Eating, Sleeping, Consoling for Neonatal Withdrawal (ESC-NOW): a Function-Based Assessment and Management Approach
Phase: NA
Conditions: Neonatal Opiate Withdrawal Syndrome
Sponsor: Advancing Clinical Trials in Neonatal Opioid Withdrawal (ACT NOW) Program

Eating, Sleeping, Consoling for Neonatal Withdrawal (ESC-NOW): a 
Function-Based Assessment and Management Approach ((ESC-
NOW)) 
NCT04057820 
Protocol Document 
March 28, 2022 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 1 of 79 
Protocol Version #: 08   Date: 28-March-2022 
 
Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW): 
a Function-Based Assessment and Management Approach 
 
UAMS IRB (cIRB) Protocol Number 239729 
Version Number: 08 
28 March 2022 
 
ClinicalTrials.gov number: 
NCT04057820 
 
NRN ID number:  
NICHD-ACT-NOW-0002 
 
Operational Principal Investigator:  Jessica Snowden, MD, University of Arkansas for Medical Sciences 
 
Lead Study Investigators: 
Leslie Young, MD, University of Vermont  
 
Lori Devlin, DO, MHA, University of Louisville 
 
Stephanie Merhar, MD, University of Cincinnati  
 
Subcommittee Members:  
Brian Smith, MD, MPH, MHS, Duke Clinical Research Institute 
 
Alan Simon, MD, National Institute of Health 
 
Jeannette Lee, PhD, UAMS 
 
Songthip Ounpraseuth, PhD, UAMS 
 
Andrew Bremer, MD, NICHD  
 
Brenda Poindexter, MD, NICHD NRN  
 
Abhik Das, PhD, RTI 
 
 
Funded by:   National Institutes of Health  
 
 
 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 2 of 79 
Protocol Version #: 08   Date: 28-March-2022 
 
Summary of Key Changes from Version 01 to Version 02: 
Affected 
Section(s) 
Summary of Revisions Made (01 to 02) 
Rationale 
Overall 
Study changed from a 1-year study to a 2-year study.  
Additional tests and contact times added.  Time points 
for assessments were modified for some assessments. 
Long-term follow-up was added 
and study was revised to be 
consisted with 2 parallel 
Neonatal Opioid Withdrawal 
Syndrome (NOWS) protocols.  
Section 1.5 Study 
Intervention/ 
Methods 
Updated time points and assessments to be consistent 
with the details provided later in the protocol. 
Long-term follow-up was added 
and study was revised to be 
consisted with 2 parallel 
Neonatal Opioid Withdrawal 
Syndrome (NOWS) protocols.  
Table 2. Study 
Objectives and 
Endpoints 
Obtained under 
Waiver of 
Consent 
Revised time points for critical safety outcomes. 
Study is now a 2-year study. 
Table 3. Study 
Objectives and 
Endpoints 
Obtained under 
Provision of 
Consent  
Added the following assessments: 
• 
Growth, weight, length, head circumference 
measurements 
• 
Bayley Scales of Infant and Toddler 
Development, 4th Ed. 
• 
Adverse Childhood Event (ACE) questionnaire 
Deleted the following assessment: 
• 
Parent’s Evaluation of Development Status 
(PEDS) 
Long-term follow-up was added 
and study was revised to be 
consisted with 2 parallel NOWS 
protocols.  
4.1.2.3; 
Additional Infant-
level Exclusion … 
Added exclusion for cases in which infant’s caregiver 
does not speak English. 
Some of the assessments are 
not validated in language(s) 
other than English. 
Table 4. Study 
Event Schedule 
Added: 
• 
New contact time points when baby is 9, 18, and 
24 months of age 
• 
Requirement to get periodic updates of 
participant’s contact information  
• 
3-month time point (additions to previous list): 
o 
Acute/urgent care and/or ER visits and 
hospital readmissions  
o 
Non-accidental trauma and death 
 
• 
24-month time point (new time point): 
New to study: 
o 
Adverse Childhood Experiences 
Questionnaire 
o 
Bayley’s Exam 
Table updated to match 
changes made to protocol for 
long term follow-up.  

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 3 of 79 
Protocol Version #: 08   Date: 28-March-2022 
Affected 
Section(s) 
Summary of Revisions Made (01 to 02) 
Rationale 
Additional time point for: 
o 
Weight, length, and head circumference  
o 
Non-accidental trauma and death (infant) 
o 
Caregiver questionnaire  
o 
Brief symptom inventory  
• 
Clarification that the window for time points is 
±3 weeks for time points ≤ 12 months and is 
±6 weeks for time points > 12 months. 
 
Deleted: 
  Deleted from study: 
• 
Questionnaire deleted (from study): 
o 
Parent’s Evaluation of Developmental Status: 
Developmental Milestones Assessment Level 
(PEDS:DM-AL) 
  Deleted from specific time point: 
• 
1-month post discharge time-point deletions are: 
o 
Brief Infant Sleep Questionnaire 
o 
Brief Symptom Inventory (Caregivers) 
o 
Maternal Postnatal Attachment Questionnaire 
o 
Parenting Sense of Competence Scale 
(PSOC) (Caregiver) 
• 
12-months of age time-point deletion: 
o 
Non-accidental trauma and death (infant) 
4.2.2.2; Consent 
for Assessment 
of Long-term 
outcomes (para. 
1) 
Added that participants will be asked to bring their baby 
for an in-person follow-up visit at 24 months 
New test (Bayley’s) added for 
long-term follow-up 
4.2.3; 
Randomization 
procedures  
(para. 2, last line, 
completing 
sentence “The 
protocol study 
team will …”) 
Replaced the following text: 
 “blind participating sites to the their randomly allocated 
time period until the point at which the site will need to 
begin planning and training activities in anticipation of 
site training and implementation of the ESC approach. 
With: 
notify sites of their allocated block following 
randomization 
Correction to method. 
4.2.6; Post-
hospital 
procedures 
Added 24 months of age as a time point for safety 
outcome(s), for administering several questionnaires, 
and for conducting the Bayley’s exam.  Also noted that 
research personnel are to maintain contact with 
participants at regular intervals. 
Study period increased from 
1 year to 2 years. New 
assessment (Bayley’s) added to 
study. 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 4 of 79 
Protocol Version #: 08   Date: 28-March-2022 
Affected 
Section(s) 
Summary of Revisions Made (01 to 02) 
Rationale 
4.2.8; 
Blinding/Masking 
Replaced the following text: 
However, it will not be possible to blind responses to 
questionnaires that are performed with the assistance of 
research personnel at the participating sites.” 
With: 
For questionnaires completed by phone, each site 
should develop a site-specific protocol to preserve 
blinding of those administering the questionnaires 
Method correction. 
4.3.2.1; 
[Secondary 
Outcomes] 
Obtained under 
Waiver of 
Consent and 
gathered … 
Item 12: [critical safety outcomes] 
Primary sentence and bullet 1 – added that critical 
safety outcomes would be evaluated at 24 months (in 
addition to other time points) 
Bullet 2: Added: “These infants may also fail to develop 
a bond with their primary caregiver(s) during the first 
months of life, which may further increase the risk for 
non-accidental trauma and death during the first two 
years of life.” 
 
Long-term follow-up was added 
and study was revised to be 
consisted with 2 parallel NOWS 
protocols.  
4.3.2.2.  
[Secondary 
Outcomes] 
Obtained for the 
Subpopulation 
who provide … 
Primary sentence: Changed from “12” to “24” months 
(for last time point) 
Item 2, primary bullet 1 and sub-bullets: New text added, 
specifically, anthropometric growth data will be 
collected. 
Item 2, primary bullet 2, sub-bullet 2: deleted “1-month 
post hospital discharge” as time point for BISQ. 
Item 2, primary bullets 5 and 6: added 24 month 
assessment time points 
Long-term follow-up was added 
and study was revised to be 
consisted with 2 parallel NOWS 
protocols.  
4.3.2.2 
(continued) 
Deleted: 
• 
A composite measure of critical safety outcomes 
based on the presence or absence of non-
accidental trauma and death will again be assessed 
at 12 months of age 
 Hypothesis: Infants managed using the ESC care 
approach will be safe during the first 12 months 
of age. 
 Infants with undertreated signs of withdrawal 
may be at increased risk for failing to develop a 
bond with their primary caregiver(s) in the first 
months of life, which increases the risk for non-
accidental trauma and death during the first two 
years of age.  
Study was changed from a 
1-year study to a 2-year study. 
4.3.2.2 
(continued) 
 
Item 3, bulleted 2  
Regarding Brief Symptom Inventory time points: 
o 
Deleted  “1-month post hospital discharge” 
o 
Added “24 months [of age]” 
Study time points / assessment 
times changed due to change 
from 1-yr to 2-yr study and to 
make study consistent with 
other NOWS protocols 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 5 of 79 
Protocol Version #: 08   Date: 28-March-2022 
Affected 
Section(s) 
Summary of Revisions Made (01 to 02) 
Rationale 
4.3.2.2. 
(continued) 
Items 4 and 5: Deleted time point at 1-month post 
hospital discharge for MPAQ and PSOC assessments, 
respectively. 
Study time points / assessment 
times changed due to change 
from 1-yr to 2-yr study and to 
make study consistent with 
other NOWS protocols 
4.3.2.2 
(continued) 
Added item 7: Assessment using Adverse Childhood 
Experience (ACE) Questionnaire 
New assessment added due to 
longer follow-up and need to 
have consistency between 
NOWS protocols.  
4.3.2.3; Obtained 
for the 
Subpopulation 
who Provide … 
Added 
 Assessment with the Bayley Scales of Infant and 
Toddler Development, 4th Ed. (New text: all of bullet 2 
and associated sub-bullet.) 
Deleted:  
The protocol study team will assess infant development 
with the PEDS: Developmental Milestones Assessment 
Level (PEDS: DM-AL) at 12 months of age. The 
caregiver will complete the questionnaire and it will be 
sent to a central location for review by the protocol study 
team. 
The PEDS: DM-AL is a validated surveillance and 
screening tool for children 0-8 years of age, designed for 
developmental follow-up. The tool enables a detailed 
look at each developmental domain (e.g. expressive 
language, receptive language, fine motor, gross motor 
and social-emotional). Researchers note that the tool 
has a high internal consistency, test-retest reliability and 
a high level of concordance between caregiver report 
and professional or paraprofessional assessment. The 
tool is also noted to have a sensitivity (85%) and 
specificity (89%) for infants between 11 and 13 months 
of age.1 
New assessment added due to 
longer follow-up and need to 
have consistency between 
NOWS protocols.  
4.4; Potential 
Risks and 
Benefits to 
Participants 
Added:  
Participants recognized to have neurodevelopmental 
impairment on the Bayley-4 exam will be referred to 
their primary care providers for follow-up.  The study 
team will communicate and share the report with the 
caregiver(s) and primary care providers if requested by 
the participants’ caregiver(s) and consent is obtained. 
New assessment added due to 
longer follow-up and need to 
have consistency between 
NOWS protocols.  
4.5.2.2.; 
Retention 
Added reimbursement plan for participants’ time.   
Revised method of reimbursement to make it flexible 
Addresses UAMS IRB 
contingency.  Flexibility added 
to method of reimbursement 
because not all sites have the 
same payment mechanisms 
available to them. 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 6 of 79 
Protocol Version #: 08   Date: 28-March-2022 
Affected 
Section(s) 
Summary of Revisions Made (01 to 02) 
Rationale 
5.1.4.1; [Analysis 
of Long-term 
Outcome 
Endpoints] Infant 
Wellness after 
discharge … 
Added 2 entire paragraphs for analysis of child’s weight, 
length, and head circumference. 
New analysis information 
needed because assessment 
added for 24 months of age. 
5.1.4.1; [Analysis 
of Long-term 
Outcome 
Endpoints] 
Deleted “1 month post discharge” as a time point for 
BISQ analysis. 
Time points of some 
assessments changed due to 
longer follow-up and need to 
have consistency between 
NOWS protocols. 
5.1.4.2;   
5.1.4.3; 
And 5.1.4.5  
[Analysis of 
Long-term 
Outcome 
Endpoints] BSI, 
MPAQ, and 
PSOC 
respectively 
Corrected time points  (deleted 1 month post discharge) 
Time points of some 
assessments changed due to 
longer follow-up and need to 
have consistency between 
NOWS protocols. 
5.1.4.7 (Bayley’s)  
and 5.1.4.8 
(ACE) 
New sections. 
New assessments added due 
to longer follow up and need to 
have consistency between 
NOWS protocols. 
Deletion from 
5.1.4 
Parents’ Evaluation of Development Status: 
Development Milestones Assessment Level 
(PEDS: DM-AL) at 12-Months of Age 
The analysis team will calculate descriptive statistics 
(mean ± SD) for each domain in the PEDS: DM-AL (i.e., 
expressive language, receptive language, fine motor, 
gross motor and social-emotional) separately for each 
treatment group. To compare the PEDS: DM-AL 
composite scores between two intervention groups, we 
will perform a linear mixed-effects model with a fixed 
effect for the intervention group and a random effect for 
study site. We will report point estimates for the group 
mean difference along with a 95% CI, and the team will 
repeat this analytical approach for each of the PEDS: 
DM-AL domains. 
Assessment is no longer going 
to be done for this protocol. 
5.2; Samples size 
and power 
estimates 
Added last paragraph. 
Method addition. 
Through-out 
Corrected minor grammar and typographical errors, 
including adding abbreviations to list of abbreviations. 
Simple corrections 
 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 7 of 79 
Protocol Version #: 08   Date: 28-March-2022 
Summary of Key Changes from Version 02 to Version 03: 
Affected 
Section(s) 
Summary of Revisions Made (02 to 03) 
Rationale 
Section 5.2; 
Sample Size and 
Power Estimates 
In the paragraph immediately following Table 5: 
• 
Noted that the 24 sites is the minimum number of 
sites and that there could be up to 28 sites. 
• 
Added “During any single study period (see 
Table 1), a site may enroll no more than 
16 infants.” 
Procedural update. 
New section. 
Section 6.  
Added new section, Section 6, Data Management, to 
specify the role of RTI International. 
This is a cIRB-requested 
change to provide details on 
RTI International’s role. 
 
Summary of Key Changes from Version 03 to Version 04: 
Affected 
Section(s) 
Summary of Revisions Made (03 to 04) 
Rationale 
Table titles 
Updated. 
Updated. 
Section 1.5, 
Study 
Intervention / 
Methods  
AND 
Section 4.2.6 
Post-hospital 
Procedures 
Second full paragraph of section 1.5 and 1st full 
paragraph of section 4.2.6: 
Clarification of term “medical records,” specifically noting 
that the term includes both primary and linked records 
Clarification 
Section 4.1.2.3., 
Additional Infant-
level Exclusion 
Criteria (…)  
AND 
Section 4.4, 
Potential Risks 
and Benefits to 
Participants 
Revised to indicate that primary caregiver must both 
speak and read English. 
Clarification. 
Section 4.2.1., 
Screening 
End of last paragraph, added: 
 
“Sites may enroll up to 16 infants per period; screen fails 
are not included in this total. Only infants enrolled in the 
study may be approached for consent and included in 
the long-term follow-up study. 
Budgetary restrictions 
necessitate limiting participants. 
Figure 1., 
Screening and 
Enrollment 
Procedures 
Added to end of footnote: 
“To optimize recruitment it will permissible to obtain 
initial consent up to one month after discharge. 
Protocol change. 
Section 4.2.4, 
Study 
Intervention and 
Comparison 
Middle of 1st paragraph, added that training can also 
occur by teleconference  
Added acceptable training 
format. 
Section 4.2.4.2, 
Transition period 
Training and Implementation, bullet 5: 
Changed “20” individuals to “10” individuals and added 
the ability to use written scenarios (as well as video 
scenarios) 
Protocol change/logistics. 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 8 of 79 
Protocol Version #: 08   Date: 28-March-2022 
Affected 
Section(s) 
Summary of Revisions Made (03 to 04) 
Rationale 
Section 4.3.2.1. 
title 
Revised sub-section title to specify that “medical 
records” includes primary on-site records and linked 
medical records 
Clarification. 
Section 4.5.2.1, 
Recruitment 
Second paragraph: 
• 
Replaced “video” with “informational brochure” in 
2nd to last sentence. 
• 
Added last sentence to paragraph, stating that 
consent may be obtained up to one month after 
discharge. 
 
Protocol correction & addition. 
Section 4.5.2.2., 
Retention 
Middle of 1st paragraph: 
Included sentence specifying contact information may 
be obtained from participant’s medical record if the 
participant cannot be reached. 
Protocol addition. 
 
Summary of Key Changes from Version 04 to Version 05: 
Affected 
Section(s) 
Summary of Revisions Made (04 to 05) 
Rationale 
List of 
Abbreviations 
Updated to add abbreviations referenced in protocol 
revisions and deleted BSI (Brief Symptom Inventory) 
Consistency with revised 
assessments. 
Tables 3 and 4 
Updated for assessments/measures referenced in 
protocol revision. Specifically, added BITSEA 
assessment and PROMIS assessment and deleted 
BSI (Brief Symptom Inventory).  Also removed 
references to Bayley sections on social-emotional 
and on adaptive behavior 
Consistency with revised 
assessments. 
Section 1.4.2.2 
and 4.1.2.2 
Updated infant level exclusion criteria to include 
diagnosis of COVID-19, which may interfere with 
non-pharmacologic care and affect study outcomes. 
Perinatal management of potential 
COVID-19 patients are rapidly 
changing and may impact study 
outcomes during the current 
pandemic. 
Section 4.1.2.3 
Clarified that participants must be able to write, as 
well as speak and read, English to participate. 
Clarifications based on study 
procedures requiring more than 
only the ability to speak and read 
English. 
Section 4.2.2.2 
Consent for Assessment of Long-term Outcomes. 
Added second paragraph to allow for remote 
consenting. 
Changed due to (a) COVID-19 
pandemic, and (b) relative 
availability of participants 
consenting after discharge. 
Section 4.3.2.2 
Replaced description of Brief Symptom Inventory 
(BSI) with description of Patient Reported Outcome 
Measurement System (PROMIS) Short Forms. 
Protocol team chose alternate tool 
for mental health measures for 
feasibility concerns and to align 
with other concurrent neonatal 
opioid studies. 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 9 of 79 
Protocol Version #: 08   Date: 28-March-2022 
Affected 
Section(s) 
Summary of Revisions Made (04 to 05) 
Rationale 
Section 4.3.2.3 
Revised protocol to indicate that Bayley-4 scales will 
be used for Cognitive, Language, and Motor 
development and BITSEA (Brief Infant-Toddler 
Social and Emotional Assessment) will be used to 
assess social-emotional concerns.  
Protocol team chose alternate tool 
for developmental measures for 
feasibility concerns and to align 
with other concurrent neonatal 
opioid studies.  
Section 4.4 
Revised protocol to indicate triggers for maternal 
intervention based on PROMIS scores for severe 
depression.  
Consistency with revised 
measures. 
Section 5.1.4.2 
and 5.1.4.8 
Revised analysis description to reflect analysis of 
PROMIS and BITSEA as detailed above.  
Consistency with revised 
measures.  
 
Summary of Key Changes from Version 05 to Version 06: 
Affected 
Section(s) 
Summary of Revisions Made (05 to 06) 
Rationale 
Section 4.2.2.1. 
Waiver of 
Consent 
To last paragraph in section:  
• 
Added option to post handout materials. 
Additional flexibility for sites. 
 
