Clinical trial NCT02486042
Conditions: Retinopathy of Prematurity
Keywords: ROP Premature infant
Sponsor: University of California, San Diego
Start date: 2014-03-01; Completion date: 2019-12-01
Enrollment: 48 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Retinopathy of prematurity (ROP) is a blinding disease affecting infants born prematurely. These infants do not have enough essential fatty acids to structurally support the retina, the nerve tissue in the eye which allows us to see. A recent study showed that giving omega-3 (n-3) fatty acids to these infants soon after birth made them less likely to need invasive treatments for eye disease. This research trial will give young infants born prematurely n-3 fish oil treatment and look at how this changes factors in the blood that promote disease. Detailed blood studies comparing infants with and without ROP will be performed and the infants will be followed over time to assess their eye development.

Detailed description:
Approximately 517,000 infants are born prematurely every year. As low birth weight and premature infants are surviving longer, they are at risk of developing severe retinopathy of prematurity (ROP).

ROP is a disease of the eye affecting prematurely-born babies. It is thought to be caused by disorganized growth of retinal blood vessels which may result in scarring and retinal detachment. ROP can be mild and may resolve spontaneously, but it may lead to blindness in serious cases. ROP is the leading cause of irreversible childhood blindness in the United States. As such, all preterm babies are at risk for ROP, and very low birth weight is an important risk factor.

Researchers have found that increasing omega-3 fatty acids and decreasing omega-6 fatty acids in the diet of mice with eye disease similar to ROP had reduced areas of blood vessel loss and abnormal blood vessel growth. These findings represent new evidence suggesting the possibility that omega-3 fatty acids act as protective factors in diseases that affect retinal blood vessels.

Omega-3 fatty acids make compounds that protect against the growth of abnormal blood vessels by preventing inflammation.

In two European studies, this treatment decreased the risk of needing laser treatment in the eye for ROP. This study has not yet been repeated in the United States. The purpose of this study is to learn how omega-3 fatty acid supplementation in low birth weight infants changes the blood profile of infants receiving this nutritional treatment.

Infants are enrolled in this study shortly after birth and receive IV and/or oral supplementation until they are full term or the retinal blood vessels have completely developed, shortly after term. Once the treatment is over, these infants will continue to be followed for growth and development of their eyes.

Arms: arm 1: Infants in this group will receive standard lipids (predominantly Omega-6 fatty acids). arm 2: Infants in this group will receive lipid supplementation with omega-3 fatty acids.
Interventions: intervention 1: Omegaven intervention 2: Standard lipids (primarily omega-6 fatty acids)
Intervention descriptions: intervention 1: Infants will receive nutritional supplementation with omega-3 fatty acids (omegaven). intervention 2: Infants will receive nutritional supplementation with standard intralipid, composed primarily of omega-6 fatty acids.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
ROP Omegaven Research Plan 
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Study Title: Omega-3 Long Chain Polyunsaturated Fatty Acid (LCPUFA) Supplementation in Very Low Birth Weight 
Infants for the Prevention of Retinopathy of Prematurity 
 
 
 
NCT Number: NCT02486042 
 
Document Date: Last amended April 22, 2019  
Uploaded September 5, 2022 
 
Document Title: Study Protocol and Statistical Analysis Plan  
Approved by the UC San Diego Institutional Review Board 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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UCSD Human Research Protections Program 
New Biomedical Application 
RESEARCH PLAN INSTRUCTIONS 
These are instructions are for completing the Research Plan that is available in MS Word format from the HRPP website. 
The headings on this set of instructions correspond to the headings of the Research Plan. 
General Instructions: Enter a response in for all topic headings.  
Enter “Not Applicable” rather than leaving an item blank if the item does not apply to this project. 
Version date: 05/11/2011 
 
Protocol Amendment 6 dated April 1, 2016 
1. 
PROJECT TITLE 
Omega-3 LCPUFA Supplementation in Very Low Birth Weight Infants for The Prevention of Retinopathy of 
Prematurity:  Proposal for a Prospective Randomized Controlled Masked Clinical Trial with Lipidomic and 
Transcriptomic Analyses 
 
2. 
PRINCIPAL INVESTIGATOR  
 Shira L. Robbins, M.D.  
 
3. 
FACILITIES 
Neonatal Intensive Care Unit (NICU) at University of California San Diego Medical Center, Hillcrest and Jacobs 
Medical Center 
4. 
ESTIMATED DURATION OF THE STUDY 
5 years 
 
5. 
LAY LANGUAGE SUMMARY OR SYNOPSIS (no more than one paragraph) 
Retinopathy of prematurity (ROP) is a blinding disease affecting infants born prematurely. These infants do not 
have enough essential fatty acids to structurally support the retina, the nerve tissue in the eye which allows us to 
see. A recent study showed that giving omega-3 (n-3) fatty acids to these infants soon after birth made them less 
likely to need invasive treatments for eye disease. We intend to give young infants born prematurely with n-3 
fish oil treatment and look at how this changes factors in the blood that promote disease. We will do detailed 
blood studies comparing infants with and without ROP and will follow these infants over time to assess their eye 
development. 
 
6. 
SPECIFIC AIMS 
The purposes of this study are the following: 
• To differentiate the phospholipid profiles and gene expression pathways of at-risk very low birth weight 
infants with and without treatment with Omegaven® (high n-3 fish oil supplement) 
• To establish whether omega-3 fatty acid supplementation in extremely low birth weight infants will reduce 
the incidence and severity of retinopathy of prematurity (ROP) 
 
7. 
BACKGROUND AND SIGNIFICANCE 
Clinical:  
Approximately 517,000 infants are born prematurely every year1, and as low birth weight and premature infants 
are surviving longer, they are at high risk of developing severe ROP. In the United States, 2,000 infants per year 
are diagnosed with severe ROP, which is the leading cause of irreversible childhood blindness in the United 
States. In our NICU, we care for between 60 and 80 infants each year that are born with low birth weight.  
 
Usual parenteral nutrition protocols do not meet the infants’ fetal accretion rates. Despite receiving 14-28 mg 
DHA/kg/day,2 preterm infants have lower serum DHA and EPA levels than they would have had in utero, and 


 
 
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their tissues have lower n-3 and n-6 fatty acid than full term infants, indicating that their dietary needs are often 
not met.3 Preterm and small for gestational age infants have altered serum phospholipid fatty acid profiles with 
lower DHA and polyunsaturated omega-3 fatty acids than appropriate for gestational age infants.4 Low birth 
weight infants often have severe lung disease and are exposed to exogenous oxygen, which causes retinal blood 
vessel attenuation, retinal hypoxia, up regulation of pro-angiogenic factors, and neovascularization, which can 
lead to irreversible vision loss.  
 
In a recent Polish prospective interventional study, Pawlik et al. showed that in preterm infants (average 28 week 
gestation, 935 gram birth weight), continuous intravenous n-3 fatty acids with Omegaven® from day one to day 
28 of life, followed by enteral omega-3 fatty acids is safe and resulted in a significantly decreased need for ROP 
laser treatment. In the treatment group, 9 of 60 infants needed laser compared with 22 of 70 infants in the control 
group.7,12 On treatment, infants had higher plasma and red blood cell DHA levels at 7 and 14 days and a lower 
risk for cholestasis. This study showed that treatment was well tolerated in preterm infants and that Omegaven® 
has a positive effect on ROP pathogenesis, but no investigations were done into the mechanisms by which ROP 
was suppressed in the experimental group compared with the control arm. There is also no clinical data that 
currently differentiates the differences in the blood biology (fatty acids, gene expression, and proteins) in infants 
with and without severe ROP.  
 
