A Prospective, Randomized, Controlled, Double-Blind, Parallel-Group, Phase 3 Study to Compare Safety and Efficacy of Smoflipid 20% to Intralipid 20% in Hospitalized Neonates and Infants Requiring 28 Days of Parenteral Nutrition
Phase: PHASE3
Conditions: Hospitalized Neonates and Infants, Expected to Require Parenteral Nutrition for 28 Days
Sponsor: Fresenius Kabi

Clinical Study Protocol SMOF-018-CP3 
Smoflipid 20% lipid injectable emulsion 
 
Version: Final 3.0 
Date: 05 OCT 2020 
 
C O N F I D E N T I A L 
Page: 1 of 79 
 
Clinical Study Protocol 
 
Title: 
A Prospective, Randomized, Controlled, Double-Blind, 
Parallel-Group, Phase 3 Study to Compare Safety and 
Efficacy of Smoflipid 20% to Intralipid 20% in Hospitalized 
Neonates and Infants Requiring 28 Days of Parenteral 
Nutrition 
 
Authority  
Identification no.: 
PIND 102137 
 
ClinicalTrials.gov  
NCT02579265 
Identifier 
  
 
FK Study Identifier: 
SMOF-018-CP3 
 
Indication: 
A source of calories and essential fatty acids for parenteral 
nutrition when oral or enteral nutrition is not possible, 
insufficient, or contraindicated. 
 
Investigational drug: 
Smoflipid 20% (lipid injectable emulsion) 
Control drug: 
Intralipid® 20% (a 20% intravenous fat emulsion) 
 
Protocol status: 
Final 3.0 
 
Date: 
05 OCT 2020 
 
Sponsor: 
Fresenius Kabi Deutschland GmbH 
 
 
 
 
 
 
 
 
In case of emergency during out-of-office-hours please contact (sponsor's medical expert 
according to ICH Guideline E6 – Good Clinical Practice): 
 
 

Clinical Study Protocol SMOF-018-CP3 
Smoflipid 20% lipid injectable emulsion 
 
Version: Final 3.0 
Date: 05 OCT 2020 
 
C O N F I D E N T I A L 
Page: 2 of 79 
 
 
 
 
 
 
 
 
This Clinical Study Protocol (CSP) is the property of Fresenius Kabi (FK). It is provided to you as a Contract Research 
Organization (CRO), Principal Investigator, potential investigator or consultant, your staff, Competent/Regulatory Authorit(-
y/-ies) and the Institutional Review Board(s)/Independent Ethics Committee(s). The information contained in this document 
is confidential and, except to the extent necessary to obtain Informed Consent, may not be disclosed unless such disclosure is 
required by national law. People to whom the information is disclosed must be informed that the information is confidential 
and may not be further disclosed by them. 
The trial will be carried out in accordance with the ICH – Guideline for good Clinical Practice (E6[R1] July 2002) including 
Explanatory Note and Comments, issued as CPMP/768/97, the Declaration of Helsinki, revised version (64th WMA General 
Assembly, Fortaleza, Brazil, October 2013), CFR - Code of Federal Regulations Title 21 and the respective national laws and 
regulations.   
The CSP and all subsequent amendments to the CSP are agreed upon between FK as the sponsor of the clinical 
trial/investigation, the CRO, the Coordinating Investigator(s), if applicable and all Principal Investigators, and are recorded 
with a justification for each amendment. 
 

Clinical Study Protocol SMOF-018-CP3 
Smoflipid 20% lipid injectable emulsion 
Version: Final 3.0 
Date: 05 OCT 2020 
 
C O N F I D E N T I A L 
 
Page 6 of 79  
 
1 
Study Outline 
 
Title: 
A Prospective, Randomized, Controlled, Double-Blind, Parallel-
Group, Phase 3 Study to Compare the Safety and Efficacy of 
Smoflipid 20% to Intralipid 20% in Hospitalized Neonates and 
Infants Requiring 28 Days of Parenteral Nutrition. 
Authority  
 
Identification no.: 
PIND 102137 
 
ClinicalTrials.gov  
NCT02579265 
Identifier 
  
 
FK Study Identifier: 
SMOF-018-CP3 
 
Indication: 
Smoflipid is indicated as a source of calories and essential fatty 
acids for parenteral nutrition when oral or enteral nutrition is not 
possible, insufficient, or contraindicated. 
 
Objectives: 
The primary objective of the study is to show the superiority in 
safety of Smoflipid over Intralipid® as measured by the number 
of study patients in each treatment group with conjugated 
bilirubin > 2 mg/dL during the first 28 days of study treatment, 
confirmed by a second sample collected 7 days after the first 
sample. 
 
The secondary objectives are to 
 
• 
compare efficacy of Smoflipid 20% to Intralipid 20% in 
neonates and infants reflected by specific nutritional 
parameters  
• 
evaluate overall safety of Smoflipid 20% in neonates 
 
 
Study drugs: 
Investigational drug:  Smoflipid 20% 
 
Control drug:  
 
Intralipid 20% 
 
 
Dosage:  
The targeted maximal lipid dose is 3.0 g/kg/day.  
 
 
In patients that are already receiving parenteral nutrition (PN) 
before starting study treatment, the lipid dose will either stay at 
3.0 g/kg/day or increased by 1 g/kg/day steps to a maximum of 
3.0 g/kg/day.  
 
 
 
In patients that have not yet started PN prior to study 

Clinical Study Protocol SMOF-018-CP3 
Smoflipid 20% lipid injectable emulsion 
Version: Final 3.0 
Date: 05 OCT 2020 
 
C O N F I D E N T I A L 
 
Page 7 of 79  
 
participation, lipid dose will be increased stepwise using the 
following regimen: 
 
Study Day 
Patients < 1500 g 
Patients ≥ 1500 g 
Day 1 
1.0 g/kg/day 
2.0 g/kg/day 
Day 2 
2.0 g/kg/day 
3.0 g/kg/day 
Day 3+ 
3.0 g/kg/day 
3.0 g/kg/day 
 
Investigational or control drug will be infused over 20 - 24 hours, 
as per hospital policy, at a weight based infusion rate.  If the blood 
draw is from the PN/lipid infusion line, then lipid (study drug) 
should be held for 4 hours prior to the time of blood sampling. 
During study treatment, serum triglycerides (TGs) will be 
monitored to adjust lipid dose keeping TG levels < 250 mg/dL.  
 
Blood samples for TG monitoring will be collected as follows: 
 
  
  
Patients < 1500 g: At 1 g, 2 g and first dose of 3 g/kg/day   
 
Patients ≥ 1500 g: At first dose of 3 g/kg/day 
 
Once the target dose has been reached TGs will be assessed on a 
weekly basis.  
 
Should TGs exceed 250 mg/dL, lipids will be paused until 
analysis of another blood sample on the following morning. If 
TGs are below 250 mg/dL lipids are restarted. If not this 
procedure has to be repeated the next morning.   
 
Dosage of other PN components: 
 
In addition to the study drug other macronutrients will be 
administered at a targeted dose as follows:  
• 
Amino acids:  
2 to 4 g/kg/day 
• 
Dextrose:   
8 to 18 mg/kg/min 
• 
Trace elements, electrolytes, vitamins will be considered 
according to hospital practice and applicable guidelines. 
• 
Use and dose of heparin and carnitine have to be 
documented in the concomitant mediation section in the 
CRF.   
 
Route of Administration: The lipid emulsions will be infused into a central or peripheral 
vein  
 
Treatment: 
Treatment group 1: Smoflipid 20% (investigational drug) 

Clinical Study Protocol SMOF-018-CP3 
Smoflipid 20% lipid injectable emulsion 
Version: Final 3.0 
Date: 05 OCT 2020 
 
C O N F I D E N T I A L 
 
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Treatment group 2: Intralipid 20% (control drug) 
 
 
Intravenous lipid dose management 
 
Conjugated bilirubin levels in plasma will be assessed on a 
weekly basis during the initial treatment phase (visits Day 1 – Day 
29) and then bi-weekly in the treatment extension phase (visits 
Day 36 - Day 85). If in the treatment extension phase conjugated 
bilirubin levels increase beyond 1.5 mg/dL, then conjugated 
bilirubin will be assessed weekly. 
 
• Lipid minimization:  
If at any point conjugated bilirubin exceeds 1.5 mg/dL (> 1.5 
mg/dL), lipid dose has to be decreased to 1 g/kg/day immediately; 
dextrose dose should be increased accordingly to maintain 
adequate energy provision. Lipid dose will be maintained at 1 
g/kg/d and not be increased again even if conjugated bilirubin 
levels decrease again below 1.5 mg/dL. 
 
• Early discontinuation:  
Should conjugated bilirubin exceed 2 mg/dL (> 2 mg/dL), a 
confirmatory analysis must be performed after 7 days. The 
patient’s dose will remain at 1 g/kg/day until analysis of the 
confirmatory blood sample. If the confirmatory analysis reveals 
that conjugated bilirubin increased further by at least 1 mg/dL, 
then the patient has to be removed from the study immediately 
and may be treated with an alternative lipid emulsion at the 
investigator’s discretion. If not, the patient continues to receive 
study medication.  
 
• Weaning of lipids and PN: 
As soon as the patient receives 80 mL/kg/day oral/enteral feeding 
and achieved tolerance (i.e. at least 3 days) the dose of study drug 
must be reduced to 1 g/kg/d.  
As soon as patient receives 100 mL/kg/day oral/enteral feeding 
and achieved tolerance (i.e. at least 3 days) study drug must be 
stopped completely. 
 
Duration of Treatment: 
The expected administration of lipid emulsions for each study 
patient should be 28 days. If PN is still indicated after 28 days, 
patients may receive the study drug for up to 84 days.  
 
Patients: 
Hospitalized neonates and infants, expected to require PN for 28 
days 
 

Clinical Study Protocol SMOF-018-CP3 
Smoflipid 20% lipid injectable emulsion 
Version: Final 3.0 
Date: 05 OCT 2020 
 
C O N F I D E N T I A L 
 
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Inclusion Criteria:  
 1. Neonates and infants, expected to require PN for 28 days  
 
2. Postmenstrual age ≥ 24 weeks 
 
3. Birth weight ≥ 750g 
4. Gastroschisis, duodenal, jejunal or ileal atresia, volvulus, 
spontaneous intestinal perforation or necrotizing enterocolitis 
(Bell’s stage 2B or higher)  
5. At least 80% of nutritional needs at Baseline are met with PN 
6. Signed and dated informed consent obtained from at least one 
parent or legal guardian 
 
Exclusion Criteria:  
1. Conjugated bilirubin > 0.6 mg/dL 
 
 2. Any known pre-, intra- or posthepatic complication that will 
increase conjugated bilirubin levels > 0.6, mg/dL during study 
participation 
3. Suspected liver disease or liver damage based on either AST, 
ALT, or GGT exceeding 2.5x upper limit of normal range 
4. Active bloodstream infection demonstrated by positive blood 
culture at screening  
5. Cystic fibrosis  
 
 
 
 
 
6. Meconium ileus  
7. Serum TGs > 250 mg/dL 
8. Cyanotic congenital heart defect 
 
 
 
 
 
9. Severe renal failure as evidenced by creatinine > 2.0 mg/dL 
 
 
 
 
 
10. History of shock requiring vasopressors 
 
 
 
 
 
11. Anasarca 
12. Extracorporeal Membrane Oxygenation (ECMO) 
13. Known inborn errors of metabolism 
 
 
 
 
 
14. Known congenital viral infection 
15. Unlikely to survive longer than 28 days 
16. Known hypersensitivity to fish-, egg-, soya- or peanut 
protein or to any of the active substances or excipients 
 
 
Primary Endpoint: 
 The primary endpoint is the number of patients in each treatment 
group with conjugated bilirubin levels > 2 mg/dL during the first 
28 days of study treatment period, confirmed by a second sample 
collected 7 days after the first sample.  
 
 
 
 
 
 
 

Clinical Study Protocol SMOF-018-CP3 
Smoflipid 20% lipid injectable emulsion 
Version: Final 3.0 
Date: 05 OCT 2020 
 
C O N F I D E N T I A L 
 
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Secondary Endpoints: 
Efficacy: 
 
• 
Body weight (change from Baseline) 
• 
Body length (change from Baseline) 
• 
Head circumference (change from Baseline) 
• 
Time to full enteral or oral feeds 
• 
Fatty acids in plasma and red blood cell membranes (change 
from Baseline) 
• 
Holman index 
 
 
 
 
 
 
Safety: 
 
• 
Length of stay in hospital 
• 
Ratio of number of independent bloodstream 
infections/number of days on study medication 
• 
Ratio of the number of patients with 1 or more bloodstream 
infections / number of patients on study medication  
• 
Number of patients who complete PN treatment without 
lipid minimization 
• 
Number of patients who need to be withdrawn from the 
study due to elevated conjugated bilirubin levels 
• 
Area under the curve of conjugated bilirubin for time period 
in which levels are > 1.5 mg/dL  
• 
Cumulative number of days patients are administered a lipid 
dose without lipid minimization 
• 
Time to conjugated bilirubin > 2mg/dL (confirmed by a 
second sample collected 7 days after the first) 
• 
Conjugated bilirubin 
• 
Total bilirubin 
• 
Serum TGs 
• 
Aspartate aminotransferase (AST) 
• 
Alanine aminotransferase (ALT) 
• 
Gamma-glutamyl transferase (GGT) 
• 
Alkaline phosphatase (ALP) 
• 
Blood glucose 
• 
Blood urea nitrogen (BUN) 
• 
Creatinine 
• 
C-reactive protein (CRP) 
• 
Sterols including phytosterols 
• 
α-tocopherol  
• 
Collection of adverse event (AE) data 
• 
Incidence of bronchopulmonary dysplasia (BPD) 
• 
Incidence of retinopathy of prematurity (ROP) 
• 
Incidence of intraventricular hemorrhage (IVH) 

Clinical Study Protocol SMOF-018-CP3 
Smoflipid 20% lipid injectable emulsion 
Version: Final 3.0 
Date: 05 OCT 2020 
 
C O N F I D E N T I A L 
 
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• 
Incidence of periventricular leukomalacia (PVL) 
• 
Incidence of necrotizing enterocolitis (NEC) 
• 
Incidence of late-onset sepsis in premature and low birth 
weight neonates 
 
 
Statistics: 
 The primary outcome measure is the number of patients in each 
treatment group with conjugated bilirubin levels > 2 mg/dL 
during the first 28 days of study treatment, confirmed by a second 
sample collected 7 days after the first sample.  
 
Due to the lack of reliable data on the effect size of Smoflipid 
compared to Intralipid a two-stage adaptive group sequential 
design according to Bauer and Köhne (Bauer, et al. 1994) will be 
performed.  
An interim analysis will be performed once 50 patients in each 
group have completed the study per protocol (at least 14 days of 
study treatment).  
A nominal significance level of 0.0102 will be applied to stage 1. 
The significance level of stage 2 will be based on error 
probabilities observed at interim-stage. Datasets from stage 1 and 
2 will be analyzed separately. 
Statistical analysis of the primary endpoint will be based on the 
risk ratio for developing cholestasis during 28 days of Smoflipid 
administration compared to Intralipid. 
 Non-inferiority will be a gatekeeper for superiority using a non-
inferiority margin of 1.2. If non-inferiority of Smoflipid can be 
demonstrated, superiority will be tested subsequently. This 
procedure corresponds to a simple closed test procedure and 
requires no multiplicity adjustment. 
If a second stage needs to be performed, the sample size 
calculation will be based on the treatment effect observed at stage 
1. The overall one-sided significance level and minimum power 
are set to 2.5% and 80%, respectively. 
If this sample size re-estimation results in a sample size that 
exceeds the maximum study size of up to 200 patients per group, 
the study will be stopped prematurely after the interim analysis 
for futility and be analysed descriptively and in an exploratory 
way. 
 
 
Evaluations/Follow-up: 
All data will be collected according to the study schedule. The 
number of blood samples collected will be minimized in this 
vulnerable target population. 
 
 
After obtaining a signed/dated informed consent form (ICF) and 
prior to administration of the first dose of study drug, baseline 

Clinical Study Protocol SMOF-018-CP3 
Smoflipid 20% lipid injectable emulsion 
Version: Final 3.0 
Date: 05 OCT 2020 
 
C O N F I D E N T I A L 
 
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assessments 
will 
be 
completed 
including: 
review 
of 
inclusion/exclusion criteria, collection of demographic data 
including race and ethnicity, the patient’s medical history and 
concomitant medications, blood sample for safety lab and 
analysis of sterols, fatty acids and α-tocopherol.  
 
  
 
Adverse events will be documented at any time point of the study 
and followed up until resolved. 
 
During treatment the following data will be recorded daily: Study 
drug 
administered, 
dextrose 
administered, 
amino 
acids 
administered, EN administered, body weight, AEs and 
concomitant medication.  
 
Body length and head circumference will be measured and 
recorded once weekly. 
 
Conjugated bilirubin, ALT, AST and GGT will be measured 
weekly up to day 29 and then biweekly until day 85 or discharge, 
respectively. If after day 29 conjugated bilirubin increases beyond 
1.5 mg/dL, it has to be assessed weekly again.    
 
Serum triglycerides will be measured and recorded once weekly. 
At TG > 250 mg/dL, TGs will be measured the following day. 
 
In case of suspected systemic infections blood cultures will be 
drawn. 
 
