A Phase II Randomized and Controlled Investigation of Six Weeks of Oral Valganciclovir Therapy in Infants and Children With Congenital Cytomegalovirus Infection and Hearing Loss
Phase: PHASE2
Conditions: Cytomegalovirus Infection
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

 
 
A PHASE II RANDOMIZED AND CONTROLLED INVESTIGATION OF 
SIX WEEKS OF ORAL VALGANCICLOVIR THERAPY IN INFANTS AND 
CHILDREN WITH CONGENITAL CYTOMEGALOVIRUS INFECTION 
AND HEARING LOSS 
DMID Protocol Number: 11-0069 
 
DMID Funding Mechanism:  HHSN272201100035C 
Pharmaceutical Support Provided by:  Genentech, Inc. 
IND Sponsor:  DMID 
Principal Investigator:  David W. Kimberlin, M.D. 
DMID Clinical Project Manager:  Walla Dempsey, Ph.D. 
DMID Medical Monitor:  Venus Shahamatdar, MD 
Version Number:  4.0 
28 April 2016  
 
 

Collaborative Antiviral Study Group 
DMID Protocol #11-0069, Version 4.0 
CASG Valgan Toddler 
28 April 2016 
 
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STATEMENT OF COMPLIANCE 
 
Each investigator must adhere to the protocol as detailed in this document.  Each 
investigator will be responsible for enrolling only those study participants who have met 
protocol eligibility criteria.  This trial will be conducted in compliance with the protocol, 
International Conference on Harmonization Good Clinical Practice 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). 
• Directive 9115071EEC: The Rules Governing Medicinal Products in the European 
Community. 
• Completion of Human Subjects Protection Training.  Refer to 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-061.html; 
http://cme.cancer.gov/clinicaltrials/learning/humanparticipant-protections.asp  

Collaborative Antiviral Study Group 
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SIGNATURE PAGE 
The signature below constitutes my agreement to conduct this protocol “A Phase II 
Randomized and Controlled Investigation of Six Weeks of Oral 
Valganciclovir Therapy in Infants and Children with Congenital 
Cytomegalovirus Infection and Hearing Loss” and attachments and provide the 
necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable U.S. clinical sites.  It is understood that no deviations 
from the protocol may be made without permission of the Sponsor. 
 
Site Investigator: 
 
Signed: 
 
Date: 
 
 
Name 
 
 
 
 
 
Title 
 
 

Collaborative Antiviral Study Group 
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28 April 2016 
 
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TABLE OF CONTENTS 
PAGE 
STATEMENT OF COMPLIANCE ................................................................................................................... II 
SIGNATURE PAGE........................................................................................................................................ III 
TABLE OF CONTENTS ................................................................................................................................. IV 
LIST OF ABBREVIATIONS ......................................................................................................................... VIII 
PROTOCOL SUMMARY ................................................................................................................................ XI 
1. 
KEY ROLES ............................................................................................................................................ 1 
2. 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ...................................................... 7 
2.1. 
BACKGROUND INFORMATION ....................................................................................................................... 7 
2.1.1. 
Retrospective diagnosis of congenital CMV ................................................................................. 8 
2.1.2. 
Treatment of Congenital CMV ........................................................................................................ 9 
2.2. 
RATIONALE ................................................................................................................................................. 11 
2.3. 
POTENTIAL RISKS AND BENEFITS .............................................................................................................. 13 
2.3.1. 
Potential Risks................................................................................................................................. 13 
2.3.2. 
Known Potential Benefits ............................................................................................................... 13 
3. 
OBJECTIVES ......................................................................................................................................... 14 
3.1. 
STUDY OBJECTIVES ................................................................................................................................... 14 
3.2. 
STUDY OUTCOME MEASURES ................................................................................................................... 14 
3.2.1. 
Primary Outcome Measure ........................................................................................................... 14 
3.2.2. 
Secondary Outcome Measures .................................................................................................... 14 
3.2.3. 
Tertiary Outcome Measures .......................................................................................................... 15 
4. 
STUDY DESIGN ..................................................................................................................................... 16 
4.1. 
SUBSTUDIES (IF APPLICABLE) .................................................................................................................... 17 
5. 
STUDY ENROLLMENT, RANDOMIZATION, AND WITHDRAWAL ................................................... 18 
5.1. 
ENROLLMENT ............................................................................................................................................. 18 
5.2. 
SUBJECT INCLUSION CRITERIA .................................................................................................................. 18 
5.3. 
SUBJECT EXCLUSION CRITERIA ................................................................................................................ 18 
5.4. 
TREATMENT ASSIGNMENT PROCEDURES ................................................................................................. 19 
5.4.1. 
Randomization Procedures ........................................................................................................... 19 
5.4.2. 
Masking Procedures ....................................................................................................................... 19 
5.4.3. 
Reasons for Withdrawal Before Randomization ........................................................................ 20 
5.4.4. 
Reasons for Withdrawal After Randomization and During Treatment .................................... 20 
5.4.5. 
Reasons for Withdrawal After Randomization and After Completion of Treatment .............. 21 
5.4.6. 
Handling of Withdrawals ................................................................................................................ 21 
5.4.7. 
Termination of Study ...................................................................................................................... 22 

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6. 
STUDY INTERVENTION/INVESTIGATIONAL PRODUCT ................................................................. 23 
6.1. 
STUDY PRODUCT DESCRIPTION ................................................................................................................ 23 
6.1.1. 
Acquisition ........................................................................................................................................ 23 
6.1.2. 
Formulation, Packaging, and Labeling ........................................................................................ 23 
6.1.3. 
Product Storage and Stability ....................................................................................................... 24 
6.2. 
DOSAGE, PREPARATION AND ADMINISTRATION OF STUDY INTERVENTION/INVESTIGATIONAL PRODUCT
 
24 
6.3. 
MODIFICATION OF STUDY INTERVENTION/INVESTIGATIONAL PRODUCT FOR A PARTICIPANT .................. 24 
6.3.1.  Neutropenia .......................................................................................................................................... 25 
6.3.2.  Thrombocytopenia ............................................................................................................................... 25 
6.3.3.  Renal Impairment ................................................................................................................................. 25 
6.3.4.  Hepatotoxicity ....................................................................................................................................... 26 
6.4. 
ACCOUNTABILITY PROCEDURES FOR THE STUDY INTERVENTION/INVESTIGATIONAL PRODUCT(S) ........ 26 
6.5. 
CONCOMITANT MEDICATIONS/TREATMENTS ............................................................................................. 27 
6.5.1.  Concomitant Medication Assessment ............................................................................................... 27 
6.5.2.  Prohibited Therapies ........................................................................................................................... 27 
6.5.3.  Drug Interactions .................................................................................................................................. 28 
7. 
STUDY SCHEDULE ............................................................................................................................... 29 
7.1. 
ENROLLMENT (WINDOW:  DAY -90 TO DAY -1) ......................................................................................... 29 
7.2. 
RANDOMIZATION AND BASELINE (WINDOW: DAY -1 TO DAY 1) ................................................................ 29 
7.3. 
TREATMENT (DAY 1 THROUGH DAY 42) .................................................................................................... 31 
7.4. 
FOLLOW-UP ................................................................................................................................................ 31 
7.4.1. 
Day 14 (± 2 days) ........................................................................................................................... 31 
7.4.2. 
Day 28 (± 2 days) ........................................................................................................................... 32 
7.4.3. 
Day 42 (± 2 days) ........................................................................................................................... 32 
7.4.4. 
Day 70 (± 4 days) ........................................................................................................................... 33 
7.4.5. 
Month 4 (± 7 days) .......................................................................................................................... 33 
7.4.6. 
Month 6 (± 7 days) .......................................................................................................................... 33 
7.5. 
FINAL STUDY VISIT .................................................................................................................................... 34 
7.6. 
EARLY TERMINATION VISIT ........................................................................................................................ 34 
7.7. 
UNSCHEDULED VISIT ................................................................................................................................. 34 
8. 
STUDY PROCEDURES/EVALUATIONS ............................................................................................. 35 
8.1. 
CLINICAL EVALUATIONS ............................................................................................................................. 35 
8.1.1.  Baseline Demographics ...................................................................................................................... 35 
8.1.2.  Growth ................................................................................................................................................... 35 
8.1.3.  Adverse Event Assessment ................................................................................................................ 35 
8.1.4.  Hearing Assessment ........................................................................................................................... 36 
8.2. 
LABORATORY EVALUATIONS ...................................................................................................................... 36 
8.2.1. 
Clinical Laboratory Evaluations .................................................................................................... 36 
8.2.2. 
Special Assays or Procedures ...................................................................................................... 37 
8.2.3. 
Specimen Preparation, Handling, and Shipping ........................................................................ 38 

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9. 
DMID SAFETY REPORTING AND SAFETY MONITORING ............................................................... 39 
9.1. 
RESPONSIBILITIES ...................................................................................................................................... 39 
9.2. 
ADVERSE EVENT (AE) ............................................................................................................................... 39 
9.2.1. 
Definition of an Adverse Event ..................................................................................................... 39 
9.2.2. 
Documentation of Reportable Adverse Events .......................................................................... 39 
9.3. 
INVESTIGATOR’S ASSESSMENT OF ADVERSE EVENT ................................................................................ 40 
9.3.1. 
Assessment of Seriousness .......................................................................................................... 40 
9.3.2. 
Assessment of Severity ................................................................................................................. 40 
9.3.3. 
Assessment of Relationship to Study Product ........................................................................... 40 
9.4. 
STUDY RELATED ADVERSE EVENTS ......................................................................................................... 41 
9.5. 
SERIOUS ADVERSE EVENT (SAE) ............................................................................................................. 41 
9.5.1. 
Definition of a Serious Adverse Event ......................................................................................... 41 
9.5.2. 
Reporting Interval ........................................................................................................................... 42 
9.5.3. 
Notification of the Sponsor of Serious Adverse Events ............................................................ 43 
9.5.4. 
Regulatory Reporting for Studies Conducted Under DMID-Sponsored IND ......................... 43 
9.6. 
HALTING RULES ......................................................................................................................................... 44 
9.6.1. 
Discontinuation of Study participation for individual subject .................................................... 44 
9.6.2. 
Discontinuation of Study Enrollment Pending Sponsor Review .............................................. 44 
9.7. 
SAFETY MONITORING BY THE DMID SAFETY OVERSIGHT MECHANISM .................................................. 46 
9.7.1. 
Data and Safety Monitoring Board ............................................................................................... 46 
10. 
CLINICAL MONITORING .................................................................................................................. 47 
10.1. 
SITE MONITORING PLAN ............................................................................................................................ 47 
11. 
STATISTICAL CONSIDERATIONS .................................................................................................. 48 
11.1. 
STUDY HYPOTHESES ................................................................................................................................. 48 
11.2. 
SAMPLE SIZE CONSIDERATIONS ................................................................................................................ 48 
11.3. 
PLANNED INTERIM ANALYSES (IF APPLICABLE) ......................................................................................... 48 
11.3.1. 
Safety Review ................................................................................................................................. 48 
11.3.2. 
Immunogenicity or Efficacy Review ............................................................................................. 49 
11.4. 
FINAL ANALYSIS PLAN ............................................................................................................................... 49 
11.4.1. 
Primary Outcome ............................................................................................................................ 49 
11.4.2. 
Secondary and Tertiary Outcomes .............................................................................................. 50 
12. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ............................... 51 
13. 
QUALITY CONTROL AND QUALITY ASSURANCE ...................................................................... 52 
14. 
ETHICS/PROTECTION OF HUMAN SUBJECTS ............................................................................ 53 
14.1. 
ETHICAL STANDARD ................................................................................................................................... 53 
14.2. 
INSTITUTIONAL REVIEW BOARD ................................................................................................................. 53 
14.3. 
INFORMED CONSENT PROCESS ................................................................................................................ 54 
14.3.1. 
Informed Consent/Assent Process (in Case of a Minor) ........................................................... 54 
14.4. 
EXCLUSION OF WOMEN, MINORITIES, AND CHILDREN (SPECIAL POPULATIONS) .................................... 55 
14.5. 
SUBJECT CONFIDENTIALITY ....................................................................................................................... 55 

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14.6. 
STUDY DISCONTINUATION ......................................................................................................................... 55 
14.7. 
FUTURE USE OF STORED SPECIMENS ...................................................................................................... 56 
15. 
DATA HANDLING AND RECORD KEEPING .................................................................................. 57 
15.1. 
DATA MANAGEMENT RESPONSIBILITIES .................................................................................................... 57 
15.2. 
DATA CAPTURE METHODS ........................................................................................................................ 58 
15.3. 
TYPES OF DATA ......................................................................................................................................... 58 
15.4. 
TIMING/REPORTS ....................................................................................................................................... 58 
15.5. 
STUDY RECORDS RETENTION ................................................................................................................... 58 
15.6. 
PROTOCOL DEVIATIONS ............................................................................................................................ 58 
16. 
PUBLICATION POLICY..................................................................................................................... 60 
17. 
LITERATURE REFERENCES ........................................................................................................... 61 
SUPPLEMENTS/APPENDICES .................................................................................................................... 63 
APPENDIX A: SCHEDULE OF EVENTS ...................................................................................................... 64 
APPENDIX B:  DIVISION OF AIDS TOXICITY TABLES ............................................................................. 65 
 
 

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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 
FWA 
Federalwide Assurance 

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GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GlaxoSmithKline 
GSK 
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, DHHS 
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 
Protected Health Information 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PO 
By Mouth 
QA 
Quality Assurance 
QC 
Quality Control 
QD 
Once Daily 

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RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SAS 
Statistical Analysis Software 
Scr 
Serum Creatinine 
SDW 
Source Document Worksheet 
S&DCC 
Statistical and Data Coordinating Center 
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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PROTOCOL SUMMARY 
Title: 
A Phase II Randomized and Controlled Investigation of Six 
Weeks of Oral Valganciclovir Therapy in Infants and Children 
with Congenital Cytomegalovirus Infection and Hearing Loss 
Phase: 
II 
Population: 
Fifty-four male and female infants/toddlers 1 month through 3 
years of age (up to the 4th birthday) with sensorineural hearing 
loss and congenital CMV infection.  Up to 20% (n=10) over-
enrollment is allowed to replace subjects who drop-out or who 
have inadequate audiology assessments.  Subjects will be 
randomized 1:1 to Investigational drug or placebo. 
Number of Sites: 
17 (listed in Section 1) 
Study Duration: 
3.5 years from enrollment of first study subject 
Subject Participation 
Duration: 
6 months 
Description of Agent or 
Intervention: 
 
 
Investigational Drug:  Valcyte (valganciclovir hydrochloride) 
Powder for oral solution:   
16.0 mg/kg twice daily  
 
Placebo: Simple Syrup as 60-90% sucrose 
Objectives: 
 
 
Primary: 
• 
The primary objective is to assess whether a six week 
course of oral valganciclovir can stabilize the hearing of 
children with congenital CMV infection who present with 
hearing loss.  This will be accomplished by evaluating 
changes in hearing in either ear at 6 months from baseline. 
Secondary: 
• 
To define the following responses as a function of systemic 
exposure to ganciclovir (active metabolite of valganciclovir): 
o CMV viral load in blood 
o CMV viral load in urine 
o CMV viral load in saliva 
• 
To define the safety and tolerability of valganciclovir in 
enrolled subjects. 
Tertiary: 

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• 
To define the pharmacokinetics of ganciclovir (metabolite) 
following administration of valganciclovir (prodrug) in 
enrolled subjects. 
Outcome Measures: 
Primary Endpoint: 
• 
Change in total ear hearing assessments (improved + no 
change versus other) between Baseline and Study Month 6 
Secondary Endpoints: 
• 
Change in best ear hearing assessments [improved + no 
change (normal to normal) versus other; improved versus 
other; worse + no change (abnormal to abnormal) versus 
other; and worse versus other] between Baseline and Study 
Month 6 
• 
Change in total ear hearing assessments (improved versus 
other; worse + no change (abnormal to abnormal) versus 
other; and worse versus other) between Baseline and Study 
Month 6 
• 
Detection of viruria by PCR six weeks and six months after 
trial entry 
• 
The quantitative log reduction in viruria detected after 6 
weeks of therapy 
• 
Detection of viremia by PCR six weeks and six months after 
trial entry 
• 
The quantitative log reduction in viremia detected after 6 
weeks of therapy 
• 
Detection of CMV in saliva by PCR six weeks and six 
months after trial entry 
• 
The quantitative log reduction in CMV viral load in saliva 
detected after 6 weeks of therapy 
• 
Correlation of change in viral load with change in total ear 
and best ear hearing at 6 months 
• 
Incidence of unanticipated medically attended visits 

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occurring from Study Day 1 through two weeks following the 
last dose of study drug 
• 
Incidence of adverse events which lead to permanent 
discontinuation of valganciclovir therapy or have an 
unresolved outcome 
Tertiary Endpoints: 
• 
Blood concentrations of ganciclovir after administration of 
valganciclovir 
Description of Study 
Design: 
This is an international, multi-center, double-blind, placebo-
controlled evaluation of 6 weeks of valganciclovir treatment for 
children (up to 4 years of age) with virologically-confirmed 
congenital CMV infection and hearing loss.  Patients who are 
between 1 month and 4 years of age and who have SNHL are 
eligible for enrollment on the study.  Enrollment on the study 
occurs when eligibility is confirmed and the informed 
consent is signed.  Following the signing of informed consent, 
the subject’s Guthrie card will be retrieved and tested for CMV 
DNA by PCR unless there is a virologically confirmed diagnosis 
of congenital CMV infection made within the first 30 days of life.  
Randomization on the study occurs when the diagnosis of 
congenital CMV infection is confirmed, and the subject then 
is assigned to either receive 6 weeks of oral valganciclovir or 6 
weeks of placebo.  Study subjects will be stratified according to 
age at randomization (1 through 11 months, 12 through 23 
months, 24 through 35 months, and ≥ 36 months) and CMV 
involvement (symptomatic and asymptomatic at birth) as a 
marker of disease severity.  The sample size of randomized, 
evaluable subjects is 54.  Dropouts and subjects with audiology 
assessments that are inadequate for study comparison will be 
replaced (up to 20%, or n=10).  Baseline study assessments 
(see Section 7.2) will be performed following randomization.  
Subjects will be followed for 6 months post randomization.  
During the six week treatment period, study subjects will be 
followed every 2 weeks.  Subjects will also be seen at  
approximately one month following the final dose (Study Day 
70), and again at Study Months 4 and 6. 
At each of the visits during the treatment phase (Study Days 1, 
14, 28, and 42), safety labs will be assessed; viral load 

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specimens from blood, urine, and saliva will be obtained; 
adverse events will be assessed; and concurrent medications 
will be recorded.  Ganciclovir concentrations for population 
pharmacokinetic assessment will be obtained at each study visit 
while the subject is receiving study medication.  Dose 
adjustments for weight change will occur at study visits during 
the subject’s treatment period, and may also occur at any time 
during the treatment period as indicated per protocol for 
neutropenia, thrombocytopenia, or renal impairment.  At the 
Study Day 70 visit, safety labs will be obtained; viral load 
specimens from blood, urine, and saliva will be obtained; 
adverse events will be assessed; and concurrent medications 
will be recorded.  Hearing will be assessed at baseline and at 
Study Month 6. 
Changes in whole blood viral load measurements will be 
correlated with hearing outcomes.  In study subjects with 
increasing whole blood viral loads during the course of 
treatment, antiviral resistance may be evaluated.  A Data and 
Safety Monitoring Board (DSMB) will be established to oversee 
the accrual, performance, safety, and efficacy of the trial. 
Estimated Time to 
Complete Enrollment: 
3.5 years from enrollment of the first study subject 
 

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*Schematic of Study Design: 
 
 
 
 
 
 
Month 6 
Month 4 
Day 70 
Day 42 
Day 28 
Day 14 
Day 1 
Hearing Test 
Timing of study visits (days, months) for collection of urine, saliva, and blood (together with safety laboratory measurements at Study Days 1, 14, 
28, 42 and 70) 
Clinical Hearing 
Test 
Study Drug 
Enrollment (signing of Informed 
Consent): 
Evaluation of Guthrie Cards or other 
documentation of congenital CMV 
Randomization   Baseline 
Assessments, including baseline 
hearing test 

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1 
 
1. 
KEY ROLES 
Individuals: 
 
Protocol Clinical Project Manager: 
Walla Dempsey, PhD 
Division of Virology 
DMID/NIAID/NIH 
Division of Microbiology and Infectious Diseases, NIAID, NIH  
Room 8E575601 Fishers Lane  MSC 9825  
Bethesda, MD  20892-9825 
Phone: 240-292-4197 
wdempsey@niaid.nih.gov 
 
Principal Investigator: 
David W. Kimberlin, M.D. 
Protocol Chair 
Co-Principal Investigator, NIAID 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 
 
Clinical Studies Manager 
Penny Jester, RN, MPH, CCRA 
Collaborative Antiviral Study Group 
The University of Alabama at Birmingham 
1600 Seventh Avenue South, CHB 303 
Birmingham, AL  35233 
Phone: 205-934-5316 
Phone: 205-996- 7800(direct line) 
Cell:    205-329-3732 
FAX: 205-975-9972 
e-mail: pjester@peds.uab.edu 
Medical Monitor:  Venus Shahamatdar, M.D. 
Office of Clinical Research Affairs 
Division of Microbiology and Infectious Diseases, NIAID, NIH  
5601 Fishers Lane, 7E54,   
Bethesda, MD  20892-9826 

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2 
 
Phone: 240-627-3369   
Email: venus.shahamatdar@nih.gov 
Institutions: 
 
University of Alabama at Birmingham  
David W. Kimberlin, M.D. 
 
