Conditions: Cholestasis
Keywords: liver parenteral nutrition fish oil omegaven children
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 62
Healthy volunteers: no

Brief summary:
The purpose of the study is to investigate if intravenous fish oil, commercially available as Omegaven, safely and effectively reverses parenteral nutrition associated cholestasis in children.

Detailed description:
Infants dependent on parenteral nutrition for greater than 1 year who develop parenteral nutrition associated cholestasis will universally face mortality unless they receive a timely liver and/or small bowel transplant. Although transplant survival has improved in recent years, survival is not guaranteed, and transplant care remains costly. Alternative nutritional and pharmacological strategies are imperative to improve the clinical outcomes of infants with intestinal failure and parenteral nutrition associated cholestasis. In both animal and human studies, intravenous fish oil, a lipid emulsion rich in omega-3 fatty acids and Vitamin E, and lacking phytosterols, has been shown to ameliorate parenteral nutrition associated cholestasis and improve morbidity and mortality. The purpose of this pilot study is to investigate if Omegaven, a commercially available intravenous fish oil, at 1 g/kg/d, will safely reverse liver disease in 80 subjects with parenteral nutrition associated cholestasis. Subjects can initially receive a maximum of 6 months (24 weeks) of intravenous fish oil. If the subject re-develops liver disease and still satisfies inclusion/exclusion criteria, the intervention can be restarted. Study subjects will be compared to a historical cohort of children with Short Bowel Syndrome and parenteral nutrition associated cholestasis who have been receiving standard intravenous soybean oil for \> 60 days. The fish oil cohort will be followed for a total of 5 years to determine if transplant-free mortality is reduced.

Arms:
arm 1: 0.5 g/kg/d IV x 2 days, then 1 g/kg/d IV for 24 weeks or until parenteral nutrition discontinuation, death or transplant, whichever comes first. Subjects are eligible to restart Omegaven should they re-satisfy inclusion/exclusion criteria.

Interventions: intervention 1: Omegaven
Intervention descriptions: intervention 1: 0.5 g/kg/d intravenous every day for 2 days, then 1 g/kg/d intravenous everyday

Protocol document:
Prot_SAP_000.pdf: 
Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
1 
Omegavenä and Parenteral Nutrition Associated Cholestasis 
(PNAC) 
 
 
 
 
 
 
Kara Calkins, MD, Principle Investigator 
Assistant Professor 
Department of Pediatrics 
Division of Developmental Biology and Neonatology  
UCLA 
 
 
James Dunn, MD, Co-investigator 
Professor 
Department of Surgery 
 
 
 
 
Stanford University 
 
Stephen Shew, MD, Co-Investigator  
Associate Professor 
Department of Surgery 
 
 
 
 
Stanford University  
 
Robert Venick, MD, Co-investigator  
Associate  Professor 
Department of Pediatrics 
Division of Pediatric Gastroenterology 
UCLA 
 
  


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
2 
Table of Contents 
 
Introductory Statement  
 
 
 
 
 
 
 
3 
 
General Investigational Plan  
 
 
 
 
 
 
4 
 
Specific Drug Information   
 
 
 
 
 
 
6 
 
Summary of Previous Human Data 
 
 
 
 
 
8 
 
Overall Plan   
 
 
 
 
 
 
 
 
13 
 
Rational and Indication  
 
 
 
 
 
 
13 
 
General Approach   
 
 
 
 
 
 
14 
 
Inclusion and Exclusion Criteria   
 
 
 
 
14 
 
Data Collection  
 
 
 
 
 
 
 
15 
 
Monitoring   
 
 
 
 
 
 
 
16 
 
Withdrawal   
 
 
 
 
 
 
 
18 
 
Possible Side Effects  
 
 
 
 
 
 
 
18 
 
Protocol 
 
 
 
 
 
 
 
 
 
26 
 
Purpose of Study  
 
 
 
 
 
 
 
26 
 
Names and Addresses of Investigators, Facilities, and IRB 
 
26 
 
Criteria for Selection/Number of Patients  
 
 
 
26 
 
Study Design  
 
 
 
 
 
 
 
27 
 
Method for Determining Dose 
 
 
 
 
 
30 
 
Description of Observations to be Made to Fulfill Study  
 
 
Objectives 
 
 
 
 
 
 
 
30 
 
Procedures to Monitor for Side Effects  
 
 
 
 
33 
 
Chemistry, Manufacturing, and Control Information 
 
 
36 
 
Pharmacology and Toxicology Information  
 
 
 
 
37 
 
Additional Information 
 
 
 
 
 
 
 
38 
 
References 
 
 
 
 
 
 
 
 
 
50 
 
 
Attachments   
 
 
 
 
 
 
 
 
54 
Manufacturer’s Insert and Additional Drug Information 
 
Published studies 
 
Curriculum Vitae for Physicians Involved 
 
  


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
3 
 
 Introductory Statement  
 
Short Bowel Syndrome (SBS) results from congenital intestinal disorders or intestinal 
resections that lead to significant malabsorption. SBS remains the most common cause of 
pediatric intestinal failure (IF) which is defined as the inability of the gastrointestinal 
tract to maintain adequate nutrient, fluid and electrolyte absorption to sustain life without 
total parenteral nutrition (PN) supplementation for > 60 days. Prior to the advent of PN, 
children unable to absorb adequate enteral nutrition (EN) due to insufficient bowel length 
or function would die of malnutrition and associated complications. Today, > 20,000 
patients with IF require PN for survival. The actual cost of maintaining a PN 
patient is estimated to be $100-150,000 per year. More importantly, 67% of SBS 
patients develop PNAC, and 25% 
progress to liver failure8.  Infants with 
IF dependent on PN for > 1 year who 
develop severe PNAC will universally 
face mortality unless they receive a 
timely 
liver 
and/or 
small 
bowel 
transplant. In North America, due to the 
shortage of available donor organs, the 
highest death rates of all patients awaiting 
solid-organ 
transplantation 
occur 
in 
children with IF and PNAC who are 
awaiting 
combined 
intestine/liver 
transplants. Transplants in and of 
themselves are not a panacea given 
that the five year survival rates post-
transplant 
remain 
low 
(50-60%)9. 
Transplants and post-transplant care 
pose a large economic burden to 
society and the healthcare system.  The 
estimated 
cost 
of 
a 
transplant 
is 
~$150,000 - $250,000 and post-transplant medications cost ~$12,000/year per child. 
Children on immunosuppressive drugs after transplant, are at higher risk for malignancy, 
life-threatening complications, and repeated, lengthy hospitalizations.  
 
Prevention and treatment of PNAC is paramount, but lacking.  The pathogenesis of 
PNAC is multifactorial.  There is now cumulating evidence that suggests soybean oil 
(SO) is a major culprit in PNAC.  SO is used to supplement PN to provide additional 
calories and prevent essential fatty acid deficiency.  However, with a high content of 
phytosterols, SO impairs biliary secretion and promotes lipid accumulation.  Moreover, 
SO contains a large amount omega-6 fatty acids and small amount of omega-3 fatty 
acids. In animal and human studies, fish oil (FO), an alternate lipid emulsion that is 
rich in omega-3 fatty acids and lacks phytosterols (Table1), has been shown to 
ameliorate PNAC and improve morbidity and mortality11,24,30-32.  By down-regulating 


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
4 
the production of inflammatory and thrombotic mediators and promoting hepatic 
protection by inducing an anti-inflammatory and anti-thrombotic state, FO could 
potentially reverse the development and progression of PNAC (Figure 1).  To date, there 
is no randomized controlled study comparing FO to standard SO.  
 
General Investigational Plan 
 
The specific aim of this pilot study is to investigate if intravenous (IV) FO, 
commercially available as Omegavenä (Fresenius Kabi), at 1 gm/kg/d, to children > 
2 weeks, but < 18 years of age, will safely reverse or ameliorate liver disease in 80 
subjects with PNAC. Study subjects will be compared to historical controls with 
PNAC who received standard SO .  The following outcomes will be measured:  
 
1)  
Reversal of PNAC in infants receiving FO 
2)  
Growth of infants receiving FO 
3)  
Safety of FO in infants with PNAC 
4) 
Mechanism of FO  
 
To address the above specific aims the following will be performed: 
1)      Serial laboratory tests to evaluate cholestasis and hepatic dysfunction (total 
and direct bilirbuin, ALT, AST, alkaline phosphatase, and GGT),  
2)  
Serial 
anthropometric 
measurements 
(weight, 
length, 
and 
head 
circumference),  
3)    
Serial laboratory tests to evaluate for safety (coagulation parameters, 
platelets and essential fatty acid profile)  
4).   
Serial serum proteomic, inflammatory markers, phytosterols, microRNA and 
microarray analysis and fatty acid analysis of red blood cell (RBC) membranes  
5) Serial fecal specimens will be collected to evaluate the intestinal microbiome in 
children at risk for PNAC. 
 
PNAC is defined as a direct bilirubin ≥ 2 mg/dL on 2 consecutive measurements.  
Reversal of PNAC will be defined as direct bilirubin < 2 mg/dL. on 2 occasions.  
Essential fatty acid deficiency will be defined as a triene:tetraene ratio ³ 0.5. 
 
Serial proteomic, microRNA, microarray analysis and analysis of fatty acids, sterols and 
markers of inflammation will provide insight into what proteins and genes/pathways are 
altered with FO treatment. Microbiome analysis will provide insight into how the 
intestinal microbiome is altered with PNAC and by FO.   By comparing baseline analyses 
to analyses during specific time points during FO treatment, we will be able to detect up-
regulation or down-regulation of specific proteins/genes.  Fatty acid analysis of RBC 
membranes will provide insight in how FO alters the RBC membrane composition.  
Alterations in the fatty acid composition of the RBC membrane affects cell function and 
membrane fluidity.  
 


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
5 
Once the subject enters the study, FO will be administered for  unlimited treatment period 
until  the subject’s PN is discontinued, the patient expires, or he/she receives a transplant. 
Should PN be terminated, FO will be stopped.  If the patient receives a liver transplant, 
FO will be discontinued. For subjects who previously received FO treatment and re-
develop biochemical evidence of PNAC off FO (direct bilirubin ³ 2 mg/dL on 2 
consecutive occasions separated by seven days), FO can be re-started if 
inclusion/exclusion criteria are satisfied. When FO is restarted, the protocol for 
laboratory and clinical monitoring will be followed. Patients who have received a liver 
transplant are NOT excluded from the study.   
 
A patient can be withdrawn at any time should he suffer any side effect or adverse event 
that could affect his safety or jeopardize his health. The primary medical team can refer 
the patient for transplant evaluation at any time.  This study will be conducted over 12-15 
years.  Prior to the beginning of the study, FDA and IRB approval will be obtained.  All 
necessary staff education will be completed prior to enrolling patients. The study’s goal is 
to enroll 80 subjects in 10-12 years.  Final data analysis will be performed after the last 
subject completes the study, and will be performed in the last 4-6 months of the study.  A 
Data Safety Monitoring Board (DSMB) will meet every 6 months to review any 
preliminary data, and assess for any side effects or adverse events.  If after 4 or more 
DSMBs have been held and there are no concerns with safety, DSMBs can be held less 
frequently, but at a 1 year minimum.  A DSMB can held at anytime should a subject, the 
study team, FDA or IRB have any concerns regarding the study in general. As of August 
2017, a DSMB can be meet on as needed basis.  
 
The primary endpoint will be time to resolution of PNAC (direct bilirubin < 2 
mg/dL on 2 consecutive measurements).  Secondary endpoints will be death, transplant, 
number of times FO is restarted, and time to full EN.   
 
Statistical significance will assigned at a p value ≤ 0.05.  Baseline difference and 
differences after intervention (liver function tests, INR, platelets, and triene:tetraene ratio, 
weight, length, and HC) between the two groups (FO vs SO) will be assessed by t tests 
for means and c2 tests for proportions. Statistical analysis will also include, but not 
limited to, Kaplan-Meir survival curves, crude and hazard ratios, and logistic regression 
analysis for co-founding variables (ie gestational age, birthweight, number of surgeries, 
EN, episodes of line sepsis).  The analysis will include an intention to treat analysis.  
 
One formal interim analysis will be performed when 7 subjects have completed the study.  
 
We will also retrospectively collect information on subjects who received FO at UCLA 
under compassionate use (EINDs 104,951, 104,766). 
 
 


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
6 
Specific Drug Information  
 
Please see attached information regarding specific drug information provided by the 
supplier, Freseniurs Kabi, Hamburg, Germany.  
 
FO, commercially available as Omegavenä (Freseniurs Kabi), is a highly refined 
fish oil composed of essential fatty acids, a-tocopherol, glycerol, and purified egg 
phosphatide. 
 
Therapy with FO will be initiated at starting dose of 0.5 gm/kg/d infused over 8 – 24 
hours on the first and second day of therapy.  On day three of the study, FO will be 
increased to 1 gm/kg/d and will not exceed 1 gm/kg/d (See Table 1). It will be infused 
intravenously through either a central or peripheral catheter in conjunction with PN.   FO 
will always be administered with a dextrose containing solution.  FO is isotonic, and will 
be kept at room temperature. It is compatible with PN solutions and may be co-infused 
via a y-site. FO may be infused through a 1.2 micron inline filter.   
 
If subjects are hospitalized at the time of enrollment, they must be observed for 48 
hours in the inpatient setting. If subjects are outpatients at the time of enrollment, 
the subject must be in observed in an outpatient clinical setting for the first two days 
that FO is administered.  The outpatient subject must in observed in the clinical setting 
for the entire infusion and for 1 hour after the infusion has been terminated.  This 
observational period will occur in the UCLA General Research Clinical Center (GCRC). 
After 48 hours of inpatient observation or 2 days of outpatient observation, and if the 
patient is considered medically stable and safe, FO can be administered at home by the 
subject’s caregivers.  
 
If FO is restarted because the subject continues to demonstrate evidence of PNAC or 
redevelops PNAC while off FO, and the subject tolerated FO originally without any 
adverse events/side effects, FO can be restarted at home. 
 
 
Dosage FO per kg body 
weight/day 
Volume of FO  
per kg body weight/day 
Day 1 and Day 2 
0.5 g 
5 mL 
Day 3 + 
1 g 
10 mL 
Table 1.  Dose of FO. 
 
FO is available as a 10% emulsion in 50 mL and 100 mL bottles. Containers will be 
shaken before use.  When patients are hospitalized, depending upon the dose prescribed, 
rates less than or equal to 2 ml/hr will be provided in 30 ml syringes. Rates less than or 
equal to 4ml/hr will be provided in 60 ml syringes.  Rates greater than 4ml/hr will be 
provided in glass bottles.  
 


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
7 
FO in the hospital can be split equally in 2 syringes/bottles.  Because patients often only 
have one site for infusions, and require multiple intravenous medications, dividing the 
dose in 2 syringes/bottles will ensure that the subject receives the entire FO dose in a 24 
hour period.  The first syringe/bottle will be administered immediately when it arrives at 
the patient’s bedside.  The second syringe/bottle will be placed in fridge temporarily until 
the first infusion is completed.  30 minutes prior to the projected start time of the second 
infusion, the second syringe/bottle of FO will be allowed to come to room temperature 
prior to infusing.   
 