An End-of-Treatment Visit has to be performed on the following 
day after receipt of the last dose of study medication. AEs, 
concomitant medications, physical examination findings, vital 
signs, body weight, body length, head circumference, conjugated 
bilirubin, safety laboratory analyses, sterols, α-tocopherol and 
fatty acids in the blood will be assessed. 
 
At the Follow-up Visit, 7 days after the End-of-Treatment Visit, 
all information regarding AEs and concomitant medications since 
the last study medication dose will be documented, and physical 
examination findings, vital signs, body weight, body length, head 
circumference and length-of-stay in the hospital will be recorded. 
If conjugated bilirubin level was > 1.5 mg/dL at the End-of-
Treatment-Visit, then conjugated bilirubin needs to be assessed 
again at the Follow-up Visit.     
 
 
 
 
 
 
 
 
 

Clinical Study Protocol SMOF-018-CP3 
Smoflipid 20% lipid injectable emulsion 
Version: Final 3.0 
Date: 05 OCT 2020 
 
C O N F I D E N T I A L 
 
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Investigators: 
Coordinating Investigator:  
 
 
 
 
 
 
Participating sites: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Clinical Study Protocol SMOF-018-CP3 
Smoflipid 20% lipid injectable emulsion 
Version: Final 3.0 
Date: 05 OCT 2020 
 
C O N F I D E N T I A L 
 
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Clinical Study Protocol SMOF-018-CP3 
Smoflipid 20% lipid injectable emulsion 
Version: Final 3.0 
Date: 05 OCT 2020 
 
C O N F I D E N T I A L 
 
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. 
 

Clinical Study Protocol SMOF-018-CP3 
Smoflipid 20% lipid injectable emulsion 
Version: Final 3.0 
Date: 05 OCT 2020 
 
C O N F I D E N T I A L 
 
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2 
Study Schedule 
 
Daily procedures and assessments during treatment (starting on day 1): Study drug administration, study drug administered, dextrose 
administered, amino acids administered, EN and oral food administered, Body Weight, Adverse Events, Concomitant Medication    
Initital Treatment Phase 
Treatment Extension Phase 
Follow-up Visit 
Assessment / Records 
Screening 
Day 1 
Baseline Day 8 Day 15 Day 22 
Day 29 / 
End of 
Treatmenta 
Day 
36 
Day 
43 
Day 
50 
Day 
57 
Day 
64 
Day 
71 
Day 
78 
Day 85 / 
End of 
Treatmenta 
7d after 
End of 
Treatment 
Time Window (d) 
Day 1 -3d 
0 
±1 
±1 
±1 
+1 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
+1 
±1 
Parent Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In- / Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics incl. race and ethnicity 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior Medication 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body Length 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Head Circumference 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Time to Full Enteral or Oral Feeds 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Length of Stay  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Blood Sampling for Conjugated 
Bilirubinb 
X 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
(X)c 
Blood Sampling for Biochemistry, 
Hematology and Coagulationd 
X 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
Blood Sample for special analysese 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
a: End of treatment visit to be performed on the following day after receiving the last dose of study medication 
b: If conjugated bilirubin exceeds 1.5 mg /dL it has to be assessed weekly, also after d29 
c: If conjugated bilirubin is > 1.5 mg/dL at the end of treatment visit a blood sample for the assessment of conjugated bilirubin has to be drawn at the Follow-up Visit  
d: Additional blood samples for assessment of TGs and blood glucose need to be drawn during ramp up of lipid dose. Should TGs exceed 250 mg/dL at any time, lipids will be withheld until 
analysis of TGs in another blood sample the following morning.   
e: Special analyses: Fatty acids, sterols, α-Tocopherol 

Clinical Study Protocol SMOF-018-CP3 
Smoflipid 20% lipid injectable emulsion 
Version: Final 3.0 
Date: 05 OCT 2020 
 
C O N F I D E N T I A L 
 
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3 
Contents 
 
RESPONSIBILITIES (SIGNATURE PAGE) ................................................................................................... 3 
1 
STUDY OUTLINE ...................................................................................................................................... 6 
2 
STUDY SCHEDULE ................................................................................................................................ 16 
3 
CONTENTS ............................................................................................................................................... 17 
3.1 
LIST OF TABLES ...................................................................................................................................... 20 
3.2 
LIST OF FIGURES ..................................................................................................................................... 20 
4 
TABLE OF ABBREVIATIONS .............................................................................................................. 21 
5 
INTRODUCTION ..................................................................................................................................... 23 
5.1 
BACKGROUND ......................................................................................................................................... 23 
5.2 
RATIONALE AND PURPOSE OF THE STUDY .............................................................................................. 24 
5.3 
BENEFIT/RISK ASSESSMENT .................................................................................................................... 24 
6 
OBJECTIVES ........................................................................................................................................... 25 
6.1 
STUDY HYPOTHESIS ................................................................................................................................ 25 
6.2 
STUDY VARIABLES ................................................................................................................................. 25 
6.2.1 
Primary Variable .......................................................................................................................... 25 
6.2.2 
Secondary Variable(s) .................................................................................................................. 26 
7 
STUDY DESIGN ....................................................................................................................................... 27 
7.1 
DESCRIPTION OF THE STUDY DESIGN ...................................................................................................... 27 
7.2 
RATIONALE OF STUDY DESIGN, INCLUDING CHOICE OF CONTROL GROUP ............................................. 29 
7.3 
RANDOMIZATION, ALLOCATION OF PATIENTS ........................................................................................ 30 
7.4 
BLINDING AND DECODING ...................................................................................................................... 31 
8 
DATA MANAGEMENT AND STATISTICS ........................................................................................ 32 
8.1 
DATA MANAGEMENT .............................................................................................................................. 32 
8.2 
STATISTICS .............................................................................................................................................. 33 
8.2.1 
Study Outcome Measures .............................................................................................................. 33 
8.2.2 
Sample Size Estimation ................................................................................................................. 34 
8.2.3 
Hypothesis Testing ........................................................................................................................ 36 
8.2.4 
Blinded Review / Final Statistical Analysis Plan .......................................................................... 37 
8.2.5 
Definition of Populations .............................................................................................................. 37 
8.2.6 
Interim and Final Analysis ........................................................................................................... 38 
8.2.7 
Analysis of Secondary Outcome Measures ................................................................................... 40 
8.3 
REPLACEMENT OF PATIENTS ................................................................................................................... 40 
9 
STUDY DURATION ................................................................................................................................ 41 
10 
PATIENT SELECTION ........................................................................................................................... 41 
10.1 
STUDY POPULATION ........................................................................................................................... 41 
10.2 
INCLUSION CRITERIA .......................................................................................................................... 41 
10.3 
EXCLUSION CRITERIA ........................................................................................................................ 42 
10.4 
WITHDRAWAL OF PATIENTS FROM THE STUDY .................................................................................. 43 
11 
STUDY DRUGS AND MEDICATION ................................................................................................... 44 
11.1 
CHARACTERIZATION OF THE INVESTIGATIONAL DRUG ...................................................................... 44 
11.2 
CHARACTERIZATION OF THE CONTROL DRUG .................................................................................... 44 

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Smoflipid 20% lipid injectable emulsion 
Version: Final 3.0 
Date: 05 OCT 2020 
 
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11.3 
PREPARATION, ADMINISTRATION AND DOSAGE OF INVESTIGATIONAL MEDICINAL PRODUCTS ......... 45 
11.4 
COMPLIANCE ...................................................................................................................................... 47 
11.5 
SUPPLY, PACKAGING, LABELLING AND STORAGE .............................................................................. 47 
11.6 
RETURN OF STUDY MATERIALS AND STUDY DRUGS .......................................................................... 48 
11.7 
DRUG ACCOUNTABILITY (DELIVERY, RECEIPT, STORAGE, USE, RETURN) ......................................... 48 
11.8 
CONCOMITANT MEDICATION ............................................................................................................. 49 
12 
STUDY SCHEDULE ................................................................................................................................ 49 
12.1 
SUMMARY OF PROCEDURES ............................................................................................................... 49 
12.2 
DETAILED DESCRIPTION OF INVESTIGATIONS .................................................................................... 49 
12.2.1 
Screening Visit ......................................................................................................................... 49 
12.2.2 
Baseline Visit/Day 1 ................................................................................................................. 51 
12.2.3 
Daily Assessments During Treatment Phase............................................................................ 52 
12.2.4 
Treatment Visits ....................................................................................................................... 52 
12.2.5 
Day 29, Day 85, and End-of-Treatment Visit ........................................................................... 53 
12.2.6 
Additional Assessments ............................................................................................................ 55 
12.2.7 
Follow-Up Visit ........................................................................................................................ 55 
12.3 
METHODS ........................................................................................................................................... 56 
12.3.1 
Experimental and Analytical Methods ..................................................................................... 56 
12.3.2 
Laboratory Variables ............................................................................................................... 56 
12.3.2.1 Standard Laboratory Values Including Conjugated Bilirubin .................................................................... 56 
12.3.2.2 Specialized Laboratory Analyses ............................................................................................................... 57 
12.4 
DOCUMENTATION OF PATIENT DATA ................................................................................................. 58 
12.4.1 
The Electronic Case Report Form ........................................................................................... 58 
13 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ................................................................ 59 
13.1 
DEFINITIONS ....................................................................................................................................... 59 
13.1.1 
Adverse Event ........................................................................................................................... 59 
13.1.2 
Serious Adverse Event .............................................................................................................. 59 
13.1.2.1 
Suspected Adverse Reaction ............................................................................................................... 60 
13.1.2.2 
Unexpected Adverse Reaction ............................................................................................................ 60 
13.1.2.3 
Serious and Unexpected Suspected Adverse Reaction ........................................................................ 60 
13.2 
ASSESSMENT OF ADVERSE EVENTS .................................................................................................... 61 
13.2.1 
Intensity/Severity ...................................................................................................................... 61 
13.2.2 
Causality .................................................................................................................................. 62 
13.2.3 
Relationship to Study Procedures ............................................................................................ 63 
13.2.4 
Action Taken ............................................................................................................................ 63 
13.2.5 
Outcome ................................................................................................................................... 64 
13.3 
REPORTING AND DOCUMENTATION PROCEDURES .............................................................................. 64 
13.3.1 
Reporting of Serious Adverse Events ....................................................................................... 65 
13.3.2 
Documentation and Reporting of Other Safety-Relevant Information and Unanticipated 
Problems  ................................................................................................................................................. 65 
13.3.3 
Safety Contact at Fresenius Kabi ............................................................................................. 66 
13.3.4 
Reporting to Competent Authorities, Institutional Review Boards, and Investigators ............. 67 
13.3.5 
Period of Observation .............................................................................................................. 67 
13.4 
UNBLINDING OF TREATMENT FOR EMERGENCIES ............................................................................... 67 
13.5 
DATA SAFETY MONITORING BOARD .................................................................................................. 68 
14 
MONITORING ......................................................................................................................................... 68 
14.1 
FUNCTION OF THE CLINICAL RESEARCH ASSOCIATE .......................................................................... 68 
14.2 
FREQUENCY OF MONITORING ............................................................................................................. 69 
15 
AUDITS AND INSPECTIONS ................................................................................................................ 69 
15.1 
AUDITS ............................................................................................................................................... 69 
15.1.1 
Auditing Procedures ................................................................................................................ 69 

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15.1.2 
Frequency of Audits ................................................................................................................. 70 
15.1.3 
Documentation of Audits .......................................................................................................... 70 
15.2 
QUALITY CONTROL OF CLINICAL TRIAL DOCUMENTS ....................................................................... 70 
16 
MODIFICATIONS DURING THE STUDY .......................................................................................... 70 
16.1 
PROTOCOL AMENDMENTS .................................................................................................................. 70 
16.2 
PROTOCOL DEVIATIONS ..................................................................................................................... 71 
16.3 
PREMATURE TERMINATION OF THE STUDY ........................................................................................ 71 
17 
FINAL CLINICAL STUDY REPORT ................................................................................................... 72 
18 
ADMINISTRATIVE REQUIREMENTS ............................................................................................... 72 
18.1 
AUTHORITY IDENTIFICATION NUMBER .............................................................................................. 72 
18.2 
INSTITUTIONAL REVIEW BOARD ........................................................................................................ 72 
18.3 
SUBMISSION TO THE COMPETENT AUTHORITY ................................................................................... 72 
18.4 
NOTIFICATION OF LOCAL AUTHORITY ............................................................................................... 73 
18.5 
PATIENT INFORMATION AND INFORMED CONSENT ............................................................................. 73 
18.6 
PATIENT INSURANCE .......................................................................................................................... 73 
18.7 
PATIENT PRIVACY .............................................................................................................................. 73 
18.8 
INITIATION OF THE STUDY .................................................................................................................. 74 
19 
AGREEMENTS ........................................................................................................................................ 74 
19.1 
CONFIDENTIALITY AGREEMENT ......................................................................................................... 74 
19.2 
PUBLICATION OF RESULTS ................................................................................................................. 74 
19.3 
PAYMENT ........................................................................................................................................... 75 
19.4 
POTENTIAL CONFLICTS OF INTEREST ................................................................................................. 75 
19.5 
INCENTIVES TO PATIENTS ................................................................................................................... 75 
19.6 
ARCHIVING......................................................................................................................................... 75 
20 
REFERENCES .......................................................................................................................................... 76 
21 
ANNEXES ................................................................................................................................................. 79 
 
 
 

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3.1 
List of Tables 
Table 1: Sample Size Calculation for Pearson Chi-Square Test for Two Proportions (alpha = 
0.025 one-sided, power = 80%). .............................................................................................. 34 
Figure 1: Sample Sizes Needed for Pearson Chi-Square Test for Two Proportions to Achieve 
a Power = 80% (alpha = 0.01 one-sided). ................................................................................ 35 
Table 2: Adverse Event/Serious Adverse Event Intensity ....................................................... 61 
Table 3: Assessment of Adverse Events Associated with Laboratory Variables and Vital Signs
.................................................................................................................................................. 62 
  
3.2 
List of Figures 
Figure 1: Sample Sizes Needed for Pearson Chi-Square Test for Two Proportions to Achieve 
a Power = 80% (alpha = 0.01 one-sided). ................................................................................ 35 

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4 
Table of Abbreviations 
 
ADR  
Adverse Drug Reaction 
AE  
Adverse Event 
ALP  
Alkaline Phosphatase 
ALT  
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BPD 
Bronchopulmonary Dysplasia 
BUN  
Blood Urea Nitrogen 
CA  
Competent/Regulatory Authority 
CBC  
Complete Blood Count 
CI 
 
Confidence Interval 
CRA  
Clinical Research Associate (Monitor) 
CRO  
Contract Research Organization 
CRP  
C-Reactive Protein 
CSR  
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSMB 
Data Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
EFAs 
Essential Fatty Acids 
FDA  
United States Food and Drug Administration 
GCP  
Good Clinical Practice 
GGT  
Gamma -Glutamyl Transferase 
GMP  
Good Manufacturing Practice 
IB 
 
Investigator’s Brochure 
ICF  
Informed Consent Form 
ICH  
International Conference on Harmonization 
IVH  
Intraventricular hemorrhage 
IFALD 
Intestinal Failure-Associated Liver Disease  
INR  
International Normalized Ratio 
IRB  
Institutional Review Board  
ITT  
Intention-To-Treat 
IV 
 
Intravenous 
IVLE 
Intravenous Lipid Emulsion 
MCT  
Medium-Chain Triglycerides 
MedDRA Medical Dictionary for Regulatory Activities 
NEC  
Necrotizing Enterocolitis 
PN 
 
Parenteral Nutrition 
PNALD 
Parenteral Nutrition Associated Liver Disease 
PP 
 
Per Protocol 
PVL  
Periventricular Leukomalacia 
ROP  
Retinopathy of Prematurity 
SAE  
Serious Adverse Event 
SAP  
Statistical Analysis Plan 

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SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TG 
Triglyceride 
US 
United States 

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5 
Introduction 
5.1 
Background 
Parenteral nutrition (PN) is a life-saving procedure enabling the physician to provide adequate 
nutritional substrates to a patient whenever the patient’s nutritional needs cannot be met with 
oral or enteral nutrition.  
Total PN provides amino acids, dextrose, lipids, vitamins, electrolytes and water.     
Within PN regimens, intravenous lipid emulsions (IVLEs) have 2 main functions: 1) to supply 
calorie-dense energy and 2) to provide essential fatty acids (Hamilton, et al. 2006, Krohn, et 
al. 2006, Mascioli, et al. 1996, Waitzberg, et al. 2006). Intravenous lipid emulsions have now 
routinely been used in PN for more than 50 years, since Intralipid was first registered in 1962.  
 
Prolonged use of PN in the setting of long-term intestinal failure has been associated with 
hepatic complications reflected by elevated bilirubin levels after approximately 2 to 3 weeks 
of PN (Christensen, et al. 2007). In this context, elevated conjugated bilirubin levels are 
considered to be a surrogate marker for evolving PN-associated cholestasis which is understood 
as the most common complication of the PN-associated liver disease (PNALD) (Colomb, et al. 
2000, Javid, et al. 2011, Koseesirikul, et al. 2012, Pichler, et al. 2012). Clinically it is difficult 
to separate PNALD from intestinal failure-associated liver disease (IFALD), as intestinal 
failure by itself can contribute to liver disease with a similar increase in surrogate markers and 
IFALD requires PN as a treatment option. Parenteral nutrition-associated liver disease is 
considered to be multifactorial, and all quantitative as well as qualitative components of PN 
may promote cholestasis (Wales, et al. 2014). In recent years, investigators focused on the role 
of the soybean oil-based lipid emulsions in the development of PNALD due to their high 
content of the ω6 fatty acid linoleic acid (C18:2ω6, 52% to 54% in Intralipid) and plant sterols 
(phytosterols) and their low content in α-tocopherol (Burrin, et al. 2014, Clayton, et al. 1998, 
Ng, et al. 2015, Wales, et al. 2014).  
 
