maintain data for each study participant enrolled in the study when other source 
documents are not used to collect original data.  All source documents should be completed in a 
neat, legible manner to ensure accurate interpretation of data.  When making a change or 
correction, cross out the original entry with a single line and initial and date the change.  DO 
NOT ERASE, OVERWRITE, OR USE CORRECTION FLUID OR TAPE ON THE ORIGINAL.   
Specific guidance to investigators and study staff on making corrections to source documents 
and eCRFs will be provided in the MOP for this study.  
Data recorded on the eCRF that differ from source documents must be explained on the 
Comments eCRF and in the subject’s source documents. 
15.1 Data Management Responsibilities 
All eCRFS must be reviewed by the investigator’s research team, under the supervision of the 
investigator, who will ensure that they are accurate and complete.  All data must be supported 
by source documents, which will remain available for review by regulatory personnel and 
monitors.  Adverse events must be graded, assessed for intensity and causality, and reviewed 
by the site investigator or designee.      
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site PI.  During the study, the investigator must maintain complete and accurate 
documentation for the study. 
The UAB Central Unit and Statistical and Data Coordinating  will be responsible for data 
management, quality review, analysis of the study data, and writing of the clinical study report.  
These tasks are detailed in the DMID 11-0067 DMP. 

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15.2 Data Capture Methods 
Clinical and laboratory data will be entered into a 21 CRF Part 11 compliant electronic Data 
Entry System (eDES)  provided by the UAB Statistical and Data Coordinating Center.  The data 
system includes password protection and internal quality checks, such as automated range 
checks, to identify data that appear to be inconsistent, incomplete, or inaccurate. 
15.3 Types of Data 
Data for this study will include clinical laboratory, pharmacokinetic, and virologic results, and 
clinical and outcome measures (e.g., PK, weight, and virology). 
15.4 Timing/Reports 
There are no planned interim analyses or safety reviews for this trial.  Stopping rules are 
detailed in Section 9.5.  Following enrollment and PK assessments on the first four study 
subjects, safety and pharmacokinetic data will be summarized and reviewed by the Sponsor 
(e.g., the DMID medical officer and the DMID medical monitor), Protocol Chair, the UAB Central 
Unit, and an independent pharmacology monitor.  The frequency of future data reviews will be 
determined at that time. 
15.5 Study Records Retention 
Records and documents pertaining to the conduct of this study, including source documents, 
consent forms, laboratory test results, and medication inventory records, must be retained by 
the investigator for at least 2 years following completion of the study.  No study records shall be 
destroyed without prior authorization from the UAB Central Unit and NIAID/DMID.  These 
documents should be retained for a longer period, however, if required by local regulations.  It is 
the responsibility of the sponsor to notifiy the UAB Central Unit, which will notify the 
investigators, when these documents no longer need to be retained. 
15.6 Protocol Deviations 
Each investigator must adhere to the protocol as detailed in this document and agree that any 
changes to the protocol must be approved by the UAB Central Unit and NIAID/DMID prior to 
seeking approval from the IRB/IEC.  Each investigator will be responsible for enrolling only 
those study participants who have met protocol eligibility criteria. 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or Manual of 
Procedures requirements.  The noncompliance may be either on the part of the study 

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44 
participant, the investigator, or the study site staff.  As a result of deviations, corrective actions 
are to be developed by the site and implemented promptly.  
These practices are consistent with ICH E6 GCP sections: 
4.5 
Compliance with Protocol, Sections 4.5.1, 4.5.2, and 4.5.3 
5.1 
Quality Assurance and Quality Control, Section 5.1.1 
5.20 
Noncompliance, Sections 5.20.1 and 5.20.2. 
It is the responsibility of the site to use continuous vigilance to identify and report deviations 
within 1 business day of identification of the protocol deviation that increases subject risk.  
Deviations that do not increase subject risk can be reported within 5 business days of 
knowledge of the event.  All deviations must be promptly reported to the UAB Central Unit.  UAB 
will report all deviations to DMID in accordance with DMID’s instructions. 
All deviations from the protocol must be addressed in the source documents.  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. A log of protocol deviation 
will be maintained in the Project Notebook. Protocol deviations must be sent to the local IRB per 
the IRB’s guidelines.  The site PI/study staff is responsible for knowing and adhering to their 
IRB/IEC requirements. 

