Clinical trial NCT04298853
Conditions: Neonatal Abstinence Syndrome Neonatal Opioid Withdrawal Neonatal Opioid Withdrawal Syndrome
Keywords: morphine Finnegan
Sponsor: Indiana University
Start date: 2020-06-30; Completion date: 2021-10-01
Enrollment: 17 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Randomized pilot trial comparing scheduled morphine dosing with a weaning protocol to intermittent morphine dosing on an as-needed basis for newborns with neonatal abstinence syndrome.

Detailed description:

Arms: arm 1: Infants randomized to the standard arm will receive morphine based on the current institutional treatment protocol: oral morphine 0.05 mg/kg/dose given every 3 hours, initiated if threshold Finnegan score is met. Once stabilized, dose will be weaned by 10% of peak dose per day until discontinuation. arm 2: Infants randomized to the study arm will receive oral morphine 0.05 mg/kg/dose as needed for an elevated Finnegan score. May receive morphine as frequently as every 3 hours if needed.
Interventions: intervention 1: Morphine PRN intervention 2: Morphine scheduled
Intervention descriptions: intervention 1: Dose given every 3 hours as-needed for severe NAS, defined by a threshold Finnegan score. intervention 2: Dose given every 3 hours on a scheduled basis and slowly weaned once stabilized.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
NCT04298853 
Optimal morphine dosing schedule 
for neonatal abstinence syndrome 
Version: June 16, 2021 
ozierja 
[Date] 
 


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Optimal morphine dosing schedule for neonatal 
abstinence syndrome 
 
Anna Thomas, MD 
 
1030 W Michigan St 
Suite 4600 
Indianapolis, IN 46202 
aeschwar@iu.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Support Provided by: 
Department of Pediatrics, Indiana University School of Medicine 
 
 
 
 
 


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Table of Contents: 
 
Study Schema 
1.0 
Background & Rationale 
2.0 
Objective(s) 
2.1 
Primary Objective 
2.2 
Secondary Objective 
2.3 
Tertiary/Exploratory/Correlative Objectives 
3.0 
Outcome Measures 
3.1 
Primary Outcome Measures 
3.2 
Secondary Outcome Measures 
3.3 
Tertiary/ Exploratory/ Correlative Outcome Measures 
4.0 
Eligibility Criteria 
4.1 
Inclusion Criteria 
4.2 
Exclusion Criteria 
5.0 
Study Design 
6.0 
Enrollment/Randomization 
7.0 
Study Procedures 
8.0 
Study Calendar 
9.0 
Reportable Events 
10.0 Data Safety Monitoring 
11.0 Study Withdrawal/Discontinuation 
12.0 Statistical Considerations 
13.0 Data Management 
14.0 Privacy/Confidentiality Issues 
15.0 Follow-up and Record Retention 
16.0 References 
17.0 Appendix 1.0 
 
 


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Abbreviations 
 
AE 
Adverse Event 
HIPAA Health Insurance Portability and Accountability Act  
IRB 
Institutional Review Board 
NAS 
Neonatal Abstinence Syndrome 
PI 
Principal Investigator 
SAE 
Serious Adverse Event 
 
1.0 
Background & Rationale 
 
Neonatal abstinence syndrome (NAS) is a pattern of withdrawal symptoms seen in newborn 
infants who are exposed to opioids in utero. The incidence of this condition has increased 
drastically over the last two decades as a result of the ongoing nationwide opioid epidemic.1-3 In 
2015, the NICU at Indiana University Health Methodist Hospital implemented a guideline for the 
management of NAS. This guideline includes the modified Finnegan scoring tool to assess 
severity of withdrawal symptoms and guide interventions, particularly when it is appropriate to 
initiate pharmacologic treatment. This guideline was successful in reducing the mean length of 
stay for infants treated for NAS from 27.7 days to 19.7 days. However, the average length of 
stay has remained stable since then and concerns have been raised that we may be treating 
infants too aggressively based on this guideline. In 2018, a total of 154 infants (≥ 35 weeks 
gestation) with intrauterine opioid exposure were born at IU Health Methodist Hospital. Of these 
infants, 43% (66 infants) required treatment with morphine with an average length of stay of 
21.5 days. 
 
