AIM 2- Prevention of Neonatal Abstinence Syndrome
Phase: PHASE2
Conditions: Narcotic Addiction, Neonatal Abstinence Syndrome
Sponsor: Stanford University

 
 
 
 
AIM 2- Prevention of Neonatal Abstinence Syndrome 
Study Protocol 
NCT01965704 
March 2, 2019 
 

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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 

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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. 

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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: 

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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 

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(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. 

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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).  

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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 

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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 

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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 

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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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15
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 

Version: 02MAR2019 
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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.”
 
 
 

Version: 02MAR2019 
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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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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.