Compassionate Use of an Intravenous Fish Oil Lipid Emulsion (Omegaven®) for the Treatment of Intestinal Failure Associated Liver Disease in Children
Conditions: Total Parenteral Nutrition-Induced Cholestasis
Sponsor: University of Nebraska

Jones, B., Department of Surgery, Children’s Hospital & Medical Center 
Cusick, R., Department of Surgery, Children’s Hospital & Medical Center 
Jones, S., Pediatric Research Office, Dept. of Pediatrics, UNMC  
Lyden, E., Department of Biostatistics, College of Public Health, UNMC 
 
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Protocol: COMPASSIONATE USE OF AN INTRAVENOUS FISH OIL LIPID 
EMULSION (OMEGAVEN®) FOR THE TREATMENT OF INTESTINAL FAILURE 
ASSOCIATED LIVER DISEASE IN CHILDREN (V3.0)  
 
Principal Investigator: Brian Jones, MD 
Secondary Investigator (s): Robert Cusick, MD; and Sara Jones, RD, LMNT 
Participating Personnel: Stephen Raynor, MD; Benjamin Infantino, MD; Michelle Brester, 
NP; Elizabeth Lyden, MS 
Funding Source: Department of Surgery, Children’s Hospital & Medical Center 
Study Population: Patients with Parenteral Nutrition Associated Liver Disease (PNALD) 
requiring parenteral nutrition therapy at Children’s Hospital & Medical Center. 
 
ABSTRACT 
In the United States, patients dependent upon parenteral nutrition (PN) receive parenteral fat 
emulsions composed of soybean oils. Lipids are necessary in PN dependent patients due to 
their high caloric value and essential fatty acid content. They have been implicated in 
predisposing patients to PN associated liver disease. Phytosterols such as those contained in 
soybean oils are thought to have a deleterious effect on biliary secretion.  Accumulation of lipids 
in the hepatic Kupffer cells may further impair liver function. 
 
Children requiring prolonged courses of  PN are at risk for developing PN associated liver 
disease. We hypothesize that although omega-6 fatty acid emulsions prevent fatty acid 
deficiency, they are not cleared in a manner similar to  enteral chylomicrons and therefore 
accumulate in the liver and resulting in steatotic liver injury. We  further hypothesize that a fat 
emulsion comprised of omega-3 fatty acids (i.e., fish oil) such as Omegaven® would be 
beneficial in the management of steatotic liver injuiry by its inhibition of de novo lipogenesis, the 
reduction of arachidonic acid-derived inflammatory mediators, prevention of essential fatty acid 
deficiency through the presence of small amounts of arachidonic acid, and improved clearance 
of lipids from the serum. Animal studies have shown that IV fat emulsions (IFE)  such as fish oil 
that are high in eicosapentaenic and docashexaaenoic acid reduce impairment of bile flow 
which is seen in cholestasis caused by conventional fat emulsions.  Furthermore, we 
hypothesize that that intravenous omega three fatty acids will be well tolerated and might 
reduce the inflammatory effect in the liver of prolonged PN exposure and could potentially 
reverse any hepatic dysfunction due to PN/IFE use.  By administering Omegaven® in place of 
conventional phytosterol/soybean fat emulsions we may reverse or prevent the progression of 
PN associated cholestasis and thus allow the patient to be maintained on adequate PN until 
they are able to ingest adequate nutrition enterally. 
 
PURPOSE 
1. To determine the safety profile of an intravenous omega-3 fat emulsion (Omegaven®) 
 
Hypothesis for Aim 1: 
1.1 – After starting Omegaven® on PN, the rate of fatty acid deficiencies and imbalances will be 
as low as before Omegaven®. Also, the rate of triglyceride events > 400 mg/dL with Omegaven® 
will be similar to that seen with PN administered with soy oil IFE (conventional emulsion, i.e., 
Intralipid®). 
1.2 – PN containing Omegaven® will be safe for patients with respect to the risk of unexpected 
bleeding, coagulopathies, and other adverse events. 

Jones, B., Department of Surgery, Children’s Hospital & Medical Center 
Cusick, R., Department of Surgery, Children’s Hospital & Medical Center 
Jones, S., Pediatric Research Office, Dept. of Pediatrics, UNMC  
Lyden, E., Department of Biostatistics, College of Public Health, UNMC 
 
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1.3 – PN containing Omegaven® will promote more short-term growth and development than 
conventional fat emulsions.  
 2. To determine if  established PN associated liver disease can be reversed or its progression 
halted by using a parenteral fat emulsion prepared from fish oil as measured by normalization of 
serum levels of hepatic enzymes and bilirubin. 
 
Hypothesis for Aim 2: 
2.1 – Our primary hypothesis is that, after reaching bilirubin levels > 2 mg/dL, patients receiving 
Omegaven® will reach a bilirubin level ≤ 2 mg/dL faster than patients receiving conventional fat 
emulsions. Additionally, while patients receiving Omegaven® will experience a decrease in their 
levels of bilirubin and other hepatic enzymes over time, patients receiving conventional 
emulsions will maintain high levels of bilirubin and other hepatic enzymes over time.  
2.2 – Patients with surgical gastrointestinal disease and cholestasis will have better clinical 
hepatic outcomes than patients receiving conventional emulsions. 
2.3 – Since patients receiving Omegaven® will have improved immune function, they will have a 
lower infection rate then patients receiving conventional fat emulsions. 
2.4 – Due to a better general hepatic condition, patients receiving Omegaven® will also 
experience lower occurrence of liver transplant, death from hepatic associated causes, and 
blood transfusions.    
 
BACKGROUND 
Parenteral Nutrition Associated Liver Disease (PNALD) 
 
Parenteral nutrition (PN) provides intravenous nutritional supplementation for patients unable to 
absorb adequate enteral nutrients secondary to insufficient intestinal length or function. PN 
contains the macronutrient building blocks of the human diet in their most elemental forms 
(amino acids and dextrose) and is commonly administered with a fat emulsion to avoid essential 
fatty acid deficiency and to provide a calorically dense source of non-protein calories. In 
addition, PN contains the essential micronutrients (electrolytes, trace elements, and vitamins) to 
provide an optimal nutritional regimen. Before the development of PN in the late 1960’s, patients 
with insufficient gastrointestinal absorptive function commonly died of starvation and 
subsequent complications of malnutrition(1, 2). Today, more than 30,000 patients are 
permanently dependent on parenteral nutrition for survival. However, PN continues to be 
associated with hepatic injury that occurs at an unpredictable rate and includes both 
biochemical, i.e., elevated serum aminotransferase and alkaline phosphatase, and histologic 
alterations such as steatosis, steatohepatitis, lipidosis, cholestasis, fibrosis, and cirrhosis (3, 4). 
These abnormalities, which may  worsen with the duration  of PN administration, is more 
prevalent in the pediatric population. Additional risk factors for this condition include prematurity, 
low birth weight, long-term use of PN, the lack of concomitant enteral intake, sepsis, and 
multiple operative procedures (5). 
  
Although the pathological features of  PNALD have been well described, the etiology, 
prevention, and treatment of this complication are not well understood. Multiple hypotheses 
exist to explain the pathogenesis of PNALD including altered gut hormonal profiles (6), the 
propensity for bacterial translocation in the absence of enteral intake (7, 8), intestinal stasis 
resulting in the reduced clearance of hepatotoxic bile acids (8), and direct deficiencies or toxic 
components of the PN solution itself resulting in excessive glucose calorie uptake, excessive 
lipid infusion, or nutritional deficiencies such as essential fatty acid deficiency (9-11). None of 
these theories has been confirmed consistently. The etiology of PNALD is currently considered 

Jones, B., Department of Surgery, Children’s Hospital & Medical Center 
Cusick, R., Department of Surgery, Children’s Hospital & Medical Center 
Jones, S., Pediatric Research Office, Dept. of Pediatrics, UNMC  
Lyden, E., Department of Biostatistics, College of Public Health, UNMC 
 
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multifactorial. Available treatment options for this disease process are limited and have 
achieved moderate success at best. Care of the PN-dependent patient is focused on gradually 
increasing enteral caloric intake as the residual bowel adapts allowing  PN to be discontinued  
(12).  In fact, it has been shown both experimentally and clinically that partial enteral nutrition, 
when tolerated, helps to protect against the development of PNALD (13-15). In severe cases of 
refractory hepatic failure, liver transplantation with or without accompanying small bowel 
transplantation remains the only treatment option.  
 
Role of Intravenous Fat Emulsion on PN Associated Liver Disease 
 
Recent evidence demonstrates that lipids are metabolized differently depending on their route of 
administration. Enteral lipids are absorbed by the enterocyte in the small bowel mucosa in the 
form of a micelle and packaged into chylomicrons which are released into the portal venous 
system for ultimate uptake and disposal in the liver. Once in the bloodstream, these particles 
rapidly acquire apolipoproteins from circulating high-density lipoproteins and can subsequently 
be metabolized by the liver. The emulsified particles of commercially made and intravenously 
administered lipid emulsions, such as Intralipid®, mimic the size and structure of chylomicrons, 
but differ in their content. In contrast to chylomicrons, artificial lipid particles primarily contain 
essential fatty acids and omega-6 triglycerides and are devoid of cholesterol or protein. Recent 
studies suggest that these omega-6 fatty acid-containing emulsions are dependent on 
lipoprotein lipase, apolipoprotein E, and low-density lipoprotein receptors for clearance, and are 
metabolized with less lipolysis and release of essential fatty acids than are chylomicrons. In fact, 
it appears that they may be cleared as whole particles by tissues other than the liver.(16) These 
factors may account for the increased incidence of steatohepatitis associated with the 
intravenous administration of Intralipid®. 
 