Summary of Key Changes from Version 06 to Version 07: 
Affected 
Section(s) 
Summary of Revisions Made (06 to 07) 
Rationale 
3.3.2.4. and 
throughout 
document when 
referencing 
training material 
location 
• 
Changed reference FROM “MOP” TO “Training and 
Implementation Manual”for location of materials related to 
ESC training. 
Change in location of 
materials. 
4.2.4.1.  Usual 
Institutional Care 
Periods 
• 
Added “Periods” to title of section 
Clarification. 
4.2.4.2. 
Transition 
Periods 
• 
Replaced “protocol study” team with “site research” team 
• 
Last bullet under “education” subsection: deleted “through 
pre/post assessments.  Post assessments will require 80% 
correct responses for completion.  Participants will be able 
to retake each of the lessons until he/she achieves a correct 
response rate of 80%. 
• 
Second bullet under “training and implementation” section: 
deleted “review of instructional manual” as part of the 
education and training requirement. 
• 
Fourth bullet under “training and implementation: 
subsection: 
Protocol clarifications 
and internal 
consistency; study 
procedure changes  

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 10 of 79 
Protocol Version #: 08   Date: 28-March-2022 
Affected 
Section(s) 
Summary of Revisions Made (06 to 07) 
Rationale 
o 
Changed “co-assess” TO “assess” 
o 
Deleted requirement to co-assess/assess “with gold-star 
raters” 
• 
Second to last bullet under “training and implementation” 
subsection: Added “training milestones” to the criteria to 
assess before moving to the ESC intervention period. 
• 
Last bullet:  
o 
changed “webinars” TO “coaching calls”  
o 
deleted requirement for calls to be biweekly 
4.2.4.3. (title 
change) 
• 
Changed section title FROM “ESC Care Approach” TO 
“ESC Intervention Periods” 
Consistency with other 
study periods 
4.2.4.3.  ESC 
Intervention 
Periods 
• 
Bullet 11:  
o 
 Deleted “The protocol study team will provide sites with 
a protocol. The protocol study team will permit (following 
review and approval) site level modifications of the 
protocol to align it with the site’s preferred practice.  
• 
Second to last bullet: 
o 
Replaced “protocol study” team with “site research” 
team  
o 
Replaced “study periods” with “ESC intervention 
periods.” 
o 
Deleted numerical (i.e., 10 individuals) requirement for 
assessing using the ESC IRR tool.  
o 
Changed methods available for the gold-star raters to 
assess clinical team: 
 
Added “a NOWS infant 
 
Deleted “scenarios on the training platform” 
o 
Deleted reference to “a centralized training platform” 
and replaced with reference to “Training and 
Implementation Manual.” 
• 
Last bullet: 
o 
Removed multiple references to the use of an electronic 
platform for training/evaluation.  
o 
Changed the last sentence FROM: The site research 
team “will enter data into the electronic application and 
will send it directly to a central repository where the 
protocol study team will analyze the data and identify 
fidelity issues that the site research team can address in 
a timely fashion.”  TO The site research team “will keep 
complete ESC Implementation Process Evaluation 
forms with other study documentation. 
Protocol correction and 
clarification; add 
flexibility  

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 11 of 79 
Protocol Version #: 08   Date: 28-March-2022 
Affected 
Section(s) 
Summary of Revisions Made (06 to 07) 
Rationale 
4.2.5, Protocol 
Adherence 
• 
Third to last bullet: Deleted “as assessed through the 
education and training platform. 
• 
Second to last bullet:  Changed FROM “Initial IRR for the 
clinical team…”  TO “Continual IRR fidelity assessment for 
the clinical team …”  
Corrected to match 
process. 
5.4.2, Site 
Training 
• 
Allow for training of site champions via video conference in 
addition to other method(s). 
Additional method 
added. 
5.5.2. Data 
Monitoring and 
Safety 
• 
Added (to 2nd sentence) that the DSMC review will when 
sites “have completed one full period using the ESC Care 
Approach.” 
Calrification. 
 
Summary of Key Changes from Version 07 to Version 08: 
Affected 
Section(s) 
Summary of Revisions Made (07 to 08) 
Rationale 
Section 4.2: 
Schedule of 
Activities 
(footnotes) 
• 
Changed window for 24-month time point.  Changed from 
± 6 weeks to ± 8 weeks. 
The ± 8 weeks allows 
for the Bailey test (part 
of 24-mo time point) to 
be done per standard 
procedure. 
 
 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 12 of 79 
Protocol Version #: 08   Date: 28-March-2022 
 
 
Contents 
Section 1. 
Abstract ................................................................................................................. 17 
1.1. 
Primary Hypothesis ................................................................................... 17 
1.2. 
Secondary Hypothesis ............................................................................... 17 
1.3. 
Study Design Type ..................................................................................... 17 
1.4. 
Eligibility Criteria ....................................................................................... 18 
1.4.1. Inclusion Criteria ........................................................................... 18 
1.4.2. Exclusion Criteria........................................................................... 18 
1.5. 
Study Intervention/Methods .................................................................... 19 
1.5.1. Study Objectives and Endpoints ................................................... 20 
Section 2. 
Conflict of Interest Disclosures ............................................................................. 22 
2.1. 
Financial Conflicts of Interest of the Institutions and Investigators ......... 22 
2.2. 
Plan for Managing Identified Financial Conflicts of Interests ................... 22 
Section 3. 
Statement of Problem ........................................................................................... 23 
3.1. 
Primary Hypothesis ................................................................................... 23 
3.2. 
Secondary Hypothesis ............................................................................... 23 
3.3. 
Background and Rationale ........................................................................ 23 
3.3.1. Public Health Impact ..................................................................... 23 
3.3.2. Background ................................................................................... 23 
Section 4. 
Methods ................................................................................................................ 28 
4.1. 
Study Population ....................................................................................... 28 
4.1.1. Inclusion Criteria ........................................................................... 28 
4.1.2. Exclusion Criteria........................................................................... 28 
4.2. 
Detailed Study Procedures ....................................................................... 30 
4.2.1. Screening ....................................................................................... 32 
4.2.2. Consent Procedures ...................................................................... 34 
4.2.3. Randomization Procedures ........................................................... 36 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 13 of 79 
Protocol Version #: 08   Date: 28-March-2022 
4.2.4. Study Intervention and Comparison ............................................. 38 
4.2.5. Protocol Adherence and Compliance Monitoring ........................ 43 
4.2.6. Post-hospital Procedures .............................................................. 43 
4.2.7. Data Quality Assurance ................................................................. 44 
4.2.8. Blinding/Masking .......................................................................... 45 
4.3. 
Study Objectives and Endpoints ............................................................... 45 
4.3.1. Primary Outcome .......................................................................... 45 
4.3.2. Secondary Outcomes .................................................................... 45 
4.4. 
Potential Risks and Benefits to Participants ............................................. 52 
4.5. 
Recruitment and Retention ...................................................................... 54 
4.5.1. Site Recruitment and Retention ................................................... 54 
4.5.2. Infant and Parent/Caregiver Recruitment and Retention ............ 54 
Section 5. 
Analytical Plan ....................................................................................................... 57 
5.1. 
Statistical Analysis Plan ............................................................................. 57 
5.1.1. General Approach ......................................................................... 57 
5.1.2. Analysis of the Primary Efficacy Endpoints ................................... 57 
5.1.3. Analysis of the Secondary Endpoints Obtained Under Waiver of Consent
 
58 
5.1.4. Analysis of the Long-term Outcome Endpoints ............................ 61 
5.2. 
Sample Size and Power Estimates ............................................................ 64 
5.3. 
Available Population ................................................................................. 66 
5.4. 
Projected Recruitment time ..................................................................... 67 
5.4.1. Site Recruitment ........................................................................... 67 
5.4.2. Site Training and Implementation ................................................ 67 
5.5. 
Study Monitoring Plan .............................................................................. 67 
5.5.1. Adverse Events .............................................................................. 67 
5.5.2. Data Monitoring and Safety .......................................................... 69 
Section 6. 
DaTA Management ............................................................................................... 70 
Section 7. 
Publication and Data Sharing Policy ..................................................................... 71 
Section 8. 
References ............................................................................................................ 72 
 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 14 of 79 
Protocol Version #: 08   Date: 28-March-2022 
List of Tables 
Table 1 
 Stepped-wedge Cluster Randomized Controlled Trial with Transition Period ................ 17 
Table 2 
Study Objectives and Endpoints: Obtained under waiver of consent .............................. 20 
Table 3 
 Study Objectives and Endpoints: Obtained under provision of consenta ....................... 21 
Table 4 
 Study Event Schedule ....................................................................................................... 30 
Table 5 
 Sample Size Estimates ...................................................................................................... 65 
Table 6 
 Sample Size Estimates for the IBQ-R for the Consented Subpopulation ......................... 66 
Table 7  
Expected Rates of Safety Outcomes ................................................................................. 70 
List of Figures 
Figure 1 
Screening and Enrollment Procedures ............................................................................. 33 
Figure 2 
Randomization Flow Diagram ........................................................................................... 38 
 
 
 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 15 of 79 
Protocol Version #: 08   Date: 28-March-2022 
List of Abbreviations 
ACE 
Adverse Childhood Experience 
AE 
Adverse Event 
Bayley-4 
Bayley Scales of Infant and Toddler Development, 4th Edition 
BISQ 
Brief Infant Sleep Questionnaire 
BITSEA 
Brief Infant-Toddler Social and Emotional Assessment 
BMI 
Body Mass Index 
CAC 
Cluster Autocorrelation Coefficient 
CI 
Confidence Interval 
COVID-19 
Severe acute respiratory syndrome coronavirus-2 
Cox PH 
Cox Proportional Hazards 
CQ 
Caregiver Questionnaire 
DCC 
Data Coordinating Center 
DSMC 
Data and Safety Monitoring Committee 
EDC 
Electronic Data Capture 
EHR 
Electronic Health Record 
ER 
Emergency Room 
ESC 
Eating, Sleeping, Consoling 
FCOI 
Financial Conflict of Interest 
FES 
Family Environmental Scale 
FNAST 
Finnegan Neonatal Abstinence Scoring Tool  
GLMM 
Generalized Linear Mixed Model 
GSI 
Global Severity Index 
HIPAA 
Health Insurance Portability and Accountability Act 
IBQ 
Infant Behavior Questionnaire 
IBQ-R 
Infant Behavior Questionnaire – Revised 
ICC 
Intracluster Correlation Coefficient 
IRB 
Institutional Review Board 
IRR 
Inter-Rater Reliability 
ISPCTN 
IDeA States Pediatric Clinical Trials Network  
LOS 
Length of Stay 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 16 of 79 
Protocol Version #: 08   Date: 28-March-2022 
MOP 
Manual of Procedures 
MPAQ 
Maternal Postnatal Attachment Questionnaire 
NIH 
National Institutes of Health 
NRN 
Neonatal Research Network  
NOWS 
Neonatal Opioid Withdrawal Syndrome  
PI 
Principal Investigator 
PROMIS 
Patient Reported Outcome Measurement Information System 
PSOC 
Parenting Sense of Competence  
QC 
Quality Control 
QI 
Quality Improvement 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
WHO 
World Health Organization 
 
 
 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 17 of 79 
Protocol Version #: 08   Date: 28-March-2022 
SECTION 1. 
ABSTRACT 
1.1. 
PRIMARY HYPOTHESIS  
Among infants evaluated for neonatal opioid withdrawal syndrome (NOWS), the Eating, Sleeping, 
Consoling (ESC) care approach will reduce the length of time until infants are medically ready for 
discharge by an average of 4 days, as compared to usual institutional care with the Finnegan Neonatal 
Abstinence Scoring Tool (FNAST) or modification thereof. 
 
1.2. 
SECONDARY HYPOTHESIS  
Among infants evaluated for NOWS, use of the ESC care approach will result in an improvement in 
infant neurobehavioral functioning and family well-being, when compared to usual institutional care 
with the FNAST or modification thereof. 
 
1.3. 
STUDY DESIGN TYPE  
In this stepped-wedge cluster randomized controlled trial with transition period, the protocol study 
team will compare the ESC care approach to usual institutional care with the FNAST or modification 
thereof. Randomization will occur at the site level. The protocol study team will randomize 
approximately 24 sites into 8 blocks. Each block will transition from usual care to the ESC care 
approach for the evaluation and management of all infants with NOWS at various time intervals (see 
Table 1). Sites will use the care approach randomly assigned to their block during each study period for 
the evaluation and management of all infants with NOWS cared for at the site. During the initial birth 
hospitalization, the site research team will collect data under waiver of consent for infants who meet 
eligibility criteria (see Section 4.1). The number of infants enrolled per period at each site will vary 
throughout the study, due to fluctuations in the number of infants managed for NOWS at each site 
during each period. However, the goal is for each site to enroll at least 4 infants per period. The site 
research team will obtain informed consent from the legal guardian(s) to obtain long-term outcomes 
for eligible infants and caregivers. Site research team members may obtain this consent at any point 
during the hospital stay for infants who meet the trial’s inclusion criteria.  
 
Table 1 
Stepped-wedge Cluster Randomized Controlled Trial with Transition Period 
Period 1** 
Period 2 
Period 3 
Period 4 
Period 5 
Period 6 
Period 7 
Period 8 
Period 9 
Period 10 
Block 1* 
Usual 
Care 
Transition 
ESC 
ESC 
ESC 
ESC 
ESC 
ESC 
ESC 
ESC 
Block 2 
Usual Care 
Usual 
Care 
Transition 
ESC 
ESC 
ESC 
ESC 
ESC 
ESC 
ESC 
Block 3 
Usual Care 
Usual 
Care 
Usual 
Care 
Transition 
ESC 
ESC 
ESC 
ESC 
ESC 
ESC 
Block 4 
Usual Care 
Usual 
Care 
Usual 
Care 
Usual 
Care 
Transition 
ESC 
ESC 
ESC 
ESC 
ESC 
Block 5 
Usual Care 
Usual 
Care 
Usual 
Care 
Usual 
Care 
Usual 
Care 
Transition 
ESC 
ESC 
ESC 
ESC 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 18 of 79 
Protocol Version #: 08   Date: 28-March-2022 
Period 1** 
Period 2 
Period 3 
Period 4 
Period 5 
Period 6 
Period 7 
Period 8 
Period 9 
Period 10 
Block 6 
Usual Care 
Usual 
Care 
Usual 
Care 
Usual 
Care 
Usual 
Care 
Usual 
Care 
Transition 
ESC 
ESC 
ESC 
Block 7 
Usual Care 
Usual 
Care 
Usual 
Care 
Usual 
Care 
Usual 
Care 
Usual 
Care 
Usual 
Care 
Transition 
ESC 
ESC 
Block 8 
Usual Care 
Usual 
Care 
Usual 
Care 
Usual 
Care 
Usual 
Care 
Usual 
Care 
Usual 
Care 
Usual 
Care 
Transition 
ESC 
* Each block will consist of 3 sites  
** Each period will be 2 months in duration, except for the transition period, which will be 3 months, and the intervention 
periods bordering the transition, which will be 1.5 months/6 weeks in duration 
 
1.4. 
ELIGIBILITY CRITERIA 
1.4.1. Inclusion Criteria 
1.4.1.1. 
Site Level 
1. The site is willing, able, and has nurse management and administrative commitment to 
transition to the ESC care approach at the randomly allocated time  
2. The site currently uses the FNAST or modification thereof for the assessment of withdrawal 
severity for infants with NOWS 
3. The site currently provides opioid replacement therapy (i.e., morphine, methadone, or 
buprenorphine) as part of their pharmacologic management of infants with NOWS 
1.4.1.2. 
Infant Level 
1. The infant is being managed for NOWS at an eligible site (i.e., receiving non-pharmacologic 
care, assessments for withdrawal severity, +/- pharmacologic care)  
2. The infant is ≥ 36 weeks gestation  
3. The infant satisfies at least 1 of the following criteria: 
a. Maternal history of prenatal opioid use  
b. Maternal toxicology screen positive for opioids during the second and/or third trimester 
of pregnancy 
c. Infant toxicology screen positive for opioids during the initial hospital stay 
1.4.2. Exclusion Criteria 
1.4.2.1. 
Site Level 
1. The site currently manages < 20 opioid exposed infants annually  
2. The site routinely discharges/transfers infants from the hospital on opioid replacement therapy 
(i.e., morphine, methadone, or buprenorphine). We define routine discharge/transfer as ≥10% 
of infants who receive opioid replacement therapy for NOWS at the site  

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 19 of 79 
Protocol Version #: 08   Date: 28-March-2022 
1.4.2.2. 
Infant Level 
1. Infant has major birth defect(s)  
2. Infant has neonatal encephalopathy (inclusive of hypoxic ischemic encephalopathy), a metabolic 
disorder, stroke, intracranial hemorrhage, or meningitis diagnosed by 60 hours of life 
3. Infant was receiving respiratory support (any positive pressure or oxygen therapy) unrelated to 
pharmacologic treatment for NOWS at 60 hours of life 
4. Infant was receiving antimicrobial(s) at 60 hours of life  
5. Infant has received any major surgical intervention in the first 60 hours of life 
6. Postnatal opioid exposure other than for treatment of NOWS in the first 60 hours of life 
7. Outborn infants transferred at >60 hours of life or treated with opioids for NOWS at the 
transferring hospital  
8.  Infant’s biological mother or primary caregiver is positive or under investigation for COVID-19 at 
60 hours of life 
1.5. 
STUDY INTERVENTION/METHODS 
The protocol study team will randomize sites into study blocks with each block transitioning from usual 
care to the ESC care approach at a randomly allocated transition period. The protocol study team will 
compare short- and long-term outcomes for infants managed with the ESC care approach compared to 
usual institutional care. During the usual care periods, sites will evaluate and manage infants using the 
usual institutional practices and protocols for the assessment of withdrawal severity and management 
of infants with NOWS. After a site’s transition to the ESC care approach, each site will use the ESC Care 
Tool for the assessment of withdrawal severity and management of infants with NOWS (see Manual of 
Procedures [MOP]). If needed, during both the usual care and ESC interventions, site preference will 
determine the opioid replacement therapy, as well as the adjuvant therapy used. After completion of 
inpatient monitoring and management for NOWS, the clinical team members will discharge infants 
based on their usual practice. The site research team will review the medical record and data collection 
forms to assess the time (days) from birth until the infant was medically ready for discharge. We define 
medically ready for discharge as the point at which the infant meets ALL of the following criteria:  
• ≥ 96 hours life 
• Off of opioid replacement therapy (e.g. morphine, methadone, or buprenorphine) for 
≥ 48 hours 
• Taking 100% of feeds by mouth for ≥ 24 hours 
• ≥ 24 hours from initiation of the maximum caloric density infant received during the initial 
hospital admission  
• Receiving no respiratory support for ≥ 24 hours 
 
The site research team will review the primary and any linked medical records of all eligible infants 
(under waiver of consent) for the composite safety outcome and the critical safety outcome during the 
first months of life.  

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 20 of 79 
Protocol Version #: 08   Date: 28-March-2022 
Primary caregivers who provide informed consent will complete multiple questionnaires between 
discharge and 24 months of age and will return at the end of the study for an in-person visit for 
assessment of infant neurodevelopment and growth (see Table 4, Study Event Schedule). The 
questionnaires will assess infant wellness, neurobehavioral functioning and development, postnatal 
attachment and bonding, caregiver well-being, and family environment. If the primary caregiver for the 
infant changes during the study period, the new caregiver will provide consent and complete the 
questionnaires, and the site research team will note the change in caregiver.  
1.5.1. Study Objectives and Endpoints  
Table 2 outlines the primary and secondary objectives and endpoints for the short-term outcomes, 
obtained under waiver of consent, and Table 3 outlines the secondary objectives and endpoints for the 
long-term outcomes, obtained under provision of consent. 
 
