Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns With Neonatal Opioid Withdrawal Syndrome (NOWS)
Phase: PHASE3
Conditions: Neonatal Opioid Withdrawal Syndrome
Sponsor: Advancing Clinical Trials in Neonatal Opioid Withdrawal (ACT NOW) Program

cIRB #: 260053                                                                                                                                      Page 1 of 83 
Protocol Version #: 11    Date:  27-September-2024 
 
Pragmatic, Randomized, Blinded Trial to Shorten 
Pharmacologic Treatment of Newborns with Neonatal Opioid 
Withdrawal Syndrome (NOWS) 
UAMS IRB (cIRB) Protocol Number 260053 
Version Number: 11 
September 27, 2024 
 
 
ClinicalTrials.gov number: 
NCT04214834  
NRN ID number:  
NICHD-ACT-NOW-0003 
Operational Principal Investigator for UAMS (central) IRB:     
                                                                  Sherry Courtney, MD 
                                                                  University of Arkansas for Medical Sciences 
 
Operational Principal Investigator:    Abhik Das, PhD 
                                                                  RTI International 
 
Lead Study Investigator(s): 
Abbot Laptook, MD, Adam Czynski, DO 
 
Brown University/Connecticut Children's Medical Center 
 
Subcommittee Members:  
Brian Smith, MD, Duke Clinical Research Institute 
Rachel Greenberg, MD, Duke Clinical Research Institute 
Robert Annett, PhD, University of New Mexico 
Songthip Ounpraseuth, PhD, UAMS 
Sherry Courtney, MD, UAMS 
Fred Prior, PhD, UAMS 
Claudia Pedroza, PhD, University of Texas, Houston 
Barry Lester PhD, Brown University/Women & Infants Hospital of Rhode 
Island  
Barry Eggleston, PhD, RTI International 
Drew Bremer, MD, NICHD NRN 
Abhik Das, PhD, NICHD NRN 
Elisabeth McGowan, MD, Brown University/Women & Infants Hospital 
of Rhode Island   
Funding: 
National Institute of Health  

cIRB #: 260053                                                                                                                                      Page 2 of 83 
Protocol Version #: 11    Date:  27-September-2024 
Summary of Key Changes from Version 01 to Version 02: 
Affected 
Section(s) 
Summary of Revisions Made  
(Version 01 to 02) 
Rationale 
Cover 
Added additional Operational PI, Abhik Das, Ph.D. 
There will be an operational PI 
for UAMS cIRB processes and 
operational PI for the study 
processes 
Throughout 
Expanded study from end time of 4-week post-
discharge to child at 24 months of age.  Specifically 
added assessments when child is 6, 12, 18, and 24 
months of age. 
New Assessments added: 
• 
Infant weight/length/head circumference 
• 
Caregiver questionnaire 
• 
Death 
• 
Bayley assessment 
• 
BITSEA assessment 
Study assessments and timing 
of assessment were revised to 
align with 2 companion 
neonatal opioid withdrawal 
protocols, including ESC-NOW 
(UAMS IRB # 239729) 
Section 1.4, 
Study 
Intervention/ 
Methods 
• 
Added last paragraph, which describes that 
assessments that will be done. 
Study assessments and timing 
of assessment were revised to 
align with 2 companion 
neonatal opioid withdrawal 
protocols, including ESC-NOW 
(UAMS IRB # 239729) 
Sections 
1.6.3.;  
3.2.3.; 
5.1.2.; 
Added secondary outcomes #10, 11, and 12 
Internal consistency (to go with 
new assessments). 
Section 1.7, 
Table 1, 
secondary 
objectives 
section 
Added last 3 objectives (listed below), as well as 
associated endpoints: 
• 
To determine whether a rapid- or slow-wean 
intervention among infants receiving an opioid 
(defined as morphine or methadone) as the 
primary treatment for neonatal opioid 
withdrawal syndrome (NOWS) affects growth 
over the first 24 months of age 
• 
To determine whether a rapid- or slow-wean 
intervention among infants receiving an opioid 
(defined as morphine or methadone) as the 
primary treatment for neonatal opioid 
withdrawal syndrome (NOWS) affects infant 
wellness after discharge and until 24 months 
of age 
• 
To determine whether a rapid- or slow-wean 
intervention among infants receiving an opioid 
Study assessments and timing 
of assessment were revised to 
align with 2 companion 
neonatal opioid withdrawal 
protocols, including ESC-NOW 
(UAMS IRB # 239729) 

cIRB #: 260053                                                                                                                                      Page 3 of 83 
Protocol Version #: 11    Date:  27-September-2024 
Affected 
Section(s) 
Summary of Revisions Made  
(Version 01 to 02) 
Rationale 
(defined as morphine or methadone) as the 
primary treatment for neonatal opioid 
withdrawal syndrome (NOWS) affects infant 
development. 
Section 3.3.2 
final 
paragraph in 
section 
Additional background information given. 
Provides additional rationale for 
study/study design. 
Section 3.3.3 
Added paragraph starting “Site Practice for 
Weaning Strategies of Pharmacological Treatments 
of NOWS.” 
Provides additional rationale for 
study/study design. 
Section 4.2.1 
(table 3) 
• 
New assessments added: 
o Infant weight, length, head circumference 
o Caregiver questionnaire 
o Death 
o Bayley Scales of Infant and Toddler 
Development, Fourth Edition (Bayley-4):  
o Brief Infant-Toddler Social and Emotional 
Assessment (BITSEA) 
• 
New time point added 
o Brief symptom inventory at 24 months (in 
addition to initial 1-month 
• 
New information to be collected 
Periodically collect participant contact information 
updates  
Study assessments and timing 
of assessment were revised to 
align with 2 companion 
neonatal opioid withdrawal 
protocols, including ESC-NOW 
(UAMS IRB # 239729) 
Section 4.2.4 
Added 
“If there are any concerns regarding the cognitive 
status of the mother, the site PI or designee will be 
consulted.  If the infant’s mother is cognitively 
impaired and is unable to provide informed 
consent to the research study, then an alternative 
legal guardian may be approached for consent per 
local guidelines. Sites will follow location-specific 
requirements for enrollment of wards of the state.  
If legal guardianship changes, the new legal 
guardian would be contacted to obtain consent for 
the study.” 
 
Addresses cIRB major 
contingency #3 (to specify 
provisions for screening and 
consenting/assenting mothers 
with cognitive impairment) and 
minor contingency #22 (to 
indicate location-specific 
requirements will be followed). 

cIRB #: 260053                                                                                                                                      Page 4 of 83 
Protocol Version #: 11    Date:  27-September-2024 
Affected 
Section(s) 
Summary of Revisions Made  
(Version 01 to 02) 
Rationale 
Section 
4.2.17. Post-
hospital 
procedures. 
Re-wrote 1st paragraph and the majority of the rest 
of this section. 
Clarified wording. Ensured new 
assessments /assessment time 
points were consistently 
described throughout the 
protocol 
Section 4.3.1. 
Rapid Wean  
The following statement was added:  
The rapid wean schedule is used routinely as 
standard of care at some U.S. hospitals. 
Addresses, in part, cIRB major 
contingency #2 (regarding what 
is considered standard of care). 
Section 4.3.2. 
Slow Wean 
The following statement was added:  
The slow wean schedule is used routinely as 
standard of care at some U.S. hospitals.   
Addresses, in part, cIRB major 
contingency #2 (regarding what 
is considered standard of care). 
Section 4.3.4, 
Maternal 
opioid use 
reporting 
requirements 
Added section with the following content: 
The responsibility for determination of whether 
neonatal opioid exposure warrants mandatory 
reporting will rest with the clinical team per local 
standards. Participation in the clinical study will 
not affect reporting requirements. 
 
Address, in part, cIRB major 
contingency #1 (regarding 
mandatory reporting 
requirements concerning 
neonatal opioid exposure) 
Section 5.1.4. 
Analysis of 
the Primary 
Hypothesis 
Added final paragraph. Specifically: 
Descriptive statistics (means, medians, SD, 
percentiles) for number of days of opioid 
treatment from the first weaning dose to cessation 
of opioid treatment will be generated and 
summarized in a table by treatment group. 
 
Simple correction/addition. 
Section 5.1.5, 
Analysis of 
Secondary 
Outcomes 
Added new bullet points and information (esp. 
new paragraphs # 4, 7, 8, 9, and 10) after the 
bullets) about analyses for newly added 
assessments/assessment time points.  
Internal consistency (to go with 
new assessments/new time 
points). 
Section 
5.1.6., 
Bayesian 
analysis 
Made statistical model/software corrections to 
paragraphs 5 and 7. 
Simple corrections/additions. 
Appendix 3. 
Recruitment 
plan 
Added that initial contact with potential 
participants will be made by clinical staff rather 
than research staff (unless research staff are part 
of the same clinic). 
Addresses contingency of UAMS 
IRB (cIRB). 
 
 

cIRB #: 260053                                                                                                                                      Page 5 of 83 
Protocol Version #: 11    Date:  27-September-2024 
Summary of Key Changes from Version 02 to Version 03: 
Affected 
Section(s) 
Summary of Revisions Made  
(Version 02 to 03) 
Rationale 
Section 4.3.4. Changed that mandatory reporting will rest “with 
the clinical team per local standards” to reporting 
will rest “with all mandatory reporters per 
requirements of those reporters.” 
Addressing IRB minor 
contingency bullet 1. 
Section 6.0, 
Data 
Management 
(new section) 
Added section 6.0, Data Management, to delineate 
the role of RTI International. 
 
 
To clarify RTI International’s role 
for ceding purposes. 
 
Summary of Key Changes from Version 03 to Version 04: 
Affected 
Section(s) 
Summary of Revisions Made  
(Version 03 to 04) 
Rationale 
Section 1.4; 
Table 1; 
Table 3; 
Section 
4.2.17; 
Section 5.1.5; 
References 
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 concur 
Table 3 
Updated windows for follow-up assessment 
Clarified and standardized 
windows for collecting follow up 
assessments 
Section 4.3.3 
Revised protocol to indicate triggers for maternal 
intervention based on PROMIS scores for severe 
depression 
Consistency with revised 
measures 
Section 5.4.1 
Clarifying assessment of enrollment targets if 
there are lags in recruitment 
Provide clearer decision tools 
for DSMC to review enrollment 
data if there are lags in 
recruitment 
Table 4; 
Table 5;  
Appendix 4; 
Appendix, 5; 
Appendix 6; 
Appendix 7; 
Appendix 8 
Dose levels listed changed from numbers to letters 
Consistency with Pharmacy 
Manual 
Appendix 8 
Updated dosing level language and graphics 
Consistency with Pharmacy 
Manual 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 6 of 83 
Protocol Version #: 11    Date: 27-September-1024 
 
Summary of Key Changes from Version 04 to Version 05: 
Affected 
Section(s) 
Summary of Revisions Made  
(Version 04 to 05) 
Rationale 
4.2.4; 
Appendix 3 
Addition of remote consenting 
Changed due to (a) COVID-19 
pandemic (b) relative availability 
of guardian (c) change of 
guardianship 
4.3.3; 4.3.4; 
table of 
contents 
Updated formatting for section 4.3.3 & 4.3.4  
Corrected headers 
 
 
Summary of Key Changes from Version 05 to Version 06: 
Affected 
Section(s) 
Summary of Revisions Made  
(Version 05 to 06) 
Rationale 
5.5.1 
Updated language for SAE reporting – “Study 
personnel will promptly report (within 24 hours of 
knowledge) all SAEs that the study intervention at 
least possibly relates to or are unexpected to the 
study sponsor and the DCC.  The designated 
Medical Monitor will review these events and will 
forward them to the Chair of the DSMC.” 
Simple Correction. Changed 
“and” to “or”. 
 
 
Summary of Key Changes from Version 06 to Version 07: 
Affected 
Section(s) 
Summary of Revisions Made  
(Version 06 to 07) 
Rationale 
1.4 
New language for NNNS training and video 
consent – “Some participating sites may need to 
train their study staff on the NNNS procedure. The 
NNNS training requires video recordings of infants 
sent to the training center at Brown University. 
Only the trainers at the Brown Center or their 
trainer designee and site trainees will have access 
to the video. The video will be deleted from the 
server once it has been reviewed for training 
purposes, and training on that video is complete. 
These infants may or may not be otherwise 
involved in the protocol. Sites may assess infants 
Consent required because we 
would not be doing this training 
or exposing these infants to this 
videotaping at this time if not 
for the study. 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 7 of 83 
Protocol Version #: 11    Date: 27-September-1024 
Affected 
Section(s) 
Summary of Revisions Made  
(Version 06 to 07) 
Rationale 
who will not enroll in the study; infants who will 
enroll, or both for this training. Because this 
training activity will not yield study data, a 
separate consent form will be used for this 
training.” 
 
 
Summary of Key Changes from Version 07 to Version 08: 
Affected 
Section(s) 
Summary of Revisions Made  
(Version 07 to 08) 
Rationale 
3.3.4; 
Rationale & 
Summary 
Correction of typographical/mathematical errors: 
FROM 8424 TO 9032 (bullet 5) and FROM 
$7,8484,808 TO $7,848,808 (bullet 6) 
Simple corrections for 
clarification. 
4.2.1, Table 
3; (Schedule 
of Activities) 
Added: 
• 
Screening to “prior to birth” and “at risk” 
columns 
• 
“randomization” to randomization column 
• 
Monitoring serious adverse events at “Post 
Intervention Evaluation” and “Hospital 
Discharge” 
• 
Check/record death for times between 
“randomization” and “1 Month Post 
Discharge,” inclusive 
Corrected 
• 
“enrollment” to “randomization” in left hand 
column 
Corrections to match protocol 
to practice. 
4.2.3; 
Screening 
Added language to allow for screening of  
• 
pregnant mothers who may give birth to 
babies with NOWS.   
• 
medical records of mothers with known 
opioid exposure/use 
• 
infants (medical records of) who may quality 
Increase the chances of 
enrolling mothers when they 
may be most receptive to the 
study and to expand the pool of 
potential participants 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 8 of 83 
Protocol Version #: 11    Date: 27-September-1024 
Affected 
Section(s) 
Summary of Revisions Made  
(Version 07 to 08) 
Rationale 
4.2.4;  
Consent; 
Appendix 3; 
Re-wrote/expanded most of section. Added new 
language: 
• 
for consenting pregnant mothers.  
• 
for consenting post-partum mothers whose 
babies have not yet met inclusion criteria but 
whose babies are likely to meet study 
criteria. 
• 
to explain the use of the infant-only and 
caregiver-only consent forms 
• 
to explain custody change processes are site-
specific due to variation in state and local 
laws and requirements 
Revised 
• 
language regarding legal guardians/legally 
authorized representatives 
• 
Change allowable time 
frame for consenting 
process and 
documentation.  This is to 
facilitate consenting in a 
potentially calmer 
environment with less 
distractions and to decrease 
the number of remote 
consents due to parent(s) 
being away from the site 
when their infant is placed 
on pharmacological therapy 
• 
To explain the purposes for 
the various consent forms 
4.2.6; Study 
Intervention 
• 
Added to subsection “Changes in Opioid Dose” 
o bullet  “Escalation of study drug dose is the 
mechanism to address NOWS… “ 
• 
Added to subsection “Other Criteria to Exit the 
Intervention” 
o unable to take enteral opioid medications 
• 
Deleted from subsection “Other Criteria to Exit 
the Intervention” 
o “change in feeding strategy (nasal-gastric 
tube feeds, IV fluids) 
• 
Added to subsection “Post Intervention”  
o Guidance for restarting pharmacological 
therapy for recurrence of NOWS symptoms 
Clarifications/ corrections 
4.2.12; 
Adverse 
events 
Deleted of “use of nasogastric tube for feeding” as 
an adverse event 
Allows for feeding via 
nasogastric tube 
General 
• 
Corrected section numbers that were non-
sequential 
• 
Added header to pages where it was missing 
• 
Reformatted tables in appendices so tables fit 
pages. 
Simple corrections/formatting. 
 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 9 of 83 
Protocol Version #: 11    Date: 27-September-1024 
Summary of Key Changes from Version 08 to Version 09: 
Affected 
Section(s) 
Summary of Revisions Made  
(Version 08 to 09) 
Rationale 
4.2.18; 
Compensation 
Section added. 
• 
Increased total amount of 24-month time point 
reimbursement from $100 to $150.  This is to 
increase reimbursement for the in-person visit 
from $50 to $100. 
• 
Added payments tables related to each 
consent form. 
• 
Increased amount for in-
person visit from $50 to 
$100 to provide more 
equitable payment. 
• 
Payment information was 
not previously included in 
the protocol 
 
Summary of Key Changes from Version 09 to Version 10: 
Affected 
Section(s) 
Summary of Revisions Made  
(Version 09 to 10) 
Rationale 
4.2.4;   
Consent 
• 
Requested a waiver of documentation of 
written consent to allow the disclosure of 
participant contact information between sites 
when it is more convenient for a participant to 
follow-up with a new site. 
• 
Will facilitate participant 
transfer between sites. 
 
Summary of Key Changes from Version 10 to Version 11: 
Affected 
Section(s) 
Summary of Revisions Made  
(Version 10 to 11) 
Rationale 
Face page 
• 
Replaced Jessica Snowden with Sherry 
Courtney in the role of Operational PI for 
UAMS. 
• 
Jessica Snowden left UAMS 
at the end of August 2024.   
Face page 
• 
Primary Investigator Adam Czynski’s affiliation 
changed from Women & Infants Hospital of 
Rhode Island to Connecticut Children's 
Medical Center 
• 
Correction 
Face page 
• 
Subcommittee roster updated 
• 
Personnel changes 
 
 
 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 10 of 83 
Protocol Version #: 11    Date: 27-September-1024 
Contents 
Section 1. 
Abstract ............................................................................................................................. 13 
1.1. 
Study Hypothesis/Question ................................................................................. 13 
1.2. 
Study Design Type ................................................................................................ 13 
1.3. 
Eligibility Criteria .................................................................................................. 13 
1.3.1. Inclusion Criteria ..................................................................................... 13 
1.3.2. Exclusion Criteria .................................................................................... 13 
1.4. 
Study Intervention/Methods ............................................................................... 14 
1.5. 
Primary Outcome ................................................................................................. 15 
1.6. 
Secondary Outcomes ........................................................................................... 15 
1.6.1. Secondary Efficacy Outcomes ................................................................. 15 
1.6.2. Secondary Safety Outcome .................................................................... 15 
1.6.3. Other Secondary Outcomes.................................................................... 16 
1.7. 
Study Objectives and Endpoints .......................................................................... 16 
1.8. 
Sample Size and Power ........................................................................................ 18 
1.9. 
Projected Recruitment Time ................................................................................ 19 
Section 2. 
Conflict of Interest Disclosures ......................................................................................... 20 
2.1. 
Financial Conflicts of Interest of the Institutions and Investigators .................... 20 
2.1.1. Plan for Managing Identified Financial Conflicts of Interests ................. 20 
Section 3. 
Statement of Problem....................................................................................................... 21 
3.1. 
Primary Hypothesis or Question .......................................................................... 21 
3.2. 
Secondary Outcomes ........................................................................................... 21 
3.2.1. Secondary Efficacy Outcomes ................................................................. 21 
3.2.2. Secondary Safety Outcome .................................................................... 21 
3.2.3. Other Secondary Outcomes.................................................................... 21 
3.3. 
Background and Rationale ................................................................................... 22 
3.3.1. Public Health Impact ............................................................................... 22 
3.3.2. Background ............................................................................................. 22 
3.3.3. Preliminary Data ..................................................................................... 25 
3.3.4. Rationale and Summary .......................................................................... 26 
Section 4. 
Methods ............................................................................................................................ 28 
4.1. 
Eligibility Criteria .................................................................................................. 28 
4.1.1. Inclusion Criteria ..................................................................................... 28 
4.1.2. Exclusion Criteria .................................................................................... 28 
4.2. 
Detailed Study Procedures .................................................................................. 29 
4.2.1. Overview ................................................................................................. 29 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 11 of 83 
Protocol Version #: 11    Date: 27-September-1024 
4.2.2. Patient Recruitment Plan ........................................................................ 31 
4.2.3. Screening ................................................................................................ 31 
4.2.4. Consent Procedures ................................................................................ 31 
4.2.5. Randomization Procedures ..................................................................... 33 
4.2.6. Study Intervention and Comparison ....................................................... 34 
4.2.7. Blinding/Masking .................................................................................... 39 
4.2.8. Control or Monitoring of Co-interventions............................................. 39 
4.2.9. Primary Outcome .................................................................................... 39 
4.2.10. Secondary Outcomes .............................................................................. 40 
4.2.11. Safety Outcomes ..................................................................................... 40 
4.2.12. Adverse Events........................................................................................ 40 
4.2.13. Serious Adverse Events ........................................................................... 40 
4.2.14. Compliance Monitoring .......................................................................... 41 
4.2.15. Data Quality Monitoring and Assurance ................................................ 41 
4.2.16. Study Specimens ..................................................................................... 43 
4.2.17. Post-Hospital Procedures ....................................................................... 43 
4.2.18. Compensation ......................................................................................... 43 
4.3. 
Potential Risks and Benefits to participants ........................................................ 45 
4.3.1. Rapid Wean ............................................................................................. 45 
4.3.2. Slow Wean .............................................................................................. 46 
4.3.3. Primary Caregiver Well-Being ................................................................. 46 
4.3.4. Maternal opioid use reporting requirements ......................................... 46 
Section 5. 
Analytical Plan ................................................................................................................... 47 
5.1. 
Statistical Analysis Plan ........................................................................................ 47 
5.1.1. Primary Hypothesis ................................................................................. 47 
5.1.2. Secondary Outcomes .............................................................................. 47 
5.1.3. Other Collected Data .............................................................................. 48 
5.1.4. Analysis of the Primary Hypothesis and Outcome ................................. 48 
5.1.5. Analyses of Secondary Outcomes ........................................................... 49 
5.1.6. Bayesian Analyses ................................................................................... 52 
5.2. 
Design Considerations, Sample Size, and Power Estimates ................................ 53 
5.2.1. Overall Trial Design ................................................................................. 53 
5.2.2. Compatibility with the ESC Trial ............................................................. 53 
5.2.3. Sample Size and Power Estimates .......................................................... 54 
5.2.4. Interval Sample Size Reassessment ........................................................ 55 
5.3. 
Available Population ............................................................................................ 56 
5.4. 
Projected Recruitment Time ................................................................................ 56 
5.4.1. Assessment of Enrollment Target ........................................................... 57 
5.5. 
Study Monitoring Plan ......................................................................................... 57 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 12 of 83 
Protocol Version #: 11    Date: 27-September-1024 
5.5.1. Reporting Adverse Events ....................................................................... 57 
5.5.2. Data Monitoring Plan and Stopping Rules .............................................. 58 
Section 6. 
DATA MANAGEMENT........................................................................................................ 60 
Section 7. 
Publication and Data Sharing policy ................................................................................. 61 
Section 8. 
References ........................................................................................................................ 62 
Section 9. 
Data Forms ........................................................................................................................ 65 
9.1. 
Screening Log ....................................................................................................... 65 
9.2. 
Randomization Form............................................................................................ 65 
9.3. 
Maternal Medical History Form ........................................................................... 65 
9.4. 
Infant Medical History Form ................................................................................ 65 
9.5. 
Weaning Intervention form ................................................................................. 65 
9.6. 
Pharmacy Drug Administration Form .................................................................. 65 
9.7. 
Status Form 65 
9.8. 
Post Discharge Form ............................................................................................ 65 
9.9. 
Adverse and Serious Adverse Events Form ......................................................... 65 
9.10. 
Protocol Violation Form ....................................................................................... 65 
9.11. 
Study Withdrawal Form ....................................................................................... 65 
Section 10. 
Appendices........................................................................................................................ 66 
Appendix 1. 
Infant Characteristics and Demographics (ACT NOW Current 
Experience) ..................................................................................... 66 
Appendix 2. 
Pharmacologic Treatment (ACT NOW Current Experience) ........... 67 
Appendix 3. 
Recruitment Plan ............................................................................ 68 
Appendix 4. 
Morphine: Example of Weaning with Dosing Every Three Hours .. 73 
Appendix 5. 
Morphine: Example of Weaning with Dosing Every Four Hours .... 74 
Appendix 6. 
Methadone: Example of Weaning with Dosing Every Eight Hours 75 
Appendix 7. 
Methadone: Example of Weaning with Dosing Every 12 Hours .... 76 
Appendix 8. 
Pharmacy Dosing Calculator ........................................................... 77 
Appendix 9. 
Changes Morphine/Methadone Dose Using Hospital Guidelines 
and Protocol Guidelines ................................................................. 79 
Appendix 10. 
Placebo Dose Utilization to Maintain the Blind in the Rapid-Wean 
Intervention .................................................................................... 80 
 
 
 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 13 of 83 
Protocol Version #: 11    Date: 27-September-1024 
 
SECTION 1. 
ABSTRACT 
1.1. 
STUDY HYPOTHESIS/QUESTION  
Among infants receiving an opioid (defined as morphine or methadone) as the primary treatment for 
neonatal opioid withdrawal syndrome (NOWS), a rapid-wean intervention will reduce the days of opioid 
treatment from the first weaning dose to cessation of opioid compared to a slow-wean intervention.   
 