The mechanism of clearance of omega-3 fatty acid containing lipid emulsions is unknown, but 
appears to be largely independent of the pathways identified above (17). Furthermore, omega-3 
fatty acid solutions have been shown to decrease de novo lipogenesis (18), prevent or attenuate 
PN-induced hepatosteatosis in rats (19) and guinea pigs and ameliorate the severity of high-fat 
diet-induced hepatosteatosis in rats (20). In addition, omega-3 fatty acids can interfere with the 
arachidonic acid pathway of inflammation (18, 21). They can displace arachidonic acid from 
tissue fatty acid pools, thereby reducing the availability for eicasanoid-synthesizing enzymes 
and inflammation (21). Table 1 summarizes the composition of Intralipid® and Omegaven® fat 
emulsions. 
                                                                                                                                                  
Rationale for Omegaven® Treatment 
 
Unlike conventional intravenous fat emulsions, Omegaven® is comprised solely of fish oils 
containing primarily omega-3 fatty acids. Animal studies have shown that IV fat emulsions such 
as fish oil that are high in eicosapentaenic and docosahexaenoic acid reduce impairment of bile 
flow as seen in cholestasis caused by conventional fat emulsions(19,20). We hypothesize that 
by administering Omegaven® in place of conventional phytosterol/soybean fat emulsions, that 
the cholestasis may be reversed and  patients will be able to be maintained on adequate PN 
until they are able to ingest adequate nutrition enterally. 
 
 
 
 

Jones, B., Department of Surgery, Children’s Hospital & Medical Center 
Cusick, R., Department of Surgery, Children’s Hospital & Medical Center 
Jones, S., Pediatric Research Office, Dept. of Pediatrics, UNMC  
Lyden, E., Department of Biostatistics, College of Public Health, UNMC 
 
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Preliminary Studies/Progress Report 
Animal Studies 
 
In initial studies conducted at Children’s Hospital Boston, it was hypothesized that the 
development of PNALD may be dependent on both the route and quantity of fat administration 
and that omega-3 fatty acids would prevent or reduce de novo lipogenesis and the subsequent 
liver injury independent of the route of administration. Specifically, they characterized a 
previously established murine model of PN-associated liver injury to investigate whether enteral 
lipid administration would protect against the development of steatohepatitis in PN-dependent 
animals. This murine model of enteral PN-induced steatohepatitis is largely due to a high 
carbohydrate load and essential fatty acid deficiency. Although this model is not replicative of 
the clinical setting, it is a model that maximizes liver steatosis. In this model, mice are treated 
with oral PN for 19 days before being sacrificed. These animals develop severe fatty liver 
changes demonstrated by MRI spectroscopy and histology (H&E, PAS, and oil red O staining), 
and also have biochemical changes consistent with liver injury (elevated alkaline phosphatase 
and serum transaminases). Experimental groups were supplemented with Intralipid® by several 
routes of administration including orally, intravenously, and subcutaneously. Other groups were 
also supplemented with omega-3 fatty acids (Omegaven®) by the same routes of 
administration.  In this study they found a consistent pattern of protection against PN-associated 
steatohepatitis by administering enteral Intralipid® (22). In mice that received the highest dose 
of enteral Intralipid®, there was a marked decrease in the extent of overall liver injury as 
measured by gross inspection, histologic analysis, liver fat content, and serum liver enzyme 
levels. In all areas of this investigation, mice treated with enteral lipid most closely resembled 
the control mice that did not receive PN as part of the experimental protocol. These results were 
in complete contrast to the extensive fatty infiltration and evidence of hepatic injury found in 
mice that received PN without lipid supplementation as well as in mice that received PN with 
intravenous Intralipid®. Mice receiving intravenous Intralipid® had the most severe liver 
changes.  Both groups of animals developed marked hepatic steatosis with macrovesicular fatty 
infiltration and significant elevations in spectroscopic liver fat content and serum transaminase 
levels. In addition, the effect of enteral Intralipid® supplementation appeared to be dose-
dependent; mice receiving one-third the dose of enteral Intralipid® showed improved liver 
histology but still demonstrated a moderate degree of liver injury by spectroscopy and serum 
liver function tests. The nutritional model employed in this study provided all experimental mice 
with enteral PN solution ad libitum. In this way, mice were not force-fed PN and self-regulated 
their PN intake by demands for growth and energy. Importantly, all mice gained weight 
throughout the 19-day protocol, and there were no differences in weight gain parameters 
between the groups. The PN solution was a typical pediatric stock formula mixed at our 
institution containing 20% dextrose and 2% amino acids. Each milliliter of this formula provides 
0.2 g (0.68 kilocalories) of dextrose and 0.02 g (0.08 kilocalories) amino acid. As the daily intake 
per animal of PN averaged 15 ml, mice were ingesting approximately 11.4 kilocalories/day and 
456 kilocalories/kg/day. This caloric load is similar to the established dietary energy needs of 
the mouse (23). The parenteral fat source used in this study was Intralipid® 20% (Baxter, 
Deerfield, Illinois), which is a soybean oil-based emulsion. Each milliliter of this emulsion 
contains 0.2 g (2.0 kcal) of fat. We recognize that the model may not completely match the 
clinical, human, setting of intravenous PN-administration; however, our goal was to produce a 
fatty liver with biochemical evidence of injury.  
 
In a second set of experiments, the same murine model was used to determine whether 
Omegaven® (Fresenius- Kabi, Bad Homburg, Germany), a commercial fish oil fat emulsion 

Jones, B., Department of Surgery, Children’s Hospital & Medical Center 
Cusick, R., Department of Surgery, Children’s Hospital & Medical Center 
Jones, S., Pediatric Research Office, Dept. of Pediatrics, UNMC  
Lyden, E., Department of Biostatistics, College of Public Health, UNMC 
 
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available in Europe, would prevent fatty liver changes by enteral or parenteral routes of 
administration, and to determine the serum fatty acid profile of these animals. Animals receiving 
Omegaven® via the oral and intravenous routes had completely normal livers on histology and 
MRI spectroscopy revealed normal liver fat content. Liver functions tests in orally treated 
animals were also within the norm, while there were minimal elevations in intravenously treated 
groups. There was no fatty acid deficiency in these groups as determined by Mead acid (5,8,11-
Eicosatrienoic acid) levels in the serum fatty acid analysis. Mead acid is the only 
polyunsaturated fatty acid of note produced de novo by animals and only accumulates under the 
conditions of essential fatty acid deficiency. Furthermore, arachidonic acid levels were low in 
Omegaven® treated animals consistent with previous reports. In a third set of experiments, 
mice were made severely fatty acid deficient. These mice were treated for 10 days with 
Omegaven® and had complete reversal of their fatty acid deficiency. 
 
Similarly, other investigators studied livers in a newborn pig model and showed that intravenous 
administration of fish oil, which consists primarily of omega-3 fatty acids, reduced parenteral 
nutrition-induced cholestasis (22). However, the study was only 3 weeks in duration and long-
term effects from administration of omega-3 fatty acids alone were not evaluated.  In fact, the 
idea that one could remove an essential fatty acid from the standard regime of nutritional 
support by PN has not been accepted.  It has been thought that reduction of an essential fatty 
acid, such as omega-6, during long-term therapy would result in fatty acid deficiency and 
deterioration of the health of the patient. Dr. Puder’s experience to date, as discussed below, 
demonstrates that the use of Omegaven® as monotherapy does not result in the development 
of essential fatty acid deficiency and it can actually be used as monotherapy to treat this 
deficiency state.   
 
Preliminary Safety and Efficacy Data for Use of Omegaven® in Other Diseases 
 
Omegaven® has been used for over 10 years as an adjunct to conventional fat emulsions.  
According to current data, an increase in the proportion of omega-3 fatty acids is thought to 
optimize nutrition in general, but in particular benefit patients whose underlying disease might 
benefit from an increase in omega-3 fatty acids.  An adequate intake of omega-3 fatty acids 
results in anti-inflammatory and immunomodulatory effects that are protective in nature from 
inflammatory tissue damage, capillary permeability, and improved immunological resistance. It 
may also reduce the risk of thrombosis and increase microvascular perfusion due to its anti-
aggregatory and vasodilatory effects. 
 
In Europe and Asia, the use of parenteral omega-3 fatty acids has been used in the following 
adult patient populations (24-28): 
 
post traumatic and post surgical patients 
 
patients experiencing early stages of sepsis/SIRS 
 
patients at risk of hyperinflammatory processes 
 
patients with inflammatory bowel disease (Crohn’s disease, ulcerative colitis) 
 
patients with inflammatory skin diseases (psoriasis, atopic eczema) 
 
The dosing used in these patients was 0.1 g (1ml) to a maximum of 0.2 (2ml) /kg body weight. 
The infusion rate used did not exceed 0.5ml/kg/body weight/hour.  Since it was intended to be 
infused in combination with conventional fat emulsions, the total fat intake was limited to 10-
20% as fish oil.  The duration of administration did not exceed 4 weeks. 
 