Table 2 
Study Objectives and Endpoints: Obtained under waiver of consent  
Primary Objective 
Primary Endpoint:  
To determine if the ESC care approach will reduce the time 
until infants being managed for NOWS are medically ready 
for discharge. 
Time from birth until medically ready for discharge (days). 
Secondary Objectives 
Secondary Endpoints:  
To determine if the ESC care approach will decrease the 
proportion of infants who receive opioid replacement 
therapy (i.e., morphine, methadone, or buprenorphine) for 
NOWS prior to hospital discharge. 
Receipt of opioid replacement therapy (yes/no). 
To determine if the ESC care approach will decrease total 
postnatal opioid exposure as compared to usual care. 
Total dose of opioid replacement therapy infant received (total 
units, units/kg, and morphine equivalents [mg/kg]). 
To assess the impact of the ESC care approach on timing of 
pharmacologic therapy initiation. 
Hour of life opioid replacement initiated. 
To assess if use of the ESC care approach will decrease the 
proportion of infants requiring adjuvant therapy (clonidine 
or phenobarbital) prior to hospital discharge. 
Receipt of adjuvant therapy (yes/no). 
To assess the impact of the ESC care approach on infant 
feeding and weight gain. 
Maximum percent weight loss during initial birth hospitalization: 
 ቂ
𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏ℎ𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤ℎ𝑡𝑡 (𝑔𝑔)−𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤ℎ𝑡𝑡 𝑛𝑛𝑛𝑛𝑑𝑑𝑑𝑑𝑑𝑑(𝑔𝑔)
𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏ℎ𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤ℎ𝑡𝑡 (𝑔𝑔)
ቃ𝑥𝑥 100 = max𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤ℎ𝑡𝑡 𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙  
To determine if use of the ESC care approach will increase 
the proportion of infants who receive maternal breastmilk 
at the time of hospital discharge. 
Type of enteral feedings (exclusive maternal breastmilk, 
combination of formula and maternal breastmilk, exclusive 
formula feeding) at time of hospital discharge. 
To determine if use of the ESC care approach will increase 
the proportion of mothers who directly breastfeed at the 
time of discharge.  
Direct breastfeeding within 24 hours of hospital discharge 
(yes/no) 
To assess if the ESC care approach will decrease the length 
of hospital stay.  
Time from birth until infants being managed for NOWS are 
discharged from the hospital 
To assess safety of ESC care approach. 
Inpatient composite safety outcome (present/absent) 
- Seizures 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 21 of 79 
Protocol Version #: 08   Date: 28-March-2022 
 
Table 3 
Study Objectives and Endpoints: Obtained under provision of consenta 
Secondary Objectives 
Secondary Endpoints:  
(See MOP for each tool/questionnaire)  
To determine if the ESC care approach, compared to usual 
care, will improve infant neurobehavioral functioning. 
Infant Behavior Questionnaire (IBQ)* 
To assess the impact of the ESC care approach on infant 
wellness after discharge and until 24 months of age 
compared to usual care.  
- 
Growth: weight (kg), length (cm), head circumference (cm), 
and weight for length percentile on the World Health 
Organization (WHO) growth curves. Anthropometric z-scores 
and Body Mass Index (BMI)-z at 24 months of age  
- 
Sleep: Brief Infant Sleep Questionnaire (BISQ) Questionnaire  
- 
Enteral feeds (exclusive maternal breastmilk, combination of 
maternal breastmilk and formula or exclusive formula) 
(Caregiver Questionnaire) (CQ) 
- 
Any direct breastfeeding (CQ) 
- 
Acute/urgent care and/or ER visits (total number of 
occurrences) (CQ) 
- 
Readmissions (number of occurrences) (CQ) 
- 
Non-accidental trauma and death (presence or absence) 
- 
Adverse Childhood Experiences (ACE) questionnaire 
To assess if the ESC care approach, compared to usual 
care, will improve maternal/caregiver wellbeing.  
Patient Reported Outcome Measurement Information System 
(PROMIS)  Short Forms 
To assess if the ESC care approach, compared to usual 
care, improves infant-caregiver attachment and bonding. 
Maternal Postnatal Attachment Questionnaire (MPAQ)  
To assess if the ESC care approach, compared to usual care 
will improve maternal/caregiver sense of competency. 
Parenting Sense of Competence (PSOC) Scale  
To assess if the ESC care approach, compared to usual 
care, will improve the family environment.  
Family Environmental Scale (FES) - Relationship Dimension Form R  
To assess if the ESC care approach, compared to usual care 
will improve infant development.  
Bayley Scales of Infant and Toddler Development, Fourth Edition 
(Bayley 4): Cognitive, Language, and Motor,  
Brief Infant-Toddler Social and Emotional Assessment (BITSEA) 
a Assessed at various time points between discharge and 24 months of age (see Study Event Schedule, Table 4) 
* Secondary outcome of primary interest for the long-term outcomes portion of the study (see Section 4.3.2.2) 
- Accidental trauma 
- Respiratory insufficiency due to opioid therapy  
Outpatient composite 3-month safety outcome (present/absent) 
− 
Acute/urgent care and/or emergency room (ER) visits  
− 
Hospital readmissions 
Critical safety outcome at discharge, 3 and 24 months 
(present/absent) 
- 
Non-accidental trauma and death  

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 22 of 79 
Protocol Version #: 08   Date: 28-March-2022 
SECTION 2. 
CONFLICT OF INTEREST DISCLOSURES 
2.1. 
FINANCIAL CONFLICTS OF INTEREST OF THE INSTITUTIONS AND INVESTIGATORS 
The study investigators will have no financial conflicts of interest (FCOIs) related to the study outlined 
in this protocol. 
2.2. 
PLAN FOR MANAGING IDENTIFIED FINANCIAL CONFLICTS OF INTERESTS 
Any potential or perceived conflicts of interest, including FCOIs, per Title 42, Code of Federal 
Regulations, Part 50, Subpart F (50.604 Responsibilities of institutions regarding investigator FCOIs), as 
amended, requires institutional officials (and all subrecipients) to notify the grants officer of any FCOIs 
prior to expenditure of any funds and within 60 days of any subsequently identified FCOI. Institutional 
officials should also notify the National Institute of Child Health and Human Development, ECHO, and 
the IDeA States Pediatric Clinical Trials Network (ISPCTN) Leadership Committee at the same time 
regarding the COI management plan following institutional guidelines of each participating center.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 23 of 79 
Protocol Version #: 08   Date: 28-March-2022 
SECTION 3. 
STATEMENT OF PROBLEM 
3.1. 
PRIMARY HYPOTHESIS  
Among infants evaluated for NOWS, the ESC care approach will reduce the length of time until infants 
are medically ready for discharge by an average of 4 days, compared to usual institutional care with the 
FNAST or modification thereof. 
3.2. 
SECONDARY HYPOTHESIS  
Among infants evaluated for NOWS, use of the ESC care approach will result in an improvement in 
infant neurobehavioral functioning and family well-being, when compared to usual institutional care 
with the FNAST or modification thereof. 
3.3. 
BACKGROUND AND RATIONALE 
3.3.1. Public Health Impact 
Increased opioid use has resulted in a dramatic increase in the number of infants born with in utero 
opioid exposure requiring management for NOWS.2, 3, 4, 5 Despite the significance of this problem, 
numerous critical gaps remain in our knowledge with respect to the best practices for identification 
and management of infants with NOWS, as well as our understanding of the outcomes of these 
infants.6, 7 The opioid epidemic particularly impacts rural and underserved communities represented by 
the ISPCTN and participating Neonatal Research Network (NRN) sites, which makes our networks well 
poised to address these critical gaps and improve the care of infants with NOWS.  
3.3.2. Background  
3.3.2.1. 
Scope of the Problem 
The medical and non-medical use of opioids has increased substantially in women of childbearing age 
during the last decade.8 In the United States, medical professionals wrote and dispensed 259 million 
opioid prescriptions in 2012 alone, an average of 82.5 opioid prescriptions for every 100 persons.9 
Approximately 28% of privately insured and 39% of Medicaid-enrolled women between 15 and 44 
years of age filled an opioid prescription annually between 2008 and 2012.10 Every 3 minutes, a woman 
seeks care in an emergency department for prescription opioid misuse. In addition, illicit opioid abuse 
is also increasing dramatically.8 Nearly 600,000 Americans reported a substance-use disorder involving 
heroin in 2015, with the strongest risk factor for heroin use being a history of prescription opioid 
misuse.11, 4 The national rate of opioid use disorders in new mothers has quadrupled between 1999 
and 2014, increasing from 1.5 to 6.5 per 1000 deliveries.12, 13 
The increased use and misuse of opioids during pregnancy has directly resulted in a 5-fold increase in 
the incidence of NOWS between 2004 and 2014.14 A retrospective analysis of a National Inpatient 
Sample showed that, among infants covered by Medicaid, the incidence of NOWS increased from 2.8 
to 14.4 per 1000 births during this same period.14 Additionally, analysis of an administrative database 
of 23 hospitals from 2013-2016 demonstrated a continued increase in the incidence of NOWS to 20 per 
1000 live births.15 Significant regional variation in the incidence of NOWS has been noted, with the 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 24 of 79 
Protocol Version #: 08   Date: 28-March-2022 
highest rates seen in the Northeast and Southeast regions of the United States.2 Researchers have 
found an increased incidence of infants with NOWS born to mothers who have high rates of long-term 
unemployment or who live in mental health shortage areas.16 Rural areas are disproportionately 
affected by NOWS, with twice the rate of growth in the number of hospital deliveries complicated by 
maternal opioid abuse in rural communities compared with the rate of growth in urban communities 
between 2004-2013.17 The proportion of infants with NOWS born into rural communities increased 
from 12.9% in 2003 to 21.2% in 2013.17 Therefore, improving care for infants with NOWS will 
particularly impact the rural areas served by many ISPCTN and NRN sites. Additionally, compared with 
their urban peers, rural infants affected by perinatal opioid misuse are more likely to come from lower-
income families who have public insurance.17 Nationally, state Medicaid programs enroll 60% of 
mothers with perinatal substance use and more than 80% of infants with NOWS.2, 3  
3.3.2.2. 
Recognition and Assessment of Neonatal Opioid Withdrawal Syndrome 
Some infants with in utero opioid exposure may have mild signs of NOWS that do not significantly 
impact the infant’s ability to feed, sleep, and function, while others may have more severe signs that 
require pharmacologic therapy to avoid negative effects on growth and development.18 Physicians use 
observer-rated scales in clinical practice to quantify the severity of withdrawal and to guide 
pharmacotherapy.5 Yet, current scales have not undergone rigorous instrument development and 
validation.19, 20 Ninety-five percent of institutions in the United States use the FNAST, with its various 
modifications.21 Preliminary data from the ACT NOW Current Experience Study, a chart review 
conducted at 25 sites within the ISPCTN and 5 sites within the NRN, found that all 30 participating sites 
used the FNAST or a modification of the FNAST for the assessment of infants with NOWS as part of 
usual institutional care. Loretta Finnegan developed the FNAST in 1975, and medical personnel 
currently use this and several modified versions. The tool was initially found to have an inter-rater 
reliability (IRR) of 0.82 (0.75-0.96), but it has not been subsequently validated for the evaluation of 
infants with NOWS, although researchers have studied normative values in newborns unexposed to 
maternal substances.22 Researchers and clinicians remain concerned about the length of the tool,23, 24 
its inherent subjectivity,25 and the need to disturb infants for formal assessments.26 In addition, 
investigators have concerns that the FNAST and modifications of the FNAST may overestimate the 
need for pharmacologic therapy, as the formal score incorporates all signs of withdrawal, including 
those that may not be clinically significant. This overestimation has been linked to increased length of 
hospital stay and hospital costs.27 
The ESC Care Tool is an alternative assessment and management tool developed and subsequently 
implemented at several sites as part of quality improvement (QI) initiatives based on the original ESC 
approach developed by Grossman and colleagues at Yale.26 The ESC Care Tool uses a non-invasive, 
simplified, function-based assessment that evaluates the infant based on his/her ability to eat, sleep, 
and be consoled. The tool's design provides continued emphases on the role of the family/caregiver in 
the assessment and care provided for their infants and on non-pharmacologic care as the first-line 
treatment for infants with NOWS. If an infant is able to feed effectively within 10 minutes of showing 
hunger (breast-feed well x 10 minutes or take 10 mL [or age-appropriate volume] by alternative 
feeding method), to sleep undisturbed for 1 hour or longer, and is able to be consoled within 10 
minutes, pharmacologic treatment is not initiated or escalated. If the care team assesses that the 
infant is having difficulties in one of these areas related to NOWS, the care team first attempts to 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 25 of 79 
Protocol Version #: 08   Date: 28-March-2022 
optimize non-pharmacologic interventions. If these attempts are unsuccessful, the care team will 
initiate or escalate pharmacologic therapy. 
3.3.2.3. 
Initial Eating, Sleeping, Consoling Approach 
The ESC approach, an approach that emphasizes parental involvement, simplifies the assessment of 
infants with NOWS, and focuses interventions on non-pharmacologic therapies, began its evolution at 
Yale-New Haven Children’s Hospital over a 5-year period of QI work. During this time, the proportion of 
infants prenatally exposed to methadone who received pharmacologic treatment for NOWS decreased 
significantly from 98% (54 out of 55 infants) in the baseline period (January 2008-February 2010) to 
14% (6 out of 44 infants) in the post-intervention period (May 2015-June 2016), P < 0.001. The average 
length of stay (LOS) for these infants also decreased significantly from 22 to 6 days (P < 0.001).26 There 
were no reported seizures during the initial birth hospitalization or need for readmission within 30 
days of discharge related to signs of withdrawal for the post-intervention group. Although the results 
of this QI work appear quite impressive, it is unclear how generalizable this work is, as the pre-
intervention rate of pharmacologic treatment was much higher than national estimates at 98% of 
methadone-exposed infants.5 Additionally many infants with NOWS are exposed to opioids other than 
methadone (e.g., buprenorphine and illicit opioids). 
On direct comparison, Yale-New Haven’s ESC approach, studied as a QI measure, appears to trigger the 
initiation of opioid replacement therapy for significantly fewer infants than use of the FNAST approach. 
The Yale group, following their transition to ESC-based assessments, completed a retrospective 
comparison of treatment decisions for 50 consecutive opioid exposed infants (March 2014-Aug 
2015).27 These infants had FNAST scores recorded every 2 to 6 hours, but clinical personnel managed 
these infants based on their ESC assessments alone. Management decisions based on the ESC 
assessment resulted in morphine initiation for 6 infants (12%), compared with 31 infants (62%) who 
medical professionals would have treated using the FNAST (P < 0.001). Additionally, using the ESC-
based assessments, medical personnel initiated or increased morphine on 8 patient days (3%), 
compared with 76 patient days (26%) predicted using the FNAST (P < 0.001).27 Again, the study 
reported no readmissions or adverse events (AEs).  
3.3.2.4. 
Eating, Sleeping, Consoling Care Tool Development  
Other groups have subsequently worked to standardize implementation of the assessment and 
management components of the ESC care approach, through the development and testing of a formal 
ESC Care Tool. Initial evaluation of the assessment component of the ESC Care Tool, using standardized 
training and simulated case scenarios, has demonstrated high inter- and intra-rater reliability.28 
Training in the use of the ESC Care Tool and the overall care approach, with standardized training 
materials, continues to be evaluated and improved, allowing for feasible implementation in even small 
community hospitals. Faculty at Children’s Hospital at Dartmouth-Hitchcock Medical Center, Boston 
Medical Center, and Yale-New Haven Children’s Hospital collaborated to develop training materials, 
including ESC Care Tool with definitions (see Training & Implementation Manual), Newborn Care Diary 
(see Training & Implementation Manual), ESC training video, and written and videotaped case 
scenarios with answer key. Sites within The Northern New England Perinatal Quality Improvement 
Network are currently using these materials to facilitate training as part of a network-wide QI initiative.  

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 26 of 79 
Protocol Version #: 08   Date: 28-March-2022 
Physicians at one of the institutions involved in these development efforts, recently published on their 
QI results following implementation of the ESC care approach. This institution utilized a pilot version of 
the ESC Care Tool and showed more modest but consistent findings to those at Yale. The researchers 
found a decrease in pharmacologic treatment from 87% to 40% and a reduction in LOS from 17 to 
11 days, with no AEs noted.29  
3.3.2.5. 
Further Study 
Although outcomes following implementation of the ESC care approach, inclusive of the ESC Care Tool, 
appear promising and initial accounts suggest that it is safe, we need to rigorously study this care 
approach to show safety, efficacy, and generalizability of its use in the care of infants with NOWS. 
Reports on the ESC care approach to date have been from hospitals where the majority of the mothers 
are compliant with medication-assisted treatment and are highly motivated to care for their infants. 
Furthermore, the potential effects of the care provided, using the ESC care approach, on infant and 
family well-being after discharge are unknown and important to assess.6, 30 In the proposed trial, 
comparison of the short- and long-term outcomes for infants managed with the ESC care approach 
versus those managed with usual care will move us closer to an evidence-based approach for the 
evaluation and management of infants with NOWS, thus meeting a top research priority in the field.6, 7  
Justification of Hypotheses 
• We hypothesize that use of the ESC care approach for the evaluation and management of 
infants with NOWS will safely reduce the average length of time until infants are medically 
ready for discharge, compared with usual care with the FNAST or modification thereof. We 
selected the primary outcome, average length of time until infants are medically ready for 
discharge, due to the potential for infants to remain in the hospital beyond this point because 
of social factors and the previously described potential impact of and link between a reduction 
in hospital stay and the following: 
o Improved maternal and infant attachment/bonding31, 32 
o Decreased hospital complications 
o Increased benefit to society in reduced healthcare costs3, 14, 33  
Additionally, we hypothesize that use of the ESC care approach will have minimal to no impact on 
infant safety, while resulting in the following outcomes: 
• Reduction in the need for initiation of opioid replacement therapy (i.e., morphine, methadone, 
or buprenorphine) 
• Decrease in the total postnatal opioid exposure 
• Improvement in the timeliness to initiation of opioid replacement therapy, when required 
• Decrease in the need for adjuvant therapy 
• Increase in the proportion of infants who directly breastfeed 
• Increase in the proportion of infants receiving their mothers’ own breastmilk  
We also hypothesize that use of the ESC care approach will improve postnatal attachment and 
bonding, and will enhance infant well-being and neurobehavioral functioning and development 
compared to usual care. Further, we hypothesize that use of the ESC care approach will enhance 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 27 of 79 
Protocol Version #: 08   Date: 28-March-2022 
maternal well-being and the family environment after discharge. An important component of the ESC 
care approach is the reported fostering of a collaborative relationship between the primary 
caregiver(s) and the inpatient clinical team through the co-assessment of the infant’s severity of 
withdrawal and shared treatment plan development. Interviews conducted with families as part of the 
QI implementation of the ESC Care Tool consistently suggest that this element may reduce the social 
and emotional impact of the infant’s hospitalization on the family. However, while many families 
expressed feeling like they were an integral part of their infants’ care team and reported decreased 
anxiety and reduction in stigma during the initial birth hospitalization,34 these families were poised to 
actively participate in the care of their infants, and such results may not be consistent across all 
families/caregivers. Thus, we must consider that families/caregivers who are not as well poised to 
actively participate in the care of their infants may experience more stress if their infants are 
discharged home earlier.  
Our assessment of key markers of infant and family well-being in the subpopulation of infants whose 
caregiver(s) provide informed consent will allow for further insight into safety. This will also provide an 
opportunity to examine not only often-assessed intermediate outcome variables (time until medically 
ready for discharge and need for opioid replacement therapy), but also to examine longer-term 
outcomes, such as infant neurobehavioral functioning and development, maternal-infant attachment 
and bonding, and family well-being and functioning.  
Justification of Study Design 
The protocol study team selected a stepped-wedge cluster design due to three main considerations:  
1. Transition to the ESC care approach requires a significant cultural shift in the management of 
infants with NOWS. This type of cultural change is most effective when applied at the level of 
the population covered by the hospital and not on a subset of random infants with NOWS 
within the hospital, thus making a cluster study design important.  
2. Interim analysis of the ACT NOW Current Experience study allowed for estimation of an 
intracluster correlation coefficient (ICC) based on the LOS outcome measure. Using LOS as a 
proxy for our primary outcome, time until infant is medically ready for discharge, the number of 
sites required to adequately power the trial based on a parallel cluster design with estimated 
ICC=0.25 would be prohibitive. The stepped wedge design makes the study feasible by allowing 
each site to serve as its own control in a pre/post analysis and thus, the variation between sites 
is of less statistical significance.  
3. Additionally, the results of QI projects have inspired many healthcare providers to consider 
transition to the ESC care approach. A brief questionnaire, sent to investigators at the available 
study sites, demonstrated an increased willingness to participate in the trial if we integrated a 
transition to the ESC care approach into the study design.  
 
For these reasons, the protocol study team has designed a stepped-wedge cluster randomized trial 
with the intervention applied at a cluster level and applied to all participating sites by the end of the 
20-month study period, with the timing of transition to ESC randomized. This study design also allows 
for differentiation between the effect of the intervention and unanticipated time-related confounders.  
 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 28 of 79 
Protocol Version #: 08   Date: 28-March-2022 
SECTION 4. 
METHODS 
4.1. 
STUDY POPULATION 
4.1.1. Inclusion Criteria 
4.1.1.1. 
Site Level  
1. The site is willing, able, and has nurse management and administrative commitment to 
transition to the ESC care approach at the randomly allocated time 
2. The site currently uses the FNAST or modification thereof for the assessment of withdrawal 
severity for infants with NOWS 
3. The site currently provides opioid replacement therapy (i.e., morphine, methadone, or 
buprenorphine) for the pharmacologic management of infants with NOWS 
4.1.1.2. 
Infant Level 
1. The infant is being managed for NOWS at an eligible site (i.e., receiving non-pharmacologic 
care, assessments for withdrawal severity, +/- pharmacologic care) 
2. The infant is ≥ 36 weeks gestation  
3. The infant satisfies at least 1 of the following criteria: 
a. Maternal history of prenatal opioid use  
b. Maternal toxicology screen positive for opioids during the second and/or third trimester 
of pregnancy 
c. Infant toxicology screen positive for opioids during the initial hospital stay 
4.1.2. Exclusion Criteria 
4.1.2.1. 
Site Level 
1. The site currently manages < 20 opioid-exposed infants annually  
2. The site routinely discharges/transfers infants from the hospital on opioid replacement therapy 
(i.e., morphine, methadone, or buprenorphine). We define routine discharge/transfer as ≥10% 
of infants who receive opioid replacement therapy for NOWS at the site 
4.1.2.2. 
Infant Level 
1. Infant has major birth defect(s)  
2. Infant has neonatal encephalopathy (inclusive of hypoxic ischemic encephalopathy), a 
metabolic disorder, stroke, intracranial hemorrhage, or meningitis diagnosed by 60 hours of life 
3. Infant was receiving respiratory support (any positive pressure or oxygen therapy) unrelated to 
pharmacologic treatment for NOWS at 60 hours of life  
4. Infant was receiving antimicrobial(s) at 60 hours of life  
5. Infant has received any major surgical intervention in the first 60 hours of life 
6. Postnatal opioid exposure other than for treatment of NOWS in the first 60 hours of life 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 29 of 79 
Protocol Version #: 08   Date: 28-March-2022 
7. Outborn infants transferred at >60 hours of life or treated with opioids for NOWS at the 
transferring hospital  
8. Infant’s biological mother or primary caregiver is positive or under investigation for COVID-19 at 
60 hours of life 
 
4.1.2.3. 
Additional Infant-level Exclusion Criteria for Consented Portion of the Study   
1.  Infant’s primary caregiver does not speak, read or write English.  

