Clinical trial NCT04555044
Conditions: Essential Fatty Acid Deficiency (EFAD)
Keywords: Essential Fatty Acids (EFA) Parenteral Nutrition Clinolipid/Clinoleic Parenteral Nutrition Associated Cholestasis (PNAC) Parenteral Nutrition Associated Liver Disease (PNALD) Intestinal Failure Associated Liver Disease (IFALD) Phytosterols Intralipid Infants/Preterm Infants FADS1 and FADS2 Short Bowel Syndrome Cancer Nutrition Olive Oil Emulsion Soybean Oil Emulsion
Sponsor: Baxter Healthcare Corporation
Start date: 2021-01-22; Completion date: 2022-11-16
Enrollment: 101 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This will be a descriptive study designed to evaluate the propensity for hospitalized pediatric patients treated adequately with Clinolipid or standard of care (Intralipid) from 7 up to 90 days to develop Essential Fatty Acid Deficiency (EFAD). Additionally, this study design will evaluate the safety and efficacy of using Clinolipid or Intralipid in a pediatric population.

Detailed description:

Arms: arm 1: Dosing based on American Academy of Pediatrics (AAP), American Academy Society for Parenteral and Enteral Nutrition (ASPEN), European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN)/ European Society for Parenteral and Enteral Nutrition (ESPEN)/ European Society of Paediatric Research (ESPR)/ Chinese Society for Parenteral and Enteral Nutrition (CSPEN) guidelines. Study treatment will be administered intravenously in the hospital setting from 7 up to 90 days using either a syringe pump or an infusion pump as appropriate for the daily volume of infusate. The flow rate will be prescribed by the Investigator to provide the daily dosage over 20 to 24 hours. arm 2: Dosing based on AAP, ASPEN, ESPGHAN/ESPEN/ESPR/CSPEN guidelines. Study treatment will be administered intravenously in the hospital setting from 7 up to 90 days using either a syringe pump or an infusion pump as appropriate for the daily volume of infusate. The flow rate will be prescribed by the Investigator to provide the daily dosage over 20 to 24 hours.
Interventions: intervention 1: Clinolipid intervention 2: Intralipid
Intervention descriptions: intervention 1: Lipid injectable emulsion, USP 20% intervention 2: Standard-of-Care Soybean Oil-Based Lipid Emulsion. 20% (lipid injectable emulsion, USP)

Protocol documents:
Prot_000.pdf: 
Clinolipid (lipid injectable emulsion, USP) 20%
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Clinical Trial Protocol #6344-001: Amendment 5.6
2022 FEB 22
Clinical Trial Protocol: 6344-001
Study Title:
A Randomized, Double-Blind, Controlled, Clinical Trial to Evaluate the Risk 
of Developing Essential Fatty Acid Deficiency in Pediatric Patients, Including 
Neonates, Receiving Either Clinolipid (lipid injectable emulsion, USP) 20% or 
Standard-of-Care Soybean Oil-Based Lipid Emulsion
Study Number:
6344-001
Study Phase:
IV
Product Name:
Clinolipid (lipid injectable emulsion, USP) 20%
Indication:
Clinolipid 20% is a lipid emulsion currently indicated for parenteral nutrition in 
adults providing a source of calories and essential fatty acids when oral or 
enteral nutrition is not possible, insufficient, or contraindicated.
Investigators:
Multi-center
Sponsor:
Baxter Healthcare Corporation
Sponsor Contact:
, PMP
, Strategy and Delivery
Worldwide Medical
Baxter R&D Europe sprl
Boulevard d’Angleterre 2-4/ B-1420 Braine l’Alleud, Belgium
Medical Monitor:
 MD, FACP
, Clinical Research Strategy – Nutrition
Worldwide Medical
One Baxter Parkway 
Deerfield, IL 60015 USA




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Clinical Trial Protocol #6344-001: Amendment 5.6
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SYNOPSIS
Sponsor:
Baxter Healthcare Corporation
Name of Finished Product:
Clinolipid (lipid injectable emulsion, USP) 20%
Name of Active Ingredient:
Refined olive oil (80%) and refined soybean oil (20%)
Study Title:
A Randomized, Double-Blind, Controlled, Clinical Trial to Evaluate the Risk of Developing Essential 
Fatty Acid Deficiency in Pediatric Patients, Including Neonates, Receiving Either Clinolipid (lipid 
injectable emulsion, USP) 20% or Standard-of-Care Soybean Oil-Based Lipid Emulsion
Study Number: 6344-001
Study Phase: IV
Rationale:
Baxter plans to conduct a postmarketing, randomized, controlled clinical trial to evaluate the risk of 
developing essential fatty acid deficiency (EFAD) in pediatric patients, including neonates, receiving 
either Clinolipid or standard-of-care soybean oil-based lipid emulsion.
Primary Objective:
To evaluate the risk of developing EFAD in pediatric patients, including neonates, receiving either 
Clinolipid or standard-of-care soybean oil-based lipid emulsion (Intralipid) as a component of parenteral 
nutrition (PN) within the hospital setting from 7 to 90 days, inclusive.
EFAD will be defined using the Holman Index (plasma triene:tetraene ratio, specifically 5,8,11-
eicosatrienoic acid [mead acid] to 5,8,11,14 eicosatetraenoic acid [arachidonic acid, ARA] ratio) value 
of >0.4.
1.
Secondary Objective(s):
2.
The secondary objectives are as follows:
3.
To evaluate the risk of developing liver disease, including parenteral nutrition-associated liver 
disease (PNALD) as defined by direct bilirubin ≥2 mg/dL when no other etiology for liver 
dysfunction is present in patients receiving with intravenous lipid emulsion (ILE)
4.
To evaluate the adequacy of nutritional intervention in patients receiving either ILE 
5.
To evaluate the safety profiles of Clinolipid and Intralipid, as assessed by adverse events (AEs), 
serious adverse events (SAEs) and AEs of special interest (AESIs)


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Study Design:
This will be a descriptive study designed to evaluate the risk for pediatric patients treated adequately 
with Clinolipid in the hospital for up to a maximum of 90 days to develop EFAD.
Additionally, this study design will evaluate the safety and efficacy of using Clinolipid in a pediatric 
population.
A randomized, double-blind study is appropriate to decrease clinician and patient bias during study 
conduct.
Approximately 100 pediatric patients, including neonates, will participate in the study. Patients will be 
randomized in a 1:1 ratio to the treatment groups (Clinolipid or Intralipid) according to a central 
dynamic randomization scheme stratified by site and age group (premature infants born <37 weeks of 
gestation (up to 1 month corrected age [CA]), full-term neonates born ≥37 weeks of gestation to <1 
month of age, infants 1 to <12 months of age, children 1 to <10 years of age, adolescent 10 to <18 years 
of age).
The primary and secondary objectives will be determined based on, but not limited to, the following 
clinical and laboratory assessments: 
•
Plasma fatty acid (FA) profiles and Holman Index;
•
Genetic polymorphisms in the FA desaturase genes FADS1 and FADS2 in a subset of patients 
(approximately 20%);
•
Hepatic function tests including alkaline phosphatase (ALP), aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), total and direct bilirubin to 
assess hepatic function and integrity;
•
Plasma phytosterol (stigmasterol, campesterol, and sitosterol), cholesterol and squalene levels to 
determine potential correlation with the development of PNALD;
•
Holman Index and fatty acid profiles will be evaluated. Select polymorphisms in the fatty acid 
desaturase genes, FADS1 and FADS2, will be determined in a subset of patients. The major 
plasma phytosterols found in the lipid emulsions (stigmasterol, campesterol, and sitosterol), 
cholesterol, and squalene also will be assessed.
After end of study treatment (maximum of 90 days), the patient will resume PN therapy as prescribed by 
their healthcare provider.
Study Population:
Key Inclusion Criteria:
1.
Patients who are expected to require PN for at least 7 days;
2.
Premature infants (born at 24 to <37 weeks of gestation with a birth weight ≥750 g) must require 
at least 80% of targeted energy requirements by PN at study entry (up to 1 month CA); full term 
infants and children must require at least 70% of targeted energy requirements by PN at entry into 
the study;
3.
A patient, or legal representative, has signed a written informed consent form per 21 CFR Part 
50.55(e).
Key Exclusion Criteria:
1.
Patients who are not expected to survive hospitalization or with a severe critical unresponsive 
illness at time of initiation with foreseeable intercurrent events that could jeopardize the patient’s 
participation in the study (i.e. unresponsive shock, sepsis, renal failure requiring dialysis, severe 
unresponsive metabolic acidosis, and/or severe unresponsive metabolic disorders), as judged by 
the Investigator;
2.
Patients with a known hypersensitivity to lipid emulsion, egg or soybean proteins, or any of the 
active substances, excipients, or components of the container or who have a history of an adverse 
event due to ILE;


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3.
Patients with liver disease including cholestasis;
4.
Patients with severe hyperlipidemia or severe disorders of lipid metabolism characterized by 
hypertriglyceridemia (i.e. triglyceride >400 mg/dL);
5.
Premature infants born <24 weeks of gestation and patients ≥18 years;
6.
Patient requires or is expected to require propofol for sedation;
7.
Patient, born to a symptomatic mother diagnosed with COVID-19 at the time of birth or before 
birth;
8.
Patient has received a diagnosis of COVID-19 (diagnosis <2 months prior and/or symptoms have 
not resolved);
9.
Female patients who are pregnant. Note: All female patients ≥12 years of age must have a 
negative urine human chorionic gonadotropin (hCG) pregnancy test at screening. For female 
patients <12 years of age, a urine hCG test at screening will be performed at the discretion of the 
investigator based on childbearing potential.
Test Product: Clinolipid (lipid injectable emulsion, USP) 20%
Reference Therapy: Intralipid (lipid injectable emulsion, USP) 20%
Mode of Administration: The dosing schedule is the same for each of the injectable lipid emulsions 
(ILEs), Clinolipid and Intralipid (control).
Table 1. Dosing Schedule for Intravenous Lipid Emulsions (g/kg/d of lipid) a
Day 1 of 
PN b
(g/kg/day)
Targeted daily 
advancement rate
(g/kg/day)
Maintenance c
(g/kg/day)
Maximum
(g/kg/day)
Preterm infants
1
1
2.5 to 3
3
Term infants (0-<1y)
1
1
2.5 to 3
3
Children (1-<10y)
1
1
2 to 3
3
Adolescents (10-<18y)
1
1
1 to 2
3
a Daily administration over 20-24 hours
b Randomization is recommended within 24 hours of signing consent but must occur within 3 days of 
signing consent. If patient is not randomized within 24 hours of informed consent, patient should be 
started on standard of care ILE on Day 1 of PN and transitioned to study drug once randomization 
has occurred.
c Unless there is a clinical reason to decrease the dose in the opinion of the Investigator
Duration of Treatment: from 7 days, up to 90 days
Statistical Methods:
Determination of Sample Size:
The sample size of 100 patients (50 in each of the 2 treatment groups: Clinolipid vs Intralipid), including 
neonates, is based on the feasibility of timely enrollment of patients for generating reference data and 
summary descriptive statistics, rather than on a formal power calculation.
Analysis Sets:
The analysis sets in this study include: the Full Analysis Set (FAS), the Per Protocol Set (PPS), and the 
Safety Analysis Set. The FAS includes all patients who are randomized to receive either Clinolipid or 
standard-of-care (SOC) soybean oil-based lipid emulsion (Intralipid), consistent with the intention-to-
treat principle. The PPS includes a subset of patients in the FAS who have Holman Index measurements 
taken at baseline and at least 1 other time point post-baseline, who have received a minimum of 7 days 


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of ILE treatment, and do not have a major protocol violation that potentially impacts the primary 
endpoint. The Safety Analysis Set includes all patients that have received treatment (Clinolipid or SOC).
Subgroup analyses of patients by age group (premature infants born <37 weeks of gestation (up to 1 
month CA), full-term neonates born ≥37 weeks of gestation <1 month of age, infants 1 to <12 months of 
age, children 1 to <10 years of age, adolescent 10 to <18 years of age) and subgroup analyses according 
to gestational age and birth weight will be conducted.
The primary endpoint analysis and secondary endpoint analyses of the development of liver disease 
including parenteral nutrition-associated liver disease (PNALD) and the adequacy of nutritional 
intervention will be conducted for both the FAS and PPS. The safety analyses (secondary endpoint no. 3) 
will be conducted for the FAS.
Primary Endpoint: 
The risk of developing EFAD (determined by Holman Index value >0.4) in pediatric patients will be 
summarized by treatment group as frequency and percentage, Time to developing EFAD will be 
analyzed using the Kaplan-Meier approach. Both incidence rate and proportion of EFAD will be 
computed for each treatment group.
Holman Index also will be summarized with descriptive statistics (number of patients, mean, standard 
deviation, median, minimum, and maximum) on an approximately 15-day basis in each of the 
2 treatment groups (Clinolipid vs Intralipid).
FA profiles will be summarized using descriptive statistics in each of the treatment groups.
FA profile, Holman Index will be assessed in the pediatric patients at baseline and approximately every 
15 days throughout the study up to end of study treatment.
Genetic polymorphisms in the FA desaturase genes FADS1 and FADS2 will be assessed in a subset of 
patients (approximately 20%) and the distribution assessed in the context of the FA profile.
•
Genetic material will be obtained from buccal smears in all patients that consent to analysis of 
FADS1 and FADS2 polymorphisms
•
From the subset of patients consenting to genetic analysis, the 10 patients (5 Intralipid and 5 
Clinolipid) with the lowest levels of ARA at any point during the study and the 10 patients (5 
Intralipid and 5 Clinolipid) with the highest levels of ARA at any point during the study will be 
selected for analysis of single nucleotide polymorphisms within FADS1 and FADS2 genes as the 
synthesis of ARA from linoleic acid (LA) requires both the delta-5 and delta-6 desaturase 
enzymes (coded for by FADS1 and FADS2).
•
Distribution of the polymorphisms within FADS1 and FADS2 genes will be assessed in the 
context various FA findings as the synthesis of gamma-LA and ARA from LA (n-6 pathway) and 
the synthesis of stearidonic acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)
from ALA (n-3 pathway) require both the delta-5 and delta-6 desaturase enzymes (coded for by 
FADS1 and FADS2 genes).
Secondary Endpoints:
The 3 secondary endpoints of the study include 1) the development of liver disease including PNALD; 
2) the adequacy of nutritional intervention; and 3) the safety profiles including AEs, SAEs and AESIs.
1.
Liver disease, including development of PNALD 
•
The risk of developing PNALD (as defined by direct bilirubin ≥2 mg/dL when no other etiology 
for liver dysfunction is present in patients receiving ILE) in pediatric patients will be summarized
by treatment group as frequency and percentage, as well as time to developing PNALD using the 
Kaplan-Meier approach. Both incidence rate and proportion of PNALD will be computed for each 
treatment group.
•
To assess the relationship of phytosterol, cholesterol and squalene blood levels and the 
development of PNALD, plasma phytosterol, cholesterol, and squalene levels will be summarized 
using descriptive statistics at baseline, at the end of study treatment, and as well as maximal 
values during the study period in each of the 2 treatment groups. In addition, the correlations 


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between plasma phytosterol levels and direct bilirubin will be assessed by computing a Pearson’s 
correlation coefficient or a Spearman correlation coefficient.
•
Hepatic integrity (ALP, AST, ALT, GGT, total and direct bilirubin) will be evaluated by 
presenting descriptive summary statistics of individual values at different measurement time 
points from baseline to end of study treatment during the study period in each of the 2 treatment 
groups. Hepatic integrity parameters will also be summarized in shift tables comparing results 
from baseline to end of study treatment (max 90 days) and to maximal value during the study 
period in each of the 2 treatment groups. In addition, assessment for drug-induced liver injury will 
be conducted according to Hy’s Law and eDISH criteria.1,2
2.
Adequacy of nutritional intervention 
The adequacy of nutritional intervention in patients receiving either Clinolipid or Intralipid will be 
assessed and results analyzed as follows:
•
Prescribed and actual nutritional intakes (calories, protein, lipids and carbohydrates) from both 
PN and enteral/oral nutrition will be collected and recorded on a daily basis and summarized daily 
for the first 2 weeks of treatment and on an approximately every 15-day basis afterwards up to the 
end of study treatment in each of the treatment groups.
•
Growth will be assessed and evaluated from baseline to end of study treatment on an 
approximately every 15-day basis using descriptive summary statistics for weight, and
height/length (and head circumference in infants <1 year) in each of the treatment groups as 
follows:
•
Gain in weight (g/kg/day in infants and g/day in children and adolescents), and gain in 
length/height (mm/week in all) and head circumference (mm/week in infants <1 year);
•
Changes in the standard deviation score (SDS or z-score) from reference growth curves (Fenton 
growth curve for premature infants, World Health Organization growth standards for infants and 
children ages 0 to 2 years, or Center for Disease Control growth charts for children age ≥2 years).
3.
Safety profiles of Clinolipid and Intralipid, including AEs, SAEs and AESIs.
The safety profiles will be assessed and analyzed as follows:
•
Vital signs and laboratory tests will be summarized using descriptive summary statistics in each 
of the 2 treatment groups. 
•
Additional neonatal morbidities including bronchopulmonary dysplasia (BPD), retinopathy of 
prematurity (ROP), intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), 
necrotizing enterocolitis (NEC), and late-onset sepsis in enrolled premature infants born <37 
weeks of gestation up to 1 month CA.
•
All AEs, SAEs, and AESI will be tabulated by body system using the Medical Dictionary for 
Regulatory Activities (MedDRA) coded terms. 
•
Adverse events and SAEs will be presented by treatment group using frequencies and 
percentages. In addition, the AE rate per 100 patient days will be reported.


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Date of Original Approved Protocol: 2014 May 20
Amendment 1: 2014 June 20
Amendment 2: 2014 September 03
Amendment 3: 2015 May 26
Amendment 4: 2019 March 22
Amendment 5: 2020 April 13
Amendment 5.1: 2020 April 21
Amendment 5.2: 2020 June 01
Amendment 5.3: 2020 June 25
Amendment 5.4: 2020 August 26
Amendment 5.5: 2022 February 03
Amendment 5.6: 2022 February 22


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Table of Contents
SYNOPSIS..........................................................................................................................3
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..............................13
1. INTRODUCTION........................................................................................................15
2. STUDY OBJECTIVES................................................................................................18
2.1 Primary Objective..................................................................................................18
2.2 Secondary Objective(s)..........................................................................................19
3. INVESTIGATIONAL PLAN .....................................................................................20
3.1 Overall Study Design and Plan.............................................................................20
3.2 Rationale for Study Design and Control Group .................................................21
3.3 Study Duration.......................................................................................................21
4. STUDY POPULATION SELECTION......................................................................21
4.1 Study Population....................................................................................................21
4.2 Inclusion Criteria...................................................................................................22
4.3 Exclusion Criteria..................................................................................................23
5. STUDY TREATMENT(S) ..........................................................................................24
5.1 Description of Treatment(s) and Dosing..............................................................24
5.1.1 Clinolipid (lipid injectable emulsion, US Pharmacopeia) 20% -
Investigational Product..................................................................................24
5.1.1.1 Clinolipid Contraindications per US Prescribing Information...........24
5.1.2 Intralipid 20% (lipid injectable emulsion, USP) – Active Control ............25
5.1.2.1 Intralipid Contraindications per US Prescribing Information ...........25
5.1.3 Dosing Schedule ..............................................................................................25
5.2 Treatments Administered .....................................................................................25
5.3 Selection and Timing of Dose for Each Patient...................................................26
5.4 Method of Assigning Patients to Treatment Groups..........................................26
5.5 Blinding...................................................................................................................27
5.6 Restrictions.............................................................................................................27
5.6.1 Prior Therapy/Concomitant Medications ....................................................27
5.6.2 Concomitant Procedures................................................................................28
5.6.3 Fluid and Food Intake....................................................................................28
5.6.4 Patient Activity Restrictions ..........................................................................28
5.7 Treatment Compliance..........................................................................................28
5.8 Packaging and Labeling........................................................................................28


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5.9 Storage and Accountability...................................................................................29
5.9.1 Storage Requirements/Stability.....................................................................29
5.9.2 Investigational Product Accountability ........................................................29
6. STUDY PROCEDURES .............................................................................................30
6.1 Informed Consent ..................................................................................................30
6.2 Demographics.........................................................................................................30
6.2.1 Neonates...........................................................................................................30
6.3 Medical History and Prior Medications ..............................................................31
6.4 Physical Examination ............................................................................................31
6.5 Weight, Height or Length, and Head Circumference ........................................31
6.6 Vital Signs...............................................................................................................32
6.7 Clinical Laboratory Tests .....................................................................................32
6.7.1 Laboratory Parameters..................................................................................32
6.7.2 Sample Collection, Storage, and Shipping ...................................................34
6.7.2.1 Hematology and Chemistry ....................................................................34
6.7.2.2 Triglycerides.............................................................................................34
6.7.2.3 Liver function tests ..................................................................................34
6.7.2.4 Fatty acid profiles, Holman Index, and phytosterol, cholesterol, 
and squalene levels...................................................................................34
6.7.2.5 Genetic polymorphism for fatty acid desaturase genes .......................35
6.8 Diagnosis and Management of Essential Fatty Acid Deficiency (EFAD).........36
6.8.1 Holman Index <0.2..........................................................................................36
6.8.2 Index between 0.2 and 0.4..............................................................................36
6.8.3 Holman Index >0.4..........................................................................................37
6.8.4 Holman Index >0.4 at baseline ......................................................................38
6.8.5 Calculating Linoleic Acid (LA) Intake from Intravenous Lipid 
Emulsion (ILE) ...............................................................................................39
6.9 Nutritional Intake ..................................................................................................40
6.10 Dispensing Study Treatment...............................................................................40
6.11 Concomitant Medications ...................................................................................40
6.12 Concomitant Procedures.....................................................................................41
6.13 Adverse Events Assessments...............................................................................41
6.13.1 Performing Adverse Events Assessments...................................................42
6.13.2 Severity ..........................................................................................................42
6.13.3 Relationship...................................................................................................43
6.13.4 Expectedness .................................................................................................44
6.13.5 Clinical Significance .....................................................................................44
6.13.6 Clinical Laboratory Adverse Events...........................................................44
6.13.7 Serious Adverse Events ................................................................................44
6.13.7.1 Definition ................................................................................................44
6.13.7.2 Reporting Serious Adverse Events.......................................................44
6.13.8 Treatment-Emergent Adverse Events ........................................................45
6.14 Removal of Patients from the Study/ Discontinuation of the Study................45


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6.15 Appropriateness of Measurements.....................................................................46
7. STUDY ACTIVITIES .................................................................................................46
7.1 Screening Period ....................................................................................................47
7.2 Study Treatment Period (Baseline to Day 90).....................................................48
7.2.1 Baseline Procedures........................................................................................48
7.2.2 Daily Procedures.............................................................................................49
7.2.3 Standard-of-Care Procedures........................................................................49
7.2.4 Days 15, 30, 45, 60, 75 and 90 or End of Study Treatment Procedures.....49
8. QUALITY CONTROL AND ASSURANCE.............................................................50
9. PLANNED STATISTICAL METHODS...................................................................51
9.1 General Considerations.........................................................................................51
9.2 Determination of Sample Size...............................................................................51
9.3 Analysis Populations..............................................................................................51
9.4 Demographics and Baseline Characteristics.......................................................52
9.5 Primary Endpoint..................................................................................................52
9.6 Secondary Endpoint(s) ..........................................................................................53
9.6.1 Liver Disease, Including Parenteral-Associated Liver Disease ..................53
9.6.1.1 Parenteral Nutrition-Associated Liver Disease.....................................53
9.6.1.2 Hepatic Integrity......................................................................................53
9.6.1.3 Plasma Phytosterol, Cholesterol, and Squalene Levels........................54
9.6.2 Adequacy of Nutritional Interventions.........................................................54
9.6.2.1 Nutritional Intake....................................................................................54
9.6.2.2 Growth......................................................................................................54
9.6.3 Safety Profile of Clinolipid and Intralipid....................................................55
9.7 Interim Analysis.....................................................................................................56
10. ADMINISTRATIVE CONSIDERATIONS............................................................56
10.1 Investigators and Study Administrative Structure...........................................56
10.2 Institutional Review Board Approval................................................................56
10.3 Ethical Conduct of the Study..............................................................................57
10.4 Patient Information and Consent.......................................................................57
10.5 Patient Confidentiality ........................................................................................58
10.6 Study Monitoring.................................................................................................58
10.7 Case Report Forms and Study Records.............................................................58
10.8 Data and Safety Monitoring Board....................................................................59
10.9 Protocol Violations/Deviations............................................................................59
10.10 Access to Source Documentation......................................................................59
10.11 Data Generation and Analysis..........................................................................60
10.12 Retention of Data ...............................................................................................60
10.13 Financial Disclosure...........................................................................................61


