Clinical trial NCT01965704
Conditions: Narcotic Addiction Neonatal Abstinence Syndrome
Keywords: Narcotic addiction during pregnancy Neonatal abstinence syndrome NAS
Sponsor: Stanford University
Start date: 2014-09-09; Completion date: 2020-09-16
Enrollment: 196 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The Investigators hope to learn if they can prevent or lessen the symptoms of neonatal abstinence syndrome (NAS) in babies born to narcotic-dependent mothers by using the drug ondansetron in the mothers prior to delivery and their babies after delivery.

The study is a randomized, double-blind, placebo-controlled study with one half the mother-baby pairs to receive ondansetron and the other half of the mother-baby pairs to receive placebo. The pregnant narcotic-dependent mothers will receive an intravenous dose of study medication prior to delivery; the neonates, after their birth, will receive the same study medication the mother received every 24 hours for up to 5 days.

The Investigators will follow up with the mother-baby pairs for 10 days after study drug has stopped and one last follow up, about 30 days after stopping study drug, to learn if the baby had any symptoms of NAS in that time period.

Detailed description:
All neonates will have a screening 12-lead EKG prior to their first dose of study medication to determine if QTc prolongation is present. A repeat 12-lead EKG will be done after each dose of study medication, approximately 2-5 hours post dose; if a neonate has prolonged QTc the study drug will be stopped.

Investigators may obtain up to 9 pharmacokinetic (PK) blood samples from the neonates over 5 days when standard of care blood samples are drawn. These samples will consist of 1 to 2 drops of blood collected on filter paper and sent to Stanford for PK analysis.

The modified Finnegan scoring system will be used to evaluate neonates for symptoms of NAS at each site and it is considered standard-of-care for babies at risk of NAS. Morphine will be the first treatment choice before other treatment medication choices (opioid or non-opioid) for NAS symptoms. Each site involved has established guidelines for starting, advancing and weaning treatment for NAS. Any medication used to treat NAS will be recorded.

Interim analysis: will be performed after the first 20 pregnant women and their neonates have been enrolled and dosed with study drug. (Interim Analysis was done on first 21 mother/baby pairs in May 2016).

To protect the confidentiality of the patients (study subjects), the lead site, Stanford University, received a Certificate of Confidentiality from the NIH.

Arms: arm 1: Pregnant Women: ondansetron 8mg intravenously (IV) within 4 hours of delivery. Neonates: ondansetron 0.07 mg/kg given orally every 24 hours starting 4-8 hours after delivery, for up to 5 days (if IV line available in neonate, ondansetron 0.04 mg/kg IV every 24 hours for up to 5 days). arm 2: Pregnant Women: placebo given intravenously prior to delivery (volume to mimic the IV volume of the ondansetron group).

Neonates: placebo given orally every 24 hours, starting 4-8 hours after delivery, for up to 5 days with volume to mimic the oral volume of the ondansetron group (if IV line available, placebo may be given IV).
Interventions: intervention 1: Ondansetron intervention 2: Placebo
Intervention descriptions: intervention 1: Pregnant women may receive a second dose of IV ondansetron if they have not delivered within 4 hours of receiving the IV study medication. 50% of the 90 mother/baby pairs will receive ondansetron; the baby will always get the same study medication as the mother. intervention 2: All doses of placebo, whether IV or oral, will mimic the same volume as the ondansetron group to maintain the blind. Pregnant women may receive a second dose of IV placebo if they have not delivered within 4 hours of being given the IV study medication. 50% of the 90 mother/baby pairs will receive placebo; the baby will always receive the same study medication as the mother.

Protocol documents:
ICF_000.pdf: 
 
Cover page for the Parental Permission ICF for AIM 2 Prevention of NAS Study 
 
 
 
 
“Can Ondansetron Prevent Neonatal Abstinence Syndrome (NAS) in Babies 
Born to Narcotic-dependent Women (AIM2NAS)” 
 
 
Parental Permission Informed Consent 
 
NCT# 01965704 
 
Date of IRB approval of the ICF:  April 26, 2016  


Participant ID: 
 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
David R. Drover, MD                            eP 27286 
Protocol Title: Aim 2:  Prevention of Neonatal Abstinence Syndrome                                        (Neonate Consent) 
 
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SUSampCons_CA_Privacy rev 1/25/13                                                                                                                      
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Expiration Date:  April 26, 2017 
 
************* 
Are you participating in any other research studies? _____ Yes _____No 
 
 
 
PURPOSE OF RESEARCH 
 
You are invited to allow your baby to participate in a research study of the Prevention of 
Neonatal Abstinence Syndrome (NAS) because we believe your baby may be at risk to 
develop NAS after he/she is born. NAS is a combination of symptoms that develop in a 
baby who is born to a mother who is dependent on (using) narcotics every day 
(examples of narcotics: methadone, morphine, codeine, oxycodone, vicodin).  The use of 
and addiction to narcotic medications has become the most rapidly increasing drug 
problem in the U.S.A., which has consequences for the pregnant mothers and their 
babies.  NAS develops in 42-94% (42 to 94 out of 100) of the babies born to these 
narcotic-dependent women. There are no treatments to prevent this severe syndrome, 
which can result in a long hospital stay and treatment in the neonatal intensive care unit 
(NICU) for the baby.  A ‘neonate’ is a baby from birth through 27 days old; ‘abstinence’ is 
the stopping of or absence of a drug that has been taken routinely, such as taking a 
baby’s access to narcotic medication away due to delivery of the baby; ‘syndrome’ is 
defined as a group of symptoms, such as: sweating, excessive crying or high-pitched 
crying, irritability, poor feeding, diarrhea, vomiting, and poor weight gain. 
  
We hope to learn if we can prevent or lessen Neonatal Abstinence Syndrome in babies by 
giving the narcotic-dependent mothers a dose of intravenous (IV) ondansetron prior to 
delivery, followed by giving their babies up to 5 days of oral (PO) ondansetron.  
Ondansetron is a drug commonly used to prevent nausea after surgery and has an 
excellent safety record in pregnant women who use it to help reduce or prevent nausea 
in the first 3-months of their pregnancy.  Based upon a genetic discovery, we 
demonstrated that administration of ondansetron prevented the symptoms of narcotic 
drug withdrawal (abstinence) in experimental studies in mice and in humans. If we can 
reduce or prevent the development of narcotic drug withdrawal symptoms in newborn 
babies, in other words, prevent NAS, this would decrease the suffering of these babies. 
 
Currently there is no standard drug used to “prevent” NAS, therefore, babies born to 
narcotic-dependent mothers are allowed to show signs and symptoms of NAS first and 
then they are treated with a narcotic (morphine is the standard of care at Stanford & the 
hospitals involved in this study) given either intravenously (IV) or orally (PO) to help 
lessen the suffering of the babies.  
 
This project was designed as a randomized, double-blinded, placebo controlled study.   


Participant ID: 
 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
David R. Drover, MD                            eP 27286 
Protocol Title: Aim 2:  Prevention of Neonatal Abstinence Syndrome                                        (Neonate Consent) 
 
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1. Randomized: there will be a computer–generated list to tell the pharmacist which 
study medication to prepare for each subject. The medical team physician cannot 
make this decision. 
2. Double-blinded: the medical team involved in the treatment of the mother and 
baby, the study team members, and the mothers themselves will be blinded (will 
not know) which one of the two treatments they will receive. Only the study 
pharmacist will know which treatment is received. 
3. Placebo controlled:  one half (45 of the 90) of the narcotic-dependent mothers 
and babies will receive placebo study medication (inactive drug made from 
inactive sugar water if given orally or salt water if given through a vein) and the 
other half (45 of 90) of the mothers and babies will receive active study 
medication, oral ondansetron, or IV ondansetron if needed.  
 
Your baby was selected as a possible participant in this study because you are pregnant, 
currently dependent on a narcotic medication (daily narcotic use for at least 3 weeks 
prior to delivery), in generally good health, 18 through 45 years old, having one baby, 
and planning to deliver at Stanford Hospital when the gestational age of your fetus is 
between 37 to 42 weeks.  
 
If you decide to stop your baby’s participation in this study, you should notify Dr. Drover 
at 650-725-0364.   
 
This research study is looking for 90 pregnant and the 90 babies born to these mothers, 
to complete this study.  The study will be done at multiple sites (approximately 5-10 
sites) across the United States of America with Stanford as the coordinating center.   
LPCH/Stanford Hospital expects to enroll up to 30 of the 90 research study participants.  
 
VOLUNTARY PARTICIPATION  
 
Your participation in this study is entirely voluntary.  Your decision not to participate will 
not have any negative effect on you or your medical care.  You can decide to participate 
now, but withdraw your consent later and stop being in the study without any loss of 
benefits or medical care to which you are entitled. 
 
DURATION OF STUDY INVOLVEMENT  
 
Your baby’s participation will start on his/her date of birth and will continue for five 
days while being treated with the study medication.  
 
 
 


Participant ID: 
 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
David R. Drover, MD                            eP 27286 
Protocol Title: Aim 2:  Prevention of Neonatal Abstinence Syndrome                                        (Neonate Consent) 
 
Page 3 of 13 
 
 
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PROCEDURES 
 
If you choose to allow your baby to participate, you must sign this consent form.  The 
Protocol Director and his research study staff will explain the study in detail to you.  If 
your baby’s father is available, we will also obtain his written signature on this parental 
permission form.  The following procedures for your baby will occur only after your 
written parental permission on this consent is obtained: 
 
Baby’s Participation Starts on Day of Birth: 
 
1. Samples of Blood from the Umbilical Cord: venous cord blood will be 
obtained after the birth of your baby when the obstetrician cuts and clamps the 
cord; most umbilical cords are not saved, they are disposed of in the biohazard 
waste at Stanford but your signature on this consent allows us to obtain blood 
from the cord to measure how much ondansetron and ondansetron metabolites 
are in the cord blood. 
 
2. Screening 12-lead electrocardiogram (ECG):  to ensure the baby’s heart is 
functioning normally prior to the first dose of study medication.  
 
3. Follow-up ECGs: there will be a 12-lead ECG done following each dose of 
study medication (up to 5 doses) to check on your baby’s heart rate and rhythm.  
Your baby may have as many as 6 ECGs for the study. 
 
4. Blood draw prior to first dose: may be done either by a heel stick or when a 
routine heel stick is ordered; if no clinical blood draw is ordered, we would like to 
obtain one blood sample (0.1 ml or approximately 1-3 drops) by heel stick before 
starting the first dose of study medication.  
 
5. Study medication: your baby will receive the same study medication you 
received prior to delivery, either placebo or ondansetron. The study medication 
for your baby will be given every 24 hours, orally (liquid syrup), for up to 5 days 
starting with the first dose given approximately4-8 hours after birth. 
 
• Placebo is made from inactive, liquid syrup that will look identical to the oral 
ondansetron syrup. The placebo group of babies will be compared to the 
ondansetron group of babies.    
 
• Ondansetron is an FDA approved drug for use in adults, pregnant women and in 
children as young as one month old, to prevent or treat nausea. In this study 
ondansetron is considered the “investigational” drug because we will be using it 
for a new reason, to try to prevent NAS in your baby. Ondansetron is not 
approved by the FDA for use in neonates; the only approved dosing for infants 


Participant ID: 
 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
David R. Drover, MD                            eP 27286 
Protocol Title: Aim 2:  Prevention of Neonatal Abstinence Syndrome                                        (Neonate Consent) 
 
Page 4 of 13 
 
 
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as young as one-month old through 5 months old, is for a single dose given 
through the vein (IV), to treat nausea.  We plan to give one dose per day for a 
total of 5 doses; most babies will start with oral study drug but it can also be 
given through the vein if that is the best way for your baby at the time. We hope 
to show that ondansetron can prevent NAS better than the placebo study 
medication.   
 
6. Blood samples after study medication is started: the majority of samples 
for our research study will be obtained whenever a standard-of-care (routine) 
heel stick is ordered by your baby’s medical doctors for standard clinical lab 
tests. We will limit our research blood samples to 9 in total. If no blood tests are 
ordered in the first 12 hours of your baby’s life, we would like to obtain a sample 
of blood by heel stick at these time points: 1) prior to the first dose of study 
medication and 2) a second blood sample after the first dose of study medication 
but before your baby has become 12 hours old. Our research samples only 
require a few drops of blood (approximately 0.1 mL or 1-3 drops of blood) to be 
placed on our special filter paper 
 
7. Close observation for safety: your baby will be closely observed for the 
possible development of symptoms of NAS according to the standard-of-care at 
Lucile Packard Children’s Hospital.  
 
8. Treatment of NAS:  if your baby shows symptoms of NAS, he/she will be 
treated the same way he/she would be cared for whether or not he/she was on 
the study.  Morphine is the current standard treatment for NAS symptoms, and is 
used by all the hospitals in this study.  If necessary, other sedative-type drugs to 
help reduce their NAS symptoms will be given as standard of care by all the 
hospitals in this study. 
 
Any blood samples left over after analysis will be destroyed when the study is 
completed.  
 
PARTICIPANT RESPONSIBILITIES           
 
As a participant and spokesperson for your baby, your responsibilities include: 
• Follow the instructions of the Protocol Director and study staff. 
• Be available for our daily phone calls after you are sent home. 
• Tell the Protocol Director or research study staff about any side effects, doctor 
visits, or hospitalizations that you or the baby may have after you go home.   
• Ask questions as you think of them. 
• Tell the Protocol Director or research staff if you change your mind about 
allowing your baby to stay in the study. 
 


Participant ID: 
 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
David R. Drover, MD                            eP 27286 
Protocol Title: Aim 2:  Prevention of Neonatal Abstinence Syndrome                                        (Neonate Consent) 
 
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SUSampCons_CA_Privacy rev 1/25/13                                                                                                                      
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Expiration Date:  April 26, 2017 
WITHDRAWAL FROM STUDY 
 
If you first agree to participate and then you change your mind, you are free to 
withdraw your consent and discontinue your baby’s participation at any time.  Your 
decision will not affect your ability to receive medical care for your baby’s disease and 
you will not lose any benefits to which your baby would otherwise be entitled.  
 
There is no risk to your baby if you change your mind and decide to stop the study 
early. 
 
If you decide to withdraw your consent for your baby to participate in this study, or the 
study medication is stopped for any reason, there are no anticipated problems, but you 
should notify Dr. David Drover at 650-725-0364 as soon as possible. 
 
