Preventing Cholestasis in Premature Infants Using SMOFLipid®
Phase: PHASE4
Conditions: Cholestasis, Psychomotor Disorders, Developmental
Sponsor: Medical University of Vienna

Preventing Cholestasis in Premature Infants Using SMOFLipid®/SMOFLipid® 
Medical University of Vienna, Department of Pediatrics 
EUDRACT Nr 2011-005456-33 
 
Date 17.9.20129.3.2012 
Version 1.21 
Page 1 of 38 
 
 
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
 
 
 
PREVENTING CHOLESTASIS IN PREMATURE INFANTS USING SMOFLIPID® 
 
 
Version 1.21 / 9.3.2012 17.9.2012 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
The information contained in this document, especially unpublished data, is the property of the 
sponsor of this study. It is therefore provided to you in confidence as an investigator, potential 
investigator, or consultant, for review by you, your staff, and an Independent Ethics Committee or 
Institutional Review Board. It is understood that this information will not be disclosed to others 
without written authorization from the Department of Pediatrics, Medical University Vienna except 
to the extent necessary to obtain informed consent from those persons to whom the study drug may 
be administered. 
 
 
Test drug (IMP) and 
Pharmaceutical Company  
SMOFlipid® 
Fresenius Kabi AG, Bad Homburg, Germany 

Preventing Cholestasis in Premature Infants Using SMOFLipid®/SMOFLipid® 
Medical University of Vienna, Department of Pediatrics 
EUDRACT Nr 2011-005456-33 
 
Date 17.9.20129.3.2012 
Version 1.21 
Page 2 of 38 
 
 
 
 
Protocol authors 
Andreas Repa, MD 
Investigators 
Andreas Repa, MD 
Nadja Haiden, MD 
Renate Fuiko, PhD 
Document type 
Clinical study protocol 
Study phase 
Phase IV 
Document status 
Version 1.21 
Date 
17.9.20129.3.2012 
Number of pages 
38 

Preventing Cholestasis in Premature Infants Using SMOFLipid®/SMOFLipid® 
Medical University of Vienna, Department of Pediatrics 
EUDRACT Nr 2011-005456-33 
 
Date 17.9.20129.3.2012 
Version 1.21 
Page 3 of 38 
 
 
 
1. SPONSOR, INVESTIGATOR, MONITOR AND SIGNATURES 
 
Sponsor/or representative (OEL) (AMG §§ 2a, 31,32)  
 
Medical University of Vienna, Austria 
O. Univ. Prof. Dr. Arnold Pollak 
 
________________ 
 
___________ 
Signature (OEL)  
 
Date 
 
 
Investigator (AMG §§ 2a, 35,36) 
 
 
PD Dr. med. univ. Nadja Haiden, Department of Pediatrics, Medical University of Vienna, Austria 
 
 
_________________ 
 
___________ 
Signature 
 
 
Date 
 
 
 
Monitor/ or Representative of CRO (AMG §§ 2a, 33,34) 
 
 
Koordinierungszentrum für Klinische Studien 
(PD.Dr. Johannes Pleiner) 
 
_________________ 
 
___________  
Signature 
 
 
Date 
 
 
Statistician 
 
 
Mag. Irene Steiner 
 
 
_________________ 
 
___________  
Signature 
 
 
Date 
 
Clinical Trials Centers: 
Medicial Universitiy of Vienna, Austria 
 
 
 

Preventing Cholestasis in Premature Infants Using SMOFLipid®/SMOFLipid® 
Medical University of Vienna, Department of Pediatrics 
EUDRACT Nr 2011-005456-33 
 
Date 17.9.20129.3.2012 
Version 1.21 
Page 4 of 38 
 
2. PROTOCOL SYNOPSIS 
 
 
TITLE 
Preventing Cholestasis in Premature Infants Using SMOFLipid® 
OBJECTIVES 
Primary Objective 
• 
To compare a mixed parenteral lipid emulsion containing fish oil 
(SMOFlipid®) with a soybean oil based lipid emulsion (Intralipid®) for its 
effect on the occurrence of parenteral nutrition associated cholestasis in 
extremely low birth weight infants  
Secondary Objectives 
• 
To assess the impact of SMOFLipid® on the long term neurocognitive 
development of extreme low birth weight infants  at 12 and 24 months of 
corrected age  
DESIGN / PHASE 
Prospective, randomized, double-blind, phase IV study. 
STUDY PLANNED DURATION First patient 
First visit 
1st 
month 
 
Last patient 
First visit 
36 
month
s 
Last patient 
Last visit 
62 months 
 
CENTER(S) 
/ COUNTRY(IES)  
Single center, Austria 
(Medical University Vienna, Austria; Department of Neonatology, Pediatric 
Intensive Care and Neuropediatrics, University Children´s Hospital,) 
PATIENTS / GROUPS 
200  patients in 2 groups 
100 patients per group 
Block randomization ratio 1:1, stratification by sex and weight (in two 
groups:  < 750 gram vs. ≥750 gram). 
 In case of twins, randomization will be applied to the firstborn; the twin will 
be assigned to the other treatment group. Triplets or higher will be excluded. 
INCLUSION CRITERIA 
• 
Infants born with a birth weight ≤ 1000 Gram (= extreme low birth 
weight infants) 
• 
Admission to the neonatal ward in the first 24 hours of life 
• 
Informed consent obtained and randomized on study drug the first 5 
days of life 
EXCLUSION CRITERIA 
• 
Triplets or higher 
• 
Conjugated bilirubin > 1.5 mg/dl before inclusion to the study 
• 
Conditions associated with cholestasis independent of parenteral 
nutrition: 
o Inborn errors of metabolism 
o Viral Infections (cytomegaly virus, HIV, Hepatitis B, C) 
o Immune mediated hemolytic diesease (e.g. Rhesus incompatibility) 
o Cystic fibrosis 
o Primary cholestatic diseases of the liver 
• For Neurodevelopmental outcome in follow up phase: Congenital 
neurological malformations 
STUDY PERIODS 
• 
Operational Phase:  The operational phase of the study will last for three 
years (months 1-39) and start with the inclusion of the first patient to the 
trial and will end with the last patient’s discharge from hospital. 
• 
Follow Up: The follow up phase will last start with the first included 
patient reaching the age of 12 months corrected age and will end at 24 
months of corrected gestational age of the last included patient (months 
15-62) 
INVESTIGATIONAL DRUG 
SMOFLIPID®: 

Preventing Cholestasis in Premature Infants Using SMOFLipid®/SMOFLipid® 
Medical University of Vienna, Department of Pediatrics 
EUDRACT Nr 2011-005456-33 
 
Date 17.9.20129.3.2012 
Version 1.21 
Page 5 of 38 
 
initial dose: 1g/kg/day  
target dose: 3g/kg/day   
COMPARATIVE DRUG 
/CONTROL CONDITION 
INTRALIPID® 
initial dose: 1g/kg/day  
target dose: 3g/kg/day 
CONCOMITANT MEDICATION In case of of cholestasis (i.e. conjugated bilirubin two times > 1.5 mg/dl), 
ursodeoxycolic acid at 20-30 mg/kg/day is the treatment of choice.  
In case of severe cholestasis (i.e. conjugated bilirubin > 6 mg/dL) and 
elevation of liver enzymes (3 times over normal) a rescue therapy using pure 
fish oil (Omegaven®) at 0.5-1 g/kg/day will be allowed. 
EFFICACY ENDPOINT 
Incidence of parenteral nutrition associated cholestasis (PNAC), defined as 
conjugated bilirubin > 1.5 mg/dl measured on two consecutive occasions by 
blood sampling performed at least every 10 +/- 4 days. 
 
Based on a present incidence of 25 % using the comparative drug at the 
study center (unpublished data 2007-9) an absolute difference of 15 % 
between the groups (25% vs. 10% incidence) was considered clinically 
significant.  
TOLERABILITY / SAFETY 
ENDPOINTS 
- 
PHARMACOKINETIC / 
PHARMACODYNAMIC 
ENDPOINTS 
- 
QUALITY OF LIFE / 
PHARMACOECONOMIC  
ENDPOINTS 
- 
STATISTICAL METHODOLOGY  Primary Endpoint 
PNAC (definition see efficacy endpoint)  
 
Null and alternative hypotheses: 
H0 : The percentage of PNAC in group 1 (investigational drug) equals group 2 
(comparative drug)  
H1: The percentage of PNAC in group 1 (investigational drug) does not equal 
group 2 (comparative drug)  
 
 
Sample size calculation 
A sample size estimation using a χ2-test indicated that 200 infants 
(100/group) are required to detect a 15% diference (10% in group 1 vs. 25% 
in group 2) with a power of 80% and a  two-sided significance level of 0.05. 
The estimated drop out rate is 22%. Therefore, a sample size of 122 patients 
per group is planned. For sample size estimation, data were assumed to be 
independent. 
 
Statistical methodology 
 
Main analysis set(s) 
A χ2-test will be used for analysis of the primary outcome PNAC.  
Additionally, the effect of treatment and other relevant influence factors (i. 
e. duration of parenteral nutrition, birth weight, necrotizing enterocolitis ) on 
the primary endpoint will be analyzed using a logistic regression model with 

Preventing Cholestasis in Premature Infants Using SMOFLipid®/SMOFLipid® 
Medical University of Vienna, Department of Pediatrics 
EUDRACT Nr 2011-005456-33 
 
Date 17.9.20129.3.2012 
Version 1.21 
Page 6 of 38 
 
stepwise selection. In case of twins, the analysis will be carried out 1) as 
mentioned above, but only including the firstborn and 2) by calculating a 
generalized linear model with mother as random factor.  
 
Other endpoints 
Bailey Scales of Infant Development II at 12 and 24 months: Differences in 
the scores of psychomotor development and neurocognitive development, 
respectively, between the groups will be analyzed by repeated measures 
ANOVAs, also accounting for confounder factors (e.g. birth weight, …). In 
case of twins, the analysis will be carried out 1) as mention above, but only 
including the firstborn and 2) by calculating a mixed model with mother and 
child as random factor. In case of too many drop outs, descriptive statistics 
will be carried out. 
For Gross Motor function measurements at 12 and 24 months, descriptive 
statistics will be conducted. 

