Prospective Observational Study of Asymptomatic cCMV Transmission to Infants for Virological Evaluation in New York State
Conditions: Congenital CMV Infection, Sensorineural Hearing Loss
Sponsor: Stony Brook University

Health Research, Inc. 
 
Prospective Observational Study of Asymptomatic cCMV 
Transmission to Infants for Virological Evaluation in New York State 
(PROACTIVE NYS) 
 
 
 
 
Sponsored by: 
 Eunice Kennedy Shriver National Institute for Child Health and Human Development 
(NICHD) 
 
 
 
 
 
Task Order: Newborn Screening Follow-up Study of Congenital Cytomegalovirus 
Infection 
Contract No.: 75N94021D00018 
Task Order No.: 75N94023F00001 
 
Non-IND Study 
 
 
Protocol Chairs: 
Andrew Handel, MD 
 
Sharon Nachman, MD 
 
 
 
 
 
 
 
Version 1.0 
25 October 2023 
 

PROACTIVE NYS, Version 1.0 
Page 2 of 64 
Version Date 25 October 2023 
Prospective Observational Study of Asymptomatic cCMV 
Transmission to Infants for Virological Evaluation in New York State 
(PROACTIVE NYS) 
 
TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE .............................................................................................. 4 
PROTOCOL TEAM ROSTER .................................................................................................... 6 
SCHEMA ................................................................................................................................... 8 
1 
INTRODUCTION ............................................................................................................ 9 
1.1 
Background ......................................................................................................................... 9 
1.2 
Rationale ........................................................................................................................... 10 
1.3 
Hypotheses ........................................................................................................................ 10 
2 
OBJECTIVES ................................................................................................................10 
2.1 
Primary Objective ............................................................................................................. 10 
2.2 
Secondary Objectives ....................................................................................................... 10 
3 
STUDY DESIGN ...........................................................................................................11 
3.1 
Study Setting ..................................................................................................................... 12 
3.2 
Facilities ............................................................................................................................ 13 
3.3 
Enrollment Estimates ........................................................................................................ 13 
4 
STUDY POPULATION ..................................................................................................14 
4.1 
Participant Recruitment & Enrollment ............................................................................. 14 
4.2 
Inclusion Criteria .............................................................................................................. 14 
4.3 
Exclusion Criteria ............................................................................................................. 15 
4.4 
Participant Withdrawal or Termination from the Study ................................................... 15 
5 
STUDY VISITS AND PROCEDURES ...........................................................................15 
5.1 
Enrollment Visit ................................................................................................................ 15 
5.2 
Follow-Up Visits ............................................................................................................... 16 
5.3 
Variables Collected ........................................................................................................... 17 
5.4 
Outcome Assessments ...................................................................................................... 17 
5.5 
Planned analyses: .............................................................................................................. 21 
6 
PARTICIPANT MANAGEMENT ....................................................................................21 
6.1 
Issues Related to Universal cCMV Newborn Screening .................................................. 21 
7 
STATISTICAL CONSIDERATIONS ..............................................................................22 
7.1 
Outcome Measures ........................................................................................................... 22 
7.2 
Randomization and Stratification ..................................................................................... 23 
7.3 
Monitoring ........................................................................................................................ 23 
7.4 
Analyses ............................................................................................................................ 24 
8 
DATA HANDLING AND RECORD KEEPING ...............................................................24 
8.1 
Statistical and Data Management Center (DMC) ............................................................. 24 
8.2 
Essential and Source Documents and Access to Source Data .......................................... 27 
8.3 
Quality Control and Quality Assurance ............................................................................ 27 
9 
COLLABORATION .......................................................................................................27 
10 
ANNUAL UPDATES .....................................................................................................28 
11 
ADVISORY COMMITTEE .............................................................................................28 
12 
HUMAN SUBJECTS PROTECTIONS...........................................................................28 
12.1 
Institutional Review Board/Ethics Committee Review and Approval ............................. 28 
12.2 
Parental Permission ........................................................................................................... 28 
12.3 
Potential Benefits .............................................................................................................. 28 
12.4 
Potential Risks .................................................................................................................. 28 
12.5 
Reimbursement/Compensation ......................................................................................... 29 

PROACTIVE NYS, Version 1.0 
Page 3 of 64 
Version Date 25 October 2023 
12.6 
Privacy and Confidentiality .............................................................................................. 29 
12.7 
Management of Incidental Findings ................................................................................. 29 
12.8 
Management of New Information Pertinent to Study Participation.................................. 29 
13 
ADMINISTRATIVE PROCEDURES ..............................................................................29 
13.1 
Protocol Registration ........................................................................................................ 29 
13.2 
Study Implementation ....................................................................................................... 29 
13.3 
Protocol Deviation Reporting ........................................................................................... 30 
13.4 
ClinicalTrials.gov ............................................................................................................. 30 
14 
PUBLICATIONS ...........................................................................................................30 
14.1 
Public Results Distribution ............................................................................................... 30 
14.2 
Academic Results Distribution ......................................................................................... 30 
15 
REFERENCES ..............................................................................................................30 
Appendix I ...............................................................................................................................32 
Appendix II ..............................................................................................................................35 
Appendix III .............................................................................................................................59 
 
 

PROACTIVE NYS, Version 1.0 
Page 4 of 64 
Version Date 25 October 2023 
 
Prospective Observational Study of Asymptomatic cCMV Transmission to 
Infants for Virological Evaluation in New York State (PROACTIVE NYS) 
Version 1.0 
 
 
 
PROTOCOL SIGNATURE PAGE 
 
 
I will conduct this study in accordance with the provisions of this protocol and all applicable protocol-
related documents. I agree to conduct this study in compliance with United States (US) Health and 
Human Service regulations (45 CFR 46); applicable US Food and Drug Administration regulations; 
standards of the International Council for Harmonisation Guideline for Good Clinical Practice (ICH E6); 
Institutional Review Board/Ethics Committee determinations; all applicable in-country, state, and local 
laws and regulations; and other applicable requirements (e.g., US National Institutes of Health, Division 
of AIDS) and institutional policies. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator of Record 
  
 
Date 
 
 
 
 
 
 
 
 
 
 
 
Name of Investigator of Record  
 
(printed) 
 
 
 
 

PROACTIVE NYS, Version 1.0 
Page 5 of 64 
Version Date 25 October 2023 
PROACTIVE NYS 
Prospective Observational Study of Asymptomatic cCMV Transmission to Infants 
for Virological Evaluation in New York State 
 
ABBREVIATIONS, ACRONYMS, and TERM DEFINITIONS 
 
Term/Acronym 
Definition 
CMV 
Cytomegalovirus 
cCMV 
Congenital Cytomegalovirus 
EC 
Ethics Committee 
NYS DOH NBS 
New York State Department of Health Newborn Screening Program 
cCMV screen 
NYS DOH NBS CMV PCR via dried blood spot 
cCMV confirmatory test 
CMV PCR or culture from a body fluid following a positive cCMV screen 
Confirmed cCMV 
Any infant with a positive cCMV screen and a confirmatory CMV PCR or 
culture from urine (preferred), blood, or cerebrospinal fluid (CSF) 
obtained within 21 days of life. 
- 
Note that this excludes saliva samples 
DMC 
Data Management Center 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
IDSCC 
Infectious Disease Specialty Care Centers 
IRB 
Institutional Review Board 
mPI 
Multiple Principal Investigators 
ND 
Neurodevelopmental 
NICHD 
National Institute for Child Health and Human Development 
NICU 
Neonatal Intensive Care Unit 
NIH 
National Institute of Health 
PCR 
Polymerase Chain Reaction 
PI 
Principal Investigator 
PO 
By mouth 
Presumed cCMV 
Any infant with a positive cCMV screen and either: 
- 
A confirmatory CMV PCR or culture from saliva obtained within 
21 days of life 
- 
OR a confirmatory CMV PCR or culture from urine, blood, CSF, 
or saliva obtained on day 22 of life or later 
QMS 
Quality Management System 
QoL 
Quality of Life  
SAP 
Statistical Analysis Plan 
sIRB 
Single Institutional Review Board 
SNHL 
Sensorineural hearing loss 
SOP 
Standard Operating Procedure 
Study Day 0 
Date of birth 
SWOT 
Strengths, Weaknesses, Opportunities, and Threats 
 
 
 
 
 
 

PROACTIVE NYS, Version 1.0 
Page 6 of 64 
Version Date 25 October 2023 
PROACTIVE NYS 
Prospective Observational Study of Asymptomatic cCMV Transmission to Infants 
for Virological Evaluation in New York State 
 
PROTOCOL TEAM ROSTER 
Protocol Chairs & Co-Principal Investigators 
Andrew Handel, MD 
Division Pediatric Infectious Disease 
Dept Pediatrics 
Renaissance School of Medicine 
SUNY Stony Brook 
631-444-7692 
Andrew.handel@stonybrookmedicine.edu 
 
Sharon Nachman, MD 
Division Pediatric Infectious Disease  
Dept Pediatrics  
Renaissance School of Medicine 
SUNY Stony Brook 
631-444-7692 
Sharon.nachman@stonybrookmedicine.edu  
 
Contact Principal Investigator 
Michele Caggana, Sc.D., FACMG 
New York State Department of Health 
Newborn Screening Program 
David Axelrod Institute / Wadsworth Center 
120 New Scotland Avenue, Albany, NY 12208 
michele.caggana@health.ny.gov 
Psychology Consultant 
Kathleen Malee, PhD 
Northwestern University Feinberg School of 
Medicine 
kmalee@luriechildrens.org 
225 E. Chicago Avenue, Box 155,  
Chicago, IL 60611 
IDSCC Medical Directors 
Margaret Aldrich, MD 
Montefiore Medical Center  
maldrich@montefiore.org  
111 East 20 Street, Bronx, NY 10467 
 
Mark Hicar, MD, Ph.D. 
State University of New York at Buffalo - Oishei 
Children's Hospital 
mhicar@upa.chob.edu  
818 Ellicott St, Buffalo, NY 14203 
 
Minnie John, MD 
New York Presbyterian Brooklyn Methodist 
Hospital 
mij9037@nyp.org  
506 Sixth Street, Brooklyn, NY 11215 
 
Sheila Nolan, MD 
Maria Fareri Children’s Hospital at Westchester 
Medical Center 
sheila_nolan@bchphysicians.org  
100 Woods Rd, Valhalla, Westchester County, 
NY 10595 
 
Christine M. Salvatore, MD 
Weill Cornell Medicine 
chs2032@med.cornell.edu  
525 East 68th Street, New York, NY 10021 
 
Gail Shust, MD 
NYU Langone Hospitals 
gail.shust@nyulangone.org  
550 First Ave, New York, NY 10016 
 
Sunil Sood, MD 
Cohen Children’s Medical Center Northwell Health 
ssood@northwell.edu  
269-01 76th Ave, New Hyde Park, Queens, NY 
11040 
 
Gillian Taormina, DO 
Albany Medical Center 
taormig@amc.edu  
43 New Scotland Ave, Albany, NY 12208 
 
Geoff Weinberg, MD 
University of Rochester Strong Memorial 
Hospital – Golisano Children’s Hospital 
geoff_weinberg@urmc.rochester.edu  
601 Elmwood Ave, Rochester, NY 14642 
 
Leonard Weiner, MD 
Upstate Golisano Children’s Hospital  
weinerl@upstate.edu  
725 Irving Avenue, Syracuse, NY 13210 

PROACTIVE NYS, Version 1.0 
Page 7 of 64 
Version Date 25 October 2023 
 
Protocol Statisticians 
 
Ting-Li Lin, PhD 
Senior Research Scientist 
Frontier Science 
440 Science Drive, Suite 401 
Madison, WI 53711 
lin@frontierscience.org 
608-535-8300 x2048 
 
Rudie Desravines, MS 
Biostatistician II 
Frontier Science 
1371 Beacon St, Suite 203 
Brookline, MA 02446 
desravi@frontierscience.org 
617-632-2000 x2032 
 
Protocol Data Managers 
 
Ken Wood, BA 
Data Management Project Manager 
Frontier Science 
4033 Maple Rd. 
Amherst, NY 14226 
wood@frontierscience.org 
716-834-0900 x7235 
 
Mark Byroads, BA 
Data Manager 
Frontier Science 
4033 Maple Rd. 
Amherst, NY 14226 
byroads@frontierscience.org 
716-834-0900 x7341 
 
 

PROACTIVE NYS, Version 1.0 
Page 8 of 64 
Version Date 25 October 2023 
 
PROACTIVE NYS 
Prospective Observational Study of Asymptomatic cCMV Transmission to Infants 
for Virological Evaluation in New York State 
 
SCHEMA 
 
Purpose: 
To gain knowledge from a large statewide cohort of cCMV-screen 
positive children to provide crucial insights into cCMV natural history, 
treatment decisions and outcomes, and the impact of statewide universal 
screening. 
 