The Protocol Director may also withdraw you from the study and the study medication 
may be stopped, without your consent for one or more of the following reasons:   
o Failure to follow the instructions of the Protocol Director and study staff. 
o The Protocol Director decides that continuing your baby’s participation could 
be harmful to your baby.  
o Your baby needs treatment not allowed in the study. 
o The study is cancelled.  
o Other administrative reasons. 
o Unanticipated circumstances. 
 
POSSIBLE RISKS, DISCOMFORTS, AND INCONVENIENCES  
 
There are risks, discomforts, and inconveniences associated with any research study.  
These deserve careful thought.  You should talk with the Protocol Director if you have 
any questions. 
 
If your baby receives ondansetron as their study medication, the dose of ondansetron 
will be 0.07 mg/kg orally every 24 hours for up to 5 days (up to 5 doses maximum).  If 
we need to give the study medication intravenously (IV), the dose will be 0.04 mg/kg 
every 24 hours IV. There is no FDA approved dosing of ondansetron for neonates at 
this time; the youngest infants to receive ondansetron in a controlled study were one 
month old. The FDA approved dose for infants as young as one month old, suffering 
from nausea, is 0.1 mg/kg IV, one time.  We have chosen a lower dose, 0.04 mg/kg IV 
(less than one half of the FDA approved dose). However, we will be dosing the drug 
once per day for up to 5 days, to newborns, a new age group to receive this 
medication.  We are not giving the newborn babies this study medication for nausea, 
we are using it to try and prevent NAS. Since the drug is given based on weight, the 


Participant ID: 
 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
David R. Drover, MD                            eP 27286 
Protocol Title: Aim 2:  Prevention of Neonatal Abstinence Syndrome                                        (Neonate Consent) 
 
Page 6 of 13 
 
 
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less a baby weighs, the less study medication the baby will receive each day. The side 
effects of ondansetron are: 
 
Common Reactions 
* headache 
* constipation 
* fatigue 
* diarrhea 
* hypoxia (decrease in oxygen in your system) 
* pyrexia (increased body temperature) 
* urinary retention 
* dizziness 
* agitation 
* pruritus (itching) 
 
Serious Reactions 
* severe hypersensitivity reaction 
* anaphylaxis (extreme allergic reaction that can be life threatening) 
* bronchospasm (spasm of the muscles around your “wind pipe”) 
* extrapyramidal symptoms (changes effecting the nerves controlling your motor 
activity) 
* oculogyric crisis (uncontrolled rolling of your eyes) 
* blindness, transient 
* QTc prolongation (change in the way your heart beats) 
 
The possible risks of obtaining blood samples from your baby are pain and bruising.  
Infection can also occur anytime the skin is broken to obtain samples, but this risk is 
extremely small as sterile supplies are used, and all hospital protocols are followed. 
 
The 12-lead ECGs for your newborn baby poses no risk to the baby other than a very 
slight risk of possible skin irritation where the sticky pads are placed on the baby’s skin. 
 
This particular treatment may involve risks to the subject, which are currently 
unforeseeable.  
 
POTENTIAL BENEFITS                              
 
If ondansetron successfully prevents or lessens the symptoms of NAS, your baby may 
benefit by having his/her symptoms eliminated or reduced.  
 
We cannot and do not guarantee or promise that you will receive any benefits from this 
study. 
 


Participant ID: 
 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
David R. Drover, MD                            eP 27286 
Protocol Title: Aim 2:  Prevention of Neonatal Abstinence Syndrome                                        (Neonate Consent) 
 
Page 7 of 13 
 
 
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ALTERNATIVES 
 
• The alternative is not to allow your baby to participate. 
• We will not withhold any standard treatments for your baby.  
• Please discuss the potential risks and benefits of not participating with a 
physician. 
 
PARTICIPANT’S RIGHTS 
 
You should not feel obligated to agree to allow your baby to participate.  Your questions 
should be answered clearly and to your satisfaction.  If you decide not to allow your 
baby to participate, tell the Protocol Director.   
 
You will be told of any important new information that is learned during the course of 
this research study, which might affect your baby’s condition or your willingness to 
continue his/her participation in this study. 
 
ClinicalTrials.gov 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law.  This Web site will not include information that can identify you.  
At most, the Web site will include a summary of the results.  You can search this Web 
site at any time. 
 
CONFIDENTIALITY 
 
Your baby’s identity & yours will be kept as confidential as possible as required by law.  
Your baby’s personal health information related to this study may be disclosed as 
authorized by you.  Your responses to questions concerning illegal drug use could be 
self-incriminating and harmful to you if they became known outside the study. As 
explained in this confidentiality statement of the consent, we do not intend to disclose 
this information.  Your baby’s research records may be disclosed outside of Stanford, 
but in this case, you will be identified only by a unique code number.  Information 
about the code will be kept in a secure location and access limited to research study 
personnel.   
 
The results of this research study may be presented at scientific or medical meetings or 
published in scientific journals.  However, your baby’s identity will not be disclosed.  
We will do everything we can to keep others from learning about your baby’s 
participation in this study. To further help us protect your baby’s privacy, we received a 
Certificate of Confidentiality from the United States Department of Health and Human 
Services (DHHS) on Aug 21, 2013, which was prior to enrolling any participants.  


Participant ID: 
 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
David R. Drover, MD                            eP 27286 
Protocol Title: Aim 2:  Prevention of Neonatal Abstinence Syndrome                                        (Neonate Consent) 
 
Page 8 of 13 
 
 
SUSampCons_CA_Privacy rev 1/25/13                                                                                                                      
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With this Certificate, we cannot be forced (for example by court order or subpoena) to 
disclose information that may identify your baby in any federal, state, local, civil, 
criminal, legislative, administrative, or other proceedings. The researchers will use the 
Certificate to resist any demands for information that would identify you or your child, 
except to prevent serious harm to your baby or others, and as explained below.  
 
You should understand that a Certificate of Confidentiality does not prevent you, or a 
member of your family, from voluntarily releasing information about yourself, your 
child, or your involvement in this study.  
 
If an insurer or employer learns about you or your baby’s participation, and obtains 
your consent to receive research information, then we may not use the Certificate of 
Confidentiality to withhold this information. This means that you and your family must 
also actively protect your own privacy.  
 
Authorization To Use Your Health Information For 
Research Purposes 
 
Because information about you and your health is personal and private, it generally 
cannot be used in this research study without your written authorization.  If you 
sign this form, it will provide that authorization.  The form is intended to inform 
you about how your health information will be used or disclosed in the study.  
Your information will only be used in accordance with this authorization form and 
the informed consent form and as required or allowed by law.  Please read it 
carefully before signing it.   
 
What is the purpose of this research study and how will my health 
information be utilized in the study? 
The purpose of this study is to determine if the drug ondansetron, if given to babies 
born to narcotic-dependent mothers, will prevent those babies from suffering from 
a syndrome called “Neonatal Abstinence Syndrome”, also called “NAS”.  We hope 
to learn if we can prevent NAS by first giving these pregnant narcotic-dependent 
women a dose of intravenous (IV) ondansetron prior to the delivery of their babies, 
followed by giving the newborn babies a dose of ondansetron once a day for up to 
5 days. Currently there is no standard-of-care medicine used to “prevent NAS” and 
babies are only treated once they suffer the symptoms of withdrawal from 
narcotics. Because this is a clinical trial, the information will be submitted to the 
sponsor, the National Institutes of Health (NIH), and the Food and Drug 
Administration (FDA). 


Participant ID: 
 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
David R. Drover, MD                            eP 27286 
Protocol Title: Aim 2:  Prevention of Neonatal Abstinence Syndrome                                        (Neonate Consent) 
 
Page 9 of 13 
 
 
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Expiration Date:  April 26, 2017 
 
Do I have to sign this authorization form? 
You do not have to sign this authorization form.  But if you do not, your baby will 
not be able to participate in this research study, including receiving any research-
related treatment.  Signing the form is not a condition for receiving any medical 
care outside the study. 
 
If I sign, can I revoke it or withdraw from the research later? 
If you decide to participate, you are free to withdraw your authorization regarding 
the use and disclosure of your baby’s health information (and to discontinue any 
other participation in the study) at any time.  After any revocation, your baby’s 
health information will no longer be used or disclosed in the study, except to the 
extent that the law allows us to continue using your information (e.g., necessary to 
maintain integrity of research).  If you wish to revoke your authorization for the 
research use or disclosure of your baby’s health information in this study, you must 
write to: David R. Drover, MD.  Stanford Medical Center, Anesthesia Department, 
MC 5117, 300 Pasteur Drive, Stanford, CA 94305.   
 
What Personal Information Will Be Obtained, Used or Disclosed? 
Your baby’s health information related to this study, may be used or disclosed in 
connection with this research study, including, but not limited to: up to 9 blood 
samples for analysis of ondansetron, gestational age, mode of delivery, birth 
weight, birth length, medical record number, 12-lead ECGs, Apgar scores at 1 min 
and 5 min, gender, date of birth, amount of narcotic needed to treat NAS, length of 
stay in hospital, Modified Finnegan scores, need for medical treatment of NAS; 
need for barbiturate treatment of NAS; duration of medical treatment of NAS; 
weight change during hospitalization; frequency and duration of breast/bottle 
feeding in hospital and at home after discharge; and all other medications used to 
treat NAS.  
 
Who May Use or Disclose the Information? 
The following parties are authorized to use and/or disclose your baby’s health 
information in connection with this research study: 
• The Protocol Director, David Drover, MD 
• The Stanford University Administrative Panel on Human Subjects in 
Medical Research and any other unit of Stanford University as necessary 
• Research Staff 
 


Participant ID: 
 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
David R. Drover, MD                            eP 27286 
Protocol Title: Aim 2:  Prevention of Neonatal Abstinence Syndrome                                        (Neonate Consent) 
 
Page 10 of 13 
 
 
SUSampCons_CA_Privacy rev 1/25/13                                                                                                                      
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Expiration Date:  April 26, 2017 
Who May Receive or Use the Information? 
The parties listed in the preceding paragraph may disclose your health information 
to the following persons and organizations for their use in connection with this 
research study:  
• The Office for Human Research Protections in the U.S. Department of 
Health and Human Services 
• National Institutes of Health (NIH) 
• The Food and Drug Administration (FDA) 
• Data Safety Monitoring Board 
Your information may be re-disclosed by the recipients described above, if they are 
not required by law to protect the privacy of the information. 
 
When will my authorization expire? 
Your authorization for the use and/or disclosure of your health information will 
end on (December 31, 2025) or when the research project ends, whichever is 
earlier.  
 
Will access to my medical record be limited during the study? 
To maintain the integrity of this research study, you may not have access to any 
health information developed as part of this study until it is completed.  At that 
point, you would have access to such health information if it was used to make a 
medical or billing decision about you (e.g., if included in your official medical 
record).  
 
__________________________________ ___ 
 
________________  
  
Signature of Legally Authorized Representative               Date 
(e.g., parent, guardian or conservator) 
 
________________________________________________________ 
Description of Representative's Authority to Act for Neonatal Participant 
 
Print Name of LAR: ______________________________________ 
 
FINANCIAL CONSIDERATIONS 
 
Payment 
You will not be paid to participate in this research study. 
 
 


Participant ID: 
 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
David R. Drover, MD                            eP 27286 
Protocol Title: Aim 2:  Prevention of Neonatal Abstinence Syndrome                                        (Neonate Consent) 
 
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Costs 
If your baby participates in this study, there may be additional costs to you.  These 
include the personal time it will take to come to all of the study visits. 
The study will pay for those services, supplies, procedures, and care associated with 
this study that are not a part of your routine medical care.  If you would like to review 
the list of such covered services, supplies, procedures and care, please tell us now or at 
any time during the study.   
Participation in this study is not a substitute for health insurance.  You and/or your 
health insurance must pay for those services, supplies, procedures, and care that you 
require during this study for routine medical care.  You will be responsible for any 
co-payments and/or deductibles as required by your insurance.   
 
Sponsor 
The National Institutes of Health (NIH) is providing financial support and/or material for 
this study.  
 
COMPENSATION for Research-Related Injury 
 
All forms of medical diagnosis and treatment – whether routine or experimental – 
involve some risk of injury.  In spite of all precautions, you might develop medical 
complications from participating in this study.  If such complications arise, the Protocol 
Director and the research study staff will assist you in obtaining appropriate medical 
treatment.  In the event that you have an injury or illness that is directly caused by 
your participation in this study, reimbursement for all related costs of care first will be 
sought from your insurer, managed care plan, or other benefits program.  You will be 
responsible for any associated co-payments or deductibles as required by 
your insurance. 
 
If costs of care related to such an injury are not covered by your insurer, managed care 
plan or other benefits program, you may be responsible for these costs.  If you are 
unable to pay for such costs, the Protocol Director will assist you in applying for 
supplemental benefits and explain how to apply for patient financial assistance from the 
hospital. 
 
You do not waive any liability rights for personal injury by signing this form. 
 
CONTACT INFORMATION  
 
Questions, Concerns, or Complaints:  If you have any questions, concerns or complaints 
about this research study, its procedures, risks and benefits, or alternative courses of 
treatment, you should ask the Protocol Director, Dr. David Drover at (650) 725-0364. 


Participant ID: 
 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
David R. Drover, MD                            eP 27286 
Protocol Title: Aim 2:  Prevention of Neonatal Abstinence Syndrome                                        (Neonate Consent) 
 
Page 12 of 13 
 
 
SUSampCons_CA_Privacy rev 1/25/13                                                                                                                      
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Expiration Date:  April 26, 2017 
You should also contact him at any time if you feel you have been hurt by being a part 
of this study. 
 
Independent Contact:  If you are not satisfied with how this study is being conducted, 
or if you have any concerns, complaints, or general questions about the research or 
your rights as a participant, please contact the Stanford Institutional Review Board 
(IRB) to speak to someone independent of the research team at (650)-723-5244 or toll 
free at 1-866-680-2906.  You can also write to the Stanford IRB, 3000 El Camino Real, 
Five Palo Alto Square, 4th Floor, MC 5579, Palo Alto, CA 94306. 
 
Alternate Contact:  If you cannot reach the Protocol Director, please contact Dr. 
Brendan Carvalho at 650-861-8607 or pager number 650-723-8222, ID #13980. 
 