1.2. 
STUDY DESIGN TYPE  
Pragmatic, randomized, blinded, trial  
 
1.3. 
ELIGIBILITY CRITERIA  
 
1.3.1. Inclusion Criteria  
1.3.1.1. Hospital Level 
1) Hospital provides pharmacologic treatment to at least an average of 12 opioid exposed infants 
each year 
2) Hospital uses a scoring system to assess for signs of NOWS (original or modified Finnegan 
Neonatal Abstinence Scoring system, Eat-Sleep or Console) 
3) Hospital provides opioid replacement therapy with either morphine or methadone as part of 
pharmacologic treatment of NOWS 
 
1.3.1.2 Infant Level 
Infants need to fulfill all of the following criteria: 
1) Gestational age ≥ 36 weeks 
2) Receiving scheduled pharmacological therapy with morphine or methadone as the primary 
drug treatment for NOWS secondary to maternal opioid use 
3) Tolerating enteral feeds and medications by mouth 
 
1.3.2. Exclusion Criteria  
1.3.2.1. Hospital Level 
1) Hospitals discharge > 10% of infants from the hospital on opioid replacement therapy on 
average per year 
 
1.3.2.2. Infant Level 
Any of the following is an infant level exclusion criterion:  
1) Major birth defect (e.g. gastroschisis) 
2) Any major surgery (minor surgery [e.g., circumcision, digit ligation, frenulectomy] is not an 
exclusion criterion) 
3) Hypoxic-ischemic encephalopathy 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 14 of 83 
Protocol Version #: 11    Date: 27-September-1024 
4) Seizures from etiologies other than NOWS 
5) Treatment with opioids for reasons other than NOWS 
6) Respiratory support (nasal cannula or greater) for > 72 hours 
7) Planned discharge from the hospital on opioids 
8) Use of other opioids (e.g., buprenorphine) as primary drugs for treatment of NOWS 
9) Weaning of morphine or methadone as the primary treatment of NOWS has started 
 
1.4. 
STUDY INTERVENTION/METHODS   
This will be a pragmatic, randomized, blinded trial comparing a rapid-wean intervention (15% 
decrements from the stabilization dose) to a slow-wean intervention (10% decrements from the 
stabilization dose) to determine whether rapid weaning will reduce the number of treatment days 
among infants receiving morphine or methadone orally as the primary treatment for NOWS. 
Participating hospitals must provide pharmacologic treatment to at least an average of 12 opioid 
exposed infants each year, use a scoring system to assess for signs of NOWS (original or modified 
Finnegan Neonatal Abstinence Scoring system, Eat-Sleep or Console), and provide opioid replacement 
therapy with either morphine or methadone as the primary drug for treating NOWS. Hospitals may 
change use of these two opioids during the trial period. We will stratify randomization by hospital. The 
study protocol will commence after NOWS signs have been controlled with an opioid (stabilization) and 
weaning of pharmacologic treatment is to be started. At or before each 24-hour interval, clinical team 
members will evaluate and score infants, per hospital practice, for signs of NOWS to determine if the 
infant will tolerate weaning of the study drug.  
• 
If the infant can tolerate weaning and is in the rapid-wean intervention arm, the clinical team 
will reduce the study drug by 15% of the stabilization dose. The clinical team will terminate the 
study drug when the infant can tolerate 25% of the stabilization dose without NOWS signs.  
• 
If the infant can tolerate weaning and is in the slow-wean intervention arm, the clinical team will 
reduce the study drug by 10% of the stabilization dose. The clinical team will terminate the 
study drug when the infant can tolerate 20% of the stabilization dose without NOWS signs.  
• 
If infants cannot tolerate weaning in either intervention arm, infants will enter a 12-hour period 
of study protocol guideline that will mandate either weaning or escalating the study drug by the 
end of the 12-hour interval. If the clinical team escalates the study drug, infants will receive 
opioid using the prior step of the assigned intervention arm. 
 
To maintain blinding of study drug dose during the interventions, the volume of the syringe will be 
constant and equal the volume of the opioid at stabilization. As the clinical team decreases the study 
drug during the interventions, the pharmacist will add normal saline to keep a constant syringe volume. 
Only the pharmacy will be aware of the opioid dose. The use of placebo (normal saline without opioid) 
in the rapid-wean intervention arm will ensure comparable duration of both weaning interventions. 
 
As part of a pragmatic trial, clinical teams will follow hospital practice for other care practices related to 
NOWS treatment (type of scoring system, threshold to initiate treatment, duration of stabilization, use 
of second-line and third line-drugs, rooming in, breast milk, etc.). After study drug cessation, the clinical 
team will observe infants in the hospital for at least 48 hours prior to discharge, which is similar to 
clinical practice. A trained examiner will administer the Neonatal Intensive Care Unit (NICU) Network 
Neurobehavioral Scale (NNNS) to assess neurobehavioral profiles after infants cease study drug and 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 15 of 83 
Protocol Version #: 11    Date: 27-September-1024 
prior to discharge. Some participating sites may need to train their study staff on the NNNS procedure. 
The NNNS training requires video recordings of infants sent to the training center at Brown University. 
Only the trainers at the Brown Center or their trainer designee and site trainees will have access to the 
video. The video will be deleted from the server once it has been reviewed for training purposes, and 
training on that video is complete. These infants may or may not be otherwise involved in the protocol. 
Sites may assess infants who will not enroll in the study; infants who will enroll, or both for this training. 
Because this training activity will not yield study data, a separate consent form will be used for this 
training.  
 
At one month post discharge, primary caregivers will complete the Parent-Reported Outcome Measure 
Information System (PROMIS) Measures, the Maternal Postnatal Attachment Questionnaire (MPAQ) and 
a caregiver questionnaire.   The site research team will contact the primary caregiver(s) to update 
contact information and/or complete questionnaires when the infant is 6 months, 12 months, 18 
months, and 24 months of age. The questionnaires will assess infant wellness, neurobehavioral 
functioning and development, postnatal attachment and bonding, and caregiver well-being.  At  24 
months, the infants will be seen during which a, certified developmental specialists, blinded to the 
intervention, will administer the Bayley Scales of Infant and Toddler Development, Fourth Edition 
(Bayley-4) to assess infant neurodevelopment.  The PROMIS Measures and the Brief Infant Toddler 
Social Emotional Assessment (BITSEA) will also be administered during the 24 month visit along with 
measures of growth. 
 
1.5. 
PRIMARY OUTCOME   
The number of days of opioid treatment (used as primary treatment), including escalation, resumption, 
and spot treatment, from the first weaning dose to cessation of opioid.   
 
1.6. 
SECONDARY OUTCOMES  
 
1.6.1. Secondary Efficacy Outcomes  
Secondary Outcome 1. The numbers of days of opioid treatment from the first weaning dose to 
cessation of opioid with a rapid and slow-wean interventions among infants treated with morphine. 
Secondary Outcome 2. The numbers of days of opioid treatment from the first weaning dose to 
cessation of opioid with a rapid and slow-wean interventions among infants treated with methadone. 
Secondary Outcome 3. The proportions of infants in the rapid and slow-wean intervention arms who 
have an escalation or resumption of opioid medication during weaning.       
Secondary Outcome 4. The total amounts of opioid from the first weaning dose to cessation of opioid 
among infants in the rapid and slow-wean intervention arms. 
Secondary Outcome 5. The proportion of infants who experience initiation and/or escalation of second-
line or third-line drugs to treat NOWS signs from the first weaning dose to cessation of opioid in the 
rapid-wean and slow-wean intervention arms.  
 
1.6.2. Secondary Safety Outcome 
Secondary Outcome 6. The proportion of infants in each intervention arm with safety outcomes of 
seizures (clinical or EEG), excessive stool output, respiratory disturbances, and feeding tolerance. 
 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 16 of 83 
Protocol Version #: 11    Date: 27-September-1024 
1.6.3. Other Secondary Outcomes 
Secondary Outcome 7. The proportion of infants in each intervention arm with an atypical NNNS 
neurobehavioral profile prior to discharge. 
Secondary Outcome 8. The lengths of hospital stay for infants in each intervention arm.  
Secondary Outcome 9. Assessments of maternal well-being and maternal-infant attachment after 
discharge in each intervention arm. 
Secondary Outcome 10. Assessments of growth in each intervention arm. 
Secondary Outcome 11. Assessment of infant wellness after discharge and until 24 months of age in 
each intervention arm. 
Secondary Outcome 12. Assessment of infant development to 24 months of age in each intervention 
arm. 
1.7. 
STUDY OBJECTIVES AND ENDPOINTS 
Table 1 outlines the study objectives and endpoints. 
 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 17 of 83 
Protocol Version #: 11    Date: 27-September-1024 
Table 1.  Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• 
To evaluate the efficacy of a rapid wean intervention compared 
with a slow-wean intervention in reducing the number of days of 
opioid treatment from the first dose of weaning to cessation of 
opioid among infants receiving an opioid (defined as morphine or 
methadone) as the primary treatment for neonatal opioid 
withdrawal syndrome (NOWS) 
• 
The number of days of 
opioid treatment from the 
first dose of weaning to 
cessation of opioid  
 
Secondary 
• 
To evaluate the efficacy of a rapid-wean intervention compared 
with a slow wean intervention in reducing the number of days of 
opioid treatment from the first dose of weaning to cessation of 
opioid among infants treated with morphine as the primary 
treatment for neonatal opioid withdrawal syndrome (NOWS) 
• 
The number of days of 
morphine treatment from 
the first dose of weaning to 
cessation of morphine  
• 
To evaluate the efficacy of a rapid-wean intervention compared 
with a slow wean intervention in reducing the number of days of 
opioid treatment from the first dose of weaning to cessation of 
opioid among infants treated with methadone as the primary 
treatment for neonatal opioid withdrawal syndrome (NOWS) 
• 
The number of days of 
methadone treatment from 
the first dose of weaning to 
cessation of methadone 
• 
To determine whether a rapid- or slow-wean intervention affects 
escalation or resumption of opioid medication during weaning 
among infants receiving an opioid (defined as morphine or 
methadone) as the primary treatment for neonatal opioid 
withdrawal syndrome (NOWS) 
• 
Escalation or resumption of 
morphine or methadone 
medication during weaning 
• 
To determine whether a rapid- or slow-wean intervention affects 
the total amounts of opioid given from the first dose of weaning 
to cessation of opioid among infants receiving an opioid (defined 
as morphine or methadone) as the primary treatment for 
neonatal opioid withdrawal syndrome (NOWS) 
• 
The total amount of 
morphine or methadone 
given from the first dose of 
weaning to cessation of 
opioid 
• 
To determine whether a rapid- or slow-wean intervention affects 
the administration of second or third line drugs to treat NOWS 
from the first dose of weaning to cessation of opioid among 
infants receiving an opioid (defined as morphine or methadone) 
as the primary treatment for neonatal opioid withdrawal 
syndrome (NOWS) 
• 
Initiation or escalation of  
second or third line drugs 
administered to treat NOWS 
signs from the first dose of 
weaning to cessation of 
opioid 
• 
To evaluate the safety and tolerability of a rapid-wean 
intervention compared with a slow-wean intervention among 
infants receiving an opioid (defined as morphine or methadone) 
as the primary treatment for neonatal opioid withdrawal 
syndrome (NOWS) 
• 
Seizures (clinical or EEG), 
excessive stool output, 
respiratory disturbances, 
and feeding tolerance 
 
 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 18 of 83 
Protocol Version #: 11    Date: 27-September-1024 
Objectives 
Endpoints 
Secondary (cont’d) 
• 
To determine whether a rapid- or slow-wean intervention affects 
neurobehavior among infants receiving an opioid (defined as 
morphine or methadone) as the primary treatment for neonatal 
opioid withdrawal syndrome (NOWS) 
• 
Atypical neurobehavioral 
profile prior to discharge on 
the NICU Network 
Neurobehavioral Scale 
(NNNS) after completion of 
study drug and prior to 
hospital discharge 
• 
To determine whether a rapid- or slow-wean intervention affects 
the total length of hospital stay among infants receiving an opioid 
(defined as morphine or methadone) as the primary treatment 
for neonatal opioid withdrawal syndrome (NOWS) 
• 
The total number of days 
spent in the hospital 
• 
To determine whether a rapid- or slow-wean intervention among 
infants receiving an opioid (defined as morphine or methadone) 
as the primary treatment for neonatal opioid withdrawal 
syndrome (NOWS) affects maternal well-being and maternal 
infant attachment at four weeks (± 7 days) after discharge 
• 
 Parent-Reported Outcome 
Measure Information 
System (PROMIS) Measures  
at 1 month after discharge 
and at 24 months of age  
• 
Maternal Post Attachment 
Questionnaire (MPAQ) at 
one month after discharge 
• 
To determine whether a rapid- or slow-wean intervention among 
infants receiving an opioid (defined as morphine or methadone) 
as the primary treatment for neonatal opioid withdrawal 
syndrome (NOWS) affects growth over the first 24 months of age 
• 
Weight (kg), length (cm), 
head circumference (cm), 
and weight for length 
percentile on the World 
Health Organization (WHO) 
growth curves. 
Anthropometric z-scores 
and BMI-z at 24 months of 
age 
• 
To determine whether a rapid- or slow-wean intervention among 
infants receiving an opioid (defined as morphine or methadone) 
as the primary treatment for neonatal opioid withdrawal 
syndrome (NOWS) affects infant wellness after discharge and 
until 24 months of age 
• 
Acute/urgent care and/or ER 
visits (total number of 
occurrences) (CQ) 
• 
Readmissions (number of 
occurrences) (CQ) 
• 
Death (presence or absence) 
• 
To determine whether a rapid- or slow-wean intervention among 
infants receiving an opioid (defined as morphine or methadone) 
as the primary treatment for neonatal opioid withdrawal 
syndrome (NOWS) affects infant development. 
• 
Bayley Scales of Infant and 
Toddler Development, 
Fourth Edition (Bayley 4): 
Cognitive, Language, Motor, 
at 24 months of age 
 
1.8. 
SAMPLE SIZE AND POWER   
The projected effect size is a 2.0 day difference in the duration of opioid treatment between infants 
randomized to a rapid-wean intervention and infants randomized to a slow-wean intervention. We 
derived this sample size by using results from a recently completed trial comparing morphine-treated 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 19 of 83 
Protocol Version #: 11    Date: 27-September-1024 
infants and methadone-treated infants in which the standard deviation was 6.9 days for the morphine-
treated infants and 8.0 days for methadone-treated infants. We used a standard deviation of 6.9 days to 
derive the sample size, anticipating that more infants will be treated with morphine. However, the 
primary analysis compares treatment regardless of drug used, and we based our sample size calculation 
irrespective of the proportion of infants treated with morphine or methadone. Table 2 is for illustrative 
purposes only, and shows the number of patients treated with morphine and methadone if 70% of 
infants receive morphine as the primary opioid treatment.  
 
The study will have two intervention arms (rapid-
wean and slow-wean) with 251 
morphine/methadone treated infants per 
intervention arm, for a total of 502 
morphine/methadone treated infants. This will 
achieve 90% power to reject the null hypothesis 
with a significance level of 0.05 using a two-sided 
two-sample t-test. The null hypothesis will be 
morphine or methadone treated infants in both arms will have equal means when the population 
difference in the duration of opioid treatment is 2.0 days with a standard deviation of 6.9 days. It is 
difficult to predict the proportion of infants treated with either morphine or methadone in the coming 
years given potential changes in practice. We will recalculate the sample size by considering the 
standard deviation from pooled data (without unblinding) after 25% of participant accrual.  
 
1.9. 
PROJECTED RECRUITMENT TIME   
We project that enrollment will require 3.3 years based on a targeted enrollment of 502 infants, with 
750 infants available each year and a 20% consent rate. This projection assumes that the research team 
will not change the sample size estimate during the trial.   
 
Table 2. Sample Size 
Intervention 
Arm 
Morphine 
Treated 
Methadone 
Treated 
Total  
Rapid-wean 
176 
75 
251 
Slow-wean 
176 
75 
251 
Total 
352 
150 
502 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 20 of 83 
Protocol Version #: 11    Date: 27-September-1024 
SECTION 2. 
CONFLICT OF INTEREST DISCLOSURES 
2.1. 
FINANCIAL CONFLICTS OF INTEREST OF THE INSTITUTIONS AND INVESTIGATORS 
The study investigators have no financial conflicts of interest (FCOI) related to the study outlined in this 
protocol. 
 
 
2.1.1. Plan for Managing Identified Financial Conflicts of Interests 
We will handle any potential or perceived conflicts of interest, including FCOI, per Title 42, Code of 
Federal Regulations, Part 50, Subpart F (50.604 Responsibilities of Institutions regarding Investigator 
financial conflicts of interest). This states that institutional officials (and all subrecipients) are required to 
notify the grants officer of any FCOI prior to expenditure of any funds and within 60 days of any 
subsequently identified FCOI. The research team will simultaneously notify NICHD, ECHO office, the NRN 
Steering Committee and the ISPCTN Steering Committee regarding the COI management plan, following 
institutional guidelines of each participating hospital.  
 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 21 of 83 
Protocol Version #: 11    Date: 27-September-1024 
SECTION 3. 
STATEMENT OF PROBLEM 
3.1. 
PRIMARY HYPOTHESIS OR QUESTION 
Among infants receiving an opioid (defined as morphine or methadone) as the primary treatment for 
NOWS, a rapid-wean intervention will reduce the days of opioid treatment from the first weaning dose 
to cessation of opioid, compared to a slow-wean intervention.  
  
3.2. 
SECONDARY OUTCOMES 
 
3.2.1. Secondary Efficacy Outcomes 
Secondary Outcome 1. The numbers of days of opioid treatment from the first weaning dose to 
cessation of opioid with rapid- and slow-wean interventions among infants treated with morphine.  
Secondary Outcome 2. The numbers of days of opioid treatment from the first weaning dose to 
cessation of opioid with rapid- and slow-wean interventions among infants treated with methadone. 
Secondary Outcome 3. The proportions of infants in the rapid- and slow-wean intervention arms who 
have an escalation or resumption of opioid medication during weaning.       
Secondary Outcome 4. The total amounts of opioid from the first weaning dose to cessation of opioid 
among infants in the rapid- and slow-wean intervention arms. 
Secondary Outcome 5. The initiation and escalation of second- or third-line drugs to treat NOWS signs 
from the first weaning dose to cessation of opioid in the rapid- and slow-wean intervention arms.  
 
3.2.2. Secondary Safety Outcome 
Secondary Outcome 6. The proportion of infants in each intervention arm with safety outcomes of 
seizures (clinical or EEG), excessive stool output, respiratory disturbances, and feeding tolerance. 
 
3.2.3. Other Secondary Outcomes 
Secondary Outcome 7.The proportion of infants in each intervention arm with an atypical 
neurobehavioral profile prior to discharge on the NICU Network Neurobehavioral Scale (NNNS). 
Secondary Outcome 8. The lengths of hospital stay for each intervention arm.  
Secondary Outcome 9. Assessments of maternal well-being and maternal-infant attachment in each 
intervention arm. 
Secondary Outcome 10. Assessments of growth in each intervention arm. 
Secondary Outcome 11. Assessment of infant wellness after discharge and until 24 months of age in 
each intervention arm. 
Secondary Outcome 12. Assessment of infant development to 24 months of age in each intervention 
arm. 
  

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 22 of 83 
Protocol Version #: 11    Date: 27-September-1024 
3.3. 
BACKGROUND AND RATIONALE 
3.3.1. Public Health Impact 
The incidence of maternal opioid use in the United States has increased substantially since 2000 (1). This 
includes an increase of opioid use during pregnancy including prescription opioids and illicit drugs, as 
well as a rise in opioid substitution programs for addiction treatment (2). As a consequence of opioid use 
during pregnancy, the incidence of neonatal opioid withdrawal syndrome (NOWS) has increased five-
fold between 2002 and 2012 (1). NOWS is a clinical syndrome that reflects signs of withdrawal from 
opioids in a newborn following in-utero exposure. Signs typically occur in the first 5-7 days following 
birth and reflect dysfunction of the brain, gastrointestinal tract and autonomic regulation. 
Simultaneously during this rise in opioid use, the pattern of use has shifted from an inner city, indigent 
population to a more socioeconomically diverse population. A systematic literature review indicated 
rural pregnant women have higher rates of polysubstance abuse, as compared to urban pregnant 
women (3). The highest incidences of NOWS were reported in the Southeast (i.e., Kentucky, Tennessee, 
Mississippi, and Alabama) and Northeast (i.e., Maine, New Hampshire, Vermont, Massachusetts and 
Rhode Island) United States (4). This increase in opioid drugs during pregnancy affects neonatal care 
across the United States. Multiple cross-sectional analyses show that NICU admission rates for NOWS 
increased from 7 to 27 cases per 1,000 admissions and that length of stay increased from 13 to 19 days 
between 2004 through 2013 (5). Mean hospital charges for infants discharged with neonatal abstinence 
syndrome (NAS) increased from $39,400 to $53,400 between 2000 and 2009, and state Medicaid 
programs bore 78% of these charges (1). The proportion of neonatal hospital costs due to NAS was 
estimated to rise from 1.6% to 6.7% between 2004 and 2014 among births covered by Medicaid (6). 
Pregnancy complicated by opioid use disorder is associated with high rates of polydrug use, mental 
health disorders, infectious diseases, poor nutrition, chronic illnesses, and limited social support (7). 
Associated risks for newborns beyond NOWS include preterm birth and fetal growth restriction.   
 
Pregnancy represents an opportunity for entry into the healthcare system and initiation of interventions 
for the mother-infant dyad. However, there are many knowledge gaps in the care of infants with NOWS. 
The executive summary of a joint workshop by the National Institute of Child Health and Human 
Development and multiple other partners identified major domains of research priorities on NOWS, 
including screening and assessment, treatment of NOWS, and transition out of the hospital and follow 
up (7).   
 