Design: 
Registry 
 
Study Population: 
All infants with a positive cCMV screen in New York State 
 
Sample Size: 
>500 infants 
 
Study Duration: 
2-year longitudinal follow-up study 
 
Primary Objective 
• 
To enroll at least 90% of all cCMV New York State Department of Health Newborn Screen-positive 
infants across NYS in a long-term follow-up study 
 
Secondary Objectives 
• 
To determine the rate of confirmed congenital CMV in a statewide cohort 
• 
To describe the distribution of neonatal features among children with confirmed congenital CMV 
• 
To describe trends in antiviral and non-pharmaceutical treatments, adverse effects, and impact on 
long-term outcomes 
• 
To assess the long-term (2 year) audiologic, neurologic, and developmental outcomes of children with 
congenital CMV 
• 
To describe the impact of a positive cCMV screen on the quality of life (QoL) of infants and families 
 
 
 

PROACTIVE NYS, Version 1.0 
Page 9 of 64 
Version Date 25 October 2023 
PROACTIVE NYS 
Prospective Observational Study of Asymptomatic cCMV Transmission to Infants 
for Virological Evaluation in New York State 
 
1 
INTRODUCTION  
1.1 
Background  
Cytomegalovirus (CMV) is the most commonly described congenital infection, affecting 0.5-
1% of all births globally [1, 2]. In the United States, it is estimated that 40,000 neonates are 
born annually with congenital CMV (cCMV) [3]. Of those congenitally infected, clinical 
manifestations vary widely. While the majority of those with congenital infection (90%) are 
asymptomatic at birth, 20% of all children with cCMV will develop long-term sequelae 
(Figure 1) [4]. Common complications of cCMV include sensorineural hearing loss (SNHL), 
cognitive impairment, and chorioretinitis [2]. Among asymptomatic neonates with cCMV, 
there is no helpful clinical tool to determine which infants will develop sequelae later in life. 
Figure 1. Frequency of Sequelae among Children with Congenital CMV Infection 
 
Much controversy exists as to which neonates are most likely to benefit from antiviral 
treatment of cCMV. Key studies have designated neonates into various categories of 
symptomatology and treated those with the most severe illness, showing modest improvement. 
Typical categorization includes ‘asymptomatic’, ‘asymptomatic with sensorineural hearing 
loss’, or ‘symptomatic’ disease [2]. Within the symptomatic cohort, they are further 
categorized as having mild, moderate, or severe disease. The first major treatment study of 
cCMV found that, among those with ‘undifferentiated symptomatic’ disease, 6 weeks of 
intravenous (IV) ganciclovir initiated within 4 weeks of life led to improved outcomes 
compared to placebo [5]. Specifically, infants treated with ganciclovir were less likely to 
experience hearing deterioration at 6 months of age than those receiving placebo. A follow up 
study found that 6 months of oral (PO) valganciclovir led to improved SNHL and 
neurodevelopmental outcomes compared to 6 weeks of PO valganciclovir when evaluated at 
24 months old [6]. Among those asymptomatic neonates with normal hearing at birth, 10-15% 
will later develop SNHL [7]. To date, long-term follow-up of minimally symptomatic and 
asymptomatic neonates has been limited, with no data on annual incidence rates of SNHL. 
Further, no clear data exist in favor of or against treatment of those who are asymptomatic 
with SNHL at birth. Adverse effects of valganciclovir, particularly severe cytopenias, are well-
described, further complicating the decision to treat or not to treat [2, 8].  

PROACTIVE NYS, Version 1.0 
Page 10 of 64 
Version Date 25 October 2023 
1.2 
Rationale 
Cytomegalovirus (CMV) is the most common congenital infection worldwide, estimated to 
occur in 0.6% of all pregnancies. Among those with cCMV, 10% of infants are symptomatic 
at birth, about 40-60% of whom will have permanent sequelae. Of the 90% who are 
asymptomatic at birth, as per the current literature, 10-15% will have long-term sequelae, most 
often SNHL. What is unknown is how accurate these frequencies are today. Previous studies 
have found that treating symptomatic infants with 6 months of oral valganciclovir can improve 
neurodevelopmental and auditory outcomes. Treatment studies of asymptomatic infants or 
those with isolated SNHL are more limited, leading to a wide range of treatment preferences 
by clinicians and parents. Further, as cCMV is most likely to be diagnosed in more severely 
affected infants, few studies have investigated long-term outcomes of asymptomatic or 
minimally symptomatic infants. 
 
On October 2, 2023, NYS implemented a 1-year, opt-out pilot program to screen neonates for 
cCMV as part of the NBS program. Universal screening offers an unprecedented opportunity 
to develop a long-term, statewide cohort study of all neonates who screen positive for cCMV. 
Through organized standard-of-care follow up and systematic outcomes evaluations, this 
cohort will allow an in-depth, long-term evaluation of cCMV. Specifically, the study will 
investigate cCMV incidence across a large, ethnically and economically diverse state, describe 
the distribution of symptoms at birth and medical interventions provided, and assess long-term 
audiologic, neurologic, and developmental outcomes. Quality of life measures and impact of 
the screening as it relates to the Recommended Uniform Screening Panel (RUSP) will also be 
investigated. Utilizing a system designed to identify and enroll all cCMV screen-positive 
infants across NYS, PROACTIVE NYS will yield a wealth of knowledge regarding 
contemporary cCMV epidemiology, response to treatment, long-term audiologic and 
neurodevelopmental outcomes, and the impact of universal cCMV screening on the NBS 
program. 
 
1.3 
Hypotheses 
1. 0.6% of all neonates screened for congenital CMV infection will have a confirmed 
infection. 
2. The majority of neonates with confirmed congenital CMV will be asymptomatic or mildly 
affected. 
3. Children will have a wide range of long-term outcomes. 
• 
Those with the most severe symptoms as neonates will experience more severe 
audiologic and neurodevelopmental outcomes. 
• 
A subset of asymptomatic or mildly symptomatic neonates will develop and/or 
experience progressive sensorineural hearing loss and cognitive impairment. 
4. Infants with more severe sequelae of cCMV will be associated with lower QoL for infants 
and parents. 
2 
OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to enroll at least 90% of all cCMV screen-positive 
infants across NYS in a long-term follow-up study.  
2.2 
Secondary Objectives 
The secondary objectives of this study are to:  

PROACTIVE NYS, Version 1.0 
Page 11 of 64 
Version Date 25 October 2023 
1. 
To determine the rate of confirmed congenital CMV in a statewide cohort 
2. 
To describe the distribution of neonatal features among children with confirmed 
congenital CMV 
3. 
To describe trends in antiviral and non-pharmaceutical treatments, adverse effects, and 
impact on long-term outcomes 
4. 
To assess the long-term (2 year) audiologic, neurologic, and developmental outcomes of 
children with congenital CMV 
5. 
To describe the impact of a positive cCMV screen on the quality of life (QoL) of infants 
and families 
 
3 
STUDY DESIGN 
This study is a systematic, longitudinal cohort study of all infants with a positive cCMV screen in 
New York State. During the 2-year longitudinal study, baseline demographic information, neonatal 
cCMV clinical features, diagnostic testing results, antiviral administration and other medical 
interventions, long-term audiologic, neurologic, and developmental outcomes are collected, and 
infant and family QoL is assessed. Evaluations occur at regularly scheduled visits using standardized 
assessment tools according to Table 2 - Schedule of Events. 
 
• 
The 1-year NYS cCMV NBS Pilot Study began screening for cCMV on October 2, 2023, as 
described in the previously awarded Contract (# 75N94021D00018). The program is 
conducted as Human Subject Research approved by the NYS Institutional Review Board 
(IRB) under Expedited Category 5. A waiver of informed consent was granted. Families will 
be given the ability to opt-out of the cCMV NBS Pilot Study. 
 
• 
The cCMV NBS Pilot Study performs universal screening for cCMV of all neonates born in 
NYS during the 12-month cCMV NBS Pilot Study. Screening results are available within 7 
days of sample collection. Upon receiving a positive cCMV screen, the infant’s primary care 
provider is notified by NBS Follow-up staff through a phone call and fax. The primary care 
provider is provided with the infant’s newborn screen report which includes the positive 
CMV result as well as information about cCMV and instructions for the next steps, including 
notifying the family of the result and referring the baby to an Infectious Disease Specialty 
Care Center (IDSCC). All infants who screen positive for cCMV are also immediately 
referred by the NYS NBS to one of eleven clinical sites designated as IDSCC for standard-of-
care follow-up testing and management. Screen positive babies are referred to the IDSCC 
clinical site that is geographically closest to their birth hospital. These IDSCC clinical sites 
have been certified by the NYS NBS Program (See Study Setting for IDSCC designation 
details). All are under the supervision of a Pediatric Infectious Diseases board-certified 
physician and have extensive experience with cCMV diagnosis and management. These 
IDSCCs are also notified by NBS Follow-up staff regarding positive infants through a FAX 
and/or phone call, to check the encrypted email, fax, and/or notification of results via the 
NYS DOH Health Commerce System, a secure website for web-based interactions within 
NYS. The primary care providers of babies who screen positive for cCMV are instructed to 
consult with the designated IDSCC, and in most cases will coordinate a visit for the 
infant/family with the clinical site as soon as possible;  in rare cases the primary care provider 
may coordinate confirmatory testing for the infant if circumstances prevent the family from 
traveling to the clinical site. All eleven clinical sites have agreed to participate in the 
longitudinal study, known as PROACTIVE NYS, allowing for potential enrollment of all 
cCMV screen-positive infants throughout the state. Once evaluated by an IDSCC, NYS DOH 
is notified of all cCMV confirmatory test results. 