Translational: 
An oxygen-hypoxia-ischemia mouse model of ROP was developed and used to examine the effects of n-3 PUFA 
rich (Japanese) and n-6 PUFA rich (western) diets on retinal vascular development in a model of severe ROP. 
The study showed that there was less retinal vascular obliteration and neovascularization in pups raised on a diet 
with 2% total fatty acids with n-3s with a 1:1 ratio of DHA: EPA in contrast to a diet in which the 2% total fatty 
acids were consistent with n-6 fatty acids.4 The n-3 diet had a 50% protective effect against pathologic 
neovascularization due to increased regrowth of vessels after vessel loss,6 and this was replicated by giving 
downstream mediators of n-3 fatty acids (resolvins and neuroprotectin). Inflammatory mediators, including TNF-
α, were also lower in the n-3  group, and neovascularization was attenuated via a PPAR-ɣ (independent of 
VEGF).7,2 In mice, EPA supplementation has been shown to increase serum IGF-1, correlating with less risk for 
ROP. n-3s are a new target for ROP treatment.8  
 
Basic: 
Docosahexaenoic acid (DHA), a vital dietary long chain polyunsaturated fatty acid (LC-PUFA) is a key 
component in the sensory and vascular retina. Eicosapentaenoic acid (EPA), a substrate for DHA, is the parent 
fatty acid that affects eicosanoids implicated in abnormal retinal neovascularization, vascular permeability, and 
inflammation.9 EPA depresses vascular endothelial growth factor (VEGF)-specific tyrosine kinase receptor 
activation and expression, a key driving force in the pathologic neovascularization.9 DHA is antinflammatory, 
neuroprotective, and also protects against neovascularization.  
 
Safety:   
In the recent Polish prospective interventional study, Pawlik et al. showed that in preterm infants (average 28 
week gestation, 935 gram birth weight), continuous intravenous n-3 fatty acids with Omegaven® from day one 
to day 28 of life (n=60), followed by enteral omega-3 fatty acids is safe, and no adverse events or increase 
mortality or morbidity was noted in the treatment group.7,10 At the Children’s National Medical Center in 
Washington DC, Omegaven® was given to ten premature infants with a median gestational age of 26.4 weeks 
(range, 23.7–34.0 weeks) with hyperbilirubinemia. They showed that the treatment was well tolerated, and there 
were no adverse events.11 The drug Omegaven is now FDA approved but not for the use specified in our study. 


 
 
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In a recent Cochrane review, LC-PUFA supplementation is considered safe in preterm infants with no increase 
in morbidity or adverse events.2,12,13,14,15,16,17,18 
 
8. 
PROGRESS REPORT 
Not Applicable; this is a new study 
 
9. 
RESEARCH DESIGN AND METHODS 
The treatment duration for the study will begin 0-7 days of life and continue until 40 weeks adjusted age (full-
term).  Intravenous treatment will start in the first few days of life and will continue until the infant can tolerate 
enteral nutrition.  Once enteral feeds can be started, supplementation by mouth will begin until 40 weeks adjusted 
age. 
 
Laboratory blood draws:  
Prior to enrollment: In addition to routine tests, blood will be tested for AST and ALT. If these tests are 
interpreted as abnormal, the infant will not be considered for enrollment in the study as it will be deemed a 
contraindication to supplemental Omegaven.  
While the infant is growing in the hospital, the doctors will need to check the infant’s blood to make sure the 
infant is developing as expected.  
 
If the infant is enrolled in the study, the infant will be randomized in blocks of 4 by gestational age to one of two 
groups. The control group will get standard of care nutrition, and the experimental group will get standard of care 
nutrition with supplemental omega-3 fatty acids. Soon after birth, most premature infants need additional 
nutrition through the vein (intravenous). For the control group, there will be no changes to the standard of care 
parenteral nutrition. For the experimental group, the infant will receive Omegaven, an intravenous lipid 
preparation prepared from highly refined fish oil, in addition to the standard of care parenteral nutrition.  In the 
instance that twins are enrolled in the study, the siblings will be randomized as one to receive the same treatment 
per request and approval from Dr. Kim. 
Transition – For the second/interventional group, Omegaven will be stopped once enteral feeds are at 120 ml/kg 
and enteral Oil will be started. There will be no overlap of parenteral and enteral n-3 supplementation. 
 
If the infant can start using his/her own stomach for digestion, he/she will get fatty acid supplementation. In the 
control group, the infant will receive standard of care feeding. If the infant is in the experimental group, the infant 
will get one fourth (1/4) teaspoon per kilogram per day (1.25mL/kg/day = 400 mg omega3 per kg of fish oil per 
day) of Carlson’s fish oil oral solution. Dose will be divided to at least twice a day dosing for better tolerance.  
 
Fatty acid supplementation will continue until the baby is full term (40 adjusted weeks of age). If the infant is 
discharged before he/she is full-term, the infant will be sent home with a bottle of the fatty acid oral solution for 
the infant to continue daily until he/she is full-term (40 weeks of age). The infant's nutritional needs will be 
carefully monitored by his/her doctor and nutritionist per NICU protocols. 
 
To monitor the amount of fatty acid nutrition getting into the blood, we will check the infant’s blood. As much 
as possible, we will coordinate the study blood collection at the same time as the routine NICU blood draws. We 
will collect 1.3 milliliters of blood at 4 different times spread apart while the infant is in the hospital. At each 
time point, we will collect about 1/4 teaspoon of blood, for a total of about 1 teaspoonful. 
 
The blood draws will occur as the following four time points: 
• Blood draw T0= Prior to parenteral nutrition, within 1st 3 days of life. This blood collection should be 


 
 
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taken from cord blood. If cord blood is not available, sample will be collected from a UAC, UVC, or 
peripheral blood draw concurrent with SOC. 
• Blood draw T1= 5 days after parenteral nutrition is started; grace period +/-3 days therefore total 2-8 days 
after parenteral nutrition started. 
• Blood draw T2= 5 days after enteral nutrition full feeds have arrived; grace period +/-3 days therefore 
total 2-8 days after full enteral nutrition arrived. 
• Blood draw T3= Prior to discharge from hospital coinciding with time that ROP may be present, ≥35 
weeks adjusted age. 
 
This blood will be used for looking at what new genes (mRNA) the infant is making and to check how many and 
what kind of fatty acids the infant has in the blood. Before testing, the blood will be stored in a storage facility at 
the UCSD Department of Ophthalmology Blood Bank and labelled with a barcode without the infants’ personal 
information. This is not the infant’s DNA, and no DNA will be isolated or tested. Samples will be stored for 10 
years. After this time point, all samples will be destroyed if not used by that time.  If the parent decides to 
withdraw consent the blood samples that were already drawn will be destroyed, however, any previously obtained 
data from sample testing will be kept. 
 
We will examine the infant’s eyes according to the standard NICU guidelines and protocols. We will also examine 
the infant’s eyes in our eye clinic after discharge over time as we do for all premature infants to support the 
infant’s visual development. 
 
During the study:  
Maternal diet questionnaires will be administered to the maternal subjects following enrollment. This 
questionnaire is the Omega 3 Fatty Acid Questionnaire and has been validated in a related study for this fatty 
acid19. It is anticipated to take 10-15mins to complete. Mothers will be asked to complete this questionnaire at 
the time of enrollment.  
 
Blood samples will be collected 4 times. When possible, and in the majority of blood draws, 1.3 cc of whole 
blood will be collected at the same time as other blood draws to avoid multiple sticks. Whole blood will be 
collected in a green or lavender top tube. One hundred μl of plasma will be isolated, and this will be aliquoted 
into in two tubes and frozen (-80ºC). 
 
Lipidomics: Plasma fatty acids will be tested using a preprandial whole-blood sample (1.3 mL) drawn 2–4 hours 
after the parenteral nutrition (PN) had ended for the day and after enteral feedings were held for 3 hours if the 
patient was also fed enterally. The schedule for sampling will be as follows: prior to parenteral nutrition within 
< 3 days of life; within 5-8 days after parenteral nutrition is started; within 5-8 days after enteral nutrition full 
feeds is started; and prior to discharge from hospital coinciding with time that ROP may be present. The samples 
will be sent to Dr. Metallo’s Institute of Engineering in Medicine Laboratory at UCSD or another UCSD 
laboratory for internal validation of assays. Dr. Radha Aayagari’s lab (UCSD Department of Ophthalmology) or 
another laboratory with similar capabilities will perform some of the RNA isolation and analysis. Capillary gas 
chromatography/mass spectroscopy will be the one of the main methods used to determine the phospholipid 
profile.  
 