Once the FO is placed in a syringe/bottle, it has an expiration of 24 hours.  Once it is 
placed on a pump, it expires in 12 hours.  Pharmacists will dispense the FO, and 
experienced health professionals or trained caregivers will administer the FO.   
 
If additional fat calories are needed, they will be provided via the enteral route. If 
additional non- protein calories are needed, they will be provided as carbohydrates.  No 
other parenteral form of fat emulsion will be used during FO therapy. The same standards 
of care provided to all patients receiving PN solution will be followed.  The primary team 
will be responsible for the patient’s medical care. 
 
At home, the vial of FO will punctured with intravenous tubing, and administered with 
the appropriate home supplies.  Parents or legal guardians will receive sufficient training 
on how to administer PN and FO. 
 
If a subject is admitted to the hospital, FO will be held on the day of admission, and 
restarted on the second hospital day.  
 
If a subject is scheduled for an elective operation, FO will be held the three days prior to 
surgery, and restarted four days after surgery. If there are any concerns for an increase 
risk of bleeding from baseline status, FO will be held until the concern has been 
addressed by the primary medical team.  IF there is an emergent surgery, FO will be held 
prior to going to the operating room for the surgery.  If at the time of consent it is known 
that elective operation is scheduled or required, FO will start 4-14 days after the 
operation is performed, depending on the patient’s risk for bleeding (age, degree of 
IFALD, other comorbid conditions).  The study team in consultation with the primary 
team will decided when to start FO. 
 
To our knowledge, the drug has not been withdrawn from a study or marketing in 
any country for any reason related to safety or effectiveness.    
 
Please attached copy of the drug’s brochure which includes a description of the drug 
substance and formulation, pharmacological and toxicological effects, pharmacokinetics 
and biological disposition.   


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
8 
 
Please attached publications by Gura, et al, and Diamond, et al, for information relating 
to safety and efficacy.  
Summary of Previous Human Experience with FO 
 
PNAC 
 
Neonates who are unable to absorb EN secondary to insufficient intestinal length and/or 
gastrointestinal disorders are dependent on PN.  The goal of PN is to provide sufficient 
calories and prevent nutritional deficiencies during protracted periods of fasting in order 
to sustain adequate growth and development.  PN, however, is associated with the 
development of PNAC, which carries significant morbidity and mortality in the neonatal 
population.  
 
Approximately 20,000 patients with intestinal failure in the United States are 
dependent on PN for survival.3  Approximately 30-60% of pediatric patients 
receiving PN develop PNAC.4  PNAC is characterized by hepatic biochemical and 
histological alterations.  Patients exhibit elevated liver function tests and direct bilirubins, 
and liver biopsies demonstrate fibrosis, cirrhosis, lipidosis, and steatosis.5 The 
development and progression of PNAC is unpredictable in the pediatric population. Risk 
factors for PNAC include SBS, frequent surgical procedures, necrotizing enterocolitis 
(NEC), prematurity, low birth weight, small for gestational age, sepsis, and lack of EN. 6 
 
SBS results from a congenital disorder or surgical resection secondary to NEC or other 
gastrointestinal pathology that causes significant malabsorption.7 Unable to maintain 
sufficient protein, fluid, electrolyte, and micronutrient intake, these patients become 
malnourished, and as a result, are dependent on PN for survival.   SBS carries significant 
morbidity and mortality.  The most common complication of SBS is PNAC; 
approximately 67% of patients with SBS develop PNAC, and 25% progress to liver 
failure.8  SBS remains the most common cause of intestinal failure in children.9 It is 
the most common pre-transplant diagnosis in this population.9  In North America, 
the highest death rates on the intestine transplant waiting list occur in young 
children who need combined intestine/liver transplants.10 
 
The ability to be weaned off of PN, or potential for bowel adaptation, depends on the 
primary diagnosis for intestinal failure, the amount of bowel remaining, the presence of 
an ileocecal valve (ICV), patient age, history of septic episodes, and presence of bacterial 
overgrowth.35,36  Patients with more ileum than jejunum are more likely to achieve 
successful adaptation.  Patients with greater than 40 cm of small bowel and an ICV are 
highly likely to attain indepenence from PN.36  In fact, it has been reported that as little as 
11 cm of jejunoileum with an ICV and as little as 25 cm without an ICV can survive and 
sustain normal growth without the assistance of PN. 37  
 
In addition to SBS, prematurity also places infants at high risk for PNAC.11  Risks factors 
in this population include an immature biliary system, absence of EN, bacterial 


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
9 
overgrowth, and sepsis12,13,8. Moreover, 5-10% of infants who weigh less than 1,500 
grams develop NEC, which may necessitate bowel resection.14  Like SBS patients, low 
birth weight neonates can remain dependent for PN for long periods of time. In fact, 
infants with a birth weight less than 750 grams have a 39% likelihood of developing 
PNAC.15 
 
Because small bowel length increases rapidly during gestation, it is questioned whether 
the amount of small bowel present in a premature infant after resection is comparable to 
full-term infant after resection.  Rather than relying by the absolute of bowel remaining at 
the time of intestinal resection, the percentage of expected normal length may be more 
accuate in predicting ability to achieve complete bowel adaptation.  Based off of existing 
data for the normal small bowel length in a neonate according gestational age, a 
percentage of their expected normal length can be calculated.  Infants with less than 10% 
of expected normal small bowel length have a 10% chance of weaning from PN, while 
those with greater than or equal to 10% have an 80% chance of weaning.38   
 
Prevention and treatment of PNAC remains critical, but is limited and lacking.  EN 
can slow the progression and reverse PNAC.16  However, for patients who are unable to 
wean sufficiently or are dependent on PN for extended periods of times, PNAC can 
progress to liver failure and in the absence of a transplant, can lead to death.  Studies 
report a mortality rate approaching 100% for patients unable to be weaned off PN 
within a year of diagnosis unless they are transplanted.1 Survival rates for combined 
small bowel and liver and liver transplants alone remain dismal.  At five years post-graft, 
approximately 43-75% and 57-75% of patients transplanted for combined small bowel 
and liver and liver alone transplants are alive.9 
 
The pathogenesis of PNAC is multi-factorial, and still poorly understood.  The etiology 
likely stems from a combination of an immature liver, bacterial overgrowth, decreased 
secretion of bile acids and enteral hormones due to fasting, and atrophic intestinal 
mucosa.17,18,19 Research has also focused on specific components or lack of components 
in PN that contribute to PNAC. Previous work has implicated excessive caloric 
administration, concentration, composition of amino acid formulations, and specific 
micronutritients.20,21,22 There is now cumulating evidence that intravenous lipids may 
play a crucial role development and progression of PNAC.    
 
 
Role of Intravenous Fat Emulsion on PNAC 
 
Intralipidä and Liposynä are standard lipid emulsions used to supplement PN to provide 
additional calories and prevent essential fatty acid deficiency. Intralipidä is soybean 
based and Liposynäis both soybean and safflower based.  Both emulsions are composed 
of phytosterols, which are thought to impair biliary secretion.  Moreover, the 
accumulation of lipids in Kupffer cells may further impair liver function.  
 


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
10 
There exists an abundance of literature that suggests the type of long chain 
polyunsaturated fatty acid (LCPUFA) present in the lipid emulsion is the primary culprit 
in the development of PNAC.  LCPUFAs, known as omega-6 and omega-3 fatty acids, 
share a common metabolic pathway and rate limiting enzymes.  Important omega-3 fatty 
acids are a-linolenic acid (ALA), eicosapentaenic acid (EPA), and docosahexaenoic acid 
(DHA).  The human body cannot synthesize omega-3 fatty acids de novo, however, it can 
utilize ALA to generate other omega-3 fatty acids.  These conversions compete with 
omega-6 fatty acids.  In other words, in the presence of high concentrations of omega-6 
fatty acids, the production of omega-3 fatty acids is slowed.   
 
The omega-6 fatty acid, arachidonic acid, produces pro-inflammatory and pro-thrombotic 
leukotrienes, prostaglandins, and eicosanoids.  As a result, the ratio omega-6 to omega-3 
fatty acids (n6:n3) creates a balance between a pro-inflammatory and anti-inflammatory 
state. Western diets are estimated to have n6:n3 ratio of approximately 16:1, and this ratio 
has been implicated in many disease processes such as cardiovascular disease.23 
 
Predominately composed of omega-6 fatty acids, Interlipidä has an n6:n3 ratio of 
5.5:1.24  Omegavenä (FO), on the other hand, is a rich in omega-3 fatty acids.  FO down- 
regulates the production of inflammatory, thrombotic mediators, and promotes hepatic 
protection by inducing an anti-inflammatory state.   
 
In addition to the ratio n6:n3 present in lipid emulsions, the mechanism of metabolism 
and route of administration of the fatty acid may contribute to PNAC.  Enteral lipids are 
packaged into chylomicrons that acquire apolipoproteins, and are eventually metabolized 
by the liver.  In contrast, the particles in Intralipidä are similar to endogenous 
chylomicrons, but differ in their content.  These artificial particles contain essential fatty 
acids and omega-6 triglycerides, and lack cholesterol and protein.  Recent studies suggest 
that lipid emulsions rich in omega-6 fatty acids, like Intralipidä are metabolized with less 
lipolysis, and may be cleared as whole particles by tissues other than the liver.25  
 
The metabolism and clearance of omega-3 fatty acids, on the other hand, is unknown, but 
appears to independent of the pathways mentioned above.26  Lipid emulsions rich in 
omega-3 fatty acids have been shown to decrease de novo lipogenesis27, stimulate b-
oxidation of fatty acids and suppress superoxidase dismutase and glutathione peroxidase,  
two enzymes responsible for oxidative injury.24 All of these mechanisms are implicated 
in the reduction of hepatic steatosis. 
 
 
Human Studies  
 
Epidemiological and experimental studies have demonstrated that a diet rich in omega-3 
fatty acids prevents certain adult-onset diseases such as the metabolic syndrome, cancer, 
and neurological disorders.39  In fact, the FDA has approved a prescription form of 
omega-3 fatty acids as a treatment for hypertriglyceridemia.40 
 


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
11 
With regards to the neonatal population, there are now published reports of the use FO 
for treatment of PNAC. In 2006, Gura et al published 2 case reports of infants with 
PNAC treated with Omegavenä at Boston Childrens’ Hospital.  In both cases, PNAC 
was reversed.30  In 2007, Gura et al published their results of 18 infants who developed 
PNAC while receiving Intralipidä and were treated with FO, available as Omegavenä 
(Fresenius Kabi).  These infants were compared to a historical cohort of 21 infants treated 
with Intralipidä.  Patients were eligible for treatment with FO if they had a bilirubin 
greater than 2 mg/dL and a predicted PN duration of 30 days or more because of an 
acquired or congenital gastrointestinal disease.  Baseline characteristics between the two 
populations did not differ.  However, although not statistically significant, the FO cohot 
had a higher direct bilirubin at the entry of the study in comparison to the historical 
patients (5.4 vs 3.5 mg/dL).  Patients in the FO cohort had their SO discontinued, and 
their Omegavenä was advanced to 1 gm/kg/day by day three of therapy.   
 
The median time to reversal of PNAC in neonates receiving FO was 9.4 weeks in 
comparison to 44.1 weeks in historical controls.  Reversal of cholestasis was defined as 
a direct bilirubin less than 2 mg/dL.  38% (7 subjects total) of the FO cohort never 
reversed their cholestasis, while 67% (14 subjects) in the historical cohort did not reverse 
their cholestasis. Those receving FO were 4.8 times more likely to reverse their PNAC, 
and 6.8 times more likely to reverse their PNAC when the analysis was adjusted for 
initial bilirubin concentration, gestational age and NEC. 
 
Two of the 7 subjects in the FO cohort who had persistant PNAC died, in comparison to 
7 of the 14 subjects in the historical cohort who had persistant PNAC.   2 patients in the 
historical cohort received a liver transplant and were amoung the deaths.  There were no 
transplants in the interventional group.  The 2 patients that died in the FO group died of 
non-liver related causes.  In comparison, 6 of the 7 patients who died in the historical 
cohort died of liver related causes.  
 
The median time to PN cessation was statistically significant between to the two groups.  
In the FO cohort, the average time to be successfully weaned off PN was 13.8 weeks, in 
comparison to 22.9 weeks in the historical cohort.  Although not statistically significant, 
the risk of death between the FO and historical cohort was 11.1% and 33.3% 
respectively.31 
 
More recently, Diamond, et al published a retrospective cohort describing 12 children 
with SBS who received FO.  Patients, received both Intralipidsä and FO at 1 gm/kg/d.   
However, if the patients did not demonstrate significant progress on this regimen, the 
Intralipidä dose was reduced or discontinued completely.  The median starting direct 
bilirubin was 8.06 mg/dL.  Of the 12 patients who received FO therapy, 9 patients 
demonstrated complete resolution of hyperbilirubinemia.  Complete resolution was 
defined as a direct bilirubin of zero.  The median time to reverse PNAC was 24 weeks.  5 
patients who received FO and Intralipids achieved complete resolution only after 
Intralipidsä were discontinued.  All patients who demonstrated reversal of cholestasis 


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
12 
were delisted for transplantation.  2 of the 3 patients whose PNAC did not resolve 
received transplants.32 
 
Safety markers have also been evaluated for patients on FO, specifically risks for 
essential fatty acid deficiency and bleeding. FO contains 0.1-0.7% linoleic acids, which 
has been demonstrated to prevent essential fatty deficiency.34  There are no reports of 
essential fatty acid deficiency with the use FO in the pediatric patient population with 
PNAC.   
 
Because omega-3 fatty acids inhibit cycloxygenase and other factors leading to decreased 
platelet aggregation, there is a potential concern that FO could increase the risk for 
bleeding.  Both Gura, et al and Diamond, et al reported no change in coagulation studies 
with use of FO.31,32 Clinical trial evidence does not support an increased risk of bleeding 
in adult patients with cardiovascular disease treated with fish oil even when used in 
combination with agents such aspirin and warafin.33,41  Boston Childrens’ Hospital has 
now treated over 100 patients with FO and has not reported any adverse events or side 
effects with this therapy.  
 
At UCLA, FO has been provided to two patients with SBS and PNAC (IND 104766, 
104951).  Both patients have not experienced any side effects or adverse events.  Patient 
1 (IND 104766) has been on FO for approximately 16 weeks, and patient 2 (IND 104951) 
has been on FO for approximately 12 weeks.  Both patients have demonstrated 
remarkable improvement in their liver function improvement.  In fact, patient 2’s baseline 
total and direct bilirubin prior to FO was 19.7 and 10.5 mg/dL; her liver enzymes, AST 
and ALT, were 466 and 296 respectively.  In addition, she had hypertriglyceridemia with 
a triglyceride trough of 244.  Her most recent total and direct bilirubin are 1 and 0.4 
mg/dL with an AST and ALT of 71 and 98.  Her triglyceride level has also improved; it 
was most recently measured at 78.   
 