PROACTIVE NYS, Version 1.0 
Page 12 of 64 
Version Date 25 October 2023 
 
3.1 
Study Setting 
The eleven IDSCC clinic locations serve as the PROACTIVE NYS clinical sites. The certified 
IDSCC designation was provided by the NYS NBS Program to pediatric infectious disease 
clinical sites with expertise in cCMV diagnosis and management. In order to obtain IDSCC 
designation, each site was required to identify a lead board-certified pediatric infectious 
disease clinician with proven cCMV expertise to serve as the Center’s director. Additional 
designated personnel required for each IDSCC included a clinical care coordinator, social 
worker, audiologist, and the institution’s laboratory director. All IDSCC applications were 
approved by the institution’s CEO or COO to demonstrate institutional support. Upon 
satisfactory review of IDSCC application materials by NYS NBS Program staff, clinical sites 
were scheduled for a virtual site visit with NBS Program staff to discuss the CMV pilot and 
the newborn screening workflow at their site. Following completion of a successful site visits, 
clinical sites were granted official IDSCC certification. See Appendix  I – IDSCC Designation 
Criteria for complete IDSCC designation criteria. 
 
All IDSCC clinical sites are affiliated with major academic medical centers strategically 
located throughout NYS (Figure 2). This allows NYS NBS to refer every cCMV screen-
positive infant in NYS during the cCMV NBS Pilot Study to a designated IDSCC for clinical 
care and enrollment in PROACTIVE NYS. 
 
Figure 2. New York State map of entities involved in PROACTIVE NYS 
 
All clinical sites have extensive clinical research experience, including CITI certification of all 
staff linked to this proposal, development of best research practices, study design, participant 
enrollment, management and follow-up, data entry, data analysis, and manuscript preparation. 
All clinical sites have access to necessary equipment in order to conduct the study, including 
appropriate clinical space, computers, and diagnostic laboratory and radiologic testing. All 
clinical sites have access to appropriate medical specialists for referral, including identified 
experts in Pediatrics, Audiology, Neurodevelopment, Neurology, Neuropsychology, 
Ophthalmology, and Otolaryngology, among many other relevant pediatric specialties. In 
addition, all eleven IDSCC clinical sites serve as Pediatric HIV Referral Centers for the NYS 
NBS Program. As a result, all clinical sites are closely linked with the NYS NBS Program, 

PROACTIVE NYS, Version 1.0 
Page 13 of 64 
Version Date 25 October 2023 
have access to the encrypted NYS Wadsworth Lab system for results, and are able to act on 
receiving urgent neonatal referrals.   
3.2 
Facilities 
As required by the IDSCC designation process, each clinical site must have access to all 
spaces, equipment, and resources necessary for conducting PROACTIVE NYS, including: 
• inpatient and outpatient facilities available according to the needs of the individual patient;  
• dedicated pediatric inpatient beds, neonatal intensive care unit as part of a Level III 
perinatal program1 and pediatric intensive care unit2; 
o 
1 If the hospital does not provide maternity services, then a neonatal intensive care unit 
is not required. 
o 
2 If the hospital does not have a pediatric intensive care unit (PICU), then a protocol 
must be described for emergent care, appropriate pediatric transport, and continuity of 
care. 
• onsite facilities for standard clinical-pathological studies, radiological studies; (i.e. X-rays, 
sonogram, CT, MRI) electrocardiogram studies, electroencephalogram studies, and nuclear 
medicine studies; 
• laboratory capability for all necessary core studies and molecular genetic testing either 
onsite or by referral to another New York State approved laboratory as specified by the 
New York State Newborn Screening Program and the Wadsworth Center; 
• an infant hearing screening program, directly or by contract, that is overseen by a licensed 
audiologist. 
In addition, all clinical sites must have access to necessary computer equipment for data entry. 
Each clinical site is provided with 2 tablets for parent response to written questionnaires/ 
assessments. All sites also must have access to Ophthalmology and Neuropsychology/Child 
Development experts as needed for patient referrals. 
3.3 
Enrollment Estimates 
During 2019 and 2020, there were approximately 207,000 and 220,000 live births in NYS. 
Prior studies estimate 0.6% of all neonates are infected with cCMV, though unpublished data 
from other regions performing universal cCMV screening have found lower rates, closer to 
0.25%.  Estimates from two ongoing universal cCMV newborn screening programs reported 
interim screen-positive rates of 0.12% (Ontario, Canada) and 0.27% (Minnesota, USA) 
(personal communication by A. Handel with Jessica Dunn, MD and Carrie Wolf, MBS, 
respectively). cCMV dried-blood spot screening assays vary in sensitivity, but generally have 
very high specificity, approaching 99-100% [9]. 
 
Below are the annual IDSCC estimates based on the above variables, assuming 210,000 live 
births in NYS during the study period, 100% assay specificity, and enrollment of 100% of 
eligible infants: 
 
cCMV screen-positive rate 
cCMV screen sensitivity 
Number of infants diagnosed with cCMV 
- 0.5% of live births 
100% 
1,050 
- 0.5% of live births 
80% 
840 
- 0.25% of live births 
100% 
525 
- 0.25% of live births 
80% 
420 
Across the 11 clinical sites identified in this proposal we have the ability to enroll at least 90% 
of those infants with confirmed cCMV. 

PROACTIVE NYS, Version 1.0 
Page 14 of 64 
Version Date 25 October 2023 
 
In addition to those identified by the NYS NBS with cCMV, it is expected to enroll a very 
small cohort of infants who have a negative screen but are identified clinically and confirmed 
to have cCMV with a positive urine or blood CMV PCR obtained within the first 21 days of 
life. 
 
It is expected that a small group of premature infants (born prior to 37 weeks gestation) are 
infected postnatally with CMV (e.g. by blood transfusion). Premature infants often undergo 
repeat NBS testing; postnatal CMV infection may therefore be detected on a sample obtained 
after 21 days of life. As this population may be at risk of developing long-term sequelae 
similar to infants infected in utero, they should be approached for enrollment in 
PROACTIVE NYS if they meet criteria described in Inclusion Criteria - Category 4. 
 
4 
STUDY POPULATION 
4.1 
Participant Recruitment & Enrollment 
Upon evaluation at an IDSCC, caregivers of all cCMV screen-positive infants are approached 
for enrollment in PROACTIVE NYS. This cohort will include those infants ultimately 
diagnosed with confirmed cCMV and those with negative confirmatory testing. Although not 
supported through the Task Order, clinical sites also enroll infants who screen negative for 
cCMV but are later diagnosed clinically with cCMV through standard clinical testing. As 
asymptomatic infants are unlikely to undergo clinical cCMV testing following a negative 
cCMV NBS result, this subset may include infants with more prominent cCMV sequelae. 
 
All parents/guardians of cCMV-screen positive infants are informed of the study at their initial 
cCMV clinical evaluation at the IDSCC. Contact information is collected at that time. If 
cCMV screening begins prior to approval from NICHD to initiate PROACTIVE NYS, these 
families are re-contacted to discuss enrollment once the study is approved. Informed consent is 
then obtained (See IRB Approval section) from the infant’s parent/legal guardian, and those 
whose parent/legal guardian agree are enrolled. 
4.2 
Inclusion Criteria 
Potential participants must meet all of the criteria specified below to be included in this study; 
in these criteria, “at entry” is used to refer to the day of enrollment in the study: 
4.2.1 
Neonates born in New York State during cCMV NBS Pilot Program (September 27, 
2023 – October 1, 2024) 
4.2.2 
cCMV evaluation provided by a designated NYS IDSCC 
4.2.3 
Family willing and able to complete all study procedures 
4.2.4 
Study participants meet criteria for one of the four following categories: 
1. Category 1 (Confirmed cCMV identified by NBS Program): 
a. cCMV screen positive AND 
b. cCMV confirmatory test positive 
2. Category 2 (Confirmed cCMV not identified by NBS Program): 
a. cCMV screen negative AND 
b. cCMV confirmatory test positive 
3. Category 3 (False-positive cCMV screen): 
a. cCMV NBS positive AND 
b. Negative cCMV confirmatory test 

PROACTIVE NYS, Version 1.0 
Page 15 of 64 
Version Date 25 October 2023 
4. Category 4 (Premature infants with confirmed CMV infection on late positive 
NBS): 
a. Infant born prior to 37 weeks gestation 
b. cCMV positive on any NBS collected prior to 44 weeks gestational age 
c. Positive cCMV confirmatory test obtained within 14 days of a positive NBS 
4.3 
Exclusion Criteria 
4.3.1 
Neonate whose parents refuse participation in the long-term follow-up study 
 
4.4 
Participant Withdrawal or Termination from the Study 
Participant caregivers may voluntarily withdraw from the study. Participants may also be 
terminated from the study by the site investigator under the following circumstances: 
• 
Participant re-locates away from the study site (with no options to transfer to another site) 
or is otherwise determined to be lost-to-follow-up 
• 
Investigator determines that continued participation in the study would be unsafe or 
otherwise not in the best interest of the participant 
• 
The study is stopped or canceled by the sponsors or government or regulatory authorities 
• 
Site participation in the study is canceled by the sponsors, government or regulatory 
authorities, or the sIRB 
For any participant who is withdrawn or is terminated from the study prior to scheduled 
completion of follow-up, study staff documents the reason for the withdrawal or termination in 
detail and makes every effort complete final evaluations. If the circumstances that led to a 
participant’s withdrawal or termination change (e.g., they return to the study site area after 
having re-located previously), the site investigator should contact the study PIs to discuss 
options for resuming follow-up. 
 
5 
STUDY VISITS AND PROCEDURES 
Data collection time points are entered in a timeline that parallels the typical clinical follow-up 
schedule for an infant with cCMV. Participant data is entered as an enrollment/initial diagnosis time 
point, followed by regularly scheduled follow-up visits. Families are encouraged to sign up for 
institutional patient portal system(s) for access to cCMV treating physician.  Urgent issues can be 
handled via telemedicine or in-person as indicated.   
 
5.1 
Enrollment Visit 
The Enrollment Visit includes data from the first 4 weeks of life. This allows for entry of all 
relevant prenatal, perinatal, and early postnatal data needed to determine if the patient has 
confirmed cCMV and to classify the infant’s cCMV disease severity based on previously 
published categories [2]. See Table 1 for cCMV category definitions. Variables collected 
include demographic information, maternal prenatal CMV status (if known) and delivery 
complications, neonatal signs and symptoms of cCMV, diagnostic testing performed to 
confirm cCMV and identify any clinical manifestations, and treatments started. As the cCMV 
NBS Pilot Study may begin prior to initiating PROACTIVE NYS, older infants may be 
enrolled in the study, with diagnostic testing obtained during the first 4 weeks of life entered 
into the age appropriate visit timepoint. 
5.1.1 
Infants with false-positive CMV newborn screening:  
Any infant who has a positive NYS DOH CMV newborn screen but a negative 
confirmatory CMV PCR may be approached for enrollment. These infants are 
considered to have a false-positive CMV newborn screen (Inclusion Criteria Category 

PROACTIVE NYS, Version 1.0 
Page 16 of 64 
Version Date 25 October 2023 
3). Baseline data is collected as clinically indicated at the Enrollment Visit. Once the 
infant is determined to not have cCMV, all subsequent study procedures and data 
collection will end. Enrolling these infants is crucial for describing the subset of 
infants with false-positive CMV newborn screening. 
Table 1. Congenital CMV Disease Severity Definitions [2] 
 
 
5.2 
Follow-Up Visits 
For those infants placed on CMV antiviral therapy, Follow-Up Visits occur every six weeks 
until the infant is 6 months old, (guidelines for completion of any drug regimen for 
symptomatic treatment), and then every 6 months until the child is 24 months old. Infants with 
confirmed cCMV who are not receiving antiviral therapy are evaluated every 6 months. 
Variables collected at Follow-Up Visits include signs and symptoms of cCMV (including 
audiology follow up), treatments given and adverse effects, and interim and final outcome 
measures. Additional details of data collected can be found in the text below and attached case 
report forms (CRFs). Most study visits are performed in-person, though virtual-visits may be 
offered as deemed appropriate by the clinical team. Additional details may be collected from 
the infant’s family or referred providers (e.g. audiology) as appropriate, including by 
electronic health record review, fax, email, telephone, or other method convenient for the 
family. 