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10.14 Publication and Disclosure Policy ....................................................................61
10.15 Health Insurance Portability and Accountability Act....................................62
11. REFERENCE LIST...................................................................................................62
List of In-Text Tables
Table 1. Fatty Acid Levels (mean levels) for Intralipid and Clinolipid......................17
Table 2. Sterol composition for Intralipid and Clinolipid (μg/mL ± SD)* .................17
Table 3. General Pediatric Parenteral Nutrition Guidelines.......................................24
Table 4. Dosing Schedule from both Intravenous Lipid Emulsiona............................25
Table 5. List of Laboratory Tests...................................................................................33
Table 6. Intralipid and Clinolipid Linoleic Acid Content............................................39
List of Appendices
Appendix 1 Schedule of Events Table............................................................................64
Appendix 2 Reference for Fatty Acid Profile Values (Mayo Clinic References) .......67
Appendix 3 Diagnosis and Management of EFAD .......................................................70
Appendix 4 Sponsor Signature .......................................................................................71
Appendix 5 Investigator’s Signature..............................................................................72


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase (also SGPT)
ALP
alkaline phosphatase
ARA
arachidonic acid
AST
aspartate aminotransferase (also SGOT)
BMI
body mass index
BPD
bronchopulmonary dysplasia
BW
body weight
CA
corrected age
CDC
Center for Disease Control
CFR
Code of Federal Regulations
CRF
case report form
CS
clinically significant
DHA
docosahexaenoic acid
DSMB
Data and Safety Monitoring Board
EDC
Electronic Data Capture
EFAD
essential fatty acid deficiency
EPA
eicosapentaenoic acid
FA(s)
fatty acid(s)
FAS
full analysis set
FADS1
fatty acid desaturase 1 gene
FADS2
fatty acid desaturase 2 gene
GA
gestational age
GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
GI
gastrointestinal
hCG
human chorionic gonadotropin
IC
informed consent
ICF
informed consent form
ICH
International Council for Harmonisation 
ILE
intravenous lipid emulsion
IP
investigational product
IRB
Institutional Review Board


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IVH
intraventricular hemorrhage
LA
linoleic acid
MedDRA
Medical Dictionary for Regulatory Activities
NEC
necrotizing enterocolitis
OO
Olive oil
PN
parenteral nutrition
PNALD
parenteral nutrition-associated liver disease
PPS
per protocol set
PUFA
polyunsaturated fatty acid
PVL
periventricular leukomalacia
ROP
retinopathy of prematurity
SAE
serious adverse event
SAP
statistical analysis plan
SDS
standard deviation score
SNP
single nucleotide polymorphism
SO
soybean oil
SOC
standard of care
USP
United States Pharmacopeia
USPI
United States Prescribing Information
WHO
World Health Organization


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1. INTRODUCTION
Although humans and other mammals can easily synthesize most fatty acids (FAs) from 
carbon groups in carbohydrates and proteins, they lack the desaturase enzymes necessary 
to insert a cis double bond at the n-6 and n-3 positions of a FA. As a result, the parent 
polyunsaturated fatty acid (PUFA) of the n-6 series, linoleic acid (LA, 18:2n-6), and the 
parent PUFA of the n-3 series, alpha-linolenic acid (ALA, 18:3n-3), are considered 
essential and indispensable for the synthesis of other long chain PUFAs of the n-6 and n-
3 series.
It is currently estimated that essential fatty acid deficiency (EFAD) may occur in human 
when LA and ALA intake is less than 2-4% and 0.25-0.5% of energy intakes, 
respectively.3 The clinical manifestations of EFAD are a flaky dry skin, hair loss, hair 
depigmentation, poor wound healing, increased susceptibility to infections, and poor 
growth in infants and children.3 Biochemical characteristics include decreased blood and 
tissue PUFAs from the n-6 and n-3 series and an elevated triene:tetraene ratio (T:T, 
Holman Index). Other biochemical manifestations of EFAD are considered non-specific 
and can include elevated liver enzymes, hyperlipidemia, thrombocytopenia and altered 
platelet aggregation.3,4
EFAD is rare under usual circumstances in healthy humans who have access to a varied 
diet or have sufficient adipose tissue that allows fat store mobilization to prevent EFAD 
when exogenous supply is limited.3,4 Thus, EFAD primarily occurs in clinical 
circumstances that severely limit fat intake, digestion, absorption and metabolism and in 
the setting of severely depleted fat stores. Due to their high requirements and limited fat 
stores, young infants are at increased risk for EFAD, especially premature infants.4,5
Parenteral nutrition (PN) is indicated for the supply of energy and essential nutrients 
when oral or enteral nutrition is not possible, insufficient, or contraindicated. Parenteral 
nutrition is essential for nutrient delivery in patients with gastrointestinal (GI) 
dysfunction who lack the capacity to absorb adequate nutrients for maintenance or 
recovery of tissue mass and function. 
Intravenous lipid emulsions (ILEs) were developed in order to prevent and treat EFAD in 
patients who require PN, as well as to provide a high-density energy source. The first 
intravenous fat preparation used to any great extent in the United States was made from 
cottonseed oil and marketed under the tradename of Lipomul® and was withdrawn from 
the market in 1965 because of numerous reports of toxicity, including "the fat-
overloading syndrome", hemorrhagic tendencies, and liver damage. The toxic 
accumulation of fat observed with Lipomul was attributed to its large particle size (1 nm


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in diameter), and possibly the emulsifying agent, pluronic F-68.6 Subsequently, for 
several years PN did not include the provision of any lipid and was associated with 
several reports of EFAD.7-9
The post-Lipomul ILEs were developed from soybean oil (SO) or safflower oil, both rich 
in LA and ALA. SO contains about 45–55 % LA, 6–9 % ALA, and very little saturated or 
monounsaturated FAs. Intralipid, a 100% SO based ILE, was invented by the Swedish 
physician and nutrition researcher Arvid Wretlind, and was approved for clinical use in 
Sweden in 1962 and 10 years later in the United States.
Experimental and clinical research suggests that these purely SO-based ILEs may exert 
an oxidative stress, may have a negative influence on immunological functions, and may
play a role in PN-associated liver disease (PNALD). These findings were felt to be 
related to its absolute high PUFA content, favoring lipid peroxidation, and the relative 
excess of n-6 PUFAs, favoring pro-inflammatory effects.10,11
Several new ILEs were subsequently developed including other sources of FAs designed 
to decrease the proportion of SO. In addition to the classic 100% SO ILEs, new 
generation composite ILEs contained other lipids including medium chain triglycerides 
derived from coconut oil or other tropical nut oils, olive oil (OO), or fish oil, or a 
combination of several sources. These new generation ILEs potentially can provide 
advantages over pure SO ILEs and are widely available in Europe and Canada but not in 
the United States.4,5,12-14
Clinolipid is an ILE comprised of a mixture of 80% OO and 20% SO. It was formulated 
with a lower SO content than currently marketed emulsions in order to reduce LA levels,
while still providing an adequate amount of EFAs to prevent and correct EFAD in adult 
and pediatric patients requiring PN.15 This OO-based ILE is rich in oleic acid, an n-9 
monounsaturated FA, that is considered immune neutral with potentially fewer adverse 
consequences on immunity compared to pure SO ILEs.10
Clinolipid has approximately one third of the LA content of a 100% SO ILE (fatty acid 
levels are provided in Table 1 and sterol composition is provided in Table 2). This 
reduction in the EFA supply could be a concern in a pediatric population, especially 
premature infants, who have higher EFA requirements than adults. Clinolipid has 
marketing authorization in approximately 50 countries. The current evidences of more 
than 20 years of clinical use suggest that Clinolipid is safe and can prevent EFAD.15,16
However, the objective of this study is to evaluate the risk of developing EFAD when 
using 20% Clinolipid in pediatric patients requiring PN compared to the use of a 100% 


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SO ILE (Intralipid 20%) that is still the standard-of-care (SOC) in current United States
hospital settings.
Table 1. Fatty Acid Levels (mean levels) for Intralipid and Clinolipid
Fatty Acid(s)
Intralipid 20%
Clinolipid 20%
Total Saturated Fatty Acids
     Myristic acid (14:0)
     Palmitic acid (16:0)
     Stearic acid (18:0)
15.6 %
0.1
11.0
3.9
16.6 %
0.0
13.0
3.3
Total monounsaturated fatty acids
     Palmitoleic acid (16:1n-7)
     Oleic acid (18:1n-9)
     Vaccenic acid (18:1n-7)
     Gondoic acid (20:1n-9)
22.8 %
0.1
20.9
1.3
0.2
63.4 %
0.9
59.7
1.7
0.2
Total polyunsaturated fatty acids
     Linoleic acid (18:2n-6)
     γ-linolenic acid (18:3n-6)
     α-linolenic acid (18:3n-3)
     Arachidonic acid (20:4n-6)
     EPA (20:5n-3)
     DHA (22:6n-3)
61.7 %
54.7
ND
6.7
0.2
ND
0.1
20.0 %
18.6
ND
1.7
0.2
ND
0.1
DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; ND = not detected; values represent 
mean % and are rounded to nearest tenth
Adapted from Harvey K et al.17
Table 2. Sterol composition for Intralipid and Clinolipid (μg/mL ± SD)*
Sterols
Intralipid (Soybean Oil-Based)
Clinolipid (Olive Oil-based)
Squalene
7.43 ± 0.10
387.45 ± 2.30
Cholesterol
274.08 ± 3.55
109.70 ± 0.38
Campesterol
55.35 ± 0.48
13.33 ± 0.12
Stigmasterol
65.05 ± 0.52
12.15 ± 0.04
β-Sitosterol
302.64 ± 2.00
240.59 ± 2.08
β-Sitostanol
7.68 ± 0.25
4.57 ± 0.16
Lanosterol
8.35 ± 2.48
3.74 ± 0.20
Total sterols
713.15 ± 9.27
384.08 ± 2.98
Total phytosterols
439.07 ± 5.72
274.38 ± 2.60


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Table 2. Sterol composition for Intralipid and Clinolipid (μg/mL ± SD)*
Sterols
Intralipid (Soybean Oil-Based)
Clinolipid (Olive Oil-based)
Phytosterols (mg) per 100 g of lipid
220 ± 2.86
137 ± 1.30
* All experiments were conducted in triplicate, and data are shown as mean ± SD; lipid emulsions analyzed 
are representative of only a single Lot number. Adapted from Xu et al.18
2. STUDY OBJECTIVES
2.1 Primary Objective
The primary objective of this study is to evaluate the risk of developing EFAD in 
pediatric patients, including neonates, receiving either Clinolipid or SOC 100% SO-based 
ILE (Intralipid) as a component of PN within the hospital setting from 7 up to 90 days.
Complete FA profile will be regularly assessed and EFAD will be defined using a 
Holman Index (plasma triene:tetraene ratio, specifically 5,8,11-eicosatrienoic acid [mead 
acid] to 5,8,11,14 eicosatetraenoic acid [arachidonic acid, ARA] ratio) value of >0.4 in 
the context of low LA, low ARA, and high eicosatrienoic acid.
Genetic polymorphisms in the  fatty acid desaturase 1 gene (FADS1) and fatty acid 
desaturase 2 gene (FADS2) will also be assessed in a subset of patients (approximately 
20%) and the distribution of the polymorphisms will be assessed in the context of the FA
profile as the synthesis of gamma-LA and ARA from LA (n-6 pathway) and the synthesis 
of stearidonic acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from 
ALA (n-3 pathway) require both the delta-5 and delta-6 desaturase enzymes (coded for 
by FADS1 and FADS2 genes). Genetic material will be obtained from buccal smears in 
all patients with consent to analysis of FADS1 and FADS2 polymorphisms. From the 
subset of patients consenting to genetic analysis, the 10 patients (5 Intralipid and 5 
Clinolipid) with the lowest levels of ARA at any point during the study and the10 
patients (5 Intralipid and 5 Clinolipid) with the highest levels of ARA at any point during 
the study will be selected for analysis of single nucleotide polymorphisms (SNPs) within 
FADS 1 and FADS2 genes.


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2.2 Secondary Objective(s)
The secondary objectives in patients receiving either Clinolipid or Intralipid are to 
evaluate: 
•
The risk of developing liver disease including PNALD:
-
PNALD will be defined by direct bilirubin ≥2 mg/dL when no other etiology 
for liver dysfunction is present;
-
Hepatic integrity will be assessed by measuring plasma liver function tests: 
alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), gamma-glutamyl transferase (GGT), and total and 
direct bilirubin;
-
Plasma main phytosterols (stigmasterol, campesterol, sitosterol), cholesterol 
and squalene levels will be assessed. Phytosterols levels will be correlated
with the risk of developing PNALD.
•
The adequacy of nutritional interventions:
-
Prescribed and actual nutritional intakes (energy, protein, carbohydrates, and 
lipid) from both PN and enteral/oral nutrition will be collected and recorded 
on a daily basis and summarized on a daily basis during the first 2 weeks of 
treatment and on an approximately 15-day basis afterwards up to the end of 
study treatment in each of the treatment groups. 
-
Growth will be assessed and evaluated from baseline to end of study treatment 
on an approximately every 15-day basis using descriptive summary statistics 
for weight, and height/length (and head circumference in infant <1 year) in 
each of the treatment groups as follows:
◦
Gain in weight (g/kg/day in infants <1 year of age, g/day in children and 
adolescents) and gain in length/height (mm/week in all) and head 
circumference (mm/week in infants <1 year);
◦
Changes in the standard deviation score (SDS or z-score) from reference 
growth curves (Fenton growth curve for premature infants, World Health 
Organization (WHO) growth standards for infants and children ages 0 to 
2 years, or Center for Disease Control (CDC) growth charts for children 
age ≥2 years).


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•
The safety profiles of Clinolipid and Intralipid, as assessed by adverse events 
(AEs), serious adverse events (SAEs) and AEs of special interest (AESIs)
-
AESIs are known AEs related to PN with ILEs, per Intralipid and Clinolipid 
United States Prescribing Information (USPI) and include the following: 
catheter related infection, thrombophlebitis; EFAD as well as ILE-related 
Immediate or Early adverse reactions including: dyspnea, cyanosis, allergic 
reactions, hyperlipemia, hypercoagulability, nausea, vomiting, headache, 
flushing, increase in temperature, sweating, sleepiness, pain in the chest and 
back, slight pressure over the eyes, dizziness, irritation at the site of infusion, 
and ILE-related delayed adverse reactions including: hepatomegaly, jaundice, 
splenomegaly, thrombocytopenia, leukopenia, transient increases in liver 
function tests, and overloading syndrome (focal seizures, fever, leukocytosis, 
hepatomegaly, splenomegaly and shock).
3. INVESTIGATIONAL PLAN
3.1 Overall Study Design and Plan
This is a multi-center, randomized, double-blind, controlled, safety and efficacy study to 
evaluate the occurrence of EFAD (diagnosed by Holman Index >0.4) in pediatric patients
receiving either Clinolipid or SOC SO-based ILE (Intralipid) in the hospital setting from 
7 up to 90 days as part of PN. The risk of developing liver disease, including PNALD 
(defined by direct bilirubin ≥2 mg/dL) when no other etiology for liver dysfunction is 
present, also will be assessed.
Approximately 100 pediatric patients, including neonates, will participate in the study.
Patients will be randomized in a 1:1 ratio to the treatment groups (Clinolipid or Intralipid) 
according to a central dynamic randomization scheme stratified by site and age group 
(premature infants born <37 weeks of gestation up to 1 month corrected age (CA), full-
term neonates born ≥37 weeks of gestation to <1 month of age, infants 1 to <12 months 
of age, children 1 to <10 years of age, adolescent 10 to <18 years of age). In the case of 
multiple birth pregnancies, the infants will be assigned to the same treatment group.
Holman Index and FA profile will be evaluated. Select polymorphisms in the FA
desaturase genes FADS1 and FADS2, will be determined in a subset of patients. The 
major plasma phytosterols found in the ILEs (stigmasterol, campesterol, sitosterol), 
cholesterol, and squalene will also be assessed.


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The study consists of a Screening Period to confirm the patient’s eligibility for the study 
after the informed consent form (ICF) is signed and a Study Treatment Period starting 
when the patient receives study treatment (See Appendix 1, Schedule of Events Table).
End of study treatment is defined as the last day of PN with Intralipid or Clinolipid; 
maximum 90 days of study treatment is allowed.
3.2 Rationale for Study Design and Control Group
This will be a descriptive study designed to evaluate the propensity for hospitalized 
pediatric patients treated adequately with Clinolipid or SOC (Intralipid) from 7 up to 
90 days to develop EFAD. Additionally, this study design will evaluate the safety and 
efficacy of using Clinolipid or Intralipid in a pediatric population.
A double-blind study is appropriate to decrease clinician and patient bias during study 
conduct.
3.3 Study Duration 
Enrollment for the study is anticipated to continue for approximately 22 months after 
initiation of the study.
4. STUDY POPULATION SELECTION
4.1 Study Population
Approximately 100 pediatric patients, including neonates, will be enrolled in the study.
The study will be conducted in approximately 15 study centers in the United States, 
focusing on institutions with neonatal and pediatric intensive care units.
A patient will be considered to be enrolled in the study after the signing of the ICF and 
confirmation of compliance with the study inclusion/exclusion criteria. Since this study is 
being conducted in a pediatric population, the patient’s legal representative must provide 
IC (i.e. sign and date the ICF). An assent form (child’s agreement to participate) will also 
be used following requirements of local or central Institutional Review Board (IRB) as 
applicable. The patient’s legal representative must provide IC (i.e. sign and date the ICF). 
Screening failures will be documented. Screen failures may be re-screened once, if 
approved by the medical monitor. All re-screens must be fully re-consented and repeat all 
screening procedures.


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4.2 Inclusion Criteria
Each patient must meet ALL of the following criteria to be enrolled in the study.
1. Patients and/or their legal representative must be able to understand the study and 
voluntarily sign the informed consent form (ICF) per 21 CFR Part 50.55(e)
2. Patients and/or their legal representative accept adherence to protocol 
requirements
3. Patients who are expected to require PN for at least 7 days
4. Premature infants (born at 24 to <37 weeks of gestation with a birth weight 
≥750g) require at least 80% of targeted energy requirements by PN at study entry
(up to 1 month CA); full term infants and children require at least 70% of targeted 
energy requirements by PN at study entry


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4.3 Exclusion Criteria
Patients who meet ANY of the following criteria will be excluded from the study:
1. Patients who are not expected to survive hospitalization or with a severe critical 
unresponsive illness at time of initiation with foreseeable intercurrent events that 
could jeopardize the patient’s participation in the study, as judged by the 
Investigator (e.g., unresponsive shock, sepsis, renal failure requiring dialysis, 
severe unresponsive metabolic acidosis, and/or severe unresponsive metabolic 
disorders);
2. Patients with a known hypersensitivity to lipid emulsion, egg or soybean proteins, 
or any of the active substances, excipients, or components of the container or who 
have a history of an adverse event due to ILE;
3. Patients with liver disease including cholestasis;
4. Patients with severe hyperlipidemia or severe disorders of lipid metabolism 
characterized by hypertriglyceridemia (triglyceride >400 mg/dL);
5. Patients who are unable to tolerate the necessary laboratory monitoring;
6. Patients who are enrolled in another clinical trial involving an investigational 
agent;
7. Patients with a known history of either severe hemorrhagic or severe hemolytic
disease as judged by the investigator;
8. Premature infants born <24 weeks of gestation and patients ≥18 years;
9. Premature infants with a birth weight <750 g;
10. Patient requires or is expected to require propofol for sedation;
11. Patient, born to a symptomatic mother diagnosed with COVID-19 at time of birth 
or before birth;
12. Patient has received a diagnosis of COVID-19 (diagnosis <2 months prior and/or 
symptoms have not resolved);
13. Female patients who are pregnant. Note: All female patients ≥12 years of age 
must have a negative urine human chorionic gonadotropin (hCG) pregnancy test 
at screening. For female patients <12 years of age, a urine hCG test at screening 
will be performed at the discretion of the investigator based on childbearing 
potential.


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5. STUDY TREATMENT(S)
5.1 Description of Treatment(s) and Dosing
The PN guidelines for the provision of macronutrient in infants, children, and adolescents
are provided in Table 3.
Micronutrients (electrolytes, minerals, trace elements and vitamins) should also be 
included in PN regimen based upon patient needs.
Table 3. General Pediatric Parenteral Nutrition Guidelines
Energy 
(kcal/kg/d)
Amino 
acids 
(g/kg/d)
Glucose (g/kg/d)
Lipids (g/kg/d)
Target
Target
Start
Target
Start
Target
Preterm infants
(<37wks)
90-120
3-4
6-8
10-14 (max.18)
0.5-1
3 (max.4)
Term infants (0-1y)
90-100
2.5-3
6-8
10-14 (max.18)
0.5-1
2.5-3 (max.3)
Children (1-10y)
55-80
1-2.5
3-6
8-10
1-2
2-3 (max.3)
Adolescents (10-18y)
30-55
0.8-2
2.5-3
5-6
1
1-2 (max.3)
Adapted from AAP 2014,19 ASPEN 2015,20 and ESPGHAN/ESPEN/ESPR/CSPEN 201821,22
5.1.1 Clinolipid (lipid injectable emulsion, US Pharmacopeia) 20% - Investigational 
Product
Clinolipid is a sterile, non-pyrogenic ILE. Clinolipid contains a mixture of refined OO
and refined SO in an approximate ratio of 4:1 (OO:SO). The lipid content is 0.20 g/mL. 
In Clinolipid, the mean composition of LA (n-6 EFA) is 35.8 mg/mL (range 27.6 to 
44.0 mL) and ALA (n-3 EFA) is 4.7 mg/mL (range 1.0 to 8.4 mg/mL). The phospholipids 
provide 470 mg or 15 mmol of phosphorus per liter.
The total energy content, including fat, phospholipids, and glycerin is 2000 kcal/L.
5.1.1.1 Clinolipid Contraindications per US Prescribing Information
The use of Clinolipid is contraindicated in patients with the following:
•
Known hypersensitivity to egg or soybean proteins or to any of the ingredients, 
including excipients.
•
Severe hyperlipidemia (serum triglyceride concentrations above 1000 mg/dL) or 
severe disorders of lipid metabolism characterized by hypertriglyceridemia.


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5.1.2 Intralipid 20% (lipid injectable emulsion, USP) – Active Control
Intralipid 20% (lipid injectable emulsion, USP) is the SOC 100% SO-based ILE. The 
lipid content of Intralipid 20% is 0.20 g/mL, with a LA content of 54.7% (approximately 
0.11 g/ml).
The total energy content, including fat, phospholipids, and glycerin is 2000 kcal/L.
5.1.2.1 Intralipid Contraindications per US Prescribing Information
The administration of Intralipid 20% is contraindicated in patients with disturbances of 
normal fat metabolism such as pathologic hyperlipemia, lipoid nephrosis or acute 
pancreatitis if accompanied by hyperlipidemia.
5.1.3 Dosing Schedule
In this study, the dosing schedule is similar for both ILE, Clinolipid or Intralipid
(Table 4).
Table 4. Dosing Schedule from both Intravenous Lipid Emulsiona
Day 1 of PNb
(g/kg/day)
Targeted daily 
advancement 
rate (g/kg/day)
Maintenance c
(g/kg/day)
Maximum
(g/kg/day)
Preterm infants (<37wks)
1
1
2.5 to 3
3
Term infants (<1y)
1
1
2.5 to 3
3
Children (1-10y)
1
1
2 to 3
3
Adolescents (10-18y)
1
1
1 to 2
3
a Daily administration over 20-24 hours
b Randomization is recommended within 24 hours of signing consent but must occur within 3 days of 
signing consent. If patient is not randomized within 24 hours of informed consent, patient should be 
started on SOC ILE on Day 1 of PN and transitioned to study drug once randomization has occurred.
c Unless there is a clinical reason to decrease the dose in the opinion of the Investigator
5.2 Treatments Administered
Study treatment will be administered intravenously in the hospital setting from 7 up to 
90 days using either a syringe pump or an infusion pump as appropriate for the daily 
volume of infusate. The flow rate will be prescribed by the Investigator to provide the 
daily dosage over 20 to 24 hours (maximum lipid infusion rate should not exceed 
0.15 g/kg/hour).


