Clinical trial NCT01601652
Conditions: Parenteral Nutrition Associated Cholestasis
Keywords: cholestasis PNAC Parenteral Nutrition Associated Cholestasis PNALD Parenteral Nutrition Associated Liver Disease
Sponsor: Arthur J De Lorimier
Start date: 2011-11-01; Completion date: 2018-12-01
Enrollment: 12 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The study will evaluate the safety and efficacy of an intravenous fish oil emulsion (omegaven) in infants with parenteral nutrition associated cholestasis.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Omegaven
Intervention descriptions: intervention 1: 1 g/kg/d iv infusion over 24h

Protocol documents:
Prot_SAP_000.pdf: 
Version date 1/12/2018 
 
Title of project: 
Use of an intravenous fish oil emulsion in infants with cholestasis 
 
 
Sponsored by: 
N/A 
 
 
Pharmaceutical Support Provided by:  [if applicable] 
N/A 
 
IND # or non-IND Protocol [Select one] 
N/A – IND# to be obtained from FDA if a patient qualifies for study 
 
Protocol Chair/Principal Investigator: 
Arthur J. de Lorimier 
Protocol Co-Chair(s)/PIs: 
N/A 
Protocol Vice Chair(s): [if applicable] 
N/A 
Clinical Trials Specialist: [if applicable] 
N/A 
DRAFT Version 0.1 
03/11/11 


Version date 1/12/2018 
 
CONTENTS 
 
 
 
Page 
 
SITES PARTICIPATING IN THE STUDY ........................................................................ 4 
PROTOCOL TEAM ROSTER ......................................................................................... 5 
STUDY MANAGEMENT ................................................................................................. 6 
ACRONYMS/ABBREVIATIONS ....................................... Error! Bookmark not defined. 
SCHEMA ......................................................................................................................... 6 
1.0 
HYPOTHESIS AND STUDY OBJECTIVES.......................................................... 7 
1.1 
Hypothesis ................................................................................................. 7 
1.2 
Primary Objective(s) .................................................................................. 7 
1.3 
Secondary Objectives ................................. Error! Bookmark not defined. 
1.4 
Substudy Objectives ................................... Error! Bookmark not defined. 
2.0 
INTRODUCTION .................................................................................................. 7 
2.1 
Background ................................................................................................ 7 
2.2 
Rationale ..................................................... Error! Bookmark not defined. 
3.0 
STUDY DESIGN ................................................................................................. 11 
4.0 
SELECTION AND ENROLLMENT OF SUBJECTS ............................................ 11 
4.1 
Inclusion Criteria ...................................................................................... 11 
4.2 
Exclusion Criteria ..................................................................................... 11 
4.3 
Study Enrollment ProceduresG ............................................................... 11 
4.4 
Substudy Enrollment Procedures (as required)Error! Bookmark not defined. 
4.5 
Coenrollment Guidelines (as required) ....... Error! Bookmark not defined. 
5.0 
STUDY TREATMENT (OR INTERVENTION) .................................................... 11 
5.1 
Regimens (or Intervention), Administration, and Duration ....................... 11 
5.2 
Study Product Formulation and Preparation ............................................ 12 
5.3 
Product Supply, Distribution, and Accountability ...................................... 12 
5.4 
Concomitant Medications ......................................................................... 13 
5.5 
Adherence Assessment (as required) ......... Error! Bookmark not defined. 
6.0 
CLINICAL AND LABORATORY EVALUATIONS .. Error! Bookmark not defined. 
6.1 
Schedule of Events ..................................... Error! Bookmark not defined. 
6.2 
Timing of Evaluations............................................................................... 14 
6.3 
Instructions for Evaluations ......................... Error! Bookmark not defined. 
7.0 
CLINICAL MANAGEMENT ISSUES ................................................................... 14 
7.1 
Toxicity ..................................................................................................... 14 
7.2 
Other Diseases ........................................................................................ 15 
7.3 
Pregnancy ................................................................................................ 15 


Version date 1/12/2018 
7.4 
Breast-feeding (if applicable) ................................................................... 15 
8.0 
CRITERIA FOR DISCONTINUATION ................................................................ 15 
8.1 
Permanent Treatment Discontinuation .................................................... 15 
8.2 
Premature Study Discontinuation ............................................................ 15 
9.0 
STATISTICAL CONSIDERATIONS .................................................................... 15 
9.1 
General Design Issues............................................................................. 15 
9.2 
Endpoints ................................................................................................. 16 
9.3 
Randomization and Stratification ............................................................. 16 
9.4 
Sample Size and Accrual ......................................................................... 16 
9.5 
Monitoring ................................................................................................ 16 
9.6 
Analyses .................................................................................................. 16 
10.0 PHARMACOLOGY PLAN .................................................................................. 16 
10.1 Pharmacology Objectives ........................... Error! Bookmark not defined. 
10.2 Pharmacology Study Design ....................... Error! Bookmark not defined. 
10.3 Primary and Secondary Data, Modeling, and Data AnalysisError! Bookmark not define
10.4 Anticipated Outcomes ................................. Error! Bookmark not defined. 
11.0 DATA COLLECTION AND MONITORING AND ADVERSE EVENT 
REPORTING ...................................................................................................... 16 
11.1 Records to Be Kept .................................................................................. 16 
11.2 Role of Data Management ....................................................................... 16 
11.3 Clinical Site Monitoring and Record Availability ....................................... 17 
11.4 Expedited Adverse Event Reporting to  ................................................... 17 
12.0 HUMAN SUBJECTS ........................................................................................... 17 
12.1 Institutional Review Board (IRB) Review and Informed Consent ............. 17 
12.2 Subject Confidentiality ............................................................................. 17 
12.3 Study Discontinuation .............................................................................. 17 
13.0 PUBLICATION OF RESEARCH FINDINGS ....................................................... 18 
14.0 BIOHAZARD CONTAINMENT .............................. Error! Bookmark not defined. 
15.0 REFERENCES ................................................................................................... 19 
APPENDIX I .................................................................................................................. 20 
 