3.3.2. Background  
A recent Journal of Pediatrics editorial emphasized the rapid rise of NOWS in the United States and 
provided a framework to target research initiatives and care delivery innovations for infants with NOWS 
(8). Specifically, research and quality improvement initiatives should be safe, effective, patient centered, 
timely, efficient, and equitable. High-quality research is needed to ensure that NOWS care is evidence-
based, eliminates non-beneficial practices, and achieves the overarching goals of limiting ongoing opioid 
exposure for infants, minimizing separation of the mother-infant dyad, and reducing healthcare 
expenditures. To date, the research community has not rigorously evaluated, through randomized 
clinical trials, many aspects of NOWS treatment regimens (9). 
 
Signs associated with NOWS reflect dysfunction in several systems: central nervous system (tremors, 
high-pitched cry, hypertonicity), gastrointestinal (poor feeding, watery, loose stools), and autonomic 
(hyperthermia). There is widespread acceptance that initial care of infants exposed to opioids in utero 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 23 of 83 
Protocol Version #: 11    Date: 27-September-1024 
should be individualized, supportive, and non-pharmacologic (2). These measures should include 
minimizing environmental stimuli (e.g., rooming in [10]), encouraging breast-feeding (in the absence of 
contraindications), and providing sufficient caloric intake. Pharmacological therapy is indicated when 
signs of NOWS cannot be controlled with non-pharmacological strategies. The objective of 
pharmacological therapy is to control NOWS signs so that an infant can appropriately bond with her or 
his mother, tolerate handling and care by healthcare providers, eat effectively with appropriate rest 
periods to ensure adequate growth, and avoid serious central nervous system dysfunction, such as 
seizures. Clinical teams traditionally initiate drug treatment when scoring assessments reach a 
predetermined severity of NOWS signs and include three phases (initiation, stabilization, and weaning). 
Initiation is the start of drug treatment, and clinical teams progressively increase the dose until the 
infant achieves stabilization. Stabilization is the interval of time during which the clinical team maintains 
a drug dose that controls NOWS signs without any indication to further increase the dose. Weaning 
consists of serial reductions in drug dose and/or lengthening the time interval between doses, and it 
often begins approximately 48 hours after stabilization. NOWS treatment goals should address four 
domains: 1) support vital neonatal functions (nutrition, appropriate sleep patterns, etc.), 2) promote 
family bonding, 3) prevent complications (seizures, excessive weight loss, unmanageable irritability), and 
4) provide education for the mother-infant dyad and integration into social services to facilitate a 
smooth transition out of the hospital (7).     
 
Medical professionals do not universally agree on a standard of care for pharmacologically treated 
NOWS infants (11). Clinical teams may use different drugs as first-line agents (e.g., morphine, 
methadone, and buprenorphine) and second-line agents (e.g., phenobarbital, benzodiazepines). At 
present, morphine is the most commonly used first-line pharmacological treatment for NOWS (12). 
Cross sectional data from the Pediatrix Clinical Data Warehouse showed that the proportion of infants 
treated with morphine for NOWS increased from 49% in 2004 to 72% in 2013 (5). Preliminary data from 
the ACT NOWS Current Experience, a retrospective chart review (Section 3.3.3) conducted among the 
IDeA States Pediatric Clinical Trials Network (ISPCTN) and Neonatal Research Network (NRN), indicated 
that morphine was the first-line drug for NOWS treatment in approximately 87% of NOWS infants 
receiving pharmacological treatment. In contrast, clinical teams used methadone in 13% of 
pharmacologically treated NOWS infants (Appendices 1 and 2).  
 
Quality improvement methods to standardize NOWS treatment have been successful in reducing the 
length of treatment and hospital stay among NOWS infants (13). In contrast, there are limited 
randomized clinical trials to guide treatment of NOWS infants who require pharmacological therapy. The 
trials that do exist compared the duration of treatment with morphine and other pharmacological 
therapies (14-19); however, these trials were small and collectively included 189 infants treated with 
morphine and 187 infants treated with phenobarbital, methadone, buprenorphine, or clonidine. There 
are no clinical trials of different approaches to initiation, stabilization, or the weaning phases of drug 
therapy. An important rationale for studying weaning of pharmacological treatment for NOWS is that 
weaning represents the longest time interval of drug treatment. Stopping medications too early may not 
completely treat NOWS symptoms and may increase the challenges for a family to successfully 
transition home. Alternatively, excess pharmacological therapy prolongs hospital stay, which increases 
healthcare utilization and separates the mother-infant dyad.  
 
Kraft et al. summarized the use of morphine and methadone treatment for NOWS (20). Morphine has a 
relatively short half-life, and medical professionals administer it every three or four hours. Two principal 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 24 of 83 
Protocol Version #: 11    Date: 27-September-1024 
algorithms for weaning morphine are a percentage reduction (10% of the stabilizing dose every 
12-48 hours with cessation at 20% of the stabilizing dose) or a fixed reduction (typically decreases of 
0.02 mg morphine/dose each day with cessation at approximately 0.02 mg/dose). Although a standard 
of care for weaning morphine does not exist, all of the referenced clinical trials weaned morphine by 
10% reductions of the stabilizing dose (14-19). However, the research community has not compared 
weaning by a 10% reduction to a different weaning rate to estimate potential reductions in treatment 
days without morphine escalation or resumption.   
 
Kraft et al. noted that methadone has a longer half-life than morphine and therefore, may be attractive 
as a therapy due to less frequent administration (20). However, there is inter-subject pharmacokinetic 
variability in newborns and children receiving methadone (21-22). A pilot study provided important data 
on the pharmacokinetics of oral methadone for NOWS treatment (22). Medical professionals have used 
such a pharmacokinetic-based treatment model to initiate treatment (0.1 mg/kg) with 6-hour dosing 
intervals. If NOWS signs are controlled, they use 12-hour dosing intervals to wean the dose from 0.075 
to 0.01 mg/kg in six weaning steps, until a final 24-hour dose interval. If medical professionals do not 
readily capture NOWS signs at initiation, they use more frequent dosing intervals (4 to 6 to 8 hours) 
before decreasing doses in 12-hour intervals. The Ohio Perinatal Quality Collaborative regimen has used 
this dosing schedule in a pre-post intervention study (23).    
 
In contrast to variations for weaning in clinical practice, randomized trials have used 10% reductions of 
the stabilizing dose.   In a single-site trial that compared methadone to morphine, clinical teams weaned 
both drugs by 10% reductions of the stabilizing dose with four-hour dosing intervals (15). The most 
recent, and largest (58 infants in each group), randomized clinical trial of NOWS treatment, performed 
by Davis et al., was a multi-center trial comparing methadone to morphine (18). In this trial, medical 
professionals weaned NOWS infants treated with methadone or morphine by 10% of the stabilization 
dose every 12 to 48 hours with cessation of drug therapy at 20% of the stabilization dose. 
Administration of methadone alternating with placebo every four hours and morphine every four hours 
facilitated blinding of nursery personnel to the opioid being used. The trial demonstrated that the length 
of treatment and hospital stay were shorter with methadone, compared to morphine, and these results 
may prompt a shift from morphine to methadone as the primary opioid to treat NOWS. There are no 
randomized trials to inform clinicians of potentially better regimens to wean morphine or methadone.   
 
Common outcomes of clinical trials of NOWS treatment are length of treatment, length of hospital stay, 
and safety outcomes. Although clinically evident brain injury on a neurological exam is not anticipated 
among infants with NOWS, there is support for abnormalities of neurobehavior (24). Such information 
may be important to understand maternal well-being after hospital discharge of a NOWS-treated baby. 
This is an important domain of NOWS research, and there is a growing recognition that outcomes of 
NOWS investigations need to broaden to include measures beyond length of treatment and length of 
hospital stay (7).     
 
The NNNS is a comprehensive evaluation of 12 domains of neurologic and behavioral functioning as well 
as signs of stress, administered by trained, certified examiners (25). The research community has used 
the NNNS to study multiple groups of high-risk infants, including those exposed to drugs in utero 
(opioids, cocaine) and prematurity (26). Among 1,248 mother-infant dyads enrolled in the Maternal 
Lifestyle Study, researchers performed NNNS assessments at one month after hospital discharge (27). 
Researchers identified five mutually exclusive neurobehavioral profiles from the 12 neurobehavioral 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 25 of 83 
Protocol Version #: 11    Date: 27-September-1024 
domains by using latent profile analysis. Profile 5 (black line, Figure 1) was the most atypical, and it was 
characterized by exaggerated scores for arousal, excitability, hypertonicity, quality of movement, and 
stress abstinence, relative to four other distinct profiles. Researchers have associated Profile 5 with early 
childhood outcomes, including more externalizing behavior problems, internalizing behavior problems, 
and total behavior problems at age three, as well as lower IQ scores after adjustment for gestational age 
and socioeconomic status (27). In this protocol, “atypical neurobehavioral profile” refers to Profile 5 in 
Figure 1.  
 
 
Figure 1. NNNS Examination Results from the Maternal Lifestyle Study. The figure depicts 
discrete neurobehavioral profiles indentified from 12 NNNS neurobehavioral domains (27). The 
Y axis represents standard deviation units. 
There is a lack of consensus on the effects of prenatal opioid exposure on neurodevelopmental 
outcomes in early childhood.  A recent comprehensive review indicated that there are discrepant 
findings with respect to the presence or absence of altered neurodevelopment with in-utero exposure 
(28).  This reflects that many studies are small and cannot adjust for potential confounding variables. 
Potential confounding variables (e.g., prenatal exposures to other substances, nutrition, socio-economic 
status, medical complications, poor prenatal care) may all impact early childhood development.  Few 
studies have examined neurodevelopment among infants who develop NOWS, and even less among 
infants who are pharmacologically treated for NOWS. A retrospective chart review of infants born in 
2011-2015 and treated for NOWS with morphine, methadone or buprenorphine had lower Bayley Scales 
of Infant Development III at 23 months compared with normative data for the Bayley Scales (29).  
Contemporary data on early childhood neurodevelopment of infants with NOWS in the presence or 
absence of pharmacologic treatment remains a major research gap. 
3.3.3. Preliminary Data 
Pilot Clinical Data. The ISPCTN and the NRN have undertaken a retrospective chart review to inform the 
design of clinical trials for infants with NOWS (Advancing clinical trials in neonatal opioid withdrawal 
syndrome [ACT NOWS] current experience: Infant exposure and treatment). Investigators reviewed 
medical records for infants ≥ 36 weeks gestational age and born between July 1, 2016 through June 30, 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 26 of 83 
Protocol Version #: 11    Date: 27-September-1024 
2017, and mothers medical records, when available, when there was opioid use, determined by 
maternal history, maternal/infant toxicology screen, or NOWS scoring. Data were collected from 
1808 infants at 23 of 28 ISPCTN sites and two of five NRN sites. The ACT NOW Current Experience infant 
characteristics and demographics are presented in Appendix 1 and infant pharmacological treatment 
are presented in Appendix 2.  
 
The salient findings from the preliminary data of the ACT NOW Current Experience retrospective chart 
review were:  
1) 
Of infants evaluated for NOWS, medical professionals treated 38.6% with pharmacologic 
therapy. 
2) 
Of infants treated with pharmacological therapy, the primary medications to control NOWS 
signs were morphine (86.1%) and methadone (12.9%).  
Site Practice for Weaning Strategies of Pharmacological Treatment for NOWS: Multiple clinical 
guidelines from IDeA States Pediatric Clinical Trials Network and the Neonatal Research Network were 
reviewed to understand the extent of variation in weaning strategies for morphine and methadone. 
Among centers that use morphine, weaning strategies included reduction by a fixed dose (n=2), 10% of 
the stabilization dose (n=6), or 10-20% of the stabilization dose (n=3).  Among centers that use 
methadone, weaning strategies included reduction by a fixed dose with changes in frequency of dosing 
(n=2), reductions by 10% of that stabilization dose (n=1), and reductions by greater than 10% of the 
stabilization dose (n=3).  This review supports a wide range of clinical practices for pharmacologic 
treatment of NOWS. 
 
Site Practice after Cessation of Pharmacological Treatment for NOWS. Seventeen ISPCTN and NRN sites 
submitted guidelines and protocols they use to treat infants with NOWS (morphine use: 12 sites, 
methadone use: 5 sites). In eight of the 17 guidelines, there were specific directives that clinical teams 
should monitor NOWS infants receiving pharmacological therapy in the hospital for at least 48 hours 
after treatment cessation. In the other nine guidelines, there were no comments on the duration of 
observation after pharmacological treatment cessation.  
NOWS Infants Cost of Care. Data was obtained from one ISPCTN site to provide an estimate of the costs 
of care for NOWS infants. The cost was $869 per day per infant, which represents the average daily cost 
among 86 infants born between October 2017 and September 2018. Infants had an average length of 
hospital stay of 19.4 days, and medical professionals cared for these infants in a family care center that 
was part of a newborn nursery. The family care center promotes non-pharmacological therapy for 
newborns exposed to opioids and provides the opportunity for mothers to room in and breast-feed, if 
there are no contraindications. Costs at hospitals that care for opioid-exposed infants in the NICU may 
be substantially higher.  
 
3.3.4. Rationale and Summary 
Medical professionals pharmacologically treat NOWS infants when non-pharmacological therapy is 
inadequate to control NOWS signs. The survey data indicate that medical professionals 
pharmacologically treat a substantial proportion of NOWS infants. There are heterogeneous practices in 
all aspects of pharmacological treatment (treatment thresholds, initiation, medication type, initial dose, 
second-line and third-line medications, weaning algorithm, and home therapy). One trial cannot address 
all the knowledge gaps, and there is limited evidence to guide current clinical management. Clinical trials 
for this group of patients are challenging for multiple reasons. First, multiple prior randomized trials 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 27 of 83 
Protocol Version #: 11    Date: 27-September-1024 
closed before meeting the projected sample size due to an inability to enroll subjects (15, 17, and 18). 
Second, hospitals and medical professionals vary in their NOWS treatment practices. Third, although a 
larger number of hospitals use morphine to treat NOWS, recent clinical trial data suggests that medical 
professionals may shift to using methadone as the primary opioid for NOWS treatment (18).   
 
Given the uncertainty of the specific opioid medical professionals will use to treat NOWS in the future, 
the ideal clinical trial would inform clinical practice for the use of either morphine or methadone. To 
that end, the proposed study is a pragmatic trial to determine whether a rapid-weaning intervention 
reduces the number of days of opioid treatment, compared to a slow-weaning intervention, and we 
powered the proposed study to detect a two-day difference in the length of treatment. Hospitals will be 
able to use either morphine or methadone with the knowledge that we may find a positive treatment 
effect for both, one, or neither drugs. We are planning secondary analyses to separately examine the 
results for each opioid.   
 
The rapidity at which a clinical team can perform weaning with infant tolerance without recurrence of 
NOWS signs is unknown. In a randomized trial of morphine versus methadone in which clinical teams 
weaned the drug by 10% of the stabilization dose (18), 48% of morphine-treated and 38% of 
methadone-treated infants needed dose escalation. With progressive increases in the percent reduction 
of drug dose, there will, presumably, be an increase in frequency of recurrence of NOWS signs that will 
mitigate the benefits of more rapid weaning. A 15% reduction of drug dose is large enough to yield 
important decreases in the length of treatment, which may enable earlier transition out of the hospital 
and decreasing healthcare costs.     
 
Shortening the weaning phase of NOWS treatment has the potential to impact healthcare costs and 
minimize the separation of the mother-infant dyad. Opioid use disorder is estimated to occur in 
6.5/1000 hospitalizations for infant delivery (30). This allows an estimate of cost savings for infant’s ≥ 36 
weeks gestations:  
• 
Births per year in the US: ≈ 4,000,000 births 
• 
Percent births ≥ 36 weeks: ≈ 90% x 4 million → 3,600,000 
• 
Opioid exposed: 6.5/1,000 deliveries 
• 
Total opioid exposed: 6.5 x 3600 → 23,400 
• 
Opioid exposed receiving pharmacological treatment: 38.6% x 23,400 → 9032 
• 
Cost of care/day: $869 x 9032 → $7,848,808 
 
A treatment reduction of 2.0 days would reduce healthcare costs by more than $15.7 million per year 
across the United States. Potential cost savings would be even greater for hospitals that care for infants 
with NOWS in facilities with higher levels of care (e.g., NICU, special care nurseries). 
 
If successful, this clinical trial would achieve the overarching goals of research initiatives for NOWS (8). 
Specifically, it would limit ongoing opioid exposure for infants, minimize separation of the mother-infant 
dyad, and reduce healthcare expenditures. 
 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 28 of 83 
Protocol Version #: 11    Date: 27-September-1024 
SECTION 4. 
METHODS 
4.1. 
ELIGIBILITY CRITERIA 
 
4.1.1. Inclusion Criteria 
4.1.1.1.  
Hospital Level 
1) Hospital provides pharmacologic treatment to at least an average of 12 opioid exposed infants 
each year 
2) Hospital uses a scoring system to assess for signs of NOWS (original or modified Finnegan 
Neonatal Abstinence Scoring system, Eat-Sleep or Console) 
3) Hospital provides opioid replacement therapy with either morphine or methadone as part of 
pharmacologic treatment of NOWS 
 
4.1.1.2.  
Infant Level 
Infants need to fulfill all of the following criteria: 
1) Gestational age ≥ 36 weeks  
2) Receiving scheduled pharmacological therapy with morphine or methadone as the primary drug 
treatment for NOWS secondary to maternal opioid use 
3) Tolerating enteral feeds and medications by mouth 
 
4.1.2. Exclusion Criteria 
4.1.2.1.  
Hospital Level 
1) Hospitals discharge> 10% of infants from the hospital on opioid replacement therapy on average 
per year 
 
4.1.2.2.  
Infant Level 
Any of the following is an infant level exclusion criterion:  
1) Major birth defect (e.g. gastroschisis)  
2) Any major surgery (minor surgery [e.g., circumcision, digit ligation, frenulectomy] is not an 
exclusion)  
3) Hypoxic-ischemic encephalopathy  
4) Seizures from etiologies other than NOWS 
5) Treatment with opioid for reasons other than NOWS  
6) Respiratory support (nasal cannula or greater) for > 72 hours  
7) Planned discharge from the hospital on opioids  
8) Use of other opioids (e.g., buprenorphine) as primary drugs for treatment 
9) Weaning of morphine or methadone as the primary treatment of NOWS has started 
 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 29 of 83 
Protocol Version #: 11    Date: 27-September-1024 
4.2. 
DETAILED STUDY PROCEDURES 
 
4.2.1. Overview  
Table 3.  Schedule of Activities 
Activity/Event 
Study Time Period 
Prior to Birth 
Prior to Randomization 
Randomization 
Initiation of Study 
Intervention/Weaning 
Completion of Study 
Intervention/Weaning 
Post Intervention 
Evaluation 
Hospital Discharge 
1 Month  Post Discharge 
6 months of age 
12 months of age 
18 months of age 
24 months of age 
At Risk for NOWS 
Initiation of 
Pharmacological 
Treatment  
Stabilization (opioid 
dose that controls 
symptoms) 
Prenatal consultation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
In-utero opioid exposure 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
NOWS Scoring 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Non-pharmacologic bundle 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
NOWS symptoms present 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Morphine or methadone treatment 
initiated 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Screening 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Start of stabilization dose 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Consent 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Baseline data collection (includes maternal 
and infant medial history, infant 
measurements at birth, etc.) 
 
 
X 
 
 
 
 
 
 
 
 
 
Eligibility confirmed, stabilization dose 
tolerated 
 
 
X 
 
 
 
 
 
 
 
 
 
Wean morphine or methadone 
 
 
 
X 
 
 
 
 
 
 
 
 
Monitoring of serious adverse events  
 
 
 
X 
X 
X 
X 
 
 
 
 
 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 30 of 83 
Protocol Version #: 11    Date: 27-September-1024 
Activity/Event 
Study Time Period 
Prior to Birth 
Prior to Randomization 
Randomization 
Initiation of Study 
Intervention/Weaning 
Completion of Study 
Intervention/Weaning 
Post Intervention 
Evaluation 
Hospital Discharge 
1 Month  Post Discharge 
6 months of age 
12 months of age 
18 months of age 
24 months of age 
At Risk for NOWS 
Initiation of 
Pharmacological 
Treatment  
Stabilization (opioid 
dose that controls 
symptoms) 
Intervention data collection (includes 
information on primary drug dose, second 
or third line drugs, etc.) 
 
 
 
X 
X 
 
 
 
 
 
 
 
NNNS assessment (24-48 hours following 
study drug cessation) 
 
 
 
 
 
X 
 
 
 
 
 
 
Discharge data collection (includes 
discharge/transfer/death) 
 
 
 
 
 
 
X 
 
 
 
 
 
PROMIS Measures (PROMIS)  
 
 
 
 
 
 
 
X 
 
 
 
X 
Maternal Postnatal Attachment 
Questionnaire (MPAQ)  
 
 
 
 
 
 
 
X 
 
 
 
 
Infant weight, length, head circumference 
 
 
 
 
 
 
X 
 
 
 
 
X 
Caregiver Questionnaire (CQ) (enteral feeds, 
acute/urgent care and/or ER visits and 
readmissions) 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Death 
    
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Bayley Scales of Infant and Toddler 
Development, Fourth Edition (Bayley-4): 
Cognitive, Language, Motor 
 
 
 
 
 
 
 
 
 
 
 
X 
Brief Infant-Toddler Social and Emotional 
Assessment (BITSEA) 
 
 
 
 
 
 
 
 
 
 
 
X 
Contact information update  
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
*Procedures occurring at 1 month post discharge may occur within ±3 weeks of stated time point. Procedures occurring at 6, 12, and 18 months of age 
may occur within ±6 weeks of stated time point.  Procedures occurring at 24 months may occur between 22 and 28 months of age.  If an appointment 
was made for a 24 month evaluation prior to 28 months, the data will be used provided the evaluation is performed prior to 30 months. 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 31 of 83 
Protocol Version #: 11    Date: 27-September-1024 
 
4.2.2. Patient Recruitment Plan 
There are 3 major components to a successful recruitment plan as follows: 
1. Understand who is providing care for pregnant patients with an Opioid Use Disorder.  
2. Disseminate information to clinics, healthcare providers and the medical community regarding 
research initiatives coupled with hospital care of the mother and newborn.  
3. Identify pregnant mothers prior to delivery and use prenatal consultation to establish trust and 
provide an overview of newborn care and the clinical trial.  
 
The first two of these components are part of a system level recruitment initiative while the third 
component is patient specific. The single most important element of the recruitment strategy is the 
prenatal consultation. If prenatal consultation is not feasible, effective antenatal dissemination of 
information regarding the clinical trial will be exceptionally important when approaching mothers after 
delivery. A detailed summary of the Recruitment Plan is provided in Appendix 3.   
 
4.2.3. Screening  
Research personnel will screen medical records of pregnant mothers to identify mothers who use 
opioids. Moreover, the research team will screen the charts of infants with known opioid exposure in 
utero and infants treated for NOWS in all areas of the hospital in which infants may receive care (e.g., 
mother-baby unit, NICU, pediatric floor). We will use hospital-specific practices to identify opioid-
exposed infants (e.g., history, urine drug screening, etc.). We will encourage research personnel to use 
information technology systems within hospitals to facilitate identification of potential participants.  
After an infant is born, research personnel will evaluate potential infant participants against the 
inclusion and exclusion criteria to determine if the infant is a potential participant. Research personnel 
will track the infant to ensure study eligibility by verifying the following: NOWS signs occurred, clinical 
team initiated morphine or methadone treatment, and weaning after stabilization on an opioid dose has 
not started. 
 