Animal studies and limited human studies have provided insight into how FO may 
possibly reverse or protect against the development of PNAC.  It is postulated that FO 
alters glucose and lipid metabolism (specifically de novo lipogenesis), decreases 
inflammation and thrombosis, and alters oxidant/antioxidant activity.  Further studies are 
needed to elucidate the exact mechanism in the SBS/PNAC population.   
 
Lastly, despite promising FO case reports, there is not a randomized controlled trial 
comparing FO to standard SO at the same dose.  
 
 
 


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
13 
 
The Overall Plan 
 
1.  Rationale and Indication 
 
Alternative nutritional and pharmacological strategies are imperative to improve the 
clinical outcome and quality of life of SBS, IF, and PNAC patients.  Recent data has 
revealed that when standard lipid emulsions are replaced with FO, which lacks 
phytosterols and is rich in omega-3 fatty acids, PNAC is ameliorated or reversed.  The 
purpose of this pilot study is to investigate the use of FO (Omegaven™), 
administered at 1 gm/kg/d IV, in children with PNAC.  We hypothesize that FO will 
be a safe therapy to reduce PNAC in children. Study subjects will be compared to 
historical controls with SBS and PNAC receiving standard SO. The following clinical 
outcomes will be measured:  
 
1)  
Reversal of PNAC in infants receiving Omegavenä    
2)  
Growth of infants receiving Omegavenä 
3)  
Safety of Omegavenä in infants with PNAC 
4) 
Mechanism of OmegavenÔ 
 
To address the above specific outcomes the following will be performed: 
1)  
Serial laboratory tests to evaluate cholestasis and hepatic dysfunction (total 
and direct biliribin, ALT, AST, alkaline phosphatase, and GGT) 
2)  
Serial 
anthropometric 
measurements 
(weight, 
length, 
and 
head 
circumference) 
3)  
Serial laboratory tests to evaluate safety (coagulation parameters, platelets 
and essential fatty acid profile) 
4) 
Serial serum microarray, proteomic, inflammatory markers, bile acids 
phytosterols and microRNA analysis and fatty acid analysis of red blood cell (RBC) 
membranes. 
5)   Serial fecal specimens will be collected to evaluate the intestinal microbiome in 
children at risk for PNAC. 
 
 
Considering the high morbidity and mortality associated with PNAC in specific 
populations, this pilot study has the potential to provide valuable information 
about a potential treatment.  Moreover, this pilot study could cautapult additional 
studies such as a randomized, controlled trial comparing FO to SO, and assessing 
FO’s impact on metabolism and neurodevelopment.   
 
 
 
 
 


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
14 
2.  General Approach 
 
This study targets a high risk population for IF and PNAC; infants with SBS and/or 
congenital gastrointestinal disorders, and premature infants with a history of nectrotizing 
entrocolitis.   
 
INCLUSION AND EXCLUSION CRITERIA 
 
INCLUSION CRITERIA: 
Clinical evidence of PNAC 
Direct bilirubin ³ 2 mg/dL on 2 consecutive measurements 
Expected PN course greater than 30 days  
Acquired or congenital GI disease  
>2 weeks of age and <18 years 
>60% of calories from TPN 
Failed standard therapies to prevent progression of liver disease 
(Actigal, cyclic PN, avoidance of overfeeding, reduction/removal of  
copper from PN if elevated by laboratory analysis, advancement of 
EN) 
  
 
 
EXCLUSION CRITERIA: 
Inborn errors of metabolism 
Extracorporeal Membrane Oxygenation (ECMO) 
Seafood, egg, or Omegavenä allergy  
Documented cause of liver disease other than PNAC 
Hemorrhagic disorder 
Anticoagulant therapy 
Hemodynamically unstable or in shock 
Comatose state 
Stroke, pulmonary embolism, recent myocardial infarction 
Diabetes 
Fatal chromosomal disorder 
Enrollment in any other clinical trial involving an investigational  
agent 
Patient, parents, or legal guardians unable or unwilling to give  
informed consent  
Patient expected to weaned from PN in 30 days  
Unable to tolerate necessary laboratory monitoring 
Patient requiring aspirin or toradel or motrin 
Patient requiring dialysis 
 
All inclusion and exclusion criteria must be satisfied in order for the subject to be 
enrolled in the pilot study. If the subject meets inclusion and exclusion criteria, and the 


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
15 
informed consent is signed, the patient will enter the study. Baby aspirin is not considered 
a contraindication.  
 
DATA COLLECTION 
 
Demographic and clinical information will be collected when the study is initiated and 
throughout the study. All labs will be drawn per the primary medical team.   
 
While it is standard that labs are drawn on MOST SBS, IF and PNAC patients on a 
weekly basis, the frequency and type of lab varies depends on the primary medical team 
and patient’s condition (extent of disease, age, gestational age, presence of anemia, 
change in baseline status, etc).  It is considered standard of care that patients who have 
been receiving PN for > 14 days, have electrolytes, renal function, glucose, total and 
direct bilirubin, and AST/ALT drawn on a weekly basis.  It is also considered standard of 
care by many physicians to draw a weekly triglyceride trough, alkaline phosphatase, 
GGT, albumin/pre-albumin, total protein and complete blood count.   
 
For patients on long-term PN (PN for couple-several months) who have demonstrated 
stability with regards to growth, electrolyte balance, and liver function, many physicians 
consider it standard of care to draw labs every 2 – 4 weeks.   
 
For patients with advanced PNAC, it is considered standard to intermittently draw 
coagulation studies.   Essential fatty acid profiles are collected for patients who are 
suspected to have an essential fatty acid deficiency (based off of clinical signs and 
symptoms) and who are not receiving sufficient essential fatty acids via the enteral and/or 
intravenous route.    
 
All of the above labs that are performed as part of standard of care by the primary 
medical team will be collected and recorded in the appropriate case report form.  Subjects 
will have labs drawn at least monthly by the primary medical team.  However, labs can 
be drawn more frequently per the primary medical team.   
 
Growth will be assessed monthly by measuring weight, length, and head circumference.  
Bedside nurses or the nurse in Intestinal Failure Clinic will perform these measurements.    
 
Serum microarray, proteomic, inflammatory markers, phytosterols, bile acids, RBC 
membrane fatty acid composition and microRNA analysis will be performed at baseline, 
2 weeks, 3 months, and 6 months.  Thereafter, serum will be collected every six- month 
until FO has been stopped and for subjects who continue to remain on PN (regardless of 
the lipid emulsion).    
 
Fecal specimens will be performed at baseline, 2 weeks, 3 months, and 6 months, and, 
thereafter every six- month until FO discontinued and/or should the subject remain PN 
dependent.  
 


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
16 
Data on the patient’s status, specifically, liver function and growth/nutrition/development 
will be collected.  Data will be collected during the study, post-FO if the patient remains 
PN dependent (regardless of the type of lipid emulsion) for a total of five years.  
 
We will also retrospectively collect information on subjects who received FO at UCLA 
under compassionate use (EINDs 104,951, 104,766). 
 
MONITORING 
 
Hospitalized Subjects: 
 
If the subject is hospitalized, he will be monitored in the inpatient setting.  If hospitalized 
at the time of enrollment, the patient must remain hospitalized for at least 48 hours to 
ensure subject’s tolerance to FO, observe for any side effects/adverse events, and 
training/counseling of the subject’s parents/legal guardians.  The patient will be 
monitored per standard clinical protocol for pediatric inpatients.  
 
Baseline and weekly/bimonthly/monthly labs will be ordered by the primary team per 
standard of care.  These laboratory results will be collected from the subjects’ chart and 
will be used to  monitor for any side effects/adverse events.  
 
The PI or any co-investigator will evaluate the patient daily for the first 48 hours of 
therapy. Thereafter, the PI or one of the co-investigators will evaluate the inpatient 
subject at least 4 times per week.  The PI or any co-investigator will review the subjects’ 
medical chart, and question the bedside nurses, medical team, and parents/legal guardians 
regarding any side effects and/or adverse events.  Please see section entitled, “Anticipated 
Side Effects” for specific details on anticipated side effects, monitoring, and recording of 
any side effect or adverse event. Physical exams will be performed daily, and bedside 
monitoring per inpatient protocol (ie vital signs, etc) will be performed daily.  
 
Prior to discharge from the hospital, the Intestinal Failure Team and medical team will 
train the parents/legal guardians on how to administer PN and FO.  Subjects will only be 
discharged home once caregivers demonstrate proficiency on how to administer PN and 
FO.   
 
Outpatient Subjects: 
 
If the subject is enrolled as an outpatient, the subject can receive the first two doses of FO 
in a clinical setting (UCLA General Research Clinical Center (GCRC)).  The subject will 
be observed for the entire infusion period and 1 hour after the infusion.  Vitals will be 
performed prior, every two hours, and 1 hour after the termination of FO.  Trained nurses 
are available at the GCRC to perform vitals and observe for any side effects/adverse 
events.   
 


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
17 
Once the subject is discharged from the inpatient setting or has received the first two 
doses of FO in the GCRC, he will be monitored in the Intestinal Failure Clinic or GCRC 
by the PI, Dr. Kara Calkins, or any of the co-investigators. The Intestinal Failure Clinic 
provides a multi-disciplinary approach to children with SBS, IF, and PNAC.  Trained 
nurses, dieticians, and social workers are available at all clinic visits.  The GCRC 
provides outpatient rooms and support personnel (clinical nurses).  Outpatient subjects 
will be seen on a weekly, bimonthly, or monthly basis in the Intestinal Failure Clinic or 
GCRC.  It is standard of care for patients with SBS/IF and advanced PNAC to be seen as 
often as bi-weekly and as infrequently as monthly as an outpatient.  Outpatient subjects 
can be seen by the study team as frequently as once a week.  At minimum, outpatient 
subjects will be seen by the study team every month.  The primary medical team per 
standard of care will determine the frequency of visits to the IF clinic.  Should a patient 
not be scheduled for the IF clinic 4 weeks after the last clinic visit, the patient will be 
scheduled to be seen by the study team in the GCRC.     
 
At each follow-up visit, parents will be questioned regarding any adverse events or side 
effects.  A full of physical exam and review of symptoms will be performed at each clinic 
visit.   Please see section entitled, “Anticipated Side Effects” for specific details on 
anticipated side effects, and monitoring and recording of any side effect or adverse event.    
 
Should any adverse events or side effects be noted, they will be promptly reported to 
the IRB and FDA.  All guidelines for reporting side effects and adverse events will be 
followed.  
 
The primary medical team, inpatient pharmacy, and parents/legal guardians will be able 
to contact the PI or one of the co-investigators at anytime regarding any questions or 
concerns regarding the study or FO via the UCLA operator.  
 
All subjects will be followed until one month after the termination of FO. During this 1 
month follow-up period, patients will be seen in the Intestinal Failure Clinic or GCRC at 
least once, and laboratory monitoring will be continued per the primary medical team.  
Should the patient continue to demonstrate evidence of PNAC or redevelop PNAC off of 
FO (if FO was previously discontinued) as indicated by a direct biliribuin ³ 2 mg/dL on 2 
consecutive occasions, FO may be restarted if inclusion and exclusion criteria are still 
satisfied. Each time, FO is restarted, the subjects will be followed according the protocol. 
After the termination of each Omegaven treatment, subjects will be followed for 1 month.   
 
Data Safety and Monitoring Board (DSMB) composed of a neonatologist (Meena Garg, 
MD), pharmacist (Christina Shin , Pharm D),and statistician (Kate Crespi, PhD) will met 
every 6-12 months to review any adverse events or side effects and assess any 
preliminary data.  This committee will be involved in performing the early evaluations of 
the data at annual intervals to determine if significant results are obtained to warrant 
discontinuation of the trial.  All complications, adverse effects, or results that warrant 
discontinuation of the trial will be promptly reported to the UCLA Institutional Review 
Board and FDA. As of date 08/03/17, the DSMB will only meet on as needed basis as 


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
18 
determined by the investigator, DSMB member, or another regulatory body. Annual 
updates will be provided to all DSMB members via email.  Confirmation that these 
annual updates were reviewed by the respective DSMB member will be documented by a 
confirmatory email from the DSMB member.  Should a DSMB member voice any 
concerns, a formal DSMB can be held to address these concerns. This documentation will 
be provided to the IRB.  
 
 
 
WITHDRAWAL CRITERIA 
 
A patient can be withdrawn at any time should he suffer any side effect or adverse event  
that could affect his safety or jeopardize his health. 
 
WITHDRAWAL CRITERIA: 
 
Patient, parent, or legal guardian request to discontinue treatment and/or  
 
observation for any reason 
 
Uncontrolled bleeding attributed to FO  
 
Anaphylaxis due to FO 
 
Decision by PI that study withdrawal is in the subject’s best medical interest 
 
Patient is lost to follow-up  
 
Serious adverse event 
 
Physician decision based on safety of the drug in this particular patient 
 
 
 
  Possible Anticipated Risks 
 
For contraindications to Omegaven™ see Table 2.  
 
Impaired lipid metabolism 
Severe hemorrhagic disorders 
Unstable diabetes mellitus 
Collapse and shock 
Stroke 
Embolism 
Recent cardiac infarction 
Undefined coma status 
Table 2.  Contraindications to Omegaven™. 
 
Omegaven™ will not be administered to anyone who is hemodynamically unstable or in 
shock, in a comatose state, and anyone who has been diagnosised with stroke, pulmonary 
embolism, or recent myocardial infarction 
 
Side Effects Specific to Omegavenä 
Side Effects Common to Fat Emulsions 
Allergy 
Fat Overload Syndrome 
Increased Risk of Bleeding 
Metabolic Overload Syndrome 
Essential Fatty Acid Deficiency 
Hyperglycemia 
Hyperglycemia 
Hypertriglyceridemia 


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
19 
Hyperinsulinemia/hypoglycemia 
Change in Temperature/Chills/Flushing 
 
Changes in Blood Pressure 
 
Cyanosis/Shortness of Breath 
 
Naseau/Vomitting 
 
Pain 
Table 3.  Possible Side Effects. 
 
See Table 3 for possible side effects to FO and fat emulsions in general. 
  
Omegaven™ will not be administered to anyone allergic to seafood or egg, who has a 
hemorrhagic disorder, or is on anticoagulant therapy.  Patients will continue to receive 
heparin in their PN. 
 