 
4 
 
 
SITES PARTICIPATING IN THE STUDY 
 
Sites Participating in the Study [remove Main if no substudy] 
UC-Davis 
 


 
Version date 1/12/2018 
PROTOCOL TEAM ROSTER 
Chair Arthur J. de Lorimier 
Co-Chairs No 
Vice Chair(s) No 
 Clinical Representative No 
Clinical Trials Specialist No 
 
Statistician(s) No 
Scientific Committee Representative (if 
assigned) No 
Data Manager No 
Pharmacist No 
Field Representative No 
Laboratory Technologist No 
Laboratory Data Coordinator No 


 
Version date 1/12/2018 
STUDY MANAGEMENT 
 
SCHEMA 
 
Use of an intravenous fish oil emulsion in infants with cholestasis 
 
 
DESIGN Observational, compassionate use, single cohort study 
DURATION Open 
SAMPLE SIZE 25 
POPULATION Infants less than 12m of age at time of recruitment 
STRATIFICATION (as required) N/A 
REGIMEN OR INTERVENTION (as required) N/A 
SUBSTUDIES (as required) N/A 


 
Version date 1/12/2018 
1.0 
HYPOTHESIS AND STUDY OBJECTIVES 
1.1 
Hypothesis 
Use of omegaven in infants with cholestasis will be temporally related to resolution of 
cholestasis. 
 
1.2 
Primary Objective(s)  
The aims of the study are to assess the effect of intravenous fish oil emulsion 
(omegaven) in place of the currently used intravenous soybean oil lipid emulsion 
(Intralipid) in subjects with short bowel syndrome and cholestasis or with PNALD 
(parenteral nutrition associated liver disease). 
 
2.0 
INTRODUCTION 
2.1 
Background 
Functional short gut (or short bowel syndrome, SBS) is defined as the inability to 
tolerate all nutritional requirements via the enteral route, and a continuing dependence 
of partial or complete parenteral nutrition. 
 
Development of SBS (short bowel syndrome) is more common in newborn infants than 
at any other age group, and may result from gastroschisis, gastrointestinal atresia, 
intestinal volvulus, or necrotizing enterocolitis. Treatment is aimed at: 
 
1. Nutritional support, through the use of parenteral nutrition. 
2. Gut rehabilitation and adaptation through gradual introduction and advancement 
of enteral feeds. 
3. Prevention of secondary problems (e.g. bile acid deficiency or bacterial 
overgrowth). 
4. Prevention of complications (e.g. cholestasis). 
 
Concerted, coordinated management, including parenteral nutrition, has greatly 
improved the survival and quality of life of subjects with SBS. However, prolonged use 
of parenteral nutrition is not without risk. Parenteral nutrition associated cholestasis 
(PNAC); also know as parenteral nutrition associated liver disease (PNALD) or intestinal 
failure associated liver disease (IFALD); is one of the leading causes of death in SBS.  
 
The causes of PNALD are unclear, but may include: 
 
1. Absence of enteral feeds. 
2. “Toxic” components in parenteral nutrition (e.g. aluminium, phytosterols, 
methionine, tryptophan). 
3. Lack of certain beneficial nutrients in parenteral nutrition (e.g. serine, choline). 
 
In recent years, much attention has been paid to the effect of parenteral lipid on PNAC. 
In the US, parenteral lipids are vegetable-based. Most widely used is Intralipid with is 


 
Version date 1/12/2018 
a mixture of soybean oil and egg phospholipids. Although it has a generally excellent 
short- and long-term safety record, there are concerns about its long term use. As it is 
vegetable based is contains relatively high amounts of phytosterols (cholesterol-like 
lipids derived from plants). In adults and children with SBS and PNAC, serum levels of 
phytosterols correlate with the degree of hepatic and biliary dysfunction. 
 
Omegaven is a fish-oil derived intravenous lipid emulsion that is not licensed in the US, 
but is widely used in Europe. It differs in composition from intralipid in many ways, for 
example it is much higher in omega-3 fats, lower in omega-6 fats, and contains no 
phytosterols. 
 