Department of Pediatrics, Division of Infectious Diseases  
1600 7th Avenue South, CHB 303 
 
Birmingham, AL 35233 
 
Phone: 205-934-5316  
Fax: 205-975-9972 
 
Email: Dkimberlin@peds.uab.edu  
 
University College London Medical School 
Paul Griffiths, M.D. 
UCL Medical 
School 
Royal Free Campus 
 Centre for Virology 
Rowland Hill Street 
London, UK NW3 
2PF Phone: 020-
7830-2997 
Fax: 020-7830-2854 
Email: p.griffiths@ucl.ac.uk 
 
Carolinas Medical Center - Charlotte  
Amina Ahmed, M.D. B.S. 
 
Department of Pediatrics 
 
1000 Blythe Boulevard 
MEB-4th 
 
Charlotte, NC 28203  
Phone: 704-381-6870  
Fax: 704-381-6841 
Email: Amina.ahmed@carolinashealthcare.org  
 
University of Utah School of Medicine 
Kwabena Ampofo, MD 
30 North 1900 East  
SOM Room # 2A100 
Salt Lake City, UT  84132 
Phone: 801-581-6791 
Fax: 801-585-3789 
Email: krow.ampofo@hsc.utah.edu  
 
Johns Hopkins Medical Institutions  
Ravit Boger, MD 
 
 
Division of Pediatric Infectious Diseases 
 
Rubinstein Child Health Building, 200 North Wolfe Street 
 
Room 3153 
 

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Baltimore, MD 21287  
Phone: 410-614-3917  
Fax: 410-614-1491 
 
Email: boger@jhmi.edu  
 
University of Rochester Medical Center 
 
Mary Caserta, M.D. 
 
601 Elmwood Avenue 
Box 690 
 
 
Rochester, NY 14642  
Phone: 585-275-5944  
Fax: 585-273-1104 
 
Email: mary_caserta@urmc.rochester.edu  
 
The Newcastle upon Tyne Hospitals NHS Foundation Trust 
Marieke Emonts 
 
Royal Victoria Infirmary 
 
Westgate Road 
 
Tyne and Wear, Newcastle Upon Tyne,  NE4 6BE 
Phone: 0 191 256 3765 
 
Fax: 0 191 256 3019  
Email:  marieke.emonts@newcastle.ac.uk  
 
Children's National Medical Center  
Roberta L. DeBiasi, MD 
 
111 Michigan Avenue, NW 
 
Pediatric Infectious Diseases, West Wing 3.5 
 
Washington, DC 20010 
 
Phone: 202-476-5051  
Fax: 202-476-3850 
 
Email: rdebiasi@cnmc.org 
 
Rhode Island Hospital 
Penelope Dennehy, MD  
Division of Pediatric Infectious Diseases 
 
593 Eddy Street      
PO Box RM 018 
 
Providence, RI 02903  
Phone: 401-444-8360  
Fax: 401-444-5650 
 
Email: pdennehy@lifespan.org  
 
University Hospital Southampton NHS Foundation Trust 
Saul N Faust, 
NIHR Wellcome Trust Clinical Facility 
University of Southampton, 
C Level, West Wing, Mailpoint 218, 
University Hospital Southampton NHS 

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Foundation Trust,  
Tremona Road,  
Southampton,  
Hampshire SO16 6YD 
Phone: 023 8079 4989 
Fax: 023 8079 5023 
Email: s.faust@soton.ac.uk 
 
University Hospitals Bristol NHS Foundation Trust 
Jolanta Bernatoniene  
 
UBH Education 
Centre Upper 
Maudlin Street 
Bristol, BS2 8AE 
Phone: 44 (0)  
117 342  0207 
Fax: 44 (0) 117 3420221 
Email: jolanta.bernatoniene@UHBristol.nhs.uk   
 
Heart of England NHS Foundation Trust 
Scott Hackett, BSc, MD, MB ChB, MRCP, DTM&H 
Birmingham Heartlands Hospital 
Bordesley Green East 
Birmingham, B9 5SS 
Phone: +44 121 424 2696 
Fax: +44 121 773 6458 
Email: scott.hackett@heartofengland.nhs.uk  
 
Oxford University Hospitals NHS Foundation Trust  
Dominic Kelly  
Department of Paediatrics, University of Oxford 
 
Level 4, John Radcliffe Hospital 
 
Oxford, Oxfordshire OX3 9DU 
 
Phone: 44 (0)1865 231693 
 
Fax: 44 (0)1865 234235 
 
Email: dominic.kelly@paediatrics.ox.ac.uk  
 
Ohio State University – Nationwide Children’s Hospital 
Pablo Sanchez, MD  
Center for Perinatal Research 
The Research Institute at Nationwide Children’s Hospital 
700 Children’s Drive, RB3WB5215 
Columbus, OH   43205-2664  
Phone: 614-355-5724  
Fax: 614-355-5899 
 
Email: pablo.sanchez@nationwidechilrens.org  
 
St. George's University Hospitals Healthcare NHS Foundation 

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Trust 
Mike Sharland, MBBS MD 
 
 
Blackshaw Road 
 
 
 
Tooting, London SW17 0QT  
Phone: +44 20 8725 3262 
 
Fax: +44 20 8725 0716 
 
Email: mike.sharland@stgeorges.nhs.uk  
 
Steven & Alexandra Cohen Children’s Medical Center of New 
York (CCMC) 
Sunil Sood, MD 
 
300 Community Drive  
9 Tower North Shore University Hospital, Room 8  
 
Manhasset, NY 11030 
 
Phone: 516-562-3957  
Fax: 516-562-3958 
 
Email: sood@lij.edu  
 
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  
 
Great Ormond Street Hospital for Children NHS Foundation 
Trust 
Nigel Klein, M.D. 
Infectious Diseases and Immunology 
Institute of Child Health and 
Great Ormond Street Hospital for Children 
30 Guilford Street,   
London WC1N 1EH 
Phone: 0207 905 2891 
Fax: 0 207 905 2882 
Email: n.klein@ucl.ac.uk 
 
The Pennine Acute Hospitals NHS Trust, Manchester 
Dr Paddy McMaster 
Consultant in Paediatric Infectious Diseases 
Limbert House 
North Manchester General Hospital 
Women and Children’s  

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The Pennine Acute Hospitals NHS Trust 
Manchester 
M8 5RB 
Direct: 0161 922 3880 
Fax: 0161 922 3990 
Mobile: 07960 753 768 
Switch: 0161 624 0420 
E-mail: Paddy.McMaster@pat.nhs.uk 
 
Sheffield Children's NHS Foundation Trust 
Dr Fiona Shackley 
Consultant Paediatrician 
Infectious disease and immunology 
Sheffield Children's Hospital 
Sheffield Children's NHS Foundation Trust 
Western Bank 
Sheffield. S10 2TH 
Direct: 0114 2717172 
Fax: 0114 271 7672 
Mobile: 07964 554327 
Switch: 0114 271 7000 
E-mail: Fiona.Shackley@sch.nhs.uk 
Statistical and Data 
Coordinating Center 
(SDCC): 
 
Statistician: 
Inmaculada "Chichi" Aban, PhD 
Associate Professor 
Department of Biostatistics 
School of Public Health 
The University of Alabama at Birmingham 
RPHB 327 
Phone: (205) 934-2732 
Fax: 
(205) 975-2541 
e-mail: caban@ uab.edu 
 

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2. 
BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
2.1. Background Information 
Congenital cytomegalovirus (CMV) infection is the most frequent known viral cause of mental 
retardation,1 and is the leading non-genetic cause of sensorineural hearing loss in many 
countries including the United States.2-4  It also is the most common congenital infection in 
humans, with approximately 1% of all live births in the United States being infected with CMV (~ 
40,000 babies per year).5  CMV can be acquired in utero during any trimester of pregnancy.  Of 
those fetuses infected, approximately 10% will be symptomatic at birth, and ~ 20% of these 
patients will die in the neonatal period; of the survivors, 90% will have significant neurologic 
sequelae.6-11  The majority of these infants will have sensorineural hearing loss, mental 
retardation, microcephaly, seizures, and/or paresis/paralysis.  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 ten to fifteen years.  
  
Children born with congenital CMV infection but without overt symptoms may nevertheless 
develop sequelae on follow-up, particularly sensorineural hearing loss.  A recent systematic 
review of all prospective studies published worldwide reports that 13.5% of babies with 
congenital CMV infection develop sensorineural hearing loss on follow-up.12  Of babies who 
develop sensorineural hearing loss, more than a quarter of babies born with symptomatic 
congenital CMV disease and almost 40% of babies born with asymptomatic CMV infection will 
have delayed-onset hearing loss, as illustrated in the following table:13 
 
Characteristics of Audiologic Sequelae in Congenital CMV Infection and Disease 
 
 Sequelae 
 
 
    Symptomatic 
 
Asymptomatic 
Sensorineural hearing loss 
 
   41% (85/209) 
 
  7.4% (48/651) 
Characteristics of loss 
 
Unilateral loss  
 
   33% (28/85)  
 
  52% (25/48) 
 
Bilateral loss  
 
   67% (57/85)  
 
  48% (23/48) 
 
High frequency loss only 
   13% (11/85)  
 
  38% (18/48) 
 
Delayed-onset loss 
 
   27% (23/85)  
 
  38% (18/48) 
 
Progressive loss 
 
   54% (46/85)  
 
  54% (26/48) 
 
Fluctuating loss 
 
   29% (25/85)  
 
  54% (26/48) 
 
Improvement of loss  
   21% (18/85)  
 
  48% (23/48) 
 

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Furthermore, the overwhelming majority who will develop delayed-onset hearing loss do so by 4 
years of age:13 
 
Cumulative Percentage of Sensorineural Hearing Loss, by Age 
 
  Age  
 
    Symptomatic 
Asymptomatic 
Birth – 1 month 
 
          43.5%  
        25.5% 
3 months 
 
 
          55.3%  
        31.4% 
6 months 
 
 
          67.2%  
        43.1% 
2 years 
 
 
          82.4%  
        47.1% 
3 years 
 
 
          88.2%  
        58.8% 
4 years 
 
 
          89.4%  
        72.5% 
6 years 
 
 
          95.3%  
        86.6% 
7 – 15 years  
 
          100% 
 
        100% 
 
The overall societal costs of providing specialized services for surviving infants and children with 
congenital CMV infections are in the billions of dollars annually.14  For all of these reasons, the 
Institute of Medicine 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 two decades away. 
2.1.1. Retrospective diagnosis of congenital CMV 
Clinical investigators are now diagnosing congenital CMV infection retrospectively when older 
children present with hearing loss by means of PCR testing on stored dried blood spots (DBS; 
Guthrie cards) which had been obtained during the neonatal period.  While the sensitivity of 
DBS PCR is variable (34-100%), the specificity is high (99-100%) such that a positive result 
confirms congenital CMV infection while a negative result does not rule out a congenital CMV 
infection.16,17  Walter et al.18 conducted a study using quantitative PCR to extend these results 
and determine if there was a threshold value of CMV genomes in a DBS above which hearing 
loss occurred more frequently.  Briefly, DBS were created from fresh blood known to be CMV 
PCR positive at various levels of viral load and tested on multiple occasions. Guthrie cards were 
also created from fresh blood known to be CMV PCR negative and stored at room temperature 
adjacent to CMV-positive cards to facilitate any possible cross-contamination.  Over a 12 month 
period, 43 negative DBS gave negative results (specificity 100%) and 39 positive DBS gave 
positive results (sensitivity 100%).  Compared to the viral load found in each fresh whole blood, 
the viral load from the DBS was initially approximately 2 logs lower but remained stable for at 
least 2 years.  These results show that the sensitivity of DBS is slightly lower than that of whole 
blood (cut-off 1000 genomes/ml vs 200 genomes/ml) but that DBS retrieved from children of the 
age required for this study should give reliable results.  Additionally, the stored DBS of 39 
children (aged 2 months-13 yrs at time of testing) with proven congenital CMV infection and 
sensorineural hearing loss were retrieved, together with those from 35 children (aged 7months 
to 15years) with unexplained SNHL.  These samples were tested under code by quantitative 
PCR.  The sensitivity was 75% (28/39 known cases of congenital infection) while 23% (8/35) of 

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cases of unexplained SNHL were PCR positive (similar to results of 20% and 25% previously 
reported for qualitative PCR).  One case of a false-positive reaction was seen (child and mother 
both CMV seronegative).  Importantly, a defined threshold effect was seen when severity of 
hearing loss was plotted against CMV viral load in DBS.  However, the shape of this curve was 
so steep that, for practical purposes, the detection of any level of viremia could be considered a 
risk factor for future hearing loss, as previously reported by the NIAID Collaborative Antiviral 
Study Group (CASG).19  We conclude from all these results that ongoing CMV replication may 
be a risk factor for progressive hearing loss and that control of viral replication may be 
considered a potential pharmacodynamic measure of successful antiviral therapy. 
2.1.2. Treatment of Congenital CMV 
CYTOVENE-IV (ganciclovir)  is indicated for the treatment of CMV retinitis in 
immunocompromised patients, including patients with acquired immunodeficiency syndrome 
(AIDS) and for the prevention of CMV disease in transplant recipients at risk for CMV disease. 
In adults, VALCYTE (valganciclovir) is indicated for the treatment of CMV retinitis in patients 
with acquired immunodeficiency syndrome (AIDS) and for the  prevention of CMV disease in 
kidney, heart, or kidney-pancreas transplant  patients at high risk. 
In pediatric patients,  valganciclovir is indicated for the prevention of CMV disease in kidney or 
heart transplant patients at high risk. 
There are no FDA approved therapies for congenital CMV.  Both intravenous ganciclovir and 
oral valganciclovir have been evaluated previously for the treatment of neonates with 
symptomatic congenital CMV.  Several studies conducted by the  CASG have indicated that 
ganciclovir therapy may be beneficial to neonates with congenital CMV. 
2.1.2.1.  Evaluations of Ganciclovir and Valganciclovir 
In one phase III study, 100 neonatal subjects were randomized to receive either 6 weeks of IV 
ganciclovir or no therapy.20  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 patients 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 best evaluable ear 
(“functional” assessment) and on total evaluable ears (“biologic” assessment).  The best ear 
assessment correlates with functional hearing impairment in daily living (e.g., a person with mild 
hearing impairment in one ear and severe hearing impairment in the other ear will function 
essentially as a mildly hearing impaired person).21,22  Total ear assessment further assesses the 
biologic effects of ganciclovir therapy.  Of these 100 subjects, 42 patients met all study entry 

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criteria, had both a baseline and 6 month follow-up BSER audiometric exam, and thus were 
evaluable for the primary endpoint.   
 
Twenty-one (84%) of 25  evaluable ganciclovir recipients either had improvement in hearing in 
their best ear between baseline and 6 months or had normal hearing at both timepoints, 
compared with 10 (59%) of 17 evaluable  patients 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 two additional 
patients who did not meet all entry criteria yielded an adjusted P-value of 0.03.  None (0%) of 25 
ganciclovir recipients had worsening in hearing in their best ear between baseline and 6 
months, compared with 7 (41%) of 17 patients in the no treatment group [adjusted P-value < 
0.001; OR 21.11 (95% CI: 2.84,∞)].  Five (21%) of 24 ganciclovir recipients had worsening in 
hearing in their best ear between baseline and ≥ 1 year, compared with 13 (68%) of 19 patients 
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 six weeks following study enrollment than did patients who did not receive antiviral 
therapy. 
 
Laboratory abnormalities reported during the study, were assessed by the development of 
Grade 3-4 toxicity utilizing NIAID Division of AIDS (DAIDS) toxicity tables. The most frequent 
adverse event was neutropenia, which was experienced by a markedly higher proportion of 
patients on the IV ganciclovir arm of the study.20  Twenty-nine (63%) of 46 ganciclovir-treated 
patients developed Grade 3 or 4 neutropenia during the six weeks of study drug administration, 
compared with 9 (21%) of 43 patients in the no treatment group over the same period of time (P 
< 0.01).  Dose adjustments were required for neutropenia in fourteen (48%)subjects, although 
only 4 patients had the drug permanently discontinued.  The mean time (± SD) of onset of grade 
3 or 4 neutropenia for patients receiving ganciclovir was 14.2 (± 12.3) days, and for the no 
treatment group was 14.3 (± 13.1) days.  Neutropenia in ganciclovir-treated patients resolved in 
12.8 (± 13.6) days, and in the no treatment group in 14.2 (± 13.5) days.  All affected patients 
resolved their neutropenia.  Anemia was also more common in patients who received IV 
ganciclovir (8%, vs. 3% untreated patients), although the incidence of thrombocytopenia 
appeared comparable in the two treatment groups (2% i.v. ganciclovir treated patients vs. 3% 
untreated patients). The incidence of bloodstream infections, hematochezia, and diarrhea was 
also higher in patients who received IV ganciclovir.  The incidence of a Grade 3-4 increase in 
serum creatinine, alanine amino transferase (ALT), and total bilirubin levels was comparable 
between groups. 
 
In summary, ganciclovir treatment of neonates with symptomatic congenital CMV disease 
involving the CNS indicates that ganciclovir therapy both improves hearing function (or 
maintains normal hearing) and prevents hearing deterioration at 6 months.  Furthermore, 
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have a more rapid resolution of their transaminase elevations and a greater degree of short 
term growth in weight and head circumference compared with untreated patients. 
 
Previous studies of ganciclovir in adult patients indicated that the AUC of ganciclovir is most 
closely related to virologic treatment success.23   In adults, valganciclovir, the mono-valyl ester 
pro-drug of ganciclovir is well absorbed and converted rapidly to ganciclovir.  The NIAID CASG 
therefore conducted a Phase I/II pharmacokinetic/pharmacodynamic investigation of oral 
valganciclovir in infants with symptomatic congenital CMV disease.24  Twenty-four subjects 
under one month of age with symptomatic congenital CMV disease were enrolled.  All subjects 
received antiviral treatment for congenital CMV, either predominantly with IV ganciclovir and 
with intermittent doses of oral valganciclovir, or predominantly with oral valganciclovir.  
 
Based on data from a previous phase II study of intravenous ganciclovir  in neonates with 
symptomatic congenital CMV disease, a target  AUC12 of 27 ugxh/mL (mean AUC12=32.3+13.7 
ugxh/mL, range 17.2 to 55.9 ugxh/mL, n=13) was defined following treatment with a 6 
mg/kg/dose q 12 hrs.25  The evaluation of valganciclovir in the same population showed that a 
median dose of oral valganciclovir of 16 mg/kg provided a ganciclovir AUC12 of 27.4 ugxh/mL.24  
The median half-life of valganciclovir in infants ranged between 2.5 to 3 hours.  This study also 
demonstrated 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 renal clearance of ganciclovir during the same 
period.  Thus, oral valganciclovir actually is a more reliable method of delivering ganciclovir to 
young infants than 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. 
 
