Conditions: Cholestasis of Parenteral Nutrition
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 24
Healthy volunteers: no

Brief summary:
Intestinal failure associated liver disease is a cholestatic liver disease associated with prolonged need for parenteral nutrition that can lead to such significant complications as liver failure. In the neonatal population, infants with history of intestinal resection and short bowel syndrome are at increased risk for this disease. The investigators plan to compare two possible lipid dosing preventative strategies including a composite, fish oil lipid and soy-based lipid reduction.

Detailed description:
Intestinal failure associated liver disease (IFALD) is a cholestatic liver disease associated with prolonged need for parenteral nutrition. This disease can lead to such serious complications as liver failure and need for transplantation. In the neonatal population, short bowel syndrome, due to intestinal resection, is the most common cause of intestinal failure. While the exact cause is yet to be determined, it is felt the lipid component of parenteral nutrition is a large contributor to the development of this disease. Currently, there is no standard preventative strategy to attempt to decrease the risk of IFALD in the high risk, post-surgical neonatal population. The investigators aim to complete a randomized trial comparing two possible preventative strategies. One group will receive a composite lipid containing fish oil (Smoflipid) and the other group will receive soy-based lipid at reduced dosing.

Arms:
arm 1: Patients randomized to this arm will receive the composite fish oil lipid, Smoflipid, at standard dosing up to 3 g/kg/day. Patients will be started on a dose of 1 g/kg/day and titrated up to maximum dose. As enteral nutrition is advanced the lipid dose will be weaned per study protocol and dietary recommendations. arm 2: Patients randomized to this arm will receive soy-based lipid (Intralipid) at a dose of 1 g/kg/day throughout their enrollment in the study. arm 3: Patients who retrospectively received soy-based lipid (Intralipid) at standard dosing of 2-3 g/kg/day were eligible for inclusion. Patients in this group were matched to prospective patients based on diagnosis, gestational age, and length of lipid therapy.

Interventions: intervention 1: Smoflipid 20% Lipid Emulsion for Injection intervention 2: Intralipid, 20% Intravenous Emulsion intervention 3: Intralipid, 20% Intravenous Emulsion
Intervention descriptions: intervention 1: Intravenous lipid containing soy, MCT, olive, and fish oils at goal doses of 3 g/kg/day intervention 2: Intravenous lipid emulsion of 20% soy oil at goal doses of 1 g/kg/day intervention 3: Intravenous lipid emulsion of 20% soy oil at goal doses of 2-3 g/kg/day

Protocol document:
Prot_SAP_002.pdf: 
1 
 
Comparison of composite lipid emulsion containing 
fish oil to soy-based lipid reduction for cholestasis 
prevention in neonates requiring abdominal surgery 
 
 
 
NCT03387579 
 
PI: Charles Vanderpool, MD 
 
Date of Last Modification: January 20, 2022 
 
IRB Approved: January 20, 2022 
 
 
 
 
 
 


2 
 
Comparison of composite lipid emulsion containing fish oil to soy-based lipid reduction for 
cholestasis prevention in neonates requiring abdominal surgery 
 
IND Number: 136696 
 
Version 7 
December 27, 2021 
 
Background  
Intestinal failure associated liver disease (IFALD) (also called Parenteral Nutrition 
associated liver disease) is a form of cholestatic liver disease in patients receiving prolonged 
parenteral nutrition [1]. IFALD is estimated to occur in 40-60% of children and up to 85% of 
neonates receiving prolonged parenteral nutrition [2]. The clinical spectrum of IFALD includes 
hepatic steatosis, cholestasis, fibrosis, and can progress to hepatic cirrhosis, portal hypertension, 
and end stage liver disease [2]. The most common cause of intestinal failure and need for 
prolonged parenteral nutrition in the neonate is short bowel syndrome [3]. There are varying 
definitions of short bowel syndrome, but a recent panel of experts defined it as, “surgical 
resection, congenital defect, or disease associated loss of absorption characterized by the 
inability to maintain protein-energy, fluid, electrolyte, or micronutrient balances when on a 
conventionally accepted normal diet [4].” Common causes of neonatal short bowel syndrome 
include necrotizing enterocolitis, gastroschisis, atresia, and volvulus [3, 5]. Because of the wide 
range of clinical symptoms and causes, many research protocols use laboratory signs of 
cholestasis with increased direct or conjugated bilirubin as a marker for development of IFALD. 
Due to the potential complications associated with the development of IFALD, research looking 
into the prevention of this disease is important.  
 
 
There have been many studies looking at the causes of IFALD in pediatric patients. 
While the ultimate cause is likely multifactorial, one of the largest culprits contributing to 
IFALD is the lipid component of parenteral nutrition [6]. Current practice in most of the United 
States includes use of a soybean oil based product (Intralipid®) for supplementation of neonates. 
It is believed this soy-based product contributes to IFALD due to its high phytosterol content, 
high amount of omega-6 polyunsaturated fatty acids (PUFA) compared to omega-3-PUFA, and 
low amount of antioxidants [1]. Two current strategies to combat this problem include use of 
alternative lipids and lowered dosing of soy-based lipid. One alternative composite lipid, 
Smoflipid®, a mixture of soybean, MCT, olive, and fish oils is promising as it provides 
necessary essential fatty acids while also providing an increased amount of omega-3-PUFA, and 
decreased phytosterols. Studies have shown a reduced risk of IFALD progression in neonates 
transitioned from a soy-based lipid to Smoflipid, with decreased bilirubin (direct, conjugated, or 
total). These studies have also shown a shift in fatty acid profile toward anti-inflammatory fatty 
acids such as DHA and EPA in patients receiving Smoflipid [7-11]. With Smoflipid having a 
potential role in reducing the risk of IFALD progression, it could be inferred that these patients 
may then have a reduced risk of IFALD development with treatment from parenteral nutrition 
initiation. However, studies on long-term Smoflipid and risk of IFALD development in at-risk 
patient populations are lacking. 
 