Composition of Different iv lipid emulsions (from Puder 2009) 
 
 
There are an increasing number of case-control studies suggesting significant clinical 
benefits to the use of omegaven in established PNALD in infants (Gura 2006, Gura 
2008, Diamond 2009, Puder 2009). 
 
The largest of these published cohorts is that of Puder, from Boston Children’s Hospital 
(see attached file). In that study 42 infants who developed PNALD on standard 
intravenous lipid emulsions were given omegaven, and compared to 49 historical 
controls. Subjects were eligible for omegaven if they had cholestasis (direct bilirubin ≥ 2 
mg/dL), were likely to be on parenteral nutrition at least 30d, and had acquired or 
congenital GI disease. Subjects with cystic fibrosis, metabolic disorders or hepatitis C 
were excluded. They were compared to historical controls who had two consecutive 
direct bilirubin measurements ≥ 2 mg/dL. Omegaven was given at a dose of 1 g/kg/d, 
and intalipid at 1-4 g/kg/d (depending on attending preference and lipid tolerance). The 
fish oil group were generally more sick at study entry than the historical controls, they 
had been on parenteral nutrition longer (63d vs. 40d, p=0.008) and their direct bilirubin 
was higher (5.5 vs. 3.3, p=0.0003). Despite these baseline differences, the fish oil group 
had a steady and sustained fall in direct bilirubin and ALT, while these measures 
continued to increase in the historical controls. 


 
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Figure Direct bilirubin and ALT in the fish oil group, and the historical controls (from 
Puder 2009). 
 
 
 
Cholestasis resolved in 45% (19/42) of the fish oil group while still on PN, compared to 
4% (2/46) of the historical cohorts. 
 
The rate of the combined outcome of death or required liver transplant was significantly 
lower in the fish oil group (9.5%) than in the historical controls (34.7%, p=0.0005). The 
crude rate of reversal of cholestasis in subjects who did not die or require liver 
transplants was 8.6x greater in the fish oil group than in the historical controls. This 
increased to 17.4x higher rate once differences in baseline characteristics were 
accounted for. 
 
The main safety measures followed (hypertriglyceridemia, and coagulopathy) 
significantly favored the fist oil group. 
 


 
Version date 1/12/2018 
Table Incidence of hypertriglyceridemia and coagulopathy in fish oil group, and the 
historical controls (from Puder 2009). 
 
 
Although there was no significant difference in INR between the groups over the entire 
study, INR began to increase in the controls near the end of the study as they 
developed worsening end-stage liver disease. In the fish oil group, INR remained low 
during the entire study. 
 
Figure INR in the fish oil group, and the historical controls (from Puder 2009). 
 
 
References 
Puder 2009. Parenteral fish oil improves outcomes in patients with parenteral nutrition-
associated liver injury. Ann Surg 2009;250:395-402. 
Gura 2006. Reversal of parenteral nutrition-associated liver disease in two infants with 


 
Version date 1/12/2018 
short bowel syndrome using parenteral fish oil: implications for future management. 
Pediatrics 2006;118:e197-201. 
Gura 2008. Safety and efficacy of a fish-oil-based fat emulsion in the treatment of 
parenteral nutrition-associated liver disease. Pediatrics 2008;121:e678-86. 
Diamond 2009. Changing the paradigm: omegaven for the treatment of liver failure in 
pediatric short bowel syndrome. J Pediatr Gastroenterol Nutr 2009;48:209-15. 
 
 
3.0 
STUDY DESIGN 
Compassionate use, single cohort, observational study. 
 
4.0 
SELECTION AND ENROLLMENT OF SUBJECTS 
4.1 
Inclusion Criteria 
Infants on parenteral nutrition who have congenital or acquired gastrointestinal diseases 
that place them at risk of short bowel syndrome (SBS) or prolonged parenteral-nutrition-
dependence, will be considered eligible for the study if either (1) they remain cholestatic 
(bilirubin > 2 mg/dL) after 4wks of reduced lipids and trace elements, or (2) If their direct 
bilirubin is > 6 mg/dL in the absence of suspected or proven infection.    
4.2 
Exclusion Criteria 
Subjects will be considered ineligible for the study if they are felt unlikely to survive 
more than 30d, or unlikely to require parenteral nutrition for at least 30d. 
 
4.3 
Study Enrollment Procedures 
Clinical nutrition rounds, between the PI and the NICU dietician, occur every 1-2wk as 
part of the routine clinical care of the infants. As part of the clinical care of the infants, 
and infant identified as having cholestasis or PNALD (direct bilirubin ≥2 mg/dL on two 
consecutive occasions ≥8d apart) have their intralipid infusion rate reduced to 1 g/kg/d 
and have the trace elements added to their parenteral nutrition reduced. The current 
protocol will not alter this. 
 
5.0 
STUDY TREATMENT (OR INTERVENTION) 
5.1 
Regimens (or Intervention), Administration, and Duration 
The intervention is the use of omegaven (an intravenous fish oil emulsion) in place of 
intralipid (the currently used soybean oil intravenous lipid emulsion, until parenteral 
nutrition is discontinued, or until cholestasis resolves. 
 