Transcriptomics:  From the plasma isolated from the whole blood samples, 50μl will be used for mRNA isolation. 
This will be collected and frozen as the study is ongoing. The fold expression of genes associated with the fatty 
acid synthesis pathway, hypoxia and pro-angiogenic pathways will be correlated with clinical disease.  
 


 
 
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Eye exams: All infants will get eye exams according to standard NICU protocols. Serial eye exams will be 
performed according to the usual intervals, which is until retinal vascularization has matured or active ROP has 
stabilized, usually at 1-2 months post-term. The area of vascularized retina, clock hours of neovascularization, 
and amount of retinal vascular dilation and tortuosity will be measured by indirect ophthalmoscopy in all infants 
at each clinical exam by an ophthalmologist masked to the treatment group.  Stage of retinopathy of prematurity 
and need for ROP treatments will be measured at 40 weeks gestation plus or minus three weeks and followed 
over time. Infants with ROP will be monitored over time for longer term visual and anatomic outcomes.  For both 
groups, infants will have SOC eye examinations prior to discharge around 40 weeks GA (>38 wks GA). For both 
groups, if infant is discharged prior to 38 weeks GA, we will collect follow-up data from their outpatient follow-
up eye exam from UCSD or other provider 
 
Nutrition: Omegaven has been approved by the FDA for use in children and infants with parenteral nutrition 
associated liver disease (PNALD). In this study we intend to use Omegaven under an IND exemption to study 
the use of the drug in reducing the incidence and severity of retinopathy of prematurity (ROP).  Our aim is to 
differentiate the phospholipid profiles and gene expression pathways of at-risk very low birth weight infants 
with and without treatment with Omegaven® (high n-3 fish oil supplement) and to establish whether omega-
3 fatty acid supplementation in extremely low birth weight infants will reduce the incidence and severity of 
retinopathy of prematurity (ROP). The study intervention “drug product” has been used in the neonatal 
population via the same route of administration safely for other disease indications internationally and 
nationally including here at University of California San Diego. This investigation does not significantly 
increase the risk or decrease the acceptability of risk of our study population. 
 
Infants in the experimental group will be getting Omegaven® for parenteral nutrition in addition to the standard 
nutritional requirements (Intralipid within a 3:1 TPN). Omegaven dose will be dosed per weight to give goal dose 
of 1 g/kg/day infused over 12 to 24 hours with the intention to run over 24 hours. Initial Omegaven dose will be 
between 0.5 g and 1 g/kg/day. If the infant’s nutritional lipid requirements are for more than 1g/kg/day, the 
remaining calories from fat in the experimental group will be derived from Intralipid (the parenteral lipid 
emulsion used most often in the UCSD’s NICU). Additional triglyceride testing should not be necessary given 
dosing20. 
 
Infants in the control group will be getting the standard of care, which is Intralipid® combined with the standard 
nutritional requirements in a 3:1 TPN. Intralipid will be used according to the Dosage and Administration 
information in the package insert up to 3.5 g/kilo/day. Initial dose is between 0.5 g and 1 g /kg, starting at 18:00 
and running for 24 hours. Total daily dose will be infused over 12 or 24 hours based on provider preference.  
Once enteral nutrition reaches desired minimum mL/kg/day (determined by the NICU neonatology team), then 
parenteral supplementation will be discontinued and enteral supplementation will begin. Carlson’s Fish oil ® 
(400 mg of omega 3 fatty acids: EPA 200 mg, DHA 125 mg, and 75 mg of other omega-3 fatty acids per ¼ tsp) 
will be given in the experimental group. Enteral fish oil supplementation of 1.25mL/kg/day (1/4 teaspoon per kg 
per day) divided at least every 12 hours for tolerance will be continued until the baby is at 40 weeks adjusted age 
or the retina is fully vascularized. We will adjust our fish oil dosage to maintain maximum enteral DHA 
supplementation to 125 mg/kg/day (omega3 400mg/kg/day). The total dose will be given BID initially. If there 
are any symptoms of GERD or other intolerance symptoms that are concerning to the primary team, then oral 
fish oil total daily dose will be divided over multiple administrations. If enteral oil is not tolerated even after 
medical management, we can decrease the amount by 25% until tolerated. We do not expect poor tolerance to 
this dose given 120 mg/kg/day has been tolerated as an emulsion via feeding tube without any complications21. 
As it is typical of this study population to require varying needs of care and drug administration, should any infant 
randomized to the Omegaven arm require discontinuation of the study drug for clinical reasons for more than 


 
 
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five days (either consecutive or accumulative), that infant will be withdrawn from the study. Drug administration 
disruptions occurring for 5 or less days (total) shall not be considered protocol deviations but will be recorded 
and noted in the annual FDA safety report.  
 
Following discharge from the NICU and prior to infants reaching 40 wks, a research team member (other than 
the PI) will contact the parents with infants in the Omegaven arm once weekly to encourage parents to continue 
with the prescribe fish oil administration for their infant until he/she has is 40 weeks adjusted age. 
 
The investigational drug pharmacy (IDS) will obtain the Omegaven and dispense it to the nurse for administration 
in a separate line than the rest of the nutrition (amino acids, sugars, etc). The NICU nutritionist will optimize the 
total nutritional calories to the infant per NICU protocols. The IDS pharmacist, nutritionist, and NICU team will 
not be blinded to ensure that the infant in the Omegaven group meets all the nutritional requirements as 
determined by the NICU neonatology attendings and fellows involved in the study. The ophthalmology team will 
be blinded to the treatment group to prevent any potential for bias during the eye exam. 
 
Outcome Measures: 
 
Outcome 1: Change in concentrations of basic fatty acids (EPA, DHA, and AA) and their bioactive 
metabolites will be assessed at multiple time points. 
Outcome 2: Change in mRNA expression of TNF-α, PPAR-ɣ, and VEGF at multiple time points.  
Outcome 3: Severity stage of ROP in Group 1 compared to Group 2.  This will be assessed at the time of 
ROP screening (approximately 31 weeks), and the outcome will be measured at approximately 40 weeks 
adjusted age. The stage of ROP at 40 weeks adjusted will be used for statistical analyses. 
 
Safety: 
A data safety monitoring board (DSMB) will be established to monitor the safety of enrolled infants in the study 
as well as identifying the efficacy of the treatment at ongoing intervals. The DSMB will meet after the first 5 
infants are enrolled and then regularly at multiple intervals during the study. Clinical safety assessments will 
occur during the hospital admission including vital signs, weight, physical exam and laboratory assessments of 
triglycerides. The neonatologist will review the assessments and determine if the subject should remain in the 
study or be removed. 
 
Statistical Analysis 
Our primary analytic approach will use generalized linear mixed models (GLMM).  These methods will address 
problems of missing data, variable timing of the subject visits, and other possible unintended violations of design.  
Although our retention and follow-up plan is designed to minimize missing data, an advantage of the GLM 
models is that they allow us to maximize statistical power by not excluding subjects with some missing data.  
More specifically, GLM assumes that the data can be missing at random (MAR) or missing completely at random 
(MCAR).  The benefit of this assumption is with a repeated measure problem (e.g., longitudinal data) you can 
still analyze data from all subjects, even if some have missing data (assumed MAR or MCAR).  Mixed regressions 
will also allow us to estimate an intercept and slope for each patient based on all available data for that individual 
augmented by the data from the entire sample, with two random effects being used to model time trends (i.e., a 
random intercept and a linear trend).  Further details of selected analyses related to each outcome are provided 
next. 
 
For Outcome (a-b), the primary outcome is DHA at a specified period of time (i.e. 40 weeks) to assess the basic 
fatty acids.  Outcome (a) posits that patients in Group 1 will differ from those in Group 2 with respect to i) DHA 


 
 
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ii) EPA iii) AA iv) bioactive metabolites. To assess Outcome (a) (i.e. to evaluate the effects of group, time, and 
their interaction on the change from baseline DHA measurements), a mixed effects model with group (IV 
Omegaven then PO baby fish oil or Intralipid), time, and group by time interaction as fixed effects, and random 
intercept and slope to account for within subject correlation.  We expect that the interaction in question will be 
significant.   
 
