Clinical trial NCT03563222
Conditions: Malnutrition, Child
Keywords: Parenteral nutrition Pediatrics Malnutrition Nutritional needs
Sponsor: Fresenius Kabi
Start date: 2019-12-18; Completion date: 2022-07-08
Enrollment: 1 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Evaluate the safety and efficacy of Smoflipid compared to standard of care lipid emulsion Intralipid 20% administered via a central vein in pediatric patients 3 months to 16 years of age who require parenteral nutrition for at least 90 days and up to 1 year.

Detailed description:

Arms: arm 1: Smoflipid is a sterile, nonpyrogenic, white, homogenous lipid emulsion for intravenous infusion. The lipid content of Smoflipid is 0.20 g/mL, and comprises a mixture of soybean oil, medium chain triglycerides, olive oil, and fish oil. 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.

The mean essential fatty acid content of Smoflipid is 35 mg/mL linoleic acid (omega-6) and 4.5 mg/mL α-linolenic acid (omega-3). arm 2: Intralipid 20% is a sterile, non-pyrogenic fat emulsion intended as a source of calories and essential fatty acids. Intralipid 20% is indicated as a source of calories and essential fatty acids for patients requiring parenteral nutrition for extended periods of time and as a source of essential fatty acids for prevention of essential fatty acid deficiency. The major component fatty acids are linoleic acid, oleic acid, palmitic acid, α-linolenic acid and stearic acid.
Interventions: intervention 1: Smoflipid intervention 2: Intralipid, 20%
Intervention descriptions: intervention 1: The study drugs will be infused via a dedicated line for parenteral nutrition (PN) into a central vein using a central venous catheter or a peripherally inserted central catheter.

The initial rate of infusion should be no more than 0.05 mL/minute for the first 10 to 15 minutes. If no untoward reactions occur, the rate can be changed to permit infusion of 0.5 mL/kg/hour.

The individual dosage of study drug should be infused at a constant rate for 10 to 24 h/d. The administration flow rate is determined by dividing the volume of study drug by the duration of the infusion. Maximum infusion rate for lipid should not exceed 0.125 g/kg/h lipid.

Study drug infusions should be given 5 to 7 days per week. Study treatment will last for a minimum of 90 consecutive days and as long as PN is indicated, up to 365 consecutive days. If the indication for PN continues after Study Day 365, PN will continue per normal institution policy. intervention 2: The study drugs will be infused via a dedicated line for parenteral nutrition (PN) into a central vein using a central venous catheter or a peripherally inserted central catheter.

The initial rate of infusion should be no more than 0.05 mL/minute for the first 10 to 15 minutes. If no untoward reactions occur, the rate can be changed to permit infusion of 0.5 mL/kg/hour.

The individual dosage of study drug should be infused at a constant rate for 10 to 24 h/d. The administration flow rate is determined by dividing the volume of study drug by the duration of the infusion. Maximum infusion rate for lipid should not exceed 0.125 g/kg/h lipid.

Study drug infusions should be given 5 to 7 days per week. Study treatment will last for a minimum of 90 consecutive days and as long as PN is indicated, up to 365 consecutive days. If the indication for PN continues after Study Day 365, PN will continue per normal institution policy.

Protocol documents:
Prot_SAP_000.pdf: 
Clinical Study Protocol SMOF-028-CP4 
Smoflipid® (lipid injectable emulsion)  
 
Version: Final 2.0 
Date: 19 Feb 2019 
C O N F I D E N T I A L 
Page 1 of 78 
 
 
Title: 
Prospective, Randomized (1:1), Double-Blind, Parallel-Group, 
Active-Controlled, Multicenter Study to Compare Safety and 
Efficacy of Smoflipid® to Intralipid® 20% in Pediatric Patients of 
3 Months to 16 Years of Age Requiring Parenteral Nutrition for 
at Least 90 Days and up to 1 Year 
Authority 
Identification no.: 
IND 102,137 
Fresenius Kabi  
Study Identifier: 
SMOF-028-CP4 
Indication: 
Smoflipid (lipid injectable emulsion) 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.  
Study phase 
4 
Investigational drug: 
Smoflipid (lipid injectable emulsion) 
Control drug: 
Intralipid 20% (a 20% I.V. fat emulsion) 
Protocol status: 
Final 2.0 
Date: 
 
19 February 2019 
Sponsor: 
Fresenius Kabi Deutschland GmbH 
  
 
 
  
Else-Kröner-Straße 1 
D - 61346 Bad Homburg  
Germany 
 
 
In case of emergency during out-of-office-hours please contact (Sponsor's medical expert 
according to ICH GCP):  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NCT03563222


Clinical Study Protocol SMOF-028-CP4 
Smoflipid® (lipid injectable emulsion)  
 
Version: Final 2.0 
Date: 19 Feb 2019 
C O N F I D E N T I A L 
Page 2 of 78 
 
This Clinical Study Protocol (CSP) is the property of Fresenius Kabi. 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) (IRB)/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 study 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), the Code of Federal Regulations (CFR) Title 21 and the respective national 
laws and regulations. 
The CSP and all subsequent amendments to the CSP are agreed upon between Fresenius Kabi 
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-028-CP4 
Smoflipid® (lipid injectable emulsion)  
 
Version: Final 2.0 
Date: 19 Feb 2019  
C O N F I D E N T I A L 
Page 3 of 78 
 
Responsibilities (Signature Page) 
The signatories confirm that this Clinical Study Protocol contains all information and 
regulations necessary for the conduct of this particular trial. We sign the protocol as an 
agreement of the details of the clinical trial and the means of data recording. We commit 
ourselves to comply with all instructions and regulations as laid down in this clinical trial 
protocol, in the current version of the Declaration of Helsinki, in the International Conference 
on Harmonisation (ICH)-Good Clinical Practice (GCP) Guideline, in the Code of Federal 
Regulations (CFR) Title 21, Part 312 and applicable national laws and regulations. Changes to 
this protocol require the written agreement of both the Investigator and Fresenius Kabi.  
 
 
Coordinating Investigator 
 
  
 
 
 
 
 
 
 
 
 
______________________ 
_________________________________ 
 
Date (DD_Month_YYYY) 
Signature 
 
 
Chief Medical Officer Fresenius Kabi 
 
  
  
  
  
 
 
 
 
 
 
______________________ 
_________________________________ 
 
Date (DD_Month_YYYY) 
Signature 
 
 
 
 
 


Clinical Study Protocol SMOF-028-CP4 
Smoflipid® (lipid injectable emulsion)  
 
Version: Final 2.0 
Date: 19 Feb 2019  
C O N F I D E N T I A L 
Page 4 of 78 
 
 
Head of Divisional Medical, Clinical and Regulatory Affairs Fresenius Kabi 
 
 
 
  
  
 
 
  
 
 
 
______________________ 
_________________________________ 
 
Date (DD_Month_YYYY) 
Signature 
 
Director Global Safety Fresenius Kabi 
 
 
 
 
 
 
 
 
 
 
 
______________________ 
_________________________________ 
 
Date (DD_Month_YYYY) 
Signature 
 
Clinical Project Manager Fresenius Kabi 
 
 
 
 
  
 
 
 
 
 
 
 
 
______________________ 
_________________________________ 
 
Date (DD_Month_YYYY) 
Signature 
 


Clinical Study Protocol SMOF-028-CP4 
Smoflipid® (lipid injectable emulsion)  
 
Version: Final 2.0 
Date: 19 Feb 2019  
C O N F I D E N T I A L 
Page 5 of 78 
 
 
Contract Research Organization (CRO) 
  
 
 
 
 
 
 
 
 
 
 
______________________ 
_________________________________ 
 
Date (DD_Month_YYYY) 
Signature 
 
 
Biostatistics 
  
 
  
 
 
 
 
 
 
 
 
_______________________ 
_________________________________ 
 
Date (DD_Month_YYYY) 
Signature 


Clinical Study Protocol SMOF-028-CP4 
Smoflipid® (lipid injectable emulsion)  
 
Version: Final 2.0 
Date: 19 Feb 2019  
C O N F I D E N T I A L 
Page 6 of 78 
 
Study outline 
Title: 
Prospective, Randomized (1:1), Double-Blind, Parallel-Group, 
Active-Controlled, Multicenter Study to Compare Safety and 
Efficacy of Smoflipid® to Intralipid® 20% in Pediatric Patients of 
3 Months to 16 Years of Age Requiring Parenteral Nutrition for 
at Least 90 Days and up to 1 Year. 
 
Authority 
Identification no.: 
IND 102,137 
Fresenius Kabi  
Study Identifier: 
SMOF-028-CP4 
 
Indication: 
Smoflipid (lipid injectable emulsion) 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. 
 
Study Phase: 
4 
 
Objectives: 
Evaluate the safety and efficacy of Smoflipid (lipid injectable 
emulsion) compared to standard of care lipid emulsion 
Intralipid 20% (a 20% I.V. fat emulsion) administered via a 
central vein in pediatric patients 3 months to 16 years of age who 
require parenteral nutrition for at least 90 days and up to 1 year. 
 
Study Hypothesis: 
Smoflipid (lipid injectable emulsion) is safe and effective in 
pediatric patients when administered for 90 days or up to 1 year. 
 
Study Drugs: 
Investigational drug: Smoflipid (lipid injectable emulsion), 
referred to as Smoflipid in the following text. 
 
Control drug: Intralipid 20% (a 20% I.V. fat emulsion), referred 
to as Intralipid 20% in the following text.  
 
Dosage of Study Drugs:  
Dosage of Smoflipid and Intralipid 20%  
The dosing of the study drugs depends on the patient’s individual 
energy requirements, age, body weight, tolerance, clinical status, 
and the ability to eliminate and metabolize lipids. A titration 
phase is necessary in patients with a new indication for PN 
treatment. Age groups are classified according to ICH (ICH 
2000). 


Clinical Study Protocol SMOF-028-CP4 
Smoflipid® (lipid injectable emulsion)  
 
Version: Final 2.0 
Date: 19 Feb 2019  
C O N F I D E N T I A L 
Page 7 of 78 
 
Study drugs will be started and advanced according to ASPEN 
pediatric nutrition recommendations (A.S.P.E.N. 2015) and 
center standards. Maximum dosage is according to the US 
Prescribing Information for Intralipid 20%, i.e., for pediatric 
patients up to 3 g/kg/d, and up to 2.5 g/kg/d for adolescents 
according to maximum dosage for adults. 
 
A)  Patients who start PN: 
 
Infants 3 months to < 2 year of age: 
start 
0.5 to 1 g/kg/d lipid 
advanced by  
0.5 to 1 g/kg/d lipid 
maximum 
up to 3 g/kg/d lipid 
 
Children 2 to < 12 years of age: 
start 
1 to 2 g/kg/d lipid 
advanced by  
0.5 to 1 g/kg/d lipid 
maximum 
up to 3 g/kg/d lipid 
 
Adolescents 12 to 16 years of age: 
start 
1 g/kg/d lipid 
advanced by  
1 g/kg/d lipid 
maximum 
up to 2.5 g/kg/d lipid 
 
B)  Patients who already receive PN: 
 
Infants 3 months to < 2 years of age: 
up to 3 g/kg/d lipid  
 
Children 2 to < 12 years of age: 
up to 3 g/kg/d lipid  
 
Adolescents 12 to 16 years of age: 
Up to 2.5 g/kg/d lipid 
 
Study drugs will be dosed at a weight-based infusion rate 
according to each patient’s lipid needs and clinical condition. 
Investigational and control drug should be infused at constant 
rate for 10 to 24 h/d. Infusions should be given 5 to 7 days per 
week. Maximum infusion rate should not exceed 0.125 g/kg/h 
lipid.  
 
Serum triglycerides and direct bilirubin will be monitored 
monthly to monitor lipid administration (see below, Study 
Treatment, Intravenous lipid dose management). 
 


Clinical Study Protocol SMOF-028-CP4 
Smoflipid® (lipid injectable emulsion)  
 
Version: Final 2.0 
Date: 19 Feb 2019  
C O N F I D E N T I A L 
Page 8 of 78 
 
Route of Administration: The study drugs will be infused into a central vein via central 
venous catheter or peripherally inserted central catheter.   
 
Dosage of Other  
PN Components:  
For total PN, amino acids, dextrose, electrolytes and 
micronutrients will be administered according to center standards 
taking into account the ASPEN recommendations for PN in 
pediatric patients (A.S.P.E.N. 2015). Age groups are classified 
according to ICH (ICH 2000). Energy needs will be estimated 
using equations for calculation (A.S.P.E.N. 2015). 
 
The following dosages for amino acids and dextrose are 
recommended in the age groups. Dosage of dextrose will be 
adjusted to reach the target parenteral calories taking into account 
the calories from prescribed lipids and amino acids. 
 
A)  Patients who start PN:  
 
Infants 3 months to < 2 years of age: 
Age 3 months to < 1 year 
• Amino Acids:  
start 
2.5 to 3 g/kg/d 
 
goal 
2.5 to 3 g/kg/d 
 
• Dextrose:  
start 
6 to 8 mg/kg/min 
 
(8.6 to 11.5 g/kg/d) 
advanced by 3.5 mg/kg/min) 
 
(5 g/kg/d) 
maximum 
14 to 18 mg/kg/min 
 
(20.2 to 25.9 g/kg/d) 
 
Age 1 year to < 2 years: 
• Amino Acids:  
start 
1.5 to 2.5 g/kg/d 
 
goal 
1.5 to 2.5 g/kg/d 
 
• Dextrose:  
start 
3 to 6 mg/kg/min 
 
(4.3 to 8.6 g/kg/d) 
advanced by 2 to 3 mg/kg/min 
 
(2.9 to 4.3 g/kg/d) 
maximum 
8 to 10 mg/kg/min 
 
(11.5 to 14.4 g/kg/d) 
 
Children 2 to < 12 years of age: 
• Amino Acids:  
start 
1.5 to 2.5 g/kg/d 
goal 
1.5 to 2.5 g/kg/d 
 
 


Clinical Study Protocol SMOF-028-CP4 
Smoflipid® (lipid injectable emulsion)  
 
Version: Final 2.0 
Date: 19 Feb 2019  
C O N F I D E N T I A L 
Page 9 of 78 
 
• Dextrose:  
start 
3 to 6 mg/kg/min 
 
(4.3 to 8.6 g/kg/d) 
advanced by 2 to 3 mg/kg/min 
 
(2.9 to 4.3 g/kg/d) 
maximum 
8 to 10 mg/kg/min 
 
(11.5 to 14.4 g/kg/d) 
 
Adolescents 12 to 16 years of age: 
• Amino Acids:  
start  
0.8 to 2 g/kg/d 
goal 
0.8 to 2 g/kg/d 
 
• Dextrose: 
start 
2.5 to 3 mg/kg/min 
 
(3.6 to 4.3 g/kg/d) 
advanced by 1 to 2 mg/kg/min 
 
(1.4 to 2.9 g/kg/d) 
 
maximum 
5 to 6 mg/kg/min 
 
(7.2 to 8.6 g/kg/d) 
 
B) Patients who already receive PN: 
 
Infants 3 months to < 2 year of age: 
Age 3 months to < 1 year 
• Amino Acids:  
goal 
2.5 to 3 g/kg/d 
• Dextrose 
maximum 
14 to 18 mg/kg/min 
 
(20.2 to 25.9 g/kg/d) 
 
Age 1 to < 2 years  
• Amino Acids:  
goal 
1.5 to 2.5 g/kg/d 
• Dextrose:  
maximum 
8 to 10 mg/kg/min 
 
(11.5 to 14.4 g/kg/d) 
 
Children 2 to < 12 years of age: 
• Amino Acids:  
goal 
1.5 to 2.5 g/kg/d 
• Dextrose:  
maximum 
8 to 10 mg/kg/min 
 
(11.5 to 14.4 g/kg/d) 
 
Adolescents 12 to 16 years of age: 
• Amino Acids: 
goal 
0.8 to 2 g/kg/d  
• Dextrose:  
maximum 
5 to 6 mg/kg/min 
 
(7.2 to 8.6 g/kg/d) 
 
Other parenteral nutrients (e.g., L-cysteine hydrochloride, 
carnitine) will be administered according to hospital practice and 
applicable guidelines (A.S.P.E.N. 2015). 
 
 


Clinical Study Protocol SMOF-028-CP4 
Smoflipid® (lipid injectable emulsion)  
 
Version: Final 2.0 
Date: 19 Feb 2019  
C O N F I D E N T I A L 
Page 10 of 78 
 
Oral or Enteral Nutrition: Patients are included if 60% or more of their calorie needs are 
provided by PN (see below, Inclusion Criteria). If a patient can 
partially be nourished orally or enterally, the energy intake will 
be calculated and the dosage of PN will be reduced 
correspondingly.  
 
Study Treatment: 
Patients will be randomized 1:1 to receive either Smoflipid 
(investigational group) or Intralipid 20% (control group).  
 
The blinded study drugs will be administered simultaneously 
with the other prescribed PN components. The patients will 
receive the study drugs according to their individual prescription 
on 5 to 7 days per week. Parenteral nutrition can be administered 
overnight (as usual in home care patients) or continuously over 
10-24 h/day (mainly in hospital setting). The maximum infusion 
rate for the study drug must not be exceeded. 
 
During the course of the study, dosage reductions of the study 
drug can be necessary as consequence of laboratory analyses. 
Serum triglyceride (TG) levels should be kept < 250 mg/dL 
throughout treatment with a study drug. If higher levels develop, 
the dosage of the lipid emulsion will be reduced. Persisting 
higher levels can lead to the decision that a patient is removed 
from the study. Also, direct bilirubin levels in plasma will be used 
to decide about dosage reduction or cessation of the study drug 
infusions. The procedures will be as follows:  
 
Serum triglycerides for intravenous lipid dose management:  
 
A)  Patients who start PN: 
 
During dose titration, levels of TG will be monitored daily. 
Should TG exceed 250 mg/dL, the study drug will be held until 
analysis of another blood sample on the following morning. If 
TG are ≤ 250 mg/dL the study drug is restarted. If not this 
procedure has to be repeated on each subsequent morning. If after 
3 days TGs still exceed 250 mg/dL, the patient will be removed 
from the study. 
 