Parents of eligible patients will be approached for consent for their infants to take part in 
the study. If they agree, the PI will contact the FDA to receive an IND number for the 
infant (copies of the required FDA paperwork will be sent to the IRB). Omegaven will be 
ordered from the manufacturer. Once the IND number is received, the IRB will be 
informed of the subjects IND number. Once the IND number is received, and 
communicated with the IRB, and the omegaven is received, intralipid infusions will be 


 
Version date 1/12/2018 
stopped and omegaven will be infused at the rate of 1 g/kg/d. Clinically-indicated labs 
will be monitored, as for all patients on prolonged parenteral nutrition, i.e. CBC, 
electrolytes, BUN, Creatinine, ALT, AST, Alkaline phosphatase, albumin, total bilirubin, 
direct bilirubin and serum triglycerides will be measured at least every 2 weeks. No 
additional labs will be required as part of the study. 
 
Adjustment of Omegaven Dosage 
Hypertriglyceridemia: If serum triglycerides are > 400, other causes will be excluded 
(e.g. renal disease, medications). If no other causes can be found, the clinical team 
caring for the baby may decide to reduce the infusion of omegaven by 25%, depending 
on their clinical assessment of risk and benefits. 
Essential Fatty Acid Deficiency: If there are concerns that essential fatty acid deficiency 
may be occurring (characteristic skin rash plus unexplained thrombocytopenia), the 
clinical team caring for the baby may decide to discontinue omegaven and re-start 
infusion of intralipid at a rate of 0.5 – 1 g.kg/d. 
Other: The clinical team caring for the baby will be allowed to withhold the omegaven 
infusion or restart the intralipid infusion for any reason if they believe that to be in the 
best interests of the patient. 
 
Discontinuation of Omegaven 
Omegaven will be discontinued either (1) once parenteral nutrition is discontinued, 
irrespective of the direct bilirubin level, or (2) once the direct bilirubin has been below 2 
mg/dL for more than 2weeks. In the later case, if the direct bilirubin rebounds above 2 
mg/dL at anytime the omegaven can be restarted. If omegaven is re-started, the 
discontinuation criteria will be the same as before: i.e. it will be discontinued when 
parenteral nutrition is discontinued or when the direct bilirubin has been below 2 mg/dL 
for more than 2 weeks. 
 
Safety Assessment 
Routine clinical labs will be used to monitor for the principal side effects of omegaven 
(thrombocytopenia, hypertriglyceridemia), and the response to treatment (direct 
bilirubin, ALT). INR and triene:tetrene ratio will be assessed as clinically indicated if 
coagulopathy or essential fatty acid deficiency are suspected. 
 
5.2 
Study Product Formulation and Preparation 
Omegaven intravenous lipid emulsion as supplied by the manufacturer. 
 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability 
 
5.3.1 Study Product Acquisition 
Parents of eligible patients will be approached for consent for their infants to take part in 
the study. If they agree, the PI will contact the FDA to receive an IND number for the 
infant (copies of the required FDA paperwork will be sent to the IRB). Omegaven will be 
ordered from the manufacturer. Once the IND number is received, the IRB will be 


 
Version date 1/12/2018 
informed of the subjects IND number. Once the IND number is received, and 
communicated with the IRB, and the omegaven is received, intralipid infusions will be 
stopped and omegaven will be infused at the rate of 1 g/kg/d. 
5.3.2 Study Product Accountability 
The FDA permits the cost of omegaven to be billed to insurance carriers, or to public 
insurance. These costs will be largely, but not completely offset by the reduction in cost 
as the standard intravenous lipid (intralipid) will not be given. No addition laboratory 
tests will be carried out. If the relevant private or public insurance provider refuses to 
cover the additional cost of omegaven (approx $50-75/d) we would expect that costs will 
be absorbed by either the UCDMC pharmacy. In the unlikely event that this does not 
prove possible, and alternative coverage for omegaven can not be found (e.g. internal 
NICU funds) the parents will be asked to pay for omegaven. The IRB will be informed of 
this eventuality should it occur. The consent form will clearly state the plans regarding 
charging for omegaven, and that the family would be payers of last resort if alternative 
methods of funding the omegaven are not successful. 
 
5.4 
Concomitant Medications 
5.4.1 Required Medications 
Current receipt of parenteral nutrition (including iv lipids), are required for the diagnosis 
of PNALD, and therefore for enrollment in the study 
5.4.2 Prohibited Medications 
None 
5.4.3 Precautionary Medications 
None 
 
