Conditions: Congenital Cytomegalovirus Infection
Keywords: Asymptomatic Congenital CMV Infection Valganciclovir Therapy
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 7
Healthy volunteers: no

Brief summary:
This is a phase II, open-label trial to evaluate valganciclovir as a treatment to prevent development of sensorineural hearing loss (SNHL) in infants with asymptomatic congenital cytomegalovirus (CMV) infection. The trial will be conducted in two phases - screening of newborns to identify eligible subjects, and treatment of those newborns who have confirmed CMV infection at birth but without outward manifestations of congenital CMV infection. 229 newborns with confirmed CMV infection but without baseline SNHL and who meet all inclusion/exclusion criteria will be enrolled into the treatment phase. Study duration is 5 years. Primary objective of this study is to estimate the proportion of subjects with asymptomatic congenital CMV infection who, following treatment with 4 months of oral valganciclovir, develop SNHL by 6 months of life.

Detailed description:
This is a phase II, open-label trial to evaluate valganciclovir as a treatment to prevent development of sensorineural hearing loss (SNHL) in infants with asymptomatic congenital cytomegalovirus (CMV) infection. The trial will be conducted in two phases - screening of newborns to identify eligible subjects, and treatment of those newborns who have confirmed CMV infection at birth but without outward manifestations of congenital CMV infection. Approximately 48,250 newborn infants with no outward manifestations of congenital CMV infection will be screened to detect approximately 241 neonates with asymptomatic congenital CMV infection; these 241 newborns then will have audiology examinations to determine baseline hearing, with approximately 229 having normal hearing in both ears. Those 229 newborns with confirmed CMV infection but without baseline SNHL and who meet all inclusion/exclusion criteria will be enrolled into the treatment phase. Enrolled subjects will be treated for four months with oral valganciclovir (16 mg/kg/dose, administered two times per day). Audiologic assessments will be made during the Screening Period and Study Months 4 (end of treatment), 6, 12, and 18. Treated infants will be followed for safety throughout the first 6 months of the study (including for 2 months post-treatment). Study duration is 5 years. Primary objective of this study is to estimate the proportion of subjects with asymptomatic congenital CMV infection who, following treatment with 4 months of oral valganciclovir, develop sensorineural hearing loss (SNHL) by 6 months of life. Secondary objectives are to: 1) define the safety and tolerability of valganciclovir in enrolled subjects, 2) estimate the proportion of subjects with asymptomatic congenital CMV infection who, following treatment with 4 months of oral valganciclovir, develop SNHL over the first 18 months of life.

Arms:
arm 1: Valganciclovir 16 mg/kg/dose orally twice daily for four months, n=229

Interventions: intervention 1: Valganciclovir
Intervention descriptions: intervention 1: Valganciclovir, 16 mg/kg/dose given orally twice daily for four months

Protocol document:
Prot_SAP_002.pdf: 
DMID Protocol #16-0095 
Version 3.0 
Collaborative Antiviral Study Group #405 
22 March 2019 
Asymptomatic CMV Treatment 
 ______________________________________________________________________________________________________  
 
 
DMID/NIAID/NIH 
 
 
 
 
 
 
 
 
 
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CONFIDENTIAL 
A PHASE II, SINGLE-STAGE, SINGLE-ARM INVESTIGATION 
OF ORAL VALGANCICLOVIR THERAPY IN INFANTS WITH 
ASYMPTOMATIC CONGENITAL CYTOMEGALOVIRUS 
INFECTION 
DMID Protocol Number: 16-0095 
 
DMID Funding Mechanism: HHSN272201600017C 
Pharmaceutical Support Provided by: Genentech, Inc. 
Other Identifying Numbers:  None 
IND Sponsor: DMID/NIAID 
Principal Investigator:  David W. Kimberlin, MD 
DMID Clinical Project Manager:  Walla Dempsey, PhD 
DMID Medical Monitor:  Soju Chang, MD 
Version Number: 3.0 
Day Month Year 
22 March 2019 
 


DMID Protocol #16-0095 
Version 3.0 
Collaborative Antiviral Study Group #405 
22 March 2019 
Asymptomatic CMV Treatment 
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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 Good Clinical Practice guidelines (GCP), and the applicable regulatory requirements, 
including: 
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR 
Part 46; 21 CFR Part 50, 21 CFR Part 54, 21 CFR Part 56, and 21 CFR Part 312); 
• International Conference on Harmonization (ICH) E6; 62 Federal Register 25691 (1997); 
• National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases 
(NIAID) Clinical Terms of Award. 
Compliance with these standards provides public assurance that the rights, safety and well-being 
of study subjects are protected, consistent with the principles that have their origin in the 
Declaration of Helsinki. 
All key personnel (all individuals responsible for the design and conduct of this study) have 
completed Human Subjects Protection Training. 
 


DMID Protocol #16-0095 
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Asymptomatic CMV Treatment 
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SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the 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 US federal regulations and ICH guidelines. 
 
Site Investigator: 
 
Signed: 
 
Date: 
 
 
Name 
______________________________________________ 
Title 
______________________________________________ 
Signature 
 
 
 


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Asymptomatic CMV Treatment 
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TABLE OF CONTENTS 
 
Statement of Compliance .................................................................................................................2 
Signature Page .................................................................................................................................3 
Table of Contents .............................................................................................................................4 
List of Tables ...................................................................................................................................8 
List of Figures ..................................................................................................................................9 
List of Abbreviations .....................................................................................................................10 
Protocol Summary .........................................................................................................................13 
1 
Key Roles ..............................................................................................................................21 
2 
Background Information and Scientific Rationale ...............................................................24 
2.1 
Background Information ...........................................................................................24 
2.2 
Rationale ...................................................................................................................29 
2.3 
Potential Risks and Benefits .....................................................................................30 
2.3.1 Potential Risks ..............................................................................................30 
2.3.2 Known Potential Benefits .............................................................................31 
3 
Objectives .............................................................................................................................32 
3.1 
Study Objectives .......................................................................................................32 
3.2 
Study Outcome Measures .........................................................................................32 
3.2.1 Primary Outcome Measures ..........................................................................32 
3.2.2 Secondary Outcome Measures ......................................................................32 
3.2.3 Exploratory Outcome Measures ...................................................................33 
4 
Study Design .........................................................................................................................34 
4.1 
Substudies (if applicable) ..........................................................................................35 
5 
Study Enrollment and Withdrawal........................................................................................36 
5.1 
Subject Inclusion Criteria .........................................................................................36 
5.2 
Subject Exclusion Criteria ........................................................................................36 
5.3 
Treatment Assignment Procedures ...........................................................................36 
5.3.1 Randomization Procedures ...........................................................................36 
5.3.2 Masking Procedures ......................................................................................36 
5.3.3 Reasons for Withdrawal ................................................................................37 
5.3.4 Handling of Withdrawals ..............................................................................38 
5.3.5 Termination of Study ....................................................................................38 
6 
Study Intervention/Investigational Product ..........................................................................39 
6.1 
Study Product Description ........................................................................................39 
6.1.1 Acquisition ....................................................................................................39 
6.1.2 Formulation, Packaging, and Labeling .........................................................39 
6.1.3 Product Storage and Stability........................................................................40 


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6.2 
Dosage, Preparation and Administration of Study Intervention/Investigational 
Product ......................................................................................................................40 
6.2.1 Dosage...........................................................................................................40 
6.2.2 Preparation ....................................................................................................40 
6.2.3 Administration ..............................................................................................40 
6.3 
Modification or Termination of Study Intervention/Investigational Product for a 
Participant .................................................................................................................40 
6.3.1 Neutropenia ...................................................................................................40 
6.3.2 Thrombocytopenia ........................................................................................41 
6.3.3 Hepatotoxicity ...............................................................................................41 
6.4 
Accountability Procedures for the Study Intervention/Investigational Product(s) ...41 
6.5 
Assessment of Subject Compliance with Study Intervention/Investigational 
Product ......................................................................................................................42 
6.6 
Concomitant Medications/Treatments ......................................................................42 
6.6.1 Concomitant Medication Assessment ...........................................................42 
6.6.2 Prohibited Therapies .....................................................................................42 
6.6.3 Drug Interactions ..........................................................................................42 
7 
Study Schedule......................................................................................................................44 
7.1 
Screening...................................................................................................................44 
7.2 
Enrollment/Baseline ..................................................................................................45 
7.2.1 Study Day 1 Assessment (Study Day -3 through Study Day 1, unless 
alternative window is specified) ...................................................................45 
7.2.2 Study Day 1...................................................................................................46 
7.2.3 Substudy Assessments ..................................................................................46 
7.3 
Follow-up ..................................................................................................................46 
7.3.1 Study Day 7 (± 2 days) .................................................................................46 
7.3.2 Study Day 14 (± 2 days) ...............................................................................47 
7.3.3 Study Day 21 (± 2 days) ...............................................................................47 
7.3.4 Study Day 28 (± 2 days) ...............................................................................48 
7.3.5 Study Day 35 (± 2 days) ...............................................................................49 
7.3.6 Study Day 42 (± 3 days) ...............................................................................49 
7.3.7 Study Day 56 (± 3 days) ...............................................................................50 
7.3.8 Study Day 70 (± 3 days) ...............................................................................51 
7.3.9 Study Day 84 (± 3 days) ...............................................................................52 
7.3.10 Study Month 4 (± 10 days, unless alternative window is specified) ............52 
7.3.11 Study Month 5 (± 10 days) ...........................................................................53 
7.3.12 Study Month 6 (± 10 days, unless alternative window is specified) ............54 
7.3.13 Study Month 12 (± 30 days, unless alternative window is specified) ..........55 
7.4 
Final Study Visit .......................................................................................................56 


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7.4.1 Study Month 18 (± 30 days, unless alternative window is specified) ..........56 
7.5 
Early Termination Visit ............................................................................................56 
7.6 
Unscheduled Visit .....................................................................................................56 
8 
Study Procedures/Evaluations ..............................................................................................57 
8.1 
Clinical Evaluations ..................................................................................................57 
8.1.1 Baseline Demographics ................................................................................57 
8.1.2 Growth Parameters........................................................................................57 
8.1.3 Adverse Event Assessment ...........................................................................57 
8.1.4 Hearing Assessment ......................................................................................57 
8.2 
Laboratory Evaluations .............................................................................................58 
8.2.1 Clinical Laboratory Evaluations ...................................................................58 
8.2.2 Special Assays or Procedures .......................................................................59 
8.2.3 Specimen Preparation, Handling, and Shipping ...........................................59 
9 
Assessment of Safety ............................................................................................................60 
9.1 
Specification of Safety Parameters ...........................................................................60 
9.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters .................................................................................................................60 
9.2.1 Adverse Events .............................................................................................60 
9.2.2 Serious Adverse Events ................................................................................62 
9.2.3 Procedures to be Followed in the Event of Abnormal Laboratory Test 
Values or Abnormal Clinical Findings .........................................................63 
9.3 
Reporting Procedures ................................................................................................63 
9.3.1 Serious Adverse Events ................................................................................63 
9.3.2 Regulatory Reporting for Studies Conducted Under DMID-Sponsored 
IND ...............................................................................................................64 
9.3.3 Other Adverse Events (if applicable) ............................................................65 
9.4 
Type and Duration of Follow-up of Subjects after Adverse Events .........................65 
9.5 
Halting Rules ............................................................................................................65 
9.5.1 Discontinuation of Study Participation for Individual Subject .....................65 
9.5.2 Discontinuation of Study Enrollment, and Study Treatment For All 
Subjects, Pending Sponsor Review...............................................................66 
9.6 
Safety Oversight (SMC) ...........................................................................................66 
9.6.1 Independent Safety Monitor (ISM) ...............................................................67 
10 
Clinical Monitoring ...............................................................................................................69 
10.1 
Site Monitoring Plan .................................................................................................69 
11 
Statistical Considerations ......................................................................................................70 
11.1 
Study Hypotheses......................................................................................................70 
11.2 
Sample Size Considerations ......................................................................................70 
11.3 
Planned Interim Analyses (if applicable) ..................................................................72 


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11.4 
Final Analysis Plan ...................................................................................................72 
11.4.1 Analysis Populations .....................................................................................72 
11.4.2 Baseline Characteristics ................................................................................73 
11.4.3 Safety Analysis Plan .....................................................................................73 
11.4.4 Efficacy Analysis Plan ..................................................................................73 
11.4.5 Missing Values and Outliers .........................................................................75 
12 
Source Documents and Access to Source Data/Documents .................................................76 
13 
Quality Control and Quality Assurance ................................................................................77 
14 
Ethics/Protection of Human Subjects ...................................................................................78 
14.1 
Ethical Standard ........................................................................................................78 
14.2 
Institutional Review Board .......................................................................................78 
14.3 
Informed Consent Process ........................................................................................78 
14.4 
Exclusion of Women, Minorities, and Children (Special Populations) ....................80 
14.5 
Subject Confidentiality .............................................................................................80 
14.6 
Study Discontinuation ...............................................................................................81 
14.7 
Future Use of Stored Specimens ...............................................................................81 
15 
Data Handling and Record Keeping .....................................................................................83 
15.1 
Data Management Responsibilities...........................................................................83 
15.2 
Data Capture Methods ..............................................................................................83 
15.3 
Types of Data ............................................................................................................83 
15.4 
Timing/Reports .........................................................................................................84 
15.5 
Study Records Retention...........................................................................................84 
15.6 
Protocol Deviations ...................................................................................................84 
16 
Publication Policy .................................................................................................................86 
17 
Literature References ............................................................................................................87 
18 
Appendix A: (Adapted From) Division of AIDS Toxicity Tables .......................................91 
19 
Appendix B: Schedule of Events ..........................................................................................96 
 
 
 
 


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LIST OF TABLES 
 
Table 1. Majority of sequelae from congenital CMV infection occurs in babies who are 
asymptomatic at birth ............................................................................................................24 
Table 2. Four-grade system utilized for this trial ...........................................................................61 
Table 3. Sample Size and Upper Bound of Estimates of SNHL ...................................................71 
 
 
 


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LIST OF FIGURES 
 
Figure 1. Schematic of study design ..............................................................................................20 
Figure 2. Whole blood viral load in subjects receiving 6 months and 6 weeks of oral 
valganciclovir ........................................................................................................................27 
 
 
 


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LIST OF ABBREVIATIONS 
ACIP 
Advisory Committee for Immunization Practices 
 
ADME 
Absorption, Distribution, Metabolism and Elimination 
 
AE 
Adverse Event/Adverse Experience 
 
AGA 
Appropriate for Gestational Age 
 
AIDS 
Acquired Immunodeficiency Syndrome 
 
ANC 
Absolute Neutrophil Count 
 
AUC 
Area Under the Curve 
 
BBB 
Blood-Brain Barrier 
 
BBU 
Biostatistics and Bioinformatics Unit 
 
BID 
Twice Daily 
 
BSER 
Brainstem Evoked Response 
 
CASG 
Collaborative Antiviral Study Group 
 
CAVH 
Continuous Arterio-Venous Hemofiltration 
 
CAVHD 
Continuous Arterio-Venous Hemodialysis 
 
CAVHDF 
Continuous Arterio Venous Demodiafiltration   
 
CDC 
Centers for Disease Control 
 
CFR 
Code of Federal Regulations 
 
CMV 
Cytomegalovirus 
 
CNS 
Central Nervous System 
 
CrCL 
Creatinine Clearance 
 
CONSORT 
Consolidated Standards of Reporting Trials 
 
CRF 
Case Report Form 
 
CRO 
Contract Research Organization 
 
CROMS 
Clinical Research Operations and Management Support 
 
CRRT 
Continuous Renal Replacement Therapy 
 
CSF 
Cerebrospinal Fluid 
 
DAIDS 
Division of AIDS 
 
DCC 
Data Coordinating Center 
 
DCF 
Data Collection Form 
 
DHHS 
Department of Health and Human Services 
 
DMID 
Division of Microbiology and Infectious Diseases, NIAID, 
NIH, DHHS 
 
DPOAE 
Distortion Product Otoacoustic Emission 
 
DSMB 
Data and Safety Monitoring Board 
 
eCRF 
Electronic Case Report Form 
 
ESRD 
End-stage Renal Disease 
 
EUA 
Emergency Use Authorization 
 
FDA 
Food and Drug Administration 
 


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FWA 
Federalwide Assurance 
 
GCP 
Good Clinical Practice 
 
GI 
Gastrointestinal 
 
HIPAA 
Health Insurance Portability and Accountability Act 
 
HIV 
Human Immunodeficiency Virus 
 
IB 
Investigator’s Brochure 
 
ICF 
Informed Consent Form 
 
ICH 
International Conference on Harmonisation 
 
ICU 
Intensive Care Unit 
 
IDE 
Investigational Device Exemption 
 
IDMS 
Isotope Dilution Mass Spectrometry 
 
IEC 
Independent or Institutional Ethics Committee 
 
IND 
Investigational New Drug Application 
 
IRB 
Institutional Review Board 
 
ISM 
Independent Safety Monitor 
 
ITT 
Intent to Treat 
 
IV 
Intravenous 
 
KG 
Kilogram 
 
MeDRA 
Medical Dictionary for Regulatory Activities 
 
MG 
Milligram 
 
MOP 
Manual of Procedures 
 
N 
Number (typically refers to subjects) 
 
N/A 
Not Applicable 
 
NCS 
Not Clinically Significant 
 
NDA 
New Drug Application 
 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH 
 
NIH 
National Institutes of Health 
 
NOAEL 
No Adverse Effect Level 
 
OAE 
Otoacoustic Emissions 
 
OCRA 
Office of Clinical Research Affairs, DMID, NIAID, NIH, 
DHHS 
 
OHRP 
Office for Human Research Protections 
 
OHSR 
Office for Human Subjects Research 
 
ORA 
Office of Regulatory Affairs, DMID, NIAID, NIH, DHHS 
 
PCR 
Polymerase Chain Reaction 
 
PD 
Pharmacodynamic 
 
PHI 
Personal Health Information 
 
PI 
Principal Investigator 
 
PK 
Pharmacokinetics 
 


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PO 
By Mouth 
 
QA 
Quality Assurance 
 
QC 
Quality Control 
 
QD 
Once Daily 
 
RNA 
Ribonucleic Acid 
 
SAE 
Serious Adverse Event/Serious Adverse Experience 
 
SAS 
Statistical Analysis Software 
 
Scr 
Serum Creatinine 
 
SDW 
Source Document Worksheet 
 
SDCC 
Statistical and Data Coordinating Center 
 
SMA 
Secondary Medical Assessor 
 
SMC 
Safety Monitoring Committee 
 
SNHL 
Sensorineural Hearing Loss 
 
SOP 
Standard Operating Procedure 
 
STI 
Sexually Transmitted Infections 
 
TEOAE 
Transient Evoked Otoacoustic Emission 
 
US 
United States 
 
USP 
United States Pharmacopeia 
 
VRA 
Visual Reinforcement Audiometry 
 
WHO 
World Health Organization 
 
 
  
 


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Asymptomatic CMV Treatment 
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PROTOCOL SUMMARY 
Title: 
A Phase II, Single-Stage, Single-Arm Investigation of Oral 
Valganciclovir Therapy in Infants with Asymptomatic 
Congenital Cytomegalovirus Infection 
Phase: 
II 
Population: 
Male and female infants with asymptomatic congenital CMV 
infection.  Approximately 229 neonates with confirmed 
congenital infection without outward manifestations of 
congenital CMV infection will be offered enrollment in the 
study. 
Number of Sites: 
9 
Study Duration: 
5 years 
Subject Participation 
Duration: 
18 months 
Description of Agent or 
Intervention: 
Valganciclovir for oral solution, 16 mg/kg/dose administered 
twice daily for 4 months. 
Objectives: 
 
Primary: 
• To estimate the proportion of subjects with asymptomatic 
congenital CMV infection who, following treatment with 4 
months of oral valganciclovir, develop sensorineural hearing 
loss (SNHL) by 6 months of life. 
Secondary: 
• 
To define the safety and tolerability of valganciclovir in 
enrolled subjects. 
• 
To estimate the proportion of subjects with asymptomatic 
congenital CMV infection who, following treatment with 4 
months of oral valganciclovir, develop SNHL over the first 
18 months of life. 
Exploratory: 


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Asymptomatic CMV Treatment 
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• To compare changes in whole blood CMV viral load versus 
plasma CMV viral load during and following antiviral 
treatment. 
• To assess correlation between CMV viral load, by body 
compartment, and SNHL. 
• To assess correlation between development of ganciclovir 
resistance, by body compartment, and SNHL. 
• To assess development of resistance to ganciclovir in the 
compartment-specific sites of blood, urine, and saliva over 
time. 
Outcome Measures: 
Primary Endpoint: 
• The number of subjects developing sensorineural hearing 
loss in at least one ear between Baseline and Study Month 6 
[both ears with normal hearing at baseline, then at least one 
ear with sensorineural hearing loss (SNHL) at the 6 month 
follow-up] 
 
Secondary Endpoints: 
• Cumulative incidence of Grade 3 or higher unsolicited 
adverse events, safety laboratory adverse events, or serious 
adverse events 
• Cumulative incidence of absolute neutrophil counts below 
500/mm3  
• Cumulative incidence of transaminase elevation during 
treatment ≥ 2-times the baseline value 
• Cumulative incidence of adverse events leading to permanent 
discontinuation of valganciclovir therapy, or any adverse 
event that is not recovered / not resolved 
• Cumulative incidence of sensorineural hearing loss in at least 
one ear between Baseline and Study Month 4 [both ears with 
normal hearing at baseline, then at least one ear with 
sensorineural hearing loss (SNHL) at the 4 month follow-up] 
• Cumulative incidence of sensorineural hearing loss in at least 
one ear between Baseline and Study Month 12 [both ears 
with normal hearing at baseline, then at least one ear with 
sensorineural hearing loss (SNHL) at the 12 month follow-
up] 


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• Cumulative incidence of sensorineural hearing loss in at least 
one ear between Baseline and Study Month 18 [both ears 
with normal hearing at baseline, then at least one ear with 
sensorineural hearing loss (SNHL) at the 18 month follow-
up] 
• Cumulative incidence of each degree of worsened hearing 
(mild, moderate, severe, profound) at Study Months 4, 6, 12, 
and 18, represented by the ear that has the larger degree of 
worsening 
• Proportion of ears of each degree of worsened hearing (mild, 
moderate, severe, profound) at Study Months 4, 6, 12, and 18 
 
Exploratory Endpoint: 
• Change in whole blood and plasma CMV viral load through 
Study Month 6 
• Correlation of change in whole blood and plasma CMV viral 
load with change in hearing at Study Months 4, 6, 12, and 18. 
• Correlation of change in urine CMV viral load with change 
in hearing at Study Months 4, 6, 12, and 18 
• Correlation of development of ganciclovir resistance in 
differing body compartments (blood, urine, saliva) with 
change in hearing at Study Months 4, 6, 12, and 18 
• Emergence and kinetics of ganciclovir resistance in differing 
body compartments (blood, urine, saliva) during antiviral 
therapy (Study Month 4), and following cessation of antiviral 
treatment (Study Months 5 and 6) 
Inclusion and Exclusion 
Criteria: 
Inclusion Criteria 
• Parent(s)/legal guardian(s) have signed informed consent 
documents* 
• Confirmation of CMV by urine PCR testing 
• Infant ≤ 30 days of age at initiation of study drug 
• Weight at study enrollment ≥ 1775 grams 
• Gestational age ≥ 32 weeks at birth 
 
* There is a screening informed consent for screening phase of 
study participation, and a treatment informed consent for 
treatment phase of study participation. 


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Exclusion Criteria 
• Symptomatic congenital CMV disease* 
• Sensorineural hearing deficits as detected by formal 
brainstem evoked response (not a screening ABR) of known 
etiology other than CMV 
• Prior or current receipt of ganciclovir, valganciclovir, 
foscarnet, cidofovir, brincidofovir, maribavir, or letermovir 
• Maternal receipt of CMV hyperimmune globulin during 
pregnancy 
• Breastfeeding from mother who is receiving ganciclovir, 
valganciclovir, foscarnet, cidofovir, brincidofovir, maribavir, 
or letermovir 
• Gastrointestinal abnormality which might preclude 
absorption of an oral medication (e.g., a history of 
necrotizing enterocolitis) 
• Infants known to be born to women who are HIV positive 
(HIV testing is not required for study entry) 
• Current receipt of other investigational drugs 
 
* Symptomatic disease is defined as one or more of the 
following: 1) thrombocytopenia, if known; 2) petechiae; 3) 
hepatomegaly; 4) splenomegaly; 5) intrauterine growth 
restriction; 6) hepatitis (elevated transaminases and/or direct 
bilirubin), if known; 7) central nervous system involvement of 
the CMV disease (such as microcephaly; radiographic 
abnormalities indicative of CMV CNS disease, if known; 
abnormal CSF indices for age, if known; chorioretinitis, if 
known; and/or positive CMV PCR from CSF, if known). 
Description of Study Design: 
 
This is a phase II, open-label trial to evaluate valganciclovir as a 
treatment to prevent development of SNHL in infants with 
asymptomatic congenital CMV infection.  The trial will be 
conducted in two phases (screening of newborns to identify 
eligible subjects, and treatment of those newborns who have 
confirmed CMV infection at birth but without outward 
manifestations of congenital CMV infection). 
 


