Compassionate Use of a Fish Oil-derived Intravenous Fat Emulsion (Omegaven) to Reverse Parenteral Nutrition (PN) Induced Cholestasis
Phase: NA
Conditions: Cholestasis
Sponsor: Children's Hospital Medical Center, Cincinnati

Protocol – Compassionate Use of a Fish Oil-derived Intravenous Fat Emulsion 
(Omegaven®) to Reverse Parenteral Nutrition (PN) Induced Cholestasis 
 
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Cincinnati Children’s Hospital Medical Center 
3333 Burnet Avenue 
Cincinnati, OH  45229-3039 
 
 
 
NCT01173159 
 
  
Compassionate Use of a Fish Oil-derived Intravenous Fat 
Emulsion (Omegaven®) to Reverse Parenteral Nutrition (PN) 
Induced Cholestasis 
 

Protocol – Compassionate Use of a Fish Oil-derived Intravenous Fat Emulsion 
(Omegaven®) to Reverse Parenteral Nutrition (PN) Induced Cholestasis 
 
Version:  2.2.15 
2
Cincinnati Children’s Hospital Medical Center 
Research Protocol 
 
 
 
Title: Compassionate Use of a Fish Oil-derived Intravenous Fat Emulsion 
(Omegaven®) to Reverse Parenteral Nutrition (PN) Induced Cholestasis 
 
Investigator:  Samuel A. Kocoshis, MD 
 
Co-Investigators:  Conrad Cole, MD, Michael Helmrath, MD, Jaimie D. Nathan, 
MD,  Jacqueline Wessel, RD, Monique Goldschmidt, MD 
 
 
I.  Abstract 
 
Infants with intestinal failure require chronic administration of parenteral nutrition 
(TPN).  The population under one year of age on TPN is at greatest risk for parenteral 
nutrition associated cholestasis (PNAC), but, even among older individuals on TPN, the 
emergence of cholestasis carries a bad prognosis.  A number of factors play a role in 
PNAC.  These include endotoxemia, prolonged fasting, immaturity of bile secretory 
mechanisms among infants, intravenous infusion of high glucose concentrations, 
intravenous infusion of high protein loads, and intravenous infusions of soy based lipid 
emulsions. Human data reveal that TPN administered to infants for over three weeks is 
associated with PNAC.  Further analysis reveals that cholestasis is closely associated 
with the administration of soy-based lipids which contain potentially hepatotoxic 
phytosterols.  Thus lipid reduction strategies have been employed for reversal of PNAC.  
They sometimes work, but put infants at risk for essential fatty acid deficiency.  An 
alternative strategy of providing lipid in the form of Omegaven®, a fish oil-derived 
emulsion, is extremely promising, and has been used successfully with virtually no 
complications in an uncontrolled trial at Boston Children's Hospital.  Ongoing controlled 
studies of Omegaven® are underway at Boston Children's Hospital, and several other 
institutions have published small case series or case reports suggesting that Omegaven® 
is effective and safe.  It is not FDA approved because none of the ongoing placebo 
controlled trials have been completed yet in the United States, but, because of its anti-
inflammatory properties, it is approved in several European countries for use in adults 
with inflammatory conditions.  Every year, we observe several children in our own 
practice who have no hope of coming off TPN for several months and who have 
progressive cholestasis.  Our own unpublished data suggest that once PNAC has been 
established in the absence of endotoxemia, it is usually reversible.  However, this may 
not be true if less than approximately 70% of daily calories are derived enterally.  We 
also have published data in abstract form suggesting that a high conjugated bilirubin to 
gamma GT ratio is a poor prognostic sign. This study provides Omegaven® for 
compassionate release to those infants within our practice who have developed 
progressive cholestasis despite reduction in parenteral lipid below one gram per kilogram 

Protocol – Compassionate Use of a Fish Oil-derived Intravenous Fat Emulsion 
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body weight per day, and who are unlikely to tolerate substantial enteral nutrition until 
several months following their small intestinal insult.   
 
II.  Purpose of Study 
 
The specific aim of this study is to ascertain whether PNAC can be reversed if a fish oil-
based intravenous lipid product (Omegaven®) at a dose of up to 1 g/kg body weight/day 
is substituted for a soy-based intravenous lipid product (Liposyn® or Intralipid®) as part 
of the daily TPN of infants and children with intestinal failure and PNAC.  Secondary 
aims will be to confirm the safety of Omegaven®. 
 
III.  Background 
 
In North America, infants and children who require parenteral nutrition (TPN) 
customarily receive solutions whose caloric distribution is balanced between glucose, 
protein, and fat to provide approximately 60-70 % of calories via glucose, 10-15 % of 
calories via protein, and 20-30% of calories via lipid.(1)  Commercial lipid solutions 
utilized in North America are customarily soy-based, and contain high quantities of 
phytosterols including sitosterol and stigmasterol.  Animal data suggest that high 
quantities of stigmasterol inhibit fxr, a nuclear receptor in the hepatocyte that helps to 
regulate bile acid homeostasis by controlling expression of bile acid export pumps. (2) 
Thus, exposure to a high quantity of stigmasterol is potentially hepatotoxic to individuals 
who have a propensity for cholestasis due to a poorly developed bile secretory process.   
 
It is known that infants and children with underlying intestinal failure are at 
extraordinarily high risk for cholestasis. (3). The cholestatic process is reversible in 
approximately ¾ of infants with parenteral nutrition associated cholestasis (PNAC), even 
when soy-based lipid emulsions are given parenterally, if those infants can experience 
small intestinal adaptation and ultimately tolerate and assimilate the majority of their 
calories via enteral nutrition.  Unfortunately, if adaptation does not occur rapidly enough, 
PNAC may progress to endstage liver disease resulting in death or necessitating 
combined liver/small intestinal transplantation. 
 