Once the target dose has been reached at level of serum TG ≤ 250 
mg/dL, TG will be assessed monthly.  
 
 
 


Clinical Study Protocol SMOF-028-CP4 
Smoflipid® (lipid injectable emulsion)  
 
Version: Final 2.0 
Date: 19 Feb 2019  
C O N F I D E N T I A L 
Page 11 of 78 
 
B)  Patients who already receive PN:  
 
Triglycerides levels will be monitored monthly. Should TG 
exceed 250 mg/dL, a confirmatory analysis must be performed 
after 7 days. If the confirmatory analysis reveals that TG still 
exceed 250 mg/L, the study drug dosage should be reduced, or 
the patient should be removed from the study, at discretion of the 
Investigator.  
 
Direct bilirubin for intravenous lipid dose management:  
 
Direct bilirubin levels will be assessed monthly. If at any point 
direct bilirubin exceeds 2.0 mg/dL (> 2.0 mg/dL), a confirmatory 
analysis must be performed after 7 days. If the confirmatory 
analysis reveals that direct bilirubin is still > 2.0 mg/dL, the lipid 
dose has to be decreased to 1 g/kg/day; 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 direct bilirubin levels decrease again to 2.0 mg/dL 
or lower. 
 
If at any point direct bilirubin exceeds 4 mg/dL (> 4 mg/dL), the 
patient must be taken off study treatment. In this case, further PN 
treatment is at the discretion of the Investigator.  
 
Duration of Treatment: 
Study treatment will last for a minimum of 90 consecutive days 
and as long as PN is indicated, up to 365 consecutive days. The 
study ends after the Final Study Visit, latest on Day 366 (see 
Section 1, Study Schedule). If the indication for PN continues 
after Study Day 365, PN will continue per normal institution 
policy. Study drugs will no longer be used. 
 
Early termination of study treatment (Before Study Day 91) 
 
The study treatment will stop if infusion of the study drug cannot 
be continued because TG or direct bilirubin levels remain above 
the defined limits (see above, Intravenous lipid dose 
management) after reduction of the dosage.  
 
The study treatment will also be stopped if the Holman Index of 
a patient (biochemical marker for essential fatty acid deficiency 
(EFAD)) reaches or exceeds 0.4 or if any clinical symptoms of 
EFAD appear or when the patient’s growth is inadequate (drop 
of 1 in z-score in a time period of 2 consecutive months). 
The study treatment will also stop if enteral food tolerance 
increases and in consequence, less than 60% of the patient’s 


Clinical Study Protocol SMOF-028-CP4 
Smoflipid® (lipid injectable emulsion)  
 
Version: Final 2.0 
Date: 19 Feb 2019  
C O N F I D E N T I A L 
Page 12 of 78 
 
energy requirements are provided by PN for at least one month. 
If PN is still indicated after termination of the study treatment, it 
will continue per normal institution policy. 
 
In case of early termination, patients will be replaced by 
randomizing additional patients unless the decision to terminate 
was made for safety reasons (including intravenous lipid dose 
management).  
 
Late termination of study treatment (Study Days 91 to 365) 
 
After Study Day 90 the study treatment will be terminated as 
soon as nutritional needs can be fully covered from enteral or oral 
nutrition or PN is continued without a lipid emulsion (i.e., PN, or 
at least the lipid emulsion, is no longer indicated).  
 
After Study Day 90 the study treatment will also stop if infusion 
of the study drug cannot be continued because TG or direct 
bilirubin levels remain above the defined limits (see above, 
Intravenous lipid dose management) after reduction of the 
dosage. In case of termination between Day 90 and Day 365, 
patients will not be replaced. 
 
The study treatment will also be stopped if the Holman Index of 
a patient (biochemical marker for essential fatty acid deficiency 
(EFAD)) reaches or exceeds 0.4 or if any clinical symptoms of 
EFAD appear or when the patient’s growth is considered 
inadequate (drop of 1 in z-score in a time period of 2 consecutive 
months).  
 
The study is terminated on Day 366 at the latest, after the Final 
Study Visit (see Section 1, Study Schedule). If the indication for 
PN continues after study Day 365, study drugs will not be 
continued. PN will be prescribed per normal institution policy. 
 
Patients: 
Pediatric patients who are expected to require PN for at least 90 
consecutive days, both in hospital or home care setting. For 
patients who remain on PN, treatment will be continued for up to 
1 year. Patients will be randomized into one of three age group 
cohorts: 
 
48 patients 3 months to < 2 years of age  
48 patients 2 years to < 12 years of age 
48 patients 12 to 16 years of age 
 
 


Clinical Study Protocol SMOF-028-CP4 
Smoflipid® (lipid injectable emulsion)  
 
Version: Final 2.0 
Date: 19 Feb 2019  
C O N F I D E N T I A L 
Page 13 of 78 
 
Inclusion Criteria:  
1. Male or female patients 3 months to 16 years of age. 
2. Patients who require PN for at least 5 days/week. 
3. Patients who receive 60% or more of their total energy 
requirements as PN at enrollment and who are expected to 
receive 60% or more of their total energy requirements as 
PN for at least 90 days. 
4.  Written informed consent from parent(s) or legal 
representative(s). If possible, patient assent must also be 
obtained (according to local law).  
 
Exclusion Criteria: 
1. Known hypersensitivity to fish, egg, soybean, or peanut 
proteins, or to any of the active ingredients or excipients of 
Smoflipid or Intralipid 20%. 
2. Hyperlipidemia 
or 
disorders 
of 
lipid 
metabolism 
characterized by hypertriglyceridemia (serum triglyceride 
concentration > 250 mg/dL). 
3. Inborn errors of amino acid metabolism. 
4. Cardiopulmonary instability (including pulmonary edema, 
cardiac insufficiency, myocardial infarction, acidosis and 
hemodynamic instability requiring significant vasopressor 
support).  
5. Hemophagocytic syndrome. 
6. Liver enzymes (either AST, or ALT, or GGT) exceeding 5 x 
upper limit of normal range 
7. Direct bilirubin ≥ 2.0 mg/dL 
8. INR > 2. 
9. Any known hepatic condition outside of IFALD that will 
increase direct bilirubin ≥ 2.0 mg/dL.  
10. Clinically significant abnormal levels of any serum 
electrolyte (sodium, potassium, magnesium, calcium, 
chloride, phosphate). 
11. Active bloodstream infection demonstrated by positive 
blood culture at screening. 
12. Severe renal failure including patients on renal replacement 
therapy. 
13. Abnormal blood pH, oxygen saturation, or carbon dioxide. 
14. Pregnancy or lactation. 
15. Participation in another clinical study. 
16. Unlikely to survive longer than 90 days. 
 
Target Variables: 
Efficacy: 
 
• 
Body weight (weight velocity as z-score change from 
baseline). 
• 
Body length/height (growth velocity as z-score change from 
baseline). 


Clinical Study Protocol SMOF-028-CP4 
Smoflipid® (lipid injectable emulsion)  
 
Version: Final 2.0 
Date: 19 Feb 2019  
C O N F I D E N T I A L 
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• 
Head circumference (patients < 36 months of age [z-score 
change from baseline]). 
• 
Fatty acid profiles including linoleic acid, α-linolenic acid, 
arachidonic acid, docosahexaenoic acid, eicosapentaenoic 
acid and Mead acid, analyzed in total plasma and in red 
blood cell membranes.  
• 
Triene/tetraene ratio (Holman Index) in total plasma to 
assess essential fatty acid deficiency (EFAD).  
 
Safety: 
 
• 
Incidence of PNALD/PNAC1: Number of patients in each 
treatment group with direct bilirubin levels > 2 mg/dL, 
confirmed by a second sample collected 7 days after the first 
sample (incidence of PNALD/PNAC1). 
• 
Time from Study Day 1 until reaching direct bilirubin levels 
> 2 mg/dL, followed up by a second sample collected 7 days 
after 
the 
first 
sample 
(time 
until 
developing 
PNALD/PNAC). 
• 
Sterols in plasma including phytosterols: β-sitosterol, 
campesterol, 
stigmasterol, 
brassicasterol, 
ergosterol, 
cholesterol, 
desmosterol, 
lanosterol, 
β-sitostanol, 
lathosterol, squalene (a sterol precursor). 
• 
Laboratory values (blood, plasma, or serum): triglycerides, 
direct bilirubin, total bilirubin, alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), gamma-glutamyl 
transferase (GGT), alkaline phosphatase (ALP), creatinine, 
urea nitrogen, electrolytes (Na, K, Mg, Cl, Ca, Phosphate), 
trace elements (ferritin, Zn, Se, Cu, Mn, Cr), glucose, total 
protein, C-reactive protein (CRP), white blood cells (WBC), 
red blood cells (RBC), and platelet counts, hemoglobin 
(hgb), hematocrit (hct), international normalized ratio (INR). 
• 
Vital signs: blood pressure, heart rate, body temperature.  
• 
All adverse events (AEs).  
• 
The relation between genetic polymorphisms in the fatty 
acid desaturase genes FADS1 and FADS2 and plasma 
concentrations of linoleic acid, α-linolenic acid, arachidonic 
acid, docosahexaenoic acid, eicosapentaenoic acid, and 
Mead acid, as well as relation to EFAD (triene/tetraene 
ratio).  
                                                 
 
1  In this study protocol, the terms PNAC and PNALD are used synonymously and are defined by direct bilirubin 
levels > 2 mg/dL. 


Clinical Study Protocol SMOF-028-CP4 
Smoflipid® (lipid injectable emulsion)  
 
Version: Final 2.0 
Date: 19 Feb 2019  
C O N F I D E N T I A L 
Page 15 of 78 
 
 
Statistics: 
Sample Size: 
Defined as 144 patients (48 patients per age group cohort), 
having completed Study Day 90 to ensure that at least 23 subjects 
are randomized to each treatment group within each age group 
cohort. 
 
Statistical evaluation: 
All target variables will be analyzed in an exploratory manner 
presenting descriptive statistics. Binary, categorical and ordinal 
parameters will be summarized by means of absolute and 
percentage numbers. Numerical data will be summarized by 
means of standard statistics. Confidence intervals (CI) will be 
determined for all outcome parameters for which mean and 
standard deviation will be calculated. The detailed list will be 
included in the Statistical Analyses Plan (SAP).  
 
Analysis sets:  
Safety population: all patients having received at least one dose 
of a study drug and at least one post-baseline safety evaluation – 
used for analysis of safety variables. 
Intention-to-treat (ITT) population: all randomized patients. 
Per-protocol (PP) population: all randomized patients having 
received study drug at least until Study Day 90, with 5 to 7 
infusions per week, and without any major protocol deviations. 
ITT and PP populations will be used for analysis of efficacy 
variables.  
 
Evaluations/Follow up: 
All data will be collected according to the study schedule (see 
Section 1). 
 
After obtaining a signed and dated informed consent form (ICF) 
and before administering the first dose of study drug, baseline 
assessments will be completed including:  
• 
Review of inclusion and exclusion criteria. Eligibility of a 
patient can be assessed from existing laboratory data if the 
data are not older than one week. 
• 
Collection of demographic data.  
• 
Recording the patient’s medical history, vital signs, physical 
examination, nutritional status (anthropometric: head 
circumference [< 3 years]) length [< 2 years], height, weight, 
BMI (body mass index) [> 2 years]), concomitant 
medications, duration and composition of current PN.  
• 
After patient eligibility is confirmed, baseline blood samples 
will be withdrawn for analyses of safety and efficacy 
laboratory parameters. 
 


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Once the ICF is signed and dated, AEs will be documented 
throughout the study and followed after receiving the first dose 
of treatment until resolved. 
 
Study Day 1 is the day on which the first administration of the 
study drug starts. Baseline assessments are performed, and the 
patient is randomized, earlier on the same day. Alternatively, 
baseline assessments and randomization can be performed on 
study Day -1, i.e., the day before Day 1. Home care patients will 
stay overnight in the hospital for the first study drug infusion and 
can leave on Day 2. Alternatively, home care patients that are 
stable on home parenteral nutrition (HPN) prior to study 
participation can also be trained and receive the first dose of 
study treatment at the hospital, returning to their home on the 
same day (Day 1).    
 
Volumes of administered study drugs, brands and volumes of 
administered parenteral amino acids and dextrose and, if 
applicable, brands and volumes administered of enteral formulas, 
volumes of human milk or milk formulas, and as far as possible, 
type and amount of ingested oral food, will be documented for 
each Study Day.  
 
Blood samples for safety and efficacy laboratory analysis, 
analyses of fatty acids and sterols will be taken monthly. Samples 
for  trace elements will be taken every 3 months (see 1. Study 
Schedule). All blood samples will be taken at the hospital during 
the monthly visit. Other measurements and examinations will be 
performed monthly as well during the hospital visits. One blood 
sample is taken during the treatment phase for genetic analysis 
(FADS1, FADS2) (see 1. Study Schedule).  
 
After cessation of the last infusion of study drug, a Final Study 
Visit will be performed (see 1. Study Schedule). 
 
Coordinating  
Investigator: 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Other Investigators/Sites: 
 sites are planned, all in the USA 
 
Final Protocol  
Submission to FDA: 
 
 
 


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1. Study Schedule 
Daily procedures and assessments during treatment phase (starting on Day 1):  
Study drug administration, study drug administered, other PN products administered, EN 
administered and oral food intake, adverse events, concomitant medication.  
 
Table 1: 
Study Schedule of Assessments and Procedures 
Study Days 
Assessments/ 
Procedures 
Screening / 
Baseline Visit 
Prior to Start of 
PN with Study 
Drugs 
Treatment Phase 
Study Drug Administration 
Day 1 to Day 365§ 
Final Study Visit / 
After End of Last 
Study PN 
Day 1 
or Day -1 
* 
Day 1 
Visit 
* 
Weekly  
Call 
(± 1 day)
Monthly 
Visit 
(± 5 days) 
Every 3 
months, 
(during a 
monthly visit)
End + 1 Day 
** 
Informed consent 
X 
 
 
 
 
 
Inclusion/exclusion criteria  
X 
 
 
 
 
 
Demographics incl. race and ethnicity  
X 
 
 
 
 
 
Pregnancy test, if applicable 
X 
 
 
 
 
Randomization 
X 
 
 
 
 
 
Medical history, demographic data 
X 
 
 
 
 
 
Prior/concomitant medication 
X 
 
 
X 
 
X 
Body weight, length/height,  
head circumference
X 
 
 
X 
 
X 
Physical examination incl. Tanner stage 
X 
 
 
X 
 
X 
Vital signs a   
X 
 
 
X 
 
X 
Blood sampling for standard laboratory b 
X 
 
 
X 
 
X 
Blood sampling for special laboratory c 
X 
 
 
X 
 
X 
Blood sampling for trace element analysis d 
X 
 
 
 
X 
 
Start of study drug infusion 
 
X 
 
 
 
 
Prior / concomitant nutrition e  
X 
 
X 
 
 
X 
Adverse events f 
X 
X 
X 
X 
 
X 
Blood sampling for genetic analysis 
(FADS1, FADS2) g
 
 
 
(X) 
 
 
* Screening, baseline assessments and randomization are performed on Day 1, prior to the start 
infusion of study PN, or alternatively on Day -1, i.e., the day before Day 1. Study drug infusion starts 
on Day 1.  
** One day after last day of study drug administration.  
§ During the treatment phase, study drug will be administered 5 to 7 days per week. A break of 1 or 2 
days per week is allowed and will not lead to prolongation of the treatment phase.   
a 
Blood pressure, heart rate, body temperature. 
b 
Triglycerides, direct bilirubin, total bilirubin, ALT, AST, GGT, ALP, creatinine, urea nitrogen, 
electrolytes (Na, K, Mg, Cl, Ca, Phosphate), glucose,  total protein, CRP, WBC, RBC, and platelet 
counts, hgb, hct, INR. 
c 
Fatty acid profiles (linoleic acid, α-linolenic acid, arachidonic acid, docosahexaenoic acid, 
eicosapentaenoic acid and Mead acid, analyzed in total plasma, and in red blood cell membranes); 


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sterols in plasma including phytosterols (β-sitosterol, campesterol, stigmasterol, brassicasterol, 
ergosterol, cholesterol, desmosterol, lanosterol, β-sitostanol, lathosterol, squalene) 
d  Trace elements (Ferritin, Zn, Se, Cu, Mn, Cr). 
e 
Prescribed daily dose, actual daily dose, infusion rates of PN products; type and quantity of enteral 
nutrition products and oral food. 
f 
Recording of AEs starts after signature of informed consent. 
g 
In all patients genetic polymorphism of two desaturase encoding genes (FADS1 and FADS2) will 
be determined. Only one blood sample is required which can be taken any time during the treatment 
period. 