 
6.0 
CLINICAL AND LABORATORY EVALUATIONS


 
Version date 1/12/2018 
6.2 
Timing of Evaluations 
 
6.2.1 Screening and Pre-Entry Evaluations  
Clinical nutrition rounds, between the PI and the NICU dietician, occur every 1-2wk as 
part of the routine clinical care of the infants. As part of the clinical care of the infants, 
and infant identified as having cholestasis or PNALD (direct bilirubin ≥2 mg/dL on two 
consecutive occasions ≥8d apart) are identified. 
6.2.2 Entry Evaluations 
Clinical nutrition rounds, between the PI and the NICU dietician, occur every 1-2wk as 
part of the routine clinical care of the infants. As part of the clinical care of the infants, 
and infant identified as having cholestasis or PNALD (direct bilirubin ≥2 mg/dL on two 
consecutive occasions ≥8d apart) have their intralipid infusion rate reduced to 1 g/kg/d 
and have the trace elements added to their parenteral nutrition reduced. The current 
protocol will not alter this. If they remain cholestatic (bilirubin > 2 mg/dL) after 4wks of 
reduced lipids and trace elements, or (2) if their direct bilirubin is > 6 mg/dL in the 
absence of suspected or proven infection they will be considered eligible for the study. 
6.2.3 Post-Entry Evaluations 
Will continue as part of the clinical nutrition rounds 
6.2.4 Discontinuation Evaluations 
Will continue as part of the clinical nutrition rounds. Omegaven will be discontinued 
either (1) once parenteral nutrition is discontinued, irrespective of the direct bilirubin 
level, or (2) once the direct bilirubin has been below 2 mg/dL for more than 2 weeks. In 
the later case, if the direct bilirubin rebounds above 2 mg/dL at anytime the omegaven 
can be restarted. If omegaven is re-started, the discontinuation criteria will be the same 
as before: i.e. it will be discontinued when parenteral nutrition is discontinued or when 
the direct bilirubin has been below 2 mg/dL for more than 2 weeks. Omegaen may also 
be discontinued at any time is desired by the family, the attending physician or the study 
PI. 
7.0 
CLINICAL MANAGEMENT ISSUES 
7.1 
Toxicity  
Routine clinical labs will be used to monitor for the principal side effects of omegaven 
(thrombocytopenia, hypertriglyceridemia), and the response to treatment (direct 
bilirubin, ALT). INR and triene:tetrene ratio will be assessed as clinically indicated if 
coagulopathy of essential fatty acid deficiency are suspected. If serum triglycerides are 
> 400, other causes will be excluded (e.g. renal disease, medications). If no other 
causes can be found, the clinical team caring for the baby may decide to reduce the 
infusion of omegaven by 25%, depending on their clinical assessment of risk and 
benefits. If there are concerns that essential fatty acid deficiency may be occurring 


 
Version date 1/12/2018 
(characteristic skin rash plus unexplained thrombocytopenia), the clinical team caring 
for the baby may decide to discontinue omegaven and re-start infusion of intralipid at a 
rate of 0.5 – 1 g/kg/d. 
 
An external Data Safety Monitor (Dr. Steven A. Abrams, Professor of Pediatrics, Section 
of Neonatology, Department of Pediatrics, Baylor College of Medicine and Texas 
Children’s Hospital, Houston, TX) will be informed of all subjects recruited to the 
protocol. He will be informed, by e-mail, of any laboratory results on the subjects at least 
monthly, or within 7d of any significant change in biochemical data. He will have the 
authority to withdraw a subject from the protocol at any time. He will be unaware of the 
subjects name, but will be made aware of any pertinent clinical data relevant to lab 
interpretation (e.g. presence or absence of infection, underlying GI diagnosis, amount of 
enteral feeds etc). Subjects will be identified by an anonymous number when 
communicating with the external safety monitor. 
 
7.2 
Other Diseases 
N/A 
 
7.3 
Pregnancy 
N/A 
 
7.4 
Breast-feeding (if applicable) 
N/A 
 
8.0 
CRITERIA FOR DISCONTINUATION 
8.1 
Permanent Treatment Discontinuation 
Omegaven will be discontinued either (1) once parenteral nutrition is discontinued, 
irrespective of the direct bilirubin level, or (2) once the direct bilirubin has been below 2 
mg/dL for more than 2 weeks. In the later case, if the direct bilirubin rebounds above 2 
mg/dL at anytime the omegaven can be restarted. If omegaven is re-started, the 
discontinuation criteria will be the same as before: i.e. it will be discontinued when 
parenteral nutrition is discontinued or when the direct bilirubin has been below 2 mg/dL 
for more than 2 weeks. 
 
8.2 
Premature Study Discontinuation 
As for 8.1 
 
9.0 
STATISTICAL CONSIDERATIONS 
9.1 
General Design Issues 
This is a compassionate use, non-hypothesis testing protocol. Summary descriptive 
statistics will be generated, e.g. time to resolution of cholestasis. 
 


 
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9.2 
Endpoints 
 
9.2.1 Primary Endpoints (including definitions) 
Time to resolution of cholestasis (direct bilirubin < 2 mg/dL without subsequent rebound 
above 2 mg/dL). 
9.2.2 Secondary Endpoints (including definitions) 
None 
9.2.3 Substudy Endpoints (as required) 
None 
9.3 
Randomization and Stratification 
N/A 
 
9.4 
Sample Size and Accrual 
Up to 25 subjects recruited 
 
(For main study and substudies.) 
9.5 
Monitoring 
As above 
 
9.5 
Analyses 
As above 
 
 
10.0 PHARMACOLOGY PLAN 
N/A 
 
11.0 DATA COLLECTION AND MONITORING AND ADVERSE EVENT REPORTING 
11.1 Records to Be Kept 
The patient’s participation will be documented in the EMR. All labs will be measured for 
clinical reasons, not for reasons related to the study. They will stay in the EMR. A list of 
patients on the study will be kept in a secure filing cabinet by the PI. 
 