A popular strategy for minimizing the toxicity of lipid emulsions is to reduce the amount 
of lipid in parenteral nutrition to between 0.5 g/kg body weigh/day and 1g/kg body 
weight/day. (4)  Preliminary results suggest that this strategy is beneficial for some 
infants, but that it is not universally effective.  One potential reason for lack of 
effectiveness among some cholestatic infants is that endotoxemia is commonplace in 
children with intestinal failure receiving TPN, and that stigmasterol potentiates the 
cholestatic effect of endotoxin upon the liver. Therefore, when the infant with a 
cholestatic propensity is exposed to endotoxin and even modest quantities of 
stigmasterol, cholestasis could progress.  
 
An alternative liver-protective strategy for children on TPN has been to provide all of the 
patients’ parenteral lipid in the form of a fish-oil based product called Omegaven®. (5) 
This product has been used for over 10 years as an adjunct to conventional fat emulsions.  

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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 against inflammatory tissue damage and capillary permeability.  In addition, 
adults on Omegaven® seem to display improved immunological resistance. Omegaven®  
may also reduce the risk of thrombosis and increase microvascular perfusion due to its 
anti-aggregatory and vasodilatory effects. 
 
In Europe and Asia, parenteral omega-3 fatty acids have been used in the following adult 
patient populations: 
 
1. post traumatic and post surgical patients 
 
2. patients experiencing early stages of sepsis/SIRS 
 
3. patients at risk of hyperinflammatory processes 
 
4. patients with inflammatory bowel disease (Crohn’s disease, ulcerative colitis) 
 
5. patients with inflammatory skin diseases (psoriasis, atopic eczema) 
 
The dosing used in these patients was 0.1 (1ml) to a maximum of 0.2 g (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. 
 
Two non-North American trials suggest that Omegaven® is safe when administered to 
young children. (6,7) These trials were performed in Germany and Taiwan. 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 

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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. 
 
While non-North American studies conclude that Omegaven® is safe and that it may 
have anti-inflammatory properties, they do not address a potential liver protective effect 
for the agent. Data from North America suggest a salutary role for Omegaven® in 
PNAC.  The group at Boston Children’s hospital had initially utilized Omegaven® in a 
child with soy allergy who required TPN. (8) Subsequently, they reported upon two 
children who received Omegaven ® for PNAC, demonstrating that cholestasis resolved 
in both and that neither of them experienced side effects. (9). A subsequent open label 
trial performed at Boston Children’s Hospital showed both safety and resolution of 
cholestasis in 18 children with advanced PNAC.(5) Historical controls receiving soy-
based lipid emulsions showed progression of cholestasis rather than resolution.  
Currently, a double blind, controlled study comparing 1 g/kg body weight/day of 
Omegaven® with 1 g/kg body weight/day of Intralipid® is being conducted in Boston, 
and results are quite promising (Kathleen Gura, personal communication).  Many other 
pediatric institutions, including our own, have utilized Omegaven® to treat PNAC.  This 
agent is available in over 30 institutions, and no significant adverse effects have been 
reported.  Small case series and case reports have been published confirming safety and 
suggesting effectiveness for PNAC (10).  
 
Our own experience with Omegaven® is confined to three patients.  The first was a 2 
year-old who underwent an extensive intestinal resection for a stage 4 neuroblastoma 
with CNS metastases at another institution.  In an attempt to resect her primary 
retroperitoneal abdominal neuroblastoma, an intraoperative vascular catastrophe 
occurred, resulting in loss of all of her small bowel except for a small duodenal stump 
which was oversewn.  Therefore, her esophagus, stomach, and proximal duodenum were 
a blind loop, and she could receive no enteral nutrition whatsoever.  Her conjugated 
bilirubin had risen to approximately 6 mg/dl, and her parents took her to Boston 
Children’s Hospital where Omegaven® was started.  She also underwent chemotherapy 
for her neuroblastoma, and while she was tumor-free, her bilirubin normalized despite 
absence of enteral alimentation and prolonged use of TPN.  Only when her tumor 
recurred and she developed hepatic metastases did her bilirubin once again climb to an 
abnormally high level. Figure 1 shows her conjugated bilirubin plotted against time.  Her 
platelet counts remained below normal because of bone marrow suppression due to 
chemotherapy, but following each course of chemotherapy, they rose to between 70,000 
and 120,000 u/L until her next course of chemotherapy.   We did not have our own 
protocol in place to offer Omegaven®, but our pharmacy dispensed Omegaven® which 
had been obtained from Boston Children’s Hospital when she was an inpatient here at 
CCHMC.  
 
Our second patient was a 14 month old ex 29 week gestation premature infant who 
developed severe necrotizing enterocolitis requiring surgery. He underwent two separate 
bowel resections, and was left with 27 cm of jejunum beyond the ligament of Trietz.  He 

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was feed by continuous feedings of an elemental formula, and his feedings were slowly 
being advanced while he concomitantly received parenteral nutrition.  His conjugated 
bilirubin level remained approximately 3 mg/dl until he developed Klebsiella sepsis with 
shock and multi-organ failure.  This septic event left him with significant neurologic 
impairment as well as worsened hepatic and pulmonary function. His conjugated 
bilirubin abruptly climbed to approximately 30 mg/dl, and his hepatic synthetic function 
deteriorated. He required mechanical ventilation. We then obtained Omegaven® by 
compassionate release after approval by the CCHMC IRB (protocol # 2009-1041). 
Omegaven® was administered for approximately 4 weeks and Figure 2 demonstrates the 
progressive fall in his conjugated serum bilirubin.  Unfortunately, he developed 
progressive respiratory failure and expired in early September of 2009 despite improving 
hepatic function.  He experienced neither worsening of platelet count nor signs of 
essential fatty acid deficiency while he was on Omegaven®.  
 