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2. Contents 
RESPONSIBILITIES (SIGNATURE PAGE) ...................................................................... 3 
STUDY OUTLINE................................................................................................................... 6 
1. 
STUDY SCHEDULE ....................................................................................... 18 
2. 
CONTENTS ..................................................................................................... 20 
3. 
LIST OF ABBREVIATIONS ......................................................................... 25 
4. 
INTRODUCTION ........................................................................................... 27 
4.1 
Background ........................................................................................................ 27 
4.2 
Rationale and Purpose of the Study ................................................................... 28 
4.3 
Benefit/Risk Assessment ................................................................................... 29 
5. 
OBJECTIVES .................................................................................................. 30 
5.1 
Study Hypothesis ............................................................................................... 30 
5.2 
Target Variables ................................................................................................. 30 
6. 
STUDY DESIGN ............................................................................................. 31 
6.1 
Description of the Study Design ........................................................................ 31 
6.2 
Rationale of Study Design, Including Choice of Control Group ....................... 33 
6.3 
Randomization, Allocation of Patients .............................................................. 35 
6.4 
Blinding and Decoding ...................................................................................... 35 
7. 
DATA MANAGEMENT AND STATISTICS............................................... 36 
7.1 
Data Management .............................................................................................. 36 
7.2 
Statistics ............................................................................................................. 37 
7.2.1 
Sample Size Estimation .............................................................................................................. 37 
7.2.2 
Analysis sets ............................................................................................................................... 37 
7.2.3 
Statistical Analysis ..................................................................................................................... 38 
7.3 
Replacement of Patients .................................................................................... 38 
8. 
STUDY DURATION ....................................................................................... 39 
9. 
PATIENT SELECTION ................................................................................. 39 


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9.1 
Study Population ................................................................................................ 39 
9.2 
Inclusion Criteria ............................................................................................... 39 
9.3 
Exclusion Criteria .............................................................................................. 39 
9.4 
Exclusion after Study Admission ...................................................................... 40 
10. 
STUDY DRUGS ............................................................................................... 41 
10.1 
Characterization of the Investigational Drug ..................................................... 41 
10.2 
Characterization of the Control Drug ................................................................ 41 
10.3 
Preparation, Administration, and Dosage of Study Drugs ................................ 42 
10.3.1 
Preparation of the Study Drugs .................................................................................................. 42 
10.3.2 
Administration Instructions ........................................................................................................ 42 
10.3.3 
Dosage of the Study Drugs......................................................................................................... 43 
10.3.4 
Intravenous Lipid Dose Management ........................................................................................ 45 
10.4 
Combination with Other Nutrition Components ............................................... 46 
10.4.1 
Parenteral Nutrition .................................................................................................................... 46 
10.4.2 
Oral or Enteral Nutrition ............................................................................................................ 48 
10.5 
Supply, Packaging, Labeling and Storage ......................................................... 49 
10.5.1 
Supply of Study Drugs ............................................................................................................... 49 
10.5.2 
Packaging and Labeling ............................................................................................................. 49 
10.5.3 
Storage Conditions ..................................................................................................................... 49 
10.6 
Study Drug Accountability ................................................................................ 50 
10.7 
Return and Destruction of Study Drugs and Materials ...................................... 50 
10.8 
Concomitant Medication and Nutrition ............................................................. 50 
11. 
STUDY SCHEDULE ....................................................................................... 51 
11.1 
Summary of Procedures ..................................................................................... 51 
11.2 
Detailed Description of Investigations .............................................................. 51 
11.2.1 
Screening Visit (Day -1 or Day 1).............................................................................................. 51 
11.2.2 
Baseline Visit (Day 1) ................................................................................................................ 53 
11.2.3 
Treatment Phase Visits ............................................................................................................... 54 
11.2.4 
Final Study Visit ........................................................................................................................ 56 
11.2.5 
Early Termination Visit .............................................................................................................. 57 
11.3 
Experimental and Analytical Methods .............................................................. 57 
11.3.1 
Anthropometric Measurements .................................................................................................. 57 


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11.3.2 
Laboratory Variables .................................................................................................................. 58 
11.4 
Documentation of Patient Data .......................................................................... 59 
11.4.1 
The Electronic Case Report Form .............................................................................................. 59 
12. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ...................... 60 
12.1 
Definitions ......................................................................................................... 60 
12.1.1 
Adverse Event (Adverse Experience, AE) ................................................................................. 60 
12.1.2 
Adverse Drug Reaction (Adverse Reaction, ADR) .................................................................... 60 
12.1.3 
Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR) .......................................... 61 
12.1.3.1 
Suspected Adverse Reaction ............................................................................................... 61 
12.1.4 
Unexpected (Serious) Adverse Reaction .................................................................................... 61 
12.1.5 
Suspected Unexpected Serious Adverse Reaction (SUSAR) ..................................................... 61 
12.2 
Assessment of Adverse Events .......................................................................... 62 
12.2.1 
Intensity/Severity ....................................................................................................................... 62 
12.2.2 
Causality/Relationship to Study Drug ........................................................................................ 63 
12.2.3 
Relationship to Study Procedures............................................................................................... 63 
12.2.4 
Outcome ..................................................................................................................................... 63 
12.2.5 
Action Taken .............................................................................................................................. 63 
12.3 
Reporting and Documentation Procedures ........................................................ 64 
12.3.1 
Documentation of (Serious) Adverse Events ............................................................................. 64 
12.3.2 
Reporting of Serious Adverse Events ........................................................................................ 65 
12.3.3 
Documentation and Reporting of Other Safety-Relevant Information and Unanticipated 
Problems..................................................................................................................................... 66 
12.3.4 
Safety Contact at Fresenius Kabi ............................................................................................... 66 
12.3.5 
Reporting to FDA, Institutional Review Boards, and Investigators ........................................... 67 
12.3.6 
Period of Observation ................................................................................................................ 67 
12.4 
Unblinding of Treatment for Emergency Reasons ............................................ 68 
12.5 
Data Safety Monitoring Board (DSMB) ............................................................ 68 
13. 
MONITORING ................................................................................................ 68 
13.1 
Monitoring Procedures and Responsibilities ..................................................... 68 
13.2 
Frequency of Monitoring ................................................................................... 69 
14. 
AUDITS AND INSPECTIONS ...................................................................... 70 
14.1 
Audits ................................................................................................................. 70 


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14.1.1 
Auditing Procedures ................................................................................................................... 70 
14.1.2 
Frequency of Audits ................................................................................................................... 70 
14.1.3 
Documentation of Audits ........................................................................................................... 70 
14.2 
Inspections ......................................................................................................... 70 
15. 
MODIFICATIONS DURING THE STUDY ................................................. 71 
15.1 
Protocol Amendments ....................................................................................... 71 
15.2 
Protocol Deviations ........................................................................................... 71 
15.3 
Premature Termination of the Study .................................................................. 72 
16. 
FINAL CLINICAL STUDY REPORT .......................................................... 72 
17. 
ADMINISTRATIVE REQUIREMENTS ..................................................... 72 
17.1 
Public Trials Registry ........................................................................................ 72 
17.2 
Institutional Review Board ................................................................................ 72 
17.3 
Submission to the Food and Drug Administration ............................................ 73 
17.4 
Notification of Local Authority ......................................................................... 73 
17.5 
Patient Information and Informed Consent ....................................................... 73 
17.6 
Patient Insurance ................................................................................................ 74 
17.7 
Patient Privacy ................................................................................................... 74 
17.8 
Initiation of the Study ........................................................................................ 74 
18. 
AGREEMENTS ............................................................................................... 74 
18.1 
Confidentiality Agreement ................................................................................ 74 
18.2 
Publication of Results ........................................................................................ 75 
18.3 
Payment ............................................................................................................. 75 
18.4 
Potential Conflicts of Interest ............................................................................ 75 
18.5 
Incentives to Patients ......................................................................................... 75 
18.6 
Archiving ........................................................................................................... 75 
19. 
REFERENCES ................................................................................................ 76 
20. 
APPENDIXES TO THIS CLINICAL STUDY PROTOCOL ..................... 78 
 
 
 


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LIST OF TABLES 
Table 1: Study Schedule of Assessments and Procedures ..................................................... 18 
Table 2: Intensity/Severity Definitions for Adverse Events and Serious Adverse Events .... 62 
Table 3: Documentation of AEs (Laboratory parameters and vital signs) ............................ 65 
 


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3. List of Abbreviations 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ASPEN 
American Society for Parenteral and Enteral Nutrition 
AST 
Aspartate aminotransferase 
BMI 
Body mass index 
CRA 
Clinical Research Associate 
CRF 
Case report form 
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DEHP 
di-2-ethylhexyl phthalate 
DSMB 
Data Safety Monitoring Board 
CFR 
Code of Federal Regulations 
eCRF 
Electronic case report form 
EFAD 
Essential Fatty Acid Deficiency 
FADS1/2 
Fatty Acid Desaturase (Genes) 1 and 2 
FDA 
Food and Drug Administration (United States) 
FDCA 
United States Federal Food, Drug, and Cosmetics Act 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transpeptidase 
GMP 
Good Manufacturing Practice 
hgb 
Hemoglobin 
hct 
Hematocrit 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IFALD 
Intestinal Failure-Associated Liver Disease 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ITT 
Intention-to-treat 
IVLE 
Intravenous Lipid Emulsion 
MCT 
Medium Chain Triglycerides 
MedDRA 
Medical Dictionary for Regulatory Affairs 
PDF/A 
Portable Document Format/A (Adobe Systems Inc.) 
PN 
Parenteral nutrition 
PNAC 
Parenteral Nutrition-Associated Cholestasis 
PNALD 
Parenteral Nutrition-Associated Liver Disease 
PP 
Per protocol 
PREA 
Pediatric Research Equity Act 
Q 
Quarter 


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RBC 
Red blood cells 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SOP 
Standard operating procedure 
SUSAR 
Suspected unexpected serious adverse reaction 
TG 
Triglycerides 
US 
United States  
WBC 
White blood cells 


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4. Introduction 
4.1 
Background 
Parenteral nutrition (PN) is a life-saving procedure enabling adequate nutritional substrates to 
be provided to a patient whenever the nutritional needs cannot be met with oral or enteral 
nutrition. Total PN provides amino acids, dextrose, lipids, electrolytes, vitamins, trace 
elements, and water. Within PN regimens, intravenous lipid emulsions (IVLEs) have two main 
functions: 1) to supply calorie-dense energy and 2) to provide essential fatty acids (Hamilton 
et al 2006, Krohn and Koletzko 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 Sweden in 1962. In the USA, Intralipid 20% was approved in 1975. 
 
Smoflipid® was first approved in Sweden in 2004 and is currently available in more than 65 
countries worldwide. The US Food and Drug Administration (FDA) approved Smoflipid for 
use in adults in July 2016.  
 
Smoflipid has been developed to optimize the fatty acid profile of the IVLE used in PN, 
providing a mixture of essential and non-essential fatty acids, including n-3, n-6, and n-9 fatty 
acids. Smoflipid is a fixed physical mixture of 4 different oils: soybean oil (30%), medium-
chain triglycerides (MCT) (30%), olive oil (25%), and fish oil (15%). Compared to pure 
soybean oil emulsions, Smoflipid has a reduced amount of n-6 fatty acid linoleic acid which is 
partially replaced by n-9 and n-3 fatty acids. Smoflipid contains 200 mg/L α-tocopherol, which 
protects unsaturated fatty acids against lipid peroxidation. Furthermore, Smoflipid contains 
only approximately 30% of amount of phytosterols contained in Intralipid 20%.  
 
The 2014 clinical guidelines of the American Society for Parenteral and Enteral Nutrition 
(A.S.P.E.N.) on support of pediatric patients with intestinal failure at risk of PNALD (Wales 
et al 2014) states that no recommendation can be made for use of a fat emulsion with soy oil, 
medium-chain triglycerides, olive oil, and fish oil (Smoflipid) until it is approved for use in the 
United States. In 2016, (A.S.P.E.N.) and the Society of Critical Care Medicine (SCCM) issued 
updated guidelines for nutrition support in critically ill adult patients, which have stated that 
alternative (oil-based) IVLEs may provide an outcome benefit over soy-based IVLEs, and 
should be considered in critically ill patients who require PN (McClave et al 2016).  
 
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  bilirubin levels are considered to be a 
marker for evolving PN-associated cholestasis (PNAC) which can lead to PN-associated liver 
disease (PNALD)2 (Colomb et al 2000, Javid et al 2011, Koseesirikul et al 2012, Pichler et al 
                                                 
 
2 In this study protocol, the terms PNAC and PNALD are used synonymously and are defined by direct bilirubin 
levels > 2 mg/dL. 


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2012). Parenteral nutrition-associated liver disease is considered to be multifactorial, and 
various aspects of PN may promote cholestasis (Wales et al 2014). In recent years, investigators 
focused on the role of the soybean oil-based IVLEs 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 of α-tocopherol (Burrin et al 2014, Clayton et al 
1998, Ng et al 2015, Wales et al 2014).  
 
Three company-sponsored studies comparing Smoflipid to Intralipid 20% in the pediatric 
population were completed in 2005 and 2006. The studies included preterm neonates, infants, 
and children up to 11 years of age (Goulet et al 2010, Rayyan et al 2012, Tomsits et al 2010). 
The data from these studies showed that the use of Smoflipid was safe and effective. A 
beneficial effect on liver parameters was found, although liver function was not the primary 
endpoint in these studies. In two studies, significantly greater decreases from baseline values 
were seen in total and direct bilirubin in the Smoflipid versus Intralipid 20% group (Goulet et 
al 2010, Rayyan et al 2012). In the third study, lower gamma-glutamyl transferase levels were 
noted in the Smoflipid group versus the Intralipid 20% group (Tomsits et al 2010). In these 
studies, PN was administrated for up to 2 weeks or for up to 4 weeks. 
 
Another company-sponsored study in the pediatric population was started in December 2015 
in the USA and is currently ongoing. This prospective, randomized, controlled, double-blind, 
parallel-group trial compares safety and efficacy of Smoflipid to Intralipid 20% in hospitalized 
neonates and infants requiring at least 28 days of PN. The targeted maximal lipid dose is 
3.0 g/kg/day. The primary objective of the study is to show the superiority in safety of 
Smoflipid over Intralipid 20% as measured by the number of patients in each treatment group 
who develop conjugated bilirubin > 2 mg/dL during the first 28 days of study treatment. This 
ongoing US Smoflipid study, and the study outlined in this clinical study protocol, will provide 
a substantial database for the short-term and long-term pediatric use of Smoflipid in the USA.  
 
4.2 
Rationale and Purpose of the Study 
Smoflipid was approved by the FDA for use in adult patients in July 2016. As required by 
section 505B(a) of the US Federal Food, Drug, and Cosmetic Act (FDCA), the safety and 
effectiveness of the new product for the claimed indications in pediatric patients must be 
assessed. For this reason, Fresenius Kabi will conduct this postmarketing study in pediatric 
patients 3 months to 16 years of age.  
 
The present protocol describes a prospective, randomized, double-blind, parallel-group, active-
controlled, multicenter study to evaluate the safety and efficacy of Smoflipid administered for 
at least 90 days, and continued for all patients who remain on PN for up to 1 year, compared to 
standard of care soybean oil based lipid emulsion (Intralipid 20%) administered for the same 
duration. Per the request of the FDA, the study’s efficacy assessments will include 
anthropometric measures and evaluation of the risk of developing essential fatty acid 
deficiency (EFAD). Genetic polymorphisms in the fatty acid desaturase genes (FADS) FADS1 
and FADS 2 should be determined in at least a subset of patients. The study’s safety 
assessments will include evaluation of the risk of developing PNALD/PNAC. Plasma 


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phytosterol levels will be included as well.  
4.3 
Benefit/Risk Assessment 
Parenteral nutrition is a lifesaving treatment if oral or enteral intake is impossible or not 
sufficient for a prolonged time. In this study only patients with indication for long-term PN 
suffering from reversible or irreversible intestinal failure will be included, e.g., patients with 
short bowel syndrome, intestinal atresia, abdominal surgical procedures due to gastroschisis or 
omphalocele closure, necrotizing enterocolitis, gastrointestinal motility disorder, or mucosal 
enteropathy.  
 
Patients will receive the study drugs as part of their PN support for at least 90 days either during 
their hospitalization or in the home care setting. It is standard clinical practice to incorporate 
lipid emulsions into the PN protocol to ensure an adequate supply of essential fatty acids and 
energy. It is not possible to supply these calories with dextrose alone, because the excess 
dextrose intake that would be required is associated with metabolic complications and liver 
damage (Koletzko et al 2005).  
 
Both study drugs, Smoflipid and Intralipid 20%, are approved in more than 60 countries for 
both adult and pediatric populations. In the USA, the comparator drug Intralipid 20% has been 
approved since 1975 for adult and pediatric use. Smoflipid was approved by the FDA for use 
in adults in July 2016. The present pediatric study is requested by the FDA as a post-marketing 
requirement for Smoflipid. 
 
According to the latest “Periodic Safety Update Report” for Smoflipid, approx. 1.0 million 
patients were treated with Smoflipid from February 2015 to January 2018. Approx. 2.2 million 
patients received Smoflipid since the first registration in February 2004.  
 
According to the latest “Periodic Safety Update Report” for Intralipid 10%, 20%, 30%, approx. 
4,159,000 patients have received Intralipid 20% from March 2014 to September 2018. Since 
July 1999 approx. 10 million patients have received Intralipid 20%.  
 
During these reporting intervals of both drugs, no actions have been taken or have been 
proposed for safety reasons. Based on the available safety data for Intralipid 20% and Smoflipid 
no change of the risk-benefit ratio of both products was identified. For both drugs the risk 
benefit balance was stated to remain positive. 
 
According to the Smoflipid Prescribing Information (Appendix 1), the adverse reactions in 
> 1% of 229 patients treated in clinical studies with Smoflipid were nausea (9%), vomiting 
(7%), hyperglycemia (5%), flatulence, pyrexia, abdominal pain (4% each), increased blood 
triglycerides, hypertension (3% each), sepsis, dyspepsia, urinary tract infection, anemia, and 
device related infection (2% each). Furthermore, the components of Smoflipid may cause 
hypersensitivity reactions. Parenterally administered lipid emulsions are an independent risk 
factor for the development of catheter-related bloodstream infections.  
 
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(Appendix 2), the most frequent adverse reactions are inseparable from the PN procedure with 
or without Intralipid 20%; these are adverse reactions due either to contamination of the I.V. 
catheter or to vein irritation by concurrently infused hypertonic solutions. Immediate or early 
adverse reactions more directly related to Intralipid 20% reported to occur in an incidence of 
< 1% in clinical trials are dyspnea, cyanosis, allergic reaction, hyperlipemia, 
hypercoagulability, nausea, vomiting, headache, flushing, increase in temperature, sweating, 
sleepiness, and others. Among delayed adverse reactions are hepatomegaly, jaundice due to 
central lobular cholestasis, splenomegaly, thrombocytopenia, leukopenia, and transient 
increases in liver function tests.  
 