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5.3 Selection and Timing of Dose for Each Patient
Patients will be randomized to 1 of 2 treatment groups (Clinolipid vs. Intralipid). In case 
of multiple birth pregnancies, the infants will be assigned to the same treatment group. 
The selection of dose for each patient will be based on Table 4, Dosing Schedule for ILE
(Table 4) and PN guidelines for other macronutrients (Table 3) as well as the patient’s 
age, weight, and medical condition as judged by the investigator.
The administration of PN with SOC ILE may be initiated as per usual practice before 
Screening. In this situation, lipid dosing should be per Table 4, if possible.
If patients are not randomized on the same day as Screening and SOC PN is initiated, 
patients should receive SOC ILE using the dosing schedule per Table 4, starting on Day 1 
of PN (until transition to study drug). Once patients transition to study drug, lipid dosing 
should continue progression per Table 4.
Study treatment will be administered as per the SOC in each study site. Intravenous lipid 
emulsion infusion may be administered over 20 to 24 hours daily, depending on hospital 
practice.
Any significant deviation (more than 3 consecutive days) to the Dosing Schedule and the 
reason for such violation should be recorded (e.g. hyperglycemia, hypertriglyceridemia, 
higher energy expenditure) in the case report form (CRF).
Parenteral nutrition therapy may be interrupted and restarted (based on the initial 
randomization) within a 1 to 2-day window, subject to adjudication from the medical 
monitor who conducts a clinical review of current patient status, assessment of any 
potential AE/SAEs, discussion/clarification with the investigator to resume or abort study 
treatment. If there is a likelihood that the patient will require a restart of PN within 1 to 2 
days of the initial stoppage, then it is recommended to delay performing the End of Study 
Treatment procedures. However, the End of Study Treatment procedures should be 
completed within 2 days of the initial stoppage if the patient has not restarted PN, as per 
Section 7.2.4 and Appendix 1 Schedule of Events.
5.4 Method of Assigning Patients to Treatment Groups
Randomization will be stratified by site and age group (premature infants born <37 weeks 
of gestation up to 1 month CA, full-term neonates born ≥37 weeks of gestation to <1 
month of age, infants 1 to <12 months of age, children 1 to <10 years of age, adolescent 
10 to <18 years of age) in a 1:1 ratio to both treatment groups using a computer-generated 
central dynamic randomization schedule.


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Preparation and labeling of treatment will be delegated by the Sponsor to the 
investigational site pharmacist(s). Patient numbers will be allocated according to the 
randomization code contained within the randomization schedule.
Study treatment will be prepared and dispensed by the investigational site pharmacist(s)
or designee in accordance with the assigned treatment for that patient.
5.5 Blinding
The study will be double-blinded. The study treatment assignment will not be known by 
the Sponsor’s or designee’s data management, biostatistician (with the exception of an 
unblinded Sponsor’s statistician who will have access to the randomization assignments), 
and medical functions; Investigator and site personnel; or by the personnel at the central 
laboratory. In order to prepare the study treatment, the designated pharmacist(s) will be 
aware of the study treatment (unblinded).
The unblinded pharmacist(s) will prepare the treatment according to the randomization 
schedule and will enter the required information on the study drug labels. These labels 
will not contain specific information pertaining to the identity of the study treatment. In 
addition, specified fields on the label will be blank so that the pharmacist(s) can enter the 
patient number, as well as other patient identifiers and information as applicable by local 
procedures. The labels will then be affixed to study treatment containers (either sterile 
syringes or flexible IV bags, as appropriate for the volume of infusate).
A Data and Safety Monitoring Board (DSMB) will be appointed by Baxter Healthcare 
Corporation to provide ongoing evaluation of safety data (refer to Section 10.8). Reports 
will be provided to the DSMB at pre-specified intervals. 
Blinded data will be entered into the database and the treatment group assignments will 
be revealed after database lock.
5.6 Restrictions
5.6.1 Prior Therapy/Concomitant Medications
There are no restrictions on prior therapy or concomitant medications for this study.
All medications should be recorded in the source documents or equivalent. Prior 
medications, defined as those taken during the 30 days prior to Screening, will be 
recorded in the CRF. Concomitant medications, including dose, frequency, start and stop 
dates, and indication for use, will be recorded in the CRF throughout the study.


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5.6.2 Concomitant Procedures
Invasive concomitant procedures, including the below list, must be documented in the 
eCRF:
•
Chest tube
•
Surgical procedure
•
Surgical central line placement
•
Blood/platelet/fresh frozen plasma or other colloid infusion
•
Pericardiocentesis, pleural or peritoneal tap
•
Lumbar puncture
5.6.3 Fluid and Food Intake 
There are no restrictions on fluid or food intake during the course of this study. The 
inclusion criteria specifying that “Premature infants (<37 weeks of gestation) require at 
least 80% of targeted energy requirements by PN at study entry (up to 1 month CA); that 
full-term infants (≥37 weeks of gestation), children and adolescents who require at least 
70% of targeted energy requirements by PN at study entry” is limited to Screening only.
All fluid and food intake will be recorded in the source document and the CRF.
5.6.4 Patient Activity Restrictions
Patients will remain hospitalized while enrolled in the study.
5.7 Treatment Compliance
Since all patients in this study will remain hospitalized, treatment compliance will be 
documented by investigational site personnel during the entire Study Treatment Period. 
Reasons for noncompliance and/or not meeting SOC targets will be tabulated and 
summarized.
5.8 Packaging and Labeling
Clinolipid is supplied in 100 mL and 500 mL CLARITY polyolefin bags (250 and 1000 
mL bags may also be used). The CLARITY container is a lipid-compatible plastic 
container (PL 2401-1). The bag is packaged in an oxygen barrier overpouch, which 
contains an oxygen absorber/oxygen indicator sachet. Use only if the color of the oxygen 
indicator is within allowable range. Do not use unless emulsion has a homogeneous 
milky appearance.


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Clinolipid will be labeled in accordance with the US Code of Federal Regulations 
21 CFR 312.6 bearing the statement “Caution: New Drug- Limited by Federal
(or United States) law to investigational use.”
Intralipid will be packaged as a standard commercial product.
The following information will be recorded for both study treatments:
a.
Lot number
b. Expiration date
5.9 Storage and Accountability
Clinolipid should be stored at 20 to 25°C (68 to 77°F) and should not be frozen.
Excessive heat should be avoided. Clinolipid should be stored in its overpouch until 
ready to use.
Intralipid should be stored as per the product/package label, specifically Intralipid 20% 
should not be stored above 25°C (77°F). Do not freeze Intralipid 20%. If accidentally 
frozen, discard the bag.
5.9.1 Storage Requirements/Stability
Clinolipid will be shipped from the final manufacturing site to a clinical depot. Upon 
receipt, the clinical depot will segregate the product prior to order preparation. The 
product and supplies will be stored according to product label specifications, or other 
specific directions provided by the Sponsor. Clinolipid will be shipped from the clinical 
depot to the investigational site.
5.9.2 Investigational Product Accountability
The clinical depot personnel, Investigator, and investigational site personnel will be 
provided with written instructions on the handling and storage of investigational product 
and clinical supplies for the trial and appropriate documentation.
Accountability of all investigational product and clinical supplies will be performed by an 
unblinded study monitor during periodic site visits. The pharmacist will fill out a product 
accountability log to document all study product movement (i.e. receipt, dispensation, 
return, and disposition).
All unused product and supplies will be destroyed or returned to the Sponsor in 
accordance with applicable regulations. If needed, the Sponsor or its designee may 


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authorize an alternative disposition of unused investigational product and supplies; 
however, disposition can only occur after the Sponsor or its designee has been notified 
and has given written authorization. The Sponsor/designee will maintain a written record 
of any disposition of the investigational product and supplies in accordance with 
applicable regulations.
The Investigator shall not administer the investigational product to any person not 
authorized to receive it. The Investigator will be required to maintain adequate records of 
the disposition of the investigational product, including dates, quantities, batch/lot 
numbers, unique code numbers, expiration dates, as applicable, and use by study patients.
All of the investigational product will be reconciled and accounted for throughout the 
study. Additionally, at the conclusion of the study, records of all investigational product 
and supplies concerning delivery, inventory, dispensation, return and disposition will be 
collected from the clinical depot, and investigational site.
It is prohibited by law to use the investigational product outside the intent of this 
protocol.
6. STUDY PROCEDURES
Study assessments include the following:
6.1 Informed Consent
Informed consent (IC) is required prior to the initiation of any study related procedures or 
assessment. Since this study is being conducted in a pediatric population, the patient’s 
legal representative must provide IC (i.e. sign and date the ICF). An assent form
(child’s agreement to participate) will also be used following requirements of local or 
central Institutional Review Board (IRB) as applicable.
6.2 Demographics
Demographic data including age, sex, race and ethnicity will be collected during 
Screening.
6.2.1 Neonates
For all neonates (premature infants born <37 weeks of gestation up to 1 month CA and 
full-term neonates <1 month of age), gestational age (GA) will be recorded at Screening 
and categorized as full-term (born ≥37 weeks of gestation), preterm (32-36 weeks of 
gestation), very preterm (28-31 weeks of gestation), or extremely preterm (<28 weeks of 
gestation), and birth weight (BW) will also be recorded at Screening and categorized as 


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normal BW (≥2500 g), low BW (1500-2499 g), very low BW (1000-1499 g), or 
extremely low BW (<1000 g).23
6.3 Medical History and Prior Medications
Medical history information, including the diagnosis requiring PN, will be collected at 
Screening and updated as necessary at Baseline.
Diagnosis for requiring PN at Screening will be recorded (e.g. prematurity; congenital 
gastrointestinal malformation; gastrointestinal obstruction diseases; inherited 
gastrointestinal dysfunction and motility disorders; necrotizing enterocolitis; sepsis; short 
bowel syndrome, enteropathies including inflammatory gastrointestinal diseases; other 
gastrointestinal dysfunctions to be specified).
Medications and nutrition supplements received within 30 days prior to randomization, 
by the patient and the nursing mother (if applicable) also will be recorded at Screening. 
The nursing mother’s medication history will be collected from the patient’s chart (if 
available). There are no restrictions for prior medications.
6.4 Physical Examination
Physical examinations will be conducted as per the SOC for the study site and 
documented for the study at Screening, Baseline and approximately every 15 days up to 
end of study treatment. In particular, clinical signs of EFAD (flaky dry skin, hair loss, 
hair depigmentation, poor wound healing, increased susceptibility to infections, growth
status) will be considered as well as liver diseases specific symptoms (e.g. jaundice, 
hepatomegaly).
Any clinically significant (CS) new abnormal condition or worsening of a preexisting 
condition from Screening will be recorded in the CRF as AE.
6.5 Weight, Height or Length, and Head Circumference
As per Appendix 1, Schedule of Events Table, body weight (g) will be assessed and 
recorded daily from Baseline to end of study treatment while length or height (cm) (and 
head circumference (cm) in infants < 1 year of age) will be assessed and recorded on an 
approximately 15-day basis from Baseline to end of study treatment.
Standard deviation score (SDS) for weight, height or length and head circumference will 
be determined and recorded based on Fenton growth curve for premature infants, WHO 
growth standards for infants and children ages 0 to 2 years, and CDC growth charts for 
children age ≥2 years.


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Body mass index (BMI, kg/m2) will be determined and recorded in children and 
adolescents.
6.6 Vital Signs
Vital signs will be recorded once daily at approximately the same time each day (e.g. 8 
AM), with a window of approximately 2-3 hours, as per Appendix 1, Schedule of Events 
Table. Vital signs include heart rate (beats/min), respiratory rate (breaths/min), systolic 
and diastolic blood pressure (mmHg), and body temperature (°C). The clinical 
significance of any abnormal vital sign values will be determined by the Investigator.
For clinically significant (CS) abnormal signs values, the Investigator will indicate if the 
value constitutes a new AE and record the associated signs, symptom, or medical 
diagnosis in the CRF as AE. Any abnormal value that persists should be followed at the 
discretion of the Investigator.
6.7 Clinical Laboratory Tests
6.7.1 Laboratory Parameters
Blood samples will be collected at Screening/Baseline and then as per the SOC for each 
investigational site and on an approximately 15-day basis as per Appendix 1, Schedule of 
Events Table. Baseline laboratory assessments do not need to be repeated if within 
±24 hours of the Screening sample.
Laboratory data will be reviewed by the Investigator. For each abnormal laboratory 
value, the Investigator will determine whether the value is CS or not. For CS abnormal 
values, the Investigator will indicate if the value constitutes a new or a worsening AE and 
record the associated signs, symptoms, or medical diagnosis in the CRF. Any abnormal 
value that persists should be followed at the discretion of the Investigator.


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Clinical laboratory tests will include the following (Table 5):
Table 5. List of Laboratory Tests
Tests Conducted at Local Laboratory
Hematology:
•
Hematocrit (Hct)
•
Hemoglobin (Hgb)
•
Mean corpuscular hemoglobin (MCH)
•
Mean corpuscular hemoglobin 
concentration (MCHC)
•
Mean corpuscular volume (MCV)
•
Platelet count
•
Mean Platelet Volume (MPV)
•
Red blood cell (RBC) count
•
White blood cell (WBC) count with 
differential
•
Urine human chorionic gonadotropin 
(hCG)a
Liver function tests:
•
Alkaline phosphatase (ALP)
•
Alanine aminotransferase (ALT; SGPT)
•
Aspartate aminotransferase (AST; SGOT)
•
Gamma-glutamyl transferase (GGT)
•
Total bilirubin
•
Direct bilirubin
Serum Chemistry:
•
Glucose
•
Triglycerides
•
Serum Albumin
•
Creatinine
•
Blood urea nitrogen (BUN)
•
Bicarbonate (CO2)
•
Sodium (Na)
•
Potassium (K)
•
Chloride (Cl)
•
Calcium (Ca)
•
Phosphorus (P)
•
Magnesium (Mg)
Tests Conducted at Central Laboratory
Fatty Acid Profile and Holman Indexb
Genetic polymorphism testing for FADS1 and 
FADS2
Phytosterol Levelsb:
•
Stigmasterol
•
Campesterol
•
Sitosterol
Cholesterol
Squalene
a All female patients ≥12 years of age must have a negative urine human chorionic gonadotropin (hCG) 
pregnancy test at screening. For female patients <12 years of age, a urine hCG test at screening will be 
performed at the discretion of the investigator based on childbearing potential.
b Testing will be conducted with a minimal amount of blood volume per sample collected.


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6.7.2 Sample Collection, Storage, and Shipping
Samples (Table 5) will be collected by site personnel as per Appendix 1, Schedule of 
Events Table.
6.7.2.1 Hematology and Chemistry
Hematology and Chemistry blood samples will be collected from all patients enrolled in 
the study. Blood samples should be collected at Screening/Baseline and then during SOC
blood draws as well as on an approximately 15-day basis (ideally, blood should be 
collected at approximately the same time on each day the sample is to be drawn).
Samples will be processed and tested as per the investigational site’s standard laboratory 
procedures.
6.7.2.2 Triglycerides
Blood samples for triglycerides will be collected from all patients enrolled in the study. 
Blood samples should be collected at Screening/Baseline and then during SOC blood 
draws as well as on an approximately 15-day basis (ideally, blood should be collected at 
approximately the same time on each day the sample is to be drawn).
Samples will be processed and tested as per the investigational site’s standard laboratory 
procedures.
6.7.2.3 Liver function tests
Blood samples for liver function tests will be collected from all patients enrolled in the 
study. Blood samples should be collected at Screening/Baseline and then during SOC 
blood draws as well as on an approximately 15-day basis (ideally, blood should be
collected at approximately the same time on each day the sample is to be drawn).
Samples will be processed and tested as per the investigational site’s standard laboratory 
procedures.
6.7.2.4 Fatty acid profiles, Holman Index, and phytosterol, cholesterol, and squalene
levels
Blood samples for the determination of FA profiles, Holman Index, and phytosterol 
(stigmasterol, campesterol, sitosterol), cholesterol, and squalene levels will be collected 
at Baseline from all patients enrolled in the study. Subsequent samples for FA profiles 
will be collected on an approximately 15-day basis at least 4 hours after interrupting ILE 
infusion in order to decrease the influence of infused ILE on FA profile. If a study site 
typically infuses ILE over 24 hours, the investigator should, to the best of their ability, 


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ensure a 4-hour lipid only infusion hold before obtaining samples for the FA profiles.
Ongoing infusion of other macro- and micronutrients from PN are allowed as required for 
the best interest of the patient per the attending physician during the 4-hour ILE hold 
before obtaining samples for the FA profiles. Blood sample volumes will be kept to a 
minimum.
Blood samples for FA profiles, determining Holman Index, and quantifying the amount 
of phytosterols, cholesterol, and squalene in samples will be processed by an external 
laboratory. The FAs will be assessed according to the Mayo Clinic method, which is 
performed as a 2-step acid-base hydrolysis followed by hexane extraction and 
derivatization with pentafluorobenzyl bromide. Separation and detection are 
accomplished by capillary gas chromatography electron-capture negative ion-mass 
spectrometry. Quantitation is based on analysis in the selected ion-monitoring mode by 
using 13 stable isotope-labeled internal standards. Handling, labeling, and shipping 
procedures will be detailed in separate Laboratory Instructions provided by the Sponsor.
Reference values can be found in Appendix 2.
6.7.2.5 Genetic polymorphism for fatty acid desaturase genes
Buccal swab samples for the determination of genetic polymorphisms for FADS1 
(rs174553) and FADS2 (rs174575, rs99780, rs174583) will be collected from all enrolled 
patients for whom consent is obtained. Buccal swabs can be collected at any time before 
the end of study treatment.
From the subset of patients consenting to genetic analysis, the 10 patients (5 Intralipid 
and 5 Clinolipid) with the lowest levels of ARA at any point during the study and the 10 
patients (5 Intralipid and 5 Clinolipid) with the highest levels of ARA at any point during 
the study will be selected for analysis of SNPs within FADS1 and FADS2 genes as the 
synthesis of ARA from LA requires both the delta-5 and delta-6 desaturase enzymes 
(coded for by FADS1 and FADS2) for synthesis.  The level of these desaturase enzymes 
modulates the synthesis of ARA from LA.
Distribution of polymorphisms within FADS1 and FADS2 genes will be assessed in the 
context of various FAs derived from EFAs (LA and ALA): 
•
Gamma-LA and ARA from the n-6 PUFA pathway;
•
Stearidonic acid, EPA, and DHA from the n-3 PUFA pathway.


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Sample handling, labeling, and shipping procedures, as well as the name and address of 
the central laboratory conducting the testing, will be detailed in separate Laboratory 
Instructions provided by the Sponsor. Buccal swabs will be destroyed once all analyses 
have been completed.
6.8 Diagnosis and Management of Essential Fatty Acid Deficiency (EFAD)
EFAD will be suspected in all patients with abnormal plasma liver enzymes tests or any 
clinical signs of EFAD. The diagnosis will be confirmed by the planned FA profile 
analyses (see Appendix 1, Schedule of Events Table).
The Holman Index will be used for the diagnosis and management of EFAD.
The Holman Index, also called plasma triene:tetraene (T:T) ratio, is the ratio of the level 
of eicosatrienoic acid (Mead acid, n-9 FA) and the level of ARA (n-6 FA).
6.8.1 Holman Index <0.2
Patients with a Holman Index of <0.2 have normal EFA status and will be followed for 
possible development of EFAD as defined in the study protocol.
6.8.2 Index between 0.2 and 0.4
Patients with a Holman Index of 0.2-0.4 are considered to be at risk for EFAD. Values in 
this range are indeterminate and may be seen in patients with adequate LA intake to 
prevent EFAD or in patients with low LA intake that are evolving toward EFAD.
The management of these patients includes first the assessment for clinical features of 
EFAD (dermatitis, diarrhea, perianal irritation, growth and development failure, recurrent 
infections, irritability, and/or poor wound healing).
Second, it implies checking if the plasma ARA levels are within normal range and that 
the unblinded pharmacist preparing the ILE determine if LA intake is adequate (See
Section 6.8.5 Calculating LA Intake from ILE).
•
If no clinical features are present:
-
If the ARA levels are within normal range with LA intake within the normal 
range (1-4% of the total energy intake), continue to follow the patient and 
check FA levels and Holman Index regularly (approximately every 15 days) 
till the Holman Index is normalized. The investigator and the patient may 
remain blinded.


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-
If the ARA level is low, increase LA intake even if in the normal range (1-4% 
of total energy intake). For example, if the level of LA intake is less than 
normal requirement (<1% of total energy intake), lipid intake will be 
increased to supply LA within the normal range (1-4 % of total energy intake). 
If the patient is receiving a LA intake in the low normal range (1-2% of 
energy intake), it needs to be increased >2% of energy intake. If the patient is 
receiving a LA intake in the high normal range (3-4% of energy intake), it 
needs to be increased >4% of energy intake. The amount of the increase in LA 
intake should be determined by the clinician considering the clinical state of 
the patient and the safety of increasing the lipid intake. The monitoring of LA 
and ARA levels Holman Index and clinical features will persist regularly 
(every 15 days) till the Holman Index is normalized.
•
If there are clinical features, increase LA intake even if in the normal range. For 
example, if the level of LA intake is less than normal requirement (<1% of total 
energy intake), lipid intake will be increased to supply LA within the normal 
range (1-4 % of total energy intake). If the patient is receiving a LA intake in the 
low normal range (1-2% of energy intake), it needs to be increased >2% of energy 
intake. If the patient is receiving a LA intake in the high normal range (3-4% of 
energy intake), it needs to be increased >4% of energy intake. The amount of the 
increase in LA intake should be determined by the clinician considering the 
clinical state of the patient and the safety of increasing LA intake. The monitoring 
of LA and ARA levels, Holman Index and clinical features will persist regularly 
(approximately every 15 days) until the Holman Index is normalized and clinical 
features disappear.
6.8.3 Holman Index >0.4
Patients with Holman index >0.4 will be considered as biochemical EFAD. It will be 
confirmed in the context of low LA, low ARA, and high eicosatrienoic acid (Mead acid).
Clinical EFAD is diagnosed in the presence of any clinical features of EFAD (dermatitis, 
diarrhea, perianal irritation, growth and development failure, recurrent infections, 
irritability, and/or poor wound healing).
The management of these patients includes the assessment, the record, and the increase of 
LA intakes until the Holman Index normalizes and clinical features, if present, disappear.  


