Non-Opiate Treatment After Prenatal Opiate Exposure to Prevent Postnatal Injury to the Young Brain
Phase: PHASE3
Conditions: Neonatal Abstinence Syndrome
Sponsor: Henrietta Bada

Document Coversheet
Study Title: Non-Opiate Treatment After Prenatal Opiate Exposure to Prevent Postnatal Injury 
to the Young Brain (No-POPPY)
Institution/Site: 
University of Kentucky
Document (Approval/Update) Date:
12/17/2024 
NCT Number:
NCT03396588
IRB Number 
43976
Coversheet created:
3/27/2025 

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Statistical Analysis Plan NCT03396588
Based on Consolidated Standards of Reporting Trials (CONSORT) standards, baseline demographic 
variables were summarized for morphine and clonidine treatment. Frequencies (%) are presented for 
categorical variables and either mean (SD) or median (min, max) for continuous variables. For outcome 
results, we present 95% confidence intervals (CIs). 
A log-rank test was used to compare treatment arms regarding LOT and LOS. To use data from infants 
withdrawn from the study, the time of withdrawal was specified as the censoring time. Cox proportional 
hazards regression modeling was used in a follow-up analysis using treatment and selected risk factors 
associated with NOWS severity (birth weight, gestational age, gender, cesarean delivery, maternal 
psychiatric disorder, inborn status, MOUD, other opioid, and non-opioid substance use). Because 
smoking was highly prevalent and alcohol use was infrequent, they were not included in the model. In 
post hoc analyses, a negative binomial regression was used to model LOT for 115 infants, excluding 
those withdrawn from the study. Empirical SE estimates were employed to ensure valid inference. 
Treatment arms were compared regarding the need for adjunct medication using frequencies (%) and x2 
tests. Of 5 infants withdrawn, only 1 received adjunct medication; the other 4 were observed for <2 
days. Utilizing data from all 120 infants, we assumed that the 4 infants did not require adjunct 
treatment. We also removed these 4 infants in a follow-up analysis. The remaining 116 infants were 
used to fit a logistic regression model, from which adjusted odds ratios were derived.  
 
Wilcoxon rank tests were used to compare treatment groups regarding the timing between initial and 
final NNNS assessments and the NNNS scores (initial, final, and change). P values were adjusted using 
the false discovery rate method because of multiple comparisons across 13 summary scores. Intention-
to-treat analyses used all available data based on treatment assignment. All tests were 2-sided, with a 
statistical significance of P <.05. Analyses were conducted in SAS v9.4 (SAS Institute Inc 2013. 
SAS/ACCESSVR 9.4 Interface to ADABAS: Reference. Cary, NC: SAS Institute Inc.). 

Informed Consent 4/5/17 
 
 1
 
 
 
 
 
Combined Consent and Authorization to Participate in a Research Study
 Non-Opiate treatment after prenatal Opiate exposure to Prevent Postnatal Injury to the Young Brain 
(No-POPPY) 
When we say “you” in this form, we mean you or your child. “We” means the doctors and other staff.
 
 
WHY ARE YOU BEING INVITED TO TAKE PART IN THIS RESEARCH? 
You are being invited to have your baby take part in a research study about drug withdrawal in newborns.  Your 
baby may participate in this research because your baby may be withdrawing from the pain medicines or other 
drugs that you took while you were pregnant.  If you volunteer for your baby to take part in this study, your child 
will be one of about 250 babies at the Kentucky Children’s Hospital to participate. 
 
WHO IS DOING THE STUDY? 
The person in charge of this study at the Kentucky Children’s Hospital is Dr. Henrietta S. Bada (Principal 
Investigator), Department of Pediatrics. Dr. Bada is a Neonatologist specializing in newborns withdrawing from 
medications or drugs they may have received before they were born. There may be other people on the 
research team assisting at different times during the study. 
 
WHAT IS THE PURPOSE OF THIS STUDY? 
Neonatal Abstinence Syndrome (NAS) is a group of withdrawal symptoms that can occur in babies when their 
mothers have taken pain medications or substances such as recreational or medical narcotics or drug 
treatments of methadone or subutex or suboxone during pregnancy; because medicines the mother takes while 
pregnant, the baby also takes. Babies usually develop symptoms of withdrawal within a few days of birth; your 
baby may experience withdrawal after delivery, and may need treatment.  There are different ways to treat 
babies with NAS - about 50% of doctors use morphine, which is an opiate, to treat these babies, the rest use 
other drugs, such as clonidine or phenobarbital. 
 