4.2.4. Consent Procedures 
Research staff may reach out to, and obtain consent from, pregnant women and post-partum women of 
eligible or potentially eligible infants at any of the following times: (a) prior to birth, (b) after birth but 
prior to the determination of the infant’s eligibility, (c) after birth and after infant’s eligibility has been 
confirmed.  The legal guardian or legally authorized representative may be approached when the 
mother does not have custody. 
Pregnant-women who are using/used opioids while the infant is in utero 
Research personnel may approach pregnant  mothers who are using (used) opioids while the infant 
is in utero.  Research personnel may use site-specific practices to introduce the study and start the 
consent process prior to the mother giving birth.   Additionally, the informed consent form may be 
completed (signed) prior to the mother giving birth.  For those mothers that consent before 
delivery, the research team will meet with the mother after delivery to obtain written confirmation 
of her continued willingness to allow her infant to be part of study and for her willingness to be a 
participant herself.   

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 32 of 83 
Protocol Version #: 11    Date: 27-September-1024 
Eligibility of the infant can only be determined after delivery.  The mother is not eligible if the infant 
is not eligible.  The research team will tell all mothers whether or not their infant met eligibility 
requirements. 
Post-partum mothers 
Research personnel may approach post-partum mothers of potentially eligible infants as well as 
mothers of infants known to meet the eligibility criteria.  
For mothers that sign the consent prior to the infant meeting eligibility requirements, the mothers 
will be informed of their infants’ eligibility status once that status has been determined. 
The time period for approaching pregnant women and post-partum mothers, therefore, includes 
prenatal clinic visits through completion of stabilization of the infant, but prior to the start of opioid 
weaning of the infant.   The mother is not eligible if the infant is not eligible.   
General 
Research personnel will obtain informed consent from the infant’s parent or legal guardian (legally 
authorized representative or LAR). If there are any concerns regarding the cognitive status of the 
mother, the site PI or designee will be consulted.  If the infant’s mother is cognitively impaired and is 
unable to provide informed consent to the research study, then an alternative legal guardian may be 
approached for consent per local guidelines. Sites will follow location-specific requirements for 
enrollment of wards of the state.  If legal guardianship changes, the new legal guardian would be 
contacted to obtain consent for the study.   
Infant-only and Caregiver-only consents 
The mother may opt to allow her infant to be in the study, but not be a participant herself. If the 
mother agrees to allow the infant to be a participant, but not be a participant herself, then she will 
sign the infant-only consent.  Similarly, if the legal guardian is not the caregiver or does not want to 
be a participant him/herself, but the legal guardian is willing to allow the infant to be a participant, 
the legal guardian will sign the infant-only consent.  If a caregiver is not the legal guardian of the 
infant, but the caregiver is willing to answer questions about him/herself, the caregiver will sign the 
caregiver-only consent. 
 
Consents for Custody Changes 
Laws vary by state.  Sites should consult with appropriate entities (e.g., local university/hospital legal 
counsel, local IRB, central IRB, study team operational principal investigator, et al.) to ensure the 
correct consents are signed and new consents obtained as needed. 
Remote Consent 
To facilitate the consenting process, due to (a) the ongoing COVID-19 pandemic, (b) the potential for 
change in guardianship, and (c) the potential for a non-emancipated minor mother reaching legal age 
of majority, remote consenting will be allowed.   When conducting remote consent, 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 process 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.  The study team will ensure the participant is provided a copy of 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 33 of 83 
Protocol Version #: 11    Date: 27-September-1024 
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 study team members working on the consenting process will ensure that any participant who is 
consenting remotely has the authority to consent. 
Participant transfer between enrolling sites 
When an enrolled participant(s) needs/want to follow up with a different study site, the original 
enrolling site will obtain and document verbal consent from the parent/LAR to disclose her/his 
contact information to the new site.  Written consent will not be required for this process.  The new 
site will contact the parent/LAR to obtain site-specific informed consent and HIPAA before 
completing any study-related activities at the new site. Alternatively, if desired by the parent/LAR, 
the enrolling site may provide the new site contact information to the parent/LAR and the 
parent/LAR can contact the new site themselves. 
 
4.2.5. Randomization Procedures  
Stratification. We will stratify randomization of infants by hospital. Stratifying by hospital will be critical 
to minimize the chance of differences between intervention arms in hospital practices, provider 
practices, and maternal characteristics. Stratification acknowledges that hospitals may have different 
practices than affiliated hospitals of a given center.     
 
Randomization. We will randomly assign infants to intervention arms of either rapid weaning (15% 
decrements from the stabilization dose) or slow weaning (10% decrements from the stabilization dose). 
The Neonatal Research Network Data Coordinating Center (NRN DCC) will centrally randomize 
participants. They will develop an allocation sequence with randomly varying block sizes, and they will 
implement this sequence through a central process that will be available 24 hours each day. The NRN 
DCC will independently randomize multiple births. Pharmacy personnel of each participating hospital 
will be the only staff with access to group assignment.  
 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 34 of 83 
Protocol Version #: 11    Date: 27-September-1024 
4.2.6. Study Intervention and Comparison  
This will be a pragmatic, randomized, blinded trial of 
opioid weaning to determine whether more rapid 
weaning, compared to slow wean, will reduce the 
number of days of opioid treatment in infants 
receiving morphine or methadone as the primary 
treatment for NOWS. Figure 2 illustrates when the 
study interventions will occur during the 
hospitalization. 
 
Consistent with the pragmatic design, hospitals will 
use their specific management practices for opioid 
treatment among NOWS infants after birth and prior 
to randomization and the start of opioid weaning. 
This may include the following management 
practices: 
• 
Location of care of the infant (mother-baby unit, 
NICU, Pediatric floor etc.). 
• 
Frequency of monitoring of vital signs and use of 
cardiopulmonary monitors. 
• 
A non-pharmacological bundle to control NOWS signs. We will recommend a standardized bundle, 
but hospitals will be able to optimize it for their own use.  
• 
Use of breast milk and breast feeding.  
• 
Scoring assessments of NOWS signs.  
• 
Scoring criteria to initiate opioid therapy. 
• 
Participation in the Eat, Sleep and Console clinical trial1.  
• 
Choice of opioid (morphine or methadone) as the primary treatment and dosing to initiate 
pharmacological therapy.  
• 
Initiation and adjustment of dosing of second-line and third-line drugs for NOWS signs (e.g., 
phenobarbital, clonidine) if NOWS signs are not adequately controlled with an opioid.  
• 
Duration of stabilization whereby the clinical team controls NOWS signs before they initiate opioid 
weaning.  
 
1 Eat, Sleep and Console (ESC) is a step wedged, cluster randomized controlled trial to determine if a simplified 
infant assessment of infants exposed to opioids would reduce the percent of infants treated with pharmacological 
therapy compared to using a Finnegan score. The trial is being conducted among hospitals of the ISPCTN and NRN.   
 
Figure 2. Overview of Study Timing and Intervention 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 35 of 83 
Protocol Version #: 11    Date: 27-September-1024 
Study Intervention. We 
will randomize infants to 
either a rapid-wean 
intervention arm or a 
slow-wean intervention 
arm (Figure 3; Table 4). 
Infants in the rapid-
wean intervention arm 
will undergo opioid 
reduction by 15% of the 
stabilization dose 
whenever the clinical 
team weans the opioid. 
The clinical team will 
terminate the opioid 
when the infant can 
tolerate 25% of the 
stabilization dose 
without NOWS signs. 
Infants in the slow-wean 
intervention arm will 
undergo opioid reduction by 10% of the stabilization dose when the clinical team weans the opioid. The 
clinical team will terminate the opioid when the infant can tolerate 20% of the stabilization dose without 
NOWS signs.   
 
Table 4. Dose Levels of the Rapid-Wean and Slow-Wean Interventions 
Dose 
Rapid wean:  % of stabilization dose 
Slow wean: % of stabilization dose 
Stabilization Dose 
100 
100 
Dose level A 
85 
90 
Dose level B 
70 
80 
Dose level C 
55 
70 
Dose level D 
40 
60 
Dose level E 
25 
50 
Dose level F 
Placebo 
40 
Dose level G 
Placebo 
30 
Dose level H 
Placebo 
20 
 
The research team will distinguish dose levels from study steps for the clinical team and the pharmacy 
during training in-services. There are eight dose levels for the rapid- and slow-wean intervention arms, 
each representing the amount of opioid the clinical team will administer. Study steps represent the 
number of time intervals between different dose levels. If opioid escalation does not occur, the infant 
will receive eight dose levels in eight study steps. However, if there are escalations, the clinical team will 
need to repeat dose levels and there will be more study steps than dose levels. The distinction between 
dose level and study steps is depicted in Table 5.   
 
Figure 3. Overview of the Study Interventions 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 36 of 83 
Protocol Version #: 11    Date: 27-September-1024 
 
Table 5: Differences Between Dose Level and Study Steps for Study Drug Escalation 
Steps 
Rapid-Wean Intervention 
Slow-Wean Intervention 
Dose Level 
% of 
Stabilization 
Dose 
Dose Level 
% of 
Stabilization 
Dose 
Step 0 
Stabilization 
100% 
Stabilization 
100% 
Step 1 
Dose level A  
85% 
Dose level A  
90% 
Step 2 
Dose level B  
70% 
Dose level B  
80% 
Step 3 
Dose level C  
55% 
Dose level C  
70% 
Step 4 
Dose level B  
70%* 
Dose level B  
80%* 
Step 5 
Dose level C  
55% 
Dose level C  
70% 
Step 6 
Dose level D  
40% 
Dose level D  
60% 
Step 7 
Dose level E  
25% 
Dose level E  
50% 
Step 8 
Placebo 
Placebo 
Dose level F  
40% 
Step 9 
Placebo 
Placebo* 
Dose level G  
30%* 
Step 10 
Dose level E  
25% 
Dose level F  
40% 
Step 11 
Placebo 
Placebo 
Dose level G  
30% 
Step 12 
Placebo 
Placebo 
Dose level H  
20% 
 
The asterisks indicate that the dose level at a given study step was not successfully completed and 
resulted in an escalation. The pharmacy will track dose levels to know where an infant is within a rapid- 
or slow-wean intervention arm. The clinical team will be blinded to the dose level and will only be aware 
of the study steps. Both the rapid- and slow-wean intervention arms are depicted to indicate that if each 
intervention arm has the same number of escalations, the study steps will be identical. This is critical to 
maintaining the clinical team blinding.  
 
Choice of Opioid and Dose Frequency.  
• 
The choice of opioid will be per individual hospital practice.  
• 
The dose interval for morphine will be either every 3 or 4 hours, per hospital practice.  
• 
The dose interval for methadone will be every 8 or 12 hours, per hospital practice. 
• 
Appendices 4-7 illustrate EXAMPLES of the magnitude of difference in doses between the rapid- 
and slow-wean intervention arms. The appendices list the absolute dose of morphine 
(Appendices 4 and 5) or methadone (Appendices 6 and 7) that infants will receive based on 
dose frequency. We will determine the dose on the day of randomization for enrolled infants by 
hospital practice, and will likely differ from the values listed in Appendices 4-7.     
 
Changes in Opioid Dose. The following are general considerations for both rapid- and slow-wean 
intervention arms from the first weaning dose to cessation of study drug:  
• 
The clinical team will use hospital specific tools to determine the severity of NOWS signs 
(Finnegan; modified Finnegan; Eat, Sleep, Console; etc.). 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 37 of 83 
Protocol Version #: 11    Date: 27-September-1024 
• 
The clinical team will assess infants for NOWS signs every three or four hours prior to care times 
(clinical assessment, vital signs, and feeding). 
• 
The clinical team will use hospital thresholds of NOWS signs (e.g., wean if all Finnegan scores are 
< 8, escalate for an average of three scores ≥ 8 or two scores ≥ 12) to trigger changes in study 
drug dose.   
o We will have one exception to hospital thresholds for changes in opioid dose based on a 
prior randomized trial (31). Clinical teams will give an infant whose NOWS score is above 
the threshold for an increase in dose the current dose, feed the infant, and rescore the 
infant within one hour of the start of the feed. We will use the lower of the two scores 
to examine serial scores.  
• 
We will provide each hospital’s pharmacy a dosing calculator (Appendix 8). After randomization, 
the pharmacy will input the weaning intervention (wean by 10% or 15% of the stabilization 
dose), the stabilization dose (mg/kg/day), the infant’s weight, and the dosing interval (every 3, 
4, 8, or 12 hours) to identify the steps of the intervention arm. The dosing calculator will provide 
the absolute dose (mg) at each step of the intervention arm.    
• 
Frequency of dose changes for weaning: 
o We will encourage clinical teams to wean study drug at least every 24 hours. 
o Clinical teams may wean infants at ≤ 24 hours of a given dose (< 8 doses when given 
every 3 hours, < 6 doses when given every 4 hours, < 3 doses when given every 8 hours 
and < 2 doses when given every 12 hours), per hospital guideline.  
o Infants not weaned by 24 hours of a given dose will enter a 12-hour period of study 
protocol guidelines (Figure 4). During this 12-hour period, the clinical team must wean 
infants who do not meet hospital specific criteria for escalation. Hospitals do not need 
to use the total 12-hour period to either wean or escalate if the infant meets the criteria 
prior to 12 hours. The research team will use dedicated in-services for all clinical teams 
of participating hospitals prior to study start on the specifics of the trial intervention 
including the 12-hour study protocol guideline.   
o The clinical team will order, “wean opioid per protocol” to trigger weaning.  
 
 
Figure 4. Overview of the Time Periods Used by Clinical Team to Either Wean or 
Escalate Study Drug. A 24-hour period for weaning or escalation, per hospital 
guidelines (light blue bar). Multiple vertical green lines represent dosing intervals; in 
this example the infant is receiving an opioid every 3 hours. If the opioid dose does not 
change after 24 hours of dosing, the infant enters a 12-hour period of study protocol 
guideline (purple bar) to ensure that hospitals either wean or escalate and do not 
remain on the same dose. This approach will be applied to both weaning interventions.   
 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 38 of 83 
Protocol Version #: 11    Date: 27-September-1024 
• 
Frequency of dose changes for escalation: 
o Clinical teams may escalate the opioid at any time during the study intervention based 
on hospital guidelines; clinical teams do not need to wait for 24 hours of dosing.  
o The clinical team will order, “Escalate opioid per protocol” to initiate escalation. 
o When the clinical team orders opioid escalation, the pharmacy will resume the 
preceding step of the intervention arm. For example, an infant receiving placebo in the 
rapid-wean intervention arm will escalate to the last opioid dose (25% of the 
stabilization dose). The clinical team will maintain the escalated dose for 24 hours, and 
then follow hospital guidelines to evaluate subsequent changes in drug dose.  
o There are no limits on the number of escalations or resumptions of opioid for either 
intervention arm. 
o Escalation of the study drug dose is the mechanism to address NOWS signs that require 
additional pharmacotherapy per each hospital’s specific assessment tool. Spot doses or 
rescue doses are not part of this trial intervention 
• 
We provide examples of decisions to wean or escalate opioid within a 24-hour period using a 
hospital guideline and a 12-hour period of protocol guideline (see Appendix 9).  
• 
The pharmacy will inform the clinical team when an infant has two dose levels remaining, which 
will allow the clinical team to be timely with discharge preparation.   
 
Exiting the Study Intervention. Infants will exit the study intervention without unblinding (but remain in 
the trial) if they have not weaned off study drug by 35 days (inclusive of the 35th day) from the first 
weaning dose. This represents more than twice the median and mean length of treatment for the 
morphine arm in the Davis et al. trial (18). This will avoid prolongation of treatment and length of 
hospital stay due to inability to tolerate the intervention guideline.   
 
Other Criteria to Exit the Intervention. 
• 
Participant who cannot ingest anything by mouth and needs intravenous opioid due to an 
increase in acuity or need of an operative procedure. 
• 
Unable to take enteral opioid medication 
• 
Participant who has a serious adverse event, including seizures, increased respiratory support, 
or intravenous fluid for increased stool output.  
• 
Parents or legal guardians wish to withdraw their infant from the intervention. 
• 
The clinical team feels it is in the best interest of the infant to be withdrawn from the 
intervention.  
 
Post Intervention. Similar to clinical practice, the clinical team should monitor participants who have 
weaned off study drug for 48-72 hours prior to discharge to ensure that recurrence of NOWS signs do 
not occur. If there is a recurrence of NOWS signs during the 48-72 hour post-intervention period, and if  
that recurrence merits pharmacologic therapy per the institution’s guideline, study drug will be 
restarted at the prior dose of the rapid wean (25% of stabilization dose) or the slow wean (20% of the 
stabilization dose) interventions.  Tolerance for weaning will then be re-evaluated after 24 hours of 
study drug administration.  When the infant has been off the opioid and prior to discharge, a trained 
examiner will administer the NNNS. The assessment takes approximately 20-25 minutes to complete. 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 39 of 83 
Protocol Version #: 11    Date: 27-September-1024 
We will not administer the NNNS at the same time relative to the last opioid exposure due to the 
unpredictable number and timing of opioid escalations in each weaning intervention and to avoid 
potential unblinding of the intervention.  
 
Data Collection. We will collect data about maternal drug use and medication assisted treatment 
programs, obstetric history, delivery events, out-born status, infant demographics, NOWS signs, 
initiation and stabilization of opioid treatment, use of second- and third-line drugs, start and end of the 
study intervention, adverse events, study outcomes, NNNS examination results, length of hospital stay, 
and post-discharge maternal assessment.  
 
4.2.7. Blinding/Masking 
We will blind all clinical providers (e.g., nurses, physicians, nurse practitioners, and physician assistants), 
parents, and research personnel to group assignment and opioid dose during the intervention. 
Pharmacy personnel will be the only unblinded individuals.  
  
To maintain treatment blind, the volume of opioid will remain constant throughout the intervention for 
the rapid-wean and slow-wean intervention arms. At the time of opioid dosing, infants will receive one 
syringe with study drug at a volume equivalent to the volume of the stabilization dose, or a volume 
greater than the stabilization to facilitate maintaining a set volume (e.g. a stabilization dose of 0.28 ml 
may be set at 0.5 ml for ease of drawing up medication with saline during weaning). As infants progress 
through the dose levels, the research pharmacist will reduce the opioid volume and the pharmacist will 
make up the difference by normal saline so that the volume of the syringe is constant throughout all 
dose levels. To ensure that infants in the rapid-wean intervention arm have an equal number of study 
steps as infants in the slow-wean intervention arm, the pharmacy will use a placebo (normal saline 
without opioid) for three dose levels. Appendix 10 provides examples of the use of placebo when 
escalation or resumption of opioid occurs in the rapid-wean intervention arm. Depending on the timing 
of escalations, the three placebo dose levels do not need to occur consecutively. We will label the study 
drugs as either morphine/study drug and the respective volume or methadone/study drug and the 
respective volume.      
   
4.2.8. Control or Monitoring of Co-interventions 
The clinical team may initiate treatment of NOWS signs with second- and third-line drugs after 
randomization, per hospital indications. The clinical team may escalate or wean the dose of these drugs 
during the study intervention per hospital guidelines.    
 
4.2.9. Primary Outcome  
The primary outcome will be the number of days of opioid treatment (used as primary treatment), 
including escalation, resumption, and spot treatment, from the first weaning dose to opioid cessation. 
We will assess the primary outcome by analyzing data from all infants undergoing rapid-wean, 
compared to slow-wean, with morphine or methadone. Predefined secondary analyses will examine the 
results for each opioid separately. We will define days on a 24-hour basis, e.g., 18 hours will represent 
0.75 days. We will express days and dosages to the nearest hundredth, and we will round up at five. 
Days of opioid treatment is a single outcome that will be a function of a) the weaning algorithm and b) 
the extent of recurrence of NOWS signs. The use of hospital guidelines combined with study protocol 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 40 of 83 
Protocol Version #: 11    Date: 27-September-1024 
guidelines will ensure that NOWS signs deemed clinically important result in appropriate treatment of 
the infant.  
 
4.2.10. Secondary Outcomes 
Secondary outcomes are listed in Section 3.2.  
 
4.2.11. Safety Outcomes 
Rapid weaning, compared to slow weaning, of opioid treatment for NOWS could precipitate an increase 
in withdrawal signs. As described in the study intervention section, clinical teams will provide infants 
with opioid treatment if the assessment used by the hospital justifies escalation or resumption of an 
opioid in either weaning intervention arm. The latter approach is identical to clinical practice.   
 
4.2.12. Adverse Events 
All study personnel will assess for adverse events from the start of study drug to hospital discharge (i.e., 
“study period” in corresponding CRF) while being blinded to the weaning intervention.  Adverse events 
will include the following: 
Seizures. The clinical team will evaluate abnormal movements for potential seizure activity. A seizure is 
defined clinically as a paroxysmal change in neurological function including motor, behavioral and/or 
autonomic function. If there is a high index of suspicion for seizures that results in a change of clinical 
management (e.g., escalation of care, initiation of anti-epileptic drugs, re-initiation or escalation of 
morphine/methadone for presumed seizure activity), infants should exit the weaning intervention and 
clinical management of NOWS should be assumed by the clinical team. We do not know the frequency 
of seizures during the weaning phase with current maternal and infant treatment. Researchers reported 
clinical seizures in 2% to 11% during the acute phase of abstinence from infants born in the 1960s to 
1970s when treatment approaches differed (32-34). EEGs were performed in a small group of infants in 
these reports (< 10%, [33, 34]) and firm conclusions cannot be drawn. More recently, small cohorts of 
infants at risk or treated for NOWS have been investigated with EEG. Amplitude integrated EEG 
recordings in 9 infants did not indicate seizures but did have abnormalities of background and sleep 
cycles (36). Among 40 infants with NOWS referred for clinical seizures, EEG and video EEG indicated an 
abnormal background in 27.5% and electrographic seizures in 7.5% (36). The latter does not represent 
the frequency of seizures among infants with NOWS since this report only reported on infants with 
presumed clinical seizures.   
Stool output. An increase in stool output that the clinical team treats with intravenous therapy.  
Respiratory Disturbances. Tachypnea (respiratory rates > 80 bpm consistently recorded over 4-6 hours 
with decreases in oxygen saturation < 85%), shallow breathing (respiratory rates < 30 bpm consistently 
recorded over 4-6 hours with decreases in oxygen saturation < 85%), or increased respiratory support 
(nasal cannula or greater for infants previously on room air). 
Feeding Strategy. A change in feeding strategy (e.g., IV fluids) due to poor feeding or emesis.  
Other Adverse Events. This will include any change in clinical status during the weaning interventions 
that is clinically significant by the Site Principal Investigator.  
 
4.2.13. Serious Adverse Events 
All study personnel will consider adverse events serious if they include any of the following:  
1) Death  

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 41 of 83 
Protocol Version #: 11    Date: 27-September-1024 
2) Life threatening adverse event  
3) Inpatient hospitalization or prolongation of existing hospitalization  
4) Persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) Important medical events that may not result in death, be life-threatening, or require 
hospitalization, but based on medical judgment may jeopardize the participant and may require 
medical or surgical intervention to prevent one of the outcomes listed above in this definition.  
 
Participants with serious adverse events will exit the intervention without unblinding the treatment 
intervention assignment, unless the clinical team considers unblinding essential to the provision of 
clinical care. The clinical team will assume the care of a participant who exits the intervention, and we 
will provide the current dose of opioid to the clinical team.  
 