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The daily monitoring of LA intakes, and the approximately every 15 day monitoring of
LA and ARA levels and Holman Index will persist until the Holman Index normalizes
and clinical features disappear. If the Holman Index does not reduce to <0.4 or if it
continues to increase, lipid intake will be further increased. The amount of the increase in 
LA intake should be determined by the clinician considering the clinical state of the 
patient and the safety of increasing the total lipid intake.
Some patients may have higher requirements for EFAs due to an underlying disease (e.g. 
high demand for growth and wound healing). Total parenteral lipid intake should usually 
remain below the maximum intake (Table 4, Dosing Schedule), which is an amount that 
is normally adequate for prevention of EFAD in all patients. The patient should receive 
the increased LA intake for at least 1 week prior to repeating the FA profile with the 
Holman Index assessments to allow time for the physiologic effects of the FA to occur.
When EFAD persists despite maximal lipid intake, the ILE should be unblinded. If the 
patient is receiving Clinolipid, the patient should be switched to Intralipid to allow for 
greater delivery of LA.
Additional LA intakes may be supplied via intravenous and/or enteral/oral routes.
If severe hypertriglyceridemia (triglycerides >400 mg/dL) develops, the cause should be 
investigated. If it is determined to be related to the ILE, lipid intake may be adjusted 
using the ILE with the higher relative content of LA.
If direct bilirubin increases above 2.5 mg/dL suggestive of cholestasis, a reduction of 
total lipid intake may be considered while continuing to provide adequate LA. The 
adequacy of LA intake needs to be confirmed by the unblinded pharmacist(s).
6.8.4 Holman Index >0.4 at baseline
Some study patients (especially premature infants) may demonstrate FA profile and 
Holman index compatible with EFAD at baseline due to their limited fat stores. The 
treatment for these infants is to administer EFA via ILE as part of their PN as described 
in Table 4, Dosing Schedule and being sure to reach the maintenance dosage. Infants with 
EFAD at baseline are to be followed regularly (approximately every 15 days) while 
receiving ILE per study protocol for improvement in their FA profile and Holman Index.  
•
If the Holman Index does not decrease with lipid administration in accordance 
with Table 4, Dosing Schedule, the patient may have greater than normal 


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requirements for EFA and the LA intake should be increased to the maximum 
dosage according to Table 4, Dosing Schedule and at the investigator’s discretion.
•
If the patient still does not respond, the investigator will be unblinded to 
determine if the patient is receiving Clinolipid or Intralipid. If the patient is 
receiving Clinolipid, the patient should be switched to Intralipid (as Intralipid 
contains a higher concentration of LA than Clinolipid).
•
If the patient does not respond to Intralipid at maximal lipid dosage, consider 
increasing the LA intake with an enteral/oral source of LA or some additional 
intravenous Intralipid intakes.
6.8.5 Calculating Linoleic Acid (LA) Intake from Intravenous Lipid Emulsion (ILE)
Clinolipid contains approximately 18.6% LA while Intralipid contains approximately 
54.7% LA. Since both are 20% ILE (20 g/dL, 0.2 g/mL, 2 kcal/ml), the content of LA is 
approximately 0.11 g/mL for Intralipid (1.1 kcal/ml from LA) and 0.04 g/mL for 
Clinolipid (0.4 kcal/ml from LA) (Table 6).
Table 6. Intralipid and Clinolipid Linoleic Acid Content
Content
20% Intralipid
20% Clinolipid
Lipid, g/ml
0.2
0.2
Energy, kcal/ml
2
2
Linoleic acid, g/ml
0.11
0.04
Linoleic acid, kcal/ml
1.1
0.4
Sample Calculation:
If a 2 kg patient receives 16 mL of Intralipid per day, the patient receives 8 ml/kg/day of 
Intralipid. It corresponds to 1.6 g/kg/day of lipid and 0.88 g/kg/day of LA. The energy 
part of LA is 8.8 kcal/kg/day. If the total energy intake is 100 kcal/kg/day, it means that 
8.8% of the energy intake comes from LA.
If a 2 kg patient receives 16 mL of Clinolipid per day, the patient receives 8 ml/kg/day of 
Clinolipid. It corresponds to 1.6 g/kg/day of lipid and 0.32 g/kg/day of LA. The energy 
part of LA is 3.2 kcal/kg/day. If the total energy intake is 100 kcal/kg/day, it means that 
3.2% of the energy intake comes from LA.


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The LA intake that normally prevents EFAD is 1-4% of total energy intake. The 
unblinded pharmacist determines if the patient has adequate LA intake for prevention of 
EFAD. The pharmacist communicates to the patient’s nutrition clinician according to the 
protocol (see Sections 6.8.2, 6.8.3 and 6.8.4.).
6.9 Nutritional Intake
Prescribed and actual macronutrient intake (fluid, energy, protein, carbohydrates, and 
lipid) of both parenteral and enteral nutrition will be collected and recorded on a daily 
basis in the CRF from Baseline to end of study treatment for each of the treatment 
groups. See Appendix 1, Schedule of Events Table, for additional details.
Intravenous intakes (fluid, amino acid, dextrose/glucose, and lipid) from PN as well as 
any intravenous macronutrient additions to the PN solution will be collected and recorded
as parenteral intakes.
For breast milk intake, the macronutrient content will be estimated from volume intakes
using mean reference values in mature human milk (640 kcal, 12 g of protein, 67 g of 
carbohydrates, and 34 g of lipid per 1 Liter of milk).23 When breastfeeding intakes cannot 
be measured, the best estimation (volume) of the investigator will be recorded. For 
commercial products including formula and human milk fortifiers, macronutrient intakes
will be recorded from volume intake and calculated from manufacturer label. For oral 
food ingestion, energy and lipid intakes only will be recorded from best estimates.
6.10 Dispensing Study Treatment
Blinded study treatment will be provided to the pediatric/neonatal unit from the study site 
pharmacist(s). The pharmacist(s) will maintain accurate and complete records of study 
treatment dispensation. Study personnel in the pediatric/neonatal unit will administer 
study treatment to the patients intravenously using either a syringe pump or an infusion 
pump, as appropriate for the volume dispensed.
The amount of lipid emulsion (g/kg/day) delivered to the patient will be collected daily 
and recorded (volume, flow rate and infusion duration) for each administration of study 
treatment (See Section 6.9).
6.11 Concomitant Medications
Ongoing medications and nutritional supplements received by the patient and nursing 
mother (if applicable) will be recorded as concomitant medication once study treatment 
has been initiated. During treatment, concomitant medications and therapies (including 


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dose, frequency, start and stop dates, and indication for use), will be recorded in the CRF
by study site personnel on a daily basis.
During treatment, both patients’ and nursing mothers’ concomitant medications (as 
documented in the patient’s chart) will be recorded.
6.12 Concomitant Procedures
Invasive concomitant procedures, including the below list, must be documented in the 
eCRF:
•
Chest tube
•
Surgical procedure
•
Surgical central line placement
•
Blood/platelet/fresh frozen plasma or other colloid infusion
•
Pericardiocentesis, pleural or peritoneal tap
•
Lumbar puncture
6.13 Adverse Events Assessments
An AE is any untoward medical occurrence in a patient or clinical investigational patient 
administered a study product, and that does not necessarily have a causal relationship 
with the treatment or drug. An AE can therefore be any unfavorable and unintended sign
(including an abnormal laboratory function), symptom (e.g., rash, pain, discomfort, fever, 
dizziness, etc.), organ dysfunction (e.g., cardiovascular failure, pancreatitis, etc.), 
systemic illness (e.g., sepsis), or outcome of death temporally associated with the use of 
the study product, whether or not the event is considered associated with the study 
product.
Laboratory and vital sign abnormalities qualify as AEs if medical intervention is required 
to treat or address the abnormality, if the patient must be discontinued from the study due 
to the abnormality, or if the value exceeds specific limits defined by the SOC as 
qualifying it as an AE.
An elective procedure/surgery that occurs during the course of a study, but is being 
performed for a documented pre-existing condition and was pre-planned prior to study 
entry, will not qualify as an AE. If, however, the pre-existing condition unexpectedly 
deteriorates during the study requiring the procedure/surgery to be performed earlier than 


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planned, the condition for which the procedure/surgery is being performed will qualify as 
an AE.
In this study, AEs will be recorded in conjunction with the first study procedure
(Screening). Adverse events occurring prior to the initiation of the first study procedure
will be recorded as signs and symptoms in the patient’s medical history. Adverse events 
occurring during Screening but prior to the administration of study treatment will be 
considered as unrelated to study treatment.
6.13.1 Performing Adverse Events Assessments
During the course of the study, and maximum 30 days after the last dose of study drug, if 
hospital discharge has not occurred, the Investigator or designee will routinely monitor
and solicit each patient for the occurrence of any AEs. If an AE occurs, a full description 
of the event, including the date and time of onset, duration, severity, actions taken, 
outcome, seriousness of the event, and causal relationship of the AE to the study 
treatment will be recorded in the patient’s CRF. All AEs will be followed by the 
Investigator until the event has resolved, stabilized, or returned to baseline.
6.13.2 Severity
The severity of an AE is defined as a qualitative assessment by the Investigator of the 
degree of intensity of the AE observed or reported by the patient. The assessment of 
severity will be made irrespective of treatment relationship or seriousness.
The severity of each AE will be recorded as mild, moderate, or severe according to the 
following definitions:
•
Mild – The AE is a transient discomfort and does not interfere in a significant 
manner with the patient’s normal functioning level and/or the AE resolves 
spontaneously or may require minimal therapeutic intervention.
•
Moderate – The AE produces limited impairment of function and may require 
therapeutic intervention and/or the AE produces no sequela/sequelae.
•
Severe – The AE results in a marked impairment of function and may lead to 
temporary inability to resume usual life pattern and/or the AE produces 
sequela/sequelae, which require (prolonged) therapeutic intervention.


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6.13.3 Relationship
Causality is a determination of whether there is a reasonable possibility that the 
investigational product/control is etiologically related to/associated with the AE. 
Causality assessment includes, for example, assessment of temporal relationships, 
dechallenge/rechallenge information, association (or lack of association) with underlying 
disease, presence (or absence) of a more likely cause, and physiologic plausibility For 
each AE, the investigator will assess the causal relationship between the investigational 
product (IP) / control and the AE using his/her clinical expertise and judgment according 
to the following most appropriate algorithm for the circumstances of the AE:
•
Not related (both circumstances must be met). 
a.
Is due to underlying or concurrent illness, complications, concurrent treatments, 
or effects of concurrent drugs. 
b. Is not associated with the IP/control (i.e., does not follow a reasonable temporal 
relationship to the administration of IP/control or has a much more likely 
alternative aetiology).
•
Unlikely related (either 1 or both circumstances are met).
a.
Has little or no temporal relationship to the IP/control.
b. A more likely alternative aetiology exists.
•
Possibly related (both circumstances must be met). 
a.
Follows a reasonable temporal relationship to the administration of IP/control. 
b. An alternative aetiology is equally or less likely compared to the potential 
relationship to the IP/control.
•
Probably related (both circumstances must be met). 
a.
Follows a strong temporal relationship to the administration of IP/control, 
which may include but is not limited to the following:
1. Reappearance of a similar reaction upon re-administration (positive 
re-challenge).
2. Positive results in a drug sensitivity test (skin test, etc.).
3. Toxic level of the IP/control as evidenced by measurement of the 
IP/control concentrations in the blood or other bodily fluid.
b. Another aetiology is unlikely or significantly less likely.


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6.13.4 Expectedness
A suspected unexpected serious adverse reaction (SUSAR) is any adverse reaction that is 
classified as serious and is suspected to be caused by the investigational drug but is not 
consistent with the information found in the current version of the Investigator’s
Brochure.
6.13.5 Clinical Significance
Clinical significance of AEs will be determined by the Investigator, based on his/her best 
medical judgement.
6.13.6 Clinical Laboratory Adverse Events
Laboratory and vital sign abnormalities qualify as AEs if medical intervention is required 
to treat or address the abnormality, if patients must be discontinued from the study due to 
the abnormality or if the value exceeds specific limits qualifying it as an AE.
6.13.7 Serious Adverse Events
6.13.7.1 Definition
A SAE is defined by federal regulation as any AE occurring at any dose that results in 
any of the following outcomes: death, life-threatening, inpatient hospitalization or 
prolongation of existing hospitalization, persistent or significant disability/incapacity or 
congenital anomaly/birth defect.
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgement, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse.
6.13.7.2 Reporting Serious Adverse Events
All SAEs or any pregnancy reports with or without an associated SAE must be reported 
to the sponsor within 24 hours of site's knowledge of the event. Further details are 
specified in the Safety Management Plan.
The Investigator will also report any SAEs to the Institutional Review Board (IRB) in 
writing based on the IRB’s reporting requirements and provide the Sponsor with a copy 
of the notification.


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All SAEs including follow-up information that occur from the date of signing of ICF 
until 30 days after the last dose of study treatment must be reported to Baxter Global 
Pharmacovigilance.
Baxter or designee will assess each SAE reported by the Investigator to determine if the 
event qualifies as an Expedited Report according to local regulations. Expedited reports 
will be submitted to the appropriate Authority by Baxter or designee. Per regulations, 
Investigators will receive a letter from Baxter or designee describing the expedited SAE. 
The Investigator should file this letter within their Investigator Site File. Additionally, the 
Expedited Report letter may need to be submitted by the Investigator to their IRB, as 
appropriate per local regulations.
6.13.8 Treatment-Emergent Adverse Events
A treatment-emergent AE is defined as any AE that occurs after the onset of study 
treatment administration through the end of the study.
6.14 Removal of Patients from the Study/ Discontinuation of the Study
Any patient/legal representative may voluntarily withdraw consent for continued 
participation and data collection at any time during the course of the study. The 
Investigator may terminate a patient’s study participation at any time during the study if 
the Investigator judges it to be in the patient’s best interest.
Patients may be withdrawn or prematurely discontinued from the study
treatment/assessments for any of the following reasons:
•
Adverse Event(s)
•
Clinically significant change in a laboratory parameter
•
Protocol violation (i.e. patient failed to meet protocol entry criteria or did not 
adhere to the protocol requirements)
•
Pregnancy
•
Patient or any legal representative requests to withdraw from the study
•
Sponsor or Investigator terminates the study
All patients randomized to Clinolipid who must receive Intralipid for rescue therapy 
purposes will be discontinued from the trial.


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Parenteral nutrition therapy may be interrupted and restarted (based on the initial 
randomization) within a 1 to 2-day window, subject to adjudication from the medical 
monitor who conducts a clinical review of current patient status, assessment of any 
potential AE/SAEs, discussion/clarification with the investigator to resume or abort study 
treatment. The outcome of the adjudication process will not preclude the monitoring for 
AE/SAEs for the subsequent 30 days and in the event of an AE, following the subject 
until the AE resolves, stabilizes or the subject returns to baseline. If there is a likelihood 
that the patient will require restart of PN within 1 to 2 days of the initial stoppage, then it 
is recommended to delay performing the End of Study Treatment procedures. However, 
the End of Study Treatment procedures should be completed within 2 days of the initial 
stoppage if the patient has not restarted PN, as per Section 7.2.4 and Appendix 1
Schedule of Events.
If a patient’s participation is discontinued, the reason(s) must be recorded in the source 
documents and in the CRF.
End of study treatment procedures should be performed when a patient withdraws or is 
discontinued from the study.
Patients who are withdrawn from the study will not be replaced.
The study may be discontinued:
•
If new safety information becomes available indicating that continuing the study 
treatment or procedures may jeopardize the safety of the patients
•
Because of an administrative decision by the Sponsor
6.15 Appropriateness of Measurements
Measurements to be performed during the course of the study (with the following 
exceptions) are standard for the indication or patient population under study: testing for 
phytosterols and genetic polymorphisms, while not standard, are appropriate for 
addressing the study endpoints.
7. STUDY ACTIVITIES
The details of the schedule of events are provided in Appendix 1, Schedule of Events 
Table.


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7.1 Screening Period
After providing written IC, patients will enter the Screening Period. The Screening Period 
is defined as the period after the ICF is signed and dated until randomization. The 
maximum duration of this period is 3 days prior to dosing. Randomization is 
recommended within 24 hours of signing consent but must occur within 3 days of signing 
consent. If patient is not randomized within 24 hours of informed consent, patient should 
be started on SOC ILE on Day 1 of PN as per Table 4 and Section 5.3. Signing and 
dating of the ICF and the Screening visit may occur on the same day, if necessary; 
however, the ICF must be signed and dated before any Screening activities can be 
conducted.
The aim of the Screening Period is to determine the eligibility (inclusion/exclusion 
criteria) of patients for randomization.
Further assessments conducted during Screening include:
•
Demographics
•
Gestational age and birth weight for infants <1 years of age only
•
Medical history (including diagnosis requiring PN)
•
Physical examination, including weight and length or height (and head 
circumference for infants <1 year of age)
•
Vital signs
•
Laboratory evaluations including hematology and chemistry (refer to Appendix 1, 
Schedule of Events Table)
•
Pregnancy test. Note: All female patients ≥12 years of age must have a negative 
urine human chorionic gonadotropin (hCG) pregnancy test at screening. For 
female patients <12 years of age, a urine hCG test at screening will be performed 
at the discretion of the investigator based on childbearing potential.
•
Nutritional intakes
•
Medication history
•
Randomization to study treatment
•
Adverse Events (AEs occurring during Screening but prior to administration of 
study treatment will be considered as unrelated to study treatment). Non-serious 
AEs during this time period will be collected as part of the medical history. 
Serious adverse events will need to be reported as per Section 6.13.7.2.


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7.2 Study Treatment Period (Baseline to Day 90)
7.2.1 Baseline Procedures
Baseline is defined as the period within ±24 hours of first study treatment administration. 
The following procedures will be performed at Baseline (≤24 hours prior to 
administration of study treatment):
•
Medical history will be updated as necessary.
•
Physical examination including weight and length or height (and head 
circumference for infants <1 year of age)
•
Vital signs
•
Nutritional intakes 
•
Concomitant medications
•
Concomitant procedures
•
AEs 
The following laboratory procedures will be performed at Baseline (±24 hours prior to 
administration of study treatment). Baseline laboratory assessments need not be repeated 
if completed within 24 hours of screening sampling:
•
Laboratory evaluations including (refer to Appendix 1, Schedule of Events 
Table):
-
Hematology and chemistry
-
Hepatic function tests
-
Triglycerides
-
Fatty acid profile
-
Holman Index
-
Phytosterol, cholesterol, and squalene levels
Buccal swab samples for the determination of genetic polymorphisms for FADS1 
(rs174553) and FADS2 (rs174575, rs99780, rs174583) will be collected from all enrolled 
patients for whom consent is obtained. Buccal swabs can be collected at any time before 
the end of study treatment.


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7.2.2 Daily Procedures
The following procedures will be performed and recorded in the CRF on a daily basis
during the Study Treatment Period.
•
Weight
•
Vital signs
•
All nutritional intakes
•
Concomitant medications
•
Concomitant procedures
•
AEs
7.2.3 Standard-of-Care Procedures
The following procedures will be performed at intervals determined by the SOC at each 
investigational site (refer to Appendix 1, Schedule of Events Table):
•
Laboratory evaluations including:
-
hematology - complete blood count 
-
chemistry - basic metabolic panel and electrolytes
•
Diagnosis of neonatal morbidities including bronchopulmonary dysplasia (BPD), 
retinopathy of prematurity (ROP), intraventricular hemorrhage (IVH), 
periventricular leukomalacia (PVL), necrotizing enterocolitis (NEC), and late-
onset sepsis in enrolled premature infants born at 24 to <37 weeks of gestation up 
to 1 month CA with a birth weight ≥750g.
7.2.4 Days 15, 30, 45, 60, 75 and 90 or End of Study Treatment Procedures
The Study Treatment Period starts when the patient receives study treatment. End of 
study treatment is defined as the last day of PN with Intralipid or Clinolipid; maximum 
90 days of study treatment is allowed.
The following procedures will be performed approximately every 15 days ±2 days for 
patients continuing on PN (days 15, 30, 45, 60, 75 and 90) and within ±2 days of the last 
day of study treatment (maximum 90 days on either Clinolipid or Intralipid) whenever 
that occurs:


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•
Physical examination including weight, length or height (and head circumference
for infants <1 year of age)
•
Vital signs
•
Concomitant medications
•
Concomitant procedures
•
AEs
•
Laboratory evaluations including:
-
Hematology parameters
-
Serum chemistry parameters
-
Hepatic integrity parameters
-
Total and direct bilirubin
-
Triglyceride levels
-
FA profile
-
Holman Index
-
Phytosterol, cholesterol, and squalene levels
In addition, the following data will be collected at end of study treatment:
•
Diagnosis of neonatal morbidities including bronchopulmonary dysplasia (BPD), 
retinopathy of prematurity (ROP), intraventricular hemorrhage (IVH), 
periventricular leukomalacia (PVL), necrotizing enterocolitis (NEC), and late-
onset sepsis in enrolled premature infants born <37 weeks of gestation up to 1 
month CA.
After end of study treatment (maximum of 90 days), the patient will receive nutritional 
intervention as prescribed by their healthcare provider as SOC if PN is still required.
8. QUALITY CONTROL AND ASSURANCE
The Sponsor is responsible for implementing and maintaining quality assurance and 
quality control systems with written SOPs to ensure that studies are conducted and that 
the data are generated, documented, and reported in compliance with the protocol and 
applicable regulatory requirements. Quality control will be applied to all stages of data 
handling to ensure reliability and correct processing. The Sponsor or designee is 


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responsible for securing agreement from all involved parties to ensure direct access to all 
study-related centers, source documents, and reports for the purpose of monitoring and 
auditing. Agreements made with the Investigator/institution will be in writing.
This study may be subject to an independent audit at the investigational study center, 
which will be conducted by the Sponsor’s quality assurance personnel or designee. Full 
consultation with appropriate personnel will be made before and during such an audit. 
The Investigator must be available during the audit. If the Investigator is contacted by 
any regulatory authority regarding an audit for this study, the Investigator must contact 
the Sponsor immediately.
9. PLANNED STATISTICAL METHODS
9.1 General Considerations
A more detailed description of the statistical analysis will be presented in the Statistical 
Analysis Plan (SAP).
9.2 Determination of Sample Size
The sample size of 100 patients (50 in each of the 2 treatment groups: Clinolipid vs 
Intralipid), including neonates, is based on the feasibility of timely enrollment of patients 
for generating reference data and summary descriptive statistics, rather than on a formal 
power calculation.
For those patients who are discontinued from PN prior to 7 days due to adequate oral or 
enteral nutrition may be replaced at the discretion of the Sponsor.
9.3 Analysis Populations 
The analysis sets in this study include: the Full Analysis Set (FAS), the Per Protocol Set 
(PPS), and the Safety Analysis Set. The FAS includes all patients who are randomized to 
receive either Clinolipid or SOC SO-based lipid emulsion (Intralipid), consistent with the 
intention-to-treat principle. The PPS includes a subset of patients in the FAS who have 
Holman Index measurements taken at baseline and at least 1 other time point post-
baseline, who have received a minimum of 7 days of ILE treatment, and are without a 
major protocol violation (i.e. violation that potentially impacts the primary endpoint). The 
Safety Analysis Set includes all patients that have received treatment (Clinolipid or 
SOC).
Subgroup analyses of patients by age group (e.g., premature infants born <37 weeks of 
gestation up to 1 month CA, full-term neonates born ≥37 weeks of gestation <1 month of 
age, infants 1 to <12 months of age, children 1 to <10 years of age, adolescent 10 to <18 


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years of age) and subgroup analyses for neonates according to GA and BW will be 
conducted.
The primary endpoint analysis and secondary endpoint analyses of liver disease including 
parenteral nutrition-associated liver disease (PNALD) and the adequacy of nutritional 
intervention will be conducted for both the FAS and PPS. All safety analyses will be 
conducted on the Safety Analysis Set.
Infants found to subsequently have baseline EFAD will not be considered to have 
treatment emergent EFAD and will be analyzed separately from infants with normal 
baseline EFAD status. Unblinded infants will be analyzed separately as well.
9.4 Demographics and Baseline Characteristics
Continuous demographic and baseline variables will be summarized using number of 
patients, mean, standard deviation, median, minimum, and maximum for each treatment 
group. Some variables such as sex, race, ethnicity, and age will be categorized and 
summarized by reporting the number and percentage of patients in each category for each 
treatment group.
9.5 Primary Endpoint
The primary endpoint is the risk of developing EFAD defined as defined by Figure in 
Appendix 3.
•
The risk of developing EFAD in pediatric patients will be summarized by 
treatment group as frequency and percentage. Time to developing EFAD will be 
analyzed using the Kaplan-Meier approach.
•
Both incidence rate and proportion of EFAD will be computed for each treatment 
group.
•
The incidence rate of EFAD will be computed as the number of patients who 
develop EFAD during the Study Treatment Period divided by the corresponding 
person time (i.e. “person-day” which is computed as “total number of patients” 
times “treatment exposure period [day]” in the corresponding treatment group), 
and reported as per 100 patient days.
•
The proportion of EFAD will be computed as the number of patients who develop 
EFAD during the Study Treatment Period divided by the corresponding total 
number of patients.