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16 
PUBLICATION POLICY 
Following completion of this study, the investigators are expected to publish the results in a 
scientific journal.  All research reports and other publications resulting from the work completed 
in this protocol shall: 
 
Acknowledge the support of the National Institutes of Health whenever publicizing the 
results from this clinical trial in any media by including an acknowledgement substantially as 
follows: 
o Be submitted to the Project Director in the form of advance copies for review and 
comment prior to the publication to ensure appropriate coordination of the research 
results. 
o Be furnished in a list of publications resulting from the research as part of the annual 
progress report submitted to the principal investigator. 
 
The International Committee of Medical Journal Editors (ICMJE) member journals have adopted 
a trials-registration policy as a condition for publication.  This policy requires that all clinical trials 
be registered in a public trials registry such as ClinicalTrials.gov, which is sponsored by the 
National Library of Medicine.  Other biomedical journals are considering adopting similar 
policies. 
Unless exempted, this trial will be registered prior to enrollment of study subjects.  It is the 
responsibility of the study’s PI (e.g., Dr. Kimberlin) to register the non-exempted trials and post 
results in compliance with Public Law 110-85, the Food and Drug Administration Amendments 
Act of 2007 (FDAAA). 

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17 
LITERATURE REFERENCES 
 
1. 
Stagno S, Whitley RJ. Herpesvirus infections of pregnancy. Part I: Cytomegalovirus and 
Epstein-Barr virus infections. N Engl J Med. 1985;313:1270-4. 
2. 
Boppana SB, Fowler KB, Vaid Y, et al. Neuroradiographic findings in the newborn period 
and long-term outcome in children with symptomatic congenital cytomegalovirus 
infection. Pediatrics. 1997;99:409-14. 
3. 
Boppana SB, Pass RF, Britt WJ, et al. Symptomatic congenital cytomegalovirus 
infection: neonatal morbidity and mortality. Pediatr Infect Dis J. 1992;11:93-9. 
4. 
Dahle AJ, Fowler KB, Wright JD, et al. Longitudinal investigation of hearing disorders in 
children with congenital cytomegalovirus. Journal of the American Academy of 
Audiology. 2000;11:283-90. 
5. 
Fowler KB, Boppana SB. Congenital cytomegalovirus (CMV) infection and hearing 
deficit. J Clin Virol. 2006;35:226-31. 
6. 
Fowler KB, McCollister FP, Dahle AJ, et al. Progressive and fluctuating sensorineural 
hearing loss in children with asymptomatic congenital cytomegalovirus infection. J 
Pediatr. 1997;130:624-30. 
7. 
Rivera LB, Boppana SB, Fowler KB, et al. Predictors of hearing loss in children with 
symptomatic congenital cytomegalovirus infection. Pediatrics. 2002;110:762-7. 
8. 
Stronati M, Lombardi G, Di Comite A, et al. Breastfeeding and cytomegalovirus 
infections. J Chemother. 2007;19 Suppl 2:49-51. 
9. 
Vochem M, Hamprecht K, Jahn G, et al. Transmission of cytomegalovirus to preterm 
infants through breast milk. Pediatr Infect Dis J. 1998;17:53-8. 
10. 
Maschmann J, Hamprecht K, Dietz K, et al. Cytomegalovirus infection of extremely low-
birth weight infants via breast milk. Clinical Infectious Diseases. 2001;33:1998-2003. 
11. 
Takahashi R, Tagawa M, Sanjo M, et al. Severe postnatal cytomegalovirus infection in a 
very premature infant. Neonatology. 2007;92:236-9. 
12. 
Vancikova Z, Kucerova T, Pelikan L, et al. Perinatal cytomegalovirus hepatitis: to treat or 
not to treat with ganciclovir. J Paediatr Child Health. 2004;40:444-8. 
13. 
Bradshaw JH, Moore PP. Perinatal cytomegalovirus infection associated with lung cysts. 
Journal of Paediatrics & Child Health. 2003;39:563-6. 