Currently there is no uniformly accepted treatment strategy for NAS and both the choice of 
primary medication and criteria for treatment vary widely.4,5 Morphine is by far the most 
commonly used medication for NAS treatment, followed by methadone.6,7 Buprenorphine is also 
gaining interest and appears to be a viable option for treatment of NAS in terms of safety and 
feasibility of dosing.8 Based on a small number of randomized trials and retrospective cohort 
studies, it appears to be superior in terms of length of treatment in comparison to methadone 
and morphine.8-10 However, there is still a need for larger scale studies. In neonates, 
buprenorphine is administered sublingually in a solution of 30% ethanol and is not as readily 
available in this form. The question of which medication is optimal to treat NAS is highly 
debated. Many studies seeking to answer this question have been published, but due to 
variability of multiple factors and overall low quality of evidence, it is difficult to come to a single 
conclusion regarding appropriate medication choice and dosing schedule.10 We have chosen to 
use morphine as it is readily available, has been used widely in newborns, and has a shorter 
half-life which makes it easier to titrate dosing quickly for symptom management.  
 
The starting dose of morphine and protocols for adjusting the dose are variable as well. In 
general, most institutions use a starting dose of 0.04 – 0.05 mg/kg of morphine given every 3-4 
hours. Our current practice is to use 0.05 mg/kg every 3 hours and to increase the dose as 
needed based on response, measured by the modified Finnegan score. Once an infant is stable 
for 48 hours on a particular dose, the weaning phase is initiated. A stable condition is defined as 
a modified Finnegan score less than 9, eating well, gaining weight and sleeping. However, 
Grossman et al had success in decreasing the length of stay for infants with NAS using 
intermittent/as needed morphine dosing in combination with a novel approach to scoring.11 In 
this model, infants are monitored with a scoring system and a dose of morphine is only given if 
the infant meets specified criteria for treatment, with a minimum interval of 3 hours between 


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doses. While this is promising, there have been no studies thus far comparing as-needed 
morphine dosing to the current standard approach of scheduled dosing with gradual weaning of 
the dose. This is an important piece of information as many centers are seeking to adopt this 
method without the supporting evidence of a randomized trial.  
 
 
2.0 
Objective(s) 
2.1 
Primary Objective: To evaluate the feasibility of conducting a randomized 
controlled trial by examining enrollment.  
2.2 
Secondary Objective: To evaluate the feasibility of conducting a randomized 
trial by identifying any concerns related to the practicality of the study protocol. 
2.3 
Tertiary Objective: To provide an estimate of means and standard deviations 
necessary to conduct a definitive RCT. 
 
3.0 
Outcome Measures/Endpoints 
3.1 
Primary Outcome Measure: Enrollment rate, drop out rate, number of 
patients switched to standard arm  
3.2 
Secondary Outcome Measure: Length of hospital stay from birth to 
discharge, 
3.3 
Total cumulative morphine exposure (per kilogram of body weight), peak 
morphine dose, and length of morphine treatment (in days) 
 
4.0 
Eligibility Criteria 
4.1 
Inclusion Criteria 
• 
Neonates ≥ 35 weeks gestation with intrauterine opioid exposure 
• 
Severe NAS (modified Finnegan score ≥9) requiring NICU admission  
 
4.2 
Exclusion Criteria 
• 
Infants with significant co-morbidities requiring analgesia or sedation due to 
clinical condition 
• 
Infants with ongoing need for respiratory support 
o Infants with suspected genetic abnormalities or significant congenital anomalies 
that would interfere with accurate modified Finnegan scoring or response to oral 
morphine 
• 
Mother and baby pairs in which the mother is under the age of 18 years old 
 
 
5.0 
Study Design 
 
This will be a pragmatic pilot randomized controlled trial comparing scheduled versus 
intermittent morphine dosing for severe neonatal abstinence syndrome, performed in the Riley 
Hospital for Children Neonatal Intensive Care Unit (NICU) at IU Health Methodist Hospital. In 
2018, 154 babies admitted to IU Health Methodist were exposed to opioids in utero. Dr. Anna 
Thomas has clinically treated and conducted research with this population since 2015. We 
hypothesize that treating NAS symptoms on an as-needed basis will result in decreased use of 
morphine and decreased length of stay. Severity of NAS will be defined by the modified 
Finnegan scoring tool, which is already in use.12 This tool is administered by the bedside nurse 