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•
The Holman Index will be summarized with descriptive statistics (number of 
patients, mean, standard deviation, median, minimum, and maximum) on an 
approximately 15-day basis in each of the 2 treatment groups (Clinolipid vs 
Intralipid).
•
FA profiles will be summarized using descriptive statistics (number of patients, 
mean, standard deviation, median, minimum, and maximum) in each of the 
2 treatment groups (Clinolipid vs Intralipid), as well as descriptive statistics of 
genetic polymorphisms in the FADS1 and FADS2 genes.
9.6 Secondary Endpoint(s)
The three secondary endpoints of the study include 1) the development of liver disease 
including PNALD; 2) the adequacy of nutritional intervention; and 3) the safety profile
including AEs, SAEs and AESIs.
9.6.1 Liver Disease, Including Parenteral-Associated Liver Disease
9.6.1.1 Parenteral Nutrition-Associated Liver Disease
The risk of developing PNALD in pediatric patients by treatment will be summarized as 
frequency and percentage, as well as time to developing PNALD using the Kaplan-Meier 
approach. Both incidence rate and proportion of PNALD will be computed for each 
treatment group.
The incidence rate of PNALD will be computed as the number of patients who develop 
PNALD during the Study Treatment Period divided by the corresponding person time 
(i.e. “person-day” which is computed as “total number of patients” times “treatment 
exposure period [day]” in the corresponding treatment group), and reported as per 
100 patient days. The proportion of PNALD will be computed as the number of patients
who develop PNALD during the Study Treatment Period divided by the corresponding 
total number of patients.
9.6.1.2 Hepatic Integrity
Hepatic integrity (ALP, AST, ALT, GGT, total and direct bilirubin) will be evaluated by 
presenting descriptive summary statistics (number of patients, mean, standard deviation, 
median, minimum, and maximum) at different measurement time points from baseline to 
end of study treatment during the study period in each of the 2 treatment groups 
(Clinolipid vs Intralipid).


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Each hepatic integrity parameter will also be summarized in shift tables comparing end of 
study treatment and maximal values during the study intervention with those at baseline
(mean, standard deviation, median, minimum, and maximum) including the delay (days) 
between baseline and maximal value in each of the 2 treatment groups (Clinolipid vs 
Intralipid). Shift categories will include normal and abnormal (>1 to 3 and >3-fold the 
upper limit of normal range). In addition, assessment for drug-induced liver injury (DILI) 
will be conducted according to Hy’s Law and eDISH criteria,1,2 with additional detail 
included in the SAP.
9.6.1.3 Plasma Phytosterol, Cholesterol, and Squalene Levels
Plasma phytosterol, cholesterol, and squalene levels will be summarized using descriptive 
statistics (mean, standard deviation, median, minimum, and maximum) at baseline and 
the end of study treatment, as well as maximal value during the study and the delay 
(days) between study baseline and maximal value in each of the 2 treatment groups 
(Clinolipid vs Intralipid). In addition, the correlations between plasma phytosterol levels 
and direct bilirubin values will be assessed by computing a Pearson’s correlation 
coefficient or a Spearman correlation coefficient depending on whether the normality 
assumption is fulfilled.
9.6.2 Adequacy of Nutritional Interventions 
9.6.2.1 Nutritional Intake
Prescribed and actual nutritional intake (fluid, energy, protein, carbohydrates, and lipids) 
from parenteral and enteral nutrition will be collected and recorded daily. They will be 
summarized on a daily basis during the first 2 weeks of treatment and on a 15-day basis 
afterwards up to end of study treatment for each of the treatment groups.
9.6.2.2 Growth
Weight at baseline and during treatment will be assessed daily and will be summarized on 
an approximately 15-day basis using descriptive summary statistics in each of the 
treatment groups.
Length or height (and head circumference for infants <1 year of age) will be assessed and 
summarized at baseline and approximately every 15 days up to end of study treatment
using descriptive summary statistics (number of patients, mean, standard deviation,
median, minimum, and maximum in each of the 2 treatment groups (Clinolipid vs 
Intralipid).


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Growth will be assessed and evaluated from baseline to end of study treatment on an 
approximately every 15-day basis using descriptive summary statistics in each of the 
treatment group as follows:
•
Gain in weight (g/kg/day in infants <1 year of age, g/day in children and 
adolescents) and gain in length/height (mm/week in all) and head circumference 
(mm/week in infants <1 year);
•
Changes in the SDS from reference growth curves (Fenton growth curve for 
premature infants, WHO growth standards for infants and children ages 0 to 
2 years, or CDC growth charts for children age ≥2 years)
9.6.3 Safety Profile of Clinolipid and Intralipid
Vital signs and clinical laboratory tests will be summarized using descriptive summary 
statistics (number of patients, mean, standard deviation, median, minimum, and 
maximum) in each of the 2 treatment groups during the study period.
The following neonatal morbidities will be summarized by treatment group using n and 
percentage: BPD, ROP, IVH, PVL, NEC, and late-onset sepsis in enrolled premature 
infants born <37 weeks of gestation up to 1 month CA.
All AEs, SAEs, and AESIs will be tabulated by body system using the Medical 
Dictionary for Regulatory Activities (MedDRA) coded terms. They will be presented by 
treatment group using frequencies and percentage.
Adverse events of special interest are known AEs related to PN with ILEs, per Intralipid 
and Clinolipid USPIs and include the following: catheter related infection,
thrombophlebitis, dyspnea, cyanosis, allergic reactions, hyperlipemia, hypercoagulability, 
nausea, vomiting, headache, flushing, increase in temperature, sweating, sleepiness, pain 
in the chest and back, slight pressure over the eyes, dizziness, irritation at the site of 
infusion, hepatomegaly, splenomegaly, thrombocytopenia, leukopenia, and overloading 
syndrome (focal seizures, fever, leukocytosis, hepatomegaly, splenomegaly and shock).
In addition, the AE rate will be estimated using person time (person-day) as the 
denominator, which is computed as “total number of patients” times “treatment exposure 
period [day]” in the corresponding treatment group. The AE rate per 100 patient days will 
be reported for the overall study period, and may be stratified into Weeks 1, 2, 3, and 4 as 
appropriate.


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9.7 Interim Analysis
No interim analysis is planned for this study.
10. ADMINISTRATIVE CONSIDERATIONS
10.1 Investigators and Study Administrative Structure
The investigator will comply with the protocol (which has been approved/given favorable 
opinion by the IRB/), International Council for Harmonisation (ICH) Good Clinical 
Practice (GCP), the ethical principles of the Declaration of Helsinki, and applicable 
regulatory requirements as described in the Clinical Study Agreement. The Investigator is 
ultimately responsible for the conduct of all aspects of the study at the study center and 
verifies by signature the integrity of all data transmitted to the sponsor. Whenever the 
term ‘investigator’ is noted in the protocol text, it may refer to either the principal 
investigator at the site, or an appropriately qualified, trained and delegated individual of 
the investigational site. Sub-investigators or other authorized study personnel are eligible 
to sign for the investigator, except where the investigator’s signature is specifically 
required.
10.2 Institutional Review Board Approval
Before enrollment of patients into this study, the protocol, ICF and assent (when 
required), any promotional material/advertisements, and any other written 
information/recruitment aids will be reviewed and approved/given favorable opinion by 
the IRB and applicable regulatory authorities.
The IRB’s composition or a statement that the IRB’s composition meets applicable 
regulatory criteria will be documented. The study will commence only upon the 
responsible party’s receipt of approval/favorable opinion from the IRB and, if required, 
upon the responsible party’s notification of applicable regulatory authority(ies) approval.
The Investigator will promptly report to their IRB any unanticipated problems associated 
with the study treatment involving risks to patients or others, whether encountered at the 
investigative site or provided as a safety report by the Sponsor.
If the protocol or any other information given to the patient is amended, the revised 
documents will be reviewed and approved/given favorable opinion by the IRB and 
relevant regulatory authorities, where applicable. The protocol amendment will only be 
implemented upon the responsible party’s receipt of approval and, if required, upon the 
responsible party’s notification of applicable regulatory authority(ies) approval.


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10.3 Ethical Conduct of the Study
This study will be conducted in accordance with the following guidelines:
•
Declaration of Helsinki (October 2013)
•
Current ICH Guidelines (ICH E6) for GCP Guidelines
•
Basic principles defined in US 21 CFR Part 312
•
All applicable regulatory requirements and laws
10.4 Patient Information and Consent
The Investigator or his/her entitled designee will obtain written IC from each patient or 
from the patient’s legal representative or designee as defined by local law. An assent 
form (child’s agreement to participate) will also be used following requirements of local 
or central IRB as applicable. Consent and assent (where required) will be obtained before 
any study-specific procedures are performed.
Preparation of the ICF and assent form is the responsibility of the Investigator. The ICF 
must include all elements required by ICH, GCP, and applicable regulatory requirements, 
and must adhere to GCPs and to the ethical principles that have their origin in the 
Declaration of Helsinki. The ICF will be reviewed and approved by the Sponsor before 
IRB review.
The Investigator must provide the patient or the patient’s legal representative with a copy 
of the ICF and written information about the study in the language in which the patient is 
most proficient. The language must be nontechnical and easily understood. The ICF will 
be reviewed with the prospective study patients or their legal representatives, and the 
Investigator will be available to answer questions regarding procedures, risks, and 
alternatives. The Investigator will allow sufficient time for the patient or the patient's 
legal representative to inquire about the details of the study and to decide whether or not 
to participate in the study. If the patient or the patient’s legal representative wishes to 
participate, the ICF will be signed and personally dated by the patient or the patient's 
legal representative and by the person who conducted the IC discussion. The patient or 
the patient’s legal representative will receive a copy of the signed ICF and any other 
written information provided to the patient before the patient’s participation in the study. 
Before the commencement of the study, the Investigator must furnish the Sponsor with a 
copy of the IRB-approved ICF to be used in this study.


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10.5 Patient Confidentiality
All patient information, medical records, and laboratory data will be kept confidential. 
Information and data may be discussed, analyzed, and reported; however, code numbers 
will identify the patient in the CRFs and in any reports, and the patient’s identity will be 
kept confidential.
10.6 Study Monitoring
Monitoring visits will occur at regularly scheduled intervals at the investigational site to 
allow for verification of source documents and comparison of source data with the 
information recorded in the CRFs.
Representatives of the Sponsor, or its designee, must be allowed to visit the study site 
periodically to assess the data quality and the integrity of the study. These representatives 
will review study records on site and directly compare these with the source documents, 
discuss the conduct of the study with the Investigator, and verify that the facilities remain 
acceptable. In addition, the study may be evaluated by Baxter’s internal auditors or a 
designee, and/or by government inspectors, who must be allowed access to CRFs, source 
documents, and other study files. The Sponsor audit reports will be kept confidential.
The Investigator or a designated member of the Investigator’s staff must be available at 
some time during monitoring visits to review data and resolve any queries and to allow 
direct access to the patient’s records (e.g. medical records, office charts, hospital charts, 
and study-related charts) for source data verification. The CRFs must be completed prior 
to each visit and be made available to the monitor so that their accuracy and 
completeness may be checked.
This study may be subject to an independent audit at the investigational site, which will 
be conducted by independent auditors. Full consultation with appropriate personnel will 
be made prior to and during such audit. The Investigator must be available during the 
audit. If the Investigator is contacted by any regulatory authority regarding an audit for 
this study or any other study, the Investigator will contact the Study Manager and 
Medical Director immediately.
10.7 Case Report Forms and Study Records
All patient medical records will be kept strictly confidential. Personally identifiable 
information will not be transmitted to Baxter, or its designee, or to any third parties. 
Patient CRFs will be maintained in an electronic data capture (EDC) system and will only 
be released to Baxter, its designee(s), or to appropriate government agencies. Code 
numbers will be used to identify the patient in CRFs and other study-related documents.


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The Investigator is required to prepare and maintain adequate and accurate case histories 
for each patient. Source data will be entered in CRFs by the study coordinator/designee. 
Data should accurately reflect the data recorded in the source documents. The CRF must 
be reviewed by the Investigator and he/she will sign off in the EDC to verify that the 
CRF data is accurate, complete, and reflects the source documentation. This review and 
sign-off may be delegated to a qualified physician appointed as a Sub Investigator by the 
Investigator.
10.8 Data and Safety Monitoring Board
An independent DSMB will be established to review and analyze all safety data on a 
regular basis. Emerging efficacy data may be considered by the DSMB in evaluating the 
potential risks and benefits of the treatment under study. The DSMB will consist of an 
independent group of expert clinicians (a minimum of 2) who are not actively recruiting 
patients for this study, and a biostatistician. Reports will be provided to the DSMB at 
pre-specified intervals. The DSMB-associated biostatistician will be provided with the 
randomization code list and database transfers, (if requested).
Serious adverse events will be reviewed by the DSMB on an ongoing basis. The DSMB
will review the frequency and severity of all AEs as well as demographic and bioactivity 
data. Ad hoc meetings may also be held for any safety concerns during the study. Based 
upon a review of the data, the DSMB will make recommendations to continue, modify, or 
stop the study if any of the stopping criteria are met (refer to Section 6.14). Further 
responsibilities and details of the DSMB will be included in the DSMB Charter.
10.9 Protocol Violations/Deviations
The Investigator will not deviate from this protocol without prior documented approval 
from the Sponsor or its designee and the IRB, except in cases of medical emergency. The 
Investigator may deviate from the protocol without prior approval only when the change 
is necessary to eliminate an apparent immediate hazard to the patient. In that event, the 
Investigator will notify the Sponsor immediately by phone, notify the IRB, and confirm 
notification to the Sponsor in writing as soon as possible, but within 5 working days after 
the change is implemented.
The Investigator is responsible for recording deviations from the protocol in the CRF.
10.10 Access to Source Documentation
The Sponsor or its designee will ensure that the protocol or other written agreement 
specifies that the Investigator/Institution provide direct access to source data/documents 
for study-related monitoring, audits, IRB review, and regulatory inspection. The Sponsor 


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2022 FEB 22
or its designee will verify that each patient has consented in writing to direct access to 
his/her original medical records for study-related monitoring, audit, IRB review, and 
regulatory inspection. The Sponsor or its designee is responsible for securing agreement 
from all involved parties to ensure direct access to all study-related centers, source 
documents, and reports for the purpose of monitoring and auditing.
10.11 Data Generation and Analysis
The Sponsor will utilize qualified individuals throughout all stages of the study process, 
from designing the protocol and CRFs, to supervising the overall conduct of the study, 
data handling and verification, conducting the statistical analyses, and preparation of final 
study reports.
The Sponsor will use an unambiguous patient identification code that allows for 
identification of all data reported for each patient.
A study database using EDC system will be created from the data in the CRFs using the 
MedDRA version 21.0 or higher for AE coding and the WHO Drug Dictionary 
(WHODRUG, version 201309) for concomitant medications coding.
Unless otherwise noted, all analyses will be performed using SAS®, SAS/GRAPH® and 
SAS/STAT® software, Version 9.4 of SAS for Windows, copyright © 2016 SAS Institute
Inc, on a Microsoft Windows Server. SAS and all other SAS Institute Inc. product or 
service names are registered trademarks or trademarks of SAS Institute Inc., Cary, NC, 
USA.
10.12 Retention of Data
The Sponsor will retain the essential documents until at least 5 years have lapsed since 
the end of this clinical study for whatever reason.
The Investigator must retain all study records including investigational product 
disposition records and source documents for the maximum period required by applicable 
regulations and guidelines or institution procedures or for the period specified by the 
Sponsor (15 years), whichever is longer. The Investigator must contact the Sponsor or its 
designee before destroying any records associated with the study. The Sponsor or its 
designee will notify the Investigator when the study records are no longer needed. If the 
Investigator departs from the study site (e.g. relocation, retirement, death), the records 
shall be transferred to a mutually agreed upon designee (e.g. another Investigator, IRB). 
The Sponsor must be notified in writing of any such transfer.


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10.13 Financial Disclosure
The financial aspects of the study will be documented in an agreement between the 
Sponsor and the Investigator.
10.14 Publication and Disclosure Policy
Any information shared by the Sponsor regarding this study, including this protocol, is 
considered proprietary information and will be kept confidential.
The data generated by this clinical study are the property of the Sponsor. These data may 
be used by the Sponsor, now and in the future, for presentation or publication at the 
Sponsor’s discretion or for submission to regulatory agencies.
The Sponsor recognizes the rights of the Investigators who qualify for authorship and 
want to publish the methods, results, and conclusions from the study. The Sponsor will 
allow the Investigator authors full access to data. The Sponsor has the right but not the 
obligation to review any publication or presentation from this study by any Investigator 
before publication or presentation to ensure intellectual property rights are respected. The 
Investigator or Institution will provide a copy of the proposed publication(s) to the 
Sponsor 60 days before submission for publication. The Sponsor will review such 
publications/presentations in a timely manner. Any differences in the interpretation or 
presentation of data will be resolved through a process of honest scientific debate.
The study will be published in a timely and responsible manner, with all articles and 
presentations conforming to good publication practice and other recognized standards. 
Premature and duplicate publications will be avoided. The Investigator agrees not to 
publish the results of the clinical study pertaining to his/her center before the publication 
of the overall clinical study results.
Authorship of publications resulting from the study will be based on the guidelines on 
authorship, such as those described in the Uniform Requirements for Manuscripts 
Submitted to Biomedical Journals. The Uniform Requirements for Manuscripts state that 
the named authors must have made a significant contribution to the design of the study or 
analysis and interpretation of the data, provided critical review of the paper, and given 
final approval of the final version. Authors also agree to be accountable for all aspects of 
the publication. Refer to http://www.icmje.org/icmje-recommendations.pdf for current 
recommendations.
The Sponsor’s support of the study and medical writing services will be acknowledged in 
all publications arising from the study.


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10.15 Health Insurance Portability and Accountability Act
In connection with this research study, the Investigator and the institution may collect 
“protected health information” as defined in Title 45 CFR Section 164.501. The 
Investigator and/or the institution shall obtain the patient’s legally authorized 
representative’s authorization to allow the Investigator and the institution to disclose the 
protected health information in accordance with the standards as set forth in Title 45 CFR 
Section 164.514. The Sponsor may use and disclose the de-identified information as 
allowed by law.
11. REFERENCE LIST
1.
Senior JR. Evolution of the Food and Drug Administration Approach to Liver 
Safety Assessment for New Drugs: Current Status and Challenges. Drug Safety. 
2014;37(1):9-17.
2.
Guidance for industry drug-induced liver injury, premarketing clinical evaluation. 
Rockville, MD :: U.S. Dept. of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research :; 2009.
3.
Fats and fatty acids in human nutrition. Report of an expert consultation. FAO 
Food Nutr Pap. 2010;91:1-166.
4.
Gramlich L, Meddings L, Alberda C, et al. Essential Fatty Acid Deficiency in 
2015: The Impact of Novel Intravenous Lipid Emulsions. JPEN J Parenter Enteral Nutr. 
2015;39(1 Suppl):61S-66S.
5.
Koletzko B, Goulet O, Hunt J, 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.
6.
Sunshine P, Kerner Jr JA. The use of intravenous fat emulsions in preterm infants. 
Nutritional Adaptation of the Gastrointestinal Tract of the Newborn, Nestle, Vevey/Raven 
Press, New York. 1983:163-175.
7.
Caldwell MD, Jonsson HT, Othersen HB. Essential fatty acid deficiency in an 
infant receiving prolonged parenteral alimentation. J Pediatr. 1972;81(5):894-898.
8.
Paulsrud JR, Pensler L, Whitten CF, Stewart S, Holman RT. Essential fatty acid 
deficiency in infants induced by fat-free intravenous feeding. Am J Clin Nutr. 
1972;25(9):897-904.
9.
Postuma R, Pease PW, Watts R, Taylor S, McEvoy FA. Essential fatty acid 
deficiency in infants receiving parenteral nutrition. J Pediatr Surg. 1978;13(4):393-398.
10.
Calder PC. Polyunsaturated fatty acids, inflammation, and immunity. Lipids. 
2001;36(9):1007-1024.
11.
Senterre T, Terrin G, De Curtis M. Parenteral nutrition in premature infants. 
Textbook of Pediatric Gastroenterology, Hepatology and Nutrition: A Comprehensive 
Guide to Practice. New York: Springer International Publishing Switzerland; 2016:73-86.
12.
Raman M, Almutairdi A, Mulesa L, Alberda C, Beattie C, Gramlich L. Parenteral 
Nutrition and Lipids. Nutrients. 2017;9(4).


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13.
Calder PC, Jensen GL, Koletzko BV, Singer P, Wanten GJ. Lipid emulsions in 
parenteral nutrition of intensive care patients: current thinking and future directions. 
Intensive Care Med. 2010;36(5):735-749.
14.
Jones CJ, Calder PC. Influence of different intravenous lipid emulsions on fatty 
acid status and laboratory and clinical outcomes in adult patients receiving home 
parenteral nutrition: A systematic review. Clin Nutr. 2018;37(1):285-291.
15.
Vahedi K, Atlan P, Joly F, et al. A 3-month double-blind randomised study 
comparing an olive oil- with a soyabean oil-based intravenous lipid emulsion in home 
parenteral nutrition patients. Br J Nutr. 2005;94(6):909-916.
16.
Olthof ED, Roelofs HM, Fisk HL, Calder PC, Wanten GJ. No Clinical or 
Biochemical Evidence for Essential Fatty Acid Deficiency in Home Patients Who 
Depend on Long-Term Mixed Olive Oil- and Soybean Oil-Based Parenteral Nutrition. 
JPEN J Parenter Enteral Nutr. 2016;40(7):982-988.
17.
Harvey K, Xu Z, Walker C, et al. Parenteral Lipid Emulsions in Guinea Pigs 
Differentially Influence Plasma and Tissue Levels of Fatty Acids, Squalene, Cholesterol, 
and Phytosterols. Vol. 49; 2014.
18.
Xu Z, Harvey KA, Pavlina T, et al. Steroidal compounds in commercial parenteral 
lipid emulsions. Nutrients. 2012;4(8):904-921.
19.
Kleinman RE, Greer FR. American Academy of Pediatrics Committee on 
Nutrition. Pediatric Nutrition. Elk Grove Village, IL: American Academy of Pediatrics; 
2014.
20.
Corkins MR, Balint J, Bobo E, Plogsted, Yaworski JA. The A.S.P.E.N. Pediatric 
Nutrition Support Core Curriculum. American Academy Society for Parenteral and 
Enteral Nutrition: Silver Spring, MD; 2015.
21.
Mesotten D, Joosten K, van Kempen A, et al. ESPGHAN/ESPEN/ESPR/CSPEN 
guidelines on pediatric parenteral nutrition: Carbohydrates. Clinical Nutrition. 
2018;37(6):2337-2343.
22.
Lapillonne A, Fidler Mis N, Goulet O, et al. ESPGHAN/ESPEN/ESPR/CSPEN 
guidelines on pediatric parenteral nutrition: Lipids. Clinical Nutrition. 2018;37(6):2324-
2336.
23.
Senterre T, Lapillone A. The Low-Birth-Weight Infants: Inpatient Care. In: 
Duggan C, Watkins J, Koletzko B, Walker W, eds. Nutrition in Pediatrics: Basic Science 
and Clinical Application - 5th Edition. Shelton, Connecticut: People’s Medical Pubishing 
House – United States of America; 2016:539-554.