Our third patient was a 26 week gestation ex premature male who developed severe 
necrotizing enterocolitis during his first week of life. He required an extensive small 
bowel resection, and was left with approximately 40 cm of jejunum beyond the ligament 
of Trietz.  His surgery was complicated by an enterocutaneous fistula which engendered a 
delay in initiating feedings. He received no more that trophic feedings of Elecare® at a 
rate of 2 ml/hour.  He was allowed to drink no more than 5 ml of formula two times 
daily.  His fistula was closed on November 5, 2009, but he could not tolerate full enteral 
feedings for approximately 16 weeks later.   Meanwhile, he received virtually all of his 
nutrition via TPN.  He developed parenteral nutrition associated cholestasis (PNAC) by 
his second week of life, and his conjugated bilirubin levels progressively increased while 
his GGT levels fell. He was started on Omegaven® when his conjugated bilirubin level 
had risen above 2 mg/dl and persisted between 2 mg/dl and 4 mg/dl for approximately six 
weeks. He was started on 1 g/kg/day of Omegaven® at the same time that feedings were 
started.  His bilirubin fell to <2 mg/dl within 10 days while his enteral intake constituted 
only 30% of his total caloric intake.  He is now on full enteral feedings with a normal 
conjugated bilirubin level. Levels of his conjugated bilirubin are demonstrated in figure 
3.  
 
PNAC is a potentially fatal disorder, and the consequences are heinous if the process 
cannot be reversed.  In Omegaven® we have an agent that is potentially life saving, and 
its use in hundreds of patients has shown little if any toxicity. After ongoing controlled 
trials of Omegaven® are completed, the agent will be evaluated for approval by the FDA.  
Until such time as FDA approval is granted, we will be unable to administer Omegaven® 
without requesting approval for compassionate use. The IRB granted approval for 
protocol 2009-1041, and this protocol will call for even stricter inclusion criteria. 
Therefore, we seek IRB approval for this study. 
 
IV.  Duration of Study 
 
Once IRB approved, enrollment of subjects into this study will occur for up to 9years.  
Subjects will receive Omegaven at a dose of up to 1 g/kg body weight/day until they no 

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longer require TPN or until their conjugated or direct bilirubin has normalized and their 
enteral lipid intake is sufficient to discontinue intravenous lipids. 
 
A total study duration of 10 years is anticipated to complete the study (enrollment, 
analyses, and report writing). 
 
V.  Potential Benefits 
 
The use of Omegaven® has the potential to benefit patients with PNAC by facilitating 
the resolution of cholestasis.  
 
VI.  Potential Risks 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: 
1. Impaired lipid metabolism  
2. Severe hemorrhagic disorders  
3. Unstable diabetes mellitus 
4. Collapse and shock 
5. Stroke/Embolism 
6. Recent cardiac infarction  
7. Undefined coma status 
 
Side Effects: 
Risks of Omegaven® 
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 
increased 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., Liposyn® or Intralipid®) include: 
 
1. Slight rise in body temperature 
 
2. Heat sensation and/or cold sensation 
3. Chills 
4. Flushing or cyanosis 
5. Lack of appetite, nausea, vomiting  
6. Dyspnea 
7. Headache, pain in the chest, bone pain 
8. Priapism 
9. Increase/decrease blood pressure 
10.Anaphylactic reactions/erythema 

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Risks for blood draw: 
• Occurrence of discomfort and/or a bruise at the site of puncture 
• Less commonly, fainting 
• The formation of a clot or swelling in the vein and surrounding tissue 
• Bleeding from the puncture site 
• On rare occasions an infection may develop at the site where the blood is 
collected 
 
 
 
Potential Risks of No Treatment 
 
Since Omegaven® will only be offered to those patients for whom no standard therapy 
has been 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. 
 
VII.  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. The potential benefits of Omegaven® in this patient population are mainly 
based on human trials and our own experience. 
 
VIII.  Risk Category 
 
 The research involves greater than minimal risk, but presents the prospect of direct 
benefit to the individual subjects.  
 
IX.  Methods 
 
A.  Subject Selection 
 
No concomitant medications will prohibit enrollment. 
 
Inclusion Criteria   
1. Males and females ages one month of age to 18 years of age 
2. Patients with intestinal failure on TPN 
3. Patients who have a conjugated or direct bilirubin of ≥3 mg/dl for more 
than 4 weeks and in whom other causes of cholestasis have been excluded 
with reasonable certainty utilizing biochemical, serologic, microbiologic, 
and radiographic techniques. Liver biopsy is not required to rule out other 
disorders, but may be utilized at the clinician’s discretion    
4. Patients in whom reduction of IV soy-based lipid load to an average 
<1.2g/kg body weight/day has failed to reduce the conjugated or direct 
bilirubin within  ≥ 30 days of implementation 

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5. Willing to use birth control during study participation for females of child-
bearing potential, as determined by investigator. 
6. Signed informed consent for use of Omegaven®  obtained  
 
Exclusion Criteria 
1. Any of the contraindications to use of Omegaven®  
• Impaired lipid metabolism (triglycerides >1000 mg/dL) while on 
1g/kg/day or less of Intralipid  
• History of severe hemorrhagic disorders (ie. hemophilia, Von 
Willebrand disease, etc.) 
• Unstable diabetes mellitus 
• Collapse and shock 
• Stroke/ Embolism 
• Cardiac infarction within the last 3 months    
• Undefined coma status 
• Pregnancy (positive pregnancy test) prior to enrollment in the 
study for females of child-bearing potential 
• Females of child-bearing potential who are unwilling to use birth 
control during study participation 
2. Parental decision to forego the use of Omegaven® 
3. Known fish or egg allergy 
4. Pregnancy 
5. Causes of liver disease other than PNAC 
 