The purpose of this study is to compare two different medicines to treat babies with withdrawal.  The 
treatment medicines in this study are morphine and clonidine.  Morphine is a narcotic medicine, which is 
included in most pain killers.  Clonidine is not a narcotic and has been used to treat other conditions as well as to 
help manage symptoms in babies with NAS.    Both drugs are effective, but the purpose of this study is to see if 
one may be better than the other at reducing babies’ symptoms and reducing how long they need to stay in the 
hospital.  We will also be looking to see if there is a difference in how the babies grow and develop later in early 
childhood. 
 
ARE THERE REASONS WHY YOU SHOULD NOT TAKE PART IN THIS STUDY? 
From the information we have about your baby, he or she qualifies to participate in the study. However, if your 
baby has had a seizure, or has been exposed to cocaine, your baby cannot participate.  If your baby shows 
symptoms of withdrawal, he or she will still be treated for NAS with one of the standard medicines prescribed by 
your baby’s doctor.   
 
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WHERE IS THE STUDY GOING TO TAKE PLACE AND HOW LONG WILL IT LAST?
The research will be conducted at Kentucky Children’s Hospital Neonatal Intensive Care Unit (NICU) and the 
NICU Graduate Clinic.  The study will start when your baby needs treatment for withdrawal and continue until 
he or she is two years old.  The treatment part of the study will end when your baby is discharged from the 
hospital.  You and your baby will be asked to come to the NICU Graduate Clinic and have developmental 
assessments done when he or she is six months, one year and again at two years old. 
 
WHAT WILL YOU BE ASKED TO DO? 
Your baby will be monitored closely for symptoms of withdrawal, using a scoring method called Finnegan 
Scoring system.  The baby’s scores for withdrawal will differ according to the number of symptoms and the 
severity of symptoms.  This system can be used for all babies with withdrawal whether they’re in the study or 
not.  If your baby’s withdrawal scores increase or stay high, this means he or she needs medicine in order feel 
better, eat, sleep, grow, and be less fussy.  If you agree for your baby to participate in this study, the pharmacy 
will randomize, or choose by chance (like a coin toss) whether to treat your baby with morphine or clonidine. 
There is a 50/50 chance of getting either drug.  The medicine will be started immediately, but the nurses, 
doctors and you will not know which drug is being used – only the pharmacist.  Both drugs will look alike and be 
given orally (by mouth).  The medicine will be given every 3 or4 hours, depending on your baby’s feeding 
schedule.   
 
The Finnegan Scoring for withdrawal will be done routinely and based on your baby’s scores; he or she may 
need an increase or decrease in the treatment dose.  If your baby does not improve even after the drug is 
increased to the maximum, phenobarbital will be added.  This is also a normal (standard) procedure in the NICU.  
If adding phenobarbital doesn’t help your baby, another drug may be used at the doctor’s choice.   
 
The treatment medicine will be increased over time until your baby’s scores start to improve. When your baby’s 
Finnegan scores start improving (this may take days or weeks),this means that the amount of treatment 
medicine is helping to control your baby’s withdrawal symptoms; then the amount of medicine will be slowly 
decreased(weaned) as long as your baby’s symptoms remain controlled.  If your baby scores go higher than 
normal again, his or her medicine will be increased till controlled and then slowly weaned again.  Every baby is 
different - some babies may only need 10 to 14 days of treatment, while other babies may need up to 3 months. 
 
Many babies have routine blood tests during the first 10 days of life.  During these blood tests an extra amount 
of blood, about 1/8 of a teaspoon, will be drawn.  These standard blood test may be done up to six times. The 
extra blood will be used to look at some DNA factors and to see how much of the treatment drug is in your 
baby’s body. Your baby could receive extra blood draws for research purposes. These blood draws will be done 
randomly and close to the time your baby is ready to go home. These tests are to look at how quickly your 
baby’s body has been processing the treatment medication (how much is still in their body). 
 
Your baby will also have research assessments (called the NNNS), done in the hospital while still on drug 
treatment.  The NNNS stands for NICU Network Neurobehavioral Scale and is used to see how your baby’s 
behavior differs from other babies.  The NNNS will be done twice – once in the beginning of withdrawal 
treatment, then when your baby is about a month old.  The assessment involves observing or handling your 
baby to see how he or she acts and reacts (like self-calms, watching objects with eyes, etc.). 
 