Jones, B., Department of Surgery, Children’s Hospital & Medical Center 
Cusick, R., Department of Surgery, Children’s Hospital & Medical Center 
Jones, S., Pediatric Research Office, Dept. of Pediatrics, UNMC  
Lyden, E., Department of Biostatistics, College of Public Health, UNMC 
 
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Preliminary Safety and Efficacy Data for Use of Omegaven® in Infants 
 
Pediatric experience with Omegaven® is limited to Dr. Puder’s clinical trial at Boston Children’s 
Hospital and 2 other unpublished clinical trials. These other trials were performed in Germany 
and Taiwan (29). The German study was a controlled, randomized, open parallel-group clinical 
study to investigate whether or not omega-3 fatty acids could be incorporated into the plasma 
phospholipids of very low birth weight preterm infants.  In this 7-day safety trial, Omegaven® 
use was evaluated on the basis of clinical, laboratory, and antioxidant parameters and lipid 
metabolism. Treatment was started on day 3-5 of life and continued for a total of 7 days. 
Patients received Omegaven® plus conventional soybean fat emulsion or soybean emulsion 
alone.  The maximum dose of Omegaven® in the study was 0.2 gm/kg/day.  The study 
concluded that the Omegaven® was well tolerated in this group of preterm infants in respect to 
both hematological and biochemical parameters. The incidence of reported adverse events 
between both study groups was similar. The eicosapentaenoic acid (EPA) content of plasma 
phospholipids increased significantly in the Omegaven® arm, with the proportion of EPA to the 
total fatty acids reaching almost three times the baseline value. The sum of omega-3 fatty acids 
showed a significantly greater increase in the Omegaven® group compared to the conventional 
treatment arm. 
 
The Taiwanese study was a single center, controlled, open-labeled study conducted to 
investigate the safety of parenteral administration of Omegaven® in preterm infants. The group 
of 20 infants were randomized to one of two treatment groups; one consisting of 
Omegaven®/conventional lipids and the other consisting of conventional lipids alone.  The 
average dose of Omegaven® in the treatment group of this 14-day study was 0.13 + 0.02 
g/kg/day.  There were no significant differences between the two groups with regard to body 
weight and length. Similarly, there was no significant difference in the hematological or 
biochemical parameters.  There were no adverse events that were attributable to Omegaven® 
use.  It was concluded that Omegaven® was well tolerated in these preterm infants. 
 
DESIGN AND METHODS 
A. Study Design  
Assessment of the effect of treatment will be based on a non-randomized, open-labeled, 
prospective study of intravenously administered Omegaven® fat emulsion to determine safety 
and preliminary efficacy in the treatment of PN associated liver injury.  
 
B. Patient Selection and Inclusion/Exclusion Criteria 
After the diagnosis of PNALD is made, patients who are followed by the Department of Surgery, 
in conjunction with the patient's primary physician, will contact Dr. Jones and an evaluation will 
be performed. Cases may also include referrals of patients with PNALD from other healthcare 
facilities or self-referrals upon transfer to our institution.  If the patient's parents or guardians 
agree to participate in the study, informed consent will be obtained. The history of present 
illness and past medical history will be reviewed with the guardian and pertinent demographic 
and medical information will be recorded on data collection forms. This form will be used to 
record all laboratory results, nutritional history, and descriptions of any liver biopsies performed.  
 
Though most patients receiving parenteral nutrition do not develop end stage liver disease, 
there is a small percentage of patients, typically infants and children on prolonged courses of 

Jones, B., Department of Surgery, Children’s Hospital & Medical Center 
Cusick, R., Department of Surgery, Children’s Hospital & Medical Center 
Jones, S., Pediatric Research Office, Dept. of Pediatrics, UNMC  
Lyden, E., Department of Biostatistics, College of Public Health, UNMC 
 
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parenteral nutrition, who do go on to develop fulminate liver failure.  The study population of this 
protocol is limited to patients felt to fulfill any one of the following conditions:  
 
a) The patient will be PN dependent and at risk for significant hepatic injury due to prolonged 
use of parenteral nutrition. 
b) Have significant hepatic dysfunction due to parenteral nutrition despite utilization of all 
conventional therapies. 
 
Inclusion Criteria: 
1. Patients will be PN dependent (unable to meet nutritional needs solely by enteral nutrition) 
and are expected to require PN for at least another 30 days. 
2. Patients considered eligible for study participation must have parenteral nutrition associated 
liver disease (PNALD) as defined as a direct bilirubin of  ≥ 2 mg/dl on at least the last two 
consecutive measures or by histology and/or currently on Omegaven through another protocol 
and unable to remain on that protocol due to transfer to our institution. Other causes of liver 
disease should be excluded. A liver biopsy is not necessary for treatment. 
3. The patient must have utilized standard therapies to prevent the progression of his/her liver 
disease including surgical treatment, cyclic PN, avoiding overfeeding, reduction/removal of 
copper and manganese from PN, advancement of enteral feeding, and the use of  ursodiol (i.e., 
Actigall®). 
4. Patients ages birth up to and including 18 years of age. 
 
Exclusion Criteria: 
1. Pregnancy 
2. Other causes of chronic liver disease (Hepatitis C, Cystic fibrosis, biliary atresia, and alpha 1 
anti-trypsin deficiency,) 
3. Enrollment in any other clinical trial involving an investigational agent (unless approved by the 
designated physicians on the multidisciplinary team) 
4. The parent or guardian or child unwilling to provide consent or assent 
 
In rare instances, patients diagnosed with PNALD may later be found to have liver disease due 
to other causes in addition to the use of PN (i.e., inborn errors of metabolism, viral infections). 
Such causes may not be known at the time of enrollment; however, these patients will be 
excluded upon identification. 
 
Screening Procedures 
All patients receiving parenteral nutrition for short bowel disorders at CH&MC are followed by 
the Department of Surgery as primary or through consults.  Eligibility for the trial will be 
discussed on rounds. Prior historical and physical information, imaging studies, biopsies, and 
other available specialized tests will be reviewed by the multidisciplinary team experienced in 
the diagnosis and treatment of parenteral nutrition associated liver disease. Additional 
biochemical monitoring will be performed as necessary. If the patient’s status supports 
consideration of treatment, the option for experimental therapy will be investigated. A similar 
process will be utilized for self-referrals and potential patients referred from distant healthcare 
facilities and will be implemented once they have been transferred to our institution.  
 
C. Description of Study Treatment 
Bottles containing 50mL or 100 mL of 10% Omegaven® will be purchased from International 

Jones, B., Department of Surgery, Children’s Hospital & Medical Center 
Cusick, R., Department of Surgery, Children’s Hospital & Medical Center 
Jones, S., Pediatric Research Office, Dept. of Pediatrics, UNMC  
Lyden, E., Department of Biostatistics, College of Public Health, UNMC 
 
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Pharmacy of Hamburg, Germany or directly from the manufacturer. FDA Approval is pending to 
allow for billing of Omegaven®. In the event that third party coverage is not available Children's 
Hospital & Medical Center will cover all Omegaven®  drug costs for patients enrolled in this 
protocol.   Omegaven® is manufactured by Fresenius Kabi AG, Bad Homburg v.d.h, Germany. 
Omegaven® is formulated as an emulsion from fish oils.  
 
While inpatient, the emulsion for all patients will be repacked into syringes to allow for 
administration via syringe pump.  If patients are to be discharged home on Omegaven®, all 
doses will be administered from the original manufacturer’s container. All study materials will be 
stored securely until the time of administration. The bottles will be stored at room temperature 
below 30° C (do not freeze). Damaged or suspect drug will be returned unused to Fresenius- 
Kabi. Containers should be shaken before use. 
 
All supplies for the study will be accompanied by accountability and shipping documents and will 
be maintained by the Investigator or deputy (e.g. research pharmacist). Information recorded on 
these accountability and shipping documents will include relevant dates, batch numbers, 
quantities received or dispensed, to whom dispensed, returned drug and drug lost or damaged. 
At the end of the study, all used and unused Omegaven® will be accounted for.  If expired, the 
remaining drug supplies will be destroyed. 
 
Details of Omegaven® Administration 
After baseline labs are obtained (Tables 2 and 3), therapy with Omegaven® will be initiated at 
the goal dose of 1 gram /kg/day and infused over 8-24 hours, so long as the infusion rate does 
not exceed 0.15g/kg/hour.  Omegaven® will be infused intravenously through either a central or 
peripheral catheter alone or in conjunction with parenteral nutrition.  If additional fat calories are 
needed, they will be provided via the enteral route. The same standards of care provided to all 
patients receiving parenteral nutrition solution will be followed. Routine nutritional monitoring is 
described in Table 3. 
 
In the event that a patient is unable to achieve adequate calories parenterally and is unable to 
tolerate enteral feeds, it may be necessary to evaluate whether or not the patient should 
continue the study with Omegaven® as monotherapy or resume therapy with conventional fat 
emulsions so that additional parenteral fat calories can be given. The clinical team, in 
conjunction with the patient's primary physician, will determine if the patient should be removed 
from the protocol. The DSMB will also be notified.   
 