PROACTIVE NYS, Version 1.0 
Page 17 of 64 
Version Date 25 October 2023 
5.3 
Variables Collected 
5.3.1 
Demographics 
Upon enrollment, demographic information is collected from all infants with 
confirmed cCMV, including: infant’s sex, race, ethnicity, gestational age, age at time 
of clinically-indicated specimen collection (note that no research biospecimen 
collection is planned at this time), birth weight, and head circumference. 
 
cCMV Diagnostics and Sequelae 
Clinically-obtained data from each child with confirmed cCMV is collected. See 
Appendix II - PROACTIVE NYS REDCap Case Report Forms for specific variables 
to be collected. The following general information will be collected: 
• 
Prenatal findings such as documented maternal acute CMV infection during 
pregnancy, prior cCMV diagnosis, maternal CMV test results (if available), and 
prenatal diagnostic imaging results 
• 
Delivery data including gestational age, any issues identified by OB, admission to 
NICU (and cause), neonatal length, weight and head circumference 
• 
Neonatal signs and symptoms of cCMV 
• 
Neonatal cCMV diagnostic testing including urine (preferred) or blood CMV 
PCR, neonatal CMV IgM/IgG results (if obtained), complete blood count, liver 
function testing, diagnostic imaging, newborn hearing screen results, 
ophthalmologic findings (if performed) 
5.3.2 
Treatment 
We will collect data on treatments provided, including specific antiviral medication 
prescribed (including intravenous ganciclovir or oral valganciclovir), dose, dosing 
interval, duration of treatment, age at treatment initiation, duration of treatment, 
adverse effects (specifically cytopenias, acute liver injury, acute kidney injury), and 
premature cessation of treatment due to adverse effects. Clinical providers are also 
asked about the rationale for starting or not starting antiviral treatment for each study 
participant. 
 
Non-Medical Interventions 
Data on non-medical interventions including cochlear implants, American Sign 
Language training and use, and specialized therapies provided such as Early 
Intervention referral and enrollment, auditory-verbal therapy, physical therapy, and 
occupational therapy is collected. 
 
5.4 
Outcome Assessments 
Outcomes are assessed using a pre-determined follow-up schedule using standardized 
approaches. All outcomes measures are readily available to clinicians across NYS, are cost-
effective, have been validated for use in the specified age group, are accessible to families 
regardless of geography or English fluency, and are maximally informative for expanding the 
evidence base on the clinical utility of conducting population-wide cCMV screening in 
newborns. All measurements planned have been reviewed to ensure they do not contain 
negative or stigmatizing language. In particular, the measurements do not perpetuate negative 
bias toward individuals with hearing impairment, physical or cognitive disabilities, or other 
vulnerable populations. All written/verbal assessments (including Neurodevelopmental and 
QoL assessments) are based on standardized tools and therefore easily reproducible. 
Audiologic and Ophthalmologic assessments will be performed with standard medical 
approaches, equipment, and documentation, allowing for reproducibility in other settings. All 

PROACTIVE NYS, Version 1.0 
Page 18 of 64 
Version Date 25 October 2023 
laboratory tests are performed in College American Pathologists (CAP) and Clinical 
Laboratory Improvement Amendments (CLIA) certified laboratories. 
5.4.1 
Audiologic Outcomes 
Audiologic testing is performed on a regular scheduled basis to assess for early and 
late onset hearing impairment. Consistent with New York State law [10], all neonates 
will undergo a newborn hearing screen regardless of cCMV testing results. Infants 
diagnosed with cCMV are referred for complete Pediatric Audiology assessment. As 
recommended by the American Academy of Audiology [11], repeat audiologic 
diagnostic testing is performed every 3-6 months. Audiologic diagnostic modality 
used is dictated by the infant’s age and developmental capabilities. Testing results are 
recorded as decibel threshold in 5-decibel intervals for each ear. If present, type of 
hearing impairment will be recorded. Any interventions provided, including hearing 
aids, cochlear implants, American Sign Language Education, and auditory-verbal 
therapy are documented. 
5.4.2 
Neurodevelopmental Outcomes 
Parents complete standardized developmental screening tools (described in Table 2 - 
Schedule of Events, available in English and Spanish) every 6 months through 2 years 
old. Parents complete the questionnaires at the beginning of each clinic session. Those 
infants who fail any domain of the developmental screening instrument are referred to 
Early Intervention. Those who fail the developmental screening questionnaires twice 
(e.g., at 6 months old and again at 12 months old) are referred to a Developmental 
Pediatric or Child Neuropsychology expert for clinical assessment. Scores within each 
developmental domain on the screening questionnaires and results of the 
neurodevelopmental assessment will be recorded in the patient’s REDCap database. 
All infants with severe cCMV (as defined by the treating provider) are referred to 
Early Intervention during infancy and receive a Neuropsychology referral at 1 year of 
age regardless of their performance on the screening instruments. 
 
Neurodevelopmental Screening Plan: 
Instruments and Timing 
• 
6 months old 
o Ages & Stages Questionnaires Third edition (ASQ-3)  
o ASQ-Social-Emotional, Second Edition (ASQ:SE-2) 
• 
12 months old 
o ASQ-3 
o ASQ:SE-2 
• 
18 months old 
o ASQ-3 
o ASQ:SE-2 
o M-CHAT-R 
• 
24 months old 
o ASQ-3 
o ASQ:SE-2 
o M-CHAT-R 
 
 
 

PROACTIVE NYS, Version 1.0 
Page 19 of 64 
Version Date 25 October 2023 
Neurodevelopmental Assessment Referral Plan: 
 
Early Intervention (EI) Referral: 
 
 
 
 
 
 
 
 
 
 
Psychology/Neuropsychology/Neurodevelopmental (“Psychology”) Referral Plan 
 
 
 
 
5.4.3 
Ophthalmologic Outcomes 
All infants with symptomatic cCMV at birth are referred for Ophthalmologic 
evaluation within the first 4 weeks of life. Recent findings from the Ottawa cohort 
found that ophthalmologic abnormalities were only identified in infants with 
symptomatic cCMV (including abnormal head ultrasound), occurring in 3% of infants 
with cCMV (personal communication). Therefore, asymptomatic infants are not 
required to undergo an ophthalmologic exam, which may be uncomfortable for the 
infant, difficult to perform, and requires extensive resources to arrange for a large 
cohort. If an abnormality is identified, the infant undergoes repeat testing as 
recommended by the Ophthalmologist, with at least one visit annually. 
5.4.4 
Quality of Life Assessment 
Two cross-sectional QoL assessments of all enrolled infants is performed at one- and 
two-years following study initiation. By assessing all infants at two time points, data is 
captured from participants at a wide range of ages and clinical stages, providing 
insight across a broad participant population. Changes are also assessed in response 
over time among those who complete both QoL assessments.  
 
 
 
ASQ-3 gray zone or 
failure (black zone) 
at any age 
ASQ:SE-2 gray zone 
or failure (black 
zone) at any age 
Refer to EI 
MCHAT-R score in the 
moderate-risk (3-7) or 
high-risk (8-20) range 
Failure at two time points of any screening instrument (e.g., 
failures at 12 and 18 months of either the same assessment 
twice or two different assessments) 
Refer to Psychology/Neuropsychology/Neurodevelopmental (“ND”) Expert 
- Request Vineland and Bailey-III assessments be performed 
EI recommendation for 
further assessment 

PROACTIVE NYS, Version 1.0 
Page 20 of 64 
Version Date 25 October 2023 
Table 2. Schedule of Events 
 
Evaluation 
Entry 
Post-Entry Evaluations 
 
Chronologic age 
Entry 
Visit 
6 weeks1 
(+/- 2 
weeks) 
 
12 weeks1 
(+/- 4 
weeks) 
18 
weeks1 
(+/- 4 
weeks) 
6 months 
(+/- 4 
weeks) 
12 
months 
(+/- 8 
weeks) 
18 
months 
(+/- 8 
weeks) 
24 months 
(+/- 8 
weeks) 
Informed Consent 
X 
 
 
 
 
 
 
 
NYS NBS CMV screen 
result 
X 
 
 
 
 
 
 
 
Maternal history 
X 
 
 
 
 
 
 
 
Medical history/new 
diagnoses 
X 
X 
X 
X 
X 
X 
X 
X 
Growth measurements 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
CMV PCR (Urine and/or 
blood) 3 
X 
X2 
X2 
X2 
X2 
X2 
X2 
X2 
CBC w/ diff 
X 
 
 
 
 
 
 
 
AST, ALT 
X 
 
 
 
 
 
 
 
Creatinine 
X2 
 
 
 
 
 
 
 
Head ultrasound 
X 
 
 
 
 
 
 
 
Audiologic assessment 4 
X 
 
 
 
X 
X 
X 
X 
Ophthalmologic 
assessment 5 
X 
 
 
 
X 
X 
X 
X 
Neurodevelopmental 
assessments 6 
 
 
 
 
X 
X 
X 
X 
Quality-of-Life 
Assessments 7 
X 
X 
Cerebrospinal fluid 
analysis 
X2 
X2 
X2 
X2 
X2 
X2 
X2 
X2 
Abdominal ultrasound 
X2 
X2 
X2 
X2 
X2 
X2 
X2 
X2 
MRI brain 
X2 
X2 
X2 
X2 
X2 
X2 
X2 
X2 
Treatment/Monitoring 
 
 
 
 
 
 
 
 
- Document antiviral 
treatment prescribed 
(Y/N)? 
X 
X 
X 
X 
X 
X 
X 
X 
- Treatment name / dose 
X 
X 
X 
X 
X 
X 
X 
X 
- Antiviral toxicity 
assessment 
 
X 
X 
X 
X 
X 
X 
X 
      - CBC w/ diff 
 
X 
X 
X 
X 
X2 
X2 
X2 
     - Creatinine 
 
X 
X 
X 
X 
X2 
X2 
X2 
      - AST, ALT 
 
X 
X 
X 
X 
X2 
X2 
X2 
      - GGT 
X2 
X2 
X2 
X2 
X2 
X2 
X2 
X2 
 
1 6-week, 12-week, 18-week assessments are only needed for those infants with confirmed cCMV 
receiving CMV antiviral therapy. Infants with confirmed cCMV not receiving CMV antiviral therapy 
undergo assessments every 6 months 
2 Optional testing as indicated by primary care team 
3 Urine CMV PCR is the preferred test for confirming cCMV diagnosis 

PROACTIVE NYS, Version 1.0 
Page 21 of 64 
Version Date 25 October 2023 
4 Audiologic testing is performed every 3-6 months for all infants with confirmed cCMV. For those 
infants with an abnormal audiologic testing, more frequent assessments may be performed at the 
discretion of the Audiologist. 
5 Ophthalmologic evaluation is not required for asymptomatic neonates. Timing of follow-up 
ophthalmologic evaluations are at the discretion of the Ophthalmologist, but must occur at least once 
annually for infants with symptomatic cCMV. 
6 Neurodevelopmental assessment schedule: Participants undergo developmental screening with the Ages 
and Stages Questionnaire-3®, (ASQ-3) and the Ages & Stages Questionnaire: Social-Emotional, 
Second Edition ®, (ASQ:SE-2) at ages 6, 12, 18, and 24 months. Participants also undergo the 
MCHAT-R ®, autism screening at 18 and 24 months old. Those who fail any developmental domain 
are referred to Early Intervention. Those who fail any two developmental screening questionnaires 
(e.g., the same or different assessments failed at 6 months old and again at 12 months old) are referred 
to a Developmental Pediatric or Child Neuropsychology (“Neurodevelopmental (ND) assessment”) 
expert for clinical assessment. Infants with severe cCMV receive an Early Intervention referral upon 
diagnosis and a Neuropsychology referral at 1 year of age regardless of their performance on the 
screening instruments. The ND assessment should include the Vineland Adaptive Behavior Scales 3rd 
Edition and the Bayley-III Bayley Scales of Infant and Toddler Development. Data from these 
assessments is entered in CRFs linked to the patient ID number of that infant.  
7 Quality-of-Life (QoL) assessment: All enrolled participants with confirmed cCMV receive a QoL 
assessment questionnaire at the one-year anniversary of the study, and again when the child is 2 years 
old. 
 