You will also be asked to return to the NICU Graduate Clinic when your baby is six months, one and two years of 
age. Your baby will have an Infant Behavior Questionnaire (6 mo), Bayley Assessments (6  mo, 1 and 2 years), 
and the Early Childhood Behavior Checklist (2 yr).  These assessments are used to see how a baby’s motor skills 
(physical abilities), cognitive skills (mental abilities) and behavior are developing.  This takes about an hour and is 
done by the physical therapist.  While you are at you baby’s visit we would like to conduct a caretaker interview 
of continuing drug use, Parenting Stress Index, brief symptom inventory, and Beck Depression Inventory. We 
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understand many of our parents/caregivers need to drive 2 – 4 hour each way to attend a follow-up
appointment in the NICU Grad Clinic, often both parents come and that is an entire day taken off from work. For 
study patients, there will be monetary assistance to off-set the cost of time and gas. 
 
We may ask for additional contact information of friends or family members to ensure we are able to contact 
you throughout the length of the study.  It is your choice to provide this contact information.  The people you 
choose as contacts will not be given any private health information concerning you or your baby. 
 
This table lists procedures that are standard of care procedures and procedures that are research procedures. 
Treatment
When
How long/often
Standard 
Care
Research
Finnegan Assessment
When withdrawal 
symptoms start
every 4-8 hrs till 
no symptoms
X
X
Treat with Morphine or 
Clonidine
When Finnegan scores are 
elevated and meet 
treatment protocol
Every 3 to 4 hours
X
X 
(because of 
randomization)
Phenobarbital 
If 2nd drug is needed 
Until withdrawal 
under control
X
Blood Level
With other labs
Up to 4 times
X 
X
Blood Level
Close to Discharge
Twice
X
NNNS
Start of treatment and 1 
month of age 
Twice
X
Infant Behavior 
Questionnaire 
6 month visit 
Once
X
Early Childhood 
Behavior Checklist CBCL
2 year visit 
Once 
X 
Bayley Scores of Infant 
Development
6 month, 1 and 2 years visit 
3 Times 
X 
X – travel/time 
assistance
Mother/Caregiver 
Interview and 
Questionnaires
Close to Discharge, 6 month 
and 2 year follow-up visit 
3 Times 
X 
 
WHAT ARE THE POSSIBLE RISKS AND DISCOMFORTS? 
Your baby may have side effects from the medicines used to treat his or her withdrawal.  Both of the medicines 
may cause constipation, vomiting, sweating, drowsiness or sleepiness, low blood pressure and even decreased 
breathing.  None of these side effects happen very often in the NICU because the dose is usually not enough to 
cause the problems.   
 
There are risks with drawing blood in babies, but since the doctors order other tests, the baby will be stuck 
anyway. The extra blood taken for this study will not increase the risks that already exist (pain, bleeding, 
infection, bruising, and soreness). Two additional blood draws will be done for research only. These blood draws 
carry the same possible discomforts and risks as if they were done as standard of care. 
 
There is always a chance that any medical treatment can harm your baby, and the investigational treatment in 
this study is no different.  In addition to the risks above, your baby may experience a previously unknown risk or 
side effect.   
 
WILL YOU BENEFIT FROM TAKING PART IN THIS STUDY? 
Your baby will be treated for symptoms of withdrawal, even if you do not agree to the study.  One drug may be 
better than the other, but that won’t be known until the study is over.  One drug may require fewer days to 
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treat and may have fewer side effects. There is no guarantee, that your baby will get any benefit from taking 
part in this study.   
 
 
 
DO YOU HAVE TO TAKE PART IN THE STUDY? 
If you decide to allow your baby to participate in the study, it should be because you really want to volunteer his 
or her participation.  Your baby will not lose any benefits or rights he or she would normally have if you choose 
not to volunteer your baby.  You can stop at any time during the study and still keep the benefits and rights you 
had before volunteering. 
 
IF YOU DON’T WANT TO TAKE PART IN THE STUDY, ARE THERE OTHER CHOICES? 
If you do not want to take part in the study, your baby will be given standard care.  At the Kentucky Children’s 
Hospital, this is treatment with an opiate medication, and if additional medications are needed, phenobarbital is 
the first choice.  Clonidine is also occasionally used rather than Phenobarbital. 
 
WHAT WILL IT COST YOU TO PARTICIPATE? 
You and/or your insurance company, Medicare or Medicaid will be responsible for the costs of all care and 
treatment your baby receives during this study that would normally be received for his or her condition.  These 
are costs that are considered medically reasonable and necessary and will be part of the care your baby receives 
even if you do not allow him or her to take part in this study. 
 