Oral valganciclovir was well tolerated with no vomiting.  The primary safety finding was the 
development of neutropenia.  Neutropenia of grade 3 or 4 developed in 38% (n=9) of study 
subjects treated with  oral valganciclovir and/or iv ganciclovir, but only 1 subject discontinued 
antiviral therapy because of neutropenia.24  Three subjects developed grade 3 anemia, 1 
developed a grade 3 elevation in AST and 1 developed a grade 3 hyperbilirubinemia.  Eleven 
subjects on this study experienced SAEs (46%).  One (neutropenia) was assessed to be 
probably related to receipt of study medication; ten were assessed as unrelated.   
2.2. Rationale 
 Because of the progressive nature of congenital CMV-associated hearing loss, there is a large 
unmet medical need for treatment options beyond the neonatal period.  Data from other CASG 
investigations support the study of antiviral treatment in infants and toddlers with CMV-
associated hearing loss: 
• 
Less than half of the hearing loss due to congenital CMV infection is present at birth.4,13 

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• 
Children with congenital CMV continue to excrete virus in the urine for three to five years or 
even longer.26 
• 
The quantity of CMV (viral load) found in the urine and blood is greater in those children 
destined to develop hearing loss.19,26,27 
• 
CMV DNA has been detected in the perilymph of children up to four years of age 
undergoing cochlear implantation for CMV-induced hearing loss.28 
• 
Six weeks of IV ganciclovir at 6mg/kg bid given to neonates with congenital CMV disease 
beginning when they are less than 31 days of age reduces the future incidence of hearing 
loss.20 
• 
Six weeks of intravenous ganciclovir given to neonates with congenital CMV disease 
beginning when they are less than 31 days of age suppresses viruria, as detected by cell 
culture, but viruria returns promptly when the drug is stopped, even at the higher dose of 
6mg/kg bid.29 
• 
The dose of oral valganciclovir that provides the same systemic exposure as the IV 
ganciclovir dose used in treatment of congenital CMV has been identified, with 16 
mg/kg/dose of oral valganciclovir equaling 6 mg/kg/dose of IV ganciclovir.24 
We hypothesize that six weeks of antiviral therapy can stabilize hearing deterioration in older 
infants, toddlers, and young children who have developed CMV-associated hearing loss.  We 
will conduct a Phase II study of valganciclovir to test this possibility.  We have powered this 
study to detect a similar difference in audiologic outcomes to that seen when ganciclovir was 
given for the same duration to neonates and young infants (i.e. worsening of hearing in 41% 
versus 0% was observed,20 whereas the more conservative difference of 40% versus 5% has 
been used for the power calculation for the current study).  Since the natural histories of CMV 
viruria and viremia have not been defined in older children, we anticipate generating valuable 
data on viral load as a potential biomarker in this population, even if the clinical primary endpoint 
of hearing is not met.  It is possible to envisage utilizing such biomarker data in the development 
of a future study evaluating a longer duration of valganciclovir or with safer medications.   
In the recently completed CASG 112 study of neonates and young infants with symptomatic 
congenital CMV disease, whole blood viral loads decreased from approximately 3.5 logs to 
under 2 logs in both groups over the course of the first six weeks of open-label valganciclovir 
therapy.  Viral loads in the two groups of subjects then diverged initially following randomization, 
but by four months the group randomized to placebo had regained virologic control.  By six 
months the two groups each had approximately 1.5 logs of virus detectable in blood, with the 
group that had received active drug throughout the six months then experiencing a rebound in 
viral load as treatment was stopped.  Viral load was not assessed beyond month seven.  Lower 
whole blood viral load area-under-the-curve during the first six weeks of therapy was associated 
with better hearing outcomes at 12 and 24 months in unadjusted (p=0.005 and p=0.003, 
respectively) and adjusted (p=0.044 and p=0.023, respectively) analyses.  However, lower 
whole blood viral load area-under-the-curve from week six to month six was not associated with 
hearing outcomes in adjusted analyses (p>0.168).  This suggests that lowering systemic viral 
load initially aids in improving audiologic outcomes, but that the additional benefit of longer-term 
treatment for six months may relate to antiviral effects within the inner ear itself, where ongoing 
viral replication and damage may be impaired with prolonged antiviral therapy. We were not 

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able to identify specific breakpoints above which the viral load could be used as a biomarker for 
those patients at higher risk of developmental or hearing sequelae. 
Furthermore, we will link this proposed study to the recently introduced national screening 
programs for hearing loss to demonstrate how CMV screening could be integrated into current 
diagnostic algorithms employed in the United States and United Kingdom, which offer a 
potentially cost-effective way to address the unmet medical problem of CMV. 
2.3. Potential Risks and Benefits 
2.3.1. Potential Risks 
The potential risks associated with oral valganciclovir administration relate primarily to the 
known toxicity of this antiviral agent, neutropenia.  Stopping rules are incorporated into this 
Phase II trial in order to limit exposure of study subjects should the potential risks be 
unacceptably high. 
In addition to neutropenia, the clinical toxicities of valganciclovir include anemia and 
thrombocytopenia.  In animal studies, ganciclovir was carcinogenic, teratogenic, and caused 
aspermatogenesis. Some additional adverse events reported with valganciclovir are diarrhea, 
nausea, vomiting and abdominal pain. General disorders reported are pyrexia and fatigue. The 
most common neurological adverse events reported are headache and insomnia.  
The risk associated with blood draws may be discomfort from the needle stick and occasional 
bruising at the site during or after the blood drawing and rarely an infection.  A small clot may 
form at the site where the needle enters the body. 
2.3.2. Known Potential Benefits 
Six weeks of intravenous ganciclovir has been proven to protect against hearing deterioration in 
patients with congenital CMV infection when treatment was initiated during the first month of 
life.20  As described above, treatment with oral valganciclovir has the potential benefit of 
improving hearing outcomes in children with congenital CMV infection and hearing loss who are 
1 month through 3 years of age. 

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3. 
OBJECTIVES 
3.1. Study Objectives 
Primary: 
• 
The primary objective is to assess whether a six week course of oral valganciclovir can 
stabilize the hearing of children with congenital CMV infection who present with hearing loss.  
This will be accomplished by evaluating changes in hearing in either ear at 6 months from 
baseline. 
 
Secondary: 
• 
To define the following responses as a function of systemic exposure to ganciclovir (active 
metabolite of valganciclovir): 
o CMV viral load in blood 
o CMV viral load in urine 
o CMV viral load in saliva 
• 
To define the safety and tolerability of valganciclovir in enrolled subjects. 
 
Tertiary: 
• 
To define the pharmacokinetics of ganciclovir (metabolite) following administration of 
valganciclovir (prodrug) in enrolled subjects. 
3.2. Study Outcome Measures 
3.2.1. Primary Outcome Measure 
• 
Change in total ear hearing assessments (improved + no change versus other) between 
Baseline and Study Month 6 
3.2.2. Secondary Outcome Measures 
• 
Change in best ear hearing assessments [improved + no change (normal to normal) versus 
other; improved versus other; worse + no change (abnormal to abnormal) versus other; and 
worse versus other] between Baseline and Study Month 6 
• 
Change in total ear hearing assessments (improved versus other; worse + no change 
(abnormal to abnormal) versus other; and worse versus other) between Baseline and Study 
Month 6 
• 
Detection of viruria by PCR six weeks and six months after trial entry 

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• 
The quantitative log reduction in viruria detected after 6 weeks of therapy 
• 
Detection of viremia by PCR six weeks and six months after trial entry 
• 
The quantitative log reduction in viremia detected after 6 weeks of therapy 
• 
Detection of CMV in saliva by PCR six weeks and six months after trial entry 
• 
The quantitative log reduction in CMV viral load in saliva detected after 6 weeks of therapy 
• 
Correlation of change in viral load with change in total ear and best ear hearing at 6 months 
• 
Incidence of unanticipated medically attended visits occurring from Study Day 1 through two 
weeks following the last dose of study drug 
• 
Incidence of adverse events which lead to permanent discontinuation of valganciclovir 
therapy or have an unresolved outcome 
3.2.3. Tertiary Outcome Measures 
• 
Blood concentrations of ganciclovir after administration of valganciclovir  

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4. 
STUDY DESIGN 
This is a Phase II international, multi-center, double-blind, placebo-controlled evaluation of 6 
weeks of valganciclovir treatment for children (up to 4 years of age) with virologically-confirmed 
congenital CMV infection and hearing loss.  Patients who are between 1 month and 4 years of 
age and who have SNHL are eligible for enrollment on the study.  Enrollment on the study 
occurs when eligibility is confirmed and the informed consent is signed.  Following the 
signing of informed consent, the subject’s Guthrie card will be retrieved and tested for CMV 
DNA by PCR unless there is a virologically confirmed diagnosis of congenital CMV infection 
made within the first 30 days of life.  Randomization on the study occurs when the 
diagnosis of congenital CMV infection is confirmed, and the subject then is assigned to 
either receive 6 weeks of oral valganciclovir or 6 weeks of placebo.  Study subjects will be 
stratified according to age at randomization (1 through 11 months, 12 through 23 months, 24 
through 35 months, and ≥ 36 months) and CMV involvement (symptomatic and asymptomatic at 
birth) as a marker of disease severity.  The sample size of randomized, evaluable subjects is 
54.  Dropouts and subjects with audiology assessments that are inadequate for study 
comparison will be replaced (up to 20%, or n=10).  Baseline study assessments (see Section 
7.2) will be performed following randomization.  Subjects will be followed for 6 months post 
randomization.  During the six week treatment period, study subjects will be followed every 2 
weeks.  Subjects will also be seen at approximately one month following the final dose (Study 
Day 70), and again at Study Months 4 and 6. 
At each of the visits during the treatment phase (Study Days 1, 14, 28, and 42), safety labs will 
be assessed; viral load specimens from blood, urine, and saliva will be obtained; adverse 
events will be assessed; and concurrent medications will be recorded.  Ganciclovir 
concentrations for population pharmacokinetic assessment will be obtained at each study visit 
while the subject is receiving study medication.  Dose adjustments for weight change will occur 
at study visits during the subject’s treatment period, and may also occur at any time during the 
treatment period as indicated per protocol for neutropenia, thrombocytopenia, or renal 
impairment.  At the Study Day 70 visit, safety labs will be obtained; viral load specimens from 
blood, urine, and saliva will be obtained; adverse events will be assessed; and concurrent 
medications will be recorded.  Hearing will be assessed at baseline and at Study Month 6. 
Changes in whole blood viral load measurements will be correlated with hearing outcomes.  In 
study subjects with increasing whole blood viral loads during the course of treatment, antiviral 
resistance may be evaluated.  A Data and Safety Monitoring Board (DSMB) will be established 
to oversee the accrual, performance, safety, and efficacy of the trial. 
Study Day 1 of the study is the day following randomization that the first dose of study 
medication is administered.  “Study drug” refers to valganciclovir or placebo (for six weeks).  
Follow-up visits referred to by Study Day will be determined by calendar day from Day 1 (e.g., if 
Study Day 1 is June 20, then Study Day 7 will be June 26); follow-up visits referred to by Study 

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Month will be determined by calendar month (e.g., if Study Day 1 is June 20, then Study Month 
1 will be July 20).   
4.1. Substudies (if applicable) 
None. 

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5. 
STUDY ENROLLMENT, RANDOMIZATION, AND 
WITHDRAWAL 
5.1. Enrollment 
Male and female infants from 1 month through 3 years of age (up to 4th birthday) with 
sensorineural hearing loss will be eligible for enrollment.  Enrollment on the study occurs 
when eligibility is confirmed and the informed consent is signed.  Following confirmation of 
inclusion/exclusion criteria and the signing of informed consent, the subject’s Guthrie card will 
be retrieved and tested for CMV DNA by PCR unless there is a virologically confirmed diagnosis 
of congenital CMV infection made within the first 30 days of life.  Enrollment will be implemented 
by the web-based enrollment system developed and maintained at the UAB Biostatistics Unit at 
the University of Alabama at Birmingham. 
Clinicians who care for these patients (e.g., audiologists, otolaryngologists, pediatricians) will be 
made aware of the study so that they can inform the parents and guardians of patients with 
sensorineural hearing loss about the availability of the study.  
5.2. Subject Inclusion Criteria 
• 
Signed informed consent from parent(s) or legal guardian(s) 
• 
Sensorineural hearing loss (≥ 21dB in one or both ears, documented within 12 weeks prior 
to study entry) 
• 
Children from 1 month through 3 years of age (up to the 4th birthday) 
5.3. Subject Exclusion Criteria 
• 
Imminent demise 
• 
Profound sensorineural hearing loss (> 90dB) in both ears 
• 
Patients receiving other antiviral agents or immune globulin 
• 
Gastrointestinal abnormality which might preclude absorption of an oral medication (e.g., a history 
of necrotizing enterocolitis) 
• 
Documented renal insufficiency, as noted by a creatinine clearance < 10 mL/min/1.73m2 at time of 
study enrollment 
• 
Breastfeeding from mother who is receiving ganciclovir, valganciclovir, foscarnet, cidofovir, or 
maribavir 
• 
Infants known to be born to women who are HIV positive (but HIV testing is not required for study 
entry). 
• 
Current receipt of other investigational drugs 
• 
Previous receipt of ganciclovir or valganciclovir 
• 
Known hypersensitivity to ganciclovir, valganciclovir, or components of the product 

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• 
Inability to attend follow-up hearing and clinical assessments 
• 
Infants with Auditory neuropathy/dyssynchrony. 
• 
Children with another known etiology for SNHL (e.g. connexin 26, syndrome or metabolic disorder 
associated with SNHL, inner ear malformation and widened vestibular aqueducts, meningitis).  
Exclusion of each of these conditions is not required for trial enrollment. 
5.4. Treatment Assignment Procedures 
5.4.1. Randomization Procedures 
Randomization on the study occurs when the diagnosis of congenital CMV infection is 
confirmed, and the subject then is assigned to either receive 6 weeks of oral valganciclovir or 6 
weeks of placebo.  Study subjects will be stratified according to age at randomization (1 through 
11 months, 12 through 23 months, 24 through 35 months, and ≥ 36 months) and CMV 
involvement (symptomatic and asymptomatic at birth) as a marker of disease severity.  Age 
stratification is justified by the differences in the hearing assessments methods utilized for 
infants younger than 12 months versus toddlers 12 months and older.  Dropouts and subjects 
with audiology assessments that are inadequate for study comparison will be replaced (up to 
20%, or n=10).   
Randomization will be implemented by the web-based randomization system developed and 
maintained at the UAB Biostatistics Unit at the University of Alabama at Birmingham.  The 
generation and maintenance of study randomization codes will be the responsibility of the UAB 
Biostatistical Unit.  The codes will be kept in a secure location in the Biostatistics Unit. 
5.4.2. Masking Procedures 
Study subjects, investigators, and staff interacting with the study subjects will be masked to 
treatment.  At the time of randomization, the site study pharmacist (who will not be masked to 
treatment) will prepare oral valganciclovir or oral placebo for distribution to the study subject.  To 
ensure masking of all other study staff and families, study drug will be dispensed in amber 
bottles, along with amber-colored syringes for drawing up all doses.  Additionally, the central 
audiologist who analyzes the audiology data will be masked to study assignment, as will all 
personnel at the UAB Central Unit (with the exception of the UAB Study Statistician). 
Upon completion of the six month follow-up period for all study subjects, or if the study is 
stopped early for any reason, the study will be unmasked after all enrolled study participants 
have completed the Month 6 follow-up assessments and the database is frozen.  In an 
emergency situation, in which knowledge of the treatment assignment will be used to 
reduce/remove an immediate hazard to a volunteer, the study PI and/or a local site PI will have 
the ability to access the treatment assignment.  In this situation (emergency unblinding) the 
study/local PI must explain and justify the nature of the event that resulted in the decision to 

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immediately unblind to the DMID Medical Monitor and the Protocol Chair as soon as possible.  
This justification will be documented as a protocol deviation, and the IRBs and regulatory 
agencies will be informed as is appropriate. 
 
Unmasking/Unblinding may also occur when the safety of a study participant is in question.  In 
non-emergency situations, a conference call will be held to determine whether or not unmasking 
of an individual study subject is necessary or appropriate.  The conference call will include the 
Protocol Chair, Protocol Statistician, DMID Medical Monitor and Clinical Project Manager. 
5.4.3. Reasons for Withdrawal Before Randomization 
The criteria for discontinuation of study participation following enrollment and before 
randomization include: 
• 
Failure to confirm congenital CMV infection 
• 
Study subject (parent/legal guardian) wishes to withdraw 
• 
Trial termination (by UAB Central Unit, FDA, DMID, NIAID, NIH, UCL, or agreement of all 
investigators) issued per safety or efficacy criteria 
• 
Any other reason which, in the opinion of the investigator, precludes the study subject's 
participation in the study.  The principal investigator must call the Protocol Chair (or 
designee) prior to discontinuing a study subject for this reason. 
5.4.4. Reasons for Withdrawal After Randomization and During Treatment 
The criteria for discontinuations during the treatment portion of the study include:  
• 
Development of a related serious adverse event warranting withdrawal of therapy 
• 
Study subject (parent/legal guardian) wishes to withdraw 
• 
Non-compliance with study procedures or medication schedule that in the opinion of the 
investigator warrants withdrawal 
• 
Deterioration in general condition for which alternative treatment is indicated and which, in 
the opinion of the investigator, warrants withdrawal 
• 
Trial termination (by UAB Central Unit, FDA, DMID, NIAID, NIH, UCL, or agreement of all 
investigators) issued per safety or efficacy criteria 

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• 
Any other reason which, in the opinion of the investigator, precludes the study subject's 
participation in the study.  The principal investigator must call the Protocol Chair (or 
designee) prior to discontinuing a study subject for this reason. 
5.4.5. Reasons for Withdrawal After Randomization and After Completion 
of Treatment 
Criteria for discontinuing study subjects from the study after completion of the study medication 
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 investigator must call the Protocol Chair 
(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 
5.4.6. Handling of Withdrawals 
Study subjects may withdraw voluntarily from participation in the study at any time. Up to 20% 
(n=10) 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 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 
electronic case report form (eCRF).  SAEs and AEs will be followed according to guidelines in 
Section 9.  The study subject should be encouraged to complete follow-up visits as part of the 
intent to treat group. 
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 randomized study subjects will continue to be followed as long as possible 
and included in the final analysis. 
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 11.4.1) 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. 

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5.4.7. Termination of Study  
The ethics committees, regulatory agencies, UAB Central Unit, or NIH have the right to 
terminate this study at any time.  Reasons for terminating the study may include, but are not 
limited to, the following: 
• 
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. 

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6. 
STUDY INTERVENTION/INVESTIGATIONAL PRODUCT 
6.1. Study Product Description 
 Valcyte Powder for Oral Solution (valganciclovir) is indicated for the treatment of CMV retinitis 
in adult patients with AIDS and for the prevention of CMV disease in adult and pediatric kidney, 
heart, and kidney-pancreas transplant recipients at high risk.  Simple Syrup (Syrup, NF) will be 
used for the placebo for valganciclovir. 
6.1.1. Acquisition 
Valcyte Powder for Oral Solution (valganciclovir) will be provided for this study by 
Genentech/Roche.  Simple Syrup (Syrup, NF) for placebo will be purchased from a commercial 
vendor by the site.  Study supply (active drug) will be maintained in a central drug repository as 
designated by the UAB Central Unit until study enrollment at a site, at which time the supply of 
study medication will be shipped to the study site pharmacist. 
6.1.2. Formulation, Packaging, and Labeling 
Valcyte Powder for Oral Solution (valganciclovir) will be supplied as a white to slightly yellow 
powder for reconstitution.  The powder is provided in a round amber glass bottle, containing 12g 
powder containing 5g valgancyclovir free base.  Upon reconstitution, the resulting oral solution 
contains 50 mg of valganciclovir free base per 1 mL (Total = 100 mL per bottle).  The inactive 
ingredients for the reconstituted oral solution are mannitol, povidone K-30, sodium benzoate, 
fumaric acid, sodium saccharin, flavoring, and purified or sterile water.  The valganciclovir oral 
solution formulation does not contain lactose anhydrous. 
 
Placebo for Valganciclovir 
The placebo for valganiclovir is Simple Syrup (Syrup NF), which contains 60-90% sucrose in 
purified water.  It is supplied as the commercial preparation. 
Valganciclovir and Simple Syrup (Syrup NF) will be labeled with the drug identification and 
dosage.  The label will comply with IND regulations, the local requirements of the country in 
which the study is being conducted and carry the required caution statement.  Blinded labeling 
of study product will be performed by the licensed pharmacist at the time of dispensing.  
Valganciclovir will be dispensed in its original bottle.  Simple Syrup will be transferred to a 
matching amber bottle.  Study products (active or placebo) will be dispensed in a new bottle at 
each study visit during the six weeks of study drug administration. 

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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 
(77ºC ); excursions permitted to 15°C to 30°C (59°F to 86°F). Store reconstituted oral solution at 
2° to 8°C (36°F to 46°F) for no longer than 49 days. Do not freeze.  Shake bottle well before 
using. 
Simple Syrup placebo is to be stored at 2° to 8°C (36°F to 46°F) for no longer than 49 days 
following dispensing for the study. 
6.2. Dosage, Preparation and Administration of Study 
Intervention/Investigational Product 
Valcyte Powder for Oral Solution (valganciclovir) will be prepared by a licensed pharmacist in 
accordance with instructions in the package insert.  Placebo for valganciclovir (Simple Syrup) 
will be transferred from the commercial bottle to identical empty amber bottles for dispensing. 
Valganciclovir should be dosed at 16mg/kg body weight, unless specific dosage adjustment 
conditions have been met (see Section 6.3), administered orally twice daily for 6 weeks.  
Placebo for valganciclovir (Simple Syrup) should be dosed using the same volume that would 
be required for the active dose, administered orally twice daily for 6 weeks.  Dose modifications 
for neutropenia, thrombocytopenia, renal impairment, and hepatotoxicity are detailed in Section 
6.3.   
Pharmacy preparation instructions for study product can be found in the protocol-specific 
Manual of Procedures (MOP), including directions for the reconstitution of the valganciclovir oral 
solution.  Once reconstituted, the oral solution must be stored under refrigeration for no longer 
than 49 days.  Valganciclovir oral solution has been shown not to adhere to syringes or to 
nasogastric tubing.  Valganciclovir oral solution or placebo for valganciclovir should be 
administered into the patient’s mouth by means of a syringe, which will be amber colored and 
provided by the study.  If the patient is unable to swallow, the study product may be 
administered via the syringe through a nasogastric or gastric tube. 
Study product administration should be timed to precede a feeding.  If the subject vomits or 
spits up following the dosing, re-dosing will not be allowed. 
6.3. Modification of Study Intervention/Investigational Product for a 
Participant 
Bone marrow suppression secondary to CMV can mimic ganciclovir toxicity.  Nevertheless, the 
dosage of valganciclovir will be reduced or interrupted if any of the following occur. 