B. Withdrawal Criteria 
1. Decision of an assenting minor/adult subject or parent/guardian to 
withdraw from the study* 
2. Anaphylaxis 
3. Evidence of spur cell anemia.  
4. Increasing anemia (hemoglobin < 7 g/dL) in the absence of 
gastrointestinal bleeding. 
5. Mucosal bleeding or bleeding from IV insertion sites requiring 
transfusion. 
6. Reproducible priapism associated temporally with the infusion 
7. Mucosal bleeding associated with abnormal platelet function 
8. Bowel adaptation such that patient can either come off TPN or such that 
enteral fat can meet the patient’s nutritional requirements  
9. Patient undergoes liver transplantation 
10. Pregnancy 
11. Patient is lost to follow up 
* If an assenting minor chooses to withdraw from the study early, even if the 
parent wants the child to participate, the child will have their wishes 
respected. 
 
C. Stopping Rules  
    If two subjects develop the same grade-3 adverse event (including liver function tests, 

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coagulation profile, and platelet count) related to the study medication that is irreversible 
upon de-escalation (does not reverse after 10 days) or upon discontinuation of the study 
drug, or any subject develops a related grade-4 adverse event, these events will be the 
cause for termination of the study. 
 
D.  Monitoring for toxicity due to Omegaven®  
Potential toxicity will be assessed by analyzing clinical and laboratory parameters 
including serum electrolytes, hematological studies, serum triglycerides, total cholesterol, 
liver function tests, and essential fatty acid profiles where applicable. Blood samples will 
be taken in accordance with current institutional standards for monitoring 
hyperalimentation. In the face of mucosal bleeding, studies of platelet function (closure 
time) will also be performed.  
 
 
E.  Patient Recruitment and Consenting Process 
 
Patient Recruitment 
 
Approximately 25 patients, ages one month to 18 years will be enrolled from Cincinnati 
Children’s Hospital.  All patients will be enrolled as inpatients.  The study will be 
explained in detail by the physician and study coordinator and the consent form (and age 
appropriate assent forms) will be reviewed per institutional IRB requirements.  These 
subjects will be recruited through the Division of Gastroenterology, Hepatology, and 
Nutrition, the Department of Surgery, or the Division of Neonatology.  The prospective 
patients will be identified through the clinical staff within all three divisions working 
collaboratively.  The clinical staff will initially inform potential subjects and families 
about the research study. The research staff will notify and obtain permission from the 
patient’s primary gastroenterologist, surgeon, or neonatologist before contacting the 
family. 
 
Subjects who drop out prior to drug initiation may be replaced with new subjects until 
target enrollment is achieved, as these will not have been given study medication. 
 
Consenting Process 
 
For those patients meeting inclusion criteria, the study purpose, procedures, costs, risks, 
benefits, and alternatives to participation will be thoroughly explained and presented to 
the patient and their family by the designated study coordinator and/or investigator, and 
subjects will be screened for willingness to participate.  Subjects and parents will be 
explicitly informed that choosing not to participate will in no way affect the quality of the 
medical care that they will receive.  Once patients and families have had enough time to 
consider participation and have expressed a willingness to participate, informed consent 
will be obtained from the parents or legal guardian and child assent when appropriate 
based on age and institutional IRB requirements.   
 
Due to the age of the subjects, an age appropriate assent form will be reviewed with 
children who are 11 to 17 years of age.  The PI and/or study coordinator will review the 

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consent with the parent/guardian, giving them time to ask questions and discuss concerns 
with the investigator.  Minors who age 11 to 17 years old will also be given an age 
appropriate assent form for their review to make certain they understand the study goals 
and procedures.  After everyone is comfortable with the study and procedures and the 
family has agreed to participate, the family will sign the parental permission form and (if 
applicable) the assent form.   
 
If a subject is 18 years of age at the time of enrollment, they will be consented as an adult 
and parental permission will not be required.  Any subject who turns 18 during the course 
of the study will be asked to provide informed consent as an adult.   
 
One copy of each consent/assent will be given to the family and one will be retained in 
the study records.  One copy will also be placed in the child’s medical record.   
 
Vulnerable Population 
 
This study will enroll children and adolescents.  To protect this population from coercion 
or undue influence, informed consent will be obtained only after a full discussion of the 
research protocol and of the risks and benefits that may occur from participation.  
Patients and parents will be explicitly informed that choosing not to participate will in no 
way affect the quality of the medical care that they will receive. 
 
Due to the age of subjects, an age appropriate assent form will be reviewed with children 
over the age of eleven.  The PI and/or study coordinator will review the consent with the 
parent/guardian, giving them time to ask questions and discuss concerns with the 
investigator.  Minors who are 11 years old or older will also be given an age appropriate 
assent form for their review to make certain they understand the study goals and 
procedures.  After everyone is comfortable with the study and procedures and the family 
has agreed to participate, the family will sign the parental permission form and (if 
applicable) the assent form.  If an assenting minor chooses not to participate, even if the 
parent wants the child to participate, the child will have their wishes respected. 
 
F.  Study Procedures 
 
The following will take place at study visits: 
 
At the screening visit (Day 0): 
• Informed consent/assent 
• Screening for eligibility, including: 
o Chart review 
For those determined to be eligible, the following will occur: 
• Complete medical history and physical exam 
• Baseline Blood Tests including: 
o TPN panel 
 Liver profile 
 Renal profile 

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 Ca 
 P04 
 Mg 
 Triglycerides 
o Essential fatty acid levels 
o Thromboelastography (TEG) - with platelet mapping preferred 
o CBC, differential, platelets. 
o PT/PTT  (at outset and then monthly)  
o Cholesterol 
• Pregnancy test (urine) for females of child-bearing potential. 
 