Preventing Cholestasis in Premature Infants Using SMOFLipid®/SMOFLipid® 
Medical University of Vienna, Department of Pediatrics 
EUDRACT Nr 2011-005456-33 
 
Date 17.9.20129.3.2012 
Version 1.21 
Page 7 of 38 
 
 
 
3. LIST OF ABBREVATIONS 
 
ELBW  
 
 
Extreme Low Birth Weight 
ICH 
 
 
 
International Conference on Harmonization 
ILE 
 
 
 
Intravenous Lipid Emulsion 
GCP 
 
 
 
Good Clinical Practice 
DHA 
 
 
 
Docosahexaenoic Acid 
DOH 
 
 
 
Declaration of Helsinki 
LC-PUFA 
 
 
Long Chain Polyunsaturated Fatty Acids 
PN 
 
 
 
Parenteral Nutrition 
PNAC  
 
 
Parenteral Nutrition Associated Cholestasis

Preventing Cholestasis in Premature Infants Using SMOFLipid®/SMOFLipid® 
Medical University of Vienna, Department of Pediatrics 
EUDRACT Nr 2011-005456-33 
 
Date 17.9.20129.3.2012 
Version 1.21 
Page 8 of 38 
 
 
4. TABLE OF CONTENTS 
 
CLINICAL STUDY PROTOCOL 
1 
PREVENTING CHOLESTASIS IN PREMATURE INFANTS USING SMOFLIPID® 
1 
1. SPONSOR, INVESTIGATOR, MONITOR AND SIGNATURES 
3 
2. PROTOCOL SYNOPSIS 
4 
3. LIST OF ABBREVATIONS 
7 
4. TABLE OF CONTENTS 
8 
TABLE 1. VISIT AND ASSESSMENT SCHEDULE 
10 
5. BACKGROUND INFORMATION 
11 
5.1 BACKGROUND 
11 
5.2 STUDY RATIONALE 
14 
6. STUDY OBJECTIVES 
14 
6.1 PRIMARY OBJECTIVE 
14 
6.2 SECONDARY OBJECTIVES 
15 
7. STUDY DESIGN 
15 
7.1 STUDY POPULATION 
15 
7.1.1 SUBJECT POPULATION 
15 
7.1.2 INCLUSION CRITERIA 
15 
7.1.3 EXCLUSION CRITERIA 
15 
7.1.4 STUDY DURATION 
16 
7.1.5 WITHDRAWAL AND REPLACEMENT OF SUBJECTS 
16 
7.1.6 PREMATURE TERMINATION OF THE STUDY 
17 
8. METHODOLOGY 
17 
8.1 STUDY MEDICATION 
17 
8.1.1 DOSAGE AND ADMINISTRATION 
18 
8.1.2 STUDY-DRUG UP- AND DOWN TITRATION 
18 
8.1.3 STUDY DRUG INTERRUPTION OR DISCONTINUATION 
18 
8.1.4 STUDY DRUG PREMATURE PERMANENT DISCONTINUATION 
18 
8.1.5 STUDY-DRUG DELIVERY & DRUG STORAGE CONDITIONS 
19 
8.1.6 STUDY DRUG PACKAGING AND LABELING 
19 
8.1.7 IMP ADMINISTRATION & HANDLING 
19 
8.1.8 DRUG ACCOUNTABILITY 
19 
8.1.9 PROCEDURES TO ASSESS SUBJECTS COMPLIANCE 
19 
8.1.10 CONCOMITANT MEDICATION 
20 
8.2 RANDOMIZATION AND STRATIFICATION 
20 
8.3 BLINDING 
20 
8.3.1 EMERGENCY PROCEDURE FOR UNBLINDING 
21 
8.3.2 UNBLINDING AT THE END OF THE STUDY. 
21 
8.4 BENEFIT AND RISK ASSESSMENT 
21 
8.5 STUDY PROCEDURES 
21 
8.5.1 GENERAL RULES FOR TRIAL PROCEDURES 
21 
8.5.2 SCREENING INVESTIGATION 
22 
8.5.3 END-OF-STUDY (EOS) EXAMINATION 
22 
8.5.4 LABORATORY TESTS 
22 
9. SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
24 
9.1 ADVERSE EVENTS (AES) 
24 

Preventing Cholestasis in Premature Infants Using SMOFLipid®/SMOFLipid® 
Medical University of Vienna, Department of Pediatrics 
EUDRACT Nr 2011-005456-33 
 
Date 17.9.20129.3.2012 
Version 1.21 
Page 9 of 38 
 
9.1.1 SUMMARY OF KNOWN AND POTENTIAL RISKS OF THE STUDY DRUG 
24 
9.1.2 DEFINITION OF ADVERSE EVENTS 
25 
9.2 SERIOUS ADVERSE EVENTS (SAES) 
26 
9.2.1 HOSPITALIZATION – PROLONGATION OF EXISTING HOSPITALIZATION 
26 
9.2.2 SAES RELATED TO STUDY-MANDATED PROCEDURES 
27 
9.2.3 SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTIONS (SUSARS) 
27 
9.3 SEVERITY OF ADVERSE EVENTS 
27 
9.4 RELATIONSHIP TO STUDY DRUG 
28 
9.5 REPORTING PROCEDURES 
292928 
9.5.1 REPORTING PROCEDURES FOR SAES 
29 
9.5.2 REPORTING PROCEDURES FOR SUSARS 
29 
9.5.3 ANNUAL SAFETY REPORT 
30 
10. FOLLOW-UP 
30 
10.1 FOLLOW-UP OF STUDY PARTICIPANTS INCLUDING FOLLOW-UP OF ADVERSE VENTS 
30 
10.2 TREATMENT AFTER END OF STUDY 
30 
11. STATISTICAL METHODOLOGY AND ANALYSIS 
30 
11.1 ANALYSIS SETS 
313130 
11.2 SAMPLE SIZE CONSIDERATIONS 
31 
11.3 RELEVANT PROTOCOL DEVIATIONS 
31 
11.4 STATISTICAL ANALYSIS PLAN 
31 
11.5 MISSING, UNUSED AND SPURIOUS DATA 
32 
11.6 ENDPOINTS ANALYSIS 
32 
11.6.1 PRIMARY ENDPOINT ANALYSIS 
32 
11.6.2 SECONDARY ENDPOINT ANALYSIS 
32 
11.6.3 SAFETY AND TOLERABILITY ENDPOINTS 
32 
11.6.4 BASELINE PARAMETERS AND CONCOMITANT MEDICATIONS 
32 
11.7 INTERIM ANALYSIS 
333332 
11.8 SOFTWARE PROGRAM(S) 
333332 
12. DOCUMENTATION AND DATA MANAGEMENT 
33 
12.1 DOCUMENTATION OF STUDY RESULTS 
33 
12.1.1 CASE REPORT FORM (CRF) 
33 
12.1.2 DATA COLLECTION 
33 
12.2 SAFEKEEPING 
343433 
12.3 QUALITY CONTROL AND QUALITY ASSURANCE 
34 
12.3.1 PERIODIC MONITORING 
34 
12.3.2 AUDIT AND INSPECTIONS 
353534 
12.4 REPORTING AND PUBLICATION 
35 
12.4.1 PUBLICATION OF STUDY RESULTS 
35 
13. ETHICAL AND LEGAL ASPECTS 
35 
13.1 INFORMED CONSENT OF SUBJECTS 
35 
13.2 ACKNOWLEDGEMENT / APPROVAL OF THE STUDY 
35 
13.2.1 CHANGES IN THE CONDUCT OF THE STUDY 
363635 
13.3 INSURANCE 
36 
13.4 CONFIDENTIALITY 
373736 
13.5 ETHICS AND GOOD CLINICAL PRACTICE (GCP) 
373736 
14. APPENDICES 
37 
15. REFERENCES 
37 

Preventing Cholestasis in Premature Infants Using SMOFLipid®/SMOFLipid® 
Medical University of Vienna, Department of Pediatrics 
EUDRACT Nr 2011-005456-33 
 
Date 17.9.20129.3.2012 
Version 1.21 
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TABLE 1. VISIT AND ASSESSMENT SCHEDULE 
 
PERIODS 
Name 
SCREENING 
TREATMENT 
FOLLOW-UP 
  
Duration 
  
 months 
2 years  
VISITS  
Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
  
Name 
Screening 
Randomizati
on 
Control 1 
Control 2 
Control 3 
Control 4 
Control 5 
Control 6 
Control 7 
End of 
Study 
Follow-up 
  
Time 
Day 0 
Day 0-2 
Week 2 
Week 4 
Week 6 
Week 8 
Week 10 
Week 12 
Week 16 
Week 18 
Month 16 and 28 
(± 4 
days) 
(± 4 
days)  
(± 4 
days) 
(± 4 
days)  
(± 5days) 
(±  7 
days) 
(± 7 
month) 
(± 1 
month)  
(± 5 days) 
Informed Consent 
X 
  
  
  
  
  
  
  
  
  
  
Inclusion / Exclusion Criteria 
X 
  
  
  
  
  
  
  
  
  
X  
Medical History 
  
X 
  
  
  
  
  
  
  
X 
X 
Physical Examination 
  
X 
  
  
  
  
  
  
  
X 
X 
Body weight and height 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant/Change in 
medication 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Vital Signs (BP, PR) 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lab Tests (Bilirubin, liver 
function) 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Visual evoked potentials 
  
  
  
  
  
  
  
  
  
X (34-
37wks)36w
ks GA) 
  
Cerebral Function Monitoring 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
  
Cerebral Ultrasound 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Adverse Events (IVH, NEC, 
ROP, BPD) 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
  
Psychomotor Developmental 
Tests 
  
  
  
  
  
  
  
  
  
  
X 
Ophtalmologic exam 
  
  
 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
  

Preventing Cholestasis in Premature Infants Using SMOFLipid®/SMOFLipid® 
Medical University of Vienna, Department of Pediatrics 
EUDRACT Nr 2011-005456-33 
 
Date 17.9.20129.3.2012 
Version 1.21 
Page 11 of 38 
 
5. BACKGROUND INFORMATION 
5.1 Background  
 
5.1.1 Parenteral nutrition associated cholestasis (PNAC) 
Since the first description of parenteral nutrition associated liver disease 1 it is well established that 
patients receiving parenteral nutrition (PN) are at risk for developing hepatic complications. In 
neonates and infants, liver injury is characterized by an early occurrence of intrahepatic cholestasis - 
i.e. parenteral nutrition associated cholestasis (PNAC) - characterized by a rise in serum conjugated 
bilirubin 2. In severe cases liver cell damage and even progressive liver dysfunction with an incidence 
of hepatic failure of up to 17 % is described 3.  
 