Possible Side effects specific to Omegavenä: 
 
Allergic Reaction: 
Definition: Allergy is defined as a disorder of the immune system; it is characterized by 
excessive activation of mast cells and basophils by IgE resulting in an inflammatory 
response. The presentation of allergy varies.  It can present with a rash (eczema or hives), 
itching or red eyes, airway symptoms (wheezing, dyspnea, or angioedema),  
gastrointestinal symptoms (abdominal distention, vomiting, or diarrhea), or anaphylaxis.  
How to Identify:  The patient will be assessed for any signs or symptoms by physical 
exam and medical and patient report.  Parents will be questioned at each clinic visit for 
any signs or symptoms of allergy.  
Treatment/Withdrawal:  In the case that the patient develops an allergy in response to the 
FO, the patient will be given Benadryl, Albuterol for respiratory symptoms, or other 
treatments per the primary medical team.  If the symptoms continue to coincide with 
additional uses of FO, the patient will be withdrawn from the study or premedicated with 
Benadryl.  The decision to withdraw or continue the patient in the study will be made 
after a discussion with the parents/legal guardians of the subject.  If the patient develops 
an anaphylactic reaction or angioedema to FO, the FO will be discontinued, and the 
appropriate steps, such as Benadryl, epinephrine, steroids, and volume and airway 
resuscitation will be given per the primary medical team.  The patient will be withdrawn 
from the study immediately.   
Note:  Patients allergic to fish or egg are excluded from receiving FO.   
 
Increased Risk of Bleeding  
Definition:  increased bleeding above baseline  
How to Identify:  Subjects will be monitored according to protocol and questioned 
regarding an increase in bleeding above baseline  
Treatment/Withdrawal:  Treatment for bleeding will be according routine practice and the 
medical team.  If bleeding is primarily attributed to the intervention, the patient can be 
withdrawn from the study.  All subjects prior to an elective operation will have 
Omegaven held for 3 days prior and 4 days after the elective operation.  If at the time of 
consent it is known that an elective operation will be performed or schedule, FO will  


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
20 
start 4-14 days after this surgery, depending on the patient’s risk for bleeding (age, degree 
of IFALD, other comorbid condition). The study team in consultation with the primary 
team will decided when to start FO. Any subject with an active bleed, that is considered 
greater than baseline, will have their Omegaven held until the bleeding has decreased or 
resolved.  All decisions to hold Omegaven will be discussed with the primary medical 
team and legal guardians/parents. In order to reduce the risk for bleeding, subjects who 
require Motrin, Toradel or Aspirin, along with dialysis will be excluded from the study.  
All subjects on the study should be maintained on an acid suppressor to reduce the risk 
for a gastrointestinal ulcer.   During the study, Motrin, Toradel and Aspirin is 
contraindicated; if these drug are medically necessary, the patient will be withdrawn from 
the study.  
Note: All subjects enrolled this study have an increased baseline risk for bleeding 
because they have cholestasis.  Subjects with advanced cholestasis and portal 
hypertension, have an even greater risk for bleeding.  While Omegaven may carry the 
risk of increased bleeding, it is unclear if the benefit outweighs the risk.   
 
Prolonged Bleeding Time 
Definition:  INR > 1.4  
How to Identify:   Coagulation studies will be collected and reviewed.  The patient will 
be assessed for any clinical bleeding by physical exam and medical and patient report.  
Parents will be questioned at each clinic visit and asked to notify the PI or any co-
investigator of any signs of clinical bleeding (petechiae, nosebleeds, blood per rectum, 
gum bleeding,  hematemesis, etc) 
Treatment/Withdrawal: Product replacement (FFP, platelets, etc) will be given per the 
primary medical team.  
Notes:  FO will not be administered to patients on anti-coagulant therapy or who have a 
hemorrhagic disorder. Should the patient require anticoagulant therapy during the study 
period, the subject will be withdrawn.  The patient will continue to receive heparin in 
their PN.  Although there is a theoretical risk that FO could prolong a patient’s bleeding 
time, published literature demonstrates that there is no difference between the INRs of 
PNAC patients on FO versus those on SO31.   
 
Essential Fatty Acid Deficiency  
Definition:  Essential fatty acid definition will be defined as triene:tetraene ratio ³ 0.5.  
How to Identify:  The ratio will be determined by an essential fatty acid profile, which 
will be monitored per the primary medical team.  The patient will assessed for any 
clinical signs of essential fatty acid deficiency by physical exam and medical and patient 
report.  Parents will be questioned at each clinic visit and asked to notify the PI or any co-
investigator of any signs of an essential fatty acid deficiency (alopecia or dermatitis).  
Moreover, since thrombocytopenia can occur with essential fatty acid deficiency, 
platelets will be monitored.  Should the patient exhibit possible signs or symptoms of this 
deficiency, an essential fatty acid profile will be performed by laboratory analysis. 
Treatment/Withdrawal:  If the patient demonstrates an essential fatty acid deficiency 
(triene:tetraene ratio ³ 0.5), the patient will be withdrawn from the study.   
 


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
21 
Hyperinsulinemia/Hypoglycemia 
Definition:  insulin concentration > 25 uU/mL and persistent hypoglycemia (glucose 
concentration < 40 mg/dL after PN has been discontinued), history of significant 
exposure to a high glucose delivery rate (glucose delivery rate > 16 mg/kg/min with 
continuous PN), and Endocrinology consult verifying hypoglycemia is not secondary to 
advaced liver disease. 
How to Identify:  Should the subject demonstrate persistent hypoglycemia when PN is 
weaned or discontinued, have been exposed to a high glucose delivery rate for a 
prolonged period of time, and the primary team have a high suspicion of 
hyperinsulinemia, a serum insulin concentration can be checked when the subject is 
hypoglycemic.  Should the insulin level be elevated, while the glucose concentration is 
depressed, the patient MAY have hyperinsulinemia.  Further investigation may be 
warranted, and a consult with Endocrinology should be sought to determine the exact 
etiology. 
Treatment/Withdrawal:  The family will be informed, and given the option to withdraw.  
The primary team will also be encouraged to slowly decrease the glucose delivery rate.   
Recommendations from Endocrinology should be followed.  
 
Side effects common to FO and other fat emulsions such as Intralipidsä include:   
Fat Overload Syndrome  
Definition:  Overdose of FO or SO can result in Fat Overload Syndrome.  Fat Overload 
Syndrome occurs when a fat emulsion is infused too rapidly, or when the patient 
experiences a change in clinical status such as sepsis or renal impairment, and the 
patient’s triglyceride trough is abnormally high (> 300 mg/dL).  
How to Identify:  Bedside nursing and parents or legal guardians will be counseled to 
infuse the FO at the prescribed rate.  The PI or any co-investigator will review the 
medical charts to ensure the FO was administered at the proper rate.  Moreover, bedside 
nursing and parents or legal guardians will be questioned at what rate the FO is being 
administered. Should the FO be infused too quickly, nurses and caregivers will be 
counseled to promptly inform the PI or any co-investigator.  
Treatment/Withdrawal: If the patient is given a rapid infusion, the FO will be infused at 
the proper rate, and triglyceride troughs will be followed serially until they normalize.  
 
Metabolic Overload Syndrome 
Definition: Metabolic Overload Syndrome is characterized by a constellation of 
symptoms that include hepatomegaly with or without icterus, a change in coagulation 
parameters leading to an increased risk to bleed, splenomegaly, anemia, leucopenia, 
thrombocytopenia, altered liver function test, hyperlipidemia, hyperglycemia, headache, 
abdominal pain, and fatigue.   
How to Identify:  Patients will have physical exams on a regular basis in the inpatient 
setting and on a weekly or bimonthly basis on the outpatient setting to assess for skin 
color, signs of bleeding, or splenomegaly.  Labs will be drawn on a weekly-monthly basis 
to assess for thrombocytopenia, anemia, leukopenia, liver function, hyperlipidemia, and 
hyperglycemia.  Parents or legal guardians and medical staff will be counseled to report 
any fatigue or abdominal pain to the PI or any co-investigator. Parents will questioned at 


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
22 
all clinic visits regarding any signs or symptoms concerning for Metabolic Overload 
Syndrome.  
Treatment/Withdrawal:  If the subject is diagnosed with Metabolic Overload Syndrome, 
the patient will be discontinued from the study.   
Notes: Metabolic Overload Syndrome usually occurs with the concomitant administration 
of cottonseed oil.  Cottonseed oil will not be administered with FO.   
 
Hyperglycemia 
Definition:  Hyperglycemia is defined as a glucose ³ 150 mg/dL 
How to identify: Plasma glucoses will be monitored at least every 12 hours in the 
inpatient setting, and every week - month in the outpatient setting. 
Treatment/Withdrawal: If hyperglycemia occurs (glucose ³ 150 mg/dL), the following 
steps will be taken: 
1.) The study team will ensure the blood drawn to measure the glucose level was 
not drawn from a port infusing a dextrose containing solution.   
2.) If mild hyperglycemia (glucose level between 150-200 mg/dL) occurs, the 
glucose will be monitored for twenty-four hours.  Should the glucose level 
remain elevated (150-200 mg/dL), the glucose delivery rate (GDR) will be 
decreased by 1-2 milligrams/kilogram/minute (mg/kg/min) and then on a 
daily basis until the patient becomes normoglycemic (<150 mg/dL).  
3.)  If the glucose level is ³ 200 mg/dL, but < 300 mg/dL, serial glucose levels 
will be followed over six hours.  If after serial glucose levels, the glucose 
remains elevated (150-300 mg/dL), the GDR will be decreased by 1-2 
mg/kg/min.  Should the hyperglycemia persist, the GDR will be slowly 
decreased to achieve normoglycemia.   
4.) If the glucose is ³300 mg/dL at anytime, a repeat glucose will be drawn.  If 
the glucose is in fact ³ 300 mg/dL, the GDR will be decreased by 1-2 
mg/kg/dL.  Serial glucose levels will be followed, and the GDR will be slowly 
decreased over twenty-four hours to achieve normoglycemia.  
5.)  Insulin use will be at the discretion of the primary medical team.   
6.) Other causes for hyperglycemia will be ruled out by the primary medical 
team. 
7.) In addition to reducing the GDR, the PN may be given over an extended  
period of time. 
 
Hypertriglyceridemia 
Definition:  Hypertriglyceridemia is defined as a triglyceride (TG) trough  > 300 mg/dL 
Identification:  TG troughs will be drawn weekly – monthly  
Treatment/Withdrawal: If hypertriglyceridemia occurs, the following steps will be taken: 
1.) The study team will ensure that TG trough was measured when the patient 
was off FO for at least 4-6 hours.  
2.) If the TG was drawn at the appropriate time, it will be repeated in 1-7 days.  
Note:  Although there is a theorectical risk that FO could cause hypertriglyceridemia, it 
should be noted that FO is now commonly prescribed for hypertriglyceridemia.  In fact, 


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
23 
Gura et al described a case report of 9 year old patient with severe hypertriglyceridemia 
secondary to fat-free PN that was successfully treated with FO42.    
 
Temperature  
Definition:  A fever is defined as a rectal temperature ≥ 100.4° F. 
Identification:  As an inpatient, the subject’s temperature will be monitored per hospital 
protocol (every 2-6 hours).  Should the subject feel febrile, the medical caregiver or 
parent or legal guardian will instructed to measure the subject’s temperature.  Should the 
patient have a fever, the PI or any co-investigator will be notified. The parents or legal 
guardian will be questioned regarding any recent fevers at all outpatient visits.  Vital 
signs will be performed at each outpatient visit. 
Treatment/Withdrawal:  If the patient experiences a fever, the appropriate work-up will 
be completed by the primary medical team to ensure the patient does not have an 
infection.  If the fever is not attributed to an infection or other causes, and the source is 
thought to be FO, Tylenol or Motrin will be administered at the appropriate dose.  If a 
fever reoccurs and is attributed to FO, the patient will be withdrawn from the study. 
 
 
Chills/Cyanosis/Shortness of Breath/Nausea/Vomiting  
Definition:  self-explanatory 
Identification:  The medical caregivers and parent or legal guardian will be counseled to 
report any of these symptoms. Should the patient have a any of these symptoms, the PI or 
any co-investigator will be notified. The parents or legal guardian will be questioned 
regarding these symptoms at all outpatient visits.  
Treatment/Withdrawal:  If the patient experiences cyanosis, shortness of breath, nausea, 
or vomiting, the appropriate work-up will be completed by the primary team to rule out 
other causes, specifically infection.  Should the symptom or symptoms be attributed to 
FO, the patient will be withdrawn from the study.    
 
Pain  
Definition:  self-explanatory 
Identification:  The medical caregivers and parent or legal guardian will be counseled to 
report any signs or symptoms of pain. Should the subject have a any of these symptoms, 
the PI or any co-investigator will be notified. The parents or legal guardian will be 
questioned regarding these symptoms at all outpatient visits.  Physical exams will be 
performed on a regular basis in the inpatient setting, and weekly-bimonthly on an 
outpatient setting to assess for pain.  
Treatment/Withdrawal:  If the patient experiences pain, the appropriate work-up will be 
completed by the primary team to rule out causes other than the FO.  Should the 
symptom or symptoms be attributed to FO, the patient will be administered Tylenol or 
Motrin at the appropriate dose for pain relief.  If the pain is not relieved or reoccurs, the 
patient will be withdrawn from the study.  
 
The above side effects/adverse events will be monitored by the following specific means 
(See Table 4 and Figure 3):   


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
24 
• Allergy—clinical observation, patient report, vital signs 
 
• Prolonged Bleeding Time—PT/PTT/INR, clinical observation, patient 
report 
 
• Essential Fatty Acid Deficiency—essential fatty acid profiles, clinical 
observation, and patient report 
 
• Hyperglycemia—glucose levels 
 
• Fat Overload Syndrome—triglyceride level, patient report  
 
• Metabolic Overload Syndrome—TG level, complete blood count, liver 
function tests, PTT/PT/INR, glucose levels, physical exam, patient report, 
clinical observation  
 
• Hypertriglyceridemia—TG levels 
 
• Changes 
in 
Blood 
Pressure/Chills/Cyanosis/Shortness 
of 
Breath/Nasuea/Vomitting—clinical observation, patient report, vital 
signs 
 
• Pain—clinical observation and patient report 
 
• Hyperinsulinemia/hypoglycemia—serum 
glucose 
and 
insulin 
concentrations 
 
• Increased risk for bleeding—clinical observation, patient report  
 
 
Should a side effect be noted, the following specific responses may occur: 
 
Side Effect 
Response 
Allergy 
Assess and treatment by Medical Team, Benadryl, 
Albuterol, possible withdrawal 
Anaphylaxis 
Assess and treatment by Medical Team, withdrawal 
Bleeding  
Treatment by Medical Team, consideration of 
withdrawal 
Essential Fatty Acid Deficiency  Treatment by Medical Team, withdrawal 
Hyperglycemia 
Changes in PN therapy, insulin 
Fat Overload Syndrome 
Monitoring of triglycerides 
Metabolic Overload Syndrome 
Withdrawal 


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
25 
Hypertriglyceridemia 
Monitoring of triglycerides 
Changes in 
Temperature/Chills/Flushing 
Assess and treatment by medical team, Tylenol, 
Motrin, withdrawal 
Changes in Blood 
Pressure/Shortness of 
Breath/Cyanosis 
Assess and treatment by medical team, withdrawal 
Pain 
Assess and treatment by Medical Team, Tylenol, 
Motrin, possible withdrawal 
Hyperinsulinemia/hypoglycemia Endocrinology consult 
Table 4.  Responses to Side Effects. 
 