For Outcome (c), we hypothesize that Group 1 and Group 2 will have a different severity stage of ROP.  To 
assess Outcome (c), we will use a Mixed-effects ordinal logistic regression model with severity stage of ROP 
after 40 weeks (Stage I, II, III, IV, V) as the outcome variable. The same fixed and random effects mentioned 
above will be used in evaluating Outcome(c).   
 
All statistical analyses will be performed using SAS software version 9.3 (SAS Institute, Cary, North Carolina, 
USA).  
 
Power Calculations 
 
The power calculations that follow were conducted using the software PASS and are based on two-sided tests, 
with a 0.05 type I error rate.  A sample size N=40 was assumed.   Power calculation for the primary outcome is 
presented below. 
 
Power for Outcome (a) 
Outcome (a) tests the effect that Group 1 has a different average DHA measurement compared to Group 2. The 
power calculation for Outcome (a) was based on a two-sided two-sample t-test with a dependent continuous 
variable (i.e. pre-post difference in DHA measurements) on a categorical independent variable (i.e. Group 1 and 
Group 2) with a sample size of 40 total subjects.  These subjects were equally distributed between each of the 
two treatment groups.  In Pawlik et al. (2013), the mean pre-post difference were 42 µmol/L for patients in Group 
1 and 27 µmol/L for patients in Group 2. Following Pawlik et al.’s sampling distribution, we also considered 6 
common standard deviation estimates for the power calculation 5, 7, 9, 11, 13, and 15. It should be noted that as 
the common standard deviation within the group decreases, the group will yield greater power to detect an 
intervention group effect.  As illustrated by the curve in Figure 1, we will have over 80% power to detect a mean 
difference among the 2 groups of average DHA measurements with a common standard deviation of 15, which 
is the smallest difference that we can detect with the proposed sample size. 
 
Figure 1:  Power for Group Effect on the DHA at 40 weeks. 
 


 
 
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Note:  Even though the data analysis plan relies on longitudinal methods (GLMM), due to unavailability of 
estimates for repeated measures, the above power calculations were based on a single time point method (two 
sample t-test).  However, the use of a longitudinal method generally results in an increase in power, therefore we 
believe we will retain sufficient power for the study based on the methods proposed here. 
 
In addition, we have determined that in order to reach a targeted sample size of 40 subjects completing treatment, 
we will need approximately 60 subjects enrolled to this protocol.  This is our target accrual. 
10. 
HUMAN SUBJECTS 
The University of California, San Diego (UCSD) is the only site participating in this study.   
 
We anticipate enrolling 60 infants and up to 60 mothers at UCSD. We will consider patients for enrollment into 
this study for 5 years.  
 
INFANT: 
 
Inclusion Criteria: 
• Infants born ≥ 23 weeks gestation and ≤ 30 weeks gestation or less than 1500 g at birth.  
• Infant whose parent or guardian signed the written consent and HIPAA form. 
 
Exclusion Criteria: 
• Patients with liver disease attributable to known causes (i.e. genetic disease, hepatitis) and/or bleeding or 
clotting abnormalities will be excluded as shown by LFTs.   
• Infants < 23 weeks gestation  
 
MOTHER: 
• Any mother 18 years of age or older that allows their infant to be enrolled. 
• Proficiently English speaking/reading and can complete questionnaire 


 
 
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Infants may still be enrolled in this study if the mother declines to be also participate in the study.  
 
Participation in research is entirely voluntary. Parents of subject may refuse to participate or withdraw at any 
time without penalty or loss of benefits to which they are entitled. If the parent of subject decides that he/she no 
longer wishes to continue in this study, the subject’s parents will be required to notify the study doctors, Dr. 
Robbins or her research staff by calling her at (858) 822-4333. 
 
The study doctor may decide to take the subject off of the study without the parent’s consent if: 
• Subject is unable to meet the requirements of the study; 
• Subject’s medical condition changes; 
• New information becomes available that indicates that participation in this study is not in the subject’s 
best interest; 
• If the study is stopped, 
• The sponsor of the study or the competent authority has the right to withdraw the subject from the 
study without the parent’s permission, 
• The study physician can withdraw the subject from the study without the parent’s consent if he/she 
comes to the conclusion that further participation is not in subject’s best interest. This can be due to 
disease or side effects or because subject does not comply with study procedures 
 
11. 
RECRUITMENT 
Waiver of Consent for Aiding in Research Recruitment:   
I am asking for a waiver of consent while recruiting subjects because: 
It would be minimal risk to the potential subjects while reviewing their private information.  For this study, the 
subjects will already be hospitalized.  The PI or sub PI will need to review the subjects’ medical records for their 
routine care and to determine treatment for the subjects.  While reviewing the medical records for their standard 
of care (SOC) treatment, the PI or sub PI may determine that the subject may qualify for the study and then 
proceed to ask the subject if they would be interested. The PI or sub PI will not review a patient’s medical record 
solely to determine if they qualify for this study. 
Reviewing patients’ medical records would not adversely affect the rights and welfare of the potential subjects 
because the patients have already signed a HIPPA form when they were admitted to the hospital.  Because the 
patient signed the form, we are allowed to review their medical records.   
 
We would not be able to determine if the patient qualifies for this study without reviewing their medical records. 
 
We will provide any new pertinent information to the subjects by providing the subject an addendum consent 
form with the information about this study.  The patient will have time review and ask questions before signing 
the addendum and will be able to withdraw their consent if they desire. 
 
I am asking for a waiver of HIPAA Authorization while recruiting subjects because: 
The research staff will only print out medical records from patients when they have signed the consent form and 
the HIPAA consent form.  If we do print out medical records, we will immediately black out any PHI on the 
documents, then copy the documents, and then again black out any PHI.  The charts will be kept in a locked 
office in a locked cabinet and only the research staff assigned to the study will have access to the charts. 
 
We would not be able to determine if the patient qualifies for this study without reviewing their medical records 
including their PHI (for example we will need contact information and mailing information). 


 
 
ROP Omegaven Research Plan 
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The benefit of allowing access to the patient’s PHI, will allow us to determine if they qualify for this study (for 
example their birth weight or gestational age). 
 
The PHI that we will be used for this study may include the infant subject’s DOB, telephone number, age, address, 
and name.  The sponsor will not have access to the patient’s PHI.  Only the PI, sub PI, and the study coordinator 
assigned to the study will have access to this information.   
Subject’s parents will be asked to provide written consent, using an IRB-approved consent form. The consent 
process will take place prior to performing any study related procedures. The Investigator, sub PI, or study 
coordinator will describe the study, including detailed information about risks and benefits, to potential subject 
parents. The PI, sub PI, or study coordinator will determine if the subject’s parents understands the study before 
they sign it by administering a post-consent quiz to determine if they understand.   
The parents of potential subjects will be encouraged to take as much time as they need to discuss the study with 
the subject’s personal physicians, family members and friends.  The parents will be encouraged to take the form 
home with them.  It will be made extremely clear to the parents, if applicable, that there is absolutely no guarantee 
that the subject will benefit personally.  The parents will be encouraged to ask questions.  Before signing of the 
consent form, the study doctor or study coordinator will ask questions to the subject’s parent to confirm that 
he/she fully understands the potential risks and discomforts, and has a realistic understanding of potential 
benefits. The informed consent will be obtained in the mother’s hospital room, after the parents determine if they 
are interested in possibly participating in this study.   
 
 As this research is subject to HIPAA privacy rule provisions, subject’s parents will also be requested to sign a 
separate authorization for the use of protected health information (i.e., HIPAA form specific to the research 
study).  The investigator or study coordinator will obtain informed consent in a language understood by the 
prospective participant. 
 