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Following consent for screening, newborns with no outward 
manifestations of congenital CMV infection who are delivered at 
one of 9 participating academic medical centers will be screened 
for CMV infection during their birth hospital stay.  A buccal 
saliva swab will be obtained by swabbing the inside of the 
newborn’s mouth for detection of CMV by PCR.  The collected 
swabs will be transported within 4 days of collection to the 
Central Laboratory at the University of Alabama at Birmingham 
for testing.  Babies screening positive for congenital CMV 
infection will have a second saliva sample and a urine sample 
collected for confirmatory PCR testing.  Study drug will not be 
started until the confirmatory PCR testing is completed; the 
likelihood of a false-positive screening test is < 0.03%, but 
performing a confirmatory test ensures that only those babies 
truly infected with CMV will be exposed to valganciclovir.  
Approximately 48,250 newborn infants will be screened to 
detect approximately 241 neonates with asymptomatic 
congenital CMV infection; these 241 newborns then will have 
audiology examinations to determine baseline hearing, with 
approximately 229 having normal hearing in both ears.  Those 
229 newborns with confirmed CMV infection but without 
baseline SNHL and who meet all inclusion/exclusion criteria will 
be offered enrollment into the treatment phase. 
 
Through this screening process, approximately 12 neonates 
congenitally infected with CMV who have SNHL at birth also 
will be identified.  Newborn patients with SNHL and who are 
being treated clinically with valganciclovir will be offered 
enrollment into an observational substudy as detailed below. 
 
After obtaining treatment informed consent, enrolled subjects 
will be treated for four months with oral valganciclovir (16 
mg/kg/dose, administered two times per day).  Study Day 1 is 
the day that the first dose of study medication is administered.  
Audiologic assessments will be made during the Screening 
Period and Study Months 4 (end of treatment), 6, 12, and 18.  A 
single, independent study audiologist will assess the audiology 
test battery for each subject and assign each ear the 
classifications of normal hearing, mild hearing loss, moderate 


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hearing loss, severe hearing loss, or profound hearing loss based 
upon their hearing thresholds (in decibels).  If a study subject 
proceeds to cochlear implantation during the course of the study, 
he/she will not require additional study-related hearing 
assessments following the implantation procedure but will 
continue with all other study-related assessments. 
 
Treated infants will be followed for safety throughout the first 6 
months of the study (including for 2 months post-treatment).  
Hematology safety laboratory assessments will be obtained 
weekly for the first six weeks of study drug administration, then 
every other week for the next six weeks of study drug 
administration, and then at months 4 and 5.  Chemistry safety 
laboratory assessments will be obtained every other week for the 
first 12 weeks (3 months) of treatment, and then at months 4, 5, 
and 6.  Adverse events will be assessed at each study visit during 
treatment, and at month 5. 
 
Whole blood viral load and plasma viral load will be obtained at 
each study visit during the course of study drug administration, 
and then at Study Months 5 and 6.  Specimens from subjects 
with increasing viral loads despite antiviral therapy may be 
evaluated for ganciclovir resistance by molecular methodologies 
(e.g., deep sequencing, Sanger sequencing, PCR).  Urine and 
saliva will be obtained at Baseline and Study Months 4, 5, and 6 
in order to obtain viral isolates to assist in detection of antiviral 
resistance. 
 
Infants with confirmed CMV but who have documented SHNL 
at baseline and who are being treated clinically with 
valganciclovir  (expected to be about 12 patients) will be offered 
enrollment into an observational substudy.  No additional 
audiologic or safety testing will be done as part of the study.  
However, available clinical audiologic and safety data will be 
redacted without alteration from the clinical medical record.  
Enrolled subjects will be followed for CMV viral load as part of 
the study.  Viral loads would not be routinely followed as part of 
clinical management (and thus will be study procedures), 
whereas the valganciclovir treatment and associated safety labs 


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as well as the serial hearing testing are part of clinical care for 
these patients.  Blood for CMV viral load will only be obtained 
at a given study visit if other blood is being obtained by 
venipuncture for clinical purposes. 
Estimated Time to Complete 
Enrollment: 
30 months from enrollment of the first study subject. 
 


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Figure 1: Schematic of Study Design: 
 
Screening  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Initiation 
 
 
 
 
Study Day 1 
Through 
Study Month 4 
 
 
 
 
 
Study Month 5 
Through 
Study Month 12 
 
 
 
 
Study Month 18 
 
 
 
Obtain screening informed consent, and screen newborns for congenital CMV infection (n=48,250) 
Obtain treatment informed consent.  
Begin valganciclovir therapy 
Administer oral valganciclovir.  Obtain clinical, laboratory, and AE assessments 
Clinical, laboratory, AE, and audiology assessments 
Final clinical and audiologic assessment 
Confirmatory testing for congenital CMV infection and SNHL testing for those screening positive 
(n=~241) 
~229 subjects 
without baseline 
SNHL 
~12 subjects with    
baseline SNHL 
Confirm valganciclovir therapy being 
started clinically.  Obtain 
observational informed consent. 


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1 
KEY ROLES 
Individuals: 
 
 
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 
Phone: 205-996-6097 (direct line) 
Fax: 
205-975-9972 
e-mail: dkimberlin@peds.uab.edu 
 
Medical Monitor:  
Soju Chang, MD 
5601 Fishers Lane 
MSC 9826 
Phone: 240-292-4178 
e-mail: changsoju@niaid.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  
 
Baylor College of Medicine – Texas Children’s Hospital 
Gail Demmler-Harrison, M.D. 
6621 Fannin Street 
Houston, Texas 77030 
Phone: 832-824-4330 
Fax: 832-825-4347 
Email: gdemmler@bcm.edu 


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Carolinas Medical Center - Charlotte  
Amina Ahmed, M.D. B.S. 
 
1000 Blythe Boulevard MEB-4th 
 
Charlotte, NC 28203  
Phone: 704-381-6870  
Fax: 704-381-6841 
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: 412-692-6786/412-915-8191  
Fax: 412-864-8977 
 
Email: marian.michaels@chp.edu  
 
The Ohio State University - Nationwide Children's Hospital 
Center for Perinatal Research 
Pablo Sánchez, MD 
700 Children's Drive, RB3, WB5215 
Columbus, OH 43205-2664 
Phone: 614-355-5724 
Fax: 614-355-5899 
Email: pablo.sanchez@nationwidechildrens.org 
 
University of Arkansas for Medical Sciences  
José 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 Louisville School of Medicine 
Claudia M. Espinosa, MD, MSC 
571 South Floyd Street, Suite 321 
Louisville, KY 40202 
Phone: 502-852-3774 
Fax: 502-852-3939 
Email: charles.woods@louisville.edu 


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University of Mississippi Medical Center 
April Palmer, MD 
2500 N. State St 
Jackson, MS 39216 
Phone: 601-984-5206 
Fax: 601-984-5981 
Email: apalmer@umc.edu 
 
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 
Statistical and Data 
Coordinating Center: 
The Emmes Corporation  
400 N. Washington Street, Suite 700 
Rockville, MD 20850 
Phone: 301-251-1161  
Fax: 301-251-1355 
E-mail: cmv@emmes.com  
Protocol Statistician: Chris Focht M.S. 
 


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2 
BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
2.1 
Background Information 
Congenital cytomegalovirus (CMV) infection is the leading non-genetic cause of sensorineural 
hearing loss (SNHL)1-4 and the most frequent known viral cause of mental retardation,5 affecting 
0.5% to 0.7% of live births in industrialized countries.6-8  With a U.S. birth cohort of 4M 
annually, between 20,000 and 28,000 babies are estimated to be born each year with congenital 
CMV infection.  Ten percent of congenitally infected neonates have symptomatic disease at 
delivery, of whom 35% have SNHL, up to 67% have neurologic deficits, and 4% die in the 
newborn period.7-11  These impairments frequently result in spastic quadriplegia requiring 
lifelong dependence on a wheelchair, along with cognitive and speech impairments which 
dramatically limit their ability to interact with and function in the world.  Patients with this 
degree of neurologic impairment generally have a life expectancy of less than 10 to 15 years. 
 
SNHL occurs at a lower rate among the 90% of congenitally infected neonates who are 
asymptomatic at delivery, but because there are so many more asymptomatic neonates than 
symptomatic ones the majority of cases of SNHL caused by CMV occurs in this asymptomatic 
group (Table 1).7,12  Overall, congenital CMV is a rare infection but accounts for 21% of hearing 
loss at birth and 24% of hearing loss by four years of age.1,13  The overall economic burden of 
congenital CMV infection exceeds $3 billion annually, adjusted for 2015 dollars.14-16  For all of 
these reasons, the Institute of Medicine recently assessed the need for a CMV vaccine as the 
highest of all priorities.15  However, the prospects for a vaccine to prevent CMV are at least one 
to two decades away. 
 
Table 1.  Majority of sequelae from congenital CMV infection occurs in babies who are 
asymptomatic at birth. 
Parameter 
Estimated Figure 
Number of live births per year 
4,248,000 
Rate of congenital CMV infection 
0.6% 
Number of infected infants 
25,488 
Number of infants symptomatic at birth (12.8%) 
3,262 
     Symptomatic at birth who have or develop disability (50%) 
1,631 
Number of infants asymptomatic at birth (87.2%) 
22,226 
     Asymptomatic at birth who have or develop disability (13.5%) 
3,001 
Total with congenital CMV-related disabilities 
4,632 
From reference 17 
 
Effective treatment has been established to prevent hearing loss or hearing deterioration in 
neonates with symptomatic congenital CMV infections.  After establishing the appropriate dose 
of intravenous ganciclovir for use in neonates,18-20 the Collaborative Antiviral Study Group 
(CASG) published the results of a Phase III randomized controlled investigation conducted 
during the 1990s of intravenous ganciclovir for the treatment of symptomatic congenital CMV 
disease involving the central nervous system (CNS).21  One hundred neonates (infants less than 


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30 days of age) with symptomatic congenital CMV disease involving the CNS were enrolled and 
were randomized to ganciclovir treatment (6 mg/kg/dose administered intravenously every 12 
hours for 6 weeks) or to no treatment.  Infants randomized to the no treatment arm were managed 
in an identical fashion to those receiving active drug.  The primary study endpoint was improved 
brain stem evoked response (BSER) audiometry by one gradation between baseline and the 6 
month follow-up (or, for those subjects with normal hearing at baseline, normal BSER at both 
timepoints).  Measures of clinical and laboratory improvement constituted the secondary 
endpoints, and growth was the tertiary endpoint of the trial.  Audiologic analyses were performed 
on the subject’s best evaluable ear (“functional” assessment) and on total evaluable ears 
(“biologic” assessment).  Twenty-one of 25 ganciclovir recipients (84%) either had improvement 
in hearing in their best ear between baseline and 6 months or had normal hearing at both 
timepoints, compared with 10 of 17 subjects (59%) in the no treatment group (adjusted p-value = 
0.06; OR 5.03 [95% CI: 0.84,45.94]).  Inclusion in the best-ear analysis of the two additional 
subjects who did not meet all entry criteria (above) yielded an adjusted p-value of 0.03.  None of 
25 ganciclovir recipients (0%) had worsening in hearing in their best ear between baseline and 6 
months, compared with 7 of 17 subjects (41%) in the no treatment group (adjusted p-value < 
0.001; OR 21.11 [95% CI: 2.84,∞]).  Five of 24 ganciclovir recipients (21%) had worsening in 
hearing in their best ear between baseline and ≥ 1 year, compared with 13 of 19 subjects (68%) 
in the no treatment group (adjusted p-value = 0.002; OR 10.26 [95% CI: 1.79,81.92]).  
Ganciclovir-treated patients had a more rapid median time to normalization of ALT (19 days) 
compared with patients in the no treatment group (66 days) (p = 0.03).  Ganciclovir-treated 
patients had a greater degree of weight gain (p = 0.02) and growth in head circumference (p < 
0.01) at 6 weeks following study enrollment than did subjects who did not receive antiviral 
therapy.  Twenty-nine of 46 ganciclovir-treated subjects (63%) developed Grade 3 or 4 
neutropenia during the 6 weeks of study drug administration, compared with 9 of 43 subjects 
(21%) in the no treatment group over the same period of time (p < 0.01).  Fourteen of the 29 
subjects (48%) required dosage adjustments, although only 4 subjects had the drug permanently 
discontinued.  The mean time (± standard deviation) of onset of grade 3 or 4 neutropenia for 
subjects receiving ganciclovir was 14.2 (± 12.3) days, and for the no treatment group was 14.3 (± 
13.1) days.  Neutropenia in ganciclovir-treated subjects resolved in 12.8 (± 13.6) days, and in the 
no treatment group in 14.2 (± 13.5) days.  All affected subjects resolved their neutropenia. 
 
The effect of treatment on neurodevelopmental outcomes of enrolled subjects was evaluated in a 
post hoc analysis.  Denver Developmental Evaluations performed at 6 weeks, 6 months, and 12 
months served as the basis for this analysis.22  Developmental milestones which ≥ 90% of normal 
children would be expected to have achieved were identified at each of these developmental 
stages.  Each randomized study subject was evaluated to determine the number of milestones that 
had been not met (‘delays’).  ‘Delays’ were categorized according to the four Denver-focused 
categories:  Personal/Social, Fine Motor, Gross Motor, and Language.  The average ‘delay’ per 
subject for each test was calculated and compared for subjects who received ganciclovir versus 
those who received no treatment.  Of the 100 subjects enrolled, Denver assessments were 
available for 74, 74, and 72 subjects at 6 weeks, 6 months, and 12 months, respectively.  At the 6 
week assessment, the average ‘delays’ per subject were 1.5 for ganciclovir recipients and 2.05 
for ‘no treatment’ subjects (p =0.13).  At 6 months, the average ‘delays’ were 4.46 and 7.51, 
respectively (p =0.06).  At 12 months, the average delays were 9.78 delays versus 17.14 delays, 


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respectively (p =0.007).  Multivariate analysis of variances (ANOVA)s were utilized to test 
independent factors known to be related to poor developmental outcomes in congenital CMV 
infection.  After adjustment for these factors, the effect of ganciclovir therapy remained 
statistically significant at the 12 month assessment (p = 0.007), and approached statistical 
significance at 6 weeks (p = 0.08) and 6 months (p = 0.08).  Thus, infants with symptomatic 
congenital CMV disease involving the CNS who received 6 weeks of IV ganciclovir therapy had 
fewer developmental delays at 12 months of age when compared with infants who did not 
receive ganciclovir.  These data suggested that ganciclovir may improve overall 
neurodevelopmental outcomes up to at least 1 year of age in patients with symptomatic 
congenital CMV involving the CNS, but given the post hoc design and the basis of the findings 
residing with Denver Developmental screening evaluations the overall suggestion of benefit in 
this study was not completely convincing. 
 
A Phase I/II pharmacokinetic/pharmacodynamic (PK/PD) investigation of oral valganciclovir in 
babies with symptomatic congenital CMV disease with or without CNS involvement then was 
conducted by the CASG from 2002 to 2007.23  This study determined that 16mg/kg/dose BID of 
oral valganciclovir solution reliably provided comparable ganciclovir blood concentrations as the 
previously studied ganciclovir dose of 6 mg/kg/dose intravenously every 12 hours.  Twenty-four 
subjects under 1 month of age with symptomatic congenital CMV disease were enrolled in this 
study.  In a previous Phase II study, the CASG determined that intravenous ganciclovir (6 
mg/kg/dose every 12 hrs) in neonates with symptomatic congenital CMV disease resulted in a 
median AUC12 of 27 ug*h/mL (mean AUC12=32.3+13.7 ug*h/mL, range 17.2 to 55.9 ug*h/mL, 
n=13).24   Data from subjects enrolled in the oral valganciclovir study demonstrated that a dose 
of 15.62 mg/kg provided an AUC12 of 27.35 ug*h/mL, thereby justifying the dose of 16 mg/kg 
noted above.  The Phase II valganciclovir trial also documented that oral bioavailability of 
valganciclovir oral solution increases in early infancy (from 48% at approximately 4 weeks of 
life to 64% at approximately 7 weeks of life), and that this increase is proportionate to the 
increase in ganciclovir clearance during the same period.23  Thus, oral valganciclovir actually is a 
more reliable method of delivering ganciclovir to young infants than is intravenous ganciclovir, 
since the increase in oral bioavailability “compensates” for the increase in ganciclovir clearance 
which occurs in the first few weeks to months of life, thereby providing more consistent 
ganciclovir blood concentrations over time. 
 
The CASG then undertook a Phase III randomized, placebo controlled trial of six weeks versus 
six months of oral valganciclovir in neonates with symptomatic congenital CMV disease.  
Results of this study recently were published in the New England Journal of Medicine.25  A total 
of 96 participants were randomly assigned to receive blinded study medication after receiving 6 
weeks of valganciclovir; 47 participants were assigned to continue receiving the active drug (the 
6-month group), and 49 were assigned to receive placebo (the 6-week group).  In the assessment 
of total-ear hearing, participants who received 6 months of valganciclovir were more likely than 
those who received 6 weeks of therapy to have improved hearing or to have maintained normal 
hearing between baseline and 12 months, after adjustment for CNS involvement at baseline (73% 
vs. 57%; odds ratio, 3.04; 95% confidence interval [CI], 1.26 to 7.35; P = 0.01). Similar results 
were evident when prematurity and age at the initiation of treatment were added to the model (P 
= 0.01).  The benefit of longer-term therapy in the total ears analysis was maintained at 24 


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months, with improved outcomes after adjustment for CNS involvement at baseline (77% in the 
6-month group vs. 64% in the 6-week group; odds ratio, 2.61; 95% CI, 1.05 to 6.43; P = 0.04).  
Similar results were evident when prematurity and age at the initiation of treatment were added 
to the model (P = 0.04).  The timing of initiation of valganciclovir within the first month of life 
(e.g., <3 weeks of age vs. 3 to 4 weeks of age) did not correlate with audiologic outcomes at 12 
months or at 24 months (P>0.23 for both comparisons). 
 
In the analysis adjusted for CNS involvement at baseline, participants randomly assigned to 
receive 6 months of valganciclovir, as compared with those randomly assigned to 6 weeks of 
treatment, had higher Bayley-III language-composite scores at 24 months (P = 0.005) and higher 
receptive-communication scale scores at 24 months (P = 0.003).  No significant interaction 
effects were found when outcome and CNS involvement at baseline were incorporated in a 
single model, indicating that the treatment benefits were similar in the group with CNS 
involvement and the group without CNS involvement.  The differences between the 6-month 
group and the 6-week group with respect to Bayley-III scores were maintained when age at the 
initiation of treatment and prematurity were added to the model (P = 0.004 and P = 0.003, 
respectively). All the other components of the Bayley-III assessments trended toward improved 
outcomes among participants in the 6-month group, as compared with those in the 6-week group. 
 
Viral loads in whole blood decreased in parallel in the two study groups during the first 6 weeks 
of open-label valganciclovir therapy and then diverged after randomization (Figure 2).  In the 
analysis that was adjusted for an interaction effect between treatment and the area under the 
curve (AUC) of the viral load, lower viral loads, as compared with higher viral loads, correlated 
with better hearing outcomes at 6, 12, and 24 months among participants in the 6-month group 
(P<0.01 for all comparisons) but not among those in the 6-week group (P>0.68 for all 
comparisons).  There was no correlation between the AUC of the viral load and 
neurodevelopmental outcomes beyond that provided by treatment. 
 
Figure 2.  Whole blood viral load in subjects receiving 6 months (green) and 6 weeks (red) of 
oral valganciclovir.25 
 
 


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Of the 109 participants, 21 (19%) had grade 3 or 4 neutropenia during the first 6 weeks of open 
label valganciclovir therapy.  From week 6 through month 6, a total of 10 of the 47 participants 
(21%) who received the active drug had grade 3 or 4 neutropenia, as compared with 13 of 49 
(27%) who received placebo (P = 0.64).  A total of 3 participants had the drug temporarily 
suspended because of an absolute neutrophil count of less than 500 per cubic millimeter.  All 
treatment interruptions occurred within the first 6 weeks of the study, and treatment was resumed 
after resolution of the neutropenia.  The alanine aminotransferase and aspartate aminotransferase 
levels increased slightly at months 4 and 5 in the group of participants who received the active 
drug, although the differences between this group and the group that received placebo were not 
statistically significant (P>0.59 for both aminotransferase comparisons) or clinically significant 
(all mean values, <90 U per liter).  No deaths occurred. There were no significant differences in 
the rate of adverse events between the two study groups. 
 
Approximately 10% of asymptomatic children will develop SNHL.  This is much higher than the 
0.1%–0.4% incidence of hearing loss within the general population.11  Of CMV-associated 
SNHL by 4 years of age, almost 75% occurs in children who were asymptomatically infected at 
birth.1  Many prospective studies of children with asymptomatic congenital CMV infection 
showed that approximately half of children with asymptomatic infection who develop hearing 
loss will have bilateral deficits, which can vary from mild high-frequency loss to profound 
impairment.  Moreover, hearing loss in these children is often progressive and/or delayed onset 
requiring ongoing audiologic evaluation.4,26 
 
The available data on viral load levels between symptomatic and asymptomatic infants 
congenitally infected with CMV consistently have demonstrated that babies born with symptoms 
of congenital CMV disease have higher viral loads than do babies born without any symptoms of 
congenital CMV infection.27-31  However, while the median values are different between the two 
groups, there is significant overlap at the individual level such that a baby with a given viral load 
could be either in the symptomatic group or in the asymptomatic group.  Additionally, 
methodologic differences (assays with different levels of detection in the published studies) 
make it difficult to compare data across these published results.  At the current time, threshold 
viral load values above which a baby could reliably be categorized as having symptoms and 
below which they could reliably be considered to be asymptomatic are not clearly delineated. 
 
Several studies that have included infants with both symptomatic and asymptomatic congenital 
CMV infection have demonstrated that higher viral loads correlate with sensorineural hearing 
loss (SNHL).28-30  Studies that have focused primarily31 or exclusively32 on asymptomatically 
infected infants have reported conflicting results.  Ross et al.’s 2009 publication31 found no 
correlation between a higher viral load and SNHL among asymptomatically infected infants, but 
found that lower viral loads (< 3,500 ge/mL) are associated with a lower risk of SNHL.  
However, Forner et al.’s recent publication32 found that asymptomatic infants with viral loads of 
≥ 17,000 copies/mL were more likely to develop SNHL.  The Forner paper, though, found no 
difference in the duration of detectable virus in the blood or urine and SNHL – in other word, 
subjects who did or did not develop SNHL shed virus in blood or urine for the same duration of 
time.  Given that higher viral loads generally would take a longer period of time to decrease 
compared with lower viral loads, these data have some intrinsic contradictions.  The Forner study 


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also was limited by a very small sample size – only 33 total infants, with only 10 having SNHL.  
Even studies by the same research group have reported conflicting results, with an earlier study 
that reported identifiable thresholds correlating with SNHL30 yielding to a later study with a 
larger sample size that did not find such correlation.31 
 
As a result of these CASG trials, the U.S. Food and Drug Administration modified the 
Valganciclovir Package Insert to cite the dose used in CASG studies,33 and the American 
Academy of Pediatrics now recommends six months of oral valganciclovir as therapy for infants 
born with symptomatic congenital CMV disease.34 
2.2 
Rationale 
Given the benefit demonstrated from longer-term antiviral treatment of babies with symptomatic 
congenital CMV disease, and recognizing the fact that most of the disease burden of CMV-
associated hearing loss is in the asymptomatically infected population, we hypothesize that 
infants with asymptomatic congenital CMV infection who are treated with valganciclovir will 
have protection against hearing deterioration.  The primary toxicity of valganciclovir is 
neutropenia; however, neutropenia rates among infants receiving valganciclovir in CASG studies 
were modest.  Specifically, the rate of neutropenia experienced by infants treated in the recent 
Phase III CASG study was not higher than that seen in the untreated babies from the earlier 
CASG study (19% in the valganciclovir group25 versus 21% in the untreated group21).  
Additionally, no long term complications from ganciclovir therapy have been identified among 
people who received treatment during the neonatal period on early CASG studies.  Specifically, 
no adolescents who had been treated on a CASG study as young infants in the 1980s developed 
cancer or pubertal abnormalities when followed up in the 2000s.35  Given this safety profile, 
systematic evaluation of the treatment of babies with asymptomatic congenital CMV infection is 
justified due to the risk of hearing abnormalities that they face. 
 
The selection of 4 months as the duration of antiviral therapy is based upon two findings in the 
CASG’s previous studies of valganciclovir in infants with symptomatic congenital CMV disease 
who were treated for either six weeks or six months.  First, the viral load data from the 6 week 
versus 6 month study demonstrated the attainment of virologic control by four months of age in 
the group that received only 6 weeks of antiviral therapy (decrease of whole blood viral load to 
the level that was seen in the group still receiving treatment) (Figure 2).  Second, potential 
hepatic toxicity was detected after 4 months of treatment in subjects receiving six months of 
therapy.25  There was no increased risk of neutropenia among subjects receiving valganciclovir 
for longer than 6 weeks.  Given that the risk of hearing impairment is lower in the asymptomatic 
congenital CMV population (that is, most babies with asymptomatic congenital CMV infection 
will not experience hearing loss), we have selected 4 months of treatment to maximize the 
likelihood of virologic control and minimize the likelihood of adverse effects of therapy 
(elevated transaminases). 
 