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6.3.1.  Neutropenia 
If the ANC reproducibly (within one week) decreases to ≤ 500 cells/mm3, study drug will be held 
until the ANC recovers to > 750 cells/mm3, and then administration of the drug will resume at 
the normal dose.  If the ANC again reproducibly (within one week) decreases to ≤ 750 
cells/mm3, the study drug 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 
cells/mm3 on the 50% dosage, then the study medication will be discontinued.  In cases of drug 
interruption, treatment will not be prolonged beyond the originally scheduled 6 week treatment 
timeframe. 
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 study drug will be held if the platelet 
count reproducibly (within one week) decreases to ≤ 50,000/mm3.  After the platelet count 
increases to ≥ 50,000/mm3, study drug administration at the normal dose will resume. 
If the platelet count at baseline was ≤ 100,000/mm3, then study drug will 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, study drug administration at the normal dose 
will resume.  If the platelet count again reproducibly (within one week) decreases by 50%, then 
the study medication will be discontinued.  In cases of drug interruption, treatment will not be 
prolonged beyond the originally scheduled 6 week treatment timeframe. 
6.3.3.  Renal Impairment 
If renal function is normal (creatinine clearance ≥ 60 mL/min/1.73m2), then administer the full 
dose of study drug at the same intervals (valganciclovir 16 mg/kg/dose BID) 
 
If renal function is reproducibly impaired (to be confirmed by repeat serum creatinine), then dose adjust 
as follows: 
 
CrCl 40 to 59 mL/min/1.73m2: 
8 mg/kg/dose PO BID  
CrCl 25 to 39 mL/min/1.73m2: 
8 mg/kg dose PO daily  

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CrCl 10 to 24 mL/min/1.73m2: 
8 mg/kg dose PO every other day. 
CrCl <10 mL/min/1.73m2: 
 
Discontinue study medication  
 
When the lab method of Scr determination is non-IDMS traceable: 
Calculation of creatinine clearance (CrCl) 30 
• 
Estimated CrCl (mL/min/1.73m2) = kL / Scr 
o k = proportionality constant 
o L = length (cm) 
o Scr = serum creatinine (mg/dL) 
• 
k values 
o If low birth weight (< 2,500 g), during first year of life:  0.33 
o If term AGA, during first year of life:  0.45 
o If ≥ 1 year of age:  0.55 
 
When the lab method of Scr determination is IDMS traceable: 
Calculation of creatinine clearance (CrCl)31 
• 
Estimated CrCl (mL/min/1.73m2) = kL / Scr 
o k = proportionality constant 
o L = length (cm) 
o Scr = serum creatinine (mg/dL) 
• 
k values 
o If low birth weight (< 2,500 g), during first year of life:  0.25 
o If term AGA, during first year of life:  0.34 
o If ≥ 1 year of age:  0.41 
6.3.4.  Hepatotoxicity 
If the ALT reproducibly (within one week) increases to > 10 times above baseline, study drug 
will be held until ALT falls to < 5 times above baseline, at which time study drug will be 
restarted. If the ALT again increases 10 times above baseline, study drug will be discontinued.  
In cases of drug interruption, treatment will not be prolonged beyond the originally scheduled 6 
week treatment timeframe. 
6.4. Accountability Procedures for the Study 
Intervention/Investigational Product(s) 
After receipt of the study products and supplies, the site pharmacist will dispense in an amber 
bottle that will be supplied by the study and distribute it to the Principal Investigator (or 
designee) or to the patient’s parent or legal guardian.  The Principal Investigator will delegate to 
the site pharmacist responsibility for drug accountability.   Each pharmacist will be responsible 
for and maintain logs of receipt, accountability, dispensation, storage conditions, and disposal of 

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study drug.  These documents will be maintained in a secure and accessible location, but 
separate from areas accessible to other study staff in order to maintain their blinding.  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 not be disposed of or returned until the study monitor 
reviews and confirms the drug accountability.   
• 
Used or partially used study product will be disposed of by the local site pharmacy in 
accordance with local regulations after completion of drug accountability by the study 
monitor. 
• 
All unopened study drug will be returned to the central drug repository 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. Concomitant Medications/Treatments 
6.5.1.  Concomitant Medication Assessment 
All concomitant medications will be recorded at each study visit  throughout the treatment period 
(start of blinded study drug administration on Day 1 through Day 70. 
6.5.2.  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 
• 
Other Investigational drugs 
 
The following concomitant medications should be used with caution: 
 
• 
Agents that interfere with renal function 
• 
Agents that interfere with bone marrow function 
• 
Imipenem-cilastatin 
 
The concomitant use of ganciclovir and imipenem-cilastatin has been associated with seizures, 
and this medication should only be used if the potential benefits outweigh the potential risks. 

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6.5.3.  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 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 
The study procedures and evaluations are summarized in Appendix A.  Signed informed 
consent will be obtained at study enrollment and before any study-related procedures.  In 
conducting the informed consent process, the research team will adhere to the standards set 
forth by their IRB for obtaining informed consent.  Study windows are provided in parentheses 
and apply to all study events described in that subsection, unless a different window is specified 
for a particular study event. 
7.1. Enrollment (Window: Day -90 to Day -1) 
Following confirmation that the patient is eligible for study enrollment and obtaining informed 
consent, if infection with CMV has not been documented within the first 30 days of life then the 
Guthrie card will be retrieved and analyzed by PCR for CMV DNA; PCR will be performed in the 
U.K. as part of routine clinical investigation protocols, while in the U.S. it will be performed at the 
UAB Central Laboratory.  If the result is positive or if there is other virologic confirmation of 
congenital CMV infection, congenital CMV is confirmed.  These subjects are eligible for 
randomization, following which the baseline assessments (see Section 7.2) will be obtained. 
Subjects who have signed the informed consent document and therefore are enrolled on the 
study but who then do not qualify for randomization in the trial (for example, because the 
Guthrie card PCR was negative) will not be counted toward the final sample size for the study.  
Consented study participants may receive nominal compensation to offset the cost of travel, 
parking, meals, etc., for study visits in accordance with local site policies and local IRB approval. 
7.2. Randomization (Window Day -30 to Day 1) and Baseline 
(Window: Day -3 to Day 1) 
• 
Document congenital CMV infection 
• 
Obtain randomization authorization from UAB data center 
• 
Baseline studies will be performed following randomization of the subject on the trial 
• 
Document baseline demographics, selected laboratory parameters, medical history, and 
baseline conditions (Study Day -30 to Study Day 1) (see Section 8.1.1) 
o Date of birth 
o Gender 
o Race 
o Ethnicity 

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o Birth weight 
o Length at birth, if available 
o Head circumference at birth, if available 
o Gestational age at birth 
o Petechiae at any time from birth through study randomization, if known 
o Thrombocytopenia at any time from birth through study randomization, if obtained 
o Hepatomegaly at any time from birth through study randomization, if noted 
o Splenomegaly at any time from birth through study randomization, if noted 
o CSF white blood cell count at any time from birth through study randomization, if 
obtained 
o CSF protein concentration at any time from birth through study randomization, if 
obtained 
o CSF CMV PCR at any time from birth through study randomization, if performed 
o Seizures at any time from birth through study randomization, if noted 
o Elevated transaminases at any time from birth through study randomization, if obtained 
o Elevated bilirubin at any time from birth through study randomization, if obtained 
o Neuroimaging abnormalities, if obtained 
o Medical history and baseline conditions prior to study randomization, by body system 
o Chorioretinitis 
o Intrauterine growth restriction 
o Urine CMV testing (e.g., viral culture, shell-vial culture, PCR) within 90 days prior to 
study enrollment, if obtained clinically 
• 
Hematology safety labs (see Sections 6.3 and 8.2.1.1) 
o WBC with differential 
o Hemoglobin 
o Platelet count 
• 
Chemistry safety labs (see Sections 6.3 and 8.2.1.2) 
o ALT 
o Total Bilirubin 
o Creatinine 
• 
Weight and length (see Section 8.1.2) 
• 
Adverse event assessment (see Section 9) 
• 
Concurrent medications assessment (see Section 6.6.1) 
• 
Obtain a new hearing assessment or record results from clinically obtained hearing 
assessment (may be obtained any time from Study Day -90 to Study Day -1) (see Section 
8.1.4) 
o BSER 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 

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reflexes) will be obtained to better define the middle or inner ear abnormality (e.g., otitis 
media). 
• 
Virology specimens for CMV viral load (see Section 8.2.2.1) 
• 
Confirm that Study Day 1 safety labs allow for dosing of study medication (see Section 6.3); 
if so, begin study medication on Study Day 1 
• 
Updated results of any etiological investigations for SNHL. 
7.3. Treatment (Day 1 through Day 42) 
Administer study medication twice daily 
7.4. Follow-up  
7.4.1. Day 14 (± 2 days) 
• 
Hematology safety labs (see Sections 6.3 and 8.2.1.1) 
o WBC with differential 
o Hemoglobin 
o Platelet count 
• 
Chemistry safety labs (see Sections 6.3 and 8.2.1.2) 
o ALT 
o Total Bilirubin 
o Creatinine 
• 
Weight and length (see Section 8.1.2) 
• 
Verbally assess previous administration of study medication by parents/ guardians 
• 
Adjust dose of study medication for weight change, if needed 
• 
Adverse event assessment (see Section 9) 
• 
Concurrent medications assessment (see Section 6.6.1) 
• 
Virology specimen for CMV viral load (see Section 8.2.2.1) 
• 
Pharmacokinetic specimen for ganciclovir concentration (see Section 8.2.2.2) 
• 
Updated results of any etiological investigations for SNHL. 

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7.4.2. Day 28 (± 2 days) 
• 
Hematology safety labs (see Sections 6.3 and 8.2.1.1) 
o WBC with differential 
o Hemoglobin 
o Platelet count 
• 
Chemistry safety labs (see Sections 6.3 and 8.2.1.2) 
o ALT 
o Total Bilirubin 
o Creatinine 
• 
Weight and length (see Section 8.1.2) 
• 
Verbally assess previous administration of study medication by parents/ guardians 
• 
Adjust dose of study medication for weight change, if needed 
• 
Adverse event assessment (see Section 8.1.3) 
• 
Concurrent medications assessment (see Section 6.6.1) 
• 
Virology specimen for CMV viral load (see Section 8.2.2.1) 
• 
Pharmacokinetic specimen for ganciclovir concentration (see Section 8.2.2.2) 
• 
Updated results of any etiological investigations for SNHL. 
7.4.3. Day 42 (± 2 days) 
• 
Hematology safety labs (see Section 8.2.1.1) 
o WBC with differential 
o Hemoglobin 
o Platelet count 
• 
Chemistry safety labs (see Section 8.2.1.2) 
o ALT 
o Total Bilirubin 
o Creatinine 
• 
Verbally assess previous administration of study medication by parents/ guardians 
• 
Discontinue study medication after Study Day 42 dosing complete 
• 
Adverse event assessment (see Section 9) 

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• 
Concurrent medications assessment (see Section 6.6.1) 
• 
Virology specimen for CMV viral load (see Section 8.2.2.1) 
• 
Pharmacokinetic specimen for ganciclovir concentration (see Section 8.2.2.2) 
• 
Updated results of any etiological investigations for SNHL. 
7.4.4. Day 70 (± 4 days) 
• 
Hematology safety labs (see Section 8.2.1.1) 
o WBC with differential 
o Hemoglobin 
o Platelet count 
• 
Chemistry safety labs (see Section 8.2.1.2) 
o ALT 
o Total Bilirubin 
o Creatinine 
• 
Adverse event assessment (see Section 9) 
• 
Concurrent medications assessment (see Section 6.6.1) 
• 
Virology specimen for CMV viral load (see Section 8.2.2.1) 
• 
Updated results of any etiological investigations for SNHL. 
7.4.5. Month 4 (± 7 days) 
• 
Virology specimen for CMV viral load (see Section 8.2.2.1) 
• 
Updated results of any etiological investigations for SNHL. 
7.4.6. Month 6 (± 7 days) 
• 
Virology specimen for CMV viral load (see Section 8.2.2.1) 
• 
Hearing assessment  (see Section 8.1.4) (to be obtained -14 days to +30 days from Study 
Month 6) 
o BSER 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 

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distinguish between sensorineural hearing loss, conductive loss, or mixed loss.  If the 
OAEs are abnormal, then acoustic emittance measures (tympanometry and acoustic 
reflexes) will be obtained to better define the middle or inner ear abnormality (e.g., otitis 
media). 
• 
Updated results of any etiological investigations for SNHL. 
7.5. Final Study Visit 
At the last clinic visit, the study subject’s parent or guardian should be notified that this is the 
last contact/visit for the study.  If the family would like to know results of the study, they will be 
asked to provide contact information (if different to information previously recorded) so that at a 
later date (after study results analyzed, the study staff can contact the parent or guardian. 
7.6. 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 encouraged to complete 
follow-up visits as part of the intent to treat group. 
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. 
7.7. 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 9.0 of this protocol. 

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8. 
STUDY PROCEDURES/EVALUATIONS 
The study procedures and evaluations are summarized in Appendix A.  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 
To characterize the study subjects, information will be recorded at the baseline study visit (Day -
30 to Day 1, unless broader window allowed below) following the obtaining of informed consent.  
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; head 
circumference at birth; and gestational age at birth.  The degree of CMV disease involvement at 
birth will be recorded, if known, including: neuroimaging abnormalities; petechiae at any time 
from birth through study randomization; thrombocytopenia at any time from birth through study 
randomization; hepatomegaly at any time from birth through study randomization; splenomegaly 
at any time from birth through study randomization; CSF white blood cell count at any time from 
birth through study randomization; CSF protein concentration at any time from birth through 
study randomization; CSF CMV PCR at any time from birth through study randomization; 
seizures at any time from birth through study randomization; elevated transaminases at any 
time from birth through study randomization; elevated bilirubin at any time from birth through 
study randomization.  Medical history and baseline conditions prior to study randomization will 
be recorded by body system. 
8.1.2.  Growth 
To adjust study medication for weight gain, weight will be recorded at multiple study visits.  To 
assess renal function, length will be recorded at multiple study visits for use in calculating 
creatinine clearance. 
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 
(see Section 9). 

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8.1.4.  Hearing Assessment 
At the study visits on Week 0 (window: Study Day -90 to Study Day -1) and Month 6 (window: -
14 days 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.  
Prior to the implantation, efforts will be made to obtain audiology testing that would have been 
performed at the Month 6 visit. 
8.2. Laboratory Evaluations 
Blood for study-specified laboratory evaluations may be obtained by methods such as the 
following:  venipuncture, heel 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, whole blood CMV viral load/resistance testing, and ganciclovir population 
pharmacokinetics.  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); 3) whole blood CMV viral load/resistance testing (third most important); and 4) 
ganciclovir population pharmacokinetics (least important).  With the exception of the hematology 
safety labs and the creatinine 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 not be 
reported as protocol deviations.  If urine is not obtainable, a protocol deviation will not be 
reported. Saliva will be collected using polyester fiber–tipped swabs.  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 
Blood will be drawn at each study visit.  For all study-related tests, a total of 8.75 mL will be 
drawn from a given study subject during the period of valganciclovir administration, and an 
additional 3.0 mL will be drawn for study labs when valganciclovir is not being administered.  

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The breakdowns of the amount of blood for individual tests are provided in Appendix A, and 
below.  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 
collected at each study visit while the study subject is receiving valganciclovir and at the two 
week visit thereafter.  The following will be tested:  white blood cell count, differential, 
hemoglobin, and platelet count.  The total amount of blood required for the hematology safety 
labs is 2.5 mL over 8 weeks. 
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 
collected at each study visit while the study subject is receiving valganciclovir and at the two 
week visit thereafter.  The following will be tested:  ALT, total bilirubin, and creatinine.  The total 
amount of blood required for the chemistry safety labs is 5.0 mL over 8 weeks. 
8.2.2. Special Assays or Procedures 
8.2.2.1. CMV Viral Load/Resistance Testing 
Assessment of CMV viral load in whole blood 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.  Whole 
blood will be collected at each study visit.  The total amount of blood required for the whole 
blood CMV viral loads is 3.5 mL over 6 months.  CMV viral load will be assessed by quantitative 
PCR. 
Urine collection by bagged or clean catch specimen will be attempted at each study visit.  If 
urine is not obtainable, a protocol deviation will not be reported. Saliva will be collected at each 
study visit.  Specimens will be shipped to the UAB Central Laboratory for analysis. 
Antiviral resistance will be performed in the UAB Viral Resistance Laboratory. 

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8.2.2.2. 
Ganciclovir Population Pharmacokinetics 
Assessment of ganciclovir plasma concentrations will be conducted at the UAB Central 
Pharmacokinetic Laboratory.  Ganciclovir concentrations will be obtained with each blood draw 
obtained while the subject is receiving valganciclovir (Study Day 14, Study Day 28, and Study 
Day 42).  Assessments on each of the Study Days will consist of a single trough specimen.  For 
each subject, one of these three draws will occur 0 to 4 hours after a valganciclovir dose, one 
will occur 4 to 8 hours after a valganciclovir dose, and one will occur 8 to 12 hours after a 
valganciclovir dose.  The required amount of whole blood for plasma ganciclovir determination 
at each timepoint is at least 200 µL (0.2 mL).  Specimens will be processed to separate the 
plasma, which will be shipped to the UAB Central Pharmacokinetic 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. 
DMID SAFETY REPORTING AND SAFETY MONITORING 
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. Responsibilities 
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 (the Central Unit notifies the sponsor, DMID), 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. Adverse Event (AE) 
9.2.1. Definition of an Adverse Event 
 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.  
9.2.2. Documentation of Reportable 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 

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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 9.5. 
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. 
9.3. Investigator’s Assessment of Adverse Event 
The determination of seriousness, severity, and causality will be made by an on-site investigator 
who is qualified (licensed) to diagnose AE information, provide a medical evaluation of AEs, and 
classify AEs based upon medical judgment. This includes 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. 
9.3.1. Assessment of Seriousness 
Event seriousness will be determined according to the protocol definition of an SAE (see 
Section 9.5). 
9.3.2. Assessment of Severity 
All reportable AEs will be graded according to the DIADS Toxicity Table (Appendix B).   
9.3.3. Assessment of Relationship to Study Product 
Relationship to Study Products:  The clinician’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. In a clinical trial, the study product 
must always be suspect.  
The investigator must provide an assessment of relationship of AEs to the study product based 
on: 
• 
Temporal relationship of the event to the administration of study product; 

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• 
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. 
9.4. Study Related Adverse Events 
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 drug related and expected adverse events as documented from prior studies 
consist of: 
o anemia 
o neutropenia 
o diarrhea, and 
o elevated alanine aminotransferase (ALT). 
9.5. Serious Adverse Event (SAE) 
9.5.1. Definition of a Serious Adverse Event 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or sponsor, it results in any of the following outcomes:  
• 
Death, 
• 
 a life-threatening adverse event*,  

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• 
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. 
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 clinician 
• 
reviewed and evaluated by a study clinician 
9.5.2. Reporting Interval 
Document all AEs and SAEs from Study Day 1 through four weeks following the last dose of 
study drug.  
All AEs and SAEs will be followed until resolution, even if this extends beyond the study-
reporting period. 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. 