12. INFORMED CONSENT 
Parents of potential subjects will be asked to provide written consent, using an IRB-approved consent form. The 
consent process will take place prior to performing any study related procedures and in a private location. The 
potential subject will already be admitted to the hospital.  The Investigator or study coordinator will describe the 
study, including detailed information about risks and benefits, to the parents of potential subjects. The investigator 
or study coordinator will provide the parent with an IRB-approved consent form. Parents will be given ample 
time to read this consent form at the same visit or may take it with them to read at another time. Parents will be 
given the opportunity to ask and receive answers to all questions they may have about the study, its risks  and 
benefits, or the consent form itself before signing the consent form.  As this research is subject to HIPAA privacy 
rule provisions, participants will also be requested to sign a separate authorization for the use of protected health 
information (i.e., HIPAA form specific to the research study).  The investigator or study coordinator will obtain 
informed consent in a language understood by the prospective participant or their legally authorized 
representative, using certified translations of study documents and qualified translators, where applicable. 
For the follow-up eye exam data, we will obtain a signed medical release authorization form for any patients 
scheduled to receive an exam outside of UCSD as their SOC.  
Subjects who fulfill the eligibility criteria will be offered further participation in this study.  Only subjects who 
have consented and provided HIPAA authorization will have identifiers or linked information (e.g., subjects 
initials, study numbers, etc.) recorded on the Screening/Enrollment Log.   
 


 
 
ROP Omegaven Research Plan 
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All signed consents will be maintained in marked binders, secured in locked filing cabinets within private 
administrative offices at UCSD’s Clinical Teaching Facility on campus accessible to study coordinators and 
principal investigators only.  
 
A copy of the HIPAA authorization and informed consent form(s) that will be used on this study are attached to 
this IRB application for your review.  
 
Oral consent will be obtained from the maternal subjects for completion of the maternal questionnaires. No PHI 
will be collected from the mother nor will her medical records be accessed.  
 
13. 
ALTERNATIVES TO STUDY PARTICIPATION 
An alternative to this study is not to participate in this study.  Subjects may or not receive benefit from this 
research study.  However, the information we obtain from this study may help us to treat patients with ROP more 
effectively in the future. 
 
14. 
POTENTIAL RISKS 
There may be risks, discomforts, or side effects that are not yet known. 
 
Possible Risks of Blood Drawing: 
The drawing of venous blood is a routine medical procedure practiced daily by medical personnel. There are only 
very minimal risks involved in the drawing of a blood sample. Occasionally bruising may occur near the insertion 
point, which is generally quickly healed by the body. In order to avoid this hospital staff will gently press for a 
few minutes on the compression bandage applied to the insertion point.  There is a possible risk of anemia which 
could contribute to the need for blood transfusion though many very low birth weight infants require a transfusion 
regardless of their participation this study. Accordingly, if transfusion is needed the additional exposure to blood 
products is noted. Blood draws can lead to rapid changes in hemodynamics of very small infants although this is 
not expected.  Extremely rare injury to the vessel wall or a nerve may occur. In extremely rare cases, although 
sterilised needles are used and the skin is disinfected before insertion of the needle, infection may occur. This 
usually is quickly healed by the body and only in rare cases is an antibiotic required. In very rare cases a blot clot 
can form. These are the same risks that occur with all blood draws that occur as part of the usual care to support 
a premature infant.  
 
Other Risks: 
Because this is a research study, there may be some unknown risks that are currently unforeseeable.  Parents of 
subjects will be informed promptly of any significant new findings. 
 
15. RISK MANAGEMENT PROCEDURES AND ADEQUACY OF RESOURCES 
Adequate measures have been taken to minimize all of the above risks prior to initiation of this study, including 
proper design specification and review, preclinical testing, and clinical evaluations. The study doctor will provide 
appropriate training to the research staff prior to our study initiation.  
 
Safety assessments will include vital signs, weight, physical exam and safety laboratory assessments.  The PI or 
sub-PIs will review the assessments and determine if the subject should remain in the study or be removed. 
 
Loss of Confidentiality: 
There is a risk of a loss of confidentiality if information on the study is lost or stolen.  Every measure will be 
taken to ensure confidentiality.  The chance of a loss of confidentiality occurring during this study is highly 


 
 
ROP Omegaven Research Plan 
Page 13 of 16 
4/22/19 
 
unlikely.  However, there is a potential risk of loss of confidentiality by participating in this study. Research 
records will be kept confidential to the extent provided by law. It is however, always possible that the information 
in the research records could become known outside of the research setting. To minimize this risk, all records 
which identify the subject will be stored in a locked file cabinet in a locked office and will only be accessible by 
study staff. Computers used to store subject’s information are password-protected and only accessible by study 
staff.  
 
A Data Safety Monitoring Board (DSMB) will be created. The function will be to monitor data regarding safety 
of the treatment in enrolled infants as well as identifying the efficacy of the treatment at ongoing intervals.   
16. PRIVACY AND CONFIDENTIALITY CONSIDERATIONS INCLUDING DATA ACCESS AND MANAGEMENT 
Absolute confidentially cannot be promised because information needs to be shared as described below. 
However, information will be collected and shared following standards of confidentiality. Subjects’ identity as a 
participant in this study will remain strictly confidential. Subjects will be identified in the study under a study-
specific code. Should results of this study be published, subjects will not be identified through their name or 
personal information. All research records will be stored in a locked cabinet at all times. Computers used to store 
electronic data information, are password-protected and only accessible by study staff.   
 
For the maternal questionnaire, no protected health information will be collected from the mothers that complete 
this form. We will instead indicate the infant’s subject ID on the form to correlate the mother’s responses with 
the data collected on their infant for this study.  
 
17. POTENTIAL BENEFITS 
Subjects may or not receive benefit from this research study.  However, the information we obtain from this study 
may help us to treat patients with ROP more effectively in the future. 
 
18. RISK/BENEFIT RATIO 
The risks of this study as listed above are more than minimal, however, the benefit (to medical science and future 
patient care) to risk ratio may be large and is in favor of performing the study. 
   
19. EXPENSE TO PARTICIPANT 
None.  Subjects will not be responsible to cover the costs of the study drug, omega-3 fatty acids.  The study doctor 
will be responsible for all cost of the study drug. 
 
20. COMPENSATION FOR PARTICIPATION 
Parents nor subjects will not be paid for their participation in this study. 
   
21. PRIVILEGES/CERTIFICATIONS/LICENSES AND RESEARCH TEAM RESPONSIBILITIES 
Shira Robbins, M.D., has the necessary privileges, certification, and licenses to perform the duties outlined in 
this research plan at UCSD. Dr. Robbins is an employee of UCSD and is supported by grant funding for her time 
and effort. Dr. Christian Metallo, PhD from the Dept of BioEngineering, will perform laboratory lipid analysis. 
Courtney Green, MS Dept of BioEngineering, will perform testing on lipid samples. Todd May, MS is a program 
manager with the Clinical and Translational Research Institute and is a co-investigator. 
 
Louise Laurent M.D. Ph. D is a co-investigator from the UCSD Department of Obstetrics and Gynecology. Vy 
Ha Tran is a research associate and co-investigator from the UCSD Department of Obstetrics and Gynecology. 
Radha Ayyagari, Ph.D and Rohan Verma, M.D. are co-investigators, both from the UCSD Department of 


 
 
ROP Omegaven Research Plan 
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Ophthalmology. Dr Ayyagari’s lab will provide some of the RNA isolation and analysis. Jennifer Bu is a medical 
student at UCSD and a co-investigator with the necessary privileges and certificates. 
 
The investigational drug office pharmacists at UCSD MC Hillcrest have all the necessary privileges, 
certifications, and licenses to perform the duties outlined in the research plan. The neonatal intensive care unit 
pharmacists and the investigational drug pharmacists will be responsible for administering the total parenteral 
nutrition to all enrolled infants in the study. The nutrition plan has been discussed in detail with Jacqueline Keller, 
the UCSD MC Hillcrest NICU principal dietician. 
 
Jessica Yu is a staff research associate at UCSD and has the necessary privileges and certificates.  She will help 
consent and recruit subjects for this study. 
 
Nancy Tang is a clinical nurse and is a co-investigator from the UCSD Department of Pediatrics. She will assist 
with patient recruitment, obtaining consent, study protocol procedures, sample processing, and data collection. 
Sarah Lazar, MPH is the Clinical Research Manager for the Division of Neonatology. Along with Sabrina Fossi 
and Melanie Crabtree, Sarah Lazar will be assisting with patient recruitment, obtaining consent, study protocol 
procedures, sample processing, and data collection, as well as regulatory assistance coordination on this project. 
 