EXPERIMENTAL SUBJECT’S BILL OF RIGHTS 
 
As a research participant you have the following rights.  These rights include but are 
not limited to the participant's right to: 
• 
be informed of the nature and purpose of the experiment;  
• 
be given an explanation of the procedures to be followed in the medical 
experiment, and any drug or device to be utilized;  
• 
be given a description of any attendant discomforts and risks reasonably to be 
expected;  
• 
be given an explanation of any benefits to the subject reasonably to be 
expected, if applicable;  
• 
be given a disclosure of any appropriate alternatives, drugs or devices that might 
be advantageous to the subject, their relative risks and benefits; 
• 
be informed of the avenues of medical treatment, if any available to the subject 
after the experiment if complications should arise;  
• 
be given an opportunity to ask questions concerning the experiment or the 
procedures involved;  
• 
be instructed that consent to participate in the medical experiment may be 
withdrawn at any time and the subject may discontinue participation without 
prejudice;  
• 
be given a copy of the signed and dated consent form; and  
• 
be given the opportunity to decide to consent or not to consent to a medical 
experiment without the intervention of any element of force, fraud, deceit, 
duress, coercion or undue influence on the subject's decision. 
 
May we contact you about future studies that may be of interest to you?  
Yes 
No 
 


Participant ID: 
 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
David R. Drover, MD                            eP 27286 
Protocol Title: Aim 2:  Prevention of Neonatal Abstinence Syndrome                                        (Neonate Consent) 
 
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SUSampCons_CA_Privacy rev 1/25/13                                                                                                                      
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Signing your name below means you agree to allow your newborn baby to be in this study 
once he/she is born. 
 
 
________________________________________ 
 ____________         
Signature of LAR (Parent, Guardian or Conservator                       
Date                 
  
of the Neonatal Participant)  
 
_____________________________________     
 _____________________________ 
Authority to act for the Neonatal Participant 
                   Printed Name of LAR 
 
 
 
_________________________________________ 
                    _____________  
Signature of Other LAR (Parent, Guardian or Conservator               
Date 
of the Neonatal Participant)  
  
                       
_____________________________________     
____________________________ 
Authority to act for Neonatal Participant  
   
    Printed Name of Other LAR 
 
The IRB determined that the permission of one parent is sufficient for research in accordance with 21 
CFR 50.55. 
 
____________________________________             ___________ 
Signature of Person Obtaining Consent  
 
Date 
 
Print Name of Person Obtaining Consent: _____________________________________ 
 
The following witness line is to be signed only if the consent is provided as a summary form and 
accompanied by a short form foreign language consent. 
 
 
___________________________________________________________________________________ 
 
________________________________ 
Signature of witness  
 
 
 
 
 
Date 
 
Print Name of Witness: __________________________________________________ 
(e.g., staff, translator/interpreter, family member, or other person who speaks both English and the 
participant’s language) 
• Translated short form must be signed and dated by both the participant (or their LAR) AND the 
witness. 
• The English consent form (referred to as the "Summary Form" in the regulations): 
o Must be signed by the witness AND the Person Obtaining Consent (POC). 
o The non-English speaking participant/LAR does not sign the English consent. 
o The non-English speaking participant/LAR should not sign the HIPAA participant line 
o If the participant or the LAR is non-English speaking, the Person Obtaining Consent (POC) must 
ensure that 1) the LAR's Description of Authority is completed and 2) that any questions or options 
presented by the consent form are documented and initialed by the POC on the Summary Form, per 
the participant's wishes, as they are understood during the consent process. 

ICF_001.pdf: 
Cover page for the Maternal ICF for AIM 2 Prevention of NAS Study 
 
 
 
 
“Can Ondansetron Prevent Neonatal Abstinence Syndrome (NAS) in Babies 
Born to Narcotic-dependent Women (AIM2NAS)” 
 
 
Maternal Informed Consent 
 
NCT# 01965704 
 
Date of IRB approval of the ICF:  April 26, 2016  


Participant ID: 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
David R. Drover, MD                            eP 27286 
Protocol Title: Aim 2:  Prevention of Neonatal Abstinence Syndrome                                      (Maternal Consent) 
 
Page 1 of 12 
 
 
SUSampCons_CA_Privacy rev 1/25/13                                                                                                                      
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Expiration Date:  April 26, 2017 
 
************* 
Are you participating in any other research studies? _____ Yes _____No 
 
 
PURPOSE OF RESEARCH 
 
You are invited to participate in a research study of the Prevention of Neonatal 
Abstinence Syndrome (NAS) because we believe your baby may be at risk to develop 
NAS and you just signed the parental permission to allow your baby to participate in this 
study. NAS is a combination of symptoms that develop in a baby who is born to a mother 
who is dependent on (using) narcotics every day (examples of narcotics: methadone, 
morphine, codeine, oxycodone, vicodin).   
  
We hope to learn if we can prevent or lessen Neonatal Abstinence Syndrome in the 
babies born to mothers dependent on narcotics, by giving the mothers a dose of 
intravenous (IV) ondansetron prior to delivery, followed by giving their babies up to 5 
days of oral (PO) ondansetron.  Ondansetron is an FDA approved drug for use in 
pregnant women and in children to prevent nausea.  In this study, the study medication 
given to you is not for prevention of nausea; but to prevent NAS in your newborn baby.   
Half of the mothers in this study will receive ondansetron, and half will receive placebo 
(an inactive liquid that contains no medicine and looks identical to the ondansetron).   
 
This is a “double-blind study”, meaning neither you or your doctor will know which one 
of the two study medications you will receive; only the pharmacist who prepares the 
study drug will know what you receive.     
 
You were selected as a possible participant in this study because you are a pregnant 
woman, currently using a daily narcotic medication, in generally good health and with no 
known history of problems with the rhythm of your heart, 18 through 45 years old, 
having one baby, and planning to deliver at Stanford’s Lucile Packard Children’s Hospital 
when the gestational age of the fetus is between 37 to 42 weeks.  
 
If you decide to terminate your participation in this study, you should notify Dr. Drover at 
650-725-0364.   
 
This research study is looking for 90 pregnant women who are dependent on narcotic 
drugs and the 90 babies born to these mothers.  The study will be done at multiple 
sites (approximately 5-10 sites) across the United States of America with Stanford as 
the coordinating center. LPCH/Stanford Hospital expects to enroll 30 of the 90 research 
study participants.  
 
 


Participant ID: 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
David R. Drover, MD                            eP 27286 
Protocol Title: Aim 2:  Prevention of Neonatal Abstinence Syndrome                                      (Maternal Consent) 
 
Page 2 of 12 
 
 
SUSampCons_CA_Privacy rev 1/25/13                                                                                                                      
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Expiration Date:  April 26, 2017 
 
VOLUNTARY PARTICIPATION  
 
Your participation in this study is entirely voluntary.  Your decision not to participate will 
not have any negative effect on you or your medical care.  You can decide to participate 
now, but withdraw your consent later and stop being in the study without any loss of 
benefits or medical care to which you are entitled. 
 
DURATION OF STUDY INVOLVEMENT  
 
Your participation will start on the day you deliver your baby. As soon as your baby is 
born, his or her participation will begin as well while they are being treated with the 
study medication with the purpose of preventing Neonatal Abstinence Syndrome (NAS).  
 
The total time for you and your baby to be involved in the study may be up to 35 days: 
up to 5 days of study drug administration for your baby in the hospital; 10 daily phone 
calls or visits, depending on whether your baby is at home or in the hospital, for follow-
up; and a final follow-up phone call or visit about 30-35 days after your baby’s last dose 
of study medication.  
The entire study is expected to take 2-3 years to complete. 
  
PROCEDURES 
 
If you choose to participate, the Protocol Director and his research study staff will 
explain the study in detail to you and obtain your written consent to participate on this 
form.  You have already signed the parental permission form to allow your baby to 
participate once the baby is born.  The following procedures will occur for you, after 
written consent is obtained: 
 
Mother’s Participation on Delivery Day:  
1. A urine sample will be obtained, before you deliver your baby, for a drug screen to 
determine all drugs in your system.  If the drug screen is positive for an illicit drug 
and was subpoenaed or somehow disclosed, an unlikely event, it could be 
incriminating. 
 
2. Study Medication: you will receive a dose of study medication, either ondansetron 
8mg or placebo (an inactive liquid that contains no medicine and looks identical to 
the ondansetron) through an intravenous line (IV) within 4 hours of delivering your 
baby. If you have not delivered your baby within 4 hours of receiving the study 
drug, a second dose will be given.  
 


Participant ID: 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
David R. Drover, MD                            eP 27286 
Protocol Title: Aim 2:  Prevention of Neonatal Abstinence Syndrome                                      (Maternal Consent) 
 
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SUSampCons_CA_Privacy rev 1/25/13                                                                                                                      
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a. Which of the two study medications you receive will be determined by a 
randomization schedule. This is like flipping a coin, you will have a 50% chance 
of receiving ondansetron and a 50% chance of receiving placebo (45 mothers 
will receive ondansetron and 45 mothers will receive placebo).  
 
3. One blood sample (approximately 1 teaspoon) will be drawn within 30 minutes of 
your delivery (either before or after delivery) to measure levels of ondansetron 
and the metabolites (what ondansetron breaks down to once it is in your body).  
Any blood samples left over after analysis will be destroyed when the study is 
completed.  
 
4. Follow up phone calls.  Once you have delivered your baby we will ask questions 
about the feeding and activity of your baby.  For example: How many times and 
for how long each time do you feed your baby?  Are you breastfeeding, formula 
feeding, or a combination of both?  Is the baby crying excessively?  Is the baby 
gaining weight?  Is the baby having diarrhea?  
 
5. With your permission, we would like the name of your baby’s pediatrician and/or 
other healthcare provider (such as, public health nurse) in case we need to 
contact them about your baby’s health.  We would contact your baby's healthcare 
provider only if we were concerned that your baby might develop neonatal 
abstinence syndrome after leaving the hospital, and would let you know that we 
contacted them.  
 
6. If you have a history of having problems with your heart’s rhythm we may order 
a 12-lead electrocardiogram (ECG) to make sure your heart rate and rhythm are 
within normal ranges prior to delivery.  We will pay for this ECG. 
 
PARTICIPANT RESPONSIBILITIES           
 
As a participant, your responsibilities include: 
• Follow the instructions of the Protocol Director and study staff. 
• Take the study drug as directed.  
• Be available for our daily phone calls after you are sent home.  
• Tell the Protocol Director or research study staff about any side effects, doctor 
visits, or hospitalizations that you or the baby may have after you go home.   
• Ask questions as you think of them. 
• Tell the Protocol Director or research staff if you change your mind about staying 
in the study. 
 


Participant ID: 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
David R. Drover, MD                            eP 27286 
Protocol Title: Aim 2:  Prevention of Neonatal Abstinence Syndrome                                      (Maternal Consent) 
 
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SUSampCons_CA_Privacy rev 1/25/13                                                                                                                      
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WITHDRAWAL FROM STUDY 
 
If you first agree to participate and then you change your mind, you are free to 
withdraw your consent and discontinue your participation at any time.  Your decision 
will not affect your ability to receive medical care for your disease and you will not lose 
any benefits to which you would otherwise be entitled.  
 
There is no risk to you or the baby if you change your mind and decide to stop the 
study early. 
 
If you decide to withdraw your consent to participate in this study, or the study 
medication is stopped for any reason, there are no anticipated problems, but you 
should notify Dr. David Drover at 650-725-0364 as soon as possible. 
 
The Protocol Director may also withdraw you from the study and the study medication 
may be stopped, without your consent for one or more of the following reasons:   
o Failure to follow the instructions of the Protocol Director and study staff. 
o The Protocol Director decides that continuing your participation could be 
harmful to you or your baby.  
o You or your baby needs treatment not allowed in the study. 
o The study is cancelled.  
o Other administrative reasons. 
o Unanticipated circumstances. 
 
POSSIBLE RISKS, DISCOMFORTS, AND INCONVENIENCES  
 
There are risks, discomforts, and inconveniences associated with any research study.  
These deserve careful thought.  You should talk with the Protocol Director if you have 
any questions. 
 
Because you would likely receive ondansetron or some other anti-nausea medication in 
the course of your standard clinical care for the delivery of your baby (whether by 
Cesarean Section or by vaginal delivery), the risks associated with the medications and 
ondansetron are not changed because of the study. Single doses of ondansetron range 
from 4 mg to 16 mg, depending on the reason for administration, making the study 
dose of 8 mg well within the safe therapeutic range for nausea.  However, we are not 
giving you the study medication to prevent or treat your nausea, we are giving you the 
study medication to get the study medication into your unborn baby. We want to get 
the study drug in your baby prior to delivery so your baby will be born with the study 
drug in their system. If you should need a medication specifically for nausea prior to 
delivery, you will receive another anti-nausea medication, not ondansetron, because 
ondansetron is one of the study medications.  


Participant ID: 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
David R. Drover, MD                            eP 27286 
Protocol Title: Aim 2:  Prevention of Neonatal Abstinence Syndrome                                      (Maternal Consent) 
 
Page 5 of 12 
 
 
SUSampCons_CA_Privacy rev 1/25/13                                                                                                                      
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The side effects of ondansetron are: 
Common Reactions 
* headache 
* constipation 
* fatigue 
* diarrhea 
* hypoxia (decrease in oxygen in your system) 
* pyrexia (increased body temperature) 
* urinary retention 
* dizziness 
* agitation 
* pruritus (itching) 
 
Serious Reactions 
* severe hypersensitivity reaction 
* anaphylaxis (extreme allergic reaction that can be life threatening) 
* bronchospasm (spasm of the muscles around your “wind pipe”) 
* extrapyramidal symptoms (changes effecting the nerves controlling your motor 
activity) 
* oculogyric crisis (uncontrolled rolling of your eyes) 
* blindness, transient 
* QTc prolongation (change in the way your heart beats) 
 
The possible risks of obtaining a blood sample from you are pain and bruising.  
Infection can also occur anytime the skin is broken to obtain samples, but this risk is 
extremely small as sterile supplies are used, and all hospital protocols are followed. 
 
The 12-lead ECG for you poses no risk other than a very slight risk of possible skin 
irritation where the sticky pads are placed on your skin. 
 
This particular treatment may involve risks to the subject, which are currently 
unforeseeable.  
 
POTENTIAL BENEFITS                              
 
There is no direct benefit to you by participating in this study.  Our belief is that the 
knowledge we gain from this study will benefit medical research about NAS and how to 
prevent it in the future.  Your baby’s participation will be spelled out in a separate 
Parental Permission Consent Form.  This consent form is only for your participation in 
the study.  
We cannot and do not guarantee or promise that you will receive any benefits from this 
study. 