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Appendix 1 Schedule of Events Table
Evaluation
Screening
Baselinea
Daily
Study Treatment Day
(every 15 days ±2 
days)
End of 
Study 
Treatmento
or Day 90
(± 2 days)
15
30
45
60
75
Informed consent / assent (as 
applicable)
X
Confirm eligibility
X
Randomizationb
X
Demographicsc
X
Medical history including 
diagnosis for requiring PN
X
X
Physical examination 
including length or height 
and head circumference
X
X
X
X
X
X
X
X
Body weightd
X
X
X
X
X
X
X
X
X
Vital signse
X
X
X
X
X
X
X
X
X
Diagnosis of neonatal 
morbiditiesf
X
Laboratory Evaluations
Hematology and serum 
chemistry
X
X
Standard-of-Care and every 15 days ±2 days
Triglyceride levels
X
X
Standard-of-Care and every 15 days ±2 days
Hepatic function tests
X
X
Standard-of-Care and every 15 days ±2 days
Fatty acid profile and 
Holman Indexg
X
X
X
X
X
X
X
Genetic polymorphism 
sample (buccal swab)h
X
Phytosterol, cholesterol, and 
squalene levelsi
X
X
X
X
X
X
X
Human chorionic 
gonadotropin (hCG)j
X
Nutritional Intake
PN lipid intakek
X
X
X
X
X
X
X
X
Other macronutrient PN 
intake
X
X
X
X
X
X
X
X
Breast milk intakel
X
X
X
X
X
X
X
X
X
Enteral formula intake
X
X
X
X
X
X
X
X
X


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Evaluation
Screening
Baselinea
Daily
Study Treatment Day
(every 15 days ±2 
days)
End of 
Study 
Treatmento
or Day 90
(± 2 days)
15
30
45
60
75
Oral food intake
X
X
X
X
X
X
X
X
X
Concomitant medications / 
nutritional supplementsm
X
X
X
X
X
X
X
X
X
Concomitant procedures
X
X
X
X
X
X
X
X
X
Adverse eventsn
X
X
X
X
X
X
X
X
X
PN=parenteral nutrition
a Baseline evaluations should be done ≤24 hours before first study treatment administration, however, 
baseline laboratory assessments may be done within ±24 hours of first study treatment administration. 
Baseline tests need not be repeated if within 24 hours of screening sampling. Buccal swabs can be 
collected at any time before the end of study treatment.
b Randomization is recommended within 24 hours of signing consent but must occur within 3 days of 
signing consent (section 7.1)
c For all neonates (premature infants born <37 weeks of gestation up to 1 month CA and full-term 
neonates <1 month of age), gestational age (GA) will be recorded at Screening and categorized as full-
term (born ≥37 weeks of gestation), preterm (32-36 weeks of gestation), very preterm (28-31 weeks of 
gestation), or extremely preterm (<28 weeks of gestation).
d Including weight and length or height (and head circumference for infants <1 year of age). For all 
neonates (premature infants born <37 weeks of gestation up to 1 month CA and full-term neonates <1 
month of age), BW will be recorded at Screening and categorized as normal BW (≥2500 g), low BW 
(1500-2499 g), very low BW (1000-1499 g), or extremely low BW (<1000 g).
e Vital signs will be collected once daily at approximately the same time each day (e.g. 8 AM), with a 
window of approximately 2-3 hours. Vital signs include heart rate (beats/min), respiratory rate 
(breaths/min), systolic and diastolic blood pressure (mmHg), and body temperature (°C).
f Diagnosis of neonatal morbidities diagnoses including BPD, ROP, IVH, PVL, NEC, and late-onset 
sepsis in enrolled premature and low birth weight neonates.  Diagnostic criteria and severity grading 
will be per standard-of-care.
g Samples are to be collected ≥4 hours after completing last lipid infusion. Samples are to be collected at 
the same time every day.
h Buccal swab samples for the determination of genetic polymorphisms for FADS1 (rs174553) and 
FADS2 (rs174575, rs99780, rs174583) will be collected from all enrolled patients for whom consent is 
obtained. Buccal swabs can be collected at any time before the end of study treatment. Buccal swabs 
will be destroyed once all analyses have been completed.
i Clarification on laboratory measurements will be provided in a separate laboratory manual.
j All female patients ≥12 years of age must have a negative urine human chorionic gonadotropin (hCG) 
pregnancy test at screening. For female patients <12 years of age, a urine hCG test at screening will be 
performed at the discretion of the investigator based on childbearing potential.
k Parenteral nutrition therapy may be interrupted and restarted (based on the initial randomization) 
within a 1 to 2-day window, subject to adjudication from the medical monitor who conducts clinical 
review of current patient status, assessment of any potential AE/SAEs, discussion/clarification with 
investigator to resume or abort study treatment. If there is a likelihood that the patient will require 
restart of PN within 1 to 2 days of the initial stoppage, then it is recommended to delay performing the 
End of Study Treatment procedures. However, the End of Study Treatment procedures should be 
completed within 2 days of the initial stoppage if the patient has not restarted PN.


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Evaluation
Screening
Baselinea
Daily
Study Treatment Day
(every 15 days ±2 
days)
End of 
Study 
Treatmento
or Day 90
(± 2 days)
15
30
45
60
75
l When breastfeeding intakes cannot be measured, the best estimation (volume) of the investigator will 
be recorded.
mMedications and nutrition supplements received within 30 days prior to randomization by the patient 
and the nursing mother (if applicable) also will be recorded at Screening. The nursing mother’s 
medication history will be collected from the patient’s chart (if available).
n Adverse events occurring prior to the initiation of the first study procedure will be recorded as signs 
and symptoms in the patient’s medical history. During the course of the study, and for 30 days after the 
last dose of study drug, the Investigator or designee will routinely monitor and solicit each patient for 
the occurrence of any AEs. All SAEs or any pregnancy reports with or without an associated SAE must 
be reported to Baxter Global Pharmacovigilance within 24 hours of site's knowledge of the event.
o End of study treatment is defined as the last day of PN with Intralipid or Clinolipid; maximum 90 days 
of study treatment is allowed. After 90 days, the patient will receive nutritional intervention as 
prescribed by their healthcare provider if still required.


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Appendix 2 Reference for Fatty Acid Profile Values (Mayo Clinic References)
Fatty Acid
Chain Length
Reference Values
Lauric Acid
C12:0
<1 year: 6-190 nmol/mL
1-17 years: 5-80 nmol/mL
> or =18 years: 6-90nmol/mL
Myristic Acid
C14:0
<1 year: 30-320 nmol/mL
1-17 years: 40-290 nmol/mL
> or =18 years: 30-450 nmol/mL
Hexadecenoic Acid
C16:1n-9
<1 year: 21-69 nmol/mL
1-17 years: 24-82 nmol/mL
> or =18 years: 25-105 nmol/mL
Palmitoleic Acid
C16:1n-7
<1 year: 20-1,020 nmol/mL
1-17 years: 100-670 nmol/mL
> or =18 years: 110-1,130 nmol/mL
Palmitic Acid
C16:0
<1 year: 720-3,120 nmol/mL
1-17 years: 960-3,460 nmol/mL
> or =18 years: 1,480-3,730 nmol/mL
Gamma-Linolenic Acid
C18:3n-6
<1 year: 6-110 nmol/mL
1-17 years: 9-130 nmol/mL
> or =18 years: 16-150 nmol/mL
Alpha-Linolenic Acid (ALA)
C18:3n-3
<1 year: 10-190 nmol/mL
1-17 years: 20-120 nmol/mL
> or =18 years: 50-130 nmol/mL
Linoleic Acid (LA)
C18:2n-6
1-31 days: 350-2,660 nmol/mL
32 days-11 months: 1,000-3,300 nmol/mL
1-17 years: 1,600-3,500 nmol/mL
> or =18 years: 2,270-3,850 nmol/mL
Oleic Acid
C18:1n-9
<1 year: 250-3,500 nmol/mL
1-17 years: 350-3,500 nmol/mL
> or =18 years: 650-3,500 nmol/mL
Vaccenic Acid
C18:1n-7
<1 year: 140-720 nmol/mL
1-17 years: 320-900 nmol/mL
> or =18 years: 280-740 nmol/mL


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Fatty Acid
Chain Length
Reference Values
Stearic Acid
C18:0
<1 year: 270-1,140 nmol/mL
1-17 years: 280-1,170 nmol/mL
> or =18 years: 590-1,170 nmol/mL
Eicosapentaenoic Acid (EPA)
C20:5n-3
<1 year: 2-60 nmol/mL
1-17 years: 8-90 nmol/mL
> or =18 years: 14-100 nmol/mL
Arachidonic Acid (ARA)
C20:4n-6
<1 year: 110-1,110 nmol/mL
1-17 years: 350-1,030 nmol/mL
> or =18 years: 520-1,490 nmol/mL
Eicosatrienoic Acid (Mead acid)
C20:3n-9
1-31 days: 8-60 nmol/mL
32 days-11 months: 3-24 nmol/mL
1-17 years: 7-30 nmol/mL
> or =18 years: 7-30 nmol/mL
Homo-Gamma-Linolenic
C20:3n-6
<1 year: 30-170 nmol/mL
1-17 years: 60-220 nmol/mL
> or =18 years: 50-250 nmol/mL
Arachidic Acid
C20:0
<1 year: 30-120 nmol/mL
1-17 years: 30-90 nmol/mL
> or =18 years: 50-90 nmol/mL
Docosahexaenoic Acid (DHA)
C22:6n-3
<1 year: 10-220 nmol/mL
1-17 years: 30-160 nmol/mL
> or =18 years: 30-250 nmol/mL
DPA
C22:5n-6
<1 year: 3-70 nmol/mL
1-17 years: 10-50 nmol/mL
> or =18 years: 10-70 nmol/mL
DPA
C22:5n-3
<1 year: 6-110 nmol/mL
1-17 years: 30-270 nmol/mL
> or =18 years: 20-210 nmol/mL
DTA
C22:4n-6
<1 year: 2-50 nmol/mL
1-17 years: 10-40 nmol/mL
> or =18 years: 10-80 nmol/mL
Docosenoic Acid
C22:1
<1 year: 2-20 nmol/mL
1-17 years: 4-13 nmol/mL


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Fatty Acid
Chain Length
Reference Values
> or =18 years: 4-13 nmol/mL
Nervonic Acid
C24:1n-9
<1 year: 30-150 nmol/mL
1-17 years: 50-130 nmol/mL
> or =18 years: 60-100 nmol/mL
Total Saturated Acid
N/A
<1 year: 1.2-4.6 mmol/L
1-17 years: 1.4-4.9 mmol/L
> or =18 years: 2.5-5.5 mmol/L
Total Monounsaturated Acid
N/A
<1 year: 0.3-4.6 mmol/L
1-17 years: 0.5-4.4 mmol/L
> or =18 years: 1.3-5.8 mmol/L
Total Polyunsaturated Acid
N/A
<1 year: 1.1-4.9 mmol/L
1-17 years: 1.7-5.3 mmol/L
> or =18 years: 3.2-5.8 mmol/L
Total n-3 Fatty Acids
N/A
<1 year: 0.0-0.4 mmol/L
1-17 years: 0.1-0.5 mmol/L
> or =18 years: 0.2-0.5 mmol/L
Total n-6 Fatty Acids
N/A
<1 year: 0.9-4.4 mmol/L
1-17 years: 1.6-4.7 mmol/L
> or =18 years: 3.0-5.4 mmol/L
Total Fatty Acids
N/A
<1 year: 3.3-14.0 mmol/L
1-17 years: 4.4-14.3 mmol/L
> or =18 years: 7.3-16.8 mmol/L






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Clinical Trial Protocol #6344-001: Amendment 5.6
2022 FEB 22
Appendix 5 Investigator’s Signature
Study Title:
A Randomized, Double-Blind, Controlled, Clinical Trial to Evaluate the 
Risk of Developing Essential Fatty Acid Deficiency in Pediatric Patients, 
Including Neonates, Receiving Either Clinolipid (lipid injectable emulsion, 
USP) 20% or Standard-of-Care Soybean Oil-Based Lipid Emulsion
Study Number:
6344-001
Original Protocol:
2014 MAY 20
Amendment 1:
2014 JUN 20
Amendment 2:
2014 SEP 03
Amendment 3: 
2015 MAY 26
Amendment 4:
2019 MAR 22
Amendment 5:
2020 APR 13
Amendment 5.1:
2020 APR 21
Amendment 5.2:
2020 JUN 03
Amendment 5.3:
2020 JUN 25
Amendment 5.4:
2020 AUG 26
Amendment 5.5:
2022 FEB 03
Amendment 5.6:
2022 FEB 22
I have read Amendment No 5.6, which outlines the changes to the protocol described 
above. I agree to comply with all applicable regulations and to conduct the study as 
described in the revised protocol in accordance with ICH guidelines and all applicable 
government regulations, including Part 54, Financial Disclosure by Clinical Investigators.
Signed:
Date:
Print Name:
Title:
Affiliation:
Address:
Phone number:

SAP_001.pdf: 
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6344-001: Statistical Analysis Plan V2.0
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Statistical Analysis Plan: 6344-001 
Study Title: 
A Randomized, Double-Blind, Controlled, Clinical 
Trial to Evaluate the Risk of Developing Essential 
Fatty Acid Deficiency in Pediatric Patients, 
Including Neonates, Receiving Either Clinolipid 
(lipid injectable emulsion, USP) 20% or Standard-
of-Care Soybean Oil-Based Lipid Emulsion  
Study Number: 
6344-001  
Study Phase:  
IV  
Study Design 
This is a multi-center, randomized, double-blind, 
controlled, 2-arm, prospective study to evaluate 
occurrence of essential fatty acid deficiency 
(EFAD) (diagnosed by Holman Index >0.4) in 100 
randomized pediatric patients including neonates, to 
either Clinolipid or standard-of-care soybean oil-
based Intralipid. The study will be conducted at 
approximately 10 sites in the US. 
Product Name: 
Clinolipid (lipid injectable emulsion, USP) 20%  
Indication: 
Clinolipid 20% is a lipid emulsion currently 
indicated for parenteral nutrition in adults providing 
a source of calories and essential fatty acids when 
oral or enteral nutrition is not possible, insufficient, 
or contraindicated 
Statistician: 
  
Sponsor: 
Baxter Healthcare Corporation 
One Baxter Parkway  
Deerfield, Illinois 60015, USA 
Responsible Medical Officer: 
, MD, FACP 
Final Date: 
30JAN2023 
 


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Table of Contents 
SIGNATURE PAGE ..........................................................................................................4 
REVISION HISTORY ......................................................................................................5 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................6 
1. STUDY DETAILS .........................................................................................................8 
1.1 Study Objectives and Endpoints ............................................................................8 
1.2 Primary Objective ....................................................................................................8 
1.3 Secondary Objective(s) ............................................................................................8 
1.4 Study Design ...........................................................................................................10 
1.4.1 Overall Study Design and Plan ......................................................................10 
1.4.2 Determination of Sample Size ........................................................................11 
1.4.3 Randomization Procedure .............................................................................11 
1.4.4 Blinding ............................................................................................................11 
1.4.5 Schedule of Visits and Procedures ................................................................12 
1.5 Analysis Populations ..............................................................................................15 
1.5.1 Definition of Analysis Populations ................................................................15 
1.5.2 Protocol Deviations .........................................................................................16 
1.6 Endpoints ................................................................................................................16 
1.6.1 Primary Endpoint ...........................................................................................16 
1.6.2 Secondary Endpoints ......................................................................................16 
1.7 Interim Analysis .....................................................................................................18 
2. ANALYSIS METHODS ..............................................................................................19 
2.1 General Principles ..................................................................................................19 
2.1.1 Definition of baseline ......................................................................................19 
2.1.2 Visit Windows .................................................................................................20 
2.1.3 Completion and Discontinuation ...................................................................20 
2.2 Patient Disposition .................................................................................................20 
2.3 Demographics and Other Baseline Characteristics ............................................21 
2.3.1 Demographics ..................................................................................................21 
2.3.2 Medical History ...............................................................................................22 
2.3.3 Prior and Concomitant Medications (Mother and Child) ..........................22 
2.3.4 Concomitant Procedures ................................................................................22 
2.3.5 Other Baseline Characteristics ......................................................................22 
2.4 Endpoint Analyses .................................................................................................22 
2.4.1 Primary Endpoint ...........................................................................................22 
2.4.1.1 Derivation of Primary Endpoint ............................................................23 
2.4.1.2 Analysis of Primary Endpoint ................................................................24 
2.4.1.3 Sensitivity Analysis of Primary Endpoint .............................................24 


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2.4.2 Secondary Endpoints ......................................................................................25 
2.4.2.1 Liver Disease, Including Parenteral-Associated Liver Disease ...........25 
2.4.2.2 Parenteral Nutrition-Associated Liver Disease (PNALD) ...................25 
2.4.2.3 Hepatic Integrity ......................................................................................26 
2.4.2.4 Plasma Phytosterols, Cholesterol, and Squalene Levels ......................27 
2.4.3 Adequacy of Nutritional Interventions .........................................................27 
2.4.3.1 Parenteral Nutritional Intake .................................................................28 
2.4.3.2 Enteral Nutritional Intake ......................................................................29 
2.4.3.3 Intravenous Fluid Nutritional Intake ....................................................33 
2.4.3.4 Overall Nutritional Intake ......................................................................33 
2.4.3.5 Growth ......................................................................................................34 
2.5 Safety Analyses .......................................................................................................35 
2.5.1 Adverse Events ................................................................................................35 
2.5.1.1 Derivation of Adverse Events .................................................................35 
2.5.1.2 Analysis of Adverse Events .....................................................................36 
2.5.2 Other Safety Endpoints ..................................................................................38 
2.5.2.1 Neonatal Morbidities ...............................................................................38 
2.5.2.2 Derivation of Vital Signs .........................................................................38 
2.5.2.3 Analysis of Vital Signs .............................................................................38 
2.5.2.4 Derivation of Laboratory Results ..........................................................38 
2.5.2.5 Analysis of Laboratory Results ..............................................................38 
2.5.2.6 Derivation of Treatment Exposure ........................................................39 
2.5.2.7 Analysis of Treatment Exposure ............................................................39 
2.5.2.8 Physical Examinations ............................................................................39 
2.5.3 Independent Data Safety Monitoring Board ................................................40 
2.6 Other general principles ........................................................................................40 
2.6.1 Adjustment for covariates ..............................................................................40 
2.6.2 Handling of Dropouts or Missing data .........................................................40 
2.6.3 Multicenter Studies .........................................................................................40 
2.6.4 Multiple Comparison/Multiplicity ................................................................40 
 ..........................................................40 
2.6.6 Rounding and Decimal Places .......................................................................40 
3. CHANGES FROM ANALYSIS PLANNED IN PROTOCOL ................................40 
4. REFERENCES .............................................................................................................41 
5. APPENDIX ...................................................................................................................43 
5.1 Appendix 1: List of Tables, Listings, and Figures ..............................................43 
 
List of Tables 
Table 1. List of Local Laboratory Tests.........................................................................18 
 




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REVISION HISTORY 
Version 
Revision 
Summary 
Reason(s) for Revision 
1.0 
Initial release 
N/A 
2.0 
Amendment 1 
Fixed incorrect formulas (gain in weight from baseline, 
gain in head circumference from baseline, treatment 
exposure) 
Updated units and formula for PN carbohydrate intake 
Added additional parameters to treatment exposure  
Added new fortifier conversions to conversion table 3 
Additional minor clarifications added to nutrition section 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADaM 
Analysis Data Models 
AE 
Adverse Event 
AESI 
AE of Special Interest 
ALP 
Alkaline Phosphate 
ALT 
Alanine Aminotransferase 
ARA 
Arachidonic Acid 
AST 
Aspartate Aminotransferase 
AT 
Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BPD 
Bronchopulmonary Dysplasia 
BUN 
Blood Urea Nitrogen 
BW 
Body Weight 
CA 
Corrected Age 
Ca 
Calcium 
CDC 
Center for Disease Control 
Cl 
Chloride 
CO2 
Bicarbonate 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
DHA 
Docosahexaenoic Acid 
DILI 
Drug Induced Liver Injury 
DSMB 
Data Safety and Monitoring Board 
eCRF 
Electronic Case Report Form 
EFAD 
Essential Fatty Acid Deficiency 
EPA 
Eicosapentaenoic Acid 
FA 
Fatty Acid 
FADS1 
Fatty Acid Desaturase 1 Gene 
FADS2 
Fatty Acid Desaturase 2 Gene 
FAS 
Full Analysis Set 
GA 
Gestational Age 
GGT 
Gamma-Glutamyl Transferase 
hCG 
Human Chorionic Gonadotropin 
Hct 
Hematocrit 
Hgb 
Hemoglobin 
ICF 
Informed Consent Form 
ILE 
Intravenous Lipid Emulsion 
IVH 
Intraventricular Hemorrhage 
IWRS 
Interactive Web Response System 
K 
Potassium 
LA 
Linoleic acid 


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MCH 
Mean Corpuscular Hemoglobin 
MCHC 
MCH Concentration 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Magnesium 
MPV 
Mean Platelet Volume 
Na 
Sodium 
NEC 
Necrotizing Enterocolitis 
P 
Phosphorus 
PN 
Parenteral Nutrition 
PNALD 
Parenteral Nutrition-Associated Liver Disease 
PPS 
Per Protocol Set 
PT 
Preferred Term 
PVL 
Periventricular Leukomalacia 
Q1 
First Quartile 
Q3 
Third Quartile 
RBC 
Red Blood Cells 
ROP 
Retinopathy of Prematurity 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDS 
Standard Deviation Score 
SDTM 
Study Data Tabulation Models 
SNPs 
Single Nucleotide Polymorphisms 
SOC 
System Organ Class 
SS 
Safety Set 
TB 
Total Bilirubin 
TEAE 
Treatment Emergent Adverse Event 
TLFs 
Tables, Listings, and Figures 
ULN 
Upper Limit of Normal 
USPI 
United States Prescribing Information 
WBC 
White Blood Cells 
WHO 
World Health Organization 
 


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1. STUDY DETAILS 
This statistical analysis plan (SAP) is provided to describe the framework for the 
reporting, summarization, and statistical analysis methodology of the safety and efficacy 
parameters measured throughout the study. It is based on clinical trial protocol 6344-001 
amendment version 5.6, dated 22 Feb 2022. 
1.1 Study Objectives and Endpoints 
1.2 Primary Objective 
The primary objective of this study is to evaluate the risk of developing essential fatty 
acid deficiency (EFAD) in pediatric patients, including neonates, receiving either 
Clinolipid or standard-of-care 100% soybean oil-based intravenous lipid emulsion (ILE: 
Intralipid) as a component of parenteral nutrition (PN) within the hospital setting from 7 
up to 90 days. 
Complete fatty acid (FA) profile will be regularly assessed and EFAD will be defined 
using a Holman Index (plasma triene:tetraene ratio, specifically 5,8,11-eicosatrienoic acid 
[mead acid] to 5,8,11,14 eicosatetraenoic acid [arachidonic acid, ARA] ratio) value of 
>0.4 in the context of low linoleic acid (LA), low ARA, and high eicosatrienoic acid. 
Genetic polymorphisms in the fatty acid desaturase 1 gene (FADS1) and fatty acid 
desaturase 2 gene (FADS2) will also be assessed in a subset of patients (approximately 
20%) through Familial Mutation Targeted Testing and the distribution of the 
polymorphisms will be assessed in the context of the FA profile as the synthesis of 
gamma-LA and ARA from LA (n-6 pathway) and the synthesis of stearidonic acid, 
eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from ALA (n-3 pathway) 
require both the delta-5 and delta-6 desaturase enzymes (coded for by FADS1 and 
FADS2 genes). Genetic material will be obtained from buccal smears in all patients with 
consent to analysis of FADS1 and FADS2 polymorphisms. From the subset of patients 
consenting to genetic analysis, the 10 patients (5 Intralipid and 5 Clinolipid) with the 
lowest levels of ARA at any point during the study and the 10 patients (5 Intralipid and 5 
Clinolipid) with the highest levels of ARA at any point during the study will be selected 
for analysis of single nucleotide polymorphisms (SNPs) within FADS1 and FADS2 
genes. 
1.3 Secondary Objective(s) 
The secondary objectives in patients receiving either Clinolipid or Intralipid are to 
evaluate:  


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 The risk of developing liver disease including parenteral nutrition-associated liver 
disease (PNALD): 
- 
PNALD will be defined by direct bi
 mg/dL when no other etiology 
for liver dysfunction is present; 
- 
Hepatic integrity will be assessed by measuring plasma liver function tests: 
alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), gamma-glutamyl transferase (GGT), and total and 
direct bilirubin; 
- 
Plasma main phytosterols (stigmasterol, campesterol, sitosterol), cholesterol 
and squalene levels will be assessed. Phytosterols levels will be correlated 
with the risk of developing PNALD. 
 The adequacy of nutritional interventions: 
- 
Prescribed and actual nutritional intakes (energy, protein, carbohydrates, and 
lipid) from both PN and enteral/oral nutrition will be collected and recorded 
on a daily basis and summarized on a daily basis during the first 2 weeks of 
treatment and on an approximately 15-day basis afterwards up to the end of 
study treatment in each of the treatment groups. 
- 
Growth will be assessed and evaluated from baseline to end of study treatment 
on an approximately every 15-day basis using descriptive summary statistics 
for weight, and height/length (and head circumference in infant <1 year) in 
each of the treatment groups as follows: 
 Gain in weight (g/kg/day in infants <1 year of age, g/day in children and 
adolescents) and gain in length/height (mm/week in all) and head 
circumference (mm/week in infants <1 year); 
 Changes in the standard deviation score (SDS or z-score) from reference 
growth curves (Fenton growth curve for premature infants, World Health 
Organization (WHO) growth standards for infants and children ages 0 to 
2 years, or Center for Disease Control (CDC) growth charts for children 
 years). 
 The safety profiles of Clinolipid and Intralipid, as assessed by adverse events 
(AEs), serious adverse events (SAEs) and AEs of special interest (AESIs) 
- 
AESIs are known AEs related to PN with Intravenous Lipid Emulsions 
(ILEs), per Intralipid and Clinolipid United States Prescribing Information 


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(USPI) and include the following: catheter related infection, thrombophlebitis; 
EFAD as well as ILE-related Immediate or Early adverse reactions including: 
dyspnea, cyanosis, allergic reactions, hyperlipemia, hypercoagulability, 
nausea, vomiting, headache, flushing, increase in temperature, sweating, 
sleepiness, pain in the chest and back, slight pressure over the eyes, dizziness, 
irritation at the site of infusion, and ILE-related delayed adverse reactions 
including: hepatomegaly, jaundice, splenomegaly, thrombocytopenia, 
leukopenia, transient increases in liver function tests, and overloading 
syndrome (focal seizures, fever, leukocytosis, hepatomegaly, splenomegaly 
and shock). 
 