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9.5.3. Notification of the Sponsor of 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 
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 20814, 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. 
9.5.4. 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-

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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 
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. 
9.6. Halting Rules 
9.6.1. Discontinuation of Study participation for individual subject 
Subjects with neutropenia, thrombocytopenia, renal impairment, or hepatotoxicity will be 
discontinued from study treatment if the criteria outlined in Section 6.3 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. 
9.6.2. Discontinuation of Study Enrollment Pending Sponsor Review 
In prior CASG studies of ganciclovir and valganciclovir that have enrolled 233 subjects, the only 
laboratory toxicity statistically associated with antiviral treatment has been neutropenia.  Halting 
rules for this study therefore have been constructed to interrupt study enrollment if an excessive 
number of subjects are experiencing neutropenia.  In the CASG 102 study, 63% of subjects 
receiving parenteral ganciclovir developed Grade 3 or Grade 4 neutropenia.20  In the CASG 109 
study, 38% of subjects receiving oral valganciclovir developed Grade 3 or Grade 4 
neutropenia.24  Whether this lower rate of neutropenia relates to the mode of drug delivery is not 
known at this time.  Assuming that 75% of subjects receiving ganciclovir developed Grade 3 or 
4 neutropenia and given that randomization is expected to be balanced between those in study 
drug and those in placebo, the stopping rule will be based on assuming that the overall event 
rate for all study participants (i.e., placebo and active subjects combined) is 37.5%.  Therefore, 
study enrollment will be stopped and an ad hoc review will be performed if a significantly higher 
proportion (37.5%) of subjects in this study experience Grade 3 or Grade 4 neutropenia, as 
detailed in the following table: 

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X of the first Y subjects enrolled have Grade 3 or Grade 4 neutropenia, according to the table 
below.  The stopping rules are based on the upper tail probabilities of the cumulative binomial 
with probability of an event set at 0.375. The cut-off numbers  were determined by obtaining the 
largest value such that the tail probability is less than but closest to 0.05. 
 
Number 
enrolled (Y) 
Stop/Investigate 
when number with 
events equals this 
number (X) 
Probability of 
observing X or 
more events 
assuming 
p=0.375 
Number 
enrolled (Y) 
Stop/Investigate when 
number with events 
equals this number (X) 
Probability of 
observing X or 
more events 
assuming 
p=0.375 
4 
4 
0.020 
30 
17 
0.025 
5 
5 
0.007 
31 
17 
0.037 
6 
5 
0.031 
32 
18 
0.024 
7 
6 
0.013 
33 
18 
0.034 
8 
6 
0.036 
34 
18 
0.048 
9 
7 
0.017 
35 
19 
0.032 
10 
7 
0.038 
36 
19 
0.044 
11 
8 
0.019 
37 
20 
0.030 
12 
8 
0.039 
38 
20 
0.041 
13 
9 
0.021 
39 
21 
0.028 
14 
9 
0.039 
40 
21 
0.038 
15 
10 
0.021 
41 
22 
0.026 
16 
10 
0.037 
42 
22 
0.035 
17 
11 
0.021 
43 
22 
0.047 
18 
11 
0.036 
44 
23 
0.032 
19 
12 
0.021 
45 
23 
0.043 
20 
12 
0.034 
46 
24 
0.030 
21 
13 
0.020 
47 
24 
0.040 
22 
13 
0.033 
48 
25 
0.028 
23 
13 
0.050 
49 
25 
0.037 
24 
14 
0.031 
50 
25 
0.048 
25 
14 
0.046 
51 
26 
0.034 
26 
15 
0.029 
52 
26 
0.044 
27 
15 
0.043 
53 
27 
0.032 
28 
16 
0.027 
54 
27 
0.041 
29 
16 
0.040 
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 DSMB will review 
cumulative safety data.  If enrollment is halted based upon the table above or the review of the 
safety data, upon completion of the review and receipt of advice of the DSMB, DMID and the 
Central Unit Administration will determine if study entry or study dosing may continue according 
to the protocol. 

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9.7. Safety Monitoring by the DMID Safety Oversight Mechanism 
9.7.1. Data and Safety Monitoring Board 
A Data and Safety Monitoring Board will be established by the DMID. The DSMB 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 the NIH.  The initial responsibility 
of the DSMB will be to review and make recommendations regarding the initiation of the study. 
A simple majority will be considered a DSMB 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 at intervals determined by the DMID, the DSMB will: 
 
1. Review the research protocol, template informed consent document and plans for data and 
safety monitoring. 
2. Evaluate the progress of the study, including periodic assessments of data quality and 
timeliness, participant recruitment, accrual and retention, participant risk versus benefit, 
performance of the trial sites, and other factors that can affect study outcome. 
3. Review study endpoints for differences between groups and to assess if  
SAEs are occurring at a rate greater than expected. 
4. Consider factors external to the study when relevant information becomes available,  
5. Monitor the confidentiality of the study data and the results of monitoring.  
  
The S&DCC will provide all data, tables, unique and repeated listings, figures, descriptive 
statistics, and tests of significance requested by the NIH for all DSMB meetings, interim analysis 
plan and final analysis.  
 

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

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11. STATISTICAL CONSIDERATIONS 
11.1. Study Hypotheses 
 We hypothesize that six weeks of antiviral therapy can stabilize hearing in older infants and 
toddlers who have developed CMV-associated hearing loss.  This study is designed as a proof 
of principle study. 
11.2. Sample Size Considerations 
Subjects will be randomized 1:1 to valganciclovir oral solution or valganciclovir placebo.  A 
sample size of 54 (27 in each arm) has 90% power to detect a worsening of hearing from 40% 
to 8.0% in the treatment group based on analyzing two correlated binary outcomes with 
correlation coefficient of 0.55 at 2.5% level of significance (using PASS 2008 program).  
Randomization will be stratified by age at randomization (1 through 11 months, 12 through 23 
months, 24 through 35 months, and ≥ 36 months) and by CMV involvement (symptomatic and 
asymptomatic at birth) as a marker of disease severity. 
Efficacy and safety analysis will be based on intent-to-treat population (ITT), defined as any 
child who receives at least one dose of study medication and who has complete hearing 
assessment data at baseline and Month 6.  Children who completed the full six weeks of study 
medication and have hearing assessment data at baseline and Month 6 will be included in a per 
protocol (PP) analysis of efficacy, which will be performed as a sensitivity analysis.  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. 
11.3. Planned Interim Analyses (if applicable) 
No interim analysis for futility or efficacy is proposed because this is a small sample study and 
the penalty for an early look at the outcome data would compromise the study.  However, a 
safety review will be done periodically. 
11.3.1. 
Safety Review  
Safety reports will be generated and sent to DMID to be disseminated to the DSMB. This report 
includes hematology and safety laboratory values and adverse events (serious and non-

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serious).  In addition, Section 9.7 provides a table of halting rules based on the number of 
subjects experiencing Grade 3 or 4 neutropenia for consideration by the DSMB. 
11.3.2. 
Immunogenicity or Efficacy Review 
None. 
11.4. Final Analysis Plan 
11.4.1. 
Primary Outcome 
Primary analysis will be based on intent-to-treat population. Categories utilized for hearing 
assessment of each ear for each time point are normal hearing, mild hearing loss, moderate 
hearing loss, and severe hearing loss. Based on the hearing assessment of each ear at Month 6 
and at Baseline, change in each ear will be categorized into binary outcomes: improved + no 
change versus other (i.e., worsened).  For example, normal in the left ear at baseline and 
moderate in the same ear at Month 6 will be considered as worsened. The primary outcome will 
be analyzed using logistic regression based on generalized estimating equations (GEE) in order 
to accommodate the correlation between the left and right ears of a subject in the modeling. In 
addition, if there are enough data available we will adjust the analyses by whether or not a 
subject at birth is asymptomatic or symptomatic from their congenital CMV infection. Additional 
analyses will be performed to adjust for age and site plus any imbalances in the demographic 
and clinical characteristics to determine if adding them to the model will impact the results. P-
values < 0.05 will be considered significant for the primary outcomes. 
A single, independent study audiologist who is masked (blinded) to treatment assignment will 
assess the audiology test battery for each subject and assign the classifications of normal 
hearing, mild hearing loss, moderate hearing loss, or severe hearing loss based upon their 
hearing thresholds (in decibels). The classifications will be assigned by ear (one for the left ear 
and one for the right ear), giving “total ear” classifications.  Following this, the study audiologist 
will assign the “best ear” classification for the subject at that study visit; for example, if a subject 
had mild hearing loss in their left ear and severe hearing loss in their right ear, then the “best 
ear” classification will be mild hearing loss. 
Primary analyses will be done on the first 54 subjects recruited.  If there were subjects enrolled 
as replacement for dropouts or missing outcome, these added subjects will be included in the 
secondary analyses. 
For those with missing outcome due to missing baseline and/or Month 6 audiology (including 
dropouts), we will exclude them from the primary analysis. However, we will perform sensitivity 
analysis by replacing all missing data with “worsening” outcome.” 

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11.4.2. Secondary and Tertiary Outcomes 
Logistic analyses will be utilized to determine if there is treatment effect based on the best ear 
outcome. As in the total ear analysis, change in the best ear will be categorized into binary 
outcomes – namely:  1) improved + no change versus others, which examines positive hearing 
outcomes defined as improved hearing or protection from hearing impairment in subjects who 
started with normal hearing at baseline; 2) worsened versus others, which examines 
deterioration or worsening of hearing; 3) improved versus others; and 4) worse + no change 
versus others.  Similar analyses will be performed for total ears (worsened versus others, 
improved versus others, and worse + no change versus others. 
For other secondary and tertiary outcomes, Fisher’s exact test will be used to compare binary 
outcomes (such as detection of viruria or subject with at least one AE or SAE), and Wilcoxon 
Rank test will be used to compare continuous outcomes (such as quantitative log reduction) 
between the two treatment groups 6 weeks and 6 months after initial treatment. 
Logistic model utilizing generalized estimating equations will also be used to determine the 
association between change in hearing and change in viral load. Change in viral load over time 
will be measured by the area under the curve computed using the trapezoidal rule. Spearman 
rank correlation will be utilized to examine the association between viral load and PK 
parameters. Poisson regression model will be used to compare the number of AEs/SAEs 
experienced by subjects between the two groups. 
As in the primary outcomes, missing change in hearing outcomes will be replaced by worsened 
outcome as sensitivity analyses for all secondary hearing outcomes.. 

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12. SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
The site will maintain appropriate medical and research records for this trial, in compliance with 
ICH E6, Section 4.9 and regulatory and institutional requirements for the protection of 
confidentiality of subjects. As part of participating, the site will permit authorized representatives 
of the sponsor(s), DMID, the UAB Central Unit and regulatory agencies to examine (and when 
required by applicable law, to copy) clinical records for the purposes of quality assurance 
reviews, audits, and evaluation of the study safety and progress. 
Documentation of source data is necessary for the reconstruction, evaluation, and validation of 
clinical findings, observations, and other activities during a clinical trial.  Source data are all 
information, original records of clinical findings, observations, or other activities in a clinical trial 
necessary for the reconstruction and evaluation of the trial.  Examples of these original 
documents and data records include, but are not limited to, hospital records, clinical and office 
charts, laboratory notes, memoranda, subjects’ evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, Source Document Worksheets (SDWs), 
copies or transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial.  Source documentation serves to substantiate the integrity of trial data, confirms 
observations that are recorded, and confirm the existence of study participants.  This standard 
also serves to ensure data quality by creating audit trails and enabling verification that data are 
present, complete, and accurate.  Sites that are participating in this trial should consult the 
MOP, and DMID/NIAID Source Document Standards (most current version) for specific 
instruction and forms. 
Local, state, institution, IRB/independent ethics committee (IEC) policies and procedures may 
be different from those stated in this standard.  The site should refer to local, state, institution, 
IRB/IEC policies and procedures and follow them if they are more stringent than the DMID 
Standards. 
According to the ICH GCP 4.9: “The investigator should ensure the accuracy, completeness, 
legibility, and timeliness of the data reported to the sponsor in the eCRFs and in all required 
reports.  Data reported on the eCRFs, which are derived from source documents, should be 
consistent with the source documents or discrepancies should be explained.” 
SDWs that mirror each data field on the eCRF will be available for use by sites to record and 
maintain data for each study participant enrolled in the study.  Some data on the SDW may be 
extracted from the medical record or other source documents, and some data may be recorded 
on the SDW as the source document. 

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13. QUALITY CONTROL AND QUALITY ASSURANCE 
The study site will have a quality management plan.  Data will be evaluated for compliance with 
the protocol and accuracy in relation to source documents.  The study will be conducted in 
accordance with procedures identified in the protocol.  Items to be reviewed include, but are not 
limited to: eligibility (including informed consent), AE reporting, study/clinical endpoints, follow-
up contacts, regulatory documents, study discontinuation, and review of clinical records.  Data 
that will be reviewed, who is responsible for implementation, and the schedule for internal 
reviews will be specified or referenced in the quality management plan.   
 
The investigational sites are responsible for conducting routine quality control (QC) and quality 
assurance (QA) activities to internally monitor study progress and protocol compliance.  The 
Principal Investigators will provide direct access to all trial-related sites, source data /source 
documents, and reports for the purpose of monitoring and auditing by the sponsor, and 
inspection by local and regulatory authorities. The Principal Investigator will ensure all study 
personnel are appropriately trained and applicable documentations are maintained on site.   
DMID clinical site monitors will verify the clinical trial is conducted and data are generated, 
documented (recorded), and reported in compliance with the protocol, Good Clinical Practice, 
and the applicable regulatory requirements.  Clinical monitoring reports will be submitted to 
DMID and to the Central Unit.. The Statistical and Data Coordinating Center (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.  Missing data or data anomalies will be 
communicated to the site(s) for clarification and resolution by the Central Unit. 
 
The  study monitors will verify that the clinical trial is conducted and data are generated, 
documented, and reported in compliance with the protocol, ICH E6(R1), and the applicable 
regulatory requirements.  Reports will be submitted to DMID on monitoring activities.  The study 
site will provide direct access to all trial-related sites, source data/documents, and reports for 
the purpose of monitoring and auditing by the sponsor and their designees. 
 
The Statistical and Data Coordinating Center (S&DCC) has extensive experience in data 
management for over approximately 16 currently active national/international collaborative 
studies, and systems and approaches employed for this proposal will be based on existing, 
highly successful platforms.  A distributed data management system, where the clinical 
centers are responsible for the entry and management of data from their own center, is both 
cost-effective (as it removes a significant number of queries) and results in higher quality 
data. 

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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.  Refer to 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-061.html; 
http://cme.cancer.gov/clinicaltrials/learning/humanparticipant-protections.asp 
The investigator will ensure that this study is conducted in full conformity with the principles set 
forth in The Belmont Report: Ethical Principles and Guidelines for the Protection of Human 
Subjects of Research of the US National Commission for the Protection of Human Subjects of 
Biomedical and Behavioral Research (April 18, 1979) and codified in 45 CFR Part 46 and/or the 
ICH E6; 62 Federal Regulations 25691 (1997). 
14.2. Institutional Review Board 
Reviewing IRBs must be registered with the OHRP to conduct FDA-regulated studies.  In the 
United States and in other countries, 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 Institutional Review 
Board (IRB) for review and must be approved before the study is initiated.  Any amendments to 
the protocol must also be approved by the IRB prior to implementing changes in the study.  
 
The investigator is responsible for keeping the IRB apprised of the progress of the study and of 
any changes made to the protocol as deemed appropriate, but in any case at least once per 
year.  The investigator must also keep the IRB informed of any significant AEs. 
All IRB approved documents as well as relevant study correspondence should be copied and 
sent to the UAB Central Unit. 

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14.3. Informed Consent Process 
The process of obtaining informed consent must be documented in the medical records, clinic 
chart, and/or research chart.  The consent form must be signed and dated by the 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 at any time.  
 
The investigational nature and research objectives of this trial, the procedure, and its attendant 
risks and discomforts will be carefully explained to the study participant/study participant’s 
parent/legal guardian.  A signed informed consent document will be obtained from each study 
participant/study participant’s parent/legal guardian prior to entry into this study.  At any time 
during participation in the protocol, if new information becomes available relating to risks, AEs, 
or toxicities, this information will be provided orally or in writing to all enrolled or prospective 
study participant/study participants’ parent/legal guardian. Documentation will be provided to the 
IRB and, if necessary, the informed consent will be amended to reflect any relevant information. 
An investigator shall seek such consent only under circumstances that provide the 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. 
Subjects/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 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. 
14.3.1. Informed Consent/Assent Process (in Case of a Minor) 
Not applicable. 

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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 
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/Roche 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/Roche, 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 S&DCC 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 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. 
14.6. Study Discontinuation 
Please see Section 5.3 for criteria for discontinuing study and / or study subject participation. 

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14.7. Future Use of Stored Specimens 
Some of the specimens obtained from study participants during this study will be stored 
indefinitely in the Children’s Diagnostic Virology Laboratory at the University of Alabama at 
Birmingham and may be used in future CMV research.  These specimens will be labeled with a 
code number and not with the study participant’s name.  At the time of consent for study 
participation, study participant’s parent/legal guardian will have the opportunity to either agree to 
have their specimens used in future CMV research or decline to have their specimens used in 
future CMV research.  The study participant’s parent/legal guardian will indicate his/her 
preference by initialing the appropriate line or checking the appropriate box of the Consent Form 
in the section entitled, “Future Use of Specimens”.  Non-protocol designated, future testing of 
samples will be performed only on samples from study participants who have consented for 
future testing of samples.  These specimens will only be utilized to better understand the natural 
history of CMV or improve diagnosis. 
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 CMV research, then 
his/her child’s specimens will be destroyed at the completion of the study. 

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15. DATA HANDLING AND RECORD KEEPING 
The investigator is responsible to ensure the accuracy, completeness, legibility, and timeliness 
of the data reported. 
Electronic case report forms (eCRFs) will be developed by the UAB Statistical and Data 
Coordinating Center.  The eCRFs will be provided electronically by the UAB Central Unit.  
Original data will be recorded on source documents (e.g., medical records, research progress 
notes, Source Document Worksheets documenting research related procedures).  Source 
Document Worksheets that contain each data field on the eCRF will be available for use by 
sites as a tool to record and maintain data for each study participant enrolled in the study when 
other source documents are not used to collect original data.  All source documents should be 
completed in a neat, legible manner to ensure accurate interpretation of data.  When making a 
change or correction, cross out the original entry with a single line and initial and date the 
change.  DO NOT ERASE, OVERWRITE, OR USE CORRECTION FLUID OR TAPE ON THE 
ORIGINAL.  Specific guidance to investigators and study staff on making corrections to source 
documents and eCRFs will be provided in the MOP for this study.  
Data recorded on the eCRF that differ from source documents must be explained on the Add 
Comment eCRF and in the subject’s source documents.  With the exception of 
calculation(s)/conversion(s) of data values, all calculation(s)/conversion(s) must be shown in the 
source documents for verification. 
The integrity of the data is ensured by limited access and password protection.  Each person (at 
study sites, the UAB Central Unit, and the DCC) is assigned access to only the portions of the 
database they need.  Each person’s access is provided under “hard” password protection (at 
least 8 characters and including both symbols and numbers) that are changed at 6 month 
intervals.  At UAB, incremental data back-ups are made on a daily basis, and complete data 
backups are made on a weekly basis and stored at an off-site repository. 
15.1. Data Management Responsibilities 
All eCRFS must be reviewed by the investigator’s research team, under the supervision of the 
investigator, who will ensure that they are accurate and complete.  All data must be supported 
by source documents, which will remain available for review by regulatory personnel and 
monitors.  Adverse events must be graded, assessed for intensity and causality, and reviewed 
by the site investigator or designee.  All laboratory values must be assessed for clinical 
significance and non clinical significance, and reviewed by the site investigator or designee.  
Sites that are participating in this trial should consult the MOP and DMID/NIAID Source 
Document Standards (most current version) for specific instruction.      

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Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site PI.  During the study, the investigator must maintain complete and accurate 
documentation for the study.   
The UAB Central Unit and Statistical and Data Coordinating  will be responsible for data 
management, quality review, analysis of the study data, and writing of the clinical study report. 
15.2. Data Capture Methods 
Clinical and laboratory data will be entered into a 21 CRF Part 11 compliant Internet Data Entry 
System (IDES)  provided by the UAB Statistical and Data Coordinating Center.  The data 
system includes password protection and internal quality checks, such as automated range 
checks, to identify data that appear to be inconsistent, incomplete, or inaccurate. 
15.3. Types of Data 
Data for this study will include safety, laboratory (e.g., clinical and virologic), and outcome 
measures (e.g., virology, audiology). 
15.4. Timing/Reports 
Safety Reports will be generated and sent to DMID at intervals identified in the DSMB Charter, 
for dissemination to the DSMB. 
15.5. Study Records Retention 
Records and documents pertaining to the conduct of this study, including source documents, 
consent forms, laboratory test results, and medication inventory records, must be retained by 
the investigator for at least 2 years following completion of the study.  No study records shall be 
destroyed without prior authorization from the UAB Central Unit and NIAID/DMID.  These 
documents should be retained for a longer period, however, if required by local regulations.  It is 
the responsibility of the sponsor to notify the UAB Central Unit, which will notify the 
investigators, when these documents no longer need to be retained. 
15.6. Protocol Deviations 
Each investigator must adhere to the protocol as detailed in this document and agree that any 
changes to the protocol must be approved by the UAB Central Unit and the Sponsor prior to 

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seeking approval from the IRB/IEC.  Each investigator will be responsible for enrolling only 
those study participants who have met protocol eligibility criteria. 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or Manual of 
Procedures requirements.  The noncompliance may be either on the part of the study 
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 to the UAB Central Unit. 
All deviations from the protocol must be addressed in the source documents.  A completed copy 
of the DMID protocol deviation form must be maintained with the completed eCRFs. A log of 
protocol deviation will be maintained in the Project Notebook. Protocol deviations must be sent 
to the local IRB per the IRB’s guidelines. 