22. BIBLIOGRAPHY 
1. Born Too Soon | March of Dimes. March Dimes Found. Partnersh. Matern. Newborn Child Heal. Save Child. 
World Heal. Organ. 2012. Available at: http://www.marchofdimes.com/mission/global-preterm.aspx. 
2. Gould JF, Smithers LG, Makrides M. The effect of maternal omega-3 (n-3) LCPUFA supplementation during 
pregnancy on early childhood cognitive and visual development: a systematic review and meta-analysis of 
randomized 
controlled 
trials. 
Am. 
J. 
Clin. 
Nutr. 
2013;97(3):531–44. 
Available 
at: 
http://www.ncbi.nlm.nih.gov/pubmed/23364006. Accessed September 4, 2013. 
3. Clandinin MT, Chappell JE, Heim T, Swyer PR, Chance GW. Fatty acid utilization in perinatal de novo 
synthesis 
of 
tissues. 
Early 
Hum. 
Dev. 
1981;5(4):355–366. 
Available 
at: 
http://www.sciencedirect.com/science/article/pii/0378378281900165. Accessed October 27, 2013. 
4. Arsić A, Vučić V, Prekajski N, et al. Different fatty acid composition of serum phospholipids of small and 
appropriate for gestational age preterm infants and of milk from their mothers. Hippokratia. 2012;16(3):230–5. 
Available 
at: 
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3738729&tool=pmcentrez&rendertype=abstract. 
Accessed December 15, 2013. 
5. Pawlik D, Lauterbach R, Walczak M, Hurkala J, Sherman MP. Fish-Oil Fat Emulsion Supplementation 
Reduces the Risk of Retinopathy in Very Low Birth Weight Infants: A Prospective, Randomized Study. JPEN. 
J. 
Parenter. 
Enteral 
Nutr. 
2013:0148607113499373–. 
Available 
at: 
http://pen.sagepub.com/content/early/2013/08/20/0148607113499373.abstract. Accessed January 7, 2014. 
6. Connor KM, SanGiovanni JP, Lofqvist C, et al. Increased dietary intake of omega-3-polyunsaturated fatty 
acids 
reduces 
pathological 
retinal 
angiogenesis. 
Nat. 
Med. 
2007;13(7):868–73. 
Available 
at: 
http://dx.doi.org/10.1038/nm1591. Accessed September 5, 2013. 
7. Stahl A, Sapieha P, Connor KM, et al. Short communication: PPAR gamma mediates a direct antiangiogenic 
effect of omega 3-PUFAs in proliferative retinopathy. Circ. Res. 2010;107(4):495–500. Available at: 
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2975617&tool=pmcentrez&rendertype=abstract. 
Accessed September 7, 2013. 
8. Smith LEH. Through the eyes of a child: understanding retinopathy through ROP the Friedenwald lecture. 
Invest. 
Ophthalmol. 
Vis. 
Sci. 
2008;49(12):5177–82. 
Available 
at: 
http://www.ncbi.nlm.nih.gov/pubmed/18708611. Accessed October 27, 2013. 


 
 
ROP Omegaven Research Plan 
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9. SanGiovanni JP, Chew EY. The role of omega-3 long-chain polyunsaturated fatty acids in health and disease 
of 
the 
retina. 
Prog. 
Retin. 
Eye 
Res. 
2005;24(1):87–138. 
Available 
at: 
http://www.ncbi.nlm.nih.gov/pubmed/15555528. Accessed December 15, 2013. 
10. Pawlik D, Lauterbach R, Turyk E. Fish-oil fat emulsion supplementation may reduce the risk of severe 
retinopathy 
in 
VLBW 
infants. 
Pediatrics. 
2011;127(2):223–8. 
Available 
at: 
http://www.ncbi.nlm.nih.gov/pubmed/21199856. Accessed September 7, 2013. 
11. Klein CJ, Havranek TG, Revenis ME, Hassanali Z, Scavo LM. Plasma fatty acids in premature infants with 
hyperbilirubinemia: before-and-after nutrition support with fish oil emulsion. Nutr. Clin. Pract. 2013;28(1):87–
94. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23319354. Accessed December 13, 2013. 
12. Heird WC. The role of polyunsaturated fatty acids in term and preterm infants and breastfeeding mothers. 
Pediatr. Clin. North Am. 2001;48(1):173–88. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11236724. 
Accessed September 7, 2013. 
13. O’Connor DL, Hall R, Adamkin D, et al. Growth and development in preterm infants fed long-chain 
polyunsaturated fatty acids: a prospective, randomized controlled trial. Pediatrics. 2001;108(2):359–71. 
Available at: http://www.ncbi.nlm.nih.gov/pubmed/11483801. Accessed September 7, 2013. 
14. Fleith M, Clandinin MT. Dietary PUFA for preterm and term infants: review of clinical studies. Crit. Rev. 
Food Sci. Nutr. 2005;45(3):205–29. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16048149. Accessed 
September 5, 2013. 
15. Smithers LG, Gibson RA, McPhee A, Makrides M. Effect of long-chain polyunsaturated fatty acid 
supplementation of preterm infants on disease risk and neurodevelopment: a systematic review of randomized 
controlled 
trials. 
Am. 
J. 
Clin. 
Nutr. 
2008;87(4):912–20. 
Available 
at: 
http://www.ncbi.nlm.nih.gov/pubmed/18400714. Accessed September 7, 2013. 
16. Fewtrell MS, Morley R, Abbott RA, et al. Double-blind, randomized trial of long-chain polyunsaturated fatty 
acid supplementation in formula fed to preterm infants. Pediatrics. 2002;110(1 Pt 1):73–82. Available at: 
http://www.ncbi.nlm.nih.gov/pubmed/12093949. Accessed September 7, 2013. 
17. Clandinin MT, Van Aerde JE, Merkel KL, et al. Growth and development of preterm infants fed infant 
formulas containing docosahexaenoic acid and arachidonic acid.; 2005:461–468. 
18. Schulzke SM, Patole SK, Simmer K. Long-chain polyunsaturated fatty acid supplementation in preterm 
infants. 
Cochrane 
database 
Syst. 
Rev. 
2011;(2):CD000375. 
Available 
at: 
http://www.ncbi.nlm.nih.gov/pubmed/21328248. Accessed December 12, 2013.  
19. Sublette ME, Segal-Isaacson CJ, Cooper TB, et al. Validation of a food frequency questionnaire to assess 
intake of n-3 polyunsaturated fatty acids in subjects with and without Major Depressive Disorder. J Am Diet 
Assoc. 2011 January ; 111(1): 117–123.e2. doi:10.1016/j.jada.2010.10.007 
20. Puder M, Valim C, Meisel JA, et al. Parenteral fish oil improves outcomes in patients with parenteral 
nutrition-associated liver injury. Ann Surg. 2009 Sep;250(3):395-402. doi: 10.1097/SLA.0b013e3181b36657. 
21. Collins CT, Sullivan TR, McPhee AJ, et al. A dose response randomised controlled trial of docosahexaenoic 
acid (DHA) in preterm infants. Prostaglandins Leukot Essent Fatty Acids. doi: 10.1016/j.plefa.2015.04.003. Epub 
2015 Apr 15. 
23. FUNDING SUPPORT FOR THIS STUDY 
The Hartwell Foundation Grant is going to fund this study and provide support for the PI and the sub PIs. An 
UCSD Academic Senate Grant is also funding clinical coordination of this study.  
 
24. BIOLOGICAL MATERIALS TRANSFER AGREEMENT 
Not Applicable 
 
25. INVESTIGATIONAL DRUG FACT SHEET AND IND/IDE HOLDER 


 
 
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Omegaven has been approved by the FDA for use in children and infants with parenteral nutrition associated 
liver disease (PNALD). In this study we intend to use Omegaven under an IND exemption to study the use of the 
drug in reducing the incidence and severity of retinopathy of prematurity (ROP).  An IND Exemption Supplement 
form has been provided to the IRB. 
26. IMPACT ON STAFF 
This study will utilize the neonatology research team to perform all duties in the protocol including performing 
the procedures/tests for each visit, utilizing EPIC system for reports pertinent to study i.e. lab reports, help with 
screening, and scheduling appointments. Nursing staff will be responsible for hanging Omegaven infusion with 
standard of care TPN or hyperal per physician orders.  
 