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 30 of 79 
Protocol Version #: 08   Date: 28-March-2022 
 
4.2. 
DETAILED STUDY PROCEDURES 
Table 4 outlines study procedures from the initial hospital stay through 24 months. 
Table 4 
Study Event Schedule 
Evaluation/Procedures 
Hospital 
Stay 
Hospital 
Discharge 
1 month 
(post 
discharge) 
3 months 
of age*  
6 months 
of age* 
9 months 
of age* 
12 months 
 of age* 
18 months  
of age* 
24 months 
of age* 
Maternal and infant medical history 
X 
 
 
 
 
 
 
 
 
Neonatal opioid withdrawal scoring/assessments 
X 
 
 
 
 
 
 
 
 
Date/time of initiation and number of doses of 
opioid 
replacement 
therapy 
administered 
(Infant)  
X 
 
 
 
 
 
 
 
 
Date/time of initiation dose and number of doses 
of adjuvant therapy administered (Infant) 
X 
 
 
 
 
 
 
 
 
Date/time when medically ready for discharge 
(Infant) 
X 
 
 
 
 
 
 
 
 
Date/time discharged (Infant) 
 
X 
 
 
 
 
 
 
 
Weight, length and head circumference (Infant) 
X 
X 
 
 
 
 
 
 
O 
Feeding type (Infant)  
X 
X 
 
 
 
 
 
 
 
Seizures, accidental trauma (i.e., dropped 
infants) and respiratory insufficiency (Infant)  
X 
X 
 
 
 
 
 
 
 
Serious Adverse Events (Infant) 
X 
X 
 
 
 
 
 
 
 
Acute/urgent care and/or ER visits and hospital 
readmissions 
 
 
 
X 
 
 
 
 
 
Non-accidental trauma & death (Infant)  
 
X 
 
X 
 
 
 
 
X 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 31 of 79 
Protocol Version #: 08   Date: 28-March-2022 
Evaluation/Procedures 
Hospital 
Stay 
Hospital 
Discharge 
1 month 
(post 
discharge) 
3 months 
of age*  
6 months 
of age* 
9 months 
of age* 
12 months 
 of age* 
18 months  
of age* 
24 months 
of age* 
Infant Behavioral Questionnaire (IBQ) – very 
short form (Infant) 
 
 
 
O 
 
 
O 
 
 
Caregiver questionnaire (CQ) (enteral feeds, 
acute/urgent care and/or ER visits and 
readmissions) (Infant) 
 
 
O 
O 
O 
 
O 
 
O 
Brief Infant Sleep Questionnaire (BISQ) (Infant) 
 
 
 
O 
 
 
O 
 
 
Patient Reported Outcome Measurement 
Information System (PROMIS) Short Forms 
(Caregiver(s))  
 
O 
 
 
O 
 
 
 
O 
Maternal Postnatal Attachment Questionnaire 
(MPAQ) (Caregiver(s)) 
 
O 
 
 
O 
 
 
 
 
Parenting Sense of Competence Scale (PSOC) 
(Caregiver(s)) 
 
O 
 
 
O 
 
 
 
 
Adverse Childhood Experiences (ACE) 
questionnaire 
 
 
 
 
 
 
 
 
O 
Family Environmental Scale (FES) – Relationship 
Dimension Form R (Caregiver(s))  
 
 
 
O 
 
 
 
 
 
Bayley Scales of Infant and Toddler 
Development, Fourth Edition (Bayley-4): 
Cognitive, Language, Motor,  
 
 
 
 
 
 
 
 
O 
Brief Infant-Toddler Social and Emotional 
Assessment (BITSEA) 
 
 
 
 
 
 
 
 
O 
Contact information update  
O 
O 
O 
O 
O 
O 
O 
O 
 
 
 
(X) Evaluations/procedures assessed under waiver of consent  
(O) Evaluations/procedures performed with informed consent  
*Procedures occurring at ≤12 months of age may occur within ±3 weeks of stated time point.  
   Procedures occurring at 18  months of age may occur within ±6 weeks of stated time point;   
   Procedures at 24 months of age may occur within ±8 weeks of stated time point. 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 32 of 79 
Protocol Version #: 08   Date: 28-March-2022 
 
4.2.1. Screening 
The protocol study team will screen interested sites for eligibility, and will randomize eligible sites into 
one of 8 blocks, as illustrated in Table 1. With this study design, all infants with NOWS cared for at a 
site, will be evaluated and managed using the care approach that the site is assigned to during the 
study period. Therefore, individual infant screening will not be required before initiation of this study 
protocol. The process will be as follows (see Figure 1), after birth the inpatient clinical team will assess 
infants as at risk for NOWS and initiate management for NOWS based on the site’s usual methods of 
identification. The initiation of clinical management for infants with NOWS will not be impacted by the 
study intervention. The site research team will identify potential participants for the trial based on 
their eligibility following review of the medical record after delivery. The site research team may obtain 
informed consent for infant and caregiver participation in the long-term outcomes portion of the study 
at any point during the hospital stay for infants who meet the trial’s inclusion criteria. The site research 
team will evaluate for exclusion criteria (Section 4.1) after the infant’s first 60 hours of life. The site 
research team will note infants as screen fails who meet any of the exclusion criteria, and will not 
collect additional data for these infants. Sites may enroll up to 16 infants per period; screen fails are 
not included in this total. Only infants enrolled in the study may be approached for consent and 
included in the long-term follow-up study.  
 
 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 33 of 79 
Protocol Version #: 08   Date: 28-March-2022 
Figure 1 
Screening and Enrollment Procedures  
  
Infant is delivered or 
transferred to the site
Infant assessed by the 
site as needing 
management for NOWS 
as per usual site practice
Infant is managed for 
NOWS per site 
allocation 
After 60 hours of life, the 
site research team will 
assess for exclusion 
criteria. Infants meeting 
any exclusion criteria will 
be considered screen fails 
and not included in the 
study 
Included 
Infant is managed for NOWS 
per site allocation. Data is 
collected and consent is 
obtained* before discharge for 
the long-term follow-up study 
Non-included/Screen fails 
Infant is managed for NOWS 
per site allocation
Infant is discharged as 
per usual site practice
The site research team will 
screen the infant for study 
eligibility, based on inclusion 
criteria, and will begin data 
collection 
*The site research team may obtain consent for the long-term follow-up portion of the study at any point 
during the hospital stay for infants who meet the trial’s inclusion criteria. To optimize recruitment, it will  be 
permissible to obtain initial consent up to one month after discharge. 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 34 of 79 
Protocol Version #: 08   Date: 28-March-2022 
4.2.2. Consent Procedures 
4.2.2.1. 
Waiver of Consent 
Since this study is a stepped-wedge cluster randomized controlled trial, the intervention will take place 
on a site-wide basis and sites will transition their practice for all infants with NOWS cared for at the site 
during the study period. Thus, we will request a waiver of consent from the central institutional review 
board (IRB) at the University of Arkansas for Medical Sciences for the primary outcome and previously 
outlined short-term secondary outcomes. There is debate in the clinical trial and ethics literature about 
the issue of individual consent for cluster-randomized trials. However, in general, a study may proceed 
without individual consent if conditions for a waiver of consent are satisfied and participants (or legally 
authorized representatives) are provided with a description of the intervention to which their cluster 
has been randomized.35  
As stated in Code of Federal Regulations [45 CFR 46.116 (d)], an IRB may approve a consent procedure 
that does not include, or that alters, some or all of the elements of informed consent set forth in this 
section, or waive the requirements to obtain informed consent, provided the IRB finds and documents 
that all of the following conditions are met:  
1. The research involves no more than minimal risk to the participants;  
2. The waiver or alteration will not adversely affect the rights and welfare of the participants;  
3. The research could not practicably be carried out without the waiver or alteration; and  
4. Whenever appropriate, the study team will provide participants with additional pertinent 
information after participation. 
The justification for a waiver of informed consent from caregiver(s) for the previously outlined short-
term outcomes (see Table 2) meets the above criteria per the following:  
1. The research involves no more than minimal risk to the participants.  
Both usual care using the FNAST and the ESC care approaches are currently used at sites across 
the country, and the optimal care approach for the management of infants with NOWS is 
unknown. Additionally, there are no study procedures or study interventions within this 
protocol that would qualify as more than minimal risk, based on federal regulations, for either 
intervention group.  
2. The waiver or alteration will not adversely affect the rights and welfare of the participants.  
As the best management for infants with NOWS is unknown, there is no universally accepted 
standard of care, and both care approaches are currently being used at sites across the country. 
Therefore, participants receiving care via either model should not have their rights and welfare 
adversely affected.  
3. The site research team could not practicably carry out this trial without the waiver or alteration.  
Carrying out this trial and obtaining generalizable results would not be feasible if obtaining 
informed consent were required. Obtaining informed consent from legally authorized 
representatives of infants in this population is difficult due to multiple factors. The 
interventions conducted in this study begin shortly after birth and recruitment during this 
vulnerable period can be extremely difficult. Researchers have experienced this difficulty in a 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 35 of 79 
Protocol Version #: 08   Date: 28-March-2022 
number of trials that have failed to successfully recruit this population shortly after birth.36, 37, 38 
Seeking consent shortly after delivery may not only result in recruitment failure, but may result 
in achieving consent only among a less generalizable group of “responders”, which may 
introduce bias and diminish generalizability. This could be particularly problematic in this trial 
where the success of the intervention may be particularly susceptible to caregiver effort and 
engagement.  
Seeking consent later in the hospital stay for the long-term follow-up portion of the study will 
allow for relationship and trust building between the consenting member of the site research 
team and the primary caregiver(s). This will likely allow for improved consent rates and 
improved generalizability. If consenting members of the site research team sought early 
consent and only a group of “responders” were consented, it is unclear whether this would 
have a differential impact across the study interventions. Additionally, the intervention is 
instituted at the site level and will represent a culture change. The site will use the assigned 
approach to care for all infants with NOWS during the trial period. Therefore, if consent were 
required, obtaining consent would not alter the care approach used for the infant. Thus, the 
benefits afforded by using a waiver of consent outweigh the risks to the infant receiving the 
same management. If the clinical team used two different care models at the same time and at 
the same site, patient safety could be at risk and care potentially compromised due to the use 
of inconsistent care practices at the site.  
4. Whenever appropriate the study team will provide participants with additional pertinent 
information after participation.  
Throughout the study, the site research team will provide participants with additional pertinent 
information when appropriate. The protocol study team will develop a handout that the site 
research team will (a) give to the caregiver(s) of all infants with NOWS cared for at the site 
throughout the study period and/or (b) post (as an enlarged copy) in appropriate location(s) 
readily visible to caregivers. This will fulfill the suggested framework35 of participants being 
“provided with a detailed description of the interventions to which their cluster has been 
randomized.”  
4.2.2.2. 
Consent for Assessment of Long-term Outcomes 
Members of the site research team will work with families/caregivers to obtain informed consent for: 
1) parent/caregiver questionnaires that will assess caregiver well-being (e.g., parenting stress, 
attachment and bonding, depression, anxiety, etc.) and infant well-being (e.g., diet, sleep, 
neurobehavioral functioning, etc.), and 2) in-person follow-up visit at 24 months to assess 
neurodevelopmental outcomes and growth measures. Consent will contain basic information on 
recognition and support (consistent with regulatory requirements at each site) for mental health issues 
including suicidality among caregivers. The consent will also contain basic information on notification 
of child protective services (consistent with state law) should researchers or members of the clinical 
team have suspicion of child neglect or abuse. The site research team will obtain written, informed 
consent from primary caregiver(s) (e.g., biological parents, adoptive parents, or state-appointed 
guardians) prior to administration of the first questionnaire.  
Per section, 4.5.2.1., Recruitment, participants may be consented up to 1 month after discharge.  To 
facilitate this process, and due to the ongoing COVID-19 pandemic, remote consenting will be allowed.   

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 36 of 79 
Protocol Version #: 08   Date: 28-March-2022 
All communications will be done via HIPAA-compliant methods such as telephone, personal delivery of 
documents, US postal service, REDCap or other compliant electronic platform.  The remote consent 
process will parallel the consent processed used for in-person consenting.  The only difference will be 
the method(s) of communication.  The study team will ensure that, as with in-person consenting, the 
participant is given sufficient opportunity to ask questions, is able to understand the nature of this 
study and what participation entails, and is provided a copy of the final, completed consent signed by 
all parties involved, including the research team member who obtained consent and, when applicable, 
the site investigator. This final, signed consent will be provided via a HIPAA-compliant method or a 
method that the participant has agreed to in writing.  The site research team members working on the 
consenting process will ensure that any participant who is consenting remotely has the authority to 
consent. 
4.2.2.3. 
Detailing Barriers to Consent and Participation  
The site research team will ask non-consenting parents/caregivers to answer questions specific to 
perceived or actual barriers to participation and their choice not to be involved in the long-term 
outcome portion of the study. The site research team will inform non-consenting parents/caregivers 
about the purpose of these questions and that they are not required to answer them. The site research 
team will record responses without linking identifiers. The protocol study team will not permit an 
amendment of the consent form for previously non-consenting parents/caregivers that wish to 
consent following these questions. The protocol study team will use the data collected to improve site-
specific and study-wide recruitment strategies for this trial and to inform future trials in this field.  
4.2.3. Randomization Procedures  
This is a stepped-wedge cluster randomized design with a transition period wherein we will randomize 
participating study sites, rather than individual infants. All sites will implement the ESC care approach 
at some point during the trial; the random elements are two-fold: 1) randomization into the blocks, 
and 2) randomization of blocks to the time point at which each block implements the ESC care 
approach, the so-called “step” of the stepped-wedge design.  
A statistician at the independent Data Coordinating Center (DCC) for the trial will generate a 
randomization list using SAS 9.4 (SAS Institute Inc., Cary, NC). The protocol study team will use the 
proportion of infants with NOWS treated pharmacologically at each site as the variable to stratify 
randomization (i.e., lowest 3rd, middle 3rd, highest 3rd). The protocol study team will identify this 
proportion using the results of the ACT NOW Current Experience Protocol, a retrospective data 
collection that details the inpatient identification, assessment, and management of infants with NOWS 
at the ISPCTN and participating NRN sites. The protocol study team will conduct a brief survey to 
obtain similar estimates from other interested sites. The protocol study team will randomize sites in 
each stratum into one of 8 blocks (Figure 2). Once the protocol study team randomizes each site into 
blocks, computer-generated random numbers from a uniform distribution will determine the order in 
which the block of sites step into the transition and implementation period for the ESC care approach. 
The DCC will hold the randomization list. Due to the nature of a stepped-wedge cluster randomized 
controlled trial, the protocol study team can only enforce limited blinding. The protocol study team will 
notify sites of their allocated block following randomization.  

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 37 of 79 
Protocol Version #: 08   Date: 28-March-2022 
Integration of the ESC care approach is a complex process and training of the hospital staff will be time-
intensive. Thus, we expect to observe no quantifiable effects on the outcomes of interest during the 
transition period. Hence, this study has a planned transition period. The site research team will collect 
data on primary and secondary outcomes for all study periods, excluding the transition period. As this 
trial has sufficient power, we have planned for the transition period to be 3 months in duration to 
allow for adequate time for training and implementation at the sites. To maintain this, the preceding 
usual care period and the initial ESC period will each be 1.5 months/6 weeks in duration.  
 
 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 38 of 79 
Protocol Version #: 08   Date: 28-March-2022 
Figure 2 
Randomization Flow Diagram 
 
 
 
 
4.2.4. Study Intervention and Comparison  
All sites will provide usual institutional care, including the use of the FNAST, or modification thereof, 
for the evaluation and management of infants with NOWS during Period 1 (see Table 1). After the first 
period, the sites in Block 1 (3 - 4 sites) will move into the transition period. During the transition period, 
sites will participate in education and training modules conducted through a centralized training 
platform. The protocol study team will standardize education and training across sites during each 
block’s designated transition period. Educational modules will include an introduction and overview of 
the ESC care approach, education on trauma informed care and bias, and a general review on caring 
for infants with NOWS and the importance of non-pharmacologic care. Training will occur in a train-
the-trainer format, and will include off-site or teleconference ESC training for a core group of site 
champions with subsequent on-site training of clinical personnel. Following the transition period, sites 
within Block 1 will move into the first ESC period and each of the other blocks will move into their next 
designated intervention period. The site research team will collect data during all intervention periods 
of the study and make comparisons between these interventions (usual care versus ESC care 
approach). 
 
 
 