5.1.2. Extreme low birth weight infants 
Preterm infants with extreme low birth weight (ELBW) < 1000 gram are often dependent on long 
term PN due to intolerance of enteral feedings 4. Additionally they frequently acquire nosocomial 
infections and are at risk for developing necrotizing enterocolitis, a severe inflammatory disease of 
the intestine with considerable long term morbidity such as short gut syndrome. Prematurity, long 
term PN, nosocomial infections, necrotizing enterocolitis and short gut syndrome are all are risk 
factors for the development of PNAC. Therefore ELBW infants are at high risk to develop this 
complication 2 .  
 
5.1.3. Parenteral lipids as pathogenic factor in PNAC  
Besides factors related to prematurity and its complications or short gut syndrome, PNAC is - as 
already proposed by the condition’s name - closely linked to aspects of PN. Hypercaloric feeds with 
an excess of glucose can result in chronic cholestasis 5. Most important however, intravenous lipid 
emulsions (ILE) seem to be implicated in the development of PNAC. Higher parenteral lipid 
administration has been documented to be correlated with cholestasis in pediatric patients 6 as well 
as very low birth weight infants 7.  
 
5.1.4. Soybean oil based intravenous lipid emulsions 
Until nowadays, standard of care for supplying lipids in PN of preterm infants and sick neonates are 
ILE based on soybean oil (Intralipid®) 2. Some of the components of soybean oil are believed to be 
implicated in the pathogenesis of PNAC. Their high content of ω-6 polyunsaturated long chain fatty 

Preventing Cholestasis in Premature Infants Using SMOFLipid®/SMOFLipid® 
Medical University of Vienna, Department of Pediatrics 
EUDRACT Nr 2011-005456-33 
 
Date 17.9.20129.3.2012 
Version 1.21 
Page 12 of 38 
 
acids may exert pro-inflammatory effects and plant sterols from soy may reduce bile flow and both 
factors were linked to the development of PNAC 8. 
 
5.1.5. Fish oil based intravenous lipid emulsions 
In recent years, ILEs containing fish oil were proposed for treatment of PNAC in pediatric patients 
mainly suffering from short gut syndrome. Two research groups consecutively described the 
successful treatment of severe PNAC in neonates using Omegaven® 9,10 an ILE composed exclusively 
of fish oil. The rationale behind the positive effects observed is built on their high content of ω-3 
fatty acids which act anti-inflammatory and are thought to improve bile flow 11. However, whether 
fish oil or only replacement of soybean oil based ILE in PN 6 caused the improvement in these 
patients , cannot be concluded. Prospective trials are required to substantiate the evidence 8. 
 
5.1.6. Preventing PNAC in ELBW infants 
In view of their high risk to develop PNAC, ELBW infants could profit from a prophylactic 
intervention. Based on the promising results in the treatment of PNAC, ILEs based on fish oil seem 
attractive candidates. However, an ILE based on 100% fish oil like Omegaven® may deliver not 
enough ω-6 fatty acids and therefore cannot be used as the exclusive ILEs for nutrition of ELBW 
infants 8. 
With a broader panel of ILEs available today, a mixture of fishoil with soybean oil, medium chain 
triglycerides and olive oil (SMOFlipid®) has recently emerged. A prospective study in a total of 60 
preterm infants showed that PN with SMOFlipid® induced lower serum γ-glutamyl transferase levels 
compared to controls receiving a soybean oil based ILE, suggesting a favourable influence on 
cholestasis and liver function 12. A prospective randomized trial in 28 pediatric patients demonstrated 
a reduction in total bilirubin levels using SMOFlipd® compared to a soybean oil based ILE 13. 
Importantly SMOFlipid® is registered for PN of preterm infants, which makes a direct comparison of 
Intralipid® and SMOFlipid® in these vulnerable patients ethically acceptable 14. 
 
5.1.7. Fish oil and neurocognitive development 
Long Chain polyunsaturated fatty acids (LC-PUFA) are both structural and functional lipids playing an 
important role in growth and development of the fetus and the newborn. In particular the 22:6 ω3-
LC-PUFA docosahexaenoic acid (DHA) is deemed to be crucial for a normal development of the fetal 
brain. In utero, high amounts of DHA cross the placenta in the last trimester. After birth mother’s 
milk is the most important source 15. 
Preterm infants – as their endogenous capacity to synthesize DHA from precursor fatty acids is 
limited – depend on exogenous supply 16. In this context, preterm infants accumulate a deficit of up 

Preventing Cholestasis in Premature Infants Using SMOFLipid®/SMOFLipid® 
Medical University of Vienna, Department of Pediatrics 
EUDRACT Nr 2011-005456-33 
 
Date 17.9.20129.3.2012 
Version 1.21 
Page 13 of 38 
 
to 44% compared to in utero accretion rates 16. In view of the documented correlation of DHA deficit 
and low birth weight 16 ELBW infants are at particular risk, as they depend PN for several weeks and 
DHA is absent in the traditional soybean oil based ILEs. As the only source of DHA for the preterm 
infant is mother’s milk or preterm formua and not ILEs, the prolonged time until full enteral feeds are 
established in these patients seems particularly critical.  
Therefore an ILE like SMOFlipid® containg fish oil that provides DHA would reduce this deficit and 
may therefore confer potential benefits for the neurocognitive development.  
 
5.1.8. Current Status of research on fish oil and parenteral nutrition associated cholestasis in 
preterm infants 
There are currently no studies published on a fish oil containing ILE for prophylaxis of PNAC.  
There is growing supportive evidence for treatment of established PNAC using ILE based on fish oil in 
pediatric patients from two observational and one prospective clinical trial, but there are no data 
from preterm infants. 
The growing belief in a therapeutic effect of fish oil containing ILEs on PNAC is based on the 
published experience of clinicians from Boston around Mark Puder 11 and Toronto around Paul Wales 
9. They both described neonates with severe short gut syndrome and PNAC that dramatically 
improved after replacing some of the 100% soybean oil based ILE “Intralipid®” with a 100% fish-oil 
based ILE (Omegaven®) (Toronto) or completely switching over to a fish oil based ILE (Boston). The 
Boston group reported a resolution of cholestasis in 45-61 % (published cases: 60) 10,17. The Toronto 
group reported a rate of resolution of 63% (published cases: 22) 18. Pooling these cases together, a 
mean of 53.6 % (44/82) of patients showed reversal of cholestasis. For comparison, historical cohorts 
of comparable patients who received the soybean oil based Intralipid® for PN, showed resolution of 
cholestasis only in 5-33 % during the disease course (published cases: 47) 10,17.  
The only prospective trial using a mixed ILE contaning fish oil (SMOFlipid®) in pediatric patients 
reported a significant reduction of total bilirubin levels compared with the soybean oil based ILE 
Intralipid®13. 
The only prospective study performed in a population of preterm infants was performed by Tomsits 
et al 12. In healthy preterm infants (birth weights 1000 – 2500 gramm) they demonstrated good 
clinical tolerance and lower γ-glutamyl transferase levels using SMOFlipid® compared to standard 
care with Intralipid®. Though liver function was only a secondary outcome parameter of the study 
and the observational period was too short to assess any effect on PNAC, this finding  supports a 
prophylactic effect of SMOFlipid® on liver function, underlining the need for further investigations.  
 
5.1.9. Current Status of research on fish oil and neurodevelopment of preterm infants 

Preventing Cholestasis in Premature Infants Using SMOFLipid®/SMOFLipid® 
Medical University of Vienna, Department of Pediatrics 
EUDRACT Nr 2011-005456-33 
 
Date 17.9.20129.3.2012 
Version 1.21 
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There are currently no studies on long term neurodevelopment of preterm – in particular ELBW - 
infants after using a fish oil containing ILE.  
There are prospective trials on enteral supplementation with LC-PUFA containing DHA from fish oil in 
preterm infants and during pregnancy with mixed results 15,19. 
Clinical studies in preterm infants focused on enteral supplementation of LC-PUFAs (including DHA) 
from fish oil in formula feedings. In this context, a Cochrane Review in 2008 by Simmer et. al 19 
concluded that currently there is no convincing evidence of a sustained improvement of 
neurodevelopment by LC-PUFA supplementation. However, as the mean birth weight of preterm 
infants enrolled in these studies was consistently > 1000 gram (1074 – 1980) the authors stressed 
that ELBW infants should be investigated 19. In this context, there is indirect evidence from two 
prospective randomized trials, that supplementation of pregnant women with fish oil converts a 
beneficial effect on later neurodevelopment of their children 15. In line with the evidence from these 
trials, using an ILE containing fish oil for parenteral nutrition of ELBW infants could close the gap until 
ELBW infants are fully nourished with mother’s milk or formula (supplemented with LC-PUFA). A 
reduction of the DHA deficit these infants normally accumulate 16 may confer a benefit to 
neurodevelopment. 
 
5.2 Study rationale 
 
Primary endpoint: 
ELBW infants are at high risk for development of parenteral nutrition associated cholestasis (PNAC). 
There is growing evidence for a positive effect of fish oil based intravenous lipid emulsions (ILE) for 
the treatment of PNAC. Primary use of a fish oil containing ILE for PN may prevent the development 
of PNAC.  
 