4.2.14. Compliance Monitoring  
Strategies to improve or monitor adherence to the study protocol will include the following:  
• 
Monthly recruitment reports of infants screened and enrolled (accrual figures)  
• 
Monthly reports detailing data received at the NRN DCC, 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.  
 
4.2.15. Data Quality Monitoring and Assurance 
To assure the quality of the data collected, the trial investigators will conduct training sessions on 
protocol implementation, data acquisition and data transfer. Sites will be required to attend a 
mandatory training session that engages multiple research team members, including at least one site 
investigator, one study coordinator, and one data entry staff. This training will consist of a walkthrough 
of the protocol, randomization procedures, study intervention, data collection procedures, the Manual 
of Operations (MOP), and demonstration of the electronic data capture system. The training will provide 
guidance specific to accuracy of data acquisition for the research coordinators at each site. The data 
collection forms will be piloted by a subset of sites to minimize the potential for errors. Additionally, in-
depth pharmacy training will be held with site pharmacists that will consist of a walkthrough of the 
protocol, randomization procedures, study drug dispensing, blinding, and demonstration of the EDC. 
Sites will be required to attend both the protocol and pharmacy training prior to study launch. Sites will 
also be required to attend annual protocol refresher sessions until enrollment is complete.  
 
The NRN DCC will employ a mixed method data quality monitoring approach that will involve a 
combination of the following methods: centralized monitoring, chart re-abstraction, and on-site 
monitoring. 
   

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 42 of 83 
Protocol Version #: 11    Date: 27-September-1024 
4.2.15.1 
Central Monitoring  
Central/remote monitoring will incorporate a variety of methods to detect and resolve potential data 
quality issues. Within the EDC, preprogrammed data edit checks (e.g., out-of-range values, required 
fields, skip patterns etc.) will trigger queries to hospitals in real time (e.g., upon data entry). The NRN 
DCC will also manually review the data monthly, which may result in the data manager manually 
entering queries in the EDC that site study staff must complete. Email communications with the site will 
be used to resolve more complex questions about the data.  
The NRN DCC will generate study-level and hospital-level status reports that will be updated and 
reviewed on a monthly basis (see Section 4.12.14). These reports will identify issues such as missing 
forms, major protocol violations, or safety events that require follow up. The trial subcommittee will 
then discuss these study-level and hospital-level status reports on monthly subcommittee calls to 
identify overall study and hospital trends that suggest deviations from the specified protocol 
procedures, data quality concerns, or occurrence of safety events of concern. Sites identified with 
concerning trends will meet with selected members of the trial subcommittee to discuss the errors and 
potential solutions. Following the conference call, if the site is identified again with concerning trends, 
the sponsor will meet with the site and remediation plan will be requested.   
 
4.2.15.2 
Chart Re-abstraction 
The site research team will re-abstract a subsample of their hospitals 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 number of charts to be re-abstracted for each 6-month interval will be based on the 
number of patients who enroll 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 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 QC abstractor. The site manager will hold a QC 
Review Meeting with the independent site QC abstractor, study coordinator, and site abstractor(s) to 
review the discrepancies and identify errors. Together they will 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 were identified during the QC Review Meeting. The research team will 
provide hospitals that have an error rate above the predefined threshold (five errors per review) with 
additional training, a hospital-specific assessment of the data collection process, and suggestions for 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 43 of 83 
Protocol Version #: 11    Date: 27-September-1024 
process improvement. The research team will track hospitals by their error rates. The research team will 
share practices of those hospitals with exceptionally low error rates with hospitals working to improve 
their own process. The trial subcommittee will review error rates and re-abstraction data during 
monthly team calls. If errors exceed five errors per review, on two consecutive reviews, a remediation 
plan will be requested and shared with the study sponsor.   
 
4.2.15.3 
Site Monitoring Visits 
Concerning trends identified through centralized monitoring and/or re-abstraction may prompt site 
monitoring visits. Staff from the Coordinating Center and NIH/NICHD personnel will visit the site(s) with 
concerning trends in order to ensure data quality and regulatory compliance and to evaluate the 
performance of site investigators and staff. Site monitoring visits will be structured and planned in 
advance. They will involve onsite review and inspection of study participant charts, essential documents, 
and research staff qualifications and responsibilities. It may also include direct observation of study 
procedures and protocol implementation, as well as inspection of facilities and pharmacies and 
interviews with key stakeholders and senior leadership at the sites. If pandemic related travel 
restrictions remain in place, such site monitoring visits may also be conducted virtually. 
 
4.2.16. Study Specimens 
Not applicable; we will not collect biological specimens during the conduct of this study. 
 
4.2.17. Post-Hospital Procedures 
Primary caregiver(s) for infants for whom the protocol study team have 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. Assessments may also take 
place in person, if there is a scheduled visit. Caregiver(s) will complete these questionnaires at 1 month 
after discharge, 6 months, 12 months, 18 months, and 24 months of age. These questionnaires will 
gather information on infant wellness, and primary caregiver(s) contact information, maternal well-
being, infant attachment, and infant behavior. In addition, there will be an in-person follow-up visit with 
neurodevelopmental assessment at 24 months of age. Study staff will maintain contact in between 
study assessments at regular intervals. Respondents to these assessments will receive a reimbursement 
to compensate them for their time.  
 
We will assess maternal well-being with Patient Reported Outcomes Measurement Information System 
(PROMIS) short forms (37). 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 (38,39). 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 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 44 of 83 
Protocol Version #: 11    Date: 27-September-1024 
hospitalized in the NICU (39).  Administration takes approximately 10 minutes and includes a total of 33 
questions. 
The PROMIS Measures will be administered at 1-month after discharge and again at 24 months of age.  
 
We will briefly assess mother-infant attachment with the Maternal Postnatal Attachment Questionnaire 
(MPAQ; [40]), a 19-item questionnaire that assesses quality of bonding, absence of hostility, and 
pleasure in interaction. Higher MPAQ scores reflect higher levels of mother-infant bonding. The MPAQ 
requires approximately 5 minutes to complete, and researchers have validated the MPAQ among 
postpartum women with substance abuse problems (41). The MPAQ will be administered at 1-month 
after discharge.  
 
Caregiver(s) will complete the caregiver questionnaire (CQ) to assess enteral feeding, number of ER visits 
and/or acute/urgent care visits, and hospital readmissions.  
 
We will assess infant neurobehavioral functioning at 24 months of age using the Brief Infant-Toddler 
Social and Emotional Assessment (BITSEA). The BITSEA is 42-item parent report screener used to 
indicate social-emotional/behavioral problems in children 12-36 months (42). It will be administered at 
the 24-month in-person visit. We chose this measure because it is brief, easy to administer, and has 
good reliability and validity (43,44).  
 
We will assess infant development with the Bayley Scales of Infant and Toddler Development, Fourth 
Edition (Bayley-IV): Cognitive, Language, Motor at 24 months of age. The Bayley-IV is recognized 
internationally as one of the most comprehensive tools to assess developmental outcomes in children. 
With the Bayley-IV, it is possible to obtain detailed information even from non-verbal children as to their 
functioning. Children are assessed in the 3 key developmental domains of cognition, language, and 
motor. Reliability and validity of the previous version of the instrument have been well established (45). 
 
4.2.18. Compensation 
Participants will be reimbursed for their time according to the tables below.  These payments will be 
provided at the contact time or shortly thereafter.  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. 
 
For those parents/guardians signing the primary consent (parent/guardian+infant): 
Contact Time 
Participated in 
Reimbursement/ 
Compensation Amount 
1-month post discharge (of 
baby from hospital)  
Answering Questionnaires 
   $50. 
Baby 6 months of age 
Answering Questionnaires 
   $50. 
Baby 12 months of age 
Answering Questionnaires 
   $50. 
Baby 18 months of age 
Answering Questionnaires 
   $50. 
Baby 24 months of age 
Bringing baby in for in-person 
Bayley’s exam and answering 
questionnaires 
$150.* 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 45 of 83 
Protocol Version #: 11    Date: 27-September-1024 
* If the parent/guardian participant answers the 24-month questionnaires, but does not 
bring their child in for the 24-month in-person visit, the parent/guardian will receive 
only $50.00 for the 24-month time-point.    
For those parents/guardians signing the infant-only consent: 
Contact Time 
Participated in 
Reimbursement/ 
Compensation Amount 
1-month post discharge (of 
baby from hospital)  
Answering Infant/child-specific 
Questionnaires 
  $25. 
Baby 6 months of age 
Answering Infant/child-specific 
Questionnaires 
  $50. 
Baby 12 months of age 
Answering Infant/child-specific 
Questionnaires 
  $50. 
Baby 18 months of age 
Answering Infant/child-specific 
Questionnaires 
  $50. 
Baby 24 months of age 
Bringing baby in for in-person 
Bayley’s exam and answering 
Infant/child questionnaires 
$130.* 
* If the parent/guardian participant answers the 24-month infant/child-only 
questionnaires, but does not bring their child in for the 24-month in-person visit, the 
parent/guardian will receive only $30 for the 24-month time-point. 
For those parents/guardians/caregiver signing the caregiver-only consent: 
Contact Time 
Participated in 
Reimbursement/ 
Compensation Amount 
1-month post discharge (of 
baby from hospital)  
Answering caregiver-specific 
Questionnaires 
$25. 
Baby 6 months of age 
n/a 
n/a 
Baby 12 months of age 
n/a 
n/a 
Baby 18 months of age 
n/a 
n/a 
Baby 24 months of age 
Answering caregiver-specific 
Questionnaires 
$20. 
 
 
4.3. 
POTENTIAL RISKS AND BENEFITS TO PARTICIPANTS 
 
4.3.1. Rapid Wean 
The rapid wean schedule is used routinely as standard of care at some U.S. hospitals. Among infants in 
the rapid-wean intervention arm, potential risks of the study intervention include a recurrence of NOWS 
signs and need to escalate and/or resume opioid treatment. If this trial is successful, potential benefits 
of the rapid-wean intervention include a shorter duration of opioid treatment, and possibly a shorter 
length of hospital stay.  
 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 46 of 83 
Protocol Version #: 11    Date: 27-September-1024 
4.3.2. Slow Wean 
The slow wean schedule is used routinely as standard of care at some U.S. hospitals.  Among infants in 
the slow-wean intervention arm, potential risks include a longer duration of opioid treatment. Benefits 
of the slow-wean intervention include potentially fewer recurrences of NOWS signs.  
 
4.3.3. Primary Caregiver Well-Being 
The research team will assess primary caregiver well-being (e.g., parenting stress, attachment, and 
bonding, depression, anxiety, etc.) during the follow-up portion of the study.  Primary caregiver well-
being will be assessed via the five PROMIS Measures and MPAQ questionnaires. It is possible that these 
questionnaires may reveal that the primary caregiver is experiencing psychological distress potentially 
requiring support. Mothers who have exposure to opioids during pregnancy may be vulnerable to 
suicidal ideation.  
 
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) (46,47) 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. 
 
We will train all personnel who administer the PROMIS Measures and MPAQ for appropriate responses 
if the caregiver expresses suicidal thoughts. This training will include additional questions to gauge the 
severity of the situation. We will require each hospital to develop a safety plan to provide the research 
team member immediate access to the Principal Investigator, designee, or other qualified individuals for 
further evaluation and direction. If there is an immediate concern by the research team member, 
knowledge of how to access local emergency responses will be available.   
4.3.4. Maternal opioid use reporting requirements 
 
The responsibility for determination of whether neonatal opioid exposure warrants mandatory 
reporting will rest with all mandatory reporters per requirements of those reporters. Participation in the 
clinical study will not affect reporting requirements. 
 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 47 of 83 
Protocol Version #: 11    Date: 27-September-1024 
SECTION 5. 
ANALYTICAL PLAN 
5.1. 
STATISTICAL ANALYSIS PLAN 
 
5.1.1. Primary Hypothesis 
Among infants receiving an opioid (defined as morphine or methadone) as the primary treatment for 
neonatal opioid withdrawal syndrome (NOWS), a rapid-wean intervention will reduce the days of opioid 
treatment from the first weaning dose to cessation of opioid compared to a slow-wean intervention.  
 
5.1.2. Secondary Outcomes 
Secondary Efficacy Outcomes. 
Secondary Outcome 1: Compare the numbers of days of opioid treatment from the first weaning dose to 
cessation of opioid with a rapid- and slow-wean intervention among infants treated with morphine. 
Secondary Outcome 2: Compare the numbers of days of opioid treatment from the first weaning dose to 
cessation of opioid with a rapid- and slow-wean intervention among infants treated with methadone. 
Secondary Outcome 3: Compare the proportions of infants in the rapid- and slow-wean intervention 
arms who have an escalation or resumption of opioid during weaning.      
Secondary Outcome 4: Compare the total amounts of opioid from the first weaning dose to cessation of 
opioid among infants in the rapid- and slow-wean intervention arms. 
Secondary Outcome 5: Compare the proportion of infants who experience initiation and/or escalation of 
second- or-third line drugs to treat NOWS signs from the first weaning dose to cessation of opioid in the 
rapid- and slow-wean intervention arms. 
 
Secondary Safety Outcome.  
Secondary Outcome 6: Compare the proportion of infants in each intervention arm with safety 
outcomes of seizures (clinical or EEG), excessive stool output, respiratory disturbances, and feeding 
tolerance. 
 
Other Secondary Outcomes. 
Secondary Outcome 7: Compare the proportion of infants in each treatment intervention arm with an 
atypical neurobehavioral profile prior to discharge on the NICU Network Neurobehavioral Scale (NNNS). 
Secondary Outcome 8: Compare the lengths of hospital stay for each treatment intervention arm.  
Secondary Outcome 9: Determine assessments of maternal well-being and maternal-infant attachment 
in each intervention arm. 
Secondary Outcome 10: Assessments of growth in each intervention arm. 
Secondary Outcome 11: Assessment of infant wellness after discharge and until 24 months of age in 
each intervention arm. 
Secondary Outcome 12: Assessment of infant development to 24 months of age in each intervention 
arm. 
 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 48 of 83 
Protocol Version #: 11    Date: 27-September-1024 
5.1.3. Other Collected Data 
Initial descriptive analyses will include weaning intervention group characteristics. We will collect data 
to characterize the following. 
• 
Stratification data 
• 
Hospital variables: participation in ESC 
• 
Maternal variables (e.g., socioeconomic status, obstetric complications, opioid medication, 
medication assisted treatment program, non-opioid drugs, cigarettes, alcohol, selective 
serotonin reuptake inhibitors, and psychiatric diagnoses) 
• 
Infant demographics at birth (e.g., gestational age, birth weight, sex, multiples, growth 
parameters, out-born, and location of care)  
• 
Characteristics of NOWS treatment (e.g., stabilization dose, age at stabilization, use of 
adjunctive drugs to the primary NOWS drug treatment) 
• 
Infant characteristics at the start of the intervention (e.g., weight, postnatal age) and when 
medically ready for discharge per the hospital standard.   
 
We will include the stratification variable (hospital) in regression modeling as a random effect, and we 
will include stabilization dose and maternal treatment as covariates. With respect to maternal 
treatment, it will be a categorical variable with four categories:  
1) Methadone use 
2) Buprenorphine ± naloxone 
3) Prescribed opioids other than methadone and buprenorphine ± naloxone 
4) Non-prescribed opioids 
 
There will be some mixing among these four groups; therefore, we will use the following rules to classify 
infants: 
• 
If methadone is used with other opioids, classify as methadone.  
• 
If buprenorphine is used with other opioids, classify as buprenorphine ± naloxone. 
• 
If methadone is used with buprenorphine, classify based on which drug has been in use for a 
longer time interval.  
 
Depending on the descriptive comparisons across weaning intervention groups, we may add other 
variables to the regression models such as medication assisted treatment programs. If the difference of 
a variable across the weaning intervention is statistically significant at a two-sided alpha of 0.05, then 
we may include the variable as a covariate in the regression models. Beyond the significant difference, 
we will consider other factors, such as the type of analysis, correlation with other variables in the model, 
and trial subcommittee discussion about the nature of the potential covariate.   
 
5.1.4. Analysis of the Primary Hypothesis and Outcome 
We will determine the outcome of the primary hypothesis on an intention to treat basis. We will assign 
infants who exit the intervention at 35 days of methadone/morphine treatment either as 35 days of 
opioid treatment or we will treat them as a censored value at 35 days. We will determine intervention 
differences of two means by analyzing the average number of days of opioid treatment from the first 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 49 of 83 
Protocol Version #: 11    Date: 27-September-1024 
weaning dose to cessation of opioid treatment. We will analyze the data using regression models that 
will include the intervention as a fixed effect and will include maternal treatment and stabilization dose 
as covariates. We will include site (hospital) in the model as a random effect. The primary test of interest 
will be the F-test of the intervention effect, and we will report the intervention difference along with 
95% confidence interval (CI).   
 
Because of possible censoring and removal of participants due to intervention failure, we will conduct 
sensitivity analysis of the primary outcome using several methods. The first sensitivity analysis will 
replicate the analysis, described above, and include other covariates in the model that were significantly 
different across the two weaning intervention groups. Sensitivity analyses will also be conducted to 
evaluate the effects of infants who were and were not part of the Eat Sleep Console trial as a covariate 
or effect modifier (see Section 5.2.2). Another possible sensitivity analysis will include non-parametric 
and/or survival regression (e.g., negative binomial, median regression, or survival analyses), as there is 
potential for skewness and censoring in the primary outcome.  
 
Finally, sensitivity analysis will include fitting a competing risks model to the data where the possible 
competing risk states are weaned, parental withdrawal, physician withdrawal, and treatment failure 
(unable to wean by 35 days of methadone/morphine treatment). We will fit Cox proportional hazards 
models to the data to estimate the intervention effect and other covariate effects on “cause-specific 
hazards.”  The analysis of the “cause-specific hazards” will allow for additional inquiry into the 
intervention effect on the primary outcome while accounting for competing safety and withdrawal 
risks.   
Descriptive statistics (means, medians, SD, percentiles) for number of days of opioid treatment from the 
first weaning dose to cessation of opioid treatment will be generated and summarized in a table by 
treatment group. 
 
 
5.1.5. Analyses of Secondary Outcomes 
We will use the same approach described in the primary outcome analysis to compare the number of 
days of opioid treatment with only infants receiving morphine as the primary pharmacological 
treatment for NOWS (Secondary Outcome 1).  We will use this same approach to compare the number 
of days of opioid treatment using only infants receiving methadone as the primary pharmacological 
treatment for NOWS (Secondary Outcome 2). 
 
We will use adjusted logistic regression models to provide an odds ratio (OR) and 95% Confidence 
Intervals (CI) for binary secondary outcomes measured only once.  These outcomes will include: 
• 
the proportion of infants by intervention arms that escalate or resume opioid medication 
during weaning, 
• 
for the proportion of infants by intervention arms with an atypical neurobehavioral profile 
(Profile 5, Figure 1), 
• 
the proportion of infants who receive an escalation of a second-line or third-line drug to treat 
NOWS signs from the first weaning dose to cessation of opioid.  
 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 50 of 83 
Protocol Version #: 11    Date: 27-September-1024 
We will adjust these models for the stratification variable (hospital), covariates of maternal treatment 
and stabilization dose, and baseline variables that may differ between groups by chance. We define the 
covariates that we may adjust for earlier in this section in the paragraph on other collected data.  
   
We will analyze the secondary outcome of the total opioid exposure from the first weaning dose to 
cessation of opioid in a similar manner as the primary outcome. We will use a regression model that will 
include: a fixed treatment effect (intervention arms) and adjustment for the stratifying variable, 
covariates of maternal treatment and stabilization dose, and baseline variables that may differ between 
groups by chance as fixed effects. We will include hospital (site) as a random effect. The primary test of 
interest will be the F-test of the intervention arm effect, and we will report the treatment difference 
along with 95% CI.   
 
We will measure the secondary outcome of maternal well-being and maternal- infant attachment by 
using PROMIS Measures and MPAQ total scores. We will analyze these in a similar manner as the 
primary outcome. We will use a regression model to analyze PROMIS Measures and MPAQ total scores. 
This model will include a fixed treatment effect (intervention arms), an adjustment for the stratifying 
variable, and fixed effects for the covariates of maternal treatment and stabilization dose. The PROMIS 
Measures outcomes are measured at 1-month after discharge and 24-months of age.  The models for 
PROMIS Measures outcomes will include the 1-month after discharge PROMIS Measures outcome as a 
covariate.  The F-test of the intervention arm effect will be the primary test of interest. We will report 
the intervention arm difference along with 95% CI. We will conduct analyses among the entire group 
and among those where the biologic mother is the primary caretaker.  
We will measure the secondary outcome of infant neurobehavioral functioning using BITSEA scores. The 
BITSEA consists of two multi-item scales, a Problem scale (31 items) and a Competence scale (11 
items).  A high score on the Problem scale or a low score on the Competence scale is less favorable. We 
will analyze these in a similar manner as the primary outcome. We will use regression models to analyze 
the BITSEA total and subscale scores. This model will include a fixed treatment effect (intervention 
arms), an adjustment for the stratifying variable, and fixed effects for the covariates of maternal 
treatment and stabilization dose. The F-test of the intervention arm effect will be the primary test of 
interest. We will report the intervention arm difference along with 95% CI. We will conduct analyses 
among the entire group and among those where the biologic mother is the primary caretaker.  
 
We will calculate binomial proportion and their corresponding 95% CI by intervention arm for each of 
the following safety adverse events: seizures (clinical or EEG), excessive stool output, respiratory 
disturbances, and feeding tolerance. We will use chi-square tests to compare the proportion of seizures 
(clinical or EEG), excessive stool output, respiratory disturbances, and feeding tolerances between 
intervention arms. In addition to unadjusted analyses, we will compare AEs across the weaning 
interventions by using adjusted logistic regression models that adjust for the stratification variable 
(hospital), covariates of maternal treatment and stabilization dose, and possibly any baseline variables 
that were significantly different between weaning interventions. We define covariates that we may 
adjust for earlier in this section within the paragraph on other collected data.    
 
We will analyze the length of hospital stay in a similar manner as the primary outcome. We will use a 
simple, unadjusted regression model to analyze the total length of stay and will include a fixed 
treatment effect (intervention arms). A second regression model will include a fixed treatment effect 
and will include adjustment for the stratifying variable and covariates of maternal treatment and 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 51 of 83 
Protocol Version #: 11    Date: 27-September-1024 
stabilization dose. The F-test of the treatment effect will be the primary test of interest. We will report 
the treatment difference along with 95% CI. Sensitivity analysis will involve time-to-event analyses using 
survival models to account for skewness and possible censoring of each outcome. 
We will analyze the caregiver questionnaire outcomes and the death outcome using a longitudinal 
GLMM or GEE model appropriate for the outcome type since the data will be collected at multiple time 
points after discharge.  Count data that tend to have more than 0 or 1 events counted will be analyzed 
using a Poisson model while binary or count data that rarely goes beyond 1 occurrence will be analyzed 
using a Logistic model.  In case of count data that rarely goes beyond 1 occurrence, this data will be 
transformed to binary data (occurrence/no occurrence).   We will present mean outcome ratios for 
count data (from Poisson models) and odds ratios for binary data (from logistic models) with respect to 
the intervention effect as well as 95% CI of the intervention effect. All analyses will be adjusted for 
repeated measures over time, so that patterns of change for these outcomes over time can be assessed 
by treatment group. 
 