Smoflipid 20% has been developed to optimize the fatty acid profile of the lipid emulsion used 
in PN, reducing the amount of ω6 fatty acid linoleic acid given to the patient by replacing it in 
part with ω9 and ω3 fatty acids. Smoflipid is a fixed physical mixture of 4 different oils being 
used in clinical practice in many countries worldwide, combining soybean oil, medium-chain 
triglycerides (MCTs) from coconut oil, olive oil, and fish oil. Smoflipid contains 200 mg/L α-
tocopherol, which protects unsaturated fatty acids against lipid peroxidation. Furthermore, 
Smoflipid contains only approximately 30% of total phytosterols compared to Intralipid. 
 
Three company-sponsored studies have compared Smoflipid to Intralipid in the pediatric 
population, including 2 studies in preterm neonates and 1 study in infants and children 1 to 11 
years of age (Goulet, et al. 2010, Rayyan, et al. 2012, Tomsits, et al. 2010). The data from these 
studies showed a beneficial effect on liver parameters, although liver function was not the 
primary endpoint in these studies.  
In 2 studies, significantly greater decreases from baseline values were seen in total and direct 
bilirubin in the Smoflipid versus Intralipid group (Goulet, et al. 2010, Rayyan, et al. 2012). In 
the third study, lower gamma-glutamyl transferase (GGT) levels were noted in the Smoflipid 

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group versus the Intralipid group (Tomsits, et al. 2010). However, in 2 of these studies, PN was 
only administrated for up to 2 weeks. Consequently, long-term data for Smoflipid in the 
pediatric population is limited.  
 
Smoflipid was first approved in Sweden in 2004 and is currently approved in 62 countries 
worldwide.  
 
5.2 
Rationale and Purpose of the Study 
Fresenius Kabi, the manufacturer of Smoflipid, has applied for approval of Smoflipid in the 
United States (US). In order to meet the request of the Food and Drug Administration (FDA), 
a post-marketing study will be performed in hospitalized neonates and infants to show safety 
superiority of Smoflipid compared with Intralipid, a currently approved lipid emulsion in the 
US. 
 
The present protocol describes a randomized, controlled, double-blind study in which either 
Smoflipid or Intralipid will be administered as part of a well-defined PN regimen to 
hospitalized preterm and term neonates and infants requiring at least 28 days of PN. The 
purpose of this study is to demonstrate the superiority in safety of Smoflipid (investigational 
drug) compared with Intralipid (reference drug) by evaluating the effect of these products on 
conjugated serum bilirubin levels. In addition, the study will explore if Smoflipid safely 
provides sufficient energy and essential fatty acids (EFAs) to ensure appropriate growth and 
development in these pediatric patients. 
 
Sterols (including phytosterols) and α-tocopherol in the blood of the study patients will be 
evaluated to assess whether a correlation exists between the sterol and/or α-tocopherol levels 
and the incidence of cholestasis (Burrin, et al. 2014, Clayton, et al. 1998, Ng, et al. 2015), to 
address specific concerns communicated by the FDA given published experimental data 
(Carter, et al. 2007, El Kasmi, et al. 2013).  
 
Per the request of the FDA, length of stay in hospital, the number of independent bloodstream 
infections and mortality (as part of serious adverse event [SAE] analyses) will be evaluated as 
well.  
 
5.3 
Benefit/Risk Assessment 
Study patients will receive the study drugs as part of their nutritional support for at least 28 
days during their hospitalization. It is standard clinical practice to incorporate lipid emulsions 
into the PN protocol in patients in whom enteral or oral nutrition is not sufficient or not feasible. 
The alternative treatment, (i.e., supply of calories by large amounts of dextrose, or dextrose 
exclusively) is associated with metabolic complications and liver damage and, therefore, is not 
appropriate (Koletzko, et al. 2005).  
In neonates, and specifically in preterm neonates, an inadequate supply of EFAs and/or their 
derived long-chain polyunsaturated fatty acids during the critical periods of rapid brain growth 
and retinal development may lead to long-term impairment of neurodevelopment and visual 

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function (Clandinin, et al. 1980, Koletzko 1992, Lapillonne 2014). Essential fatty acids and 
polyunsaturated fatty acids cannot be synthesized from other metabolites and need to be 
provided to the neonates as part of their nutritional regimen. Therefore, the administration of 
IVLEs has to be initiated within days of birth in neonates who cannot be fed enterally (Driscoll, 
et al. 2008).  
 
Both study drugs are approved in more than 60 countries. In addition, the comparator drug 
Intralipid is approved for use in the US. Like any other injectable lipid preparation, uncommon 
side effects of Smoflipid may include hypertriglyceridemia, nausea, chills, thrombocytopenia, 
cholestasis, and hepatic impairment after long-term treatment. However, since its introduction 
in 2006, no particular safety issue regarding the use of Smoflipid has been identified. In 
contrast, in the phase 1 study performed by Fresenius Kabi, the increase in serum triglyceride 
(TG) concentrations during infusion of Smoflipid was less pronounced, and elimination of TGs 
after the end of infusion was faster than during infusion of the standard soybean emulsion 
Lipovenös® 20%. This difference was probably due to the MCT portion in Smoflipid. It is 
expected that the fatty acid profile of Smoflipid will have a beneficial effect on the hepatic 
health patients compared to Intralipid (Driscoll, et al. 2008, Rangel, et al. 2012, Vanek, et al. 
2012). The purpose of the present study is to confirm this beneficial effect. 
 
 
6 
Objectives 
The primary objective of the study is to show the superiority in safety of Smoflipid over 
Intralipid as measured by the number of study patients in each treatment group with conjugated 
bilirubin > 2 mg/dL during the first 28 days of study treatment, confirmed by a second sample 
collected 7 days after the first sample.  
 
The secondary objectives are to compare the 2 treatment arms with regards to nutritional 
efficacy, and to evaluate the overall safety of Smoflipid.   
 
6.1 
Study Hypothesis 
The study hypothesis is that the number of study patients who develop cholestasis, defined as 
a conjugated bilirubin level > 2 mg/dL, during the first 28 days of study treatment and 
confirmed by a second sample collected 7 days after the first sample, will be significantly lower 
in the Smoflipid group than in the comparator group. 
 
6.2 
Study Variables 
6.2.1 Primary Variable 
The primary study variable is the number of patients in each treatment group with conjugated 
bilirubin levels > 2 mg/dL during the first 28 days of study treatment, confirmed by a second 
sample collected 7 days after the first sample.  
 
 

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6.2.2 Secondary Variable(s) 
Secondary variables include: 
 
Efficacy: 
• 
Body weight (change from Baseline) 
• 
Body length (change from Baseline) 
• 
Head circumference (change from Baseline) 
• 
Time to full enteral or oral feeds 
• 
Fatty acids in plasma and red blood cell membranes (change from Baseline) 
• 
Holman index 
 
 
Safety: 
• 
Length of stay in hospital 
• 
Ratio of number of independent bloodstream infections / number of days on study 
medication 
• 
Ratio of the number of patients with 1 or more bloodstream infections / number of 
patients on study medication  
• 
Number of patients who complete PN treatment without lipid minimization 
• 
Number of patients who need to be withdrawn from the study due to elevated 
conjugated bilirubin levels 
• 
Area under the curve of conjugated bilirubin for time period in which levels are 
> 1.5 mg/dL  
• 
Cumulative number of days patients are administered a lipid dose without lipid 
minimization  
• 
Time to conjugated bilirubin > 2 mg/dL (confirmed by a second sample collected 7 days 
after the first)   
• 
Conjugated bilirubin 
• 
Total bilirubin 
• 
Serum TGs 
• 
Aspartate aminotransferase (AST) 
• 
Alanine aminotransferase (ALT) 
• 
Gamma-glutamyl transferase (GGT) 
• 
Alkaline phosphatase (ALP) 
• 
Blood glucose 
• 
Blood urea nitrogen (BUN) 
• 
Creatinine 
• 
C-reactive protein (CRP) 
• 
Sterols including phytosterols 
• 
α-tocopherol  
• 
Collection of AE data 
• 
Incidence of bronchopulmonary dysplasia (BPD) 
• 
Incidence of retinopathy of prematurity (ROP) 
• 
Incidence of intraventricular hemorrhage (IVH) 

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• 
Incidence of periventricular leukomalacia (PVL) 
• 
Incidence of necrotizing enterocolitis (NEC) 
• 
Incidence of late-onset sepsis in premature and low birth weight neonates 
 
 
7 
Study Design 
 
7.1 
Description of the Study Design 
This is a prospective, randomized, controlled, double-blind, parallel-group, phase 3 multicenter 
study to compare safety and efficacy of Smoflipid to Intralipid in hospitalized preterm and term 
neonates/infants requiring 28 days of parenteral nutrition.  
 
Treatment group 1: Smoflipid (investigational drug) 
 
Treatment group 2: Intralipid (control drug) 
 
The study drugs, Smoflipid and Intralipid, are lipid emulsions for infusion and will be provided 
in 100-mL bags. Detailed information on dose of study drug, packaging, and labelling is 
provided in Section 11. 
 
The study population will be hospitalized preterm and term neonates/infants who are expected 
to require PN for at least 28 days. Randomization will be stratified depending on the underlying 
disease to ensure that those diseases are evenly distributed in both treatment groups.  
 
Randomization group 1: No necrotizing enterocolitis (NEC) 
 
Randomization group 2: NEC  
 
Criteria for stratification into randomization group 2: 
 
At least one of the following clinical signs present: 
• Bilious gastric aspirate or emesis 
• Abdominal distension 
• Occult or gross blood in stool (no fissure) 
 
And 
 
At least one of the following radiographic findings present: 
• Pneumatosis intestinalis 
• Hepato-biliary gas 
• Pneumoperitoneum 
Patients who do not meet criteria for randomization group 2 will be stratified to randomization 
group 1. 
 

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At the Screening Visit, the signed and dated patient informed consent will be collected from 
the parent or guardian, demographics including race and ethnicity, medical history, prior 
medication, physical examination, vital signs, body weight, body length, and head 
circumference will be measured and documented and a blood sample will be collected to assess 
the eligibility of the patient (refer to Section 10.3).  
 
Within 72 hours of the Screening Visit, the Day 1 Visit must take place, during which the 
eligibility of the patient must be confirmed, taking into consideration the result of the blood 
sample analysis. Upon confirmation of eligibility, an additional blood sample will be collected 
for determination of sterol, and α-tocopherol and fatty acids before the patient’s random 
allocation to a treatment group and first infusion of study drug. Patients will receive PN, 
including study drug, and have their body weight assessed.  
 
During treatment the following data must be documented daily: study drug administered, 
dextrose administered, amino acids administered, EN administered, body weight, AEs and 
concomitant medication.   
 
During the first 28 days of treatment (initial treatment phase) physical examination findings, 
vital signs, body length, head circumference, conjugated bilirubin and results of biochemistry, 
hematology and coagulation analyses must be recorded weekly. If, at the end of the initial 28 
days of treatment, PN is still indicated, patients may continue to receive the study drug until 
Day 84 (study extension phase).  
 
On Day 29 the following criteria will be assessed: AEs, concomitant medications, physical 
examination findings, vital signs, body weight, body length, head circumference, conjugated 
bilirubin, results of biochemistry, hematology and coagulation analyses, α-tocopherol, sterols 
and fatty acids. 
 
In the study extension phase physical examination findings, vital signs, body height, and head 
circumference must be recorded weekly. A blood sample for conjugated bilirubin, 
biochemistry, hematology and coagulation analyses will be collected every other week. 
However, should conjugated bilirubin exceed 1.5 mg/dL, it must be assessed weekly until 
conjugated bilirubin is again ≤ 1.5 mg/dL. On Day 57 and Day 85, an additional blood sample 
will be collected for the determination of sterols, α-tocopherol and fatty acids.    
 
Whenever a patient receives his/her last dose of study medication, an End-of-Treatment Visit 
will be performed the following day. The assessments for the End-of-Treatment Visit are the 
same as for the Day 29 Visit. If administration of IV lipids is required after the End-of-
Treatment Visit, the standard lipid emulsion used in the daily routine at the respective 
participating site will be used.  
 
 
A Follow-Up Visit must be performed 7 days after the End of Treatment Visit. At the Follow-
Up Visit, all information regarding AEs and concomitant medications since the last study 
medication dose will be documented, and physical examination findings, vital signs, body 

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weight, body length, and head circumference must be recorded. In addition, length-of-stay in 
the hospital will be recorded.     
 
If at the End of Treatment visit the conjugated bilirubin level was > 1.5 mg/dL, then conjugated 
bilirubin must be assessed at the follow up visit and followed up until conjugated bilirubin is ≤ 
1.5 mg/dL.     
 
Study start is scheduled for Q3 2015 (first patient in), and study finish is anticipated to be Q4 
2017 (last patient out). 
 
To ensure safety of patients during their participation in the study, medical monitoring must be 
performed on all safety-relevant information collected during the trial: medical history, prior 
and concomitant medications, AEs, and laboratory results. A medical expert will be available 
for safety related questions 24 hours per day throughout the study. 
 
An interim analysis will be performed once 50 patients in each group have completed the study 
per protocol (at least 14 days of study treatment) to calculate the final sample size (refer to 
Sections 8.2.2 and 8.2.68.2.6). 
 
7.2 
Rationale of Study Design, Including Choice of Control Group 
Fresenius Kabi has been requested to perform a study demonstrating superiority of Smoflipid 
compared to Intralipid in terms of a safety benefit as reflected by changes in biochemical 
markers of liver health. 
Long-term use of PN in neonates is sometimes associated with hepatic complications, including 
biochemical alterations (i.e., elevated bilirubin and transaminases) considered to be markers 
for early cholestasis (Colomb, et al. 2000, Javid, et al. 2011, Koseesirikul, et al. 2012, Pichler, 
et al. 2012). These biochemical alterations may worsen with prolonged PN and lipid 
administration and are more prevalent in neonates born at an early gestational age or in 
neonates with a surgical condition (Christensen, et al. 2007, Gura, et al. 2008, Javid, et al. 2011, 
Koseesirikul, et al. 2012). 
 
The incidence of cholestasis in neonates receiving PN for 14 to 28 days ranges from 14% to 
33%, depending on the underlying disease (Christensen, et al. 2007). Javid and colleagues 
reported a median time to cholestasis (defined as 2 consecutive bilirubin levels > 2 mg/dL 
obtained within 14 days) of 23 days in the groups of surgical neonates and 77% of the infants 
who developed cholestasis did so within 5 weeks of PN (Javid, et al. 2011). Consequently, a 
safety benefit of Smoflipid will only become visible, on average, after at least 3 weeks of PN.  
 
 
 
The median time of exposure to PN in this patient group has been reported to be 28 days, with 
approximately 15% of patients still receiving PN after 3 months (8% after 6 months) (Javid, et 
al. 2011). As the number of patients on PN in a given population decreases over time, it may 

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be difficult to enroll enough patients who receive PN for more than 28 days to identify a 
statistically significant difference.  
 
The major constraints for a superiority study comparing any IVLE to Intralipid are that 1) only 
a relatively small subgroup of patients will actually experience negative reactions to the 
standard soybean-oil based emulsion Intralipid, and  
2) to date, no reliable markers have been identified permitting the detection of patients who 
may be at risk of having a negative experience with Intralipid prior to starting PN.  Therefore, 
the present study is performed in a population which, in general, is highly sensitive to 
complications and drug-related side effects, including those for IVLEs (Christensen, et al. 
2007). A study in this population could potentially demonstrate superiority in the safety of 
Smoflipid compared to Intralipid.  
 
Superiority of Smoflipid over Intralipid will be assessed by comparing the number of patients 
in each treatment group developing conjugated bilirubin > 2 mg/dL within the first 28 days of 
study treatment, confirmed by analysis of a second serum sample taken 7 days after the first 
sample. The study will have an adaptive design as the effect size of Smoflipid is unknown. The 
data of the first 50 patients per arm that have completed the study per protocol (at least 14 days 
of study treatment) will be used to calculate the final sample size (refer to Sections 8.2.2 and 
8.2.6). 
 
Additionally, plasma sterol levels, including phytosterols, will be evaluated to assess whether 
a correlation exists between the sterol levels in the blood and the incidence of cholestasis, 
addressing specific concerns the FDA communicated based on experimental data (Carter, et al. 
2007, El Kasmi, et al. 2013).  
 
7.3 
Randomization, Allocation of Patients 
Eligible subjects will be stratified by their underlying disease: 
 
Randomization group 1: No NEC   
 
Randomization group 2: NEC   
 
Criteria for adjudication to randomization group 2: 
 
At least one of the following clinical signs present: 
• Bilious gastric aspirate or emesis 
• Abdominal distension 
• Occult or gross blood in stool (no fissure) 
 
And 
 
At least one of the following radiographic findings present: 
• Pneumatosis intestinalis 

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• Hepato-biliary gas 
• Pneumoperitoneum 
 
Patients that do not meet criteria for randomization group 2 will be stratified to randomization 
group 1. 
 