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every 3-4 hours and uses graduated scoring of 21 items which are then added together to give 
the modified Finnegan score.  
The current guideline for pharmacologic treatment of neonatal abstinence syndrome uses the 
modified Finnegan score to determine the severity of symptoms. Modified Finnegan scoring 
should be performed every 3 hours after a feeding. If an infant reaches the threshold score for 
treatment (≥ 9), morphine is initiated at 0.05 mg/kg/dose orally every 3 hours. If the modified 
Finnegan score continues to be elevated, the dose is escalated per a protocol until the modified 
Finnegan score is in an acceptable range. Once the infant’s modified Finnegan score has been 
stable for at least 48 hours on a particular morphine dose, the weaning phase begins. Morphine 
is weaned by 10% of the peak dose every 24 hours as tolerated based on symptoms. When the 
dose has been weaned to < 0.02 mg/kg/dose, it may be discontinued. In order to be 
discharged home from the hospital, the infant needs to remain stable off of morphine for at 
least 48 hours. The study group will also be assessed using the modified Finnegan scoring tool. 
These infants will receive morphine at the same starting dose of 0.05 mg/kg/dose but on an as-
needed basis as often as every 3 hours if the modified Finnegan score reaches the threshold for 
treatment. Our goal is to enroll 24 participants with 12 patients on each arm. A success rate 
would be a retention of 80% (approximately 20 participants).  
 


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Admission 
to NICU 
 
 
 
 
 
 
 
 
 
 
Prior to  
morphine 
 
 
 
Meets criteria 
for morphine 
 
 
 
NICU 
hospital stay  
 
 
 
Discharge  
from NICU 
 
 
 
 
4-6 weeks  
post-discharge 
 
 
 
6.0 
Enrollment/Randomization 
 
Patients will be assessed for eligibility at the time of birth based on known intrauterine opioid 
exposure. The parents will not be approached for participation in the study unless the infant is 
admitted to the NICU with severe NAS symptoms. If eligible, the mother will be approached for 
informed consent upon admission to the NICU or, if already admitted to the NICU, upon 
recognition that the infant has severe symptoms that may need morphine. Once consent has 
been obtained, the infant will be randomized via paper process that has been designed by a 
biostatistician in block sizes of 4-6 patients with a 1:1 ratio. Randomization can occur after the 
first dose of morphine as the second dose of morphine is considered a study procedure.  
Total N: 24  Screen potential participants by inclusion and exclusion criteria. 
Obtain informed consent. 
Baseline data will be collected from the medical record. 
Infants will be monitored per current institutional guidelines using the modified 
Finnegan scoring (MFS) tool. 
Once the infant has had stable MFS off morphine for at least 48 hours, they will 
be ready for discharge. 
Data will be collected from the medical record, including length of stay and total 
cumulative morphine dose. 
Infants will continue to be monitored with the MFS and morphine discontinued 
per protocol once symptoms are stable. 
Phone call to family to follow-up 
and assess re-admission rate. 
 
Study arm 
N = 12 
Control arm 
N = 12 
Morphine will be started per protocol. 
Infants in the control arm will receive morphine per standard dosing. 
Infants in study arm will receive morphine per study arm dosing. 
Randomize 
1:1 


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7.0 
Study Procedures 
 
Newborns will be screened for enrollment if they are exposed to opioids in utero. We will not 
approach the parents of infants with opioid withdrawal if they are stable and remain in the well 
newborn nursery. Once the newborn is enrolled and randomized prior to the second dose of 
morphine they will continue to be monitored per standard care with the modified Finnegan 
score. Information will be collected from the mother’s medical chart, including her age, medical 
problems, Hepatitis C status, labor and delivery complications, prior history of drug use, current 
medications, prenatal screening labs, and urine toxicology results. Information will also be 
collected from the newborn’s chart, including gestational age at birth, mode of delivery, Apgar 
scores, birth weight, modified Finnegan scores, length of time in the newborn nursery prior to 
NICU admission, nutrition (breastfeeding vs formula), urine, meconium, and umbilical cord 
toxicology screens.  
 
All infants will receive optimal non-pharmacologic interventions per standard care, such as 
parental rooming-in when possible, breastfeeding when possible, quiet and dimly-lit 
environment with low stimulation, close contact with caregiver for soothing, pacifier, and on-
demand feedings.  
 