All patients will be followed as inpatients within the Regional Center for Neonatal Care 
(RCNC), the Department of Surgery, and the Division of Gastroenterology.  As 
outpatients they will be followed within the Comprehensive Nutrition Clinic (CNC).  
Laboratory monitoring of patients with intestinal failure on TPN can be found on 
Compliance 360.  Inpatients undergo the same monitoring, but a TPN panel and CBC are 
performed once weekly.  Outpatients will undergo weekly monitoring of vital signs and 
fluid balance as well as inspection of gastrostomies, enterostomies, and central venous 
catheter exit sites by home healthcare nurses.  
 
While they are on Omegaven® they will be seen and examined twice a month for study 
visits, and they will undergo blood sampling twice a month to obtain repeat levels of their 
baseline tests for the first 6 months.  After the first 6 months, they will be seen and 
examined monthly and will undergo monthly blood sampling.  Adverse events and 
concomitant medication information will be collected and documented at each study visit. 
 
Below is a description of the study procedures: 
 
Medical History and Physical 
 
A complete, comprehensive history and physical will be performed at the beginning and 
end of the study.  An interim medical history and a brief physical exam will be performed 
at all other study visits. 
 
Clinical and demographic data will also be obtained to include:  age, gender, race, and 
current medications. 
 
At other study visits, an abbreviated physical exam will be performed and changes in 
medical history or concomitant medications will be noted. 
 
Phone Calls: 
 
For the first 6 months of the study, a study coordinator will contact research 
participants/families weekly to assess for any changes in health status and changes to 
medications.  Thereafter, the coordinator will contact participants/ families monthly 

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approximately midway between monthly clinic visits.   Changes in clinical status and 
concomitant medications will be monitored until the end of the study.   
 
Contact will occur by telephone unless subjects are seen in the clinic or are hospitalized.   
Applicable clinical records obtained at clinic visits and during hospitalizations such as 
H&Ps, labs, and medications can be used for research purposes. 
 
Treatment with Investigational Drug 
 
For the first two days of treatment, subjects will receive Omegaven® at 0.5 g/kg per day 
to assess tolerance and will progress to a maintenance dosage range of0.8 to 1.2 g/kg/day 
over 12 hours at an infusion rate approximating 1 g/kg/12 hours (10 ml/kg/12 hours).  
The 12-hour infusion time will be used to minimize waste because of Centers for Disease 
Control and Prevention requirements that source containers of lipid emulsion be changed 
every 12 hours.  Dosing is based on previously described dosing of fish-oil emulsions as 
monotherapy noted within the literature (8).  Omegaven® will be infused intravenously 
through either a central or peripheral catheter in conjunction with other parenteral 
nutrition containing dextrose and amino acids.  Omegaven® is isotonic.  It is compatible 
with parenteral nutrition solutions and may be co-infused via y-site.   
 
While hospitalized, serum triglyceride levels will be monitored weekly to insure that 
triglyceride concentrations do not exceed 1000 mg/dl during the infusion of fat emulsion. 
During hospitalization, coagulation studies will also be conducted weekly. PT and PTT 
will be conducted at baseline and then monthly.  Other laboratory tests will be conducted 
to monitor for blood glucose metabolism, electrolyte and fluid balance and liver and 
kidney function in accordance with current institutional standards for monitoring 
hyperalimentation.  Thromboelastography (prefer with platelet mapping) will be obtained 
at baseline and approximately 10 days prior to scheduled surgery to access platelet 
aggregation dysfunction. 
 
Urine pregnancy tests will be performed at baseline and monthly thereafter for females of 
child-bearing potential. 
  
The patient will be observed for signs of metabolic overload and other adverse events.  
Adverse events will be documented by the study staff and may be used as a rationale for 
dosage adjustments of the study drug.  
 
Study Drug Administration 
 
While patients are inpatients, the study drug will be administered by the CCHMC 
pharmacy.  After patients have been discharged, the drug will be administered by 
Cincinnati Children’s Hospital Home Care Pharmacy and/or the family.  The study drug 
may be delivered by the Children’s Hospital Home Care Service just as Intraplipid® is 
currently delivered or provided by the study team at the participants’ outpatient 
appointments.     
 

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Dose Reduction: 
 
If hypertriglyceridemia develops, operationally defined as serum triglyceride levels 
>1000 mg/dL, after a patient has been enrolled in the study, the following will be 
considered prior to reducing the dose: 
1. If the level was obtained while the patient was receiving a continuous 12-hour 
infusion of Omegaven®, a repeat serum triglyceride level will be obtained while 
the patient is off the infusion just prior to resuming the infusion. 
2. Other sources of hypertriglyceridemia should be considered and addressed. 
 
If the triglycerides continue to remain high after considering the above interventions, a 
dosage reduction of 25% should be considered. The rationale for a twenty five percent 
reduction is to offer a reasonable possibility for improvement in triglyceride levels while 
maintaining a lipid dose high enough to prevent essential fatty acid deficiency. 
Persistently elevated triglyceride values above 1000 mg/dl after 72 hours of a 25% dose 
reduction will result in a further 25% reduction.  This process will be repeated every 72 
hours until either the triglyceride levels have fallen below 1000 mg/dl or Omegaven® is 
stopped.   
 
The rationale for operationally defining hypertriglyceridemia at a much higher level 
(>1000 mg/dl) than customarily defined (>200 mg/dl) is that levels of 200 to 1000 are 
commonplace among patients on TPN and intravenous lipid.  These levels, while 
abnormal, are customarily secondary to cholestasis rather than being secondary to 
lipoprotein lipase deficiency, metabolic syndrome, or other causes of 
hypertriglyceridemia.  We have chosen to make 1000 mg/dl our cut off because it is the 
level wherein serious complications such as pancreatitis and lipid overload syndrome 
may occur mandating immediate lipid reduction.  
 