 
Figure 3.  Monitoring of Side Effects or Adverse Events. 
 
See attached CRF 4 for recording of side effects, adverse events, or serious adverse 
events. 


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
26 
Protocol 
 
1.  Purpose of the study 
 
The specific aim of this pilot study is to investigate if providing FO, at 1 gm/kg/d IV, to 
children with PNAC will safely reverse or ameliorate their PNAC.  Study subjects will be 
compared to 40-80 historical controls with SBS and PNAC, who received standard SO, 
1gm/kg/d IV, available as Intralipid™ for > 60 days.  The following clinical outcomes 
will be measured:  
 
1)  
Reversal of PNAC in infants receiving Omegavenä    
2)  
Growth of infants receiving Omegavenä 
3)  
Safety of Omegavenä in infants with PNAC 
4) 
Mechanism of Omegavenä 
 
To address the above specific aims the following will be performed: 
1.)  
Serial laboratory tests to evaluate cholestasis and hepatic dysfunction (total 
bilirubin, direct bilirubin, ALT, AST, alkaline phosphatase, and GGT)  
2.)  
Serial 
anthropometric 
measurements 
(weight, 
length, 
and 
head 
circumference) 
3.)  
Serial laboratory test to evaluate safety (coagulation parameters, platelets 
and essential fatty profile) 
4.) 
Serial serum proteomic, inflammatory markers, bile acids, phytosterols, 
microRNA and microarray analysis and fatty acid analysis of red blood cell (RBC) 
membranes. 
5)   Serial fecal specimens will be collected to evaluate the intestinal microbiome in 
children at risk for PNAC. 
  
PNAC will be defined as a direct bilirubin ≥ 2 mg/dL on 2 consecutive measurements.  
Reversal of PNAC will be defined as direct bilirubin < 2 mg/dL.  Essential fatty acid 
deficiency will be defined as a triene:tetraene ratio ³ 0.5. 
 
2.  Names and Addresses of Investigators, Facilities, and Institutional 
Review Board 
See Form 1572.   
 
3.  Criteria for Patient Selection/Estimate Number of Patients to be 
Studies 
The study will target to enroll 80 subjects.  


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
27 
 
INCLUSION CRITERIA: 
-Clinical evidence of PNAC 
-Direct bilirubin ³ 2 mg/dL on 2 consecutive measurements 
-Expected parenteral nutrition course greater than 30 days  
-Acquired or congenital GI disease  
->2 weeks of age and <18 years of age 
->60% of calories from TPN 
-Failed available, standard therapies for PNAC (ie advancement of    
feeds, cycle PN, Actigal, avoidance of overfeeding, removal or 
reduction of copper in PN if elevated by laboratory analysis) 
 
EXCLUSION CRITERIA: 
-Inborn errors of metabolism 
-Extracorporeal Membrane Oxygenation (ECMO) 
-Seafood, egg, or Omegavenä allergy  
-Documented cause of liver disease other than PNAC 
-Hemorrhagic disorder 
-Anticoagulant therapy 
-Hemodynamically unstable or in shock 
-Comatose state 
-Stroke, pulmonary embolism, recent myocardial infarction 
-Diabetes 
-Fatal chromosomal disorder 
-Enrollment in any other clinical trial involving an investigational  
agent 
-Patient, parents, or legal guardians unable or unwilling to give  
Informed consent  
-Patient expected to weaned from PN in 30 days  
-Unable to tolerate necessary laboratory monitoring 
-Patient requiring aspirin or toradel or motrin 
-Patient requiring dialysis 
  
 
 
The gender and ethnic make-up of the subjects will reflect the gender and ethnic make-up 
of the patients admitted and seen at Mattel Children’s Hospital and Pediatric outpatient 
clinics.  
 
4.  Description of the Study Design  
 
Experimental Group (FO): 
If the patient meets the inclusion and exclusion criteria, and the parents/legal guardians 
sign the consent form, the subject will be enrolled.  Demographic, clinical, laboratory, 
and safety monitoring data will be collected.  Patients will receive FO at 0.5 gm/kg/d IV 


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
28 
for 2 days, then 1 gm/kg/d IV for the remainder of the study.  Subjects will be followed 
for 1 month after the termination of FO.  Data will be collected for up to 5 years after the 
termination of FO intervention.  
 
Once the subject enters the study, FO will be administered for the duration of PN.  
Should PN be terminated, FO will be stopped.  If the subject re-develops biochemical 
evidence of PNAC (direct bilirubin ³ 2 mg/dL on 2 consecutive occasions) at later date 
and is PN-dependent, but not receiving FO, FO can be re-started  as long as inclusion and 
exclusion criteria are satisfied. FO will be continued for the duration of PN. Should FO 
be restarted at a later date, subjects will be followed for 1 month after the termination of 
FO.   
 
Historical Controls (SO): 
Subjects will be compared to 40-80 historical controls with SBS and PNAC who have 
received SO.  PNAC will be defined as a direct bilirubin ≥ 2 mg/dL on 2 consecutive 
measurements. 
 
Methods: 
The following clinical outcomes will be measured:  
 
1)  
Reversal of PNAC in infants receiving Omegavenä    
2)  
Growth of infants receiving Omegavenä 
3)  
Safety of Omegavenä in infants with PNAC 
4) 
Mechanism of FO 
 
To address the above specific outcomes the following will be performed: 
 
1)   
Serial laboratory tests to evaluate cholestasis and hepatic dysfunction.   
The total and direct bilirubin, ALT, AST, alkaline phosphatase, and GGT will be 
collected.  These labs are performed as part of standard care for patients with 
SBS/IF and PNAC. Reversal of cholestasis will be defined a direct bilirbuin < 2 
mg/dL.  
 
2)  
Serial anthropometric measurements of weight, length, and head 
circumference 
The above measurements will be performed on a monthly basis.  The information will be 
collected from the subject’s chart.  The bedside nurse or the Intestinal Failure nurse will 
perform these measurements. 
 
3)  
Serial laboratory test including coagulation parameters, platelets and 
essential fatty profiles.  
Coagulation parameters (PTT/PT/INR), and platelets will be collected.  These labs are 
considered standard of care of patients with SBS/IF and PNAC.  Essential fatty acid 
profiles will be performed per the primary team, and results will be collected if the profile 
is performed.  


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
29 
 
4) 
Serial serum proteomic, inflammatory markers, bile acids, phytosterols, 
microRNA and microarray analysis and fatty acid analysis of the RBC membrane 
Serum will be collected at baseline, 2 weeks, 3 months, and 6 months, and every six 
months while the subject is PN dependent. Samples will be coded and collaborators will 
not be provided the key code. Proteomic analysis will be performed in conjunction with 
the laboratories of James LeBlanc, PhD (UCLA).  Microarray analysis will be conducted 
in conjunction with the Microarray Core (UCLA).   Fatty acid analysis of the RBC 
membrane in conjunction with Susan Henning, PhD (UCLA).  MicroRNA analysis will 
be performed in conjunction with Sherin Devaskar, MD (UCLA).  Phytosterol analysis 
will be performed in conjunction with Robert Steiner, MD (University of Wisconsin) and 
Jogchum Plat (Maastricht University, Netherlands). Bile acid analysis will be performed 
in conjunction with Robert Steiner, MD (University of Wisconsin). These analyses will 
only be performed before, during, and after the first 6 months of FO treatment.  In other 
words, if a subject redevelops or continues to have PNAC and FO is restarted, these 
analyses will not be performed.    
 
For microarray analysis, 1 cc of blood will be collected at room temperature, and placed 
into a PAXgene tube.  RNA will then be isolated using the QiAMP RNA blood mini kit 
(Qiagen, California), and then frozen and stored at -80°C.  Microarray analysis will be 
performed using an Affymetrix microarray (Affymetrix, California).   
 
For proteomic analysis, phytosterols, bile acids, microRNA and RBC membrane fatty 
acid composition, 2.5 cc of blood will be collected into an EDTA tube.  The blood will be 
separated into RBCs and plasma.  The plasma will be stored at -80 °C for proteomic 
analysis via mass spectroscopy.  The RBCs will also be stored at -80 °C for RBC fatty 
acid membrane composition analysis via thin layer chromatography.  
 
If there is concern that a subject is septic at the time of blood collection, the collection 
will be delayed until there is indication that the sepsis has resolved.  Resolution of sepsis 
is determined by a negative blood culture.  If blood is unable to be obtained at the 
scheduled collection time if the subject is an outpatient due to problems with the subjects’ 
line, blood can be collected at the next clinic visit scheduled for routine purposes.  
 
5) Serial fecal specimens will be performed to evaluate of the intestinal microbiome 
in children at risk for PNAC. Fecal specimens will be collected at baseline, 2 weeks, 
3 months, and 6 months of FO therapy, and every 6 months thereafter for subjects 
who remain PN dependent. The OMR-200 device (OMNIgene-gut, OMR-200, DNA 
Genotek) will be used for fecal specimens.  This collection kit is intended for the non-
invasive self-collection and stabilization of microbial DNA in human stool. The device is 
designed to enable safe and effective collections by naive users and medically trained 
personnel, alike. It is to be used for research purposes only. Detailed pictorial instructions 
are included with each collection device. Users may also view an online video which 
demonstrates proper sample collection with OMR-200. Per the provided instructions, 
bulk stool (approximately 400 g) is collected from the diaper, stoma bag or toliet into an 


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
30 
appropriate receptacle. The user then takes a small amount of stool using the provided 
'spatula', fills the top of the collection device, and caps the tube. The action of capping 
seals the device and automatically extrudes the stool sample from the measuring chamber 
into the collection tube.  Inside the tube is a non-toxic stabilizing reagent and mixing 
apparatus. After the sample is collected, and the tube is capped, the user then vigorously 
shakes the tube for 30 seconds to homogenize it. At that point, the sample is liquefied, 
and the relative abundance of DNA contributed by the gut microbiota is stabilized, such 
that a 'snapshot' of the in vivo state is preserved for 14 days at ambient temperatures.  If 
stool cannot be collected at the time of research visit and the subject is not in the inpatient 
setting, the family will be provided with OMR-200 kit for stool collection.  The specimen 
will be returned to the study team within 14 days of the next research/clinic visit.  A stool 
sample collected in this device is compliant with IATA regulations, and may be shipped 
at ambient temperatures internationally. 
 
DNA Genotek designs and manufactures products in accordance with the ISO 13485 
Quality System (for medical devices), Good Manufacturing Practices, and FDA QSR 
820.DNA extraction and 16S rRNA microbiome profiling will be performed by DNA 
Genotek.  After no longer than 14 days, samples will be frozen for future analysis. 
 
 
All plasma and RBC samples will be stored in the Neonatal Research Center.  
 
A DSMB will meet every 6 months to evaluate any side effects or adverse events, assess 
the subject's progress, and analyze any preliminary data.   After several DSMBs, the 
frequency of DSMB meetings can be decreased to at minimum once a year. As of 
08/03/17, DSMB will only meet on as needed basis.  
 
All deviations to the protocol will be recorded and described.  All deviations will be 
reported to the appropriate personnel (ie UCLA IRB) according to IRB 
guidelines/regulations. Moreover, the reason for the deviation, and response to the 
deviation will be recorded.  See CRF 5 for specifics. 
 
5.  Method for Determining Dose, Maximum Dose, and Duration  
 
The dose of Omegavenä was previously published by Gura, et al31,32.   Therapy will 
begin at 0.5 gm/kg/d IV.  After 2 days, therapy will be advanced to 1 gm/kg/d IV.  The 
dose will remain at 1 gm/kg/d.  FO can be restarted if the subject continues to 
demonstrate evidence of PNAC or redevelops PNAC off FO.    
 
6.  Description of the Observations to be made to fulfill the Study 
Objectives  
 
PNAC  


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
31 
Improvement in PNAC will be assessed by labs evaluating cholestasis and liver function 
(total and direct bilirubin, ALT, AST, alkaline phosphatase, and GGT).  These labs will 
be ordered per the primary medical team, 
 
Safety  
Safety of Omegavenä will be assessed by laboratory studies and monitoring for any side 
effects or adverse events.  These labs will be ordered per the primary medical team.  
 
PN labs, coagulation parameters (PT/PTT/INR), and platelets will be drawn per the 
primary team...  Subjects will be monitored either in the inpatient or outpatient setting for 
adverse events or side effects.  All adverse events and side effects will be described, 
tracked, and reported to appropriate persons/institutions.  
 
Growth  
Growth (weight, length, and head circumference) will be measured monthly by the 
bedside nurse or nurse in the Intestinal Failure Clinic.   
 
Mechanism 
Currently, there is a paucity of information regarding how FO reverses IFALD.  Since SO 
contains phytosterols and FO lacks phytosterol.  As a result, the liver’s exposure to 
phytosterols is decreased with FO. Sterols are known to interfere with bile acid transport 
resulting in cholestasis—the hallmark of pediatric IFALD.  Major sterols include 
stimgasterol, sitosterol, and campesterol. SO is made up of 57% phytosterols.  FO is 
made up of cholesterol only.43 Approximately 5% of orally ingested phytosterols are 
absorbed by the intestine, while 95% are excreted in the feces. However, intravenous 
fatty acid emulsions bypass the intestine, and rely up on the canicular ABCG5/G8 
transporter to secrete phytosterols into the bile.  Sitosterol inhibits the cholesterol 7α-
hydroxlase, the rate-limiting step that converts cholesterol into bile acids, which act as an 
important lipid emulsifier and stabilizer and plays an important role in cholesterol 
homeostasis (Boberg, 1989).  Moreover, stigmasterol antagonizes the farnesoid X 
receptor (FXR), a nuclear receptor that protects the liver from hepatoxic bile acids by: 1. 
reducing bile acid import via suppressing a bile acid co-transporter (NTCP, SLC10A1), 
2. reducing bile acid synthesis by suppressing CYP7A1, and 3. increasing bile acid efflux 
by up-regulating the bile salt export pump (BSEP) ABC11 and organic solute transporter 
(OST).  In animal models, FXR knockouts develop liver injury, while treatment with 
FXR agonists protect against cholestasis.44 In cell lines, stigmasterol antagonizes BSEP 
(Carter 2007).  In fact, mice infused with PN and FO exhibited less liver injury compared 
to those infused with PN and SO.  When stigmasterol was added to FO, these animals 
developed cholestasis.45 In humans, phytosterol concentrations in control children have 
been reported at 40 µmol/L, while concentrations in children with IFALD were as high as 
1500 µmol/L.46 A linear correlation between PN duration with serum phytosterols has 
been documented.47,48  
Bile acid transport is not only regulated by phytosterols, but also inflammation.  Children 
with IF at are high risk for inflammation secondary to gut injury and bloodstream 