Retrospective baseline data collection through ACT 
NOW Current Experience Study 
(hospital volume of infants with NOWS, hospital 
level, percentage of non-pharmacologic treatment) 
Recruitment Sites = Approximately 24  
Stratified randomization of sites to groups based on 
the proportion of infants treated pharmacologically 
Lowest 3rd 
Block 1 = 𝑁𝑁1,𝐿𝐿 
Block 2 = 𝑁𝑁2,𝐿𝐿 
Block 3 = 𝑁𝑁3,𝐿𝐿 
Block 4 = 𝑁𝑁4,𝐿𝐿 
Block 5 = 𝑁𝑁5,𝐿𝐿 
Block 6 = 𝑁𝑁6,𝐿𝐿 
Block 7 = 𝑁𝑁7,𝐿𝐿 
Block 8 = 𝑁𝑁8,𝐿𝐿 
 Designate each site as low, medium, or 
high based on the proportion of infants 
with NOWS treated pharmacologically 
Middle 3rd 
Block 1 = 𝑁𝑁1,𝑀𝑀 
Block 2 = 𝑁𝑁2,𝑀𝑀 
Block 3 = 𝑁𝑁3,𝑀𝑀 
Block 4 = 𝑁𝑁4,𝑀𝑀 
Block 5 = 𝑁𝑁5,𝑀𝑀 
Block 6 = 𝑁𝑁6,𝑀𝑀 
Block 7 = 𝑁𝑁7,𝑀𝑀 
Block 8 = 𝑁𝑁8,𝑀𝑀 
Highest 3rd 
Block 1 = 𝑁𝑁1,𝐻𝐻 
Block 2 = 𝑁𝑁2,𝐻𝐻 
Block 3 = 𝑁𝑁3,𝐻𝐻 
Block 4 = 𝑁𝑁4,𝐻𝐻 
Block 5 = 𝑁𝑁5,𝐻𝐻 
Block 6 = 𝑁𝑁6,𝐻𝐻 
Block 7 = 𝑁𝑁7,𝐻𝐻 
Block 8 = 𝑁𝑁8,𝐻𝐻 
RANDOMIZATION 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 39 of 79 
Protocol Version #: 08   Date: 28-March-2022 
4.2.4.1. 
Usual Institutional Care Periods 
Intervention  
• Following delivery or transfer, the care team will initiate care for NOWS per usual practice. The 
clinical team will use institutional practices and protocols to guide non-pharmacologic care, to 
assess the infant using the FNAST or modification thereof, and to guide pharmacologic care.  
• If needed, the clinical team will initiate pharmacologic treatment per the site’s usual practice 
and/or treatment protocol, and escalation, weaning, and discontinuation of pharmacologic care 
will be per the site’s usual care. Opioid replacement therapy given (morphine, methadone, or 
buprenorphine) will be per site preference, as will adjuvant therapy used (clonidine or 
phenobarbital). 
• The clinical team will monitor each infant requiring opioid replacement therapy for signs of 
escalating withdrawal symptoms following discontinuation of this treatment and will consider 
discharge per the site’s usual practice.  
• The clinical team will use FNAST or modification thereof to assess infants after birth and 
consider discharge for infants who do not require pharmacologic treatment per the site’s usual 
practice. 
• The DCC will develop a monitoring plan for each site’s compliance with usual care during this 
period. 
• Infants with antenatal opioid exposure born or transferred to the site during the usual 
institutional care intervention will be managed per this care approach throughout their 
admission (this includes infants who remain admitted when the site enters the transition 
period), and the site research team will collect their data and use it for the study analysis. 
4.2.4.2. 
Transition Periods 
Intervention 
Education  
• All research and clinical nurses, advanced practice providers, and physicians who care for 
infants with NOWS at each participating site will complete educational modules. These modules 
will include an introduction and overview of the ESC care approach, education on trauma 
informed care and bias, and a general review specific to caring for infants with NOWS. The 
latter will include an emphasis on the importance of non-pharmacologic care, as well as on the 
importance of differentiating the etiology of symptoms common to NOWS. 
• The protocol study team will assess completion of these modules.  
Training and Implementation 
• The protocol study team will conduct all training in a train-the-trainer format supported by 
nationally known clinical experts.  
• The protocol study team will train a core group of site champions, which may include research 
and clinical nurses and physicians, in the use of the ESC care approach during the designated 
transition period. Education and training on the optimal use of the ESC care approach will 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 40 of 79 
Protocol Version #: 08   Date: 28-March-2022 
include an introduction and overview of the ESC care approach, review of the ESC Care Tool 
with definitions and Newborn Care Diary, ESC training video, and review of written and 
videotaped case scenarios. The site champions will access the components of this training 
through the educational platform, and the protocol study team will track completion through 
pre/post assessments. The protocol study team will provide an electronic copy of the ESC 
Training and Implementation Manual for each site in anticipation of entry into the transition 
period.  
• After the training, the core group of site champions will view and score cases until each 
member of the group consistently attains 100% reliability on standardized patient assessment 
cases (6/6 items). We define this as three consecutive assessments with 100% reliability as 
compared to national experts in the field. Once consistently achieving 100% reliability, the 
protocol study team will consider these individuals the "gold-star raters."  
• This core group will train all other clinical personnel who care for infants with NOWS at their 
site, including, but not limited to, nurses, advanced practice providers, and physicians in all 
areas where these infants receive care. These areas may include, but are not limited to, the 
well-baby nursery, pediatric unit, and neonatal intensive care unit. After the training, clinical 
personnel will view and assess cases using the ESC IRR tool (see Training & Implementation 
Manual) until clinical personnel consistently achieve 80% agreement (5/6 items). Once a 
member of the clinical team reaches 80% IRR, the site research team will clear the trainee for 
independent assessment. If the trainee consistently achieves 100% reliability, the site research 
team will consider him/her to be a “gold-star rater”, and may ask the trainee to function in this 
capacity. Site staffing levels will determine the number of “gold-star raters" at a site, with the 
goal of having one “gold-star rater” available on each shift. The protocol study team will require 
clinical personnel who are unable to attain 80% reliability to complete supplementary training. 
Clinical personnel hired after the initial training will complete the educational modules and ESC 
training at the site inclusive of assessing cases using the ESC IRR tool to demonstrate 80% 
agreement.  
• To ensure fidelity of the assessments, the site research team will assess the reliability of “gold-
star raters” at each site during the implementation phase of the transition period (see Training 
& Implementation Manual). The protocol study team anticipates each “gold-star rater” will 
maintain 100% reliability in scoring on patient assessment cases. The “gold-star raters” will then 
gauge reliability of the clinical team by assessing individuals during the implementation phase 
by using the ESC IRR tool and written or video case scenarios (see Training and Implementation 
Manual).  For clinical personnel who fail to maintain the target of 80% reliability in scoring 
during the implementation phase of the transition period, the site research team will utilize 
just-in-time training through a centralized training platform until he/she achieves 80% reliability 
in assessments. When staffing allows, members of the care team who have reliability less than 
80% should not be assigned to care for infants with NOWS until improved reliability is 
demonstrated through the just-in-time training process.  
• Infants with antenatal opioid exposure born or transferred to the site during the transition 
period but before the site has implemented ESC, will be managed with usual institutional care. 
Once a site implements ESC, the site will manage all infants born or transferred to the site with 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 41 of 79 
Protocol Version #: 08   Date: 28-March-2022 
the ESC care approach. For those infants receiving ongoing care for NOWS at the time of ESC 
implementation, the protocol study team will leave the care approach used for the continued 
care of these infants to the discretion of the clinical team.  
• Infants born or transferred to the site during the transition period will not have their data 
collected and these infants will not be included in the study analysis.   
• Clinical leads from each discipline (i.e., nursing and medicine) and the site research team will 
assess for completeness of training milestones and the ESC care approach implementation prior 
to the site’s formal movement into the ESC intervention period.  
• ESC experts will conduct coaching calls for each block of sites through the transition and initial 
intervention period(s). These coaching calls will provide continued support to the sites during 
this initial period of implementation, and ESC experts will continue to conduct these coaching 
calls or educational meetings on a monthly basis throughout the subsequent ESC intervention 
period(s).  
4.2.4.3. 
ESC Intervention Periods  
Intervention  
• After delivery or transfer to the site, the care team will initiate non-pharmacologic care for 
NOWS, as detailed in the ESC training materials, and non-pharmacologic care will remain in 
place for the full duration of the infant’s management for NOWS.  
• Non-pharmacologic care can include: primary caregiver(s) involvement (rooming-in if possible), 
promoting breastfeeding (for eligible infants based on the institution’s established 
breastfeeding guideline), encouraging on-demand feeding, enhancement of low light and 
minimal noise exposure, supporting clustered care (doing assessments, vitals, and all other care 
around feeding, to promote sleep), swaddling, and skin-to-skin care by primary caregiver(s) or 
holding by family/staff volunteers. 
• Not all sites will be able to offer all forms of non-pharmacologic care and not all infants will be 
able to receive all non-pharmacologic interventions available at the site. Acknowledging this, 
the clinical team will make every attempt to optimize the non-pharmacologic care provided to 
each infant.  
• The clinical team will encourage primary caregiver(s) to participate in the care and evaluation of 
their infants. The clinical team will also encourage the primary caregiver(s) to record the 
infant’s feedings (timing and duration, and/or volume), sleeping (quality and quantity), and 
ability to be consoled, in the Newborn Care Diary, a component of the ESC care approach. 
• The clinical team, in collaboration with the primary caregiver(s), will use the ESC Care Tool to 
assess the infant with respect to the ESC items (eating, sleeping and consoling) by 
approximately 4 to 6 hours of life (if risk for NOWS is known) or upon identification of the need 
for NOWS management.  
• The clinical team will perform ESC care assessments every 2 to 4 hours after feedings, clustering 
other infant and maternal care (i.e., vital signs) at the same time. These assessments will 
include a collaborative review with the primary caregiver(s) (when available) of the ESC items 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 42 of 79 
Protocol Version #: 08   Date: 28-March-2022 
since the last assessment, using the Newborn Care Diary. If the primary caregiver(s) are not 
available, the clinical team who participated in the care of the infant during the assessment 
period will complete the assessment.  
• If during an assessment the infant has a "Yes" for any ESC item or obtains a score of “3” for 
“Consoling Support Needed” on the ESC Care Tool, the primary caregiver(s) and clinical team 
will conduct a “Parent/Caregiver huddle” to determine: 1) if the "Yes" is due to NOWS and 
2) which non-pharmacologic care interventions the care team can optimize further. The 
“Parent/Caregiver Huddle” could include, but is not limited to, the parent/caregiver and the 
bedside nurse.  
• If the care team can optimize non-pharmacologic interventions, they will do so and will 
continue to assess the infant.  
• If it is unclear if the infant’s difficulties with eating, sleeping, or consoling are due to NOWS, the 
care team will indicate a "Yes" on the ESC Care Tool and will continue to monitor the infant 
closely while optimizing all non-pharmacologic care interventions.  
• If the infant has a second consecutive "Yes" for any ESC item (or “3” for “Consoling Support 
Needed”) on the ESC Care Tool (or other significant concerns are present), despite maximal 
non-pharmacologic care, the care team will conduct a “Full-Care Team Huddle” to determine if: 
1) the "Yes" is due to NOWS and 2) the infant needs pharmacologic treatment. A “Full-Care 
Team Huddle” could include, but is not limited to, the parent/caregiver and the bedside nurse, 
in addition to the physician and/or advanced practice providers caring for the infant.  
• The clinical team will initiate pharmacologic treatment if the infant scores "Yes" due to NOWS 
on an ESC item or scores a “3” for “Consoling Support Needed” on the ESC Care Tool despite 
optimization of non-pharmacologic care. If an infant requires pharmacologic treatment, sites 
will initiate a treatment protocol to guide care. A treatment protocol should include dose 
initiation, escalation, and weaning parameters.. Opioid replacement therapy given (morphine, 
methadone, or buprenorphine) will be per site preference, as will adjuvant therapy (clonidine 
or phenobarbital).  
• The clinical team will monitor each infant requiring opioid replacement therapy for signs of 
escalating withdrawal symptoms following discontinuation of this treatment and will consider 
discharge per the site’s usual practice.  
• The clinical team will use the ESC Care Tool to monitor infants following birth and consider 
discharge for infants who do not require pharmacologic treatment per the site’s usual practice.  
• To ensure fidelity of the assessments, the site research team will randomly assess the reliability 
of “gold-star raters” at each site throughout the ESC intervention periods. The protocol study 
team anticipates that each “gold-star rater” will maintain 100% reliability in scoring. The “gold-
star raters” will then assess reliability of the clinical team once per ESC intervention period, 
using the ESC IRR tool and a NOWS infant, written cases, or video cases. The protocol study 
team anticipates that each member of the clinical team will maintain 80% reliability in scoring. 
If a member of the clinical team fails to meet this target during the assessment, the site 
research team will utilize just-in-time training (see Training and Implementation Manual) until 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 43 of 79 
Protocol Version #: 08   Date: 28-March-2022 
the clinical team member achieves 80% reliability. The protocol study team would ask that 
members of the care team with reliability less than 80% not be assigned to care for infants with 
NOWS until improved reliability is demonstrated through the just-in-time training process. 
• To ensure fidelity of ESC implementation, “gold-star raters” will discretely evaluate, in real time, 
how nurses implement the ESC care approach  using the ESC Implementation Process 
Evaluation form (see Training and Implementation Manual). The protocol study team will use 
this tool to evaluate how consistent  nurses are in their evaluation of infant symptoms, 
recommendations for care team huddles, as described by the ESC Care Tool, and 
implementation of the ESC Care Tool (inclusive of non-pharmacologic care interventions). The 
site research team will keep complete ESC Implementation Process Evaluation forms with other 
study documentation. 
4.2.5. Protocol Adherence and Compliance Monitoring  
The DCC will monitor protocol deviations per site in relation to the number of participants enrolled and 
visits conducted. All sites will receive re-education via regularly scheduled teleconferences to help 
other sites prevent similar deviations. If a particular deviation is recurrent at one site or across the 
sites, the DCC may implement operational tools, such as additional reminders, source document 
worksheets, and/or checklists, to reduce the likelihood of deviations. The DCC will review protocol 
deviations throughout the study, and it may schedule additional on-site visits, as needed, to review 
regulatory documents, data points, key issues, etc. or to retrain site staff to improve processes and 
provide additional education. 
Strategies to improve or monitor adherence to the study protocol will include the following:  
• Monthly recruitment reports of infants screened, enrolled, and consented (accrual figures)  
• Screen fails will be reviewed by the protocol study team to assess for bias in inclusion/exclusion 
decisions   
• Monthly reports detailing data received at the data center, data consistency, missing data, 
performance measures, and adherence to the study protocol (with appropriate measures taken 
to preserve the blinding of study personnel and investigators)  
• Supplementary blinded reports requested by the study investigators or subcommittee that do 
not disclose allocation-group–specific outcomes (primary, secondary, or any safety outcomes)  
The DCC will generate the aforementioned reports. 
Additionally, the protocol study team will monitor protocol adherence through collection of the 
following data:  
• Completion of modules and training by the research and clinical teams.  
 
• Continual IRR fidelity assessments for the clinical team (reevaluated each period). 
• Assessed adherence to the assigned care approach.  
4.2.6. Post-hospital Procedures 
The site research team will assess for the outpatient composite safety outcome at approximately 3 
months of age as well as the critical safety outcome through review of the medical records (including 
the site’s primary and any linked electronic medical record systems) and media review for all infants 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 44 of 79 
Protocol Version #: 08   Date: 28-March-2022 
enrolled in the study at approximately 3 and 24 months of age. Primary caregiver(s) for infants for 
whom the protocol study team obtained informed consent will receive questionnaires via electronic 
application or via phone interview, if caregiver(s) have limited access to cellular/internet service or 
prefer this modality of communication. Caregiver(s) will complete these questionnaires at discharge, 
1-month post discharge, and 3 months, 6 months, 12 months, and 24 months of age. These 
questionnaires will gather information on infant neurobehavioral functioning, infant wellness, primary 
caregiver(s) well-being, family environment, and caregiver-infant interactions, as detailed in Section 
4.3.2.2. In addition, there will be an in-person follow-up visit with neurodevelopmental assessment and 
anthropometric measures at 24 months of age. The site research team will maintain contact in 
between study assessments at regular intervals, as detailed in Table 4. As there will likely be 
differences between the populations who provide consent for follow-up and those who do not, we will 
collect socioeconomic data (insurance and maternal educational status), marital status, and maternal 
receipt of medication-assisted treatment for all populations to examine for possible bias. 
4.2.7. Data Quality Assurance 
To assure the quality of the data collected, the protocol study team will provide training specific to 
accuracy of data acquisition for the research coordinators at each site. The protocol study team will 
design data collection forms, which a subset of sites will subsequently pilot to minimize the potential 
for errors. Additionally, the protocol study team will allocate sufficient funds to allow for quality data 
collection. The site research team will re-abstract a subsample of their own charts and assess the error 
rate. Re-abstraction will focus on critical data elements related to the primary and secondary 
objectives of the protocol. The protocol study team will base the number of charts a site re-abstracts, 
for each 6-month interval, on the number of patients enrolled in the study during the 6-month period 
at each site as shown below: 
No. of patients enrolled in a 
6-month period 
No. of charts to be re-abstracted 
0 
0 
1-14 
1 
15-24 
2 
25-34 
3 
35-44 
4 
45-54 
5 
55-64 
6 
 
The DCC will provide sites with the randomly selected subject IDs for re-abstraction. The site research 
team will identify an independent site quality control (QC) abstractor who will re-abstract and enter 
data into the electronic data capture system (EDC) only for the QC process and will not abstract study 
data while QC activities are taking place. The DCC will generate a discrepancy report comparing study 
data abstracted by the site with the source information abstracted by the independent abstractor. The 
site manager will hold a QC Review Meeting with the independent site QC abstractor, research 
coordinator, and site abstractor(s) to review the discrepancies and identify errors. Together they will 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 45 of 79 
Protocol Version #: 08   Date: 28-March-2022 
discuss and document the corrective action for each error identified. The DCC will create manual 
queries in the EDC to make any necessary corrections to the data that QC Review members identify. 
The protocol study team will provide hospitals that have an error rate above the predefined threshold 
with additional training, a hospital-specific assessment of the data collection process, and suggestions 
for process improvement. The protocol study team will track hospitals by their error rates. The 
protocol study team will share practices of those hospitals with exceptionally low error rates with 
hospitals working to improve their own process. The protocol study team will review error rates and 
re-abstraction data during monthly team calls. If errors exceed the predefined threshold on 2 
consecutive reviews, a remediation plan will be requested and shared with the study sponsor.  
Sites that have an error rate above the predefined threshold will receive additional training, a site-
specific assessment of the data collection process and suggestions for process improvement. The 
protocol study team will highlight sites with exceptionally low error rates, and these sites will share 
aspects of their data collection process with sites working to improve their own process.  
4.2.8. Blinding/Masking 
The protocol study team will assure blinding of the electronically performed follow-up questionnaires 
through the use of a centralized computer scoring system. For questionnaires completed by phone, 
each site should develop a site-specific protocol to preserve blinding of those administering the 
questionnaires. The protocol study team will note the method of questionnaire completion.    
4.3. 
STUDY OBJECTIVES AND ENDPOINTS 
4.3.1. Primary Outcome 
The primary outcome is the time from birth until infants are medically ready for discharge. We define 
medically ready for discharge as when the infant meets ALL of the following criteria: 
1. ≥ 96 hours of life 
2. Off opioid replacement therapy (e.g. morphine, methadone, or buprenorphine) for ≥ 48 hours 
3. Taking 100% of feeds by mouth for ≥ 24 hours 
4. ≥ 24 hours from initiation of the maximum caloric density infant received during the initial 
hospital admission  
5. Receiving no respiratory support for ≥ 24 hours 
 
• Hypothesis: Among infants evaluated for NOWS, the ESC care approach will reduce the length 
of time until infants are medically ready for discharge by an average of 4 days, compared to 
usual institutional care with the FNAST or modification thereof. 
4.3.2. Secondary Outcomes 
4.3.2.1. 
Obtained Under Waiver of Consent and Gathered by Authorized Site Research Personnel  
from the On-Site Medical Records, Linked Medical Records and Research Forms 
1. Receipt of opioid replacement therapy (morphine, methadone, or buprenorphine) for 
NOWS prior to hospital discharge  