1.4 Study Design 
1.4.1 Overall Study Design and Plan 
This is a multi-center, randomized, double-blind, controlled, safety and efficacy study to 
evaluate the occurrence of EFAD (diagnosed by Holman Index >0.4) in pediatric patients 
receiving either Clinolipid or standard-of-care soybean oil-based ILE (Intralipid) in the 
hospital setting from 7 up to 90 days as part of PN. The risk of developing liver disease, 
including PNALD (defined by 
 mg/dL) when no other etiology for liver 
dysfunction is present, also will be assessed. 
Approximately 100 pediatric patients, including neonates, will participate in the study. 
Patients will be randomized in a 1:1 ratio to the treatment groups (Clinolipid or Intralipid) 
according to a central dynamic randomization scheme stratified by site and age group 
(premature infants born <37 weeks of gestation, full-
gestation to <1 month of age, infants 1 to <12 months of age, children 1 to <10 years of 
age, adolescent 10 to <18 years of age).  In the case of multiple birth pregnancies, the 
infants will be assigned to the same treatment group.  
Holman Index and FA profile will be evaluated. Select polymorphisms in the FA 
desaturase genes FADS1 and FADS2, will be determined in a subset of patients. The 
major plasma phytosterols found in the ILEs (stigmasterol, campesterol, sitosterol), 
cholesterol, and squalene will also be assessed. 
The study consists of a Screening Pe
after the informed consent form (ICF) and assent (if applicable) is signed and a Treatment 
Period, where study Day 1 is defined as the first day the patient receives study treatment. 


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End of study treatment is defined as the last day of PN with Intralipid or Clinolipid; 
maximum 90 days of study treatment is allowed. 
1.4.2 Determination of Sample Size 
The sample size of 100 patients (50 in each of the 2 treatment groups: Clinolipid vs 
Intralipid), including neonates, is based on the feasibility of timely enrollment of patients 
for generating reference data and summary descriptive statistics, rather than on a formal 
power calculation. No formal hypothesis testing is planned.  
1.4.3 Randomization Procedure  
Approximately 100 pediatric patients, including neonates, will participate in the study. 
Patients will be randomized in a 1:1 ratio to the treatment groups (Clinolipid or Intralipid) 
according to a central dynamic randomization scheme stratified by site and age group 
(premature infants born <37 weeks of gestation, full-
gestation to <1 month of age, infants 1 to <12 months of age, children 1 to <10 years of 
age, adolescent 10 to <18 years of age).  In the case of multiple birth pregnancies, the 
infants will be assigned to the same treatment group. 
For this study, a patient should be randomized within 24 hours of signing informed 
consent, when possible, but must be randomized within 3 days of signing informed 
consent. See randomization plan for more details.  
1.4.4 Blinding  
This is a double blinded study and most study roles will be blinded except the unblinded 
statistician, unblinded clinical project manager, clinical supplies manager and unblinded 
CRA. The pharmacist(s) involved in the study medication preparation will also be 
unblinded. 
The dynamic randomization will be built using Prancer software and no end user will 
have direct access to the patient level randomization codes. The statistician that reviews 
the randomization scheme via simulations will not have any access to the patient level 
randomization codes and therefore will remain blinded.  
Planned unblinding of the study will take place for the Data Safety and Monitoring Board 
(DSMB) meetings and all unblinding activities are outsourced to a secondary team at the 
Contract Research Organization (CRO). See DSMB Charter for more details.  
Dry runs of SDTM/ADaM data and tables, listings, and figures (TLFs) will be conducted 
in a blinded manner. 








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1.5 Analysis Populations  
Three main analysis sets are defined for this study. 
1.5.1 Definition of Analysis Populations 
Full analysis set (FAS): all patients who are randomized to receive either Clinolipid or 
standard of care soybean oil-based lipid emulsion (Intralipid) and have received at least 
one randomized study treatment.  This dataset will follow the intent-to-treat principle and 
will analyze patients by planned randomized arm. 
Per protocol set (PPS):  all patients in the FAS who have Holman Index measurements 
taken at baseline and at least 1 other timepoint post-baseline, who have received a 
minimum of 7 days of ILE treatment, and are without a major protocol violation (i.e. 
violation that potentially impacts the primary endpoint).   
Deviations that could be considered for exclusion in a PP analysis 
 Randomization or treatment errors 
 Investigational product not handled properly  
 Key exclusion criteria such as: 
o Patients with liver disease including cholestasis 
o Patients with severe hyperlipidemia or severe disorders of lipid 
metabolism  
o Patients who are unable to tolerate necessary laboratory monitoring 
o Patient requires or is expected to require propofol for sedation  
 
Deviations that should not lead to exclusion of data in a PP analysis 
 Patients who violate inclusion/exclusion criteria relating to patient safety 
 Missed informed consent signature/date 
 Any deviation that does not directly impact the primary endpoint 
Safety analysis set (SS): the set of all patients who have been administered study 
treatment (Clinolipid or Intralipid).  Patients will be analyzed according to treatment 
received.  


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1.5.2 Protocol Deviations 
Protocol deviations will be summarized for all patients in the FAS pooled together. 
Patient counts will be presented for minor protocol deviations, major protocol deviations, 
and for each category of major protocol deviation. 
Protocol deviations will also be listed for the FAS. The listing will include patient id, age, 
randomized treatment, verbatim description of the protocol deviation, the assigned 
category of protocol deviation, major/minor status and whether the protocol deviation 
was determined to be exclusionary for PPS. 
1.6 Endpoints 
1.6.1 Primary Endpoint 
 Risk of EFAD.  EFAD will be defined using the Holman Index value of >0.4. 
Supportive of the primary endpoint 
 Time to developing EFAD 
 The Holman Index 
 Fatty acid (FA) profiles 
 Genetic polymorphisms in FADS1 and FADS2 genes 
 
1.6.2 Secondary Endpoints 
The secondary objectives in patients receiving either Clinolipid or Intralipid are to 
evaluate:  
 The risk of developing liver disease including PNALD: 
- 
PNALD will be 
 mg/dL when no other etiology 
for liver dysfunction is present; 
- 
Hepatic integrity will be assessed by measuring plasma liver function tests: 
alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), gamma-glutamyl transferase (GGT), and total and 
direct bilirubin; 
- 
Plasma main phytosterols (stigmasterol, campesterol, sitosterol), cholesterol 
and squalene levels will be assessed. Phytosterols levels will be correlated 
with the risk of developing PNALD. 
 The adequacy of nutritional interventions: 


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- 
Prescribed and actual nutritional intakes (energy, protein, carbohydrates, and 
lipid) from both PN and enteral/oral nutrition will be collected and recorded 
on a daily basis and summarized on a daily basis during the first 2 weeks of 
treatment and on an approximately 15-day basis afterwards up to the end of 
study treatment in each of the treatment groups.  
- 
Growth will be assessed and evaluated from baseline to end of study treatment 
on an approximately every 15-day basis using descriptive summary statistics 
for weight, and height/length (and head circumference in infant <1 year) in 
each of the treatment groups as follows: 
 Gain in weight (g/kg/day in infants <1 year of age, g/day in children and 
adolescents) and gain in length/height (mm/week in all) and head 
circumference (mm/week in infants <1 year); 
 Changes in the standard deviation score (SDS or z-score) from reference 
growth curves (Fenton growth curve for premature infants, World Health 
Organization (WHO) growth standards for infants and children ages 0 to 
2 years, or Center for Disease Control (CDC) growth charts for children 
 years). 
 The safety profiles as evaluated by: 
 Adverse events (AEs) 
 Serious adverse events (SAEs) 
 Adverse events of special interest (AESIs)  
 AESIs are known AEs related to PN with ILEs, per Intralipid and 
Clinolipid United States Prescribing Information (USPI) and include 
the following: catheter related infection, thrombophlebitis; EFAD as 
well as ILE-related Immediate or Early adverse reactions including: 
dyspnea, cyanosis, allergic reactions, hyperlipemia, 
hypercoagulability, nausea, vomiting, headache, flushing, increase in 
temperature, sweating, sleepiness, pain in the chest and back, slight 
pressure over the eyes, dizziness, irritation at the site of infusion, and 
ILE-related delayed adverse reactions including: hepatomegaly, 
jaundice, splenomegaly, thrombocytopenia, leukopenia, transient 
increases in liver function tests, and overloading syndrome (focal 
seizures, fever, leukocytosis, hepatomegaly, splenomegaly and shock). 




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2. ANALYSIS METHODS 
2.1 General Principles  
Unless otherwise specified, summary statistics (n, mean, standard deviation [SD], 
median, minimum, and maximum values) will be presented for continuous variables. 
Counts and, if relevant, percentages will be presented for categorical variables.   
Unless otherwise specified, data listings will include patient ID, treatment group, sex, age 
at screening (given in months) and baseline weight. 
Unless otherwise noted, all analyses will be performed using SAS/Graph® 9.4 software, 
SAS/STAT® 15.1 software, and Base SAS® 9.4. Copyright © 2016, SAS Institute Inc. 
SAS and all other SAS Institute Inc. product or service names are registered trademarks 
or trademarks of SAS Institute Inc., Cary, NC, USA. All Rights Reserved 
Except for height, weight, head circumference, or otherwise specified, the estimated 
mean, Q1, median, and Q3 for a set of values will be displayed to 1 more significant digit 
than the original values, standard deviations will be displayed to 2 more significant digits, 
and minimum and maximum values will be displayed with the same number of 
significant digits as the original values.  If an original value has more than 2 decimal 
places, the significant digits will be counted as if there are 2 decimal places.  All 
percentages will be displayed with 1 decimal place unless more decimal places are 
needed to show 1 significant digit (i.e. a percentage of 0.01 will be shown as 0.01 as 
opposed to 0.0).  For height, weight, and head circumference, up to 4 reported decimals 
are shown.  
Unless otherwise specified, age group will be defined and stratified as follows:  Pre-Term 
Neonate (24 weeks to <37 weeks), Full Term Neonate ( 37 weeks to <1 month), Infant 
( 1 month to <12 months), Child ( 1 year to <10 years), and Adolescent ( 10 years to 
<18 years) 
Unless otherwise spec
Low (1500-2499 g), Very Low (1000-1499 g), and Extremely Low (<1000 g).  
2.1.1 Definition of baseline 
Unless otherwise specified, baseline is defined as the values collected at the baseline 
visit. The value closest to the start of treatment will be used for baseline if multiple 
values (e.g. laboratory re-tests) are available. If the value at baseline is missing, then the 
value at the screening visit will be used as baseline.  


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Any medical condition that is present at the time that a participant is screened will be 
considered baseline medical history and will not be reported as an adverse event. 
Change from baseline variables will be calculated as the post-treatment value minus the 
value at baseline.  
2.1.2 Visit Windows 
The study visits can be obtained from the eCRF and need not be derived 
programmatically. The visits will be displayed as: Screening, Day 1 (Baseline), Day 2, 
Day 14, Day 15, Day 30, Day 45, Day 60, Day 75, Day 90/End of treatment (EOT).   
Results from unscheduled visits will not be included in table summaries.  These values 
will only be presented in the listings. 
2.1.3 Completion and Discontinuation  
A patient is considered to have completed the study when he/she ceases active 
participation in the study because the patient has, or is presumed to have, completed all 
study procedures according with the protocol (with or without protocol deviations). Any 
other cases are classified as discontinuation.  
Reasons for early termination will be reported on the Completion/Discontinuation 
electronic case report form (eCRF), including:  
 Adverse Event 
 Clinically significant change in laboratory parameter 
 Protocol violation 
 Pregnancy 
 Patient or any legal representative requests to withdraw from the study 
 Sponsor or Investigator terminates study 
 Other 
Regardless of the reason, all data available for the patient up to the time of 
completion/discontinuation should be recorded on the appropriate eCRF. 
2.2 Patient Disposition  
Patient disposition will be summarized by treatment group and will include: 
 Number of patients who signed informed consent (enrolled) 


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 Number of patients who screen fail.  These patients will also be summarized by 
primary reason for screen failure from the study. The percentage associated with 
each reason will have the total number of patients who screen fail as the 
denominator.  
 Number of patients eligible for randomization. This will be calculated by taking 
the number enrolled minus the number of screen failures. 
 Number of patients randomized 
 Number of patients treated with study treatment (SS) 
 Number of patients in the FAS 
 Number of patients in the PPS. Patients included in the FAS but excluded from 
the PPS will be summarized by reason for removal (missing Holman Index 
measurement at baseline and/or one other timepoint, did not receive a minimum 
of 7 days of ILE treatment, or protocol deviation). The denominator for the 
percentage will be based off of the total number of patients excluded.  
 Number of patients who completed the study in the FAS 
 Number of patients who discontinued (withdrew early) from the study in the FAS. 
These patients will also be summarized by primary reason for withdrawal from 
the study. The percentages associated with each reason for early withdrawal will 
have the total number of patients who withdrew early as the denominator. 
A listing of all patients enrolled in the study will be created including patient ID, age (in 
months), sex, treatment group, whether the patient is in each of the analyses sets, 
completion status, reason for discontinuation (if applicable), and the number of days that 
the patient remained in the study. The number of days the patient was in the study will be 
calculated using the following:  
 
2.3 Demographics and Other Baseline Characteristics 
Demographics and other baseline characteristics will be summarized descriptively by 
treatment group for the FAS population. Listings will also be provided for this 
population.  
2.3.1 Demographics 
Demographics including sex, race, and ethnicity will be summarized descriptively by 
treatment group. Age will be summarized by age group and treatment as follows: Pre-


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Term Neonate (GA in weeks, age at consent in days), Full Term Neonate (GA in weeks 
and days, age at consent in days), Infant (age at consent in months), Child (age at consent 
in years), Adolescent (age at consent in years).  Diagnosis for PN will also be included in 
this summary.  
To calculate gestational age, gestational age (weeks) will be added to gestational age 
(days)/7 to get the gestational age in weeks.  
2.3.2 Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and summarized by treatment group.  Medical history will also be listed. 
2.3.3 Prior and Concomitant Medications (Mother and Child) 
Prior and concomitant medications for both mother and child will be summarized using 
WHODrug Anatomical Therapeutic Chemical (ATC) class level 4 and PT by treatment 
group.  A listing will also be prepared.  
2.3.4 Concomitant Procedures 
Concomitant procedures will be listed only.   
2.3.5 Other Baseline Characteristics 
Baseline characteristics will be summarized descriptively by treatment group and 
stratified by age groups: a. Pre-Term Neonate, b. Full Term Neonate, c. Infant, d. Child, 
e. Adolescent as follows: 
 length (a and b) height (c, d, e) 
 head circumference (a, b, c) 
 weight (a, b, c, d, e) 
 body mass index (d and e) 
 birth weight (a and b) 
2.4 Endpoint Analyses 
2.4.1 Primary Endpoint 
The primary efficacy analysis will be carried out on the FAS with a supportive analysis 
performed on the PPS.  


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2.4.1.1 Derivation of Primary Endpoint  
The primary endpoint is the incidence of EFAD which is defined in the protocol and will 
be derived based on the Holman Index (Triene/Tetraene Ratio) provided by the central 
laboratory. 
 Holman Index <0.2: normal EFA 
 Holman Index 0.2  0.4: at risk for EFAD 
 Holman Index >0.4: EFAD 
of 0.2  0.4 at any timepoint during the study treatment.  
A patient will be considered as 
if they have a Holman 
Index >0.4 at any timepoint during the study treatment.   
For time to EFAD Kaplan Meier analyses, the index time will be the start of treatment.  
The first incident of EFAD will be considered the event and will use the date of EFAD 
(date first lab with Holman Index >0.4 reported).   Patients will be censored if they do not 
develop EFAD during their follow-up or if they die before developing EFAD at the time 
of their last Holman Index laboratory measurement.  Time to EFAD will be calculated for 
each patient who develops EFAD as follows and standardized to days: 
 
The incidence rate of EFAD (events per 100 patient days) will be calculated as the 
following per treatment group: 
 
The total number of patient days will be calculated per treatment group as follows: 
 
Where n is the total number of patients per treatment group.  If a patient develops EFAD, 
then the date of first EFAD occurrence will be used, and if they do not, then end date of 
treatment will be used.  If more than one instance of EFAD occurs, the patient will be 
counted once and the date of first occurrence will be used.  This will then be standardized 
to days.  


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2.4.1.2 Analysis of Primary Endpoint  
Holman index scores will be summarized descriptively by timepoint per treatment group 
using n, mean, standard deviation, minimum, Q1, median, Q3, and maximum.   
The frequency and percentage of patients at risk of developing EFAD (Holman Index 
0.2-0.4) as well as those who developed EFAD (Holman Index >0.4) will be summarized 
by timepoint and at the maximum by treatment group.  The denominator for the 
percentage of patients will be the number of patients in the population who had at least 
one post-baseline Holman Index measurement available.   The incidence rate (per 100 
patient days) of EFAD will also be calculated per treatment group.  
If there are more than 5 cases of EFAD per arm, then time to develop EFAD will be 
analyzed using survival analysis approach (cumulative incidence), and the mean, standard 
error, Q1, median, Q3, minimum, and maximum for each treatment group will be 
displayed, where calculable.  A cumulative incidence plot will also be produced.  If there 
are less than 5 cases of EFAD in each treatment arm, then time to developing EFAD will 
be summarized descriptively by treatment group using n, mean, standard deviation, 
minimum, Q1, median, Q3, and maximum.  If no events occur, then time to EFAD will 
not be calculated.   
A spaghetti plot consisting of Holman index values over time will be produced with one 
line representing each patient, and different types of lines or symbols (e.g. solid and 
dashed) representing each treatment group.  Two bolded lines will be added at y=0.2 and 
y=0.4 to represent the bounds for being at risk of EFAD and developing EFAD.   
As a supportive analysis to the primary endpoint, the following will be analyzed: 
 FA profiles will be summarized using descriptive statistics (number of patients, 
mean, standard deviation, median, minimum, and maximum) in each of the 
2 treatment groups (Clinolipid vs Intralipid), as well as descriptive statistics of 
genetic polymorphisms in the FADS1 and FADS2 genes for the patients with 
buccal swabs with the 5 highest and 5 lowest arachidonic acid values in each 
treatment group. 
2.4.1.3 Sensitivity Analysis of Primary Endpoint  
A sensitivity analysis of the primary endpoint may be done looking at patients who 
received SMOF vs Intralipid as pre-randomization lipids.  If less than ten patients 
received SMOF pre-randomization, then this sensitivity analysis will not be done.   


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2.4.2 Secondary Endpoints 
All secondary endpoints will be performed on the FAS.   
2.4.2.1 Liver Disease, Including Parenteral-Associated Liver Disease 
2.4.2.2 Parenteral Nutrition-Associated Liver Disease (PNALD) 
2.4.2.2.1 Derivation of PNALD 
PNALD will be determined 
mg/dL at any 
timepoint in the study.   
Time to PNALD will be derived using the start of treatment as the index date and the date 
of developing PNALD as the event date.  It will be calculated for each patient as follows 
(standardized to the number of days):  
 
Patients will be censored at the time of their last lab value if they do not develop PNALD.  
Each patient will have their person time (or total exposure to potentially develop 
PNALD) calculated 
as: 
 
If a patient develops PNALD, then date of first occurrence of PNALD will be used.  If a 
patient does not develop PNALD, then end date of treatment will be used.  If a patient 
has more than 1 lab indicating PNALD, they will only be counted once at the date of their 
first instance.  For incidence rate calculations, the total person time per group will be the 
sum of all 
 
 
2.4.2.2.2 Analysis of PNALD 
PNALD will be summarized at each visit as well as at the post-baseline maximal value 
 by treatment group using 
frequencies and percentages.   
If there are more than 5 cases of PNALD per arm, then time to develop PNALD will be 
analyzed using survival analysis approach (cumulative incidence), and the mean, standard 
error, Q1, median, Q3, minimum, and maximum for each treatment group will be 


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displayed, where calculable.  A cumulative incidence plot will also be produced.  If there 
are less than 5 cases of PNALD in each treatment arm, then time to developing PNALD 
will be summarized descriptively by treatment group for all patients developing PNALD 
using n, mean, standard deviation, minimum, Q1, median, Q3, and maximum.  If no 
events occur, then time to PNALD will not be calculated.   
The incidence rate of PNALD will be computed and displayed per treatment group.  The 
proportion of PNALD will be summarized per treatment group as the number of patients 
who develop PNALD divided by the corresponding total number of patients in each 
group. 
A spaghetti plot consisting of direct bilirubin values over time will be produced with one 
line representing each patient, and different types of lines or symbols (e.g. solid and 
dashed) representing each treatment group.  A bolded line will be added at y=2 to 
represent the bound for PNALD.   
2.4.2.3 Hepatic Integrity 
Hepatic integrity (ALP, AST, ALT, GGT, total and direct bilirubin) will be evaluated by 
presenting descriptive summary statistics (number of patients, mean, standard deviation, 
Q1, median, Q3, minimum, and maximum) at different measurement time points from 
baseline to end of study treatment during the study period in each of the 2 treatment 
groups (Clinolipid vs Intralipid). Change from baseline will also be summarized.  
Each hepatic integrity parameter will also be summarized in shift tables comparing end of 
study treatment and post-baseline maximal values during the study intervention with 
those at baseline.  Shift categories will include normal and abnormal (>1 to 3 and >3-fold 
the upper limit of normal range).  If a patient is below the normal range, they will be 
 
The delay (days) between baseline and post-baseline maximal value in each of the 
2 treatment groups (Clinolipid vs Intralipid) will also be summarized using n, mean, 
standard deviation, minimum, Q1, median, Q3, and maximum.  Days between baseline 
and post-baseline maximal value will be calculated by the following: 
 
If there are two instances of the same maximal value post-baseline, then the first instance 
of the maximal value will be used as the date of maximal lab value.  


