Trial Outcomes & Findings for Omega-3 Long Chain Polyunsaturated Fatty Acid (LCPUFA) Supplementation in Very Low Birth Weight Infants for The Prevention Retinopathy of Prematurity (NCT NCT02486042)

Last Updated: 2022-12-29

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

48 participants

Primary outcome timeframe

T0 as defined in study protocol: prior to parental nutrition, within first three days of life

Results posted on

2022-12-29

Participant Flow

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.

7 participants were consented but not assigned to an arm or group due to meeting exclusion criteria after birth -- 6 were consented before birth but were born over 30 weeks gestation, 1 had high liver function tests (LFTs) that were potentially indicative of liver disease.

Participant milestones

Participant milestones
Measure	Standard of Care (Standard Nutrition) Infants in this group will receive standard lipids (predominantly Omega-6 fatty acids). Standard lipids (primarily omega-6 fatty acids): Infants will receive nutritional supplementation with standard intralipid, composed primarily of omega-6 fatty acids.	Omegaven Infants in this group will receive lipid supplementation with omega-3 fatty acids. Omegaven: Infants will receive nutritional supplementation with omega-3 fatty acids (omegaven).
Overall Study STARTED	20	21
Overall Study COMPLETED	17	10
Overall Study NOT COMPLETED	3	11

Reasons for withdrawal

Reasons for withdrawal
Measure	Standard of Care (Standard Nutrition) Infants in this group will receive standard lipids (predominantly Omega-6 fatty acids). Standard lipids (primarily omega-6 fatty acids): Infants will receive nutritional supplementation with standard intralipid, composed primarily of omega-6 fatty acids.	Omegaven Infants in this group will receive lipid supplementation with omega-3 fatty acids. Omegaven: Infants will receive nutritional supplementation with omega-3 fatty acids (omegaven).
Overall Study Physician Decision	1	7
Overall Study Hospital transfer	2	2
Overall Study Withdrawal by Subject	0	2

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Standard of Care (Standard Nutrition) n=20 Participants Infants in this group will receive standard lipids (predominantly Omega-6 fatty acids). Standard lipids (primarily omega-6 fatty acids): Infants will receive nutritional supplementation with standard intralipid, composed primarily of omega-6 fatty acids.	Omegaven n=21 Participants Infants in this group will receive lipid supplementation with omega-3 fatty acids. Omegaven: Infants will receive nutritional supplementation with omega-3 fatty acids (omegaven).	Total n=41 Participants Total of all reporting groups
Age, Customized Gestational age	27.7 Gestational age (weeks) STANDARD_DEVIATION 1.7 • n=5 Participants	27.2 Gestational age (weeks) STANDARD_DEVIATION 1.6 • n=7 Participants	27.5 Gestational age (weeks) STANDARD_DEVIATION 1.7 • n=5 Participants
Sex: Female, Male Female	7 Participants n=5 Participants	16 Participants n=7 Participants	23 Participants n=5 Participants
Sex: Female, Male Male	13 Participants n=5 Participants	5 Participants n=7 Participants	18 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	9 Participants n=5 Participants	12 Participants n=7 Participants	21 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	11 Participants n=5 Participants	9 Participants n=7 Participants	20 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	6 Participants n=5 Participants	1 Participants n=7 Participants	7 Participants n=5 Participants
Race (NIH/OMB) White	6 Participants n=5 Participants	11 Participants n=7 Participants	17 Participants n=5 Participants
Race (NIH/OMB) More than one race	2 Participants n=5 Participants	3 Participants n=7 Participants	5 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	5 Participants n=5 Participants	6 Participants n=7 Participants	11 Participants n=5 Participants
Birth length	34.8 centimeters STANDARD_DEVIATION 3.4 • n=5 Participants	33.7 centimeters STANDARD_DEVIATION 3.8 • n=7 Participants	34.3 centimeters STANDARD_DEVIATION 3.6 • n=5 Participants
Birth head circumference	24.8 centimeters STANDARD_DEVIATION 2.0 • n=5 Participants	24.8 centimeters STANDARD_DEVIATION 3.0 • n=7 Participants	24.8 centimeters STANDARD_DEVIATION 2.5 • n=5 Participants
Birth weight	935 grams STANDARD_DEVIATION 239 • n=5 Participants	914 grams STANDARD_DEVIATION 259 • n=7 Participants	925 grams STANDARD_DEVIATION 246 • n=5 Participants

PRIMARY outcome

Timeframe: T0 as defined in study protocol: prior to parental nutrition, within first three days of life

Population: Due to low RNA yield, we were unable to analyze all biomarkers of interest and could only analyze up to 3 biomarkers per sample. We chose to analyze STC-1 in the remaining batch of samples post-COVID-19 pandemic after updated literature review. This low RNA yield is why some groups below (e.g. Omegaven STC-1) have fewer analyzed blood samples than the other groups. One blood sample was analyzed per participant.

