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

Retinopathy of Prematurity Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02486042
• Other study ID #: 140253
• Status: Completed
• Phase: Phase 2
• Start date: March 2014
• Est. completion date: December 2019

Study information

• Verified date: November 2022
• Source: University of California, San Diego
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 48
• Est. completion date: December 2019
• Est. primary completion date: December 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 7 Days

Eligibility

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

Related Conditions & MeSH terms

• Birth Weight
• Premature Birth
• Retinal Diseases
• Retinopathy of Prematurity

Intervention

Drug:
• Omegaven
Infants will receive nutritional supplementation with omega-3 fatty acids (omegaven).

Dietary Supplement:
• Standard lipids (primarily omega-6 fatty acids)
Infants will receive nutritional supplementation with standard intralipid, composed primarily of omega-6 fatty acids.

Locations

Country	Name	City	State
United States	University of California, San Diego Jacobs Medical Center	La Jolla	California

Sponsors (2)

Lead Sponsor	Collaborator
University of California, San Diego	The Hartwell Foundation

Country where clinical trial is conducted

United States, 

References & Publications (18)

Arsic A, Vucic V, Prekajski N, Tepsic J, Ristic-Medic D, Velickovic V, Glibetic M. Different fatty acid composition of serum phospholipids of small and appropriate for gestational age preterm infants and of milk from their mothers. Hippokratia. 2012 Jul;16(3):230-5. — View Citation

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.

Clandinin MT, Chappell JE, Heim T, Swyer PR, Chance GW. Fatty acid utilization in perinatal de novo synthesis of tissues. Early Hum Dev. 1981 Sep;5(4):355-66. doi: 10.1016/0378-3782(81)90016-5. — View Citation

Clandinin MT, Van Aerde JE, Merkel KL, Harris CL, Springer MA, Hansen JW, Diersen-Schade DA. Growth and development of preterm infants fed infant formulas containing docosahexaenoic acid and arachidonic acid. J Pediatr. 2005 Apr;146(4):461-8. doi: 10.1016/j.jpeds.2004.11.030. — View Citation

Connor KM, SanGiovanni JP, Lofqvist C, Aderman CM, Chen J, Higuchi A, Hong S, Pravda EA, Majchrzak S, Carper D, Hellstrom A, Kang JX, Chew EY, Salem N Jr, Serhan CN, Smith LEH. Increased dietary intake of omega-3-polyunsaturated fatty acids reduces pathological retinal angiogenesis. Nat Med. 2007 Jul;13(7):868-873. doi: 10.1038/nm1591. Epub 2007 Jun 24. — View Citation

Fewtrell MS, Morley R, Abbott RA, Singhal A, Isaacs EB, Stephenson T, MacFadyen U, Lucas A. Double-blind, randomized trial of long-chain polyunsaturated fatty acid supplementation in formula fed to preterm infants. Pediatrics. 2002 Jul;110(1 Pt 1):73-82. doi: 10.1542/peds.110.1.73. — View Citation

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. doi: 10.1080/10408690590956378. — View Citation

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 Mar;97(3):531-44. doi: 10.3945/ajcn.112.045781. Epub 2013 Jan 30. — View Citation

Heird WC. The role of polyunsaturated fatty acids in term and preterm infants and breastfeeding mothers. Pediatr Clin North Am. 2001 Feb;48(1):173-88. doi: 10.1016/s0031-3955(05)70292-3. — View Citation

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 Feb;28(1):87-94. doi: 10.1177/0884533612469989. — View Citation

O'Connor DL, Hall R, Adamkin D, Auestad N, Castillo M, Connor WE, Connor SL, Fitzgerald K, Groh-Wargo S, Hartmann EE, Jacobs J, Janowsky J, Lucas A, Margeson D, Mena P, Neuringer M, Nesin M, Singer L, Stephenson T, Szabo J, Zemon V; Ross Preterm Lipid Study. Growth and development in preterm infants fed long-chain polyunsaturated fatty acids: a prospective, randomized controlled trial. Pediatrics. 2001 Aug;108(2):359-71. doi: 10.1542/peds.108.2.359. — View Citation

Pawlik D, Lauterbach R, Turyk E. Fish-oil fat emulsion supplementation may reduce the risk of severe retinopathy in VLBW infants. Pediatrics. 2011 Feb;127(2):223-8. doi: 10.1542/peds.2010-2427. Epub 2011 Jan 3. — View Citation

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. 2014 Aug;38(6):711-6. doi: 10.1177/0148607113499373. Epub 2013 Aug 20. — View Citation

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 Jan;24(1):87-138. doi: 10.1016/j.preteyeres.2004.06.002. — View Citation

Schulzke SM, Patole SK, Simmer K. Long-chain polyunsaturated fatty acid supplementation in preterm infants. Cochrane Database Syst Rev. 2011 Feb 16;(2):CD000375. doi: 10.1002/14651858.CD000375.pub4. — View Citation

Smith LE. Through the eyes of a child: understanding retinopathy through ROP the Friedenwald lecture. Invest Ophthalmol Vis Sci. 2008 Dec;49(12):5177-82. doi: 10.1167/iovs.08-2584. Epub 2008 Aug 15. No abstract available. — View Citation

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 Apr;87(4):912-20. doi: 10.1093/ajcn/87.4.912. — View Citation

Stahl A, Sapieha P, Connor KM, Sangiovanni JP, Chen J, Aderman CM, Willett KL, Krah NM, Dennison RJ, Seaward MR, Guerin KI, Hua J, Smith LE. Short communication: PPAR gamma mediates a direct antiangiogenic effect of omega 3-PUFAs in proliferative retinopathy. Circ Res. 2010 Aug 20;107(4):495-500. doi: 10.1161/CIRCRESAHA.110.221317. Epub 2010 Jul 15. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Changes in mRNA Expression in Blood of STAT3, PPAR-?, 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-?: protective anti-angiogenic factor. Higher PPAR-?=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
Primary	Changes in mRNA Expression in Blood of STAT3, PPAR-?, 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-?: protective anti-angiogenic factor. Higher PPAR-?=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.
Primary	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-?: protective anti-angiogenic factor. Higher PPAR-?=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.
Primary	Changes in mRNA Expression in Blood of STAT3 and PPAR-? 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-?: protective anti-angiogenic factor. Higher PPAR-?=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	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.
Secondary	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)
Secondary	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)