Secondary Endpoint: 
ELBW infants accumulate a deficit of ω3-LC-PUFA (especially DHA), which are important for 
neurodevelopment. An ILE containing fish oil provides these fatty acids and would reduce the deficit 
in ELBW infants, which may improve their neurocognitive development. 
6. STUDY OBJECTIVES 
6.1 Primary Objective 
 

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To investigate whether ELBW infants treated with two different ILEs (investigational drug: 
SMOFlipid®, comparative drug: Intralipid®) differ in the occurrence of PNAC (conjugated bilirubin > 
1.5 mg/dl, measured on two consecutive occasions). 
6.2 Secondary Objectives 
 
To investigate whether ELBW infants treated with two different ILEs (investigational drug: 
SMOFlipid®, comparative drug: Intralipid®) differ in their neurodevelopment (Bailey Scales of Infant 
Development II) at 12 and 24 months of corrected gestational age  
7. STUDY DESIGN 
 
7.1 Study population 
7.1.1 
Subject population 
 
Population: Extreme low birth weight (ELBW) infants 
Recruitment: About 90 ELBW infants are admitted to our unit each year in the first 24 hours of life. 
We expect to recruit 90 % (81 patients/a year) to the study.  
Drop Outs: Based on a mortality of 22% in 2010 (Klebermasz K., unpublished data) and a conservative 
calculation, we expect 18/81 patients to drop out, leaving 63 patients a year for analysis of the 
primary outcome. We do not expect any other reasons for drop out.  
Losses to follow up: 63 patients are expected to be discharged from hospital each year. Based on a 
follow up rate of 60% after discharge in 2009 (Fuiko R, unpublished data), we expect about 38/63 
patients to be available for anaylsis of the secondary outcome each year. In the end we expect to 
lose 80/200 patients to follow up. 
 
7.1.2 
Inclusion criteria 
- Infants with a birth weight ≤ 1000 Gram  
- Admission to the neonatal ward in the first 24 hours of life 
- Randomization on the respective study drug in the first 5 days of life 
7.1.3 
Exclusion criteria 
 
Triplets or higher 
Conjugated bilirubin > 1.5 mg/dl before inclusion to the study 
Conditions associated with cholestasis independent of parenteral nutrition: 

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- Inborn errors of metabolism 
- Viral Infections (cytomegaly virus, HIV, Hepatitis B, C) 
- Immune mediated hemolytic diesease (e.g. Rhesus incompatibility) 
- Diagnosis of cystic fibrosis 
- Primary cholestatic diseases of the liver 
At follow up: 
- Congenital neurological malformations will be excluded from follow up analysis (except 
screening for adverse events)   
7.1.4 
Study duration 
 
The interventional phase starts with randomization on the study drug in the first 5 days of life and 
ends with discontinuation of PN, typically after 6 weeks (mean 44 days +/- SD 34 days, personal 
data).  
 
The follow up phase ends at 24 months (2 years) of corrected gestational age. 
 
7.1.5 
Withdrawal and replacement of subjects 
 
Criteria for withdrawal 
 
Premature discontinuation from the study is to be understood when the subject did not undergo End 
of Study (EOS) examination and / or all pivotal assessments during the study. 
 
Subjects must be withdrawn under the following circumstances: 
• 
at their parent´s request at any time 
• 
if the investigator feels it would not be in the best interest of the subject to continue 
• 
if the subject violates conditions laid out in the consent form / information sheet or 
disregards instructions by the study personal 
• 
if the subject is transferred to another hospital before parenteral nutrition is discontinued 
• 
if the study drug was not provided < 80% of time as planed per protocol 
• 
If an exclusion criterion is met, after inclusion to the study (except neurological malformation 
which only leads to withdrawal from follow up analysis except screening for adverse events) 
• 
death before day of life 28 
 
In all cases, the reason why subjects are withdrawn must be recorded in detail in the CRF and in the 
subject’s medical records. Should the study be discontinued prematurely, all study materials 
(complete, partially completed and empty CRFs) will be retained. 
 
Follow-up of patients withdrawn from the study 

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In case of premature discontinuation after study drug intake, the investigations scheduled for the 
EOS visit will be performed 7 +/-4 days after study drug discontinuation. The subjects will be advised 
that participation in these investigations is voluntary. Furthermore, they may request that from the 
time point of withdrawal no more data will be recorded and that all biological samples collected in 
the course of the study will be destroyed. 
 
Replacement policy 
 
Patients withdrawn from the study < 28 days (outcome cannot be calculated) will be replaced and 
the next free subject number will be allocated. Drops outs will be included in the sample size. If 
patients are withdrawn from the study and the outcome can be calculated, (more than two blood 
samples taken), they will be considered in the intention to treat analysis (see chapter 10) 
7.1.6 
Premature termination of the study 
 
The sponsor has the right to close this study at any time. The IEC and the competent regulatory 
authority must be informed within 15 days of early termination. 
The trial or single dose steps will be terminated prematurely in the following cases: 
• 
If adverse events occur which are so serious that the risk-benefit ratio is not acceptable. 
• 
If the number of dropouts is so high that proper completion of the trial cannot realistically be 
expected. 
 
8. METHODOLOGY 
 
8.1 Study medication 
 
Active agent and characteristics:  
 
Investigational Product 
Trade name of the agent:  
SMOFlipid 200 mg/ml Emulsion zur Infusion 
Manufacturer:   
 
Fresenius Kabi Austria GmbH  
Drug supply:  
 
 
Fresenius Kabi Austria GmbH 
Storage Instructions:  
 
Do not freeze, do not store > 25° Celsius, protect from light 
Route of administration:  
Intravenous 
 
Comparator 
Trade name of the agent:  
Intralipid 20% - Emulsion zur Infusion 
Manufacturer:   
 
Fresenius Kabi Austria GmbH  
Drug supply:  
 
 
Fresenius Kabi Austria GmbH 
Storage Instructions:  
 
Do not freeze, do not store > 25° Celsius, protect from light 
Route of administration:  
Intravenous 
 

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8.1.1 
Dosage and administration 
 
Initial dose:  
 
  
1 g/kg/d (= 5 ml/kg/d) 
Maintenance dose:  
 
3 g/kg/d (=15 ml/kg/d) 
Route of administration:  
Intravenous 
Duration: 
 
 
As long as parenteral nutrition is needed 
 
8.1.2 
Study-drug up- and down titration 
 
According to a stepwise increase or reduction of enteral feedings a proportional increase or 
reduction of parenteral nutrition will performed including a reduction of the study drug / 
comparator. The study drug/comparator will be finished as soon as full enteral feeds are reached and 
PN is stopped (at 140-160 ml/kg/d of total fluid volume depending on the fluid needs of the infant).  
8.1.3 
Study drug interruption or discontinuation 
 
The investigator must temporarily interrupt or permanently discontinue the study drug if continued 
administration of the study drug is believed to be contrary to the best interests of the patient. 
The interruption or premature discontinuation of study drug might be triggered by an AE, a 
diagnostic or therapeutic procedure, an abnormal assessment (e.g., laboratory abnormalities), or for 
administrative reasons, in particular withdrawal of the patient’s consent. 
 
Hypertriglceridemia: The study drug will be interrupted for 24 hours at triglyeride levels > 400 mg/dl 
or down titrated at triglyceride levels of 251-400 mg/dl. Control measurements of triglycride levels 
will be performed in the next 24-72 hours to control for successful normalization of triglyceride levels 
under parenteral nutrition. 
 
The reason for study drug interruption or premature permanent discontinuation must be 
documented in the CRF. 
 
8.1.4 
Study drug premature permanent discontinuation 
 
Study drug premature permanent discontinuation due to an adverse event 
If the reason for premature permanent discontinuation of study treatment is an AE, the patient 
should have a “Premature End of Study (EOS)” visit with all the assessments performed before the 
study drug discontinuation, whenever possible.  
 
Study drug premature permanent discontinuation due to another reason than adverse event 
If the reason for premature permanent discontinuation of study treatment is not an AE, the patient 
should be withdrawn from the study (withdrawal of consent) and have the end of study (EOS) visit 
with all the assessments performed before the study drug discontinuation, whenever possible. 
 

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8.1.5 
Study-drug delivery & drug storage conditions 
 
The study drug will be delivered from the supplying company to the investigators and stored at room 
temperature under controlled conditions (22°C +/- 3°C) in a locked room. A min/max thermometer 
will be used to control for temperature in the storage room. Full documentation of delivery, storage 
and disposition will be maintained. 
 
8.1.6 
Study drug packaging and labeling 
 
The study drugs are delivered in sterile glass contaniners of 100 ml by the manufacturer and will be 
re-labelled at the study site as described in section 8.3. Storage is described in section 8.1.5.  
For application to study subjects, the study drugs will be brought to the neonatal wards by a member 
of the bliniding team.  For IV application, the study drugs will be transferred from the re-labelled 
commercial containers to perfusor syringes connected to perfuors lines suitable for IV application. 
Perfusor syringes will be labelled (see sample labels 1 and 2 below). Preparation for IV application 
will be done in a laminar air hood under sterile conditions by trained intensive care nurses, forming 
part of the blinding team.  
 
 
Sample Label Number 1 
 
 
 
Sample Label Number 2 
 
 
 
 
8.1.7 
IMP administration & handling 
 
The IMP or comparator must not be frozen or stored > 25° C, application is performed in light 
protected perfusor syringes and perfusor lines. Application may be performed IV via central and 
peripheral venous catheters. The IMP or comparator must not be mixed with any other drug besides 
the commercially available vitamin solutions “Soluvit N” and “Vitalipid” (Fresenius Kabi Austria 
GmbH).  
 