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
32 
injections.  Sepsis is considered be a major culprit in the pathogenesis of IFALD.8,49  
Lipopolysaccharides and cytokines are known to alter BSEP and NTCP expression.50,51  
When liver macrophages were stimulated with either stigmasterol, lipopolysaccride, or 
placebo, cells subjected to stigmasterol or lipopolysaccride exhibit increased transcription 
of IL-6 and TNF-α.45  
The dose and polyunsaturated fatty acid composition of the IFE product may further 
exacerbate inflammation.  SO is composed mainly of pro-inflammatory omega-6 fatty 
acids. FO, on the other hand, is composed of mainly anti-inflammatory omega-3 fatty 
acids.  As a result, FO alters downstream production of pro- and anti-inflammatory 
compounds.52  In fact, prior to transitioning to FO, animals and children receiving SO 
exhibited a shift from high concentrations inflammatory eicosanoids to anti-inflammatory 
eicosanoids and pro-resolving lipid mediators.52,53    
The dose and type of fatty acid emulsion may also effect lipid metabolism and hepatic 
architecture.  In animal experiments, high omega-6:omega-3 fatty acid ratios correlate 
with hepatic lipid accumulation and steatosis by regulating peroxisome proliferator-
activated receptor Υ (PPAR-Υ) and sterol regulatory element binding proteins  
(SREBPs).52,54,55  PPAR-Υ regulates fatty acid storage, while SREBPs are involved in 
cholesterol synthesis and fatty acid uptake.  As fat accumulates in hepatic cells, 
phagocytic dysfunction and impaired endotoxin clearance occurs, resulting in hepatic 
injury.  
In summary, we believe that phytosterolemia and inflammation, which are influenced by 
sepsis and polyunsaturated fatty acids, act synergistically and simultaneously to: 1. 
inhibit the liver’s ability to promote bile acid secretion and 2. promote hepatic 
remodeling—subsequently, resulting in the biochemical and histological features of 
IFALD.  While there is evidence to suggest these links, there is a paucity of human 
studies investigating this hypothesis.  
Proteomic, microarray, and microRNA analysis will provide insight into what proteins 
and genes are altered (up-regulated or down-regulated) by FO intervention in this specific 
population. Specific microRNAs are small RNAs that contain seed sequences that 
complement the 3'-untranslated region of mRNAs, post-transcriptionally regulating gene 
expression. MicroRNAs are seen in non-cell based serum or plasma, these levels 
correlate with cellular injury or inflammation. In the case of IFALD, where there is 
established cholestatic liver injury, certain liver-specific miRNAs are seen in the serum 
as biomarkers of liver injury.  In this study, we plan to examine subjects who have 
incurred liver injury as seen with elevation of serum direct bilirubin and transaminases, to 
determine if liver-specific microRNAs increase. With intervention with FO, when the 
liver injury abates, liver specific microRNAs will be evaluated in serum to see if their 
concentrations diminish. This study is designed to see if the microRNAs are specific and 
sensitive in predicting liver injury and resolution of the same. With regards to the 
proteomic and microarray studies, areas of interest include: inflammation, thrombosis, 
lipid and glucose metabolism, insulin resistance, and oxidation/antioxidation.  
Phytosterol and bile acid analysis will provide insight into how FO alters sterols over 
time.   


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
33 
 
Serial fecal specimens will provide insight into how the gut microbiome is altered by intravenous 
fat and cholestasis. Animal models of PNAC have demonstrated that:  1.) phytosterols in 
soybean oil cause dysbiosis and 2.) dysbiosis causes hepatic injury via the activation of the toll-
like receptor-4 by bacteria.  In rodents receiving PN and soybean oil who have PNAC, 
FXR/LXR expression is reduced and colonic Erysipelotrichacease (a gram negative bacteria) is 
increased by 20-30% in comparison to controls. In contrast, in rodents who received PN and fish 
oil, biliary flow is preserved and their fecal microbiota is distinctly different when compared to 
rodents who received soybean oil. In addition, lack of enteral nutrition results in intestinal 
atrophy and inflammation.  As the gut’s permeability increases, bacteria secondary to bacterial 
overgrowth translocate into the bloodstream resulting in infections and hepatic inflammation. 
Like phytosterols, the cytokine interleukin-6 (IL-6) inhibits FXR/LXR, causing cholestasis.  
High omega-6:omega-3 ratios further increase hepatic inflammation and accelerate liver injury. 
Studies have demonstrated that the type of dietary fat (oral or IV) alters the microbiome. In fact, 
fish oil positively influences the microbiome resulting in improved metabolic and liver health.  
However, it is unknown how the microbiome is altered in children receiving PN and whether the 
type of IV fatty acid alters intestinal bacteria. 
 
These time-points were selected for specific reasons.  The literature supports that the 
biochemical effect of FO can be detected as early as 6 weeks, but as late as 3-6 
months30,31.  Collecting blood 4 months after FO has terminated, will provide information 
on whether the effect of the drug is sustained.  
 
By assessing the RBC membrane over time, we will be able to detect changes in the fatty 
acid composition.  Changes in the lipid content of the cell membrane effects cell function 
and fluidity which may impact transcription and translation.  
 
7. Clinical Procedures, Laboratory Tests, and other Measures to be 
taken to Monitor for Side Effects 
 
Clinical Procedures 
Monitoring for any possible side effects or adverse events will include, but not limited to: 
 
 
INPATIENT SETTING: 
 
 
-bedside monitoring per inpatient protocol (vital signs, etc) 
 
 
-daily physical exams 
 
 
-primary care and observation by primary medical team 
 
 
-labs per primary team 
 
 
-patient report 
 
 
-clinical observation 
 
 
-assessment by PI or any co-investigator at least 4 times/week 
 
 
-medical staff and parents/legal guardians will be questioned for any of the  
 
 
anticipated side effects of FO at least 4 times/week 
 
 
-medical chart review 


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
34 
 
 
OUTPATIENT SETTING: 
-weekly/bimonthly/monthly clinic visits to the Intestinal Failure Clinic per 
the primary medical team or GCRC 
 
 
-labs per protocol 
 
 
-patient report  
 
 
-clinical observation 
 
 
-full physical exams 
 
 
-full review of systems  
 
 
-parents/legal guardians will be questioned for any of the  
 
 
anticipated side effects  
 
 
-medical chart review 
 
Laboratory Tests 
All blood will be taken from existing catheters using a sterile technique.  In the rare case 
that the subject does not have an intravenous tube to draw blood, blood will be taken 
from a vein or small artery. All labs will be per the primary medical team and part 
standard of care.  
 
At baseline and at the 2 weeks and 3 and 6 months, and every 6 months thereafter (for 
subjects who remain PN dependent), blood (3.5 cc) will be collected every six- month 
until FO or PN has been stopped.  The microarray requires 1/5 (0.2) teaspoon (1 cc) of 
blood.  The mircoRNA analysis requires 1/10 (0.1) teaspoon (0.5 cc) of blood. The 
proteomic, phytosterols, and bile acid analysis and/or RBC membrane fatty acid analysis 
will require 2/5 (0.4) teaspoon (2 cc) of blood.  
 
Study 
Amount of Blood Required  
Microarray 
1 cc 
MicroRNA  
0.5 cc  
Proteomic, Inflammatory markers, Phytosterols, Bile 
acids, RBC fatty acids 
2 cc 
Fecal specimens collection  
400 g at least  
 
 
Due their small size and limitations in blood sampling, neonates weighing less 1.5 kg at 
enrollment, microarray, microRNA, inflammatory markers, phytosterols, bile acids, 
proteomic, and RBC membrane composition analyses will not be performed during the 
study period.  
 
The microarray, proteomic, inflammatory markers, phytosterols, bile acids, microRNA 
and RBC fatty acid membrane composition analysis are not considered standard labs for 
routine care.  The study will pay for these labs.  
 


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
35 
At baseline and at the 2 week and 3 and 6 month, thereafter every six-months (if the 
subject continues to receive PN), 400 g of fecal specimens will be collected to evaluate 
the intestinal microbiome. 
 
 
Other Measures  
 
Collection of Safety Data: 
 
If an adverse event or serious adverse event occurs, it will be described accordingly per 
312.32 and 312.33:   
1) “Associated with the use of the drug:  There is a reasonable possibility that the 
experience may have been caused by the drug. 
2) Disability. A substantial disruption of a person's ability to conduct normal life 
functions. 
3) Life-threatening adverse drug experience:  Any adverse drug experience that 
places the patient or subject, in the view of the investigator, at immediate risk of 
death from the reaction as it occurred, i.e., it does not include a reaction that, had 
it occurred in a more se  vere form, might have caused death. 
4) Serious adverse drug experience: Any adverse drug experience occurring at any 
dose that results in any of the following outcomes: Death, a life-threatening 
adverse drug experience, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant disability/incapacity, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be 
life-threatening, or require hospitalization may be considered a serious adverse 
drug experience when, based upon appropriate medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
5) Unexpected adverse drug experience : Any adverse drug experience, the 
specificity or severity of which is not consistent with the current investigator 
brochure; or, if an investigator brochure is not required or available, the 
specificity or severity of which is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current 
application, as amended. For example, under this definition, hepatic necrosis 
would be unexpected (by virtue of greater severity) if the investigator brochure 
only referred to elevated hepatic enzymes or hepatitis. Similarly, cerebral 
thromboembolism and cerebral vasculitis would be unexpected (by virtue of 
greater specificity) if the investigator brochure only listed cerebral vascular 
accidents. "Unexpected," as used in this definition, refers to an adverse drug 
experience that has not been previously observed (e.g., included in the 
investigator brochure) rather than from the perspective of such experience not 


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
36 
being anticipated from the pharmacological properties of the pharmaceutical 
product.” 
In addition to the above classification, further details that will be recorded: 
 
6) Timing:   when the event occurred and any temporal associations.   
 
7) Resolution: If and when the event resolves, details of the resolution will be 
recorded.   
 
8) Response to Event:  Response to event includes any treatment, withdrawal from 
the study, and communication with the IRB and FDA 
 
9) Other Event:  Not a serious adverse drug experience, life-threatening, or 
associated with a disability  
 
 
8.  Chemistry, Manufacturing, and Control Information  
 
(a-c)  Please see attached information from the manufacturer of the drug, Fresenius Kabi.  
 
(d)  Labeling—n/a 
 
(e) A claim for categorical exclusion under 25.30 or 25.31 is being made.  
  


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
37 
Pharmacology and Toxicology Information 
 
Pharmacology and drug disposition  
Studies in animal are limited with respect to Omegavenä. 
 
However, there are studies comparing FO to standard soybean oil and their effect on 
PNAC.  Studies have demonstrated that animals receiving standard lipid emulsions 
develop histological evidence of hepatic steatosis, reduced bile flow, and alterations in 
liver enzymes. These changes, however, can be ameliorated or prevented when standard 
lipids are replaced with FO.   Van Aerde et al. compared bile flow rates in piglets 
administered FO or SO.   While the piglets who received soybean fat emulsion had 
elevated bilirubin concentrations and reduced bile flow, the piglets who received FO had 
similar bilirubins and bile flow rates when compared to control.28 
 
A murine model was employed by Alwayn et al. to collaborate the above findings.  Mice 
received a fat-free, high carbohydrate diet in combination with FO, either enteral or 
intravenous, or standard intravenous Intralipidsä.  Animals that received the high-
carbohydrate, fat free diet alone or in combination with Intralipidsä demonstrated severe 
liver disease, characterized by elevations in hepatic enzymes, abnormal liver biopsies, 
and increased hepatic fat content.  Histological staining revealed diffuse steatosis, and 
MR-spectroscopy demonstrated marked increase in hepatic fat content.  Liver biopsies 
from the group that received enteral or intravenous FO, however, were similar to control, 
and had significantly decreased hepatic fat content compared to the other experimental 
groups.29 
 
There is theoretical concern that the use of FO as the sole source of fat in PN could lead 
to essential fatty acid deficiency.  However, when mice were fed various percentages of 
fish oil for 9 weeks, 1 and 5% fish oil groups demonstrated evidence of essential fatty 
acid deficiency, while the 10% fish oil group did not display any evidence of essential 
fatty acid deficiency as measured by a triene-tetrane ratio.34 
 
Please see information supplied by the manufacturer of FO for additional information.   
Please see section entitle, “Previous Human Experience with FO” for information 
regarding human experience with this drug.  
  
 
 


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
38 
Additional Information 
 
This study will be performed in children who are considered a vulnerable population.  All 
regulations will be adhered to as dictated by the governing IRB. 
Human Subjects Research: 
 
PROTECTION OF HUMAN SUBJECTS 
 
1. Risks to Subjects: 
 
Human subjects involvement and characteristics: 
Subject identification and recruitment will be carried out in the at Mattel Children’s 
Hospital Neonatal Intensive Care Unit, Pediatric Floor, Pediatric Intestinal Failure Clinic 
at UCLA Medical Center, and Santa Monica UCLA Medical Center and Orthopedic 
Hospital.  UCLA Medical Center is one of the largest medical centers in Southern 
California.  The NICU, Pediatric Floor, and clinics are state-of-the-art clinical facilities 
with a well respected, a group of pediatricians and subspecialists with diverse expertise,. 
The subjects involved in this must have clinical evidence of PNAC, a direct bilirubin ≥ 2 
mg/dL on 2 consecutive measurements, expected PN course > 30 d, and be > 2 weeks of 
age and < 18 years of age.  The gender and ethnic backgrounds of the eligible neonates 
will undoubtedly reflect the background of children admitted to the Pediatric service. 
Patients with inborn errors of metabolism, on Extracorporeal Membrane Oxygenation 
(ECMO), a seafood, egg or Omegavenä allergy, documented case of liver disease other 
than PNAC, hemorrhagic disorder, on anticoagulant therapy, hemodynamically unstable 
or in shock, in a comatose state, have a history of stroke, pulmonary embolism, or recent 
myocardial infarction, diabetes, or a fatal chromosomal disorder are excluded from the 
study.  All subjects enrolled will be vulnerable patients as they are children. 
 
Sources of Materials: 
Type of Specimens, Data, or Records: 
The specimens and data collected from patients enrolled in this study will used 
specifically for this study alone.  The only specimens collected are blood samples.  The 
data collected concerning the subject will be obtained from the subject’s medical records.   
The study team will review the entire medical record, including the following: 
diagnosises, birthweight, gestational age, hospital where the subject was born, PN data 
(PN calories/day, EN calories/day, PN dextrose dose/day, PN protein dose/day, PN lipid 
dose/day), feeds with breastmilk, candidate for transplant, liver biopsy data, abdominal 
ultrasound data, types of gastrointestinal surgeries, episodes of sepsis, date and cause of 
death. 
  
The following growth measurements and laboratory information will be collected:  
weight, length, head circumference, fluid balance, vital signs, urine sugar/ketones, 
laboratory tests (sodium, potassium, chloride, carbon dioxide, bicarbonate, glucose, 


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
39 
BUN, creatinine, triglycerides, calcium, magnesium, phosphorus, prealbumin, albumin, 
total protein, alkaline phosphatase, bilirubin (total and direct), GGT, ALT, AST, essential 
fatty acid profile, hemoglobin, hematocrit, red blood cell, white blood cell, platelets, PT, 
PTT, selenium, copper, zinc, iron, carnitine, Vitamins A, D, and E, and aluminum).   
 