5.5 
Planned analyses: 
• 
Descriptive statistics is used to determine the rates of participants with abnormalities in 
clinical, laboratory, and imaging abnormalities. 
• 
Descriptive statistics is used to describe patterns in diagnostic and treatment practices. 
• 
Clinical variables are analyzed when participants reach 6, 12, 18, and 24 months of age. 
Some participants will be on study for longer than 24 months. Percentage of participants 
with deficits in the outcome measures who is calculated. The outcome measures of those 
with abnormalities in clinical, laboratory, and imaging evaluations are compared to those 
without abnormalities. Participants are also categorized by previously published disease 
severity criteria [2] and a comparative analysis is performed. See Table 2 for category 
definitions. 
 
6 
PARTICIPANT MANAGEMENT 
6.1 
Issues Related to Universal cCMV Newborn Screening 
As cCMV is not yet included in the Recommended Uniform Screening Panel, understanding 
its implications for parents and children is crucial. cCMV treatment recommendations vary 
widely between region and provider, particularly among those infants with less severe 
sequelae. Making a diagnosis of cCMV is therefore wrought with sensitive, challenging topics 
that often lack a clear answer. Carefully addressing and studying those concerns is crucial to 
determining the strengths and limitations of universal cCMV screening. 
6.1.1 
Under- and over-diagnosis 
cCMV “under-diagnosis” refers to those infants with a negative cCMV newborn 
screen but diagnosed clinically with cCMV (through CMV urine PCR obtained during 
the first 21 days of life). As most infants with cCMV are asymptomatic, well infants 
with a negative cCMV NBS are unlikely to undergo clinical testing. As a result, 
“missed cases” identified clinically consist of more severely affected infants or those 
with hearing loss detected at birth. Any infants with “missed cCMV” on newborn 

PROACTIVE NYS, Version 1.0 
Page 22 of 64 
Version Date 25 October 2023 
screening are invited to enroll in our study. This small cohort provides important 
information about infants who are not identified through universal cCMV screening. 
 
cCMV “over-diagnosis” refers to those infants who screen positive for cCMV but 
have a negative urine CMV PCR. Prior studies show that this is uncommon [12]. 
Since all cCMV-screen positive infants are referred to their local IDSCC, These 
infants are systematically followed through PROACTIVE NYS. Since these infants 
are not be diagnosed with cCMV, they are followed less frequently than those with 
confirmed cCMV, but remain available for QoL evaluations and other targeted follow-
up. 
6.1.2 
Under and Overtreatment of screen-positive infants 
Treatment data from all infants who screen positive for cCMV is collected. Treatment 
decisions are made by the treating clinician and family. Data is analyzed by severity of 
symptoms, including infants who are clinically asymptomatic, asymptomatic with 
isolated hearing loss, and more severely affected. The number of infants treated for 
cCMV is described and treatment rates, medication toxicity rates, and outcomes by 
symptoms and severity of symptoms are compared. 
6.1.3 
Parental anxiety & vulnerable child syndrome 
Parent and infant QoL measurements are performed as a cross sectional single 
assessment one year after study initiation. This approach allows responses to be 
obtained from a broad range of families, including those with young infants and those 
whose infants (symptomatic or not) are approaching one year of age. In addition, the 
assessment includes families whose children experience a wide range of cCMV 
sequelae. Parents of children who had a false-positive cCMV screen, whose 
experience is likely very different from those of cCMV-infected infants are included. 
Additional assessments are  planned following the initial enrollment period. 
6.1.4 
Added burden on state NBS programs, especially follow-up 
The long-term follow-up study is being conducted in close coordination with the NYS 
cCMV NBS Pilot Study, as described above. This allows for close integration of the 
programs’ impact on the NBS Program and referral implications for the IDSCCs. 
 
7 
STATISTICAL CONSIDERATIONS 
7.1 
Outcome Measures 
The following goals are used to assess success in enrolling and maintaining follow-up of 
infants with confirmed cCMV throughout PROACTIVE NYS. 
• 
Enrollment: ≥90% of cCMV screen-positive infants are enrolled in PROACTIVE NYS 
• 
1-year follow-up: ≥90% of enrolled infants with confirmed cCMV attend a 1-year follow-
up visit 
• 
2-year follow-up: ≥80% of enrolled infants with confirmed cCMV attend a 2-year follow-
up visit 
 
In addition, study co-PIs and Frontier Science Statistical and Data Management Center 
(DMC) closely monitor enrollment rates at each clinical site through the continuously 
updated interactive dashboard and REDCap database. Missing data queries and low 
enrollment rates are reviewed with the IDSCC clinical site PI. Those sites failing to enroll 
≥60% of referred infants over the course of the year are not funded during the subsequent 
calendar year. 
 

PROACTIVE NYS, Version 1.0 
Page 23 of 64 
Version Date 25 October 2023 
7.2 
Randomization and Stratification 
This study does not involve randomization or stratification. 
 
7.3 
Monitoring 
Implementation of this study is monitored at multiple levels, consistent with standard clinical 
trial procedures. A study monitoring plan that details monitoring roles and responsibilities and 
data to be reviewed at each level will be prepared before the study opens to accrual. Sections 
11 and 12 provide for more information on on-site monitoring and quality management at the 
site level. Further information on monitoring of study progress, quality of study conduct, and 
participant safety across sites is provided below. 
7.3.1 
Monitoring by the Protocol Team 
Study Progress and Quality of Study Conduct 
The protocol team (under guidance of PI S. Nachman) is responsible for continuous 
monitoring of study progress, including timely achievement of key milestones, and 
quality of study conduct.  
 
The protocol team will monitor participant accrual based on reports that will be 
generated at least monthly by the DMC. The team has developed a study accrual plan 
that includes site-specific and total enrollment projections over the course of the 
accrual period, and actual accrual will be monitored relative to these projections. This 
includes enrollment of 90% of infants referred to that site for positive CMV Newborn 
Screen results. Distal monitoring will include check of birth date information with 
NYS screening results, and confirmation of CMV via blood or urine PCR testing.  
 
The protocol team will monitor the timing of site-specific study activation, which will 
determine when each site will begin accruing participants, and actual accrual 
following activation. The number of potential participants screened, reasons for screen 
failures, and number of participants enrolled will be closely monitored. Sites will be 
put on probation after 3 months of continual falling below 80% enrollment, asked to 
do a SWOT analysis, and will have conference to monitor further progress.  
 
Accrual performance will be reported by the DMC, by site and across sites, and the 
team will review and discuss study progress at least monthly. For any site that is 
delayed in completing the study activation process, or that falls short of its accrual 
projections, the team will communicate with the site to identify the barriers the site 
has encountered and the operational strategies and action plans to address these. Sites 
that fail to enroll above 60% over the entire year will be dropped from further funding. 
 
The protocol team will also monitor participant retention as defined as completion of 
every 6-month study visits and completion of all neurodevelopmental assessments.  
 
On behalf of the protocol team, the DMC will monitor other key indicators of the 
quality of study conduct (e.g., data quality, data completeness) based on reports 
generated by the DMC and take action with study sites as needed to ensure high 
quality study conduct throughout the period of study implementation.  
 
 
 

PROACTIVE NYS, Version 1.0 
Page 24 of 64 
Version Date 25 October 2023 
Participant Safety 
The protocol team (including a medical representative from each site) will closely 
monitor participant safety through routine review of safety data reports generated by 
the DMC. As this is not a treatment study and has no protocol defined therapy, all 
adverse events and safety events will be reported and collated. Sites are to use 
standard of care when administering any medications. These reports will be reviewed 
monthly. The protocol mPI will continually evaluate the pattern and frequency of 
reported events and assess for any individual occurrences or trends of concern.  
 
7.4 
Analyses 
Data from each site will be included in all analyses.  It will include parameters as indicated by 
the items collected. Each subtype of disease state will be assessed (severe, moderate, mild or 
asymptomatic disease) Analysis planning will include input from site PIs as well as team 
statisticians.  
 
8 
DATA HANDLING AND RECORD KEEPING 
8.1 
Statistical and Data Management Center (DMC) 
8.1.1 
Infrastructure 
All software used by Frontier Science is verified and validated to ensure that it is audit 
ready. The following core software  is  custom configured to support the specific 
needs of PROACTIVE NYS: 
8.1.2 
Project Website 
A custom project website, which includes a public webpage and a Portal Gateway 
webpage (restricted to designated study and participating site staff to access data 
management systems and other resources needed to conduct the study), is available 
to aid in the organization of data management activities and ensure that the study 
team and clinical sites have centralized access to the necessary data and adjoining 
metadata, study resources, and computerized systems needed to guide their efforts. 
The public website will serve as the “face” of the study, and host generally available 
information such as an overview of the study, introduction to key personnel, study 
resources, updates on study progress, and contact information. It will provide the 
public with transparency into the study and its resulting progress.  More importantly, 
it will serve as the access point to the secure Portal Gateway sign-in (Figure 3). 
Figure 3. Study Website 

PROACTIVE NYS, Version 1.0 
Page 25 of 64 
Version Date 25 October 2023 
The Portal Gateway website will provide the clinical sites with direct and 
centralized access to all software applications required for data management 
support.  It will host all project data management operations, including data 
collection and management systems required to support all data collection activities. 
Using a two-factor authentication system, the study team will additionally have 
access to web-based study specific resources such as study documents, 
announcements, and training materials. The website will be designed to provide 
entry into all software and systems required to enter, review, collate, organize, and 
report on the data collection activities throughout the course of the study. 
Furthermore, the study team and designated statisticians will be able to securely 
access data on the Portal Gateway. The website also will provide administrative 
information and support to collaborators, such as email lists, other contact 
information, and various team reports. Document perusal/retrieval facilities and 
linkages/interfaces to other websites will also be made available depending on the 
needs of the study team. 
8.1.3 
Central Database 
A Central Database will be created for the study using a relational database 
management system. The Central Database will serve as a warehouse for enrollment 
data and study data collected using REDCap Academic (see below). Data queried 
from the Central Database will be used as the source for quality assurance auditing 
and on-demand retrieval for statistical analysis and reporting. The use of a centralized 
database allows for additional reporting and quality control activities not otherwise 
available in an out-of-the-box commercial EDC system such as REDCap. Accessing 
and querying database tables in a variety of ways allows countless reports, metrics, 
tables and listings to be generated on demand providing greater flexibility to meet the 
specific needs of the study team and its collaborators. 
 