8.1.8 
Drug Accountability 
 
Drug Accountability will be recorded at on-going basis on paper form/source data, Drug dispensing 
have to be entered into the CRF. Furthermore the correct intake of IMP or any variations concerning 
that will be recorded in the CRF at each visit during treatment period 
 
8.1.9 
Procedures to assess subjects compliance 
 

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Whether the IMP or comparator where administered correctly will be followed from the 
documentation in the electronic patient documentary system used at the neonatal ICU.  
8.1.10 Concomitant medication 
 
The well-being of the patient has the first priority, and modifications of concomitant treatment 
during the trial are allowed as necessary. They should be documented in the patient’s records. 
In case of of cholestasis (i.e. conjugated bilirubin two times > 1.5 mg/dl), 
Ursodeoxycolic acid at 20-30 mg/kg/day is the treatment of choice. 
 
 
 
Omegaven® is allowed as as add on at 1g/kg/d, if conj. bilirubin > 6 mg/dl,  
 
8.2 Randomization and stratification  
 
On day 0, patients are randomized to one of the two study groups and the study medication is 
provided. Study subjects will be block randomized (ratio 1:1) and stratified according to sex and birth 
weight (in two groups: < 750 gram vs. ≥ 750 gram) using an online randomization programme 
provided by the Center for Medical Statistics, Informatics, and Intelligent Systems of the Medical 
University of Vienna. In case of twins, randomization will be applied to the firstborn; the twin will be 
assigned to the other treatment group. 
8.3 Blinding 
 
Blinding of subjects, investigators and outcome assessors will be performed as follows:  
First re-labelling of the study drug containers (see sample label 1 and 2 below)  will be performed by 
two members of the blinding team not involved in the collection of data, treatment of study subjects 
or preparation of the study drugs for IV application. The study drugs are kept in glass containers of 
100 ml and will be re-labelled with samples as indicated (see sample label 1 and 2 below) and stored 
as described (section 8.1.5).  
Second, for delivery to study subjects the study drugs will be brought to the wards by a member of 
the blinding team, where the preparation for IV application will be done in a laminar air hood by a 
member of the blinding team as described in section 8.1.7. As intensive care nurses involved in 
caretaking of the patients form part of the bliding team, nursing caregivers are not blinded. Medical 
doctors prescribing the daily amounts of the IMP remain blinded. 
 
Sample Label Number 1  
 
   Sample Label Number 2: 
 
 

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8.3.1 
Emergency procedure for unblinding 
 
If unblinding of a study participant is required due to an emergency, the code can be broken by the 
Investigator. Code breaking will be fully documented. 
 
8.3.2 
Unblinding at the end of the study. 
 
Codes will be broken after data analysis of the primary outcome, this is after the last patient has finished active 
phase. Investigators involved in asessment of data in the follow up phase (secondary outcome 
neurodevelopment)  will remain blinded.  
Codes will be broken after the close-out Monitoring Visit and the cleaning of the database. 
 
8.4 Benefit and risk assessment 
 
8.4.1 Benefit for the patient 
If the hypothesis is correct, participating patients receiving the study medication will benefit from a 
reduced risk of developing liver injury due to long term parenteral nutrition. They will benefit from a 
improved long term neurodevelopment. 
 
8.4.2 Risk for the patient 
The drug under investigation fulfilled the criteria for registration for application in preterm infants. 
Therefore, risk for patients receiving the study drug should not be higher compared to standard care. 
In the worst case we expect that there will be no benefit. 
 
8.5 Study procedures 
8.5.1 
General rules for trial procedures 
 
• 
All study measures like blood sampling and measurements (ultrasound etc.) have to be 
documented with date (dd:mmm:yyyy).  
• 
In case several study procedures are scheduled at the same time point, there is no specific 
sequence that should be followed. 
• 
The dates of all procedures should be according to the protocol. The time margins mentioned 
in the study flow chart are admissible. If for any reason, a study procedure is not performed 
within scheduled margins a protocol deviation should be noted, and the procedure should be 
performed as soon as possible or as adequate. 
• 
If it is necessary for organizational reasons, it is admissible to perform procedures which are 
scheduled for one visit at two different time points. Allowed time margins should thereby 
not be exceeded. 

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8.5.2 
Screening investigation 
At screening, the patient´s demographic data and lab results (see Section 7.1.2 and 7.1.3 Inclusion 
and Exclusion Criteria) will be evaluated for eligibility to the study. 
8.5.3 
End-of-study (EOS) examination 
At discharge of the patient from hospital, patients undergo the end-of-study examination that entails 
Weight, crown heel length, head circumference and a basic blood test (red and white blood count, 
liver function tests, electrolytes) performed in clinical routine in all ELBW infants. 
8.5.4 
Laboratory Tests 
 
Blood counts and complete blood chemistry is routinely perperformed according to the local 
standard of care at the unit at least every 10 +/-4 days until discharge from hospital.  No additional 
blood sampling or analyses will be performed in study subjects in comparison to standard of care of 
ELBW infants. 
 
All laboratory parameters of interest for the study routinely performed are: 
denomination  
 
 
 
Variable 
 
time of measurement 
Conjugated bilirubin  
 
 
 
mg/dL  
 
every 7-14d until discharge 
ALAT   
 
 
 
 
U/L 
 
 
every 7-14d until discharge 
ASAT   
 
 
 
 
U/L 
 
 
every 7-14d until discharge 
γ-glutamyltransferase   
 
 
U/L 
 
 
every 7-14d until discharge 
Alkaline phosphatase   
 
 
U/L 
 
 
every 7-14d until discharge 
Triglycerides  
 
 
 
 
mg/dL  
 
every 7-14d until discharge 
 
Additional parameters used for the study 
All additional parameters of interest are documented or produced routinely during the patient’s 
admission to the unit or follow-up according to the local standard of care. No additional 
interventions will need to be performed.  
 
denomination  
 
 
 
Variable 
 
time of measurement 
Basic demographic data 
Sex  
 
 
 
 
 
m/f 
 
 
at birth 
Gestational age  
 
 
 
days 
 
 
at birth 
Twin 
 
 
 
 
 
yes/no  
 
at birth 
Mode of delivery  
 
 
 
caesarean/spontaneous at birth 

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Prenatal steroids for lung maturation   
yes/no  
 
at birth 
Birth weight  
 
 
 
 
gram, Z Score  
at birth 
Birth crown heel length  
 
 
cm, Z Score 
 
at birth 
Birth head circumference 
 
 
cm, Z Score 
 
at birth 
Small for gestational age 
 
 
yes/no  
 
at birth 
Apgar scores at 1, 5 and 10 minutes  
 
0-10 
 
 
at birth 
Umbilical artery pH at birth 
 
 
range 6.7 – 7.6  
at birth 
 
Growth and nutrition parameters 
Time on parenteral nutrition  
 
 
days 
 
 
at discharge 
Total amount of parenteral lipids  
 
gram 
 
 
at discharge 
Enteral nutrition in 1st first week of life  
ml/day  
 
day 0-6 
Weight at discharge  
 
 
 
gram, Z Score  
at discharge from hospital 
Crown heel length at discharge  
 
gram, Z Score  
at discharge from hospital 
Head circumference at discharge  
 
gram, Z Score  
at discharge from hospi 
 
Death > 28 days 
 
 
 
yes/no  
 
day of life 28 - discharge 
(Death before 28 days = drop out) 
If death 
 
 
 
 
day of life 
 
day of life 28 - discharge 
 
Neonatal (preterm) morbidities 
Intraventricular hemorrhage Grad 3/4   
yes/no  
 
at discharge 
Cystic periventricular leucomalacia  
 
yes/no   
 
at discharge 
Chronic lung disease  
 
 
 
yes/no   
 
at discharge 
Received steroids for chronic lung disease  
yes/no   
 
at discharge 
Treatment for pulomanry hypertension  
yes/no  
 
at discharge 
(Sildenafil, iNO) 
Culture proven sepsis   
 
 
yes/no   
 
at discharge 
Necrotizing enterocolitis Bell´s Stage ≥ IIa 
yes/no   
 
at discharge 
Focal intestinal peforation  
 
 
yes/no   
 
at discharge 
Abdominal surgery 
 
 
 
yes/no  
 
at discharge 
Ibuprofen for PDA  
 
 
 
yes/no   
 
at discharge 
Surgical ligation of PDA  
 
 
yes/no  
 
at discharge  
Highest ROP Grade  
 
 
 
0-5 
 
 
at discharge 
ROP treated with laser  
 
 
yes/no  
 
at discharge 

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ROP treated with anti VEGF 
 
 
yes/no  
 
at discharge 
 
Other parameters 
Length of hospital stay  
 
 
days 
 
 
at discharge 
Age at discharge  
 
 
 
days 
 
 
at discharge 
 
Other investigations 
Cerebral function monitoring 
 
 
% continouos pattern weekly 
Visual evoked potentials 
 
 
N2 latency in ms 
at 347-3740 wks gestational 
age 
 
Assessment of neurodevelopmental outcome 
Bailey Scales of Infant Development II   
metric (points)  
at 12 and 24 months of 
Gross motor development  
 
 
0-5 points 
 
corrected gestational age. 
 