It is critical that this trial be undertaken now.  In 2013, the state of Utah passed a law that 
requires babies who fail their newborn hearing screen to be tested for CMV infection.  Other 
states (Illinois, Connecticut, Tennessee, Texas, New York, and Florida among them) are 


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considering similar legislation in their 2015 legislative sessions.  This type of “targeted 
screening” for congenital CMV infection will not identify the overwhelming majority of at-risk 
neonates, since only 25% of babies with asymptomatic congenital CMV who ultimately develop 
CMV-associated SNHL have hearing loss present in the first month of life (with the remaining 
75% developing hearing loss in later months or the first few years of life).10  However, targeted 
screening portends universal screening for congenital CMV infection, as has recently been 
recommended by a Consensus Conference of leading world experts who gathered before the 5th 
International Congenital CMV Conference in Brisbane, Australia, on April 19, 2015.36  A similar 
staged implementation was seen in the 1990s with hearing screening, whereby testing newborns 
for hearing abnormalities began in a targeted fashion and only later expanded to universal 
hearing screening for all babies born in the United States.37,38  Once asymptomatic babies are 
identified through targeted or universal screening programs, there will be tremendous pressure 
on the managing physician to “do something,” which inevitably will mean treating with oral 
valganciclovir.  Therefore, the window of time to assess the benefit, if any, versus the risk in the 
asymptomatically infected congenital CMV population is narrow.  Failure to establish the 
estimates of clinical effectiveness and to define the risks from treatment now could lead to 
widespread treatment outside of the confines of a clinical trial, thereby putting babies treated in 
such a manner at risk of harm with no opportunity to assess for evidence of benefit. 
2.3 
Potential Risks and Benefits 
2.3.1 Potential Risks 
The dose of oral valganciclovir to be used in this trial will be 16 mg/kg/dose administered twice 
daily.  This is the dose evaluated in previous CASG studies of symptomatic congenital CMV 
disease for as well as safety,23,25 pharmacokinetics/pharmacodynamics,23,39 and efficacy.25  The 
primary clinical toxicity of valganciclovir, which is metabolized to ganciclovir, at this dose in 
this population is neutropenia.  In the CASG’s Phase III randomized controlled study of 6 weeks 
of parenteral ganciclovir versus no treatment in babies with symptomatic congenital CMV 
disease, 63% of treated neonates developed Grade 3 or 4 neutropenia utilizing the Division of 
AIDS Toxicity Tables40 during the six week course of treatment, compared with 21% of the 
subjects randomized to no treatment.21  In the CASG study of the pharmacokinetics of oral 
valganciclovir, neonatal subjects received approximately two weeks of parenteral ganciclovir 
and four weeks of oral valganciclovir, and 38% developed Grade 3 or 4 neutropenia.23  In the 
recently published CASG study of six weeks versus six months of oral valganciclovir in babies 
with symptomatic congenital CMV disease, 19% developed Grade 3 or 4 neutropenia during the 
first six weeks of treatment during which all babies received active therapy,25 which is 
comparable to the 21% of babies in the no treatment arm of the original study.21  This difference 
in rates of neutropenia with intravenous ganciclovir and oral valganciclovir likely relates to the 
higher maximum concentration of the drug associated with intravenous versus oral drug 
delivery,25 and suggests that administration of the oral prodrug (valganciclovir) is a safer way to 
administer ganciclovir into the body than intravenous ganciclovir.  Subjects treated with oral 
valganciclovir from week six to month six were not more likely to have neutropenia compared 
with those receiving placebo (21% versus 27%, respectively; p=0.64).25  Thus, neutropenia 
induced by oral valganciclovir occurs much less frequently than with parenteral ganciclovir, and 


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appears to be limited to the first six weeks of therapy.  Among subjects receiving six months of 
therapy with oral valganciclovir in the recent CASG study of longer-term treatment in babies 
with symptomatic congenital CMV disease, there was a suggestion of elevation in transaminases 
after four months of therapy, although this did not reach statistical significance.25  All laboratory 
abnormalities associated with valganciclovir (neutropenia and possibly transaminitis) were fully 
reversible upon temporary cessation of the drug. 
 
In addition to neutropenia, the clinical hematologic toxicities of valganciclovir include anemia, 
thrombocytopenia, pancytopenia, and aplastic anemia.  In animal studies, ganciclovir was 
carcinogenic, mutagenic, and caused aspermatogenesis.33  However, no long-term complications 
from ganciclovir therapy have been identified among people who received treatment during the 
neonatal period on early CASG studies.  Specifically, no adolescents who had been treated on a 
CASG study as young infants in the 1980s developed cancer or pubertal abnormalities when 
followed up in the 2000s.35  Some additional adverse events reported in the valganciclovir 
package insert are diarrhea, vomiting, hypertension, upper respiratory tract infection, urinary 
tract infection, pyrexia, and headache. 
 
Subjects will be asked to provide personal health information (PHI).  All attempts will be made 
to keep this PHI confidential within the limits of the law.  However, there is a chance that 
unauthorized persons will see the subjects’ PHI.  All records will be kept in a locked file cabinet 
or maintained in a locked room at the participating CASG sites.  Electronic files will be 
password protected.  Only people who are involved in the conduct, oversight, monitoring, or 
auditing of this study will be allowed access to the PHI that is collected.  Any publications from 
this study will not use information that will identify subjects by name.  Organizations that may 
inspect and/or copy research records maintained at the participating CASG sites for quality 
assurance and data analysis include groups such as National Institute of Allergy and Infectious 
Diseases (NIAID) and their authorized representatives, the Food and Drug Administration 
(FDA), and the study’s pharmaceutical collaborator Genentech, Inc. (which would only occur 
with the consent of NIAID as the holder of the IND for the study). 
2.3.2 Known Potential Benefits 
There may be no direct benefit from the experimental treatment to the asymptomatically infected 
subjects enrolled in this study.  However, six weeks of intravenous ganciclovir has been proven 
to protect against hearing deterioration in patients with symptomatic congenital CMV disease 
when treatment was initiated during the first month of life.21  Six months of oral valganciclovir 
has been proven to provide enhanced protection against hearing deterioration in this population 
when compared with six weeks of treatment, and to improve neurodevelopmental outcomes.  
This trial will determine whether prolonged oral valganciclovir therapy can protect against 
hearing deterioration in infants congenitally infected with CMV who are asymptomatic at birth.  
Subjects who participate will contribute to the knowledge about the safety and effectiveness of 
valganciclovir in congenitally CMV infected neonates. 
 


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3 
OBJECTIVES 
3.1 
Study Objectives 
Primary:  
• To estimate the proportion of subjects with asymptomatic congenital CMV infection who, 
following treatment with 4 months of oral valganciclovir, develop sensorineural hearing loss 
(SNHL) by 6 months of life. 
 
Secondary: 
• To define the safety and tolerability of valganciclovir in enrolled subjects. 
• To estimate the proportion of subjects with asymptomatic congenital CMV infection who, 
following treatment with 4 months of oral valganciclovir, develop SNHL over the first 18 
months of life. 
 
Exploratory: 
• To compare changes in whole blood CMV viral load versus plasma CMV viral load during 
and following antiviral treatment. 
• To assess correlation between CMV viral load, by body compartment, and SNHL. 
• To assess correlation between development of ganciclovir resistance, by body compartment, 
and SNHL. 
• To assess development of resistance to ganciclovir in the compartment-specific sites of 
blood, urine, and saliva over time. 
3.2 
Study Outcome Measures 
3.2.1 Primary Outcome Measures 
• 
The number of subjects developing sensorineural hearing loss in at least one ear between 
Baseline and Study Month 6 [both ears with normal hearing at baseline, then at least one ear 
with sensorineural hearing loss (SNHL) at the 6 month follow-up] 
3.2.2 Secondary Outcome Measures 
• Cumulative incidence of Grade 3 or higher unsolicited adverse events, safety laboratory 
adverse events, or serious adverse events 
• Cumulative incidence of absolute neutrophil counts below 500/mm3  
• Cumulative incidence of transaminase elevation during treatment ≥ 2-times the baseline 
value 
• Cumulative incidence of adverse events leading to permanent discontinuation of 
valganciclovir therapy,  or any adverse event that is not recovered / not resolved 


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• Cumulative incidence of sensorineural hearing loss in at least one ear between Baseline and 
Study Month 4 [both ears with normal hearing at baseline, then at least one ear with 
sensorineural hearing loss (SNHL) at the 4 month follow-up] 
• Cumulative incidence of sensorineural hearing loss in at least one ear between Baseline and 
Study Month 12 [both ears with normal hearing at baseline, then at least one ear with 
sensorineural hearing loss (SNHL) at the 12 month follow-up] 
• Cumulative incidence of sensorineural hearing loss in at least one ear between Baseline and 
Study Month 18 [both ears with normal hearing at baseline, then at least one ear with 
sensorineural hearing loss (SNHL) at the 18 month follow-up] 
• Cumulative incidence of each degree of worsened hearing (mild, moderate, severe, profound) 
at Study Months 4, 6, 12, and 18, represented by the ear that has the larger degree of 
worsening 
• Proportion of ears of each degree of worsened hearing (mild, moderate, severe, profound) at 
Study Months 4, 6, 12, and 18 
3.2.3 Exploratory Outcome Measures 
• Change in whole blood and plasma CMV viral load through Study Month 6 
• Correlation of change in whole blood and plasma CMV viral load with change in hearing at 
Study Months 4, 6, 12, and 18. 
• Correlation of change in urine CMV viral load with change in hearing at Study Months 4, 6, 
12, and 18. 
• Correlation of development of ganciclovir resistance in differing body compartments (blood, 
urine, saliva) with change in hearing at Study Months 4, 6, 12, and 18. 
• Emergence and kinetics of ganciclovir resistance in differing body compartments (blood, 
urine, saliva) during antiviral therapy (Study Month 4), and following cessation of antiviral 
treatment (Study Months 5 and 6) 
 


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4 
STUDY DESIGN 
This is a phase II, open-label trial to evaluate valganciclovir as a treatment to prevent 
development of SNHL in infants with asymptomatic congenital CMV infection.  The trial will be 
conducted in two phases (screening of newborns to identify eligible subjects, and treatment of 
those newborns who have confirmed CMV infection at birth but without outward manifestations 
of congenital CMV infection). 
 
Following consent for screening, newborns with no outward manifestations of congenital CMV 
infection who are delivered at one of 9 participating academic medical centers will be screened 
for CMV infection during their birth hospital stay.  A buccal saliva swab will be obtained by 
swabbing the inside of the newborn’s mouth for detection of CMV by PCR.  The collected swabs 
will be transported within 4 days of collection to the Central Laboratory at the University of 
Alabama at Birmingham for testing.  Babies screening positive for congenital CMV infection 
will have a second saliva sample and a urine sample collected for confirmatory PCR testing.  
Study drug will not be started until the confirmatory PCR testing is completed; the likelihood of 
a false-positive screening test is < 0.03%, but performing a confirmatory test ensures that only 
those babies truly infected with CMV will be exposed to valganciclovir.  Approximately 48,250 
newborn infants will be screened to detect approximately 241 neonates with asymptomatic 
congenital CMV infection; these 241 newborns then will have audiology examinations to 
determine baseline hearing, with approximately 229 having normal hearing in both ears.  Those 
229 newborns with confirmed CMV infection but without baseline SNHL and who meet all 
inclusion/exclusion criteria will be offered enrollment into the treatment phase. 
 
Through this screening process, approximately 12 neonates congenitally infected with CMV who 
have SNHL at birth also will be identified.  Newborn patients with SNHL and who are being 
treated clinically with valganciclovir will be offered enrollment into an observational substudy 
as detailed below. 
 
After obtaining treatment informed consent, enrolled subjects will be treated for four months 
with oral valganciclovir (16 mg/kg/dose, administered two times per day).  Study Day 1 is the 
day that the first dose of study medication is administered.  Audiologic assessments will be made 
during the Screening Period and Study Months 4 (end of treatment), 6, 12, and 18.  A single, 
independent study audiologist will assess the audiology test battery for each subject and assign 
each ear the classifications of normal hearing, mild hearing loss, moderate hearing loss, severe 
hearing loss, or profound hearing loss based upon their hearing thresholds (in decibels).  If a 
study subject proceeds to cochlear implantation during the course of the study, he/she will not 
require additional study-related hearing assessments following the implantation procedure but 
will continue with all other study-related assessments. 
 
Treated infants will be followed for safety throughout the first 6 months of the study (including 
for 2 months post-treatment).  Hematology safety laboratory assessments will be obtained 
weekly for the first six weeks of study drug administration, then every other week for the next 
six weeks of study drug administration, and then at months 4 and 5.  Chemistry safety laboratory 


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assessments will be obtained every other week for the first 12 weeks (3 months) of treatment, 
and then at months 4, 5, and 6.  Adverse events will be assessed at each study visit during 
treatment, and at month 5. 
 
Whole blood viral load and plasma viral load will be obtained at each study visit during the 
course of study drug administration, and then at Study Months 5 and 6.  Specimens from subjects 
with increasing viral loads despite antiviral therapy may be evaluated for ganciclovir resistance 
by molecular methodologies (e.g., deep sequencing, Sanger sequencing, PCR).  Urine and saliva 
will be obtained at Baseline and Study Months 4, 5, and 6 in order to obtain viral isolates to 
assist in detection of antiviral resistance. 
4.1 
Substudies (if applicable) 
Infants with confirmed CMV but who have documented SHNL at baseline and who are being 
treated clinically with valganciclovir  (expected to be about 12 patients) will be offered 
enrollment into an observational substudy.  No additional audiologic or safety testing will be 
done as part of the study.  However, available clinical audiologic and safety data will be redacted 
without alteration from the clinical medical record.  Enrolled subjects will be followed for CMV 
viral load as part of the study.  Viral loads would not be routinely followed as part of clinical 
management (and thus will be study procedures), whereas the valganciclovir treatment and 
associated safety labs as well as the serial hearing testing are part of clinical care for these 
patients.  Blood for CMV viral load will only be obtained at a given study visit if other blood is 
being obtained by venipuncture for clinical purposes.  Inclusion of these substudy subjects will 
enhance the understanding of antiviral effects on audiologic outcomes from congenital CMV 
infection, bridging the gap between the completely asymptomatic population in the main study 
and the symptomatic populations assessed in prior CASG trials.18-21,23,25 
 


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5 
STUDY ENROLLMENT AND WITHDRAWAL 
5.1 
Subject Inclusion Criteria 
• Parent(s)/legal guardian(s) have signed informed consent documents* 
• Confirmation of CMV by urine PCR testing 
• Infant ≤ 30 days of age at initiation of study drug 
• Weight at study enrollment ≥ 1775 grams 
• Gestational age ≥ 32 weeks at birth 
 
* There is a screening informed consent for screening phase of study participation, and a 
treatment informed consent for treatment phase of study participation. 
5.2 
Subject Exclusion Criteria 
• Symptomatic congenital CMV disease* 
• Sensorineural hearing deficits as detected by formal brainstem evoked response (not a 
screening ABR) of known etiology other than CMV 
• Prior or current receipt of ganciclovir, valganciclovir, foscarnet, cidofovir, brincidofovir, 
maribavir, or letermovir 
• Maternal receipt of CMV hyperimmune globulin during pregnancy 
• Breastfeeding from mother who is receiving ganciclovir, valganciclovir, foscarnet, cidofovir, 
brincidofovir, maribavir, or letermovir 
• Gastrointestinal abnormality which might preclude absorption of an oral medication (e.g., a 
history of necrotizing enterocolitis) 
• Infants known to be born to women who are HIV positive (HIV testing is not required for 
study entry) 
• Current receipt of other investigational drugs 
 
* Symptomatic disease is defined as one or more of the following: 1) thrombocytopenia, if 
known; 2) petechiae; 3) hepatomegaly; 4) splenomegaly; 5) intrauterine growth restriction; 6) 
hepatitis (elevated transaminases and/or direct bilirubin), if known; 7) central nervous system 
involvement of the CMV disease (such as microcephaly; radiographic abnormalities indicative 
of CMV CNS disease, if known; abnormal CSF indices for age, if known; chorioretinitis, if 
known; and/or positive CMV PCR from CSF, if known). 
5.3 
Treatment Assignment Procedures 
5.3.1 Randomization Procedures 
This is a single-arm study; subjects will not be randomized to treatment. 
5.3.2 Masking Procedures 
This is a single-arm open-label study.  No masking procedures will be done. 


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5.3.3 Reasons for Withdrawal 
5.3.3.1 Reasons for Withdrawal Prior to Initiation of Study Drug 
The criteria for discontinuation of study participation following confirmation of congenital CMV 
infection in the screening process but prior to initiation of study medication in the treatment 
portion of the study: 
• Study subject (parent/legal guardian) wishes to withdraw 
• The study is terminated 
• Any other reason which, in the opinion of the investigator, precludes the study subject's 
participation in the study.  Note: The site principal investigator must call the study Principal 
Investigator (or designee) prior to discontinuing a study subject for this reason. 
5.3.3.2 Reasons for Withdrawal During Treatment 
The criteria for discontinuations during the time that study medication is being provided include:  
 
• Discontinuation of Study Product 
o Development of a related serious adverse event warranting withdrawal of therapy 
o Deterioration in general condition for which alternative treatment is indicated and which, 
in the opinion of the investigator, warrants withdrawal of therapy 
o Development of a medical disease or condition, or any new clinical findings for which 
continued participation, in the opinion of the site principal investigator or appropriate 
sub-investigator, would compromise the safety of the subject, would interfere with the 
subject's successful completion of this study, or would interfere with the evaluation of 
responses. 
 
• Subject Withdrawal 
o Study subject (parent/legal guardian) wishes to withdraw 
o Non-compliance with study procedures or medication schedule that in the opinion of the 
investigator warrants withdrawal 
o The study is terminated 
o Any other reason which, in the opinion of the investigator, precludes the study subject's 
participation in the study.  The site principal investigator must call the study Principal 
Investigator (or designee) prior to discontinuing a study subject for this reason. 
5.3.3.3 Reasons for Withdrawal After Completion of Treatment 
Criteria for discontinuing study subjects from the study after study medication is complete are: 
• Study subject (parent/legal guardian) wishes to withdraw 
• Any other reason, which in the opinion of the investigator, should preclude the study 
subject's continued participation in the study.  The site principal investigator must call the 
study Principal Investigator (or designee) prior to discontinuing a study subject for this 
reason. 
• Any subject that is terminated due to loss to follow-up will be considered as withdrawn 
 


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5.3.4 Handling of Withdrawals 
Study subjects may withdraw voluntarily from participation in the study at any time. Up to 20% 
over-enrollment is allowed to replace subjects who drop-out or who have inadequate audiology 
assessments.  Study subjects also may withdraw voluntarily from receiving the study 
intervention for any reason.  If a study subject withdraws from the study or discontinues study 
intervention at any time prior to completion of the study, the reason for this decision will be 
recorded on the appropriate electronic case report form (eCRF).  SAEs and AEs will be followed 
according to guidelines in Section 9.  The study subject should be asked to complete follow-up 
visits. 
 
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 enrolled study subjects will continue to be followed as long as possible. 
 
Since the primary endpoint requires comparison of baseline and 6 month audiology assessments, 
dropouts and subjects with audiology assessments that are inadequate for study comparison 
(Section 11.2) will be replaced.  Characteristics of the dropouts and those with missing outcomes 
will be compared to determine if there is a difference between the two treatment groups.  If 
differences are observed, this will be included in the primary outcome reporting as a limitation. 
5.3.5 Termination of Study  
The ethics committees, FDA, UAB Central Unit, or DMID have the right to terminate this study 
at any time.  Reasons for terminating the study may include, but are not limited to, the following: 
• The incidence or severity of adverse events in this or other studies indicates a potential health 
hazard to study subjects 
 
• Study subject enrollment is unsatisfactory 
 
• Data recording is inaccurate or incomplete 
 
• The Investigator has not been adhering to the protocol or applicable regulatory guidelines in 
conducting the study 
 


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6 
STUDY INTERVENTION/INVESTIGATIONAL PRODUCT 
6.1 
Study Product Description 
Valganciclovir is marketed for the treatment of CMV retinitis and the prevention of CMV 
disease in select transplant patients.  In adults, valganciclovir is approved for the treatment of 
CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS), and for the 
prevention of CMV disease in kidney, heart, and kidney-pancreas high-risk transplant patients.  
Valganciclovir is approved for the prevention of CMV disease in kidney transplant patients (4 
months to 16 years of age) and heart transplant patients (1 month to 16 years of age) at high 
risk.33 
6.1.1 Acquisition 
Valganciclovir for Oral Solution will be provided for this study by Genentech Inc.  Purified 
water (USP) for preparation of nonparenteral pharmaceutical products will be obtained at the 
local investigational pharmacy.  Upon request by DMID, the study products will be shipped to 
the following address: 
 
DMID-Clinical Agents Repository Contract (CAR) 
Fisher BioServices 
20439 Seneca Meadows Parkway 
Germantown, MD 20876 
Tel: (240) 477-1350 
Fax: (240) 477-1360 
Email: DMID.CAR@ThermoFisher.com 
 
Study product (valganciclovir) will be shipped to the investigational site upon request and 
approval by DMID. 
6.1.2 Formulation, Packaging, and Labeling 
Valganciclovir for oral solution will be supplied as a white to slightly yellow powder for 
constitution, forming a colorless to brownish yellow tutti-frutti flavored solution in the following 
strength: 50 mg per mL.  It will be packaged in glass bottles containing approximately 100 mL of 
solution after constitution.  The valganciclovir oral solution formulation does not contain lactose 
anhydrous.   
6.1.2.1 Packaging and Labeling 
The study drug will be supplied in its original manufacturer’s bottle.  Each container will also be 
labeled in compliance with applicable regulatory requirements, including the FDA-required 
cautionary statement “Caution- New drug -Limited by Federal (or United States) Law to 
Investigational Use Only.” 
 


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6.1.3 Product Storage and Stability 
Valganciclovir will be provided as a powder for oral solution.  Dry powder is to be stored at 25ºC 
(77ºF ); excursions permitted to 15 ºC to 30 ºC (59 ºF to 86 ºF).  Store reconstituted oral solution 
at 2° to 8°C (36 ºF to 46 ºF) for no longer than 49 days.  Do not freeze.  Shake bottle well before 
using. 
6.2 
Dosage, Preparation and Administration of Study 
Intervention/Investigational Product 
6.2.1 Dosage 
Valganciclovir should be dosed at 16 mg/kg body weight, unless specific dosage adjustment 
conditions (e.g., renal function) have been met, administered orally twice daily for 4 months.  
Specific dosing volumes will be provided for each subject.  Dose modifications for neutropenia, 
thrombocytopenia, and hepatotoxicity are detailed in Section 6.3.  
6.2.2 Preparation 
Valganciclovir for Oral Solution will be prepared by the site Research Pharmacist for dispensing 
to the subject.  A new bottle will be reconstituted and dispensed monthly during the 4 month 
treatment period.  Instructions for reconstitution will be provided in the protocol-specific Manual 
of Procedures (MOP).   
6.2.3 Administration 
Valganciclovir oral solution has been shown not to adhere to syringes or to nasogastric tubing.  
Valganciclovir oral solution should be administered into the subject’s mouth via an oral dosing 
syringe.  Valganciclovir will be dispensed monthly.  Parent/guardians will be provided with 
specific storage and administration instructions. 
 
Study product administration should be timed with a feeding.  If the subject vomits or spits up 
following the dosing, re-dosing is not allowed. 
6.3 
Modification or Termination of Study Intervention/Investigational 
Product for a Participant 
Bone marrow suppression secondary to CMV can mimic valganciclovir toxicity.  Nevertheless, 
the dosage of valganciclovir will be reduced or terminated if any of the following occur: 
6.3.1 Neutropenia 
If the ANC reproducibly (within one week) decreases to < 500 cells/mm3, valganciclovir will be 
held until the ANC recovers to ≥ 750 cells/mm3, and then administration of drug will resume at 
the normal dose.  If the ANC again reproducibly (within one week) decreases to < 750 
cells/mm3, the valganciclovir dosage will be reduced by 50% and maintained there as long as the 
ANC remains ≥ 500 cells/mm3.  If the ANC reproducibly (within one week) decreases to < 500 


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cells/mm3 on the 50% dosage, then the study medication will be discontinued.  Administration of 
granulocyte colony stimulating factor (GCSF) is allowed.  All administered GCSF doses will be 
recorded on the concomitant medication sheet.  The decision to utilize GCSF is left to the 
medical discretion of the participating investigator.  The parameters for dose adjustment stated 
above, based upon ANC, will remain in effect even if the patient is receiving GCSF. 
6.3.2 Thrombocytopenia 
If the platelet count at baseline was ≥ 100,000/mm3, then valganciclovir may be held if the 
platelet count reproducibly (within one week) decreases to < 50,000/mm3.  After the platelet 
count increases to ≥ 50,000/mm3, valganciclovir administration at the normal dose may resume.  
If the platelet count at baseline was < 100,000/mm3, then valganciclovir may be held if the 
platelet count reproducibly (within one week) decreases by 50% from baseline value.  After the 
platelet count increases above 50% from baseline value, valganciclovir administration at the 
normal dose may resume.  Recurrence of platelet count below these threshholds will lead to 
study drug discontinuation. 
6.3.3  Hepatotoxicity 
If the ALT reproducibly (within one week) increases to ≥ 5-times the baseline value, 
valganciclovir will be held until ALT falls to ≤ 2-times the baseline value, at which time 
valganciclovir will be restarted. If the ALT again increases ≥ 5-times the baseline value, study 
drug will be discontinued. 
6.4 
Accountability Procedures for the Study Intervention/Investigational 
Product(s) 
After receipt of the study product, the site principal investigator (PI) is responsible for study 
product distribution and disposition and has ultimate responsibility for study product 
accountability.  The Site PI will delegate to the site Research Pharmacist the responsibility for 
study product accountability.  The site pharmacist will dispense valganciclovir in its original 
bottle and distribute it to the PI (or designee) or to the patient’s parent or legal guardian.  Each 
pharmacist will be responsible for and maintain logs of receipt, accountability, dispensation, 
storage conditions, and disposal of study drug.  All study product, whether administered or not, 
must be documented on the appropriate study product accountability record or dispensing log.  
Parents/guardians will be instructed to return used bottles to the PI each month.  At study 
completion, the sites will be required to return the drug accountability log to the UAB Central 
Unit upon request, retaining a copy of the drug accountability form in their study files.  
 
