A Phase 2 interventional study of Omegaven and Standard lipids (primarily omega-6 fatty acids) in Retinopathy of Prematurity, sponsored by University of California, San Diego. Completed at 1 site in United States. Open to participants aged Up to 7 Days. Per ClinicalTrials.gov, last updated 2022-12-29.
Sponsored by University of California, San Diego · Phase 2, Interventional, and Prevention
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.
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.
815 studies on the registry are indexed under Retinal Diseases; 105 are open to participants now.
This study's enrollment of 48 is below the median of 60 across 500 interventional studies indexed under Retinal Diseases.
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Of its 110 completed or terminated interventional studies of FDA-regulated products, 70 (64%) have results posted.
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Exclusion Criteria:
Infants in this group will receive standard lipids (predominantly Omega-6 fatty acids).
Dietary Supplement: Standard lipids (primarily omega-6 fatty acids)
Infants in this group will receive lipid supplementation with omega-3 fatty acids.
Drug: Omegaven
Infants will receive nutritional supplementation with omega-3 fatty acids (omegaven).
Also known as: Omega-3
Infants will receive nutritional supplementation with standard intralipid, composed primarily of omega-6 fatty acids.
Also known as: Intralipid
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: T3 as defined in study protocol: Prior to discharge from hospital coinciding with time that ROP may be present, ≥35 weeks adjusted age.
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.
Time frame: 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
Time frame: 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.
Time frame: approximately 31 to 40 weeks (adjusted age = gestation + post-natal age)
Subjects were recruited from October 2015 to November 2019 at University of California San Diego. Expectant parents of preterm infants were recruited and consented to the trial after admission to the hospital, either prior to or shortly after delivery.
| Milestone | Standard of Care (Standard Nutrition) | Omegaven |
|---|---|---|
| Started | 20 | 21 |
| Completed | 17 | 10 |
| Not completed | 3 | 11 |
| Withdrew: Physician decision | 1 | 7 |
| Withdrew: Hospital transfer | 2 | 2 |
| Withdrew: Withdrawal by subject | 0 | 2 |
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.
| delta Ct (amplification cycles) | Standard of Care (Standard Nutrition) | Omegaven |
|---|---|---|
| STAT3 | 4.19 ± 1.72 | 7.58 ± 2.98 |
| PPAR-gamma | 6.43 ± 2.17 | 11.32 ± 3.53 |
| STC-1 | 22.21 ± 5.22 | 21.03 ± 3.90 |
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.
| pmol/ml plasma | Standard of Care (Standard Nutrition) | Omegaven |
|---|---|---|
| EPA | 6826 ± NA | 132669 ± 19088 |
| DHA | 61541 ± NA | 229583 ± 32725 |
| AA | 334721 ± NA | 345122 ± 67435 |
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
| percentage of eyes | Standard of Care (Standard Nutrition) | Omegaven |
|---|---|---|
| Stage 0 | 76.3 | 42.1 |
| Stage 1 | 5.3 | 7.9 |
| Stage 2 | 18.4 | 26.3 |
| Stage 3 | 0 | 23.7 |
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.
| Participants | Standard of Care (Standard Nutrition) | Omegaven |
|---|---|---|
| Number of Patients Requiring Laser Treatment in Arm 1 Versus Arm 2 | 0 | 5 |
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.
| delta Ct (amplification cycles) | Standard of Care (Standard Nutrition) | Omegaven |
|---|---|---|
| STAT3 | 5.28 ± 4.79 | 6.98 ± 1.95 |
| PPAR-gamma | 8.60 ± 5.38 | 10.51 ± 3.44 |
| STC-1 | 20.73 ± 6.98 | 23.09 ± 4.02 |
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.
| delta Ct (amplification cycles) | Standard of Care (Standard Nutrition) | Omegaven |
|---|---|---|
| STAT3 | 11.12 ± 2.80 | 4.66 ± 1.51 |
| PPAR-gamma | 18.67 ± 3.64 | 7.31 ± 3.55 |
| STC-1 | 28.42 ± 3.10 | 18.66 ± 3.87 |
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.
| delta Ct (amplification cycles) | Standard of Care (Standard Nutrition) | Omegaven |
|---|---|---|
| STAT3 | 3.90 ± 1.71 | 9.94 ± NA |
| PPAR-gamma | 9.15 ± 3.16 | 16.11 ± NA |
Collected over Adverse event data was collected while patients were actively enrolled in the study from October 2015 to December 2019. Each participant was assessed for adverse events for the duration of their active participation in the study, from 0-7 days of life until 40 weeks adjusted age (or withdrawal if prior to study completion).. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Standard of Care (Standard Nutrition) | 0/20 (0%) | 0/20 (0%) | 0/20 (0%) |
| Omegaven | 0/21 (0%) | 0/21 (0%) | 2/21 (9.5%) |
| Event | Standard of Care (Standard Nutrition) | Omegaven |
|---|---|---|
| Omegaven infusion rate discrepancySurgical and medical procedures | 0/20 | 1/21 |
| Necrotizing enterocolitisGastrointestinal disorders | 0/20 | 1/21 |
| Age, Customized(Gestational age (weeks)) | Standard of Care (Standard Nutrition) | Omegaven | Total |
|---|---|---|---|
| Gestational age | 27.7 ± 1.7 | 27.2 ± 1.6 | 27.5 ± 1.7 |
| Sex: Female, Male(Participants) | Standard of Care (Standard Nutrition) | Omegaven | Total |
|---|---|---|---|
| Female | 7 | 16 | 23 |
| Male | 13 | 5 | 18 |
| Ethnicity (NIH/OMB)(Participants) | Standard of Care (Standard Nutrition) | Omegaven | Total |
|---|---|---|---|
| Hispanic or Latino | 9 | 12 | 21 |
| Not Hispanic or Latino | 11 | 9 | 20 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Race (NIH/OMB)(Participants) | Standard of Care (Standard Nutrition) | Omegaven | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 |
| Asian | 1 | 0 | 1 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 6 | 1 | 7 |
| White | 6 | 11 | 17 |
| More than one race | 2 | 3 | 5 |
| Unknown or Not Reported | 5 | 6 | 11 |
| Birth length(centimeters) | Standard of Care (Standard Nutrition) | Omegaven | Total |
|---|---|---|---|
| Mean | 34.8 ± 3.4 | 33.7 ± 3.8 | 34.3 ± 3.6 |
| Birth head circumference(centimeters) | Standard of Care (Standard Nutrition) | Omegaven | Total |
|---|---|---|---|
| Mean | 24.8 ± 2.0 | 24.8 ± 3.0 | 24.8 ± 2.5 |
| Birth weight(grams) | Standard of Care (Standard Nutrition) | Omegaven | Total |
|---|---|---|---|
| Mean | 935 ± 239 | 914 ± 259 | 925 ± 246 |
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University of California, San Diego