In general, it can be concluded that study patients treated with either Smoflipid or 
Intralipid 20% are not exposed to higher risk than patients who are not included in the study 
and would receive PN according to institutional policy. In fact, study patients might even 
benefit from participating in the study as they will be more intensively monitored than under 
standard medical care.  
 
 
5. Objectives 
The objective of the study is to evaluate the safety and efficacy of Smoflipid compared to 
standard of care lipid emulsion Intralipid 20% administered via a central vein in pediatric 
patients 3 months to 16 years of age who require PN to meet their nutritional needs for at least 
90 days and up to 1 year. 
5.1 
Study Hypothesis 
The study hypothesis is that Smoflipid is safe and effective in pediatric patients when 
administered for 90 days or up to 1 year. 
5.2 
Target Variables 
Efficacy variables:  
 
• 
Body weight (weight velocity as z-score change from baseline). 
• 
Body length/height (growth velocity as z-score change from baseline). 
• 
Head circumference for patients who are < 36 months of age (z-score change from 
baseline). 
• 
Fatty acid profiles including linoleic acid, α-linolenic acid, arachidonic acid, 
docosahexaenoic acid, eicosapentaenoic acid, and Mead acid in total plasma (according 
to Mayo Medical Laboratories standards) and in red blood cell membranes.  
• 
Triene/tetraene ratio (Holman Index) in plasma to assess essential fatty acid deficiency 
(EFAD). Severity of EFAD will be graded based on triene/tetraene ratio, as suspected 
≥ 0.05, moderate ≥ 0.20 and severe ≥ 0.40 (Cober et al 2012). 
 
 


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Safety variables:  
 
• 
Incidence of PNALD/PNAC3: Number of patients in each treatment group with direct 
bilirubin levels > 2 mg/dL, confirmed by a second sample collected 7 days after the first 
sample (incidence of PNALD/PNAC). Time from Study Day 1 until reaching direct 
bilirubin levels > 2 mg/dL, followed up by a second sample collected 7 days after the 
first sample (time of developing PNALD/PNAC). (i.e., presented as the Study Day on 
which for the first time the direct bilirubin level was found > 2 mg/dL.) 
• 
Sterols in plasma including phytosterols: β-sitosterol, campesterol, stigmasterol, 
brassicasterol, ergosterol, cholesterol, desmosterol, lanosterol, β-sitostanol, lathosterol, 
squalene (a sterol precursor). 
• 
Laboratory values: (blood, plasma, or serum): triglycerides, direct bilirubin, total 
bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-
glutamyl transferase (GGT), alkaline phosphatase (ALP), creatinine, urea nitrogen, 
electrolytes (Na, K, Mg, Cl, Ca, Phosphate), trace elements (ferritin, Zn, Se, Cu, Mn, Cr), 
glucose, total protein, C-reactive protein (CRP), white blood cells (WBC), red blood cells 
(RBC), and platelet counts, hemoglobin (hgb), hematocrit (hct), international normalized 
ratio (INR). 
• 
Vital signs: blood pressure, heart rate, body temperature.  
• 
All adverse events (AEs). 
• 
The relation between genetic polymorphisms in the fatty acid desaturase genes FADS1 
and FADS2 and plasma concentrations of linoleic acid, α-linolenic acid, arachidonic 
acid, docosahexaenoic acid, eicosapentaenoic acid, and Mead acid, as well as relation to 
EFAD (triene/tetraene ratio).  
 
 
6. Study Design 
6.1 
Description of the Study Design 
This is a prospective, randomized, double-blind, parallel-group, active-controlled, phase 4 
multicenter study to assess safety and efficacy of Smoflipid compared to Intralipid 20% in 
pediatric patients requiring long-term PN. 
 
 
Treatment group 1: Smoflipid (investigational drug) 
 
Treatment group 2: Intralipid 20% (control drug) 
 
The study drugs, Smoflipid and Intralipid 20%, are lipid emulsions for infusion and will be 
provided in bags containing100 mL, 250 mL, or 500 mL. Detailed information on packaging, 
                                                 
 
3 In this study protocol, the terms PNAC and PNALD are used synonymously and are defined by direct bilirubin 
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labelling, and dose of study drug is provided in Section 10. 
 
The study population will be pediatric patients of 3 months to 16 years of age with indication 
for PN that is expected to continue for 90 days at minimum, as consequence of reversible or 
irreversible intestinal failure. This condition can be present in patients with, e.g., short bowel 
syndrome, intestinal atresia, abdominal surgical procedures due to gastroschisis or 
omphalocele closure, necrotizing enterocolitis, gastrointestinal motility disorder, or mucosal 
enteropathy. Study patients will be hospitalized or treated in the home care setting, and the 
study will also continue during transmission from hospital to home PN or during re-
hospitalization. During the first 90 days, study treatment will last as long as PN is required to 
cover 60% or more of the patient’s total energy requirement. Unless terminated in the first 90 
days, study treatment will last as long as any PN including intravenous lipids is required, but 
at maximum for 1 year in total.  
 
If a patient is found to be potentially eligible for participation in the study, a signed and dated 
informed consent form (ICF) will be obtained from the patient’s parent(s) or legal 
representative(s) prior to the performance of any study-specific procedures or assessments. If 
possible, patient assent must also be obtained. 
 
Randomization into the 3 age group cohorts will be distributed evenly so as to have 48 subjects 
in each age group with at least 23 subjects in each treatment group per cohort (see Section 6.3):  
 
 
Randomization group 1:  48 patients 3 months to < 2 years of age  
 
Randomization group 2:  48 patients 2 years to < 12 years of age 
 
Randomization group 3:  48 patients 12 to 16 years of age 
 
Before initiation of study treatment, demographics, including medical history, race and 
ethnicity, starting date and composition of current PN, current medications, physical 
examination findings, vital signs, body weight and length/height, BMI (> 2 years) and head 
circumference (< 3 years) will be documented, and blood samples will be obtained for the 
assessment of baseline laboratory values.  
 
During the treatment phase, concomitant medications and all safety and efficacy parameters 
will be recorded according to the study schedule (see Section 11). All I.V. energy sources 
(study drugs, other PN components, propofol, dextrose from drug carrier solutions), enteral 
formulas, and oral intake will be documented daily to assure that total energy content from all 
sources does not exceed the prescribed caloric target. Changes in dosage of the study drugs or 
other PN components, and the reason for these changes will be recorded.  
 
Study treatment will last for a minimum of 90 consecutive days and, as long as PN including 
lipids is indicated, up to 365 consecutive days. The study will be terminated if infusion of the 
study drug cannot be continued because of increased TG or direct bilirubin levels (see 10.3.4 
Intravenous lipid dose management).  
 
Up to Study Day 90 the study treatment will be terminated (i.e., early termination of study 
treatment) if less than 60% of the patient’s energy requirements are provided by PN for at least 


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one month. If PN is still indicated after termination of the study treatment, it will continue per 
normal institution policy. Study drugs will no longer be used.  
 
Between study Day 91 and Study Day 365, the study treatment will be terminated (i.e., late 
termination of study treatment) as soon as nutritional needs can be fully covered from enteral 
or oral nutrition, or is continued without a lipid emulsion (i.e., PN, or at least the lipid emulsion, 
is no longer indicated). 
 
Whenever a patient has received his/her last dose of study drug, a Final Study Visit will be 
performed the following day to perform the end-of-study procedures. If after the last dose of 
study medication PN is still indicated, it will continue per normal institution policy. 
 
 
To ensure safety of the patients during their study participation, medical monitoring will be 
performed on all safety relevant information collected during the trial. A medical safety officer 
will be available for safety related questions throughout the study. 
6.2 
Rationale of Study Design, Including Choice of Control Group 
The FDA requested that Fresenius Kabi perform a postmarketing study in pediatric patients 
3 months to 16 years of age to evaluate the safety and efficacy of Smoflipid administered for 
at least 90 days, and continued for all patients who remain on PN for up to 1 year, compared to 
standard of care soybean oil based lipid emulsion (Intralipid 20%) administered for the same 
duration. Per the request of the FDA, the study’s efficacy assessments will include 
anthropometric measures and evaluation of the risk of developing essential fatty acid 
deficiency (EFAD). Genetic polymorphisms in the fatty acid desaturase genes (FADS) FADS1 
and FADS 2 should be determined in a subset of patients. The study’s safety assessments will 
include evaluation of the risk of developing PNALD and PNAC. Plasma phytosterol levels will 
be included as well.  
 
 
The current multicenter study to evaluate safety and efficacy of Smoflipid for nutrition in 
pediatric patients 3 months to 16 years of age was designed to meet Pediatric Research Equity 
Act (PREA) requirements, i.e. to provide: 
• 
Evidence-based information on the correct dosing for these pediatric age groups,  
• 
Evidence-based information on nutritional efficacy and  
• 
Evidence-based information on pediatric safety issues as indicated by possible adverse 
events  
 
Smoflipid and the comparator, Intralipid 20%, will be dosed according to each patient’s caloric 
needs and clinical condition. The maximum lipid dosage for the age groups (see Section 10.3) 
is according to the US Prescribing Information for Intralipid 20%, i.e., for pedatric patients up 
to 3 g/kg/d, and up to 2.5 g/kg/d for adolescents according to maximum dosage for adults. The 
dose infused will be assessed for safety and efficacy in pediatric patients. The same maximum 
dosage for lipids in infants and children, i.e., 3 g/kg/day, applies for Smoflipid in countries 


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where the pediatric use is approved. 
 
The specific outcome measures selected to evaluate nutritional efficacy in the current 
Smoflipid protocol are: 
• 
Body weight and length/height and head circumference (patients < 36 months of age) 
• 
Fatty acid profiles including linoleic acid, α-linolenic acid, arachidonic acid, 
docosahexaenoic acid, eicosapentaenoic acid and Mead acid, analyzed in total plasma 
and in red blood cell membranes  
• 
Triene/tetraene ratio (Holman Index) in total plasma to assess essential fatty acid 
deficiency (EFAD)  
 
PREA requirements are designed to obtain evidence-based safety information on pediatric 
patients to help the prescribing physicians understand what adverse events can be anticipated. 
In the current study protocol, specific safety outcomes as listed below were selected to capture 
changes in standardized safety assessment, and safety assessment particularly referring to 
safety aspects of different parenteral lipid components: 
 
• 
Number of patients in each treatment group with direct bilirubin levels > 2 mg/dL, 
(incidence of PNALD/PNAC) 
• 
Time until reaching direct bilirubin levels > 2 mg/dL (time until developing 
PNALD/PNAC) 
• 
Sterols in plasma including phytosterols 
• 
Laboratory values  
• 
Vital signs  
• 
Adverse events  
• 
The relation between genetic polymorphisms in the fatty acid desaturase genes FADS1 
and FADS2 and plasma concentrations of linoleic acid, α-linolenic acid, arachidonic 
acid, docosahexaenoic acid, eicosapentaenoic acid, and Mead acid, as well as relation to 
and EFAD (triene/tetraene ratio).  
 
As Smoflipid and its components have been used widely and given world-wide with a very rare 
incidence of adverse drug reactions (ADRs)/serious adverse events (SAEs), no confirmatory 
hypotheses will be tested. All target variables will be analyzed in an exploratory manner 
presenting descriptive statistics. The trial will not be powered. To power this trial, selection of 
one single parameter would be required as a primary safety endpoint to show a clinically 
meaningful difference between the treatment groups (the treatment effect) in a reasonable 
sample size and trial duration. As mentioned above, both Smoflipid and Intralipid 20% provide 
parenteral lipids. Selecting a single parameter to power the study as a superiority study or as a 
non-inferiority study with a reasonable non-inferiority margin would be difficult because the 
similar treatment concept would require more patients than could be obtained under any 
reasonable circumstances due to very low incidence of adverse drug reactions.  


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6.3 
Randomization, Allocation of Patients 
Eligible subjects will be randomized into 3 cohorts based on their age:  
 
 
Randomization Cohort 1:  48 patients 3 months to < 2 years of age  
 
Randomization Cohort 2:  48 patients 2 years to < 12 years of age 
 
Randomization Cohort 3:  48 patients 12 to 16 years of age 
 
Within each cohort, subjects will be randomized at baseline in a 1:1 ratio to receive either 
Smoflipid or Intralipid 20%. Randomization will be implemented by the unblinded site 
pharmacist using 
 interactive web response system. 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 
. 
 
 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. 
 
Patients 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 four 
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 0402 will be number 0402-001. 
 
The unblinded site pharmacist will pick the study drug (either Smoflipid or Intralipid 20% in 
adequate bag size) as indicated by 
 for each randomized subject. The correctness of 
the picked study drug will be checked and confirmed by 
 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. 
6.4 
Blinding and Decoding 
As this is a double-blind study, the allocation to the treatment groups will not be known by the 
Investigator and staff, patients and their relatives, or members of the Fresenius Kabi Clinical 
Research Department until completion of the study.  
 
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 000 001 to 100 000 
will be randomly assigned to Smoflipid or Intralipid 20% to ensure that numbers are not 
indicative of study treatment.  
 
Smoflipid and Intralipid 20% will be delivered to the hospital pharmacists in 100 mL, 250 mL, 
and 500 mL infusion bags, together with the appropriate documentation (e.g., Certificates of 
Analysis). 


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The bags will have a blinded label in accordance with the requirements of Good Clinical 
Practice (GCP) and Good Manufacturing Practice (GMP), and each bag will be labeled with 
an individual bag number. Both study drugs are white emulsions which precludes unblinding 
by visual inspection. 
 
The bags are packed in cartons, with 10 bags containing the same product and bag size in one 
carton. The cartons will have unblinded labels attached identifying the product. They are 
delivered to the hospital research pharmacy; the pharmacist will be the only unblinded study 
team member (The pharmacist can delegate the study procedures to his/her staff; they also 
would be unblinded). 
 
For the individual patient, the pharmacist will receive the randomization information from the 
system (group allocation: Smoflipid or Intralipid 20%) as described in Section 6.3. Information 
about the individual daily dosage will be provided from the prescription, and the pharmacist 
will choose the appropriate bag size for the individual patient to ensure that the daily lipid 
dosage can be administered from 1 bag per day.  
 
The pharmacist will dispense the appropriate study drug bags to the blinded site personnel. For 
patients in the home care setting, study drugs will be provided for a full month, i.e., until the 
next site visit of the patient. In this case, the pharmacist will also hand out a study medication 
log and the corresponding dispensing labels to the patient. The dispensing labels have to be 
applied to the study medication log immediately when a bag is prepared for infusion. 
 
Emergency subject unblinding will be managed in 
. In the event an Investigator 
needs to unblind a study subject, authorized study personnel at the site will log into the 
appropriate 
 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, 
 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 the specific treatment 
arm. Note that this information will also be captured in the study audit trail, so it will be more 
secure than other forms of unblinding.  
 
 
7. Data Management and Statistics 
7.1 
Data Management 
This study will be monitored regularly by a Clinical Research Associate (CRA) as described 
in the Monitoring Manual and Electronic Case Report Form (eCRF) Completion Guidelines. 
The CRA will check for completion of the entries on the eCRFs, their compliance with the 
study protocol and GCP, and will compare the eCRF entries with the source data. A 100% 
source data verification and ICF check will be performed. In case of any data discrepancies, 


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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 monitored by the CRA 
will be signed electronically 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 
described in Section 11.4.1. 
7.2 
Statistics 
7.2.1 Sample Size Estimation 
Sample size was defined as 144 patients (48 patients 3 months to < 2 years of age, 48 patients 
2 years to < 12 years of age, and 48 patients 12 to 16 years of age), having completed Study 
Day 90. This is to ensure that at least 23 subjects are randomized to each treatment group within 
each age group. 
 
Based on a presentation at the FDA’s Pediatric Clinical Investigators Training in 2014, where 
it was noted that the minimum of 100 pediatric subjects is required to assess safety (Lewis 
2014), the planned patient numbers (24 in each arm within each age group, or 144 total) are 
adequate to provide sufficient information on safety of pediatric dosing considering the low 
risk safety profile of Smoflipid in adults. The current study will enroll approximately 72 
patients in the investigational group. Additional data for pediatric patients (neonates and 
infants) receiving Smoflipid will come from the clinical study started in December 2015 in the 
USA (see Section 4.1).  
 
An exploratory study using descriptive statistical analysis of the target variables will be 
performed. There is no primary outcome parameter and the study is not powered. Reasons for 
this study design are explained in Section 6.2. 
7.2.2 Analysis sets 
Safety Set 
The safety population will consist of all patients having received at least one dose of a study 
drug and at least one post-baseline safety evaluation. The safety population will be used for 
analysis of safety variables. 
 
Intention-to-Treat Set 
The intention-to-treat (ITT) population will consist of all randomized patients. 
 
Per-Protocol Set 
The per-protocol (PP) population will consist of all randomized patients having received study 
drug at least until Study Day 90, with 5 to 7 infusions per week, and without any major protocol 
deviations (see Section 15.2).  
 


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ITT and PP populations will be used for analysis of efficacy variables. 
7.2.3 Statistical Analysis 
The study outcome measures were selected in order to assess the safety and nutritional efficacy 
of the PN lipid emulsion. No primary and secondary measures are defined. Outcome measures 
will be evaluated as they are documented. Laboratory values will be transformed into SI 
(Système International d'Unités) if necessary. 
 
A comprehensive Statistical Analysis Plan (SAP), covering details of all methods used to 
analyze the various parameters will be prepared. It will also include information on the 
handling of missing values. The SAP will be reviewed, and if needed, updated before data 
analysis. The SAP will be approved and signed off prior to unblinding the study. 
 
All target variables will be analyzed in an exploratory manner presenting descriptive statistics. 
Binary, categorical and ordinal parameters will be summarized by means of absolute and 
percentage numbers (including ‘missing data’ as valid category). Numerical data will be 
summarized by means of standard statistics (e.g., number of available data, mean, standard 
deviation, minimum, median, maximum, and lower and upper quartile). Confidence intervals 
(CI) will be determined within treatment for all outcome parameters for which mean and 
standard deviation will be calculated. 
 