Within each stratum, subjects will be randomized at Baseline in a 1:1 ratio to receive either 
Smoflipid or Intralipid. 
 
Randomization will be implemented by the unblinded site pharmacist using TEMPOTM 
interactive web response system. Randomization allocation will be 1:1 to Smoflipid and 
Intralipid, respectively. Appropriate randomization codes will be provided on the screen 
immediately after randomization for a subject is requested. The assigned treatment code will 
be stored in TEMPOTM. 
 
TEMPOTM is a web-based platform that integrates the most important functions of this clinical 
study, including patient enrollment, randomization and unblinding procedure, study drug 
management and accountability, eCRF and safety reporting. All individual functions of the 
platform are validated and CFR 21 Part 11 compliant. 
 
Subjects will be identified using a sequential numbering system. During the course of 
screening, the subject will be given a seven-digit number having an underscore following the 
first three digits. The first four digits of this number will be the site number. The last three 
digits will refer to the individual subject according to his/her sequence of entry into the study. 
For example, the first subject screened at site 1802 will be number 1802-001. The unblinded 
site pharmacist will pick the study drug (either Smoflipid or Intralipid) as indicated by 
TEMPOTM for each randomized subject. The correctness of the picked study drug will be 
checked and confirmed by TEMPOTM based on the individual bag number, which the 
pharmacist will be required to type into the system.  The unblinded site pharmacist will affix 
an additional label with the subject (randomization) number onto the bag of the study drug 
when dispensing. 
 
7.4 
Blinding and Decoding 
As this is a double-blind study, the allocation to the treatment groups will not be known by the 
Investigator, patient/ relatives, or members of the Fresenius Kabi Clinical Research Department 
until completion of the study.  
 
Study drug will be delivered to the unblinded site pharmacist in cartons containing 10x 100mL 
bags with study drug type (Smoflipid or Intralipid) indicated on the carton. Both study drugs 
(investigational drug and comparator) are white emulsions and all bags will bear the same study 
specific label which precludes unblinding by visual inspection.  
 
The bags will be labelled individually in accordance with the requirements of Good Clinical 
Practice (GCP)/Good Manufacturing Practice (GMP). The unblinded pharmacist will 

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implement the randomization of the patient as described in Section 7.3 and dispense individual 
blinded bags to the blinded site personnel to preserve the blind for investigator and study 
patient.  
 
A bag ID list will be prepared and provided to Fresenius Kabi manufacturing operations for 
the production of uniquely numbered bag labels. Bag ID numbers from 00001 to 25000 will be 
randomly assigned to Smoflipid or Intralipid to ensure that numbers are not indicative of study 
treatment.  
 
Emergency subject unblinding will be managed in TEMPOTM. In the event an investigator 
needs to unblind a study subject, authorized study personnel at the site will log into the 
appropriate TEMPOTM unblinding workflow, to request access to the unblinded randomization 
code for the subject in question. In order to do so, the investigator will have to acknowledge 
the serious nature of unblinding. Upon taking these steps, TEMPOTM will then provide the 
investigator the specific treatment arm for that subject. Upon exiting the unblinding workflow, 
an email notification of this action will automatically be sent to appropriate management and 
safety officials acknowledging the subject unblinding without providing specific treatment 
arm. Note that this information will also be captured in the study audit trail, so will be more 
secure than other forms of unblinding.  
 
An interim analysis of the unblinded data of the first 50 patients per arm will be performed as 
soon as they have completed the study per protocol (at least 14 days of study treatment) in 
order to establish the final sample size. In accordance with the ICH Guideline E9 – Statistical 
Principals for Clinical Trials the execution of the interim analysis must be a completely 
confidential process. All staff involved in the conduct of the trial - except for those who are 
directly involved in the execution of the interim analysis - will remain blinded to the results of 
the analysis.  
 
 
8 
Data Management and Statistics 
8.1 
Data Management 
This study will be monitored regularly by a Clinical Research Associate (CRA) from the CRO. 
The CRA will check for completion of the entries on the eCRF, compliance with the study 
protocol and GCP, and will compare the eCRF entries with the source data. 100% source data 
verification will be performed. In case of any data discrepancies, queries will be generated 
automatically by the system or manually by Data Management, the Medical Monitor, or the 
CRA. All eCRFs that have been completely reviewed by the CRA will be electronically signed 
by the Investigator when all data queries have been resolved and Data Management has 
confirmed the eCRF is clean.  
 
Data Management will process the data according to the Data Management Plan. 
 
The procedure of eCRF handling from the source up to submission to Data Management is 

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described in Section 12.4. 
 
 
8.2 
Statistics 
 
8.2.1 Study Outcome Measures 
The primary outcome measure is the number of patients in each treatment group with 
conjugated bilirubin > 2 mg/dL during the first 28 days of study treatment, confirmed by 
analysis of a second sample collected 7 days after the first sample. 
 
The secondary outcome measures are: 
 
Efficacy: 
 
• 
Body weight (change from Baseline) 
• 
Body length (change from Baseline) 
• 
Head circumference (change from Baseline) 
• 
Time to full enteral or oral feeds 
• 
Fatty acids in plasma and red blood cell membranes (change from Baseline) 
• 
Holman index  
 
Safety: 
 
• 
Length of stay in hospital 
• 
Ratio of number of independent bloodstream infections / number of days on study 
medication 
• 
Ratio of number of patients with 1 or more bloodstream infections / number of patients 
who received study medication 
• 
Number of patients who complete the PN treatment without lipid minimization 
• 
Number of patients who need to be withdrawn from the study due to elevated 
conjugated bilirubin levels 
• 
 
• 
Area under the curve of conjugated bilirubin for time period in which levels are > 1.5 
mg/dL  
• 
Cumulative number of days patients are administered a lipid dose without lipid 
minimization 
• 
Time to conjugated bilirubin > 2mg/dL (confirmed by a second sample collected 7 days 
after the first) 
• 
Conjugated bilirubin 
• 
Total bilirubin 
• 
Serum TGs 
• 
AST 
• 
ALT 
• 
GGT 

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• 
ALP 
• 
Blood glucose 
• 
BUN 
• 
Creatinine 
• 
CRP 
• 
Sterols including phytosterols 
• 
α-tocopherol 
• 
Collection of AE data 
• 
Incidence of Bronchopulmonary Dysplasia (BPD) 
• 
Incidence of Retinopathy of Prematurity (ROP) 
• 
Incidence of Intraventricular hemorrhage (IVH) 
• 
Incidence of Periventricular Leukomalacia (PVL) 
• 
Incidence of Necrotizing Enterocolitis (NEC) 
 
8.2.2 Sample Size Estimation 
Determination of sample size depends on the primary outcome measure.  
 
There are no reliable data available on the effect size of Smoflipid compared to Intralipid 20% 
with respect to the primary endpoint. Depending on different assumptions a wide range of 
sample sizes is possible. 
 
In the following table the sample size per group is displayed which is required for a 2-group 
Pearson Chi-square test with a one-sided significance level of 0.025 to have 80% power to 
detect the difference between groups depending on different risk probabilities p1 (Intralipid) 
and p2 (Smoflipid) for conjugated bilirubin levels > 2 mg/dL during the first 28 days of the 
study treatment period. 
 
Table 1: Sample Size Calculation for Pearson Chi-Square Test for Two Proportions 
(alpha = 0.025 one-sided, power = 80%). 
Intralipid 
p1 
Smoflipid 
p2 
Relative risk 
p2 / p1 
N  
per Group 
Performance 
0.5 
0.225 
0.45 
47 
Best case 
 
0.325 
0.65 
124 
 
0.4 
0.180 
0.45 
66 
 
 
0.260 
0.65 
176 
Average case 
0.3 
0.195 
0.65 
264 
Worst case 
 
The demonstration of superiority of the safety of Smoflipid versus Intralipid is the primary 
objective of this study (see also Section 6). However, non-inferiority testing will be used as a 
gatekeeper for superiority. If superiority cannot be demonstrated with a reasonable sample size, 
based on the prognostic recruitment rate, the sample size may be adjusted in order to 
demonstrate non-inferiority instead of superiority in the final analysis. In this case non-

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inferiority of Smoflipid compared with Intralipid can be shown if the upper limit of the 97.5% 
confidence interval (CI) would be < ∆ = 1.2 - the predefined limit of non-inferiority.  
 
Based on the scenarios given above a 2-stage adaptive group sequential procedure will be 
performed with an interim analysis performed after 100 patients (50 patients per treatment arm) 
complete the study per protocol (see also Section 8.2.3 and Section 8.2.6). A maximum study 
size of up to 200 patients per group appears to be feasible for the scheduled recruitment period, 
based on recruitment estimates from the participating sites.  
 
Depending on the probability for conjugated bilirubin levels > 2 mg/dL during the first 28 days 
of treatment with Intralipid and the relative risk (Smoflipid/Intralipid) there is a chance to 
terminate the study early after the first stage due to efficacy as visualized in the following 
figure. It displays the number of patients which is required for a 2-group Pearson Chi-square 
test with a one-sided significance level of α1 = 0.01 - the upper limit for the premature 
termination of the study at stage 1 (see Section 8.2.6) and power of 80% to detect the difference 
between groups. 
 
Figure 1: Sample Sizes Needed for Pearson Chi-Square Test for Two Proportions to 
Achieve a Power = 80% (alpha = 0.01 one-sided). 
 
Depending on the result of this interim analysis, the study will either be terminated prematurely 
based on the significance limits determined by Bauer and Köhne (Bauer, et al. 1994), or the 
second part of the trial will be planned with an adaptation of the sample size in an effort to 
demonstrate the superiority (or non-inferiority) of Smoflipid compared with Intralipid. If the 
interim analysis results in an adaption of the sample size that exceeds the maximum study size 
of up to 200 patients per group, the study will be stopped prematurely for futility after the interim 
analysis. 

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8.2.3  Hypothesis Testing 
A detailed and comprehensive Statistical Analysis Plan (SAP) will be prepared and signed 
before the study is unblinded (i.e., before the interim analysis). Any changes to the statistical 
methods set out in this protocol need not be reported as a protocol amendment, but must be 
documented in the SAP and the Clinical Study Report. 
 
The confirmatory analysis is based on the primary efficacy endpoint (number of patients in each 
treatment group with conjugated bilirubin > 2mg/dL during the first 28 days of treatment 
confirmed by analysis of a second sample collected 7 days after the first sample).  
 
Two hypotheses will be tested stepwise: 
 
• H10:   Smoflipid is inferior to Intralipid  
H1A:  Smoflipid is equal or superior to Intralipid 
• H20 :  Smoflipid  is equal to Intralipid  
H2A:  Smoflipid is superior to Intralipid  
 
H20 will be tested only if H10 can be rejected. In this case, there is no multiplicity argument 
because it corresponds to a simple closed test procedure. 
The global significance level will be one-sided (0.025) for non-inferiority as a gatekeeper for 
superiority. Non-inferiority will be investigated using confidence intervals with a predefined 
margin of 1.2 for the risk ratio. Superiority will be based on statistical hypothesis testing (p-
value) 
 
The intention to treat (ITT) population will be the primary population for demonstration of 
superiority. The primary analysis of non-inferiority will be performed using the per protocol 
population. 
An interim analysis will be performed after 100 patients in total (50 in each arm) have completed 
the study per protocol. Depending on the result of the interim analysis, the study will either be 
continued with an adapted sample size (if required and feasible) at a power of at least 80%, to 
achieve a statistically meaningful result or terminated prematurely on the basis of significance 
limits according to Bauer and Köhne (Bauer, et al. 1994) or – if the interim analysis results in 
an adaption of the sample size that exceeds the maximum study size of up to 200 patients per 
group – the study will be stopped prematurely after the interim analysis for futility and be 
analysed descriptively and in an exploratory way.  
The demonstration of superiority of the safety of Smoflipid versus Intralipid is the primary 
objective of the present study.  Only if it is determined that superiority cannot be demonstrated 
with a feasible sample size, based on the prognostic recruitment rate, the final analysis will 
attempt to demonstrate at least non-inferiority. If even non-inferiority cannot be demonstrated 
with a feasible sample size the study will be stopped prematurely after the interim analysis for 
futility and will be analysed descriptively and in an exploratory way. This adaptation – especially 

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the drop of confirmatory hypotheses – is considered appropriate because the respective 
statistical tests will suffer from a serious lack of power and cannot provide appropriate results 
for reliable decisions on the study hypotheses. This situation will be discussed with the FDA at 
that time prior to terminating the study prematurely to determine the feasibility of converting it 
to a non-inferiority study due to considerations of sample size. At present a maximum study size 
of 200 patients per group appears to be feasible for the scheduled recruitment period 
 
The null-hypotheses will be analyzed stratified by the patients’ underlying diseases 
(randomization group 1 or 2, see section 7.3) using the estimates of the common relative risk - 
controlling for stratum (non-inferiority hypothesis) - and the Cochran-Mantel-Haenszel 
statistics of general association for the combined strata (hypothesis of superiority). 
 
The analysis of non-inferiority will be performed using the per-protocol population; superiority 
has to be shown on base of the intention-to-treat (ITT) population.  Sensitivity analyses will be 
performed using the ITT population for demonstrating non-inferiority and the per protocol 
population for demonstrating superiority. 
 
Exploratory subgroup analyses will be performed by race and ethnicity. 
 
8.2.4  Blinded Review / Final Statistical Analysis Plan 
The Sponsor will convene a Blinded Data Review after the data have been cleaned, but before 
the study is unblinded (i.e., interim analysis).  The review will be performed within the 
framework of the requirements of ICH E9. 
 
The terms of reference of the Blinded Data Review shall include, but not be limited to: 
• the determination of whether protocol violations are 'major' or 'minor' 
• the allocation of patients to analysis sets 
• a review of missing data and outliers, their assessment and definition of handling 
• a review of the distribution of the efficacy variables, considering any implications for 
the proposed methods for statistical analysis 
• a review of whether additional covariates need to be included in the analyses 
• the finalization of the SAP 
 
The Blinded Data Review Report will include the definition of major and minor protocol 
deviations and the final allocation of patients to analysis sets.  
 
The Blinded Data Review Report will be finalized before the blind will be broken. Formal 
records shall be kept of when the statistical analysis plan was finalized as well as when the 
blind was subsequently broken. 
 
8.2.5  Definition of Populations 
Safety population 
The safety analysis set will consist of all randomised patients who received at least one dose of 
study medication. 

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Intention-to treat (ITT) population) 
The primary confirmatory analysis of superiority will be performed using the ITT population. 
The ITT analysis set will consist of all randomised patients. 
  
Per protocol (PP) population (main analysis) set   
The primary analysis of non-inferiority will be performed using the PP population. The PP 
analysis set includes all patients who receive study drug for at least 14 days without major 
protocol violations. Major protocol deviations are those that may significantly impact the 
completeness, accuracy, and/or reliability of the study data. A patient may be excluded from 
the PP analysis set for, but not limited to, any of the following conditions: 
• Patient does not meet critical inclusion/exclusion criteria 
• Patient is removed from the study prior to day 28 for other reasons than elevated 
conjugated bilirubin levels 
• Incorrect administration of study product  
 
A blinded review will be performed before breaking of the blind in order to assess and define 
the handling of missing data, data issues as well as to classify major and minor protocol 
violations. The final allocation of patients to analysis sets will be performed during the blinded 
review as described in Section 8.2.4. 
 
8.2.6  Interim and Final Analysis 
A two-stage adaptive group-sequential procedure will be performed, using a global significance 
level of =0.025. After 100 patients in total (50 in each arm) have completed the study per 
protocol an interim analysis will be performed. For the interim analysis, the following limits for 
a premature termination of the trial will be defined (Bauer, et al. 1994):  
 
 
0 = 0.5  
lower limit for the premature termination of the trial with negative   
 
 
 
result 
 
1 = 0.0102  
upper limit for the premature termination of the trial with rejection 
 
 
 
of the null-hypothesis 
 
According to the one-sided formulation of the alternative hypotheses all p-values and confidence 
intervals in the following sections must be calculated one-sided.  
 
At the interim analysis the primary efficacy criterion will be assessed as described in 
Section 8.2.3 at the significance level α1. The null-hypothesis H10 can be rejected if the upper 
limit of the (1-α1)100% CI is less than 1.2 (related to the NI hypothesis), H20 can be rejected if 
the corresponding p-value p1 is less than α1 (hypothesis of superiority). In this case the study may 
be terminated early due to efficacy.  
 
If the upper bound of an (1- α*)100% CI is less than 1.2 only for α* ≥ α0 the null hypotheses 
will be considered accepted which allows early termination due to lack of efficacy. 
 

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If non-inferiority cannot be shown at the time of the interim analysis, but the upper-bound of the 
(1- α*)100% CI is less than 1.2 for any α* with α1<α* <α0 (non-inferiority hypothesis) then the 
second part of the trial will be planned with an adaptation of the sample size. The results of the 
interim analysis at stage 1 influence the second stage as follows:  
 
Let p1= min (α*| upper bound of (1-*)100%-CI is < 1.2) the actual level of significance for 
non-inferiority at stage 1. In order not to exceed the global significance level  = 0.025, the 
corresponding level of significance in the second stage p2 needs to satisfy p1*p2  0.0038. Thus, 
the required number of patients can be calculated for the significance level p2 = 0.0038/p1 
(i.e., non-inferiority of Smoflipid compared to Intralipid is shown if the upper limit of the 
 (1- p2)100% CI is < 1.2 at the second stage).  
 