Blood will also be used for microarray, proteomic, micro RNA, inflammatory markers, 
phytosterol, bile acids, and RBC membrane fatty acid analysis. 
 
No identifying information will be included in any of the manuscripts or reports of the 
data. 
 
Data Collection, Storage, and Confidentiality: 
Data will collected on Case Report Forms (CRFs) (See attached CRFs). The subject will 
be assigned a code to protect his or her privacy.  The coded CRFs, along with consents, 
will be stored in a locked file/protected computer database accessible only by study 
personnel.   Only the study staff will be able to link the subject ID numbers to personal 
identifiers.  No data with subject identifiers will be released to anyone as required by law. 
All data will be stored by the principal investigator in a locked cabinet in locked room or 
protected computer database and kept in the manner and length of time required by the 
federal and state authorities.  All data collected under this protocol will be confidential.  
When the results of the research are published or discussed in conferences, no 
information will be included that would reveal the patients identity.  If photographs, 
videos, or audiotape recordings will be used for educational purposes, then the patient’s 
identity will be protected or disguised.   
 
All blood (plasma and RBCs) will be stored in the Neonatal Research Center.  Tubes will 
be labeled with the subject’s assigned code.  
 
Potential Risks:  
Risks of Fish Oil (Omegavenä): 
Omegavenä is not approved for use in the United States and the clinical experience with 
it is limited. Due to lack of experience in certain life threatening situations, the 
manufacturer does not recommend the use of this product in certain patients.  The 
manufacturer specifically does not recommend Omegavenä in patients with severe liver 
or renal insufficiency, children, or premature infants.  The manufacturer also states that 
patients should not receive Omegavenä for more than four weeks. Therefore, 
considering this study is targeting children with liver disease, there may be risks that are 
currently unforeseeable with the use of this unapproved drug. 
 
In general, Omegavenä is not recommended in patients who are in a coma, or who have 
unstable diabetes, or had a heart attack, stroke, or clot.  Patients who are in shock should 
not receive Omegavenä.  The manufacturer has indicated that there may be increased 
risk of an allergic reaction to this product in patients with egg or shellfish allergies.  
Omegavenä can cause problems with bleeding.  It is therefore not recommended for 


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
40 
anyone who has severe hemorrhagic disorders.  There is a concern that patients receiving 
Omegavenä could develop an essential fatty acid deficiency.  
 
In order avoid potential risks, patients must met inclusion and exclusion criteria. In an 
effort to minimize risks, patients with a hemorrhagic disorder, on anticoagulant therapy, 
hemodynamically unstable or in shock, in a comatose state, who have a history of stroke, 
pulmonary embolism, recent myocardial infarction, or diabetes are excluded from the 
study.  Moreover, coagulation parameters and liver function tests will be monitored on a 
weekly basis, and an essential fatty acid profile will be monitored at baseline, and 3 and 6 
months of therapy..  
 
Risks of Intravenous Fats: 
Preliminary studies in animals and limited studies in humans have indicated that the risks 
of Omegavenä are similar to the risks other intravenous fat. Omegavenä, like other 
intravenous fats, can cause hyperglycemia, hypertriglyceridemia, and a metabolic 
acidosis.  If a patient receives an overdose of an intravenous lipid, or if it is given too 
quickly, “fat overload syndrome” can occur.   It is also possible that an intravenous lipid 
can cause “metabolic overload.”  
 
In order to assess for these conditions or complications, patients will be monitored by 
report, physical exam, and scheduled laboratory tests.   While patients are hospitalized, 
glucoses will monitored on a daily basis, and with any change in TPN.  As an outpatient, 
glucoses will monitored, and with any change in TPN.  A triglyceride trough, along with 
electrolytes, and arterial, venous or capillary gas will be performed on a weekly basis.  
 
In the advent of hyperglycemia occurs (glucose ³ 150 mg/dL), the following steps will be 
taken: 
1.)  We will ensure the blood drawn to measure the glucose level was not drawn 
from a port infusing a dextrose containing solution.   
2.)  If mild hyperglycemia (glucose level between 150-250 mg/dL) occurs, the 
glucose will be monitored for twenty-four hours.  Should the glucose level remain 
elevated (150-250 mg/dL), the glucose delivery rate (GDR) will be decreased by 
1-2 milligrams/kilogram/minute (mg/kg/min).  If the patient remains 
hyperglycemic, the GDR will slowly be decreased until the patient becomes 
normoglycemic (<150 mg/dL).  
3.)   If the glucose level is ³ 250 mg/dL, but < 300 mg/dL, serial glucose levels 
will be followed over twelve hours.  If after serial glucose levels, the glucose 
remains elevated (150-300 mg/dL), the GDR will be decreased by 1-2 mg/kg/min.  
Should the hyperglycemia persist, the GDR will be slowly decreased to achieve 
normoglycemia.   
4.) If the glucose is ³300 mg/dL at anytime, a repeat glucose will be drawn.  If the 
glucose is in fact ³ 300 mg/dL, the GDR will be decreased by 1-2 mg/kg/dL.  
Serial glucose levels will be followed, and the GDR will be slowly decreased over 
twenty-four hours to achieve normoglycemia.  
5.)  Insulin use will be at the discretion of the primary medical team.   


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
41 
6.)  Other causes for hyperglycemia will be ruled out by the primary medical 
team.   
7.) In addition to decreasing the GDR, the daily dose of PN may be given over a 
longer period of time to prevent hyperglycemia.  
 
Hypertriglyceridemia is defined as a TG> 300 mg/dL.  In the advent of 
hypertriglyceridemia, the following steps will be taken:  
1.) The study team will ensure that the triglyceride (TG) level was not drawn 
when the patient was receiving FO or SO. All TG trough levels will be obtained 
~6 hours after lipid infusion. 
2.) If the TG level was drawn at the appropriate time, the TG level will be 
repeated in 1-7 days.   
 
All other changes to the PN will be made at the discretion of the treating physician.  
 
Hyperinsulinemia and hypoglycemia are defined as an insulin concentration > 25 uU/mL 
and persistant hypoglycemia (glucose < 40 mg/dL) in the face of a prolonged high 
glucose delivery rate (> 16 mg/kg/min) along with an Endocrinology consult confirming 
that the hyperinsulinemia and hypoglycemia are NOT secondary to advanced liver 
disease.  
 
Also like other intravenous fats, Omegaven™ can be associated with changes in body 
temperature, chills, flushing, cyanosis, changes in blood pressure, decreased appetite, 
nausea or vomiting, shortness of breath, headache, and chest, back, or bone pain.  In very 
rare cases, intravenous fats can cause an erection.  
 
Risks of blood drawing:  
All blood will be obtained from existing catheters. In the event that an intravenous 
catheter is not present, the blood draw may be associated with pain from a heel stick or 
blood draw from a small vein or artery.  Mild pain and bruising may be associated with 
these types of blood draws but every effort will be made to take the blood test at the same 
time that other tests are obtained.  
 
Parents or legal guardians will counseled regarding all potential risks associated with this 
study.  
 
Risk Classification:   
Because Omegavenä is not an FDA approved drug, the overall risk is greater than 
minimal.  
 
Therapeutic Alternatives: 
 
Children not participating in this study will receive standard PN supplemented with a 
standard intravenous fat emulsion.  
 
Risk/Benefit Ratio: 


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
42 
There is greater than minimal risk because Omegavenä is an unapproved by the FDA.  
Potential benefits of this study include a reduction in morbidity and mortality children 
with PNAC.  The knowledge gained from this study will contribute to the general 
knowledge of how alternative nutritional strategies can not only reduce morbidity and 
mortality associated with PNAC, but also other inflammatory diseases is enormous.   
 
Information Withheld from Subjects: 
No information about the research purpose, design, and procedures will be withheld.   
 
2. Adequacy of Protection Against Risks: 
 
Requirement and Informed Consent: 
Capacity to Consent: 
Informed consent will be obtained from the parents or guardians of subjects designated to 
give consent for their children.   
 
Personnel Inviting Participants: 
Potential subjects will be known to the investigators by virtue of their involvement in 
their standard medical care.  In addition, faculty in the Departments of Pediatrics and 
Pediatric Surgery will be made aware of this study and may refer potentially eligible 
subjects to the investigators.  
 
Process of Consent: 
Parents/legal guardians of potential subjects and potential subjects who meet inclusion 
and exclusion criteria will be identified by the principal and co-investigators.  Potential 
subjects will be approached by either Kara Calkins, MD, Robert Venick, MD. A consent 
form, and when appropriate, an assent form, will be provided to the subject and/or their 
family/caretakers in their primary language for their consideration . Upon agreement, the 
patient may be approached by the principal investigator or co-investigators who will 
further explain the study, procedures involved, and potential risks and benefits. Potential 
participants will be invited to read the informed consent.  Potential participants will be 
encouraged to ask questions, and consult other health professionals for a second opinion.  
They will be encouraged to take ample time discuss the study with other physicians, 
family, and friends.  All verbal and written information will be provided in the subject’s 
and/or parents’/legal guardians’ primary language.  The person inviting participants will 
be a legally licensed physician or surgeon (California licensure) experienced in delivering 
healthcare to the pediatric population.   All members of this research team have 
completed UCLA PHRS and HIPAA clinical research certifications.  All subjects will 
continue to receive standard of care irrespective of their decision to participate in the 
study.   
 
This study targets children 2 weeks - < 18 years of age.  However, it is possible, that a 
subject may reach 18 years of age, during the study period.  
 
Consent for Children < 7 years of age: 


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
43 
For children < 7 years of age, one parent or legal guardian will be required to sign the 
consent form (“Parent Permission for a Minor to Participate in Research”). 
 
Consent/Assent Process for Children 7 – 12 years of age: 
For children 7 -12 years, the child will be required to sign to the assent (“Assent to 
Participate in Research”), and ONE parent/legal guardian will be required to sign the 
consent form. (“Parent Permission to a Minor to Participate in Research”).    
 
Consent/Assent Process for Children 13 – 17 years of age: 
For children 13 – 17 years age, the subject must sign the assent form (“Youth 
Assent/Adult Consent”), and ONE parent/legal guardian must  sign the consent form 
(“Parent Permission for a Minor to Participate in Research”).  
 
Consent Process for Adults ³ 18 years of age: 
Should a subject reach the age of 18 years of age during the study, the adult subject must 
provide a consent (“Youth Assent/Adult Consent”).  
 
Comprehension of the Information Provided: 
The parent(s) or legal guardian(s) of the subject and subject when appropriate, will be 
given time to read the consent form and ask questions regarding the study prior to 
deciding to allow their child to participate in the study. The parents will be questioned by 
the investigator to ensure their understanding of the information in the consent form 
including the risks, the potential benefits, and the alternatives to participation in the 
study. The investigator will also explain that the decision to participate or not to 
participate in this research study does not affect the care of their child and that they have 
the right to withdraw consent at any time without any consequences. 
 
Consent/Assent Forms: 
This study targets children 2 weeks - < 18 years of age.  However, it is possible, that a 
subject may reach 18 years of age, during the study period.  
 
Consent for Children < 7 years of age: 
For children < 7 years of age, one parent or legal guardian will be required to sign the 
consent form (“Parent Permission for a Minor to Participate in Research”). 
 
Consent/Assent Process for Children 7 – 12 years of age: 
For children 7 -12 years, the child will be required to sign to the assent (“Assent to 
Participate in Research”), and ONE parent/legal guardian will be required to sign the 
consent form. (“Parent Permission to a Minor to Participate in Research”).    
 
Consent/Assent Process for Children 13 – 17 years of age: 
For children 13 – 17 years age, the subject must sign the assent form (“Youth 
Assent/Adult Consent”), and ONE parent/legal guardian must  sign the consent form 
(“Parent Permission for a Minor to Participate in Research”).  
 


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
44 
Consent Process for Adults ³ 18 years of age: 
Should a subject reach the age of 18 years of age during the study, the adult subject must 
provide a consent (“Youth Assent/Adult Consent”).  
 
A consent/assent forms will be used to obtain consent/assent.. Consents/assents will also 
be available in Spanish for Spanish speaking families. 
 
Protection Against Risk: 
The procedural risks from the study are greater than minimal since Omegavenä in not 
approved by the FDA.   In order to minimize risk, patients will be screened to ensure they 
met inclusion and exclusion criteria.   Side effects will assessed by physical exam, patient 
report, and scheduled laboratory tests.  All attempts will be made to obtain blood from 
pre-existing sampling catheters whenever available and/or obtain the blood sample at the 
same time as other scheduled blood tests.  To date, there are no published side effects of 
Omegavenä in infants with PNAC. 
 
Financial Obligations of the Subjects: 
The hospital will attempt to obtain reimbursement for OmegavenÔ provided to the 
subject while in the hospital.  The home health agency providing the subject’s IV 
nutrition and OmegavenÔ at home will attempt to obtain reimbursement from the 
insurance company to pay for the cost of Omegavenä and home health supplies. 
 
It is possible that the medical insurer will not pay for all the treatments and tests the 
subject receives in this research study.  That is because many insurance companies, 
HMOs, and health benefit plans do not cover for experimental treatments.  If 
that happens, the charges the subject will have to pay are as follows: 
1.) home health supplies (IV infusion pumps, IV tubing, and outpatient pharmacy 
dispensing charges).  
2.) OmegavenÔ at home 
 
It is estimated that home health supplies may cost approximately $500.00-$900.00 per 
month. It is estimated that OmegavenÔ may cost $1500.00-$2100.00 per month 
 
If the insurance company, HMO, or health benefit plan refuses to pay for some costs, the 
study will cover the cost of the following: 
 
1.) OmegavenÔ in the hospital 
 
The study will not cover the cost of labs consider standard of care.   
 
Microarray, proteomic, inflammatory markers, microRNA, phytosterol, bile acids, and 
RBC membrane composition analysis will be paid for the study.  
 
Emergency Care and Compensation for Research-Related Injury: 


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
45 
In the unlikely event of an injury or illness resulting from this study, emergency 
treatment will be provided. 
 
3. Potential Benefits of the Proposed Research to the Subjects and Others 
Potential Benefits: 
Participation in this study may not directly benefit the subject.  However, knowledge 
gained from this study may used to support the use of parenteral FO in infants with 
PNAC.  
 
Payment for Participation: 
There is no payment for participation in this study. 
 
 
 
 
DATA AND SAFETY MONITORING PLAN 
 
A committee comprised of a pediatrician (Dr. Meena Garg), research pharmacist 
(Christina Shin, Pharm D), and statistician (Kate Crespi, PhD) will review potential 
complications or adverse effects that arise from the study. This committee together will 
also be involved in performing the early evaluations of the data at annual intervals to 
determine if significant results are obtained to warrant discontinuation of the trial.  All 
complications, adverse effects, or results that warrant discontinuation of the trial will be 
promptly reported to the UCLA Institutional Review Board and FDA. 
 
As of August 2017, annual updates will be provided to all DSMB members via email, 
and annual meetings will not be required. Confirmation that these annual updates were 
reviewed by the respective DSMB member will be documented by a confirmatory email 
from the DSMB member.  Should a DSMB member voice any concerns, a formal DSMB 
can be held to address these concerns. This documentation will be provided to the IRB.  
 