Wherever useful, the summary statistics will be presented by Study Day. Results will be 
presented stratified by study drug and age group, and overall. In addition, appropriate figures 
(e.g., bar charts, Box-Whisker-Plots) may be presented to summarize the results for some 
parameters also in a graphical way.  
 
7.3 
Replacement of Patients 
Patients withdrawn from study after randomization but before receiving any study drug will be 
counted as “early drop-outs”. These patients will be replaced (i.e., by randomizing additional 
patients) and will not undergo procedures of the Final Study Visit. 
 
Early termination of study treatment (Before Study Day 91) 
 
Patients who received study drug at least once (i.e., first study infusion was at least started) but 
who didn’t complete at least 90 days of study treatment, will be counted as “late-drop-outs”. 
 
The study treatment will stop if infusion of the study drug cannot be continued because TG or 
direct bilirubin levels remain above the defined limits (see 10.3.4 Intravenous Lipid Dose 
Management). The study treatment will also stop if less than 60% of the patient’s energy 
requirements need to be covered from PN for at least one week.  
 
In case of early termination patients will undergo final examination. They will be replaced 
unless the decision to terminate was made for safety reasons. Patients who were withdrawn 


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from study treatment due to a safety issue (including intravenous lipid dose management), will 
be counted as “withdrawals”. These patients will not be replaced. 
 
Late termination of study treatment (Study Days 91 to 365) 
 
Between Study Day 91 and Study Day 365 the study treatment will be terminated as soon as 
nutritional needs can be fully covered from enteral or oral nutrition or is continued without a 
lipid emulsion (i.e., PN, or at least the lipid emulsion, is no longer indicated). After Study Day 
90 the study treatment will also stop if infusion of the study drug cannot be continued because 
TG or direct bilirubin levels remain above the defined limits (see 10.3.4 Intravenous Lipid 
Dose Management).  
 
In case of late termination, independent of the reason, patients will not be replaced. 
 
 
8. Study Duration 
End of the study is defined as completion of last visit of the last patient undergoing the study. 
 
 
9. Patient Selection 
9.1 
Study Population 
The current study will be performed in infants, children and adolescents, male or female, 
3 months to 16 years of age. This study population was selected to fulfill Pediatric Research 
Equity Act (PREA) requirements (Section 505B(a) of the FDCA). It will evaluate the safety 
and efficacy of Smoflipid administered for at least 90 days in pediatric patients 3 months of 
age or older.  
9.2 
Inclusion Criteria 
1. 
Male or female patients 3 months to 16 years of age. 
2. 
Patients who require PN for at least 5 days/week. 
3. 
Patients who receive 60% or more of their total energy requirements as PN at enrolment 
and who are expected to receive 60% or more of their total energy requirements as PN 
for at least 90 days. 
4.  
Written Informed Consent from parent(s) or legal representative(s). If possible, patient 
assent must also be obtained (according to local law).  
9.3 
Exclusion Criteria 
1. 
Known hypersensitivity to fish, egg, soybean, or peanut proteins, or to any of the active 
substances or excipients of Smoflipid or Intralipid 20%. 


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2. 
Hyperlipidemia or disorders of lipid metabolism characterized by hypertriglyceridemia 
(serum triglyceride concentration > 250 mg/dL). 
3. 
Inborn errors of amino acid metabolism. 
4. 
Cardiopulmonary instability (including pulmonary edema, cardiac insufficiency, 
myocardial infarction, acidosis and hemodynamic instability requiring significant 
vasopressor support).  
5. 
Hemophagocytic syndrome. 
6. 
Liver enzymes (either AST or ALT or GGT) exceeding 5 x upper limit of normal range 
7. 
Direct bilirubin ≥ 2.0 mg/dL 
8. 
INR > 2. 
9.  
Any known hepatic condition outside of IFALD that will increase direct bilirubin levels 
≥ 2.0 mg/dL .  
10. 
Clinically significant abnormal levels of any serum electrolyte (sodium, potassium, 
magnesium, calcium, chloride, phosphate). 
11. 
Active bloodstream infection demonstrated by positive blood culture at screening. 
12. 
Severe renal failure including patients on renal replacement therapy. 
13. 
Abnormal blood pH, oxygen saturation, or carbon dioxide. 
14. 
Pregnancy or lactation. 
15. 
Participation in another clinical study. 
16. 
Unlikely to survive longer than 90 days. 
9.4 
Exclusion after Study Admission 
Once a patient has received any amount of a study drug, the Investigator will make every 
reasonable effort to keep the patient in the study. However, the Investigator may withdraw a 
patient, in his/her clinical judgment, if it is either in the best interest of the patient or if the 
patient cannot comply with the study protocol. More specifically, the patient can be withdrawn 
from the study by any of the points as follows: 
 
• Withdrawal of Informed Consent by the patient’s parent(s) or legal representative(s) (or 
of patient assent if it was obtained according to local law). 
• Severe or deliberate violation of the study protocol. 
• Failure or success of therapeutic efficacy causing an unacceptable risk/benefit ratio. 
• Discontinuation of study treatment for other reasons (e.g., up to Study Day 90, if less 
than 60% of the patient’s energy requirements need to be covered from PN for at least 
one month, or after Study Day 90 if PN, or at least the lipid emulsion, is no longer 
indicated because of recovery of gastrointestinal function). 
 
The patient’s parent(s) or legal representative(s) 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 
representative(s) refuse(s) to have the patient continue with study participation, a complete 
final examination should be performed after cessation of the last dose of study drug. If consent 


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is withdrawn, the final examination can only be performed legally if there is permission from 
the patient’s parent(s) or legal representative(s) to do it.  
 
The reasons for withdrawal must be recorded in the eCRF.  
 
Patients who are withdrawn from the study due to AEs/SAEs will be treated and followed 
according to established medical practice to evaluate the course of the AE and to ensure 
resolution or stabilization (see also Section 12). Any attempts of contacting a patient who is 
lost for follow up should be documented in the source notes. 
 
Fresenius Kabi reserves the right to discontinue the entire study for internal reasons at any time 
(see 15.3 Premature Termination of the Study). 
 
 
10. Study Drugs  
10.1 
Characterization of the Investigational Drug 
Smoflipid is a sterile, nonpyrogenic, white, homogenous lipid emulsion for intravenous 
infusion. The lipid content of Smoflipid is 0.20 g/mL, and comprises a mixture of soybean oil, 
MCT, 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. 
The mean essential fatty acid content of Smoflipid is 35 mg/mL (range of 28 to 50 mg/mL) 
linoleic acid (omega-6) and 4.5 mg/mL (range of 3 to 7 mg/mL) α-linolenic acid (omega-3). 
Further description of the fatty acids contained in Smoflipid is provided in the Prescribing 
Information of Smoflipid (Appendix 1). 
Each 100 mL of Smoflipid contains approximately 6 g soybean oil, 6 g MCT, 5 g olive oil, 3 g 
fish oil, 1.2 g egg phospholipids, 2.5 g glycerin, 16.3 to 22.5 mg all-rac-α-tocopherol, 0.3 g 
sodium oleate, water for injection, and sodium hydroxide for pH adjustment (pH 6 to 9). 
The phosphate content is 15 mmol/L.  
The total energy content, including fat, phospholipids, and glycerol is 2000 kcal/L. 
Smoflipid has an osmolality of approximately 380 mOsm/kg water (which represents an 
osmolarity of 270 mOsm/L).  
10.2 
Characterization of the Control Drug 
Intralipid 20% is a sterile, non‑pyrogenic fat emulsion intended as a source of calories and 
essential fatty acids. Intralipid belongs to the pharmacotherapeutic group: “Solutions for 


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parenteral nutrition, fat emulsions” (ATC-code: B05BA02). 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. 
 
The major component fatty acids are linoleic acid (44-62%), oleic acid (19-30%), palmitic acid 
(7-14%), α-linolenic acid (4-11%) and stearic acid (1.4-5.5%). Further description of the fatty 
acids contained in Intralipid 20% is provided in the Prescribing Information of Intralipid 20% 
(Appendix 2). 
 
Intralipid 20% is made up of 20% soybean oil (20 g/100 mL), 1.2% egg yolk phospholipids, 
2.25% glycerin, and water for injection. In addition, sodium hydroxide is added to adjust the 
pH so that the final product pH is 8 (pH range is 6 to 8.9).  
 
The phospholipids present contribute 47 milligrams or approximately 1.5 mmol of phosphorus 
per 100 mL of the emulsion. 
 
The total caloric value, including fat, phospholipid and glycerin, is 2.0 kcal per mL of Intralipid 
20%.  
 
Intralipid 20% has an osmolality of approximately 350 mOsmol/kg water (which represents 
260 mOsmol/L of emulsion). 
10.3 
Preparation, Administration, and Dosage of Study Drugs 
10.3.1 Preparation of the Study Drugs  
Smoflipid and Intralipid 20% will be delivered to the hospital pharmacists in 100 mL, 250 mL, 
and 500 mL infusion bags, together with the appropriate documentation (e.g., Certificates of 
Analysis). Each bag is wrapped in an overpouch that contains the infusion bag, an integrity 
indicator sachet (Oxalert®) and an oxygen absorber.  
 
The study drugs will have a blinded label, and each bag will be labeled with an individual bag 
number. The bags are packed in cartons, with 10 bags containing the same product and bag 
size in one carton. The cartons will have unblinded labels identifying the product. They are 
delivered to the hospital research pharmacy; the pharmacist will be the only unblinded study 
team member.  
 
For the individual patient, the pharmacist will receive the randomization information from the 
system: (group allocation: Smoflipid or Intralipid 20%), and information about the adequate 
bag size from the prescription. The pharmacist will dispense the appropriate study drug bags 
for the individual patient, as described in Section 6.4.  
10.3.2 Administration Instructions 
The bags have to be stored in overpouch until ready for use. After removing the overpouch, the 


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lipid emulsion should be infused immediately. 
 
Prior to infusion, the study drug bags should be inspected visually to ensure that the emulsion 
has not separated. The emulsion should be a homogenous liquid with a milky appearance. Any 
bag in which there appears to be an oiling out on the surface of the emulsion must not be used. 
The bag has to be discarded as well if any signs of discoloration, particulates, or leakage are 
observed or if the integrity indicator (Oxalert®) is black. 
 
The study drugs will be infused via a dedicated line for PN into a central vein using a central 
venous catheter or a peripherally inserted central catheter. 
 
The study drugs can be infused concurrently into the same vein as dextrose-amino acid 
solutions (as part of PN) by a Y-connector located near the infusion site; flow rates of each 
solution should be controlled separately by infusion pumps. 
 
A 1.2 micron in-line filter should be used. Filters of less than 1.2 micron pore size must not be 
used. 
 
To prevent air embolism, a non-vented infusion set should be used or on a vented set, the vent 
should be closed. Multiple connections should be avoided and flexible bags should not be 
connected in series. Residual gas in the bag has to be fully evacuated prior to administration. 
Flexible bags are not to be pressurized to increase flow rates, and if administration is controlled 
by a pumping device, the pump has to be turned off before the bag runs dry. 
 
Administration sets and lines that contain di-2-ethylhexyl phthalate (DEHP) must not be used. 
Administration sets that contain polyvinyl chloride (PVC) components have DEHP as a 
plasticizer. 
 
The intravenous tubing used to infuse the study drugs must be changed every 24 hours to 
prevent catheter related blood stream infections. 
 
Fresenius Kabi will provide detailed handling instructions for study drugs. The caregivers of 
home care patients (usually the child’s parents) will be trained on the study drug administration 
and documentation during the Screening Visit (see 11.2.1).  
 
The hospital pharmacist will provide the necessary tubing for infusion via Y-connector to home 
care patients together with the study drugs. 
10.3.3 Dosage of the Study Drugs 
The dosing of the study drugs depends on the patient’s individual energy requirements, age, 
body weight, tolerance, clinical status, and the ability to eliminate and metabolize lipids. A 
titration phase is necessary in patients with a new indication for PN treatment.  
 
When determining dose, energy supplied by dextrose and amino acids from PN, as well as 
energy from oral or enteral nutrition, has to be taken into account. Energy and lipid provided 


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from lipid-based medications should also be taken into account (e.g., propofol). 
 
Prior to administration of the study drugs, or any PN product, severe fluid and electrolyte 
disorders should be corrected. 
 
Study drugs will be started and advanced according to ASPEN pediatric nutrition support 
guidelines and center standards. Maximum lipid dosage is according to the US Prescribing 
Information for Intralipid 20%, i.e., for pediatric patients up to 3 g/kg/d, and up to 2.5 g/kg/d 
for adolescents according to maximum dosage for adults (Appendix 2). Age groups classified 
according to ICH (ICH 2000). 
 
The study drugs are given concurrently with amino acids and dextrose containing PN products. 
 
A) 
Patients who start PN 
 
The initial rate of infusion should be no more than 0.05 mL/minute for the first 10 to 
15 minutes. If no untoward reactions occur, the rate can be changed to permit infusion of 
0.5 mL/kg/hour.  
 
Infants 3 months to < 2 year of age: 
start 
0.5 to 1 g/kg/d lipid 
advanced by  
0.5 to 1 g/kg/d lipid 
maximum 
up to 3 g/kg/d lipid 
 
Children 2 to < 12 years of age: 
start 
1 to 2 g/kg/d lipid 
advanced by  
0.5 to 1 g/kg/d lipid 
maximum 
up to 3 g/kg/d lipid 
 
Adolescents 12 to 16 years of age: 
start 
1 g/kg/d lipid 
advanced by 
1 g/kg/d lipid 
maximum 
up to 2.5 g/kg/d lipid 
 
B) 
Patients who already receive PN: 
 
Infants 3 months to < 2 years of age: 
up to 3 g/kg/d lipid  
 
Children 2 to < 12 years of age: 
up to 3 g/kg/d lipid  
 
Adolescents 12 to 16 years of age: 
up to 2.5 g/kg/d lipid 
 
The individual dosage of study drug should be infused at a constant rate for 10 to 24 h/d. The 


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administration flow rate is determined by dividing the volume of study drug by the duration of 
the infusion. Maximum infusion rate for lipid should not exceed 0.125 g/kg/h lipid. 
 
Study drug infusions should be given 5 to 7 days per week.  
 
Serum triglycerides and direct bilirubin will be monitored to adjust or stop lipid administration 
if necessary (see 10.3.4 Intravenous Lipid Dose Management). 
 
During the course of the study, dosage reductions of the study drugs can be necessary as 
consequence of laboratory analyses as follows.  
10.3.4 Intravenous Lipid Dose Management 
Serum TG levels should be kept < 250 mg/dL throughout treatment with a study drug. If higher 
levels develop, the dosage of the lipid emulsion will be reduced. Persisting higher levels can 
lead to the decision that a patient is removed from the study. Also direct bilirubin levels in 
plasma will be used to decide about dosage reduction or cessation of the study drug infusions. 
Furthermore, cessation of study drug infusion will be obligatory in case EFAD or inadequate 
growth is observed.  
 
The procedures will be as follows: 
 
Serum TG levels for intravenous lipid dose management:  
 
A)  Patients who start PN: 
 
During dose titration, levels of TGs will be monitored daily. Should TGs exceed 250 mg/dL 
(> 250 mg/dL), the study drug will be held until analysis of another blood sample on the 
following morning. If TGs are ≤ 250 mg/dL the study drug is restarted. If not this procedure 
has to be repeated on each subsequent morning. If after 3 days TGs still exceed 250 mg/dL, the 
patient will be removed from the study. 
 
Once the target dose has been reached at level of serum TG ≤ 250 mg/mL, TG levels will be 
assessed monthly.  
 
B)  Patients who already receive PN:  
 
Triglycerides levels will be monitored monthly. Should TGs exceed 250 mg/dL (> 250 mg/dL), 
a confirmatory analysis must be performed after 7 days. If the confirmatory analysis reveals 
that TGs still exceed 250 mg/L (> 250 mg/dL), the study drug dosage should be reduced, or 
the patient should be removed from the study, at discretion of the Investigator.  
 
Direct bilirubin for intravenous lipid dose management:  
 
Direct bilirubin levels will be assessed monthly. If at any point direct bilirubin exceeds 
2.0 mg/dL (> 2.0 mg/dL), a confirmatory analysis must be performed after 7 days. If the 


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confirmatory analysis reveals that direct bilirubin is still > 2.0 mg/dL the 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 direct bilirubin levels decrease again to 2.0 mg/dL or lower). 
 
If at any point direct bilirubin exceeds 4 mg/dL (> 4 mg/dL), the patient has to be taken off 
study treatment. In this case, further PN treatment is at the discretion of the Investigator.   
 
For each Study Day, the prescribed dose, the dose actually infused, and the infusion time of 
study drug administration will be recorded in the eCRF. 
 
 
Stopping study drug infusion due to EFAD: 
 
At each of the monthly visits blood samples will be drawn for the analysis of fatty acids in 
plasma and red blood cells. Based on the results the triene-tetraene ratio (Holman Index) will 
be calculated to assess EFAD. Severity of EFAD will be categorized according to Cober et al 
2012: 
 
Suspected EFAD: 
Triene/tetraene ratio ≥ 0.05 and < 0.20 
Moderate EFAD:  
Triene/tetraene ratio ≥ 0.20 and < 0.40 
Severe EFAD: 
 
Triene/tetraene ratio ≥ 0.40 
 
The site will be informed immediately as soon as severe EFAD is observed according to the 
Holman Index result and the patient must be permanently taken off study medication 
immediately. The investigators will also have to permanently discontinue study medication 
infusion in case clinical symptoms of EFAD are observed.  
 
Stopping study drug infusion due to inadequate growth: 
 
At each visit the patient’s height, length or head circumference will be assessed and the z-score 
of the patient’s growth will be obtained. If an absolute drop of 1 in the z-score is observed in a 
time period of 2 consecutive months, then the patient will have to be taken off study treatment. 
 