Used and unused study product will be retained at the site until monitored and released for 
disposition as applicable.   
• Upon release for disposition, used or partially used study product will be disposed of by the 
local site pharmacy in accordance with local regulations. 
• Upon completion or termination of the study and after the final monitoring visit, final 
disposition of the unused study product will be determined by DMID and communicated to 
the UAB central unit by the DMID Clinical Project Manager for the study.  Specifically, all 


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unopened study drug either will be returned to the Clinical Agents Repository (CAR) from 
the local site pharmacy or destroyed at the site in accordance with local regulations following 
the direction from the UAB Central Unit or its designee. 
6.5 
Assessment of Subject Compliance with Study 
Intervention/Investigational Product  
Assessment of compliance with administration of study medication throughout the 4 month 
treatment period will be achieved by utilization of a medication diary.  The parent(s) or legal 
guardian(s) will complete this diary on a daily basis, indicating the time of drug administration 
and whether the subject vomited following the dose.  The diary will be collected at each study 
visit, and a new diary provided at that time. 
6.6 
Concomitant Medications/Treatments 
6.6.1 Concomitant Medication Assessment 
All concomitant medications will be recorded at each study visit throughout the 4 month 
treatment period.  Administration of any medications will be documented in the subject’s source 
documentation and reported on the subject’s electronic case report form (eCRF).  Concomitant 
medications will include all medications, vitamins, and supplements taken within the 4 month 
study treatment schedule. 
6.6.2 Prohibited Therapies 
Use of the following concomitant medications during the time of administration of antiviral 
medication in this clinical trial will not be allowed: 
 
• Cidofovir 
• Foscarnet 
• Probenecid 
• Zidovudine 
• Didanosine 
• Mycophenolate mofetil 
• Other Investigational drugs, including but not limited to brincidofovir, maribavir, or 
letermovir 
6.6.3 Drug Interactions 
In pharmacokinetic studies, the concomitant use of ganciclovir and didanosine (ddI) has been 
associated with increases in ddI concentrations of greater than 100%.  Accordingly, the 
possibility of increased ddI toxicity should be considered in patients receiving both medications. 
Coadministration of trimethoprim with oral ganciclovir in adults statistically significantly 
decreased the renal clearance of ganciclovir by 16.3%, and this was associated with a statistically 
significant decrease in the terminal elimination rate and corresponding increase in half-life by 
15%.  However, these changes are unlikely to be clinically significant, as the AUC0-8 and Cmax 


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were unaffected.  The only statistically significant change in trimethoprim pharmacokinetic 
parameters when coadministered with ganciclovir was a 12% increase in Cmin.  However, this is 
unlikely to be of clinical significance and no dose adjustment is recommended. 


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7 
STUDY SCHEDULE 
7.1 
Screening  
It is anticipated that screening of neonates will occur at most sites within the first 2 days of life, 
prior to discharge from the birth hospital.  A screening informed consent form will be utilized for 
permission to conduct the screening test, which consists of obtaining a swab of the buccal 
mucosa for saliva PCR for CMV DNA.  Babies screening positive for congenital CMV infection 
will have sensorineural hearing testing performed, as is standard of care for babies identified as 
being congenitally infected with CMV.  A second saliva sample and a urine sample will be 
collected by study personnel (which will be covered by the screening informed consent) for 
confirmatory PCR testing.  The likelihood of a false-positive screening test is < 0.03%, but 
performing a confirmatory test ensures that only those babies truly infected with CMV will be 
exposed to valganciclovir. 
 
Sensorineural hearing testing will consist of a BSER (to assess neuro-otologic status) and OAEs 
(DPOAE or TEOAE).  If the BSER is abnormal, then bone conduction will be obtained to 
distinguish between sensorineural hearing loss, conductive loss, or mixed loss.  If the OAEs are 
abnormal, then acoustic immittance measures (tympanometry and acoustic reflexes) will be 
obtained to better define the middle or inner ear abnormality (e.g., otitis media). 
 
Neonates who screen positive for CMV DNA on their confirmatory PCR testing and who do not 
have sensorineural hearing loss (SNHL) will be offered enrollment in the treatment portion of the 
study if they meet all inclusion criteria and do not meet any exclusion criteria. 
 
Neonates who screen positive for CMV DNA on their confirmatory PCR testing and who have 
SNHL will be offered enrollment into an observational substudy if they are being treated 
clinically with valganciclovir and meet all inclusion criteria and no exclusion criteria.  For this 
group with SNHL at baseline, all clinical audiologic and safety data will be redacted without 
alteration from the clinical medical record to the study case report forms.  The only research 
laboratory samples that will be obtained are the whole blood, plasma, urine, and saliva 
specimens for viral load determination (see Footnote ‘m’ in the Schedule of Events, Appendix 
B); viral loads would not be routinely followed as part of clinical management (and thus will be 
study procedures), whereas the valganciclovir treatment and associated safety labs as well as the 
serial hearing testing are part of clinical care for these patients.  Blood for CMV viral load will 
only be obtained at a given study visit if other blood is being obtained by venipuncture for 
clinical purposes.  Non-study clinical and laboratory assessments that are not performed 
according to the intervals and listings in Appendix B (Schedule of Events) will not be assessed as 
protocol deviations, nor will failure to obtain the virology specimen if a venipuncture is not 
performed as part of clinical care at a given study visit.  An observational informed consent 
signed by the neonate’s parent(s) or guardian(s) must be signed prior to enrollment into the 
observational substudy. The observational consent will be signed following the confirmatory 
PCR testing for CMV DNA and prior to or on Day 1. 
 


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7.2 
Enrollment/Baseline 
7.2.1 Study Day 1 Assessment (Study Day -3 through Study Day 1, unless alternative 
window is specified) 
• After reviewing inclusion/exclusion criteria for treatment portion of the study, confirm that 
the treatment informed consent from parent or legally authorized representative has been 
signed; treatment informed consent will be obtained prior to starting any subject-related 
assessments or study drug administration. 
• Document baseline demographics and clinical assessments 
o Date of birth 
o Gender 
o Race 
o Ethnicity 
o Birth weight 
o Length at birth, if available 
o Head circumference at birth, if available 
o Gestational age at birth 
o Medical history and baseline conditions prior to study enrollment, by body system 
• Obtain 0.5 mL of blood for hematology safety labs 
o WBC count with differential 
o Hemoglobin concentration 
o Platelet count 
• Obtain 1.0 mL of blood for chemistry safety labs 
o Alanine aminotransferase (ALT) 
o Direct bilirubin 
o Serum creatinine 
• Measure growth parameters 
o Length in centimeters 
o Weight in kilograms 
o Head circumference in centimeters 
• Review of adverse events and serious adverse events (for Adverse Events that occur 
following the first dose of study medication) 
• Record concomitant medications 
• Obtain 0.7 mL of blood for CMV viral load 
o Urine collection by bagged specimen (if obtainable) and saliva collected by buccal swab 
will be attempted on Study Day 1 (window: Study Day -3 to Study Day 7 for whole 
blood and urine; and Study Day -30 to Study Day 7 for saliva).  If urine is obtainable, it 
will be frozen and sent to the Central Unit Central Laboratory for processing.  If urine is 
not obtainable, a note will be made on the CRF but a protocol deviation will not be 
reported. 
• Medication diary will be distributed and parent or legal guardian will be instructed on its use. 


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7.2.2 Study Day 1 
• The first dose of study drug will be administered (and this day will be known as Study Day 
1) 
7.2.3 Substudy Assessments 
• For the approximately 12 patients identified as being asymptomatically congenitally infected 
with CMV and with SNHL, the virology specimen for CMV viral load is the only study-
related laboratory specimen collected for them; this specimen will be obtained only if the 
subject is having a venipuncture performed as part of clinical care.  All other data will be 
redacted without alteration from the clinical chart, if available as part of the subject’s clinical 
care.  Non-study clinical and laboratory assessments that are not performed according to the 
intervals and listings in Appendix B (Schedule of Events) will not be assessed as protocol 
deviations.  If a venipuncture is not performed as part of clinical care at a given study visit, 
then the failure to obtain the virology specimen also will not be reported as a protocol 
deviation. 
7.3 
Follow-up  
7.3.1 Study Day 7 (± 2 days) 
• Obtain 0.5 mL of blood for hematology safety labs 
o WBC count with differential 
o Hemoglobin concentration 
o Platelet count 
• Measure growth parameters 
o Length in centimeters 
o Weight in kilograms 
o Head circumference in centimeters 
• Review of adverse events and serious adverse events 
• Record concomitant medications 
• Obtain 0.7 mL of blood for CMV viral load 
• Obtain any updated results from etiological investigations for SNHL 
• Collect medication diary, and distribute new one 
• Adjust dose of study medication for weight change, if needed 
7.3.1.1 Substudy Assessments 
• For the approximately 12 patients identified as being asymptomatically congenitally infected 
with CMV and with SNHL, the virology specimen for CMV viral load is the only study-
related laboratory specimen collected for them; this specimen will be obtained only if the 
subject is having a venipuncture performed as part of clinical care.  All other data will be 
redacted without alteration from the clinical chart, if available as part of the subject’s clinical 
care.  Non-study clinical and laboratory assessments that are not performed according to the 
intervals and listings in Appendix B (Schedule of Events) will not be assessed as protocol 


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deviations.  If a venipuncture is not performed as part of clinical care at a given study visit, 
then the failure to obtain the virology specimen also will not be reported as a protocol 
deviation. 
7.3.2 Study Day 14 (± 2 days) 
• Obtain 0.5 mL of blood for hematology safety labs 
o WBC count with differential 
o Hemoglobin concentration 
o Platelet count 
• Obtain 1.0 mL of blood for chemistry safety labs 
o Alanine aminotransferase (ALT) 
o Direct bilirubin 
o Serum creatinine 
• Measure growth parameters 
o Length in centimeters 
o Weight in kilograms 
o Head circumference in centimeters 
• Review of adverse events and serious adverse events 
• Record concomitant medications 
• Obtain 0.7 mL of blood for CMV viral load 
• Obtain any updated results from etiological investigations for SNHL 
• Collect medication diary, and distribute new one 
• Adjust dose of study medication for weight change, if needed 
7.3.2.1 Substudy Assessments 
• For the approximately 12 patients identified as being asymptomatically congenitally infected 
with CMV and with SNHL, the virology specimen for CMV viral load is the only study-
related laboratory specimen collected for them; this specimen will be obtained only if the 
subject is having a venipuncture performed as part of clinical care.  All other data will be 
redacted without alteration from the clinical chart, if available as part of the subject’s clinical 
care.  Non-study clinical and laboratory assessments that are not performed according to the 
intervals and listings in Appendix B (Schedule of Events) will not be assessed as protocol 
deviations.  If a venipuncture is not performed as part of clinical care at a given study visit, 
then the failure to obtain the virology specimen also will not be reported as a protocol 
deviation. 
7.3.3 Study Day 21 (± 2 days) 
• Obtain 0.5 mL of blood for hematology safety labs 
o WBC count with differential 
o Hemoglobin concentration 
o Platelet count 
• Measure growth parameters 
o Length in centimeters 


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o Weight in kilograms 
o Head circumference in centimeters 
• Review of adverse events and serious adverse events 
• Record concomitant medications 
• Obtain 0.7 mL of blood for CMV viral load 
• Obtain any updated results from etiological investigations for SNHL 
• Collect medication diary, and distribute new one 
• Adjust dose of study medication for weight change, if needed 
7.3.3.1 Substudy Assessments 
• For the approximately 12 patients identified as being asymptomatically congenitally infected 
with CMV and with SNHL, the virology specimen for CMV viral load is the only study-
related laboratory specimen collected for them; this specimen will be obtained only if the 
subject is having a venipuncture performed as part of clinical care.  All other data will be 
redacted without alteration from the clinical chart, if available as part of the subject’s clinical 
care.  Non-study clinical and laboratory assessments that are not performed according to the 
intervals and listings in Appendix B (Schedule of Events) will not be assessed as protocol 
deviations.  If a venipuncture is not performed as part of clinical care at a given study visit, 
then the failure to obtain the virology specimen also will not be reported as a protocol 
deviation. 
7.3.4 Study Day 28 (± 2 days) 
• Obtain 0.5 mL of blood for hematology safety labs 
o WBC count with differential 
o Hemoglobin concentration 
o Platelet count 
• Obtain 1.0 mL of blood for chemistry safety labs 
o Alanine aminotransferase (ALT) 
o Direct bilirubin 
o Serum creatinine 
• Measure growth parameters 
o Length in centimeters 
o Weight in kilograms 
o Head circumference in centimeters 
• Review of adverse events and serious adverse events 
• Record concomitant medications 
• Obtain 0.7 mL of blood for CMV viral load 
• Obtain any updated results from etiological investigations for SNHL 
• Collect medication diary, and distribute new one 
• Adjust dose of study medication for weight change, if needed 


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7.3.4.1 Substudy Assessments 
• For the approximately 12 patients identified as being asymptomatically congenitally infected 
with CMV and with SNHL, the virology specimen for CMV viral load is the only study-
related laboratory specimen collected for them; this specimen will be obtained only if the 
subject is having a venipuncture performed as part of clinical care.  All other data will be 
redacted without alteration from the clinical chart, if available as part of the subject’s clinical 
care.  Non-study clinical and laboratory assessments that are not performed according to the 
intervals and listings in Appendix B (Schedule of Events) will not be assessed as protocol 
deviations.  If a venipuncture is not performed as part of clinical care at a given study visit, 
then the failure to obtain the virology specimen also will not be reported as a protocol 
deviation. 
7.3.5 Study Day 35 (± 2 days) 
• Obtain 0.5 mL of blood for hematology safety labs 
o WBC count with differential 
o Hemoglobin concentration 
o Platelet count 
• Measure growth parameters 
o Length in centimeters 
o Weight in kilograms 
o Head circumference in centimeters 
• Review of adverse events and serious adverse events 
• Record concomitant medications 
• Obtain 0.7 mL of blood for CMV viral load 
• Obtain any updated results from etiological investigations for SNHL 
• Collect medication diary, and distribute new one 
• Adjust dose of study medication for weight change, if needed 
7.3.5.1 Substudy Assessments 
• For the approximately 12 patients identified as being asymptomatically congenitally infected 
with CMV and with SNHL, the virology specimen for CMV viral load is the only study-
related laboratory specimen collected for them; this specimen will be obtained only if the 
subject is having a venipuncture performed as part of clinical care.  All other data will be 
redacted without alteration from the clinical chart, if available as part of the subject’s clinical 
care.  Non-study clinical and laboratory assessments that are not performed according to the 
intervals and listings in Appendix B (Schedule of Events) will not be assessed as protocol 
deviations.  If a venipuncture is not performed as part of clinical care at a given study visit, 
then the failure to obtain the virology specimen also will not be reported as a protocol 
deviation. 
7.3.6 Study Day 42 (± 3 days) 
• Obtain 0.5 mL of blood for hematology safety labs 
o WBC count with differential 


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o Hemoglobin concentration 
o Platelet count 
• Obtain 1.0 mL of blood for chemistry safety labs 
o Alanine aminotransferase (ALT) 
o Direct bilirubin 
o Serum creatinine 
• Measure growth parameters 
o Length in centimeters 
o Weight in kilograms 
o Head circumference in centimeters 
• Review of adverse events and serious adverse events 
• Record concomitant medications 
• Obtain 0.7 mL of blood for CMV viral load 
• Obtain any updated results from etiological investigations for SNHL 
• Collect medication diary, and distribute new one 
• Adjust dose of study medication for weight change, if needed 
7.3.6.1 Substudy Assessments 
• For the approximately 12 patients identified as being asymptomatically congenitally infected 
with CMV and with SNHL, the virology specimen for CMV viral load is the only study-
related laboratory specimen collected for them; this specimen will be obtained only if the 
subject is having a venipuncture performed as part of clinical care.  All other data will be 
redacted without alteration from the clinical chart, if available as part of the subject’s clinical 
care.  Non-study clinical and laboratory assessments that are not performed according to the 
intervals and listings in Appendix B (Schedule of Events) will not be assessed as protocol 
deviations.  If a venipuncture is not performed as part of clinical care at a given study visit, 
then the failure to obtain the virology specimen also will not be reported as a protocol 
deviation. 
7.3.7 Study Day 56 (± 3 days) 
• Obtain 0.5 mL of blood for hematology safety labs 
o WBC count with differential 
o Hemoglobin concentration 
o Platelet count 
• Obtain 1.0 mL of blood for chemistry safety labs 
o Alanine aminotransferase (ALT) 
o Direct bilirubin 
o Serum creatinine 
• Measure growth parameters 
o Length in centimeters 
o Weight in kilograms 
o Head circumference in centimeters 
• Review of adverse events and serious adverse events 


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• Record concomitant medications 
• Obtain 0.7 mL of blood for CMV viral load 
• Obtain any updated results from etiological investigations for SNHL 
• Collect medication diary, and distribute new one 
• Adjust dose of study medication for weight change, if needed 
7.3.7.1 Substudy Assessments 
• For the approximately 12 patients identified as being asymptomatically congenitally infected 
with CMV and with SNHL, the virology specimen for CMV viral load is the only study-
related laboratory specimen collected for them; this specimen will be obtained only if the 
subject is having a venipuncture performed as part of clinical care.  All other data will be 
redacted without alteration from the clinical chart, if available as part of the subject’s clinical 
care.  Non-study clinical and laboratory assessments that are not performed according to the 
intervals and listings in Appendix B (Schedule of Events) will not be assessed as protocol 
deviations.  If a venipuncture is not performed as part of clinical care at a given study visit, 
then the failure to obtain the virology specimen also will not be reported as a protocol 
deviation. 
7.3.8 Study Day 70 (± 3 days) 
• Obtain 0.5 mL of blood for hematology safety labs 
o WBC count with differential 
o Hemoglobin concentration 
o Platelet count 
• Obtain 1.0 mL of blood for chemistry safety labs 
o Alanine aminotransferase (ALT) 
o Direct bilirubin 
o Serum creatinine 
• Measure growth parameters 
o Length in centimeters 
o Weight in kilograms 
o Head circumference in centimeters 
• Review of adverse events and serious adverse events 
• Record concomitant medications 
• Obtain 0.7 mL of blood for CMV viral load 
• Obtain any updated results from etiological investigations for SNHL 
• Collect medication diary, and distribute new one 
• Adjust dose of study medication for weight change, if needed 
7.3.8.1 Substudy Assessments 
• For the approximately 12 patients identified as being asymptomatically congenitally infected 
with CMV and with SNHL, the virology specimen for CMV viral load is the only study-
related laboratory specimen collected for them; this specimen will be obtained only if the 
subject is having a venipuncture performed as part of clinical care.  All other data will be 


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redacted without alteration from the clinical chart, if available as part of the subject’s clinical 
care.  Non-study clinical and laboratory assessments that are not performed according to the 
intervals and listings in Appendix B (Schedule of Events) will not be assessed as protocol 
deviations.  If a venipuncture is not performed as part of clinical care at a given study visit, 
then the failure to obtain the virology specimen also will not be reported as a protocol 
deviation. 
7.3.9 Study Day 84 (± 3 days) 
• Obtain 0.5 mL of blood for hematology safety labs 
o WBC count with differential 
o Hemoglobin concentration 
o Platelet count 
• Obtain 1.0 mL of blood for chemistry safety labs 
o Alanine aminotransferase (ALT) 
o Direct bilirubin 
o Serum creatinine 
• Measure growth parameters 
o Length in centimeters 
o Weight in kilograms 
o Head circumference in centimeters 
• Review of adverse events and serious adverse events 
• Record concomitant medications 
• Obtain 0.7 mL of blood for CMV viral load 
• Obtain any updated results from etiological investigations for SNHL 
• Collect medication diary, and distribute new one 
• Adjust dose of study medication for weight change, if needed 
7.3.9.1 Substudy Assessments 
• For the approximately 12 patients identified as being asymptomatically congenitally infected 
with CMV and with SNHL, the virology specimen for CMV viral load is the only study-
related laboratory specimen collected for them; this specimen will be obtained only if the 
subject is having a venipuncture performed as part of clinical care.  All other data will be 
redacted without alteration from the clinical chart, if available as part of the subject’s clinical 
care.  Non-study clinical and laboratory assessments that are not performed according to the 
intervals and listings in Appendix B (Schedule of Events) will not be assessed as protocol 
deviations.  If a venipuncture is not performed as part of clinical care at a given study visit, 
then the failure to obtain the virology specimen also will not be reported as a protocol 
deviation. 
7.3.10 Study Month 4 (± 10 days, unless alternative window is specified) 
• Obtain 0.5 mL of blood for hematology safety labs 
o WBC count with differential 
o Hemoglobin concentration 


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o Platelet count 
• Obtain 1.0 mL of blood for chemistry safety labs 
o Alanine aminotransferase (ALT) 
o Direct bilirubin 
o Serum creatinine 
• Measure growth parameters 
o Length in centimeters 
o Weight in kilograms 
o Head circumference in centimeters 
• Review of adverse events and serious adverse events 
• Record concomitant medications 
• Obtain a new hearing assessment or record results from clinically obtained hearing 
assessment (Window: -10 to +30 days) 
o BSER (to assess neuro-otologic status) and OAEs (DPOAE or TEOAE) will be obtained.  
If the BSER is abnormal, then bone conduction will be obtained to distinguish between 
sensorineural hearing loss, conductive loss, or mixed loss.  If the OAEs are abnormal, 
then acoustic immittance measures (tympanometry and acoustic reflexes) will be 
obtained to better define the middle or inner ear abnormality (e.g., otitis media). 
• Obtain 0.7 mL of blood for CMV viral load 
o Urine collection by bagged specimen (if obtainable) and saliva collected by buccal swab 
will be attempted on Study Month 4.  If urine is obtainable, it will be frozen and sent to 
the Central Unit Central Laboratory for processing.  If urine is not obtainable, a note will 
be made on the CRF but a protocol deviation will not be reported. 
• Obtain any updated results from etiological investigations for SNHL 
• Collect medication diary 
7.3.10.1 Substudy Assessments 
• For the approximately 12 patients identified as being asymptomatically congenitally infected 
with CMV and with SNHL, the virology specimen for CMV viral load is the only study-
related laboratory specimen collected for them; this specimen will be obtained only if the 
subject is having a venipuncture performed as part of clinical care.  All other data will be 
redacted without alteration from the clinical chart, if available as part of the subject’s clinical 
care.  Non-study clinical and laboratory assessments that are not performed according to the 
intervals and listings in Appendix B (Schedule of Events) will not be assessed as protocol 
deviations.  If a venipuncture is not performed as part of clinical care at a given study visit, 
then the failure to obtain the virology specimen also will not be reported as a protocol 
deviation. 
7.3.11 Study Month 5 (± 10 days) 
• Obtain 0.5 mL of blood for hematology safety labs 
o WBC count with differential 
o Hemoglobin concentration 
o Platelet count 


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• Obtain 1.0 mL of blood for chemistry safety labs 
o Alanine aminotransferase (ALT) 
o Direct bilirubin 
o Serum creatinine 
• Measure growth parameters 
o Length in centimeters 
o Weight in kilograms 
o Head circumference in centimeters 
• Review of adverse events and serious adverse events 
• Obtain 0.7 mL of blood for CMV viral load 
o Urine collection by bagged specimen (if obtainable) and saliva collected by buccal swab 
will be attempted on Study Month 5.  If urine is obtainable, it will be frozen and sent to 
the Central Unit Central Laboratory for processing.  If urine is not obtainable, a note will 
be made on the CRF but a protocol deviation will not be reported. 
• Obtain any updated results from etiological investigations for SNHL 
7.3.11.1 Substudy Assessments 
• For the approximately 12 patients identified as being asymptomatically congenitally infected 
with CMV and with SNHL, the virology specimen for CMV viral load is the only study-
related laboratory specimen collected for them; this specimen will be obtained only if the 
subject is having a venipuncture performed as part of clinical care.  All other data will be 
redacted without alteration from the clinical chart, if available as part of the subject’s clinical 
care.  Non-study clinical and laboratory assessments that are not performed according to the 
intervals and listings in Appendix B (Schedule of Events) will not be assessed as protocol 
deviations.  If a venipuncture is not performed as part of clinical care at a given study visit, 
then the failure to obtain the virology specimen also will not be reported as a protocol 
deviation. 
7.3.12 Study Month 6 (± 10 days, unless alternative window is specified) 
• Obtain 1.0 mL of blood for chemistry safety labs 
o Alanine aminotransferase (ALT) 
o Direct bilirubin 
o Serum creatinine 
• Measure growth parameters 
o Length in centimeters 
o Weight in kilograms 
o Head circumference in centimeters 
• Obtain a new hearing assessment or record results from clinically obtained hearing 
assessment (Window: -10 to +30 days) 
o BSER and/or VRA (to assess neuro-otologic status) and OAEs (DPOAE or TEOAE) will 
be obtained.  If the BSER and/or VRA is abnormal, then bone conduction will be 
obtained to distinguish between sensorineural hearing loss, conductive loss, or mixed 
loss.  If the OAEs are abnormal, then acoustic immittance measures (tympanometry and 


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acoustic reflexes) will be obtained to better define the middle or inner ear abnormality 
(e.g., otitis media). 
• Obtain 0.7 mL of blood for CMV viral load 
o Urine collection by bagged specimen (if obtainable) and saliva collected by buccal swab 
will be attempted on Study Month 6.  If urine is obtainable, it will be frozen and sent to 
the Central Unit Central Laboratory for processing.  If urine is not obtainable, a note will 
be made on the CRF but a protocol deviation will not be reported. 
• Obtain any updated results from etiological investigations for SNHL 
7.3.12.1 Substudy Assessments 
• For the approximately 12 patients identified as being asymptomatically congenitally infected 
with CMV and with SNHL, the virology specimen for CMV viral load is the only study-
related laboratory specimen collected for them; this specimen will be obtained only if the 
subject is having a venipuncture performed as part of clinical care.  All other data will be 
redacted without alteration from the clinical chart, if available as part of the subject’s clinical 
care.  Non-study clinical and laboratory assessments that are not performed according to the 
intervals and listings in Appendix B (Schedule of Events) will not be assessed as protocol 
deviations.  If a venipuncture is not performed as part of clinical care at a given study visit, 
then the failure to obtain the virology specimen also will not be reported as a protocol 
deviation. 
7.3.13 Study Month 12 (± 30 days, unless alternative window is specified) 
• Measure growth parameters 
o Length in centimeters 
o Weight in kilograms 
o Head circumference in centimeters 
• Obtain a new hearing assessment or record results from clinically obtained hearing 
assessment (Window: -10 to +30 days) 
o BSER and/or VRA (to assess neuro-otologic status) and OAEs (DPOAE or TEOAE) will 
be obtained.  If the BSER and/or VRA is abnormal, then bone conduction will be 
obtained to distinguish between sensorineural hearing loss, conductive loss, or mixed 
loss.  If the OAEs are abnormal, then acoustic immittance measures (tympanometry and 
acoustic reflexes) will be obtained to better define the middle or inner ear abnormality 
(e.g., otitis media). 
• Obtain any updated results from etiological investigations for SNHL 
7.3.13.1 Substudy Assessments 
• For the approximately 12 patients identified as being asymptomatically congenitally infected 
with CMV and with SNHL, all data will be redacted without alteration from the clinical 
chart, if available as part of the subject’s clinical care. 