3 
 
The role of soy-based lipid reduction as a preventative strategy for IFALD has also been 
investigated at dosing of ≤ 1g/kg/d compared to standard dosing of 2-3 g/kg/d. These studies 
have shown mixed reviews, with some showing a decrease in bilirubin (direct, conjugated, or 
total) and risk of IFALD development, while others have shown no difference in cholestasis 
development with lipid reduction [12-14]. Even studies showing no difference in cholestasis 
development, have shown other differences when soy-based lipids are reduced, including a 
smaller degree of change in direct bilirubin in the soy-based lipid reduction group [15].  
 
Lipid intake in the neonatal period is crucial for retinal and brain development along and 
an important source of calories for growth [16]. Due to this essential nature of lipid intake during 
the neonatal period, concern has been raised regarding lipid restriction and its effects on neonatal 
growth and neurodevelopmental outcomes. Studies investigating neurodevelopmental outcomes 
of infants treated with lipid restriction have shown development within normal ranges for the 
patient’s age and similar to those of patients treated with standard soy-based lipid dosing [17, 
18]. Studies have shown mixed results with regards to growth and neonates treated with lipid 
restriction. Rollins et al showed a greater increase in weight z-score for patients on standard soy-
based dosing compared to reduced dosing, but found no difference in length or head 
circumference [13]. Other studies have found similar growth when comparing patients both in 
the neonatal period and into early childhood [18, 19]. The role of the various lipid strategies in 
the prevention of IFALD is still unclear at this time. Further studies are needed to better 
understand this disease, its prevention, and its outcomes. During this study we hope to compare 
two possible preventative strategies and determine a future direction for studying Smoflipid and 
soy-based lipid reduction. 
 
 
Specific Aim 
 
This study is designed to be a single center, pilot study to evaluate the prevention of cholestasis 
in neonates requiring abdominal surgery with intestinal failure, divided into two treatment 
groups, one receiving composite lipid emulsion (Smoflipid® 20%) at standard dosing and the 
other receiving soy-based lipid (Intralipid® 20%) at reduced dosing. The rate of cholestasis 
development in the two treatment groups will be compared to a historical control cohort which 
received soy-based lipid (Intralipid® 20%) at standard dosing of 2 to 3 g/kg/d.  
 
 
Study Objectives 
1. Primary: The primary objective of this study is to determine the number of infants receiving 
Smoflipid at typical dosing (2-3 g/kg/d) and the number of infants receiving Intralipid 
reduction (1g/kg/day) that develop cholestasis compared to historical controls receiving 
Intralipid at standard dosing (2-3g/kg/day). Cholestasis will be defined as direct bilirubin 
greater than 2mg/dL for at least two measurements, 5-7 days apart.  
 
2. Secondary (comparison of each listed parameter between the prospective treatment groups in 
addition to comparison of each treatment group with historic controls): 
a. Growth (rate of change) 


4 
 
i. Weight, length, and head circumference at enrollment, on a weekly basis 
while receiving study lipid, and 2-3 weeks post-study lipid completion. 
ii. Weight, length, and head circumference at 36 weeks corrected gestational 
age and time of discharge.  
b. Essential fatty acid profile differences and development of deficiency 
c. Average total caloric intake for all patients on weekly basis 
i. Average lipid dose delivered on weekly basis 
d. Feeding tolerance/ percentage of total calories from enteral feeds 
i. Time to achievement of enteral autonomy (full enteral feedings) 
ii. Percentage of enteral calories at end of study 
iii. Percentage of patients in each group with enteral autonomy 
e. Transaminase, alkaline phosphatase, GGT levels at enrollment, every 4 week time 
point, and end of study 
f. Triglyceride concentration at baseline, weekly, and end of study 
g. Rates of other diagnoses in each study group 
i. Retinopathy of prematurity as diagnosed by Ophthalmologic examination 
ii. Chronic lung disease as defined by need for oxygen at time of discharge or 
36 weeks corrected gestational age (if at least 28 days of age), whichever 
comes first.  
h. Rates of adverse and serious adverse events in each group 
i. Length of stay 
j. Two year neurodevelopmental differences using ASQ-3 screening 
 
Study Population 
 
Inclusion criteria  
 
Infants admitted to the Riley Hospital Neonatal Intensive Care Unit (NICU), regardless of 
postmenstrual or corrected gestational age, with anticipated need for parenteral nutrition for four 
or more weeks PLUS one or more of the additional inclusion criteria listed below will be eligible 
for inclusion within the study and for randomization. Inclusion criteria include: 
• Anatomic intestinal defect: Neonate with intestinal atresia, omphalocele, gastroschisis or 
volvulus with or without intestinal resection and need for parenteral nutrition pre or post-
operatively.  
• Ischemic/perforation intestinal injury: Neonates with spontaneous intestinal perforation 
or necrotizing enterocolitis requiring surgical intervention with need for parenteral 
nutrition post-operatively.  
 