In all cases where study medication infusion needs to be permanently discontinued, the further 
PN treatment is at the discretion of the Investigator.   
 
10.4 
Combination with Other Nutrition Components  
10.4.1 Parenteral Nutrition 
The study drugs will be given concomitantly with other PN components. For total PN, amino 
acids, dextrose, electrolytes and micronutrients will be administered according to center 
standards taking into account the ASPEN recommendations for PN in pediatric patients 


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(A.S.P.E.N. 2015). Age groups are classified according to ICH (ICH 2000). Energy needs will 
be estimated using equations for calculation (A.S.P.E.N. 2015). 
 
For home care patients, the other PN components will be compounded in the home care 
pharmacy and delivered and stored according to the usual routine (e.g., delivered weekly by 
the home care provider as part of their normal standard of care, and kept in a fridge). 
 
The following dosages for amino acids and dextrose are recommended in the age groups. 
Dosage of dextrose will be adjusted to reach the target parenteral calories taking into account 
the calories from prescribed lipids and amino acids. 
 
A) 
Patients who start PN:  
 
Infants 3 months to < 2 year of age: 
Age 3 months to <1 year 
• Amino Acids:  
start 
2.5 to 3 g/kg/d 
 
goal 
2.5 to 3 g/kg/d 
 
• Dextrose:  
start 
6 to 8 mg/kg/min 
 
 
(8.6 to 11.5 g/kg/d) 
 
advanced by 3.5 mg/kg/min) 
 
 
(5 g/kg/d) 
 
maximum 
14 to 18 mg/kg/min 
 
 
(20.2 to 25.9 g/kg/d) 
 
Age 1 year to < 2 years: 
• Amino Acids:  
start 
1.5 to 2.5 g/kg/d 
 
goal 
1.5 to 2.5 g/kg/d 
 
• Dextrose:  
start 
3 to 6 mg/kg/min 
 
 
(4.3 to 8 .6 g/kg/d) 
 
advanced by 2 to 3 mg/kg/min 
 
 
(2.9 to 4.3 g/kg/d) 
 
maximum 
8 to 10 mg/kg/min 
 
 
(11.5 to 14.4 g/kg/d) 
 
Children 2 to < 12 years of age: 
• Amino Acids:  
start 
1.5 to 2.5 g/kg/d 
 
goal 
1.5 to 2.5 g/kg/d 
 
• Dextrose:  
start 
3 to 6 mg/kg/min 
 
 
(4.3 to 8.6 g/kg/d) 
 
advanced by 2 to 3 mg/kg/min  
 
 
(2.9 to 4.3 g/kg/d) 
 
maximum 
8 to 10 mg/kg/min 
 
 
(11.5 to 14.4 g/kg/d) 


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Adolescents 12 to 16 years of age: 
• Amino Acids:  
start  
0.8 to 2 g/kg/d 
 
goal 
0.8 to 2 g/kg/d 
 
• Dextrose: 
start 
2.5 to 3 mg/kg/min 
 
 
(3.6 to 4 .3 g/kg/d) 
 
advanced by 1 to 2 mg/kg/min 
 
 
(1.4 to 2.9 g/kg/d) 
 
maximum 
5 to 6 mg/kg/min 
 
 
(7.2 to 8.6 g/kg/d) 
 
B) 
Patients who already receive PN: 
 
Infants 3 months to < 2 year of age: 
Age 3 months to < 1 year 
• Amino Acids: 
goal 
2.5 to 3 g/kg/d 
• Dextrose: 
maximum 
14 to 18 mg/kg/min 
 
 
(20.2 to 25.9 g/kg/d) 
 
Age 1 to < 2 years: 
• Amino Acids:  
goal 
1.5 to 2.5 g/kg/d 
• Dextrose:  
maximum 
8 to 10 mg/kg/min 
 
 
 
(11.5 to 14.4 g/kg/d) 
 
Children 2 to < 12 years of age: 
• Amino Acids:  
goal 
1.5 to 2.5 g/kg/d 
• Dextrose:  
maximum 
8 to 10 mg/kg/min 
 
 
(11.5 to 14.4 g/kg/d) 
 
Adolescents 12 to 16 years of age: 
• Amino Acids: 
goal  
0.8 to 2 g/kg/d  
• Dextrose:  
maximum 
5 to 6 mg/kg/min 
 
 
(7.2 to 8.6 g/kg/d) 
 
Other parenteral nutrients (e.g., carnitine, L-cysteine hydrochloride) will be administered 
according to hospital practice and applicable guidelines (A.S.P.E.N. 2015). 
 
The prescribed dosages, the dosages actually infused, and the infusion times of all PN products 
will be recorded in the eCRF. 
10.4.2 Oral or Enteral Nutrition 
Patients are included if 60% or more of their calorie needs are provided by PN, i.e., up to < 40% 
of energy can be covered from enteral formulas or oral intake. Oral food intake or enteral 
nutrition is not limited by the study procedures but will be decided by the Investigator 


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depending on the underlying disease and gastrointestinal tolerance.  
 
If a patient can be partially nourished orally or enterally, the energy intake will be calculated 
and the dosage of PN will be reduced correspondingly.  
 
If before Study Day 90 enteral nutrition or oral food intake covers 40% or more of the energy 
requirements during at least one month, the study will be terminated. Between Study Day 90 
and Study Day 365 the study will be terminated as soon as nutritional needs can be fully 
covered from enteral or oral nutrition or PN is continued without a lipid emulsion (i.e., PN, or 
at least the lipid emulsion, is no longer indicated) (see 9.4 Exclusion after Study Admission).  
10.5 
Supply, Packaging, Labeling and Storage 
10.5.1 Supply of Study Drugs 
Fresenius Kabi will provide the Investigator’s Pharmacy with a sufficient amount of study 
medication in the 3 bag sizes together with the respective Certificates of Analysis. A 
temperature recording device will document the temperature of the study medication during 
the transport to site.  
 
The medication is the property of Fresenius Kabi and must not be passed on to third parties. 
10.5.2 Packaging and Labeling 
The blinded study drugs, Smoflipid and Intralipid 20%, will be provided in 3 bag sizes (100 
mL, 250 mL, 500 mL) as ordered by the site pharmacies. The bags will be labeled in accordance 
with the requirements of GCP and GMP. Each bag wears a uniquely numbered label with a bag 
ID numbers from 000 001 to 100 000, randomly assigned to Smoflipid or Intralipid 20% to 
ensure that numbers are not indicative of study treatment. 
 
The unblinded pharmacist will provide the study personnel with the appropriate blinded bags, 
as described in Section 6.4.  
10.5.3 Storage Conditions 
Throughout the study and until distribution, the study drugs will be stored in a securely locked 
area, only accessible to authorized personnel, at 20° to 25°C (68° to 77°F). Excessive heat has 
to be avoided and study drugs must not freeze. If accidentally frozen, bags have to be discarded. 
 
Storage conditions (e.g., temperature) of the final blinded product should follow the 
instructions of the pharmacist. Independent from the pharmacy instructions, the final product 
is not allowed to be frozen or stored > 25°C. For the transportation of study drugs, home care 
patients will be provided with isothermic containers equipped with temperature data loggers. 
If required, appropriate cabinets for temperature control (20 to 25°C) will be provided to the 
patients’ homes. 
 


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The bags have to be stored in overpouch until ready for use. After removing the overpouch, the 
lipid emulsion should be infused immediately.  
10.6 
Study Drug Accountability 
Receipt of study drugs as well as return of any unused bag will be documented by the 
Investigator on a form provided by Fresenius Kabi. The study drugs are property of Fresenius 
Kabi and must not be passed to third parties. 
 
Study drugs will be stored separately and safely and will be used exclusively for this study as 
described in this protocol. Any use of a study drug is documented on each patient’s eCRF. For 
each bag the bag size, batch number, prescribed volume, and infused volume will be specified. 
 
At the end of the study, the Investigator will explain any discrepancies between delivery, use, 
and return of the study drugs (drug accountability). 
10.7 
Return and Destruction of Study Drugs and Materials 
Unused study drugs and unused study documentation forms will be returned to Fresenius Kabi 
for destruction at the end of the study or earlier. Alternatively, after written notice from 
Fresenius Kabi, unused forms and study drugs may be destroyed at the investigational site. 
Destruction will be documented. 
 
In home care patients, the use of study drugs is documented on the medication log where the 
dispensing label for each used bag has to be attached (see 6.4 Blinding and Decoding). The 
study medication logs and unused products have to be returned to the clinical site at the next 
study visit. Any used bag can be discarded by the home care provider; they will provide a 
respective certificate of destruction.  
10.8 
Concomitant Medication and Nutrition 
From the time of inclusion and throughout the trial period, the use of concomitant medications 
will be allowed as clinically needed with the exception of: 
 
- 
Beta-carotene, lutein, lycopene, vitamin A, vitamin C and vitamin E as sole parenteral 
additives or food supplements 
- 
Any IV lipid emulsion other than the study medication or propofol 
- 
Enteral administration of fish oil (except as component of milk formulas)  
 
The use of concomitant medication must be documented in the eCRFs (type, start date, end 
date, dosage, frequency, route, indication for use). Prior and concomitant volume replacement 
with blood, plasma, or colloid transfusions will be recorded. 
 
Concomitant nutrition, including micronutrient and electrolyte additions to PN, enteral 
formulas, human milk or milk formulas, food and food supplements, and total energy intake 
(including energy intake from non-nutritional sources, e.g., propofol), will be documented in 


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the eCRFs during the entire treatment period. 
 
 
11. Study Schedule 
11.1 
Summary of Procedures 
A complete overview of all study procedures to be performed at the individual study visits is 
presented in Section 1. All procedures must be documented in the eCRF. 
11.2 
Detailed Description of Investigations 
11.2.1 Screening Visit (Day -1 or Day 1) 
The Screening Visit has to take place on Study Day 1, or alternatively on Study Day -1, i.e., 
the day before Day 1. The Screening Visit is performed at the Investigator’s clinical site.  
 
The procedures of the Screening Visit have to be executed in the following sequence: 
 
A. 
Informed consent process 
 
A signed/dated informed consent form must be obtained from the patient’s parent(s) or legal 
representative(s) prior to the performance of any study related procedures or evaluations. If 
possible, patient assent must also be obtained (according to local law). 
 
The parent(s) or legal representative(s) of the child or adolescent will be informed of the nature 
of the study by the Investigator or a designated Sub-Investigator of the study team as 
documented on the study responsibility log. The parent(s) or legal representative(s) will also 
receive a copy of the “parent information sheet”. 
 
The Investigator will inform the parent(s) or legal representative(s) of the patient on 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 legal representative(s) of the child or adolescent will be given the 
opportunity to discuss the study, ask questions about the study, and have those questions 
answered by the Investigator. The parent(s) or legal representative(s) of the patient will be 


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allowed sufficient time to consider this information. 
 
Two copies of the ICF will need to be signed and dated by the parent(s) or legal 
representative(s) and the Investigator; one copy will be provided to the parent(s) or legal 
representative(s) of the patient. The other copy will be kept in the patient’s medical file. The 
patient’s medical file must also document that the parent(s) or legal representative(s) provided 
consent prior to participation in the study.  
 
B. 
Assignment of subject number and completion of the screening log 
 
C. 
Review of inclusion and exclusion criteria 
 
Patients will be assessed for eligibility (see 9.2 Inclusion Criteria, and 9.3 Exclusion Criteria). 
The patient can only be considered as eligible 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 randomized. 
 
Existing laboratory analyses will be accepted for assessment of eligibility if they are not older 
than one week. A pregnancy test will be performed in female patients who have had their 
menses. 
 
If a patient is erroneously randomized into the study without meeting all of the enrolment 
criteria, the patient will be withdrawn from the study and replaced. 
 
D. 
Randomization 
 
If the patient meets all enrolment criteria, randomization according to age group cohort will be 
performed as described in Section 6.3. 
 
E. 
Baseline documentation 
 
These procedures will be performed or assessed during Screening Visit prior to the first dose 
of study medication: 
 
• 
Recording of demographic data:  
- 
date of birth 
- 
age 
- 
sex 
- 
race 
- 
ethnicity  
 
• 
Recording of physical examination findings and body measurements 
- 
physical inspection 
- 
body weight 
- 
body length (patients < 2 years of age) or body height 


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- 
head circumference (patients < 36 months of age) 
- 
BMI (patients > 2 years of age) 
- 
Tanner stage 
 
• 
Recording of vital signs  
- 
blood pressure 
- 
heart rate 
- 
body temperature 
 
• 
Recording of the patient medical history 
• 
Results of a pregnancy test (only in female patients who have had their menses) 
• 
Recording of prior medication and prior nutrition support (i.e., medication and nutrition 
support at obtaining the signed/dated ICF) 
• 
After the ICF is signed and dated: recording of AEs/SAEs, if applicable 
 
F. 
Blood sampling 
 
Blood is sampled for laboratory analysis of the following parameters: 
 
• 
From blood, plasma, or serum:  
- 
triglycerides 
- 
urea nitrogen 
- 
ALT 
- 
AST 
- 
direct bilirubin, total bilirubin 
- 
GGT 
- 
ALP 
- 
creatinine  
- 
electrolytes: sodium, potassium, calcium, magnesium, chloride, phosphate 
- 
trace elements: ferritin, zinc, selenium, copper, manganese, chromium 
- 
glucose 
- 
total protein 
- 
CRP 
- 
hematology: WBC count, RBC count, platelets count, hgb, hct  
- 
coagulation: INR 
- 
sterols: β-sitosterol, campesterol, stigmasterol, brassicasterol, ergosterol, 
cholesterol, desmosterol, lanosterol, ß-sitostanol, lathosterol, squalene. 
- 
fatty acids: alpha linolenic acid, linoleic acid, arachidonic acid, docosahexaenoic 
acid, eicosapentaenoic acid, and Mead acid, in total plasma, and in red cell 
membranes. 
11.2.2 Baseline Visit (Day 1) 
Study Day 1 is per definition the day on which the first study drug infusion starts. All other 
Visits and Study Days are relative to the Baseline Visit. The Baseline Visit is performed at the 


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Investigator’s clinical site.  
 
The first study drug infusion will be started during Baseline Visit. In new home care patients 
it will usually be in the evening of Day 1 as these patients will stay overnight in the hospital 
for the first study drug infusion and  leave on Day 2. Patients that have been stable on HPN 
prior to study participation can receive the first dose during Day 1 and leave the hospital on the 
same day. 
 
Patients will be trained on handling and administration of study drug and on documentation of 
daily nutrition intake of all sources. 
 
The procedures of the Baseline Visit have to be executed in the following sequence: 
 
A. 
Completion of baseline documentation 
 
Before start of the first administration of the study drug on Day 1, all baseline documentation 
has to be completed (see 11.2.1 Screening Visit). Furthermore, the Investigator has to confirm 
that all eligibility criteria are still fulfilled. 
 
B. 
Administration of Study Drug as Part of PN  
 
If none of the exclusion criteria, and all inclusion criteria, related to the baseline documentation 
are met, the Investigator can proceed with the procedures of administration of the study drug. 
 
Start of infusion of the study drug in the prescribed individual dosage with dosage titration in 
patients who did not receive PN before (see Section 10.3). In these patients who start PN, the 
initial rate of infusion of the study drug should be no more than 0.01 g fat/minute (0.05 mL/min 
of the study drug) for the first 10 to 15 minutes.  
 
The study drug will be infused concomitantly with the other PN components as prescribed.  
 
Warnings and precautions included in the Prescribing Information of both Smoflipid 
(Appendix 1) and Intralipid 20% (Appendix 2) will be considered before and during each 
administration of a Study Drug. 
 
C. 
Recording  
 
• 
Recording of medication, nutrition, and adverse reactions 
- 
concomitant medication 
- 
parenteral nutrition 
- 
oral or enteral nutrition 
- 
adverse events (AEs) 
11.2.3 Treatment Phase  
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of their PN regimen.  
 
The frequency of Treatment Phase weekly calls is 7 ± 1 days up to Day 365. In addition, 
monthly visits will take place at the Investigator’s clinical site. The monthly site visits will be 
performed in a time window of 30 ± 5 days. 
 
During Treatment Phase Visits, the following procedures will be executed:  
 
A. 
Recording of therapies and adverse events 
 
During each weekly call and each monthly visit, the following will be recorded for each study 
day in the interval between the last and the current visit: 
 
• 
Recording of therapies and adverse reactions 
- 
concomitant medication 
- 
new AEs and outcome of formerly recorded AEs (see Section 12) 
- 
in home care patients: hospital readmission (date, reason) 
- 
in hospitalized patients: transition to home care (date) 
 
• 
Recording of nutrition per study day  
- 
study drugs: dose prescribed, dose administered, timing  
- 
other PN products: dose prescribed, dose administered, timing 
- 
oral or enteral nutrition: products, dose prescribed, dose administered amounts and 
energy content; if possible, type of food and beverages, 
- 
  
B. 
Measurements and examination 
 
The following parameters will be measured and examinations performed monthly: 
 
- 
body weight, body length/height, head circumference (patients < 36 months of age)  
- 
physical examination including Tanner stage 
- 
vital signs: blood pressure, heart rate, body temperature 
 
C. 
Blood sampling 
 
• 
Blood is sampled monthly for the following laboratory analyses (in blood, plasma or 
serum) 
- 
triglycerides 
- 
urea nitrogen 
- 
ALT 
- 
AST 
- 
direct bilirubin, total bilirubin 
- 
GGT 
- 
ALP 
- 
creatinine  


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- 
electrolytes: sodium, potassium, calcium, magnesium, chloride, phosphate 
- 
glucose 
- 
total protein 
- 
hematology: WBC count, RBC count, platelets count, hgb, hct  
- 
coagulation: INR 
 
- 
fatty acids: alpha linolenic acid, linoleic acid, arachidonic acid, docosahexaenoic 
acid, eicosapentaenoic acid, and Mead acid, in total plasma, and in red cell 
membranes. 
 