Outcome measures

Outcome measures
Measure	Standard of Care (Standard Nutrition) n=2 Participants Infants in this group will receive standard lipids (predominantly Omega-6 fatty acids). Standard lipids (primarily omega-6 fatty acids): Infants will receive nutritional supplementation with standard intralipid, composed primarily of omega-6 fatty acids.	Omegaven n=4 Participants Infants in this group will receive lipid supplementation with omega-3 fatty acids. Omegaven: Infants will receive nutritional supplementation with omega-3 fatty acids (omegaven).
Changes in mRNA Expression in Blood of STAT3, PPAR-ɣ, and STC-1 at T0 STAT3	4.19 delta Ct (amplification cycles) Standard Deviation 1.72	7.58 delta Ct (amplification cycles) Standard Deviation 2.98
Changes in mRNA Expression in Blood of STAT3, PPAR-ɣ, and STC-1 at T0 PPAR-gamma	6.43 delta Ct (amplification cycles) Standard Deviation 2.17	11.32 delta Ct (amplification cycles) Standard Deviation 3.53
Changes in mRNA Expression in Blood of STAT3, PPAR-ɣ, and STC-1 at T0 STC-1	22.21 delta Ct (amplification cycles) Standard Deviation 5.22	21.03 delta Ct (amplification cycles) Standard Deviation 3.90

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Standard of Care (Standard Nutrition) n=7 Participants Infants in this group will receive standard lipids (predominantly Omega-6 fatty acids). Standard lipids (primarily omega-6 fatty acids): Infants will receive nutritional supplementation with standard intralipid, composed primarily of omega-6 fatty acids.	Omegaven n=7 Participants Infants in this group will receive lipid supplementation with omega-3 fatty acids. Omegaven: Infants will receive nutritional supplementation with omega-3 fatty acids (omegaven).
Changes in mRNA Expression in Blood of STAT3, PPAR-ɣ, and STC-1 at T1 PPAR-gamma	8.60 delta Ct (amplification cycles) Standard Deviation 5.38	10.51 delta Ct (amplification cycles) Standard Deviation 3.44
Changes in mRNA Expression in Blood of STAT3, PPAR-ɣ, and STC-1 at T1 STC-1	20.73 delta Ct (amplification cycles) Standard Deviation 6.98	23.09 delta Ct (amplification cycles) Standard Deviation 4.02
Changes in mRNA Expression in Blood of STAT3, PPAR-ɣ, and STC-1 at T1 STAT3	5.28 delta Ct (amplification cycles) Standard Deviation 4.79	6.98 delta Ct (amplification cycles) Standard Deviation 1.95

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Standard of Care (Standard Nutrition) n=3 Participants Infants in this group will receive standard lipids (predominantly Omega-6 fatty acids). Standard lipids (primarily omega-6 fatty acids): Infants will receive nutritional supplementation with standard intralipid, composed primarily of omega-6 fatty acids.	Omegaven n=7 Participants Infants in this group will receive lipid supplementation with omega-3 fatty acids. Omegaven: Infants will receive nutritional supplementation with omega-3 fatty acids (omegaven).
Changes in mRNA Expression in Blood of STAT3, PPAR-gamma, and STC-1 at T2 STAT3	11.12 delta Ct (amplification cycles) Standard Deviation 2.80	4.66 delta Ct (amplification cycles) Standard Deviation 1.51
Changes in mRNA Expression in Blood of STAT3, PPAR-gamma, and STC-1 at T2 PPAR-gamma	18.67 delta Ct (amplification cycles) Standard Deviation 3.64	7.31 delta Ct (amplification cycles) Standard Deviation 3.55
Changes in mRNA Expression in Blood of STAT3, PPAR-gamma, and STC-1 at T2 STC-1	28.42 delta Ct (amplification cycles) Standard Deviation 3.10	18.66 delta Ct (amplification cycles) Standard Deviation 3.87

PRIMARY outcome

Timeframe: T3 as defined in study protocol: Prior to discharge from hospital coinciding with time that ROP may be present, ≥35 weeks adjusted age.

Population: Due to low RNA yield and significant participant drop-out by the final time point, we only had one participant from the Omegaven group with a T3 blood sample that yielded enough RNA for gene expression analyses. As a result we were limited to analyzing only PPAR-gamma and STAT-3 and were unable to conduct statistical analyses on this time point. One blood sample was analyzed per participant.

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.

Outcome measures

Outcome measures
Measure	Standard of Care (Standard Nutrition) n=5 Participants Infants in this group will receive standard lipids (predominantly Omega-6 fatty acids). Standard lipids (primarily omega-6 fatty acids): Infants will receive nutritional supplementation with standard intralipid, composed primarily of omega-6 fatty acids.	Omegaven n=1 Participants Infants in this group will receive lipid supplementation with omega-3 fatty acids. Omegaven: Infants will receive nutritional supplementation with omega-3 fatty acids (omegaven).
Changes in mRNA Expression in Blood of STAT3 and PPAR-ɣ at T3 STAT3	3.90 delta Ct (amplification cycles) Standard Deviation 1.71	9.94 delta Ct (amplification cycles) Standard Deviation NA only 1 participant (see above)
Changes in mRNA Expression in Blood of STAT3 and PPAR-ɣ at T3 PPAR-gamma	9.15 delta Ct (amplification cycles) Standard Deviation 3.16	16.11 delta Ct (amplification cycles) Standard Deviation NA only 1 participant (see above)

SECONDARY outcome

Timeframe: 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.