Each group will be monitored with the use of the modified Finnegan score to quantify the 
severity of NAS, per the current standard care. It is performed by the bedside nurse every 
3-4 hours following a feeding. Due to the pragmatic nature of this pilot trial, FINN scores 
obtained outside this window will not be a deviation.  Bedside nursing is trained in the modified 
Finnegan scoring process. If a patient meets the threshold for morphine (modified Finnegan 
score ≥ 9, or a score of  ≥ 12), a second nurse should immediately perform a separate score to 
confirm. The threshold for initial dose of morphine will be the same for both the standard care 
control and the study group. All infants with intrauterine opioid exposure will remain inpatient 
for observation for a minimum of 5 days before discharge, per standard care. The details of 
treatment for each group are outlined below. 
 
Standard Care (Control) Group 
1. Initiation of morphine and stabilization 
a. Non-pharmacologic care (infant soothing techniques) should be optimized prior 
to initiating morphine or increasing the dose. If the clinical team feels non-
pharmacologic care has not been optimized, it is appropriate to do so and re-
evaluate the next modified Finnegan score before initiating or increasing 
morphine. 
b. Treatment should be initiated if an infant has two consecutive modified 
Finnegan scores ≥ 9 or one score ≥ 12. 
i. Initial dose: morphine 0.05 mg/kg/dose every 3 hours. 
c. Modified Finnegan scoring will continue every 3 hours.  
i. If the infant’s modified Finnegan score remains ≥ 12, a rescue dose of 
double the previous dose should be given. For instance, if an infant is 
given 0.05 mg/kg/dose and the next modified Finnegan score is ≥ 12, a 
rescue dose of 0.1 mg/kg/dose should be given x1. 
ii. If the modified Finnegan score is < 12 after the rescue dose is given, that 
dose should be given as the maintenance dose every 3 hours.  


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iii. If the modified Finnegan score remains > 8 but < 12, escalate the 
morphine dose by 0.03 mg/kg/dose every 3 hours until the scores are ≤ 
8.  
iv. Before increasing the dose, ensure that there has been sufficient 
time to observe the patient’s response to the previous dose 
given. For example, if an infant receives a morphine dose at the 
time of a feeding, the Finnegan score is then assigned 1 hour 
after the feeding. This is not sufficient time to reflect the 
response to the most recent morphine dose. There should be a 
full period of observation (at least 2 hours) after a dose before a 
decision is made to escalate the dose. 
 
d. Once the modified Finnegan scores are consistently ≤ 8, continue the 
maintenance dose for 48 hours before beginning the weaning phase. 
e. If the morphine dose exceeds 0.3 mg/kg/dose, consider adding phenobarbital as 
an adjunctive medication. 
i. Loading dose: phenobarbital 10 mg/kg/dose q12 hours x2 doses 
ii. Maintenance: phenobarbital 5 mg/kg/dose q24 hours 
 
2. Weaning 
a. Once the infant has been stable for 48 hours, begin weaning the dose of morphine 
by 10% of the original maintenance dose (the dose on which the infant has been 
stable) every 24 hours. For example, if the maintenance dose is 0.05 mg/kg/dose, 
each wean should decrease by 10% of that dose = 0.005 mg/kg/dose. 
i. Maintain the dosing interval of every 3 hours throughout the 
entire weaning process. 
b. If the infant has two consecutive modified Finnegan scores ≥ 9, increase back to the 
previous dose at which the infant was stable. 
i. 
If modified Finnegan scores continue to be > 8 after going back to the 
previous dose, continue to increase the dose in a stepwise fashion. Consider 
weight-adjusting the dose if appropriate. 
ii. Remember to optimize non-pharmacologic measures and rule out other 
causes of agitation before increasing the dose. 
c. Once the infant is stable again for 48 hours, resume weaning by 10% of the original 
maintenance dose. 
d. Once a single dose is < 0.02 mg/kg, discontinue morphine. 
e. If the infant is receiving phenobarbital, discontinue at second to last step of 
morphine wean. 
f. 
Infants should be monitored for a minimum of 48 hours after discontinuing morphine 
prior to discharge. 
g. If the infant qualifies for treatment based on modified Finnegan scoring 
AFTER discontinuation of morphine, restart morphine at the previous dose 
at which the infant was stable (the ending dose of the weaning schedule). 
i. 
Once infant is stable for 48 hours, consider weaning an additional step prior 
to discontinuing morphine. 
ii. If the infant meets criteria for a rescue dose, give a one-time dose of double 
the previous dose at which infant was stable. 