Orders for Omegaven® will be entered in Epic and must contain the following data elements: 
• 
Total daily dose to be administered in mL 
• 
The hourly infusion rate (total daily dose ÷ the number of hours to be infused) 
Prior to the administration of each Omegaven® dose, two nurses will check the dose dispensed 
against the physician’s orders and verify that the infusion pump settings (hourly rate, volume to 
be infused) are correct before the infusion is started. 
 
As previously mentioned, Omegaven® may be infused in the same manner as conventional fat 
emulsions through either a central or peripheral line. The emulsion is isotonic. It is compatible 
with parenteral nutrition solutions and may be co-infused via y-site. Per Infection Control, source 
containers must be changed every 12 hours and unused product discarded. Omegaven® may 
be infused through a 1.2micron inline filter. 
 

Jones, B., Department of Surgery, Children’s Hospital & Medical Center 
Cusick, R., Department of Surgery, Children’s Hospital & Medical Center 
Jones, S., Pediatric Research Office, Dept. of Pediatrics, UNMC  
Lyden, E., Department of Biostatistics, College of Public Health, UNMC 
 
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Dose Modification 
Lipid Intolerance 
 
If lipid intolerance develops, defined as serum triglyceride levels > 200 mg/dL, the following will 
be considered prior to reducing the dose: 
a) If the level was obtained while the patient was receiving a continuous 24-hour infusion of 
Omegaven®, the total dose should be infused over 20 hours, and a repeat serum 
triglyceride level obtained prior to resuming the infusion 4 hours later. 
b) Other sources of lipid intolerance should be considered and addressed (drugs, renal 
disease) 
 
If the triglycerides continue to remain high despite the aforementioned interventions, a dosage 
reduction of 25% of the current dose will be considered. 
 
Duration of Therapy 
Patients will remain on Omegaven® until weaned from PN. Patients may continue monotherapy 
with Omegaven® as an additional source of calories after the dextrose/protein portion of PN is 
discontinued. 
 
In the event that a patient who has been listed for a liver or liver/intestinal transplant has an 
organ become available, the participation in this protocol will not preclude them from receiving 
the transplant. 
 
Disruption of Therapy 
In event that Omegaven® cannot be administered (i.e. loss of central venous catheter access, 
fluid restrictions, need to administer an incompatible medication/blood product), the infusion of 
Omegaven® may be interrupted and resumed when the conflicting situation is resolved. Some 
potential interventions that can be used include:  
 
Situation 
Possible Solution 
Loss of central venous access 
Administer via peripheral route 
Fluid restriction 
Consult with pharmacy to concentrate PN, 
medications to allow for administration 
Limited access, need to administer 
incompatible medications 
Stop Omegaven® infusion, flush catheter with 
either NS or dextrose, administer incompatible 
medication, flush catheter, resume infusion; 
may be necessary to infuse Omegaven® over 
8 -24 hours. Multiple syringes should be used 
so as to keep maximum hang time of 
Omegaven® source container less than 12 
hours) Regardless of the infusion time, the 
infusion rate  cannot exceed 0.15g/kg/hour.  
 
Discontinuation of Therapy 
Patients will continue to be followed by the Department of Surgery upon discontinuation of 
therapy with Omegaven® for a minimum of 2 months after the treatment is stopped.  
 
 
 

Jones, B., Department of Surgery, Children’s Hospital & Medical Center 
Cusick, R., Department of Surgery, Children’s Hospital & Medical Center 
Jones, S., Pediatric Research Office, Dept. of Pediatrics, UNMC  
Lyden, E., Department of Biostatistics, College of Public Health, UNMC 
 
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Resumption of Therapy 
For patients who have been off the protocol more than 1 year, in the event  that the patient  
must receive intravenous  fat emulsion, treatment with Omegaven® will resume only if the 
patient shows evidence of PN liver damage (elevations in direct bilirubin >2 or  pathology 
findings consistent with cholestasis). Otherwise, the patient will be treated with conventional fat 
emulsion. 
 
D. Definition of Primary and Secondary Outcomes/Endpoints 
Generally, primary safety analyses will be based on time from baseline or 30 days after baseline 
until two months after patients first reached direct bilirubin levels < 2mg/dL. Baseline will be 
defined as information collected at the date that treatment starts for Omegaven® patients and 
on the date that patient reached bilirubin levels > 2 for soybean oil fat emulsion patients. 
Information on mortality and transplant will be collected during the whole treatment with 
Omegaven®. Primary efficacy analysis will include time from baseline until the patient 
normalizes bilirubin (presents three consecutive direct bilirubin ≤ 2 mg/dL or a direct bilirubin ≤ 2 
mg/dL and weaned from TPN). 
 
Outcome/Endpoints 
 
Treatment safety 
Our primary outcome for treatment safety will be based on patient’s essential fatty acid profile. 
We will compare patients before treatment with Omegaven® started and after treatment started 
(one month after treatment started until treatment stopped) with respect to the frequency with 
which triene/tetraene ratio > 0.2 at any time. Primary analyses for these and all other safety 
outcomes will be based on a follow-up time for Omegaven® starting 30 days after baseline, i.e., 
30 days after treatment started for Omegaven® patients and 2 months after the first direct 
bilirubin level < 2 mg/dL was recorded.  
  
Additional comparisons across treatment periods for subjects receiving Omegaven® will be 
aimed to assess occurrence of spontaneous bleeding (e.g., unexplained bruising, oozing from 
gums/incision sites), and maximum triene/tetraene ratio, minimum platelets, maximum 
international normalized ratio (INR), and trends in pre-albumin (age standardized levels). We 
will also explore trends in coagulopathies based on curves of platelets, prothrombin time (PT), 
partial thromboplastin time (PTT) over time, and INR. We will also describe the rate with which 
INR ratios were > 2 (number of days/follow-up time), as a marker of coagulopathies. 
 
Additional evaluation of Omegaven® will be performed with regards to rate in which albumin is > 
3 g/dL, maximum triglyceride level, rate of blood stream infections (number of positive blood 
cultures/follow-up-time under PN after baseline), rate of central venous catheter (CVC) 
infections (number of CVC infections/follow-up time and number of gram positive CVC 
infections/follow-up time), and occurrence of anaphylatic reactions after baseline.  
 
We will describe trends over time for all outcomes associated with fatty acid profiles (including 
triene/tetraene ratios, triglycerides, total omega-6 fatty acids, total omega-3 fatty acids, total 
saturated, total monounsaturated, and total polysaturated fatty acids). Specific fatty acids such 
as arachidonic, palmoteleic, palmitic, oleic, stearic, and linoleic fatty acids will also be evaluated 
and described.  
 
 

Jones, B., Department of Surgery, Children’s Hospital & Medical Center 
Cusick, R., Department of Surgery, Children’s Hospital & Medical Center 
Jones, S., Pediatric Research Office, Dept. of Pediatrics, UNMC  
Lyden, E., Department of Biostatistics, College of Public Health, UNMC 
 
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E. Data Collection Methods, Assessments and Schedule 
Data will be collected by the PI (BJ), the managing co-investigator (RC) and the clinical 
coordinator (MD). Hospital charts will be reviewed for pertinent clinical information. Results of 
liver biopsies and blood chemistries will be obtained from Epic within the computer system at 
Children’s Hospital & Medical Center.  Specifically, the history of present illness, past medical 
history, and birth history, pertinent physical exam findings including patient weight, the results of 
liver biopsies, and parenteral and enteral feeding history will be collected. The information will 
be recorded on hard copy data collection forms. 
 
F. Study Timeline 
This study will end when the results of an FDA approved clinical trial proves Omegaven® 
treatment to be ineffective, the product is approved for use in the United States, or funding 
mechanism no longer exists to supply Omegaven® to study participants.  
 
G. Adverse Event Criteria and Reporting Procedures 
Adverse events (AEs) will be assessed and reported from the time of the first Omegaven® 
infusion until exit from the study in accordance with UNMC Pediatric IRB reporting 
requirements. In particular, the patient will be observed during and shortly after Omegaven® 
administration for the occurrence of anaphylactic or allergic reactions.  Other expected adverse 
events include death, blood stream infection; transfer to ICU for treatment of respiratory distress 
or hemodynamic instability; re-hospitalization for treatment of blood stream infection, 
dehydration, electrolyte abnormalities, catheter malfunctions, bowel obstructions, and urinary 
tract infection.  Unexpected adverse events will also be assessed and reported in compliance 
with the UNMC Pediatric IRB requirements. Patients experiencing any adverse events that are 
moderate or severe in nature and that may be related to Omegaven® will have their treatment 
temporarily halted until the adverse event has resolved. Dose modifications will occur as 
described above. If a dose reduction is made for adverse events later considered to be 
unrelated to Omegaven®, the Omegaven® dose will be increased back to the dose prescribed 
prior to the dose reduction.  Patients with anaphylactic or allergic reactions will not continue 
Omegaven® treatment. 
 
Any serious or unsuspected adverse events will be reported to the IRB and the FDA  within 72 
hours of the occurrence being known, or immediately if the event is fatal or life threatening as 
per UNMC Pediatric IRB Policy on Adverse and Unexpected Events and Unanticipated Risks to 
Research Subjects and Others. This will be done in person, by telephone, or email, and by 
completion of the IRB’s form for adverse/unexpected event reporting. 
 