Population: As stated in limitations or caveats, due to delays caused by the COVID-19 pandemic, funding limitations, and a clinical assessment of ROP outcomes in standard of care versus Omegaven infants, we elected to not conduct full fatty acid analyses for our remaining samples. As a result this data is only a pilot analysis and participant numbers were limited, and we could not conduct reliable statistical analyses for this outcome.

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.

Outcome measures

Outcome measures
Measure	Standard of Care (Standard Nutrition) n=1 Participants Infants in this group will receive standard lipids (predominantly Omega-6 fatty acids). Standard lipids (primarily omega-6 fatty acids): Infants will receive nutritional supplementation with standard intralipid, composed primarily of omega-6 fatty acids.	Omegaven n=4 Participants Infants in this group will receive lipid supplementation with omega-3 fatty acids. Omegaven: Infants will receive nutritional supplementation with omega-3 fatty acids (omegaven).
Pilot Assay of Basic Fatty Acid Concentrations in Blood at Time T2 AA	334721 pmol/ml plasma Standard Deviation NA 1 participant (see analysis population description)	345122 pmol/ml plasma Standard Deviation 67435
Pilot Assay of Basic Fatty Acid Concentrations in Blood at Time T2 EPA	6826 pmol/ml plasma Standard Deviation NA 1 participant (see analysis population description)	132669 pmol/ml plasma Standard Deviation 19088
Pilot Assay of Basic Fatty Acid Concentrations in Blood at Time T2 DHA	61541 pmol/ml plasma Standard Deviation NA 1 participant (see analysis population description)	229583 pmol/ml plasma Standard Deviation 32725

SECONDARY outcome

Timeframe: approximately 31 to 40 weeks (adjusted age = gestation + post-natal age)

Population: As noted previously, 21 patients were enrolled in the Omegaven group, however for outcomes only 20 were analyzed because 1 patient was dropped from the study immediately after enrollment (deemed by the physician to be too sick from anemia and never started Omegaven).

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

Outcome measures

Outcome measures
Measure	Standard of Care (Standard Nutrition) n=40 eyes Infants in this group will receive standard lipids (predominantly Omega-6 fatty acids). Standard lipids (primarily omega-6 fatty acids): Infants will receive nutritional supplementation with standard intralipid, composed primarily of omega-6 fatty acids.	Omegaven n=40 eyes Infants in this group will receive lipid supplementation with omega-3 fatty acids. Omegaven: Infants will receive nutritional supplementation with omega-3 fatty acids (omegaven).
Percentage of Eyes at the Furthest Stage of ROP Achieved Stage 0	76.3 percentage of eyes	42.1 percentage of eyes
Percentage of Eyes at the Furthest Stage of ROP Achieved Stage 1	5.3 percentage of eyes	7.9 percentage of eyes
Percentage of Eyes at the Furthest Stage of ROP Achieved Stage 2	18.4 percentage of eyes	26.3 percentage of eyes
Percentage of Eyes at the Furthest Stage of ROP Achieved Stage 3	0 percentage of eyes	23.7 percentage of eyes

SECONDARY outcome

Timeframe: approximately 31 to 40 weeks (adjusted age = gestation + post-natal age)

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.

Outcome measures

Outcome measures
Measure	Standard of Care (Standard Nutrition) n=20 Participants Infants in this group will receive standard lipids (predominantly Omega-6 fatty acids). Standard lipids (primarily omega-6 fatty acids): Infants will receive nutritional supplementation with standard intralipid, composed primarily of omega-6 fatty acids.	Omegaven n=20 Participants Infants in this group will receive lipid supplementation with omega-3 fatty acids. Omegaven: Infants will receive nutritional supplementation with omega-3 fatty acids (omegaven).
Number of Patients Requiring Laser Treatment in Arm 1 Versus Arm 2	0 Participants	5 Participants

Adverse Events

Standard of Care (Standard Nutrition)

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Omegaven

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Standard of Care (Standard Nutrition) n=20 participants at risk Infants in this group will receive standard lipids (predominantly Omega-6 fatty acids). Standard lipids (primarily omega-6 fatty acids): Infants will receive nutritional supplementation with standard intralipid, composed primarily of omega-6 fatty acids.	Omegaven n=21 participants at risk Infants in this group will receive lipid supplementation with omega-3 fatty acids. Omegaven: Infants will receive nutritional supplementation with omega-3 fatty acids (omegaven).
Surgical and medical procedures Omegaven infusion rate discrepancy	0.00% 0/20 • 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).	4.8% 1/21 • Number of events 1 • 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).
Gastrointestinal disorders Necrotizing enterocolitis	0.00% 0/20 • 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).	4.8% 1/21 • Number of events 2 • 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).

Additional Information

Sarah Lazar, clinical research manager

UC San Diego Health

Phone: (858) 249-1711

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place