To determine the sample size necessary to prove superiority of Smoflipid compared to Intralipid 
after non-inferiority is shown at the second stage of the study, the p-value p1' of the actual 
difference between Smoflipid and Intralipid at the first stage will be calculated. It determines the 
level of significance p2' = 0.0038/p1' at which H20 must be tested after H10 is rejected at the 
second stage in order not to exceed the global one-sided significance level  = 0.025. 
 
If H10 can be rejected at the significance level α1 but α1 < p1' < α0 with p1' the p-value of the actual 
difference between Smoflipid and Intralipid at the first stage, then the second part of the trial will 
be planned with an adaptation of the sample size in order to enable rejection of the null hypothesis 
H20 (superiority). Similar to the explanation in the preceding section, the required number of 
patients can be calculated for the significance level p2' = 0.0038/p1'. 
 
Additionally, the risk ratio between Smoflipid and Intralipid with respect to the primary 
outcome parameter observed in the first part of the trial will be taken as a basis for the relevant 
difference when adapting sample size for the second part of the study. 
 
The conditional power for planning stage 2 should be at least 80%. 
 
If the resulting sample size for the second part of the study with respect to the non-inferiority 
hypothesis is greater than the prognostic recruiting rate the study will be terminated after the first 
part of the study. Based on current estimates a maximum study size of 200 patients per group 
may be feasible for the scheduled recruitment period. In this case all data will be analysed 
descriptively and in an exploratory way. Confirmatory hypothesis testing will be dropped 
because the respective statistical tests will suffer from a serious lack of power and cannot 
provide appropriate results for reliable decisions on the study hypotheses. 
 
To assure the stochastic independence of the two p-values, both trial parts must be analysed 
separately. This procedure ensures a global significance level of  = 2.5 %. 
 
In accordance with ICH E9, the execution of the interim analysis must be a completely 
confidential process. All staff involved in the conduct of the trial - except for those who are 
directly involved in the execution of the interim analysis - will remain blinded to the results of 
the analysis. Investigators will only be informed about the decision to discontinue the trial if 

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the trial will be terminated prematurely based of the result of the interim analysis. A second 
statistician, other than the trial statistician, and who is independent from the study will conduct 
the interim analysis. Further details will be provided in the interim analysis plan and/or Data 
Safety Monitoring Board (DSMB) charter. 
After the interim analysis, the Statistical Report will be forwarded to an independent DSMB 
(refer to Section 13.5).  
 
8.2.7 Analysis of Secondary Outcome Measures 
Exploratory analysis of the secondary outcome measures for efficacy and safety as described 
in Section 8.2.1 will be performed comparing both treatment groups: 
 
Summary tables will be presented. Between groups comparisons will be performed with 
adequate statistical tests (e.g. repeated measurement analyses examining the course of variables 
over time, the Kaplan-Meier method for time to event measures, Wilcoxon tests for continuous 
and Fisher's exact tests for binary outcome measures). The corresponding effect size measures 
and confidence intervals will be presented in addition. 
 
If the study is stopped prematurely after the interim analysis because the required sample size 
to demonstrate superiority or non-inferiority for the primary outcome measure is too large to 
be feasible, the analyses of secondary outcome measures will be performed only with 
descriptive statistics and the statistical tests planned above will be dropped. 
(In some cases, model-based analyses (such as competitive risk analysis) might be used to 
examine differences between treatment groups since they provide helpful parameters to 
describe treatment effects. Respective results will only be interpreted in an exploratory and 
descriptive manner. Details will be planned in the SAP for the final analyses.) 
 
Adverse events (AEs) will be categorized by primary system organ class. The number, 
intensity, relation to study medication and action taken will be described by frequency tables. 
Serious adverse events will be discussed separately. 
 
The analysis of the secondary efficacy outcome parameters will be performed using the ITT 
population (intention-to-treat) and the per protocol population (per protocol) in the sense of 
sensitivity analyses. 
 
The analysis of the secondary safety outcome parameters will be performed using the safety 
population. 
 
A comprehensive SAP covering the details of all methods used to analyze the various 
parameters will be prepared before unblinding. The SAP will be reviewed, and if needed, 
updated before unblinding. 
 
8.3 
Replacement of Patients 
Patients withdrawn from study after randomization but before receiving any study drug will be 

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counted as “early drop-outs”. These patients will be replaced and will not have any additional 
assessments. 
 
 
9 
Study Duration 
 
The patients may receive the study drug up to Day 84. Every patient who has a conjugated 
bilirubin level > 1.5 mg/dL will be followed up until the conjugated bilirubin level returns to ≤ 
1.5 mg/dL. 
 
10 
Patient Selection 
10.1 
Study Population 
Long-term use of PN may be associated with hepatic complications, including biochemical 
alterations (i.e., elevated bilirubin and transaminases) considered to be markers reflecting the 
beginning of cholestasis (Colomb, et al. 2000, Javid, et al. 2011, Koseesirikul, et al. 2012, 
Pichler, et al. 2012). These biochemical alterations may worsen with prolonged lipid 
administration as part of PN and are more prevalent in neonates born at an early gestational 
age or in neonates with a surgical condition (Christensen, et al. 2007, Gura, et al. 2008, Javid, 
et al. 2011, Koseesirikul, et al. 2012).  
 
Identifying these patients at the beginning of the PN regimen who may experience these hepatic 
complications is not possible (Christensen, et al. 2007). This study must therefore be performed 
in a population with a high likelihood of developing hepatic complications during prolonged 
PN to increase the chances to obtain a statistically significant result. According to literature, 
the incidence of cholestasis in surgical neonates who received PN for 14 to 28 days ranges 
from 14% for patients with diaphragmatic hernia to 33% for patients with jejunal atresia 
(Christensen, et al. 2007). Other indications related to a high incidence of PN-associated 
hepatic complications include surgical NEC (including spontaneous intestinal perforations; 
33%), gastroschisis (18%), volvulus and spontaneous intestinal perforations (Christensen, et 
al. 2007, Javid, et al. 2011).  
While the incidence of PNALD increases with the duration of PN, the number of patients 
requiring PN decreases rapidly with the duration of the PN (Javid, et al. 2011). The study 
treatment duration of 28 days was chosen as a compromise between the minimum duration to 
observe enough cases of PNALD and a maximum duration that still allows recruiting enough 
patients to obtain statistically significant results.   
 
10.2 
Inclusion Criteria 
1. Neonates and infants, expected to require PN for 28 days  
 
2. Postmenstrual age ≥ 24 weeks  
 
3. Birth weight ≥ 750 g 

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4. Gastroschisis, duodenal, jejunal or ileal atresia, volvulus, spontaneous intestinal 
perforation, or NEC (Bell’s stage 2B or higher)   
 
5. At least 80% of nutritional needs at Baseline are met with PN 
 
6. Signed and dated informed consent obtained from at least 1 parent or legal guardian 
 
10.3 
Exclusion Criteria 
1. Conjugated bilirubin > 0.6 mg/dL 
 
2. Any known pre-, intra- or posthepatic complication that will increase conjugated bilirubin 
levels > 0.6 mg/dL during study participation 
 
3. Suspected liver disease or damage based on either AST, ALT, or GGT exceeding 2.5 × upper 
limit of normal range 
 
4. Active bloodstream infection demonstrated by positive blood culture at screening 
 
5. Cystic fibrosis 
 
6. Meconium ileus  
 
7. Serum TGs > 250 mg/dL 
 
8. Cyanotic congenital heart defect 
 
9. Severe renal failure as evidenced by creatinine > 2.0 mg/dL 
 
 
 
 
 
 
10. History of shock requiring vasopressors 
 
11. Anasarca 
 
12. Extracorporeal Membrane Oxygenation (ECMO) 
 
13. Known inborn errors of metabolism 
 
14. Known congenital viral infection 
 
15. Unlikely to survive longer than 28 days  
 
16. Known hypersensitivity to fish-, egg-, soya- or peanut protein, or to any of the active 
substances or excipients 
 

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10.4 
Withdrawal of Patients from the Study 
Patients withdrawn from study after randomization but before receiving any study drug will be 
counted as “early drop-outs”. These patients will be replaced and will not undergo additional 
assessments. 
The patient’s parent or guardian may voluntarily withdraw the patient from participation in the 
study or prevent the administration of study medication at any time without needing to provide 
any reason. 
If the Investigator has to withdraw a patient from the study, or if the patient´s parent(s) or legal 
guardian(s) refuses to have the patient continue with study participation, patient’s parents or 
legal representatives should be asked to allow that the assessments for the Final Visit the day 
after receiving the last dose of study medication are completed. The reason(s) for study 
withdrawal must be documented.  
Patients who are withdrawn from the study due to AEs or SAEs will be treated and followed 
according to established medical practice to evaluate the course of the AE and ensure 
reversibility or stabilization (also see Section 13). 
The following are justifiable reasons for the Investigator to withdraw a patient from the study: 
 
• 
Intolerable AEs/SAEs 
• 
Deteriorating liver function (see below) 
• 
Unacceptable risk/benefit ratio 
• 
Major protocol deviation(s) 
 
Major protocol deviations are those that may significantly impact the completeness, accuracy, 
and/or reliability of the study data or may affect the patient's rights, safety, or well-being. In 
case of any potential major deviation, the Investigator has to notify the CRA immediately. 
 
Fresenius Kabi reserves the right to discontinue the entire study for internal reasons at any time 
(see also Section 16.3). 
 
Withdrawal Due to Deteriorating Liver Function 
 
If conjugated bilirubin levels exceed 2 mg/dL, a confirmatory sample must be assessed after 
7 days. If conjugated bilirubin levels have increased by at least 1 mg/dL, the Investigator must 
withdraw the patient from the study so the patient can receive an alternative lipid emulsion 
according to standard of care. If conjugated bilirubin levels increased less than 1 mg/dL, the 
patient will remain in the study and continue to receive study medication. Weekly conjugated 
bilirubin analyses must be performed until the patient’s conjugated bilirubin level is again ≤ 
1.5 mg/dL.   
 

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11 
Study Drugs and Medication 
 
11.1 
Characterization of the Investigational Drug 
Smoflipid is a lipid emulsion containing soybean oil, MCTs, olive oil, and fish oil. Smoflipid 
belongs to the pharmacotherapeutic group: “Solutions for parenteral nutrition, fat emulsions” 
(ATC-code: B05BA02).  
 
Smoflipid is indicated as a source of calories and essential fatty acids for parenteral nutrition 
when oral or enteral nutrition is not possible, insufficient, or contraindicated.  
 
1000 mL of emulsion for infusion contain: 
 
Active ingredients: 
Soya-bean oil 
 
 
 
 
60.0 g 
Triglycerides, medium-chain  
 
60.0 g 
Olive oil, refined  
 
 
 
50.0 g 
Fish oil, rich in omega-3-acids 
 
30.0 g 
 
 
Excipients:  
Glycerol (anhydrous)  
 
 
25.0 g 
Purified egg phospholipids 
 
 
12.0 g 
all-rac-α-Tocopherol  
 
 
163 to 225 mg 
Water for Injection 
 
 
 
ad 1000 mL 
Sodium hydroxide for pH adjustment 
pH approx. 8 
Sodium oleate 
 
 
 
 
0.3 g 
 
Total energy 
 
 
 
 
8.4 MJ/L (= 2000 kcal/L) 
pH-value  
 
 
 
 
6 to 9 
Osmolality  
 
 
 
 
approx. 380 mOsm/kg 
Osmolarity  
 
 
 
 
270 mOsm/L 
 
Smoflipid is manufactured at the Fresenius Kabi facilities in Uppsala, Sweden. The Fresenius 
Kabi plant in Uppsala has been inspected and approved by the FDA for production of parenteral 
emulsions (e.g., Intralipid). 
 
11.2 
Characterization of the Control Drug 
Intralipid is a long-chain triglyceride emulsion derived from purified soybean oil and egg yolk 
phospholipids. Intralipid belongs to the pharmacotherapeutic group: “Solutions for parenteral 
nutrition, fat emulsions” (ATC-code: B05BA02).  
 

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Intralipid® 20% is indicated as a source of calories and essential fatty acids for patients 
requiring parenteral nutrition for extended periods of time (usually for more than 5 days) and 
as a source of essential fatty acids for prevention of essential fatty acid deficiency. 
 
1000 mL of the emulsion contains:  
 
Active ingredients:  
Soybean oil  
 
 
 
 
200 g 
 
Excipients: 
Glycerol (anhydrous) 
 
 
 
22.5 g 
 Egg yolk phospholipids  
 
 
12 g 
Sodium hydroxide for pH adjustment 
pH approx. 8 
Water for injections 
 
 
 
ad 1000 mL 
 
Total energy 
 
 
 
 
8.4 MJ/L (= 2000 kcal/L) 
pH-value  
 
 
 
 
6 to 8.9 
Osmolality  
 
 
 
 
approx. 350 mOsm/kg water 
Osmolarity  
 
 
 
 
260 mOsm/L 
 
11.3 
Preparation, Administration and Dosage of Investigational 
Medicinal Products 
Both products will be delivered to the hospital pharmacists in 100 mL bags together with the 
appropriate documentation (e.g., Certificates of Analysis). 
 
Storage conditions (e.g., temperature) of the final product should follow the instructions of the 
pharmacists. Independent from the pharmacy instructions, the final product is not allowed to 
be frozen or stored > 25°C. 
 
The hospital pharmacist(s) will compound all PN components following the Investigator´s 
prescription and according to local regulations and procedures. Only those PN products and 
combinations are allowed during the study treatment period which have been agreed upon with 
Fresenius Kabi and for which compatibility tests have been performed. 
 
The dosage of other macro- and micronutrients should reflect applicable guidelines such as 
those published by the American Society for Parenteral and Enteral Nutrition (ASPEN): 
 
Amino acids:  
 
Infants 
Initiation 
Advance by 
Goal 
preterm 
1.5-3.0 g/kg/day 
1.0 g/kg/day 
3.0-4.0 g/kg/day 
term 
1.5-3.0 g/kg/day 
1.0 g/kg/day 
2.0-3.0 g/kg/day 
 

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Dextrose: 
 
Infants 
Initiation 
Advance by 
Goal 
preterm 
5.0-7.0 mg/kg/min 
1.4-1.7 mg/kg/min 8.0-18.0 mg/kg/min 
term 
6.0-9.0 mg/kg/min 
3.5 mg/kg/min 
12.0-18.0 mg/kg/min 
 
Trace elements, electrolytes and vitamins will be provided according to the Investigator’s 
prescription, hospital practice approved by Fresenius Kabi and applicable guidelines.  
 
Use and dose of heparin and carnitine must be documented.   
 
Amino acid solution together with dextrose and micronutrients (trace elements, electrolytes, 
vitamins), heparin and carnitine may be mixed together in one container.  
 
The study drug will be assigned according to the randomization scheme and administered 
separately. No total nutrient admixtures will be allowed using the study drug. 
 
The type of venous access should follow clinical routine and is in the responsibility of the 
Investigator considering variables such as osmolarity. 
 
In case of administration via a central vein, lipid will be connected to a Y-connector before 
entering the body.  All required compatibility data will be provided by Fresenius Kabi. 
 
The target lipid dose is 3 g/kg/day. In patients that are already receiving PN before starting 
study treatment, the lipid dose will either stay at 3.0 g/kg/days or increased in 1g/kg/days steps 
to a maximum of 3.0 g/kg/day. In patients that have not yet started PN prior to study 
participation, lipid dose will be increased stepwise using the following regimen: 
 
 
 
Study Day 
Patients < 1500 g 
Patients ≥ 1500 g 
Day 1 
1.0 g/kg/day 
2.0 g/kg/day 
Day 2 
2.0 g/kg/day 
3.0 g/kg/day 
Day 3+ 
3.0 g/kg/day 
3.0 g/kg/day 
 
The investigational or control drug will be infused over 20 - 24 hours, as per hospital policy, 
at a weight based infusion rate. The respective hospital policy will be filed in the investigator 
site file. If the blood draw is from the PN/lipid infusion line, then lipid (study drug) should be 
held for 4 hours prior to the time of blood sampling. 
 
Blood samples for TGs and blood glucose monitoring during dose ramp-up will be taken as 
follows: 
 
 
 
Neonates < 1500 g:  
At 1 g/kg/day, 2 g/kg/day and first dose of 3 g/kg/day  
 
 
Neonates ≥ 1500 g:  
At first dose of 3 g/kg/day  
 

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Once the target dose has been reached, TGs must be checked weekly.  
 
Should TGs exceed 250 mg/dL at any time, lipids will be withheld until analysis of another 
blood sample the following morning. If TGs are then ≤ 250 mg/dL, lipids will be restarted. If 
not, this procedure will be repeated the next morning.   
 
Conjugated bilirubin values must be assessed weekly. If the conjugated bilirubin level exceeds 
1.5 mg/dL, the lipid dose must be decreased to 1 g/kg/day. Dextrose will be increased 
accordingly to maintain adequate energy provision. Once the lipid dose is minimized to 
1 g/kg/day, it will not be increased again.   
 
If conjugated bilirubin exceeds 2 mg/dL the patient’s dose will remain at 1 g/kg/day until 
analysis of the next weekly blood sample. If conjugated bilirubin has increased further by at 
least 1 mg/dL, the patient must be withdrawn from the study and the Investigator will use 
institutional standard of care for the provision of PN. If not, the patient will remain in the study 
and will continue to receive study medication. Weekly conjugated bilirubin analyses should be 
performed until the patient’s conjugated bilirubin level is again ≤ 1.5 mg/dL.  
 