Adverse events are detected by Children’s Hospital & Medical Center acute care medical and 
nursing staff during provision of standard care services including the routine monitoring of vital 
signs and daily physical exam data.   Adverse events identified by Children’s Hospital & Medical 
Center staff are reported to the Principal Investigator immediately by telephone or pager, and 
subsequently to the appropriate board or committee. 
 
A Committee of the Study Investigators (Drs. Jones, Cusick) will be responsible for assuring that 
adverse event reporting requirements are actually met. The Investigator Committee will meet 
not less than monthly to conduct clinical case reviews of all patients receiving Omegaven® to 
review recruitment data, adverse events and protocol deviations; and to evaluate overall safety 
of Omegaven® therapy.  Staff dieticians caring for Omegaven® patients will participate in the 
Investigator meetings as necessary.   Any patients who have agreed to participate in the trial, 

Jones, B., Department of Surgery, Children’s Hospital & Medical Center 
Cusick, R., Department of Surgery, Children’s Hospital & Medical Center 
Jones, S., Pediatric Research Office, Dept. of Pediatrics, UNMC  
Lyden, E., Department of Biostatistics, College of Public Health, UNMC 
 
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but who have not yet undergone intervention, will be informed of adverse events. A revised 
consent document will be submitted to the IRB with the adverse event form for review and 
approval. All adverse events will be classified by the Principal Investigator as definitely, 
probably, possibly, or unrelated to administration of study drug. 
 
Patients will be withdrawn from the study for any of the following: 
a) Toxicity considered unacceptable by the Principal Investigator (i.e.  Evidence of burr cell 
anemia (reported toxicity); Continued lipid intolerance (triglyceride >200) despite dose reduction 
attempts and administration modification; evidence of coagulopathy (INR> 2.0)). 
b) Patient/guardian requests to discontinue treatment and/or observation for any reason. 
c) A suitable organ has been located and the patient is able to undergo a liver or liver/intestinal 
transplant. 
d) Decision by the Principal Investigator that termination is in the patient’s best medical interest. 
e) Patient is lost to follow up. 
 
In the event that a patient is withdrawn from the protocol, study staff will document the date of 
withdrawal, the reason for withdrawal, and the results of all measurements of interest made up 
to date of withdrawal. 
 
DATA STORAGE & CONFIDENTIALITY 
This study is being conducted under an FDA Investigational New Drug Application. As such, 
FDA regulations must be followed. Personal Health Information (PHI) will be protected using 
standard policies and procedures developed through UNMC according to HIPAA guidelines. 
Subjects will be assigned specific reference numbers and maintained in a password protected 
database. The subject’s name and medical record number along with the corresponding 
reference number will be stored in a separate access page. All the research data gathered and 
stored will be identified by reference number only. The research data will only be accessible to 
the investigators and data/administrative and healthcare personnel involved in the study. 
Consent forms and files will be stored in a locked office. Information will not be stored on any 
personal computer or laptop. The de-identified data will be used for research or regulatory 
purposes or to prepare research publications. The child’s name will never appear in any reports 
or publications, or in any future disclosures. The child’s PHI will be shared, as necessary, with 
the Institutional Review Board (IRB) and with any person or agency required by law. The 
research data is subject to disclosure for the duration of the research and until data analysis is 
complete. 
 
Retention of Records 
The study coordinator will maintain a comprehensive and centralized filing system of all study 
related documentation which is suitable for inspection at any time by various regulatory 
agencies.  These include: 
 
a. Patient files including source documentation and Informed Consent 
b. Study files, including the protocol with all amendments, copies of all regulatory 
documentation, and all correspondence with the FDA and IRB 
c. Pharmacy files including drug shipment, dispensing, and accountability records, and 
pharmacy-related correspondence 
 
 
Per FDA regulations and industry standards, the Primary Investigator will retain records for a 
period of no less than five (5) years following discontinuation of the study. 

Jones, B., Department of Surgery, Children’s Hospital & Medical Center 
Cusick, R., Department of Surgery, Children’s Hospital & Medical Center 
Jones, S., Pediatric Research Office, Dept. of Pediatrics, UNMC  
Lyden, E., Department of Biostatistics, College of Public Health, UNMC 
 
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INFORMED CONSENT 
The Investigator will be responsible for obtaining an Informed Consent signed by each patient or 
his/her legally authorized representative prior to his/her participation in the study in accordance 
with the Code of Federal Regulations, Title 21, Part 50.20. Informed Consent will be obtained 
from a patient or his/her legally authorized representative after a full explanation of the purpose 
of the study, the risks and discomforts involved, potential benefits, etc. have been provided by 
the Investigator or designee, both verbally and in writing. The original of the signed consent 
must be maintained in the patient’s research binder; a copy will be maintained in the patient’s 
medical record. The person who signed the consent must also be given a copy of the signed 
consent form. 
 
DATA ANALYSIS PLAN 
Using graphical methods (including boxplots) and descriptive statistics, we will assess 
assumptions required for validity of statistical methods and presence of outliers. Continuous 
variables will be summarized via means (and standard deviations) or medians (and interquartile 
ranges, when appropriate. When appropriate, variables will be transformed.  
 
Primary analyses of the primary outcome will be based on the intention-to-treat analysis i.e., 
patient will be considered receiving Omegaven® throughout the whole follow-up period, 
regardless of temporary discontinuation of treatment due to infections or other causes. 
 
Analysis of Baseline Characteristics 
For statistical purposes, baseline values will be defined as the last measurement before starting 
to administer Omegaven®. Descriptive statistics for all baseline relevant risk factors will be 
summarized using counts and percentages for categorical variables and means (and standard 
deviations) or medians (and interquartile ranges), when appropriate for continuous variables.   
 
Analysis of Safety and Tolerability of Omegaven® 
All primary safety and tolerability analyses will be based on descriptive statistics. In secondary 
analyses, we will also assess the statistical significance of differences. The period receiving 
Omegaven® will start 30 days after beginning PN with Omegaven® for the main analysis. 
Outcomes measured in the Omegaven® will be described for a period starting 30 days after 
baseline. 
 
Primary outcomes measured will include whether the triene/tetraene ratio was ever > 0.2 during 
the intervention period and whether the INR was ever > 2.  Secondary outcomes measured will 
include platelets, prothrombin time (PT), partial thromboplastin time (PTT), and other 
components of the fatty acid profile. Analysis of all categorical outcomes will be based on 
proportions and of all continuous outcomes will be based on means or medians of the individual 
mean, maximum or minimum values, as appropriate, during the respective follow-up period. 
Comparisons between periods (pre and post-treatment) will be performed based on paired 
tests, parametric or non-parametric, as appropriate. We will also explore trends over time (e.g., 
decreasing for INR and increasing for pre-albumin) and estimate p-values via regression models 
using generalized estimating equations or random effects to account for within subject 
correlations. When describing outcomes over time, we will explore the effect of predictors of 
poor hepatic outcomes, such as use of antifungal agents (e.g.., amphotericin) and antidiarrheal 
agents (e.g., loperamide), on potential spikes.   
 
 

Jones, B., Department of Surgery, Children’s Hospital & Medical Center 
Cusick, R., Department of Surgery, Children’s Hospital & Medical Center 
Jones, S., Pediatric Research Office, Dept. of Pediatrics, UNMC  
Lyden, E., Department of Biostatistics, College of Public Health, UNMC 
 
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We will also evaluate nutritional outcomes including difference in weight-for- age Z-scores and 
height-for-age Z-scores from baseline to the moment in which the child starts enteral feeding 
and to the moment in which the child receives less than 10% of their calories from PN.  Using 
linear regression, we will explore adjustment for baseline alternative predictors of interest. 
Trends over time in Z-scores will also be explored using regression with repeated measure 
methods. 
 
Analysis of Efficacy of Omegaven® 
The primary outcome to gain preliminary evidence of efficacy will be based on the time from 
baseline to normalization of bilirubin level, i.e., first time point among three consecutive in which 
bilirubin is < 2 mg/dL. We do not anticipate that any subject will present a rebound on direct 
bilirubin after normalization. However, we will describe the cohort with respect to the frequency 
of rebounds in bilirubin levels. 
 
Time to normalize direct bilirubin levels will be estimated using Kaplan-Meier curves. We will 
estimate hazard ratios and adjust for potential baseline confounders using Cox-proportional 
hazard models. For all survival analysis based on non-parametric or semi-parametric methods, 
we will attribute an infinite time to event for subjects who die or receive a liver transplant before 
bilirubin is normalized. Subjects who die before their bilirubin levels normalize (particularly due 
to liver failure) have in fact the worst outcome (infinite time to normalize bilirubin) and were not 
censored before reaching the endpoint of interest. Results of these analyses will be compared 
with results of analysis excluding subjects who die or are transplanted. Time to reach a total 
bilirubin of 1.2 will also be estimated using survival analysis methods. Analyses of this outcome 
will proceed as described for direct bilirubin.   
 