Participant ID: 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
David R. Drover, MD                            eP 27286 
Protocol Title: Aim 2:  Prevention of Neonatal Abstinence Syndrome                                      (Maternal Consent) 
 
Page 6 of 12 
 
 
SUSampCons_CA_Privacy rev 1/25/13                                                                                                                      
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ALTERNATIVES 
 
• The alternative is not to participate. 
• We will not withhold any standard treatments for you or the baby.  
• Please discuss the potential risks and benefits of not participating with a physician. 
 
PARTICIPANT’S RIGHTS 
 
You should not feel obligated to agree to participate.  Your questions should be 
answered clearly and to your satisfaction.  If you decide not to participate, tell the 
Protocol Director.   
 
You will be told of any important new information that is learned during the course of 
this research study, which might affect your condition or your willingness to continue 
participation in this study. 
 
ClinicalTrials.gov 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law.  This Web site will not include information that can identify you.  
At most, the Web site will include a summary of the results.  You can search this Web 
site at any time. 
 
CONFIDENTIALITY 
 
Your identity will be kept as confidential as possible as required by law.  Your personal 
health information related to this study may be disclosed as authorized by you.  Your 
responses to questions concerning illegal drug use could be self-incriminating and 
harmful to you if they became known outside the study. As explained in this 
confidentiality statement of the consent, we do not intend to disclose this information.  
Your research records may be disclosed outside of Stanford, but in this case, you will be 
identified only by a unique code number.  Information about the code will be kept in a 
secure location and access limited to research study personnel.   
 
The results of this research study may be presented at scientific or medical meetings or 
published in scientific journals.  However, your identity will not be disclosed.  
We will do everything we can to keep others from learning about your participation in 
this study. To further help us protect your privacy, we received a Certificate of 
Confidentiality from the United States Department of Health and Human Services 
(DHHS) on Aug 21, 2013, which was prior to enrolling any participants.  
 


Participant ID: 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
David R. Drover, MD                            eP 27286 
Protocol Title: Aim 2:  Prevention of Neonatal Abstinence Syndrome                                      (Maternal Consent) 
 
Page 7 of 12 
 
 
SUSampCons_CA_Privacy rev 1/25/13                                                                                                                      
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With this Certificate, we cannot be forced (for example by court order or subpoena) to 
disclose information that may identify you in any federal, state, local, civil, criminal, 
legislative, administrative, or other proceedings. The researchers will use the Certificate 
to resist any demands for information that would identify you or your child, except to 
prevent serious harm to you or others, and as explained below.  
 
You should understand that a Certificate of Confidentiality does not prevent you, or a 
member of your family, from voluntarily releasing information about yourself, your 
child, or your involvement in this study.  
 
If an insurer or employer learns about your participation, and obtains your consent to 
receive research information, then we may not use the Certificate of Confidentiality to 
withhold this information. This means that you and your family must also actively 
protect your own privacy.  
 
 
Authorization To Use Your Health Information For 
Research Purposes 
 
Because information about you and your health is personal and private, it generally 
cannot be used in this research study without your written authorization.  If you 
sign this form, it will provide that authorization.  The form is intended to inform 
you about how your health information will be used or disclosed in the study.  
Your information will only be used in accordance with this authorization form and 
the informed consent form and as required or allowed by law.  Please read it 
carefully before signing it.   
 
What is the purpose of this research study and how will my health 
information be utilized in the study? 
The purpose of this study is to determine if the drug ondansetron, if given to babies 
born to narcotic-dependent mothers, will prevent those babies from suffering from 
a syndrome called “Neonatal Abstinence Syndrome”, also called “NAS”.  We hope 
to learn if we can prevent NAS by first giving these pregnant narcotic-dependent 
women a dose of intravenous (IV) ondansetron prior to the delivery of their babies, 
followed by giving the newborn babies a dose of ondansetron once a day for up to 
5 days. Currently there is no standard-of-care medicine used to “prevent NAS” and 
babies are only treated once they suffer the symptoms of withdrawal from 
narcotics. Because this is a clinical trial, the information will be submitted to the 
sponsor, the National Institutes of Health (NIH), and the Food and Drug 
Administration (FDA). 


Participant ID: 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
David R. Drover, MD                            eP 27286 
Protocol Title: Aim 2:  Prevention of Neonatal Abstinence Syndrome                                      (Maternal Consent) 
 
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SUSampCons_CA_Privacy rev 1/25/13                                                                                                                      
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Do I have to sign this authorization form? 
You do not have to sign this authorization form.  But if you do not, you will not be 
able to participate in this research study, including receiving any research-related 
treatment.  Signing the form is not a condition for receiving any medical care 
outside the study. 
 
If I sign, can I revoke it or withdraw from the research later? 
If you decide to participate, you are free to withdraw your authorization regarding 
the use and disclosure of your health information (and to discontinue any other 
participation in the study) at any time.  After any revocation, your health 
information will no longer be used or disclosed in the study, except to the extent 
that the law allows us to continue using your information (e.g., necessary to 
maintain integrity of research).  If you wish to revoke your authorization for the 
research use or disclosure of your health information in this study, you must write 
to: David R. Drover, MD.  Stanford Medical Center, Anesthesia Department, MC 
5117, 300 Pasteur Drive, Stanford, CA 94305.   
 
What Personal Information Will Be Obtained, Used or Disclosed? 
Your health information related to this study, may be used or disclosed in 
connection with this research study, including, but not limited to, for the pregnant 
narcotic-dependent women: one blood sample for analysis of ondansetron, one 
possible ECG, one urine drug screen prior to delivery; name, medical record 
number, demographic information (such as, date of birth, height, weight, ethnicity, 
race, pregnancy history), medication history (including any prescription meds, any 
street drugs and any narcotics used in the 2 months prior to delivery and through 1 
month following delivery), medical and surgical history, tobacco history, and name 
and contact information of baby’s pediatrician and/or other healthcare provider 
(such as public health nurse); frequency and duration of breast/bottle feeding in 
hospital and at home after discharge, and all other drugs taken for 1 month after 
delivery while breast/bottle feeding the baby.  
 
Who May Use or Disclose the Information? 
The following parties are authorized to use and/or disclose your health information 
in connection with this research study: 
• The Protocol Director, David Drover, MD 
• The Stanford University Administrative Panel on Human Subjects in 
Medical Research and any other unit of Stanford University as necessary 
• Research Staff 


Participant ID: 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
David R. Drover, MD                            eP 27286 
Protocol Title: Aim 2:  Prevention of Neonatal Abstinence Syndrome                                      (Maternal Consent) 
 
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SUSampCons_CA_Privacy rev 1/25/13                                                                                                                      
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Expiration Date:  April 26, 2017 
 
Who May Receive or Use the Information? 
The parties listed in the preceding paragraph may disclose your health information 
to the following persons and organizations for their use in connection with this 
research study:  
• The Office for Human Research Protections in the U.S. Department of 
Health and Human Services 
• National Institutes of Health (NIH) 
• The Food and Drug Administration (FDA) 
• Data Safety Monitoring Board 
Your information may be re-disclosed by the recipients described above, if they are 
not required by law to protect the privacy of the information. 
 
When will my authorization expire? 
Your authorization for the use and/or disclosure of your health information will 
end on (December 31, 2025) or when the research project ends, whichever is 
earlier.  
 
Will access to my medical record be limited during the study? 
To maintain the integrity of this research study, you may not have access to any 
health information developed as part of this study until it is completed.  At that 
point, you would have access to such health information if it was used to make a 
medical or billing decision about you (e.g., if included in your official medical 
record).  
 
________________________________                    
_____________ 
Signature of Adult Female Participant                           
Date 
 
Print Name of Adult Participant: ________________________________________  
 
 
FINANCIAL CONSIDERATIONS 
 
Payment 
You will not be paid to participate in this research study. 
 
 
Costs 
If you participate in this study, there may be additional costs to you.  These include the 
personal time it will take to come to all of the study visits.   


Participant ID: 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
David R. Drover, MD                            eP 27286 
Protocol Title: Aim 2:  Prevention of Neonatal Abstinence Syndrome                                      (Maternal Consent) 
 
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SUSampCons_CA_Privacy rev 1/25/13                                                                                                                      
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Expiration Date:  April 26, 2017 
 
The study will pay for those services, supplies, procedures, and care associated with 
this study that are not a part of your routine medical care.  If you would like to review 
the list of such covered services, supplies, procedures and care, please tell us now or at 
any time during the study.   
 
Participation in this study is not a substitute for health insurance.  You and/or your 
health insurance must pay for those services, supplies, procedures, and care that you 
require during this study for routine medical care.  You will be responsible for any 
co-payments and/or deductibles as required by your insurance.   
 
Sponsor 
The National Institutes of Health (NIH) is providing financial support and/or material for 
this study.  
 
COMPENSATION for Research-Related Injury 
 
All forms of medical diagnosis and treatment – whether routine or experimental – 
involve some risk of injury.  In spite of all precautions, you might develop medical 
complications from participating in this study.  If such complications arise, the Protocol 
Director and the research study staff will assist you in obtaining appropriate medical 
treatment.  In the event that you have an injury or illness that is directly caused by 
your participation in this study, reimbursement for all related costs of care first will be 
sought from your insurer, managed care plan, or other benefits program.  You will be 
responsible for any associated co-payments or deductibles as required by 
your insurance. 
 
If costs of care related to such an injury are not covered by your insurer, managed care 
plan or other benefits program, you may be responsible for these costs.  If you are 
unable to pay for such costs, the Protocol Director will assist you in applying for 
supplemental benefits and explain how to apply for patient financial assistance from the 
hospital. 
 
You do not waive any liability rights for personal injury by signing this form. 
 
CONTACT INFORMATION  
 
Contact information should include the following as appropriate.  
Questions, Concerns, or Complaints:  If you have any questions, concerns or complaints 
about this research study, its procedures, risks and benefits, or alternative courses of 
treatment, you should ask the Protocol Director, Dr. David Drover at (650) 725-0364. 
You should also contact him at any time if you feel you have been hurt by being a part 
of this study. 


Participant ID: 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
David R. Drover, MD                            eP 27286 
Protocol Title: Aim 2:  Prevention of Neonatal Abstinence Syndrome                                      (Maternal Consent) 
 
Page 11 of 12 
 
 
SUSampCons_CA_Privacy rev 1/25/13                                                                                                                      
IRB Use Only 
Approval Date:   April 26, 2016 
Expiration Date:  April 26, 2017 
 
Independent Contact:  If you are not satisfied with how this study is being conducted, 
or if you have any concerns, complaints, or general questions about the research or 
your rights as a participant, please contact the Stanford Institutional Review Board 
(IRB) to speak to someone independent of the research team at (650)-723-5244 or toll 
free at 1-866-680-2906.  You can also write to the Stanford IRB, 3000 El Camino Real, 
Five Palo Alto Square, 4th Floor, MC 5579, Palo Alto, CA 94306. 
 
Alternate Contact:  If you cannot reach the Protocol Director, please contact Dr. 
Brendan Carvalho at 650-861-8607 or pager number 650-723-8222, ID #13980. 
 
EXPERIMENTAL SUBJECT’S BILL OF RIGHTS 
 
As a research participant you have the following rights.  These rights include but are 
not limited to the participant's right to: 
• 
be informed of the nature and purpose of the experiment;  
• 
be given an explanation of the procedures to be followed in the medical 
experiment, and any drug or device to be utilized;  
• 
be given a description of any attendant discomforts and risks reasonably to be 
expected;  
• 
be given an explanation of any benefits to the subject reasonably to be 
expected, if applicable;  
• 
be given a disclosure of any appropriate alternatives, drugs or devices that might 
be advantageous to the subject, their relative risks and benefits; 
• 
be informed of the avenues of medical treatment, if any available to the subject 
after the experiment if complications should arise;  
• 
be given an opportunity to ask questions concerning the experiment or the 
procedures involved;  
• 
be instructed that consent to participate in the medical experiment may be 
withdrawn at any time and the subject may discontinue participation without 
prejudice;  
• 
be given a copy of the signed and dated consent form; and  
• 
be given the opportunity to decide to consent or not to consent to a medical 
experiment without the intervention of any element of force, fraud, deceit, 
duress, coercion or undue influence on the subject's decision. 
 
 
 


Participant ID: 
 
 
STANFORD UNIVERSITY   Research Consent Form 
Protocol Director: 
David R. Drover, MD                            eP 27286 
Protocol Title: Aim 2:  Prevention of Neonatal Abstinence Syndrome                                      (Maternal Consent) 
 
Page 12 of 12 
 
 
SUSampCons_CA_Privacy rev 1/25/13                                                                                                                      
IRB Use Only 
Approval Date:   April 26, 2016 
Expiration Date:  April 26, 2017 
May we contact you about future studies that may be of interest to you?   
 
____ Yes  ____ No 
 
 
Signing your name means you agree to be in this study and that you were given a copy of 
this consent form. 
 
  
___________________________________ 
                
____________ 
Signature of Adult Female Participant 
 
           
Date 
 
Printed Name of Adult Participant: ________________________________________ 
 
 
 
____________________________________              
___________ 
Signature of Person Obtaining Consent  
 
   
Date 
 
Printed Name of Person Obtaining Consent: __________________________________ 
 
 
 
The following witness line is to be signed only if the consent is provided as a summary 
form and accompanied by a short form foreign language consent. 
 
 
_____________________________________             
___________ 
Signature of witness                     
 
 
     
Date 
 
Print Name of Witness: _________________________________________________ 
 
(e.g., staff, translator/interpreter, family member, or other person who speaks both English and the 
participant’s language) 
 
• Translated short form must be signed and dated by both the participant (or their LAR) AND the 
witness. 
• The English consent form (referred to as the "Summary Form" in the regulations): 
o Must be signed by the witness AND the Person Obtaining Consent (POC). 
o The non-English speaking participant/LAR does not sign the English consent. 
o The non-English speaking participant/LAR should not sign the HIPAA participant line 
o If the participant or the LAR is non-English speaking, the Person Obtaining Consent (POC) must 
ensure that 1) the LAR's Description of Authority is completed and 2) that any questions or options 
presented by the consent form are documented and initialed by the POC on the Summary Form, per 
the participant's wishes, as they are understood during the consent process. 
 