In addition to time of discharge and 24 months of age, anthropometric outcomes will be measured at 
birth.  We will calculate anthropometric z-scores at each of the three assessment periods for the 
purpose of analysis based on age and gender specific WHO norms. The approach to analyzing weight is 
given next. 
We will provide the mean and SD of infants' weights (z-scores) separately for each treatment group. We 
will use a mixed linear model to evaluate the effect of treatment arm on weight (z-scores). 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). We will carry out assessment across 3 time points: birth, hospital 
discharge, and 24 months of age. The mixed model longitudinal 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, unadjusted and adjusted GLMMs will be fit to the data. 
Initially, the unadjusted mixed model 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. 
 
We will examine the impact of the treatment arm on length, HC, and infant weight for length (z-scores) 
using the same analytical methods described for weight (z-scores) above. Additionally, we 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 link 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. 
 
To compare Bayley-IV scores between intervention arms, 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-IV domains.  
Descriptive statistics (means, medians, SD, percentiles) for continuous secondary outcomes and 
frequency based statistics (N and percentages) for binary secondary outcomes will be generated and 
summarized in a tabular form by treatment group. 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 52 of 83 
Protocol Version #: 11    Date: 27-September-1024 
 
5.1.6. Bayesian Analyses 
Other randomized trials of NOWS have ended prior to meeting the projected enrollment, indicating the 
challenges in studying this population (15, 17, and 18). In case of insufficient enrollment, we will pre-
specify Bayesian analyses of the final data in addition to the frequentist analyses, defined above. Below, 
we first define the Bayesian analyses that will mirror the above defined frequentist analyses of the 
primary outcome.  
 
We will analyze the primary outcome with a linear regression that will include treatment group 
(intervention arms), stabilization dose and maternal treatment as covariates, and we will include 
hospital as a random effect. We will use a neutral prior for treatment effect that is centered at a mean 
difference of 0 and a standard deviation of three, normal (μ=0, σ=3) distribution. For the intercept term, 
we will use a normal (μ=0, σ=10) prior. For all other baseline covariates in the model, we will use weakly 
informative neutral normal (μ=0, σ=2) priors. We will use a weakly informative half-normal (μ=0, σ=1) 
prior for the standard deviation of the random hospital effect. For all models, we will report posterior 
medians and 95% credible intervals (CrI) for the group mean differences and the probability that a rapid-
wean intervention will reduce the days of opioid treatment, compared to a slow-wean intervention. For 
sensitivity analyses, we will analyze the primary outcome with skeptical and enthusiastic priors. We will 
center the skeptical prior at a mean difference of two, indicating the view of a skeptic with belief that 
the study intervention will increase the number of days of opioid treatment by two days. We will center 
the enthusiastic prior at a mean difference of -2, meaning a priori that an enthusiast expects the study 
intervention to reduce the number of days of opioid treatment by two days. In both the enthusiastic and 
skeptic priors, the standard deviation will be three. As with the primary frequentist analysis, sensitivity 
analyses may be done using Bayesian analyses, where normal (μ=0, σ=2) priors will be placed on all 
covariates. 
 
Subgroup analysis for secondary outcomes 1 and 2: To estimate possible treatment effect heterogeneity 
for the primary outcome, we will use a Bayesian hierarchical model with main effects and interaction 
term between intervention group and type of narcotic (morphine or methadone). This approach allows 
us to specify a priori how likely (or unlikely) it is for subgroup differences to be present and to shrink the 
subgroup estimates to the overall mean treatment effect. We will specify a model that allows different 
standard deviations of the outcome for the two subgroups (as observed in Davis et al). Prior 
distributions for main effects will be the same as for the primary outcome. Neutral and skeptical priors 
will be used for the interaction terms. Point estimates of treatment effect and 95% credible intervals will 
be reported for each subgroup along with probability of subgroup treatment differences. 
 
We will analyze secondary binary outcomes with Bayesian logistic regression models, including 
treatment group, maternal treatment, and stratification dose as covariates, and we will include hospital 
as a random effect. We will use a neutral prior centered at 1.0 with 95% CrI of 0.33-3.0 (to allow for 
large range of ORs) for the treatment effect. In the log OR scale, this prior will be normal (0, SD=0.57), 
and all other priors will be the same as above. 
 
We will analyze secondary outcomes of the total opioid exposure and assessments of maternal well-
being, maternal-infant attachment, infant neurobehavioral functioning, infant development, and growth 
with a similar linear regression model used for the primary outcome.   

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 53 of 83 
Protocol Version #: 11    Date: 27-September-1024 
 
We will analyze secondary outcome of length of stay with a linear regression model similar to the one 
used to analyze the primary outcome; however, we will also fit survival analysis models to study the 
effects of skewness. 
 
We will implement all Bayesian models via Markov chain Monte Carlo methods (MCMC) by using R or 
SAS software. For SAS, the procedure will be PROC MCMC. For R, possible software is ‘RJAGS’ which is an 
interface to JAGS MCMC software, ‘rstan,’  ‘rstanarm’ and ‘brms, ’ which are packages that interface 
with the Stan language. For each analysis, we will run three MCMC chains with randomly drawn starting 
values. We will use a burn-in of 3,000 iterations, with sampling from a further 30,000 iterations for each 
chain. Thinning will be used as necessary to reduce autocorrelation among the samples to improve 
posterior sampling. To monitor convergence, we will use trace plots and the Gelman-Rubin convergence 
diagnostic (Rhat < 1.1 indicating convergence) for all parameters. 
 
5.2. 
DESIGN CONSIDERATIONS, SAMPLE SIZE, AND POWER ESTIMATES 
 
5.2.1. Overall Trial Design 
During our initial sample size analyses, we considered trial designs that would power two hypothesis 
tests: one test for the weaning effect of morphine and one test for the weaning effect of methadone. 
These designs accounted for multiple comparison adjustment (adjusted for two comparisons) and 
unadjusted comparisons. When we adjusted the two comparisons for multiple comparisons using a 
Bonferroni adjustment, we rejected a test if the p-value is ≤ 0.025, and we would require at least 1,032 
randomized infants for 90% power. If we did not use an adjustment, then the required sample size was 
still at least 826 randomized infants.  In both cases, the assumed standard deviation was 6.9 days. If the 
standard deviation is larger, then in both cases the required sample sizes would be even larger. Given 
the low probability of enrolling around 1,000 infants, we chose a design that would compare weaning 
interventions regardless of drug used (morphine/methadone). Given that the chosen design would 
primarily focus on estimating the weaning intervention effect regardless of drugs, we added two 
secondary analyses examining the intervention effect within each drug (Secondary Outcomes 1 and 2). 
In addition to frequentist analyses of Secondary Outcomes 1 and 2, Bayesian analyses are planned to 
derive evidence that may be clinically meaningful from the limited data available for each drug.  
  
5.2.2.   Compatibility with the ESC Trial 
We expect that a substantial number of sites in the IDeA States Pediatric Clinical Trials Network and NRN 
may participate in both this trial and the concurrent Eat, Sleep, and Console (ESC) trial, a stepped-wedge 
cluster randomized controlled trial that will compare the ESC care approach to usual institutional care 
with the Finnegan Neonatal Abstinence Scoring Tool (FNAST) or modification thereof. Thus, babies 
enrolled into the Weaning trial may also be co-enrolled into ESC. This situation presents both statistical 
benefits and challenges.  
 
The benefits of co-enrollment with the ESC trial mainly derive from better control over variability in site 
practice differences (that are apparent from the results of the ACT NOW Current Experience Study—a 
medical record abstraction of 1808 opioid-exposed neonates across 30 clinical centers) that would not 
otherwise be possible outside of the ESC trial. Specifically, clinical sites have a wide range of practice 
differences, and there are indications that practice may be drifting increasingly towards ESC because of 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 54 of 83 
Protocol Version #: 11    Date: 27-September-1024 
the currently well documented limitations of the FNAST approach. This is an especially pertinent issue 
for the Weaning trial because of its relatively long expected enrollment period of 3.3 years. Without co 
enrollment into the ESC trial, we may have difficulty knowing when and how site practices imperceptibly 
shift from FNAST to ESC and the different variations thereof, and imbalance in such site practices could 
make it difficult to achieve overall balance on this criterion across the Weaning treatment arms. This will 
likely increase center differences, potentially in an imbalanced manner, increasing the overall variability 
in the data, which makes it more difficult to detect a treatment signal.  
 
In contrast, co-enrollment into the ESC trial will allow us to precisely know when groups of sites switch 
over to ESC from FNAST, with all sites having transitioned to the ESC care tool at the end of that trial, 
which will have a shorter duration than the Weaning trial. Together with randomization within site for 
Weaning, this ensures that we have precise and detailed information on site practices at all times 
through the duration of the ESC trial, increased opportunity to achieve overall balance for this aspect of 
clinical practice across the Weaning treatment arms, and more uniformity in site practices at the end of 
the trial. This will reduce center differences and provide more detailed information on center practices 
over time which will reduce the overall variability in the data. 
 
The challenges of co-enrollment mainly involve potential confounding issues between the different 
interventions being tested across the different trials and any biases that may thus result. However, 
confounding is less of a concern here because of the following reasons: 
a) The two interventions in the two trials are applied at different levels – Weaning tests an 
individualized intervention whereby each baby within a center is randomized. ESC tests a 
practice change at the center level using a stepped wedge design, whereby entire groups of sites 
switch to ESC according to a randomized schedule.  
b) Bias will be further minimized by ensuring that the Weaning trial randomizes individual babies 
within each site (regardless of when it is scheduled to switch over to ESC), using a block 
randomization approach to assure a relatively equal distribution of babies in each arm within 
each center within a unit of time. In contrast, ESC uses block randomization (using time as a 
blocking factor) to randomize entire groups of sites to switch over to ESC.  
 
In order to further address concerns regarding confounding and bias, we will conduct sensitivity 
analyses by adding a variable that represents whether a baby in the Weaning trial was 1) in the FNAST 
stage of the ESC trial, 2) in the ESC stage of the ESC trial, or 3) was at a site that was not participating in 
the ESC trial as a covariate and potential effect modifier for babies in the Weaning trial.  
 
5.2.3. Sample Size and Power Estimates 
Eligible infants are those in the ISPCTN and NRN sites that clinical teams are pharmacologically treating 
for NOWS with an opioid as the primary drug treatment and have a gestational age ≥ 36 weeks (see 
Section 4.1). We used the most recent randomized trial comparing morphine to methadone to 
determine sample size and power estimates (18). In that trial, researchers enrolled 116 
pharmacologically treated NOWS infants from February 2014 until March 2017. The research team 
randomly allocated 58 infants to morphine treatment and 58 infants to methadone treatment. The 
standard deviation for the morphine arm was 6.9 days, while the standard deviation for the methadone 
arm was 8.0 days. We used these statistics to derive sample size estimates (Table 6). The total sample 
size estimates given in Table 6 assume that the clinical team will treat 70% of enrolled infants with 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 55 of 83 
Protocol Version #: 11    Date: 27-September-1024 
morphine. This trial will enroll a total of 502 infants (251 infants to each of the rapid and slow wean 
interventions) irrespective of the proportion of infants treated with morphine or methadone.  
 
Table 6. Sample Size Estimates 
Power 
N 
per Arm 
Total 
N 
Morphine* 
N 
Methadone* 
N 
LOT-
difference 
SD 
alpha 
0.9 
251 
502 
352 
150 
2 
6.9 
0.05 
0.9 
296 
592 
414 
178 
2 
7.5 
0.05 
0.9 
337 
674 
472 
202 
2 
8.0 
0.05 
0.85 
214 
428 
300 
128 
2 
6.9 
0.05 
0.85 
253 
506 
354 
152 
2 
7.5 
0.05 
0.85 
288 
576 
403 
173 
2 
8.0 
0.05 
0.80 
187 
374 
262 
112 
2 
6.9 
0.05 
0.80 
221 
442 
309 
133 
2 
7.5 
0.05 
0.80 
252 
504 
353 
151 
2 
8.0 
0.05 
*includes infants randomized to either rapid-wean or slow-wean interventions 
ǂLOT: length of treatment days 
 
A difference of 2.0 days in the length of treatment represents the minimum clinically important 
treatment effect for clinical care. If we can demonstrate a 2.0-day difference, there will likely be a 
reduction in hospital resources (bed, nursing, pharmacy, and physician) and cost. In addition, this effect 
size should facilitate a faster transition out of the hospital and keep the maternal-infant dyad together in 
a better environment than a hospital. The proposed intervention difference is similar to a recent trial 
comparing morphine to methadone (18). Group sample sizes of 251 infants per treatment arm (total 
enrollment, 502 infants) will achieve 90% power to reject the null hypothesis of equal means when the 
population difference is 2.0 days with a standard deviation of 6.9 days and with a significance level of 
0.05 using a two-sided two sample t-test. If the standard deviation is as high as 8.0 days, a similar 
sample size will achieve 80% power to reject the null hypothesis using a two-sample t-test and a two-
sided significance level of 0.05. 
With respect to analysis of the Bayley IV at 24 month follow-up, if the FU is at least 60%, then with a 
two=sided alpha of 0.05 we will be able to detect a difference in any composite score of 5.7 or greater 
with at least 80% power and will be able to detect a difference in any scaled score of 1.06 with at least 
80% power. 
 
 
5.2.4. Interval Sample Size Reassessment    
We defined length of treatment for the proposed trial as the average number of days of opioid 
treatment from the first weaning dose to cessation of opioid treatment. Due to a lack of available 
studies with published parameter estimates, we based the standard deviation used in the power 
calculations (6.9 to 8.0 days) on the number of days of opioid treatment for the entire interval of drug 
treatment, from initiation to cessation of morphine or methadone treatment (18). We anticipate that a 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 56 of 83 
Protocol Version #: 11    Date: 27-September-1024 
smaller standard deviation may be present in the proposed trial since we are only studying weaning. To 
address the concerns that the standard deviation may be lower than 6.9 days for our primary outcome, 
we will perform an interval sample size reassessment.  
 
The interval sample size reassessment will occur after 25% of the enrolled infants are medically ready 
for discharge, which will be 126 infants, assuming full enrollment of 502 infants. This coincides with the 
first Data Monitoring and Safety Committee (DSMC) safety review (see Section 5.5.2). The NRN DCC will 
re-estimate the sample size and provide the DSMC with this report. To re-estimate the sample size, we 
will use the pooled variance estimate calculated across both intervention groups from blinded data 
observed in 126 study participants. This blinded look at the interim data used for sample size refinement 
will not require any alpha adjustment in the final primary outcome analysis.  
 
5.3. 
AVAILABLE POPULATION 
In the fall of 2017, a ISPCTN and NRN site survey found that during a one-year period, there were 
approximately 2,700 infants exposed to opioids, of which, medical professionals pharmacologically 
treated approximately 43%. Among those treated pharmacologically, medical professionals treated 76% 
with morphine, 24% with methadone, and 4% with buprenorphine. These observations provide a 
starting to point to estimate the number of participants available for this trial. However, there is some 
uncertainty regarding how many NOWS infants would meet the inclusion criteria without meeting any 
exclusion criteria (Exclusion Criteria, Section 1). In addition, there may be changes in hospital practices 
within the ISPCTN and NRN given ongoing NOWS initiatives. Multiple clinical trials have not achieved 
enrollment of the projected sample size (15, 17, and 18), and we expect low consent rates in this 
population. Use of the Recruitment Plan (Appendix 3) was associated with a 35% consent rate at 
Women and Infants Hospital for the methadone vs morphine trial conducted by Davis et al (18) in 
contrast to 26% among all participating centers.  Table 7 provides an estimate of the number of infants 
enrolled per year based on estimates of available infants ranging from 1,250 to 750 and consent rates 
ranging from 20% to 30%. Twenty hospitals in the NRN and ISPCTN have expressed interest in 
participation in this clinical trial.  
 
Table 7. Estimated Enrollment per Year  
Consent Rate 
Enrollment by Consent Rate and Infant Numbers 
 
1,250 available infants 
1,000 available infants 
750 available infants 
20% 
250 
200 
150 
25% 
313 
250 
188 
30% 
375 
300 
225 
  
5.4. 
PROJECTED RECRUITMENT TIME 
Based on the estimates of the available population and a target enrollment of 502 infants, a 
conservative estimate to complete the trial would be 3.3 years (750 infants available for the trial each 
year and a consent rate of 20%). This translates to an average monthly enrollment requirement of 12-13 
infants. If enrollment is slower than projected, we may consider other hospitals through the National 
Center for Advancing Translational Science and the National Institutes of Drug Abuse Clinical and 
Translational Science Awards.  

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 57 of 83 
Protocol Version #: 11    Date: 27-September-1024 
 
5.4.1. Assessment of Enrollment Target   
The study subcommittee will review subject accrual at two years after 100% of participating hospitals 
have been IRB approved and are screening infants for enrollment. This review will permit a more precise 
determination of attainable sample size with continued enrollment into the trial. The projected sample 
size and recruitment duration requires an enrollment of 12-13 infants each month. Variables that we 
could evaluate, other than meeting the projected enrollment rate, include an increasing enrollment rate 
between year one and two, and/or enrollment of >75% of the target. In addition, if the monthly 
recruitment into the trial at this point, based on a three-month moving average, falls below 5, the DSMC 
will be asked to conduct a review of study feasibility. This review may include ad hoc safety, efficacy and 
futility analyses that will allow the DSMC to make a recommendation regarding trial termination or 
continuation to the leadership of the participating Networks and NIH. 
 
Meeting Recruitment Targets. Infants with NOWS are a challenging patient group to study given 
parental concerns about social or legal ramifications of enrolling their infants in trials, as seen in 
randomized trials that have been unable to enroll the projected sample size (15, 17, and 18). The 
approach to the care and management of opioid addiction during pregnancy and the newborn has 
shown a growing appreciation that care should be multidisciplinary, collaborative, non-judgmental, and 
centered on the mother-infant pair (2). To minimize the number of hospitals with slow recruitment, we 
will provide participating hospitals the following framework. 
• 
Prior to the initiation of screening, each hospital will provide a hospital specific recruitment 
plan, the expected number of available patients and a proposed schema to identify patients 
(before and after birth), including a plan for tracking to ensure eligibility and establishing points 
of contact(s) with the mother. 
• 
Once screening has been ongoing for six months, the Data Coordinating Centers (DCCs) of both 
networks will review screening logs, the number of eligible infants, consent rates, and reasons 
for eligible but not consented infants.  
• 
We will conduct conference calls with hospitals that are not meeting recruitment metrics. The 
calls will involve the DCCs, trial Principal Investigators and NIH personnel. The purpose of these 
calls is to ensure that hospitals have examined their process and identified changes in their 
approach to improve recruitment. The DCCs will offer successful recruitment practices from 
other hospitals.  
 
5.5. 
STUDY MONITORING PLAN 
 
5.5.1. Reporting Adverse Events 
Study personnel will report all AEs (Section 4.2.12) and SAEs (Section 4.2.13) on the appropriate form 
and enter the data into the electronic data capture system (EDC). Refer to Section 4.2.12 for a listing of 
the adverse events.  
 
Study personnel will promptly report (within 24 hours of knowledge) all SAEs that the study intervention 
at least possibly relates to or are unexpected to the study sponsor and the DCC. The designated Medical 
Monitor will review these events and will forward them to the Chair of the DSMC. Study personnel must 
complete an initial SAE form, including details of the current SAE, and provide an Investigator 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 58 of 83 
Protocol Version #: 11    Date: 27-September-1024 
assessment of the causal relationship between the event and study procedures. Study personnel must 
document information not available at the time of the initial report on a follow-up SAE form.  
 
5.5.2. Data Monitoring Plan and Stopping Rules 
There is wide variability in weaning opioid drug treatment across IDeA States and NRN hospitals. Well-
characterized AEs and a DSMC will be critical to monitor the trial and to assure that the interventions 
are safe. The DSMC will assess safety after 25%, 50%, and 75% of the enrolled infants are medically 
ready for discharge, and it will assess efficacy and futility after 50% of the enrolled infants are medically 
ready for discharge. All interim analyses will utilize Bayesian modeling and predictive posterior inference 
based on neutral, enthusiastic, and skeptical priors. We will use Bayesian modeling for the interim 
analyses because the predictive posterior inference makes a clear statement about what to expect when 
we complete frequentist analysis on final data, given the interim results. The DSMC will receive an 
independent presentation of interim results, prepared by the study statistician. In preparation for the 
DSMC meeting, we will prepare a summary report of recruitment (by hospital), known outcome events, 
and any AEs (including medication side effects).  
 
Interim Futility and Efficacy Analysis. For interim efficacy, we will use Bayesian posterior predictive 
probabilities to predict the final outcome of the trial based on interim results. For this predictive 
probability calculation, we will use a frequentist criterion: reject null hypothesis if final analysis p-value 
is less than or equal to 0.05. Given this criterion and the neutral, enthusiastic, and skeptical priors 
defined above, we will calculate three predictive probabilities of success (PPoS) when 50% of the total 
sample is collected by using the three reference priors: neutral, skeptical, and enthusiastic. To calculate 
a PPoS, we will take the following steps: 
4. Choose the neutral, enthusiastic, or skeptical prior for the treatment effect. 
5. Fit a Bayesian linear regression model to the primary outcome using the interim data.  Include 
maternal treatment and stabilization dose as covariates.   
6. Calculate the posterior distributions for all regression terms. 
7. Use the interim data to calculate the observed distribution of maternal treatment. 
8. Use the interim data to calculate the observed distribution of the stabilization dose.  May 
approximate with a normal distribution if suitable.   
9. Determine how many infants we still need to randomize in each arm. 
10. For each arm, generate data for the required number of hypothetical participants by doing the 
following for each required hypothetical participants: 
o Sample a single value from each posterior distribution. 
o Make a random draw from the observed distribution for maternal treatment. 
o Make a random draw from the observed or approximated distribution for stabilization 
dose. 
o Use the appropriate sampled values from steps 7a – 7c to generate a hypothetical 
outcome. 
11. Use the data observed plus the hypothetical data generated in Step 7, above, to create a 
hypothetical complete trial and calculate the p-value under the null hypothesis of θ = 0. Use a 
linear regression model that includes treatment, maternal treatment, and stabilization dose.     

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 59 of 83 
Protocol Version #: 11    Date: 27-September-1024 
12. Repeat Steps 7 and 8 many times. The PPoS is the proportion of hypothetical completed trials 
that achieve a p-value for the treatment effect that is 0.05 or less.2  
 
The PPoS will be a helpful measure for the DSMC to use as it makes decisions about stopping the trial 
early for efficacy or futility or continuing to enroll. Below are two suggested guidelines for using the 
PPoS, but as stated in the DSMC charter, all protocol suggested stopping guidelines are advisory and the 
DSMC can choose to ignore them. If the PPoS is 0.99 or greater under the skeptical prior, then the DSMC 
may consider stopping the trial for efficacy. If the frequentist PPoS is 0.1 or less under the enthusiastic 
prior, then the DSMC may consider stopping the trial for futility. The PPoS under the neutral prior will 
also be available to aid interpretation of the PPoS estimates calculated under the skeptical and 
enthusiastic priors.   
 