We will also describe individual profiles over time (i.e., 2 months before baseline or birth until 
end of follow-up period) for all subjects using graphical methods. Trends in liver function 
markers over time will be explored using generalized linear models in which correlations of 
observations within subjects will be accounted using a generalized equations or random effects 
approach. We will perform these analyses including only subjects who did not die or undergo 
transplantation and including all subjects but assigning for subjects who died or underwent a 
transplant their worse possible outcome after they died or had the transplant. Using descriptive 
statistics, we will also explore the association between spikes in blood tests over time and 
predictors including transfusions of red blood cell products and blood stream infections.               
 
Assessment of efficacy will be also based on comparison of means (or medians) of the mean 
and maximum modified PELD scores of each subject across all follow-up weeks. Adjustments of 
these comparisons for potential confounders will be based on linear regression models. Mean 
rates of infection will be compared using logrank and Cox proportional hazards models.  
 
Missing Values 
Since data will be prospectively collected, we anticipate that data will be nearly complete, 
particularly for the safety outcomes. We will explore imputing any laboratory values that are 
missing up to two visits in the middle of the follow-up period using linear or non-linear 
interpolation, as appropriate. To interpolate direct and total bilirubin, we will primarily use the 
two closest observations, since bilirubin could be very different in points in time located further 
apart from the missing observation. We will compare conclusions of analyses based on imputed 
values with analyses based on the available information. 
 

Jones, B., Department of Surgery, Children’s Hospital & Medical Center 
Cusick, R., Department of Surgery, Children’s Hospital & Medical Center 
Jones, S., Pediatric Research Office, Dept. of Pediatrics, UNMC  
Lyden, E., Department of Biostatistics, College of Public Health, UNMC 
 
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Statistical Power and Sample Considerations 
The number of subjects included in the study will be based on a compassionate use protocol 
and not on study power considerations. The primary safety analysis will be descriptive and not 
based on statistical significance. However, in Table 4 we outline power to detect several 
differences in the frequency of adverse events, assuming 20, 25, or 30 patients, diverse 
proportion of subjects with adverse event in either treatment period and not with the adverse 
event in either treatment period and not with the adverse event in the other (proportion of 
discordant pairs), for a two-sided 5% significance level McNemar’s tests. 
 
For lower proportions of discordant pairs, we would generally attain close to 80% power in 
McNemar’s test. Even for higher proportions of discordant pairs, assuming the high differences 
between before and after treatment that we expect to observe, e.g., 50% or more, 80% power 
can be attained in McNemar’s test (Table 4). 
 
Table 4—Power to detect varying differences in proportions before and after treatment with 
Omegaven® in a McNemar’s test. All calculations based on an alpha significance level of 0.05 
 
Difference 
between 
proportions 
Proportion 
of 
discordant pairs 
McNemar’s Test 
Sample Size 
20 
25 
30 
30% 
40% 
59% 
72% 
81% 
60% 
44% 
55% 
63% 
50% 
60% 
92% 
97% 
99% 
80% 
79% 
88% 
93% 
80% 
85% 
>99% 
>99% 
>99% 
95% 
>99% 
>99% 
>99% 
 
 
DATA AND SAFETY MONITORING PLAN 
Patients will be monitored while receiving Omegaven® treatment to observe for signs of 
Omegaven® toxicity. At the start of Omegaven® therapy, patients will be monitored closely 
during and shortly after initial Omegaven® administration to observe for signs of allergic reaction 
and anaphylaxis.  In the event the patient demonstrated signs or symptoms of allergic reaction, 
the Omegaven® will be discontinued and the PI and attending physician will be notified. 
Selected safety labs will be evaluated by attending staff and the Study Investigators for both 
clinical and research purposes. Blood samples will be taken prior to the start of therapy 
(baseline), and thereafter in accordance with the scheduled represented in the tables below.  
 
Reversal Study Lab Schedule: 
Patient Status 
Parameter 
Tests to be Performed 
Frequency 
Inpatient/receiving 
Omegaven® 
Direct bilirubin > 2 
mg/dL 
PN profile, AST, GGT, 
CRP, lipid Panel, PT, PTT, 
INR, fibrinogen, EFA Panel 
Weekly 
Direct bilirubin < 2 
mg/dL 
PN profile 
Weekly 
PN profile, AST, GGT, 
CRP, PT, PTT, INR, 
fibrinogen, EFA panel, lipid 
panel  
Monthly 

Jones, B., Department of Surgery, Children’s Hospital & Medical Center 
Cusick, R., Department of Surgery, Children’s Hospital & Medical Center 
Jones, S., Pediatric Research Office, Dept. of Pediatrics, UNMC  
Lyden, E., Department of Biostatistics, College of Public Health, UNMC 
 
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Inpatient/off 
Omegaven® 
Direct bilirubin > 2 
mg/dL 
PN profile 
Weekly 
Direct bilirubin < 2 
mg/dL 
PN profile, AST, GGT, 
CRP, lipid Panel, PT, PTT, 
INR, fibrinogen, EFA Panel  
one complete set of  
post-Omegaven labs 
Outpatient/on 
Omegaven® 
Direct bilirubin > 2 
mg/dL 
PN profile, AST, GGT, 
CRP, lipid Panel, PT, PTT, 
INR, fibrinogen, EFA Panel  
Weekly  
Direct bilirubin < 2mg/dL PN profile, AST, GGT, 
CRP, lipid Panel, PT, PTT, 
INR, fibrinogen, EFA Panel 
Monthly until off  
Omegaven and at least 
1 direct serum bilirubin     
< 2 mg/dL 
 
 
 
Safety Labs Schedule:  
Lab Name 
Schedule* 
Serum triglycerides  
At baseline, weekly for 4 weeks, monthly thereafter 
Coagulation labs 
At baseline, weekly until direct bilirubin is < 2mg/dl, monthly thereafter 
Fatty acid profile 
At baseline, monthly thereafter 
*minimum requirements, may be performed more frequently for routine clinical care 
 
If under the discretion of the principal investigator the patient is able to return home and receive 
Omegaven®, the patient is required to return to Children’s Hospital & Medical Center every 2 
months or other mutually agreed upon schedule for evaluation and follow up. The Principle 
Investigator  also requires for arrangements to be made through the patient’s home health care 
agency for the required weekly or monthly blood draws the patient will need while at home in 
order to remain on Omegaven®. The lab results then must be faxed to Children’s Hospital & 
Medical Center in a timely manner. Additionally, measures will be taken to decrease the chance 
of administration errors when Omegaven® is given in the home. Families will be provided with a 
letter outlining strategies for reducing medication administration errors, such as independent 
double-checks.  
 
Dose reduction will occur if there is evidence of lipid intolerance (serum triglycerides > 
200mg/dL) or evidence of bleeding. Growth indices include weight, length, and head 
circumference will also be monitored.   
 
Other standard care laboratory results will be captured for the Omegaven® protocol.  These are 
listed along with the standard schedule in Table 3.  
 
The frequency of laboratory monitoring may be reduced to monthly or as clinically necessary, 
for patients who have been on a stable regimen of Omegaven® for a minimum of 4 months and 
whose serum bilirubin and hepatic enzymes have normalized. 
 
The study team will round on all inpatients receiving Omegaven® therapy. A complete 
comprehensive case review for all inpatients receiving Omegaven® therapy under the 
compassionate-use protocol and any outpatients issues will be discussed among Dr. Jones, Dr. 
Cusick, and the study coordinator. All pertinent medical, nutritional, and psychosocial outpatient 
information will be reviewed during these case reviews.  
 

Jones, B., Department of Surgery, Children’s Hospital & Medical Center 
Cusick, R., Department of Surgery, Children’s Hospital & Medical Center 
Jones, S., Pediatric Research Office, Dept. of Pediatrics, UNMC  
Lyden, E., Department of Biostatistics, College of Public Health, UNMC 
 
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This study will be monitored by an independent data safety monitoring board (DSMB). The 
DSMB will have 3 members [Dr. Shahab Abdessalam (Chair), Dr. Nicole Birge, and Dr. Gleb 
Haynatzki]. The Chair will receive copies of all adverse events reports and may call a DSMB 
meeting based on the reports received.  The DSMB will meet formally after the first 4 enrolled 
subjects and then annually to review preliminary safety data.  
 
The responsibilities of this board will include:  
  
• 
Analysis of the success and safety of the experimental therapy. Success will be 
measured by each patient's improvement in biochemical markers and avoidance of end 
stage liver failure.   
 
• 
Review the research protocol, and amendments, informed consent documents, and 
plans for data and safety analysis. 
 
• 
Evaluate the progress of the intervention, including assessment of data quality and 
timeliness of data entry, participant recruitment, accrual and retention, and any other 
factors that may affect the study outcome. 
 
• 
Review any factors external to the study when relevant, such as scientific or therapeutic 
developments that may have an impact on the safety of the subjects or the ethics of the 
trial. 
 
• 
Ensure the confidentiality of the trial data. 
 
The DSMB will be able to contact the investigators at any time by telephone or pager to facilitate 
adequate feedback of information to medical decision-makers. This will ensure that research felt 
to involve excessive risk in relation to anticipated benefits is terminated appropriately. To 
prevent potential or real conflicts of interest, if the research procedure is deemed by the DSMB 
to involve excessive risk in relation to anticipated benefits, the investigators will be contacted by 
phone or pager. The research will then be suspended pending further investigation, or 
terminated at the suggestion of the Board. 
 