Opthalmologic exams at follow up 
Visual fixation  
 
 
 
yes/no  
 
at 12 and 24 months of 
Tracking movements   
 
 
yes/no   
 
corrected gestational age. 
Strabism 
 
 
 
 
yes/no  
 
 
Refraction measured by skiascopy 
 
metric (dioptres) 
 
Binocular visualization (Lang Stereo test) 
pos/neg 
 
at 24 months of  
 
 
 
 
 
 
 
 
 
corrected gestational age 
9. SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
9.1 Adverse events (AEs) 
9.1.1 
Summary of known and potential risks of the study drug 
 
Undesirable effects observed during the administration of fat emulsions: 
 
Common  
(≥1/100 to <1/10) 
Uncommon 
(≥1/1000 to 
<1/100) 
Rare 
(≥1/10000 to 
<1/1000) 
Very rare 
(<1/10000) 
Respiratory, 
thoriacic and 
mediastinal 
disorders 
 
 
Dyspnoea 
 

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Gastrointestinal 
disorders 
 
Lack of appetite, 
nausea, vomiting 
 
 
Vascular disorders  
 
Hypotension, 
hypertension 
 
General disorders 
and administration 
site conditions 
Slight increase in 
body temperature 
Chills 
Hypersensitivity-
reactions (e.g. 
anaphylactic or 
anaphylactoid 
reactions, skin 
rash, urticaria, 
flush, headache), 
heat or cold 
sensation, 
paleness, cyanosis, 
pain in the neck, 
back, bones, chest 
and loins 
 
Reproductive 
system  disorders 
 
 
 
Priapism 
 
9.1.2 
Definition of adverse events 
 
An AE is any untoward adverse change from the subject's baseline condition, i.e., any unfavorable 
and unintended sign including an abnormal laboratory finding, symptom or disease which is 
considered to be clinically relevant by the physician that occurs during the course of the study, 
whether or not considered related to the study drug. 
Adverse events include: 
• 
Exacerbation of a pre-existing disease. 
• 
Increase in frequency or intensity of a pre-existing episodic disease or medical condition. 
• 
Disease or medical condition detected or diagnosed after study drug administration even 
though it may have been present prior to the start of the study. 
• 
Continuous persistent disease or symptoms present at baseline that worsen following the 
start of the study. 
• 
Lack of efficacy in the acute treatment of a life-threatening disease. 
• 
Events considered by the investigator to be related to study-mandated procedures. 
• 
Abnormal assessments, e.g., ECG and physical examination findings, must be reported as AEs 
if they represent a clinically significant finding that was not present at baseline or worsened 
during the course of the study. 
• 
Laboratory test abnormalities must be reported as AEs if they represent a clinically significant 
finding, symptomatic or not, which was not present at baseline or worsened during the 
course of the study or led to dose reduction, interruption or permanent discontinuation of 
study drug. 
Adverse events do not include:  

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• 
Pre-planned interventions or occurrence of endpoints specified in the study protocol are not 
considered AE´s, if not defined otherwise (eg.as a result of overdose) 
• 
Medical or surgical procedure, e.g., surgery, endoscopy, tooth extraction, transfusion. 
However, the event leading to the procedure is an AE. If this event is serious, the procedure 
must be described in the SAE narrative. 
• 
Pre-existing disease or medical condition that does not worsen. 
• 
Situations in which an adverse change did not occur, e.g., hospitalizations for cosmetic 
elective surgery or for social and/or convenience reasons. 
• 
Overdose of either study drug or concomitant medication without any signs or symptoms. 
However, overdose must be mentioned in the Study Drug Log. 
 
9.2 Serious Adverse Events (SAEs) 
 
A Serious Adverse Event (SAE) is defined by the International Conference on Harmonization (ICH) 
guidelines and WHO GCP guidelines as any AE fulfilling at least one of the following criteria: 
• 
Results in deaths. 
• 
Life-threatening – defined as an event in which the subject was, in the judgment of the 
investigator, at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death had it been more severe. 
• 
Requiring subject's hospitalization or prolongation of existing hospitalization – inpatient 
hospitalization refers to any inpatient admission, regardless of length of stay. 
• 
Resulting in persistent or significant disability or incapacity (i.e., a substantial disruption of a 
person’s ability to conduct normal life functions). 
• 
Congenital anomaly or birth defect. 
• 
Is medically significant or requires intervention to prevent at least one of the outcomes listed 
above. 
Life-threatening refers to an event in which the subject was at risk of death at the time of the event. 
It does not refer to an event that hypothetically might have caused death if it were more severe. 
Important medical events that may not immediately result in death, be life-threatening, or require 
hospitalization may be considered as SAEs when, based upon appropriate medical judgment, they 
may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in the definitions above. 
 
9.2.1 
Hospitalization – Prolongation of existing hospitalization 
 
Hospitalization is defined as an overnight stay in a hospital unit and/or emergency room. 
An additional overnight stay defines a prolongation of existing hospitalization. 
Hospitalization as criterium for SAE classification severy limited in this study.In this study, patients 
are hospitalized from study start until end of treatment. Hospitalization – prolongation of existing 
hospitalization should be applied as criterium for SAE classification only in case of AEs directly leading 
to a prolongation of hospitalization.  
The criterium should not be applied AEs occurring during the routine hospitalization.  
The following is not considered an SAE and should be reported as an AE only: 

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• 
Treatment on an emergency or outsubject basis for an event not fulfilling the definition of 
seriousness given above and not resulting in hospitalization. 
The following reasons for hospitalizations are not considered AEs, and therefore not SAEs: 
• 
Hospitalizations for cosmetic elective surgery, social and/or convenience reasons. 
• 
Standard monitoring of a pre-existing disease or medical condition that did not worsen, e.g., 
hospitalization for coronary angiography in a subject with stable angina pectoris. 
• 
Elective treatment of a pre-existing disease or medical condition that did not worsen, e.g., 
hospitalization for chemotherapy for cancer, elective hip replacement for arthritis. 
 
9.2.2 
SAEs related to study-mandated procedures 
 
Such SAEs are defined as SAEs that appear to have a reasonable possibility of causal relationship (i.e., 
a relationship cannot be ruled out) to study-mandated procedures (excluding administration of study 
drug) such as discontinuation of subject's previous treatment during a washout period, or 
complication of a mandated invasive procedure (e.g., blood sampling, heart catheterization), or car 
accident on the way to the hospital for a study visit, etc. 
 
9.2.3 
Suspected unexpected serious adverse reactions (SUSARs) 
 
SUSARs are all serious adverse reactions with suspect causal relationship to the study drug that is 
unexpected (not previously described in the SmPC - Summary of Product Characteristics or 
Investigator’s brochure) and serious.  
 
9.3 Severity of adverse events 
 
The severity of clinical AEs is graded on a three-point scale: mild, moderate, severe, and reported on 
specific AE pages of the CRF. 
If the severity of an AE worsens during study drug administration, only the worst intensity should be 
reported on the AE page. If the AE lessens in intensity, no change in the severity is required.  
If an AE occurs during a washout or placebo run-in phase and afterwards worsens during the 
treatment phase, a new AE page must be filled in with the intensity observed during study drug 
administration.  
 
Mild 
Event may be noticeable to subject; does not influence daily activities; the AE resolves spontaneously 
or may require minimal therapeutic intervention;  
 
Moderate 
Event may make subject uncomfortable; performance of daily activities may be influenced; 
intervention may be needed; the AE produces no sequelae. 
 
Severe 

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Event may cause noticeable discomfort; usually interferes with daily activities; subject may not be 
able to continue in the study; the AE produces sequelae, which require prolonged therapeutic 
intervention. 
A mild, moderate or severe AE may or may not be serious. These terms are used to describe the 
intensity of a specific event (as in mild, moderate, or severe myocardial infarction). However, a 
severe event may be of relatively minor medical significance (such as severe headache) and is not 
necessarily serious. For example, nausea lasting several hours may be rated as severe, but may not 
be clinically serious. Fever of 39°C that is not considered severe may become serious if it prolongs 
hospital discharge by a day. Seriousness rather than severity serves as a guide for defining regulatory 
reporting obligations. 
 
9.4 Relationship to study drug 
 
For all AEs, the investigator will assess the causal relationship between the study drug and the AE 
using his/her clinical expertise and judgment according to the following algorithm that best fits the 
circumstances of the AE: 
Unrelated 
• 
May or may not follow a reasonable temporal sequence from administration of the study 
product 
• 
Is biologically implausible and does not follow known response pattern to the suspect study 
drug (if response pattern is previously known). 
• 
Can be explained by the known characteristics of the subject’s clinical state or other modes 
of therapy administered to the subject. 
• 
Unlikely 
• 
May or may not follow a reasonable temporal sequence from administration of the study 
product 
• 
Is biologically not very plausible  
• 
May be explained by the known characteristics of the subject’s clinical state or other modes 
of therapy administered to the subject. 
 
Possible related 
• 
Follows a reasonable temporal sequence form administration of the study drug. 
• 
May follow a known response pattern to the study drug (if response pattern is previously 
known). 
• 
Could not be reasonably explained by the known characteristics of the subject’s clinical state 
or other modes of therapy administered to the subject, if applicable. 
• 
Probable 
• 
Follows a reasonable temporal sequence form administration of the study drug. 
• 
Follows a known response pattern to the study drug (if response pattern is previously 
known). 
• 
other causes for the event are unlikely 
 
Definitely related 
• 
Follows a reasonable temporal sequence form administration of the study drug. 

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• 
Follows a known response pattern to the study drug (if response pattern is previously 
known). 
• 
No other reasonable cause is present. 
 
9.5 Reporting procedures 
 
A special section is designated to adverse events in the case report form. The following details must 
thereby be entered: 
• 
Type of adverse event 
• 
Start (date and time) 
• 
End (date and time) 
• 
Severity (mild, moderate, severe) 
• 
Serious (no / yes) 
• 
Unexpected (no / yes)  
• 
Outcome (resolved, ongoing, ongoing – improved, ongoing – worsening) 
• 
Relation to study drug (unrelated, possibly related, definitely related) 
Adverse events are to be documented in the case report form in accordance with the above 
mentioned criteria. 
 
9.5.1 
Reporting procedures for SAEs  
 
In the event of serious, the investigator has to use all supportive measures for best patient 
treatment.   A written report is also to be prepared and made available to the clinical investigator 
immediately. The following details should at least be available: 
• 
Patient initials and number 
• 
Patient: date of birth, sex, ethical origin 
• 
The suspected investigational medical product (IMP) 
• 
The adverse event assessed as serious 
• 
Short description of the event and outcome 
If applicable, the initial report should be followed by the Follow up report, indicating the outcome of 
the SAE. 
 