11.2 Role of Data Management 
N/A. 


 
Version date 1/12/2018 
11.3 Clinical Site Monitoring and Record Availability 
N/A 
 
11.4 Expedited Adverse Event Reporting to  
An external Data Safety Monitor (Dr. Steven A. Abrams, Professor of Pediatrics, Section 
of Neonatology, Department of Pediatrics, Baylor College of Medicine and Texas 
Children’s Hospital, Houston, TX) will be informed of all subjects recruited to the 
protocol. He will be informed, by e-mail, of any laboratory results on the subjects at least 
monthly, or within 7d of any significant change in biochemical data. He will have the 
authority to withdraw a subject from the protocol at any time. He will be unaware of the 
subject name, but will be made aware of any pertinent clinical data relevant to lab 
interpretation (e.g. presence or absence of infection, underlying GI diagnosis, amount of 
enteral feeds etc). Subjects will be identified by an anonymous number when 
communicating with the external safety monitor. 
 
The IRB will also be informed of any adverse events. The FDA will be informed of any 
adverse events only to the extent required by law. 
 
12.0 HUMAN SUBJECTS 
12.1 Institutional Review Board (IRB) Review and Informed Consent 
This protocol and the informed consent document (pending) and any subsequent 
modifications will be reviewed and approved by the IRB or ethics committee responsible 
for oversight of the study. A signed consent form will be obtained from the subject (or 
parent, legal guardian, or person with power of attorney for subjects who cannot 
consent for themselves, such as those below the legal age of consent). The consent 
form will describe the purpose of the study, the procedures to be followed, and the risks 
and benefits of participation. A copy of the consent form will be given to the subject, 
parent, or legal guardian, and this fact will be documented in the subject’s record. 
 
12.2 Subject Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records that leave the site 
will be identified by coded number only to maintain subject confidentiality. All records 
will be kept locked. All computer entry and networking programs will be done with coded 
numbers only. Clinical information will not be released without written permission of the 
subject, except as necessary for monitoring by IRB, the FDA, the , the OHRP, or the 
pharmaceutical supporter(s) or designee. 
12.3 Study Discontinuation 
The study may be discontinued at any time by the IRB, the pharmaceutical supporter(s), 
the FDA, the OHRP, or other government agencies as part of their duties to ensure that 
research subjects are protected.  


 
Version date 1/12/2018 
13.0 PUBLICATION OF RESEARCH FINDINGS 
Publication of the results of this trial will be governed by policies.  
  


 
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15.0 REFERENCES 
Puder 2009. Parenteral fish oil improves outcomes in patients with parenteral nutrition-
associated liver injury. Ann Surg 2009;250:395-402. 
Gura 2006. Reversal of parenteral nutrition-associated liver disease in two infants with 
short bowel syndrome using parenteral fish oil: implications for future management. 
Pediatrics 2006;118:e197-201. 
Gura 2008. Safety and efficacy of a fish-oil-based fat emulsion in the treatment of 
parenteral nutrition-associated liver disease. Pediatrics 2008;121:e678-86. 
Diamond 2009. Changing the paradigm: omegaven for the treatment of liver failure in 
pediatric short bowel syndrome. J Pediatr Gastroenterol Nutr 2009;48:209-15. 
 
.


 
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APPENDIX I 
 
This format will allow the title and first page number of each appendix to appear in the 
Table of Contents. 
 
The Sample Informed Consent will continue to be numbered as it has been (i.e., Page 1 
of X). 
 