RISKS AND DISCOMFORT 
 
Potential Risk of Omegaven® Treatment 
Omegaven® has been studied in animal pre-clinical models as well as Phase I, II, III, and post 
marketing human trials in both Europe and Asia. Prolonged bleeding time and an inhibited 
platelet aggregation can occur. It should not be administered to patients known to be allergic to 
fish or egg protein. 
 
Contraindications to Omegaven® include the following: 
Impaired lipid metabolism 
Severe hemorrhagic disorders 
Unstable diabetes mellitus 
Collapse and shock 
Stroke/Embolism 
Recent cardiac infarction 
Undefined coma status 

Jones, B., Department of Surgery, Children’s Hospital & Medical Center 
Cusick, R., Department of Surgery, Children’s Hospital & Medical Center 
Jones, S., Pediatric Research Office, Dept. of Pediatrics, UNMC  
Lyden, E., Department of Biostatistics, College of Public Health, UNMC 
 
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Side effects: 
The infusion of Omegaven® can lead to a prolonged bleeding time and an inhibited platelet 
aggregation. In rare cases, patients may experience a fishy taste. 
 
The administration of Omegaven® should be stopped or reduced if there is a marked increase 
in blood glucose levels during the Omegaven® infusion. Undesirable effects that are seen 
during the infusion of Omegaven® that may also occur with conventional fat emulsions (i.e. 
Intralipid®) include: 
 
Slight rise in body temperature 
Heat sensation and/or cold sensation 
Chills 
Flushing or cyanosis 
Lack of appetite, nausea, vomiting 
Dyspnea 
Headache, pain in the chest, bone pain 
Priapism 
Increase/decrease in blood pressure 
Anaphylactic reactions/erythema 
 
Other expected adverse events that are common to all patients with short bowel syndrome, 
regardless of the type of fat emulsion they receive, include blood stream infections and re-
admittance to hospital. Causes for re-hospitalization include dehydration, bloodstream 
infections, electrolyte abnormalities, bowel obstruction, and central venous catheter malfunction. 
 
Overdose: 
In the event of an overdose of Omegaven®, there is a risk of developing fat overload syndrome 
that may occur when the triglyceride level rises >200 mg/dL acutely as a result of too rapid a 
rate of infusion, or chronically at high infusion rates in associated with a change in the patient’s 
clinical condition (e.g., renal dysfunction, sepsis).  In such cases, the infusion should be stopped 
or, if necessary, continued at a reduced dose. Metabolic acidosis has occurred in patients 
receiving Omegaven® at excessive doses without simultaneous administration of dextrose. 
 
Potential Risks of No Treatment 
Since Omegaven® will only be offered to those patients for whom no standard therapy is likely 
to be safe and effective, the risks of not being treated are those allowing for the natural history 
of their disease and associated clinical manifestations to progress. These include fulminate liver 
failure and death. 
 
Additional Risks  
Risk of loss of privacy/confidentiality: There is a slight risk of loss of confidentiality, but this will 
be minimized as described in the Data Storage and Confidentiality section. 
 
Summary – Overall Risk Assessment 
Patients will be at some risk inherent in taking a pharmaceutical agent that has not been fully 
evaluated for long duration treatment. However, the availability of safety data demonstrates no 
life-threatening risks or toxicities to vital organs or physiologic functions. Prolonged bleeding 
times and inhibition of platelet aggregation are a potential risk, especially to those patients with 
an underlying coagulopathy or those being treated with an anticoagulant. The potential benefits 

Jones, B., Department of Surgery, Children’s Hospital & Medical Center 
Cusick, R., Department of Surgery, Children’s Hospital & Medical Center 
Jones, S., Pediatric Research Office, Dept. of Pediatrics, UNMC  
Lyden, E., Department of Biostatistics, College of Public Health, UNMC 
 
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of Omegaven® in this patient population are mainly based on the experimental evidence. 
However, the study will only be available to those for whom no standard therapy is available or 
appropriate, or has already failed. The risks and potential benefits will require careful individual 
assessment by both the investigators and patients.  The heterogeneity of clinical manifestations 
will lead to non-uniform risk-benefit ratios across the eligible patient population. 
 
BENEFITS 
 
Potential Benefit of Omegaven® Treatment 
Omegaven® may be effective in stabilizing or reversing hepatic injury associated with the use of 
parenteral nutrition. It may allow the patient to continue to receive the majority of his/her caloric 
intake from parenteral nutrition while advancing on enteral nutrition or awaiting liver or 
liver/intestinal transplant 
 
The potential benefits of this study apply directly to the patient in question and to possible 
improvement in the treatment of future patients. If successful, the experimental treatment will 
provide a safe and effective means of avoiding liver failure requiring transplant or that may lead 
to death.  Thus, the potential complications of surgery or fulminant hepatic failure may be 
avoided.  
 
PN associated liver disease is a life threatening condition. Available therapies (liver/small bowel 
transplant, intestinal lengthening, ursodiol, and combination enteral/parenteral feedings) are 
often inadequate.  Phytosterol containing intravenous fat emulsions containing large quantities 
of omega 6 fatty acids have been associated with PN associated liver disease. The safety 
profile of Omegaven® has been demonstrated to be acceptable for the diseases treated and 
should be considered as an option for patients requiring a form of intravenous fat emulsion. 
 
FINANCIAL CONSIDERATIONS 
Although the FDA has approved charging 3rd party payers for the cost of the drug/shipping, few 
third party payers in the United States allow these charges currently. We do not intend to bill the 
patient’s insurance carrier for the cost of the drug and related shipping charges.  
 
CLINICALTRIALS.GOV (NCT#): 02328768 
IND#: 125210 
 
 
 
 
 
 
 
 
 

Jones, B., Department of Surgery, Children’s Hospital & Medical Center 
Cusick, R., Department of Surgery, Children’s Hospital & Medical Center 
Jones, S., Pediatric Research Office, Dept. of Pediatrics, UNMC  
Lyden, E., Department of Biostatistics, College of Public Health, UNMC 
 
20 | P a g e                        
 
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REFERENCES 
1.  Dudrick SJ, Wilmore DW, Vars HM, Rhoads JE. Long-term total parenteral nutrition with 
growth, development, and positive nitrogen balance. Surgery 1968;64:134-42. 
2.  Wilmore DW, Dudrick SJ. Growth and development of an infant receiving all nutrients 
exclusively by vein. JAMA 1968;203:860-4. 
3.  Mullick FG, Moran CA, Ishak KG. Total parenteral nutrition: a histopathologic analysis of the 
liver changes in 20 children. Mod Pathol 1994;7:190-4. 
4.  Freund HR. Abnormalities of liver function and hepatic damage associated with total 
parenteral nutrition. Nutrition 1991;7:1-5; discussion 5-6. 
5.  Beath SV, Davies P, Papadopoulou A, Khan AR, Buick RG, Corkery JJ, Gornall P, Booth IW. 
Parenteral nutrition-related cholestasis in postsurgical neonates: multivariate analysis of risk 
factors. J Pediatr Surg 1996;31:604-6. 
6.  Greenberg GR, Wolman SL, Christofides ND, Bloom SR, Jeejeebhoy KN. Effect of total 
parenteral nutrition on gut hormone release in humans. Gastroenterology 1981;80:988-93. 
7.  Yeh SL, Chen WJ, Huang PC. Effects of L-glutamine on induced hepatosteatosis in rats 
receiving total parenteral nutrition. J Formos Med Assoc 1995;94:593-9. 
8.  Kubota A, Yonekura T, Hoki M, Oyanagi H, Kawahara H, Yagi M, Imura K, Iiboshi Y, Wasa 
K, Kamata S, Okada A. Total parenteral nutrition-associated intrahepatic cholestasis in infants: 
25 years' experience. J Pediatr Surg 2000;35:1049-51. 
9.  Moss RL, Das JB, Ansari G, Raffensperger JG. 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. 
10. Helms RA, Christensen ML, Mauer EC, Storm MC. Comparison of a pediatric versus 
standard amino acid formulation in preterm neonates requiring parenteral nutrition. J Pediatr 
1987;110:466-70. 
11. Moss RL, Haynes AL, Pastuszyn A, Glew RH. Methionine infusion reproduces liver injury of 
parenteral nutrition cholestasis. Pediatr Res 1999;45:664-8. 
12. Meehan JJ, Georgeson KE. Prevention of liver failure in parenteral nutrition-dependent 
children with short bowel syndrome. J Pediatr Surg 1997;32:473-5. 
13. Whalen GF, Shamberger RC, Perez-Atayde A, Folkman J. A proposed cause for the hepatic 
dysfunction associated with parenteral nutrition. J Pediatr Surg 1990;25:622-6. 
14. Zamir O, Nussbaum MS, Bhadra S, Subbiah MT, Rafferty JF, Fischer JE. Effect of enteral 
feeding on hepatic steatosis induced by total parenteral nutrition. JPEN J Parenter Enteral Nutr 
1994;18:20-5. 
15. Kaminski DL, Adams A, Jellinek M. The effect of hyperalimentation on hepatic lipid content 
and lipogenic enzyme activity in rats and man. Surgery 1980;88:93-100. 
16. Hultin M, Carneheim C, Rosenqvist K, Olivecrona T. Intravenous lipid emulsions: removal 
mechanisms as compared to chylomicrons. J Lipid Res 1995;36:2174-84. 
17. Qi K, Al-Haideri M, Seo T, Carpentier YA, Deckelbaum RJ. 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. 
18. Nestel PJ. Effects of N-3 fatty acids on lipid metabolism. Annu Rev Nutr 1990;10:149-67. 
19. Chen W. Effects of fat emulsions with different fatty acid composition on plasma and hepatic 
lipids in rats receiving total parenteral nutrition. Clinical Nutrition 1996;15:24. 
20.  Yeh S. Effects of fish oil and safflower oil emulsions on diet-induced hepatic steatosis in 
rats receiving total parenteral nutrition. Clinical Nutrition 1996;15:80. 
21. Kinsella JE, Lokesh B, Broughton S, Whelan J. Dietary polyunsaturated fatty acids and 
eicosanoids: potential effects on the modulation of inflammatory and immune cells: an overview. 
Nutrition 1990;6:24-44; discussion 59-62. 