- 
sterols: β-sitosterol, campesterol, stigmasterol, brassicasterol, ergosterol, 
cholesterol, desmosterol, lanosterol, ß-sitostanol, lathosterol, squalene. 
 
In case of a suspected blood stream infection CRP will be assessed in addition. 
 
• Blood is sampled every 3 months for the assessment of  
- 
trace elements: ferritin, zinc, selenium, copper, manganese, chromium 
 
 
• 
Blood is sampled once during the treatment phase for the following laboratory analyses: 
- 
In all patients genetic polymorphism of two desaturase encoding genes (FADS1 
and FADS2) will be determined. The Investigator will decide the time point at 
which the blood sample is withdrawn. 
 
According to the specific situation of a patient, blood samples can be drawn during the infusion 
of the study drug and/or other PN products (hospitalized patients with PN over 24 h/day) or 
between two infusions (mainly home care patients). The sampling time and the time of the last 
or current study drug infusion will be documented. 
 
D. 
Revision of dose of Study Drug and other PN components 
 
Dosage of the study medication and the other PN products will be checked and, if necessary 
adapted to changes in the clinical or metabolic condition of the patient (e.g., possible higher 
infusion volume as consequence of weight gain, or possible dosage reduction due to proceeding 
gastrointestinal adaptation). 
 
Any changes in the prescription of the study drug or other PN products, and their reasons, will 
be recorded. If no changes are made, the continuation of the current dosage has to be confirmed. 
 
Warnings and precautions included in the Prescribing Information of Smoflipid (Appendix 1) 
and of Intralipid 20% (Appendix 2) will be considered before the dosing of the study drug is 
changed or confirmed. 
11.2.4 Final Study Visit 
The Final Study Visit will take place after cessation of the last study drug infusion. Study 


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treatment can last up to 365 consecutive days, i.e., for one year after randomization. No patient 
will receive study medication beyond Study Day 366.  
 
Up to Study Day 90, study treatment will be terminated if enteral food tolerance increases and 
in consequence, if less than 60% of the patient’s caloric requirements are provided by PN for 
at least one week (see 9.4 Exclusion after Study Admission).  
 
After Study Day 90 the study treatment will be terminated as soon as nutritional needs can be 
fully covered from enteral or oral nutrition or PN is continued without a lipid emulsion (i.e., 
PN, or at least the lipid emulsion, is no longer indicated). 
 
The study will be terminated at any time, if infusion of the lipid emulsion cannot be continued 
because TG or direct bilirubin levels remain above the defined limits (cf. 10.3.4) after reduction 
of the study drug dosage. 
 
During Final Study Visit, the same procedures will be executed as in the monthly  Treatment 
Phase Visits (see above, 11.2.3). Additionally, the reason for study termination will be recorded 
if it takes place before Study Day 365. 
 
Note: Should the Final Study Visit be performed between Day 90 and Day 365 and less than 
1 week after the collection of the last blood samples, then the blood sampling will not be 
repeated at the Final Study Visit.  
 
If a patient is withdrawn from the study at any time due to an AE, the patient should be followed 
until an outcome of the AE can be defined. 
 
In case the study participation is terminated because of withdrawal of the informed consent, 
the Final Study Visit, or single procedures of this visit, will only be executed if allowed by the 
patient’s parent(s) or legal representative(s). 
 
If the termination occurs before Study Day 365 because of cessation of PN, and PN is restarted 
later, a re-treatment with study drug is not allowed. 
11.2.5 Early Termination Visit 
There is no specific definition of an Early Termination Visit because the study can be 
terminated for various reasons and at any time point. Independent of the reason and the time 
point of termination, a Final Study Visit (see above, 11.2.4) will be performed unless it is 
refused by the patient’s parent(s) or legal representative(s).  
11.3 
Experimental and Analytical Methods 
11.3.1 
Anthropometric Measurements 
Assessment of body weight: 
Scales used for measuring body weight of the patients must be calibrated and revised according 


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to applicable local requirements. The relevant documentation must be updated and available 
on request. 
 
Assessment of body length/height: 
Body length/height of the patients will be assessed in lying/standing position with the help of 
a length board/stadiometer. 
 
Assessment of head circumference (patients < 3 years of age): 
An accurate head circumference measurement is obtained with a non-stretchable measuring 
tape. The measurement should be made around the widest possible circumference of the head, 
i.e., over the most prominent part on the back of the head (occiput) and just above the eyebrows 
(supraorbital ridges).  
11.3.2 Laboratory Variables 
Laboratory analyses will be performed in the local laboratories or in central laboratories (only 
fatty acids, sterols, and FADS1 and FADS2 genes).  
 
All blood sample volumes will be specified and included in the ICFs and IRB submission 
documents.  
 
Analyses in local laboratories 
 
Determination of the laboratory values will be assessed using established validated techniques 
at the local laboratory of the clinical site. Valid normal ranges for the age groups and 
certifications from all laboratories will be obtained before start of the study. 
 
Blood samples which are drawn at home (home care patients) will be sent to the clinical site 
for analysis. An exact description of the methodology for drawing, handling and shipping of 
the samples for the analysis will be provided to the home care providers. 
 
The Investigators will review all laboratory results. Laboratory values outside the normal range 
will be assessed concerning their clinical significance by the Investigator. If the out-of-range 
value is considered clinically significant, it will be recorded as an AE (see Section 12) and 
documented in the eCRF (see Section 11.4.1). 
 
Analyses of fatty acids and sterols 
 
Analysis of fatty acids (linoleic acid, α-linolenic acid, arachidonic acid, docosahexaenoic acid, 
eicosapentaenoic acid and Mead acid, analyzed in total plasma and in red blood cell membranes 
and of sterols (β-sitosterol, campesterol, stigmasterol, brassicasterol, ergosterol, cholesterol, 
desmosterol, lanosterol, β-sitostanol, lathosterol, squalene) in plasma will be performed at  the 
following specialized laboratory: 
 
 


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An exact description of the methodology for drawing, handling and shipping of the samples 
for the analysis of fatty acids and sterols at the central lab will be provided to the clinical sites.  
 
Fatty acid profiles will be used for assessment of EFAD. Severity of EFAD will be graded 
based on triene/tetraene ratio, e.g., as suspected ≥ 0.05, moderate ≥ 0.20 and severe ≥ 0.40 
(Cober et al 2012). 
 
Analysis of fatty acid desaturase encoding genes (FADS1 and FADS2) 
 
Analysis is performed only once for each patient, at the following specialized laboratory:  
  
 
 
 
An exact description of the methodology for drawing, handling and shipping of the blood 
sample for the genetic analysis at the central lab will be provided to the clinical sites.  
11.4 
Documentation of Patient Data 
All patient data generated during the study will be documented in the patient’s medical records 
(source data). Source data is defined as all information in original records and certified copies 
of original records regarding 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 "Site Delegation of 
Authority Log" provided by Fresenius Kabi) will transcribe patient data from the source data 
into the eCRF. 
 
All evaluations reported in the eCRF must be supported by source documents. 
11.4.1 The Electronic Case Report Form 
All patient data generated during the study will be recorded in the eCRFs provided by Fresenius 
Kabi/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. Clinical Trial Data 
will be captured in the validated 
 system designed and tested to exceed FDA 21 CFR 
11 standards, and to support the study specific protocol specifications. All completed 
documentation of the Operational Qualification, User Acceptance Testing, and Installation 
Qualification will be maintained by Clinipace. The completed project specific Data 
Management Plan (DMP) will further describe, in detail, how the 
 Study instance 
will be utilized to manage this Clinical Trial. 
 
Only the Investigator and authorized co-workers (as listed on the form "Site Delegation of 


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Authority Log" provided by Fresenius Kabi and trained appropriately on the eCRF system) 
will complete eCRFs or make corrections to the eCRF entries, and will have access to the data 
or may change data, without the possibility of deleting the original entries. All study personnel 
involved in data entry or data review will have to adhere to the eCRF completion guidelines. 
After completion, each eCRF will be electronically signed and dated by the Investigator.  
 
For all laboratory data, the units or any transformation of units must be clearly defined. 
Transformation of data during the data processing will be documented. 
 
This study will be monitored regularly by a CRA from Clinipace. The CRA will check for 
completion of the entries in the eCRFs, their compliance with the study protocol and with GCP, 
and will compare the eCRF entries with the source data. Source data verification will be 
performed for all patients and 100% of the data. A 100% accuracy and completeness check 
will be performed on the ICFs. A detailed list of all monitoring activities to be performed during 
the study will be included in the Monitoring Manual (see Section 13).  
 
 
12. Adverse Events and Serious Adverse Events  
12.1 
Definitions 
12.1.1 Adverse Event (Adverse Experience, AE) 
Adverse event (AE) means any untoward medical occurrence in a patient administered a 
pharmaceutical/medicinal product and which does not necessarily have to have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended sign 
(e.g., an abnormal laboratory finding), symptom, or disease temporally associated with the use 
of a pharmaceutical/ medicinal product, whether or not considered related to the 
pharmaceutical/medicinal product. 
 
An AE may be: 
• 
A new illness 
• 
Worsening of a sign or symptom of the condition under treatment or of a concomitant (pre-
existing) illness 
• 
An effect of the study medication 
• 
An effect of a comparator drug 
• 
Unrelated to participation in the clinical study 
• 
A combination of such factors 
12.1.2 Adverse Drug Reaction (Adverse Reaction, ADR) 
For marketed products, all noxious and unintended responses to a pharmaceutical/medicinal 
product related to doses normally used in human for prophylaxis, diagnosis, or therapy of 
disease or for modification of physiological functions should be considered as Adverse Drug 


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Reactions. 
12.1.3 Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR) 
An SAE or SAR is any untoward medical occurrence (effect, reaction) that at any dose: 
• 
Results in death 
• 
Is life-threatening* 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect 
• 
Is of medical importance** 
 
*  The 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 might have caused death if it were more severe. 
**  Important 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 be considered as serious. 
Important medical events should also usually be considered serious (21 CFR 312.32(a)). 
 
Events that do not fit in any of the above categories are to be considered non-serious AEs or 
non-serious ADRs. 
12.1.3.1 Suspected Adverse Reaction 
Suspected adverse reaction means any AE for which there is a reasonable possibility that the 
drug caused the AE. For the purposes of IND safety reporting, ‘reasonable possibility’ means 
there is evidence to suggest a causal relationship between the drug and the AE. A suspected 
adverse reaction implies a lesser degree of certainty about causality than adverse reaction, 
which means any AE caused by a drug (21 CFR 312.32(a)).  
12.1.4 Unexpected (Serious) Adverse Reaction  
An Unexpected (Serious) Adverse Reaction is a reaction, where the nature or severity or 
outcome is not consistent with the applicable reference safety information. Reports which add 
significant information on the specificity, increase of occurrence, or severity of a known, 
already documented (serious) adverse reaction constitute unexpected events. 
 
The reference safety information for assessment of expectedness is the current version of the 
Prescribing Information for Smoflipid (Appendix 1) and Intralipid 20% (Appendix 2).  
12.1.5 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
Suspected unexpected serious adverse reactions (SUSARs) are all ADRs that are considered to 
be both: 
• 
Serious, and 


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• 
Unexpected  
12.2 
Assessment of Adverse Events 
For each AE, the Investigator will assess: 
• 
Seriousness (as defined in section 12.1.3) 
• 
Intensity/Severity 
• 
Causality (to study drugs and study procedures) 
• 
Outcome 
• 
Action taken 
12.2.1 Intensity/Severity 
For the intensity/severity 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 (see Appendix 3). The Common 
Terminology Criteria for AEs is a descriptive terminology which can be utilized for AE 
reporting. A grading (severity) scale is provided for each AE term. 
 
If these criteria are not reasonably applicable to an AE, the event’s intensity/severity 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). 
Table 2: 
Intensity/Severity Definitions for Adverse Events and Serious Adverse Events 
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/Disabling*
Life-threatening consequences; urgent intervention 
indicated.  
5 
Fatal** 
Death related to the AE. 
 
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thus will qualify as SAEs. 
12.2.2 Causality/Relationship to Study Drug 
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: 
A causal relationship between a drug and an AE can be assumed if there is at least a reason-
able possibility for such a causal relationship. The expression “reasonable possibility” is meant 
to convey in general that there are facts (evidence) or arguments to suggest a causal 
relationship. A causally related AE is equal to an ADR.  
 
Not related:  
Not related with the use of a drug means that the criteria mentioned above are not met, or that 
a causal relationship is ruled out. 
 
Each causality assessment should be substantiated by the Investigator; in case of “not related” 
at least one (e.g. the most probable) alternative cause should be provided with the assessment. 
12.2.3 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. 
12.2.4 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 (i.e., 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 dies 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). 
12.2.5 Action Taken 
The action taken to study drugs by the Investigator as a result of the AE will be classified in 
one of the following categories: 
 
1. 
None (= continuing according to protocol) 


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2. 
Dose reduced; this could mean: 
a) Reducing the dose of the study drug 
b) Maintaining the dose level, despite required increase as per protocol 
c) Reducing the frequency of administration 
3. 
Study drug discontinued and restarted 
4. 
Study drug discontinued permanently 
 
In addition, the Investigator needs to provide information on other therapy or 
countermeasures, such as: 
a) Drug therapy was initiated to counteract the AE 
b) Dose of concomitant medication was changed 
c) Non-drug remedial therapy was initiated 
 
If considered necessary, the Investigator may decide to withdraw patients from the study as a 
consequence of AEs. 
12.3 
Reporting and Documentation Procedures 
In this study, all AEs – except AEs based on abnormal laboratory parameters or vital signs with 
an intensity/severity grade 1 (see Table 2) that has no clinical relevance – have to be 
documented and reported. 
 
If the same AE occurs frequently during the study and all episodes have the same main AE 
characteristics (intensity, causal relationship, outcome), this should be documented as one AE 
with multiple episodes. 
 
All other AEs, including those known to be associated with the study drugs, are to be 
completely documented and reported. 
12.3.1 Documentation of (Serious) Adverse Events 
All AEs including SAEs must be documented by the Investigator on the AE page of the eCRF. 
 
Adverse events based on clinical signs and symptoms are to be assessed according to the 
CTCAE V4.03 intensity criteria (Appendix 3) or – if CTCAE is not applicable – according to 
the general intensity/severity criteria provided in the Table 2 in Section 12.2.1.  
 
Adverse events based on abnormal laboratory parameters or vital signs are to be assessed 
according to the CTCAE V4.03 intensity/severity criteria and their clinical relevance as 
outlined in Table 3 below. For such AEs the clinical picture should be described, if applicable, 
rather than the laboratory parameter or vital sign only (e.g., “hypertension” instead of 
“increased systolic and diastolic blood pressure” or “hyperthyroidism” instead of “elevated 
thyroid hormones”). 
 


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Table 3: 
Documentation of AEs (Laboratory parameters and vital signs) 
Severity Grade* Clinically relevant
Documentation as 
1 
Yes 
AE in eCRF 
No 
No documentation necessary 
2 
Yes/No 
AE in eCRF 
3 
Yes (typical) 
AE in eCRF; if serious, additionally on SAE 
report form
4 
Yes 
AE in eCRF; additionally on SAE report form 
5 
Yes 
AE in eCRF; additionally on SAE report form 
*According to CTCAE V4.03 (Appendix 3) as far as possible 
If a patient is withdrawn due to an AE at the end of the study treatment period, the 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.  
 
AEs are generally coded according to Medical Dictionary for Regulatory Affairs (MedDRA). 
At the end of the study before the clinical data base is closed, all AEs will be re-coded according 
to the latest MedDRA version available. 
12.3.2 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 the eCRF, in any 
case, no later than 24h after becoming aware of the SAE. 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 
• 
Action taken to the study drug 
 
If necessary, the Investigator will provide follow-up reports immediately after knowledge of 
further relevant information. 


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12.3.3 Documentation and Reporting of Other Safety-Relevant Information 
and Unanticipated Problems 
Any: 
• Pharmaceutical quality issue regarding study medication 
• Report of overdose 
• Report of misuse 
• Report of use outside the scope of this clinical study protocol 
• Report of pregnancies or drug exposure via parent 
must be documented and reported immediately but within 24 hours at the latest of awareness 
on a “Serious Adverse Event Form” or “Drug Exposure via Parent Data Collection Form” form 
to the e-mail address provided below (see 12.3.4, Safety Contact at Fresenius Kabi). 
 
For instance, a report of overdose has to be completed if the total administered dose of the 
study drug exceeds the maximal dosage as defined in this protocol. 
 
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 
AEs 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 (see 12.3.4). 
 
Accordingly, to satisfy the Investigator’s obligation to notify the IRB of unanticipated 
problems, Fresenius Kabi will process and analyze AE information and other safety relevant 
information for the entire study and assess whether an AE occurrence is both unanticipated 
and a problem for the study. Fresenius Kabi will provide the Investigator with the report for 
submission to IRB. 
 
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. 
12.3.4 Safety Contact at Fresenius Kabi 
The Safety Associate of Clinipace Worldwide 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: 
 
 


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Date: 19 Feb 2019  
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In case of urgent questions regarding any safety aspect of this study, the Global Safety, 
Fresenius Kabi, OR Global Medical Affairs Officer at Clinipace Worldwide can be reached as 
follows: 
 
 
 
 
 
 
 
 
 
 
 
 
 
12.3.5 Reporting to FDA, Institutional Review Boards, and Investigators 
Fresenius Kabi as the Sponsor of this trial will inform the FDA and IRBs about unanticipated 
problems involving risk to human subjects or others, including AEs that should be considered 
unanticipated problems on an expedited basis (21 CFR 312.66). 
 
Fresenius Kabi will also provide Periodic Safety Update Reports or line listings to the IRBs as 
required. General and local requirements will be followed. All Investigators participating in 
the study will receive Safety Reports and information on unanticipated problems. 
12.3.6 Period of Observation 
The period of observation will begin the day the patient’s parent(s) or legal representative(s) 
has/have signed the ICF. The end of the observation period is defined as the time of the last 
Final Study Visit. The Final Study Visit takes place after cessation of the last infusion of study 
drug. 
 
