Omega-3 Long Chain Polyunsaturated Fatty Acid (LCPUFA) Supplementation in Very Low Birth Weight Infants for The Prevention Retinopathy of Prematurity

Study Overview
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Brief Summary
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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
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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.

Official Title
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Omega-3 Long Chain Polyunsaturated Fatty Acid (LCPUFA) Supplementation in Very Low Birth Weight Infants for The Prevention Retinopathy of Prematurity: Proposal for a Prospective Randomized Controlled Masked Clinical Trial With Lipidomic and Transcriptomic Analyses

Conditions
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Retinopathy of Prematurity

Intervention / Treatment
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* Drug: Omegaven
* Dietary Supplement: Standard lipids (primarily omega-6 fatty acids)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Infants born less than or equal to 30 weeks gestation or less than 1500 g at birth Exclusion Criteria: Patients with liver disease as tested by liver function tests (LFTs) ≤ 500 grams birthweight

Ages Eligible for Study
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Maximum Age: 7 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard of Care (Standard Nutrition)<br>Infants in this group will receive standard lipids (predominantly Omega-6 fatty acids). | Dietary Supplement: Standard lipids (primarily omega-6 fatty acids)<br>* Infants will receive nutritional supplementation with standard intralipid, composed primarily of omega-6 fatty acids.<br>* Other names: Intralipid;|
| Experimental: Omegaven<br>Infants in this group will receive lipid supplementation with omega-3 fatty acids. | Drug: Omegaven<br>* Infants will receive nutritional supplementation with omega-3 fatty acids (omegaven).<br>* Other names: Omega-3;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in mRNA Expression in Blood of STAT3, PPAR-ɣ, and STC-1 at T0 | Calculated using RNA extraction from blood, then quantitative polymerase chain reaction (qPCR) analysis. Biomarker significance: STAT3: role in hypoxia pathway leading to ROP (retinopathy of prematurity). Higher STAT3=greater ROP risk PPAR-ɣ: protective anti-angiogenic factor. Higher PPAR-ɣ=lower ROP risk STC-1: stress response protein. Higher STC-1=lower ROP risk Delta Ct meaning: qPCR gene expression analysis outputs Ct values for each genetic sample tested. A Ct value is the number of qPCR amplification cycles required for fluorescence, a proxy of gene expression, to cross a threshold. Lower Ct means less cycles of gene amplification needed for detectable fluorescence, therefore higher gene expression. Then target gene expression is calculated relative to a housekeeping control gene. Delta Ct=Ct(target gene)-Ct(control). Therefore, a HIGHER delta Ct value corresponds to a LOWER gene expression of the gene of interest relative to control. | T0 as defined in study protocol: prior to parental nutrition, within first three days of life | 
| Changes in mRNA Expression in Blood of STAT3, PPAR-ɣ, and STC-1 at T1 | Calculated using RNA extraction from blood, then quantitative polymerase chain reaction (qPCR) analysis. Biomarker significance: STAT3: role in hypoxia pathway leading to ROP (retinopathy of prematurity). Higher STAT3=greater ROP risk PPAR-ɣ: protective anti-angiogenic factor. Higher PPAR-ɣ=lower ROP risk STC-1: stress response protein. Higher STC-1=lower ROP risk Delta Ct meaning: qPCR gene expression analysis outputs Ct values for each genetic sample tested. A Ct value is the number of qPCR amplification cycles required for fluorescence, a proxy of gene expression, to cross a threshold. Lower Ct means less cycles of gene amplification needed for detectable fluorescence, therefore higher gene expression. Then target gene expression is calculated relative to a housekeeping control gene. Delta Ct=Ct(target gene)-Ct(control). Therefore, a HIGHER delta Ct value corresponds to a LOWER gene expression of the gene of interest relative to control. | T1 as defined in study protocol: 5 days after parenteral nutrition is started; grace period +/-3 days therefore total 2-8 days after parenteral nutrition started. | 