Interim Safety Analysis. In addition to monitoring AEs and SAEs, as described in section 5.5.1 above, the 
DSMC will use Bayesian analyses to monitor seizure occurrence. The DSMC will assess seizure 
occurrence at three interim reviews, 25%, 50%, and 75% of enrollment. Within the slow-wean 
intervention, we expect the seizure proportion to be 0.03, and within the rapid-wean intervention, we 
expect this proportion to be higher. Based on clinical experience, the study team offers the following 
guideline for stopping the trial early for safety. Yet as with Efficacy and Futility, per the DSMC charter, all 
protocol suggested stopping guidelines are advisory and the DSMC can choose to ignore them. If the 
seizure proportion is 0.03 in the slow-wean intervention, and the seizure proportion is greater than 0.10 
in the rapid-wean intervention, then the DSMC may consider stopping the trial for safety. As such, the 
interim analyses of safety will focus on reporting information about the seizure proportion in the slow-
wean intervention and the difference between seizure proportions in both interventions. At each 
interim analysis of safety, we will calculate the posterior distribution of seizure proportion within each 
intervention by using a simple Bayesian logistic regression model, intercept and treatment effect 
parameters with neutral priors on the intercept and the intervention effect parameter. We will place a 
normal (μ=0, σ=10) on the intercept, and we will place a normal (μ=0, σ=3) on the intervention effect 
term.  Let θ1 = proportion of infants with seizures in the rapid-wean intervention and θ2 = proportion of 
infants with seizures in the rapid-wean intervention minus the proportion of infants with seizures in the 
slow-wean intervention. We will calculate the posterior distribution of θ1 and θ2 by using 
transformations of the MCMC values that make up the estimated posterior distributions for the 
intercept and the intervention effect parameter.  If Pr(θ1 > 0.1 | Data) ≥ 0.95, and Pr(θ2 > 0.07 | Data) 
≥ 0.95, then the DSMC may want to consider stopping the trial for safety.   
 
Under this guideline, the DSMC may consider stopping the trial for safety, if there is convincing evidence 
that the seizure proportion among rapid-wean infants is greater than 0.1 and there is convincing 
evidence that the seizure proportion among rapid-wean infants is more than seven percentage points 
greater than the seizure proportion among slow-wean infants. Finally, as with efficacy and futility, the 
DSMC charter states trial stoppage guidelines can be ignored if the DSMC determines it is necessary.   
 
 
2 Based on presentation by Ben Saville at Berry Consultants.  Presentation located at: 
https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=3&ved=2ahUKEwjJyaaQmePeAhVPm-
AKHcr_DCYQFjACegQIBxAC&url=https%3A%2F%2Fwww.diaglobal.org%2Fen%2F~%2Fmedia%2Fdiaglobal%2Ffiles%2Fresources
%2Ftopics-of-interest%2Fedm%2Fthe-utility-of-bayesian-predictive-probabilities.pdf&usg=AOvVaw1XpV0DJ1qy_h0h-iUS-QdZ 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 60 of 83 
Protocol Version #: 11    Date: 27-September-1024 
SECTION 6. 
DATA MANAGEMENT  
RTI International will provide the following: 
• 
Collaborates in the development, implementation, and monitoring of Weaning protocol.    
• 
Provides biostatistical leadership in statistical design aspects of Weaning protocol. 
• 
Provides data management, including development of CRFs and appropriate data collection 
systems. 
• 
Supervising data entry activities, including instructing and certifying data entry personnel in 
software and hardware usage, quality assurance of data entry, etc.  
• 
Designs and maintains central randomization system.   
• 
Manages the Data Safety and Monitoring Committee for the trial.  Including scheduling 
meetings, the DSMC charter and preparing interim monitoring reports for the DSMC.   
• 
Oversees the receipt and reconciliation of safety data.   
• 
Supervises NRN site quality assurance efforts, including conducting site visits and remote 
monitoring of data.   
• 
Prepares and distributes monthly reports, detailing data received, data consistency, miss 
data and adherence to protocol.   
• 
Disburses capitation payments to clinical centers on the basis of enrolled patients and other 
study-specific milestone triggers specified in the study protocols.  
• 
Provides the logistical support necessary to run an efficient and productive network.  
• 
Provides biostatistical leadership for collaborative analysis of study data and publication of 
results.   
• 
Prepares public-use data files.   
 
 
 
 
 
 
 
 
 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 61 of 83 
Protocol Version #: 11    Date: 27-September-1024 
SECTION 7. 
PUBLICATION AND DATA SHARING POLICY 
This study will comply with the 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 results. We will submit primary outcome results from 
this trial to ClinicalTrials.gov.  
• 
Publish results. We will make every attempt to publish results in peer-reviewed journals. We 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 Institutional 
Review Board (IRB) approvals and guidelines for protection of personally identifiable data, we 
will deposit de-identified data from this study in an appropriate, NIH-approved data repository.  

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 62 of 83 
Protocol Version #: 11    Date: 27-September-1024 
SECTION 8. 
REFERENCES 
1. Patrick SW et al, Neonatal abstinence syndrome and associated health care expenditures. 
United States, 2000-2009. JAMA 2012;307(18):1934-1940. 
2. McQueen, K and Murphy-Oikonen J., Neonatal Abstinence syndrome. New England Journal of 
Medicine. 2016;375(25):2468-2479. 
3. Jumah NA, Rural, Pregnant, and Opioid Dependent: A systematic review. Substance Review 
2016;Suppl 1:35-41. 
4. Patrick SW et al, Increasing incidence and geographic distribution of neonatal abstinence 
syndrome: United States, 2009 to 2012. Journal of Perinatology, 2015;35:650-655. 
5. Tolia VN et al, Increasing incidence of the neonatal abstinence syndrome in US Neonatal ICUs. 
New England Journal of Medicine, 2015;372;22:21182126. 
6. Tyler NA et al, Incidence and costs of neonatal abstinence syndrome among infants with 
Medicaid: 2004-2014. Pediatrics 2018;141(4):20173250 
7. Reddy UM et al, Opioid use in pregnancy, neonatal abstinence syndrome and childhood 
outcomes. Obstetrics and Gynecology, 2017;130:10-28. 
8. Patrick SW, The triple aim for neonatal abstinence syndrome. Journal of Pediatrics, 
2015;167:1189-1191. 
9. Wachman EM et al, Neonatal Abstinence Syndrome: Advances in Diagnosis and Treatment. 
JAMA, 2018:319(13):1362-1374. 
10. Holmes AV et al, Rooming in to treat neonatal abstinence syndrome: improve family-centered 
care at lower cost. Pediatrics, 2016;137(6):e20152929. 
11. Patrick SW et al, Variation in treatment of neonatal abstinence syndrome in US Children’s 
Hospitals, 2004-2011. Journal of Perinatology, 2014;34:867-872. 
12. Stover MW et al, Opioids in pregnancy and neonatal abstinence syndrome. Sem Perinatology, 
2015;39:561-565. 
13. Walsh MC et al, Ohio perinatal quality collaborative improves care of neonatal abstinence 
syndrome. Pediatrics 2018;141(4):e20170900. 
14. Jackson L et al, A randomized controlled trial of morphine versus phenobarbitone for neonatal 
abstinence syndrome. Arch Dis Child Fetal Neonat Ed, 2004;89:F300-F304. 
15. Brown MS et al, Methadone versus morphine for treatment of neonatal abstinence syndrome: A 
prospective randomized trial. Journal of Perinatology 2015:35:278-283. 
16. Nayeri F et al, Phenobarbital versus morphine in the management of neonatal abstinence 
syndrome, a randomized controlled trial. BMC Pediatrics, 2015;15:57.doi:10.1186/s12887-015-
0377-9. 
17. Kraft W et al, Buprenorphine for the treatment of the neonatal abstinence syndrome. New 
England Journal of Medicine, 2017;376:2341-2348.  
18. Davis JM et al, Comparison of safety and efficacy of methadone vs morphine for treatment of 
neonatal abstinence syndrome. A randomized trial. JAMA Pediatrics, 2018: 172(8):741-748. 
19. Bada HS et al, Morphine versus clonidine for neonatal abstinence syndrome. Pediatrics, 
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20. Kraft WK et al, Neonatal abstinence syndrome: Pharmacologic strategies for the mother and 
infant. Seminars in Perinatology, 2016;40:203-212. 
21. Ward RM et al, The pharmacokinetics of methadone and its metabolites in neonates, infants 
and children.  Pediatric Anesthesia, 2014;24:591-601. 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 63 of 83 
Protocol Version #: 11    Date: 27-September-1024 
22. Wiles JR et al, Pharmacokinetics of oral methadone in the treatment of neonatal abstinence 
syndrome: A pilot study.  Journal of Pediatrics 2015;167:1214-1220. 
23. Hall ES et al, Cohort analysis of a pharmacokinetic-modeled methadone weaning optimization 
for neonatal abstinence syndrome.  J Pediatrics, 2015;167:1221-1225 
24. Coyle MG et al, Neurobehavioral effects of treatment for opiate withdrawal. Arch Dis Child Fetal 
Neonatal Ed 2005;90:F73-74. 
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26. Lester B, et al, The maternal lifestyle study: effects of substance exposure during pregnancy on 
neurodevelopmental outcome in 1 month old infants. Pediatrics, 2002;110:1182-1192. 
27. Liu J et al, Neonatal neurobehavior predicts medical and behavioral outcome. Pediatrics 
2010;125:e90-98. 
28. Conradt E et al, Prenatal Opioid exposure: Neurodevelopmental consequences and future 
research priorities. Pediatrics, 2019;144(3):e20190128. 
29. Merhar ST et al, Retrospective review of neurodevelopmental outcomes in infants treated for 
neonatal abstinence syndrome. J Perinatology, 2018;38(5):587-592. 
30. Haight SC et al, Opioid use disorder documented at delivery hospitalization-United States, 1999-
2014. Morbidity and Mortality Weekly Report, 2018;67(31):845-849. 
31. Jones HE et al, Neonatal abstinence syndrome after methadone or buprenorphine exposure, 
New England Journal of Medicine, 2010;363(24):23202331.  
32. Zelson C et al, Neonatal narcotic addiction: 10 year observation. Pediatrics, 1971;48:178-189. 
33. Kandall SR et al, Late presentation of drug withdrawal symptoms in newborns. Am J Dis Child, 
1974:127;58-61. 
34. Herzlinger RA et al, Neonatal seizures associated with narcotic withdrawal. J Pediatr, 
1977:91;638-641.  
35. Limjoco J, et al, Amplitude integrated EEG use in neonatal abstinence syndrome; a pilot cohort 
study. The Journal of Maternal-Fetal and Neonatal Medicine, 2019; 
DOI:10.1080/14767058.2019.1579190. 
36. Palla MR, et al, EEG findings in infants with neonatal abstinence syndrome presenting with 
clinical seizures. Frontiers in Pediatrics 2019; DOI10.3389/fped.2019.00111. 
37. Cella, D., Riley, W., Stone, A. A., Rothrock, N., Reeve, B. B., Yount, S., Amtmann, D., D., B., Choi, 
S., Cook, K. F., et al. The Patient Reported Outcomes Measurement Information System 
(PROMIS) developed and tested its first wave of adult selfreported health outcome item banks: 
2005-2008. Journal of Clinical Epidemiology. 2010;63: 1179-1194. 
38. Thomas KA, Spieker S. Sleep, Depression, and Fatigue in Late Postpartum. MCN Am J Matern 
Child Nurs 2016, 41(2): 104-109. 
39. Busse M, Stromgren K, Thorngate L, Thomas KA. Parents' responses to stress in the neonatal 
intensive care unit. Crit Care Nurse 2013, 33(4): 52-59; quiz 60. 
40. Condon, et al, The assessment of parent-infant attachment: Development of a self-report 
questionnaire instrument.  Journal of Reproductive and Infant Psychology, Vol 16(1), Feb, 1998 
pp. 57-76. 
41. Rossen L, et al, Predictors of postnatal mother-infant bonding: the role of antenatal bonding, 
maternal substance use and mental health. Arch Womens Ment Health. 2016 Aug;19(4):609-22. 
doi: 10.1007/s00737-016-0602-z.  
42. Briggs-Gowan M, Carter A. Brief Infant-Toddler Social and Emotional Assessment (BITSEA). Yale 
University: New Haven, CT, 2002. 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 64 of 83 
Protocol Version #: 11    Date: 27-September-1024 
43. Briggs-Gowan MJ, Carter AS, Irwin JR, Wachtel K, Cicchetti DV. The Brief Infant-Toddler Social 
and Emotional Assessment: screening for social-emotional problems and delays in competence. 
J Pediatr Psychol 2004, 29(2): 143-155. 
44. Karabekiroglu K, Briggs-Gowan MJ, Carter AS, Rodopman-Arman A, Akbas S. The clinical validity 
and reliability of the Brief Infant-Toddler Social and Emotional Assessment (BITSEA). Infant 
Behav Dev 2010, 33(4): 503-509. 
45. Albers CA, Grieve AJ. Review of Bayley Scales of Infant and Toddler Development--Third Edition. 
Journal of Psychoeducational Assessment 2007, 25(2): 180-190. 
46. Gibbons LE, Feldman BJ, Crane HM, Mugavero M, Willig JH, Patrick D, et al. Migrating from a 
legacy fixed-format measure to CAT administration: calibrating the PHQ-9 to the PROMIS 
depression measures. Qual Life Res 2011, 20(9): 1349-1357. 
47. Pilkonis PA, Yu L, Dodds NE, Johnston KL, Maihoefer CC, Lawrence SM. Validation of the 
depression item bank from the Patient-Reported Outcomes Measurement Information System 
(PROMIS) in a three-month observational study. J Psychiatr Res 2014, 56: 112-119. 
 
 
 
  

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 65 of 83 
Protocol Version #: 11    Date: 27-September-1024 
SECTION 9. 
DATA FORMS 
9.1. 
SCREENING LOG 
 
9.2. 
RANDOMIZATION FORM 
 
9.3. 
MATERNAL MEDICAL HISTORY FORM 
 
9.4. 
INFANT MEDICAL HISTORY FORM 
 
9.5. 
WEANING INTERVENTION FORM 
 
9.6. 
PHARMACY DRUG ADMINISTRATION FORM 
 
9.7. 
STATUS FORM 
 
9.8. 
POST DISCHARGE FORM 
 
9.9. 
ADVERSE AND SERIOUS ADVERSE EVENTS FORM 
 
9.10. PROTOCOL VIOLATION FORM 
 
9.11. STUDY WITHDRAWAL FORM 
 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 66 of 83 
Protocol Version #: 11    Date: 27-September-1024 
SECTION 10. APPENDICES 
APPENDIX 1. 
INFANT CHARACTERISTICS AND DEMOGRAPHICS (ACT NOW CURRENT EXPERIENCE) 
 
Data listed in Appendices 1 and 2 represent a summary of selected infant characteristics and variables 
related to NOWS from a retrospective chart review for infants exposed to opioids during pregnancy 
(Advancing clinical trials in neonatal opioid withdrawal syndrome [ACT NOW] current experience: Infant 
exposure and treatment). These researchers reviewed the medical records for infants ≥ 36 weeks of 
gestational age and born between July 1, 2016 through June 30, 2017, and mothers medical records, 
when available, when there was opioid use (maternal history, maternal/infant toxicology screen, or 
NOWS scoring). In Appendices 1 and 2, we provide the results for full data from 1,808 infants collated 
from submitted records.  
 
Variable 
N 
Value 
Birth weight, kg (mean ± sd) 
1,805 
3.1 ± 0.5 
Gestational age wks (mean ± sd) 
1,800 
38.7 ± 1.3 
Apgar 1 min, median IQR 
1,776 
8 (8-9) 
Apgar 5 min, median IQR 
1,775 
9 (9-9) 
male % 
934 
51.7 
female % 
873 
48.3 
Race - % white/black/other 
1,338/217/253 
74.0/12.0/14.0 
urban % 
1,713 
94.7 
in-born % 
1,518 
84.0 
Location of care %1 
 
 
newborn nursery 
1,351 
74.7 
special care nursery 
309 
17.1 
NICU 
446 
24.7 
regional NICU 
346 
19.1 
pediatric unit 
77 
4.3 
1 Infants may be cared for in more than on location.  
 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 67 of 83 
Protocol Version #: 11    Date: 27-September-1024 
APPENDIX 2. 
PHARMACOLOGIC TREATMENT (ACT NOW CURRENT EXPERIENCE) 
 
Variable 
N 
Value 
Drug treatment % 
698 out of 1,808 
38.6 
Scoring assessment 
698 
 
Finnegan (original) % 
285 
40.8 
Finnegan (modified) % 
383 
54.9 
Primary medication 
698 
 
morphine % 
601 
86.1 
methadone % 
90 
12.9 
buprenorphine % 
2 
0.3 
phenobarbital % 
2 
0.3 
clonidine % 
3 
0.4 
Secondary medication 
223 
 
clonidine % 
123 
55.2 
phenobarbital % 
81 
36.3 
 
 
 
 
 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 68 of 83 
Protocol Version #: 11    Date: 27-September-1024 
APPENDIX 3. 
RECRUITMENT PLAN 
As documented in the protocol, enrollment of infants in clinical trials to improve the treatment of NOWS 
has been challenging. There are three major components for a successful recruitment plan: 
1. Understand who is providing care for pregnant patients with an Opioid Use Disorder.  
2. Disseminate information regarding research initiatives coupled with hospital care of the mother 
and newborn.  
3. Identify pregnant mothers prior to delivery and use prenatal consultation to establish trust and 
provide an overview of newborn care, an overview of the clinical trial and obtain consent as 
appropriate. 
 
The first two of these components are part of a system level recruitment initiative while the third 
component is patient specific. The summary below provides important lessons learned from Women & 
Infants Hospital of Rhode Island on the approach to mothers with an Opioid Use Disorder concerning 
clinical care and research initiatives. 
 
NOTE:   Initial contact with potential participants will be made by clinical staff rather than research staff 
(unless research staff are part of the same clinic). 
 
1) Who is providing care for pregnant patients with Opioid Use Disorder (System Level):  
 
Mothers with Opioid Use Disorder during pregnancy will acquire opioids through 4 major pathways:  
 
a) Methadone treatment programs 
 
b) Buprenorphine treatment programs 
 
c) Pain management or primary care providers 
 
d) Illicitly  
 
Methadone and buprenorphine treatment programs will be the easiest to identify; while identifying 
specific providers in the community may be more challenging.   
 
The Department of Health and Human Services, Substance Abuse and Mental Health Services 
Administration (SAMHSA), Center for Substance Abuse Treatment, Division of Pharmacologic Therapies) 
provides a user friendly link to locate all methadone and buprenorphine providers by state. Use the links 
below to find providers: 
• 
Methadone providers:  
https://dpt2.samhsa.gov/treatment/directory.aspx 
• 
Buprenorphine providers:  
https://www.samhsa.gov/medication-assisted-treatment/practitioner-program-
data/treatment-practitioner-locator 
 
2) Disseminate information to clinics, healthcare providers and the medical community regarding 
research initiatives coupled with hospital care of the mother and newborn (System Level): 
Disseminating information regarding the trial should occur in two phases. The first phase should be a 
face to face contact with methadone clinics, buprenorphine providers, support groups, peer recovery 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 69 of 83 
Protocol Version #: 11    Date: 27-September-1024 
coach networks, and other community support programs for women with opioid use disorders. The goal 
of the first phase is to establish a working dynamic with community partners. The research team should 
communicate to the community that they are a critical member of the team. The second phase will be 
to maintain contact with the community partners and support their efforts to identify patients. To 
improve the success of either of these phases the research team should have prepared marketing 
material to share with the community. This recruitment plan will benefit by the creation of marketing 
material before engaging the community.  
 
Methadone Clinics / Community Support Programs / Peer Recovery Coach Networks: 
Before the team makes contact with any community support programs they should identify programs 
that have a trusted reputation among mothers who utilize the services. Use available information 
(electronic records, hospital data bases, social workers, discussions with mothers with Opioid Use 
Disorder) to understand which of the many community programs are used most frequently by pregnant 
patients delivering or being transferred to the hospital participating in the trial. Since there will be many 
programs in the community, prioritize those programs where mothers with Opioid Use Disorder feel 
best supported and who they trust. The research team should build a list of high value programs to 
focus the team’s efforts. In some states the local health department lists programs that are considered 
to be excellent performers for their mission. Trusted centers are more likely to have a network that is 
able to identify eligible patients. 
• 
Establish contact with a community program/methadone treatment program is an essential first 
step. Initial contacts should be done face to face with members of the research leadership team 
and the community program/methadone clinic leadership team. The first meeting should 
discuss national gaps in NOWS care, the local model of NOWS care, how the trial is addressing 
gaps in NOWS care, and how the community program/methadone treatment program can help 
support the clinical trial. Identification of a liaison at the treatment program is ideal for 
continued contact. The research team should prepare to leave informational material with the 
center. Follow-up contact can occur by phone calls, mailings, and/or e-mail. 
• 
The research team should identify a liaison at each center as points of contact. The point of 
contact should be a member of the treatment program who would champion the clinical trial. 
The team would depend on this person to alert the research team when a patient becomes 
pregnant or if a new patient is pregnant.  
• 
Contacts with community program/methadone treatment programs typically need to be 
repetitive to maintain an awareness of the clinical trial. The research team should verify the 
accuracy of contact information, intake of new patients and the status of previously identified 
patients as they progress to birth. In addition, women who attend methadone treatment 
centers are likely to receive substance use counseling in other group settings and often share 
new information with others. Word of mouth within the community can be powerful. 
• 
There could be discussion of the research team attending a group meeting to enable study 
personnel to have a better understanding of the challenges that women with Opioid Use 
Disorder are confronted with.  
• 
In addition to addressing knowledge gaps, the research team should provide a clear line of 
communication for referral of a pregnant mother for a prenatal consultation.   
• 
The research team should maintain a log of the number of referrals from specific methadone 
treatment programs and monitor patient progression to delivery. Logs should be reviewed and 
updated at frequent intervals. Depending on local practice, the research team may need to 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 70 of 83 
Protocol Version #: 11    Date: 27-September-1024 
communicate with clinical providers at the birthing hospitals to ensure awareness of pregnant 
mothers during pregnancy.   
 
Buprenorphine Providers / Pain Management Specialists / Obstetricians 
Buprenorphine providers, pain management specialists and selected obstetricians represent another 
group of medical providers caring for pregnant mothers with an Opioid Use Disorder. Women with an 
opioid use disorder that do not attend methadone clinics and are not obtaining illicit opioids will have a 
buprenorphine provider. Medication-assisted treatment with buprenorphine is an accepted form of 
treatment. Buprenorphine can be prescribed by any medical provider who obtains a waiver from the 
FDA. The study team can work with local health departments, professional organizations and Opioid Use 
Disorder support groups to identify a group of buprenorphine providers in the community. The SAMHSA 
link above can also help locate buprenorphine providers in your local community.  
• 
Establishing contact with these specialists will be more challenging than community programs or 
methadone clinics. The team should prepare a brief communication or script in advance that 
addresses the key elements of the trial and provides clear directions or how to request a 
prenatal consultation for NOWS. Providers with office based practices will often not be able to 
provide substantial time to review the details of the trial. The goal when speaking with these 
practices is for the research team to communicate the opportunity for prenatal NOWS 
consultation. 
• 
In addition to the providers above, the research team should raise awareness of the proposed 
clinical trial in the medical community. This can involve mailing and/or email a description of the 
trial with study marketing materials to hospital affiliates such as Maternal Fetal Medicine, Family 
Medicine programs, Obstetric practices, Prenatal Clinics and Primary Care clinics. Marketing 
and/or Human Resource Departments may facilitate obtaining a list of providers. Organizing 
Grand Rounds or other lecture/symposium formats within the hospital, community, Health 
Department outreach, or support groups may be effective ways to disseminate information 
regarding NOWS and the clinical trial.  
• 
In addition to addressing knowledge gaps, the research team should provide a clear line of 
communication for referral of a pregnant mother for a prenatal consultation.   
• 
The research team should maintain a log of the number of referrals from specific providers and 
monitor patient progression to delivery. Logs should be reviewed and updated at frequent 
intervals. Depending on local practice, the research team may need to communicate with 
clinical providers at the birthing hospitals to ensure awareness of pregnant mothers during 
pregnancy. 
 