Exclusion criteria at time of study enrollment 
• Infant with current weight less than 750 grams 
• AST or ALT greater than 5 times the upper limit of normal within 2 weeks of enrollment 


5 
 
• Direct bilirubin  greater than 2 mg/dL on any consecutive measurement 5-7 days apart 
within 2 weeks of enrollment 
• Severe coagulopathy with elevated INR greater than 2.0 or clinically significant bleeding 
as determined by the primary and research teams 
• Culture confirmed sepsis with positive blood, urine, or CSF culture within 2 weeks (14 
days) of enrollment 
• Renal failure requiring dialysis 
• Cyanotic heart disease requiring prostaglandin therapy 
• Hypertriglyceridemia (greater than 250mg/dL) at time of enrollment 
 
Enrollment/Randomization 
 
A maximum total of 50 prospective patients, 25 per arm, will be enrolled in the study. Patients 
will be eligible for enrollment if they meet the above listed enrollment criteria. Once patients are 
determined to meet enrollment criteria, the parents of the patient will be approached and 
informed consent will be obtained. Please see separate informed consent document for full 
consent details.  
 
Stratified randomization will be used to divide patients into each treatment group. Patients will 
be initially stratified based on the diagnosis of necrotizing enterocolitis or spontaneous intestinal 
perforation (ischemic/perforation group) or anatomic intestinal abnormality. Once stratified 
based on diagnosis, patients in each stratum will then be randomized to receive either Smoflipid 
or Intralipid reduction as described below. Group randomization will be based on premade 
concealed envelopes.  
 
This study will not be blinded as the caloric dose of the lipid strategies will vary and potentially 
influence other TPN dosing. Both IV lipids will be given as a solution separate from the 
remaining TPN. This separate IV lipid will be given as two 12 hour infusions over a 24 hour 
period.  
 
In the event of slower than anticipated patient enrollment, a minimum of 24 patients (12 per 
treatment group) will be enrolled in order to obtain needed feasibility data. 
 
 
Historic Controls 
 
A group of 24 patients previously treated in the Riley NICU from the years 2016 – 2017 will be 
used as a historic control cohort. Historic patients will be eligible for enrollment in the study if 
they have one of the above listed diagnoses, received post-operative parenteral nutrition, and 
were treated with soy-based lipid at standard dosing (2-3 g/kg/day). Historic patients will be 
ineligible to participate if any of the above listed exclusion criteria are true at the time of their 
abdominal surgery. Historic patients will be matched to prospective patients when able. This 
matching will first utilize in order: 1. days of parenteral lipid therapy, 2. diagnosis, 3. birth 
gestational age, and 4. birth weight when selecting for inclusion. 
 


6 
 
 
Study Procedures 
1. Smoflipid® (20% lipid emulsion) treatment group 
a. Advancement:  
i. Smoflipid will be started at 1 g/kg/d on day 1 of parenteral nutrition after 
enrollment and advanced by 1 g/kg/d each subsequent day to a goal 
maximum of 3 g/kg/d 
b. Maintenance and weaning [8]:  
i. The Table below will be used as a guide for weaning Smoflipid as enteral 
nutrition is initiated and advanced.  
ii. Patients will continue to be monitored by a clinical dietician and 
pharmacist as per standard of care. Pending their recommendations, along 
with the clinical state of the child, the actual dose of Smoflipid needed 
may vary by individual patient. 
c.  Other parenteral nutrition components 
i. Amino acid will be provided to meet estimated protein requirements only 
and will not be increased as a form of caloric intake.  
1. Term infant approximate goal of 3 g/kg/day and preterm infant 
approximate goal of 3.5 – 4 g/kg/day.  
ii. Glucose infusion will be utilized and advanced per standard protocol to 
provide remainder of estimated non-protein caloric need of each 
individual patient.  
1. Maximum glucose infusion rate (GIR) while enrolled in study of 
16 mg/kg/min. If further caloric intake is required, Smoflipid will 
be increased to a maximum of 3 g/kg/d. 
 
Table 1: Smoflipid dosage recommendations for weaning as enteral feeds advanced 
% calories 
from PN 
Volume 
enteral 
feeds 
(ml/kg/d) 
Enteral 
calories 
(kcal/kg/d) 
Lipid 
(g/kg/d) 
80-100% 
≤20-40 
≤30 
3 
60-80% 
40-60 
30-40 
3 
50-60% 
60-80 
40-50 
2.5 
40-50% 
80-100 
50-60 
2 
30-40% 
100-110 
60-70 
1.5 
20-30% 
120 
70-90 
1 
<20% 
>120 
>90 
0 
 
2. Intralipid® (20% lipid emulsion) reduction treatment group 
a. Advancement: 
i. Intralipid:  
1. Intralipid will be started on day 1 of parenteral nutrition at 1g/kg/d 


7 
 
2. Intralipid dose will be maintained at 1g/kg/d while enrolled in the 
study and receiving parenteral nutrition, unless other clinical 
concerns arise as documented by primary team.  
a. If further caloric intake is required, Intralipid may be 
increased at the discretion of the treating faculty based on 
the needs of the individual patient. 
ii. Other parenteral nutrition components: 
1. Amino acid will be provided to meet estimated protein 
requirements only and will not be increased as a form of caloric 
intake.  
a. Term infant approximate goal of 3 g/kg/day and preterm 
infant approximate goal of 3.5 – 4 g/kg/day.  
2. Glucose infusion will be utilized and advanced per standard 
protocol to provide remainder of estimated non-protein caloric 
need of each individual patient.   
a. Maximum glucose infusion rate (GIR) while enrolled in 
study of 16 mg/kg/min. If further caloric intake is required, 
Intralipid will be increased at the discretion of the treating 
faculty based on needs of the individual patient.  
 