As soon as the patient receives 80 mL/kg/day oral/enteral feeds and achieved sustained 
tolerance (i.e. at least 3 days), the dose of study drug will be reduced to 1 g/kg/day. Patients 
will be weaned off study drug upon receiving 100 mL/kg oral/enteral feeds and achieving 
sustained tolerance (i.e. at least 3 days).  
 
The expected administration of study drug for each patient should be at least 28 days. If PN is 
still indicated at the end of 28 days, patients may receive the study drug for up to Day 84 (refer 
also to Section 12.2.4). If administration of parenteral lipids is required after termination of the 
12 week study period, the standard lipid emulsion used at the respective participating site will 
be used.  
 
11.4 
Compliance 
Study drug will be administered under the supervision of the (Sub-) Investigator and 
documented in the eCRF. 
 
In the hospital pharmacy the CRA (refer also to Section 14.1) will perform checks of any 
used/unused study medication in the context of drug accountability. 
 
Any interruption of the study drug infusion for longer than 4 hours has to be explained and 
documented in the eCRF. Any other deviations from planned infusions will be documented in 
the eCRF. 
 
11.5 
Supply, Packaging, Labelling and Storage 
Fresenius Kabi will provide the Investigator with a sufficient amount of study medication 
together with the respective Certificates of Analysis and a temperature record documenting the 
temperature of the study medication during the transport to site. 

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The study mediation will be provided in 100 mL bags. The bags of both study drugs are labelled 
with the same study specific blinded clinical label. To ensure the traceability of each bag of the 
study drugs, each bag is labelled additionally with a uniquely numbered bag label according to 
a bag ID list provided to Fresenius Kabi manufacturing operations, as described in Section 7.4. 
All manufacturing and labelling operations are performed in accordance with the requirements 
of Good Manufacturing Practice (GMP)/Good Clinical Practice (GCP) and local regulations 
by authorized personnel. The information included on the clinical labels is attached to this 
protocol in Annex 1. 
 
Study drugs will be delivered to the unblinded site pharmacist in cartons with non-blinded 
clinical labels (Smoflipid or Intralipid) containing 10 x 100mL bags. In addition to the study 
drugs, subject randomization tear-off labels will be delivered to the unblinded site pharmacist. 
The unblinded pharmacist will implement the randomization of the patient as described in 
Section 7.3. The pharmacist will affix an additional label with the subject (randomization) 
number onto the overpouch (secondary bag) of the study drug prior to  dispensing the individual 
blinded bags to the blinded site personnel to preserve the blind for investigator and study patient 
relatives.   
The investigator will receive blinded and randomized study drug. Directly prior to 
administration, the investigator will open the overpouch and transfer the label with the subject 
(randomization) number from the overpouch to the primary bag for the time of the duration of 
the infusion. 
Throughout the study and until administration, the drugs will be stored in a securely locked 
area, only accessible to authorised personnel, at 20° to 25°C (68° to 77°F) [see USP Controlled 
Room Temperature]. 
TEMPOTM will automatically record the use of study medication and order resupply when the 
trigger value has been reached.   
Samples of the clinical supplies used in a clinical study must be retained by the organization 
that conducted the study and stored under conditions that will maintain the integrity, identity, 
strength, quality, and purity of the samples. Therefore, reference samples of each study drug 
will be kept by Fresenius Kabi. The retention period is at least 2 years after completion or 
formal discontinuation of the present clinical trial. Any reference samples must be retained and 
stored under conditions consistent with product labelling in a segregated area, locked, and with 
limited access.  
 
11.6 
Return of Study Materials and Study Drugs 
Unused study documentation forms and any unused study drug will be returned to Fresenius 
Kabi (or a designated provider) for destruction at the end of the study or earlier. Alternatively, 
after written notice from Fresenius Kabi, unused forms and study medication may be destroyed 
at the investigational site. Destruction will be documented. Any used bags can be destroyed 
after the drug accountability check by the pharmacist, Investigator, or study nurse.  
 
11.7 
Drug Accountability (Delivery, Receipt, Storage, Use, Return) 
Receipt of study medication (investigational/control medication), as well as return of any 

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unused medication will be documented by the Investigator in TEMPOTM. The study medication 
is property of Fresenius Kabi and must not be provided to third parties. It will be stored 
separately and safely and will be used exclusively for this study as described in this protocol. 
Any use of study medication is documented on each patient’s eCRF. At the end of the study, 
the Investigator will have to explain any discrepancies between delivery, use, and return of 
study drug (drug accountability). 
 
11.8 
Concomitant Medication 
From the time of receipt of the signed/dated informed consent form and throughout the trial 
period, any concomitant medication will be allowed as clinically needed to treat concomitant 
diseases with the exception of: 
 
- Beta-carotene, Lutein, Lycopene, Selenium, Vitamin A, Vitamin C and Vitamin E as 
sole additives 
- Any IV lipid emulsion other than the study medication 
- Enteral administration of fish oil   
 
The use of concomitant medications must be documented in the eCRFs (type, start, end, 
dosage, frequency, route, indication for use). Prior and concomitant volume replacement with 
blood, plasma, or colloid transfusions will be recorded. 
 
Concomitant nutrition, including enteral and oral feeding and also micronutrients, will be 
documented in the eCRFs during the study (type, dosage, route, caloric content). 
 
Heparin and carnitine used in the PN will be documented on a specific eCRF page, as they are 
not related to a specific underlying disease but part of the PN regimen. 
 
 
12 
Study Schedule 
12.1 
Summary of Procedures 
Please refer to the study schedule (Section 2) for a complete overview of all procedures to be 
performed at the individual study visit. All procedures must be documented in the eCRF. 
 
12.2 
Detailed Description of Investigations 
12.2.1 Screening Visit  
The Screening Visit has to take place no more than 3 days before the Day 1 visit. 
 
The procedures of the Screening Visit have to be executed in the following sequence: 
 
Informed consent process 
A signed/dated informed consent form must be obtained from the patient’s parent(s) or 

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legal guardian(s) prior to the performance of any study related procedures or evaluations.  
The parent(s) or guardian(s) of the patient will be informed of the nature of the study by the 
Principal Investigator or a designated Investigator of the study team to whom the Principal 
Investigator has delegated this task as documented on the study responsibility log. The 
parent(s) or guardian(s) will also receive a copy of the “parent information sheet”. 
The Investigator will inform the parent(s) or guardian(s) of the patient regarding the following 
aspects of the study: 
 
- Voluntary participation 
- Description of the clinical investigation 
- Risks  
- Benefits 
- Alternative procedures or treatments 
- Confidentiality 
- Medical treatment in event of injury 
- Contact person for any questions or study related issues 
 
In addition, the parent(s) or guardian(s) of the neonate or infant will be given the opportunity 
to discuss the aspects of the study, ask questions about the study, and have those questions 
answered by the Investigator.  
The parent(s) or guardian(s) of the neonate or infant will be allowed sufficient time to consider 
this information.  
Two copies of the informed consent form will have to be signed and dated by the parent(s) or 
guardian(s) and Investigator; one copy will be provided to the parent(s) or guardian(s) of the 
neonate or infant, and the other copy will be kept in the investigator’s site file and the date of 
consenting will be documented in  the patient’s medical file. The patient’s medical file must 
also document that the parent(s) or guardian(s) provided consent prior to participation in the 
study.  
 
Review of inclusion and exclusion criteria 
The patients will be assessed for eligibility (Section 10.2 and Section 10.3). The patient will be 
enrolled in the study only if all inclusion criteria are met and none of the exclusion criteria 
apply. Otherwise the patient will be considered a screening failure and will not be enrolled. 
If a patient is enrolled in the study without meeting all of the enrolment criteria, the patient will 
be withdrawn from the study and replaced. 
 
Additional procedures performed or assessed during the screening visit: 
 
▪ Recording of demographic data:  
- age, defined as postmenstrual age in weeks   
- date of birth 
- sex  

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- race 
- ethnicity  
 
▪ Assignment of patient number and completion of the screening log 
 
▪ Recording of physical examination findings and body weight 
- physical inspection 
- body weight 
 
▪ Recording of vital signs  
- blood pressure (systolic and diastolic) 
- heart rate 
- body temperature 
 
▪ Recording of the patient’s medical history 
 
▪ Recording of prior medications (e.g., medications prescribed / taken prior to obtaining 
signed and dated informed consent) 
 
▪ Collection of blood sample for local laboratory analysis of the following parameters: 
- Biochemistry:  total bilirubin, AST, ALT, GGT, ALP, TGs, creatinine, glucose, CRP 
- Hematology: CBC, leukocytes, platelets, erythrocytes, hemoglobin, hematocrit 
- Coagulation: INR 
 
▪ Collection of a blood sample for central laboratory analysis of conjugated bilirubin 
 
12.2.2 Baseline Visit/Day 1 
During Baseline Visit, the patient receives the first dose of study medication. Thus, the day of 
this visit is defined as Day 1. All other Visits and Study Days are relative to the Baseline Visit; 
therefore, there is no time window defined for the Baseline Visit.  
 
Prior to randomization and administration of the first dose of study drug, the Investigator must 
review the results of the analysis of the blood sample collected at the Screening Visit to ensure 
that none of the exclusion criteria is met. 
 
If none of the exclusion criteria related to the laboratory analysis are met, the Investigator 
can proceed with the procedures for the Baseline/Day 1 Visit in the following sequence: 
 
▪ Confirmation that all eligibility criteria are still fulfilled 
 
▪ Collection of a blood sample for the specialized lab analyses (fatty acids, sterols and α-
tocopherol) in babies that can tolerate the blood draw (1mL) 
 
▪ Recording of physical examination findings and body measurements 

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- physical inspection 
- body weight 
- body length measured by a length board 
- head circumference 
 
▪ Recording of vital signs  
- blood pressure 
- heart rate 
- body temperature 
 
▪ Randomization to study drug  
 
▪ Administration of study drug in PN regimen 
 
▪ Recording of oral, enteral, and parenteral nutrition 
 
▪ Recording of AEs 
 
▪ Recording of concomitant medication 
 
12.2.3 Daily Assessments During Treatment Phase 
During treatment, the patient receives study medication every day and the following 
patient data will have to be documented daily: 
 
▪ Amount of study drug administered (dose in g/kg/day and volume in mL) 
 
▪ Dose of dextrose administered (mg/kg/min) 
 
▪ Dose of amino acids administered (g/kg/day) 
 
▪ Amount of parenteral nutrition administered excluding study drug (volume and caloric 
content) 
 
▪ Amount of enteral nutrition administered (volume and caloric content)  
 
▪ Oral nutrition administered (volume and caloric content) 
 
▪ Body weight   
 
▪ Adverse events 
 
▪ Concomitant medication 
 
12.2.4 Treatment Visits  
All treatment visits should occur in a time window of ±1 day relative to the scheduled day of 

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the visit. 
 
The following procedures will be performed at each treatment visit: 
 
▪ Recording of physical examination and body measurements 
- physical examination 
- body weight 
- body length measured by a length board 
- head circumference 
 
▪ Recording of vital signs  
- blood pressure 
- heart rate 
- body temperature 
 
Additional procedures performed only on visits on Days 8, 15, 22, 43, 57 and 71: 
 
▪ Collection of a blood sample for local laboratory analysis of the following parameters: 
- Biochemistry: total bilirubin, AST, ALT, GGT, ALP, TGs, creatinine, glucose, CRP 
- Hematology: CBC, leukocytes, platelets, erythrocytes, hemoglobin, hematocrit 
- Coagulation: INR 
 
▪ Collection of a blood sample for central laboratory analysis of conjugated bilirubin 
 
Additional procedures only performed on visit on Day 57: 
 
▪ Collection of a blood sample for the specialized lab analyses (fatty acids, sterols and α-
tocopherol) 
 
12.2.5 Day 29, Day 85, and End-of-Treatment Visit  
The same procedures have to be performed on Day 29 (end of initial treatment phase), Day 85 
(end of treatment extension phase), and the first day after receipt of the last dose of study 
medication (End-of-Treatment Visit), independent of the reason for which the study medication 
was stopped. 
 
Conditions for continuing in the study after Day 29 / End-of-Treatment Visit: 
 
Patients may continue in the study after the Day 29 / End-of-Treatment Visit if: 
 
- PN is still indicated, 
and/or 
- Conjugated bilirubin > 1.5 mg/dL  
If the patient will continue to receive PN into the study extension phase (after Day 28) and later 

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weaned from study medication with a conjugated bilirubin value ≤ 1.5 mg/dL, then the End-
of-Treatment Visit must be performed on the first day after receipt of the last dose of study 
medication. 
If the patient has been weaned from study medication with a conjugated bilirubin value 
> 1.5 mg/dL, the patient needs to complete the End-of-Treatment Visit on the first day after 
receipt of the last dose of study medication, but will continue to be followed up until conjugated 
bilirubin levels are ≤ 1.5 mg/dL. Conjugated bilirubin levels must be assessed weekly until 
they are ≤ 1.5 mg/dL. As the patient will receive no study medication after the End-of-Study 
Visit, no additional evaluations will be performed.   
If consent is withdrawn, the parent(s) or guardian(s) of the patient should be encouraged to 
allow the patient to complete scheduled evaluations, including the End-of-Treatment Visit 
evaluations and the Follow-Up Visit, and informed that the patient will be given appropriate 
care under medical supervision until any ongoing AEs resolve or until the patient’s condition 
becomes stable. 
 
No patient will receive study medication beyond Day 84 of the study.  
 
The following procedures will be performed 
 
▪ Recording of physical examination and body measurements 
- physical inspection 
- body weight 
- body length measured by a length board 
- head circumference 
 
▪ Recording of vital signs  
- blood pressure 
- heart rate 
- body temperature 
 
▪ Collection of a blood sample for local laboratory analysis of the following parameters: 
- Biochemistry: total bilirubin, AST, ALT, GGT, ALP, TGs, Cr, glucose, CRP 
- Hematology: CBC, leukocytes, platelets, erythrocytes, hemoglobin, hematocrit 
- Coagulation: INR 
 
▪ Collection of a blood sample for central laboratory analysis of conjugated bilirubin 
 
▪ Collection of a blood sample for the specialized lab analyses (fatty acids , sterols and α-
tocopherol) (1mL) 
 
▪ Time to full enteral or oral feeds (if study treatment ended)  
 
▪ Recording of AEs 
 

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▪ Recording of concomitant medication 
 
Note: Should the End-of-Treatment Visit be performed within the study extension phase and 
<2 weeks after the collection of the last blood samples for the specialized lab analyses, then 
this blood sample will not be collected again at the End-of-Treatment Visit 
 
12.2.6 Additional Assessments 
During the course of the study, blood samples will need to be collected in order to monitor 
TGs. This monitoring will occur whenever the lipid dose is changed: 
 
• During initial increase in lipid dose 
• With lipid pause or reduction due to increased plasma TG > 250 mg/dL 
 
Investigators must collect blood samples for blood cultures in case of clinical symptoms of a  
bloodstream infection.  
 
Bloodstream infections will be considered independent if at least one blood culture analysis 
between two positive blood cultures has given a negative result.  
 
These additional assessments will be performed at the local laboratory of the individual site. 
 
12.2.7 Follow-Up Visit  
The Follow-Up Visit will be performed 7 days after the End-of-Treatment Visit to ensure the 
safety of the patient after study participation.  
 
The following procedures have to be performed: 
 
▪ Recording of adverse events  
 
▪ Recording of concomitant medication 
 
▪ Recording of physical examination and body measurements 
- physical examination 
- body weight 
- body length measured by a length board 
- head circumference 
 
▪ Recording of vital signs  
- blood pressure 
- heart rate 
- body temperature 
 
▪ Recording of Length of Stay in the hospital 

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▪ Recording of AEs 
 
▪ Recording of concomitant medication 
 
The Length of Stay in the hospital will be calculated using the worksheet provided in Annex 4 
to this protocol. 
 
All unresolved AE and SAEs will be followed by the Investigator until the events are resolved, 
the patient is lost to follow-up, or the adverse event is otherwise explained.  
 
All patients that had conjugated bilirubin levels >1.5 mg/dL at the Follow up visit will have 
the conjugated bilirubin level assessed at the Follow-Up Visit, and then it should be assessed 
weekly until conjugated bilirubin is again ≤ 1.5 mg/dL.    
 
12.3 
Methods 
12.3.1 Experimental and Analytical Methods 
Assessment of Body Length 
Body length of the patients will be assessed in lying position with the help of a length board.  
 
Assessment of Body Weight 
Scales used for measuring body weight of patients must be calibrated and revised according to 
applicable local requirements. The relevant documentation must be updated and available on 
request.    
 
Calculation of Length-of-Stay 
Length of stay in hospital will be calculated using the Worksheet from Annex 4 to the protocol. 
 