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

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17. LITERATURE REFERENCES 
1. 
Elek SD, Stern H. Development of a vaccine against mental retardation caused by 
cytomegalovirus infection in utero. Lancet. 1974;1:1-5. 
2. 
Fowler KB, McCollister FP, Dahle AJ, et al. Progressive and fluctuating sensorineural hearing 
loss in children with asymptomatic congenital cytomegalovirus infection. J Pediatr. 1997;130:624-
30. 
3. 
Harris S, Ahlfors K, Ivarsson S, et al. Congenital cytomegalovirus infection and sensorineural 
hearing loss. Ear & Hearing. 1984;5:352-5. 
4. 
Fowler KB, Dahle AJ, Boppana SB, et al. Newborn hearing screening: will children with hearing 
loss caused by congenital cytomegalovirus infection be missed? J Pediatr. 1999;135:60-4. 
5. 
Demmler GJ. Infectious Diseases Society of America and Centers for Disease Control. Summary 
of a workshop on surveillance for congenital cytomegalovirus disease. Rev Infect Dis. 
1991;13:315-29. 
6. 
Stagno S, Whitley RJ. Herpesvirus infections of pregnancy. Part I: Cytomegalovirus and Epstein-
Barr virus infections. N Engl J Med. 1985;313:1270-4. 
7. 
McCracken GH, Jr., Shinefield HM, Cobb K, et al. Congenital cytomegalic inclusion disease. A 
longitudinal study of 20 patients. Am J Dis Child. 1969;117:522-39. 
8. 
Pass RF, Stagno S, Myers GJ, et al. Outcome of symptomatic congenital cytomegalovirus 
infection: results of long-term longitudinal follow-up. Pediatrics. 1980;66:758-62. 
9. 
Weller TH. The cytomegaloviruses: ubiquitous agents with protean clinical manifestations. I. N 
Engl J Med. 1971;285:203-14. 
10. 
Weller TH, Hanshaw JB. Virologic and clinical observations on cytomegalic inclusion disease. N 
Engl J Med. 1962;266:1233-1244. 
11. 
Conboy TJ, Pass RF, Stagno S, et al. Early clinical manifestations and intellectual outcome in 
children with symptomatic congenital cytomegalovirus infection. J Pediatr. 1987;111:343-8. 
12. 
Dollard SC, Grosse SD, Ross DS. New estimates of the prevalence of neurological and sensory 
sequelae and mortality associated with congenital cytomegalovirus infection. Rev Med Virol. 
2007. 
13. 
Dahle AJ, Fowler KB, Wright JD, et al. Longitudinal investigation of hearing disorders in children 
with congenital cytomegalovirus. Journal of the American Academy of Audiology. 2000;11:283-
90. 
14. 
Yow MD, Demmler GJ. Congenital cytomegalovirus disease--20 years is long enough. N Engl J 
Med. 1992;326:702-3. 
15. 
Arvin AM, Fast P, Myers M, et al. Vaccine development to prevent cytomegalovirus disease: 
report from the National Vaccine Advisory Committee. Clin Infect Dis. 2004;39:233-9. 
16. 
Boppana SB, Ross SA, Novak Z, et al. Dried blood spot real-time polymerase chain reaction 
assays to screen newborns for congenital cytomegalovirus infection. JAMA. 2010;303:1375-82. 

Collaborative Antiviral Study Group 
DMID Protocol #11-0069, Version 4.0 
CASG Valgan Toddler 
28 April 2016 
 
 
62 
 
17. 
Barbi M, Binda S, Caroppo S. Diagnosis of congenital CMV infection via dried blood spots. Rev 
Med Virol. 2006;16:385-92. 
18. 
Walter S, Atkinson C, Sharland M, et al. Congenital cytomegalovirus: Association between dried 
blood spot viral load and hearing loss. Arch Dis Child Fetal Neonatal Ed. 2007;2007 Nov 26 
[Epub ahead of print]. 
19. 
Bradford RD, Cloud G, Lakeman AD, et al. Detection of cytomegalovirus (CMV) DNA by 
polymerase chain reaction is associated with hearing loss in newborns with symptomatic 
congenital CMV infection involving the central nervous system. J Infect Dis. 2005;191:227-33. 
20. 
Kimberlin DW, Lin CY, Sanchez PJ, et al. Effect of ganciclovir therapy on hearing in symptomatic 
congenital cytomegalovirus disease involving the central nervous system: a randomized, 
controlled trial. J Pediatr. 2003;143:16-25. 
21. 
Berg FS. Characteristics of the target population. In: Berg FS, Blair JC, Viehweg SH, Wilson-
Vlotman A, eds. Educational Audiology for the Hard of Hearing Child. Orlando: Grune and 
Stratton, 1986. 
22. 
Habilitation and rehabilitation. In: Northern JL, ed. Hearing Disorders. Boston: Little, Brown, and 
Company, 1976. 
23. 
Investigator's Brochure. Ro107-9070 (Valcyte , Valganciclovir). 2002. 
24. 
Kimberlin DW, Acosta EP, Sanchez PJ, et al. Pharmacokinetic and pharmacodynamic 
assessment of oral valganciclovir in the treatment of symptomatic congenital cytomegalovirus 
disease. J Infect Dis. 2008;197:836-45. 
25. 
Trang JM, Kidd L, Gruber W, et al. Linear single-dose pharmacokinetics of ganciclovir in 
newborns with congenital cytomegalovirus infections. Clinical Pharmacology & Therapeutics. 
1993;53:15-21. 
26. 
Stagno S, Reynolds DW, Tsiantos A, et al. Comparative serial virologic and serologic studies of 
symptomatic and subclinical congenitally and natally acquired cytomegalovirus infections. J Infect 
Dis. 1975;132:568-77. 
27. 
Boppana SB, Fowler KB, Pass RF, et al. Congenital cytomegalovirus infection: association 
between virus burden in infancy and hearing loss. J Pediatr. 2005;146:817-823. 
28. 
Bauer PW, Parizi-Robinson M, Roland PS, et al. Cytomegalovirus in the perilymphatic fluid. 
Laryngoscope. 2005;115:223-5. 
29. 
Whitley RJ, Cloud G, Gruber W, et al. Ganciclovir treatment of symptomatic congenital 
cytomegalovirus infection: results of a phase II study. J Infect Dis. 1997;175:1080-6. 
30. 
Schwartz GJ, Brion LP, Spitzer A. The use of plasma creatinine concentration for estimating 
glomerular filtration rate in infants, children, and adolescents. Pediatric Clinics of North America. 
1987;34:571-590. 
31. 
Schwartz GJ, Muñoz A, Schneider MF, et al. New equations to estimate GFR in children with 
CKD. J Am Soc Nephrol. 2009;20:629-637. 
  

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63 
SUPPLEMENTS/APPENDICES 
 
 
 
 

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DMID Protocol #11-0069, Version 4.0 
CASG Valgan Toddler 
28 April 2016 
 
64 
APPENDIX A: SCHEDULE OF EVENTS 
 
Enrollment 
(Window: Day -
90 to Day -1) 
Randomization 
(Window: Day -30 
to Day 1) 
Study Day 
Study Month 
1          
(day -3 to 
day 1) 
14 
 (± 2 
days) 
28 
 (± 2 
days) 
42 
 (± 2 
days) 
70 
 (± 4 
days) 
4 
 (± 7 
days) 
6 
(± 7 
days) 
Following study enrollment, testing of 
Guthrie card for CMV DNA by PCR (if 
congenital CMV infection has not already 
been documented during first month of life) 
X 
 
 
 
 
 
 
 
 
Confirmation of congenital CMV infection 
by documentation during first month of life 
or by PCR-positive Guthrie card 
 
X 
 
 
 
 
 
 
Baseline demographicsa 
 
X 
 
 
 
 
 
 
Hematology Safety Labsb 
 
 
X 
X 
X 
X 
X 
 
 
Chemistry Safety Labsc 
 
 
X 
X 
X 
X 
X 
 
 
Weight and Length 
 
 
X 
X 
X 
 
 
 
 
Adverse Event Assessment 
 
 
X 
X 
X 
X 
X 
 
 
Concurrent Medications 
 
 
X 
X 
X 
X 
X 
 
 
Updated results of any etiological 
investigations for SNHL 
 
 
X 
X 
X 
X 
X 
X 
X 
Hearing Assessment 
 
Xd 
Day -90 to Day -1 
 
 
 
 
 
 
X 
-14 to 
+30 
days 
Virology Specimens for CMV Viral Loade 
 
 
X 
X 
X 
X 
X 
X 
X 
Ganciclovir Population Pharmacokineticsf 
 
 
 
X 
X 
X 
 
 
 
Valganciclovir vs. Placebo Administrationg 
 
 
 
 
 
 
Total volume of blood required 
 
 
2.0 mL 
2.25 
2.25 
2.25 
2.0 
0.5 
0.5 mL 

Collaborative Antiviral Study Group 
DMID Protocol #11-0069, Version 4.0 
CASG Valgan Toddler 
28 April 2016 
 
65 
mL 
mL 
mL 
mL 
mL 
a. 
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; and gestational age at birth.  Degree of CMV disease involvement consists of neuroimaging abnormalities if imaging was performed; petechiae at 
any time from birth through study randomization, if known; thrombocytopenia at any time from birth through study randomization, if obtained; hepatomegaly at 
any time from birth through study randomization, if noted; splenomegaly at any time from birth through study randomization, if noted; CSF white blood cell 
count at any time from birth through study randomization, if obtained; CSF protein concentration at any time from birth through study randomization, if 
obtained; CSF CMV PCR at any time from birth through study randomization, if performed; seizures at any time from birth through study randomization, if 
noted; elevated transaminases at any time from birth through study randomization, if obtained; elevated bilirubin at any time from birth through study 
randomization, if obtained; medical history and baseline conditions prior to study randomization, by body system, chorioretinitis, intrauterine growth restriction; 
urine CMV testing (e.g., viral culture, shell-vial culture, PCR) within 90 days prior to study enrollment, if obtained clinically 
b. 
WBC with differential, hemoglobin, Platelet enumeration (approximate total blood needed for these tests is 0.5 mL) 
c. 
ALT, total bilirubin, creatinine (approximate total blood needed for these tests is 1.0 mL) 
d. 
BSER and/or VRA (to assess neuro-otologic status) and OAEs 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, and 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). 
e. 
Required amount of whole blood for quantitative CMV PCR is at least 0.5 mL. Urine collection by bagged or clean catch specimen for quantitative PCR. Saliva 
collection by polyester fiber–tipped swabs for quantitative PCR. 
f. 
Required amount of whole blood for plasma ganciclovir determination is at least 0.25 mL 
g. 
Valganciclovir or placebo administration begins on Day 1 of the study; study medication dose adjusted for weight change, if needed, at each study visit while 
on treatment 
 
 
 

Collaborative Antiviral Study Group 
DMID Protocol #11-0069, Version 4.0 
CASG Valgan Toddler 
28 April 2016 
 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, 
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
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66 
 
 
CLINICAL 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
ESTIMATING SEVERITY GRADE 
Clinical adverse event 
NOT identified 
elsewhere in this 
DAIDS AE grading 
table  
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Symptoms causing 
inability to perform usual 
social & functional 
activities 
Symptoms causing 
inability to perform basic 
self-care functions OR 
Medical or operative 
intervention indicated to 
prevent permanent 
impairment, persistent 
disability, or death  
SYSTEMIC 
Acute systemic 
allergic reaction  
Localized urticaria 
(wheals) with no 
medical intervention 
indicated 
Localized urticaria with 
medical intervention 
indicated OR Mild 
angioedema with no 
medical intervention 
indicated 
Generalized urticaria 
OR Angioedema with 
medical intervention 
indicated OR 
Symptomatic mild 
bronchospasm 
Acute anaphylaxis OR 
Life-threatening 
bronchospasm OR 
laryngeal edema 
Chills 
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Symptoms causing 
inability to perform usual 
social & functional 
activities 
NA 
Fatigue 
Malaise 
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Symptoms causing 
inability to perform usual 
social & functional 
activities 
Incapacitating fatigue/ 
malaise symptoms 
causing inability to 
perform basic self-care 
functions 
Fever (nonaxillary) 
37.7 – 38.6°C 
38.7 – 39.3°C 
39.4 – 40.5°C 
> 40.5°C  
APPENDIX B:  DIVISION OF AIDS TOXICITY TABLES 

Collaborative Antiviral Study Group 
DMID Protocol #11-0069, Version 4.0 
CASG Valgan Toddler 
28 April 2016 
 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, 
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
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67 
 
CLINICAL 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Pain (indicate body 
site) 
DO NOT use for pain 
due to injection (See 
Injection Site 
Reactions: Injection 
site pain) 
See also Headache, 
Arthralgia, and 
Myalgia 
Pain causing no or 
minimal interference 
with usual social & 
functional activities 
Pain causing greater 
than minimal 
interference with usual 
social & functional 
activities 
Pain causing inability to 
perform usual social & 
functional activities 
Disabling pain causing 
inability to perform basic 
self-care functions OR 
Hospitalization (other 
than emergency room 
visit) indicated 
Unintentional weight 
loss 
NA 
5 – 9% loss in body 
weight from baseline 
10 – 19% loss in body 
weight from baseline 
≥ 20% loss in body 
weight from baseline OR  
Aggressive intervention 
indicated [e.g., tube 
feeding or total 
parenteral nutrition 
(TPN)] 
INFECTION 
Infection (any other 
than HIV infection) 
Localized, no 
systemic antimicrobial 
treatment indicated 
AND Symptoms 
causing no or minimal 
interference with 
usual social & 
functional activities 
Systemic antimicrobial 
treatment indicated 
OR Symptoms 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Systemic antimicrobial 
treatment indicated 
AND Symptoms causing 
inability to perform usual 
social & functional 
activities OR Operative 
intervention (other than 
simple incision and 
drainage) indicated 
Life-threatening 
consequences (e.g., 
septic shock) 
INJECTION SITE REACTIONS 
Injection site pain 
(pain without touching) 
Or 
Tenderness (pain 
when area is touched)  
Pain/tenderness 
causing no or minimal 
limitation of use of 
limb 
Pain/tenderness 
limiting use of limb OR 
Pain/tenderness 
causing greater than 
minimal interference 
with usual social & 
functional activities 
 
Pain/tenderness 
causing inability to 
perform usual social & 
functional activities 
 
Pain/tenderness causing 
inability to perform basic 
self-care function OR 
Hospitalization (other 
than emergency room 
visit) indicated for 
management of 
pain/tenderness 
Injection site reaction (localized) 

Collaborative Antiviral Study Group 
DMID Protocol #11-0069, Version 4.0 
CASG Valgan Toddler 
28 April 2016 
 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, 
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
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68 
 
CLINICAL 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Adult > 15 years 
 
Erythema OR 
Induration 
of 5x5 cm – 9x9 cm 
(or 25 cm2 – 81cm2) 
Erythema OR 
Induration OR Edema  
> 9 cm any diameter 
(or > 81 cm2) 
Ulceration OR 
Secondary infection OR 
Phlebitis OR Sterile 
abscess OR Drainage 
Necrosis (involving 
dermis and deeper 
tissue) 
 
Pediatric ≤ 15 
years 
Erythema OR 
Induration OR Edema 
present but ≤ 2.5 cm 
diameter 
Erythema OR 
Induration OR Edema 
> 2.5 cm diameter but 
< 50% surface area of 
the extremity segment 
(e.g., upper arm/thigh) 
Erythema OR Induration 
OR Edema involving  
≥ 50% surface area of 
the extremity segment 
(e.g., upper arm/thigh) 
OR Ulceration OR 
Secondary infection OR 
Phlebitis OR Sterile 
abscess OR Drainage 
Necrosis (involving 
dermis and deeper 
tissue) 
Pruritis associated 
with injection  
See also Skin: Pruritis 
(itching - no skin 
lesions) 
Itching localized to 
injection site AND 
Relieved 
spontaneously or with 
< 48 hours treatment  
Itching beyond the 
injection site but not 
generalized OR Itching 
localized to injection 
site requiring ≥ 48 
hours treatment  
Generalized itching 
causing inability to 
perform usual social & 
functional activities 
NA 
SKIN – DERMATOLOGICAL 
Alopecia 
Thinning detectable 
by study participant 
(or by caregiver for 
young children and 
disabled adults) 
Thinning or patchy hair 
loss detectable by 
health care provider 
Complete hair loss 
NA 
Cutaneous reaction – 
rash 
Localized macular 
rash  
Diffuse macular, 
maculopapular, or 
morbilliform rash OR 
Target lesions  
Diffuse macular, 
maculopapular, or 
morbilliform rash with 
vesicles or limited 
number of bullae OR 
Superficial ulcerations 
of mucous membrane 
limited to one site 
Extensive or generalized 
bullous lesions OR 
Stevens-Johnson 
syndrome OR Ulceration 
of mucous membrane 
involving two or more 
distinct mucosal sites 
OR Toxic epidermal 
necrolysis (TEN) 
Hyperpigmentation 
Slight or localized 
Marked or generalized 
NA 
NA 
Hypopigmentation 
Slight or localized  
Marked or generalized 
NA 
NA 

Collaborative Antiviral Study Group 
DMID Protocol #11-0069, Version 4.0 
CASG Valgan Toddler 
28 April 2016 
 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, 
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
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69 
 
CLINICAL 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Pruritis (itching – no 
skin lesions)  
(See also Injection 
Site Reactions: 
Pruritis associated 
with injection) 
Itching causing no or 
minimal interference 
with usual social & 
functional activities 
Itching causing greater 
than minimal 
interference with usual 
social & functional 
activities 
Itching causing inability 
to perform usual social 
& functional activities  
NA 
 
CARDIOVASCULAR 
Cardiac arrhythmia 
(general) 
(By ECG or physical 
exam) 
Asymptomatic AND 
No intervention 
indicated 
Asymptomatic AND 
Non-urgent medical 
intervention indicated 
Symptomatic, non-life-
threatening AND Non-
urgent medical 
intervention indicated  
Life-threatening 
arrhythmia OR Urgent 
intervention indicated 
Cardiac-
ischemia/infarction 
NA 
NA 
Symptomatic ischemia 
(stable angina) OR 
Testing consistent with 
ischemia  
Unstable angina OR 
Acute myocardial 
infarction 
Hemorrhage 
(significant acute 
blood loss) 
NA 
Symptomatic AND No 
transfusion indicated 
Symptomatic AND 
Transfusion of ≤ 2 units 
packed RBCs (for 
children ≤ 10 cc/kg) 
indicated  
Life-threatening 
hypotension OR 
Transfusion of > 2 units 
packed RBCs (for 
children > 10 cc/kg) 
indicated 
Hypertension 
Adult > 17 years 
(with repeat 
testing at same 
visit) 
 
> 140 – 159 mmHg 
systolic 
OR 
> 90 – 99 mmHg 
diastolic 
> 160 – 179 mmHg 
systolic 
OR 
> 100 – 109 mmHg 
diastolic 
 
> 180 mmHg systolic 
OR 
> 110 mmHg diastolic 
 
Life-threatening 
consequences (e.g., 
malignant hypertension) 
OR Hospitalization 
indicated (other than 
emergency room visit) 
Pediatric ≤ 17 
years 
(with repeat 
testing at same 
visit) 
 
NA 
91st –  94th percentile 
adjusted for age, 
length, and gender 
(systolic and/or 
diastolic) 
≥ 95th percentile 
adjusted for age, length, 
and gender (systolic 
and/or diastolic) 
Life-threatening 
consequences (e.g., 
malignant hypertension) 
OR Hospitalization 
indicated (other than 
emergency room visit) 

Collaborative Antiviral Study Group 
DMID Protocol #11-0069, Version 4.0 
CASG Valgan Toddler 
28 April 2016 
 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, 
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
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70 
 
CLINICAL 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Hypotension 
NA 
Symptomatic, 
corrected with oral 
fluid replacement 
Symptomatic, IV fluids 
indicated 
Shock requiring use of 
vasopressors or 
mechanical assistance 
to maintain blood 
pressure 
 
Pericardial effusion 
Asymptomatic, small 
effusion requiring no 
intervention 
 
Asymptomatic, 
moderate or larger 
effusion requiring no 
intervention 
 
Effusion with non-life 
threatening physiologic 
consequences OR 
Effusion with non-urgent 
intervention indicated 
Life-threatening 
consequences (e.g., 
tamponade) OR Urgent 
intervention indicated 
Prolonged PR interval 
 