3. All Study Patients:  
a. Enteral feedings:  
i. Enteral breast milk or formula choice will be at the discretion of the 
primary faculty physician and advanced per physician practice.  
 
b. Anthropometric Measurements: 
i. Each group will have growth monitored per standard protocol with daily 
weights and weekly head circumference (OFC) and length. 
ii. Weekly measurements used for research purposes will include weekly 
weight, length, and OFC as documented directly by the research team 
(primary investigators or same registered dietician).  
iii. Corrected measurements will also be documented with weight, length, and 
OFC documented at 36 weeks (+/- 3 days) corrected gestational age.  
iv. Follow-up measurements at 2 – 3 weeks after stopping study lipid or time 
of discharge, whichever comes first. 
v. At each time point, anthropometric measurements will be replicated in 
triplicate and the average value for that measurement will be reported 
within the study.  
vi. In the event of safety concerns to the patient or research team, as raised by 
the research team, patient care team, or regulatory entities, the study 
measurements will be conducted by the bedside patient nurse. These 
measurements will include length board use.  
 


8 
 
c. Diagnoses associated with Prematurity:  
i. Each patient’s chart will be reviewed for documentation of retinopathy of 
prematurity or bronchopulmonary dysplasia (chronic lung disease). The 
absence or presence of these diseases at the time of discharge will be 
noted for each study patient, particularly those patients born prematurely 
at less than 37 weeks gestation.  
 
d. Length of Stay:  
i. An ICU length of stay will be calculated for each patient based on their 
admit date and discharge date from the Riley NICU.  
ii. For patients transferred to another unit prior to discharge the transfer date 
will also be documented. For these patients a NICU length of stay and 
total hospital length of stay will be calculated. 
 
e. Laboratory monitoring (see Table 2 below for reference schedule): 
i. Effort will be made to draw all study lab tests along with other standard of 
care, routinely scheduled labs.  
ii. The schedule outlined here is a schedule of minimum laboratory work to 
be obtained. These studies may be obtained more often by the patient’s 
primary clinical team. Any lab test obtained by the primary team within 3 
days for weekly labs or within one week for less frequent labs will be used 
in place of the research lab test.  
iii. Of note all lab tests listed could be considered standard of care, with the 
exception of INR.  
iv. Essential fatty acid profiles will be obtained every 4 weeks (28 days) 
while receiving study lipid regimen. 
1. Blood volume needed 0.3-1mL 
2. Considered standard of care in any patient on alternative lipid 
dosing, such as patients enrolled in this study.  
3. If diagnosed with essential fatty acid disorder, defined as 
triene:tetraene ratio >0.05: 
a. If Smoflipid dose is less than 3 g/kg/d, SMOF will be 
increased by 0.5 g/kg/d or to 3 g/kg/d maximum 
b. Those receiving Smoflipid at 3 g/kg/d will be changed to 
Intralipid at current Smoflipid dose 
c. Those receiving Intralipid will have their dose increased by 
0.5 g/kg/d to maximum of 3 g/kg/d 
v. Total and fractioned bilirubin levels will be monitored at least once 
weekly (7 days) 
vi. Liver function panel and gamma-glutamyl transferase (GGT) will be 
monitored at least every 2 weeks (14 days).  
vii. Triglyceride levels will be monitored within the first 48 hours of lipid 
initiation and then once weekly (7 days).  


9 
 
1. If triglyceride level >250 mg/dL will decrease dose of study lipid 
by 1g/kg/d to minimum of 2 g/kg/d of Smoflipid or 1 g/kg/d three 
days per week for Intralipid 
2. Lipid infusion will be held if triglyceride level > 400 mg/dL  
a. Once triglyceride level <400 mg/dL lipid infusion can be 
restarted. A lower dose can be used if deemed necessary by 
the primary care team and dietician. 
viii. Bleeding studies 
1. Platelets will be monitored once weekly until stable (minimum 2 
consistent values, 5-7 days apart) and then once every 4 weeks.  
2. INR will be measured once weekly until stable (at least 2 
consistent values, 5-7 days apart) and then once every 4 weeks.  
a. Blood volume 1.7 mL  
b. Because this lab is not standard of care, the cost will be 
covered by research funds, not by the individual patient.  
ix. Glucose will be monitored at initiation of parenteral nutrition until stable 
and then with significant changes in glucose infusion rate. This can be 
performed via basic metabolic profile (BMP), point of care (POC) 
glucose, or any other lab source that provides a blood glucose 
measurement.  
1. If the blood glucose is >200 mg/dL on more than one measurement 
separated by at least 3 hours, the primary team will consider 
decreasing the patient’s GIR.  
2. If blood glucose is <50 mg/dL the primary team will consider 
increasing the GIR.  
x. Blood volume:  
1. Minimum blood volume per each phlebotomy event are listed in 
Table 2.  
2. Total minimum blood volume 24.4 mL per patient over the 14 
blood draws during the study.  
xi. Post-study monitoring:  
1. As indicated in Table 2, triglyceride, hepatic function panel, GGT, 
essential fatty acid panel, platelet count, and INR will be measured 
2-3 weeks post-study completion or at time of discharge, 
whichever comes first.  
a. This time frame will be for all patients enrolled in the 
study, regardless of their length of time within the study.  
b. If the patient is to be discharged from the hospital prior to 
this 2-3 week time period, labs will be drawn within 3 days 
of discharge, prior to leaving the hospital. 
Table 2: Minimum laboratory requirements while enrolled in study (TG= triglyceride, HFP 
= Hepatic Function Panel, FB = fractionated bilirubin, GGT= gamma glutamyl transferase, EFA = essential 
fatty acids, PLT= platelet count) (Blood volume is minimum required to perform all tests listed) 