| Changes in mRNA Expression in Blood of STAT3, PPAR-gamma, and STC-1 at T2 | Calculated using RNA extraction from blood, then quantitative polymerase chain reaction (qPCR) analysis. Biomarker significance: STAT3: role in hypoxia pathway leading to ROP (retinopathy of prematurity). Higher STAT3=greater ROP risk PPAR-ɣ: protective anti-angiogenic factor. Higher PPAR-ɣ=lower ROP risk STC-1: stress response protein. Higher STC-1=lower ROP risk Delta Ct meaning: qPCR gene expression analysis outputs Ct values for each genetic sample tested. A Ct value is the number of qPCR amplification cycles required for fluorescence, a proxy of gene expression, to cross a threshold. Lower Ct means less cycles of gene amplification needed for detectable fluorescence, therefore higher gene expression. Then target gene expression is calculated relative to a housekeeping control gene. Delta Ct=Ct(target gene)-Ct(control). Therefore, a HIGHER delta Ct value corresponds to a LOWER gene expression of the gene of interest relative to control. | T2 as defined in study protocol: 5 days after enteral nutrition full feeds have arrived; grace period +/-3 days therefore total 2-8 days after full enteral nutrition arrived. | 
| Changes in mRNA Expression in Blood of STAT3 and PPAR-ɣ at T3 | Calculated using RNA extraction from blood, then quantitative polymerase chain reaction (qPCR) analysis. Biomarker significance: STAT3: role in hypoxia pathway leading to ROP (retinopathy of prematurity). Higher STAT3=greater ROP risk PPAR-ɣ: protective anti-angiogenic factor. Higher PPAR-ɣ=lower ROP risk Delta Ct meaning: qPCR gene expression analysis outputs Ct values for each genetic sample tested. A Ct value is the number of qPCR amplification cycles required for fluorescence, a proxy of gene expression, to cross a threshold. Lower Ct means less cycles of gene amplification needed for detectable fluorescence, therefore higher gene expression. Then target gene expression is calculated relative to a housekeeping control gene. Delta Ct=Ct(target gene)-Ct(control). Therefore, a HIGHER delta Ct value corresponds to a LOWER gene expression of the gene of interest relative to control. | T3 as defined in study protocol: Prior to discharge from hospital coinciding with time that ROP may be present, ≥35 weeks adjusted age. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pilot Assay of Basic Fatty Acid Concentrations in Blood at Time T2 | We measured concentrations of basic fatty acids in the blood plasma samples: eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and arachidonic acid (AA). Blood samples were processed by the University of California San Diego lipidomics core and fatty acid concentrations in pmol/ml plasma were determined using gas chromatography-mass spectrometry. | T2 as defined in study protocol: 5 days after enteral nutrition full feeds have arrived; grace period +/-3 days therefore total 2-8 days after full enteral nutrition arrived. | 
| Percentage of Eyes at the Furthest Stage of ROP Achieved | Furthest severity stage of ROP achieved by patients in Arm 1 compared to Arm 2, per eye as assessed by weekly ROP screenings from approximately 31 weeks through 40 weeks adjusted age. Severity staging was determined in an eye exam per accepted clinical guidelines by a trained clinician and retinopathy of prematurity specialist. Briefly, staging is assigned based on the junction of the vascularized and avascular retina when viewed using indirect ophthalmoscopy. The higher the stage, the more severe the ROP. Per the American Association for Pediatric Ophthalmology and Strabismus, Stage 0: no clear demarcation line between vascularized and non-vascularized retina Stage 1: demarcation line that separates normal from premature retina Stage 2: ridge with height and width Stage 3: growth of fragile new abnormal blood vessels | approximately 31 to 40 weeks (adjusted age = gestation + post-natal age) | 
| Number of Patients Requiring Laser Treatment in Arm 1 Versus Arm 2 | Number of patients with retinopathy of prematurity severe enough to require laser treatment by the adjusted age of 40 weeks, as assessed by weekly ROP screenings from approximately 31 weeks through 40 weeks adjusted age. | approximately 31 to 40 weeks (adjusted age = gestation + post-natal age) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ROP, Premature infant