Adult > 16 years 
PR interval  
0.21 – 0.25 sec 
PR interval 
> 0.25 sec 
Type II 2nd degree AV 
block OR Ventricular 
pause > 3.0 sec 
Complete AV block  
 
Pediatric ≤ 16 
years 
1st degree AV block 
(PR > normal for age 
and rate) 
Type I 2nd degree AV 
block  
Type II 2nd degree AV 
block  
Complete AV block 
Prolonged QTc 
Adult > 16 years 
 
Asymptomatic, QTc 
interval 0.45 – 0.47 
sec OR Increase 
interval < 0.03 sec 
above baseline 
Asymptomatic, QTc 
interval 0.48 – 0.49 
sec OR Increase in 
interval 0.03 – 0.05 
sec above baseline 
Asymptomatic, QTc 
interval ≥ 0.50 sec OR 
Increase in interval  
≥ 0.06 sec above 
baseline 
Life-threatening 
consequences, e.g. 
Torsade de pointes or 
other associated serious 
ventricular dysrhythmia 
Pediatric ≤ 16 
years 
Asymptomatic, QTc 
interval 0.450 –  
0.464 sec  
Asymptomatic, QTc 
interval 0.465 –  
0.479 sec  
Asymptomatic, QTc 
interval ≥ 0.480 sec  
Life-threatening 
consequences, e.g.  
Torsade de pointes  or 
other associated serious 
ventricular dysrhythmia 
Thrombosis/embolism 
NA 
Deep vein thrombosis 
AND No intervention 
indicated (e.g., 
anticoagulation, lysis 
filter, invasive 
procedure)  
Deep vein thrombosis 
AND Intervention 
indicated (e.g., 
anticoagulation, lysis 
filter, invasive 
procedure)  
Embolic event (e.g., 
pulmonary embolism, 
life-threatening 
thrombus)  

Collaborative Antiviral Study Group 
DMID Protocol #11-0069, Version 4.0 
CASG Valgan Toddler 
28 April 2016 
 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, 
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
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 _____________________________________________________________________________________________  
71 
 
CLINICAL 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Vasovagal episode 
(associated with a 
procedure of any kind) 
Present without loss 
of consciousness  
Present with transient 
loss of consciousness 
NA  
NA 
Ventricular 
dysfunction 
(congestive heart 
failure) 
NA 
Asymptomatic 
diagnostic finding AND 
intervention indicated 
New onset with 
symptoms OR 
Worsening symptomatic 
congestive heart failure 
Life-threatening 
congestive heart failure 
GASTROINTESTINAL 
Anorexia 
Loss of appetite 
without decreased 
oral intake 
 
Loss of appetite 
associated with 
decreased oral intake 
without significant 
weight loss  
 
Loss of appetite 
associated with 
significant weight loss  
Life-threatening 
consequences OR 
Aggressive intervention 
indicated [e.g., tube 
feeding or total 
parenteral nutrition 
(TPN)] 
Ascites 
Asymptomatic 
Symptomatic AND 
Intervention indicated 
(e.g., diuretics or 
therapeutic 
paracentesis) 
Symptomatic despite 
intervention 
Life-threatening 
consequences 
Cholecystitis 
NA 
Symptomatic AND 
Medical intervention 
indicated 
 
Radiologic, endoscopic, 
or operative intervention 
indicated 
Life-threatening 
consequences (e.g., 
sepsis or perforation)  
Constipation  
NA 
Persistent constipation 
requiring regular use 
of dietary 
modifications, 
laxatives, or enemas  
Obstipation with manual 
evacuation indicated 
Life-threatening 
consequences (e.g., 
obstruction) 
Diarrhea 
Adult and 
Pediatric ≥ 1 year 
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 – 6 stools over 
baseline per 24-hour 
period 
Bloody diarrhea OR 
Increase of ≥ 7 stools 
per 24-hour period OR 
IV fluid replacement 
indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 

Collaborative Antiviral Study Group 
DMID Protocol #11-0069, Version 4.0 
CASG Valgan Toddler 
28 April 2016 
 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, 
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
12-28-04 
 
 Version 1.0 
 
 _____________________________________________________________________________________________  
72 
 
CLINICAL 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Pediatric < 1 year 
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 
Liquid stools resulting in 
severe dehydration with 
aggressive rehydration 
indicated OR 
Hypotensive shock 
Dysphagia-
Odynophagia  
Symptomatic but able 
to eat usual diet 
Symptoms causing 
altered dietary intake 
without medical 
intervention indicated 
Symptoms causing 
severely altered dietary 
intake with medical 
intervention indicated 
Life-threatening 
reduction in oral intake 
Mucositis/stomatitis  
(clinical exam) 
Indicate site (e.g., 
larynx, oral) 
See Genitourinary for 
Vulvovaginitis  
See also Dysphagia-
Odynophagia and 
Proctitis 
Erythema of the 
mucosa 
Patchy 
pseudomembranes or 
ulcerations  
Confluent 
pseudomembranes or 
ulcerations OR Mucosal 
bleeding with minor 
trauma 
Tissue necrosis OR 
Diffuse spontaneous 
mucosal bleeding OR 
Life-threatening 
consequences (e.g., 
aspiration, choking) 
Nausea  
Transient (< 24 hours) 
or intermittent nausea 
with no or minimal 
interference with oral 
intake 
Persistent nausea 
resulting in decreased 
oral intake for 24 – 48 
hours 
Persistent nausea 
resulting in minimal oral 
intake for > 48 hours 
OR Aggressive 
rehydration indicated 
(e.g., IV fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Pancreatitis 
NA 
Symptomatic AND 
Hospitalization not 
indicated (other than 
emergency room visit) 
Symptomatic AND 
Hospitalization indicated 
(other than emergency 
room visit) 
Life-threatening 
consequences (e.g., 
circulatory failure, 
hemorrhage, sepsis) 
Proctitis (functional- 
symptomatic) 
Also see 
Mucositis/stomatitis  
for clinical exam 
 
 
Rectal discomfort 
AND No intervention 
indicated 
 
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities OR Medical 
intervention indicated  
Symptoms causing 
inability to perform usual 
social & functional 
activities OR Operative 
intervention indicated  
Life-threatening 
consequences (e.g., 
perforation) 
 

Collaborative Antiviral Study Group 
DMID Protocol #11-0069, Version 4.0 
CASG Valgan Toddler 
28 April 2016 
 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, 
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
12-28-04 
 
 Version 1.0 
 
 _____________________________________________________________________________________________  
73 
 
CLINICAL 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Vomiting 
Transient or 
intermittent vomiting 
with no or minimal 
interference with oral 
intake 
Frequent episodes of 
vomiting 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) 
NEUROLOGIC 
Alteration in 
personality-behavior 
or in mood (e.g., 
agitation, anxiety, 
depression, mania, 
psychosis) 
Alteration causing no 
or minimal 
interference with 
usual social & 
functional activities  
Alteration causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Alteration causing 
inability to perform usual 
social & functional 
activities  
Behavior potentially 
harmful to self or others 
(e.g., suicidal and 
homicidal ideation or 
attempt, acute 
psychosis) OR Causing 
inability to perform basic 
self-care functions  
Altered Mental Status  
For Dementia, see 
Cognitive and 
behavioral/attentional 
disturbance (including 
dementia and 
attention deficit 
disorder) 
Changes causing no 
or minimal 
interference with 
usual social & 
functional activities 
Mild lethargy or 
somnolence causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Confusion, memory 
impairment, lethargy, or 
somnolence causing 
inability to perform usual 
social & functional 
activities 
Delirium OR 
obtundation, OR coma 
Ataxia  
Asymptomatic ataxia 
detectable on exam 
OR Minimal ataxia 
causing no or minimal 
interference with 
usual social & 
functional activities 
Symptomatic ataxia 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Symptomatic ataxia 
causing inability to 
perform usual social & 
functional activities  
Disabling ataxia causing 
inability to perform basic 
self-care functions 
Cognitive and 
behavioral/attentional 
disturbance (including 
dementia and 
attention deficit 
disorder)  
Disability causing no 
or minimal 
interference with 
usual social & 
functional activities 
OR Specialized 
resources not 
indicated 
Disability causing 
greater than minimal 
interference with usual 
social & functional 
activities OR 
Specialized resources 
on part-time basis 
indicated 
Disability causing 
inability to perform usual 
social & functional 
activities OR 
Specialized resources 
on a full-time basis 
indicated 
Disability causing 
inability to perform basic 
self-care functions OR 
Institutionalization 
indicated 

Collaborative Antiviral Study Group 
DMID Protocol #11-0069, Version 4.0 
CASG Valgan Toddler 
28 April 2016 
 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, 
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
12-28-04 
 
 Version 1.0 
 
 _____________________________________________________________________________________________  
74 
 
CLINICAL 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
CNS ischemia 
(acute) 
NA 
NA 
Transient ischemic 
attack 
Cerebral vascular 
accident (CVA, stroke) 
with neurological deficit  
Developmental delay 
– Pediatric ≤ 16 
years 
Mild developmental 
delay, either motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting  
Moderate 
developmental delay,  
either motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting  
Severe developmental 
delay, either motor or 
cognitive, as determined 
by comparison with a 
developmental 
screening tool 
appropriate for the 
setting  
Developmental 
regression, either motor 
or cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Headache  
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Symptoms causing 
inability to perform usual 
social & functional 
activities 
Symptoms causing 
inability to perform basic 
self-care functions OR 
Hospitalization indicated 
(other than emergency 
room visit) OR 
Headache with 
significant impairment of 
alertness or other 
neurologic function  
Insomnia 
NA 
Difficulty sleeping 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Difficulty sleeping 
causing inability to 
perform usual social & 
functional activities 
Disabling insomnia 
causing inability to 
perform basic self-care 
functions 
Neuromuscular 
weakness  
(including myopathy & 
neuropathy)  
Asymptomatic with 
decreased strength 
on exam OR Minimal 
muscle weakness 
causing no or minimal 
interference with 
usual social & 
functional activities 
Muscle weakness 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Muscle weakness 
causing inability to 
perform usual social & 
functional activities  
Disabling muscle 
weakness causing 
inability to perform basic 
self-care functions OR 
Respiratory muscle 
weakness impairing 
ventilation 

Collaborative Antiviral Study Group 
DMID Protocol #11-0069, Version 4.0 
CASG Valgan Toddler 
28 April 2016 
 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, 
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
12-28-04 
 
 Version 1.0 
 
 _____________________________________________________________________________________________  
75 
 
CLINICAL 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Neurosensory 
alteration (including 
paresthesia and 
painful neuropathy) 
Asymptomatic with 
sensory alteration on 
exam or minimal 
paresthesia causing 
no or minimal 
interference with 
usual social & 
functional activities  
Sensory alteration or 
paresthesia causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Sensory alteration or 
paresthesia causing 
inability to perform usual 
social & functional 
activities 
Disabling sensory 
alteration or paresthesia 
causing inability to 
perform basic self-care 
functions 
 
Seizure: (new onset)  
– Adult ≥ 18 years 
See also Seizure: 
(known pre-existing 
seizure disorder) 
NA 
1 seizure  
2 – 4 seizures  
Seizures of any kind 
which are prolonged, 
repetitive (e.g., status 
epilepticus), or difficult 
to control (e.g., 
refractory epilepsy) 
Seizure: (known pre-
existing seizure 
disorder)  
– Adult ≥ 18 years 
For worsening of 
existing epilepsy the 
grades should be 
based on an increase 
from previous level of 
control to any of these 
levels. 
NA 
Increased frequency of 
pre-existing seizures 
(non-repetitive) without 
change in seizure 
character OR 
Infrequent break-
through seizures while 
on stable medication 
in a previously 
controlled seizure 
disorder 
Change in seizure 
character from baseline 
either in duration or 
quality (e.g., severity or  
focality)  
Seizures of any kind 
which are prolonged, 
repetitive (e.g., status 
epilepticus), or difficult 
to control (e.g., 
refractory epilepsy) 
Seizure  
– Pediatric < 18 
years 
Seizure, generalized 
onset with or without 
secondary 
generalization, lasting 
< 5 minutes with < 24 
hours post ictal state 
Seizure, generalized 
onset with or without 
secondary 
generalization, lasting 
5 – 20 minutes with  
< 24 hours post ictal 
state 
Seizure, generalized 
onset with or without 
secondary 
generalization, lasting  
> 20 minutes  
Seizure, generalized 
onset with or without 
secondary 
generalization, requiring 
intubation and sedation 
Syncope (not 
associated with a 
procedure) 
NA 
Present 
NA 
NA 

Collaborative Antiviral Study Group 
DMID Protocol #11-0069, Version 4.0 
CASG Valgan Toddler 
28 April 2016 
 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, 
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
12-28-04 
 
 Version 1.0 
 
 _____________________________________________________________________________________________  
76 
 
CLINICAL 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Vertigo 
Vertigo causing no or 
minimal interference 
with usual social & 
functional activities 
Vertigo causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Vertigo causing inability 
to perform usual social 
& functional activities 
Disabling vertigo 
causing inability to 
perform basic self-care 
functions 
RESPIRATORY 
Bronchospasm (acute) 
FEV1 or peak flow 
reduced to  
70 – 80% 
FEV1 or peak flow  
50 – 69% 
FEV1 or peak flow  
25 – 49%  
Cyanosis OR FEV1 or 
peak flow < 25% OR 
Intubation 
Dyspnea or respiratory distress 
Adult ≥ 14 years 
Dyspnea on exertion 
with no or minimal 
interference with 
usual social & 
functional activities  
Dyspnea on exertion 
causing greater than 
minimal interference 
with usual social & 
functional activities  
Dyspnea at rest causing 
inability to perform usual 
social & functional 
activities  
Respiratory failure with 
ventilatory support 
indicated 
Pediatric < 14 
years 
Wheezing OR 
minimal increase in 
respiratory rate for 
age 
Nasal flaring OR 
Intercostal retractions 
OR Pulse oximetry 90 
– 95% 
Dyspnea at rest causing 
inability to perform usual 
social & functional 
activities OR Pulse 
oximetry < 90% 
Respiratory failure with 
ventilatory support 
indicated 
MUSCULOSKELETAL 
Arthralgia 
See also Arthritis 
Joint pain causing no 
or minimal 
interference with 
usual social & 
functional activities 
Joint pain causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Joint pain causing 
inability to perform usual 
social & functional 
activities 
Disabling joint pain 
causing inability to 
perform basic self-care 
functions 
Arthritis 
See also Arthralgia 
Stiffness or joint 
swelling causing no or 
minimal interference 
with usual social & 
functional activities 
Stiffness or joint 
swelling causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Stiffness or joint 
swelling causing 
inability to perform usual 
social & functional 
activities 
Disabling joint stiffness 
or swelling causing 
inability to perform basic 
self-care functions  
Bone Mineral Loss 

Collaborative Antiviral Study Group 
DMID Protocol #11-0069, Version 4.0 
CASG Valgan Toddler 
28 April 2016 
 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, 
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
12-28-04 
 
 Version 1.0 
 
 _____________________________________________________________________________________________  
77 
 
CLINICAL 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Adult ≥ 21 years 
BMD t-score  
-2.5 to -1.0  
BMD t-score < -2.5 
Pathological fracture 
(including loss of 
vertebral length) 
Pathologic fracture 
causing life-threatening 
consequences  
Pediatric < 21 
years 
BMD z-score  
-2.5 to -1.0 
BMD z-score < -2.5 
Pathological fracture 
(including loss of 
vertebral length) 
Pathologic fracture 
causing life-threatening 
consequences  
Myalgia 
(non-injection site) 
Muscle pain causing 
no or minimal 
interference with 
usual social & 
functional activities 
Muscle pain causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Muscle pain causing 
inability to perform usual 
social & functional 
activities 
Disabling muscle pain 
causing inability to 
perform basic self-care 
functions 
Osteonecrosis 
NA 
Asymptomatic with 
radiographic findings 
AND No operative 
intervention indicated 
Symptomatic bone pain 
with radiographic 
findings OR Operative 
intervention indicated 
Disabling bone pain with 
radiographic findings 
causing inability to 
perform basic self-care 
functions 
GENITOURINARY 
Cervicitis  
(symptoms) 
(For use in studies 
evaluating topical  
study agents)  
For other cervicitis see 
Infection: Infection 
(any other than HIV 
infection)  
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities  
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Symptoms causing 
inability to perform usual 
social & functional 
activities  
 
Symptoms causing 
inability to perform basic 
self-care functions  
Cervicitis  
(clinical exam) 
(For use in studies 
evaluating topical  
study agents)  
For other cervicitis see 
Infection: Infection 
(any other than HIV 
infection)  
Minimal cervical 
abnormalities on 
examination 
(erythema, 
mucopurulent 
discharge, or friability) 
OR Epithelial 
disruption  
< 25% of total surface 
Moderate cervical 
abnormalities on 
examination 
(erythema, 
mucopurulent 
discharge, or friability) 
OR Epithelial 
disruption of 25 – 49% 
total surface 
Severe cervical 
abnormalities on 
examination (erythema, 
mucopurulent 
discharge, or friability) 
OR Epithelial disruption  
50 – 75% total surface 
Epithelial disruption  
> 75% total surface 

Collaborative Antiviral Study Group 
DMID Protocol #11-0069, Version 4.0 
CASG Valgan Toddler 
28 April 2016 
 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, 
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
12-28-04 
 
 Version 1.0 
 
 _____________________________________________________________________________________________  
78 
 
CLINICAL 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Inter-menstrual 
bleeding (IMB) 
Spotting observed by 
participant OR 
Minimal blood 
observed during 
clinical or colposcopic 
examination 
Inter-menstrual 
bleeding not greater in 
duration or amount 
than usual menstrual 
cycle 
Inter-menstrual bleeding 
greater in duration or 
amount than usual 
menstrual cycle 
Hemorrhage with life-
threatening hypotension 
OR Operative 
intervention indicated 
Urinary tract 
obstruction (e.g., 
stone) 
NA 
Signs or symptoms of 
urinary tract 
obstruction without  
hydronephrosis or 
renal dysfunction 
Signs or symptoms of 
urinary tract obstruction 
with hydronephrosis or 
renal dysfunction 
Obstruction causing life-
threatening 
consequences 
Vulvovaginitis  
(symptoms) 
(Use in studies 
evaluating topical 
study agents)  
For other 
vulvovaginitis see 
Infection: Infection 
(any other than HIV 
infection) 
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities  
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Symptoms causing 
inability to perform usual 
social & functional 
activities  
 
Symptoms causing 
inability to perform basic 
self-care functions  
Vulvovaginitis  
(clinical exam) 
(Use in studies 
evaluating topical 
study agents)  
For other 
vulvovaginitis see 
Infection: Infection 
(any other than HIV 
infection) 
Minimal vaginal 
abnormalities on 
examination OR 
Epithelial disruption  
< 25% of total surface 
Moderate vaginal 
abnormalities on 
examination OR 
Epithelial disruption of 
25 - 49% total surface 
Severe vaginal 
abnormalities on 
examination OR 
Epithelial disruption  
50 - 75% total surface 
Vaginal perforation OR 
Epithelial disruption 
> 75% total surface 
OCULAR/VISUAL 
Uveitis 
Asymptomatic but 
detectable on exam 
Symptomatic anterior 
uveitis OR Medical 
intervention indicated 
Posterior or pan-uveitis 
OR Operative 
intervention indicated 
Disabling visual loss in 
affected eye(s)  

Collaborative Antiviral Study Group 
DMID Protocol #11-0069, Version 4.0 
CASG Valgan Toddler 
28 April 2016 
 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, 
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
12-28-04 
 
 Version 1.0 
 
 _____________________________________________________________________________________________  
79 
 
CLINICAL 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Visual changes (from 
baseline) 
Visual changes 
causing no or minimal 
interference with 
usual social & 
functional activities 
Visual changes 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Visual changes causing 
inability to perform usual 
social & functional 
activities 
Disabling visual loss in 
affected eye(s) 
ENDOCRINE/METABOLIC 
Abnormal fat 
accumulation 
(e.g., back of neck, 
breasts, abdomen) 
Detectable by study 
participant (or by 
caregiver for young 
children and disabled 
adults) 
Detectable on physical 
exam by health care 
provider 
Disfiguring OR Obvious 
changes on casual 
visual inspection 
NA 
Diabetes mellitus 
NA 
New onset without 
need to initiate 
medication OR 
Modification of current 
medications to regain 
glucose control 
New onset with initiation 
of medication indicated 
OR Diabetes 
uncontrolled despite 
treatment modification 
Life-threatening 
consequences (e.g., 
ketoacidosis, 
hyperosmolar non-
ketotic coma)  
Gynecomastia 
Detectable by study 
participant or 
caregiver (for young 
children and disabled 
adults) 
Detectable on physical 
exam by health care 
provider 
Disfiguring OR Obvious 
on casual visual 
inspection 
NA 
Hyperthyroidism  
Asymptomatic 
 