ICF_001.pdf: 
EXPERIMENTAL SUBJECT’S BILL OF RIGHTS
              
Medical Research Studies
The rights below are the rights of every person who is asked to be in a medical research study.  As an 
experimental subject, you have the following rights:
1)
To be told what the study is trying to determine.
2)
To be told what will happen to you and whether any of the procedures, drugs, or devices is different from what 
would be used in standard practice.
3)
To be told about the frequent and/or important risks, side effects, or discomforts of the things that will happen to 
you for research purposes.
4)
To be told if you can expect any benefit from participating and, if so, what the benefit might be.
5)
To be told the other choices you have and how they may be better or worse than being in the study.
6)
To be allowed to ask any questions concerning the study, both before agreeing to be involved and during the 
course of the study.
7)
To be told what sort of medical treatment is available if any complications arise.
8)
To refuse to participate or to change your mind about participating after the study is started. This decision will not 
affect your right to receive the care you would receive if you were not in the study.
9)
To receive a copy of the signed and dated consent form.
10) To be free of pressure when considering whether you wish to agree to be in the study.
If you have other questions, please ask the researcher or research assistant.  In addition, you may contact the Institutional Review  
Board, which is concerned with protecting volunteers in research projects.  You may reach the IRB office by calling (916) 703-
9151, from 8:00 a.m. to 5:00 p.m., Monday through Friday, or by writing to the Institutional Review Board, CTSC Bldg., Suite 
1400, Rm. 1429, 2921 Stockton Blvd., Sacramento, California 95817.
              Signature of Subject or                                
     Date
              Legal Representative
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UNIVERSITY OF CALIFORNIA, DAVIS
CONSENT TO PARTICIPATE IN A RESEARCH STUDY
Investigator’s Name: ARTHUR J. de Lorimier, MD
Department: PEDIATRICS, GASTROENTEROLOGY
STUDY TITLE: Use of an intravenous fish oil emulsion in infants with cholestasis
INTRODUCTION
Your baby needs TPN (total parenteral nutrition - the mixture of sugars, proteins and fats that is given into a vein) to 
help them grow.
Your baby’s jaundice level (called the direct bilirubin) is high, and this makes us think that your baby’s liver is being 
damaged. We have tried to help your baby’s liver by making changes in the ingredients in your baby’s TPN but this has 
not worked. This is a problem because if the liver continues to be damaged it can bleeding, infections and even death. 
One possible treatment for this jaundice is a special type of fat (called OMEGAVEN) that we would use instead of the 
fat already in your baby’s TPN (called INTRALIPID - this is the milky colored solution you may have seen going into 
your baby’s iv line).). Omegaven is not licensed in the US so we would not normally be able to give it to your baby and 
we can not be completely sure how helpful this type of fat is, or whether it might lead to other problems for your baby. 
WHY IS THIS STUDY BEING DONE?
The reason for this study is to see whether giving your baby Omegaven instead of intralipid into their vein as part of 
their TPN might help your baby’s liver recover. 
HOW MANY CHILDREN WILL TAKE PART IN THE STUDY?
Your baby will be one of twenty-five babies studied.
WHAT WILL HAPPEN IF I TAKE PART IN THIS RESEARCH STUDY?
Your baby will be given Omegaven as part of their TPN instead of intralipid. Once we decide to give the Omegaven it 
can take several weeks for it be start because in needs to be delivered from Europe, and we may need to get approval 
from your insurance provider. The first dose of Omegaven must be given in the hospital, if you baby has already been 
discharged from the hospital when we decide to start Omegaven, he/she will need to be readmitted for about 24 hours 
so we can give the first dose in hospital.
We will continue to follow your baby’s blood tests very closely, just as we would with any baby with serious liver 
disease, and any baby on TPN for a long time. Taking part in this study will not change which tests are measured, or 
how often. 
The ONLY thing that should change as part of this study is what type of fat your baby receives as part of their TPN: 
Omegaven rather than intralipid.
 
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If your baby does go home on Omegaven they will need to come back to the out-patient clinic at UC Davis every 
month where their growth will be checked and blood will be taken (2ml or just under ½ teaspoon) to assess your baby's 
blood count, blood clotting, serum chemistry, and bilirubin levels.
Babies must be monitored in hospital for their first dose of Omegaven. If you baby has gone home before getting 
Omegaven they will need to come back into the hospital overnight for their first dose. Before we do this we will need to 
make sure your insurance company/ other payor is willing to pay for this.
HOW LONG WILL MY CHILD BE IN THE STUDY?
Your baby will be in the study until their liver has recovered, or until they do not need to be TPN (i.e. do not need to be 
feed into their vein). If your baby no longer needs TPN we will have to stop Omegaven, whether or not your baby’s liver 
has recovered.
If your baby goes home, or goes to another hospital, and their liver has not healed and the jaundice level is still high 
we will try and arrange for Omegaven to continue at home if your baby is still on TPN. This may not be possible, 
however, depending on who your doctor is and who pays for your medical bills.
CAN I STOP BEING IN THE STUDY?
Yes, you can stop being in the study at any time and for any reason. It will NOT affect anything about the rest of your 
baby’s care.
WHAT SIDE EFFECTS OR RISKS CAN I EXPECT FROM BEING IN THE STUDY?
When people started using Omegaven they were worried about high lipid levels, low platelets (cells that help the blood 
clot) and increased bleeding problems. These problems do not seem to be worse in babies getting Omegaven than in 
other babies with serious liver disease.
Omegaven does not include some fats that the body might need, but the current studies have not shown that to be a 
problem. But if we see signs that might be due to too little of these fats we will either try and test for that, or give some 
of those fats (in intralipid).
We are not sure, however, about the risk of Omegaven as only a few hundred children have received it. Because 
Omegaven is not licensed by the FDA it can be difficult to tell how safe Omegaven really is. There have been concerns 
that Omegaven might cause problems with bleeding or inadequate platelets (which help blood to clot), but these 
problems seem to be less common in babies that get Omegaven than those with cholestasis who stay on intralipid. If 
we find out more about the risk of Omegaven during the course of the study we will let you know.
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
We hope Omegaven will help your baby’s liver heal we do not know for sure whether this will happen. 
WHAT OTHER CHOICES DO I HAVE IF MY CHILD DOES NOT TAKE PART IN THIS STUDY?
If you do not wish to take part in this study you do not have to. Your baby’s care and treatment will not be affected by 
your decision (except that Omegaven will not be given).
WILL MY CHILD’S MEDICAL INFORMATION BE KEPT PRIVATE?
We will do our best to make sure that your personal information will be kept confidential. However, we cannot 
 