Jones, B., Department of Surgery, Children’s Hospital & Medical Center 
Cusick, R., Department of Surgery, Children’s Hospital & Medical Center 
Jones, S., Pediatric Research Office, Dept. of Pediatrics, UNMC  
Lyden, E., Department of Biostatistics, College of Public Health, UNMC 
 
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22. Alwayn IPJ, Gura K, Nose V, Zausche B, Javid P, Garza J, Verbesey J, Voss S, Ollero M, 
Andersson C, Bistrian B, Folkman J, Puder M. Omega-3 fatty acid supplementation prevents 
hepatic steatosis in a murine model of nonalcoholic fatty liver disease. Pediatr Res. 2005 
Mar;57(3):445-52. Epub 2005 Jan 19.  
23.Van Aerde JE, Duerksen DR, Gramlich L, Meddings JB, Chan G, Thomson AB, Clandinin 
MT 1999 Intravenous fish oil emulsion attenuates total parenteral nutrition-induced cholestasis 
in newborn piglets. Pediatr Res 45:202-208. 
24. Morlion BJ, Torwesten E, Lessire Al, et al. The effect of parenteral fish oil n leukocyte 
membrane fatty acid composition and leukotriene synthesizing capacity in postoperative trauma. 
Metabolism 1996; 45:1208-1213. 
25. Grimminger F, Führer D, Papavassilis C, et al. Influence of intravenous n-3 liipid 
supplementation on fatty acid profiles and lipid mediator generation in patients with severe 
ulcerative colitis. Eur J Clin Invest 1993; 23:706-15. 
26. Grimminger F, Mayser P, Papavassilis C, et al. A double blind randomized, placebo-
controlled trial on n-3 fatty cid based lipid infusion in acute, extended guttate psoriasis. Rapid 
improvement of clinical manifestations and changes in neutrophil leukotriene profile. Clin Invest 
1993; 7:634-43. 
27. Mayeser P, Mrowietz U, Arenberger P, et al. ω-3 fatty acid  based lipid emulsion in patients 
with chronic plaque psoriasis. J Am Acad Dermatol 1998; 38:539-47.  
28. Heller AR, Fischer S, Rössel T, Impact of n-3 fatty acid supplemented parenteral nutrition on 
haemostasis patterns after major abdominal surgery. Br J  Nutr 2002; 87; Suppl 1:95-101. 
29. Kolezko BV, Fürst P. Fish oil in parenteral nutrition in infants: clinical evidence and 
experience. Data on file, Fresenius- Kabi AG, Bad Homburg v.d.h. 
30.  Gura KM, Parsons SK, Bechard LJ, Henderson T, Dorsey M, Phipatanakul W, Duggan CP, 
Puder M Lenders C.  Use of a fish oil-based lipid emulsion to treat essential fatty acid deficiency 
in a soy allergic patient receiving parenteral nutrition. Clinical Nutrition. 2005 Oct;24(5):839-47. 
31. Andorsky DA, Lund DP, Lillehei CW, Jaksic T, DiCanzio J, Richardson D, Collier S, Lo C, 
Duggan C. Nutritional and other postoperative management of neonates with short-bowel 
syndrome correlates with clinical outcome. J Pediatr, 2001; 139:27-33. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Jones, B., Department of Surgery, Children’s Hospital & Medical Center 
Cusick, R., Department of Surgery, Children’s Hospital & Medical Center 
Jones, S., Pediatric Research Office, Dept. of Pediatrics, UNMC  
Lyden, E., Department of Biostatistics, College of Public Health, UNMC 
 
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APPENDIX 
 
Table 1: Comparison of Parenteral Fat Emulsions (10 grams fat/100 mL) 
OIL 
Intralipid® 
Liposyn® II 
Omegaven® 
Soybean 
10 
5 
 
Safflower 
 
5 
 
Fish 
 
 
10 
% FATS 
 
 
 
Linoleic 
50 
65 
0.1-0.7 
α-linolenic 
9 
4 
<0.2 
E.P.A. 
 
 
1.3-2.8 
D.H.A. 
 
 
1.4-3.1 
Arachidonic acid 
 
 
0.1 -0.4 
Glycerol 
2.3 
2.5 
2.5 
Egg Phospholipid 
1.2 
1.2 
1.2 
Available in the   United 
States 
Yes 
Yes 
No 
 
 
 
 
Table 2: Schedule for Required Safety Monitoring for Omegaven® Therapy  
 
Lab Name 
Schedule* 
Serum triglycerides  
At baseline, weekly for 4 weeks, monthly thereafter 
Coagulation labs 
At baseline, weekly until direct bilirubin is < 2mg/dl, monthly thereafter 
Fatty acid profile 
At baseline, monthly thereafter 
*minimum requirements, may be performed more frequently for routine clinical care 
 
 
 
 
 
 
 
 
 

Jones, B., Department of Surgery, Children’s Hospital & Medical Center 
Cusick, R., Department of Surgery, Children’s Hospital & Medical Center 
Jones, S., Pediatric Research Office, Dept. of Pediatrics, UNMC  
Lyden, E., Department of Biostatistics, College of Public Health, UNMC 
 
23 | P a g e                        
 
3  J a n u a r y  2 0 1 7  
 
Table 3: Suggested Monitoring Schedule for Omegaven® Therapy 
Parameter 
 
Baseline 
(pre-
Omegaven) 
Daily 
Q  week* 
Until direct  
Bili  < 2mg/dL 
Monthly* once       
direct bilirubin   
<2.0 mg/dL 
Periodically* 
Tube type  
volume 
Weight 
X 
X 
 
 
 
Fluid balance 
X 
X 
 
 
 
Vital Signs 
X 
X 
 
 
 
 
 
 
 
 
 
1.5mL 
lithium heparin 
or 2  
microtainers 
 
Catheter site/function 
X 
X 
 
 
 
Laboratory test: 
 
 
 
 
 
Sodium 
X 
 
X 
X 
 
Potassium 
X 
 
X 
X 
 
Chloride 
X 
 
X 
X 
 
Glucose 
X 
 
X 
X 
 
BUN 
X 
 
X 
X 
 
Creatinine 
X 
 
X 
X 
 
Triglycerides 
X 
 
X 
X 
 
Calcium 
X 
 
X 
X 
 
Magnesium 
X 
 
X 
X 
 
Phosphorus 
X 
 
X 
X 
 
Prealbumin 
X 
 
X 
X 
 
C reactive protein 
X 
 
X 
X 
 
Albumin 
X 
 
X 
X 
 
Total protein 
X 
 
X 
X 
 
SGPT 
X 
 
X 
X 
 
Alkaline phosphatase 
X 
 
X 
X 
 
Bili (total and direct) 
X 
 
X 
X 
 
GGT 
X 
 
X 
X 
 
AST 
X 
 
X 
X 
 
Ess. Fatty Acid Profile 
X 
 
X 
X 
 
2 mL red top 
Free cholesterol 
X 
 
X 
X 
 
Free fatty acids 
X 
 
X 
X 
 
Lipid Panel 
X 
 
X 
X 
 
Hemoglobin 
X 
 
X 
X 
 
0.6ml purple 
top 
Hematocrit 
X 
 
X 
X 
 
RBC 
X 
 
X 
X 
 
WBC 
X 
 
X 
X 
 
Platelets 
X 
 
X 
X 
 
PT 
X 
 
X 
X 
 
1.5ml blue top 
PTT 
X 
 
X 
X 
 
INR 
X 
 
X 
X 
 
Fibrinogen 
X 
 
X 
X 
 
Selenium 
 
 
 
 
X 
Navy blue 
Metal free 
Zinc 
 
 
 
 
X 
Aluminum 
 
 
 
 
X 
Copper 
 
 
 
 
X 
Iron 
 
 
 
 
X 
Carnitine 
 
 
 
 
X 
lithium heparin 
Vitamins A,D,E 
 
 
 
 
X 
Call lab control 
Retinol binding protein 
(check when getting Vit A) 
 
 
 
 
X 
3 ml red top 
*More often as necessitated by clinical course; may be reduced in patients who are stable (i.e., home patients) and whose biochemical markers have improved.