Symptomatic causing 
greater than minimal 
interference with usual 
social & functional 
activities OR Thyroid 
suppression therapy 
indicated 
Symptoms causing 
inability to perform usual 
social & functional 
activities OR 
Uncontrolled despite 
treatment modification  
Life-threatening 
consequences (e.g., 
thyroid storm) 
Hypothyroidism 
Asymptomatic 
Symptomatic causing 
greater than minimal 
interference with usual 
social & functional 
activities OR Thyroid 
replacement therapy 
indicated 
Symptoms causing 
inability to perform usual 
social & functional 
activities OR 
Uncontrolled despite 
treatment modification  
Life-threatening 
consequences (e.g., 
myxedema coma) 

Collaborative Antiviral Study Group 
DMID Protocol #11-0069, Version 4.0 
CASG Valgan Toddler 
28 April 2016 
 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, 
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
12-28-04 
 
 Version 1.0 
 
 _____________________________________________________________________________________________  
80 
 
CLINICAL 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Lipoatrophy 
(e.g., fat loss from the 
face, extremities, 
buttocks) 
Detectable by study 
participant (or by 
caregiver for young 
children and disabled 
adults) 
Detectable on physical 
exam by health care 
provider 
Disfiguring OR Obvious 
on casual visual 
inspection 
NA 

Collaborative Antiviral Study Group 
DMID Protocol #11-0069, Version 4.0 
CASG Valgan Toddler 
28 April 2016 
 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, 
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
12-28-04 
 
 Version 1.0 
 
 _____________________________________________________________________________________________  
81 
 
 
 
LABORATORY 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
HEMATOLOGY 
Standard International Units are listed in italics 
Absolute CD4+ count  
– Adult and Pediatric  
> 13 years 
(HIV NEGATIVE ONLY) 
300 – 400/mm3 
300 – 400/µL 
200 –  299/mm3 
200 – 299/µL 
100 – 199/mm3 
100 – 199/µL 
< 100/mm3 
< 100/µL 
Absolute lymphocyte 
count  
– Adult and Pediatric  
> 13 years 
(HIV NEGATIVE ONLY) 
600 – 650/mm3 
0.600 x 109 – 
0.650 x 109/L 
500 – 599/mm3 
0.500 x 109 –  
0.599 x 109/L 
350 – 499/mm3 
0.350 x 109 –   
0.499 x 109/L 
< 350/mm3 
< 0.350 x 109/L 
Absolute neutrophil count (ANC)  
Adult and Pediatric,  
> 7 days 
1,000 – 1,300/mm3 
1.000 x 109 – 
1.300 x 109/L 
750 – 999/mm3 
0.750  x 109 –  
0.999 x 109/L 
500 – 749/mm3 
0.500  x 109 –  
0.749 x 109/L   
< 500/mm3 
< 0.500 x 109/L 
 
Infant∗†, 2 – ≤ 7 days 
1,250 – 1,500/mm3 
1.250  x 109 –  
1.500 x 109/L 
1,000 – 1,249/mm3 
1.000 x 109 –  
1.249 x 109/L 
750 – 999/mm3 
0.750  x 109 –  
0.999  x 109/L 
< 750/mm3 
< 0.750 x 109/L 
 
Infant∗†, 1 day 
4,000 – 5,000/mm3 
4.000 x 109 –  
5.000 x 109/L 
3,000 – 3,999/mm3 
3.000 x 109 –  
3.999 x109/L 
1,500 – 2,999/mm3 
1.500 x 109 –  
2.999 x 109/L 
< 1,500/mm3 
< 1.500 x 109/L 
Fibrinogen, decreased 
100 – 200 mg/dL 
1.00 – 2.00 g/L 
OR 
0.75 – 0.99 x LLN 
75 – 99 mg/dL 
0.75 – 0.99 g/L 
OR 
0.50 – 0.74 x LLN 
50 – 74 mg/dL 
0.50 – 0.74 g/L 
OR 
0.25 – 0.49 x LLN 
< 50 mg/dL  
< 0.50 g/L 
OR 
< 0.25 x LLN 
OR  
Associated with gross 
bleeding  
Hemoglobin (Hgb) 

Collaborative Antiviral Study Group 
DMID Protocol #11-0069, Version 4.0 
CASG Valgan Toddler 
28 April 2016 
 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, 
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
12-28-04 
 
 Version 1.0 
 
 _____________________________________________________________________________________________  
82 
 
 
LABORATORY 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Adult and Pediatric 
≥ 57 days 
 
(HIV POSITIVE 
ONLY) 
8.5 – 10.0 g/dL 
1.32 – 1.55 mmol/L 
7.5 – 8.4 g/dL 
1.16 – 1.31 mmol/L 
6.50 – 7.4 g/dL 
1.01 – 1.15 mmol/L 
< 6.5 g/dL 
< 1.01 mmol/L 
Adult and Pediatric  
≥ 57 days  
(HIV NEGATIVE 
ONLY)  
10.0 – 10.9 g/dL 
1.55 – 1.69 mmol/L 
OR 
Any decrease  
2.5 – 3.4 g/dL 
0.39 – 0.53 mmol/L 
9.0 – 9.9 g/dL 
1.40 – 1.54 mmol/L 
OR 
Any decrease  
3.5 – 4.4 g/dL 
0.54 – 0.68 mmol/L 
7.0 – 8.9 g/dL 
1.09 – 1.39 mmol/L 
OR 
Any decrease  
≥ 4.5 g/dL 
≥ 0.69 mmol/L 
< 7.0 g/dL 
< 1.09 mmol/L 
 
 
Infant∗†, 36 – 56 days 
(HIV POSITIVE OR 
NEGATIVE) 
8.5 – 9.4 g/dL 
1.32 – 1.46 mmol/L 
7.0 –  8.4 g/dL 
1.09 – 1.31 mmol/L 
6.0 – 6.9 g/dL 
0.93 – 1.08 mmol/L 
< 6.00 g/dL 
< 0.93 mmol/L 
 
Infant∗†, 22 – 35 days 
(HIV POSITIVE OR 
NEGATIVE) 
9.5 – 10.5 g/dL 
1.47 – 1.63 mmol/L 
8.0 – 9.4 g/dL 
1.24 – 1.46 mmol/L 
7.0 – 7.9 g/dL 
1.09 – 1.23 mmol/L 
< 7.00 g/dL 
< 1.09 mmol/L 
 
Infant∗†, 1 – 21 days 
(HIV POSITIVE OR 
NEGATIVE) 
12.0 – 13.0 g/dL 
1.86 – 2.02 mmol/L 
10.0 – 11.9 g/dL 
1.55 – 1.85 mmol/L 
9.0 – 9.9 g/dL 
1.40 – 1.54 mmol/L 
< 9.0 g/dL 
< 1.40 mmol/L 
International Normalized 
Ratio of prothrombin time 
(INR) 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.1 – 3.0 x ULN 
> 3.0 x ULN 
Methemoglobin 
5.0 – 10.0% 
10.1 – 15.0% 
15.1 – 20.0% 
> 20.0% 
Prothrombin Time (PT) 
1.1 – 1.25 x ULN 
1.26 – 1.50 x ULN 
1.51 – 3.00 x ULN 
> 3.00 x ULN 
Partial Thromboplastin 
Time (PTT) 
1.1 – 1.66 x ULN 
1.67 – 2.33 x ULN 
2.34 – 3.00 x ULN 
> 3.00 x ULN 
Platelets, decreased 
100,000 –  
124,999/mm3 
100.000 x 109 – 
124.999 x 109/L 
50,000 –  
99,999/mm3 
50.000 x 109 – 
99.999 x 109/L 
25,000 –  
49,999/mm3 
25.000 x 109 – 
49.999 x 109/L 
< 25,000/mm3 
< 25.000 x 109/L 

Collaborative Antiviral Study Group 
DMID Protocol #11-0069, Version 4.0 
CASG Valgan Toddler 
28 April 2016 
 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, 
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
12-28-04 
 
 Version 1.0 
 
 _____________________________________________________________________________________________  
83 
 
 
LABORATORY 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
WBC, decreased 
2,000 – 2,500/mm3 
2.000 x 109 –  
2.500 x 109/L 
1,500 – 1,999/mm3 
1.500 x 109 –  
1.999 x 109/L 
1,000 – 1,499/mm3 
1.000 x 109 –  
1.499 x 109/L 
< 1,000/mm3 
< 1.000 x 109/L 
CHEMISTRIES 
 
Standard International Units are listed in italics  
Acidosis 
NA 
pH < normal, but ≥ 7.3 
pH < 7.3 without life-
threatening 
consequences 
pH < 7.3 with life-
threatening 
consequences 
Albumin, serum, low 
3.0 g/dL – < LLN 
30 g/L – < LLN 
2.0 – 2.9 g/dL 
20 – 29 g/L 
< 2.0 g/dL 
< 20 g/L 
NA 
Alkaline Phosphatase 
1.25 – 2.5 x ULN† 
2.6 – 5.0 x ULN† 
5.1 – 10.0 x ULN† 
> 10.0 x ULN† 
Alkalosis 
NA 
pH > normal, but ≤ 7.5 
pH > 7.5 without life-
threatening 
consequences 
pH > 7.5 with life-
threatening 
consequences  
ALT (SGPT) 
1.25 – 2.5 x ULN 
2.6 – 5.0 x ULN 
5.1 – 10.0 x ULN 
> 10.0 x ULN 
AST (SGOT) 
1.25 – 2.5 x ULN 
2.6 – 5.0 x ULN 
5.1 – 10.0 x ULN 
> 10.0 x ULN 
Bicarbonate, serum, low 
16.0 mEq/L – < LLN 
16.0 mmol/L – < LLN 
11.0 – 15.9 mEq/L 
11.0 – 15.9 mmol/L 
8.0 – 10.9 mEq/L 
8.0 – 10.9 mmol/L 
< 8.0 mEq/L 
< 8.0 mmol/L 
Bilirubin (Total) 
Adult and Pediatric > 
14 days 
1.1 – 1.5 x ULN 
1.6 – 2.5 x ULN 
2.6 – 5.0 x ULN 
> 5.0 x ULN 
Infant∗†, ≤ 14 days 
(non-hemolytic) 
NA 
20.0 – 25.0 mg/dL 
342 – 428 µmol/L 
25.1 – 30.0 mg/dL 
429 – 513 µmol/L 
> 30.0 mg/dL 
> 513.0 µmol/L 
Infant∗†, ≤ 14 days 
(hemolytic) 
NA 
NA 
20.0 – 25.0 mg/dL 
342 – 428 µmol/L 
> 25.0 mg/dL 
> 428 µmol/L 
Calcium, serum, high (corrected for albumin) 
Adult and Pediatric  
≥ 7 days 
10.6  – 11.5 mg/dL 
2.65 – 2.88 mmol/L 
11.6  – 12.5 mg/dL 
2.89 – 3.13 mmol/L 
12.6  – 13.5 mg/dL 
3.14 – 3.38 mmol/L 
> 13.5 mg/dL 
> 3.38 mmol/L 

Collaborative Antiviral Study Group 
DMID Protocol #11-0069, Version 4.0 
CASG Valgan Toddler 
28 April 2016 
 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, 
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
12-28-04 
 
 Version 1.0 
 
 _____________________________________________________________________________________________  
84 
 
 
LABORATORY 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Infant∗†, < 7 days 
11.5 – 12.4 mg/dL 
2.88 – 3.10 mmol/L 
12.5 – 12.9 mg/dL 
3.11 – 3.23 mmol/L 
13.0 – 13.5 mg/dL 
3.245 – 3.38 mmol/L 
> 13.5 mg/dL 
> 3.38 mmol/L 
Calcium, serum, low (corrected for albumin) 
Adult and Pediatric  
≥ 7 days  
7.8  – 8.4 mg/dL 
1.95 – 2.10 mmol/L 
7.0  – 7.7 mg/dL 
1.75 – 1.94 mmol/L 
6.1  – 6.9 mg/dL 
1.53 – 1.74 mmol/L 
< 6.1 mg/dL 
< 1.53 mmol/L 
Infant∗†, < 7 days 
6.5 – 7.5 mg/dL 
1.63 – 1.88 mmol/L 
6.0 – 6.4 mg/dL 
1.50 – 1.62 mmol/L 
5.50 – 5.90 mg/dL 
1.38 – 1.51 mmol/L 
< 5.50 mg/dL 
< 1.38 mmol/L 
Cardiac troponin I (cTnI) 
NA 
NA 
NA 
Levels consistent with 
myocardial infarction 
or unstable angina as 
defined by the 
manufacturer 
Cardiac troponin T (cTnT) 
NA 
NA 
NA 
≥ 0.20 ng/mL 
OR 
Levels consistent with 
myocardial infarction 
or unstable angina as 
defined by the 
manufacturer 
Cholesterol (fasting) 
Adult ≥ 18 years 
200 – 239 mg/dL 
5.18 – 6.19 mmol/L 
240 – 300 mg/dL 
6.20 – 7.77 mmol/L 
> 300 mg/dL 
> 7.77 mmol/L 
NA 
Pediatric < 18 years 
170 – 199 mg/dL 
4.40 – 5.15 mmol/L 
200 – 300 mg/dL 
5.16 – 7.77 mmol/L 
> 300 mg/dL 
> 7.77 mmol/L 
NA 
Creatine Kinase 
3.0 – 5.9 x ULN† 
6.0 – 9.9 x ULN† 
10.0 – 19.9 x ULN† 
≥ 20.0 x ULN† 
Creatinine 
1.1 – 1.3 x ULN† 
1.4 – 1.8 x ULN† 
1.9 – 3.4 x ULN† 
≥ 3.5 x ULN† 
Glucose, serum, high  
 
Nonfasting 
116 – 160 mg/dL 
6.44 – 8.88 mmol/L 
161 – 250 mg/dL 
8.89 – 13.88 mmol/L 
251 – 500 mg/dL 
13.89 – 27.75 mmol/L 
> 500 mg/dL 
> 27.75 mmol/L 

Collaborative Antiviral Study Group 
DMID Protocol #11-0069, Version 4.0 
CASG Valgan Toddler 
28 April 2016 
 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, 
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
12-28-04 
 
 Version 1.0 
 
 _____________________________________________________________________________________________  
85 
 
 
LABORATORY 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
   Fasting 
110 – 125 mg/dL 
6.11 – 6.94 mmol/L 
126 – 250 mg/dL 
6.95 – 13.88 mmol/L 
251 – 500 mg/dL 
13.89 – 27.75 mmol/L 
> 500 mg/dL 
> 27.75 mmol/L 
 
Glucose, serum, low  
Adult and Pediatric  
≥ 1 month 
55 – 64 mg/dL 
3.05 – 3.55 mmol/L 
40 – 54 mg/dL 
2.22 – 3.06 mmol/L 
30 – 39 mg/dL 
1.67 – 2.23 mmol/L 
< 30 mg/dL 
< 1.67 mmol/L 
Infant∗†, < 1 month 
50 – 54 mg/dL 
2.78 – 3.00 mmol/L 
40 – 49 mg/dL 
2.22 – 2.77 mmol/L 
30 – 39 mg/dL 
1.67 – 2.21 mmol/L 
< 30 mg/dL 
< 1.67 mmol/L 
Lactate 
< 2.0 x ULN without 
acidosis 
≥ 2.0 x ULN without 
acidosis 
Increased lactate with 
pH < 7.3 without life-
threatening 
consequences  
Increased lactate with 
pH < 7.3 with life-
threatening 
consequences  
LDL cholesterol (fasting) 
Adult ≥ 18 years 
130 – 159 mg/dL 
3.37 – 4.12 mmol/L 
160 – 190 mg/dL 
4.13 – 4.90 mmol/L 
≥ 190 mg/dL 
≥ 4.91 mmol/L 
NA 
Pediatric > 2 - < 18 
years 
110 – 129 mg/dL  
2.85 – 3.34 mmol/L 
130 – 189 mg/dL 
3.35 – 4.90 mmol/L 
≥ 190 mg/dL 
≥ 4.91 mmol/L 
NA 
Lipase 
1.1 – 1.5 x ULN 
1.6 – 3.0 x ULN 
3.1 – 5.0 x ULN 
> 5.0 x ULN 
Magnesium, serum, low 
1.2  – 1.4 mEq/L 
0.60 – 0.70 mmol/L 
0.9 – 1.1 mEq/L 
0.45 – 0.59 mmol/L 
0.6 – 0.8 mEq/L 
0.30 – 0.44 mmol/L 
< 0.60 mEq/L 
< 0.30 mmol/L 
Pancreatic amylase 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.1 – 5.0 x ULN 
> 5.0 x ULN 
Phosphate, serum, low 
Adult and Pediatric  
> 14 years 
2.5 mg/dL – < LLN 
0.81 mmol/L – < LLN 
2.0 – 2.4 mg/dL 
0.65 – 0.80 mmol/L 
1.0 – 1.9 mg/dL 
0.32 – 0.64 mmol/L 
< 1.00 mg/dL 
< 0.32 mmol/L 
Pediatric 1 year – 14 
years  
3.0 – 3.5 mg/dL 
0.97 – 1.13 mmol/L 
2.5 – 2.9 mg/dL 
0.81 – 0.96 mmol/L 
1.5 – 2.4 mg/dL 
0.48 – 0.80 mmol/L 
< 1.50 mg/dL 
< 0.48 mmol/L 
Pediatric < 1 year 
3.5 – 4.5 mg/dL 
1.13 – 1.45 mmol/L 
2.5 – 3.4 mg/dL 
0.81 – 1.12 mmol/L 
1.5 – 2.4 mg/dL 
0.48 – 0.80 mmol/L 
< 1.50 mg/dL 
< 0.48 mmol/L 

Collaborative Antiviral Study Group 
DMID Protocol #11-0069, Version 4.0 
CASG Valgan Toddler 
28 April 2016 
 
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally 
appropriate eating implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, 
use of transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, 
play activities, learning tasks, etc.). 
12-28-04 
 
 Version 1.0 
 
 _____________________________________________________________________________________________  
86 
 
 
LABORATORY 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE-THREATENING 
Potassium, serum, high 
5.6 – 6.0 mEq/L 
5.6 – 6.0 mmol/L 
6.1 – 6.5 mEq/L 
6.1 – 6.5 mmol/L 
6.6 – 7.0 mEq/L 
6.6 – 7.0 mmol/L 
> 7.0 mEq/L 
> 7.0 mmol/L 
Potassium, serum, low 
3.0 – 3.4 mEq/L 
3.0 – 3.4 mmol/L 
2.5 – 2.9 mEq/L 
2.5 – 2.9 mmol/L 
2.0 – 2.4 mEq/L 
2.0 – 2.4 mmol/L 
< 2.0 mEq/L 
< 2.0 mmol/L 
Sodium, serum, high 
146 – 150 mEq/L 
146 – 150 mmol/L 
151 – 154 mEq/L 
151 – 154 mmol/L 
155 – 159 mEq/L 
155 – 159 mmol/L 
≥ 160 mEq/L 
≥ 160 mmol/L 
Sodium, serum, low 
130 – 135 mEq/L 
130 – 135 mmol/L 
125 – 129 mEq/L 
125 – 129 mmol/L 
121 – 124 mEq/L 
121 – 124 mmol/L 
≤ 120 mEq/L 
≤ 120 mmol/L 
Triglycerides (fasting) 
NA 
500 – 750 mg/dL 
5.65 – 8.48 mmol/L 
751 – 1,200 mg/dL 
8.49 – 13.56 mmol/L 
> 1,200 mg/dL 
> 13.56 mmol/L 
Uric acid 
7.5 – 10.0 mg/dL 
0.45 – 0.59 mmol/L 
10.1 – 12.0 mg/dL 
0.60 – 0.71 mmol/L 
12.1 – 15.0 mg/dL 
0.72 – 0.89 mmol/L 
> 15.0 mg/dL 
> 0.89 mmol/L 
URINALYSIS 
 
Standard International Units are listed in italics 
Hematuria (microscopic) 
 6 – 10 RBC/HPF 
> 10 RBC/HPF 
Gross, with or without 
clots OR with RBC 
casts 
Transfusion indicated 
Proteinuria, random 
collection 
1 + 
2 – 3 + 
4 + 
NA 
Proteinuria, 24 hour collection 
Adult and Pediatric  
≥ 10 years 
200 – 999 mg/24 h 
0.200 – 0.999 g/d 
1,000 – 1,999 mg/24 h 
1.000 – 1.999 g/d 
2,000 – 3,500 mg/24 h 
2.000 – 3.500 g/d 
> 3,500 mg/24 h 
> 3.500 g/d 
Pediatric > 3 mo -  
< 10 years 
201 – 499 mg/m2/24 h 
0.201 – 0.499 g/d 
500 – 799 mg/m2/24 h 
0.500 – 0.799 g/d 
800 – 1,000  
mg/m2/24 h 
0.800 – 1.000 g/d 
> 1,000 mg/ m2/24 h 
> 1.000 g/d