9.5.2 
Reporting procedures for SUSARs 
 
It must be remembered that the regulatory authorities, and in case of SUSARs which could possibly 
concern the safety of the study participants, also the Institutional Review Board / Independent Ethics 
Committee (IRB / IEC) are to be informed. Such reports shall be made by the study management and 
the following details should be at least available: 
• 
Patient initials and number 
• 
Patient: date of birth, sex, ethical origin 
• 
Name of investigator and investigating site 
• 
Period of administration 

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• 
The suspected investigational medical product (IMP) 
• 
The adverse event assessed as serious and unexpected, and for which there is a reasonable 
suspected causal relationship to the IMP 
• 
Concomitant disease and medication 
• 
Short description of the event: 
• 
Description 
• 
Onset and if applicable, end 
• 
Therapeutic intervention 
• 
Causal relationship 
• 
Hospitalization of prolongation of hospitalization 
• 
Death, life-threatening, persistent or significant disability or incapacity 
Electronic reporting should be the expected method for reporting of SUSARs to the competent 
authority. In that case, the format and content as defined by Guidance (28) should be adhered to. 
The latest version of MedDRA should be applied. Lower level terms (LLT) should be used. 
 
9.5.3 
Annual Safety Report 
 
The Annual Safety Report will be provided by the principal investigator at least once a year. 
This report will also be presented annually to the Independent Ethics (IEC) and to the competent 
authorities by the sponsor. 
 
 
10. FOLLOW-UP 
 
10.1 
Follow-up of study participants including follow-up of adverse vents 
 
All study participants will be followed up to 24 months of corrected gestational age to assess 
neurodevelopment, growth parameters and ophthalmologic exams (visual development (according 
to the standards of our follow – up outpatient clinic for extremely premature infants. SAEs including 
death will be monitored. Adverse events will be followed until they have been completely resolved or 
stabalized according to the investigators discretion. 
 
10.2 
Treatment after end of study 
 
There is no treatment after the end of the study  
 
11. STATISTICAL METHODOLOGY AND ANALYSIS 
 

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11.1 
Analysis sets  
 
Two different analysis sets are defined: 
 
(Modified) Intention to treat set 
This analysis set includes all subjects where the outcome can be calculated (more than two blood 
samples taken), even though the subject was not observed the full 18 weeks.  
 
Per-protocol set 
This analysis set comprises all subjects who were observed the full 18 weeks, received the study drug 
as planned and did not violate the protocol in a way that might affect the evaluation of the effect of 
the study drug on the primary objective, i.e., without major protocol violations.  
11.2 
Sample size considerations 
 
Data investigating the incidence of PNAC in our unit showed an incidence of 25 % from 2007-9 
(unpublished data). We considered a difference of 15% between the groups (incidence of PNAC: 25% 
for Intralipid and 10% for SMOFlipid, respectively) as a clinically relevant effect. A sample size 
estimation based on a χ2-test indicated that 200 infants (100/group) are required to detect a 
difference of 15% between the groups with a power of 80% and a significance level of 0.05. The 
estimated drop out rate is 22%. Therefore, a sample size of 122 patients per group is planned. For 
sample size estimation, data were assumed to be independent. 
 
11.3 
Relevant protocol deviations 
Protocol deviations will have to be documented and should be discussed with the Sponsor.  
 
 
All protocol deviations will be listed in the study report and reported to the sponsor.  
11.4 
Statistical analysis plan 
 
A statistical analysis plan (SAP) will provide full details of the analyses, the data displays and the 
algorithms to be used for data derivations. The SAP furthermore will include definitions of major and 
minor protocol deviations and the link of deviations to the analysis set, which also will be covered in 
the final study report.  
Procedures of reporting any deviations from the original statistical plan (any deviations from the 
original statistical plan should be described and justified in the protocol and/or in the final report, as 
appropriate. 
 
The SAP should preferably be a separate document. In the protocol this document should be 
referenced. Alternatively the SAP could be fully included in the study protocol.  
 

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11.5 
Missing, unused and spurious data 
If less than two blood samples of a patient were taken, the outcome cannot be calculated and 
therefore, this patient will be excluded from the analysis. The analysis will be carried out per 
protocol.  
If the outcome of a patient can be calculated (more than two blood samples taken) but the patient 
was withdrawn from the study before week 18, analysis will be carried out 1) by intention to treat 
analysis, with the duration of treatment as additional covariable and 2) per protocol. 
 
 
11.6 
Endpoints analysis 
11.6.1 Primary endpoint analysis 
A χ2-test will be used for analysis of the primary outcome PNAC.  
Additionally, the effect of treatment and other relevant influence factors (i. e. duration of parenteral 
nutrition, birth weight, amount of enteral feeds in the first week of life) on the primary endpoint will 
be analyzed using a logistic regression model with stepwise selection  
In case of twins, the analysis will be carried out 1) as mentioned above, but only including the 
firstborn and 2) by calculating a generalized linear model with mother as random factor.  
11.6.2 Secondary endpoint analysis 
Bailey Scales of Infant Development II at 12 and 24 months: Differences in the scores of psychomotor 
development and neurocognitive development, respectively, between the groups will be analyzed by 
repeated measures ANOVA, also accounting for confounders (e.g. birth weight, IVH Grade 3/4, cystic 
periventricular leucomalacia, NEC). In case of twins, the analysis will be carried out 1) as mention 
above, but only including the firstborn and 2) by calculating a mixed model with mother and child as 
random factor. In case of too many drop outs, descriptive statistics will be carried out. 
For Gross Motor function measurements at 12 and 24 months, descriptive statistics will be 
conducted. 
11.6.3 Safety and tolerability endpoints 
Hypertriglyceridemia: Peak level in mg/dl  
11.6.4 Baseline parameters and concomitant medications 
 
The following parameters will be investigated: 
Sex (m/f) 
Age at birth (gestational weeks + days) 
Twin (yes/no) 
Mode of delivery (caesarean section/spontaneous delivery) 
Received any prenatal steroids for lung maturation (yes/no). 
Weight (gram) at birth 
Length (cm) at birth 
Head circumference (cm) at birth 
Small for gestational age (< 10. percentile birth weight, yes/no) 
Apgar scores at 1, 5 and 10 minutes (0-10) 
Umbilical artery pH 
 

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Comcomitant medications and changes in concomitant medication will be documented by the 
Investigator. 
11.7 
Interim analysis 
No interim analysis planned. 
 
11.8 
Software program(s) 
SAS 9.2 
Microsoft Excel 
12. DOCUMENTATION AND DATA MANAGEMENT 
 
12.1 
Documentation of study results 
 
A subject screening and enrollment Log will be completed for all eligible or non-eligible subjects with 
the reasons for exclusion. 
 
12.1.1 Case report form (CRF) 
 
For each subject enrolled, regardless of study drug initiation, a paper CRF must be completed and 
signed by the investigator or a designated sub-investigator. This also applies to those subjects who 
fail to complete the study. If a subject withdraws from the study, the reason must be noted on the 
CRF. Case report forms are to be completed on an ongoing basis. 
CRF entries and corrections will only be performed by study site staff, authorized by the investigator.  
In a “Paper-CRF” all forms should be completed and must be legible.  Errors should be crossed out 
but not obliterated, the correction inserted, and the change initialed and dated by the investigator, 
co-investigator or study nurse. 
The entries will be checked by trained personnel (Monitor) and any errors or inconsistencies will be 
checked immediately.  
The monitor will collect original completed and signed CRFs at the end of the study. A copy of the 
completed and signed CRFs will remain on site. 
Completed CRFs will be passed to the Statistician for further analysis. 
 
 
12.1.2 Data Collection 
 
Data collected at all visits are entered into an interactive form. The CRFs will be source documents 
verified following guidelines established before study onset as detailed in the Monitoring Plan.  
 
 
 

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12.2 
Safekeeping 
 
The investigator will maintain adequate and accurate records to enable the conduct of the study to 
be fully documented and the study data to be subsequently verified (according to ICH-GCP “essential 
documents”). These documents will be classified into two different categories: investigator's file, and 
subject clinical source documents. 
The investigator's file will contain the protocol/amendments, EudraCT forms, CRFs (eCRF printout), 
standard operation procedures (SOPs), data clarification and query forms, EC/IRB and Health 
Authority approval with correspondence, informed consent, drug records, staff curriculum vitae and 
authorization forms, screening and enrollment logs, and other appropriate 
documents/correspondence as per ICH/Good Clinical Practice (GCP) and local regulations. 
Subject clinical source documents include, but are not limited to subject hospital/clinic records, 
physician’s and nurse’s notes, appointment book, original laboratory reports, ECG, X-ray, pathology 
and special assessment reports, consultant letters, etc. 
 
These two categories of documents must be kept on file by the investigator for as long as needed to 
comply with national and international regulations (in Austria 15 years after discontinuing clinical 
development or after the last marketing approval). If source documents are not durable as long as 
needed (e.g. ECG printouts) they must be preserved as a copy. No study document should be 
destroyed without prior written approval from the Department of …… 
When source documents are required for the continued care of the subject, appropriate copies 
should be made for storing outside of the site. 
 
 
12.3 
Quality Control and Quality Assurance 
 
12.3.1 Periodic Monitoring 
 
According to GCP at least 3 monitoring visits are scheduled. An initiation visit, one routine visit and a 
close out visit after the last patient has finished the study or data base lock.  
 
The designated monitor will contact and visit the investigator regularly and will be allowed to have 
access to all source documents needed to verify the entries in the CRFs and other protocol-related 
documents provided that subject confidentiality is maintained in agreement with local regulations. It 
will be the monitor's responsibility to inspect the CRFs at regular intervals according to the 
monitoring plan throughout the study, to verify the adherence to the protocol and the completeness, 
consistency and accuracy of the data being entered on them. The monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs and the recording of the main efficacy, safety, and tolerability endpoints. 
The monitor will be working according to SOPs and will provide a monitoring report after each visit 
for the Sponsor. Depending on the quality of the data, additional monitoring visits may be necessary 
according to the sponsor’s discretion. The investigator will resolve discrepancies of data. 
 

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Monitoring will be performed by Koordinierungszentrum für Klinische Studien on a regular basis and 
will follow a detailed Monitoring Plan. 
 