Prot_002.pdf: 
 
 
 
 
AIM 2- Prevention of Neonatal Abstinence Syndrome 
Study Protocol 
NCT01965704 
March 2, 2019 
 


Version: 02MAR2019 
1
Aim 2: PREVENTION OF NEONATAL ABSTINENCE SYNDROME (NAS2) 
 
Contents 
Aim 2: PREVENTION OF NEONATAL ABSTINENCE SYNDROME (NAS2) ............................ 1 
1.0 Background and Purpose ................................................................................................. 1 
2.0 Protection of Human Subjects .......................................................................................... 2 
2.1 Risks to Human Subjects ............................................................................................. 2 
2.2 Collaborating Sites ....................................................................................................... 8 
3.0 Study Team ...................................................................................................................... 8 
4.0 
Sources of Materials ..................................................................................................... 9 
4.1 Maternal and Neonatal Tissue ...................................................................................... 9 
4.2 Maternal data.............................................................................................................. 10 
4.3 Neonatal data ............................................................................................................. 10 
5.0 Potential Risks ............................................................................................................... 10 
6.0 Adequacy of Protection against Risks ............................................................................ 13 
6.1 Recruitment and Informed Consent ............................................................................ 13 
6.2 Protection against Risks ............................................................................................. 13 
6.3 Protection of confidentiality ......................................................................................... 16 
7.0 Potential Benefits of the Proposed Research to the Subjects and Others ..................... 16 
8.0 Importance of the Knowledge to be Gained ................................................................... 17 
9.0 Data and Safety Monitoring Plan ................................................................................... 17 
10. Clinical Trials.gov Requirements .................................................................................... 19 
11. Inclusion of Women and Minorities ................................................................................ 19 
12. Targeted/Planned Enrollment Tables ............................................................................. 20 
13. References ..................................................................................................................... 22 
Appendix .............................................................................................................................. 26 
 
 
 
1.0 Background and Purpose 
 
The misuse of and addiction to opioid medications has become the most rapidly increasing 
drug problem in the US, which has consequences for pregnant mothers and their babies. The 
prevalence of maternal opioid drug use at the time of delivery in California is approximately 
one percent. The neonatal abstinence syndrome (NAS) is a constellation of narcotic drug 
withdrawal symptoms that develops in 42 to 94 percent of infants born to narcotic dependent 
mothers. There are no preventative treatments for this severe syndrome, which can result in a 
prolonged hospitalization and treatment in a neonatal intensive care unit.  
 
Based upon a genetic discovery, we demonstrated that administration of a 5-HT3 antagonist 
(ondansetron) prevented the symptoms of narcotic drug withdrawal in experimental studies in 
mice and in humans. From this, we hypothesize that ondansetron administration to pregnant 
narcotic-using mothers just prior to delivery, followed by a 3 to 5-day period of ondansetron 


Version: 02MAR2019 
2
administration to the neonate, could reduce the incidence or severity of NAS symptoms. 
Ondansetron is a broadly utilized drug with a substantial safety record in pregnant women. We 
now understand the pharmacokinetics of ondansetron at birth based on PK analysis of 
placental and neonatal blood samples in babies whose mothers’ were given ondansetron 
prophylactically prior to cesarean delivery (Aim 1 of the protocol, Prevention of Neonatal 
Abstinence Syndrome).  In this study, (Aim 2) we will conduct a multi-center, randomized, 
double blind, and placebo-controlled trial to determine whether ondansetron treatment will 
reduce the incidence (percentage of infants requiring narcotic drug treatment) or severity (total 
amount of narcotic drug required, length of hospitalization, symptom severity scores) of NAS in 
babies born to narcotic-using mothers.  
 
This project tests a very novel approach for preventing an important pregnancy-related 
complication of narcotic drug abuse. If a brief period of ondansetron administration to the 
mothers that use narcotic drugs, and to their babies, can prevent or ameliorate the 
development of narcotic drug withdrawal symptoms in neonates, this would reduce human 
suffering and the growing societal cost of opiate abuse.  
 
2.0 Protection of Human Subjects  
 
2.1 Risks to Human Subjects  
2.1.1 Human Subjects Involvement, Characteristics, and Design 
This study will include up to 120 opioid-addicted, otherwise healthy and with no cardiac history 
of prolongation of the QTc interval, 18-45 years of age, pregnant women ≥ 37 weeks through  
< 42 weeks gestation and their newborns. Subjects will be recruited from about 5-10 sites 
around the country with some hospitals joining the study and then dropping out if they are not 
able to enroll enough subjects.  Locally, we are enrolling at two Bay Area hospitals: Lucile 
Packard Children’s Hospital at Stanford and Santa Clara Valley Medical Center. The sites 
outside of California are: Johns Hopkins Bayview Medical Center in Baltimore, Maryland, the 
University of Tennessee Health Science Center in Memphis, Tennessee, the University of 
Louisville in Louisville, Kentucky, and Thomas Jefferson University Hospital in Philadelphia, 
Pennsylvania.   
Informed consent will be obtained by either a member of the research team or a member of the 
participant’s medical team during the course of her prenatal care with her obstetrician or at a 
pre-scheduled visit with the anesthesiologist prior to delivery, or lastly, and the least likely time 
to get consent may be on admission to labor and delivery, only if time allows true informed 
consent in that setting. Because this study involves the newborn infant, as well as the mother, 
consent will be obtained from both parents where fathers are involved and competent to 
provide consent. After admission to the labor and delivery suite, the mother-infant pair will be 
randomized to one of two treatment groups (placebo or ondansetron) by the pharmacy. 
Randomization will be done between all sites to ensure that the first 20 mother-infant pairs 
enrolled will have an equal number of placebo and active treatment participants. The medical 
team, the research team, and the participant will be blinded to the treatment assignment 
(double-blind study). The pharmacy will hold the key to the treatment assignment and will un-
blind the study only if deemed medically necessary. 


Version: 02MAR2019 
3
 
A. Safety Monitoring of Participants: 
1. Neonates admitted to Well Baby Nursery:  
a.  ECG: The neonate will be stabilized after birth and then will receive a screening 12-
lead ECG to rule out QTc Bazett greater than or equal to 480ms. Once the neonate 
is medically stable and a normal QTc confirmed by the treating physician, the 
neonate will receive the same ‘blinded’ study drug (ondansetron or placebo) as his 
or her mother; this first dose of study drug is to be given between 4-8 hours after 
delivery. A repeat 12-lead ECG will be done on all neonates following each of the 5 
doses of study drug, between 2-5 hours after each dose of study drug.  Any neonate 
that shows significant ECG changes will be excluded from further dosing of study 
medication but will continue safety follow-up.   
i. If the QTc is prolonged, the neonate will be transferred to the NICU for 
continuous cardiac monitoring, if the standard of care indicates the neonate 
should be admitted to NICU; this will be determined on a case-by-case basis 
at each site. In addition, a blood test to check the potassium, magnesium, 
calcium, and ionized calcium levels will be done if the clinical team believe it 
is necessary for the neonates safety; if the levels are abnormal, electrolytes 
will be normalized using IV or oral supplements as indicated per standard of 
care. 
ii. All ECGs, from all sites, will be sent to Stanford to be interpreted by a 
cardiologist, who is not a member of the study team, to confirm the accuracy, 
and consistency of the initial readings. 
b. Standard of Care for Well Baby Nursery: 
i. Vital Signs:  heart rate (HR), respiratory rate (RR), and temperature will be 
monitored every 4-8 hours depending on the infant’s history, and blood 
pressure at least once per day. 
1. If the HR is less than 80 beats per minute, a rhythm strip or 12-lead 
ECG is ordered to evaluate the QTc interval, a Neonatal Intensive 
Care Unit (NICU) physician will assess the neonate and a blood 
pressure will be obtained. 
2. If the QTc is prolonged, see “ECG” above which discusses the 
possibility of the neonate being transferred to the NICU for continuous 
cardiac monitoring if deemed necessary by standard of care 
ii. A member of the study team will visit the Well Baby Nursery at least once per 
day to ensure the neonate is doing well and that everyone on the clinical 
team understands the protocol and knows how to contact the principal 
investigator to answer questions as needed. 
iii. Modified Finnegan Evaluation (Scoring) to be done per standard of care at 
each institution since they are all similar and have been in place for many 
years. Each site involved in this study has established guidelines for starting, 
advancing and weaning treatment for NAS (see attached guidelines for each 
site).  All the data regarding the treatment for NAS will be collected for the 
study.  
 
2. Neonates Admitted to the NICU after Birth: 


Version: 02MAR2019 
4
a. ECG, Vital Signs, and Pulse Oximetry:  the neonate will be stabilized after birth and 
then will receive a screening 12-lead ECG to rule out QTc Bazett greater than or 
equal to 480ms.  Once the neonate is medically stable and a normal QTc confirmed 
by the treating physician, the neonate will receive the same study drug 
(ondansetron or placebo) as his or her mother; this first dose of study drug is to be 
given between 4-8 hours after delivery. A repeat 12-lead ECG will be done on all 
neonates following each of the 5 doses of study drug, between 2-5 hours after each 
dose of study drug.  Any neonate that shows significant ECG changes will be 
excluded from further dosing of study medication but will continue safety follow-up 
b. Standard of Care for the NICU: 
i. Blood pressure is measured at least once per shift. Depending on acuity and 
access, blood pressure will be monitored either continuously (if indwelling 
line is indicated for clinical care) or every 4-8 hours using non-invasive 
oscillometry. 
ii. Continuous ECG, heart rate, respiratory rate and oxygen saturation 
monitoring are done on all NICU patients; the HR, RR, and oxygen 
saturations are documented in the medical record every 1-4 hours as per 
standard of care, with vitals documented more frequently in acutely ill infants.   
iii. A member of the study team will visit the NICU at least once per day to 
ensure the neonate is doing well and that everyone on the clinical team 
understands the protocol and knows how to contact the principal investigator 
to answer questions as needed. 
iv. Modified Finnegan Evaluation (Scoring) to be done per standard of care at 
each institution since they are all similar and have been in place for many 
years. Each site involved in this study has established guidelines for starting, 
advancing and weaning treatment for NAS (see attached guidelines for each 
site).  All the data regarding the treatment for NAS will be collected for the 
study.  
 
Interim Analysis: an interim analysis will be performed after a total of twenty (20) pregnant 
women and their twenty (20) neonates have been enrolled and dosed with study medication. 
The analysis will include all the ECG measurements, blood concentration levels for 
pharmacokinetics (PK) and a reassessment of the PK of ondansetron in neonates, all to be 
reviewed by the DSMB. The study will only proceed if the DSMB gives their approval. These 
20 neonates will be the “First cohort” of neonatal patients. (Note, this was done between April 
and May 2016) 
B.  Study Medication Dosing 
Adult Pregnant Participant’s Dose: The amount and timing of the dose of ondansetron 
to be administered to the pregnant participants, who are randomized to the ondansetron group, 
will be 8 mg (IV) within 4 hours of delivery. Should the participant be undelivered 4 hours 
following the initial dose of study drug, a second dose will be administered. The study 
medication will be delivered intravenously to the mother prior to either vaginal or cesarean 
delivery.  Exception: if the pregnant participant does not want to receive any study medication 
prior to delivery because she is not experiencing nausea, she may still continue to be a part of 
the study and her neonate will be assigned to the study medication she would have been 
randomized to receive.  This allows for an adult patient to not be given the study medication 


Version: 02MAR2019 
5
(ondansetron or placebo) if they feel they do not need it.  The neonate’s participation will 
continue as planned. 
 Neonatal Participant’s Dose:  The neonates who are born to the mothers, who are 
randomized to receive ondansetron, will have an initial oral dose of ondansetron 0.07 mg/kg 
given between 4-8 hours after delivery. The subsequent doses of ondansetron will be 0.07 
mg/kg orally every 24 hours for up to 5 doses maximum. 
The timing and volume of placebo administration for the 50% of subjects in the placebo group 
will mimic that of the 50% of subjects in the ondansetron group.  Placebo will consist of either 
normal saline for IV administration or inactive oral syrup for oral administration. 
For those neonates who require an intravenous catheter for any other medical reason, these 
neonates will receive an ondansetron dose of 0.04 mg/kg IV every 24 hours for up to 5 doses 
maximum. 
 
C.  Study Procedures 
Adult Pregnant Participant’s Procedures:   
1. Maternal blood for ondansetron concentration (PK) will be collected within 30 
minutes of delivery (either pre- or post-delivery).  
2. Maternal urine will be collected for toxicology analysis prior to delivery to 
identify possible polysubstance abuse (polysubstance use is not an exclusion criteria) 
3. Once delivery is complete, the mother’s participation will consist mainly of 
answering questions about her own medication use and the baby’s feeding habits over 
the remainder of the study while the neonate participates in the study.  
  
Neonatal Participant’s Procedures:  
 
1. The Modified Finnegan scoring system will be used to evaluate neonates for 
symptoms of NAS at each site involved in the study and is considered standard-of-care 
for babies who are at risk for NAS. Treatment with the study medication will continue for 
a maximum of five days (starting within approximately 4-8 hours after birth).  
 
2. Treatment of NAS: morphine will be the first treatment choice before other 
treatment medication choices (opioid or non-opioid) for NAS symptoms. This is the 
standard-of-care at all participating sites.  Each site involved has established guidelines 
for starting, advancing and weaning treatment for NAS.  Any medication used to treat 
the symptoms of NAS will be noted as to name, dose, route, reason for dosage 
(Finnegan score or other reason) and time of administration. If the neonate develops 
nausea and clinical treatment of the nausea would include ondansetron then an 
alternate antiemetic should be considered. The infant may already have a full 
therapeutic level of ondansetron and additional dosage will not help treat the nausea. 
Ondansetron is not strictly contraindicated by this protocol as some neonates will have 
received placebo. For those infants that have been randomized to ondansetron, an 
additional dose of ondansetron will not be harmful.  
 
3.  12-Lead ECG:  all neonates, whether they are cared for in Well Baby Nursery 
or the NICU, will have a screening 12-lead ECG prior to their first dose of study drug 
and a follow-up 12-lead ECG within 2- 5 hours after each dose of study drug. 


Version: 02MAR2019 
6
 
4. Umbilical cord blood (venous) will be collected at delivery and evaluated for 
ondansetron and ondansetron metabolite concentration.  The standard of care at most 
hospitals is to discard the umbilical cord in the hospital biological waste system unless 
the parents have asked for it to be saved.  We will only take these cord samples if the 
mother agrees to let us have them. 
 