Collaborative Antiviral Study Group                                                    DMID Protocol #11-0067, Version 2.0  
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47 
14. 
Hsu ML, Cheng SN, Huang CF, et al. Perinatal cytomegalovirus infection complicated 
with pneumonitis and adrenalitis in a premature infant. Journal of Microbiology, 
Immunology & Infection. 2001;34:297-300. 
15. 
Neuberger P, Hamprecht K, Vochem M, et al. Case-control study of symptoms and 
neonatal outcome of human milk-transmitted cytomegalovirus infection in premature 
infants. J Pediatr. 2006;148:326-31. 
16. 
Kothari A, Ramachandran VG, Gupta P. Cytomegalovirus infection in neonates following 
exchange transfusion. Indian J Pediatr. 2006;73:519-21. 
17. 
Mussi-Pinhata MM, Yamamoto AY, do Carmo Rego MA, et al. Perinatal or early-
postnatal cytomegalovirus infection in preterm infants under 34 weeks gestation born to 
CMV-seropositive mothers within a high-seroprevalence population. J Pediatr. 
2004;145:685-8. 
18. 
Yasuda A, Kimura H, Hayakawa M, et al. Evaluation of cytomegalovirus infections 
transmitted via breast milk in preterm infants with a real-time polymerase chain reaction 
assay. Pediatrics. 2003;111:1333-6. 
19. 
Vollmer B, Seibold-Weiger K, Schmitz-Salue C, et al. Postnatally acquired 
cytomegalovirus infection via breast milk: effects on hearing and development in preterm 
infants. Pediatr Infect Dis J. 2004;23:322-7. 
20. 
Hamprecht K, Maschmann J, Jahn G, et al. Cytomegalovirus transmission to preterm 
infants during lactation. J Clin Virol. 2008;41:198-205. 
21. 
Kimberlin DW, Lin CY, Sanchez PJ, et al. Effect of ganciclovir therapy on hearing in 
symptomatic congenital cytomegalovirus disease involving the central nervous system: a 
randomized, controlled trial. J Pediatr. 2003;143:16-25. 
22. 
Oliver SE, Cloud GA, Sanchez PJ, et al. Neurodevelopmental outcomes following 
ganciclovir therapy in symptomatic congenital cytomegalovirus infections involving the 
central nervous system. J Clin Virol. 2009;46 Suppl 4:S22-6. 
23. 
Investigator's Brochure. Ro107-9070 (Valcyte , Valganciclovir). 2002. 
24. 
Trang JM, Kidd L, Gruber W, et al. Linear single-dose pharmacokinetics of ganciclovir in 
newborns with congenital cytomegalovirus infections. Clinical Pharmacology & 
Therapeutics. 1993;53:15-21. 
25. 
Kimberlin DW, Acosta EP, Sanchez PJ, et al. Pharmacokinetic and pharmacodynamic 
assessment of oral valganciclovir in the treatment of symptomatic congenital 
cytomegalovirus disease. J Infect Dis. 2008;197:836-45. 
26. 
Englund JA, Fletcher CV, Balfour HH, Jr. Acyclovir therapy in neonates. J Pediatr. 
1991;119:129-35. 