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7.4 
Final Study Visit 
7.4.1 Study Month 18 (± 30 days, unless alternative window is specified) 
• Measure growth parameters 
o Length in centimeters 
o Weight in kilograms 
o Head circumference in centimeters 
• Obtain a new hearing assessment or record results from clinically obtained hearing 
assessment (Window: -10 to +30 days) 
o BSER and/or VRA (to assess neuro-otologic status) and OAEs (DPOAE or TEOAE) will 
be obtained.  If the BSER and/or VRA is abnormal, then bone conduction will be 
obtained to distinguish between sensorineural hearing loss, conductive loss, or mixed 
loss.  If the OAEs are abnormal, then acoustic immittance measures (tympanometry and 
acoustic reflexes) will be obtained to better define the middle or inner ear abnormality 
(e.g., otitis media). 
• Obtain any updated results from etiological investigations for SNHL 
7.4.1.1 Substudy Assessments 
• For the approximately 12 patients identified as being asymptomatically congenitally infected 
with CMV and with SNHL, all data will be redacted without alteration from the clinical 
chart, if available as part of the subject’s clinical care. 
7.5 
Early Termination Visit 
Study subjects may withdraw voluntarily from participation in the study at any time.  Study 
subjects may also withdraw voluntarily from receiving the study intervention for any reason.  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 CRFs.  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.  The study subject should be asked to complete follow-up 
visits. 
 
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  
Should an unscheduled visit occur, it would likely be due to an adverse event.  At this visit, the 
study subject will be assessed as standard of care.  Recording of SAEs or AEs will be done 
according to Section 9 of this protocol. 
 


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8 
STUDY PROCEDURES/EVALUATIONS 
The study procedures and evaluations are summarized in Appendix B.  Allowable windows for 
each study visit have been described previously.  Some assessments and medical history 
information may be collected from the subject’s medical charts as outlined below. 
8.1 
Clinical Evaluations 
8.1.1 Baseline Demographics 
Data collected will include basic demographics and selected laboratory parameters.  The 
following information will be collected from the subjects medical records to the extent the 
information is available:  date of birth; gender; race; ethnicity; birth weight; length at birth, if 
available; head circumference at birth, if available; gestational age at birth; medical history and 
baseline conditions prior to study enrollment, by body system. 
8.1.2 Growth Parameters 
To adjust study medication for weight gain, weight will be recorded at multiple study visits.  To 
assess additional growth parameters, length and head circumference will be recorded at multiple 
study visits. 
8.1.3 Adverse Event Assessment 
At each study visit from the receipt of first dose of study drug and continuing through four weeks 
following the final dose of study drug, the study subject will be assessed for any adverse events. 
8.1.4 Hearing Assessment 
During the Screening Period (window: ≤ 30 days of age) and at Study Month 4 (window: -10 to 
+30 days), Study Month 6 (window: -10 to +30 days), Study Month 12 (window: -10 to +30 
days), and Study Month 18 (window: -10 to +30 days), age-appropriate assessments of hearing 
will be performed.  Results of hearing assessments conducted for clinical care may be utilized if 
conducted within the study window. BSER and/or visual reinforcement audiometry (VRA) (to 
assess neuro-otologic status) and OAEs (DPOAE or TEOAE) will be obtained.  If the BSER 
and/or VRA is abnormal, then bone conduction will be obtained to distinguish between 
sensorineural hearing loss, conductive loss, or mixed loss.  If the OAEs are abnormal, then 
acoustic immittance measures (tympanometry and acoustic reflexes) will be obtained to better 
define the middle or inner ear abnormality (e.g., otitis media). 
 
If a study subject proceeds to cochlear implantation during the course of the study, he/she will 
not require additional study-related hearing assessments following the implantation procedure 
but will continue with all other study-related assessments.  Prior to the implantation, efforts will 
be made to obtain audiology testing that would have been performed at the Month 6 visit. 
 


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8.2 
Laboratory Evaluations 
Blood for study-specified laboratory evaluations may be obtained by methods such as the 
following:  venipuncture, heal stick, indwelling heparin- or saline-locked intravenous catheter, 
etc.  As detailed below, blood will be obtained for assessment of hematology safety labs, 
chemistry safety labs, and whole blood CMV virology studies.  If an insufficient volume of 
blood is obtained for all of the tests at any given study visit, the following prioritization as to 
which tests to send will apply (most important to least important):  1) hematology safety labs 
(most important); 2) chemistry safety labs (second most important); and 3) whole blood CMV 
virology studies (third most important).  With the exception of the hematology safety labs and 
ALT assessments, those lab tests which are unable to be obtained due to lack of sufficient blood 
or parental refusal at a given study visit will be noted but will not be reported as protocol 
deviations. 
 
If possible, urine collection by bagged or clean catch specimen will be attempted at designated 
study visits (Study Day 1, and Months 4, 5, and 6).  Inability to collect urine will be documented 
but not reported as a protocol deviation. Saliva will be collected using polyester fiber-tipped 
swabs at each of these designated study visits as well.  Specimens will be shipped to the UAB 
Central Laboratory for analysis. 
 
As far as possible safety labs and other research specimens should be taken to coincide with 
clinical care.  If it is not possible to obtain samples for safety labs at a study visit and bloods 
were obtained for clinical care within 2 days of the study visit, the data may be extracted from 
the medical records. 
8.2.1 Clinical Laboratory Evaluations 
The breakdowns of the amount of blood for individual tests are provided in Appendix B.  
Clinical laboratory results can be used for chemistry and hematology safety labs if collected for 
clinical care and within the required study window.  If labs drawn for the study required 
assessments are not evaluable, blood draws will not be repeated. 
8.2.1.1.  Hematology Safety Labs 
All hematology safety laboratory assessments will be conducted at the PI’s local lab.  These 
assessments will provide information on the safety of administering the study drug.  They will be 
obtained weekly for the first six weeks of study drug administration, then every other week for 
the next six weeks of study drug administration, and then at months 4 and 5.  The following will 
be tested:  white blood cell count, differential, hemoglobin, and platelet count. 
8.2.1.2.  Chemistry Safety Labs 
All chemistry safety laboratory assessments will be conducted at the PI’s local lab.  These 
assessments will provide information on the safety of administering the study drug.  They will be 
obtained every other week for the first 12 weeks (3 months) of treatment, and then at months 4, 
5, and 6.  The following will be tested:  ALT, direct bilirubin, and creatinine. 
 


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8.2.2 Special Assays or Procedures 
8.2.2.1 CMV Virologic Testing 
Assessment of CMV viral load by quantitative PCR will be conducted at the UAB Central 
Laboratory.  In study subjects with increasing whole blood viral loads during the course of 
treatment, assessment for antiviral resistance may be undertaken on the serially collected 
samples. 
 
Antiviral resistance will be performed in the UAB Viral Resistance Laboratory. 
8.2.3 Specimen Preparation, Handling, and Shipping 
8.2.3.1 Instructions for Specimen Preparation, Handling, and Storage 
Specific instructions on specimen collection, preparation, handling, and storage will be provided 
in the Manual of Procedures for this study. 
8.2.3.2 Specimen Shipment 
Specific instructions on specimen shipping will be provided in the Manual of Procedures for this 
study. 
 


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9 
ASSESSMENT OF SAFETY 
Regulatory requirements including the Food and Drug Administration (FDA) regulations, 
International Conference on Harmonisation (ICH) Guidelines for Good Clinical Practice (GCP), 
and European Union (EU) Clinical Trials Directive set forth safety monitoring and reporting 
responsibilities of sponsors and investigators to ensure the safety and protection of human 
subjects participating in clinical trials. 
9.1 
Specification of Safety Parameters 
An Adverse Event is any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of medicinal (investigational) 
product whether or not considered drug related. The occurrence of an AE may come to the 
attention of study personnel during study visits and interviews of a study recipient presenting for 
medical care, or upon review by a study monitor. 
 
Investigators participating in this clinical trial are responsible for and will: 
• Evaluate subject safety including assessment of adverse events (AEs) for seriousness, 
severity, and causality; 
• Notify the Central Unit, CROMS PVG, and EMMES of protocol-defined serious 
adverse events (SAEs) within 24 hours; (details provided in the MOP) 
• Provide detailed written reports, including necessary documentation requested by the  
sponsor or institutional review board (IRB)/independent ethics committee (IEC), 
promptly following immediate initial reports; and 
• Inform the IRB/IEC of AEs as required by applicable regulatory requirements. 
9.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters 
9.2.1 Adverse Events 
Information to be collected on reportable AEs includes event description, time of onset, 
clinician’s assessment of severity, relationship to study product (assessed only by those with the 
training and authority to make a diagnosis, which would include MD or DO), and time of 
resolution/stabilization of the event. All AEs occurring from Study Day 1 through four weeks 
following the last dose of study drug must be documented appropriately regardless of 
relationship. All AEs will be followed to adequate resolution. SAE reporting is described in 
section 9.2.2. 
 


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Any medical condition that is present at the time that the patient is randomized should be 
considered as a baseline condition and not reported as an AE. However, if the event meets the 
criteria in Section 9.2.1 and the grade of the event worsens at any time during the study, it should 
be recorded as an AE. 
 
The determination of seriousness, severity, and causality will be made by an on-site investigator 
who is qualified (licensed) to diagnose AE information, provide a medical evaluation of AEs, 
and classify AEs based upon medical judgment. This includes MD or DO.  Events will be 
identified by assessing the subject at each visit.  If a subject is hospitalized, the medical record 
should be reviewed to identify AEs.  The PI is responsible for identifying and reporting AEs 
according to protocol guidelines. 
 
Severity of Event:  All reportable AEs will be graded by the investigator according to the 
protocol toxicity tables (Appendix A) using a four-grade system (Table 2).  For safety laboratory 
results with an absolute number in the toxicity tables (e.g., hemoglobin), grading of the AEs will 
be according to the toxicity tables and not according to the local laboratory reference range.  For 
safety laboratory results with a reference to the Upper Limit Normal (ULN) in the toxicity tables 
(e.g., AST or SGOT), grading of the AEs will utilize the ULN of the local laboratory reference 
range in determining grading of the event per the toxicity tables. Grade 4 AEs will be only 
reported as SAE if the event meets one of the regulatory definitions of SAE described below 
(9.2.2) based on the study site physician judgment.  The functional table below should be used to 
grade the severity of an AE that is not specifically identified in the grading table.  In addition, all 
deaths related to an AE are to be classified as grade 5. 
 
Table 2. Four-grade system utilized for this trial (see also Appendix A) 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE-
THREATENING 
Clinical adverse 
event  NOT 
identified 
elsewhere in the 
grading table 
Mild symptoms 
causing no or 
minimal interference 
with usual social & 
functional activities 
with intervention not 
indicated 
Moderate symptoms 
causing greater than 
minimal interference 
with usual social & 
functional activities 
with intervention 
indicated 
Severe symptoms 
causing inability to 
perform usual social & 
functional activities with 
intervention or 
hospitalization indicated 
Potentially life-threatening 
symptoms causing inability to 
perform basic self-care 
functions with intervention 
indicated to prevent 
permanent impairment, 
persistent disability, or death 
 
The severity of the events will be mapped to a 3 Grade system for reporting events to the FDA, 
in accordance with CDISC standards.  The four-grade system allows direct comparisons to 
previous studies.  The investigators and the data coordinating center will develop the mapping 
algorithm to collapse the 4 grades that allow for comparison across studies down to the 3 grades 
needed to meet CDISC standards. 


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9.2.2 Serious Adverse Events 
Event seriousness will be determined according to the protocol definition of an SAE. 
 
An adverse event or suspected adverse reaction is considered “serious” (will be an SAE) if, in 
the view of either the investigator or sponsor, it results in any of the following outcomes:  
• Death, 
• a life-threatening adverse event*,  
• inpatient hospitalization or prolongation of existing hospitalization,  
• a persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions, or  
• a congenital anomaly/birth defect.   
• Important medical events that may not result in death, be life-threatening, or require 
hospitalizations may be considered serious when, based upon appropriate medical judgment 
they may jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.  Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
 
* Life-threatening adverse event. An adverse event is considered “life-threatening” if, in the 
view of either the investigator or sponsor, its occurrence places the patient or subject at 
immediate risk of death.  It does not include an adverse event that, had it occurred in a more 
severe form, might have caused death.  It does not necessarily include all grade 4 AEs according 
to the toxicity tables in Appendix A. 
 
Events related to cochlear implantation will be recorded on the CRF, but will not be considered 
an AE or SAE unless meeting one or more of the above outcomes. 
 
All SAEs will be: 
• recorded on the appropriate SAE eCRF 
• followed through resolution or stabilization by a study physician 
• reviewed and evaluated by a study physician 
 
Relationship to Study Products:  The physician’s assessment of an AE's relationship to 
valganciclovir study drug is part of the documentation process, but it is not a factor in 
determining what is or is not reported in the study.  If there is any doubt as to whether a clinical 
observation is an AE, the event should be reported. All AEs must have their relationship to study 
product assessed using the terms “related” or “not related,” and should be followed through 
resolution or stabilization. In a clinical trial, the study product must always be suspect.  
 
The investigator must provide an assessment of relationship of AEs to the study product based 
on: 


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• Temporal relationship of the event to the administration of study product; 
• Whether an alternative etiology has been identified; 
• Biological plausibility; and 
• Existing therapy, and/or concomitant medications.  
 
To help assess, the following guidelines are used: 
• Related– There is a reasonable possibility that the study product caused the adverse 
event. Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event. 
• Not Related– There is not a reasonable possibility that the administration of the study 
product caused the event. 
9.2.3 Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings 
If baseline clinical labs performed on Study Day 1 fall within Grade 1 abnormalities, then a 
laboratory AE is reported only if the value changes such that it falls into Grade 2 or higher at 
subsequent visits.  For laboratory results that are abnormal according to the local laboratory 
reference range but not considered a Grade 1 abnormality, these will not be recorded as AEs. 
 
Laboratory parameters other than those specified in sections 8.2.1.1 (hematology safety labs) and 
8.2.1.2 (chemistry safety labs) as part of the CBC and complete metabolic panel need to be 
evaluated by the site physician, recorded in the source document, and reported as laboratory AEs 
if clinically significant. 
9.3 
Reporting Procedures 
9.3.1 Serious Adverse Events 
When a site identifies any SAE that meets the protocol-defined serious criterion, a call will first 
be made to the Clinical Studies Administrator at the Central Unit.  Within 24 hours of 
identification, the SAE will be entered into the eCRF and the original signed SAE document will 


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be faxed to the Central Unit.  If a signature from the PI is not obtained within 24 hours, it will be 
faxed without the signature. 
 
 
Fax: 205-935-8559 to the attention of Central Unit Safety Coordinator. 
 
The Central Unit will report all serious adverse events to DMID pharmacovigilance contractor, at 
the following email address:  SAE Email address - PVG@dmidcroms.com. 
 
Should it be necessary for the Central Unit to contact the DMID Pharmacovigilance Group the 
following is contact information: 
 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS) 
6500 Rock Spring Dr., Suite 650 
Bethesda, MD 20817, USA 
SAE Hot Line: 1-800-537-9979 (US) or 1-301-897-1709 (outside US) 
SAE FAX Phone Number: 1-800-275-7619 (US) or 1-301-897-1710 (outside US) 
 
Other supporting documentation of the event may be requested by the DMID pharmacovigilance 
contractor and should be provided as soon as possible.  The DMID pharmacovigilance contractor 
will notify the DMID medical monitor and clinical protocol manager. The DMID medical 
monitor will review and assess the SAE for regulatory reporting and potential impact on study 
subject safety and protocol conduct. At any time after completion of the study, if the investigator 
becomes aware of an SAE that is suspected to be related to study product, the investigator will 
report the event to the DMID Pharmacovigilance Group. 
9.3.2 Regulatory Reporting for Studies Conducted Under DMID-Sponsored IND 
Following notification from the Central Unit, DMID, the IND sponsor, will report to FDA any 
suspected adverse reaction that is both serious and unexpected.  DMID will report an adverse 
event as a suspected adverse reaction only if there is evidence to suggest a causal relationship 
between the drug and the adverse event.  DMID will notify FDA and all participating 
investigators (i.e., all investigators to whom the sponsor is providing drug under its INDs or 
under any investigator’s IND) and the Central Unit in an IND safety report of potential serious 
risks from clinical trials or any other source, as soon as possible, but in no case later than 15 
calendar days after the sponsor determines that the information qualifies for reporting as 
specified in 21 CFR Part 312.32. DMID will also notify FDA of any unexpected fatal or life-
threatening suspected adverse reaction as soon as possible but in no case later than 7 calendar 
days after the sponsor’s initial receipt of the information.  Relevant follow-up information to an 
IND safety report will be submitted as soon as the information is available. Upon request from 


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FDA, DMID will submit to FDA any additional data or information that the agency deems 
necessary, as soon as possible, but in no case later than 15 calendar days after receiving the 
request.  
 
All serious events designated as “not related” to study product(s), will be reported by DMID to 
the FDA at least annually in a summary format.   
 
The Site Investigator is responsible for informing the Ethics Committee and/or IRB of the SAE 
as per local requirements.  For non-US sites, the site investigator is responsible for also 
informing their Regulatory Authority as required by their local regulations. 
9.3.3 Other Adverse Events (if applicable) 
In earlier investigations of ganciclovir and valganciclovir in infants, the side effect that was seen 
commonly was neutropenia.  Therefore, neutropenia occurring during the course of the treatment 
period of the study will be assumed to be associated with study medication.  The study site will 
notify the Statistical and Data Coordinating Center within 24 hours of identification of the 
following safety laboratory AEs: 
• Any absolute neutrophil count (ANC) < 500 cells/mm3 
• Any platelet count < 50,000/mm3 
• Any ALT value ≥ 5-times the baseline value 
9.4 
Type and Duration of Follow-up of Subjects after Adverse Events 
Document all AEs, including safety laboratory AEs, from Study Day 1 through four weeks 
following the last dose of study drug.  Document all SAEs from Study Day 1 through one month 
after completion of study medication. 
 
All AEs and SAEs will be followed until resolution, even if this extends beyond the study-
reporting period, which is 4 weeks following the last dose of study product. Resolution of an AE 
is defined as the return to pretreatment status or stabilization of the condition with the 
expectation that it will remain chronic.  
 
At any time after completion of the study, if the investigator becomes aware of an SAE that is 
suspected to be related to study product, the investigator will report the event. 
9.5 
Halting Rules 
9.5.1 Discontinuation of Study Participation for Individual Subject 
Subjects with neutropenia, thrombocytopenia, or hepatotoxicity while on study medication will 
be discontinued from study treatment if the criteria outlined in Section 6.3 (Modification or 


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Termination of Study Intervention/Investigational Product for a Participant) or in Section 5.3.3 
(Reasons for Withdrawal) are met.  Since the primary endpoint requires comparison of baseline 
and 6 month audiology assessments, dropouts and subjects with audiology assessments that are 
inadequate for study comparison will be replaced in order to reach the target of sample size. 
9.5.2 Discontinuation of Study Enrollment, and Study Treatment For All Subjects, 
Pending Sponsor Review 
Enrollment and study product administration will be halted for Safety Monitoring Committee 
(SMC) review/recommendation if any of the following is reported: 
• Two or more subjects experience a study product-related SAE. 
• 10% or more subjects (with a minimum of 3 subjects) experience the same severe 
(Grade 3 or higher) study product-related unsolicited AE. 
• 20% or more subjects (with a minimum of 3 subjects) experience the same severe 
(Grade 3 or higher) study product-related non-neutropenia safety laboratory AE. 
• 30% or more subjects (with a minumum of 3 subjects) experience severe (Grade 3 or 
higher) study product-related neutropenia safety laboratory AE. 
• 10% or more subjects (with a minimum of 3 subjects) permanently discontinue study 
treatment according to the criteria outlined in Section 6.3. 
Additionally, DMID and the Central Unit may interrupt study dosing and/or study entry at any 
time if medically indicated.  To minimize risk, the medical monitor and the SMC will review 
cumulative safety data.  If enrollment is halted based upon the study halting criteria above or the 
review of the safety data, upon completion of the review and receipt of advice of the SMC, 
DMID and the Central Unit Administration will determine if study entry or study dosing may 
continue according to the protocol. 
9.6 
Safety Oversight (SMC) 
Safety oversight will be conducted by an SMC that is an independent group of experts that 
monitors subject safety and advises DMID.  The SMC members will consist of persons 
independent of the investigators or study team with no financial, scientific, or other conflict of 
interest with the study, and will be selected by Sponsor (DMID).  The SMC will consist of 
members with appropriate expertise to contribute to the interpretation of the data from this trial.  
The SMC meetings will include the following: an organizational meeting; scheduled data 
reviews; ad hoc (for identified safety issues) meetings as needed; and the final meeting at the end 
of the study when the final clinical study report is available. 


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The initial responsibility of the SMC will be to review and make recommendations regarding the 
initiation of the study.  A simple majority will be considered a SMC quorum for voting and 
meeting purposes.  Members will be able to submit data review comments electronically if they 
are not able to participate in a data review meeting teleconference.  After the initiation of the 
study and during the course of the study, the SMC will convene at as follows:  when 20% of 
enrolled subjects have available safety data through 4 weeks following the last study product 
administration, and at least once annually thereafter.  A final SMC review meeting will take 
place 6 to 8 months after clinical database lock to review the cumulative unblinded safety and 
immunogenicity data for this trial.  The data will be provided in a standard summary format.  
The SMC may be asked to provide recommendations in response to questions posed by DMID. 
 