8.1.4 
REDCap® Academic 
REDCap® Academic (REDCap hereafter) is used as the EDC system for 
PROACTIVE NYS.  
 
In addition to providing blank eCRFs, Frontier Science provides an eCRF Completion 
Guide for the study. The eCRF Completion Guide provides additional study-specific 
instructions and help text that clinical sites can use as they onboard new studies and 
determine how to design their source data collection materials for the study. 
 
See Appendix II - PROACTIVE NYS REDCap Case Report Forms. 
8.1.5 
Stars 
Stars is the enrollment system which ensures that the participating clinical sites are 
approved to enroll participants onto the study and verify the participant is eligible via 
a series of questions assessing the study’s eligibility criteria, known as the eligibility 
checklist. Clinical site responses to the eligibility checklist provide a real-time 
assessment of eligibility before a participant is enrolled. Upon successful enrollment, a 
PID is assigned to the participant in the study.  
8.1.6 
Data Exchange System 
Frontier Science will configure its data exchange system to transfer participant 
enrollment information, in real- time, from Stars to REDCap, and to transfer REDCap 
clinical data into the Central Database to facilitate additional reporting, querying and 
exchanging of data with study stakeholders. Other project-specific integrations can be 
implemented as needed. 

PROACTIVE NYS, Version 1.0 
Page 26 of 64 
Version Date 25 October 2023 
 
8.1.7 
Reports 
Frontier Science creates and distributes monthly accrual reports to project leadership 
to facilitate accrual tracking. Existing standardized programs and reports will be 
configured and used wherever possible, but additional programs and reports will be 
created as deemed necessary by the study team and NICHD study leadership.  
8.1.8 
Data Visualization 
Data dashboard: The visualization tools configured by Frontier Science will assist in 
conveying the findings in a more accessible and timely manner, facilitating decision-
making and collaboration (refer to Figure 4 for a prototype of an Interactive Data 
Visualization Dashboard).   In addition, to foster data sharing per the mandated NIH 
Data Management & Sharing Policy, some interactive data visualizations will be 
running on a public-facing website. See Sharing Results section for more details. 
Figure 4. Interactive Data Visualization: Dashboard 
8.1.9 
Data Retrieval 
Authorized users have access to the clinical data in REDCap. In addition, study data is 
made available to the study team and designated statisticians on demand using 
Frontier Science’s data retrieval tools. As mentioned above, all retrieval tools will be 
made centrally available in the Portal Gateway. 
8.1.10 External user training 
Frontier Science provides training to all participating entities on the study to ensure 
that they are familiar with the various tools that are used to enter, collect, and transfer 
the study data to Frontier Science. All end users of Frontier Science systems are 
provided with 24/7/360 user support.  
8.1.11 Quality assurance and quality control measures 
Frontier Science operates within a Quality Management System (QMS) framework 
that ensures that the organization acts in accordance with contemporary ethical and 

PROACTIVE NYS, Version 1.0 
Page 27 of 64 
Version Date 25 October 2023 
regulatory principles. Frontier Science observes, within the context of its QMS 
system, regulatory principles including 21 Code of Federal Regulations (CFR) Part 11, 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA), and the 
Federal Information Security Management Act of 2002 (FISMA). It also adheres to 
accepted guidelines and best practices per ICH E6 (R2) (GCP), the Society of Clinical 
Data Managers (SCDM) Good Clinical Data Management Practices (GCDMP), and 
Good Automated Manufacturing Practice (GAMP®5).  
8.1.12 Biostatistics 
The Frontier Science Biostatistical team supports data analysis and creates specific 
data monitoring reports throughout the study. A statistical analysis plan (SAP), based 
on the study protocol, is written by the statistical team. The SAP will provide details 
of the methodology and planned analyses to address the study objectives and will 
undergo a review process with study leadership. 
 
Each analysis will be performed using SAS and will include tables and figures 
specified in the SAP. All tables and figures from each of the analyses will undergo 
validation and QC activities by Frontier Science. 
8.1.13 Database archival and disposition 
At the conclusion of the study, all data is archived and given to the sponsor and 
clinical sites will be provided a copy of the data entered by their facility. An inventory 
is maintained to track all items in the study archive as well as any requests for archival 
access.   
8.1.14 Linkage to Identifying Information 
Our study tracks infants longitudinally over two years at pre-determined time points. 
As a result, each participant is assigned a PID, which will be used to add new data to 
their REDCap file. Each clinical site maintains a password-protected, encrypted log of 
their enrolled study participants, contact information, and assigned PIDs. The PID log 
will not be available for access by the other study clinical sites, including the study 
Co-PIs. 
 
8.2 
Essential and Source Documents and Access to Source Data 
All data entered on CRFs will be with study-specific PIDs. Sites will keep a log in a locked 
file of individuals by PID who are enrolled on study. Outside of site staff at that site, no one 
else will have access to unblinded data. All unblinded source documents will be kept as per 
each site’s IRB regulations.  
 
8.3 
Quality Control and Quality Assurance 
Study sites must ensure that essential documents and participant research records are subject to 
continuous quality control and quality assurance procedures consistent with the sites IRBs 
SOPs.  
 
9 
COLLABORATION 
Starting late 2022, a close collaborative effort has already been implemented by NYS DOH cCMV 
NBS and the eleven study sites. NYS NBS has arranged monthly virtual meetings of NYS cCMV 
NBS Pilot Study staff and all IDSCC clinical site directors. Meeting agendas have included roll-out 
of the cCMV NBS Pilot Study, discussion of best practices for cCMV diagnosis and treatment, and 
PROACTIVE NYS study design. Meeting minutes are available to all clinical sites, DOH 
collaborators, and the NICHD. The two programs and the IDSCC clinical sites are therefore already 
seamlessly integrated, with feedback provided continuously between the NYS NBS and IDSCC 

PROACTIVE NYS, Version 1.0 
Page 28 of 64 
Version Date 25 October 2023 
leaders who oversee clinical management of cCMV positive infants and enrollment/follow-up in 
PROACTIVE NYS. 
 
10 ANNUAL UPDATES 
Each IDSCC site is be required to submit annual updates regarding confirmation of CMV 
methodology, staff changes to be added to PROACTIVE NYS log on, and any changes to site 
leadership.  
 
11 ADVISORY COMMITTEE 
The NYS cCMV NBS Pilot Study has engaged a group of cCMV experts to serve as Advisory 
Committee Members. This groups includes experts in Audiology, Newborn Screening Programs, 
Bioethics, Pediatric Infectious Diseases, and a parent of a child with cCMV who is a national leader 
in cCMV advocacy. Some of these individuals may be invited to serve on the advisory committee 
for PROACTIVE NYS. The PROACTIVE NYS Advisory Committee will be convened at least 
once annually, and individual members may be contacted more frequently for concerns specific to 
their expertise. 
 
12 HUMAN SUBJECTS PROTECTIONS 
12.1 Institutional Review Board/Ethics Committee Review and Approval  
A sIRB is utilized for all clinical sites participating in PROACTIVE NYS. Advarra serves as 
the sIRB. All IRB reliance agreements comply with the NIH sIRB Policy (NOT-OD-16-094). 
The parent/guardian informed consent document will be approved by the sIRB and available 
in English and Spanish. As per local site regulations, consents will be provided either on paper 
or with eConsent. For those parents who prefer a language other than English or Spanish, 
screening, informed consent, and clinical care is performed in the preferred language with the 
assistance of a certified medical translator, which is appropriately documented in the informed 
consent documentation. All institutional (local) required and applicable regulatory, ethics, and 
other approvals of PROACTIVE NYS are obtained and adhered to. 
 
12.2 Parental Permission 
Informed consent will be obtained from the parents/guardians of all study participant prior to 
enrollment. The informed consent document will be reviewed and approved by Advarra, the 
study sIRB. 
 
12.3 Potential Benefits 
Information learned in this study may be of benefit to participating children and others in the 
future, particularly information that may lead to more treatment options for children living 
with cCMV. 
 
12.4 Potential Risks  
This study is observational and without required interventions or collection of biospecimen. 
There is a small risk of loss of confidentiality and privacy because personal health information 
is being exchanged. However, strict confidentiality procedures will minimize this risk.  
 

PROACTIVE NYS, Version 1.0 
Page 29 of 64 
Version Date 25 October 2023 
12.5 Reimbursement/Compensation 
There is no compensation for study visits as they are part of routine medical care for infants 
with congenital CMV. There are no specific study procedures. Rather, data will be collected 
on any and all routine care procedures.  
 
12.6 Privacy and Confidentiality 
All study procedures will be conducted in private, and every effort will be made to protect 
participant privacy and confidentiality to the extent possible. Participant information will not 
be released without written permission to do so except as necessary for review, monitoring, 
and/or auditing as described in Section 11.2.  
 
All study-related information will be stored securely. Participant research records will be 
stored in locked areas with access limited to study staff. All laboratory specimens, CRFs, and 
other documents that may be transmitted off-site will be identified by PID only. Likewise, 
communications between study staff and protocol team members regarding individual 
participants will identify participants by PID only.  
 
12.7 Management of Incidental Findings 
Site clinicians will inform parents (or guardians if applicable)] of all clinically meaningful 
physical exam findings and laboratory test results, including results of any clinically 
performed relevant tests. When applicable, site clinicians will provide referrals to non-study 
sources of medical care for further evaluation and/or treatment of these findings.  
 
12.8 Management of New Information Pertinent to Study Participation 
Study staff will provide participants with any new information learned over the course of the 
study that may affect their willingness to remain in follow-up. 
 
13 ADMINISTRATIVE PROCEDURES 
13.1 Protocol Registration 
Prior to implementation of this protocol, and any subsequent full version amendments, each 
site must have the protocol and the study informed consent forms approved, as appropriate, by 
applicable IRBs/ECs, and any other applicable regulatory entities; this includes the sIRB.  
 
For any future protocol amendments, upon receiving final IRB/EC and other applicable 
regulatory entity approvals, as well as meeting any additional study-specific requirements as 
determined by the protocol team, sites should implement the amendment immediately. A copy 
of the Amendment Registration Notification should be retained in the site's regulatory files. 
 
13.2 Study Implementation 
This study will be conducted in accordance with the protocol and all applicable US, local, and 
international regulations.  
 
Study implementation at each site will also be guided by site-specific SOPs. These SOPs 
should be updated and/or supplemented as needed to describe roles, responsibilities, and 
procedures for this study. 
 

PROACTIVE NYS, Version 1.0 
Page 30 of 64 
Version Date 25 October 2023 
13.3 Protocol Deviation Reporting 
All protocol deviations must be documented in participant research records. Reasons for the 
deviations and corrective and preventive actions taken in response to the deviations should 
also be documented.  
 