Follow-Up Assessments 
 
(See Study Treatment Procedures Table below) 
 
Following completion of the study medication, subjects will be seen for a final study visit 
within1 month for a follow-up assessment.  A complete, comprehensive history and 
physical will be performed.  Blood samples will be collected and a urine pregnancy test 
will be done for females of childbearing potential. Adverse events and concomitant 
medications will be documented by the study staff. 
 
 

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The following table summarizes Study Procedures: 
 
Study Procedures Table 
 
 
Baseline  
(Day 0) 
Weekly 
while 
Inpatient 
Weekly 
for first 
6 months 
Twice a 
month 
for the 
first 6 
months 
Monthly 
 
Final 
Visit  
(within 1 
month 
after 
treatment) 
Signed informed 
consent/assent 
X 
 
 
 
 
 
History 
X 
 
 
X 
X 
X 
Physical Exam 
X 
X 
 
X 
X 
X 
Blood specimen 
(4.4 mcl using 
microtainers)#  
X 
X 
 
X 
X 
X 
Urine pregnancy 
test* 
 
X 
 
 
 
 
X 
 
X 
Phone calls 
(clinical status 
and concomitant 
medication 
collection) 
 
 
X 
 
X ** 
 
 
# At baseline and then monthly for PT/PTT. At baseline and then weekly  
for other laboratory studies (see Section IX, E). 
 
 
* For females of child-bearing potential. 
 
 
** Phone calls will take place monthly (between the monthly visits)  
 
G.  Data Collection 
 
Demographic and clinical information will be collected whenever clinical data are 
available via uniform baseline and follow up clinical data extraction forms to ensure 
accuracy and consistency.  The essential demographic information includes age at 
diagnosis, gender, race and ethnicity, birth history, past medical history, and family 
history.  The clinical information includes presence or absence of jaundice, 
hepatosplenomegaly, or ascites. 
 
H.  Compensation 
 
Participants will not be compensated for study participation.  Subjects will receive study 
medication, clinical supplies, and laboratory evaluations that are obtained outside the 
standard of care free of charge.   
 
I.  Withdrawal 

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Data collected from patients who withdraw from the study will be included in the final 
analysis using intent to treat. Patient enrollment will continue until all 25 patients 
complete all requested study requirements outlined.  It will be recommended that patients 
withdrawn from the protocol resume a reduced lipid intake, treat infections promptly as 
they occur and advance feedings as quickly as tolerated. 
 
X.  Assessment of Efficacy 
 
The primary endpoint will be reduction in conjugated or direct bilirubin level to below 1 
mg/dl. Data from previous retrospective analyses and prospective uncontrolled studies 
suggest that from the inception of Omegaven® therapy, conjugated or direct bilirubin 
will remain elevated for approximately 8 weeks at levels comparable to those observed 
prior to administration of Omegaven®. Subsequently, levels are expected to fall by 
approximately 1 mg/dl/week until they normalize.  The time to normalization will vary 
according to each patient’s baseline conjugated or direct bilirubin level.  Thus, a patient 
who begins Omegaven® with a conjugated or direct bilirubin level of 7 mg/dl is likely to 
experience normalization within 14 weeks (8+6 weeks). We will compare the group 
receiving Omegaven® with historical controls from our internal registry who have 
demonstrated cholestasis while on Intralipid®. We will compare changes in 
conjugated/direct bilirubin concentration over time between groups via Kaplan-Meier 
analysis (see Statistics section XIII). 
 
Secondary endpoints will be: normalization of total bilirubin and liver enzymes. 
Differences in these values at the end of 14 weeks of therapy will be compared with those 
of controls via Kaplan-Meier analysis identical to that employed for conjugated and 
direct bilirubin levels. Furthermore, we expect that elevated triglyceride levels which 
might be present at the initiation of therapy will have normalized at the same time that 
liver profiles have normalized.    
 
XI.  Assessment of Safety/Data Safety Monitoring Board 
 
A DSMB will monitor the study for the occurrence of adverse events (both serious and 
otherwise).  A significant increase in the rate of adverse events would be cause for 
concern for the safety of participants in the study.  Information on adverse events will be 
presented in several ways:  (1) listings of serious adverse events with accompanying 
narrative summary by the PI: (2) summaries of adverse events by body system and type 
of event.  This information will be presented to the DSMB. 
 
The DSMB will also monitor the efficacy and the conduct of the study.  Interim 
monitoring reports for the DSMB will include, but will not be limited to, such tabulations 
as:   
 
      1.   platelet counts 
2. essential fatty acid profiles 
3. coagulation studies 
4. liver profiles 

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5. renal profiles 
 
The DSMB will meet at least once per year and possibly more frequently given the 
expected speed of recruitment and study medication administration. 
 
The DSMB chair (or designee) will be asked to review SAE reports within 7 days after 
initial receipt of the information by the investigator(s), to review the PIs assignment of 
SAEs as related or unrelated to treatment, to confirm the grading of any toxicities and 
assure that they do not meet stopping criteria. 
 
A safety analysis will be performed after approximately 5 patients have received 4 weeks 
of treatment or, if enrollment begins slowly, 12 months after the first patient is enrolled.  
Safety data will be shared with the Data and Safety Monitoring Board (DSMB).  There 
will be no further enrollment until the DSMB makes recommendations.  An investigator 
in this study may not be a member of the DSMB.  Members of the DSMB will receive 
safety data approximately every 2 to 3 months for review.  Safety assessments will 
consist of vital signs, AEs, and laboratory evaluations.  A cumulative listing of patient 
withdrawals, dose adjustments, and serious adverse events (SAEs) will also be reviewed.  
DSMB members will be notified of all SAEs reported expeditiously to regulatory 
authorities.   
 