 
5. Blood Samples:  between one (1) and nine (9) 0.1 mL blood samples (about 1-
3 drops) will be collected from the neonate after birth to measure ondansetron and 
metabolite concentrations. These samples will be collected during clinically indicated 
blood sampling whenever possible to prevent additional trauma to the infant. When and 
if an intravenous cannula is inserted for administration of other treatments and then the 
study drug, a blood sample may be obtained during the insertion of this cannula, if 
possible, to avoid a heel stick for the PK blood draw done prior to starting IV dosing of 
study drug.  If there are no clinically indicated blood draws ordered for a neonate in the 
first 12 hours of life, it may be necessary for one or two of these research PK samples 
to be drawn separately from clinically indicated sampling. For example, if there are no 
clinically indicated labs that need to be done prior to the first dose of study drug, then 
the first PK sample of blood would be done for research only, if the mother agrees to a 
heel stick. The second PK sample is scheduled to be drawn after the first dose of study 
drug but before the infant is 12 hours old and that would be an extra heel stick if there 
are no clinically ordered labs during this time period. During the following days of 
treatment, additional 0.1 ml of blood will be obtained when clinically indicated blood 
sampling occurs up to a grand total of 9 times during the study. Times will be noted to 
the nearest minute for all blood samples.  
 
6.  Follow-up calls/visits:  a research team member will call the mother of the 
baby once they have been discharged home, if the baby is discharged prior to Day 15 
of their life. We want to follow up on the babies and learn how they are doing and 
make sure they are not going into “Delayed” NAS.  For babies who are discharged 
early it is more likely they could go into delayed NAS and that is why we plan to call 
the mothers daily, for up to 10 days after the baby takes their last dose of study 
medication, to ask about their baby’s status. We are interested in how the baby is 
feeding, are they breast or bottle feeding the baby, what is the baby’s mood (crying 
excessively, fussy, agitated), sleeps for how many hours after feeding, sneezing a lot, 
sweating, vomiting, gaining weight, loose stools or watery stools, etc. We also need to 
ask the mother all the medications she is taking, if she is breastfeeding her baby, 
since we know these medications will enter the baby’s system through the breast milk.  
If a baby is not discharged before day 15 of their life, the research team member will 
visit the baby in the hospital daily, for 10 days after their last dose of study drug, to 
check on the status of the baby from the clinical team caring for the baby.  If the 
mother is home while the baby remains hospitalized, the research team member will 
also call the mother on a daily basis to maintain contact and to ask the mother all the 
medications she is taking if she is breastfeeding her baby (we know these medications 
may enter the baby’s system through the breast milk).  


Version: 02MAR2019 
7
 
7. The final follow-up call (or visit if the baby is still in the hospital)  will occur 
approximately 30 days after the baby’s last dose of study medication; this call (or visit) 
will be to determine if any previously reported adverse events have resolved and/or if 
any new adverse events have occurred since the last follow-up call or visit.  
  
The primary endpoint will be the incidence of NAS in enrolled neonates and will be measured 
by the need for pharmacologic treatment for the symptoms of NAS (Morphine). The secondary 
endpoint of the severity of NAS will be measured by the length of the hospitalization (birth to 
discharge), the total dose of narcotic required to treat the symptoms of NAS, and the need to 
include barbiturates in the treatment of symptoms of NAS.  
 
2.1.2 Inclusion/Exclusion  
 
Criteria 
Subjects 
Inclusion Criteria 
Exclusion Criteria 
Maternal/Paternal 
 
Women of reproductive age 
(18-45 years old, inclusive) 
and their fetuses/neonates. 
Daily opioid use for at least 3 
weeks prior to delivery 
Gestational age of ≥- 37 
weeks to < 42 weeks at 
delivery.  
Competent mother willing to 
sign the informed consent for 
herself and both parents 
competent and willing to sign 
consent/permission for their 
neonate. 
Any condition that, in the 
opinion of the investigator, 
would compromise the 
health of the participant 
(both mother and fetus) or 
the integrity of the data. 
 
Known allergy to the study 
medication. 
 
Screening 12-lead ECG, if 
done, showing prolonged 
QTc will stop the mother 
from receiving any study 
drug but her neonate can 
still be included in the 
study. 
 
Maternal ingestion or 
administration of 
ondansetron within 24 
hours prior to delivery, for 
reasons other than study 
purposes, will exclude the 
mother and neonate. 
 
Neonatal 
 
Participating mother 
Maternal (and paternal if 
QTcB greater than or equal 
to 480ms on any 12-lead 


Version: 02MAR2019 
8
present and competent) 
consent 
ECG post delivery will stop 
the dosing of the study 
drug, but safety follow up  
will be done including blood 
samples & 12-lead ECG(s) 
if the mother or baby 
received at least one dose 
of study drug. 
This study will include special classes of participants: pregnant women and their newborns. The focus 
of this study is specific to these sensitive populations of pregnant women and neonates and as such 
warrants their inclusion. We feel that, in balance, the potential for significant benefit to the neonatal 
population in this study and in future patients outweighs the risks (section 5.0 Potential Risks below). 
2.2 Collaborating Sites 
This study will occur at the following hospital sites. 
1. Lucile Packard Children’s Hospital/ Stanford University Affiliate (Stanford, California) 
2. Santa Clara Valley Medical Center/ Stanford University Affiliate (San Jose, California) 
3. Johns Hopkins Bayview Medical Center/ Johns Hopkins University Affiliate (Baltimore, 
Maryland). 
4. University of Tennessee Health Science Center/ University of Tennessee Affiliate (Memphis, 
Tennessee) 
5. Kosair Charities Pediatric Clinical Research Unit / University of Louisville Affiliate (Louisville, 
Kentucky) 
6.  Thomas Jefferson University Hospital / Thomas Jefferson University Affiliate (Philadelphia, 
Pennsylvania) 
These medical centers have collaborated multiple times in ongoing, prospective, maternal-fetal 
studies (43). Stanford University will act as the coordinating center, managing all aspects of 
the study including grant management, enrollment oversight, protocol compliance, PK 
specimen processing, subcontracting, and safety monitoring. All four sites will enroll and treat 
participants and be responsible for the safety of participants and integrity and safety of data at 
their respective sites. 
 
3.0 Study Team 
We have assembled an outstanding team of clinicians and scientists  
Role/ Location 
People 
Clinical 
Coordinator/PI  
Lucile Packard 
Children’s Hospital 
David Drover, MD 
Clinical Team 
1. Lucile Packard 
Children’s Hospital 
(LPCH, site 1) 
 
2. Santa Clara Valley 
 
Deirdre Lyell, MD; Ronald S. Cohen, MD; Brendan Carvalho, 
MBBCh, FRCA, MDCH; Carol Cohane, RN 
 
 
Balaji Govindaswami, MD; Priya Jegatheesan, MD 


Version: 02MAR2019 
9
Medical Center 
(SCVMC, site 2) 
 
 
3. Johns Hopkins 
Bayview Medical 
Center (JHBMC,    
site 5) 
 
4. University of 
Tennessee Health 
Science Center 
(UTHSC, site 6) 
 
5. University of 
Louisville  (U of L, 
site 8) 
 
6. Thomas Jefferson 
University Hospital 
(TJU, site 7) 
 
 
 
 
Lauren M. Jansson, MD 
 
 
 
 
Ramasubbareddy Dhanireddy, MD 
 
 
 
 
Lori A. Devlin, D.O. 
 
 
 
Walter K. Kraft, MD;   Susan Adeniyi-Jones, MD 
Science Team 
Lead/co-PI 
 
Clinical research RN 
 
Statistician 
 
Mass Spectroscopy 
 
 
Clinical 
Pharmacology 
David Drover, MD 
 
 
Carol Cohane, RN 
 
Ming Zheng, PhD 
 
Manhong Wu, PhD 
 
 
 
Robert Ward, MD 
 
4.0 
Sources of Materials  
4.1 Maternal and Neonatal Tissue 
Maternal Tissue: one maternal blood sample for ondansetron levels will be collected 
within 30 minutes of delivery (pre- or post-delivery) but as close to time of birth as possible. 
Time of this blood sample will be recorded as accurately as possible and related to the time of 
birth. A maternal urine sample will be obtained prior to delivery for a toxicology screen to 
determine possible polysubstance abuse. 
Neonatal tissue: umbilical cord blood (venous) will be collected at delivery and 
evaluated for ondansetron and metabolite concentrations. Between one and nine 0.1 mL blood 
samples (1-3drops) will be collected from the neonate to measure ondansetron and metabolite 
concentrations after birth. Most of these samples will be collected during clinically indicated 


Version: 02MAR2019 
10
blood sampling to prevent additional trauma to the infant. (See Section 2.1.1. under section C. 
Study Procedures, #4, for details on blood draws) 
4.2 Maternal data 
1. Age, 2. Weight, 3. Height, 4. Race & Ethnicity, 5. Drug(s) of abuse used, and dose, 
frequency and duration of use, 6. Name, 7. Other substance abuse, 8. Tobacco use and 
amount/day, 9. Medications used during pregnancy that might induce or inhibit metabolism of 
ondansetron or change QT (e.g., CYP 3A4, 2D6, barbiturates, fluconazole, erythromycin, etc.), 
10. Maternal co-morbidities, 11. Plan to breast feed, and level of success as measured by 
number and length of feedings per day, number of formula feedings per day, 12. Type of 
labor/C-section analgesia, 13. Opioid and other drug use during breast feeding. 14. Gravida 
15. Para, 16. Date of Birth, 17. PK blood results for ondansetron, 18. Urine drug screen results 
19. Medical record number.20. Name & contact number of their baby’s pediatrician and/or 
other healthcare provider, such as public health nurse. 20. Results of 12-lead ECG, if done.  
4.3 Neonatal data 
1. Gestational age, 2. Mode of delivery, 3. Birth weight, 4. Birth Length (height), 5. Neonatal 
co-morbidities, 6. Duration of hospital stay (birth to discharge), 7. Need for medical treatment 
of NAS, 8. Time from birth to initial pharmacological treatment of NAS, 9. Need for barbiturate 
treatment for NAS, 10. Duration of medical treatment of NAS, 11. Weight change during 
hospitalization, 12. Gender, 13. Modified Finnegan scores, 14. All 12-lead ECG results, 15. 
Frequency and duration of breast/bottle feeding in hospital and home after discharge, 16. 
Apgar 1min, Apgar 5 min 17. All medications used to treat NAS (drug name, dosage, route, 
reason for dosing, time & date), 18. pharmacokinetic blood results for ondansetron, 19. Date of 
birth, 20. Medical record number. 
 
Data Security 
Study team members at all sites will have access to the identifiable protected health 
information (PHI) of participants. During the data-collection phase of this study, all identifiable 
data will be kept in a locked environment. All electronic data will be encrypted and kept on a 
password-protected computer. A REDCap database will be designed and maintained by the 
study team for the compilation of all study data. This database meets all regulatory standards 
for safe and confidential storage and management of human subject research data. At the 
earliest possible time, after complete analysis and confirmation of accuracy of the data 
collected, all data will be de-identified. 
A unique study number will be assigned to each participant. The code to link this number to 
PHI will be encrypted and kept in a password-protected computer. Tissue specimens for 
ondansetron levels will be labeled with this coded study number only and will not include any 
information that would link the sample to the participant. The urine toxicology screens will be 
analyzed in the respective hospital laboratories. 
Due to the sensitive nature of the data collected and to protect the rights of the study 
participants, a Certificate of Confidentiality was obtained from the NIH on August 21, 2013.  
 
5.0 Potential Risks  
Potential Risks 
Ondansetron 


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Potential Risks 
To Mother 
Well-studied in adults and considered safe  
Routinely given to pregnant women in first trimester for hyperemesis gravidarum and during labor as antiemetic 
Routine doses used in this protocol minimize risks to the mother 
To Fetus  
Classified as pregnancy class B (not shown to cause teratogenicity in animal studies and not well-studied in humans)  
Commonly used clinically in labor and delivery to treat maternal nausea, thus exposing the fetus transplacentally 
Considered to have minimal risk to the fetus 
To Neonate 
Not well-studied in this age group  
Used clinically to treat postoperative nausea in infants and young children and considered to carry minimal risk 
One double-blinded, randomized, controlled trial compared ondansetron to placebo for preventing postoperative emesis in 1-24 
month olds {#22}. No differences were found in number or pattern of adverse events between groups 
Delayed onset of NAS 
To Mother Not applicable 
To Fetus 
Onset of NAS symptoms may be delayed as a result of ondansetron treatment 
Given the prolonged effects of methadone, the late-onset risk may be particularly relevant to patients on methadone 
To Neonate 
If neonates do not demonstrate symptoms of NAS prior to discharge from the hospital; parents will be instructed to closely 
observe for symptoms when home and told to either call their baby’s doctor or take their baby to their pediatrician if the baby is 
showing signs of NAS 
Phlebotomy 
To Mother  
Minimal risk  
Approximately 5 cc (one teaspoon) maximum of blood will be drawn from the mother by needle stick or she can have a finger 
stick if the site uses the filter paper to obtain dried blood spots. 
Rare side effect is hematoma and/or infection 
To Fetus Not applicable 
To Neonate 
Study drug will be administered to the neonate either orally or via standardized intravenous infusion (IV) technique for this 
population, posing no additional risk 
 
Heel Stick 
To Mother Not applicable 
To Fetus Not applicable 
To Neonate 
Do heel stick to collect 1-3 drops of blood at least twice after delivery only if blood not collected for clinical reasons in the first 12 
hours after birth 
 Minimal risk of hematoma or infection 
Electrocardiogram  
To Mother  
May have a screening ECG if she has a history of prolongation of QTc or the investigator believes there may be a cardiac history 
of arrhythmia.  Small risk of skin irritation from the stickers used for the ECG 
To Fetus Not applicable  
To Neonate 
A screening ECG will be done shortly after birth (must be done & interpreted before study drug administration). Repeat ECG 
done after each dose of study medication. 
 Small risk of skin irritation from the stickers used for the ECG. 
Urine toxicology screen 
To Mother 
Done for all study participants  
Has legal and social implications 
 Routinely done on pregnant woman with known history of substance abuse 
Risks not significantly different from those not participating in study  
Confidentiality 
All Subjects  
Conduct enrollment in private rooms away from public workspaces  
Only protocol- trained and HIPAA-trained personnel will enroll patients, assuring confidentiality and security of patient 