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48 
27. 
Zhou XJ, Gruber W, Demmler G, et al. Population pharmacokinetics of ganciclovir in 
newborns with congenital cytomegalovirus infections. Antimicrob Agents Chemother. 
1996;40:2202-5. 
28. 
Whitley RJ, Cloud G, Gruber W, et al. Ganciclovir treatment of symptomatic congenital 
cytomegalovirus infection: results of a phase II study. J Infect Dis. 1997;175:1080-6. 
29. 
Acosta EP, Brundage RC, King JR, et al. Ganciclovir population pharmacokinetics in 
neonates following intravenous administration of ganciclovir and oral administration of a 
liquid valganciclovir formulation. Clin Pharmacol Ther. 2007;81:867-72. 
30. 
Trang JM, Kidd L, Gruber W, et al. Linear single-dose pharmacokinetics of ganciclovir in 
newborns with congenital cytomegalovirus infections. Clin Pharmacol Ther. 1993;53:15-
21. 
31. 
Ohls RK, Ehrenkranz RA, Wright LL, et al. Effects of early erythropoietin therapy on the 
transfusion requirements of preterm infants below 1250 grams birth weight: a 
multicenter, randomized, controlled trial. Pediatrics. 2001;108:934-42. 
32. 
Kirpalani H, Whyte RK, Andersen C, et al. The Premature Infants in Need of Transfusion 
(PINT) study: a randomized, controlled trial of a restrictive (low) versus liberal (high) 
transfusion threshold for extremely low birth weight infants. J Pediatr. 2006;149:301-307. 
33. 
von Lindern JS, Khodabux CM, Hack KE, et al. Long-term outcome in relationship to 
neonatal transfusion volume in extremely premature infants: a comparative cohort study. 
BMC Pediatr. 2011;11:48. 
34. 
Wiltshire H, Hirankarn S, Farrell C, et al. Pharmacokinetic profile of ganciclovir after its 
oral administration and from its prodrug, valganciclovir, in solid organ transplant 
recipients. Clin Pharmacokinet. 2005;44:495-507. 
 
  

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49 
SUPPLEMENTS/APPENDICES 

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50 
APPENDIX A: SCHEDULE OF EVENTS 
(FOLLOWING ACQUISITION OF INFORMED CONSENT) 
Table 1. Schematic of Study Design for Gan Premie 
NOTE: Required Studies in Black Font, Optional Studies in Blue Font 
 
Period 1 
(Study 
Assessm
ent Day 
1 
through 
Study 
Assessm
ent Day 
3) 
Period 2 
(Study 
Assessment 
Day 4 
through 
Study 
Assessment
Day 10)a 
Period 3 
(Study 
Assessment 
Day 11 
through 
Study 
Assessment
Day 17)a 
Period 4 
(Study 
Assessm
ent Day 
18 
through 
Study 
Assessm
ent Day 
24)a 
Period 5 
(Study 
Assessm
ent Day 
25 
through 
Study 
Assessm
ent Day 
31)a 
Period 6 
(Study 
Assessment 
Day 32 
through 
Study 
Assessment
Day 38)a 
Period 7 
(Study 
Assessm
ent Day 
39 
through 
Study 
Assessm
ent Day 
42)a 
Baseline 
demographic
sb 
Xc 
 
 
 
 
 
 
Hematology 
labsd 
Xc,e 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Chemistry 
labsf 
Xc,e 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Creatinine 
Xg 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Ganciclovir 
pharmacokin
etics 
Xh 
 
Xi,j 
 
 
 
Virology 
blood 
specimens 
for CMV viral 
loadk 
Xl 
Xl 
Xl 
Xl 
Xl 
Xl,m 
Xl,n 
CMV 
detection 
from 
noninvasive 
urine 
specimen 
Xo 
Xo 
Xo 
Xo 
Xo 
Xo 
Xo 
Ganciclovir 
dosing 
information 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
Xp 
PRBC 
transfusion 
assessment 
Xq 
Xq 
Xq 
Xq 
Xq 
Xq 
Xq 

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Assessment 
for AEs or 
SAEs 
 