12.3.2 Laboratory Variables 
12.3.2.1 Standard Laboratory Values Including Conjugated Bilirubin 
Determination of the standard laboratory values will be assessed using established validated 
techniques at the local laboratory of the site except for plasma conjugated bilirubin which 
will be assessed using established validated techniques at the central laboratory: 
 
  
The following parameters will be assessed at the local laboratory: 
 
Biochemistry: total bilirubin, AST, ALT, GGT, ALP, TGs, creatinine, glucose, CRP 
 

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Hematology: CBC (total white blood cells, total red blood cells, hemoglobin, hematocrit, mean 
corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin 
concentration, red blood cell distribution width and platelets) 
 
Coagulation: INR 
 
The valid normal ranges and a certification from the local laboratory will be obtained before 
start of the study.  
The blood samples needed for the assessment of conjugated bilirubin at the central laboratory 
will be obtained at the same time as the blood sample for the local laboratory, to reduce the 
number of needle pricks. 1ml of full blood will be required for the analysis.  
An exact description of the methodology for drawing, handling and shipping of the samples as 
well as the methodology used for the analysis of conjugated bilirubin at the central lab is 
outlined in the lab manual.  
 
The investigators must review all laboratory results. Laboratory values outside the normal 
ranges must be assessed concerning their clinical significance by the respective investigator 
and the assessment must be documented on the lab report / in the patient’s medical file. If the 
out of range value is considered clinically significant then it is an AE (see Section 13) and must 
be documented in the eCRF (see Section 12.4.1).   
 
Assessments are preferably done at each visit. If the blood draw is from the PN/lipid infusion 
line, then lipid (study drug) should be held for 4 hours prior to the time of blood sampling.  
Study investigators must draw additional blood samples to monitor TG levels during initial 
increase in lipid dose and if TG increases beyond 250 mg/dL. The Investigators must also draw 
blood samples for blood cultures if a patient shows clinical symptoms of a bloodstream 
infection.   
 
12.3.2.2 Specialized Laboratory Analyses  
Blood samples for analysis of fatty acids (in red blood cell membranes and plasma), sterols 
(including phytosterols) and α-tocopherol will be taken on Day 1 (Baseline) and Day 29 (End-
of-Treatment Visit). 
In case patients continue on study treatment beyond Day 29 additional samples should be taken 
on Day 57 and on Day 85 (End-of-Treatment Visit).   
The blood samples needed for the specialized laboratory will be obtained at the same time as 
the blood sample for the local laboratory, whenever possible, to reduce the number of needle 
pricks. 1ml of full blood will be required for the analysis 
 
Fatty acids to be assessed: linoleic acid, α-linolenic acid, Mead acid, eicosapentaenoic acid 
(EPA), arachidonic acid, docosahexaenoic acid (DHA).  
 
The Holman index will be calculated to evaluate whether the minimum requirement for the 
essential fatty acid linoleic acid has been met (Holman 1960). The value of 0.2 will be 
considered as upper limit of the normal range (Holman, et al. 1979).  

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Sterols to be assessed: sitosterol, desmosterol, brassicasterol, lanosterol, ergosterol, 
campesterol, stigmasterol, sitostanol, lathosterol, squalene (a sterol precursor), and cholesterol. 
 
Vitamin to be assessed: α-tocopherol  
 
Those special assessments will be performed at the following specialized laboratory: 
 
 
An exact description of the methodology for drawing, handling and shipping of the samples 
for the specialized laboratory analyses is outlined in the lab manual.  
 
The sites will not receive any laboratory reports for those specialized analyses to maintain the 
blind, as the differences in the respective sterol, fatty acid and α-tocopherol content between 
study and control drug are expected to be reflected in the results of the blood sample analyses.  
 
12.4 
Documentation of Patient Data 
All patient data generated during the study will be documented in the patient’s medical records 
(source data). The definition of source data is: all information in original records and certified 
copies of original records of clinical findings, including observations or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial. 
Only the investigator and authorized co-workers (as listed on the form "Authorisation of 
medical staff" provided by Fresenius Kabi) will transcribe the patient data from the source data 
into the eCRF. 
 
All evaluations that are reported in the eCRF must be supported by source documents. 
 
12.4.1 The Electronic Case Report Form  
All patient data generated during the study will be recorded in the electronic Case Report Forms 
(eCRFs) provided by Clinipace. The eCRF is specifically designed to meet the data recording 
requirements of the Clinical Study Protocol and the requirements of FDA 21 CFR Part 11. Only 
the investigator and authorized co-workers (as listed on the form "Authorisation of medical 
staff" provided by Fresenius Kabi and trained appropriately on the eCRF system) are allowed 
to fill-in the eCRFs or to make corrections, and will have access to the data or may change 
data, without the possibility of deleting the original entries. The documentation of this training 
will we kept in the investigator’s site file.  
 
After completion, each eCRF will be signed and dated by the investigator electronically. For 
all laboratory data, the units or any transformation of units must be clearly defined.  
 
Transformation of data during data processing will be documented.  

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The eCRF will be validated to comply with FDA 21 CFR Part 11 requirements. Validation 
documentation will be filed in the Trial Master File 
 
This study will be monitored regularly by a CRA from a CRO. The CRA will check for 
completion of the entries on the eCRFs, their compliance with the study protocol and with 
Good Clinical Practice, and will compare the eCRF entries with the source data. Source data 
verification will be performed for all patients and 100% of the data, including all informed 
consent forms.  
 
Archiving has to be done according to requirements as described in Section 19.6 and the 
process for Data Management is described in Section 8.1. 
 
 
13 
Adverse Events and Serious Adverse Events  
13.1 
Definitions 
13.1.1 Adverse Event  
Adverse event means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  
An adverse event (also referred to as an adverse experience) can be any unfavorable and 
unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a drug, and does not imply any judgment about causality. An adverse 
event can arise with any use of the drug (e.g., off-label use, use in combination with another 
drug) and with any route of administration, formulation, or dose, including an overdose (21 
CFR 312.32(a)). 
 
A treatment-emergent adverse event is an event that emerges during treatment, having been 
absent pretreatment, or worsens relative to the pretreatment state 
 
13.1.2 Serious Adverse Event  
An SAE is any untoward medical occurrence that: 
• Results in death 
• Is life-threatening1 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is of medical importance2 
 
1The term “life-threatening” in the definition of “serious” refers to an event in which the patient 
was at risk of death at the time of the event; it does not refer to an event which hypothetically 

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might have caused death if it were more severe. 
2Important medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the patient and may require intervention to prevent one of 
the other outcomes listed in the definition above, should also usually be considered serious (21 
CFR 312.32(a)). 
 
This definition permits either the sponsor or the investigator to decide whether an event is 
serious. The investigator’s perspective may be informed by having actually observed the event, 
while the sponsor is likely to have broader knowledge of the drug and its effects to inform its 
evaluation of the significance of the event. Because serious adverse events are critically 
important for the identification of significant safety problems, FDA believes taking into 
account both the investigator’s and the sponsor’s assessment is important.  
Therefore, if either the sponsor or investigator believes that the event is serious, the event must 
be considered serious and evaluated by the sponsor for expedited reporting (21 CFR 312.32(a) 
and 312.32(c)(1)). 
13.1.2.1 
Suspected Adverse Reaction  
Suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety reporting, 
‘reasonable possibility’ means there is evidence to suggest a causal relationship between the 
drug and the adverse event. A suspected adverse reaction implies a lesser degree of certainty 
about causality than adverse reaction, which means any adverse event caused by a drug (21 
CFR 312.32(a)).  
13.1.2.2 
Unexpected Adverse Reaction  
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in 
the investigator brochure or is not listed at the specificity or severity that has been observed; 
or, if an investigator brochure is not required or available, is not consistent with the risk 
information described in the general investigational plan or elsewhere in the current 
application, as amended. 
The Smoflipid IB and the current version of the Product Information for Intralipid 20% (Annex 
5) will serve as the main reference documents to assess expectedness. Referring to these 
documents, the expectedness of an Adverse Reaction is assessed by Fresenius Kabi 
exclusively. 
13.1.2.3 Serious and Unexpected Suspected Adverse Reaction  
Serious and unexpected suspected adverse reactions are all adverse reactions that are 
considered to be: 
• Serious (by the investigator and/or Fresenius Kabi) 
• Unexpected (by Fresenius Kabi) 
If either the sponsor or investigator believes that the event is serious, the event must be 
considered serious and evaluated by the sponsor for expedited reporting (21 CFR 312.32(a) 
and 312.32(c)(1)). The sponsor is responsible for determining whether there is a reasonable 

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possibility that the drug caused the adverse event, taking into consideration the investigator’s 
assessment.  
 
13.2 
Assessment of Adverse Events 
For each AE, the investigator has to perform an assessment on: 
• Intensity (severity) 
• Seriousness 
• Clinical relevance 
• Causality (to study drug and study procedures) 
• Outcome 
• Action taken 
 
13.2.1 Intensity/Severity 
For the intensity assessment of AEs based on clinical signs and symptoms, abnormal laboratory 
parameters or vital signs, the "Common Terminology Criteria for Adverse Events" (CTCAE) 
V4.03 should be used as far as reasonable (Annex 3). If these criteria are not reasonably 
applicable to an AE, the event’s intensity should be classified according to the investigator’s 
discretion as close as possible to CTCAE V4.03 based on the comparison with the most severe 
case encountered in past training and clinical experience. For such events the following general 
category descriptions may be used. 
Table 2: Adverse Event/Serious Adverse Event Intensity 
Grade Category 
Definition/Explanation 
1 
Mild 
Asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
2 
Moderate 
Minimal, local or non-invasive intervention indicated; 
limiting age-appropriate instrumental activities of daily 
living. 
3 
Severe 
Severe or medically significant but not immediately 
life-threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; limiting self care 
activities of daily living. 
4 
Life-Threatening* 
Life-threatening consequences; urgent intervention 
indicated.  
5 
Fatal** 
Death related to the AE. 
NOTE: *Life-threatening or **fatal AEs will also meet the identical seriousness criteria and 
thus will qualify as SAEs. 

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All AEs, including those related to laboratory values (see Section 12.3.2) and vital signs will 
be classified according to the CTCAE V4.03, if applicable. 
 
Table 3: Assessment of Adverse Events Associated with Laboratory Variables and Vital 
Signs 
CTCAE current 
version grading  
adverse events 
Rating of clinical relevance Consequence 
grade 1 
clinically relevant1 
document as Adverse Event 
not clinically relevant 
no further action 
grade 2 
clinically relevant1 
document as Adverse Event 
not clinically relevant 
Investigator must explain 
his rating that AE is not 
clinically relevant 
grade 3 
usually clinically relevant 
document as Adverse Event 
grade 4 
usually clinically relevant 
document as Serious Adverse 
Event 
grade 5 (“death”) 
always clinically relevant 
document as Serious Adverse 
Event 
 
CTCAE V4.03 (Annex 3) 
1An event is clinically relevant if it resulted in a clinical intervention.  
 
For classification of other AEs (e.g., constipation, diarrhea) see CTCAE V4.03. Adverse 
Events that are not listed should be classified according to the Investigator’s discretion as close 
as possible to CTCAE V4.03 (Annex 3). 
 
In case the AE is reported as the result of an abnormal laboratory parameter or vital sign, the 
respective clinical manifestation should be described, if applicable. Indicating the laboratory 
parameter or vital sign only is unsufficient. All assessments will be supervised by the monitor, 
the data management (query), and the medical review. 
 
13.2.2 Causality 
For all AEs, the causal relationship to study drug and to study procedures is to be assessed by 
the investigator (regardless of whether they occurred under investigational drug or control 
drug). 
 
Related 
“Related” means that a clinical event has a “reasonable causal relationship” to a medicinal 
product. A causal relationship between the study drug and the clinical event is at least a 

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reasonable possibility, i.e., the relationship cannot be ruled out. The expression “reasonable 
causal relationship” is meant to convey in general that there are facts (evidence) or arguments 
to suggest a causal relationship (ICH E2A).  
Clinical events which are not rated as “not related” are to be reported as related. A related event 
is equal to an adverse drug reaction. The following facts may indicate a “reasonable causal 
relationship”: 
 
- Situations where it cannot be excluded that the study drug has caused or contributed to 
the AE/SAE. 
- A plausible temporal relationship between AE/SAE and administration of the 
investigational medicinal product. 
- No alternative reason can be confirmed by laboratory or other investigations or testing. 
 
In case of “no reasonable causal relationship” the alternative cause should be clearly stated, if 
available. 
 
Not related with the use of the tested investigational medicinal product means that the criteria 
mentioned above are not met. 
 
13.2.3 Relationship to Study Procedures 
Relationship to Study Procedures means that there is a reasonable possibility that the event 
is caused by specific circumstances of the protocol such as diagnostic or administration 
procedures. 
 
13.2.4 Action Taken 
The action taken by the Investigator as a result of the AE will be classified in one of the five 
following categories: 
1. None (= continuing according to protocol). 
2. Dose reduced, possibly meaning: 
a) Reducing the dose of the study drug. 
b) Maintaining the dose level, despite required increase as per protocol. 
c) Reducing of the infusion rate. 
3. Study drug discontinued and restarted. 
4. Study drug discontinued permanently. 
5. Other therapy, e.g.: 
- Drug therapy was initiated to counteract the AE. Action taken other than the above, e.g. 
reduced dose of concomitant medication, or initiated non-drug remedial therapy.  
 
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consequence of AEs. 
 
13.2.5 Outcome 
The outcome of the AE (and NOT the patient’s outcome) is to be assessed at the time of 
documentation of the AE based on the following categories: 
1. Resolved (= complete resolution of AE). 
2. Resolved with sequelae. 
3. Not resolved (includes AEs which are improving but not yet resolved completely, AEs 
which are ongoing at time of documentation, and AEs which are still present when a patient 
deceases due to other causes or due to another AE). 
4. Fatal (= death due to the AE). 
5. Unknown (e.g. if patient is lost to follow-up). 
 
13.3 
Reporting and Documentation Procedures 
In this study, all AEs have to be documented and reported.  
 
All AEs including SAEs must be documented by the investigator on the AE page of the eCRF.  
 
ALL SAEs must be entered into the eCRF and reported to the Sponsor within 24 hours of first 
knowledge of the event by study personnel. 
 
If considered necessary, the investigator may decide to withdraw patients from the study as a 
consequence of SAEs or AEs (including Suspected Adverse Reactions). Similarly, the entire 
study may be prematurely terminated by Fresenius Kabi for medical or ethical reasons. 
 
If a patient is withdrawn from the study due to an AE at the end of the study treatment period, 
the study patient should be followed-up until an outcome of the event can be defined. If this is 
not possible due to clinical or organizational reasons, an outcome assessment has to be 
performed by the investigator. A final examination should be performed.  
 
Adverse events (AEs) will be coded by data management using the latest version of Medical 
Dictionary for Regulatory Activities (MedDRA) and displayed in tables and listings using 
MedDRA system organ class and Preferred Term.  
 
The list of undesirable effects observed during administration of Smoflipid or Intralipid is 
displayed in the current version of the IB for Smoflipid or the current Product Information for 
Intralipid 20% (Annex 5).  
If any of these side-effects occur then the investigator should assess if infusion of study 
medication should be stopped or continued at a reduced dosage. 
 
 

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13.3.1 Reporting of Serious Adverse Events 
The Investigator should not delay initial SAE report entry due to missing data. As soon as the 
minimum information is available the initial SAE report will be entered into eCRF, in any case, 
no later than 24h after becoming aware of the SAE/SUSAR. The eCRF will automatically 
generate a notification e-mail that will inform the safety associate at Clinipace and the director 
global safety at Fresenius Kabi that an SAE has been reported.  
 
Each initial SAE report should contain at least the following information: 
• Study number. 
• Patient number. 
• Patient’s date of birth (or age). 
• Investigator’s name and address. 
• AE (description, start date, outcome on the day of the report). 
• Investigator’s assessment of seriousness and intensity (severity). 
• Investigator’s assessment of causal relationship to study drug and study procedures.  
If necessary, the investigator will provide follow-up reports immediately after knowledge of 
further relevant information. 
 
13.3.2 Documentation and Reporting of Other Safety-Relevant Information 
and Unanticipated Problems 
Any: 
• Pharmaceutical quality issue regarding study medication 
• Report of overdose 
• Report of use outside the scope of this clinical study protocol 
must be documented and reported immediately but within 24 hours at the latest of awareness 
to the Safety Contact at Fresenius Kabi via e-mail (Section 13.3.3). 
 
For studies conducted under 21 CFR part 312, investigators are required to promptly report “to 
the IRB … all unanticipated problems involving risk to human subjects or others,” including 
adverse events that should be considered unanticipated problems requiring a significant, and 
usually safety-related, change in the protocol such as revising inclusion/exclusion criteria or 
including a new monitoring requirement, informed consent, or investigator’s brochure (§§ 
312.66, 312.53(c)(1)(vii), and 56.108(b)(1)).  
For this purpose, investigators must report all unanticipated problems immediately to the Safety 
Contact at Fresenius Kabi (section 13.3.3 Safety Contact at Fresenius Kabi). 
 

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An individual AE occurrence ordinarily does not meet these criteria because, as an isolated 
event, its implications for the study cannot be understood. 
Therefore, FDA recommends that there should be careful consideration of whether an AE is an 
unanticipated problem that must be reported to IRBs. Fresenius Kabi will conduct ongoing 
safety evaluations, including periodic review and analyses of its entire safety database, not only 
for IND safety reporting purposes, but also to update investigator brochures, protocols, and 
consent forms with new safety information. 
Accordingly, to satisfy the investigator’s obligation to notify the IRB of unanticipated 
problems, Fresenius Kabi will process and analyze adverse event information and other safety 
relevant information for the entire study and assess whether an adverse event occurrence is 
both unanticipated and a problem for the study.  Fresenius Kabi will provide the investigator 
with the report for submission to IRB.  
 