12.3.2 Audit and Inspections 
 
Upon request, the investigator will make all study-related source data and records available to a 
qualified quality assurance auditor mandated by the sponsor or to competent authority inspectors. 
The main purposes of an audit or inspection are to confirm that the rights and welfare of the subjects 
have been adequately protected, and that all data relevant for assessment of safety and efficacy of 
the investigational product have appropriately been reported to the sponsor. 
 
12.4 
Reporting and Publication  
 
12.4.1 Publication of study results  
 
The findings of this study will be published by the sponsor (investigators) in a scientific journal and 
presented at scientific meetings. The manuscript will be circulated to all co-investigators before 
submission. Confidentiality of subjects in reports/publications will be guaranteed.  
13. ETHICAL AND LEGAL ASPECTS 
13.1 
Informed consent of subjects 
 
Following comprehensive instruction regarding the nature, significance, impact and risks of this 
clinical trial, a patient´s caregiver (mother or father) must give written consent to participation in the 
study. 
During the instruction the trial participants are to be made aware of the fact that they can withdraw 
their consent – without giving reasons – at any time without their further medical care being 
influenced in any way. 
In addition to the comprehensive instructions given to the trial participants by the investigator, the 
trial participants also receive a written patient information sheet in comprehensible language, 
explaining the nature and purpose of the study and its progress. 
The patients must agree to the possibility of study-related data being passed on to relevant 
authorities. 
The patients must be informed in detail of their obligations in relation to the trial participants 
insurance in order not to jeopardize insurance cover. 
 
13.2 
Acknowledgement / approval of the study 
 
The investigator (or a designated CRO) will submit this protocol and any related document provided 
to the subject (such as subject information used to obtain informed consent) to an Ethics Committee 

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(EC) or Institutional Review Board (IRB). Approval from the committee must be obtained before 
starting the study.  
The clinical trial shall be performed in full compliance with the legal regulations according to the Drug 
Law (AMG - Arzneimittelgesetz) of the Republic of Austria. 
An application must also be submitted to the Austrian Competent Authorities (Bundesamt für 
Sicherheit im Gesundheitswesen (BASG) represented by the Agency for Health and Food Safety 
(AGES PharmMed) and registered to the European Clinical Trial Database (EudraCT) using the 
required forms. The timelines for (silent) approval set by national law must be followed before 
starting the study. 
 
13.2.1 Changes in the Conduct of the Study 
 
 
 
Protocol amendments 
Proposed amendments must be submitted to the appropriate CA and ECs. Substantial amendments 
may be implemented only after CA/EC approval has been obtained. Amendments that are intended 
to eliminate an apparent immediate hazard to subjects may be implemented prior to receiving CA/EC 
approval. However, in this case, approval must be obtained as soon as possible after implementation. 
 
Study Termination 
If the sponsor or the investigator decides to terminate the study before it is completed, they will 
notify each other in writing stating the reasons of early termination. In terminating the study, the 
sponsor and the investigator will ensure the adequate consideration is given to the protection of the 
subject interests. The investigator, sponsor or (designated CRO on behalf of the sponsor) will notify 
the relevant CA and EC. Documentation will be filed in the Trial Master and Investigator Files.     
   
Clinical Study Report (CSR) 
Within one year after the final completion of the study, a full CSR will be prepared by the sponsor 
and submitted to the EC and the competent authority. 
The Investigator will be asked to review and sign the final study report. 
 
13.3 
Insurance 
 
During their participation in the clinical trial the patients will be insured as defined by legal 
requirements.  The investigator of the clinical trial will receive a copy of the insurance conditions of 
the 'patients insurance'. The sponsor is providing insurance in order to indemnify (legal and financial 
coverage) the investigator/center against claims arising from the study, except for claims that arise 
from malpractice and/or negligence. The compensation of the subject in the event of study-related 
injuries will comply with the applicable regulations. 
Details on the existing patients insurance are given in the patient information sheet. 
 
Patients will be insured by the Zürich-Versicherung (Nr. 07229622-2) according tot he Austrian law. 
Please indicate insurance details! 
 

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13.4 
Confidentiality  
 
The information contained in this document, especially unpublished data, is the property of the 
sponsor. It is therefore provided to you in confidence as an investigator, potential investigator, or 
consultant, for review by you, your staff, and an Ethics Committee or Institutional Review Board. It is 
understood that this information will not be disclosed to others without written authorization from 
the sponsor. 
 
13.5 
Ethics and Good Clinical Practice (GCP) 
 
The investigator will ensure that this study is conducted in full conformance with the principles of the 
"Declaration of Helsinki" (as amended at the 56th WMA General Assembly, Tokyo, Japan, 2008) and 
with the laws and regulations of the country in which the clinical research is conducted. 
The investigator of the clinical trial shall guarantee that only appropriately trained personnel will be 
involved in the study. All studies must follow the ICH GCP Guidelines (June 1996) and, if applicable, 
the Code of Federal Regulations (USA). In other countries in which GCP Guidelines exist, the 
investigators will strictly ensure adherence to the stated provisions. 
Therefore this study follows the EU Directive embedded in the Austrian drug act. 
 
14. APPENDICES 
 
Appendix 1. Informed Consent Form (Version 1.0; Date 8.11.11) 
Appendix 2. Summary of product characteristics 
15. REFERENCES 
 
1. 
Peden, V.H., Witzleben, C.L. & Skelton, M.A. Total parenteral nutrition. The Journal of 
pediatrics 78, 180-181 (1971). 
2. 
Lloyd, D.A. & Gabe, S.M. Managing liver dysfunction in parenteral nutrition. The Proceedings 
of the Nutrition Society 66, 530-538 (2007). 
3. 
Sondheimer, J.M., Asturias, E. & Cadnapaphornchai, M. Infection and cholestasis in neonates 
with intestinal resection and long-term parenteral nutrition. Journal of pediatric 
gastroenterology and nutrition 27, 131-137 (1998). 
4. 
Commare, C.E. & Tappenden, K.A. Development of the infant intestine: implications for 
nutrition support. Nutr Clin Pract 22, 159-173 (2007). 
5. 
Messing, B., Colombel, J.F., Heresbach, D., Chazouilleres, O. & Galian, A. Chronic cholestasis 
and macronutrient excess in patients treated with prolonged parenteral nutrition. Nutrition 
(Burbank, Los Angeles County, Calif 8, 30-36 (1992). 
6. 
Colomb, V., et al. Role of lipid emulsions in cholestasis associated with long-term parenteral 
nutrition in children. Jpen 24, 345-350 (2000). 
7. 
Shin, J.I., Namgung, R., Park, M.S. & Lee, C. Could lipid infusion be a risk for parenteral 
nutrition-associated cholestasis in low birth weight neonates? European journal of pediatrics 
167, 197-202 (2008). 

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8. 
Koletzko, B. & Goulet, O. Fish oil containing intravenous lipid emulsions in parenteral 
nutrition-associated cholestatic liver disease. Current opinion in clinical nutrition and 
metabolic care 13, 321-326 (2010). 
9. 
Diamond, I.R., Sterescu, A., Pencharz, P.B., Kim, J.H. & Wales, P.W. Changing the paradigm: 
omegaven for the treatment of liver failure in pediatric short bowel syndrome. Journal of 
pediatric gastroenterology and nutrition 48, 209-215 (2009). 
10. 
Gura, K.M., et al. Safety and efficacy of a fish-oil-based fat emulsion in the treatment of 
parenteral nutrition-associated liver disease. Pediatrics 121, e678-686 (2008). 
11. 
de Meijer, V.E., Gura, K.M., Le, H.D., Meisel, J.A. & Puder, M. Fish oil-based lipid emulsions 
prevent and reverse parenteral nutrition-associated liver disease: the Boston experience. 
Jpen 33, 541-547 (2009). 
12. 
Tomsits, E., et al. Safety and efficacy of a lipid emulsion containing a mixture of soybean oil, 
medium-chain triglycerides, olive oil, and fish oil: a randomised, double-blind clinical trial in 
premature infants requiring parenteral nutrition. Journal of pediatric gastroenterology and 
nutrition 51, 514-521 (2010). 
13. 
Goulet, O., et al. A new intravenous fat emulsion containing soybean oil, medium-chain 
triglycerides, olive oil, and fish oil: a single-center, double-blind randomized study on efficacy 
and safety in pediatric patients receiving home parenteral nutrition. Jpen 34, 485-495 (2010). 
14. 
Baer, G.R. & Nelson, R.M. Ethical challenges in neonatal research: Summary report of the 
ethics group of the newborn drug development initiative. Clinical therapeutics 28, 1399-1407 
(2006). 
15. 
Belkind-Gerson, J., Carreon-Rodriguez, A., Contreras-Ochoa, C.O., Estrada-Mondaca, S. & 
Parra-Cabrera, M.S. Fatty acids and neurodevelopment. Journal of pediatric gastroenterology 
and nutrition 47 Suppl 1, S7-9 (2008). 
16. 
Lapillonne, A. & Jensen, C.L. Reevaluation of the DHA requirement for the premature infant. 
Prostaglandins, leukotrienes, and essential fatty acids 81, 143-150 (2009). 
17. 
Puder, M., et al. Parenteral fish oil improves outcomes in patients with parenteral nutrition-
associated liver injury. Annals of surgery 250, 395-402 (2009). 
18. 
Diamond, I.R. Combination Therapy with Omegaven and Intralipid in Children with intestinal 
failure and Advanced Parenteral Nutrition Associated Liver disease (PNALD). in XI 
International Small Bowel Transplant Symposium (Bologna, 2009). 
19. 
Simmer, K., Schulzke, S.M. & Patole, S. Longchain polyunsaturated fatty acid 
supplementation in preterm infants. Cochrane database of systematic reviews (Online), 
CD000375 (2008). 
20. 
Bines, J. Parenteral Nutrition - Associated Liver Disease in Walker's pediatric gastrointestinal 
disease: physiology, diagnosis, management Vol. 1; 614 (People´s Medical Publishing House, 
Shelton, 2008).