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i. For example, if the previous dose at which the infant was stable was 
0.07 mg, give 0.14 mg x1 and resume the maintenance dose at 0.07 
mg. Do not use 0.14 mg as the new maintenance dose unless infant 
requires a repeat rescue dose. 
 
Study Group 
1. Non-pharmacologic care (infant soothing techniques) should be optimized prior to giving 
a morphine dose. If the clinical team feels non-pharmacologic care has not been 
optimized, it is appropriate to do so and re-evaluate the next Finnegan score before 
giving morphine. 
2. If the modified Finnegan score is ≥9 for two consecutive scores or ≥ 12 for one score, 
the infant will be given a one time dose of 0.05 mg/kg of morphine orally.  
3. If any subsequent modified Finnegan score is ≥ 9, the infant may receive a repeat dose 
of morphine 0.05 mg/kg. Before repeating a dose, there should be an adequate period 
of observation after the prior dose was given (at least 2 hours) for the Finnegan score to 
reflect the response to a dose. 
a. If an infant has received 3 consecutive doses of 0.05 mg/kg/dose every 3 hours 
and continues to qualify for a 4th dose consecutively, that dose will be increased 
to 0.075 mg/kg/dose 
b. The infant will then receive 0.075 mg/kg dose when indicated. 
c. The morphine dose may be escalated to 0.1 mg/kg if the infant receives 3 
consecutive doses of 0.075 mg/kg and again qualifies for a 4th consecutive dose 
d. If it has been more than 24 hours since the previous dose of morphine and the 
infant again qualifies for a dose, it will be decreased back to the lower dose 
4. If an infant receives all 8 possible doses of morphine within a 24-hour period (i.e. the 
infant receives morphine every 3 hours for 24 hours consecutively), the infant will be 
removed from the study protocol and placed on morphine per the standard guideline 
5. An infant will be eligible for potential discharge once they have been stable for 48 hours 
without receiving a dose of morphine. 
 
8.0 
Study Calendar 
 
 
Timeline Birth 
Admission to 
NICU 
Treatment 
Discharge 
Follow-up 
 
Screening for 
potential 
eligibility based 
on opioid 
exposure 
Determine 
eligibility and 
approach for 
enrollment 
Follow treatment 
course 
Final data 
collection on 
outcomes 
Phone call/chart 
review) at 4-8 
weeks of age to 
assess for re-
admission 
 
 
Collect baseline 
maternal and 
newborn data 
Monitor for 
protocol 
deviations, issues, 
AEs, SAEs 
Confirm contact 
information for 
follow-up phone 
call 
 
 
 
Randomize 
Continue data 
collection 
 
 
 
 
 
9.0 
Reportable Events 
Study Procedures 


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An adverse event (AE) is defined as any untoward medical occurrence in a subject in the 
investigation. AEs must be assessed for expectedness, severity, attribution (relatedness to the 
study intervention), and seriousness by the investigator, or another qualified study team 
member as characterized below. AEs deemed related to the intervention must be reported as 
serious adverse events (SAEs) if they become serious (become life-threatening, result in death, 
or prolong hospitalization). Recording of such adverse events will start at the time of the study 
consent and will stop upon discharge from the hospital. 
 
The following criteria will be used to define relatedness:  
Definite: The AE is clearly related to the study intervention  
Probable: The AE is likely related to the study intervention  
Possible: The AE may be related to the study intervention  
Unrelated: The AE is clearly not related to the study intervention 
  
The severity of AEs will be described as: 
Mild: asymptomatic or mild symptoms, no intervention indicated  
Moderate: clinically significant requiring minimal noninvasive intervention 
Severe: severe or medically significant but not immediately life-threatening, need for intensive, 
emergent, or invasive intervention  
Life-threatening: life-threatening physiological consequences, need for intensive or emergent 
invasive intervention  
 
 
Newborns with NAS are at risk of several complications related to their withdrawal symptoms. 
They may experience excessive weight loss in the first 1-2 weeks of life (>10% of their birth 
weight), they may have oromotor dysfunction and require supplement gavage feedings to 
support growth, and in rare cases, they can have seizures. Adverse events will be monitored 
monthly by the study team and collected in REDCap. Infants who receive morphine are at risk 
of over-sedation and decreased level of consciousness, as well as respiratory depression that 
can result in apnea. While this risk is mitigated by the fact that infants with NAS are opioid-
tolerant, it remains a risk especially when escalating the dose. Per standard care, all infants 
receiving morphine remain on cardiopulmonary monitoring throughout their treatment.  
 