The Kentucky Children’s Hospital is not allowed to bill your insurance company or Medicaid for the medical 
procedures done strictly for research.  All research costs will be paid by a grant, and SHOULD not be billed to 
you.  These research costs include the medicine he or she is given for withdrawal symptoms while he or she is a 
patient in the hospital, blood levels of the drug, special assessments (NNNS, Bayley’s, IBQ,CBCL).  If you have any 
questions regarding Medicaid coverage you should contact Medicaid at 1-800-635-2570. 
 
WHO WILL SEE THE INFORMATION THAT YOU GIVE? 
We will make every effort to keep private all research records that identify you and your baby to the extent 
allowed by law. Your baby’s information will be combined with information from other babies in the study.  
When we write about the study to share it with other researchers, we will write about the combined 
information we have gathered. Your baby will not be personally identified in these written materials.  
 
We will make every effort to prevent anyone who is not on the research team from knowing your baby’s 
information, or what that information is.  Your baby’s information will be seen in the hospital electronic medical 
record files and the patient chart.  The information required for the research study will be put in a password 
protected computer, located in the NICU Research Office (locked when not in use).  
 
You should know that there are some circumstances in which we may have to show your baby’s information to 
other people.  Since your baby is a patient here at UK in the NICU, all the information used for research is the 
same as information used in the NICU.  Officials of the Food and Drug Administration and the University of 
Kentucky may look at portions of records that identify your baby. 
 
CAN YOUR TAKING PART IN THE STUDY END EARLY? 
If you decide to allow your baby to take part in the study you still have the right to decide at any time that you 
no longer want to continue.  You will not be treated differently if you decide to stop your baby from taking part 
in the study.  In addition, the doctors conducting the study may need to withdraw your baby.  This may occur if 
they find that the study is not benefiting your baby. If your baby is taken off study for any reason, the study drug 
will be stopped and your baby will have treatment as decided by your baby’s doctor.  Your baby will continue to 
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be closely monitored. If your baby is ready to go home, and is still receiving drug treatment, he or she will be 
taken off the study treatment.  The doctors will decide whether to keep your baby on the same drug or change 
medicines.  Since the study treatment will be over when your baby goes home, the medicine will no longer be 
paid for by the research grant. We ask that you continue with the follow-up behavior /development assessment 
visits at 6 months, 1 and 2 years.  
 
CAN YOU PARTICIPATE IN ANOTHER RESEARCH STUDY AT THE SAME TIME? 
Your baby cannot participate in another study if enrolled in this study. 
 
WHAT HAPPENS IF YOU GET HURT OR SICK DURING THE STUDY? 
If you believe your baby is hurt or gets sick because of something that is due to the study, you should contact Dr. 
Henrietta Bada or the doctor on-call at the NICU clerk’s desk - 859-323-5744 immediately.  The clerk at the desk 
can have the doctor return your call.  You can also ask your baby’s nurse in the NICU to contact the doctor.  The 
doctor will determine what type of treatment, if any, that is best for your baby at that time. 
 
It is important for you to understand that the University of Kentucky does not have funds set aside to pay for the 
cost of any care or treatment that might be necessary because your baby gets hurt or sick while taking part in 
this study.  Also, the University of Kentucky will not pay for any wages you may lose if he or she is harmed by this 
study.  The medical costs related to your baby’s care and treatment because of research related harm will be 
your responsibility. 
 
WILL YOU RECEIVE ANY REWARDS FOR TAKING PART IN THIS STUDY? 
You will not receive any payment for allowing your baby to take part in the study.  However, for study patients, 
there will be monetary assistance for time and to come to the follow-up visits, plus millage for travel costs. 
 
Visit 
Amount 
Discharge
$25.00 
1 month **
$50.00 
6 months * 
$50.00  
1 year *
$75.00 
2 year *
$100.00  
 
*Round trip mileage reimbursement will also be included for each visit attended at the NICU Graduate Clinic. 
** The 1 month assessment may take place while your baby is still in the hospital depending on how long their 
treatment lasts. If your baby has been discharged from the hospital before 1 month of age, we ask that you 
return to the NICU Graduate Clinic for this assessment and mileage will be included with this visit. 
 