The SMC will operate under the rules of a DMID-approved charter that will be written at the 
organizational meeting of the SMC.  At this time, each data element that the SMC needs to 
assess will be clearly defined.  Procedures for SMC reviews/meetings will be defined in the 
charter.  The SMC will review applicable data to include, but not limited to, study progress and 
participant, clinical, and safety data.  Reports may include enrollment and demographic 
information, medical history, concomitant medications, physical assessments, clinical laboratory 
values, dosing compliance, and solicited and unsolicited AE/SAEs.  Additional data may be 
requested by the SMC, and interim statistical reports may be generated as deemed necessary and 
appropriate by DMID.  The SMC will meet and review these data at the intervals determined by 
the SMC charter, or ad hoc as needed during this trial.  As an outcome of each review/meeting, 
the SMC will make a recommendation as to the advisability of proceeding with study 
vaccinations (as applicable), and to continue, modify, or terminate this trial. 
 
Additionally, Statistical and Data Coordinating Center (SDCC) web reports using data entered 
into AdvantageEDC will be monitored to determine if any of the halting rules described in 
Section 9.5 (Halting Rules) are met. 
9.6.1 Independent Safety Monitor (ISM) 
For certain clinical trials, DMID will require an Independent Safety Monitor (ISM) to be 
assigned for each study site and the requirement for an ISM will be specified in the protocol. An 
ISM is a physician with relevant expertise whose primary responsibility is to provide to DMID 
an independent safety assessment in a timely fashion. Participation is for the duration of the 
DMID study and is a voluntary position that does not receive payment. The ISM must meet the 
requirements of the NIAID conflict of interest policy. 
 
For this clinical trial an ISM is not required.  However, at each participating site, upon 
DMID Medical Monitor request, the principal investigator (PI) will identify a physician with 


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relevant expertise, to act as a Secondary Medical Assessor (SMA). The SMA will examine a 
subject and/or medical records and provide a medical assessment (or second medical opinion) to 
the DMID of the safety event in question. The PI will send to the DMID MM, a summary of the 
event and include the PI and SMA assessments.   
Note: In the case that DMID has requested this type of evaluation multiple times, DMID may 
request the site(s) identify an ISM to assist DMID with safety oversight.   
 
 


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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, ICH/GCP, and regulatory guidelines, and that the study is 
conducted in accordance with the protocol and study manuals.  DMID, the sponsor of this study, 
or its designee will conduct site monitoring visits as detailed in the monitoring plan. 
 
Site visits will be made at standard intervals in accordance with the monitoring plan.  More 
frequent visits may be made if needed.  Monitoring visits will include, but are not limited to, 
review of informed consents, source documentation, hospital records, clinical and office charts, 
laboratory notes, memoranda, 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.  Data collection forms used as source documents will 
be derived from the eCRFs and be provided by the SDCC.  Study monitors will meet with 
investigators to discuss any problems and actions to be taken and document visit findings and 
discussions. 
 


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11 
STATISTICAL CONSIDERATIONS 
11.1 Study Hypotheses 
Given the benefit demonstrated from longer-term antiviral treatment of babies with symptomatic 
congenital CMV disease, and recognizing the fact that most of the disease burden of CMV-
associated hearing loss is in the asymptomatically infected population, we hypothesize that 
infants with asymptomatic congenital CMV infection who are treated with valganciclovir will 
have protection against hearing deterioration. 
11.2 Sample Size Considerations 
This is a Phase II, multi-center, single-stage, single-arm (open label) evaluation of 4 months of 
valganciclovir treatment for infants with virologically-confirmed congenital CMV infection who 
are asymptomatic at birth.  The study sample size is 176 male and female infants under 1 month 
of age with asymptomatic congenital CMV infection without baseline sensorineural hearing loss 
(SNHL) who are evaluable for the primary endpoint.  The goal of the study is to investigate the 
possible efficacy of valganciclovir therapy in asymptomatic infants congenitally infected with 
CMV for the prevention of SNHL.  All infants enrolled will be given valganciclovir per the 
protocol.  Since the hearing assessments will be based on specific measurements from brainstem 
auditory evoked response (BSER) evaluation of hearing, which yields objective data, there will 
not be bias in the measurement of hearing outcomes due to the open label design.  A 95% 
estimate of the upper bound for the true proportion of asymptomatic infants who will develop 
SNHL by the time they are 6 months of age will be calculated using the exact Clopper-Pearson 
method.  Table 3, below, displays the different sample size scenarios and the estimated upper 
bound if (1) none, (2) exactly 1, and (3) exactly 2 out of the total sample size develop SNHL.  
Given our sample size of 176 subjects, the 95% upper confidence bound for the true proportion 
who will develop SNHL within 6 months of birth is 1.69% and 2.67% if none or exactly 1, 
respectively, develops SNHL.  If these scenarios are observed, they will provide preliminary 
evidence that valganciclovir treatment of infants with asymptomatic congenital CMV infection 
may decrease the rate of SNHL based on the landmark study by Dahle et al. that estimates 3.18% 
of asymptomatic CMV infected infants develop SNHL by 6 months of age.10  Knowledge of 
these confidence bounds will allow us to estimate whether antiviral therapy in this population is 
likely to be of benefit.  If the 95% upper confidence bound is lower than the 3.18% estimate from 
Dahle et al., our data would suggest the possibility of treatment benefit.  Upon completion of the 
audiology analyses from the CHIMES study (which screened 100,000 neonates for 
asymptomatic congenital CMV infection at seven study sites in the United States from March 
2007 through November 2009 and then followed them for audiologic outcomes over the first 
several years of life41,42), we will compare our 95% upper confidence bound with the 
contemporaneous CHIMES estimates as well. 


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Table 3.  Sample Size and Upper Bound of Estimates of SNHL 
Sample 
Size 
95% Upper Bound 
Assuming No 
Subjects Develop 
SNHL 
95% Upper Bound 
Assuming One 
Subject Develops 
SNHL 
95% Upper Bound 
Assuming Two 
Subjects Develop 
SNHL 
80 
3.68% 
5.79% 
7.66% 
100 
2.95% 
4.66% 
6.16% 
150 
1.98% 
3.12% 
4.14% 
176 
1.69% 
2.67% 
3.50% 
 
Approximately 229 subjects with asymptomatic congenital CMV infection without SNHL will 
be identified and offered enrollment in order to meet the sample size requirements of 176 
evaluable subjects.  A recent NIDCD study designed to develop screening methodologies for 
detection of congenital CMV infection (the CHIMES Study, PI: S. Boppana, who is a co-
investigator in this trial) determined that 0.5% of neonates born in the United States have 
congenital CMV infection, although higher rates of 0.6% to 1.0% were seen in southern states.42  
Additionally, CHIMES data also suggest that 4.9% of neonates with asymptomatic congenital 
CMV infection will have baseline SNHL and 95.1% will have normal hearing at birth (S 
Boppana, personal communication).  Therefore, to detect 229 neonates with asymptomatic 
congenital CMV infection without baseline SNHL to offer enrollment in this trial, an anticipated 
48,250 babies will be screened for congenital CMV infection by buccal saliva swab PCR, the 
high sensitivity of which (97.4%) was recently reported by the CHIMES investigators.42  A 
screening informed consent form will be utilized for permission to conduct the screening test.  
Of these 48,250 infants, we anticipate that 241 (0.5%) will have asymptomatic congenital CMV 
infection.  This is a conservative estimate, since we have selected study sites that are in regions 
of the country where congenital CMV incidence rates are in the 0.6% to 1.0% range.  Babies 
screening positive for congenital CMV infection will have sensorineural hearing testing 
performed, as is standard of care for babies identified as being congenitally infected with CMV.  
A second saliva sample and a urine sample will be collected by study personnel (which will be 
covered by the screening informed consent) for confirmatory PCR testing.  The likelihood of a 
false-positive screening test is < 0.03%, but performing a confirmatory test ensures that only 
those babies truly infected with CMV will be exposed to valganciclovir.  We estimate that 12 
patients (4.9% of 241) will have baseline SNHL, and that 229 patients (95.1% of 241) will have 
normal hearing.  These approximately 229 asymptomatically infected neonates without 
sensorineural hearing loss will be assessed for all inclusion criteria, and offered enrollment on 
the treatment portion of the trial if they meet all inclusion criteria and no exclusion criteria.  The 
approximately 12 patients identified as being asymptomatically congenitally infected with CMV 
and with SNHL very likely will be treated clinically with 6 months of oral valganciclovir.25,34  If 


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they are treated, they will be offered enrollment into an observational substudy and all clinical 
audiologic and safety data will be redacted without alteration from the clinical medical record to 
the study case report forms.  For these 12 subjects, the only research laboratory samples that will 
be obtained are the whole blood and plasma specimens for viral load determination (see Footnote 
m in the Schedule of Events, Appendix B); viral loads would not be routinely followed as part of 
clinical management (and thus will be study procedures), whereas the valganciclovir treatment 
and associated safety labs as well as the serial hearing testing are part of clinical care for these 
patients.  Blood for CMV viral load will only be obtained at a given study visit if other blood is 
being obtained by venipuncture for clinical purposes.  Non-study clinical and laboratory 
assessments that are not performed according to the intervals and listings in Appendix B 
(Schedule of Events) will not be assessed as protocol deviations, nor will failure to obtain the 
virology specimen if a venipuncture is not performed as part of clinical care at a given study 
visit. 
 
With an expected 5% (11 of 229, leaving 218) identified as being congenitally infected but 
electing to not enroll in the treatment study, another 10% enrolling but failing to complete the 6 
month hearing evaluation (22 of 218, leaving 196), and a final 10% enrolling but with inadequate 
baseline or 6 month hearing data to adequately assess change over that time (20 of 196, leaving 
176), these 229 subjects will be sufficient to result in 176 subjects evaluable for the primary 
endpoint.  These estimates are based on the real-world experiences of the CASG study of longer-
term treatment in infants with symptomatic congenital CMV disease,25 and of the NIDCD 
CHIMES study (PI: S. Boppana, who is a co-investigator in this trial) that screened 100,000 
babies for congenital CMV infection and identified the methodology that will be employed in 
this study.42  Up to 20% over-enrollment will be allowed for operational reasons.  
11.3 Planned Interim Analyses (if applicable) 
There will be no interim analyses for efficacy for this study.  The demographics of the screened 
population may be assessed and presented prior to completion of the study. 
11.4 Final Analysis Plan 
11.4.1 Analysis Populations 
11.4.1.1 Intent to Treat Population 
Any child who receives at least one dose of study medication will be included in an intention to 
treat (ITT) analysis of safety. 


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11.4.1.2 Per Protocol Population 
Children who complete the full four months of study medication will be included in a per 
protocol (PP) analysis of efficacy. 
11.4.1.3 Safety Population 
The Safety Population will consist of all subjects who have received at least one dose of study 
product and for whom any data on safety are available. 
11.4.1.4 Screened Population 
The Screened Population will consist of all patients who signed the screening informed consent 
and for whom the saliva PCR for CMV DNA is available. 
11.4.2 Baseline Characteristics 
Baseline characteristics will be summarized.  For both continuous and categorical variables, 
appropriate summary statistics will be applied.  For continuous variables, descriptive statistics 
will include the number of non-missing values, mean, standard deviation, median, minimum, and 
maximum.  For categorical variables, descriptive statistics will include counts and percentages 
per category. 
11.4.3 Safety Analysis Plan 
Safety evaluations will be based on the incidence, severity, and type of AEs.  Safety variables 
will be tabulated and presented for all subjects in the safety population.  All tests will use a 5% 
significance level, i.e., p-values<0.05 will be considered significant, and for estimation a 95% 
confidence level will be used. 
11.4.4 Efficacy Analysis Plan 
Primary analysis:  
The primary analysis is estimating the proportion of subjects with asymptomatic congenital 
CMV infection who, following treatment with 4 months of oral valganciclovir, develop SNHL 
by 6 months of life in at least one ear.  Due to the small expected number of subjects who will 
develop SNHL by 6 months, the Clopper-Pearson method will be used to calculate an exact 95% 
upper confidence bound for the primary outcome.  
 
Secondary analyses:  


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For the proportion of subjects who develop SNHL at 4, 12, and 18 months post baseline, we will 
also use the Clopper-Pearson method to obtain an estimate of the 95% upper confidence bounds 
separately for each period.  In each of these hearing outcomes, we will provide a breakdown on 
the degree of worsening (mild, moderate, severe).  This method will also be used to define safety 
and tolerability of valganciclovir by estimating the incidence of adverse events of interest.  If 
there is enough information in the data collected, we will use a large-sample method for 
estimating the 95% confidence interval of interest over the more conservative Clopper-Pearson 
method. 
 
Analysis of actual viral load will be done using log base 10 transformation for both whole blood 
and plasma CMV viral loads.  Undetectable viral load value will be replaced by a value of 10.  
To investigate the change over time, we will model the log base 10 viral load using mixed model 
to accommodate repeated measures.  The covariance structure (selected among unstructured, 
exchangeable, autoregressive, exponential, and toeplitz) that best describes the correlation 
among the repeated measures over time will be selected using the AIC model selection index.  
Note that there will be 13 time points for which viral load will be measured.  Hence, if time will 
be represented as discrete variables in the model, this will require spending 12 degrees of 
freedom in the model, which we believe is unnecessary.  In our modeling we will represent time 
as a continuous variable and will consider fitting linear, quadratic, and cubic to approximate non-
linear trends.  The simplest model with a good fit based on the test of the coefficients, as well as 
the profile curves, will be selected.  Modeling will be done separately for whole blood and 
plasma viral loads. 
 
The same method of modeling will be employed to compare the whole blood and plasma CMV 
viral loads.  However, the outcome will be the difference between the whole blood and plasma 
CMV viral load values for each subject at each time point.  If the differences over time are found 
to be modeled by a linear function and there is no evidence to show that the slope of this line is 
significantly different from zero, then there is no evidence to conclude a difference between the 
average viral loads based on whole blood and plasma.  Otherwise, there is a difference and this 
difference will be examined and discussed in more details based on the results of the fitted 
model. 
 
We will investigate the how viral load is related to hearing outcomes using generalized linear 
model for binary outcome at each time point relative to baseline hearing. 
 
All tests will use a 5% significance level, i.e., p-values<0.05 will be considered significant. 
 
Ganciclovir resistance will be assessed by molecular methodologies (e.g., deep sequencing, 
Sanger sequencing, PCR).  Blood, urine, and saliva specimens will be obtained serially. 


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11.4.5 Missing Values and Outliers 
Missing safety and/or hearing outcome data will not be imputed.  No search for outliers will be 
performed. 
 


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12 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported. 
Data reported in the eCRF derived from the data collection forms should be consistent with the 
source documents or the discrepancies should be explained. 
 
Each site will permit authorized representatives of the DMID, its designees, and appropriate 
regulatory agencies to examine (and when required by applicable law, to copy) clinical records 
for the purposes of quality assurance reviews, audits, monitoring, and evaluation of the study 
safety and progress.  These representatives will be permitted access to all source data, which 
include, but are not limited to, review of informed consents, hospital records, clinical and office 
charts, laboratory notes, memoranda, 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. Data collection forms used as source 
documents will be derived from the eCRFs and be provided by the SDCC. 
 


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13 
QUALITY CONTROL AND QUALITY ASSURANCE 
Each study site will have a quality management plan.  Following a written DMID-accepted site 
quality management plan, the investigational site is responsible for conducting routine quality 
assurance and quality control activities to internally monitor study progress and protocol 
compliance.  The PI will provide direct access to all trial-related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local 
and regulatory authorities.  The PI will ensure all study personnel are appropriately trained and 
applicable documentation is maintained on site. 
DMID-designated clinical monitors will verify that the clinical trial is conducted and data are 
generated, documented (recorded), and reported in compliance with the protocol, ICH/GCP 
guidelines, and the applicable regulatory requirements.  Clinical monitoring reports will be 
submitted to DMID. 
 
The SDCC will implement quality control procedures beginning with the data entry system and 
generate data quality control checks that will be run on the database.  Any missing data or data 
anomalies will be communicated to the site(s) for clarification and resolution. 
 


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14 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
14.1 Ethical Standard 
This trial will be conducted in compliance with the protocol, International Conference on 
Harmonization Good Clinical Practice E6 (ICH-GCP), and the applicable regulatory 
requirements, including: 
• U.S. Code of Federal Regulations applicable to clinical studies (45 CFR 46 and 21 CFR 
including parts 50 and 56 concerning informed consent and IRB regulations, if under IND, 
21 CFR 312). 
• Completion of Human Subjects Protection Training.  
 
The investigator will ensure that this study is conducted in full conformity with the principles set 
forth in The Belmont Report: Ethical Principles and Guidelines for the Protection of Human 
Subjects of Research of the US National Commission for the Protection of Human Subjects of 
Biomedical and Behavioral Research (April 18, 1979) and codified in 45 CFR Part 46, 21 CFR 
50 and 56, 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, institutions are required to hold a current US Federalwide 
Assurance (FWA) issued by OHRP. 
 
This protocol, informed consent documents, relevant supporting information, and all types of 
volunteer recruitment or advertisement information will be submitted to the site’s Institutional 
Review Board (IRB) for review and must be approved before the study is initiated.  The 
responsible official for the IRB will sign the IRB letter of approval of the protocol prior to the 
start of this trial and a copy will be provided to DMID.  The IRB FWA number will be provided 
to DMID.  Should amendments to the protocol be required, the amendments will be written by 
the sponsor and provided to the site principal investigator for submission to the IRB. 
 
The investigator is responsible for keeping the IRB apprised of the progress of the study and of 
any changes made to the protocol as deemed appropriate, but in any case at least once per year.  
The investigator must also keep the IRB informed of any significant AEs. 
All IRB approved documents as well as relevant study correspondence should be copied and sent 
to the UAB Central Unit. 
14.3 Informed Consent Process 
All subjects must sign an informed consent form that complies with the requirements of both 21 
CFR 50 and 45 CFR 46.  This study will utilize three consent forms:  for the ~ 229 subjects 
without SNHL, one for the screening portion of the study and one for the interventional portion 
of the study; and for the ~ 12 patients with SNHL, one for the screening portion of the study 
(identical to that used for the ~ 229 study subjects) and one for the observational portion of the 


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study.  A signed informed consent document will be obtained from each study participant’s 
parent/legal guardian prior to entry into each of the portions of this study, and prior to 
conducting any study procedures. 
 
Prior to participation in the trial, subjects will receive a comprehensive explanation of the 
proposed product, including the nature and risks of the trial, alternate therapies, any known AEs, 
the investigational status of the components, and the other elements that are part of obtaining 
proper informed consent.  Subjects will also receive a detailed explanation of the proposed use 
and disclosure of their protected health information, including specifically their blood samples.   
DMID will provide the investigator, in writing, any new information that significantly affects 
risk related to a subject’s receipt of the investigational product.  This new information will be 
communicated by the investigator to subjects who consent to participate in the trial in accordance 
with IRB requirements.  The informed consent document will be updated and subjects will be re-
consented, if necessary. 
 
Site staff may utilize IRB-approved recruitment methods prior to the subject consenting; 
however, before any protocol-specific procedures are performed to determine protocol eligibility 
an informed consent form must be signed.  Subjects will be given a copy of all consent forms 
that they sign. 
 
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 study 
participant/study participant’s parent/legal guardian before participation in the study.  A copy of 
the signed consent form must be provided to the study participant/study participant’s parent/legal 
guardian.  Signed consent forms must remain in each study participants study file and must be 
available for verification by study monitors. 
 
An investigator shall seek such consent only under circumstances that provide the prospective 
subject or the representative 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 or the representative shall be in language understandable to the subject or the 
representative. 
 
Subject’s parent/legal guardian will sign the informed consent document prior to any procedures 
being done specifically for the study.  Subjects/subject’s parent/legal guardian should have the 
opportunity to discuss the study with their family, friends or personal physician, or think about it 
prior to agreeing to participate.  Subjects/subject’s parent/legal guardian may withdraw consent 
at any time throughout the course of the trial.  A copy of the signed informed consent document 
will be given to the subjects /subject’s parent/legal guardian 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. 
 


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14.4 Exclusion of Women, Minorities, and Children (Special Populations) 
This pediatric study will not exclude young children, females, or minorities.  This study will be 
inclusive of all children who meet the inclusion/exclusion criteria, regardless of religion, gender, 
or ethnic background. 
14.5 Subject Confidentiality 
This research is covered by a Certificate of Confidentiality from the NIH.  Subject 
confidentiality is strictly held in trust by the participating investigators, their staff, and the 
sponsor(s) and their agents.  This confidentiality includes documentation, investigation data, 
subject’s clinical information, and all other information generated during participation in the 
study. The investigators and their staff may not disclose or use information documents, or 
biospecimens that may identify the subjects in any federal, state, or local civil, criminal, 
administrative, legislative or other action, or be used as evidence unless the subject has 
consented. This does not apply to requests for information from the NIH or its representatives 
that are needed to monitor or audit the study, or for information that must be disclosed in order to 
meet FDA requirements. 
 
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 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 and 
forwarded to Genentech Inc. 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 NIAID/DMID, Genentech Inc., and the UAB 
Central Unit may use information obtained during the conduct of this study in connection with 
the development of the study drug.   
 
The study investigator is obliged to provide the Sponsor (DMID/NIAID) and the SDCC with 
complete test results and all data developed in this study.  The Sponsor may disclose this 
information to appropriate regulatory authorities 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 Sponsor, UAB Central Unit, and/or 
the IRB/IEC for each study site. 


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Every effort will be made to maintain the anonymity and confidentiality of subjects during this 
study.  Only people who are involved in the conduct, oversight, monitoring, or auditing of this 
study will be allowed access to the PHI that is collected.  Any publications from this study will 
not use information that will identify subjects by name.  Organizations that may inspect and/or 
copy research records maintained at the participating CASG sites for quality assurance and data 
analysis include groups such as National Institute of Allergy and Infectious Diseases (NIAID) 
and their authorized representatives, the Food and Drug Administration (FDA), and the study’s 
pharmaceutical collaborator Genentech, Inc. (which would only occur with the consent of NIAID 
as the holder of the IND for the study). 
14.6 Study Discontinuation 
If the study is discontinued, enrolled subjects will continue to be followed for safety assessments.  
No further study product will be administered. 
14.7 Future Use of Stored Specimens 
Some of the specimens obtained from study participants during this study will be stored 
indefinitely in the Molecular Diagnostic Laboratory at the University of Alabama at Birmingham 
and may be used in future infectious disease research.  These specimens will be labeled with a 
code number and not with the study participant’s name.  Samples will not be used for human 
genetic testing.  Samples may be shared with other investigators at other institutions.  The 
samples will not be sold for production of any commercial product. 
 
There are no benefits to subjects in the collection, storage, and subsequent research use of 
specimens.  Reports about future research done with a subject’s samples will not be kept in their 
health records.  At the time of consent for study participation, study participant’s parent/legal 
guardian will have the opportunity either to agree to have their specimens used in future 
infectious disease research or to have their samples destoyed at the end of the study.  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.  A subject’s 
parent/legal guardian’s decision can be changed at any time up to the point the specimens are 
released for research use by notifying the study doctors or nurses in writing.  However, if a 
subject consents to future use and some of their blood has already been used for research 
purposes, the information from that research may still be used. 
 


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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. 
 
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 infectious disease 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.  All source documents should be completed in a neat, legible manner to ensure 
accurate interpretation of data.  Blue or black ink is required to ensure clarity of reproduced 
copies.  When making changes or corrections, 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. 
 
Copies of the electronic CRF (eCRF) will be provided for use as source documents and 
maintained for recording data for each subject enrolled in the study.  Data reported in the eCRF 
derived from source documents should be consistent with the source documents or the 
discrepancies should be explained.  DMID and/or it designee will provide guidance to 
investigators on making corrections to the source documents and eCRF. 
 
15.1 Data Management Responsibilities 
All source documents and laboratory reports must be reviewed by the clinical team and data 
entry staff, who will ensure that they are accurate and complete.  Adverse events must be graded, 
assessed for severity and causality, and reviewed by the site PI 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 Emmes Corporation will serve as the Statistical and Data Coordinating Center for this study 
and will be responsible for data management, quality review, analysis, and reporting of the study 
data. 
15.2 Data Capture Methods 
Clinical data (including AEs, concomitant medications, and reactogenicity data) and clinical 
laboratory data will be entered into a 21 CFR Part 11-compliant Internet Data Entry System 
(IDES) provided by The Emmes Corporation.  The data system includes password protection and 
internal quality checks, such as automatic range checks, to identify data that appear inconsistent, 
incomplete, or inaccurate.  Clinical data will be entered directly from the source documents. 
15.3 Types of Data 
Data for this study will include safety, virologic, clinical laboratory, audiologic, and outcome 
measures. 


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15.4 Timing/Reports 
Safety data will be reviewed by the SMC per the SMC charter for this study.  Interim statistical 
reports may be generated as deemed necessary and appropriate by DMID.  Safety data may be 
shared with Roche/Genentech as needed to permit required regulatory updates. 
15.5 Study Records Retention 
Each participating 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. 
 