Study Monitoring 
 
The Translational Research Trials Office (TRTO) will act as the independent monitor for the 
study.  Routine monitoring visits shall occur one or more times during the period after study 
initiation but before study closeout.  Guidelines for scheduling monitoring visits shall be 
determined according to the development, complexity of the study, the rate of subject 
accrual and other factors.  Monitoring visits are conducted for routine monitoring only and 
are intended to ensure that the protocol and applicable regulatory requirements are being 
followed, that subjects’ rights and safety are protected, and to confirm data integrity and 
quality. 
 
XII.  Adverse Events  
 
An adverse event (AE) is any untoward medical occurrence in a patient participating in 
this trial.  An adverse event can be an unfavorable and/or unintended sign (including an 
abnormal laboratory finding), symptom, syndrome or disease associated with or 
occurring during the use of an investigational product whether or not considered related 
to the investigational product.   
 
A serious adverse event (SAE) is one that: 
 
1. results in death 
2. is life threatening 
3. requires an inpatient hospitalization or prolonged a hospitalization 
4. is disabling 

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5. is a congenital anomaly/birth defect 
6. is an event that dose not meet the above criteria but may jeopardize the patient or 
may require medical or surgical intervention to prevent one of the outcomes listed 
above. 
 
IRB Notification of SAEs 
 
Per CCHMC Institutional Review Board (IRB) Requirements, the Investigator will report 
adverse events to the IRB Office within the appropriate timelines documented in the 
institutional policies for reporting SAE and AE . .   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAE’s require expedited reporting when meeting the following criteria: 
• The incident is serious 
• Unexpected – any adverse experience, the specificity or severity of which 
is not consistent with the underlying disease of the patient or with the risk  
described in the protocol  
• At least possibly related to the study agent or other protocol specific 
activity 
 
 
Recording of Adverse Events  
 
Adverse event recording will begin after administration of study medication.   
 
Diagnostic and therapeutic non-invasive and invasive (i.e. surgical) 
procedures will not be reported as adverse events. However, the medical 
condition for which the procedure was performed must be reported if it 
meets the definition of an adverse event, unless it is pre-existing (prior to 
initiating Omegaven®). 
 
Medical conditions/diseases present before starting drug are only considered 
adverse events if they worsen after starting treatment.  
 
Symptoms of the original or targeted disease are not to be considered 
adverse events in this treatment.  The following symptoms are indicative of 
underlying disease and will not be reported as adverse events:  
hyperbilirubinemia, elevated creatinine/renal failure, weight gain, 
encephalopathy, hypoxia / respiratory failure, ascites, hepatomegaly and 
right upper quadrant pain, sepsis (culture positive or negative), emesis or 

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increase in stool output with the advancement of feeds or bleeding due to 
liver failure.   
 
Abnormal laboratory values or test results constitute adverse events if they 
induce clinical signs or symptoms or require therapy.  They are to be 
recorded on the Adverse Events CRF under the signs, symptoms or 
diagnoses associated with them.   
 
As far as possible, each adverse event will be assessed by the Investigator 
with respect to its duration (start and end dates), the severity grade (mild, 
moderate, severe, life-threatening, fatal), its relationship to the drug 
(unrelated, unlikely to be related, possibly, probably and definitely related), 
the action(s) taken, the outcome (i.e. resolved, resolved with sequelae, 
continuing), gravity (SERIOUS or NOT SERIOUS), and 
expected/unexpected on the basis of drug insert. 
 
Expected drug related events are those that have been previously identified 
as resulting from administration of the protocol therapy, short bowel 
syndrome, or parenteral nutrition as outlined in the potential risks section of 
this protocol or the package insert. Unexpected adverse events are those that 
have not been previously associated with Omegaven, short bowel syndrome, 
liver failure, parenteral nutrition support or any standard care for subjects 
with short bowel syndrome.   
 
Adverse events will be reported by diagnosis unless a diagnosis cannot be 
determined.   
 
 
 
Grading (Severity) of Adverse Events 
 
Each adverse event will be graded to describe its intensity according to the 
following Severity scale: 
 
1= 
Mild: 
does not interfere 
with patient’s 
usual function 
2=  
Moderate: 
interferes to some 
extent with 
patient’s usual 
function 
3= 
Severe: 
interferes 
significantly with 
patient’s usual 
function 

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4= 
Life-
threatening: 
puts the patient at 
immediate risk of 
death 
5= 
Fatal: 
patient died 
 
The NCI’s Common Terminology Criteria for Adverse Events Version 4.0 
(Appendix A) will be used if applicable. 
 
Relationship to Drug 
 
For all adverse events that occur while the patient is on drug, the relationship 
to the drug must be assessed by the Investigator using the following scale: 
 
1 = not related   
 
2 = unlikely 
 
 
3 = possibly related  
 
4 = probably related   
5 = definitely related   
 
For Grade > 3 adverse reactions which are possibly (3), probably (4) or 
definitely (5) related to the drug, study medication should be discontinued as 
described above. 
 
Please note: For safety data analysis, not related and unlikely are considered 
“not attributable;” possible, probable and definite are considered 
“attributable.”  Assessment of relationship to drug must be carried out by the 
Investigator according to the 5-point scale above. 
 
Gravity (Seriousness) of Adverse Events 
 
Each adverse event is to be classified by the Investigator as SERIOUS or 
NOT SERIOUS.   
 
Follow-Up after Adverse Events 
 
All adverse events will be followed until they are resolved or the patient’s 
participation in the treatment ends (i.e., until a final report is completed for 
that patient).  
 