WHAT IF YOU HAVE QUESTIONS, CONCERNS, or COMPLAINTS? 
Before you decide whether to accept this invitation to allow your baby to take part in the study, please ask any 
questions that might come to mind now.  Later, if you have questions, suggestions, concerns, or complaints 
about the study, you can contact the investigator, Dr. Bada at 859-323-5744.  If you have any questions about 
your rights as a volunteer in this research, contact the staff in the Office of Research Integrity at the University of 
Kentucky at 859-257-9428 or toll free at 1-866-400-9428. We will give you a signed copy of this consent form to 
take with you. 
 
WHAT IF NEW INFORMATION IS LEARNED DURING THE STUDY THAT MIGHT AFFECT YOUR DECISION TO 
PARTICIPATE? 
If the researcher learns of new information in regards to this study, and it might change your willingness to stay 
in this study, the information will be provided to you.  You may be asked to sign a new informed consent form if 
the information is provided to you after you have joined the study. 
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WHAT ELSE DO YOU NEED TO KNOW? 
The National Institutes of Health (NIH) has provided funding to help with this study. The study medicine is paid 
for by the NIH grant while your baby is in the hospital, but if he or she goes home still requiring treatment, 
you/your insurance will be responsible for that cost.  The samples of blood that came from your baby might be 
used in studies that lead to new products for research, diagnosis or treatment.  These products might have some 
commercial value.  There are no plans to provide financial compensation to you should this occur. 
 
AUTHORIZATION TO USE OR DISCLOSE YOUR IDENTIFIABLE HEALTH INFORMATION  
 
The privacy law, HIPAA (Health Insurance Portability and Accountability Act), requires researchers to protect 
your health information.  The following sections of the form describe how researchers may use your health 
information. 
 
My and My baby’s health information that may be used and released includes: 
 
Date of Birth 
Gestational Age
Birth weight 
Gender, Race, Ethnicity 
Date of NICU Discharge 
General clinical status/diagnoses information, and diagnoses dates  
Medications required during hospitalization 
Pregnancy, labor and delivery information 
Developmental Assessment at 6 months,1 and 2 years old 
 
My and My baby’s health information will be used for: 
 
Learning if there are better ways to treat babies with withdrawal symptoms using two different 
medicines. 
PHI is necessary to conduct the research, and meet legal, institutional and accreditation 
requirements
 
The Researchers may use and share my baby’s health information with: 
 
The University of Kentucky’s Institutional Review Board/Office of Research Integrity. 
Law enforcement agencies when required by law. 
University of Kentucky representatives. 
UK Hospital 
Food and Drug Administration 
Investigational Drug Service (IDS) – to dispense the study drug 
National Institutes of Health (NIH) 
 
The researchers agree to only share your health information with the people listed in this document.   
Should your health information be released to anyone that is not regulated by the privacy law, your health 
information may be shared with others without your permission; however, the use of your health information 
would still be regulated by applicable federal and state laws.   
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You may not be allowed to participate in the research study if you do not sign this form.   If you decide not to 
sign the form, it will not affect your: 
Current or future healthcare at the University of Kentucky 
Current or future payments to the University of Kentucky   
Ability to enroll in any health plans (if applicable) 
Eligibility for benefits (if applicable) 
 
After signing the form, you can change your mind and NOT let the researcher(s) collect or release your health 
information (revoke the Authorization). If you revoke the authorization: 
 
You will send a written letter to: Henrietta Bada, MD at 138 Leader Ave, Lexington, KY 40506 to inform 
her of your decision. 
Researchers may use and release your health information already collected for this research study. 
Your protected health information may still be used and released should you have a bad reaction. 
 
The use and sharing of your information has no time limit.  
 
If you have not already received a copy of the Privacy Notice, you may request one.  If you have any questions 
about your privacy rights, you should contact the University of Kentucky’s Privacy Officer between the 
business hours of 8am and 5pm EST, Mon-Fri at: (859) 323-1184. 
 
You are the subject or are authorized to act on behalf of the subject.  You have read this information, and you 
will receive a copy of this form after it is signed. 
 
 
 
__________________________________________                    _____________________________
Signature of research subject’s legal representative 
 
 
 
Date 
_____________________________________________
_____________________________
Printed name of research subject’s legal representative  
Representative’s relationship to  
 
 
 
 
 
 
 
 
research subject 
 
*(If, applicable) Please explain Representative’s relationship to subject and include a description of 
Representative’s authority to act on behalf of subject: 
_____________________________________________________________________________
_____________________________________________________________________________
________________________________________________________________          _________
Name of [authorized] person obtaining informed consent/HIPAA authorization     
Date 
_________________________________________
Signature of Principal Investigator or Sub/Co-Investigator 
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