Adverse Event monitoring will include: 
1. Depressed level of consciousness  
Grade 1: Decreased level of alertness 
Grade 2: Sedation; slow response to stimuli; sleeping longer than expected or     
needing to be aroused at feeding times 
Grade 3: Difficult to arouse 
Grade 4: Life-threatening consequences; coma; urgent intervention indicated 
Grade 5: Death 
2. Other events classified as serious and unexpected 
3. Other events resulting in death or classified as Serious or Related (to study procedures) 
 
 
 
A depressed level of consciousness grades 1-3 will be considered an AE, while grade 4 will be 
considered a SAE. All SAEs and AEs reported during this study will be followed until resolution 
or until the investigator confirms that the AE/SAE has stabilized and no more follow-up is 
required. All deaths and SAEs that are at least possibly related and all unexpected SAEs will be 


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reported to the investigator within 24 hours of the study team becoming aware. An initial SAE 
form must be as complete as possible, including details of the current serious adverse event, 
including an investigator assessment of the causal relationship between the event and study 
procedures. Information not available at the time of the initial report must be documented on a 
follow-up SAE form. All unexpected SAEs will be reported to the IRB within 5 working days. The 
study team will begin tracking AEs and SAEs at the time of consent and will conclude tracking 
after the follow-up phone call has been made when the infant is 4-8 weeks of age.  
 
We will not report deviations as clinical care is being followed. This is a pragmatic pilot trial that 
is not intended to alter the standard of care treatment. It is ideal that the morphine is dosed 
every 3 hours/FINN scores obtained for those on the standard arm. However, there will be 
times this does not occur, and it will not be considered a protocol deviation. 
 
10.0 Data Safety Monitoring 
Given that this will be a small pragmatic pilot study, data safety monitoring will be done by the 
study team. The neonatal research nurses/coordinator will monitor data quality, subject 
recruitment, accrual, retention, outcome and adverse event data, and procedures designed to 
protect the privacy of subjects on a monthly basis. Any AE or SAE will be immediately discussed 
as described above. The study team, consisting of neonatal research nurses, coordinators, and 
the PI, will meet every 6 months to review the above factors as well as the results of any 
related studies that may impact subject safety. 
 
11.0 Study Withdrawal/Discontinuation 
 
Infants may be withdrawn from the study at any time at the request of the parent(s). If 
withdrawn from the study, they will receive standard treatment for neonatal abstinence 
syndrome, consistent with the control group. Infants may also be withdrawn from the study if 
there is a change in clinical status rendering it necessary to deviate from the study protocol per 
physician discretion. 
 
12.0 Statistical Considerations 
 
Based on previous data a sample size of 108 per group would be necessary to have 80% power 
to detect a 5-day reduction in length of stay; this is not feasible for a single site trial. In order to 
better design a larger RCT, a pilot study will be conducted.  
A sample size of 12 per group has been suggested as appropriate for pilot studies to evaluate 
feasibility and to estimate means and standard deviations.13 All calculations assume a two-sided 
two-sample t-test conducted at a 5% significance level. This pilot data will be necessary to 
design a larger scale randomized trial. 
 
13.0 Statistical Data Management 
 
Data management and interpretation 
Data will be collected using prepared forms, then entered and managed using REDCap 
electronic capture tools hosted and managed by IUPUI Biostatistics. The REDCap platform is a 
secure, web-based application designed to support data capture for research studies, providing: 
1) an intuitive interface for validated data entry; 2) audit trails for tracking data manipulation 
and export procedures; 3) automated export procedures for seamless data downloads to 


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common statistical packages and 4) procedures for importing data from external sources.  Only 
IRB approved research team members will have access to the REDCap data platform. Each 
team’s members will be granted access to the REDCap data system through a secure login. In 
the REDCap data platform, primary data and data backups are secured at separate Indiana 
University Data centers. Operating system security includes: secure logins, data encryption at 
rest, remote system logging and configuration and change management. Data backups are 
encrypted both in flight and at rest. Copies of data are replicated to the remote data center 
every 15 minutes. There are 100+ point-in-time copies of data available at any time. Disaster 
recovery has been tested and confirmed. 
  