10 
 
 
Week 
Test 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
+2-3 
TG 
TG 
TG 
TG 
TG 
TG 
TG 
TG 
TG 
TG 
TG 
TG 
TG 
TG 
HFP 
FB 
HFP 
FB 
HFP 
FB 
HFP 
FB 
HFP FB 
HFP 
FB 
HFP 
HFP 
GGT 
 
GGT 
 
GGT 
 
GGT 
 
GGT 
 
GGT 
 
GGT GGT 
 
 
 
 
EFA 
 
 
 
EFA 
 
 
 
EFA 
EFA 
PLT PLT 
 
 
PLT 
 
 
 
PLT 
 
 
 
PLT 
PLT 
INR 
INR 
 
INR 
 
 
 
INR 
 
 
 
INR 
 
INR 
Blood 
Volume 
(mL) 
3.1 
2.8 
0.8 
2.2 
1.7 
0.5 
0.8 
2.2 
1.7 
0.5 
0.8 
2.2 
1.7 
3.4 
 
f. Neurologic Follow-up:  
i. ASQ-3 at 2 years of age:  
1. All prospective patients will have an ASQ-3 obtained during the 
2nd year of life (age 2 year 0 day to 2 year 364 days). 
2. ASQ-3 will be obtained in one of three manners: 
a. In person: if patient has previously scheduled appointment 
at Riley 
b. Via phone: if able to confirm identity of parent or guardian 
c. Via mail (electronic or standard): if able to confirm proper 
mailing address of patient and parent/guardian 
3. ASQ-3 will be completed by the subject’s parent or guardian with 
the aid of one of the primary investigators.  
4. If the subject receives a score within the “monitoring zone” or 
below threshold of “normal” in any developmental area:  
a. Parent/guardian will be notified of this score 
b. If known developmental delays exist will document if 
patient is receiving services for delay.  
c. If no previously known developmental delay will refer 
patient to their primary care physician for further 
developmental screening and referral for proper services 
and follow-up.  
 
g. Stopping study Lipid:  
i. Once a study subject reaches one of the following parameters they will 
stop receiving study lipid, whichever parameter occurs first: 
1. Maximum time of 12 weeks (84 days).  
2. Cholestasis with direct bilirubin of ≥3 mg/dL on two consecutive 
lab draws at least 5-7 days apart. 
3. Lipid or parenteral nutrition discontinuation for more than one 
week (7 days). 
4. Subject is discharged home or transferred from Riley Hospital for 
Children.  


11 
 
ii. Once a subject reaches one of these time points, their lipid treatment, 
including lipid choice and dose, will be at the discretion of their primary 
treating physician.  
iii. Subjects will continue to be followed by the research team in order to have 
the following information documented: 
1. Anthropometric measurements at 36 weeks corrected gestational 
age.  
2. Follow-up anthropometric measurements at 2 – 3 weeks after 
stopping study lipid or at the time of discharge.  
3. Follow-up laboratory testing at 2 – 3 weeks after stopping study 
lipid if still admitted to Riley Hospital for Children.  
4. Documentation of prematurity complications.  
5. Discharge and/or transfer date to determine length of stay.  
6. ASQ-3 screen during the second year of life. 
iv. Subjects leaving the study secondary to parental request may not have 
further follow-up performed if at the request of the parent.  
 
 
Historic Controls 
 
Historic controls will have their charts reviewed to document the same information as for 
prospective patients. For historic controls, this information will be limited to their time admitted 
to Riley Hospital only. Information recorded will include:  
1. Diagnosis and procedures:  
a. Documentation of diagnosis making eligible for study participation 
b. Documentation of surgery performed 
2. Parenteral nutrition:  
a. Length of parenteral nutrition: Documentation of total days of parenteral nutrition 
including start date, stop date, and dates not receiving parenteral nutrition.  
b. Lipid dosing: maximum lipid dose, average lipid dose on weekly basis 
c. Glucose dosing: documentation of glucose infusion rate (GIR) including 
maximum dose and weekly average GIR dose 
d. Protein dosing: documentation of maximum amino acid dose received and weekly 
average amino acid dose 
e. Discontinuation of parenteral nutrition: including reason for discontinuing and for 
what length of time.  
3. Enteral Feeding:  
a. Autonomy: the time from start of enteral feeding until complete enteral autonomy 
(enteral feeding only) will be documented for each patient.  
b. Weekly enteral feeding: On a weekly basis an average of enteral feeding intake 
will be determined both in volume and calories. Based on these calculations a 
percentage of overall intake related to parenteral nutrition will be determined.  