 
INCLUSION OF CHILDREN 
 
The subjects involved in this study must have clinical evidence of PNAC, a direct 
bilirubin ≥ 2 mg/dL on 2 consecutive measurements, expected TPN course > 30 d, and be 
> 2 weeks of age and < 18 years of age. The purpose of this study is focused on this 
patient population as they are at a discernable propensity for specific diseases that may be 
alleviated by omega-3 fatty acids. The principal investigator and other contributors 
involved in the study demonstrate expertise in the care of this patient population. 
 


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
46 
 
Table 6 
Monitoring Schedule for Patients with SBS/IF and PNAC 
Parameter 
Weekly-
Monthly 
Periodic 
Comments 
Weight 
 
 
 
Fluid Balance 
 
 
 
Vital Signs 
 
 
 
Urine 
Sugar/Ketones 
 
 
 
Cathetar 
site/function 
 
 
 
Labs 
 
 
 
Sodium 
X 
 
2 yellows (0.5 cc 
each) 
Potassium 
X 
 
Chloride 
X 
 
Glucose 
X 
 
BUN 
X 
 
Creatinine 
X 
 
Magnesium 
X 
 
Phosphorous 
X 
 
ALT 
X 
 
AST 
X 
 
Total Bilirubin 
X 
 
Direct Bilirubin 
X 
 
Total Protein 
 
X 
Albumin 
 
X 
Pre-albumin 
 
X 
WBC 
X 
 
1 lavendar (0.5 
cc) 
RBC 
X 
 
Hemoglobin 
X 
 
Hematocrit 
X 
 
Platelets 
X 
 
Triglyceride 
X 
 
2 reds (0.5 cc 
each) 
GGT 
 
X 
PT/PTT/INR 
 
X 
1 blue (1.8 cc) 
Essential Fatty 
Acids 
 
X 
1 red (0.8 cc) 
Vitamins A, D, E 
 
X 
2 reds (0.5 cc 
each) 
Selenium 
 
X 
 
Copper 
 
X 
 
Zinc 
 
X 
 
Aluminum 
 
X 
 


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
47 
Iron 
 
X 
 
Carnitine 
 
X 
 
Microarray 
Analysis 
 
X 
Paxgene (1 cc), 
research lab 
Proteomic, 
Inflammatory 
Marker, 
Phytosterol, Bile 
Acid, RBC Fatty 
Acid Analysis 
 
X 
EDTA (2 cc), 
research lab 
microRNA 
Analysis 
 
X 
EDTA (0.5 cc) 
research lab 
 
Fecal specimens  
 
X 
400 g in MOR- 
200 device, 
research lab  
 
All of the above labs except for the microarray, microRNA, proteomic, 
inflammatory makers, phytosterols, and bile acids and RBC membrane analysis are 
considered standard of care for SBS/IF subjects with PNAC and will be ordered per 
the primary medical team. 


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
48 
 
 
Case Report Form 4: Side Effects, Adverse Events, Serious Adverse Events 
 
Subject: 
Date: 
Time: 
Side Effect or Adverse Event Description: 
 
 
 
 
 
 
Intervention: 
 
 
 
 
 
Resolution:  
 
 
 
 
Is this Event: 
 
Unexpected?  Y or N    If yes, desribe.  
 
 
 
 
Associated with a Diability?  Y or N   If yes, describe.  
 
 
 
 
Life Threatening?  Y or N   If yes, describe.  
 
 
 
 
Serious Drug Expereince?   Y or N   If yes, describe.  
 
 
 
Withdrawal from Study Warranted:  Y or N  
 
Date Reported to IRB and FDA: 


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
49 
Case Report Form 5:  Deviations from Protocol 
 
Subject: 
Date: 
Deviation 
 
 
 
 
Why deviation occurred: 
 
 
 
 
Response to deviation: 
 
 
 
 


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
50 
References 
 
1. Wales, PW. Neonatal short bowel syndrome; a cohort study. J Pediatr 
Surg;2005;40:755-62.  
2. Jugie, M. Study of the impact of liver transplantation on the outcome of intestinal 
liver transplantation on the outcome of intestinal grafts in children. 
Transplantation;2006;81:992-97.  
3. Digestive Diseases Interagency Coordinating Committee (DDICC). Short Gut and 
Small Bowel Transplantation. Meeting Minutes. June 25, 2002. Available at: 
www2.niddk.nih.gov/NR/rdonlyres/9CCC34A3-3CFE-4D89-93DF-
1ADEE3AA3E32/0DDICC_June-25-2002_Minutes.pdf.  
4. Buchman, A. Total parenteral nutrition-assocated intrahepatic liver disease. 
JPNEN J Parenter Enteral Nutr. 2002;26:S43-8.  
5. Freund, H. Abnormalities of liver functin and hepatic damage associated with out 
total parenteral nutrition. Nutrition;1991;7:1-5; discussion 6.  
6. Beath, 
S. 
Parenteral 
nutrition-related 
cholestasis 
in 
postsurgical 
neonates:multivariate analysis of risk factos. J Pediatr Surg;1996;31;604-6.  
7. O’Keefe, S. Short bowel syndrome and intestinal failure: consensus definaitions 
a. and overview. Clin Gastroenterol Hepatol;2006:6-10.  
8. Sondheimer, J. Infection and cholestatsis in neonates with intestinal resection and 
long-term parenteral nutrition. J Pediatr Gastroenterol Nutr. 1998;27:131-7.  
9. Grant, D. 2003 Report of the Intestin Transplant Registry: a new era has dawned. 
Ann of Surg. 2005;241:607-13.  
10. Fryer, J. Mortality in candidates waiting for combined liver-intestin transplants 
exceeds that for other candidates waiting for liver transplants. Liver Transpl. 
20039:748-53.  
11. Shin, J. Could lipid infusion be a risk for parenteral nutrition-associated 
cholestasis in low birth weight infants? Eur J Pediatr. 2008;167:197-202. 
12. Btaiche, I. Parenteral nutrition-associated liver complications in children. 
Pharmacotherapy.2002;22:188-211.  
13. Owings, E. Management of cholestasis in infants with very low birth weight. 
Semin Pediatr Surg. 2000;9:96-102. 
14. Thompson, A. Necrotizing enterocolitis in newborns, pathogenesis, prevention, 
and management. Drugs. 2008;68:1227-38.  
15. Christensen, R. Identifiying patients, on the first day of life, at high-riskof 
developing parenteral nutrition-associated liver disease. Journ of Perinatology. 
2007;5:284-90. 
16. Javid, P. The role of enteral nutrition in the reversal of parenteral nutrition-
associated liver dysfunction in infants. Journ of Ped Surg. 2005;40:1015-18.   
17. Greenberg, G. Effect of total parenteral nutrition on gut hormone release in 
humans. Gastroenterology. 1981;80:988-93.  
18. Yeh, S. Effects of L-glutamine oninduced hepatosteatosis in rats receiving total 
parenteral nutrition. J Formos Med Assoc. 1995;94:593-9.  


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
51 
19. Kubota, A. Total parenteral nutrition-associated intrahepatic cholestasis in infants: 
25 years experience. J Pediatr Surg. 2000;35:1049-51.  
20. Moss R. Hepatobiliary dysfunction during total parenteral nutrition is caused by 
infusate, not the route of administration. J Pediatr Surg 1993;28:391-6; discussion 
396-7. 
21. Helms RC. Comparison of a pediatric versus standard amino acid formulation in 
preterm neonates requiring parenteral nutrition. J Pediatr 1987;110:466-70. 
22. Moss R. Methionine infusion reproduces liver injury of parenteral nutrition 
cholestasis. Pediatr Res 1999;45:664-8. 
23. Simopoulos, A. Evolutionar aspects of diet and essential fatty acids. World Rev 
Nutr Diet. 2001;88:18-27.  
24. Diamond, I. The rationale for the use of parenteral omega-3 lipids in children with 
short bowel syndrome. Pediatr Surg Int. 2008;24:773-78.  
25. Hultin M. Intravenous lipid emulsions: removal mechanisms as compared to 
chylomicrons. J Lipid Res 1995;36:2174-84. 
26. Qi K. Effects of particle size on blood clearance and tissue uptake of lipid 
emulsions with different triglyceride compositions. JPEN J Parenter Enteral Nutr 
2003;27:58-64. 
27. Nestel P. Effects of N-3 fatty acids on lipid metabolism. Annu Rev Nutr 
1990;10:149-67. 
28. Alwayn, I. Omega-3 fatty acid supplementation prevents hepatiti steatosis in a 
murine model of nonalcoholic fatty liver disease. Pediat Res 2005;57:445-452.  
29. VanAerde, J. Intravenous fish oil emulsion attenuates total parenteral nutrition 
induced cholestasis sin new born piglets. Pediatr Res;1999;45:202-8.  
30. Gura, K. Reversal of parenteral nutrition-associated liver disease in two infants 
with short bowel syndrome using parenteral fish oil: implications for future 
management. Pediatr. 2006;118(1).  
31. Gura, K. Safety and efficacy of a fish oil based fat emulsion in the treatment of 
parenteral nutrition associated liver disease. Pediatr. 2008:121:678-86.  
32. Diamond, I. Changing the paradigm: Omegaven for the treatment of liver failure 
in pediatric short bowel. Journ of Ped Gastroent and Nutr. 2009:48:209-15.  
33. Bays, H. Safety considerations with omega-3 fatty acid therapy. Am Journ of 
Card. 2007:99:35-43.  
34. Strijbosch, R. fish oil prevents essential fatty acid deficiency and enhances 
growth: clinical and biochemical implications. Metabol. 2008:57:698-707.  
35. Duro, D. Overview of pediatric short bowel sydnrome. JPGN. 2008:47:S33-6.  
36. Diamanti, A. Irreversible intestinal failure: prevalence and prognositic factors. 
JPGN. 2008:47:450-7.  
37. Spencer, A. Pediatric short bowel syndrome: redefining predictors of success. 
Ann of Surg. 2005:242:403-12.  
38. Dorney, S. Improved survival in very short small bowel of infancy with use of 
long-term parenteral nutrition. J Pediatr. 1985:107:521-5.  
39. Assissi, A. Fish oil and mental health: the role of n-3 long chain polyunsaturated 
fatty acids in cognitive development and neurological disorders. International Clin 
Psychopharm. 2006:21:319-36.  


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
52 
40. McKenney, J. Role of prescription omega-3 fatty acids in the treatment of 
hypertriglyceridemia. Pharmacotherapy. 2007:27:715-28.  
41. Harris, W. Expert opinion: omega-3 fatty acids and bleeding—cause for concern? 
Amer Journ of Cardio. 2007:99. 
42. Gura, K. The role of an intravenous fat emulsion composed of fish oil in 
parenteral nutrition dependent patient with hypertriglyceridemia. Nutr Clin Prac. 
2007;22;664-72.  
43. Forchielli ML, Bersani G, Tala S, Grossi G, Puggioli C, Masi M. The spectrum of 
plant and animal sterols in different oil-derived intravenous emulsions. Lipids. 
2010; 45(1):63-71.  
44. Liu Y, Binz J, Numerick MJ, Dennis S, Luo G, Desai B, et al. Hepatoprotection 
by the farnesoid X receptor agonist GW4064 in rat models of intra- and 
extrahepatic cholestasis. J Clin Invest. 2003;112(11):1678-1687. 
45. Kasmi KC, Anderson AL, Devereaux MW, et al. Phytosterols promote liver 
injury and kupffer cell activation in parenteral nutrition-associated liver disease. 
Sci Transl Med. 2013;5(206):206ra137. 
46. Clayton PT, Bowron A, Mills KA, Massoud A, Casteels M, Milla PJ. 
Phytosterolemia in children with parenteral nutrition-associated cholestatic liver 
disease. Gastroenterology. 1993;105(6):1806-1813. 
47. Bindl L, Lutjohann D, Buderus S, Lentze MJ, Bergmann KV. High plasma levels 
of phytosterols in patients on parenteral nutrition: a marker of liver dysfunction. J 
Pediatr Gastroenterol Nutr. 2000;31(3):313-316. 
48. Kurvinen A, Nissinen MJ, Gylling H, Miettinen TA, Lampela H, Koivusalo AI, et 
al. Effects of long-term parenteral nutrition on serum lipids, plant sterols, 
cholesterol metabolism, and liver histology in pediatric intestinal failure. J 
Pediatr Gastroenterol Nutr. 2011;53(4):440-446. 
49. Squires RH, Duggan C, Teitelbaum DH, Wales PW, Balint J, Venick R, et al. 
Natural history of pediatric intestinal failure: initial report from the pediatric 
intestinal failure consortium. J Pediatr. 2012. 
50. Moseley RH, Wang W, Takeda H, et al. Effect of endotoxin on bile acid transport 
in rat liver: a potential model for sepsis-associated cholestasis. Am J Physiol. 
1996;271(1 Pt 1):G137-146. 
51. Ghose R, Zimmerman TL, Thevananther S, Karpen SJ. Endotoxin leads to rapid 
subcellular relocalization of hepatic RXRalpha: a novel mechanism for reduced 
hepatic gene expression in inflammation. Nucl Recept. 2004;2(1):4. 
52. Kalish BT, Le HD, Gura KM, Bistrian BR, Puder M. A metabolic analysis of two 
intravenous lipid emulsions in a murine model. PloS One. 2013;8(4):e59653. 
53. Kalish BT, Le HD, Fitzgerald JM, et al. Intravenous fish oil emulsion promotes a 
shift towards anti-inflammatory-pro-resolving lipid mediators. Am J Physiol 
Gastrointest Liver Physiol. doi: 10.1152/ajpgi.00106.2013. 
54. Perez-Echarri N, Perez-Matute P, Marcos-Gomez B, Marti A, Martinez JA, 
Moreno-Aliaga MJ.  Down-regulation in muscle and liver lipogenic genes: EPA 
ethyl ester treatment in lean and overweight (high-fat-fed) rats. J Nutr Biochem. 
2009;20(9):705-714. 


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
53 
55. Takeuchi H, Kojima K, Sekine S, Murano Y, Aoyama T. Effect of dietary n-6/n-3 
ratio on liver n-6/n-3 ratio and peroxisomal beta-oxidation activity in rats. J Oelo 
Sci. 2008;57(12):649-657. 
56. Harris JK, El Kasmi KC, et al. Specific microbiome changes in a mouse 
model of parenteral nutrition associated liver injury and intestinal 
inflammation.  PLoS One. 2014 Oct 20;9(10):e110396. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Kara L. Calkins, MD 
CFR 312.23, 12. 2-9. 
 
 
 
Revisions:  January 12, 2011, June 9, 2011, January 11, 2012, May 31, 2012, December 7, 2012, 
August 2013, November 21, 2013, November 13, 2014, March 6, 2015, May 6, 2015, June 02, 2015, 
March 5, 2016, February 12, 2018 
IND 105, 326  
54 
 
 
ATTACHMENTS 
 
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