Performance Monitoring:  Standard reports can be generated from the study database by 
the research office. These will include monthly reports that provide the number of infants 
enrolled, missing data, adherence to study protocols, and a variety of performance measures, 
including adverse events. 
 
14.0 Privacy/Confidentiality Issues 
 
Security measures to protect subject identities include the use of coded files to unlink research 
records from names and other identifiers, locked storage areas, and password-protected 
computer files.  Subjects’ names are linked to their IDs as noted above.  Access to computer 
systems housing sensitive information is strictly regulated.  Credentials permitting access to 
these systems are granted only to essential investigators and research personnel.  All systems 
are secured from external attack through a combination of hardware and software firewalls and 
are updated with necessary security patches as they become available.  Related hardware and 
back-up storage media are maintained in a secure environment to which only essential 
personnel have physical access. All consent and research procedures will be compliant with 
Subpart B of the Code of Federal Regulations Title 45, Part 46 - Protection of Human Subjects 
with Additional Protections for Pregnant Women, Human Fetuses and Neonates Involved in 
Research (66 FR 56778, Nov. 13, 2001).   
 
 
15.0 Follow-up and Record Retention 
 
The duration of the study will from be from enrollment through 4-8 weeks of age. The majority 
of the data collection and monitoring will be done during the initial hospital stay. Once the 
infant is discharged from the NICU, we plan to contact the parent via phone for follow-up to 
determine if the infant has required readmission to the hospital for any issues potentially related 
to neonatal abstinence syndrome in the first month of life. If the baby stays in the IU Hospital 
system after birth, the study team will look for recent appointments that may contain the follow 
up information.  
 
 
16.0 References 
 
1. Patrick SW, Schumacher RE, Benneyworth BD, et al. Neonatal abstinence syndrome 
and associated healthcare expenditures: United States, 2000-2009. JAMA. 
2012;307(18):1934-40 
 


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2. Patrick SW, Davis MM, Lehmann CU, et al. Increasing incidence and geographic 
distribution of neonatal abstinence syndrome: United States 2009 to 2012. J 
Perinatol. 2015;35(8):650-5 
 
3. Tolia VN, Patrick SW, Bennett MM, et al.  Increasing incidence of the neonatal abstinence 
syndrome in U.S. neonatal ICUs. N Engl J Med. 2015;372(22):2118‐26. 
 
4. Kocherlakota P. Neonatal abstinence syndrome. Pediatrics. 2014;134(2):e547-561 
 
5. Jones HE, Fielder A. Neonatal abstinence syndrome: Historical perspective, current focus, 
future directions. Prev Med. 2015;80:12-17 
 
6. Patrick SW, et al. Improving care for neonatal abstinence syndrome. Pediatrics. 
2016;137(5): doi: 10.1542/peds.2015-3835 
 
7. Mehta A, Forbes KD, Kuppala VS. Neonatal abstinence syndrome management from 
prenatal counseling or postdischarge follow-up care: results of a national survey. Hosp 
Pediatr. 2013;3(4):317-23 
 
8. Kraft WK. Buprenorphine in neonatal abstinence syndrome. Clin Pharmacol Ther. 
2018;103(1):112-119 
 
9. Kraft WK, et al. Buprenorphine for the treatment of neonatal abstinence syndrome. N 
Engl J Med. 2017;376:2341-2348 
 
10. Wachman EM, Schiff DM, Silverstein M. Neonatal abstinence syndrome: advances in 
diagnosis and treatment. JAMA. 2018;319(13):1362-1374 
 
11. Grossman MR, Berkwitt AK, Osborn RR, et al. An initiative to improve the quality of care 
of infants with neonatal abstinence syndrome. Pediatrics. 2017;139(6):e20163360 
 
 
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assessment and management. Addict Dis. 1975;2(1‐2):141‐158 
 
13. Julious SA. Sample size of 12 per group rule of thumb for a pilot study. Pharmaceutical 
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