12 
 
c. Milk intake: The particular milk prescribed to each patient will be documented 
along with the particular form of additives and fortification used.  
4. Measurements:  
a. Weight, length, and head circumference will be recorded on a weekly basis for 
each patient.  
b. Corrected measurements will also be obtained for each patient at 36 weeks 
corrected gestational age and the time of discharge from the Riley NICU. Given 
these are historic patients, the values obtains closest to these dates will be used for 
the purposes of this study.  
5. Laboratory values:  
a. Laboratory values listed above for prospective patients will be documented for 
historic patients if available within the electronic medical record.  
b. If cholestasis is diagnosed the interventions and treatments received by the 
patients will be documented.  
6. Diagnoses of prematurity 
a. Patients born less than 37 weeks will also have their chart reviewed for 
documentation of retinopathy of prematurity and bronchopulmonary dysplasia or 
chronic lung disease. Presence or absence of these diagnoses will be documented.  
7. Length of stay:  
a. The admit date and discharge date from the Riley NICU will be documented and a 
length of calculated for each patient.  
b. For patients transferred from the Riley NICU to the floor the transfer date and 
discharge date from the hospital will also be documented and a NICU length of 
stay and overall hospital length of stay will be documented.  
8. Neurologic Follow-up:  
a. Any patient that has an ASQ-3 performed during year 2 of life will have this 
information documented. 
i. This is not required to be included in the study and will only be 
documented if information is available.  
 
Study Duration 
 
Patients will continue to receive study lipid until one of the following points, whichever should 
come first: 
1. The maximum time for receiving study lipid per the study team will be 12 weeks (84 days).  
2. Cholestasis with direct bilirubin of ≥3 mg/dL on two consecutive lab draws at least 5-7 days 
apart. 
3. Lipid or parenteral nutrition discontinuation for more than one week (7 days). 
4. Discharge home or transfer to another facility outside of Riley Hospital for Children. 
Once one of these parameters are met, as noted previously, the lipid dosing would be at the 
discretion of the patient’s primary physician. The patient will remain in the study to have follow-
up laboratory, growth, and neurodevelopmental information collected.  
 


13 
 
 
Adverse Events and Serious Adverse Events 
 
All patients will be monitored on a daily basis for the development of any adverse events (AE) 
from the start of the study lipid until one week (7 days) after leaving the study. An adverse event 
is defined as any untoward medical occurrence in a research subject temporally associated with 
the use of the study drug, whether or not it is related to the drug. Any worsening of a pre-existing 
condition or illness is considered an adverse event. This includes pre-existing and or new clinical 
conditions or morbidities associated with prematurity or the patient’s underlying diagnoses. 
Laboratory abnormalities or vital sign changes are considered adverse events only if they meet 
the specific criteria listed in the table below. A serious adverse event (SAE) is an AE that leads 
to death of a subject, life-threatening event, persistent or significant disability, or an important 
medical event requiring medical or surgical intervention to prevent a serious outcome. 
 
Many possible AE and SAE are listed in Table 3 below. Patients will be monitored continuously 
by one of the principal investigators, Dr. Huff or Dr. Vanderpool, for possible AEs and SAEs. 
Clinical significance and relation to the study will be determined by Dr. Huff and/or Dr. 
Vanderpool based on best medical judgement. Unanticipated events that are determined to be an 
AE related or possibly related to the research drug will be promptly reported to the IRB by Dr. 
Huff or Dr. Vanderpool within 5 business days. Major protocol issues, including drug 
administration issues or errors, will also be reported to the IRB within 48 hours. Events that are 
determined to be an SAE or lead to death of a patient will be promptly reported to the IRB within 
24 hours.  
 
A separate Data and Safety Monitoring Committee (DSMC) will be used to monitor patient 
outcomes and AE along with SAE events. The DSMC members will not include the primary 
investigation team and will be made up of other experts from Neonatology (Dr. Ed Liechty), 
Pediatric General Surgery (Dr. Matthew Landman), Pediatric Gastroenterology (Dr. Emily Hon), 
and Statistics. The DSMC will meet within 2 weeks following enrollment of the first 10 patients. 
Further enrollment will be put on hold pending initial DSMC review. If no safety concerns are 
found by independent DSMC review, patient enrollment will proceed. DSMC will meet 
subsequently every 6 months for the duration of the study. 
 
Adverse events are defined using the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0. Modifications to these definitions may be made if inappropriate for the 
neonatal patient population. Some specific events and definitions are listed in Table 3 below. 
This table does not include the CTCAE v4.0 grade 5, as this is defined as death in a patient. 
Therefore, any death of a patient will be defined as grade 5, irrelevant of the specific diagnostic 
category within CTCAE v4.0 or listed below.   
 