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Potential Risks 
information  
Upon signed consent, mother-infant pairs will be randomized by designated clinical pharmacist, based on computer-
generated randomization scheme  
The names and medical records of mother-infant pairs will be kept in pharmacy log, kept in locked files accessible only to the 
designated clinical pharmacist  
The clinical pharmacist assigns mother-infant pair a coded number used for data collection  
For statistical analysis, at study conclusion clinical pharmacist gives primary study investigators the logs that link coded 
numbers with study medication. These logs will be kept separate from the final outcome database.  
For clarification, the clinical pharmacist will assign the patient a study number to be used for randomization and for clinical 
data collection after patient enrollment  
After study completion and one year after manuscript publication, destroy records linking participants’ identities to study ID 
numbers 
Do not reveal participants’ identities in any publications 
Keep consent forms in locked files and maintain confidentiality of all study-related records in accordance with State and 
Federal laws 
Obtain Certificate of Confidentiality from NIH to protect identifiable research information from forced disclosure 
Certificate application will list Stanford University (the lead institution) and all sub-award sites to protect all participants from 
forced data disclosure 
To Fetus Not applicable  
To Neonate Not applicable 


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6.0 Adequacy of Protection against Risks 
 
6.1 Recruitment and Informed Consent 
We will recruit patients from the Obstetric clinics affiliated with each study site as early as 
possible in the woman’s pregnancy.  Many of these pregnant women have what is considered 
‘high risk’ pregnancy due to their own narcotic-dependence.  These women will most likely be 
seen by the Anesthesia Department in a scheduled visit prior to their due date to allow the 
anesthesiologist time to evaluate the mother’s health and anesthetic needs for her delivery; 
during this visit the women will be told about the study and asked if a study team member can 
explain the study to them in detail.  The least likely method of recruitment will be a patient who 
presents to Labor and Delivery to deliver their baby and who has not been seen in advance by 
the study team.  Among this group, we will not approach or enroll women who are in active 
labor; we may approach women who are not yet in labor or who are in very early labor (as 
occurs with many other Labor and Delivery studies), allowing them sufficient time to consider 
study participation and allowing sufficient time for us to activate all study related events.  All 
women invited to join this study will be advised that regardless of their decision to participate, 
they will receive the full spectrum of standard treatment on Labor and Delivery and 
postpartum.   
 
Staff at local methadone maintenance clinics will also inform their pregnant clients about the 
study and be given an IRB approved flyer with the name and telephone number of a study 
team member to call; or they may prefer a study team member to call them, and if they give 
the clinic their verbal permission, then and only then, a study team member will call them to 
explain the study.  
 
Written information about the study, including the purpose of the study, the nature of the 
subject’s participation, and the potential benefits of participation will be offered. All necessary 
human subjects’ reviews and approvals are obtained prior to implementation of any study 
related procedures at any recruitment site.  
 
When a potential participant indicates an interest in participating in the study, a member of the 
study team will describe the study in greater detail, ensuring mental competence and full 
understanding of the implications of participation. A signed, informed consent will be obtained 
after the participant is given time to ask questions about the study.  
Once delivered, the neonate will become the participant. Given this, a “Parental Permission” 
consent will be obtained from both the father and the mother at the time of maternal 
enrollment. We understand that we do not have to obtain consent of the father if he is unable 
to consent because of unavailability, incompetence, or a temporary incapacity, or if the 
pregnancy resulted from rape or incest. Each individual (the mother and father if present and 
competent to provide consent) providing consent for participation in this study will be fully 
informed regarding the reasonable foreseeable impact of the research on the neonate. 
 
6.2 Protection against Risks 
All subjects in the study will be cared for by the same team of physicians and nurses, both on 


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the Labor and Delivery unit and in the neonatal intensive care unit, just as patients would be 
cared for if they were not part of the study. All teams will be led by appropriately trained 
attending physicians, both obstetricians and pediatricians. Of note, mothers, fetuses and 
neonates will receive the standard of care for all medical problems that arise. This includes 
administration of narcotic medications for signs or symptoms of neonatal narcotic withdrawal 
according to each hospital’s established protocol; narcotic administration is dependent upon 
the Modified Finnegan score and clinical assessment of the clinical team. Thus, neonates in 
both the placebo and the ondansetron group will receive the standard of care for neonatal 
abstinence syndrome.  
 
All participants will be closely observed for adverse events. If a study drug related serious 
adverse event is noted, the study drug will be discontinued and the adverse event reported to 
the principal investigator, the IRB and the Data Safety Monitoring Board (DSMB). Detailed 
information regarding data safety and monitoring will be described in section 9.0 Data and 
Safety Monitoring Plan. 
 
Due to the nature of this study, this research involves vulnerable populations, including 
pregnant women, fetuses, and children (neonates). We feel the risk to both the mother and 
neonate are minimal, and the least possible to achieve the goals of this project, and that the 
potential benefits to narcotic exposed fetuses and neonates greatly outweigh the risks. Specific 
information regarding the risks follows. 


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Specific risks include the following: 
Specific Risks 
Ondansetron 
To Mother 
Maternal risk is minimal, as medication is commonly used in setting and population 
To Fetus  
Risk of ondansetron exposure is same as currently occurs during standard of care treatment of pregnant women at risk for 
nausea and emesis 
To Neonate 
Risk is no greater than placebo risk  
To minimize risk, screen for QT prolongation and give dose (determined in Aim 1) to reach blood level predicted to have 
desired clinical effect  
Dose will be within dose limits studied in slightly older infants (less than 0.15 mg/hr in 12hours) 
 Duration of exposure will be minimized by stopping study drug after a maximum of five days of study drug treatment,  
Will be discontinued if related adverse events occur  
If QTc interval abnormalities occur or a neonate has QTcB greater than or equal to 480 ms, the neonate’s study drug will be 
stopped and no further dosing will occur; follow up ‘safety’ EKGs will be done until the QTc has returned to 479ms or less, if 
possible. 
All neonates will have a screening ECG prior to their first dose of study medication & an ECG after each dose for a maximum 
of 6 ECGs in 5 days. 
Delayed onset of NAS 
To Mother Not applicable 
To Fetus 
Risk will be managed by educating the parents about the NAS symptoms  
Provide parents with contact information for both their clinical caregivers and the research team  
Ask parents to report delayed onset to both groups 
Appropriate medical care will be provided  
Parents may receive a maximum of 10 daily follow-up telephone calls if the baby is discharged before Day 15 of life; the calls 
are being done to review continuation or recurrence of NAS symptoms and the occurrence of other adverse events.  The 
research staff will call daily, through a maximum of 10 days after the last dose of study drug.  If the baby is still in the hospital 
through Day 15 of life, this information will be gathered by the research staff visiting the neonate in the hospital.   
The final follow-up phone call to the parents will occur approximately 30 days after the baby’s last dose of study medication 
to check for any occurrence of new adverse events and to inquire about the resolution of any previously reported adverse 
events. 
To Neonate Not applicable 
Phlebotomy 
To Mother 
Minimize risks of hematoma and infection by following all hospital guidelines including using aseptic technique and applying 
pressure to site after sample collection  
Only qualified personnel may collect blood samples for analysis 
To Fetus Not applicable 
To Neonate 
Minimize risks of hematoma and infection by following all hospital guidelines including using aseptic technique and applying 
pressure to site after sample collection  
Only qualified personnel may collect blood samples for analysis 
Heel Stick 
To Mother Not applicable 
To Fetus Not applicable 
To Neonate 
Minimize risks of hematoma and infection by following all hospital guidelines including using aseptic technique and applying 
pressure to site after sample collection  
Only qualified personnel may collect blood samples for analysis 
Electrocardiogram  
To Mother Not applicable 
To Fetus Not applicable  
To Neonate 
Minimize skin irritation with ECG pads designed for neonates, and observe sites for signs of irritation and inflammation 
Urine toxicology screen 
To Mother 
Reduce social and legal risks by following all HIPAA and human subject research regulations  


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Specific Risks 
Prior to study enrollment, obtain a Certificate of Confidentiality from NIH to protect identifiable research information from 
forced disclosure  
To Fetus Not applicable  
To Neonate Not applicable 
6.3 Protection of Confidentiality 
We will take extensive precautions to maintain participant confidentiality throughout the study. 
The enrollment will be conducted in private rooms away from public workspaces. Only 
protocol-trained and HIPAA-trained personnel will enroll patients. Upon signed consent, 
mother and infant pairs will be randomized by the pharmacy based on a computer-generated 
randomization scheme. Only the pharmacy log will have the name and medical record of the 
mother-infant pairs. The log will be kept in locked files in the pharmacy and will be accessible 
only to the clinical pharmacist designated by the coordinators. The pharmacy will then assign 
the patient a coded number that will be used for data collection. At the conclusion of the study, 
the pharmacy will provide the primary study investigators the logs linking the numbers with the 
study medication for statistical analysis of the data. The logs linking the names and medical 
record numbers will be kept separately from the final outcome database. 
For clarification, the pharmacy will assign the patient a study number used for randomization 
and for clinical data collection after patient enrollment.  
All study personnel are HIPAA trained and certified and appreciate the importance of 
confidentiality and the security of personal information.  
Participants’ identities will not be revealed in any publication that may result from the proposed 
study. Consent forms will be kept in locked files, and the confidentiality of all study-related 
records will be maintained in accordance with State and Federal laws.  
 
A Certificate of Confidentiality was obtained from the NIH on August 21, 2013, to protect the 
identifiable research information from forced disclosure. The application will include Stanford 
University (the lead institution) and all sub-award sites listed in this application. It is of utmost 
importance to protect all participants from forced disclosure of this data.  
In the event of study related adverse events, Dr. Drover, in his role as Clinical Medical 
Coordinator and Primary Investigator in this study, will provide direct care, or facilitate 
appropriate referrals to ensure successful resolution of the AE. A Data Safety Monitoring 
Board will be established, and will be described in greater detail in section 9.0. 
 
7.0 Potential Benefits of the Proposed Research to the Subjects and Others  
Mother-infant pairs randomized to the ondansetron arm may benefit from the following: 
decreased need for medical intervention for the neonate, decreased amounts of post-natal 
narcotic given to the neonate, decreased neonatal weight loss, and decreased length of 
neonatal hospital stay. There is no direct benefit to mother-infant pairs randomized to placebo. 
However, physician interest in mothers and neonates with narcotic exposure may make this 
population of women feel better understood and better cared for by the medical community. 
This may improve the patient’s satisfaction with her care.  
Because of ondansetron’s safety record, the severe nature of NAS, and the significant animal 
and human pre-clinical data suggesting that ondansetron reduces or abolishes opioid 
withdrawal, we believe that the benefits of this trial far outweigh the risks. 
 


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8.0 Importance of the Knowledge to be Gained  
The long-term research goal is to develop safe treatments that decrease the extent and 
severity of Neonatal Abstinence Syndrome for infants born to mothers using narcotics during 
pregnancy. We believe there will be significant benefit from improvement in initial neonatal 
disability and decrease in the length of the hospital stay for infants affected by neonatal 
abstinence syndrome due to maternal narcotic use. We believe the benefits to be obtained 
outweigh the minimal risks of involvement in this study.  
Well-controlled research evaluating medications during pregnancy and the neonatal period is 
needed, so that patients can receive the best care possible from their providers. Providing 
pregnant women and their neonates with a safe and effective way to decrease withdrawal 
symptoms in the neonates will potentially benefit thousands of women and their children. In 
addition, if the duration of neonatal symptoms is limited, the reduction in neonatal hospital stay 
could save millions of dollars. 
The knowledge gained from this study may also impact treatment in the following ways:  
Established treatment practices may be altered in response to the information gained from this 
study.  
Experience from this study and developed infrastructure will allow for the evaluation of other 
medications within this research team to advance the treatment of drug-dependent pregnant 
women and their drug-exposed children. 
Increased information about the pharmacokinetic changes of ondansetron in pregnant women 
may be extrapolated to other medications with similar pathways of clearance used in pregnant 
women.  
From examination of maternal transfer of ondansetron to the neonate by measuring uterine 
cord blood and neonatal concentrations of drug, we will better understand the transfer of drug 
to the neonate form the mother. 
From examination of metabolite profiles of ondansetron in the neonate and comparison of 
umbilical venous and arterial concentrations, we anticipate being able to estimate the hepatic 
enzyme activity of the fetus and neonate. 
 