Deviations should be reported to applicable IRBs/ECs and other applicable review bodies in 
accordance with the policies and procedures of these review bodies. Serious deviations that are 
associated with increased risk to one or more study participants and/or significant impacts on 
the integrity of study data must also be reported to leadership of PROACTIVE within 7 
business days 
 
13.4 ClinicalTrials.gov 
This study is not subject to the Food and Drug Administration Amendments Act of 2007 or the 
NIH Policy on Dissemination of NIH-funded Clinical Trial Information. However, it will be 
registered in ClinicalTrials.gov to meet International Committee of Medical Journal Editors 
requirements. 
 
14 PUBLICATIONS 
14.1 Public Results Distribution 
The findings of this study are disseminated through readily-available, timely mechanisms. The 
cCMV Online Dashboard is available in two formats: a password-protected, in-depth database 
available for clinical sites only, and a public-facing website with higher-level findings in order 
to ensure patient confidentiality. The website serves as a parent resource with outward facing 
educational materials, links to each of the 11 clinical sites and links to any manuscripts 
accepted for publication.  
 
The study website is: www.proactivenys.org 
 
14.2 Academic Results Distribution 
In addition to the interactive dashboard and PROACTIVE NYS website, results will be 
published in academic settings. Manuscripts will be submitted to major general medical and 
pediatric journals describing the cohort’s findings at birth and outcomes assessments at 6, 12, 
and 24 months old. Additional publications will describe treatments provided and adverse 
effects, predictors of delayed SNHL or delayed cognitive/language development, QoL 
assessments, and lessons learned / impact on the NYS NBS Program, among others. Findings 
will also be reported at academic conferences, including the Congenital Cytomegalovirus 
Public Health & Policy Conference and IDWeek. 
 
15 REFERENCES 
1. 
Fowler, K.B. and S.B. Boppana, Congenital cytomegalovirus infection. Semin Perinatol, 2018. 
42(3): p. 149-154. 
2. 
Rawlinson, W.D., et al., Congenital cytomegalovirus infection in pregnancy and the neonate: 
consensus recommendations for prevention, diagnosis, and therapy. Lancet Infect Dis, 2017. 
17(6): p. e177-e188. 
3. 
Society for Maternal-Fetal, M., B.L. Hughes, and C. Gyamfi-Bannerman, Diagnosis and 
antenatal management of congenital cytomegalovirus infection. Am J Obstet Gynecol, 2016. 
214(6): p. B5-B11. 

PROACTIVE NYS, Version 1.0 
Page 31 of 64 
Version Date 25 October 2023 
4. 
Cannon, M.J., Congenital cytomegalovirus (CMV) epidemiology and awareness. J Clin Virol, 
2009. 46 Suppl 4: p. S6-10. 
5. 
Kimberlin, D.W., 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(1): p. 16-25. 
6. 
Kimberlin, D.W., et al., Valganciclovir for symptomatic congenital cytomegalovirus disease. N 
Engl J Med, 2015. 372(10): p. 933-43. 
7. 
Fowler, K.B., Congenital cytomegalovirus infection: audiologic outcome. Clin Infect Dis, 2013. 
57 Suppl 4(Suppl 4): p. S182-4. 
8. 
Kimberlin, D.W., et al., Red book : 2021-2024 report of the Committee on Infectious Diseases. 
32nd edition ed. 2021, Itasca, IL: American Academy of Pediatrics. 
9. 
Dollard, S.C., M.R. Schleiss, and S.D. Grosse, Public health and laboratory considerations 
regarding newborn screening for congenital cytomegalovirus. J Inherit Metab Dis, 2010. 
33(Suppl 2): p. S249-54. 
10. 
Early Intervention Program Memorandum 2003-3 - Newborn Hearing Screening. 2003; 
Available from: 
https://www.health.ny.gov/community/infants_children/early_intervention/memo03-3.htm. 
11. 
Kettler, M., et al., American Academy of Audiology Position Statement on Early Identification of 
Cytomegalovirus in Newborns. J Am Acad Audiol, 2023. 
12. 
Dollard, S.C., et al., Sensitivity of Dried Blood Spot Testing for Detection of Congenital 
Cytomegalovirus Infection. JAMA Pediatr, 2021. 175(3): p. e205441. 
 
 
 

PROACTIVE NYS, Version 1.0 
Page 32 of 64 
Version Date 25 October 2023 
APPENDIX I 
IDSCC Designated Criteria
 

PROACTIVE NYS, Version 1.0 
Page 33 of 64 
Version Date 25 October 2023 

PROACTIVE NYS, Version 1.0 
Page 34 of 64 
Version Date 25 October 2023 
 

PROACTIVE NYS, Version 1.0 
Page 35 of 64 
Version Date 25 October 2023 
APPENDIX II 
PROACTIVE NYS Redcap Case Report Forms 
 
 
 

PROACTIVE NYS, Version 1.0 
Page 36 of 64 
Version Date 25 October 2023 
 

PROACTIVE NYS, Version 1.0 
Page 37 of 64 
Version Date 25 October 2023 

PROACTIVE NYS, Version 1.0 
Page 38 of 64 
Version Date 25 October 2023 

PROACTIVE NYS, Version 1.0 
Page 39 of 64 
Version Date 25 October 2023 
 
 
 

PROACTIVE NYS, Version 1.0 
Page 40 of 64 
Version Date 25 October 2023 

PROACTIVE NYS, Version 1.0 
Page 41 of 64 
Version Date 25 October 2023 

PROACTIVE NYS, Version 1.0 
Page 42 of 64 
Version Date 25 October 2023 

PROACTIVE NYS, Version 1.0 
Page 43 of 64 
Version Date 25 October 2023 

PROACTIVE NYS, Version 1.0 
Page 44 of 64 
Version Date 25 October 2023 

PROACTIVE NYS, Version 1.0 
Page 45 of 64 
Version Date 25 October 2023 

PROACTIVE NYS, Version 1.0 
Page 46 of 64 
Version Date 25 October 2023 

PROACTIVE NYS, Version 1.0 
Page 47 of 64 
Version Date 25 October 2023 

PROACTIVE NYS, Version 1.0 
Page 48 of 64 
Version Date 25 October 2023 
 
 
 

PROACTIVE NYS, Version 1.0 
Page 49 of 64 
Version Date 25 October 2023 

PROACTIVE NYS, Version 1.0 
Page 50 of 64 
Version Date 25 October 2023 

PROACTIVE NYS, Version 1.0 
Page 51 of 64 
Version Date 25 October 2023 

PROACTIVE NYS, Version 1.0 
Page 52 of 64 
Version Date 25 October 2023 

PROACTIVE NYS, Version 1.0 
Page 53 of 64 
Version Date 25 October 2023 

PROACTIVE NYS, Version 1.0 
Page 54 of 64 
Version Date 25 October 2023 

PROACTIVE NYS, Version 1.0 
Page 55 of 64 
Version Date 25 October 2023 

PROACTIVE NYS, Version 1.0 
Page 56 of 64 
Version Date 25 October 2023 

PROACTIVE NYS, Version 1.0 
Page 57 of 64 
Version Date 25 October 2023 

PROACTIVE NYS, Version 1.0 
Page 58 of 64 
Version Date 25 October 2023 
 

PROACTIVE NYS, Version 1.0 
Page 59 of 64 
Version Date 25 October 2023 
APPENDIX III 
Statistical and Data Management Center (DMC) 
1. History/Background 
Based on the excellence of their past performances, and the large and complicated dataset this study is 
expected to generate, Frontier Science and Technology Research Foundation, Inc. (FSTRF, also 
known as Frontier Science) is designated as the Statistical and Data Management Center (DMC) for 
the follow-up study. Frontier Science is an accomplished not-for-profit organization whose mission is 
to collaborate with investigators and sponsors to conduct scientifically meaningful high-quality 
clinical trials, while advancing the application of statistical science and practice and data management 
techniques in science, health care and education. Since its founding in 1975, Frontier Science has 
provided innovative, yet cost-effective, data management, biostatistics, and technical services to 
research networks, pharmaceutical companies, and academic investigators.  
 
With a reputation as a highly capable research partner, Frontier Science lends its expertise to the 
design, conduct, analysis, and reporting of clinical trials (Phase I through IV) and observational 
studies. Comprising three locations in the United States and European affiliates in Greece and 
Scotland, the organization collaborates with investigators, clinical sites, laboratory centers and 
technicians in more than 1,200 establishments worldwide. With its main office located in Amherst, 
New York, Frontier Science is well-poised to focus on the impact of cCMV as it relates to all New 
Yorkers.  
 
Frontier Science maintains a successful history of partnering on clinical trials, and has supported 
statistical, data management and coordinating centers for numerous projects. It has participated in 
several multi-site, multi-trial clinical research networks, including more than thirty-three years with 
the AIDS Clinical Trials Group (ACTG); the Pediatric AIDS Clinical Trials Group and its successor, 
the International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT) Network; the 
Eastern Cooperative Oncology Group (ECOG) during 1975-2016;  International Breast Cancer Study 
Group (IBCSG) for forty-two years and the Pediatric HIV/AIDS Cohort Study (PHACS) for 17 years. 
It also currently directs the Data Management and Report Unit (DMRU) of the Data Management, 
Auditing, and Coordinating Center (DMACC) for the Cancer Prevention Clinical Trials Network 
(CP-CTNet), as well as the Coordinating Center for the HIV/Cervical Cancer Prevention 
‘CASCADE’ Clinical Trials Network and Tuberculosis RePORT International Coordinating Center 
(TB-RICC) for TB-RePORT (Regional Prospective Observational Research in Tuberculosis) 
International (TBRI).  
 
Frontier Science maintains a highly-trained workforce committed to delivering quality service and 
meeting the unique needs of each of its collaborators. With more than 300 dedicated staff members, 
including statisticians, statistical programmers, protocol and laboratory data managers, medical 
coders, software programmers, randomization coordinators, database operations administrators and 
information technology (IT) security professionals, Frontier Science provides a comprehensive 
approach to each of its projects. It also maintains a team of technical writers and business analysts 
who are trained in quality systems documentation and computer systems validation. Most staff have 
backgrounds in statistics, health care disciplines, computing science and related fields, and all staff 
undergo continuous education and training. Additionally, Frontier Science has established in-house 
working groups of relevant subject matter experts and exceptionally experienced individuals to 
analyze and integrate industry trends, best practices and new technologies to ultimately ensure that 
the organization remains apprised of the ever-evolving clinical trial landscape. 
 
Frontier Science's operations require it to ensure complete business continuity in the event of an 
emergency. Therefore, the organization places critical emphasis and planning towards its ability to 
effectively maintain and quickly restore all vital functions during and after an emergency. Frontier 

PROACTIVE NYS, Version 1.0 
Page 60 of 64 
Version Date 25 October 2023 
Science’s Business Continuity Plan (BCP) has been developed with these factors in mind, and 
carefully sets forth the factors and steps necessary to prepare for a crisis (disaster or emergency). The 
BCP allows the organization to remain functional for the duration of the crisis, and take all 
appropriate actions to help ensure the organization’s continued viability.  
 