Records and documents pertaining to the conduct of this study, including CRFs, data collection 
forms, other source documents, consent forms, laboratory test results, and medication inventory 
records, must be retained by the investigator for at least 2 years after a marketing application is 
approved for the drug for the indication for which it is being investigated; or if no application is 
to be filed or if an application is not approved for the drug, until 2 years after the investigation is 
discontinued and FDA has been notified.  These documents should be retained for a longer 
period, however, if required by local regulations.  No study records will be destroyed without 
prior authorization from the sponsor, DMID.  Informed consent forms for future use will be 
maintained as long as the samples exist.  It is the responsibility of the sponsor to inform the 
investigator when these documents no longer need to be retained. 
15.6 Protocol Deviations 
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 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 GCP: 
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 5 working days of identification of the protocol deviation, or within 5 working days of the 
scheduled protocol-required activity.  However, if the deviation increases study subject risk, the 
reporting timeline is expedited, requiring submission of deviation within 1 working day of 
identification.  All deviations must be promptly reported via The Emmes Corporation’s IDES.  
All deviations from the protocol must be addressed in study subject source documents.  A 
completed copy of the DMID Protocol Deviation Form (IDES form) must be maintained in the 
regulatory file, as well as in the subject’s source document.  Protocol deviations must be sent to 


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the local IRB/IEC per their 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. 
It is the responsibility of DMID to register this trial in an acceptable registry.  Any clinical trial 
starting enrollment after 01 July 2005 must be registered on or before patient enrollment.  For 
trials that began enrollment prior to this date, the ICMJE member journals will require 
registration by 13 September 2005, before considering the results of the trial for publication. 
The ICMJE defines a clinical trial as any research project that prospectively assigns human 
subjects to intervention or comparison groups to study the cause-and-effect relationship between 
a medical intervention and a health outcome.  Studies designed for other purposes, such as to 
study pharmacokinetics or major toxicity (e.g., Phase I trials), would be exempt from this policy. 
 


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17 
LITERATURE REFERENCES 
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3. 
Fowler KB, Dahle AJ, Boppana SB, Pass RF. Newborn hearing screening: will children 
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4. 
Fowler KB, Boppana SB. Congenital cytomegalovirus (CMV) infection and hearing 
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Elek SD, Stern H. Development of a vaccine against mental retardation caused by 
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Dollard SC, Grosse SD, Ross DS. New estimates of the prevalence of neurological and 
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Manicklal S, Emery VC, Lazzarotto T, Boppana SB, Gupta RK. The "silent" global 
burden of congenital cytomegalovirus. Clin Microbiol Rev. 2013;26:86-102. 
9. 
Williamson WD, Desmond MM, LaFevers N, Taber LH, Catlin FI, Weaver TG. 
Symptomatic congenital cytomegalovirus. Disorders of language, learning, and hearing. 
American Journal of Diseases of Children. 1982;136:902-5. 
10. 
Dahle AJ, Fowler KB, Wright JD, Boppana SB, Britt WJ, Pass RF. Longitudinal 
investigation of hearing disorders in children with congenital cytomegalovirus. Journal of 
the American Academy of Audiology. 2000;11:283-90. 
11. 
Boppana SB, Ross SA, Fowler KB. Congenital cytomegalovirus infection: clinical 
outcome. Clin Infect Dis. 2013;57 Suppl 4:S178-81. 
12. 
Centers for Disease Control and Prevention. U.S. public health impact of congenital 
cytomegalovirus infection. MMWR - CDC Surveillance Summaries. 1992;41:35-39. 
13. 
Grosse SD, Ross DS, Dollard SC. Congenital cytomegalovirus (CMV) infection as a 
cause of permanent bilateral hearing loss: a quantitative assessment. J Clin Virol. 
2008;41:57-62. 
14. 
Yow MD, Demmler GJ. Congenital cytomegalovirus disease--20 years is long enough. 
New England Journal of Medicine. 1992;326:702-3. 
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Arvin AM, Fast P, Myers M, Plotkin S, Rabinovich R. Vaccine development to prevent 
cytomegalovirus disease: report from the National Vaccine Advisory Committee. Clinical 
Infectious Diseases. 2004;39:233-9. 
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United States Department of Labor. Bureau of Labor Statistics CPI Inflation Calculator. 
http://www.bls.gov/data/inflation_calculator.htm. April 29, 2015 
17. 
Cannon MJ, Griffiths PD, Aston V, Rawlinson WD. Universal newborn screening for 
congenital CMV infection: what is the evidence of potential benefit? Rev Med Virol. 
2014;24:291-307. doi: 10.1002/rmv.1790. Epub 2014 Apr 24. 


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18. 
Whitley RJ, Cloud G, Gruber W, Storch GA, Demmler GJ, Jacobs RF, Dankner W, 
Spector SA, Starr S, Pass RF, Stagno S, Britt WJ, Alford C, Jr., Soong S, Zhou XJ, 
Sherrill L, FitzGerald JM, Sommadossi JP, for the National Institute of Allergy and 
Infectious Diseases Collaborative Antiviral Study Group. Ganciclovir treatment of 
symptomatic congenital cytomegalovirus infection: results of a phase II study. Journal of 
Infectious Diseases. 1997;175:1080-6. 
19. 
Trang JM, Kidd L, Gruber W, Storch G, Demmler G, Jacobs R, Dankner W, Starr S, Pass 
R, Stagno S, Alford C, Soong SJ, Whitley RJ, Sommadossi JP, for the National Institute 
of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Linear single-
dose pharmacokinetics of ganciclovir in newborns with congenital cytomegalovirus 
infections. Clinical Pharmacology & Therapeutics. 1993;53:15-21. 
20. 
Zhou XJ, Gruber W, Demmler G, Jacobs R, Reuman P, Adler S, Shelton M, Pass R, Britt 
B, Trang JM, Whitley RJ, Sommadossi JP, for the NIAID Collaborative Antiviral Study 
Group. Population pharmacokinetics of ganciclovir in newborns with congenital 
cytomegalovirus infections. Antimicrobial Agents & Chemotherapy. 1996;40:2202-5. 
21. 
Kimberlin DW, Lin CY, Sanchez PJ, Demmler GJ, Dankner W, Shelton M, Jacobs RF, 
Vaudry W, Pass RF, Kiell JM, Soong SJ, Whitley RJ, for the National Institute of Allergy 
Infectious Diseases Collaborative Antiviral Study Group. Effect of ganciclovir therapy on 
hearing in symptomatic congenital cytomegalovirus disease involving the central nervous 
system: a randomized, controlled trial. Journal of Pediatrics. 2003;143:16-25. 
22. 
Oliver SE, Cloud GA, Sanchez PJ, Demmler GJ, Dankner W, Shelton M, Jacobs RF, 
Vaudry W, Pass RF, Soong SJ, Whitley RJ, Kimberlin DW, for the National Institute of 
Allergy and Infectious Diseases Collaborative Antiviral Study Group. 
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. 
Kimberlin DW, Acosta EP, Sanchez PJ, Sood S, Agrawal V, Homans J, Jacobs RF, Lang 
D, Romero JR, Griffin J, Cloud GA, Lakeman FD, Whitley RJ. Pharmacokinetic and 
pharmacodynamic assessment of oral valganciclovir in the treatment of symptomatic 
congenital cytomegalovirus disease. J Infect Dis. 2008;197:836-45. 
24. 
Trang JM, Kidd L, Gruber W, Storch G, Demmler G, Jacobs R, Dankner W, Starr S, Pass 
R, Stagno S, Alford C, Soong SJ, Whitley RJ, Sommadossi JP, the National Institute of 
Allergy and Infectious Diseases Collaborative Antiviral Study Group. Linear single-dose 
pharmacokinetics of ganciclovir in newborns with congenital cytomegalovirus infections. 
Clinical Pharmacology & Therapeutics. 1993;53:15-21. 
25. 
Kimberlin DW, Jester PM, Sanchez PJ, Ahmed A, Arav-Boger R, Michaels MG, Ashouri 
N, Englund JA, Estrada B, Jacobs RF, Romero JR, Sood SK, Whitworth MS, Abzug MJ, 
Caserta MT, Fowler S, Lujan-Zilbermann J, Storch GA, DeBiasi RL, Han JY, Palmer A, 
Weiner LB, Bocchini JA, Dennehy PH, Finn A, Griffiths PD, Luck S, Gutierrez K, 
Halasa N, Homans J, Shane AL, Sharland M, Simonsen K, Vanchiere JA, Woods CR, 
Sabo DL, Aban I, Kuo H, James SH, Prichard MN, Griffin J, Giles D, Acosta EP, 
Whitley RJ. Valganciclovir for symptomatic congenital cytomegalovirus disease. N Engl 
J Med. 2015;372:933-43. doi: 10.1056/NEJMoa1404599. 
26. 
Williamson WD, Demmler GJ, Percy AK, Catlin FI. Progressive hearing loss in infants 
with asymptomatic congenital cytomegalovirus infection. Pediatrics. 1992;90:862-6. 


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27. 
Stagno S, Reynolds DW, Tsiantos A, Fuccillo DA, Long W, Alford CA. Comparative 
serial virologic and serologic studies of symptomatic and subclinical congenitally and 
natally acquired cytomegalovirus infections. Journal of Infectious Diseases. 
1975;132:568-77. 
28. 
Walter S, Atkinson C, Sharland M, Rice P, Raglan E, Emery VC, Griffiths PD. 
Congenital cytomegalovirus: association between dried blood spot viral load and hearing 
loss. Arch Dis Child Fetal Neonatal Ed. 2008;93:F280-5. 
29. 
Lanari M, Lazzarotto T, Venturi V, Papa I, Gabrielli L, Guerra B, Landini MP, Faldella 
G. Neonatal cytomegalovirus blood load and risk of sequelae in symptomatic and 
asymptomatic congenitally infected newborns. Pediatrics. 2006;117:e76-83. 
30. 
Boppana SB, Fowler KB, Pass RF, Rivera LB, Bradford RD, Lakeman FD, Britt WJ. 
Congenital cytomegalovirus infection: association between virus burden in infancy and 
hearing loss. Journal of pediatrics. 2005;146:817-823. 
31. 
Ross SA, Novak Z, Fowler KB, Arora N, Britt WJ, Boppana SB. Cytomegalovirus blood 
viral load and hearing loss in young children with congenital infection. Pediatr Infect Dis 
J. 2009;28:588-92. 
32. 
Forner G, Abate D, Mengoli C, Palu G, Gussetti N. High Cytomegalovirus (CMV) 
DNAemia Predicts CMV Sequelae in Asymptomatic Congenitally Infected Newborns 
Born to Women With Primary Infection During Pregnancy. J Infect Dis. 2015;212:67-71. 
doi: 10.1093/infdis/jiu627. Epub 2014 Nov 11. 
33. 
Valganciclovir Package Insert. 
http://www.gene.com/download/pdf/valcyte_prescribing.pdf. May 1, 2015 
34. 
American Academy of Pediatrics. Cytomegalovirus infection. In: Kimberlin DW, Brady 
MT, Jackson MA, Long SS, eds. Red Book: 2015 Report of the Committee on Infectious 
Diseases. 30th ed. Elk Grove Village, IL: American Academy of Pediatrics, 2015:317-
322. 
35. 
Roche Ltd. Investigator's Brochure, 16th Version, June 2014 RO1079070. 2014. 
36. 
Rawlinson WD, Boppana SB, Fowler KB, Kimberlin DW, Lazzarotto T, Alain S, Daly 
K, Doutre S, Gibson L, Giles ML, Greenlee J, Hamilton ST, Harrison GJ, Hui L, Jones 
CA, Palasanthiran P, Schleiss MR, Shand AW, van Zuylen WJ. Congenital 
cytomegalovirus infection in pregnancy and the neonate: consensus recommendations for 
prevention, diagnosis, and therapy. Lancet Infect Dis. 2017;10:30143-3. 
37. 
Bess FH, Paradise JL. Universal screening for infant hearing impairment: not simple, not 
risk-free, not necessarily beneficial, and not presently justified. Pediatrics. 1994;93:330-
4. 
38. 
Erenberg A, Lemons J, Sia C, Trunkel D, Ziring P. Newborn and infant hearing loss: 
detection and intervention.American Academy of Pediatrics. Task Force on Newborn and 
Infant Hearing, 1998- 1999. Pediatrics. 1999;103:527-30. 
39. 
Acosta EP, Brundage RC, King JR, Sanchez PJ, Sood S, Agrawal V, Homans J, Jacobs 
RF, Lang D, Romero JR, Griffin J, Cloud G, Whitley R, Kimberlin DW. Ganciclovir 
population pharmacokinetics in neonates following intravenous administration of 
ganciclovir and oral administration of a liquid valganciclovir formulation. Clinical 
Pharmacology & Therapeutics. 2007;81:867-72. 
40. 
NIAID Division of AIDS. DAIDS Toxicity Tables. http://rsc.tech-res.com/clinical-
research-sites/safety-reporting/daids-grading-tables. January 24, 2017 


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41. 
Boppana SB, Ross SA, Novak Z, Shimamura M, Tolan RW, Jr., Palmer AL, Ahmed A, 
Michaels MG, Sanchez PJ, Bernstein DI, Britt WJ, Fowler KB. Dried blood spot real-
time polymerase chain reaction assays to screen newborns for congenital 
cytomegalovirus infection. Jama. 2010;303:1375-82. 
42. 
Boppana SB, Ross SA, Shimamura M, Palmer AL, Ahmed A, Michaels MG, Sanchez PJ, 
Bernstein DI, Tolan RW, Jr., Novak Z, Chowdhury N, Britt WJ, Fowler KB. Saliva 
polymerase-chain-reaction assay for cytomegalovirus screening in newborns. N Engl J 
Med. 2011;364:2111-8. 
 
 
 


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18 
APPENDIX A: (ADAPTED FROM) DIVISION OF AIDS 
TOXICITY TABLES 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Petechiae 
Localized to one 
area 
Localized to more 
than one area 
Generalized 
NA 
Diarrhea 
≥ 1 year of age 
Transient or 
intermittent episodes 
of unformed stools 
OR Increase of ≤ 3 
stools over baseline 
per 24-hour period 
Persistent episodes of 
unformed to watery 
stools OR Increase of 
4 to  6 stools over 
baseline per 24-hour 
period 
Increase of ≥ 7 stools 
per 24-hour period 
OR IV fluid 
replacement indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
< 1 year of age 
Liquid stools (more 
unformed than usual) 
but usual number of 
stools 
Liquid stools with 
increased number of 
stools OR Mild 
dehydration 
Liquid stools with 
moderate dehydration 
Life-threatening 
consequences (e.g., liquid 
stools resulting in severe 
dehydration, hypotensive 
shock) 
Vomiting 
Transient or 
intermittent AND No 
or minimal 
interference with oral 
intake 
Frequent episodes 
with no or mild 
dehydration 
Persistent vomiting 
resulting in orthostatic 
hypotension OR 
Aggressive 
rehydration indicated 
(e.g., IV fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Fever (non-axillary 
temperatures only) 
38.0 to < 38.6°C or 
100.4 to < 101.5°F 
≥ 38.6  to < 39.3°C 
or ≥ 101.5 to < 102.7°F
≥ 39.3 to < 40.0°C or ≥ 
102.7 to < 104.0°F 
≥ 40.0°C or ≥ 104.0°F 
Seizures 
New Onset Seizure 
< 18 years of age 
(includes new or pre- 
existing febrile 
seizures) 
Seizure lasting < 5 
minutes with < 24 
hours postictal state 
Seizure lasting 5 to < 
20 minutes with 
< 24 hours postictal 
state 
Seizure lasting ≥ 20 
minutes OR > 24 
hours postictal state 
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR Difficult 
to control (e.g., 
refractory epilepsy) 


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PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
A Pre-existing Seizure 
NA 
Increased frequency 
from previous level 
of control without 
change in seizure 
character 
Change in seizure 
character either in 
duration or quality 
(e.g., severity or 
focality) 
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR Difficult 
to control (e.g., 
refractory epilepsy) 
Acute Allergic 
Reaction 
Localized urticaria 
(wheals) with no 
medical 
intervention 
indicated 
Localized urticaria 
with intervention 
indicated OR Mild 
angioedema with no 
intervention indicated 
Generalized urticaria 
OR Angioedema with 
intervention indicated 
OR Symptoms of 
mild bronchospasm 
Acute anaphylaxis OR 
Life-threatening 
bronchospasm OR 
Laryngeal edema 
ALT or SGPT, High 
Report only one 
1.25  to < 2.5 
x ULN 
2.5 to < 5.0 x ULN 
5.0  to < 10.0 x ULN 
≥ 10.0 x ULN 
AST or SGOT, High 
Report only one 
1.25  to < 2.5 
x ULN 
2.5  to < 5.0 x ULN 
5.0  to < 10.0 x ULN 
≥ 10.0 x ULN 
Bilirubin 
Direct Bilirubin, 
High 
> 28 days of age 
NA 
NA 
> ULN 
> ULN with life- 
threatening 
consequences (e.g., signs 
and symptoms of liver 
failure) 
≤ 28 days of age 
ULN to ≤ 1 mg/dL 
> 1 to ≤ 1.5 mg/dL 
> 1.5 to ≤ 2 mg/dL 
> 2 mg/dL 
Total Bilirubin, High 
> 28 days of age 
1.1 to < 1.6 x ULN 
1.6 to < 2.6 x ULN 
2.6 to < 5.0 x ULN 
≥  5.0 x ULN 
≤ 28 days of age 
See Appendix A. 
Total Bilirubin for 
Term and Preterm 
Neonates 
See Appendix A. 
Total Bilirubin for 
Term and Preterm 
Neonates 
See Appendix A. 
Total Bilirubin for 
Term and Preterm 
Neonates 
See Appendix A. Total 
Bilirubin for Term and 
Preterm Neonates 
Creatinine, High 
1.1 to 1.3 x ULN 
> 1.3 to 1.8 x ULN 
OR Increase of 
> 0.3 mg/dL above 
baseline 
> 1.8  to < 3.5 
x ULN OR Increase 
of 1.5 to < 2.0 x 
above baseline 
≥ 3.5 x ULN OR 
Increase of ≥ 2.0 x above 
baseline 
Absolute Neutrophil 
Count (ANC), Low 
(cells/mm3; cells/L) 
> 7 days of age 
800 to 1,000 
0.800 x 109 to 1.000 
x 109 
600 to 799 
0.600 x 109 to 0.799 x 
109 
400 to 599 
0.400 x 109 to 0.599 x 
109 
< 400 
< 0.400 x 109 


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PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
2 to 7 days of age 
1,250 to 1,500 
1.250 x 109 to 1.500 
x 109 
1,000 to 1,249 
1.000 x 109 to 1.249 x 
109 
750 to 999 
0.750 x 109 to 0.999 x 
109 
< 750 
< 0.750 x 109 
≤ 1 day of age 
4,000 to 5,000 
4.000 x 109 to 
5.000 x 109 
3,000 to 3,999 
3.000 x 109 to 3.999 x 
109 
1,500 to 2,999 
1.500 x 109 to 2.999 x 
109 
< 1,500 
< 1.500 x 109 
Hemoglobin, Low 
(g/dL; mmol/L) 
≥ 13 years of age 
(male only) 
10.0 to 10.9 
6.19 to 6.76 
9.0 to < 10.0 
5.57 to < 6.19 
7.0 to < 9.0 
4.34 to < 5.57 
< 7.0 
< 4.34 
≥ 13 years of age 
(female only) 
9.5 to 10.4 
5.88 to 6.48 
8.5 to < 9.5 
5.25 to < 5.88 
6.5 to < 8.5 
4.03 to < 5.25 
< 6.5 
< 4.03 
57 days of age to < 13 
years of age 
(male and female) 
9.5 to 10.4 
5.88 to 6.48 
8.5 to < 9.5 
5.25 to < 5.88 
6.5 to < 8.5 
4.03 to < 5.25 
< 6.5 
< 4.03 
36 to 56 days of age 
(male and female) 
8.5 to 9.6 
5.26 to 5.99 
7.0 to < 8.5 
4.32 to < 5.26 
6.0 to < 7.0 
3.72 to < 4.32 
< 6.0 
< 3.72 
22 to 35 days of age 
(male and female) 
9.5 to 11.0 
5.88 to 6.86 
8.0 to < 9.5 
4.94 to < 5.88 
6.7 to < 8.0 
4.15 to < 4.94 
< 6.7 
< 4.15 
8 to ≤ 21 days of age 
(male and female) 
11.0 to 13.0 
6.81 to 8.10 
9.0 to < 11.0 
5.57 to < 6.81 
8.0 to < 9.0 
4.96 to < 5.57 
< 8.0 
< 4.96 
≤ 7 days of age 
(male and female) 
13.0 to 14.0 
8.05 to 8.72 
10.0 to < 13.0 
6.19 to < 8.05 
9.0 to < 10.0 
5.59 to < 6.19 
< 9.0 
< 5.59 
Platelets, Decreased 
(cells/mm3; cells/L) 
100,000  to 
< 124,999 
100.000 x 109  to 
< 124.999 x 109 
50,000  to 
< 100,000 
50.000 x 109  to 
< 100.000 x 109 
25,000  to 
< 50,000 
25.000 x 109  to 
< 50.000 x 109 
< 25,000 
< 25.000 x 109 
WBC, Decreased 
(cells/mm3; cells/L) 
> 7 days of age 
2,000 to 2,499 
2.000 x 109 to 2.499 
x 109 
1,500 to 1,999 
1.500 x 109 to 1.999 x 
109 
1,000 to 1,499 
1.000 x 109 to 1.499 x 
109 
< 1,000 
< 1.000 x 109 


DMID Protocol #16-0095 
Version 3.0 
Collaborative Antiviral Study Group #405 
22 March 2019 
Asymptomatic CMV Treatment 
 _____________________________________________________________________________________________________  
  
DMID/NIAID/NIH 
 
 
 
 
 
 
 
 
 
94 
CONFIDENTIAL 
 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
≤ 7 days of age 
5,500 to 6,999 
5.500 x 109 to 6.999 
x 109 
4,000 to 5,499 
4.000 x 109 to 5.499 x 
109 
2,500 to 3,999 
2.500 x 109 to 3.999 x 
109 
< 2,500 
< 2.500 x 109 


DMID Protocol #16-0095 
Version 3.0 
Collaborative Antiviral Study Group #405 
22 March 2019 
Asymptomatic CMV Treatment 
 ______________________________________________________________________________________________________  
 
DMID/NIAID/NIH 
 
 
 
 
 
 
 
 
 
95 
CONFIDENTIAL 
 
Total Bilirubin Table for Term and Preterm Neonates 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Total Bilirubin a, High 
(mg/dL; µmol/L)b 
Term Neonatec 
< 24 hours of age 
4 to < 7 
68.4 to < 119.7 
7 to < 10 
119.7 to < 171 
10  to < 17 
171  to < 290.7 
≥ 17 
≥ 290.7 
24 to < 48 hours of 
age 
5 to < 8 
85.5 to < 136.8 
8 to < 12 
136.8 to < 205.2 
12  to < 19 
205.2  to < 324.9 
≥ 19 
≥ 324.9 
48 to < 72 hours of 
age 
8.5 to < 13 
145.35 to < 222.3 
13 to < 15 
222.3 to < 256.5 
15  to < 22 
256.5  to < 376.2 
≥ 22 
≥ 376.2 
72 hours to < 7 days 
of age 
11 to < 16 
188.1 to < 273.6 
16 to < 18 
273.6 to < 307.8 
18  to < 24 
307.8  to < 410.4 
≥ 24 
≥ 410.4 
7 to 28 days of age 
(breast feeding) 
5 to < 10 
85.5 to < 171 
10 to < 20 
171 to < 342 
20 to < 25 
342 to < 427.5 
≥ 25 
≥ 427.5 
7 to 28 days of age 
(not breast feeding) 
1.1 to < 1.6 x ULN 
1.6 to < 2.6 x ULN 
2.6 to < 5.0 x ULN 
≥  5.0 x ULN 
Preterm Neonatec 
35 to < 37 weeks 
gestational age 
Same as for Total 
Bilirubin, High, Term 
Neonate (based on 
days of age). 
Same as for Total 
Bilirubin, High, Term 
Neonate (based on 
days of age). 
Same as for Total 
Bilirubin, High, 
Term Neonate (based 
on days of age). 
Same as for Total 
Bilirubin, High, Term 
Neonate (based on 
days of age). 
32 to < 35 weeks 
gestational age and 
< 7 days of age 
NA 
NA 
10 to < 14 
171 to < 239.4 
≥ 14 
≥ 239.4 
28 to < 32 weeks 
gestational age and 
< 7 days of age 
NA 
NA 
6 to < 10 
102.6 to < 171 
≥ 10 
≥ 171 
< 28 weeks 
gestational age and 
< 7 days of age 
NA 
NA 
5 to < 8 
85.5 to < 136.8 
≥ 8 
≥ 136.8 
7 to  28 days of age 
(breast feeding) 
5 to < 10 
85.5 to < 171 
10 to < 20 
171 to < 342 
20 to < 25 
342 to < 427.5 
≥ 25 
≥ 427.5 
7 to 28 days of age 
(not breast feeding) 
1.1 to < 1.6 x ULN 
1.6 to < 2.6 x ULN 
2.6 to < 5.0 x ULN 
≥  5.0 x ULN 
 
a Severity grading for total bilirubin in neonates is complex because of rapidly changing total bilirubin normal ranges in the first week of 
life followed by the benign phenomenon of breast milk jaundice after the first week of life.  Severity grading in this appendix corresponds 
approximately to cut-offs for indications for phototherapy at grade 3 and for exchange transfusion at grade 4. 
bA laboratory value of 1 mg/dL is equivalent to 17.1 µmol/L. 
c Definitions: Term is defined as ≥ 37 weeks  gestational age; near-term, as ≥ 35 weeks  gestational age; preterm, as < 35 weeks gestational age; 
and neonate, as 0 to 28 days of age. 