All unresolved AEs will be followed by the Investigator until the events are resolved, the 
patient is lost to follow-up, or the SAE is otherwise explained. 
 
When the patient has been discharged from the hospital, or has been in home care, the 
Investigator should instruct the patient’s personal physician (only if patient’s legal 
representative/s allow/s) to report any SAE and any AE that this physician believes might 
reasonably be related to participation in this study. The Investigator should notify Fresenius 
Kabi immediately of any such SAE. 


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12.4 
Unblinding of Treatment for Emergency Reasons 
In case of a medical emergency requiring identification of the study lipid emulsion 
administered to the patient, the treatment code may be unblinded. For unblinding procedure 
see Section 6.4.  
 
After completing the unblinding procedure, 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.  
 
If an emergency unblinding becomes necessary, the Investigator should notify the 
Sponsor/Medical Monitor, if possible, prior to unblinding.  
 
If an Investigator, patient, or parent/legal representative 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 
reporting, should be unblinded before submission to the FDA. 
 
In case of unblinding, the blindness of Fresenius Kabi’s (and the CRO’s) clinical study team 
must be maintained wherever possible, i.e., no information with regard to a broken treatment 
code must be communicated to any blinded member of the study team. The unblinding must 
be notified immediately to the CRA responsible for the site. 
12.5 
Data Safety Monitoring Board (DSMB) 
In this study an independent DSMB will be involved. The DSMB is a multidisciplinary group 
consisting of clinical study scientists and statisticians experienced in managing PN in pediatric 
patients 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.  
 
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. 
 
 
13. Monitoring 
13.1 
Monitoring Procedures and Responsibilities 
Site monitoring is conducted to ensure the patient protection, compliance with the study 
protocol, study progress, adherence to study procedures, study interventions, and 


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administration of study drugs. The monitoring and collection of data will be performed in high 
quality manner in compliance with ICH/GCP, valid Standard Operating Procedures (SOPs), 
and other regulatory guidelines, if appropriate. 
 
This study will be monitored regularly by a CRA from the CRO. The CRA will check all inform 
consent documents and the appropriate documentation as well as the completion of the entries 
in the eCRFs, their compliance and accuracy with the study protocol and will compare the 
eCRF entries with the source data. This source data verification will be performed for all 
patients on all data. Administration of study drugs and the investigator site file will be 
monitored as well. Further details will be defined in the Monitoring Manual. 
 
In addition, the monitor will check whether all AEs and SAEs have been documented and 
reported appropriately within the required time periods.  
 
The Investigator and his staff will be expected to cooperate with the CRA, to be available 
during a sufficient portion of the monitoring visit to answer questions and to provide any 
missing information. 
 
In addition the Investigator is required to:  
• 
Have all data properly recorded in the eCRF and the patient file before each 
monitoring visit.  
• 
Have the source documents available at the monitoring visits. 
• 
Record all study drugs dispensed in the eCRF and drug accountability records.  
• 
Provide investigator site file for verification of completeness and accuracy. 
 
All patients who were screened, but not enrolled into the study will be listed on the patients 
screening log and will be monitored as well.  
 
Monitoring will also be conducted to detect any misconduct or fraud.  
 
Monitoring will be performed by:  
  
 
 
 
 
 
 
 
13.2 
Frequency of Monitoring 
During the treatment phase of the study, each site will be visited by the monitor as soon as 
possible after first patient of each site has been screened and ICF was signed, followed by visits 
approximately every  weeks, or as appropriate. 


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14. Audits and Inspections 
14.1 
Audits 
14.1.1 Auditing Procedures 
Audits (quality assurance) may be performed to ensure compliance of the study with GCP 
requirements. The Auditor will work on behalf of Fresenius Kabi, but will be independent from 
the operational departments within Fresenius Kabi. The Investigator and Clinipace will permit 
the respective person direct access to source data/documents. 
 
At the study site, the Auditor will check the following: 
• 
Preconditions to start the study 
• 
Completeness and correctness of the ICFs 
• 
Compliance of study with study protocol 
• 
Source data check 
• 
Drug accountability 
• 
General compliance of the study with GCP and national law 
• 
Organization of the study and delegation of staff responsibilities 
• 
Patient recruitment, screening, enrolment and treatment allocation/randomization 
• 
Changes in study or routine hospital procedures, if any 
• 
Handling of (Serious) AEs inclusive reporting and follow-up 
14.1.2 Frequency of Audits 
Audits will be performed according to an audit plan. 
At least one on-site audit is planned for this trial, but audits may be performed at any time at 
any site during the study as considered necessary.  
14.1.3 Documentation of Audits 
After each audit the Auditor will compile an audit report including an audit certificate. A copy 
of the certificate will be sent to the Investigator to be filed in the Investigator’s site file. 
14.2 
Inspections 
The Investigator will permit study related IRB review, and regulatory inspection(s), providing 
direct access to source data/documents. 
 
 


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15. Modifications during the Study 
15.1 
Protocol Amendments 
If both Fresenius Kabi and the Coordinating Investigator agree upon a change or addition in 
the study protocol during the course of the study, this will be documented in a written protocol 
amendment. These amendments will become part of the study protocol. 
 
Minor modifications, minor deviations, or specifications of the study protocol can be described 
in a non-substantial amendment.  
 
Substantial amendments must be submitted to the IRBs and the FDA. In case of substantial 
amendments that affect information submitted to both the FDA and the IRBs, Fresenius Kabi 
will make arrangements to submit the notifications in parallel. For substantial amendments to 
information that only the FDA assesses, Fresenius Kabi will not only submit the amendment 
to the FDA, but also make arrangements to inform the IRBs about this application. Similarly, 
Fresenius Kabi will inform the FDA of any substantial amendment to information for which 
only the IRB is responsible (e.g. facilities for the trial). 
 
Examples for substantial amendments, but not limited to these, are: 
• 
Change in study design 
• 
Changes in measures of efficacy 
• 
Changes of inclusion or exclusion criteria 
• 
Changes of safety reporting or evaluation 
• 
Changes likely to have an impact on the safety of study patients 
• 
Changes in the interpretation of the scientific documents in support of the conduct of 
the study 
• 
Changes deemed otherwise significant 
15.2 
Protocol Deviations 
No deviation from the study protocol will be allowed unless a formal amendment is made to 
the protocol. However, 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, 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. 
 
Protocol deviations will be assessed and graded in the blinded data review meeting prior to the 
final analysis of the study data. 


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15.3 
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 include: 
• 
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 completed appropriately) 
• 
The incidence or severity of AEs/SAEs in this or in parallel studies indicate a potential 
health hazard caused by treatment with a study drug 
• 
Fresenius Kabi is requested by the FDA to terminate the study 
• 
Fresenius Kabi decides to terminate the study due to internal reasons 
 
In case of premature termination of the study, Fresenius Kabi will notify the FDA and IRBs 
within 15 days and give reasons for termination, which should clearly be explained. 
Additionally, the Investigators will be notified by Fresenius Kabi and will receive instruction, 
if necessary, as to what final examinations are required. 
 
 
16. Final Clinical Study Report 
Fresenius Kabi is responsible for compilation of the final clinical study report (CSR). The final 
CSR will be submitted to the Coordinating Investigator and all Principal Investigators for 
approval and signature. A copy of the final signed CSR will be sent to each Investigator for the 
study site file. 
 
17. Administrative Requirements 
The trial will be carried out in accordance with the current version of ICH E6 - Guidelines for 
Good Clinical Practice (June 2017), the Declaration of Helsinki, revised version (64th WMA 
General Assembly, Fortaleza, Brazil, October 2013), and the Code of Federal Regulations 
(CFR) Title 21. 
17.1 
Public Trials Registry 
Fresenius Kabi will obtain a Clinical Trials Registry Number for the clinical study from the 
ClinicalTrials.gov database, via internet, by filling in an application form. This number 
identifies a study unambiguously. 
17.2 
Institutional Review Board 
Fresenius Kabi will submit the study protocol including the ICF 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.  


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Amendments that are substantial must be notified to the FDA and the IRBs; Fresenius Kabi 
will make arrangements to submit the notifications in parallel. For substantial amendments to 
information that only the FDA assesses, Fresenius Kabi will not only submit the amendment 
to the FDA but also make arrangements to inform the IRBs that they have made the application. 
Similarly Fresenius Kabi will inform the FDA of any substantial amendment to information 
for which only the IRB is responsible (e.g., facilities for the study). 
 
During the study the IRBs will be informed of any ADRs which are both serious and 
unexpected and any other SAEs as required by the IRB. Changes increasing the risk to patients 
or affecting significantly the conduct of the study will also be reported to the IRBs. 
Fresenius Kabi will notify the IRBs of the end of the study within 90 days. 
17.3 
Submission to the Food and Drug Administration  
Fresenius Kabi is responsible for submission of study-related documents to the FDA (Center 
for Drug Evaluation and Research, Division of Gastroenterology Products) before study start. 
Approval by the FDA is a pre-requisite for initiation of the study. 
Fresenius Kabi will notify the FDA of the end of the study within 90 days. 
17.4 
Notification of Local Authority  
Not applicable in the USA. 
17.5 
Patient Information and Informed Consent 
It is the responsibility of the Investigator to give each legal representative 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 has to 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 enrollment. 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 ICF from each legal representative prior to inclusion of a patient 
in the study. 
 
The legal representative(s) should have enough time (ample time) and opportunity to enquire 
about details of the study and to decide whether or not to allow participation in the study. 
 


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If possible, patient assent must also be obtained (according to local law). 
 
The dated and signed ICFs should be filed by the Investigator for mandatory review by study 
CRA or for possible audits and inspections where this is permitted or required. The Investigator 
will confirm the receipt of ICF from each legal representative in the CRF. 
17.6 
Patient Insurance 
In accordance with current ICH E6 – Good Clinical Practice, and national requirements, 
Fresenius Kabi has taken out a personal liability insurance (HDI-Gerling America Insurance 
Company, 161 North Clark Street – 48th Floor, Chicago, IL 60601; policy no. CTD5460500S) 
in the amount of USD 5.000.000 for each patient participating in the trial. 
17.7 
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. The data will be blinded 
correspondingly in all data analyses. 
 
In compliance with the ICH GCP guidelines 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. 
17.8 
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 Coordinating Investigator and his co-investigator(s). 
• 
List of laboratory normal values of local laboratory including methods and certificates  
 
 
18. Agreements 
18.1 
Confidentiality Agreement 
This study protocol is provided to the Coordinating Investigator, potential investigator, or 
consultant, and the IRB for review. The information contained in this protocol is confidential 


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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 Investigators 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. 
18.2 
Publication of Results 
Publication of study results is intended. The publication of study results will be ruled by the 
agreement between the Investigator/Institution and Fresenius Kabi. 
18.3 
Payment 
Financial obligations of Fresenius Kabi are outlined in a separate agreement between the 
Investigator/Institution and Fresenius Kabi. 
18.4 
Potential Conflicts of Interest 
A financial disclosure form according to 21 CFR Part 54 will have to be signed by each 
Investigator participating in the study. 
18.5 
Incentives to Patients 
Not applicable. 
18.6 
Archiving 
At the end of the study the Investigator will receive an electronic copy of the eCRF in PDF/A 
format on CD/DVD. The Investigator must ensure that data remains readable throughout the 
requirement archiving period.  
 
All records and documents pertaining to the conduct of the study (particularly eCRFs, ICFs, 
drug accountability sheets, original data including the patient files) must be retained. According 
to the CFR Chapter I, §312.62(c) the Investigator shall retain records required to be maintained 
under this part for a period of 2 years following the date a marketing application is approved 
for the drug for the indication for which it is being investigated; or, if no application is to be 
filed or if the application is not approved for such indication, until the investigation is 
discontinued and FDA is notified. Retrospective identification of all patients must be possible 
at any time. The Investigator shall discard any records only after consultation with Fresenius 
Kabi. 
 
Any transfer of ownership of the content of the clinical trial master file shall be documented. 
The new owner shall assume the responsibilities set out in this section. 
 


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The media used to archive the content of the clinical trial master file shall be such that the 
content remains complete and legible throughout the period referred to in this paragraph. Any 
alteration to the content of the clinical trial master file shall be traceable. 
 
 
19. References 
A.S.P.E.N. Pediatric assessment and interventions. In: MR C, editor. Pediatric Nutrition 
Support Handbook 2nd edition: American Society for Parenteral and Enteral Nutrition 2015. 
p. 121-66. 
Burrin DG, Ng K, Stoll B, Saenz De Pipaon M. Impact of new-generation lipid emulsions on 
cellular mechanisms of parenteral nutrition-associated liver disease. Adv Nutr. 2014;5(1):82-
91. 
Christensen RD, Henry E, Wiedmeier SE, Burnett J, Lambert DK. Identifying patients, on the 
first day of life, at high-risk of developing parenteral nutrition-associated liver disease. J 
Perinatol. 2007;27(5):284-90. 
Clayton PT, Whitfield P, Iyer K. The role of phytosterols in the pathogenesis of liver 
complications of pediatric parenteral nutrition. Nutrition. 1998;14(1):158-64. 
Cober MP, Killu G, Brattain A, Welch KB, Kunisaki SM, Teitelbaum DH. Intravenous fat 
emulsions reduction for patients with parenteral nutrition-associated liver disease. J Pediatr. 
2012;160(3):421-7. 
Colomb V, Jobert-Giraud A, Lacaille F, Goulet O, Fournet JC, Ricour C. Role of lipid 
emulsions in cholestasis associated with long-term parenteral nutrition in children. JPEN J 
Parenter Enteral Nutr. 2000;24(6):345-50. 
Goulet O, Antebi H, Wolf C, Talbotec C, Alcindor LG, Corriol O, et al. A new intravenous fat 
emulsion containing soybean oil, medium-chain triglycerides, olive oil, and fish oil: a single-
center, double-blind randomized study on efficacy and safety in pediatric patients receiving 
home parenteral nutrition. JPEN J Parenter Enteral Nutr. 2010;34(5):485-95. 
Hamilton C, Austin T, Seidner DL. Essential fatty acid deficiency in human adults during 
parenteral nutrition. Nutr Clin Pract. 2006;21(4):387-94. 
ICH. Guidance for Industry E11, Clinical Investigation of Medicinal Products in the Pediatric 
Population; U.S. Department og Health and Human Services Food and Drug Administration, 
Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and 
Research (CBER). ICH. 2000(December). 
Javid PJ, Malone FR, Dick AA, Hsu E, Sunseri M, Healey P, et al. A contemporary analysis 
of parenteral nutrition-associated liver disease in surgical infants. J Pediatr Surg. 
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Koletzko B, Goulet O, Hunt J, Krohn K, Shamir R, Parenteral Nutrition Guidelines Working 
G, et al. 1. Guidelines on Paediatric Parenteral Nutrition of the European Society of Paediatric 
Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the European Society for 
Clinical Nutrition and Metabolism (ESPEN), Supported by the European Society of Paediatric 
Research (ESPR). J Pediatr Gastroenterol Nutr. 2005;41 Suppl 2:S1-87. 
Koseesirikul P, Chotinaruemol S, Ukarapol N. Incidence and risk factors of parenteral 
nutrition-associated liver disease in newborn infants. Pediatr Int. 2012;54(3):434-6. 
Krohn K, Koletzko B. Parenteral lipid emulsions in paediatrics. Curr Opin Clin Nutr Metab 
Care. 2006;9(3):319-23. 
Lewis L. Assessing pre-market safety in pediatric drug development: The DAVP perspective. 
FDA Pediatric Clinical Investigators Training, September 22, 2014. 
Mascioli EA, Lopes SM, Champagne C, Driscoll DF. Essential fatty acid deficiency and home 
total parenteral nutrition patients. Nutrition. 1996;12(4):245-9. 
McClave SA, Taylor BE, Martindale RG, Warren MM, Johnson DR, Braunschweig C, et al. 
Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult 
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Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr. 2016;40(2):159-
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Ng K, Stoll B, Chacko S, Saenz de Pipaon M, Lauridsen C, Gray M, et al. Vitamin E in New-
Generation Lipid Emulsions Protects Against Parenteral Nutrition-Associated Liver Disease in 
Parenteral Nutrition-Fed Preterm Pigs. JPEN J Parenter Enteral Nutr. 2015. 
Pichler J, Horn V, Macdonald S, Hill S. Intestinal failure-associated liver disease in 
hospitalised children. Arch Dis Child. 2012;97(3):211-4. 
Rayyan M, Devlieger H, Jochum F, Allegaert K. Short-term use of parenteral nutrition with a 
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2012;36(1 Suppl):81s-94s. 
Tomsits E, Pataki M, Tolgyesi A, Fekete G, Rischak K, Szollar L. Safety and efficacy of a lipid 
emulsion containing a mixture of soybean oil, medium-chain triglycerides, olive oil, and fish 
oil: a randomised, double-blind clinical trial in premature infants requiring parenteral nutrition. 
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Waitzberg DL, Torrinhas RS, Jacintho TM. New parenteral lipid emulsions for clinical use. 
JPEN J Parenter Enteral Nutr. 2006;30(4):351-67. 
Wales PW, Allen N, Worthington P, George D, Compher C, Teitelbaum D. A.S.P.E.N. Clinical 
Guidelines: Support of Pediatric Patients With Intestinal Failure at Risk of Parenteral Nutrition-
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20. Appendixes to this Clinical Study Protocol 
 
APPENDIX 1: 
Smoflipid Prescribing Information 
 
APPENDIX 2: 
Intralipid 20% Prescribing Information 
 
APPENDIX 3: 
Common Terminology Criteria for Adverse Events (CTCAE) v 4.03. 
U.S.DEPARTMENT OF HEALTH AND HUMAN SERVICES National 
Institutes of Health National Cancer Institute, Publish Date: June 14, 2010.