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In addition, assessment for drug-induced liver injury (DILI) will be conducted according 
,1,2.  This will be assessed using two scatterplots in the 
log log scale between the peak aminotransferase (AT) levels (x upper limit normal 
(ULN)) and peak total bilirubin (TB) level (xULN) per patient.  The two ATs that will be 
used are AST and ALT.  
for the normal range as well as y=3 and x
(when peak AT > 3xULN and peak TB >2xULN).  To calculate peak AT/TB x ULN,  
 
Different symbols will be used per treatment group.  
the time course of all liver tests (ALT, 
AST, ALP, and TB) will be shown per patient (one graph per patient 
criteria).  The y axis will be the test values x ULN on the log scale, and the x axis will be 
the time from start of treatment.    
2.4.2.4 Plasma Phytosterols, Cholesterol, and Squalene Levels 
Plasma phytosterols (stigmasterol, campesterol, and sitosterol), cholesterol, and squalene 
levels will be summarized using descriptive statistics (mean, standard deviation, Q1, 
median, Q3, minimum, and maximum) at baseline and the end of study treatment, as well 
as post-baseline maximal value during the study and the delay (days) between study 
baseline and post-baseline maximal value in each of the 2 treatment groups (Clinolipid vs 
Intralipid). In addition, the correlation between plasma phytosterol levels and direct 
Spearman correlation coefficient depending on whether the normality assumption is 
fulfilled.  Normality will be assessed visually with a QQ plot.  Values will be paired by 
patient and visit.  A scatterplot of plasma phytosterol and direct bilirubin values will also 
be produced with different symbols for each of the two different treatment groups.  
2.4.3 Adequacy of Nutritional Interventions  
Prescribed (ordered) and actual (administered) nutritional intake (fluid, energy, protein, 
carbohydrates, and lipids) from parenteral, enteral nutrition, and IV fluids will be 
collected and recorded daily. They will be summarized descriptively on a daily basis 
during the first 2 weeks of treatment and on a 15-day basis afterwards up to end of study 
treatment for each of the treatment groups.  Summaries of overall nutritional intake will 
also be done.  Box plots will also be produced by day and treatment group.   


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2.4.3.1 Parenteral Nutritional Intake 
Data from parental nutrition will be calculated as follows: 
Fluid intake ordered (mL/kg/24 hours):  
 
Fluid intake administered (mL/kg/24 hours):  
 
Energy intake ordered (kCal/kg/24 hours):  
Total calories (kCal) should first be calculated as3:  
 
 
Then energy intake can be calculated as: 
 
Energy intake administered (kCal/kg/24 hours):  
 
Protein intake ordered (g/kg/24 hours): 
 
Protein intake administered (g/kg/24 hours): 
 


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Carbohydrate intake ordered (g/kg/24 hours): 
 
Carbohydrate intake administered (g/kg/24 hours): 
 
Lipid intake ordered (g/kg/24 hours):  
 
Lipid intake administered (g/kg/24 hours):  
 
If lipid dosing weight is missing, PN dosing weight will be used instead.  If both are 
missing, the recorded weight on the closest, prior non-missing day will be used.  
2.4.3.2 Enteral Nutritional Intake 
Nutrition from formula, breast milk, nutritional shakes, fortifiers, MCT oil, and other 
enteral intakes are recorded on the CRF.  The below data will be calculated and 
summarized by treatment group.  Similarly, all enteral nutrition given on each day will be 
added together and summarized by treatment group. If weight on that day is missing, then 
the weight from the prior non-missing day will be used.  If the patient had multiple 
records of the same intake (i.e. 2 different records of breastmilk with no fortifier) on the 
same day, then the records should be summed together to get the total in a 24 hour 
period.  All units presented below for intake are in mL. If data is given in ounces, 
multiply the amount of ounces by 29.57 to get mL. 
Breastmilk or formula (no additive or fortifier): 
Fluid intake ordered (mL/kg/24 hours):  


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If total volume ordered is recorded in ml/3 hours, then the amount should be multiplied 
by 8 to find the total volume ordered in mL per 24 hours.  If total volume ordered is 
recorded in ml/2 hours, then the amount should be multiplied by 12.  
Fluid intake administered (mL/kg/24 hours):  
 
Energy intake ordered (kCal/kg/24 hours):  
 
Energy intake administered (kCal/kg/24 hours):  
 
Protein intake ordered (g/kg/24 hours): 
 
Protein intake administered (g/kg/24 hours): 
 
Carbohydrate intake ordered (g/kg/24 hours): 
 
Carbohydrate intake administered (g/kg/24 hours): 
 


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Lipid intake ordered (g/kg/24 hours):  
 
Lipid intake administered (g/kg/24 hours):  
 
Table 2. Conversion Factors 
Enteral Nutrition Type 
Protein 
Carbohydrate 
Lipid 
Breastmilk4 
0.012 g/mL 
0.074 g/mL 
0.036 g/mL 
Formula: Alfamino5  
0.019 g/mL 
0.074 g/mL 
0.034 g/mL 
Formula: Alfamino Junior6 
0.033 g/mL 
0.122 g/mL 
0.044 g/mL 
Formula: Enfamil 
Neuropro7 
0.014 g/mL 
0.076 g/mL 
0.036 g/mL 
Formula: Pregestimil8
0.019 g/mL 
0.069 g/mL 
0.038 g/mL 
Formula: Similac Special 
Care9 
0.024 g/mL 
0.083 g/mL 
0.044 g/mL 
Formula: Similac Neosure10 
0.021 g/mL 
0.075 g/mL 
0.041 g/mL 
Formula: Kate Farms 
Pediatric Peptide 1.511 
0.052 g/mL 
0.16 g/mL 
0.068 g/mL 
Other: Pedialyte12 
0 g/mL 
0.028 g/mL 
0 g/mL 
Breastmilk or formula (with additive or fortifier): The amount of additive/fortifier 
received will need to be calculated and used in the formulas.  It can be calculated as: 
 
Fluid intake ordered (mL/kg/24 hours):  
 
If total volume ordered is recorded in ml/3 hours, then the amount should be multiplied 
by 8 to find the total volume ordered in mL per 24 hours.  If total volume ordered is 
recorded in ml/2 hours, then the amount should be multiplied by 12.  
Fluid intake administered (mL/kg/24 hours):  


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Energy intake ordered (kCal/kg/24 hours):  
 
Energy intake administered (kCal/kg/24 hours):  
 
Protein intake ordered (g/kg/24 hours): 
 
Protein intake administered (g/kg/24 hours): 
 
Carbohydrate intake ordered (g/kg/24 hours): 
 
Carbohydrate intake administered (g/kg/24 hours): 
 
Lipid intake ordered (g/kg/24 hours):  
 
Lipid intake administered (g/kg/24 hours):  
 


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Table 3. Additive and Human Milk Fortifier (HMF) Conversions 
Additive/Fortifier  
Protein 
Carbohydrate Lipid 
Enfamil liquid HMF13
0.084 g/mL 
0.056 g/mL 
0.116 g/mL 
Similac HMF Concentrated Liquid14 
0.07 g/mL 
0.162 g/mL 
0.054 g/mL 
ASimilac Hydrolyzed HMF15 
0.5 g/packet 
0.75 g/packet 0.21 g/packet 
Similac Neosure Powder16 
0.021 g/mL 
0.075 g/mL 
0.041 g/mL 
Pregestimil Powder8
0.019 g/mL 
0.069 g/mL 
0.038 g/mL 
Prolacta +417
0.06 g/mL 
0.095 g/mL 
0.095 g/mL 
ASimilac HMF Powder18
0.25 g/packet 
0.45 g/packet 0.09 g/packet  
ANeocate Infant Powder19
0.135 g/g 
0.52 g/g 
0.245 g/g 
AFor all additives given as powder (g or packets), the volume of this additive is assumed 
to be 0 for fluid intake calculations.    
2.4.3.3 Intravenous Fluid Nutritional Intake 
Only fluid intake administered, energy intake administered, and carbohydrate intake 
administered will be calculated for intravenous fluid intake as protein and lipid intake are 
0 g/mL.  These will be calculated as follows: 
Fluid intake administered (mL/kg/24 hours): 
 
Energy intake administered (kcal/kg/24 hours):  
 
Carbohydrate intake administered (g/kg/24 hours):  
 
2.4.3.4 Overall Nutritional Intake 
Overall nutritional intake (ordered and administered) will be calculated per patient per 
day for fluid intake and energy intake by summing the following: 


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The percentage of PN and EN for fluid and energy intake will be calculated as follows:  
Percentage of PN administered:  
 
Percentage of EN administered: 
 
2.4.3.5 Growth 
Weight at baseline and during treatment will be assessed daily and will be summarized on 
an approximately 15-day basis using descriptive summary statistics in each of the 
treatment groups. 
Length or height (and head circumference for infants <1 year of age) will be assessed and 
summarized at baseline and approximately every 15 days up to end of study treatment 
using descriptive summary statistics (number of patients, mean, standard deviation, 
median, minimum, and maximum in each of the 2 treatment groups (Clinolipid vs 
Intralipid). 
Growth will be assessed and evaluated from baseline to end of study treatment on an 
approximately every 15-day basis using descriptive summary statistics in each of the 
treatment group as follows: 
 Gain in weight over last 15 days (g/kg/day in infants <1 year of age; i.e. the 
change between day 15 and baseline, day 30 and day 15, day 45 and day 30, etc): 
 
 Gain in weight from baseline (g/kg/day in infants <1 year of age):  
 
 Gain in weight over last 15 days (g/day in children and adolescents):  


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 Gain in weight from baseline (g/day in children and adolescents):  
 
 Gain in length/height over last 15 days (mm/week in all): 
 
 Gain in length/height from baseline (mm/week in all): 
 
 Gain in head circumference over last 15 days (mm/week in infants <1 year); 
 
 Gain in head circumference from baseline (mm/week in infants <1 year); 
 
 Changes in the SDS from reference growth curves over last 15 days (Fenton 
growth curve for premature infants19, WHO growth standards20 for infants and 
children ages 0 to 2 years, or CDC growth charts21 
 years):  
 
 Changes in the SDS from reference growth curves from baseline (Fenton growth 
curve for premature infants, WHO growth standards for infants and children ages 
0 to 2 years, or CDC 
 years):  
 
Boxplots will also be given for each of the growth parameters by treatment group.   
2.5 Safety Analyses 
All safety analyses will be performed on the SS.  
2.5.1 Adverse Events  
2.5.1.1 Derivation of Adverse Events 
Adverse events (AEs) will be coded using MedDRA. They will be classified as follows:  
Pre-treatment adverse event  An adverse event that starts between the date of signing 
the informed consent form (ICF) and the study treatment 




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3. Treatment emergent non-serious AEs 
4. Treatment-emergent serious AEs (SAEs)  
5. Treatment-emergent AEs of special interest (AESIs)  
6. Treatment-emergent AEs related to study treatment 
7. Treatment-emergent SAEs related to study treatment 
8. Treatment-emergent AEs leading to death 
Additional listings and tables on the above categories (with the exception of #1) will be 
given by SOC and PT.  Pre-treatment adverse events (those occurring between informed 
consent and treatment) will also be listed. For SAE listings, the seriousness criteria will 
be included in the listing. 
The tables below will display the total number of patients, the percentage of patients (%), 
the number of events, the number of events per 100 patient days, system organ class 
(SOC), and preferred term by treatment group. Table summaries will be produced for: 
 Treatment-emergent AEs by severity 
 Treatment-emergent SAEs by severity 
 Treatment-emergent AEs by relationship to study treatment  
 Treatment-emergent SAEs by relationship to study treatment 
 Treatment-
patients (in either Clinolipid or 
Intralipid group) 
Tables by preferred term and tables by system organ class (SOC) and preferred term will 
be sorted in descending order by the percentage of patients. 
Adverse event listings will be sorted by patient ID and adverse event start date. They will 
include primary AE number, SOC, PT, verbatim term, adverse event start and end date 
and its duration, treatment date, relationship to study treatment, alternate causality, 
severity, action taken, seriousness, outcome, whether the event is ongoing, and whether 
AE led to discontinuation from study.  


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2.5.2 Other Safety Endpoints 
2.5.2.1 Neonatal Morbidities 
Neonatal morbidities at the end of treatment are defined in the eCRF as 
bronchopulmonary dysplasia, retinopathy of prematurity, intraventricular hemorrhage, 
periventricular leukomalacia, necrotizing enterocolitis, and late-onset sepsis. 
Frequencies and percentages of premature infants born <37 weeks of gestation up to 1 
month CA developing neonatal morbidities will be summarized descriptively by 
treatment group. 
2.5.2.2 Derivation of Vital Signs 
Vital signs including heart rate (beats/min), respiratory rate (breaths/min), systolic and 
diastolic blood pressure (mmHg), and body temperature (°C). are collected daily. Change 
from baseline will be calculated for all visits using the formula below: 
 
2.5.2.3 Analysis of Vital Signs 
Vital signs will be summarized descriptively using n, mean, standard deviation, 
minimum, median, and maximum for each visit.  Change from baseline will also be 
summarized descriptively for all post-baseline visits.  
2.5.2.4 Derivation of Laboratory Results 
Laboratory testing (clinical parameters analyzed at local lab) is collected at baseline and 
then as per the SOC for each investigational site and on an approximately 15-day basis. 
Missingness in data is expected since laboratory parameters are collected per SOC and 
laboratory collection listed are optional.  
Any quantitative laboratory parameters that are given as '<xx' or '>xx' in the database will 
be imputed with the absolute value of the number without the sign (e.g., <2.2 will be 
imputed as 2.2) for the calculation of the changes from baseline, the descriptive statistics, 
and shift tables. 
2.5.2.5 Analysis of Laboratory Results 
Laboratory parameters will be summarized descriptively using n, mean, standard 
deviation, minimum, median, and maximum at each visit.  Change from baseline will 
also be provided for all cases where baseline assessments are available.  




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2.5.3 Independent Data Safety Monitoring Board 
There is a DSMB for this study that reviews data at four different time points in the study 
(10%, 50%, and 90% of enrollment).  Refer to the DSMB Charter as well as the DSMB 
SAP for DSMB activities and analyses for the study.   
2.6 Other general principles  
2.6.1 Adjustment for covariates  
There are no adjustments for covariates for any analyses in this study.  
2.6.2 Handling of Dropouts or Missing data 
All data collected up to the point where the patient drops out will be used for analyses.    
Aside from missing weight in the calculation of nutritional intake, no missing data will be 
imputed for this study.   
2.6.3 Multicenter Studies 
This study was conducted in approximately 10 sites across the United States.  Data from 
all sites will be pooled together for analyses.   
2.6.4 Multiple Comparison/Multiplicity 
No formal statistical tests are calculated for this study, so no multiplicity adjustments are 
needed.   
2.6.5 
 
A sensitivity analysis of the primary endpoint will be completed on the per protocol set.  
The PPS (as defined in section 1.5.1) is a subset of the full analysis set.  
2.6.6 Rounding and Decimal Places 
The estimated mean, Q1, median, and Q3 for a set of values will be displayed to 1 more 
significant digit than the original values, standard deviations will be displayed to 2 more 
significant digits, and minimum and maximum values will be displayed with the same 
number of significant digits as the original values.  All percentages will be displayed out 
to 1 decimal place. For height, weight, and head circumference, up to 4 reported decimals 
are shown. 
3. CHANGES FROM ANALYSIS PLANNED IN PROTOCOL  
There are no planned changes in analyses from the protocol.  


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4. REFERENCES 
1. Senior JR. Evolution of the Food and Drug Administration Approach to Liver Safety 
Assessment for New Drugs: Current Status and Challenges. Drug Safety. 2014;37(1):9-
17.  
2. Guidance for industry drug-induced liver injury, premarketing clinical evaluation. 
Rockville, MD: U.S. Dept. of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research; 2009.  
3. Gottslich et al. The A.S.P.E.N. NUTRITION SUPPORT CORE CURRICULUM: 
A CASE-BASED APPROACH
THE ADULT PATIENT. Chapter 15; pg 279 
4. Nommsen LA, Lovelady CA, Heinig MJ, Lonnerdal B, Dewey KG. Determinants of 
energy, protein, lipid, and lactose concentrations in human milk during the first 12 mo of 
lactation: the DARLING Study. The American journal of clinical nutrition. 
1991;53(2):457 465. 
5. Nutritional Information Alfamino. 2022. https://www.alfamino.com/product/alfamino-
infant 
6. Nutritional Information Alfamino Junior Alfamino 2022. 
https://www.alfamino.com/product/alfamino-
junior?gclid=CjwKCAjw6MKXBhA5EiwANWLODKA4cK5AbT1SUQwgWINugM8qs
43lZFpAumU7tXhugnMCPT12GmvaoxoCJE8QAvD_BwE&gclsrc=aw.ds 
7. Enfamil Neuropro Infant Mead Johnson Nutrition. 2022. 
https://www.hcp.meadjohnson.com/s/product/a4R4J000000PpQdUAK/enfamil-
neuropro-infant 
8. Pregestimil Infant Formula Powder Enfamil. 2022. 
https://www.enfamil.com/products/pregestimil-powder-formula/powder-can-1-lb-can/ 
9. Similac Special Care Premature Abbott. 2022. https://abbottstore.com/infant-and-
child/similac/similac-special-care/similac-special-care-24-infant-formula-with-iron-2-fl-
oz-bottle-case-of-48-67446.html 
10. Similac Neosure Infant Powder Similac. 2022. 
https://www.similac.com/products/preemie-formula/neosure-powder/22-8oz-can-
4pack.html 


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11. Kate Farms Pediatric Peptide 1.5 Vanilla Kate Farms. 2022. 
https://www.katefarms.com/for-clinicians/products/pediatric-peptide-1-5-vanilla-formula/ 
12. Pedialyte Classic Unflavored Pedialyte. 2022. 
https://pedialyte.com/products/classic/unflavored 
13. Enfamil Liquid Human Milk Fortifier Standard Protein Mead Johnson. 2022. 
https://www.hcp.meadjohnson.com/s/product/a4R4J000000PpQmUAK/enfamil-liquid-
human-milk-fortifier-standard-protein 
14. Similac Human Milk Fortifier Concentrated Liquid Abbott. 2022. 
https://www.abbottnutrition.com/our-products/similac-human-milk-fortifier-
concentrated-liquid 
15. Similac Human Milk Fortieifer Hydrolyzed Protein Concentrated Liquid Abbott. 
2022. https://www.abbottnutrition.com/our-products/similac-human-milk-fortifier-
hydrolyzed-protein-concentrated-liquid 
16. Nutrition Information Prolacta Bioscience. 2022. 
https://www.prolacta.com/documents/10/nutrition-info.pdf 
17. Similac Human Milk Fortifier Abbott. 2022. https://abbottstore.com/infant-and-
child/similac/similac-human-milk-fortifier-powder/similac-human-
milkfortifierpowder/similac-human-milk-fortifier-powder-0-9-g-packet-50-pack-
54598p50.html 
18. Nutricia Neocate Neocate Infant DHA/ARA. 2022. 
https://www.neocate.com/shop/hypoallergenic-formula-and-products/infant-dha-ara 
19. Chou JH, Roumiantsev S, Singh R. PediTools Electronic Growth Chart Calculators: 
Applications in Clinical Care, Research, and Quality Improvement. J Med Internet Res. 
2020 Jan 30;22(1):e16204. doi: 10.2196/16204. PMID: 32012066; PMCID: 
PMC7058170. 
20. WHO  World Health Organization  Child growth standards. 
https://www.who.int/tools/child-growth-standards/software. 13JUN2022 
21. CDC  National Center for Health Statistics  Clinical Growth Charts. 
https://www.cdc.gov/growthcharts/clinical_charts.htm. 13JUN2022.  




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14.3.1.3.4 
SS 
Serious Treatment Emergent Adverse Events 
by Treatment, SOC, Preferred Term, and 
Relationship to Study Treatment  
14.3.4.1 
SS 
Listing of Abnormal Hematology Values 
14.3.4.2 
SS 
Listing of Abnormal Liver Function Values 
14.3.4.3 
SS 
Listing of Abnormal Serum Chemistry Values 
14.3.4.4 
SS 
Listing of Abnormal Fatty Acid Profile 
Values 
14.3.5.1.1 
FAS 
Primary Endpoint: Essential Fatty Acid 
Deficiency 
14.3.5.1.2 
PPS 
Primary Endpoint: Essential Fatty Acid 
Deficiency 
14.3.5.2.1 
FAS 
Primary Endpoint: Holman Index Values 
14.3.5.2.2 
PPS 
Primary Endpoint: Holman Index Values 
14.3.5.3.1 
FAS 
Primary Endpoint: Time to EFAD 
14.3.5.3.2 
PPS 
Primary Endpoint: Time to EFAD 
14.3.5.4.1 
FAS 
Fatty Acid Profile 
14.3.5.4.2 
PPS 
Fatty Acid Profile 
14.3.5.5.1 
FAS 
Genetic Polymorphism  
14.3.5.5.2 
PPS 
Genetic Polymorphism 
14.3.6.1.1 
FAS 
Parenteral Nutrition-Associated Liver Disease 
14.3.6.2.1 
FAS 
Hepatic Integrity 
14.3.6.2.2 
FAS 
Shift Table of Hepatic Integrity for End of 
Treatment and Maximum Values 
14.3.6.2.3 
FAS 
Hepatic Integrity: Days from Baseline to 
Maximum Value 
14.3.6.3.1 
FAS 
Plasma Phytosterols, Cholesterol, and 
Squalene Levels 
14.3.6.3.2 
FAS 
Plasma Phytosterols Correlation with Direct 
Bilirubin 
14.3.6.4.1 
FAS 
Nutritional Intake from Parenteral Nutrition 
14.3.6.4.2 
FAS 
Nutritional Intake from Enteral Nutrition  
14.3.6.4.3 
FAS 
Nutritional Intake from IV Fluids 
14.3.6.4.4 
FAS 
Overall Nutritional Intake 
 
 
 
14.3.7.1 
SS 
Neonatal Morbidities at End of Treatment 
14.3.8.1 
SS 
Vital Signs Summary and Change from 
Baseline 
14.3.9.1 
SS 
Hematology Summary and Change from 
Baseline 
14.3.9.2 
SS 
Liver Function Test Summary and Change 
from Baseline 
14.3.9.3 
SS 
Serum Chemistry Summary and Change from 
Baseline 


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14.3.10 
SS 
Treatment Exposure 
 
Listing Number 
Analysis 
Population 
Listing Name 
16.2.1 
N/A 
Patient Disposition 
16.2.2 
FAS 
Protocol Deviations 
16.2.3.1 
N/A 
Patients Excluded from Efficacy Analyses 
16.2.4.1 
FAS 
Demographic and Baseline Characteristics  
16.2.4.2.1 
FAS 
Medical History 
16.2.4.2.2 
FAS 
Diagnosis for Parenteral Nutrition 
16.2.4.3.1 
FAS 
Concomitant Medications for Patient  
16.2.4.3.2 
FAS 
Concomitant Medications for Mother 
16.2.4.4 
FAS 
Concomitant Procedures 
16.2.5.1 
SS 
Treatment Exposure 
16.2.6.1 
FAS 
Growth Parameters 
16.2.7.1.1 
SS 
Pre-Treatment Adverse Events 
16.2.7.1.2 
SS 
Treatment Emergent Adverse Events 
16.2.7.1.3 
SS 
Serious Pre-Treatment Adverse Events 
16.2.7.1.4 
SS 
Serious Treatment Emergent Adverse Events 
16.2.7.1.5 
SS 
Treatment Emergent Adverse Events of 
Special Interest 
16.2.7.1.6 
SS 
Treatment Emergent AEs related to study 
treatment 
16.2.7.1.7 
SS 
Serious Treatment Emergent AEs related to 
study treatment 
16.2.7.1.8 
SS 
Treatment Emergent AEs leading to 
withdrawal  
16.2.7.1.9 
SS 
Treatment Emergent AEs leading to death 
16.2.7.2.1 
SS 
Neonatal Morbidities 
16.2.8.1.1 
FAS 
Holman Index Measurements 
16.2.8.1.2 
FAS 
Fatty Acid Profile 
16.2.8.1.3 
FAS 
Genetic Polymorphism 
16.2.8.2.1 
FAS 
Parenteral Nutrition-Associated Liver Disease 
(PNALD) Values 
16.2.8.2.2 
FAS 
Hepatic Integrity Values 
16.2.8.2.3 
FAS 
Drug Induced Liver Injury 
16.2.8.2.4 
FAS 
Plasma Phytosterols, Cholesterol, and 
Squalene Levels 
16.2.8.3.1 
SS 
Hematology Laboratory Values 
16.2.8.3.2 
SS 
Liver Function Test Values 
16.2.8.3.3 
SS 
Serum Chemistry Values 
16.2.9.1 
SS 
Vital Signs 
16.2.10.1 
SS 
Physical Examinations 
16.2.11.1.1 
FAS 
Parenteral Nutrition Intake