DMID Protocol #16-0095 
 
 
 
 
 
Version 3.0 
Collaborative Antiviral Study Group #405 
 
 
 
 
 
 
 
 
 
 
 
 
          22 March 2019 
Asymptomatic CMV Treatment 
 _____________________________________________________________________________________________________________________________________________________________  
 
DMID/NIAID/NIH 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
96 
CONFIDENTIAL 
 
19   APPENDIX B: SCHEDULE OF EVENTS 
 
Screening 
Treatment Study Day 
Treatment Study Month 
 
 
(≤ 30 days 
of age) 
1 
(day 
-3 to 
day 
1) 
7 
(week 
1) 
(± 2 
days) 
14 
(week 
2) 
(± 2 
days) 
21 
(week 
3) 
(± 2 
days) 
28 
(week 
4) 
(± 2 
days) 
35 
(week 
5) (± 2 
days) 
42 
(week 
6) 
(± 3 
days) 
56 
(week 
8) 
(± 3 
days) 
70 
(week 10) 
(± 3 days) 
84 
(week 
12) 
(± 3 
days) 
4 
(± 10 
days) 
5 (± 
10 
days) 
6 
(± 10 
days) 
12 
(± 30 
days) 
18 
(± 30 
days) 
Screening Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Saliva for screening 
detection of CMV 
DNA by PCR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine and saliva for 
confirmatory detection 
of CMV DNA by 
PCRa 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment or 
Observational 
Informed Consent 
Xb 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline 
demographicsc  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology Safety 
Labsd  
 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Chemistry Safety 
Labsf  
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Growth Parametersg  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event 
Assessment 
 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Concomitant 
Medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Hearing Assessment 
Xi 
 
 
 
 
 
 
 
 
 
 
Xj 
 
Xk 
Xk 
Xk 
Virology Specimen for 
CMV Viral Loadl,m  
 
Xn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xo 
Xo 
Xo 
 
 
Updated results of any 
available etiological 
investigations for 
SNHL 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Determination of 
appropriate dose 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Valganciclovir 
Administrationp 
 
 
 
 
 
 
Total volume of blood 
required for study 
0.0 
mL 
2.2 
mL 
1.2 
mL 
2.2 
mL 
1.2 
mL 
2.2 
mL 
1.2 
mL 
2.2 
mL 
2.2 
mL 
2.2 
mL 
2.2 
mL 
2.2 
mL 
2.2 
mL 
1.7 
mL 
0.0 
mL 
0.0 
mL 


DMID Protocol #16-0095 
 
 
 
 
 
Version 3.0 
Collaborative Antiviral Study Group #405 
 
 
 
 
 
 
 
 
 
 
 
 
          22 March 2019 
Asymptomatic CMV Treatment 
 _____________________________________________________________________________________________________________________________________________________________  
 
DMID/NIAID/NIH 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
97 
CONFIDENTIAL 
 
 
 
a) Babies screening positive for congenital CMV infection will have a second saliva sample and a urine sample collected for confirmatory PCR testing.  Screening will occur 
most commonly during the birth hospitalization, and with enough time for initial and confirmatory PCR specimens to be obtained and run. 
b) The treatment consent or observational consent will be signed following the confirmatory PCR testing for CMV DNA and prior to or on Day 1. 
c) Baseline demographics and birth history consist of date of birth; gender; race; ethnicity; birth weight; length at birth, if available; head circumference at birth, if available; 
gestational age at birth; medical history and baseline conditions prior to study enrollment, by body system 
d) WBC with differential, Hgb, Plt (approximate total blood needed for these tests is 0.5 cc) 
e) Absolute neutrophil count will be determined prior to the first dose of study medication 
f) 
ALT, direct bilirubin, and creatinine (approximate total blood needed for these tests is 1.0 cc) 
g) Growth parameters consist of length, weight, and head circumference 
h) Adverse events that occur following the first dose of study medication 
i) 
Babies screening positive for congenital CMV infection on their first saliva sample will have sensorineural hearing testing performed, as is standard of care for babies 
identified as being congenitally infected with CMV.  BSER (to assess neuro-otologic status) and OAEs (DPOAE or TEOAE) will be obtained.  If the BSER is abnormal, then 
bone conduction will be obtained to distinguish between sensorineural hearing loss, conductive loss, or mixed loss.  If the OAEs are abnormal, then acoustic immittance 
measures (tympanometry and acoustic reflexes) will be obtained to better define the middle or inner ear abnormality (e.g., otitis media). 
j) 
BSER (to assess neuro-otologic status) and OAEs (DPOAE or TEOAE) will be obtained.  If the BSER is abnormal, then bone conduction will be obtained to distinguish 
between sensorineural hearing loss, conductive loss, or mixed loss.  If the OAEs are abnormal, then acoustic immittance measures (tympanometry and acoustic reflexes) will 
be obtained to better define the middle or inner ear abnormality (e.g., otitis media) (window: -10 to + 30 days). 
k) BSER and/or VRA (to assess neuro-otologic status) and OAEs (DPOAE or TEOAE) will be obtained.  If the BSER and/or VRA is abnormal, then bone conduction will be 
obtained to distinguish between sensorineural hearing loss, conductive loss, or mixed loss.  If the OAEs are abnormal, then acoustic immittance measures (tympanometry and 
acoustic reflexes) will be obtained to better define the middle or inner ear abnormality (e.g., otitis media) (window: -10 to +30 days). 
l) 
Required amount of whole blood for plasma and whole blood CMV PCR is at least 0.7 mL. 
m) For the approximately 12 patients identified as being asymptomatically congenitally infected with CMV and with SNHL, Virology specimens for CMV viral load will be the 
only study-related laboratory specimen collected for them; all other data on the valganciclovir treatment and associated safety labs as well as the serial hearing testing are part 
of clinical care for these patients, and will be redacted without alteration from the clinical chart.  Non-study clinical and laboratory assessments that are not performed 
according to the intervals and listings in Appendix A (Schedule of Events) will not be assessed as protocol deviations. 
n) In addition to whole blood for CMV viral load, urine collection by bagged specimen and saliva collected by buccal swab will be attempted on Study Day 1 (Window: Study 
Day -3 to Study Day 7 for whole blood and urine; and Study Day -30 to Study Day 7 for saliva).  If urine is obtainable, it will be frozen and sent to the Central Unit Central 
Laboratory for processing.  If urine is not obtainable, a protocol deviation will not be reported. 
o) In addition to whole blood for CMV viral load, urine collection by bagged specimen and saliva collected by buccal swab will be attempted on Study Month 4 (Window: ± 10 
days), Study Month 5 (Window: ± 10 days), and Study Month 6 (Window: ± 10 days).  If urine is obtainable, it will be frozen and sent to the Central Unit Central Laboratory 
for processing.  If urine is not obtainable, a protocol deviation will not be reported. 
p) Valganciclovir administration begins on Study Day 1; drug should be administered within 49 days of reconstitution.  Study medication diary will be collected and distributed 
at each study visit throughout the treatment period. 
 
 

ICF_003.pdf: 
Page 1 of 10 
IC Version Date: 05/15/19 
 
 
 
 
DMID 16‐0095 
Protocol Version Date: 
3/22/2019 
 
 
 
CONSENT FORM 
 
TITLE OF RESEARCH: 
A Phase II, Single‐Stage, Single‐Arm Investigation of Oral Valganciclovir 
Therapy in Infants with Asymptomatic Congenital Cytomegalovirus 
Infection 
 
SCREENING CONSENT 
 
IRB PROTOCOL NO.: 
IRB‐ 300001001 
 
INVESTIGATOR: 
David Kimberlin, MD 
 
SPONSOR: 
National Institutes of Allergy and Infectious Disease and Genetech, Inc. 
 
SPONSOR PROTOCOL NO.: 
DMID 16‐0095 
 
Purpose of the Research 
 
 
General Information 
You are being asked to take part in a research study. This research study is 
voluntary, meaning you do not have to take part in it. The procedures, risks, and 
benefits are fully described further in the consent form. 
Purpose 
The purpose of the study is to evaluate if treatment with an approved drug 
called Valganciclovir, will reduce the risk of hearing loss developing in babies 
with Congenital CMV, but have no symptoms at birth. 
Duration & Visits 
You will be in this portion of the study for less than 30 days. We will swab your 
baby’s mouth and if the results are positive, we will schedule your baby to have 
a second swab, a urine specimen collection and a hearing test done. 
Overview of Procedures  If your baby’s first swab of their mouth is positive a second mouth swab and a 
urine specimen will be collected will be done to confirm the test results. Both 
CMV tests are done by a simple cheek swab. The urine specimen will be 
collected by way of cotton balls in diaper or from a urine collection bag.  
This phase of the study will include 2 mouth swabs and a urine collection. 
hearing evaluation.  
Risks 
The mouth swab and the urine collection should not cause discomfort to 
your baby.  There are no risks associated with these procedures. 
Benefits 
The benefit to you for participation in this study is that you will find out if your 
baby does or does not have a congenital CMV infection.  If your baby is positive 
for congenital CMV infection you will be given the opportunity to participate in 
our treatment study. 
Alternatives 
The alternative is to not participate in this screening for CMV. The study doctor 
will be available to discuss with you the alternatives to your baby’s participation 
and their risks and benefits. 
UAB IRB
Approved
22-May-2019
until
21-May-2020


Page 2 of 10 
IC Version Date: 05/15/19 
DMID 16‐0095 
Protocol Version Date: 3/22/19 
 
 
 
You are being asked to allow your baby to participate in a research study of cytomegalovirus 
infection. Cytomegalovirus (CMV) is the leading cause of congenital infection ‐ infection of the baby 
while it is still in the mother’s womb. It is estimated that 5 to 10 out of every 1000 babies born will 
have a congenital CMV infection. Although most babies with congenital CMV infection do not have 
any problems due to the virus, around 15% will have hearing loss, visual problems, physical or 
developmental disabilities. The hearing loss due to congenital CMV infection can be present at birth 
or can develop later during childhood. Overall Congenital CMV is a rare infection at birth, but it 
accounts for 21% of hearing loss at birth and 24% of hearing loss by age 4. 
 
This study is being done to evaluate if treatment with an approved drug called Valganciclovir, will 
reduce the risk of hearing loss developing in babies with Congenital CMV, but have no symptoms at 
birth. 
 
We are screening newborns at UAB for CMV, to identify those who are born with CMV infection, but 
show no outward symptoms. 
 
 
 
Study Participation and Procedures 
 
In this study, we plan to screen approximately 48,250 newborns at all study sites across the USA We 
plan to screen approximately 5361 newborns at this site to identify eligible subjects (those with a 
positive CMV screening test). If your baby’s screening test is positive a second test will be done to 
confirm the test results. Both CMV tests are done by a simple cheek swab at no cost to you, but with 
your consent. The study doctor will discuss with you your responsibilities as a participant. 
 
If you allow your baby to participate in this study, we will start by obtaining consent to participate. 
We will then test to see if your baby has CMV. Your participation will include filling out the contact 
form with your name, address, phone number and demographics such as date of birth and race. We 
will ask you to sign a form allowing us to access your UAB medical records to gather information for 
the study such as the hearing assessment or other interventions for the baby or for you.   
 
 If your baby’s CMV test is negative in the screening phase of the study, your participation is 
complete.  There is no further study related activity or involvement.  
 If your baby’s initial screening CMV test is positive: 
1. We will schedule a second CMV test and urine collection to confirm the results. 
2. We will give you a urine collection kit containing cotton balls and instructions which you can 
use prior to returning to us for the second confirmatory test.  
3. We will schedule your baby for a complete hearing exam. 
4. We will also obtain the results of your baby’s newborn hearing test done at UAB. 
 
If your baby is positive for a congenital CMV infection, you will be contacted regarding 
recommendation for follow up for CMV.  We will also discuss your options to allow your baby 
to participate in the treatment study with Valganciclovir.  If you decide to allow your baby to 
participate in the treatment portion of this study, another informed consent will be presented 


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IC Version Date: 05/15/19 
DMID 16‐0095 
Protocol Version Date: 3/22/19 
 
 
and discussed in detail. We plan to give you the information and will send a letter informing 
your pediatrician of the diagnosis at your request.  
Risks and Discomforts 
 
 
Saliva Collection: 
Your baby will have the inside of his/her cheek swabbed to collect a saliva sample.  This should not be 
uncomfortable for your baby. And there are no associated risks with this procedure. 
 
Urine Collection:  
Your baby will have cotton balls placed in his/her diaper and we will obtain the urine from those cotton 
balls or a urine bag placed over his/her genitals once you return to the CHRU for the second 
confirmatory oral swab. There are no associated risks with this procedure other than slight redness 
where the urine bag is attached to the skin.  We will give you a kit containing cotton balls and 
instructions to use in case of a positive CMV oral swab.  
 
Benefits 
 
 
The benefit to you for participation in this study is that you will find out if your baby does or does not 
have a congenital CMV infection.  If your baby is positive for congenital CMV infection you will be 
given the opportunity to participate in our treatment study. 
 
Alternatives 
 
 
The alternative is to not participate in this screening for CMV. The study doctor can be available to 
discuss with you the alternatives to your baby’s participation and their risks and benefits. 
 
Confidentiality 
 
 
Federal regulations give you certain rights related to your baby’s health information. These include 
the right to know who will be able to get the information and why they may be able to get it. The 
study doctor must get your authorization (permission) to use or give out any health information that 
might identify your baby. The information obtained about your baby for this study will be kept 
confidential to the extent allowed by law.  Your baby’s personal information will be kept secure in a 
locked file and all other data will be secure on a database as well as coded by a number and not your 
baby’s name or personal information.  Some of your baby’s information may be transmitted 
electronically (by email or by fax) but it will be coded to assure confidentiality.  A copy of your baby’s 
consent form will be placed in your baby’s medical record at Children’s Hospital 
 
Therefore, research information that identifies your baby may be shared with the UAB Institutional 
Review Board (IRB) and others who are responsible for ensuring compliance with laws and 
regulations related to research, including people on behalf of your baby’s doctor and the research 
study team, and the FDA according to regulation 21 CFR 50.25(a(5). 
 
Monitors, auditors, the Institutional Review Board for Human Use, and regulatory authorities will be 


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DMID 16‐0095 
Protocol Version Date: 3/22/19 
 
 
granted direct access to your original medical records for verification of trial procedures and/or data 
without violating confidentiality. 
 
Data and samples collected for this study will use a study ID # as a unique identifier. There is a 
minimal risk of a break in confidentiality.  
 
What protected health information may be used and/or given to others? 
All medical information, including but not limited to information and/or records of any diagnosis or 
treatment of disease or condition, which may include sexually transmitted diseases (e.g., HIV, etc.) or 
communicable diseases, drug/alcohol dependency, etc.; all personal identifiers, including but not 
limited to your name, social security number, medical record number, date of birth, dates of service, 
etc.; any past, present, and future history, examinations, laboratory results, imaging studies and 
reports and treatments of any kind, including but not limited to drug/alcohol treatment, 
psychiatric/psychological treatment; financial/billing information, including but not limited to copies of 
your medical bills; any other information related to or collected for use in the research study, 
regardless of whether the information was collected for research or non‐research (e.g., treatment) 
purposes; records about any study drug you received or about study devices used; and consent forms 
from past studies that might be in your baby’s  medical record. 
 
Your baby’s consent form will be placed in your baby’s medical record at UAB Health System or 
Children’s of Alabama. This may include either a paper medical record or electronic medical record 
(EMR). An EMR is an electronic version of a paper medical record of your baby’s care within this 
health system. Your baby’s EMR may indicate that your baby is on a clinical trial and provide the name 
and contact information for the principal investigator. 
 
If your baby is receiving care or has received care within this health system (outpatient or inpatient) 
and is participating in a research study, results of research tests or procedures (i.e. laboratory tests, 
imaging studies and clinical procedures) may be placed in your baby’s existing medical record. 
 
If your baby has never received care within this health system (outpatient or inpatient) and is 
participating in a research study, a medical record will be created for your baby to maintain results of 
research tests or procedures. 
 
Results of research tests or procedures may be placed in your baby’s medical record. All information 
within your baby’s medical record can be viewed by individuals authorized to access the record. 
 
Information relating to this study, including your baby’s name, medical record number, date of birth 
and social security number, may be shared with the billing offices of UAB and UAB Health System 
affiliated entities, along with Children’s of Alabama and its billing agents so costs for clinical services 
can be appropriately paid for by either the study account or by your insurance. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law. This Web site will not include information that can identify your baby. At most, the Web site will 
include a summary of the results. You can search this Web site at any time. 
 


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Who may use and give out information about you? 
Information about your health may be used and given to others by the study doctor and staff. They 
might see the research information during and after the study. 
 
Who might get this information? 
All Individuals/entities listed in the informed consent document(s), including but not limited to, the 
physicians, nurses and staff and others performing services related to the research (whether at UAB or 
elsewhere). Your information may also be given to the sponsor of this research. “Sponsor” includes any 
persons or companies that are working for or with the sponsor, or are owned by the sponsor, or are 
providing support to the sponsor (e.g., contract research organization). 
 
Information about you and your health which might identify you may be given to: 
 the Office for Human Research Protections (OHRP) 
 the U.S. Food and Drug Administration (FDA) 
 Department of Health and Human Services (DHHS) agencies 
 Governmental agencies in other countries 
 Governmental agencies to whom certain diseases (reportable diseases) must be reported 
 the University of Alabama at Birmingham ‐ the physicians, nurses and staff working on the research 
study (whether at UAB or elsewhere); other operating units of UAB, UAB Hospital, UAB Highlands 
Hospital, University of Alabama Health Services Foundation, Children’s of Alabama, Eye Foundation 
Hospital, and the Jefferson County Department of Health, as necessary for their operations; the 
UAB IRB and its staff 
 the billing offices of UAB and UAB Health Systems affiliates and/or Children’s of Alabama and its 
billing agents 
 
Why will this information be used and/or given to others? 
Information about you and your health that might identify you may be given to others to carry out the 
research study. The sponsor will analyze and evaluate the results of the study. In addition, people from 
the sponsor and its consultants will be visiting the research site. They will follow how the study is 
done, and they will be reviewing your information for this purpose. 
 
This research is covered by a Certificate of Confidentiality from the National Institutes of Health. The 
researchers  may  not  disclose  or  use  your  baby’s  information,  documents,  or  specimens  that  may 
identify  your  baby  in  any  federal,  state,  or  local  civil,  criminal,  administrative,  legislative,  or  other 
action  such  as  a  suit  or  other  proceeding without your  consent. If  there is  a  court subpoena, 
information,  documents  or  specimens  collected  about  your  baby  as  part  of  this  study  cannot  be 
disclosed to anyone else who is not connected with the research, except if there is a law that requires 
disclosure (such as to report child abuse or a communicable disease). This certificate does not prohibit 
requests for information from the groups listed above, who are responsible for overseeing the study. 
 
The Certificate cannot be used to refuse a request for information from personnel of the United 
States federal or state government agency sponsoring the project that is needed for auditing or 
program evaluation by the National Institutes of Health which is funding this project or for 
information that must be disclosed in order to meet the requirements of the federal Food and Drug 
Administration (FDA). You should understand that a Certificate of Confidentiality does not prevent 


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you from voluntarily releasing information about yourself or your involvement in this research. If you 
want your research information released to an insurer, medical care provider, or any other person 
not connected with the research, you must provide consent to allow the researchers to release it. 
 
The Certificate of Confidentiality will not be used to prevent disclosure for any purpose you have 
consented to in this informed consent document. 
 
What if I decide not to give permission to use and give out my health information? 
By signing this consent form, you are giving permission to use and give out the health information 
listed above for the purposes described above. If you refuse to give permission, you will not be able 
to be in this research. 
 
May I review or copy the information obtained from me or created about me? 
You have the right to review and copy your health information. However, if you decide to be in this 
study and sign this permission form, you will not be allowed to look at or copy your information until 
after the research is completed. 
 
May I withdraw or revoke (cancel) my permission? 
Yes, but this permission will not stop automatically. The use of your personal health information will 
continue until you cancel your permission. 
 
You may withdraw or take away your permission to use and disclose your health information at any 
time. You do this by sending written notice to the study doctor. If you withdraw your permission, you 
will not be able to continue being in this study. 
 
When you withdraw your permission, no new health information which might identify you will be 
gathered after that date. Information that has already been gathered may still be used and given to 
others. This would be done if it were necessary for the research to be reliable. 
 
Is my health information protected after it has been given to others? 
If you give permission to give your identifiable health information to a person or business, the 
information may no longer be protected. There is a risk that your information will be released to 
others. Including others outside of UAB, without your permission. 
 
Voluntary Participation and Withdrawal 
 
 
Whether or not you allow your baby to take part in this study is your choice. There will be no penalty 
if you decide to withdraw your baby from the study. If you decide not to allow your baby to be in the 
study, you will not lose any benefits otherwise owed. You are free to withdraw your baby from this 
research study at any time. Your choice to withdraw your baby from the study will not affect your 
baby’s relationship with this institution. 


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Your baby may be removed from the study without your consent if the sponsor ends the study, or if 
for any other reasons in the opinions of both the site investigator as well as the study chairperson, 
that ending study participation is the best course of action for your baby. 
 
Cost of Participation 
 
 
There will be no cost to your baby for taking part in this study. 
 
The costs of your baby’s standard medical care will be billed to you and/or your insurance company in 
the usual manner. 
 
Payment for Participation in Research 
 
 
The study will provide a small gift as a token of appreciation (valued approximately $10) at the time 
of the initial screening.  If your baby’s initial test is positive for Congenital CMV, you will be asked to 
return for a second screening. After you complete the second screening and hearing test, you will be 
paid $25. Ask the study staff about the method of payment that will be used for this study (e.g., 
check, cash, gift card, direct deposit). 
 
Payment for Research‐Related Injuries 
 
 
UAB, Genentech and the sponsor (National Institutes of Health), have not provided for any payment 
if your baby is harmed as a result of taking part in this study. If such harm occurs, treatment will be 
provided. However, this treatment will not be provided free of charge. 
 
Significant New Findings 
 
 
You will be told by doctor or the study staff if any new information becomes available that might 
affect your choice to stay keep your baby in the study. 
 
Questions 
 
 
If you have any questions, concerns, or complaints about the research or a research‐related injury 
including available treatments, please contact the research doctor, Dr. Kimberlin will be glad to 
answer any of your questions. Dr. Kimberlin’s number is 205‐934‐2424.  Dr. Kimberlin may also be 
reached after hours by paging him at 205‐934‐3411. 
 
If you have questions about your baby’s rights as a research participant, or concerns or complaints 
about the research, you may contact the UAB Office of the IRB (OIRB) at (205) 934‐3789 or toll free at 
1‐855‐860‐3789. Regular hours for the OIRB are 8:00 a.m. to 5:00 p.m. CT, Monday through Friday. 
You may also call this number in the event the research staff cannot be reached or you wish to talk to 
someone else. 
 


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Legal Rights 
 
 
You are not waiving any of your baby’s legal rights by signing this informed consent document. 


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Storage of Specimens for Future Use 
 
 
Some specimens obtained from your baby during this study will be stored indefinitely in laboratories 
at the University of Alabama at Birmingham (UAB) and may be used in future virus research at UAB 
and at other laboratories.  These specimens will be labeled with a code number that can be linked to 
your baby but will not include your baby’s name.  Any additional research studies beyond the current 
study using your baby’s identifiable samples/cultures will be reviewed by the investigator’s 
Institutional Review Board (IRB), a special committee that oversees medical research studies to 
protect the rights and welfare of the human subject volunteers.  There will be no human genetic tests 
performed on your baby’s samples/cultures. 
 
All results from future studies using your baby’s specimens will be included in the study records. No 
results from these studies will be placed in your baby’s medical records. 
 
Please indicate whether you will permit your baby’s specimens to be used in future virus research by 
initialing one of the following statements: 
 
  
  I agree to allow my baby’s specimens to be preserved for future virus research. 
 
  
  I do not agree to allow my baby’s specimens to be preserved for future virus research. 
 
If, in the future, you decide that you do not want your baby’s specimens used for virus research, 
please notify Dr. Kimberlin or the Study RN at this number 205‐934‐2424, or in writing at this address, 
1600 7th Avenue South, CHB 303, Birmingham, Al 35233, and your specimens will be destroyed. 
 
If you decide that you do not want your baby’s specimens used for future virus research, your baby 
may still participate in the study. Your baby’s specimens will be destroyed once all study tests are 
completed. 
 
Signatures 
 
 
You are making a decision whether or not to have your baby participate in this study.  Your signature 
indicates that you have read (or have been read) the information provided above and decided to 
allow your baby to participate.  You will receive a copy of this signed consent form. 
 
The assent of 
(name of baby/child/minor) was waived because 
of age. 
 
 
 
Signature of Parent or Guardian 
Date 
 
 
 
Signature of Parent or Guardian 
Date 
 


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Signature of Principal Investigator or Person Obtaining Consent 
Date