27. CONFLICT OF INTEREST 
There is no financial relationship between any of the investigators on the project.  This includes no relationship 
involving consulting, participation in speakers, bureaus, stock or stock option ownership, or service on advisory 
boards or the board of directors of a company, or service as a company officer. 
 
28. SUPPLEMENTAL INSTRUCTIONS FOR CANCER-RELATED STUDIES 
Not Applicable 
 
29. OTHER APPROVALS/REGULATED MATERIALS 
Not Applicable 
 
30. PROCEDURES FOR SURROGATE CONSENT AND/OR DECISIONAL CAPACITY ASSESSMENT 
Not Applicable 
 
 

ICF_001.pdf: 
Human Research
Protections Program
UCSan Diego
Approved
Current Approv al
12/06/2019
Do not use ate
01/02/2021
Pages7
University of California, San Diego
Parent Consent for Child to Act as a Research Subject
IRB # 140253
Omega-3 LCPUFA Supplementation in Very Low Birth Weight Infants for the Prevention
of Retinopathy of Prematurity: Proposal for a Prospective Randomized Controlled
Masked Clinical Trial with Lipidomic and Transcriptomic Analyses
The purpose of this form is to give you information about the research study. If you decide that
you would like your infant to take part in the study, you will be asked to sign this form. By
signing this fonn, you are giving your pennission for your infant to take part in the study and
become a study participant.
This form describes the purpose, procedures, benefits, risks,
discomforts and precautions of the research study. Take time to read the following information
carefully and discuss it if you wish with a friend, relatives, and/or with your personal doctor.
You may refuse and not allow your infant to take part or you may withdraw your infant from this
study at any time without this decision affecting your infant's care at UCSD. Before you decide
and agree to have your infant to take part, it is important for you to know why the research study
is being done and what it will involve. Ask as many questions as needed.
You should not sign
this form if you have any questions that have not been answered to your satisfaction.
Who is conducting the study, why your child been asked to participate, how yyour child was
selected, and what is the approximate number ofparticipants in the study?
Dr. Shira Robbins and her research staff arc conducting a research study to learn more about how
omega-3 fatty acid supplementation in low birth weight infants changes the blood profile of
infants that receive this nutritional treatment.
For many very low birth weight infants or infants born at 30 weeks gestation or less, it is
necessary to give them additional nutrition through the vein (intravenous) to promote growth and
development. This nutrition consists of a mixture of supplements, including fatty acids. and is
routinely given to infants as a part of their standard of care.
Approximately 517,000 infants arc born prematurely every year and as low birth weight and
premature infants are surviving longer, they are at risk of developing severe retinopathy of
prematurity (ROP). ROP is a disease of the eye affecting prematurely-born babies. It is thought
to be caused by the abnormal growth of retinal blood vessels which may result in scarring and
retinal detachment. ROP can be mild and may resolve spontaneously, but it may lead to
blindness in serious cases. ROP is the leading cause of irreversible childhood blindness in the
United States.
As such, all preterm babies are at risk for ROP, and very low birth weight is an
additional risk factor.
Recent research suggests that omega-3 fatty acids may act as protective factors in diseases
ROP Omegaven Consent
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IRB # 140253
affecting retinal blood vessels. Omega-3 fatty acids make compounds that protect against the
growth of abnonnal blood vessels by preventing inflammation.
For this study, the researchers will add the Omega-3 fatty acid to the nutritional feedings that are
routinely given to low birthweight infants receiving nutritional supplements for their growth. The
addition of the Omega-3 fatty acid is the experimental part of this study. Omega-3 fatty acids
have been used in a recent international and US based studies where
140 infants received the
drug and no adverse (bad) events were reported. If your baby had been born at full term (not
born early), then he/she would have received higher doses of Omega-3 fatty acids naturally as
this fatty acid is provided by the mother's body while still inside the womb.
You are being asked to allow your infant to participate in this study because your infant was born
at 30 weeks gestation or less or he/she weighed less than 1,500 grams (3.3 lbs) at birth and will
be
receiving
nutritional
supplements
during
their
stay
in
the
hospital.
There
will
be
approximately 120 participants (60 infants and up to 60 mothers) enrolled in this study at UCSD
Medical Center Hillcrest and Jacobs Medical Center.
This study is being funded by several grants including those provided by UC San Diego and the
Hartwell Foundation.
HOW LONG WILL YOUR INFANT BE IN THE STUDY?
Your infant will be enrolled until he/she is full term or until their retinal blood vessels have
completely developed (shortly after term).
We may continue to follow your infant for at least
until 5 years of age.
This will depend on your infant's progress over the years by standard
clinical eye exam in our outpatient clinic.
WHAT IS INVOLVED IN THE STUDY?
If you agree to have your infant participate in this study, you will be asked to sign this consent
form.
Your infant will be randomized (selected by chance) to one of two groups. Your infant will have
a 50/50 chance of being placed in either group one or two.
If your infant is randomized to group one, he/she will receive the standard nutrition supplements.
For this group, there will be no changes to the standard nutrition your child would receive
regardless of their participation in this study.
If your infant is randomized to group two, he/she will receive the standard nutrition plus omega-
3 fatty acids (also known as Omegavcn). Your infant will receive the additional fatty acid
supplementation of Carlson's baby fish oil in a split dose with their standard nutrition. This fatty
acid supplementation will continue until the baby is full term (40 adjusted weeks of age). If your
infant is discharged before he/she is full-term, your infant will be sent home with a bottle of the
fatty acid supplementation for you to continue daily until he/she is full-term (40 weeks of age).
ROP Omegaven Consent
11/4/19
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Human Research
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For both groups. the infants' nutritional needs will be carefully monitored by their doctor and a
nutritionist.
To monitor the amount of nutrition getting into your infant's blood, we will collect samples of
blood and perform tests. As much as possible, we will coordinate the study collection of blood to
occur at the same time as the standard of care blood draws routinely done to monitor your
infant's health. We will collect 1.3 milliliters (about '/ teaspoon) of blood at 4 different times
spread apart while your infant is in the hospital. We will collect a total of about I teaspoonful of
blood.
This blood will be used for looking at what new genes (mRNA) that your infant is making and to
check how many fatty acids your infant has in the blood. Before testing, the blood will be stored
in a storage facility at the UCSD and labelled with a barcode without your infants' personal
information. This is not your infant's DNA, and no DNA will be isolated or tested. Samples will
be stored for 10 years. After this time point, all samples will be destroyed if not used by that
time. If you decide to withdraw your consent the blood samples that were already drawn will be
destroyed, however, any data we obtained from testing the samples will be kept.
For both groups, we will examine your infant's eyes according to the standard NICU guidelines
and protocols. We will also examine your infant's eyes in our eye clinic after discharge over time
as we do for all premature infants to support your infant's visual development.
WHAT ARE THE RISKS OF THE STUDY?
Blood Drawing:
Risks of drawing blood from your infant may include bruising or bleeding at the site where the
blood will be drawn. Your infant may have mild pain, irritation of the vein, and swelling. There
may also be a possibility of infection. This will be minimized by making your infant experience
the minimum number of separate blood draws. The blood draws will usually occur as part of
routine NICU care so your infant will already be having a blood draw.
Many preterm infants require blood transfusion. Since this study involves removing a small
amount of blood ( 1/4 teaspoon at a time), the risk of anemia and blood transfusion is slightly
higher. The change of blood volume in very low birth weight infants can lead to changes in
blood pressure. If a transfusion
is needed there
is the risk of exposure to blood products
including the risk of a negative reaction to the blood transfusion in the organs and tissues in the
body
You should report any problems to the baby's neonatal doctor. For more information about these
risks, ask your infant's study doctor.
Because this is an investigational study there may be some unknown risks that arc currently
unforeseeable. You will be informed of any new significant new findings.
ROP Omegaven Consent
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IRB # 140253
There is a risk of a loss of confidentiality if information on the study is lost or stolen.
Every
measure will be taken to ensure confidentiality.
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
We will monitor your infant's liver for problems that we would not normally check for soon after
birth. It is possible that the omega-3 nutrition your infant receives may decrease the risk of your
infant needing laser treatment for rctinopathy of prematurity and gallbladder problems, based on
previous studies done if randomized to group two. It is also possible that yam infant will not
benefit by being in this study.
We hope the information learned from this study will benefit
other premature infants in the future.
WHAT OTHER OPTIONS ARE THERE?
The alternative is to not participate.
INVOLUNTARY REMOVAL FROM THE STUDY:
The study doctors may decide to take your infant out of this study if your infant's condition gets
worse or if your infant has a serious side effect or needs treatment not allowed in the study. The
study doctors may also take your infant out of the study if they decide it is no longer in your
infant's best interest to continue.
If this occurs, you will be told and your study doctor will talk
to you about other options.
WHAT ABOUT CONFIDENTIALITY?
Study records that identify your infant will be kept confidential as required by law. Federal
Privacy Regulations provide safeguards for privacy, security, and authorized access.
Except
when required by law, your infant will not be identified by name, social security number,
address, telephone number, or any other direct personal identifier in study records disclosed
outside of UCSD Medical Center. For records disclosed outside of UCSD Medical Center, we
will assign a unique code number. The key to the code will be kept in a locked drawer or on a
password protected computer in the study's research office.
Every effort will be made to maintain your confidentiality or the confidentiality of your infant's
medical records, however, this cannot be guaranteed. There is the potential
risk of loss of
confidentiality. Certain offices and people other than the researchers may look at your infant's
medical charts and study records. These include people from:
•
The Food and Drug Administration (FDA), (because they oversee the use of new drugs in
the U.S).
•
The Department of Health and Human Services (DHHS)
•
The University San Diego, California's (UCSD) Institutional Review Board
Your infant's records will not be used for any purpose other than learning about the purpose of
the study or shared with anyone else without your pennission. The results from this study may be
published; however, you infant will not be mentioned by name or any other personal identifiers.
ROP Omegaven Consent
11/4/19
4 of7
Human Research
Protections Program
UC San Diego
Approved
Current Approval
1206/2019
Do not use ate
0102/2021