Table 3: Definition of Specific Adverse and Serious Adverse Events 
Event 
Mild 
(Grade 1) 
Moderate  
(Grade 2) 
Severe 
(Grade 3) 
Life 
Threatening  
(Grade 4) 
Definition of adverse 
event 
Mild transient 
symptoms only 
Moderate illness 
or condition with 
Severe illness or 
condition 
Life threatening 
illness or 


14 
 
monitored or 
symptomatic 
treatment. 
Aware of 
symptom but 
tolerated and no 
functional 
interference 
new or 
significant 
altered 
treatment, causes 
some 
interference with 
normal activity 
or care. 
unresponsive to 
medical 
treatment, 
incapacitating 
with inability to 
perform usual 
activity and 
interference with 
normal functions. 
condition, 
required major 
surgery or 
respiratory 
support.  
Hyperthermia 
(axillary 
temperature) 
38.0-38.5 ºC on 
single 
measurement 
38.5-39.0 ºC on 
single 
measurement 
≥38.5 ºC on two 
or more 
consecutive 
measurements 
≥39.0 ºC for 
two or more 
measurements 
despite 
environmental 
intervention or 
need for 
increased IV 
fluid volume 
Pulmonary 
deterioration 
Not applicable 
FiO2 increase by 
0.20-0.30 or new 
non-invasive 
ventilation or 
increase in MAP 
>3 during study 
drug infusion 
FiO2 increase by 
0.31-0.50 or new 
invasive 
ventilation or 
increase in MAP 
>5-7 during study 
drug infusion 
FiO2 increase 
>0.50 or need 
for escalation in 
type of invasive 
ventilation or 
increase in 
MAP >7 during 
study drug 
infusion 
Hypertension 
(defined as systolic 
blood pressure 
greater than the 
95%ile for 
postmenstrual age) 
Hypertension 
for less than a 
24 hour period 
and no 
treatment 
needed 
Hypertension 
24-48 hours and 
no treatment 
needed 
Hypertension for 
>48 hours or 
requiring 
treatment 
Hypertension 
requiring 
multiple 
treatment types  
Hyperglycemia 
Transient 
glucose 
>180mg/dL for 
single 
determination 
with no further 
action taken 
Glucose 180-
250mg/dL for at 
least 2 
determinations 6 
hours apart 
Glucose 251-
350mg/dL for at 
least 2 
determinations 6 
hours apart or 
need for insulin or 
change in IV fluid 
Glucose 
>350mg/dL, 
change in 
mental status, 
diuresis or 
dehydration 
Hypoglycemia 
Transient 
glucose 
<50mg/dL on 
single measure 
Glucose 
<50mg/dL on 
repeated 
measures, 
responds to 
treatment with 
Glucose 
<40mg/dL on 
repeated measures 
or need for 
multiple dextrose 
boluses or need 
Glucose 
<40mg/dL with 
change in 
mental status, 
seizures, 
glucose 


15 
 
single 
intervention 
for change in IV 
glucose infusion 
to >10mg/kg/min 
unresponsive to 
glucose 
infusions, or 
need for 
glucagon or 
steroids 
Elevated liver 
enzymes (AST 
and/or ALT) 
1.5-2.0x normal 
(90-125 U/L) 
2.1-4.0x normal 
(126-245 U/L) 
4.1-10.0x normal 
(246-600 U/L) 
>10.0x normal 
(>600 U/L) 
Hypertriglyceridemia  150-250 mg/dL 
250-500 mg/dL 
500-1000 mg/dL 
>1,000 mg/dL 
Elevated creatinine 
(at >72 hours of age 
or older) 
1.3-1.8 mg/dL  
1.9-2.3 mg/dL 
2.4-3.4 mg/dL 
≥ 3.5mg/dL 
Oliguria (urine 
output (UO) over 24 
hour period) 
UO <1.0 
mL/kg/h 
UO 0.5-1.0 
mL/kg/h 
UO <0.5 mL/kg/h 
UO <0.3 
mL/kg/h 
Anemia (based on 
laboratory value) 
Hct <34% 
Hct <28% 
Hct <24% 
Hct <20% 
and/or 
cardiovascular 
instability from 
the anemia 
Thrombocytopenia 
(platelet counts in 
1000/cumm) 
75-100 
50-75 
25-50 with no 
bleeding 
<10 and/or 
bleeding 
Coagulation study 
abnormalities 
INR 1.5-2.0 
INR 2.0-2.5 
INR >2.5 with no 
clinically 
significant 
bleeding 
INR >3.0 
and/or >2.5 
with clinically 
significant 
bleeding 
Thrombosis 
(thrombus confirmed 
with imaging and 
radiographic report) 
Non-inclusive 
thrombus with 
no associated 
symptoms.  
Non-inclusive 
thrombus but 
with symptoms 
such as edema.  
Thrombus leading 
to need for 
anticoagulation 
therapy but with 
no organ 
compromise.  
Need for anti-
coagulation 
therapy with 
compromise of 
extremity or 
organ related to 
thrombus. 
Neutropenia 
(Absolute neutrophil 
count) 
1600-2000 
1000-1599 
500-999  
<500 
Mental status 
Mild irritability, 
possibly within 
normal range 
Persistently 
irritable and/or 
intermittent 
lethargy 
Lethargy, stupor, 
still arousable, 
single seizure 
Non-
responsive, 
need for 
respiratory 
intervention 
due to change 


16 
 
Systemic infection 
(including sepsis 
and/or bacteremia 
with positive blood 
culture) 
Positive blood 
culture but not 
treated (felt to 
be contaminant) 
Treated ≥5 days 
of consecutive 
antibiotics, 
antivirals or 
antifungals with 
no 
cardiovascular 
instability.  
Treated for 
systemic 
symptoms, 
including 
cardiovascular 
instability and ≥5 
days of anti-
microbial with 
response to 
treatment. 
Treated for 
systemic 
symptoms, 
including 
cardiovascular 
instability and 
≥5 days of anti-
microbial no or 
slow response 
to treatment. 
 