13.3.3 Safety Contact at Fresenius Kabi 
The Clinipace Safety Associate will contact the site for clarification of data entered onto the 
eCRF, or to obtain missing information. In the event of questions regarding SAE reporting, 
the site may contact: 
 
 
In case of urgent questions regarding any safety aspect of this trial, Safety in Clinical Trials at 
Fresenius Kabi OR Global Medical Affairs Officer at Clinipace can be reached as follows: 
 
 
 
 
 

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13.3.4 Reporting to Competent Authorities, Institutional Review Boards, 
and Investigators 
Fresenius Kabi as the sponsor of this trial will inform the concerned competent authority on 
IND safety reports  and IRBs about unanticipated problems involving risk to human subjects 
or others, including adverse events that should be considered unanticipated problems on an 
expedited basis (21 CFR 312.66).  
Fresenius Kabi will also provide periodic safety reports and/or line listings to the IRBs as 
required. General and local requirements will be followed.  
All investigators participating in the study will receive IND Safety Reports and information on 
unanticipated problems. 
 
13.3.5 Period of Observation 
The period of observation begins on the day the patient’s legal representatives have signed the 
Informed Consent Form. The end of the observation period is defined as the time of the last 
follow-up visit.  
 
All unresolved AEs should be followed-up by the Investigator until the outcome can be defined 
but at least until the last follow-up visit. 
 
All patients, in whom study medication was stopped due to increased conjugated bilirubin 
levels, will be followed up until the conjugated bilirubin levels have decreased below 1.5 
mg/dL.    
 
All unresolved serious adverse events will be followed by the Investigator until the events are 
resolved, the patient is lost to follow-up, or the adverse event is otherwise explained. 
 
When the patient has been discharged from the hospital, the Investigator should instruct the 
patient’s personal physician (only if parent/guardian allows) to report any SAE/AE that this 
physician believes might reasonably be related to participation in this trial. The investigator 
should notify Fresenius Kabi immediately of any such SAE. 
 
13.4 
Unblinding of Treatment for Emergencies 
In case of a medical emergency requiring identification of the treatment of the patient, the 
treatment blind may be broken. For unblinding procedure see Section 7.4. 
 
If an emergency unblinding becomes necessary, the Investigator should notify the 
Sponsor/Medical Monitor, if possible, prior to unblinding.  
 
If an Investigator, or patient, is unblinded, the patient must be withdrawn from the clinical 
study and procedures accompanying withdrawal are to be performed. 
 
Serious and Unexpected Suspected Adverse Reactions, which are subject to expedited 

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reporting, should be unblinded before submission to the Competent Authorities.  
In case of unblinding, the blinding of Fresenius Kabi’s (and the CRO’s) clinical trial team must 
be maintained wherever possible, i.e., no information as to a broken treatment code must be 
communicated to any blinded member of the trial team. The unblinding must be notified 
immediately to the CRA responsible for the site. 
 
13.5 
Data Safety Monitoring Board 
In this trial an independent DSMB will be involved. The DSMB is a multidisciplinary group 
consisting of clinical trial scientists and statisticians experienced in managing PN in preterm 
and term neonates as well as conducting and analysing randomized clinical trials. The DSMB 
members are not otherwise participating in the trial. The DSMB will be responsible for the 
monitoring of patient safety. The DSMB can request any analysis during the course of the study 
on either a blinded or unblinded basis.  
In this study an unblinded interim analysis will be performed (Section 8.2.6) and the DSMB 
will make recommendations on further study conduct including the final sample size based on 
the safety and efficacy data from the Interim Analysis.  
 
The working principles will be defined in a DSMB charter describing the composition of the 
DSMB, responsibilities, organization, flow of information, evaluation and decision principles, 
and interactions. 
 
 
14 
Monitoring 
Site monitoring is conducted by CRAs to ensure the human patient protection, study 
procedures, laboratory, study intervention administration, and data collection processes are of 
high quality and meet sponsor, ICH E6 – Good Clinical Practice and, when appropriate, 
regulatory guidelines.  
 
14.1 
Function of the Clinical Research Associate 
The Investigator will permit the CRA to monitor the study. The purposes of this monitoring 
are: 
• To check that a valid signed informed consent form is on file for each study patient  
• To check for pharmaceutical quality issues regarding study medication. 
• To check for unreported overdose and report, if required. 
• To assess the progress of the study. 
• To review the compliance with the Clinical Study Protocol. 
• To discuss any problems. 
• To help the investigators dealing with the investigator’s file. 

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• To check all signed Informed Consent forms for accuracy and completeness 
• To check the completed CRFs for accuracy and completeness. 
• To verify CRF’s content against source documents 
• To check if the staff has changed and if so whether the new employees have been accurately 
trained and informed about their tasks. 
• To assess the status of drug storage, dispensing and retrieval. 
• To review the documentation retention. 
• To supervise, assist, initiate AE- and SAE-reporting, if applicable. 
• To check for unreported safety issues (hidden AEs) and to assist with SAE reconciliation. 
 
The Investigators and their staff will be expected to cooperate with the CRA, to be available 
during at least a portion of the monitoring visit to answer questions and to provide any missing 
information. The CRA will schedule such site visits in advance and not arrive unannounced. 
 
Monitoring will be performed by:  
 
 
14.2 
Frequency of Monitoring 
During the clinical part of the study, each study site will be visited by the monitor as soon as 
possible after first patient of each site has been screened and informed consent was signed, 
followed by visits approximately every 6 weeks, as appropriate. 
 
15 
Audits and Inspections 
Auditing (quality assurance) and inspections may be performed to ensure compliance of the 
study with Good Clinical Practice (GCP) requirements. The auditor works on behalf of 
Fresenius Kabi but is independent from the operational departments within Fresenius Kabi. 
The investigator and Contract Research Organization permit the respective person direct access 
to source data/documents. 
 
15.1 
Audits 
15.1.1 Auditing Procedures 
At the study site the auditor will check the following: 

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• Preconditions to start the study. 
• Completeness and correctness of the patient Informed Consent. 
• Compliance of study with study protocol. 
• Source data check. 
• Drug accountability. 
• General compliance of the study with GCP and national law. 
• Organization of the trial and delegation of staff responsibilities. 
• Patient recruitment, screening, enrolment and treatment allocation/randomization. 
• Changes in trial or routine hospital procedures, if any. 
• Handling of (Serious) AEs inclusive reporting and follow-up. 
 
15.1.2 Frequency of Audits 
Auditing will be performed according to an audit plan. 
 
Four on-site audits are planned for this trial, but audits may be performed at any time at any 
site during the study as considered necessary.  
 
15.1.3 Documentation of Audits 
After each auditing visit the auditor will compile an audit report including an audit certificate. 
A copy of the certificate may be passed on to the investigator on request. 
 
15.2 
Quality Control of Clinical Trial Documents 
All key elements of a clinical study (e.g. Clinical Study Protocol, CRFs, Informed Consent, 
Clinical Study Report) will be checked internally, e.g. by an appropriate member of the clinical 
research department, at Fresenius Kabi.  
 
16 
Modifications During the Study 
16.1 
Protocol Amendments 
If both Fresenius Kabi and the Coordinating Investigators agree upon a change or addition in 
the study protocol during the course of the study this must be documented in a written protocol 
amendment. These amendments become part of the study protocol. 
 
Minor modifications, minor deviations or specifications of the study protocol can be described 
in a non-substantial amendment or a file note, as appropriate. 
Substantial amendments must be submitted to the IRBs and the authorities. In case of 
substantial amendments that affect information submitted to both the CA and the IRBs, the 
sponsor should make arrangements to submit the notifications in parallel. For substantial 
amendments to information that only the CA assesses, the sponsor should not only submit the 

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amendment to the CA but also make arrangements to inform the IRBs about this application. 
Similarly, the sponsor should inform the CA of any substantial amendment to information for 
which only the IRB is responsible (e.g. facilities for the trial). 
 
Examples for substantial amendments are: 
• Change in trial design. 
• Change in measures of efficacy. 
• Change of inclusion and exclusion criteria. 
• Change of safety reporting and evaluation. 
• Changes that are likely to have an impact on the safety of the trial patient. 
• Change of the interpretation of the scientific documents in support of the conduct of the 
trial. 
• Changes that are otherwise significant. 
 
16.2 
Protocol Deviations 
No deviation from the study protocol is allowed unless a formal amendment is made. In case a 
deviation has occurred, the Investigator must document it in the eCRF.  
 
Major protocol deviations are those protocol deviations that may significantly impact the 
completeness, accuracy, and/or reliability of the study data or that may affect the patient's 
rights, safety, or well-being. In case of any potential major deviation the investigator has to 
notify the CRA immediately.  
 
16.3 
Premature Termination of the Study 
Fresenius Kabi has the right to terminate the study at a specific study site or completely at any 
time. Reasons which may require termination are: 
• Patient enrolment is too slow. 
• The investigator fails to comply with the study protocol or legal requirements. 
• Data recording is not accurate, e.g. eCRFs are not completely filled in. 
• The incidence and/or severity of AEs/SAEs in this or in parallel studies indicate a potential 
health hazard caused by treatment with the study medication/control medication. 
• Fresenius Kabi is requested by CA to terminate the study. 
• Fresenius Kabi decides to terminate the study due to internal reasons. 
 
In case of prematurely termination of the study, the sponsor shall notify the CA and IRBs within 
15 days and give reasons for termination, which should clearly be explained. Additionally, the 
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final examinations are required. 
 
 
17 
Final Clinical Study Report 
Fresenius Kabi is responsible for compilation of the final clinical study report (CSR). The 
report will be written according to the ICH E3 guideline. The final report will be submitted to 
the Coordinating Investigator and all Principal Investigators for approval and signature. A copy 
of the final CSR will be sent to each Principal Investigator for his/her file. 
 
 
18 
Administrative Requirements 
The trial will be carried out in accordance with the ICH E6 - Guidelines for Good Clinical 
Practice, the Declaration of Helsinki, revised version (64th WMA General Assembly, 
Fortaleza, Brazil, October 2013), CRF Code of Federal Regulations Title 21 and all applicable 
national laws.  
 
18.1 
Authority Identification Number 
Fresenius Kabi has obtained an NCT identification number for the clinical study from the 
ClinicalTrials.gov database, via internet, by filling in an application form. This number 
identifies a trial unambiguously. 
 
18.2 
Institutional Review Board 
Fresenius Kabi will submit the study protocol including the Informed Consent to the 
responsible IRBs for review. Approval by the IRB is a pre-requisite for initiation of the study. 
Fresenius Kabi will provide the investigator with a copy of the approval letter and a list of the 
names and occupations of the committee members. Amendments that are substantial must be 
notified to the CA and the IRBs and the sponsor should make arrangements to submit the 
notifications in parallel. For substantial amendments to information that only the CA assesses, 
the sponsor should not only submit the amendment to the CA but also make arrangements to 
inform the IRBs that they have made the application. Similarly, the sponsor should inform the 
CA of any substantial amendment to information for which only the IRB is responsible (e.g. 
facilities for the trial). 
 
During the study the IRBs will be informed of any ADRs which are both serious and un-
expected and any other SAEs as required by the IRB. Changes increasing the risk to patients 
and/or affecting significantly the conduct of the trial will also be reported to the IRBs. 
Fresenius Kabi will notify the IRBs of the end of the trial within 90 days. 
 
18.3 
Submission to the Competent Authority 
Fresenius Kabi is responsible for submission of study-related documents to the CA (Food and 
Drug Administration, Center for Drug Evaluation and Research, Division of Gastroenterology 
Products) before study start. Approval by the CA is a prerequisite for initiation of the study. 

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Fresenius Kabi will notify the CA of the end of the trial within 90 days. 
 
18.4 
Notification of Local Authority  
Not applicable in the US.  
 
18.5 
Patient Information and Informed Consent 
It is the responsibility of the investigator to give each legal representative(s) of the patient full 
and adequate verbal and written information regarding the objective and procedures of the 
study and the potential benefits, discomforts and risks involved prior to inclusion in the study. 
The investigator must inform the legal representative(s) about appropriate alternative 
procedures or courses of treatment, if any, that might be advantageous to the patient. The legal 
representative(s) must be informed in writing about their right to withdraw the patient from the 
study at any time without specification of reasons. The legal representative(s) have to be 
informed that refusal to participate and a discontinuation of participation at any time will 
involve no penalty or loss of benefits to which the patient is otherwise entitled. The legal 
representative(s) have to be informed that they are covered by insurance and, therefore, need 
the consent of the investigator if other medical treatment (e.g. to treat a concomitant illness) is 
required, except in an emergency situation. Written patient information should be given to each 
legal representative(s) before enrolment. The written patient information must not be changed 
without prior agreement with Fresenius Kabi. Furthermore, it is the responsibility of the 
investigator to obtain a signed Informed Consent Form (ICF) from all legal representative(s) 
prior to inclusion of the patient into the study. 
 
The legal representative(s) should have enough time (ample time) and opportunity to enquire 
about details of the trial and to decide whether or not to allow participation in the trial.  
The dated and signed Informed Consent forms should be filed by the investigator for mandatory 
review by study CRA or for possible future audits and inspections where this is permitted 
and/or required. The investigator will confirm the receipt of ICF from each legal representative 
by signing the appropriate page(s) of the eCRF.  
 
18.6 
Patient Insurance 
In accordance with ICH E6 – Good Clinical Practice and national requirements, Fresenius Kabi 
has taken out a personal liability insurance 
 
 in the amount 
of US$ 5.000.000 for each patient participating in the trial.  
 
18.7 
Patient Privacy 
Fresenius Kabi confirms and upholds the principle of the patients’ right to protection against 
invasion of privacy. Throughout the study, all data which will be passed on to Fresenius Kabi 
will only be identified by patient numbers and patients’ date of birth as this is mandatory to 
know for the evaluation of the study. The data will be blinded correspondingly in all data 
analyses. 

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In compliance with ICH E6 – Good Clinical Practice concerning the acceptance of clinical 
studies, source data verification will be done in detail by the on-site monitor at each visit or 
during a study audit by the auditor. The source data verification will be performed according 
to local data protection law. 
 
18.8 
Initiation of the Study 
The Investigator may not enroll any patient prior to completion of a formal study initiation visit 
with the CRA. 
The following documents will be provided in original by the Investigator to Fresenius Kabi 
prior to study start: 
• Signed protocol. 
• Investigators’ agreement on the clinical study. 
• Financial disclosure according to 21 CRF Part 54 
• Curriculum vitae of the PI and his co-investigator(s). 
• List of normal laboratory values of local laboratory incl. methods and certificates.  
 
 
19 
Agreements 
19.1 
Confidentiality Agreement 
This study protocol is provided to the Principal Investigator, potential investigator, or 
consultant, and the IRB for review. The information contained in this protocol is confidential 
and, except for the extent necessary to obtain Informed Consent, may not be disclosed unless 
such disclosure is required by law. People to whom the information is disclosed must be 
informed that the information is confidential and may not be further disclosed by them. 
 
Similarly, the Investigator and their staff will not pass any other study-related information, 
documents or medication to third parties. All study materials and documents provided by 
Fresenius Kabi including this protocol, are property of Fresenius Kabi. 
 
19.2 
Publication of Results 
Fresenius Kabi is free to use all study results for registration, for world-wide scientific product 
information, and for publication. 
 
The Investigator may publish a publication relating to the study in scientific or medical journals 
and may present an abstract or presentation relating to the study at medical and scientific 
conferences and meetings; provided, however, that Fresenius Kabi shall determine authorship 
of the multicenter publication for the study and the Investigator shall withhold its proposed 
publication, presentation, or abstract relating to the study until publication of the multicenter 
publication. In the event the multicenter publication does not occur within 365 days after the 

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completion of the study at all sites, the Investigator may publish its own abstract under the 
terms and conditions defined in the individual clinical trial agreement, between the 
investigator, the institution and Fresenius Kabi. 
 
19.3 
Payment 
Financial obligations of Fresenius Kabi are outlined in the clinical trial agreement between the 
institution (investigator) and Fresenius Kabi. 
 
19.4 
Potential Conflicts of Interest 
A financial disclosure form according to 21 CRF Part 54 will have to be signed by each 
investigator participating in the study. 
 
19.5 
Incentives to Patients 
Not applicable. 
 
19.6 
Archiving 
Electronic CRF: At the end of the study, the investigator will receive a CD with the eCRFs of 
his study patients for archiving.  
 
All records and documents pertaining to the conduct of the study (including eCRFs, patient in-
formed consent forms, drug accountability sheets, original data including the patient files) must 
be retained by the investigator until Fresenius Kabi notifies the investigator(s)/institution(s) in 
writing that the trial related records are no longer needed ( if not otherwise specified in national 
requirements and respective contracts with sites). It is the responsibility of the investigator to 
ensure that the data saved on electronic media remains readable thought the archiving period. 
Retrospective identification of all patients must be possible at any time. 
 
 

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20 
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21 
Annexes  
 
ANNEX 1: Study Drug Label Information 
 
ANNEX 2: Signature pages for Principal Investigators  
 
ANNEX 3: Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03,  
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of 
Health National Cancer Institute, Publish Date: June 14, 2010.   
 
ANNEX 4: Length of Stay calculation Worksheet  
 
ANNEX 5: Product Information for INTRALIPID 20% (a 20% intravenous fat emulsion), 
revised May 2015.