Frontier Science approaches each of its projects in a calculated manner to ensure compliance with 
various regulations, and to ensure full data quality and integrity. As part of this process, and as part of 
its commitment to industry standards such as those set forth in the Good Clinical Data Management 
Practices (GCDMP) published by the Society of Clinical Data Management, each study is required to 
have a corresponding data management plan (DMP). The DMP will act as a governing document for 
Frontier Science Data Management staff assigned, specifically including the role of the data 
managers, medical coders, and data manager assistants (DMAs) in maintaining data quality and best 
practices for quality assurance and quality control that apply to a specific study. The DMP will also 
list all critical milestones and data review activities, along with material about study-specific reports, 
communications, or other information that the Data Managers will need to successfully monitor and 
clean all incoming data. The DMP is accompanied by a Quality Assurance/Quality Control (QA/QC) 
plan that sets forth the specific schedule required for all quality control activities. Data managers use 
these documents to guide their efforts during the course of the study and to track each data check 
activity required to ensure for complete and accurate data. 
 
Utilizing its established infrastructure, Frontier Science will provide the PROACTIVE NYS study a 
wide range of technical services and support to: 
• 
Design and implement data collection instruments in REDCap Academic promoted in a 
cloud-based environment 
• 
Provide technical and infrastructure support for all electronic software data collection systems 
utilized on the study, in addition to any other applications required to ensure adequate 
oversight and administration of the study (reporting, study administration, data visualization, 
etc.) 
• 
Collaborate on compliance issues to ensure participant safety and data 
security/confidentiality, including the provision of guidance documentation and quality 
assurance support 
• 
Provide study clinical site training on database use and entry 
• 
Maintain and provide quality control of data submitted across all study sites 
• 
Manage an interactive, continuously updated visualization dashboard of all enrolled 
participants 
• 
Provide biostatistical support for interim and final analyses 
• 
Design and maintain public and private (study personnel only) websites for distribution of 
preliminary study data 
• 
Assist with manuscript preparation 
 
2. 
REDCap® Academic 
REDCap has been validated as a commercial system fit for use by Frontier Science Quality 
Assurance department, and bespoke software built by Frontier Science developers to interface with 
REDCap is validated in accordance with the Frontier Science software lifecycle policy. REDCap can 
be configured as required for both cloud-based and offline-setting for both facility-based and 
remote/field-based data collection activities. Frontier Science will ensure that the REDCap software 
is appropriately configured for the most efficient use on the study by working with all relevant 
partners to establish requisite data flow activities and utilizing and leveraging its global eCRF library 
(e.g. neuropsychology eCRFs) which contains thousands of forms from its decades of experience 
supporting NIH-funded large clinical trials groups. Once configured for the needs of the project, 
REDCap will be available to IDSCC sites who will enter the data collected from the participants into 

PROACTIVE NYS, Version 1.0 
Page 61 of 64 
Version Date 25 October 2023 
the system directly. All data will be transferred to Frontier Science, who will store the data and 
maintain adequate safeguards to ensure full security and integrity of the study database. 
 
As part of its data validation procedures, Frontier Science data managers utilize automated edit 
checks on Electronic Case Report Forms (eCRFs) to identify potential errors at the time of data entry 
for key data elements by flagging required fields, potential errors or questionable data as well as 
requiring the clinical site user to take action to resolve them. Skip logic is integrated in the eCRFs 
for the purpose of directing clinics to complete each required field based on previously answered 
questions and preventing data entry for unnecessary fields. Frontier Science will also implement 
range checks that require explicit data entry confirmation for overwrite, as well as non-conformant 
data checks for missing and non-conformant data. 
3. 
Coding and Utilities 
Frontier Science contains a Medical Coding Department comprised of individuals trained and 
certified in medical and drug coding procedures.  The Coding Department uses MedDRA to encode 
clinical and adverse events, and WHO Drug Dictionary to encode medications taken by participants.  
Frontier Science Medical Coders are certified by the American Health Information Management 
Association and/or the American Academy of Professional Coders, and perform all medical coding 
tasks required for the various studies in which they participate within the context of Frontier Science.  
The Coding Department adheres to standard procedures and review processes to ensure consistency 
through a collection of SOPs, work instructions, reference guides, and templates. This includes 
checklists to guide coding, quality review, and ancillary tasks such as dictionary up-versioning 
which is performed twice annually. For ongoing studies, this may require that certain records in the 
database are recoded as the new dictionary and accompanying codes are released. A working group 
comprised of Frontier Science coders as well as representatives from other collaborating associations 
submit requests for new MedDRA terms as needed and if reflected in the new release, incorporates 
them into their current terms. Requests for new medication codes are submitted online through a 
designated change request page provided by the WHO Drug vendor.  
4. 
Data acquisition and processing 
Figure 5 illustrates the relationship among several inflow and outflow components of the proposed 
infrastructure. As depicted, there will be multiple sources of study data. Frontier Science will acquire 
participant enrollment information from the clinical sites. Users at the clinical sites will then enter 
study data into REDCap. Frontier Science will configure its data exchange system which will 
transfer participant enrollment information, in real-time, from Stars to REDCap to initialize the list 
of participants, and will transfer the Stars participant enrollment information and REDCap study data 
into the Central Database. Data from the Central Database will be used as the source for quality 
assurance, medical coding, reporting, data visualization dashboards, on-demand retrievals for 
statistical analysis, and exchanging data with the study team. 

PROACTIVE NYS, Version 1.0 
Page 62 of 64 
Version Date 25 October 2023 
Figure 5. Virtual Data Management Infrastructure and Data Flow  
5. 
Quality assurance and quality control measures 
Frontier Science maintains a robust quality management system (QMS) that is supported by a team 
of experienced quality assurance professionals. Components of the QMS include internal audits, 
CAPA and incident tracking, a comprehensive training plan (discussed above), guidance document 
creation and management, and continuous improvement.  All of these activities collectively ensure 
that Frontier Science is inspection ready and also allows Frontier Science to assist other participating 
entities in establishing their own quality systems.  A full time, independent Compliance Officer 
oversees the Quality Management activities at Frontier Science. 
6. 
Data storage 
All data is stored at Frontier Science’s production site, located in Albany, NY, and which is a SOC II 
certified data center. The data center is equipped with a dedicated oxygen-depleting fire suppression 
system and dedicated climate control units. In addition, the data center has backup systems in place. 

PROACTIVE NYS, Version 1.0 
Page 63 of 64 
Version Date 25 October 2023 
For example, the data center is provisioned with Uninterruptible Power Supplies (UPSs) which 
provide surge protection and uninterrupted switchover to short term backup, while diesel generator 
power provides indefinite power backup. Physical access is restricted and monitored by designated 
colocation support staff. A Disaster Recovery site is located in a blast-hardened storage bunker in 
Romulus, NY. 
7. 
Database development and validation 
In order to ensure full data integrity and proper design of the study within the electronic 
environment, Frontier Science executes a robust study build validation process that ensures full 
testing and documentation of the entire build process. Study Build at Frontier Science closely 
mirrors a software development lifecycle (SDLC) which has been vetted over the course of several 
vendor audits. These audits have provided evidence that the organization’s SDLC is not only 
sufficient but extremely robust per industry standard. Study builders are similarly trained extensively 
in the “SDLC process”, or validation process, followed for study build.  Each study build is 
documented with a validation package that includes a study requirements workbook (analogous to 
functional requirements) to define the data elements and edit checks for each eCRF. Test cases are 
drafted and a testing plan is reviewed and signed prior to formal testing in a User Acceptance 
Testing (UAT) environment. Results of test cases are tracked in VersionOne (a COTS validated 
agile software development product) and a testing report is developed and signed to document the 
results of formal UAT testing, prior to pushing an eCRF version to production. A traceability matrix 
ensures that all forms and edit checks are tested prior to release. 
8. 
Database archival and disposition 
The data may be stored indefinitely as Frontier Science follows a robust backup process and 
maintains all backups for as long as required by the sponsor. Archival likewise follows a robust 
procedure, whereby a designated individual or individuals will be responsible for ensuring that the 
study archive is complete.  
9. 
Team governance and organizational structure 
The PROACTIVE NYS project will be under an mPI leadership model. Two of the PIs both works 
at the Renaissance School of Medicine at the State University of New York at Stony Brook, while 
the third works at the New York State Department of Health (DOH). Dr. Caggana’s focus will be on 
the management of the initial cCMV newborn screening and the initial follow-up and diagnostic 
work-up of those babies, which will help determine their eligibility for PROACTIVE NYS.  
 
Additionally, Dr. Caggana will serve as the Contact PI for this project.  Drs. Nachman and Handel 
have been collaborating on similar projects for the past 6 years. The expected work has been divided, 
with Dr. Nachman primarily focusing on management issues such as finances, collaboration with the 
Wadsworth Newborn Screening program, and FSTRF data completeness and data queries. She will 
also participate in periodic evaluation of research progress and publication policies. Dr. Handel will 
focus primarily on the scientific rationale of the study, including objectives, CRF development, 
analysis of data, and publication of results. 
 
All three leads have been working together for the past year designing the project, having calls with 
the study sites and NYS DOH, and helping to design the study website, hosted by Frontier Science 
(FSTRF), the study’s data management center, developing patient facing forms regarding the new 
diagnostic tool and the study as well as planning site budgets and accountability.  
 
Meeting schedule with agenda: Dr. Handel will run monthly meetings with each of the sites, 
focusing on addressing issues related to illness, newly identified hearing loss, and medication 
toxicities. Minutes will be kept from these calls and added to an electronic trial master file (eTMF) 
for organizational and track record purposes. Dr. Nachman will participate in these meetings by 

PROACTIVE NYS, Version 1.0 
Page 64 of 64 
Version Date 25 October 2023 
addressing recruitment and CRF completion rates, as well as missing data from each site. Dr. 
Caggana will update sites on sensitivity and specificity of the testing in an ongoing basis.  
 
Dr. Handel and Dr. Nachman will be meeting weekly after study kickoff. Their agenda will depend 
on issues identified that week. Urgent meeting can also be scheduled as their offices are several 
doors from each other and they have extensively collaborated on both research and patient care 
issues on an ongoing basis for the past 6 years. Their weekly collaborations may move to every other 
week during year two and three of the study. 
 
A yearly progress report will be co-authored and submitted to the funding agency. A publication 
SOP will be developed for the study and include solicitation of topics, authorship, and timelines for 
abstract and manuscript review.   
10. Conflict resolution procedures 
If a potential conflict develops, the PIs shall meet and attempt to resolve the dispute. If they fail to 
resolve the dispute, the disagreement shall be referred to an arbitration committee consisting of 
senior Pediatric ID members from each site, along with a senior representative from NYS DOH, and 
FSTRF. 
11. Decision process for scientific direction and allocating funds and resources 
Dr. Caggana will focus on QA of the Newborn Screen CMV PCR testing and assessing the 
sensitivity and specificity of cCMV by confirmation of status on all infants identified. Drs. Handel 
and Nachman have agreed that their focus will be long term follow-up at this time. The next steps 
will be evaluation of events by each study timepoint, with the potential to engage outside 
collaborators when issues are identified. This includes possible development of a serum/plasma 
repository for infants with hearing loss, genetic assessments for other causes of hearing loss, and a 
proposal for longer term follow-up past 2 years of age. Key to these proposals will be an assessment 
of how often events are noted in the first years in this cohort of cCMV infants. Funding will need to 
be identified to assess these projects. 
 
Currently, the budget is specific for each site and includes funds for purchase of tools needed for the 
study. Budget for the data management center is also specific and matches the needs of the study. 
The distribution of the submitted budget takes into consideration existing resources and the 
dissemination of work. Each PI will be responsible for their own operational budget, but will work 
together to manage the overall budget and reallocate funds as necessary.