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guarantee total privacy. Your personal information may be released if required by law. If we access protected health 
information (e.g., your medical record), you will be asked to sign a separate form to give your permission. Your medical 
records may become part of the research record. If that happens, your medical records may be looked at by the 
sponsor of this study and government agencies or other groups associated with the study. They may not copy or take 
your personal health information from your medical records unless permitted or required by law. Designated University 
officials, including the Institutional Review Board, the Food & Drug Administration have the authority to review research 
records. A description of this clinical trial will be available on http://www.ClinicalTrials.gov , as required by U.S. Law. At 
most, the Web site will include a summary of the results. You can search this Web site at any time. If information from 
the study is published or presented at scientific meetings, your name and other personal information will not be used.
WHAT HAPPENS IF MY CHILD IS INJURED BECAUSE SHE/HE TOOK PART IN THIS STUDY? 
It is important that you promptly tell the Researcher if you believe that your child has been injured because of taking 
part in this study.  If your child is injured as a result of being in this study, the University of California will provide 
necessary medical treatment.  The costs of the treatment may be covered by University or the study sponsor or may 
be billed to your insurance company just like other medical costs.  The University and the study sponsor do not 
normally provide any other form of compensation for injury. You do not lose any legal rights by signing this form.
WHAT ARE THE COSTS OF TAKING PART IN THIS STUDY?
Omegaven costs about $50-100 a day. The FDA allows us to bill your private or public insurance carrier for this. But it 
is possible that they will refuse to pay for Omegaven. If this happens, we will try and pay for Omegaven from our own 
funds, or from the UCDMC pharmacy funds, or from UCDMC NICU funds. 
If your baby has already been discharged from the hospital, we will ask your insurance provider to pay for the costs of 
the Omegaven and the 24h hospital admission. We will not admit your baby to the hospital of start Omegaven until we 
know that your insurance provider is okay with this.
We expect that families will not have to pay for Omegaven. BUT if your private or public insurance carrier will not pay 
for Omegaven, and if neither UCDMC pharmacy, or the UCDMC NICU has funds to pay for Omegaven; we may need 
to ask you to pay. HOWEVER, if this happens, we will tell you about it and you will have the option to stop Omegaven 
and not have to pay any money.
WHAT ARE MY RIGHTS IF MY CHILD TAKES PART IN THIS STUDY?
If you decide to take part in this study, your rights are
1.
To decide if your baby takes part in this study
2.
To decide whether your baby continues to the end of this study 
3.
To decide when your baby stops being in this study 
4.
To be told about any new information we have about Omegaven in babies with liver disease that might affect 
whether you want your baby to be in the study
DOES THE RESEARCHER HAVE A FINANCIAL INTEREST IN THIS RESEARCH STUDY? 
The Investigator does not have any personal or financial interest in this study.
WHO CAN ANSWER MY QUESTIONS ABOUT THE STUDY?
If you have questions, please ask us.  You can talk to the Investigator about any questions or concerns you 
have about this study at:
 
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Arthur J. de Lorimier MD
at pager number   
916 816 1931 
(anytime, emergency)
These numbers are for pagers. After you hear the message type in your telephone number and press #. Dr. de 
Lorimier will get back to you as soon as possible.
For questions about your rights while taking part in this study call the IRB Administration at (916) 703-9151 or 
write to IRB Administration, CTSC Building, Suite 1400, Room 1429, 2921 Stockton Blvd., Sacramento, CA 
95817.  The IRB Administration will inform the Institutional Review Board which is a group of people who 
review the research to protect your rights.  The IRB Administration has also developed a web site designed to 
make you familiar with your rights.  The web site discusses your basic rights as a research participant, an 
explanation of the informed consent process, the basic requirement that written consent be in a language 
understandable to you, and suggested sample questions to ask the research investigator regarding your 
participation in the study.  This web site can be accessed at:  www.research.ucdavis.edu/IRBAdmin.
ARE THERE OTHER RESEARCH OPPORTUNITIES?
If you are interested in being contacted for future research, please provide your phone number and/or email. 
This is completely optional.
____ (initials) Yes, I am willing to be contacted for future research opportunities. My phone number and/or 
email: _________________________________.
My signature below will indicate that I have decided to participate in this study as a research subject.  I have 
read and understand the information above.  I understand that I will be given a signed and dated copy of this 
consent form and the Bill of Rights.  
__________________________________________                   ___________________________________________
Signature of Subject or Legal Representative      
Print Name
__________________________________________
Date                    
__________________________________________
__________________________________________
Signature of Person Obtaining Consent
Print Name of Person Obtaining Consent
__________________________________________
Date
 
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