X 
X 
X 
X 
X 
X 
Total volume 
of blood 
required for 
study 
procedures 
1.75 mL 
0.5 mL 
0.5 mL 
0.5 mL 
or 1.5 
mLi 
0.5 mL 
0.5 mL 
0.5 mL 
a) 
Data and specimens in this column to be captured if subject still receiving ganciclovir as clinical treatment 
b) 
Gestational age at delivery, date of birth, day of life at initiation of IV ganciclovir therapy, gender, race, 
ethnicity, birth weight, weight at enrollment, length in centimeters at enrollment, reason ganciclovir being 
administered, ganciclovir dose and dosing frequency, manufacturer of the ganciclovir lot utilized at the 
treating facility, date ganciclovir therapy was initiated 
c) 
Window: Birth through Study Assessment Day 3) 
d) 
WBC with differential, hemoglobin, platelet count.  Optional laboratory draws are not required by the 
protocol, and so no documentation on a source document will be required. 
e) 
If being drawn for clinical reasons; any laboratory value obtained during the window will suffice, with an effort 
being made to capture the most abnormal value.  Optional laboratory draws are not required by the protocol, 
and so no documentation on a source document will be required. 
f) 
AST, ALT.  Optional laboratory draws are not required by the protocol, and so no documentation on a 
source document will be required. 
g) 
To be drawn on the calendar day that ganciclovir PKs are being drawn.  Study related laboratory draws will 
be delayed or deferred if the investigator believes that obtaining them might increase subject risk.  
Additionally, a study-related laboratory specimen that is unevaluable due to clotting or laboratory related 
issues will not be repeated.  If a study related laboratory draw is delayed or deferred, study staff will 
document this on a source document. 
h) 
Ganciclovir concentrations will be obtained with one of the Study Assessment Doses 3, 4, 5, 6, 7, or 8 
(Window: Study Assessment Day 1 through Study Assessment Day 5) at the following time points:  0h 
(immediately prior to IV ganciclovir dose; window: -15 min), 1h (immediately after the end of the IV 
ganciclovir dose; window: +15 min), 2-3h, 5-7h, and 10-12h; required amount of whole blood for plasma 
ganciclovir determination at each time point is 200 L (0.2 mL).  Study related laboratory draws will be 
delayed or deferred if the investigator believes that obtaining them might increase subject risk.  Additionally, 
a study-related laboratory specimen that is unevaluable due to clotting or laboratory related issues will not 
be repeated.  If a study related laboratory draw is delayed or deferred, study staff will document this on a 
source document. 
i) 
If desired by the treating physicians, ganciclovir concentrations may be obtained around one dose during the 
window at the following time points:  0h (immediately prior to IV ganciclovir dose; window: -15 min), 1h 
(immediately after the end of the IV ganciclovir dose; window: +15 min), 2-3h, 5-7h, and 10-12h; required 
amount of whole blood for plasma ganciclovir determination at each time point is 200 L (0.2 mL).  Optional 
laboratory draws are not required by the protocol, and so no documentation on a source document will be 
required. 
j) 
If subject weighs < 575 grams, the second set of PK draws cannot be performed (would exceed blood draw 
parameters of 7 mL/kg over 42 days) 
k) 
To be obtained only once per study period; ideally, at least 72 hours should separate viral loads being 
obtained in different study periods 
l) 
Required amount of whole blood for CMV PCR is 0.5 mL.  Study related laboratory draws will be delayed or 
deferred if the investigator believes that obtaining them might increase subject risk.  Additionally, a study-
related laboratory specimen that is unevaluable due to clotting or laboratory related issues will not be 
repeated.  If a study related laboratory draw is delayed or deferred, study staff will document this on a 
source document. 
m) 
If subject weighs < 600 grams, the virology specimen for CMV viral load will not be performed (would exceed 
blood draw parameters of 7 mL/kg over 42 days) 
n) 
If subject weighs < 650 grams, the virology specimen for CMV viral load will not be performed (would exceed 
blood draw parameters of 7 mL/kg over 42 days) 
o) 
Urine collection will be non-invasive (e.g., bagged, indwelling foley catheter, excess clinical specimen, etc.).  
If urine is obtainable, it will be frozen and sent to the UAB Central Laboratory for processing. If an attempt to 

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52 
obtain urine for CMV detection is unsuccessful, study staff will document the failed attempt on a source 
document. 
p) 
mg/dose, dosing interval, subject weight 
q) 
Once during each Study Period the study team will record the number of PRBC transfusions received by the 
study subject since enrollment (for the Period 1 documentation) or since the last recording (for 
documentation for Periods 2-7).  A PRBC transfusion is defined as ≥ 10 mL/kg of PRBCs within a 24 hour 
period.