Marketing Material: 
• 
The primary study team will create attractive marketing materials that will be approved by the 
central IRB. Marketing materials may include study brochures, posters with tear off contact 
information, business cards, badge buddies, and social media posts.  Materials will have places 
to insert local contact information.   
• 
Marketing material should be considered for specific research initiatives in addition to any 
specific information regarding care practices at the birthing facility which mothers should be 
aware of.  
• 
Educational material about NOWS including current approaches to NOWS treatment, current 
gaps in NOWS care, local barriers to improving care, the purpose of the proposed clinical trial 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 71 of 83 
Protocol Version #: 11    Date: 27-September-1024 
and identifying ways in which the research team can help support medication assisted 
treatment programs. 
The research team should consider offering educational forums (community based, hospital based) 
which can be used to disseminate information regarding NOWS, maternal and newborn care in the 
birthing facility and the proposed clinical trial.   
 
3) Identify pregnant mothers prior to delivery and use prenatal consultation to establish trust and 
provide an overview of newborn care and the clinical trial. (Patient Specific):  
The single most important element of the recruitment strategy is the prenatal consultation. The 
prenatal consultation is most likely the first time that the family will meet the research study PI or 
designee. The mother may be aware of the clinical trial if the system wide elements of the 
recruitment strategy are in place. The consultation is the opportunity for the provider to gain and 
strengthen the 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, 
a detailed description of the local approach to NOWS, and the research opportunities at the local 
hospital to improve care. The prenatal consultation should also be an opportunity for the medical 
team to remove any guilt or anxiety the family might have about having a baby at risk for NOWS. 
Specific areas of focus during a consultation include:  
• 
Address any fears the family may have of NOWS or the hospital course. Providers should be 
prepared to hear questions about child protective services, breastfeeding, length of 
hospitalization and long term risk to their infant. An awareness of the local state’s laws will help 
guide families to the best resource with regards to child protective services.  
• 
Establish a common, core understanding of NOWS. Families should be informed about how 
NOWS develops and manifests. Providers should be objective and reinforce that the mother did 
not cause NOWS and her medication treatment did not harm her baby. Reinforcing objective 
knowledge should help remove potential maternal guilt.  
• 
Identify gaps in the current understanding of NOWS to show the family that the medical 
community is aware of limitations in the approach to care, and a willingness to improve.  
• 
Review local practices to reduce anxiety about delivering a baby at risk for NOWS. Provide as 
much concrete information about the clinical team's approach to NOWS care with the goal of 
reducing the number of “unknowns” for the family. Examples are the location of care, the 
number of different nurses who will care for the baby, visitation hours and what happens after 
the mother is discharged. Families that have fewer unknowns feel more empowered and are 
willing to engage in conversation about research.  
• 
Discuss the research protocol with families. This should include gaps in care and the potential 
impact of a clinical trial on the overall care of NOWS. The family should be free to discuss the 
possibility and given time to review privately. The study team should collect contact information 
for the family and plan to contact them at a later date or if necessary in the hospital.  
• 
If prenatal consultation is not feasible, effective ante-natal dissemination of information 
regarding the clinical trial will be exceptionally important to approach mothers after delivery. 
Since randomization needs to occur prior to the start of weaning, there should be time for 
research personnel to meet the mother, establish a relationship and introduce or remind 
mothers about the research initiative to improve the care of infants exposed to opioids. Follow-

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 72 of 83 
Protocol Version #: 11    Date: 27-September-1024 
up visits to the mother can be coordinated with other maternal and infant providers to be able 
to present the clinical trial during a quiet time with as little interruptions as possible.  When in-
person contact is not available or advisable, due to COVID-19 pandemic, remote contact can be 
made via a HIPAA-compliant method such as telephone, personal delivery of documents, US 
postal service, REDCap or other compliant electronic platform.  The remote contact process will 
parallel the contact process used for in-person contact.  The only difference will be the 
method(s) of communication.  

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 73 of 83 
Protocol Version #: 11    Date: 27-September-1024 
APPENDIX 4. 
MORPHINE: EXAMPLE OF WEANING WITH DOSING EVERY THREE HOURS 
For this and subsequent scenarios (Appendices 5-7), the difference in opioid dose between rapid and 
slow wean interventions is illustrated. Since there are no escalations, the intervention steps correspond 
to the dose levels listed in Table 4 (Section 4.2.6).  
Scenario. 3.2 kg infant treated with morphine, stabilized on 0.06 mg/kg/dose, and undergoing either a 
rapid-wean or slow-wean intervention with medication administered at three-hour intervals.  
Protocol. At the start of weaning, the morphine dose is decreased by 15% of the stabilization dose (rapid 
wean) or 10% of the stabilization dose (slow wean). The dose represents the actual mg administered. 
 
Intervention Dose 
Level  
Rapid Wean 
 
Intervention Dose 
Level 
Slow Wean 
Day of Randomization 
100% of stabilization 
0.19 mg q 3 h 
 
Day of Randomization 
100% of stabilization 
0.19 mg q 3 h 
Dose level A 
85% of stabilization 
0.16 mg q 3 h 
 
Dose level A 
90% of stabilization 
0.17 mg q 3 h 
Dose level B 
70% of stabilization 
0.13  mg q 3 h 
 
Dose level B 
80% of stabilization 
0.15  mg q 3 h 
Dose level C 
55% of stabilization 
0.11 mg q 3 h 
 
Dose level C 
70% of stabilization 
0.13 mg q 3 h 
Dose level D 
40% of stabilization 
0.08 mg q 3 h 
 
Dose level D 
60% of stabilization 
0.11 mg q 3 h 
Dose level E 
25% of stabilization 
0.05 mg q 3 h 
 
Dose level E 
50% of stabilization 
0.10 mg q 3 h 
Dose level F 
0% of stabilization 
Placebo 
 
Dose level F 
40% of stabilization 
0.08 mg 3  h 
Dose level G 
0% of stabilization 
Placebo 
 
Dose level G 
30% of stabilization 
0.06 mg q 3 h 
Dose level H 
0% of stabilization 
Placebo 
 
Dose level H 
20% of stabilization 
0.04 mg q 3 h 
 
Observe off 
study drug 
 
 
Observe off 
study drug 
 
Observe off 
study drug 
 
 
Observe off 
study drug 
 
 
 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 74 of 83 
Protocol Version #: 11    Date: 27-September-1024 
APPENDIX 5. 
MORPHINE: EXAMPLE OF WEANING WITH DOSING EVERY FOUR HOURS 
 
Scenario. 3.2 kg infant treated with morphine, stabilized on 0.08 mg/kg/dose, and undergoing either a 
rapid or slow wean with medication administered at four-hour intervals. 
Protocol. At the start of weaning, the morphine dose is decreased by 15% of the stabilization dose (rapid wean) or 
10% of the stabilization dose (slow wean). The dose represents the actual mg administered. 
 
Intervention Dose 
Level 
Rapid Wean 
 
Intervention Dose 
Level 
Slow Wean 
Day of Randomization 
100% of stabilization 
0.26 mg q 4 h 
 
Day of Randomization 
100% of stabilization 
0.26 mg q 4 h 
Dose level A 
85% of stabilization 
0.22 mg q 4 h 
 
Dose level A 
90% of stabilization 
0.23 mg q 4 h 
Dose level B 
70% of stabilization 
0.18  mg q 4 h 
 
Dose level B 
80% of stabilization 
0.21 mg q 4 h 
Dose level C 
55% of stabilization 
0.14 mg q 4 h 
 
Dose level C 
70% of stabilization 
0.18 mg q 4 h 
Dose level D 
40% of stabilization 
0.10 mg q 4 h 
 
Dose level D 
60% of stabilization 
0.16 mg q 4 h 
Dose level E 
25% of stabilization 
0.07 mg q 4 h 
 
Dose level E 
50% of stabilization 
0.13 mg q 4 h 
Dose level F 
0% of stabilization 
Placebo 
 
Dose level F 
40% of stabilization 
0.10 mg q 4 h 
Dose level G 
0% of stabilization 
Placebo 
 
Dose level G 
30% of stabilization 
0.08 mg q 4 h 
Dose level H 
0% of stabilization 
Placebo 
 
Dose level H 
20% of stabilization 
0.05 mg q 4 h 
 
Observe off 
study drug 
 
 
Observe off 
study drug 
 
Observe off 
study drug 
 
 
Observe off 
study drug 
 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 75 of 83 
Protocol Version #: 11    Date: 27-September-1024 
APPENDIX 6. 
METHADONE: EXAMPLE OF WEANING WITH DOSING EVERY EIGHT HOURS 
 
Scenario. 3.2 kg infant treated with methadone, stabilized on 0.1 mg/kg/dose, and undergoing either a 
rapid or slow wean with medication administered at eight-hour intervals.  
Protocol. At the start of weaning, the methadone dose is decreased by 15% of the stabilization dose 
(rapid wean) or 10% of the stabilization dose (slow wean). The dose represents the actual mg 
administered. 
 
Intervention Dose 
Level 
Rapid Wean 
 
Intervention Dose 
Level 
Slow Wean 
Day of Randomization 
100% of stabilization 
0.32 mg q 8 h 
 
Day of Randomization 
100% of stabilization 
0.32 mg q 8 h 
Dose level A 
85% of stabilization 
0.27 mg q 8 h 
 
Dose level A 
90% of stabilization 
0.29 mg q 8 h 
Dose level B 
70% of stabilization 
0.22  mg q 8 h 
 
Dose level B 
80% of stabilization 
0.26 mg q 8 h 
Dose level C 
55% of stabilization 
0.18 mg q 8 h 
 
Dose level C 
70% of stabilization 
0.22 mg q 8 h 
Dose level D 
40% of stabilization 
0.13 mg q 8 h 
 
Dose level D 
60% of stabilization 
0.19mg q 8 h 
Dose level E 
25% of stabilization 
0.08 mg q 8 h 
 
Dose level E 
50% of stabilization 
0.16 mg q 8 h 
Dose level F 
0% of stabilization 
Placebo 
 
Dose level F 
40% of stabilization 
0.13 mg q 8 h 
Dose level G 
0% of stabilization 
Placebo 
 
Dose level G 
30% of stabilization 
0.10 mg q 8 h 
Dose level H 
0% of stabilization 
Placebo 
 
Dose level H 
20% of stabilization 
0.06 mg q 8 h 
 
Observe off 
study drug 
 
 
Observe off 
study drug 
 
Observe off 
study drug 
 
 
Observe off 
study drug 
 
 
 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 76 of 83 
Protocol Version #: 11    Date: 27-September-1024 
APPENDIX 7. 
METHADONE: EXAMPLE OF WEANING WITH DOSING EVERY 12 HOURS 
 
Scenario: 3.2 kg infant treated with methadone, stabilized on 0.15 mg/kg/dose, and undergoing either a 
rapid or slow wean with medication administered at 12-hour intervals. 
Protocol: At the start of weaning, the methadone dose is decreased by 15% of the stabilization dose 
(rapid wean) or 10% of the stabilization dose (slow wean). The dose represents the actual mg 
administered. 
 
Intervention Dose 
Level 
Rapid Wean 
 
Intervention Dose 
Level 
Slow Wean 
Day of 
Randomization 
100% of stabilization 
0.48 mg q 12 h 
 
Day of Randomization 
100% of stabilization 
0.48 mg q 12 h 
Dose level A 
85% of stabilization 
0.41 mg q 12 h 
 
Dose level A 
90% of stabilization 
0.43 mg q 12 h 
Dose level B 
70% of stabilization 
0.34  mg q 12 h 
 
Dose level B 
80% of stabilization 
0.38 mg q 12 h 
Dose level C 
55% of stabilization 
0.26 mg q 12 h 
 
Dose level C 
70% of stabilization 
0.34 mg q 12 h 
Dose level D 
40% of stabilization 
0.19 mg q 12 h 
 
Dose level D 
60% of stabilization 
0.29 mg q 12 h 
Dose level E 
25% of stabilization 
0.12 mg q 12 h 
 
Dose level E 
50% of stabilization 
0.24 mg q 12 h 
Dose level F 
0% of stabilization 
Placebo 
 
Dose level F 
40% of stabilization 
0.19 mg q 12 h 
Dose level G 
0% of stabilization 
Placebo 
 
Dose level G 
30% of stabilization 
0.14 mg q 12 h 
Dose level H 
0% of stabilization 
Placebo 
 
Dose level H 
20% of stabilization 
0.10 mg q 12 h 
 
Observe off 
study drug 
 
 
Observe off 
study drug 
 
Observe off 
study drug 
 
 
Observe off 
study drug 
 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 77 of 83 
Protocol Version #: 11    Date: 27-September-1024 
APPENDIX 8. 
PHARMACY DOSING CALCULATOR 
 
We will provide hospital pharmacies with access to a web based dosing calculator. (see below). Once the 
research team consents and randomizes an infant, the pharmacist can enter the infant’s dosing weight, 
drug (medication), dose interval, and stabilization dose (mg/kg/dose) in the appropriate boxes. The 
pharmacist will only have the option to select morphine or methadone from the program for the drug 
(medication).  Once the drug is selected the pharmacy team will only have the option of selecting the 
dosing interval matched to each drug.  For infants receiving morphine the dosing interval will be either 
every 3 hours or 4 hours.  For infants receiving methadone the dosing interval will be either every 8 
hours or 12 hours. Once the pharmacist chooses these variables, the spreadsheet will generate the 
randomization dose (mg/dose) and the sequential dose reductions for each dose level of the rapid-wean 
(Image A) and slow-wean (image B) interventions. The calculator also provides the final (cessation) dose 
of study drug.  
 
Image A: Rapid Wean 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 78 of 83 
Protocol Version #: 11    Date: 27-September-1024 
 
Image B: Slow Wean 
 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 79 of 83 
Protocol Version #: 11    Date: 27-September-1024 
APPENDIX 9. CHANGES MORPHINE/METHADONE DOSE USING HOSPITAL GUIDELINES AND PROTOCOL 
GUIDELINES 
 
The examples below illustrate decreases or increases opioid dose based on hospital specific guidelines 
and study protocol guidelines. In each example, there is a 24-hour interval after a previous change in 
opioid dose for hospitals to use their guidelines to change the opioid (light blue horizontal bar, labeled 
24 hours). If the clinical team does not change the opioid dose by 24 hours, infants enter a 12-hour 
period of study protocol guidelines (horizontal purple bar, labeled weaning window). During this 12-
hour period, clinical teams must wean infants who do not meet hospital specific criteria for escalation. 
The clinical team does not need to use the total 12-hour period to either wean or escalate, if the infant 
meets criteria prior to 12 hours. 
 
In the examples below, the green lines indicate the time of opioid administration and the boxes contain 
the assessment score. These examples depict a hospital that uses Finnegan or modified Finnegan scores 
and the hospital guideline is to wean opioid if the average of three consecutive Finnegan scores is < 8. 
Hospitals would use a parallel process that follows assessment criteria of ACT NOWS Eat, Sleep, Console. 
 
A 
B 
C 
D 
E 
F 
A. Elevated scores occur prior to 24 hours and the clinical team should escalate the opioid dose. B. Elevated Finnegan scores 
occur at the end of the 24-hour interval, and the clinical team should escalate the opioid. C. Finnegan scores during the 24-
hour interval of hospital guidelines do not meet escalation criteria. Once in the 12-hour study protocol guideline, the 
Finnegan scores meet the hospital guidelines and the clinical team should wean the opioid, preferably as early in the 12-
hour interval, as possible. D. Finnegan scores during the 24-hour window of using hospital guidelines should have prompted 
weaning the opioid. Once in the 12-hour study protocol guidelines, the Finnegan scores do not meet the hospital’s 
escalation requirements, and the clinical team should wean the opioid. E. Finnegan scores at the end of the 24-hour window 
do not meet the hospital escalation criteria, and the clinical team weans the opioid. F. Finnegan scores at the end of the 24-
hour interval meet criteria for weaning the opioid. Subsequently, Finnegan scores increase and meet hospital criteria for 
opioid escalation, and the clinical team escalates the dose. 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 80 of 83 
Protocol Version #: 11    Date: 27-September-1024 
APPENDIX 10. PLACEBO DOSE UTILIZATION TO MAINTAIN THE BLIND IN THE RAPID-WEAN 
INTERVENTION 
 
All infants that are randomized to the rapid-wean intervention will need to complete three placebo dose 
levels to maintain the blind (Appendices 4-7). Placebo administration only occurs after the infant has 
weaned from the 25% of stabilization dose level. We will consider a placebo dose level complete if the 
infant meets the following two criteria: 
1) The infant tolerates the placebo without NOWS signs prompting a resumption of opioid.  
2) The clinical team starts the next dose level in the intervention (i.e., the clinical team orders 
“wean opioid.”). If during a placebo dose the clinical team orders “escalate opioid”, then we will 
not consider the placebo dose complete. The clinical team needs to repeat a placebo dose that 
is not complete.    
 
For infants who experience the same number of escalations or resumptions, placebo use in the rapid-
wean intervention will result in study drug discontinuation after the same number of study steps as 
infants in the slow-wean intervention. Examples below demonstrate how placebo use in the rapid-wean 
intervention will maintain the blind (infant A). These examples include an infant without escalations 
(example A), an infant who has two escalations prior to reaching placebo (example B), an infant with 
one escalation that occurs during a placebo dose level (example C), an infant with two escalations: one 
that occurs during an opioid dose level and one that occurs during a placebo dose level (example D), and 
an infant with two escalations that both occur during the placebo levels (example E). For each example, 
we show an infant randomized to the slow-wean intervention with an identical number of escalations or 
resumptions of opioid (infant B). 
 
We present the examples in terms of steps (not dose levels) to illustrate that there will be more study 
steps than dose levels when there are escalations of the opioid. In the examples, every infant 
randomized to the rapid-wean intervention needs to complete three placebo dose levels. We will 
consider placebo dose levels incomplete if opioid resumption interrupts them. The three placebo dose 
levels do not need to occur consecutively. For the research team to consider a placebo level complete, it 
needs to lead to a successful wean to another placebo level or off study drug. 

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 81 of 83 
Protocol Version #: 11    Date: 27-September-1024 
 
A 
B 
A. No Escalations. Infant A stops opioid at step 5. Infant B continues opioid until step 8. To maintain the blind, infant A receives placebo for steps 6-8. 
Both infants stop receiving “opioid/study drug” at step 8. B. Two Escalations during Opioid Steps. Both infants escalate at steps 3 and 5. Infant A 
discontinues opioid at step 9. Infant B discontinues opioid at step 12. Infant A receives 3 steps of placebo (10-12) to preserve blind. Both infants 
discontinue “study drug” at step 12.  
 
 
 
 
Infant A
Infant B
Rapid wean:
Slow wean:
15 % of stabilization dose 10 % of stabilization dose
Stabilization Dose
100
100
Step 1
85
90
Step 2
70
80
Step 3
55
70
Step 4
40
60
Step 5
25
50
Step 6
Placebo*
40
Step 7
Placebo*
30
Step 8
Placebo*
20
Dose Medication is discontinued 
Placebo Step
Key:
Infant A
Infant B
Rapid wean:
Slow wean:
15 % of stabilization dose 10 % of stabilization dose
Stabilization Dose
100
100
Step 1
85
90
Step 2
70
80
Step 3
85
90
Step 4
70
80
Step 5
85
90
Step 6
70
80
Step 7
55
70
Step 8
40
60
Step 9
25
50
Step 10
Placebo*
40
Step 11
Placebo*
30
Step12
Placebo*
20
Escalation
Dose Medication is discontinued 
Placebo Step
Key:

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 82 of 83 
Protocol Version #: 11    Date: 27-September-1024 
C 
 
D 
C. One Escalation after Start of Placebo. Both infants have one escalation at step 8. Infant A step 8 occurs after placebo initiation. Infant A completes 
first placebo step (step 6) because the clinical team weans the study drug and starts placebo (step 7). Placebo dose at step 7 is not complete because it 
prompted the clinical team to escalate study drug and an opioid is resumed (25% of stabilization dose). Placebo step 7 will need to be repeated when 
the clinical team weans study drug.  The latter will represent step 9.   Three complete steps of placebo ensure that both infants end “study drug” at 
step 10.  
D. Two Escalations: One during Opioid and One during Placebo. Both infants have two escalations at steps 6 and 9. The escalation at step 6 follows the 
same approach as example B. The escalation at step 9 occurs after the patient was started on placebo and study drug increases to 25% of the 
stabilization dose.    The step 8 placebo for infant A is not complete and the clinical team needs to repeat it (step 10). Three complete steps of placebo 
(10-12) ensure that both infants end “study drug” at step 12. 
 
Infant A
Infant B
Rapid wean:
Slow wean:
15 % of stabilization dose 10 % of stabilization dose
Stabilization Dose
100
100
Step 1
85
90
Step 2
70
80
Step 3
55
70
Step 4
40
60
Step 5
25
50
Step 6
Placebo*
40
Step 7
Placebo*
30
Step 8
25
40
Step 9
Placebo*
30
Step 10
Placebo*
20
Escalation from Previous Dose and Discontinue
Key:
Placebo Step
Dose Medication is discontinued 
Escalation
Incompleted Placebo Step
Infant A
Infant B
Rapid wean:
Slow wean:
15 % of stabilization dose 10 % of stabilization dose
Stabilization Dose
100
100
Step 1
85
90
Step 2
70
80
Step 3
55
70
Step 4
40
60
Step 5
25
50
Step 6
40
60
Step 7
25
50
Step 8
Placebo*
40
Step 9
25
50
Step 10
Placebo*
40
Step 11
Placebo*
30
Step12
Placebo*
20
Escalation from Previous Dose and Discontinue
Key:
Placebo Step
Dose Medication is discontinued 
Escalation
Incompleted Placebo Step

Title:  Pragmatic, Randomized, Blinded Trial to Shorten Pharmacologic Treatment of Newborns  
           with Neonatal Opioid Withdrawal Syndrome (NOWS) 
Sponsor:  National Institutes of Health 
cIRB #: 260053                                                                                                                                      Page 83 of 83 
Protocol Version #: 11    Date: 27-September-1024 
E.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
E. Two Escalations during Placebo Steps. Both infants have two escalations at steps 8 and 10 after infant A starts placebo. NOWS signs reoccur during 
step 7 causing opioid resumption at 25% of the stabilization dose. Infant A does not tolerate weaning opioid at step 9, and the clinical team resumes 25% of 
the opioid stabilization dose. Steps 7 and 9 of placebo for infant A did not end in a successful wean to another placebo step and neither is complete. Three 
complete placebo steps (6, 11, and 12) ensure that both infants end “study drug” at step 12 
 
Infant A
Infant B
Rapid wean:
Slow wean:
15 % of stabilization dose 10 % of stabilization dose
Stabilization Dose
100
100
Step 1
85
90
Step 2
70
80
Step 3
55
70
Step 4
40
60
Step 5
25
50
Step 6
Placebo*
40
Step 7
Placebo*
30
Step 8
25
40
Step 9
Placebo*
30
Step 10
25
40
Step 11
Placebo*
30
Step 12
Placebo*
20
Escalation from Previous Dose and Discontinue
Key:
Placebo Step
Dose Medication is discontinued 
Escalation
Incompleted Placebo Step