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 46 of 79 
Protocol Version #: 08   Date: 28-March-2022 
• Hypothesis: The use of the ESC care approach will decrease the proportion of infants 
who receive opioid replacement therapy. 
• This is a yes/no outcome, and it will enable us to determine the percentage of 
infants receiving opioid replacement therapy in each intervention group. 
2. Total postnatal opioid exposure prior to hospital discharge 
• Hypothesis: The use of the ESC care approach will decrease total opioid exposure, 
compared to usual care.  
• Each dose of opioid replacement therapy (total units and units/kg and morphine 
equivalents [mg/kg]) that infants received throughout the initial birth hospitalization 
will be collected to determine total postnatal opioid exposure.  
3. Hour of life opioid replacement initiated  
• Hypothesis: The use of the ESC care approach will not delay the initiation of 
pharmacologic therapy.  
• Use of the ESC Care Tool for the assessment of infants may delay the initiation of 
pharmacologic therapy and thus infants may be at an advanced state of withdrawal 
and more difficult to “capture”. Alternatively, there is some evidence to suggest27 
that use of the ESC Care Tool ultimately allows for more timely recognition of infants 
requiring pharmacologic therapy, compared to usual care using the FNAST.  
4. Receipt of adjuvant therapy (clonidine or phenobarbital) prior to hospital discharge  
• Hypothesis: The use of the ESC care approach will decrease the proportion of infants 
who receive adjuvant therapy. 
• This is a yes/no outcome, and it will allow us to determine the percentage of infants 
receiving adjuvant therapy. 
5. Maximum percent weight loss during the initial birth hospitalization  
• Hypothesis: Use of the ESC care approach will not result in more excessive weight loss 
than usual care. 
• Poor feeding and excessive weight loss are signs of suboptimal control of NOWS. 
Birth weight and daily weights (g) will be collected throughout the initial birth 
hospitalization to determine the impact of NOWS on growth, and the maximum 
percent weight loss will be calculated as:  
                         ቂ
𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏ℎ𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤ℎ𝑡𝑡 (𝑔𝑔)−𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤ℎ𝑡𝑡 𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛(𝑔𝑔)
𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏ℎ𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤ℎ𝑡𝑡 (𝑔𝑔)
ቃ𝑥𝑥 100 = max 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤ℎ𝑡𝑡 𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙 
6. Type of enteral feedings (exclusive maternal breastmilk, combination of formula and 
maternal breastmilk, exclusive formula feeding) at time of hospital discharge  
• Hypothesis: Use of the ESC care approach will increase the proportion of infants who 
receive maternal breastmilk at the time of discharge from the initial birth 
hospitalization. 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 47 of 79 
Protocol Version #: 08   Date: 28-March-2022 
•  Studies have shown that the receipt of maternal breastmilk decreases withdrawal 
signs in infants in a dose-dependent fashion.39, 40  
• The site research team will assess and collect the type of enteral feeding at the time 
of discharge from the initial birth hospitalization. 
7. Direct breastfeeding at the time of hospital discharge 
• Hypothesis: Use of the ESC care approach will increase the proportion of mothers 
who directly breastfeed at the time of discharge from the initial birth hospitalization. 
• The site research team will assess and collect direct breastfeeding occurrences 
within 24 hours of the time of discharge from the initial birth hospitalization. 
8. Length of hospital stay 
• Hypothesis: Infants managed with ESC will have a decrease in the LOS. 
• The site research team will report the LOS in addition to the length of time until 
infants are medically ready for discharge. The differences in these measures will 
allow the protocol study team to assess the impact of social factors on the length of 
hospitalization. 
9. A composite measure of infant safety during the initial birth hospitalization (seizures, 
accidental trauma [i.e., dropped infants], and respiratory insufficiency due to opioid 
therapy, including documented apnea or need for respiratory support [positive pressure or 
supplemental oxygen]) 
• Hypothesis: Infants managed using the ESC care approach will be safe during the 
initial birth hospitalization. 
• Use of the ESC care approach may delay initiation of pharmacologic therapy, which 
could result in an increase in withdrawal-related seizures. Therefore, monitoring for 
the presence or absence of seizures will help to build the safety profile for ESC.  
• Increased primary caregiver(s) involvement is thought to result from the ESC care 
approach. In this case, parent/caregiver skin-to-skin time and holding may increase, 
which could increase the risk of infants being dropped if primary caregiver(s) are 
fatigued and/or chemically impaired.  
• Use of the ESC care approach may delay initiation of pharmacologic therapy, which 
could result in the infant receiving a higher dose of opioid replacement therapy. 
Higher doses of opioids may increase the risk of respiratory insufficiency. Therefore, 
monitoring for respiratory insufficiency will help to build the safety profile for ESC. 
10. A composite measure of critical infant safety outcomes during the initial birth 
hospitalization (non-accidental trauma and death) 
• Hypothesis: Infants managed using the ESC care approach will be safe during the 
initial birth hospitalization. 
• Use of the ESC care approach encourages parents/caregivers to provide extensive 
non-pharmacologic care and rooming-in. This may increase stress and fatigue and 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 48 of 79 
Protocol Version #: 08   Date: 28-March-2022 
lead to undesired caregiver-infant interactions. Inclusion of a critical composite 
safety outcome inclusive of non-accidental trauma and death will help to build the 
safety profile for ESC  
11. A composite measure of infant safety during the first 3 months of life based on the 
presence or absence of acute/urgent care and/or ER visits and hospital readmissions 
• Hypothesis: Infants managed using the ESC care approach will be safe during the 
first 3 months of life. 
• Discharge of an infant earlier from the initial hospitalization and/or increased 
primary caregiver involvement during the initial hospitalization may increase the 
stress and fatigue experienced by the caregiver(s) and lead to increased risk for poor 
outcomes, and increased healthcare utilization. 
12.  A composite measure of critical safety outcomes based on the presence or absence of 
non-accidental trauma and death at discharge and during the first 3 and 24 months of life 
 Hypothesis: Infants managed using the ESC care approach will be safe during the 
first 3 and 24 months of life. 
 Infants with undertreated signs of withdrawal may be at increased risk for non-
accidental trauma and death due to the potential for increased primary caregiver 
stress and fatigue during the hospital admission and following discharge. These 
infants may also fail to develop a bond with their primary caregiver(s) during the 
first months of life, which may further increase the risk for non-accidental trauma 
and death during the first two years of life. 
4.3.2.2. 
Obtained for the Subpopulation who Provide Informed Consent and Acquired through 
Questionnaires 
Assessed at various time points between discharge and 24 months of age (see Table 4). 
1. Infant neurobehavioral functioning following discharge 
• Hypothesis: Infants managed using the ESC care approach will have improved infant 
neurobehavioral functioning when compared to usual care.  
• Assessed with Infant Behavior Questionnaire - Revised (IBQ-R) very short form at 3 and 
12 months of age. The caregiver will complete the survey and it will be sent to a central 
location for review by the protocol study team  
 The IBQ–R is a well-established caregiver report measure of neurobehavioral 
functioning through assessment of temperament for infants between 3 and 12 
months of age.41 The questionnaire has demonstrated good internal consistency, 
reliability, and validity.42, 43, 44, 45 The IBQ-R consists of 191 items and takes 
approximately 1 hour to complete which makes it impractical for this study. The very 
short form consists of 37 questions that measure surgency, negative affect, and 
effortful control of the infant caregiver. This form takes approximately 12 minutes to 
complete.46 The very short form has been shown to have reliability and stability that 
are similar to the IBQ–R and other temperament measures.46 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 49 of 79 
Protocol Version #: 08   Date: 28-March-2022 
2. Infant wellness following discharge as independently assessed by:  
• Anthropometric growth (weight, height, head circumference) 
 Hypothesis: Use of the ESC care approach will not impact growth long-term when 
compared to usual care. 
 Assessed with percentile measurements of weight, length, head circumference (HC), 
and weight for length on WHO growth curves. The research team will assess weight, 
length, head circumference and weight for length at hospital discharge and 
24 months of age. The study team will calculate anthropometric z-scores at these 
time points, and will assess BMI at 24 months of age and calculate BMI-z.  
• Sleep  
 Hypothesis: The infant’s sleep will improve after use of the ESC care approach 
compared to usual care.  
 Assessed with the Brief Infant Sleep Questionnaire (BISQ)47 at 3 and 12 months of 
age. The caregiver will complete the survey and it will be sent to a central location 
for review by the protocol study team.  
• Enteral feeds during the first 6 months of life (exclusive maternal breastmilk, 
combination of maternal breastmilk and formula, or exclusive formula feeding) 
 Hypothesis: Use of the ESC care approach will increase the proportion of infants who 
receive maternal breastmilk following discharge compared to usual care.  
 Assessed with the Caregiver Questionnaire (CQ) at 1-month post hospital discharge, 
and 3, and 6 months of age. The caregiver will complete the questionnaire and it will 
be sent to a central location for review by the protocol study team.  
• Direct breastfeeding during the first 6 months of life 
 Hypothesis: Use of the ESC care approach will increase the proportion of mothers 
who directly breastfeed following discharge compared to usual care.  
 Assessed with the CQ at 1-month post hospital discharge, and 3, and 6 months of 
age. The caregiver will complete the questionnaire and it will be sent to a central 
location for review by the protocol study team.  
• Number of ER visits and/or acute/urgent care visits  
 Hypothesis: Use of the ESC care approach will not result in an increase in the 
number of ER or acute/urgent care visits compared to usual care.  
 Assessed at 1-month post hospital discharge, and 3, 6, 12, and 24 months of age via 
completion of the CQ and submission for review by a protocol study team. The site 
research team will also assess the site’s electronic health record (EHR) and include 
any visits not reported, if observed.  
• Readmissions  
 Hypothesis: Use of the ESC care approach will not result in an increase in the 
number of readmissions following initial hospital discharge compared to usual care.  

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 50 of 79 
Protocol Version #: 08   Date: 28-March-2022 
 Assessed at 1-month post hospital discharge, and 3, 6, 12, and 24 months of age via 
completion of the CQ and reviewed by the protocol study team. The site research 
team will also assess the sites’ EHR and include any visits not reported, if observed. 
3. Maternal/caregiver well-being  
• Hypothesis: Use of the ESC care approach will improve maternal/caregiver well-being 
compared to usual care.  
• Assessed with Patient Reported Outcomes Measurement Information System (PROMIS) 
short forms at discharge, 6 months and 24 months. 48 Standardized short forms  
examining mental health, specifically the areas of anxiety (PROMIS Short Form v1.0 - 
Anxiety - 8a 31May2019), depression (PROMIS_SF_v1.0_-_ED-Depression_8a_5-31-
2019), anger (PROMIS Short Form v1.1 - Anger - 5a 27Apr2016), life meaning and 
purpose (PROMIS Short Form v1.0 - Meaning and Purpose - 8a 18Jul2017), and social 
support (PROMIS v2.0 - Emotional Support Short Form 4a 23June2016) will be 
completed by the primary caregiver and will be sent to a central location for review by 
the protocol study team.  
• The standardized short form for each of the PROMIS Measures consists of between four 
to eight 5-point Likert scale questions.  The PROMIS Depression Short form has been 
validated in the postpartum period and has been found to be strongly correlated with 
the Edinburgh Postnatal Depression Scale, the most extensively studied measure of 
depression in the postpartum period. 49, 50  In addition, the PROMIS anxiety measure has 
been correlated with the Mood and Anxiety Questionnaire (MASQ) and has been shown 
to be a valid measurement tool for anxiety in the post-partum period in a sample of 
parents whose infants were hospitalized in the NICU. 50  Administration takes 
approximately 10 minutes and includes a total of 33 questions. 
4. Infant-caregiver bonding and attachment  
• Hypothesis: Use of the ESC care approach will result in improved infant-caregiver 
bonding and attachment, compared to usual care.  
• The protocol study team will assess with the Maternal Postnatal Attachment 
Questionnaire (MPAQ) at discharge and 6 months of age. The caregiver will complete 
the questionnaire and it will be sent to a central location for review by the protocol 
study team.  
• Primary caregiver-infant interactions will be assessed with the MPAQ,51 a 19-item 
questionnaire that assesses quality of bonding, absence of hostility, and pleasure in 
interaction. The MPAQ requires approximately 5 minutes to complete, and researchers 
have validated the tool for postpartum women with substance-abuse problems.52  
• The focus of the MPAQ is primarily upon the caregiver(s) subjective experiences in 
relation to their infant in the first year of life.53 Established risk quartiles exist, and the 
protocol study team will note caregiver(s) for entry and exit into these high-risk 
quartiles at each time point.  
5. Parenting efficacy 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 51 of 79 
Protocol Version #: 08   Date: 28-March-2022 
• Hypothesis: Use of the ESC care approach will result in improved caregiver sense of 
competency in caring for their infants compared to usual care. 
• The protocol study team will assess with the Parenting Sense of Competence (PSOC) 
Scale at discharge and 6 months of age. The caregiver will complete the questionnaire 
and it will be sent to a central location for review by the protocol study team. 
• The PSOC is a self-reporting instrument that measures and assesses parent self-efficacy. 
It is a 17-item publicly available scale that measures satisfaction (degree of liking a 
person has for their role as a parent) and efficacy (an individual’s perceived competence 
in their role as a parent). 
• Researchers have used this tool to assess the impact of parenting efficacy on the 
likelihood of out-of-home placement and loss of custody in mothers with mental health 
and substance use disorders.54 
6. Family environment  
• Hypothesis: Use of the ESC care approach will enhance family environment when 
compared to usual care. 
• The protocol study team will assess with Family Environmental Scale (FES) - Relationship 
Dimension - Form R at 3 months of age. The caregiver will complete the questionnaire 
and it will be sent to a central location for review by the protocol study team.  
• The Relationship dimension of the FES consists of the Cohesion, Expressiveness, and 
Conflict subscales. Form R for each subscale is composed of 9 true-false items.  
• The relationship dimension assesses the degree of commitment, help, and support that 
family members provide each other, the extent to which family members are 
encouraged to act openly and to express their feelings directly, and the amount of 
openly expressed anger, aggression, and conflict among family members.55 
• Researchers frequently use the FES to assess the home environment and it has been 
found to have strong psychometric properties.55 
7. Influence of maternal childhood experiences on infant outcomes 
• Hypothesis: Maternal history of adverse childhood experiences will be associated with 
worse infant behavioral functioning and developmental outcomes.  
• The protocol study team will assess adverse childhood experiences using the Adverse 
Childhood Experience (ACE) Questionnaire at 24 months of age.  
 The ACE56 is a self-report measure used to capture specific childhood experiences 
correlating with future social risk factors and negative health outcomes.  
4.3.2.3. 
Obtained for the Subpopulation who Provide Informed Consent and Acquired through an 
In-person Visit at 24 months of age 
1. Infant development  

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 52 of 79 
Protocol Version #: 08   Date: 28-March-2022 
• Hypothesis: Use of the ESC care approach will improve infant development, compared 
to usual care.  
• The protocol study team will assess infant development with the Bayley Scales of Infant 
and Toddler Development, Fourth Edition (Bayley-4): Cognitive, Language, and Motor, at 
24 months of age. The Bayley-4 will be administered by a trained examiner blinded to 
neonatal history who has undergone extensive training and been certified to perform 
exams. 
 The Bayley Scales are recognized internationally as one of the most comprehensive 
tools to assess developmental outcomes in children.  With the Bayley-4, it is even 
possible to obtain detailed information from non-verbal children as to their 
functioning.  Children are assessed with 3 key developmental domains:  cognition, 
language, and motor.  Reliability and validity of the previous version of the 
instrument have been well established.57 
• The protocol study team will assess infant behavioral development with the Brief Infant-
Toddler Social and Emotional Assessment (BITSEA) at 24 months of age.  The BITSEA is a 
standardized and normed referenced instrument designed to assess for social-
emotional, behavior concerns, and social competence in infants-toddlers. 58 
 The 42-item parent rating form is a shorted version of the Infant-Toddler Social 
and Emotional Assessment. Scores include ratings of internalizing behaviors, 
externalizing behaviors, executive function (dysregulation), psychosocial 
competence, social relatedness; maladaptive, and atypical behavior. The 
behavioral indices included in the BITSEA have been observed to correspond 
with neurodevelopmental functioning among infants at risk for 
neurodevelopmental problems. 
4.4. 
POTENTIAL RISKS AND BENEFITS TO PARTICIPANTS 
Under the proposed study design, the protocol study team will randomize each site into blocks with 
each block transitioning from usual care to ESC at a randomly allocated time. At any given time during 
the study enrollment period, all infants managed for NOWS at a site will receive care consistent with 
the care approach assigned by the protocol study team. Sites throughout the country are currently 
using both care approaches described in this study for the evaluation and management of NOWS. Use 
of either care approach will not expose infants in this study to risk beyond that of usual/accepted 
clinical care. 
Involvement in the study will not increase the risk to the family of legal ramifications associated with 
the in utero opioid exposure of their infants, as only infants who have been identified by the site as at 
risk for NOWS and for whom management for NOWS has begun, will be screened for enrollment in the 
trial. There will be no additional toxicology screening (maternal or infant) performed beyond what 
medical professionals would typically obtain as part of usual institutional care at the site. Thus, there 
will be no additional information garnered with respect to substance use during pregnancy due to 
one’s involvement in the trial.  

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 53 of 79 
Protocol Version #: 08   Date: 28-March-2022 
The protocol study team will assess primary caregiver well-being (e.g. parenting stress, attachment and 
bonding, depression, anxiety, etc.) as well as infant well-being, neurobehavioral functioning, and 
development during the follow-up portion of the study.   
The protocol study team will assess primary caregiver wellness with 5 PROMIS Measures (see 4.3.2.2). 
It is possible that these questionnaires may reveal that the primary caregiver is experiencing 
psychological distress potentially requiring support.  The study team has determined that a 
standardized scoring threshold for the PROMIS Depression Measure will be used to identify these 
individuals.  As thresholds specific to postpartum women with opioid dependency have yet to be 
established and given that severe depression (a t-score >70, or 2 standard deviations above the mean 
for the normative population is the threshold for severe depressive symptoms. 59  60) is most likely to 
impact family well-being, a score of >70 was chosen for this threshold.   
If a primary caregiver has a t-score >70 on the PROMIS Depression measure, the primary caregiver will 
be provided with national hotline support numbers within the electronic questionnaire platform.  In 
addition, after the questionnaire is completed in REDCap an email will be automatically generated and 
sent to the study coordinator and PI.  Each site will develop a plan to provide support for the primary 
caregivers at risk and connect them with local mental health resources in response to those emails.  
The protocol study team will collect a copy of this plan from each site. 
 
SAMHSA NATIONAL HELP LINE – 1-800-662-4357 (HELP)  
• https://www.samhsa.gov/find-help/national-helpline  
• SAMHSA’s National Helpline is a free, confidential, 24/7, 365-day-a-year treatment referral and 
information service (in English and Spanish) for individuals and families facing mental and/or 
substance use disorders. 
NATIONAL DOMESTIC VIOLENCE HOTLINE - 1−800−799−7233 (SAFE) 
• https://www.thehotline.org  
• Advocates are available 24/7/365 to talk confidentially with anyone experiencing domestic 
violence, seeking resources or information, or questioning unhealthy aspects of their 
relationship.  
NATIONAL SUICIDE PREVENTION LIFELINE – 1-800-273-8255 
• https://suicidepreventionlifeline.org  
• The National Suicide Prevention Lifeline is a national network of local crisis centers that 
provides free and confidential emotional support to people in suicidal crisis or emotional 
distress 24 hours a day, 7 days a week. 
 
Additionally, a response plan will be in place at each site for questions specific to incidental findings of 
or suspicions for child abuse and/or neglect.  
Participants recognized to have neurodevelopmental impairment on the Bayley-4 exam will be referred 
to their primary care providers for follow-up.  The study team will communicate and share the report 
with the caregiver(s) and primary care providers if requested by the participants’ caregiver(s) and 
consent is obtained. 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 54 of 79 
Protocol Version #: 08   Date: 28-March-2022 
The infants in the study may not benefit directly from participation. There may be a benefit to the 
infant of information garnered from the developmental screening portion of the study. By virtue of 
inclusion in a research study, participants are at risk of loss of confidentiality of medical-record 
information because participants will have their medical records reviewed by research personnel. The 
protocol study team will institute measures to protect the privacy of medical information, including the 
coding of all HIPAA (Health Insurance Portability and Accountability Act) identifiers in medical records, 
limitation of access to the medical records to research personnel, and removal of any individual 
identifiers in reports and publications generated from the study. Research personnel will keep any hard 
copies of research records in a locked cabinet and will destroy these records after the study is 
complete and the protocol study team publishes the results. In this study, infants themselves are the 
primary research focus, thus justifying the inclusion of children. The protocol study team will not 
exclude a subject based on race, ethnicity, or gender. However, some of the study questionnaires that 
will be used have not been validated in languages other than English. Thus, the population for the 
consented portion of the study will be limited to infants of English-speaking, reading and writing 
caregivers. Due to the demographic distribution of NOWS, the proportion of low socioeconomic-status 
infants will likely be higher than in the general population.   
4.5. 
RECRUITMENT AND RETENTION 
4.5.1. Site Recruitment and Retention 
The protocol study team began to optimize the potential for recruitment during initial protocol 
development, through an assessment of potential ISPCTN and NRN sites’ willingness to participate in 
and enthusiasm for various study designs. The study design chosen for this protocol incorporates the 
feedback from these sites. During the site assessment process, the protocol study team will expect 
each site to commit in writing to the site’s participation in and completion of the trial with 
maintenance of the site’s allocated intervention for the duration of the study. The protocol study team 
will facilitate retention of sites through the focused allocation of funds to support participation, 
through assessment of needs, provision of support, and troubleshooting at each site, as needed.  
4.5.2. Infant and Parent/Caregiver Recruitment and Retention  
The site research teams will need to obtain participant consent for the long-term follow-up portion of 
the study. Historically, enrollment of infants with NOWS in clinical trials that seek to improve their care 
has been challenging. In response to this, the protocol study team plans to utilize a robust recruitment 
and retention plan developed to support and optimize the participation of this population in the 
follow-up portion of this study.  
4.5.2.1. 
Recruitment 
The single most important element of the recruitment strategy is to establish trust with the primary 
caregiver(s) and provide an introduction to the research plan prior to delivery. The prenatal 
consultation is most likely the first time that the family will meet the site PI or designee and is an ideal 
time to introduce the trial. The consultation is the opportunity for the provider to gain trust with the 
family and reaffirm a partnership with the family. The consultation will include establishing a 
foundation of knowledge about NOWS, outlining gaps in current national care, and a detailed 
description of the research approach.  

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 55 of 79 
Protocol Version #: 08   Date: 28-March-2022 
In anticipation that prenatal consultations will not be feasible for all patients, effective dissemination 
of information regarding the clinical trial will be exceptionally important. The protocol study team will 
provide an informational pamphlet to all parent/caregiver(s) of infants receiving care for NOWS at 
participating sites soon after delivery. The consenting member of the site research team will begin 
trust building with the parent/caregiver(s) in anticipation of the consenting process. The site research 
team will present information about the study in person, and/or via an informational brochure 
developed by the protocol study team and distributed to the sites. To further optimize recruitment, if 
informed consent is not able to be obtained during the initial hospitalization, it is permissible to obtain 
consent up to one month after discharge. 
The protocol study team will assess site recruitment for long-term follow-up each month following site 
enrollment. If the protocol study team assesses the site as below target, the study team will evaluate 
the site’s processes for recruitment, and the site will receive additional training and/or modifications 
to the recruitment approach as suggested by a recruitment and retention expert from the protocol 
study team.  
Additionally, the protocol study team will assess for barriers to participation, perceived or actual, of 
non-consenters (see Section 4.2.2) and utilize their responses to further improve site-specific and 
study-wide recruitment strategies.  
4.5.2.2. 
Retention 
The protocol study team will optimize infant and parent/caregiver(s) retention soon after a site obtains 
consent, by sending a note of thanks to the parent/caregiver(s) and acknowledging the importance of 
their contribution to the future care we provide these infants. The site research team will further 
optimize retention via text messaging for reminders, and access to questionnaires through a centrally 
located electronic platform. The site research team will use the electronic health record to update a 
participant’s contact information as needed, in the event that the contact information provided by the 
participant is not sufficient. The site research team can conduct questionnaires via phone interview if 
the caregiver(s) has limited access to cellular/internet service or prefer this modality of 
communication. If a participant answers questions for questionnaires or comes to an in-person visit, 
the parent/caregiver(s) will receive compensation for their time.  This compensation will be provided 
at – or very near – the time the participant finishes that contact time.  
Participants will be reimbursed for their time according to the following plan: 
Contact Time 
Participated in 
Reimbursement/ 
Compensation Amount 
Hospital Discharge 
Answering Questionnaires 
   $50. 
1-month post discharge 
(of baby from hospital)  
Answering Questionnaires 
   $50. 
Baby 3 months of age 
Answering Questionnaires 
   $50. 
Baby 6 months of age 
Answering Questionnaires 
   $50. 
Baby 12 months of age 
Answering Questionnaires 
   $50. 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 56 of 79 
Protocol Version #: 08   Date: 28-March-2022 
Baby 24 months of age 
Bringing baby in for in-
person Bayley’s exam and 
answering questionnaires 
$100. 
 