Criteria for Stopping Study 
1) Individual Patient Stopping Criteria:  
a) Development of progressive cholestasis as defined by direct bilirubin of 3 mg/dL or 
greater on two separate lab draws 5 to 7 days apart.  
b) Clinically significant laboratory abnormalities that change the clinical course of the 
patient, or the patient’s care and are deemed related to the study drug by the primary 
investigators (Dr. Huff or Dr. Vanderpool). The laboratory abnormalities include, but are 
limited to:  
i) Change in liver function with AST or ALT greater than 5 times the upper limit of 
normal or GGT greater than 3 times the upper limit of normal for patient age. 
ii) Creatinine greater than 2 times upper limit of normal for patient age.  
iii) Clinically significant coagulopathy with INR greater than 2.5 or INR greater than 1.5 
and clinically significant bleeding.  
iv) Clinically significant thrombocytopenia with platelet count less than 30 or less than 
50 with bleeding.  
v) Persistent hyperglycemia with glucose greater than 200 mg/dL despite changes in 
parenteral nutrition glucose infusion rate. 
(1) Inability to tolerate appropriate calorie intake due to elevated glucose infusion 
rate that may be required with lipid reduction.  
vi) Persistent hypertriglyceridemia (on 3 or more lab draws each at least 24 hours apart) 
greater than 250 mg/dL despite decreasing or holding lipid dose. 
c) At the request of the parent or legal guardian.  
d) At the request or recommendation of the patient’s primary physician and care team.  
If the patient is withdrawn from the study, treatment including parenteral nutrition administration 
and macronutrient content will be provided at the discretion of the primary faculty physician 
providing patient care.  
2) Study Stopping Criteria:  
a) DSMC or primary investigator initiated study cessation:  
i) As noted a Data Safety and Monitoring Committee (DSMC) of experts from 
Neonatology, Gastroenterology, Surgery and Statistics will meet within 2 weeks of 
the first 10 subjects and following at least every six months during the remainder of 
the study period. They will review patient recruit, patient outcomes, and adverse 
events in both prospective patient populations. Significant patient safety concerns will 


17 
 
be determined by the DSMC. These patient concerns include, but are limited to, 
finding a significant amount of AE or SAE within one study group or a large 
difference in outcomes between study treatment arms.  
ii) In adequate patient recruitment. We anticipate recruiting an average of 4 patients per 
study month. If there is a significant lag and will be unable to obtain our full number 
of patients within a reasonable time, this will be reason to terminate the study early.  
b) Principle investigators will consider study cessation if SAEs occur within a specific 
treatment arm out of proportion to what would be expected from typical disease course.  
 
Statistical Considerations 
 
Our goal is to recruit 25 patients into each group. Given this is a pilot study, the minimum 
number needed per arm would be 12 patients as per published statistician recommendations [21]. 
The reasoning for using a pilot study include determining the feasibility of performing a larger 
scale study. Performing a pilot study prior to the large-scale study will give us information on 
patient recruitment and retention, along with design flaws that may be remedied prior to future 
studies.  
 
All data will be summarized by group at each time point; summaries will include frequencies and 
proportions for categorical variables and mean, standard deviation, and range for continuous 
variables. Distributions of continuous variables will be examined. Parenteral nutrition 
characteristics will be recorded and tabulated. Tabulated categorical outcomes will include: 
proportions of subjects with cholestasis or IFALD, essential fatty acid deficiency, enteral 
autonomy at end of study, retinopathy of prematurity, chronic lung disease, and adverse events. 
Tabulated continuous measurements will include: growth rates, essential fatty acid profile, total 
caloric intake, percentage of calories from enteral intake, time to enteral autonomy, lipid dose 
delivered, bilirubin level, liver enzymes, gamma-glutamyl transferase (GGT), triglycerides, and 
length of stay. Fisher’s Exact Tests will be used to compare between groups for categorical 
variables. Time to enteral autonomy will be evaluated using Kaplan-Meier survival curves and a 
log-rank test. Mixed models will be used to compare between groups and compare within groups 
over time for continuous variables measured throughout the study. Length of stay will be 
compared using a Wilcoxon Rank Sum test. A 5% significance level will be used for all tests 
mentioned.  
 
Privacy/Confidentiality Issues 
 
Patient information will be kept only in de-identified and encrypted manners in print or 
electronically. A single REDCap database with encrypted patient information will be used and 
shared only between the investigators. A single encrypted key with limited patient information to 
identify patients will be maintained by the study investigator to identify patients in the event of 
adverse events related to the study.  
 
 
Follow-up and record retention 
 


18 
 
The time period of study lipid dosing and monitoring is anticipated to be 12 – 15 months. As 
noted, patient follow-up will take place 2 years after study completion with a 
neurodevelopmental screen. The information obtained from this study will be retained by the 
primary investigators for a period of 7 years after study completion in compliance with all 
regulations that apply. During this time, all information will be maintained in a secure fashion 
with no further access granted outside of the primary investigation team.  
 
 
 
 
 
 


19 
 
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