In addition, all SAEs and those non serious events assessed by the 
Investigator as attributable (i.e. possibly, probably, definitely related to the 
drug) will continue to be followed even after the patient’s participation in the 
treatment is over. Such events will be followed until they resolve or until the 
Investigator assesses them as "chronic" or "stable."  Resolution of such 
events is to be documented in the CRF. 
 

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XIII.  Statistics  
 
We selected a study number of 25 patients (5 patients a year for 5 years) even though, 
statistically, a number of 19 will be satisfactory based upon power analysis. We know 
from our current registry that 10% of historic controls will experience resolution of 
cholestasis within 8 weeks while receiving Intralipid®, and we know from the data of 
Gura, et al (5) that approximately 50% of experimental subjects will experience 
resolution of cholestasis within eight weeks while receiving Omegaven®. Thus, achieving 
an alpha of 0.05 and a beta of 0.80, a sample size of 19 patients and 19 controls will be 
adequate (11).  However, insofar as this is a compassionate release protocol, we will not 
refuse entry into the study even if we have shown statistically that Omegaven® is 
efficacious.  We estimate that at most we will acquire five patients per year, and we 
anticipate that within five years, Omegaven® or SMOF (soy, MCT, olive oil and fish oil) 
parenteral lipids will have obtained FDA approval for clinical use. 
 
The analysis populations will include (1) subjects receiving Omegaven® under this 
protocol and (2) historical controls from our internal registry who have demonstrated 
cholestasis while on Intralipid®.  Paired t-tests will be used to report the statistical 
significance of differences between means.  A p value of 0.05 or less will be considered 
significant.  Wilcoxon Tests will be used to report the statistical significant differences 
between medians, and x2 tests/Fisher’s exact tests will be used to report proportions.  A 
Kaplan-Meier analysis will compare changes in conjugated/direct bilirubin concentration 
over time between groups.  Cox proportional hazard models will be used to estimate 
crude and adjusted hazard ratios.  Analyses will be performed via SAS 9.2 (SAS Institute 
Inc, Cary, NC) and S-Plus 8.1.1 (Insightful, Inc, Seattle, WA).  
 
IX.   Data Management 
 
Each subject will be given a unique identifier.  Only members of the study team will be 
able to link this identifier to the subject.  No patient identifiers will be published. 
 
The specific data items to be captured are age (in years), gender, race, and current 
medications,.  All data will be stored in a secure area or in a password protected 
electronic file.   
 
X.  Financing 
 
Funding will be sought from private foundations and both local and national 
philanthropic groups. Insurance companies will also be billed for standard of care 
procedures.   If funding cannot be obtained from any source, internal funding by 
Cincinnati Children’s Hospital Medical Center will be reviewed on a case by case basis.   
 

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Figure 1.  Conjugated bilirubin versus time in patient on Omegaven® which was started 
in June of 2006 when her conjugated bilirubin was approximately 6.5 mg/dl.  It remained 
below 2 mg/dl until she developed hepatic metastases of her neuroblastoma in March of 
2008. 
 
 
 
 
 
 
 
 
 
Figure 2.  Conjugated bilirubin levels over time in a patient starting Omegaven® on 
approximately 8/1/09. Levels progressively fell while this critically ill patient was 
receiving minimal enteral nutrition and on TPN within the critical care unit.  At the time 
of death, his conjugated bilirubin was less than half the level it had been when 
Omegaven® was started. 
 

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Figure 3.  Conjugated bilirubin levels over time in a patient starting Omegaven® on 
approximately 11/15/09 when his conjugated bilirubin level was nearly at its peak.  He 
remained on Omegaven ®, and feedings were soon begun.  Within 61/2 weeks, his 
conjugated bilirubin had fallen below 1 mg/dl.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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XI.  References 
 
1. Marion, M, Pediatric Nutrition Support.  Nutrition in Clinical Practice, 1993; 8,(5): 
199-209. 
2. Carter BA, Taylor OA, Prendergast DR, Zimmerman TL, et al. Stigmasterol, a soy 
lipid-derived phytosterol, is an antagonist of the bile acid nuclear receptor FXR. Pediatr 
Res. 2007 Sep;62(3):301-6. 
3. Bueno J, Ohwada S, Kocoshis S, et al. Factors impacting the survival of children with 
intestinal failure referred for intestinal transplantation. J Pedatr Surg. 1999;34:27-32. 
4. Bianchi A. From the cradle to enteral autonomy: the role of autologous 
gastrointestinal reconstruction. Gastroenterology. 2006 Feb;130(2 Suppl 1):S138-46. 
5. Gura, K.M., et al, Safety and efficacy of a fish-oil based fat emulsion in the treatment 
of parenteral nutrition-associated liver disease. Pediatr, 2008. 121(3):678-86. 
6. Kolezko, B.V., Fürst, P., Fish oil in parenteral nutrition in infants: clinical evidence 
and experience. Data on file, Fresenius- Kabi AG, Bad Homburg v.d.h. 
7. Lee, S.I., et al, Impact of fish oil-based lipid emulsion on serum triglyceride, bilirubin, 
and albumin levels in children with parenteral nutrition-associated liver disease. Pediatr 
Res, 2009. 66(6):698-703. 
8. Gura KM, Parsons SK, Bechard LJ, et al. Use of a fish oil-based lipid emulsion to treat 
essential fatty acid deficiency in a soy allergic patient receiving parenteral nutrition. Clin 
Nutr. 2005 Oct;24(5):839-47. 
9. Gura, K.M., et al, 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):197-201. 
10. Diamond IR, Sterescu A, Pencharz PB. Changing the Paradigm: Omegaven for the 
Treatment of Liver Failure in Pediatric Short Bowel Syndrome. Journal of Pediatric 
Gastroenterology and Nutrition 2009; 48 (2):209-215. 
11. Dupont WD. Power calculations for matched case-control studies. Biometrics 1988; 
44:1157-1168.