The mechanism of payment (gift card, check, etc.) will be site specific and will be according to each 
site’s mechanism for making such payments.   
The site research team will provide text reminders to the parent/caregiver(s) to optimize timely 
completion of the questionnaires. Additionally, the site research team at each site will include a 
retention coordinator, and the protocol study team will allocate funds to support this role. 
Additionally, the protocol study team will explore other methods to optimize both recruitment and 
retention. This could include, but is not limited to, discussions with stakeholders and 
parent/caregiver(s) from the community who have had infants treated for NOWS and understand the 
importance of being able to successfully complete this trial.  

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 57 of 79 
Protocol Version #: 08   Date: 28-March-2022 
SECTION 5. 
ANALYTICAL PLAN 
5.1. 
STATISTICAL ANALYSIS PLAN 
5.1.1. General Approach 
The material of this section is the basis for the statistical analysis plan of this study. The protocol study 
team may revise the plan during the study to accommodate clinical trial protocol amendments and to 
make changes to adapt to unexpected issues in study execution and data that affect planned analyses. 
The protocol study team will conduct all statistical analyses following the statistical principles for clinical 
trials as specified in International Council on Harmonization Topic E9. The protocol study team will 
describe and justify any deviations from the planned analyses in the final integrated clinical study report. 
The protocol study team will present overall and study site-specific data and summary tables. 
The protocol study team will present the characteristics of infants and mothers by intervention groups 
(usual care versus ESC care approach) and their outcomes for each site. We do not expect significant 
differences in the demographics of the study population during the 20-month study period. Each site 
covers a different population mix, and while each hospital will contribute both usual care and ESC 
participants, they will do so in different proportions depending on when the protocol study team 
randomizes the hospital to the intervention. This will contribute greatly to any demographic differences 
between the usual institutional care and ESC groups. Whilst we do not intend to test for demographic 
differences between the usual institutional care and ESC groups for the full cohort, we will adjust the 
analyses for the covariates described because of potential imbalance across sites and across steps. We 
will present numerical variables as means [standard deviation (SD)] or medians (interquartile range), 
depending on their distribution, and categorical variables as counts and percentages. 
We will use the principles of intention-to-treat for all statistical analyses related to primary and 
secondary endpoints.  
5.1.2. Analysis of the Primary Efficacy Endpoints 
For the primary efficacy variable, we will test the following null hypothesis: 
H0: There is no treatment difference in average length of time until medically ready for discharge 
between usual care and the ESC care approach. 
Versus 
H1: There is a treatment difference in average length of time until medically ready for discharge between 
usual care and the ESC care approach. 
We will consider the length of time until medically ready for discharge measure a count measure and 
has the potential to follow a skewed distribution. Initially, we will assess the distributional assumption. 
We will evaluate the associations of potential confounders (e.g., gestational age, birth weight, 
race/ethnicity, hospital volume, rural/urban indicator) at both the participant and site level with the 
intervention. An additional potential confounder that we will evaluate will be the presence of other 
ongoing clinical trials in our trial sites that might impact the outcome of this study, including the 
“Prospective Randomized Blinded Trial to Shorten Pharmacologic Treatment of Newborns with Neonatal 
Opioid Withdrawal Syndrome (NOWS)”. 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 58 of 79 
Protocol Version #: 08   Date: 28-March-2022 
We will use a generalized linear mixed-effects model (GLMM) to compare the expected length of time 
until medically ready for discharge between the two treatment interventions (usual care and ESC care 
approach). Specifically, we will use a GLMM with a negative binomial distribution and log-link to account 
for potential over-dispersion, as an infant level analysis, and accounting for correlations between 
observations in the same hospital by including hospital in the model as a random effect. We will report 
point estimates for the group mean difference along with a 95% confidence interval (CI). The model-
building approach for our primary outcome will follow four analyses steps: 1) an unadjusted before/after 
of the effect of the ESC care approach (ignoring period/time effect); 2) the time period (i.e., steps) to 
examine if any potential intervention effect relates only to the intervention or also to an independent 
effect of calendar time; 3) an adjustment for infant-level and maternal characteristics and potential 
hospital-level confounders, such as hospital volume and rural/urban indicator; 4) the possible 
interaction between period and intervention effect. The impact of the ESC care approach on the primary 
outcome could potentially change over time, as the improvement in outcome could increase with time 
as the staff gains experience. However, the impact could also decrease after an initial improvement as 
the level of initial enthusiasm decreases. We aim to explore this question through the inclusion of an 
interaction between period/time and intervention effect in Model 4.  
In certain circumstances, medical personnel may discharge an infant prior to being medically ready for 
discharge as defined in our protocol (e.g., sent home on opioids such as methadone, morphine, or 
buprenorphine). Therefore, to compare the 2 interventions based on the primary outcome, we will 
censor these infants. Since one can view the time until medically ready for discharge as a time-to-event 
outcome, we will use the log-rank test adjusted for a cluster randomized design to compare the median 
time the infant is medically ready for discharge between the intervention groups.61 Additionally, we will 
use a Cox proportional hazards (Cox PH) model with the Lin and Wei robust sandwich estimate of the 
variance-covariance matrix, to account for clustering, to adjust for infant and maternal demographics. 
We expect the amount of censoring to be minimal, therefore the results from the Cox PH model will 
serve as a sensitivity analysis for our primary analysis based on a GLMM with log-link.  
5.1.3. Analysis of the Secondary Endpoints Obtained Under Waiver of Consent 
5.1.3.1. 
Receipt of Opioid Replacement Therapy (Morphine, Methadone, or Buprenorphine) for 
Neonatal Opioid Withdrawal Syndrome Prior to Hospital Discharge  
The analysis team will compare the proportion of receipt of opioid replacement therapy for NOWS prior 
to hospital discharge between the intervention groups using a GLMM with a logistic link function. We 
will follow the same four modeling strategies described for the primary outcome. We will also present 
odds ratio estimate of receipt of opioid replacement therapy for NOWS for the intervention effect (ESC 
versus usual institutional care) with 95% CI. 
5.1.3.2. 
Total Opioid Exposure Prior to Hospital Discharge 
The analysis team will provide the median and range of the total opioid exposure prior to hospital 
discharge for each treatment group. For the unadjusted analysis, the team will compare the median 
opioid exposure of the treatment groups using the Wilcoxon rank-sum test for clustered data proposed 
by Rosner, Glynn, and Lee (2003).62 Their test statistic extends the Wilcoxon rank-sum test under the 
assumptions that all participants from the same cluster belong to the same treatment group, that 
observations within any cluster are exchangeable, and that the intracluster dependence does not vary 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 59 of 79 
Protocol Version #: 08   Date: 28-March-2022 
across treatment groups. Additionally, the team will use median mixed regression to account for the 
potential skewness of maximum dose of opioid replacement therapy and of clustered data and allow 
adjustment for covariates. The team will use the same four model building sequence described for the 
primary outcome except that the team will replace GLMM with a median mixed regression model. 
5.1.3.3. 
Hour of Life Opioid Replacement Initiated 
The analysis team will provide median and range for the hour of life when opioid replacement was 
initiated, and will do so separately for each treatment group. We anticipate that most of the infants will 
not receive opioid replacement, therefore we will use a hurdle model to model the expected hour of life 
until medical personnel initiate opioid replacement (i.e., count data) while handling excess zeros and 
over dispersion. More specifically, the team will fit the first part of the model with a binary logit model, 
which models whether an infant receives opioid replacement or not. In the second part, the team will 
utilize a negative binomial mixed model to account for the stepped-wedge design and adjust for 
potential infant and maternal demographics. 
5.1.3.4. 
Receipt of Adjuvant Therapy (Clonidine or Phenobarbital) Prior to Hospital Discharge 
The analysis team will compare the proportion of receipt of adjuvant therapy between the treatment 
groups using a GLMM with a logistic link function. We will follow the same four modeling strategies 
described for the primary outcome. We will present odds ratio estimate of receipt of adjuvant therapy 
for the intervention effect (ESC versus usual institutional care) with 95% CI. 
5.1.3.5. 
Maximum Percent Weight Loss during Birth Hospitalization 
The analysis team will provide the mean and SD of percent weight loss during birth hospitalization 
separately for each treatment group. The team will use a GLMM with an identity link function to 
compare average percent weight loss between the ESC care approach versus usual institutional care. 
The analysis team will report point estimates for the group mean difference along with a 95% CI. The 
team will use the same four model building sequence described for the primary outcome. 
5.1.3.6. 
Type of Enteral Feedings (exclusive maternal breastmilk/breastfeeding, combination of 
maternal breastmilk and formula, exclusive formula feeding) at Time of Hospital Discharge 
The analysis team will compare the proportion of infants receiving any maternal breastmilk (i.e., 
exclusive breastmilk/breastfeeding or combination) at discharge between the treatment groups using a 
GLMM with a logistic link function. We will follow the same four modeling strategies described for the 
primary outcome, and we will present the odds ratio estimate of receiving any maternal breastmilk for 
the intervention effect (ESC versus usual institutional care) with 95% CI. 
5.1.3.7. 
Breastfeeding at the Time of Hospital Discharge 
The analysis team will compare the proportion of breastfeeding at the time of hospital discharge 
between the treatment groups using a GLMM with a logistic link function. We will follow the same four 
modeling strategies described for the primary outcome. We will present odds ratio estimate of 
breastfeeding at the time of hospital discharge for the intervention effect (ESC versus usual institutional 
care) with 95% CI. 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 60 of 79 
Protocol Version #: 08   Date: 28-March-2022 
5.1.3.8. 
Length of Hospital Stay  
Similar to the primary outcome (i.e., length of time until medically ready for discharge measure), we will 
consider LOS a count measure. Therefore, we will complete the analysis of LOS using a GLMM with log 
link assuming a negative binomial distribution to account for over-dispersion. The protocol study team 
will report point estimates for the group mean difference along with a 95% CI. Similar to the primary 
analysis, we will start with an unadjusted analysis and conclude with a model that includes possible 
interaction between period and intervention effect.  
5.1.3.9. 
Composite Measure of Infant Safety during Birth Hospitalization (seizures, accidental 
trauma [i.e., dropped infants], respiratory insufficiency due to opioid therapy, including 
documented apnea or need for respiratory support [positive pressure or supplemental 
oxygen]) 
We will be monitoring for the presence or absence of safety indicators such as seizures, accidental 
trauma, and respiratory insufficiency due to opioid therapy. To assess the safety concerns of the ESC 
care approach, we will create a binary composite measure of inpatient infant safety. The binary 
composite measure will have a value of 1 if there is a presence for any inpatient infant safety indicator 
and 0 otherwise. We will compare the proportion of positive inpatient safety concerns between the 
treatment groups using a GLMM with a logistic link function. We will follow the same four modeling 
strategies described for the primary outcome, and we will present odds ratio estimate of inpatient 
safety concerns for the intervention effect (ESC versus usual institutional care) with 95% CI.  
5.1.3.10. Composite Measure of Infant Safety during the First 3 Months of Life (acute/urgent care 
and/or ER visits and readmissions) 
To assess the safety concerns of the ESC care approach, we will create a second composite measure 
consisting of outpatient infant safety indicators. We will base this outpatient composite measure on the 
presence or absence of acute/urgent care and/or ER visits, or readmissions during the first 3 months of 
life. Similar to the inpatient composite safety measure found in Section 5.1.3.9, we will compare the 
proportion of positive outpatient safety concerns between the treatment groups using a GLMM with a 
logistic link function. We will follow the same four modeling strategies described for the primary 
outcome, and we will present odds ratio estimate of outpatient safety concerns for the intervention 
effect (ESC versus usual institutional care) with 95% CI.  
5.1.3.11. Composite Measure of Critical Safety Outcomes during the First 24 Months of Life 
(non-accidental trauma and death) 
The analysis team will compare the proportion of non-accidental trauma and death between the 
treatment groups using a GLMM with a logistic link function. We will follow the same four modeling 
strategies described for the primary outcome, and we will present odds ratio estimate of non-accidental 
trauma and death for the intervention effect (ESC versus usual institutional care) with 95% CI. 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 61 of 79 
Protocol Version #: 08   Date: 28-March-2022 
5.1.4. Analysis of the Long-term Outcome Endpoints 
5.1.4.1. 
Infant Wellness after Discharge under Provision of Consent 
Growth Assessed with Respect to Weight, Length, Head Circumference, and Weight-for-length 
Normalized to World Health Organization Growth Curves  
We will calculate anthropometric z-scores at each assessment period for the purpose of analysis based 
on age- and gender-specific WHO norms. The analysis team will provide the mean and SD of infants' 
weights (z-scores) separately for each treatment group. The team will use a GLMM with appropriate link 
function (i.e., identity link for continuous outcome) to evaluate the effect of ESC on weight (z-scores). 
The model will examine the how the treatment means differ (i.e., main treatment effect), how 
treatment means change over time (i.e., main time effect), and how differences between treatment 
means change over time (i.e., treatment-by-time effect). The team will carry out assessment across 
2 time points: hospital discharge and 24 months of age. The GLMM analytical approach allows us to 
analyze correlated data obtained repeatedly from the same participant and account for the ICC among 
participants nested within with same clinical site. To account for potential imbalance in key demographic 
and site-level characteristics, the analysis team will utilize both unadjusted and adjusted GLMMs. 
Initially, the unadjusted GLMM will include the fixed categorical effects of intervention, time, and 
intervention-by-time interaction and the random-site effect. We will calculate the point estimates and 
their respective CIs for the changes in infants' weights for each intervention group and for the difference 
in the estimated change between intervention groups. Additionally, the team will present the p-value of 
the difference in point estimates between intervention groups. 
The analysis team will examine the impact of the ESC care approach on length, head circumference, and 
infant weight for length (z-scores) using the same analytical methods described for weight (z-scores). 
Additionally, the team will provide the mean and SD of infant BMI-z at 24 months for each treatment 
group. The team will use a GLMM with an identity to compare average BMI-z between the groups, and 
the team will report point estimates for the group mean difference along with a 95% CI. 
Sleep Assessed with the Brief Infant Sleep Questionnaire (BISQ)  
The analysis team will provide the mean and SD of the BISQ survey separately for each treatment group. 
The team will use a generalized linear mixed model (GLMM) with appropriate link function (i.e., identity 
link for continuous outcome) to evaluate the effect of ESC on infant sleep duration. The model will 
examine how the treatment means differ (i.e., main treatment effect), how treatment means change 
over time (i.e., main time effect), and how differences between treatment means change over time (i.e., 
treatment-by-time effect). The team will carry out assessment at 3 months and 12 months of age. The 
GLMM analytical approach allows us to analyze correlated data obtained repeatedly from the same 
infant and account for the intracluster correlation coefficient among infants nested within with same 
clinical site. To account for potential imbalance in key demographic and site-level characteristics, the 
analysis team will utilize both unadjusted and adjusted GLMMs. Initially, the unadjusted GLMM will 
include the fixed categorical effects of intervention, time, and intervention-by-time interaction and the 
random-site effect. We will calculate the point estimates and their respective CIs for the changes in 
infants' BISQ scores for each intervention group and for the difference in the estimated change between 
intervention groups. Additionally, the team will present the p-value of the difference in point estimates 
between intervention groups. 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 62 of 79 
Protocol Version #: 08   Date: 28-March-2022 
Enteral Feeds during the First 6 Months of Life 
We will measure enteral feeds on a nominal scale (i.e., exclusive maternal breastmilk, combination of 
maternal breastmilk and formula, or exclusive formula feeding). The analysis team will tabulate count 
and relative frequency for each level and for each treatment group. To evaluate the association between 
enteral feeds with intervention, the team will use a mixed-effects multinomial logistic regression model 
to account for the longitudinal cluster study design and potential participant and site-level covariates. 
Breastfeeding during the First 6 Months of Life 
The analysis team will report the proportion of direct breastfeeding for each treatment group during 
each of the assessment periods (1 month post-discharge, and 3 months and 6 months of age). To 
evaluate the association between breastfeeding with intervention, the team will use a mixed-effects 
logistic regression model to account for the longitudinal cluster study design and potential participant 
and site-level covariates. We will present odds ratio estimate of breastfeeding at each assessment 
period for the intervention effect (ESC versus usual institutional care) with 95% CI. 
Number of Emergency Room Visits and/or Acute/Urgent Care Visits 
The analysis team will examine the impact of the ESC care approach on the reduction of ER visits and/or 
acute/urgent care visits using the same analytical steps described for the primary outcome. Given that 
the outcome measure is count (number of ER visits, integers ≥ 1), we expect that Poisson regression 
analysis, adjusted for clustering at hospital will be appropriate. However, if the distribution should be 
approximate to normal or if the team observes over-dispersion, we will consider linear mixed-effect 
regression or negative binomial models. Again, the team will use the same four model building sequence 
described for the primary outcome. Specifically, we will start with an unadjusted model and conclude 
with a model that will include possible interaction between period and intervention effect. 
Readmissions 
The analysis team will compare the proportion readmissions between the treatment groups using a 
GLMM with a logistic link function. We will follow the same four modeling strategies described for the 
primary outcome, and we will present odds ratio estimate of readmissions for the intervention effect 
(ESC versus usual institutional care) with 95% CI. 
5.1.4.2. 
Patient-Reported Outcomes Measurement Information System (PROMIS) Short Forms  
The analysis team will measure primary caregiver(s)’ well-being with PROMIS Short Forms. The team will 
convert raw scores to T-scores and report descriptive statistics (mean ± SD) for each of the five domains 
(i.e., emotional support, meaning and purpose, anger, anxiety, and depression) separately for each 
treatment group.  To compare each domain composite scores between the ESC care approach and usual 
care, the team will use a GLMM model with identity link with a fixed effect for the intervention group, 
time, and group-by-time and a random effect for study site.  Assessment periods will include at 
discharge, and at 6 months and 24 months.  The team will report point estimates for the group mean 
difference along with a 95% CI.  Again, this analytical approach will be repeated for each of the 
5 PROMIS domains.    