9.0 Data and Safety Monitoring Plan  
A Data Safety Monitoring Board (DSMB) will be established to ensure the safety and welfare of 
the subjects enrolled, to ensure the quality of the data, and to make intermittent 
recommendations whether to continue, modify or stop the trial. The members of the DSMB will 
be appointed by and report to Dr. David Drover. The Board members will be independent of 
the study group. Members will possess expertise in obstetrics, neonatology, addiction, 
biostatistics, and medical ethics. The Board will also include a public ombudsman, a member 
from outside of the investigators’ institution, and a non-voting secretary, who will keep a written 
record of every meeting. 
DSMB members will disclose in writing to the IRBs of all study institutions any potential 
conflicts of interest, actual or implied by appearance. At the start of each new member’s term, 
the individual will sign a confidentiality statement promising not to disclose any proprietary and 
nonproprietary data. 
An initial DSMB meeting to discuss the protocol and to establish specific guidelines for 
monitoring the study will occur before the trial is started. Once the trial commences, interim 
reports will be sent to the DSMB before each scheduled meeting. The content of the reports 
will be determined by the DSMB. During the course of the study, any changes to the trial 


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and/or reporting activities will be made as required by NIH and/or the DSMB.  
The DSMB will have discretion to un-blind any results or conduct any inquiry needed to ensure 
the safety and efficacy of the trial at the request of the DSMB chair. The secretary will maintain 
a written record of its meetings. Meetings will be scheduled every six months; expedited 
meetings will be scheduled to review any serious adverse events or adverse events judged by 
the investigators to be study-drug-related.  
The meetings will be divided into three sessions: open, closed, and executive. During the open 
session, Dr. David Drover will present relevant information about the trial including the 
following: 1) number of subjects enrolled, 2) problems with data accrual or follow up, 3) 
baseline demographic data, 4) compliance issues, 5) frequency of adverse events, 6) 
documentation of efficacy endpoints, 7) data quality issues, 8) flow of forms, and 9) data based 
protocol modification issues. Following the open session, a closed session will be held. During 
the closed session, the DSMB chair will conduct a review of all issues and put each issue to a 
vote. The discussion will focus on treatment safety, efficacy of data, and whether the primary 
study question has been answered in order to determine when the study data may be released 
or if an interim analysis is necessary. Following the closed session, an executive meeting may 
be held to discuss any unmasked analysis of the trial and any sensitive issues surrounding the 
trial. DSMB recommendations will be made in writing by the DSMB chair to Dr. Drover. 
The secretary will prepare meeting minutes for inclusion in the DSMB report. The report 
prepared by the DSMB will outline and summarize all discussions during the open and closed 
sessions of the meeting. The draft report will be reviewed by all Board members prior to 
issuance of the final report. DSMB recommendations will then be forwarded to the NIH 
program officer and to the IRB at each study site.  
We are most concerned with the risk of ondansetron exposure to the neonate, although we do 
not expect significant adverse events attributable to ondansetron compared to placebo (see 
description of known risk in section 5.0 Potential Risks). The Common Rule defines adverse 
events (AEs) as unanticipated problems. We will use this definition in our reporting and in 
addition include the potential risks defined in this application. Minor events would include 
hematoma at phlebotomy site, neonatal rash at electrocardiogram lead sites, or minor 
maternal side effects mentioned above in section 5.0 Potential Risks. We will use the FDA 
definition of serious adverse events (SAEs) in our reporting. Members of the study team at 
each site will report AEs and SAEs to Dr. David Drover and to their local IRB as required at 
each site. SAEs will be reported within 24 hours of each site's awareness of that event. Within 
ten working days after receiving a report, Dr. David Drover will report related AEs and SAEs to 
the following: Stanford's IRB as the Lead Site IRB, the Data Safety Monitoring Board (DSMB), 
and the NIH funding institute. He will then follow-up with a written report within 10 working 
days. The DSMB will determine appropriate action following review of any reported event, and 
this will be communicated to all study sites, the IRB and NIH funding institute.  
Each party (Stanford University as the lead site, and all sub-award sites mentioned in this 
application) will indemnify for its own negligent acts or omissions. Indemnification will be 
addressed in the contracts with the sub-award sites, but the specific language is not 
predetermined, and is therefore not available. The study medication will be subject to normal 
market warranties for proper manufacturing and labeling.  
Dr. Drover has applied for an Investigational New Drug (IND) application for ondansetron in 
neonates to prevent neonatal abstinence syndrome.  IND #112007.  The application was 
accepted by the FDA on May 23, 2014, when the Full Clinical Hold was removed for this 


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protocol. We are proposing a novel clinical investigation that will evaluate the efficacy of a drug 
for this novel indication. Although Dr. Drover has applied for this IND for a new indication of 
ondansetron, we are not using this data to obtain a new use indication or a label change for 
this drug from the FDA.  
 
10. Clinical Trials.gov Requirements 
This project includes an applicable clinical trial that required registration in ClinicalTrials.gov.  
The CT.gov number is:  NCT01965704.  This registration was accomplished prior to 
enrollment of any study participant. 
 
11. Inclusion of Women and Minorities  
All adult participants in the study will be female. Males will be excluded because the research 
question is only relevant to the female gender. Neonates may be either male or female, and 
we expect an essentially even neonatal gender distribution. No racial or ethnic groups will be 
excluded from participating in this study, and we expect participants to represent the ethnic mix 
of San Francisco, San Mateo, and Santa Clara counties.  
The Targeted/Planned Enrollment Table immediately following the Human Subjects Section 
gives a breakdown of anticipated participants by ethnicity, race, and gender.  
 


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12. Targeted/Planned Enrollment Tables 
Targeted/Planned Enrollment Table 1 
 
 
Total Planned Enrollment : 120 Neonates 
 
TARGETED/PLANNED ENROLLMENT: Number of Subjects 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
8 
8 
16 
Not Hispanic or Latino 
52 
52 
104 
Ethnic Category: Total of All Subjects * 
60 
60 
120 
Racial Categories 
 
American Indian/Alaska Native 
3 
3 
6 
Asian 
16 
16 
32 
Native Hawaiian or Other Pacific Islander  
4 
4 
8 
Black or African American  
3 
3 
6 
White 
34 
34 
68 
Racial Categories: Total of All Subjects * 
60 
60 
120 
* The “Ethnic Category: Total of All Subjects” must be equal to the “Racial Categories: Total of All 
Subjects.”
 
 
 


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Targeted/Planned Enrollment Table 2 
 
 
Total Planned Enrollment: Up to 120 maternal subjects 
 
TARGETED/PLANNED ENROLLMENT: Number of Subjects 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
16 
0 
16 
Not Hispanic or Latino 
104 
0 
104 
Ethnic Category: Total of All Subjects * 
120 
0 
120 
Racial Categories 
 
American Indian/Alaska Native 
6 
0 
6 
Asian 
32 
0 
32 
Native Hawaiian or Other Pacific Islander  
8 
0 
8 
Black or African American  
6 
0 
6 
White 
68 
0 
68 
Racial Categories: Total of All Subjects * 
120 
0 
120 
* The “Ethnic Category: Total of All Subjects” must be equal to the “Racial Categories: Total of All 
Subjects.”
 
 


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13. References 
 
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The epidemiology of unintentional drug poisoning in the United States 
[http://www.slidefinder.net/t/epidemiology_unintentional_drug/poisoning_united_states/1917516] 
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Department of Health and Human Services: Results from the 2006 National Survey 
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http://www.oas.samhsa.gov/NSDUH/2k6NSDUH/2k6results.cfm#5 
3. 
Vega WA, Kolody B, Hwang J, Noble A: Prevalence and magnitude of perinatal 
substance exposures in California. N Engl J Med 1993, 329(12):850-854. 
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Maas U, Kattner E, Weingart-Jesse B, Schafer A, Obladen M: Infrequent neonatal 
opiate withdrawal following maternal methadone detoxification during pregnancy. J 
Perinat Med 1990, 18(2):111-118. 
5. 
Neonatal Drug Withdrawal. Pediatrics 1998, 101(6):1079-1086. 
6. 
Seligman NS, Salva N, Hayes EJ, Dysart KC, Pequignot EC, Baxter JK: Predicting 
length of treatment for neonatal abstinence syndrome in methadone-exposed neonates. 
Am J Obstet Gynecol 2008, 199(4):396 e391-397. 
7. 
Kraft WK, Dysart K, Greenspan JS, Gibson E, Kaltenbach K, Ehrlich ME: Revised dose 
schema of sublingual buprenorphine in the treatment of the neonatal opioid abstinence 
syndrome. Addiction 2010. 
8. 
Jones HE, Johnson RE, Jasinski DR, O'Grady KE, Chisholm CA, Choo RE, Crocetti M, 
Dudas R, Harrow C, Huestis MA et al: Buprenorphine versus methadone in the treatment 
of pregnant opioid-dependent patients: effects on the neonatal abstinence syndrome. 
Drug Alcohol Depend 2005, 79(1):1-10. 
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Liang DY, Liao G, Lighthall G, Peltz G, Clark JD: Genetic Variants of the P-
Glycoprotein Gene  Abcb1b  Modulate Opioid-Induced Hyperalgesia, Tolerance and 
Dependence. Pharmacogenetics and Genomics 2006, 16:825-835. 
10. 
Liang D, Liao G, Wang J, Usuka J, Guo YY, Peltz G, Clark JD: A Genetic Analysis of 
Opioid-Induced Hyperalgesia in Mice  Anesthesiology 2006, 104:1054-1062. 
11. 
Chu LF, Liang D-Y, Li X, Sahbaie P, D'Arcy N, Liao G, Peltz G, Clark JD: From Mouse 
to Man: The 5-HT3 Receptor Modulates Physical Dependence on Opioid Narcotics. 
Pharmacogenetics and Genomics 2009, 19:193-205. 
12. 
Liao G, Wang J, Guo J, Allard J, Cheng J, Ng A, Shafer S, Puech A, McPherson JD, 
Foernzler D et al: In Silico Genetics: Identification of a Functional Element Regulating 
H2-Ea Gene Expression. Science 2004, 306(5696):690-695. 
13. 
Wang J, Liao G, Usuka J, Peltz G: Computational Genetics: From Mouse to Man? 
Trends in Genetics 2005, 21(9):526-532. 
14. 
Smith SB, Marker CL, Perry C, Liao G, Sotocinal SG, Austin JS, Melmed K, David Clark 
J, Peltz G, Wickman K et al: Quantitative trait locus and computational mapping identifies 
Kcnj9 (GIRK3) as a candidate gene affecting analgesia from multiple drug classes. 
Pharmacogenetics and Genomics 2008, 18(3):231-241. 
15. 
Handelsman L, Cochrane KJ, Aronson MJ, Ness R, Rubinstein KJ, Kanof PD: Two new 
rating scales for opiate withdrawal. Am J Drug Alcohol Abuse 1987, 13(3):293-308. 
16. 
Einarson A, Maltepe C, Navioz Y, Kennedy D, Tan MP, Koren G: The safety of 
ondansetron for nausea and vomiting of pregnancy: a prospective comparative study. 
BJOG 2004, 111(9):940-943. 


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17. 
Asker C, Norstedt Wikner B, Kallen B: Use of antiemetic drugs during pregnancy in 
Sweden. Eur J Clin Pharmacol 2005, 61(12):899-906. 
18. 
Sheehan P: Hyperemesis gravidarum--assessment and management. Aust Fam 
Physician 2007, 36(9):698-701. 
19. 
Holdsworth MT, Raisch DW, Frost J: Acute and delayed nausea and emesis control 
in pediatric oncology patients. Cancer 2006, 106(4):931-940. 
20. 
Cohen IT: An overview of the clinical use of ondansetron in preschool age 
children. Ther Clin Risk Manag 2007, 3(2):333-339. 
21. 
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Appendix  
 Pharmacy Instructions for NICHD Protocol  
Aim 2: Prevention of Neonatal Abstinence Syndrome (NAS2) 
 
Double-blind study therefore only the pharmacist will know which study medication 
(ondansetron or placebo) the pregnant woman will receive; the neonate is assigned the same 
study medication their mother received.  (Only one randomization number for the 
maternal/neonate pair). 
 
Pregnant women randomized to IV ondansetron: 
• The IV dose of ondansetron will always be 8mg per dose (ondansetron concentration is 
2mg/mL, thus 4 mL = 8mg) 
• The woman’s dose may be repeated one time if she does not deliver her baby within 
4 hours of the first dose of ondansetron. 
Pregnant women randomized to IV placebo:   
• IV placebo is prepared to "mimic the volume" of the 8mg dose of ondansetron. 
• Prepare IV placebo with normal saline 4 mL (0.9% Sodium Chloride injection). 
• The pregnant woman’s dose may be repeated one time if she does not deliver her 
baby within 4 hours of the first dose of placebo. 
 
Neonates assigned to ondansetron: 
• Dose is based on birth weight. 
• Oral dose is 0.07 mg/kg every 24 hours starting the day of birth, between 4-8 hours of 
life, and continuing for a maximum of 5 doses of study medication. 
• Concentration of oral ondansetron 0.8 mg/mL 
• IV dose is 0.04 mg/kg every 24 hours starting the day of birth, between 4-8 hours of 
life, and continuing for a maximum of 5 doses of study medication. 
• The route of dosing may start with oral or IV doses or may be switched from oral to IV 
dosing at any time if the NICU/Research teams believe it is best for the baby.  
•  Concentration of IV ondansetron is 2mg/mL 
 
Neonates assigned to placebo:  
• Dose is based on the birth weight.  
• Simple Syrup will be used for oral placebo doses. (Manufacturer: Humco.  NDC # 
0395-2661-16;  16 oz bottle) 
• Oral placebo must "mimic the volume" of a dose of ondansetron, as if the baby had 
been assigned to oral ondansetron 0.07 mg/kg. 
• Normal saline (0.9% Sodium Chloride injection) will be used for IV placebo doses. 
• IV Placebo must "mimic the volume" of a dose of ondansetron, as if the baby had been 
assigned to IV ondansetron 0.04 mg/kg per dose. 

SAP_003.pdf: 
AIM 2- Prevention of Neonatal Abstinence Syndrome 
Statistical Analysis Plan 
NCT01965704 
March 30, 2022 
 
Only infants who received at least one dose of study medication and met the inclusion criteria 
were included in the efficacy analysis. All infants and mothers who were allocated and received 
at least one dose of study medication were included in the safety analysis. Power analysis effect 
size was based upon NPOW response data that was obtained from the healthy opioid-naïve adult 
volunteers under controlled conditions. In that study, there was a difference of 2.38 between the 
means of the control and ondansetron-treated withdrawal responses, with standard deviations of 
2.23 and 0.89, respectively. Based upon these numbers, 13 patients per treatment arm would 
have 90% power to ensure that a treatment difference (ondansetron vs. control) could be detected 
at the p=0.05 level. However, because of the very large of differences between opioid-naive 
adults analyzed under experimentally controlled conditions and infants that are exposed in utero 
to opioids, the actual relative effect size of ondansetron treatment was assumed to be 25-33% of 
that estimated from the pilot data in normal subjects. This revised effect size estimate provided 
45 infants in each arm to provide the same statistical power. For the categorical outcomes in the 
primary and secondary endpoints (the fraction of infants requiring pharmacologic therapy with 
morphine and the need for adjunctive phenobarbital or clonidine therapy), Fisher’s Exact test 
was used to perform the analysis of independence. Because the need for morphine was not 
impacted by the sex of the neonates or by the race/ethnicity of the mother, these stratification 
factors were not corrected for in the analysis of primary outcome. 
 
The null hypothesis for the Fisher’s Exact test was that the need for morphine treatment and 
study drug allocation were independent. The continuous outcomes of secondary endpoints were 
examined using the two-sided Wilcoxon Rank-Sum test (equivalent to the Mann-Whitney test), 
where the null hypothesis is stated as the outcomes in the ondansetron and placebo arms are 
equal. Inclusion of neonates in the safety population was based upon receipt of ondansetron in 
any form (study drug administered to infant or exposure through maternal transfer). QTc values 
in the safety population were analyzed by two sample t-test to determine if the mean QTc of two 
groups were equal. All tests were two-sided, and the p-values obtained from statistical tests were 
compared with the significance level (α=0.05) to determine whether null hypothesis could be 
rejected or retained. Statistical analyses were performed using R software (version 3.6.1).