IRB # 140253
Study records will be retained for IO years after the end of the study or per local/state regulations
or until participants reach 21
years of age, whichever is longer. Study information in your
infant's medical records will be kept forever.
Although every effort will be made to keep research records private, there may be times when
federal or state law requires the sharing of such records, including information that may identify
your infant. This
is very unlikely, but if sharing the information
is ever required, UCSD's
Institutional Review Board will take steps allowable by law to protect the privacy of personal
information.
A copy of this permission form will go into your infant's medical record.
Please review and sign the attached HIPAA form
to complete your authorization for use and
disclosure of your infant's personal health information.
WHAT ARE THE COSTS?
There will be no additional costs to you as a result of your infant being in this study. However,
routine medical care for your infant's condition (care your infant would have received whether or
not in this study) will be charged to you or your insurance company.
You will not be responsible to cover the costs of the study nutritional drug, omega-3. That will
be the study doctor's responsibility.
WHAT IF YOUR CHILD JS INJURED TN THE STUDY?
If your infant is injured as a direct result of participation in this research, The University of
California, San Diego, will provide any medical care needed to treat those injuries.
The
University of California, San Diego, will not provide any other form of compensation to you if
your infant is injured. You may call the Human Research Protections Program Office at (858)
246-4777 for more information about this, to inquire about your infant's rights as a research
participant or to report research-related problems.
WILL YOU OR YOUR CHILD BE COMPENSATED?
You or your infant will not receive any compensation for participation in this research study.
WHO DO YOU CALL IF YOU OR YOUR CHILD HAVE QUESTIONS OR
PROBLEMS?
For questions about the study or a research-related injury, contact the study doctors at:
Shira Robbins, MD (858) 822-4333
WHAT ARE YOUR INFANT'S RIGHTS AS A PARTICIPANT?
Taking part in this study is voluntary. You may choose not to let your infant take part or you may
choose to leave the study at any time. Your decision will not result in any penalty or loss of
benefits to which your infant is entitled. If you have questions about your infant's rights you may
call:
ROP Omegaven Consent
11/4/19
5 of7
Human Research
Protections Program
UCSan Diego
Approved
Current Approv al
1206/2019
Do not use ate
01/02/2021


1RB # 140253
University of California, San Diego
Human Research Protections Program
(858) 246-4777
You will be told about any new information that may affect your infant's health, welfare, or
willingness to stay in this study. You may choose for your infant not to be in the study, or, if you
agree to be in the study, you may withdraw your infant from the study at any time.
If you
withdraw your infant from the study, no new data about your infant will be collected for study
purposes other than data needed to keep track of your withdrawal.
Your decision not to participate or to withdraw your infant from the study will not involve any
penalty or loss of benefits to which you or your infant is entitled, and will not affect your or your
infant's access to health care at University of California, San Diego.
If you do decide to
withdraw your infant, we ask that you contact Dr. Robbins in one of the following ways:
in
writing, telephone call, or tell her that you arc withdrawing your infant from the study.
Dr.
Robbins' telephone number is (858) 822-4333 and her mailing address is 9415 Campus Point Dr,
La Jolla CA 92093-0946. Blood samples that have already been collected cannot be withdrawn.
We may decide to take your infant off this study if your infant's condition gets worse, or we
determine that it is no longer in your infant's best interest to continue.
SIGNATURE AND CONSENT TO BE IN THE STUDY:
Your signature below means that you have read the above information about this study and have
had a chance to ask questions to help you understand what your infant will do in this study and
how your infant's information will be used.
You can change your mind later if you want to. You will be given a copy of this signed consent
form and a copy of the Participant's Bill of Rights. By signing this consent form you are not
giving up any of your or your infant's legal rights. You agree to allow your infant to participate
in this research study.
NAME OF PARTICIPANT
NAME OF PARENT OR GUARDIAN
SIGNATURE OF PARENT OR GUARDIAN
AGE
DATE/TIME
PERSON PROVIDING THE EXPLANATION OF INFORMED CONSENT:
ROP Omegaven Consent
11/4/19
6 of7
Human Research
Protections Program
UC San Diego
pproved
Current Approval
12062019
Do not useate
0102/2021


Person's Name:; (Please Print).
Person's Signature, Date.
IRB # 140253
ROP Omegaven Consent
11/4/19
7 of7
Human Research
Protections Program
UC SanDiego
pproved
Current Approv al
Do not use a!er
120620 19
0102/2021


IRB # 140253
PARTICIPANT'S BILL OF RJGHTS
It is important that the purpose and procedures of the research study are fully understood and that
consent is offered willingly. A participant in a research study or someone, who is asked to give
consent on behalf of another person for such participation, has the right to the following:
1.
Be informed of the nature and purpose of the research.
2.
Be given an explanation of all procedures to be followed and of any drug or device to be
used.
3.
Be given a description of any risks or discomforts, which can be reasonably expected to
result from this research study.
4.
Be given an explanation of any benefits, which can be reasonably expected to the
participant as a result of this research study.
5.
Be informed of any appropriate alternative procedures, drugs, or devices that may be
advantageous and of their relative risks and discomforts.
6.
Be infonned of any medical treatment, which will be made available to the participant if
complications should arise from this research.
7.
Be given an opportunity and encouraged to ask any questions concerning the study or the
procedures involved in this research.
8.
Be made aware that consent to participate in the research may be withdrawn and that
participation may be discontinued at any time without affecting continuity or quality of
medical care.
9.
Be given a copy of the signed and dated written consent form.
10.
Not be subjected to any element of force, fraud, deceit, duress, coercion, or any influence
in reaching the decision to consent or to not consent to participate in the research.
If you have any further questions or concerns about your child's rights as a research participant,
please contact your research doctor or the UCSD Human Research Protections Program at (858)
246-4777
ROP Omegaven Consent
11/4/19
8 of7
Human Research
protections Program
UC San Diego
Approved
Current Approv al.
1206/2019
DOo not use after
0102/2021