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 63 of 79 
Protocol Version #: 08   Date: 28-March-2022 
5.1.4.3. 
Maternal Postnatal Attachment Questionnaire  
The analysis team will examine the impact of the ESC care approach on the composite score of the 
MPAQ and its three subscales (quality, absence of hostility towards infant, and pleasure). Since these 
measures are continuous, the team will apply the GLMM with the normal link function. In addition, the 
model will examine the ESC intervention impact at hospital discharge and 6 months of age. 
5.1.4.4. 
Family Environment Scale (FES) at 3 Months 
Initially, we will base the overall assessment of the FES using the relationship dimension on a composite 
score of the 30 true-false items found on form R (i.e., range of 0-30). The analysis team will provide the 
mean and SD of the composite FES scores separately for each treatment group, and the team will use a 
GLMM with an identity link function to compare average FES scores between the ESC care approach and 
usual care. We will report point estimates for the group mean difference along with a 95% CI. The team 
will use the same four model building sequence described for the primary outcome. Additionally, we will 
repeat the analytical for each relationship dimension, namely, Cohesion, Expressiveness, and Conflict 
subscales.  
5.1.4.5. 
Parenting Sense of Competence Scale (PSOC) 
The analysis team will report descriptive statistics (mean ± SD) for the composite PSOC score separately 
for each treatment group. The team will compare the PSOC composite scores assessed at hospital 
discharge and 6-months of age using a GLMM model with identity link with a fixed effect for the 
intervention group, time, and group-by-time and a random effect for study site. We will calculate the 
point estimates and their respective CIs for the changes in PSOC scores for each intervention group and 
for the difference in the estimated change between intervention groups. Additionally, the team will 
present the p-value of the difference in point estimates between intervention groups. 
5.1.4.6. 
Infant Behavior Questionnaire (IBQ-R) Revised Very Short Form at 3 and 12 Months of Age 
The analysis team will report descriptive statistics (mean ± SD) for each domain of the IBQ-R (i.e., 
positive affectivity/surgency, negative emotionality, and orienting/regulatory capacity) separately for 
each treatment group. The team will compare the IBQ-R composite scores for each domain using 
separate GLMM models with identity link with a fixed effect for the intervention group, time, and group-
by-time and a random effect for study site. The team will report point estimates for the group mean 
difference along with a 95% CI for each domain. 
5.1.4.7. 
Bayley Scales of Infant and Toddler Development, Fourth Edition (Bayley-4): Cognitive, 
Language, and Motor at 24-Months of Age 
The analysis team will calculate descriptive statistics (mean ± SD, medians, percentiles) for each domain 
in the Bayley-4 separately for each treatment group. To compare the scores between the ESC and usual 
care groups, we will perform a linear mixed-effects model with a fixed effect for the intervention group 
and a random effect for study site. We will report point estimates for the group mean difference along 
with a 95% CI, and the team will repeat this analytical approach for each of the Bayley-4 domains.  
5.1.4.8. 
Brief Infant-Toddler Social and Emotional Assessment (BITSEA) at 24-Months of Age 
The analysis team will calculate descriptive statistics (mean ± SD, medians, percentiles) for BITSEA 
problem scale and BITSEA competence scale separately for each treatment group. To compare the 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 64 of 79 
Protocol Version #: 08   Date: 28-March-2022 
scores between the ESC and usual care groups among the two BITSEA scales, we will perform separate 
linear mixed-effects model with a fixed effect for the intervention group and a random effect for study 
site. We will report point estimates for the group mean difference along with a 95% CI.  
5.1.4.9. 
Influence of Maternal Childhood Experiences on Infant Outcomes 
The analysis team will calculate descriptive statistics (mean ± SD, medians, percentiles) for the ACE 
Questionnaire separately for each treatment group. To examine the relationship between the ACE 
Questionnaire with the IBQ-R scores and Bayley-4, the analysis team will compute separate marginal 
Pearson correlation coefficients,63 which is an analog of the standard Pearson correlation coefficient for 
clustered data. If significant, we will perform a sensitivity analysis in which we include the ACE 
Questionnaire scores as a covariate in the final analytic models for Bayley-4 and IBQ-R scores. 
5.1.4.10. Interim Analysis  
In a stepped-wedge randomized controlled trial, interim analyses for outcomes carried out early in the 
trial will have a large imbalance between numbers of observations exposed to usual care and 
intervention conditions. The imbalance will likely have power implications and will make a power 
analysis infeasible. The clustered natures of the data will also impact the analysis.64, 65 Therefore, the 
protocol study team will not conduct an interim analysis on the primary outcome for the purpose of 
study termination due to inferiority or superiority of the ESC care approach. The protocol study team 
will conduct an interim analysis for the long-term follow-up portion of the study to assess for futility due 
to under-recruitment. The projected informed consent rate for long-term follow-up is 30-40%. After 
each block of two periods (approximately 6 months), the protocol study team will compare the informed 
consent rate with the projected informed consent rate. If the actual informed consent rate over a block 
of two periods is below 30%, then the protocol study team will monitor the informed consent rate for 
another block of two periods. If the cumulative informed consent rate remains below 30%, then the 
protocol study team will ask the Data and Safety Monitoring Committee (DSMC) to review accrual 
trajectories and to determine, with the protocol study team, if measures can be taken to improve the 
accrual rate. The DSMC will consider whether to stop accrual to the long-term follow-up portion of the 
study due to an insufficient informed consent rate. Additionally, the DSMC will monitor the study for 
safety concerns (see Section 5.5.2). 
5.2. 
SAMPLE SIZE AND POWER ESTIMATES 
We based the sample size estimate (Table 5) on the primary outcome, which is the comparison of the 
average length of time until the infant is medically ready for discharge between groups (ESC care 
approach versus usual care). In much of the literature, researchers tend to report overall length of 
inpatient hospital stay (LOS). The average reported LOS for infants managed for NOWS is approximately 
18 days (SD=8)29; we expect a reduction of 4 days with use of the ESC care approach. For this study, we 
used preliminary data from the ACT NOW Current Experience Study to obtain the mean and standard 
deviation estimate for LOS. For the purpose of our sample size justification, we used these estimates as 
a proxy for our estimates of the average length of time until the infant is medically ready for discharge. 
Based on the Current Experience Study, the average LOS is approximately 11 days (SD=11). Additionally, 
we derived an estimate of the ICC of 0.25 from this preliminary data analysis. Richard Hooper and 
colleagues66 noted that most sample size justifications for stepped-wedge design studies follow a mixed-
effects regression approach for cross-sectional stepped-wedge design, as described by Hussey and 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 65 of 79 
Protocol Version #: 08   Date: 28-March-2022 
Hughes,67 which assumes that the within-period ICC and between-period ICC are equal. They define the 
cluster autocorrelation coefficient (CAC) as the ratio of the between-period ICC over the within-period 
ICC.  
We calculated statistical power based on the methodology for stepped-wedge with transition period 
design proposed by Hooper et al using the R-Shiny app written by Hemming and Kasza.66 Given that our 
primary outcome is a count measure, we used the ACT NOW Current Experience Study to obtain an 
estimate of the over-dispersion parameter (φ). McCullagh and Nelder suggested that the over-
dispersion parameter estimate (φ) is simply a ratio of the deviance or the Pearson chi-square to its 
associated degrees-of-freedom.68 Thus, a total sample size of 864 infants would achieve 90% power to 
detect a difference of 4 days between the groups with an estimated CAC of 0.8 and φ=10. This assumes 
an 8-step stepped-wedge with transition period design with 24 total sites. We will randomize each site 
into 1 of 8 blocks, and we expect each site to enroll an average of 4 infants during each period for 36 
total infants per site during the study duration. Since we have no prior information regarding the CAC 
estimate, Table 5 provides the total sample size required assuming a CAC ranging between 0.6 to 0.8 and 
differences of 3 days, 3.5 days, and 4 days. Based on the ACT NOW Current Experience Study, the 
expected number of infants with NOWS delivered at participating sites annually will be approximately 
1500-2000 infants. Therefore, our study will still be sufficiently powered (i.e., 85%) to detect a difference 
of 3 days between the groups with CAC=0.8. The power calculation assumes significance level of 5%, 
delivery of infants with NOWS equally distributed across hospital groupings, and analysis by Negative 
Binomial GLMM. 
Table 5 
Sample Size Estimates 
  
  
3 days 
3.5 days 
4 days 
Power 
CAC 
Cluster 
Size 
N 
Cluster 
N 
Cluster 
Size 
N 
Size 
90% 
0.8 
10 
2160 
6 
1296 
4 
864 
85% 
0.8 
8 
1728 
5 
1080 
3 
648 
80% 
0.8 
6 
1296 
4 
864 
3 
648 
90% 
0.7 
14 
3024 
7 
1512 
5 
1080 
85% 
0.7 
10 
2160 
6 
1296 
4 
864 
80% 
0.7 
8 
1728 
5 
1080 
3 
648 
90% 
0.6 
26 
5616 
9 
1944 
5 
1080 
85% 
0.6 
14 
3024 
6 
1296 
4 
864 
80% 
0.6 
10 
2160 
5 
1080 
3 
648 
CAC = cluster autocorrelation coefficient 
To address the primary study hypothesis, the protocol study team will randomize a minimum of 24 sites, 
and a maximum of 28 sites to 1 of 8 blocks of a stepped wedge with transition design (Table 1), with 
each site enrolling an average of 36 infants. During any single study period (see Table 1), a site may 
enroll no more than 16 infants.  Although we calculated the sample size for the overall trial using the 
power calculation for the primary hypothesis, we conducted the following power calculations to assure 
adequacy of sample size to show potential effect of the intervention on infant neurobehavioral 
functioning and development. To evaluate the impact of the ESC care approach on infant 
neurobehavioral function and development using measures such as the IBQ-R and Bayley-4, we must 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 66 of 79 
Protocol Version #: 08   Date: 28-March-2022 
obtain primary caregiver consent. We anticipate that not all participants will provide consent for the 
long-term outcome portion of the study. Table 6 provides an estimate of the effect size based on varying 
consent rates and CAC estimates with the study having 80% power. Again based on the ACT NOW 
Current Experience Study, we expect the number of infants with NOWS delivered at participating sites 
annually will be approximately 1500 infants. Thus, for a 17-month enrollment period, the protocol study 
team expects a total of 2125 infants with NOWS will be delivered at participating study sites. Assuming a 
40% or 30% consent rate, this produces a total sample size of 850 (40% consent rate) or 638 (30% 
consent rate) infants. Cohen defined effect size as the mean differences, 𝜇𝜇1 −𝜇𝜇2, divided by the 
standard deviation, σ, of either group.69 However, Rosnow and Rosenthal noted that in practice, 
researchers commonly use the pooled SD (defined as the root mean square of the 2 SDs).70 Effect sizes 
are generally classified as small (≤ 0.3), medium (~0.5), and large (≥ 0.75). For infant neurobehavioral 
functioning based on the IBQ-R, the study will have 80% power to detect an expected mean difference 
of 0.28 points in the Orienting/Regulatory Capacity domain, assuming a 30% consent rate and CAC=0.8, 
based on a mixed-effects model with a fixed treatment effect and random site effect with a significance 
level of 0.05. With a SD of 0.70, the detectable mean difference constitutes a moderate effect size. We 
based our estimated mean (5.0) and SD (0.70) for the Orienting/Regulatory Capacity domain using the 
summary statistics provided by Putnam and colleagues,46 in which the authors provided summary data 
of the IBQ-R domains extracted from six standard form data samples.   
Table 6 
Sample Size Estimates for the IBQ-R for the Consented Subpopulation 
 
Consent Rate 
Total  
Sample 
Size 
Effect Size 
(Δ) 
Mean 
Difference 
 
CAC 
 
Power 
40% 
850 
0.35 
0.25 
0.8 
0.80 
40% 
850 
0.38 
0.27 
0.7 
0.80 
40% 
850 
0.40 
0.28 
0.6 
0.80 
30% 
638 
0.40 
0.28 
0.8 
0.80 
30% 
638 
0.43 
0.30 
0.7 
0.80 
30% 
638 
0.45 
0.32 
0.6 
0.80 
CAC = cluster autocorrelation coefficient 
For the neurodevelopmental outcome based on the Bayley-4, the study will have 80% power to detect 
an expected mean difference of 6 points, assuming a 30% consent rate and CAC=0.8, based on a mixed-
effects model with a fixed treatment effect and random site effect with a significance level of 0.05. With 
a SD of 15, the detectable mean difference constitutes a moderate effect size. 
5.3. 
AVAILABLE POPULATION 
In December 2018, we completed data abstraction for the ACT NOW Current Experience Study. Twenty-
five ISPCTN and 5 NRN sites participated in this study. We collected data for 1808 infants with opioid 
exposure across these networks. Of these infants, approximately 40% were treated pharmacologically 
during the 1-year target period of July 1, 2016, to June 30, 2017 (86% morphine, 13% methadone, <1% 
buprenorphine).  

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 67 of 79 
Protocol Version #: 08   Date: 28-March-2022 
5.4. 
PROJECTED RECRUITMENT TIME 
5.4.1. Site Recruitment 
We will recruit 24 sites for this study. We will randomize these sites into 8 blocks. Initial assessment of 
site interest in study participation across the networks suggests an adequate number of sites to meet 
our site recruitment goal. The site’s ability to initiate a change in practice within their organization will 
impact actual site recruitment. Recruitment of all sites will take an estimated 3 months. We will 
randomize sites into blocks once recruitment is complete. 
5.4.2. Site Training and Implementation 
Site training and implementation will take approximately 3 months, as we will first train a core group of 
site champions, followed by training of all site personnel by the core group. The protocol study team will 
train the site champions via video conference or off-site and as such, training may occur in parallel with 
the end of the final usual care period at the site. Once a site has achieved the training milestones (see 
Training and Implementation Manual), the site will clinically implement ESC. After this initial 
implementation, the site will step into the ESC period (see Table 1). Total enrollment period is 
20 months with each site actively enrolling infants for 17 of the 20 months. If the site research team 
obtains consent for the long-term follow-up portion of the trial, the site research team will follow the 
infant for 24 months. Total length of the study will be approximately 44 months. 
5.5. 
STUDY MONITORING PLAN 
We will conduct clinical site monitoring to ensure that we protect the rights and well-being of study 
participants, that the reported trial data are accurate, complete, and verifiable, and that the conduct of 
the study complies with the currently approved protocol/amendment(s), with International Council for 
Harmonisation Good Clinical Practice, and with applicable regulatory requirements (for details specific to 
Protocol Adherence see Section 4.2.5)  
• A member of the DCC clinical operations staff or their designee will monitor the study. 
• The clinical monitoring team will plan and conduct an on-site visit at least once during the course 
of the study and more often if needed for cause. 
• Details of clinical site monitoring are in the Clinical Monitoring Plan, which will be included in the 
MOP. The plan describes who will conduct the monitoring, at what frequency monitoring will 
occur, at what level of detail monitoring will be performed, and how monitoring reports will be 
distributed.  
5.5.1. Adverse Events 
5.5.1.1. 
Definition of Adverse Events and Serious Adverse Events 
 
Adverse event (AE): AE means any untoward medical occurrence associated with the use of an 
intervention in humans, whether or not considered intervention related.  
Serious Adverse Event (SAE): An AE is considered "serious" if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes: 
1. Death 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 68 of 79 
Protocol Version #: 08   Date: 28-March-2022 
2. Life-threatening AE (life-threatening means that the study participant was, in the opinion of the 
investigator or sponsor, at immediate risk of death from the reaction as it occurred and required 
intervention)  
3. Persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
4. Inpatient hospitalization or prolongation of existing hospitalization 
5. Important medical event that may not result in 1 of the above outcomes but may jeopardize the 
health of the study participant or require medical or surgical intervention to prevent 1 of the 
outcomes listed in the above definition of serious event  
5.5.1.2. 
Classification of an Adverse Event 
Severity of Event 
For AEs, the site research team will use the following guidelines to describe severity. The site 
investigator will determine severity. 
• Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life threatening or 
incapacitating. Of note, the term “severe” does not necessarily equate to “serious.” 
Relationship to Study Intervention 
The site research team will grade the degree of certainty about causality by using the categories below.  
• Related – The AE is known to occur with the study procedures, there is a reasonable possibility 
that the study procedures caused the AE, or there is a temporal relationship between the study 
procedures and the event. Reasonable possibility means that there is evidence to suggest a 
causal relationship between the study procedures and the AE. 
• Not Related – There is not a reasonable possibility that the study procedures caused the event, 
there is no temporal relationship between the study procedures and event onset, or an alternate 
etiology has been established. 
Expected AEs  
Expected AEs include - seizures, accidental trauma, severe weight loss (greater than 15% from 
birthweight) and respiratory insufficiency. Expected AEs that could occur during the follow-up portion of 
the study include acute/urgent care and or ER visits for worsening symptoms of NOWS. Hospital 
readmission to assess and manage symptoms of NOWS and non-accidental trauma may also occur. We 
note anticipated rates in Table 7.  

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 69 of 79 
Protocol Version #: 08   Date: 28-March-2022 
5.5.1.3. 
Time Period and Frequency for Event Assessment and Follow Up 
For this study, the protocol study team will collect the following AEs: 1) all expected AEs (seizures, 
accidental trauma, severe weight loss, and respiratory insufficiency), and 2) SAEs related to study 
procedures. The occurrence of an AE or SAE may come to the attention of study personnel during the 
hospital stay, by the clinical team with administration of questionnaires, or by the medical monitor upon 
reviewing data. The site research team will capture all AEs on the appropriate case report form. 
Information to be collected includes event description, date/time of onset, date/time of resolution, 
clinician’s assessment of severity, relationship to study intervention and time of resolution/stabilization 
of the event. Site research teams must follow all AEs until the AE meets one of the following criteria: 
resolution, the condition stabilizes, the event is otherwise explained or is judged by the protocol study 
team to be no longer clinically significant, or the participant is lost to follow-up. The site research team 
will collect AEs during the initial hospitalization through hospital discharge.  
5.5.2. Data Monitoring and Safety  
The independent DSMC will have overall responsibility for interim data monitoring and operate based on 
the ISPCTN and NRN charter for the DSMC. The DSMC will formally review interim safety data in a 
sequential fashion using interim monitoring boundaries after approximately 25%, 50%, and 75% of the 
study sites (6, 12, and 18 sites, respectively) have transitioned to the ESC care approach and have 
completed one full period using the ESC care approach. Treatment groups will be compared statistically 
using the analysis planned for the final analyses for safety outcomes (as specified in Section 5.1.3). 
Safety oversight will be under the direction of a DSMC. Safety outcomes include the components of the 
inpatient composite safety outcome and those of the outpatient composite safety outcome (see Table 
7). The DSMC may request other outcomes at their discretion. Formal statistical testing for an imbalance 
of seizures, accidental trauma, or respiratory insufficiency due to opioid therapy, in either treatment 
group, will be based on a comparatively liberal Lan DeMets Pocock boundary at the three interim safety 
reviews to guard against any occurrence of false positives while at the same time allowing for stopping 
at reasonable levels of evidence. Thus, at each interim, an increased incidence of seizures in either 
treatment group with P < 0.0179 (for 4 total tests) will be considered a statistically significant evidence 
of harm that the DSMC can use to recommend suspension of the trial for safety reasons. This same 
statistical testing will also be conducted for the components of the outpatient composite safety 
outcome. In addition to the formal safety outcomes, the DSMC will examine other safety outcomes, 
including all reported SAEs by treatment group in considering a recommendation to suspend the trial for 
safety reasons. 
The Medical Monitor will provide input on safety considerations, evaluate safety trends, and provide 
oversight throughout the life cycle of the clinical research, in accordance with the approved protocol. 
This role includes reviewing and monitoring safety events on a regular basis, advising the protocol 
investigators on trial-related medical questions or problems, reviewing cumulative participant safety 
data, and making recommendations regarding the data to the DSMC.  

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 70 of 79 
Protocol Version #: 08   Date: 28-March-2022 
 Table 7  
Expected Rates of Safety Outcomes 
Safety Outcomes 
Expected Rate 
 
Inpatient Safety Composite  
 
Seizures71, 72 
1% 
Accidental trauma (i.e., dropped infants)73, 74 
4 falls per 10,000 births 
Respiratory insufficiency due to opioid therapy 
0.5% 
 
Outpatient Safety Composite 
 
Acute/urgent care and/or ER visits – 1 visit in first 6 months of life75 
35% 
Hospital Readmissions in the first 6 months of life75 
7% 
 
SECTION 6. 
DATA MANAGEMENT  
The data management center, RTI International, will: 
• Collaborate in the development, implementation, and monitoring of ESC protocol.    
• Provide data management, including development of CRFs and appropriate data collection 
systems 
• Supervise data entry activities, including instructing and certifying data entry personnel in 
software and hardware usage, quality assurance of data entry, etc.  
• Manage the Data Safety and Monitoring Committee for the trial.  This will include scheduling 
meetings and the DSMC charter.   
• Oversee the receipt and reconciliation of safety data.   
• Supervise NRN-site quality assurance efforts, including conducting site visits and remote 
monitoring of data.   
• Prepare and distributes monthly reports, detailing data received, data consistency, missing data 
and adherence to protocol.   
• Disburse capitation payments to clinical centers on the basis of enrolled participants and other 
study-specific milestone triggers specified in the study protocol.  
• Provide the logistical support necessary to run an efficient and productive network.  
 
 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 71 of 79 
Protocol Version #: 08   Date: 28-March-2022 
SECTION 7. 
 PUBLICATION AND DATA SHARING POLICY 
This study will comply with the National Institutes of Health (NIH) Public Access Policy, which ensures 
that the public has access to the published results of NIH-funded research. The study will also comply 
with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical Trial 
Information and the Clinical Trials Registration and Results Information Submission rule. 
As such, this study will: 
• Register with ClinicalTrials.gov and submit primary outcome results.  The ClinicalTrial.gov 
number is NCT04057820. 
• Publish results. The protocol study team will make every attempt to publish results in peer-
reviewed journals. The team will submit all final peer-reviewed journal manuscripts from this 
study to the digital archive PubMed Central upon acceptance for publication. 
• Deposit data for data sharing with other researchers. Within the bounds of relevant IRB 
approvals and guidelines for protection of personally identifiable data, the protocol study team 
will deposit de-identified data from this study in an appropriate, NIH-approved data repository. 
 
 

Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 72 of 79 
Protocol Version #: 08   Date: 28-March-2022 
SECTION 8. 
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Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 73 of 79 
Protocol Version #: 08   Date: 28-March-2022 
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Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 74 of 79 
Protocol Version #: 08   Date: 28-March-2022 
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Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 75 of 79 
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Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 76 of 79 
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Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 77 of 79 
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Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 78 of 79 
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Title:  Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal (ESC-NOW):  
           A Function-Based Assessment and Management Approach 
Sponsor:  National Institutes of Health 
cIRB #: 239729                                                                                                                                                   Page 79 of 79 
Protocol Version #: 08   Date: 28-March-2022