Bilirubin EncephalopathyPhase 2NCT04584983

Bilirubin Neurotoxicity (BN) and Neurodevelopmental Impairment (NDI) in Extremely Preterm (EP) Infants: Avoidable by Reducing the Usual Intravenous Lipid (UL) Administration

A Phase 2 study testing usual prescribed intralipid (UL) regimen and restricted prescribed intralipid (RL) regimen in people with Bilirubin Encephalopathy, run by The University of Texas Health Science Center, Houston at 1 site in United States.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record

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Trial summary

The purpose of this study is to evaluate the effect of usual versus reduced lipid intake on unbound bilirubin levels, brainstem auditory evoked responses, and neurodevelopmental outcome at 2 years in extremely preterm infants. Read more about this study

Who is it for?: Ages Up to 27 weeks
Conditions the study is for: Bilirubin Encephalopathy
What is being tested?: usual prescribed intralipid (UL) regimen and restricted prescribed intralipid (RL) regimen
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 134 participants
Where: 1 siteUnited States
Study dates: 11 Feb 2021to 14 Jun 2026
Phase: Phase 2
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages Up to 27 weeks
All sexes
No healthy volunteers
Child

Who may be able to join

no major congenital anomaly or overt nonbacterial infection
mother has consented to inclusion of the infant for the Neonatal Research Network (NRN) Cycled Phototherapy Trial

Who cannot join

has received Intralipid

Trial locations and contacts

1 site in 1 country.

United States1 site

The University of Texas Health Science Center at Houston
Houston, Texas, 77030

Other trials in United States

About this study

Conditions: Bilirubin Encephalopathy
Being tested: usual prescribed intralipid (UL) regimen, restricted prescribed intralipid (RL) regimen
Keywords: preterm, bilirubin, lipid emulsions, unbound bilirubin, unbound free fatty acids
Medical subject headings: Kernicterus, Premature Birth

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

usual prescribed intralipid (UL) regimenDrug
Intralipid will be started at 1 g/kg/day and routinely advanced by 1 g/kg/day each day to a max of 3 g/kg/day as per usual clinical practice
restricted prescribed intralipid (RL) regimenDrug
Intralipid will be started at 0.5 g/kg/day and routinely advanced by 0.5 g/kg/day each day to a max of 1.5 g/kg/day (half rate of usual clinical practice).

Study groups in NCT04584983
Study group	Role	What they receive
usual prescribed intralipid (UL) regimen	Active comparator	Not described Receives: Drug: usual prescribed intralipid (UL) regimen
restricted prescribed intralipid (RL) regimen	Experimental	Not described Receives: Drug: restricted prescribed intralipid (RL) regimen

What is being measured

The primary outcome is the main question the study is designed to answer.

Number of Patients With Unbound Bilirubin (UB) Concentration Greater Than 30 Nanomoles Per Liter (Nmol/L)
Measured: within first 14 days of life
Average Unbound Bilirubin (UB) Concentration
6 UB measurements will be taken per participant .Average of the 6 readings will be reported
Measured: within first 14 days of life
Brain Stem Auditory-evoked Response (BAER) V Latency
Brainstem auditory evoked response (BAER) testing is a procedure used to assess the auditory pathways of the brainstem and evaluate hearing ability. Wave latency, measured in milliseconds, is the measure of electric transmission of sound. If the wave latency is prolonged, this means that something is in the way of electric sound wave transmission, such as bilirubin which has an affinity for depositing in a specific area of the brainstem that wave V measures.
Measured: 38 weeks post menstrual age(PMA)

Secondary outcomes (19)

Peak Free Fatty Acid Uptake (FFAU)
Measured: within first 14 days of life
Peak UB Concentration
Measured: within first 14 days of life
Total Unbound Free Fatty Acids (FFA)
6 FFA measurements will be taken for each participant.Average of the 6 readings will be reported
Measured: within first 14 days of life
Peak Total Serum Bilirubin
Measured: within first 14 days of life
Number of Patients With Direct Bilirubin Greater Than 1.5 mg/dL
Measured: Before discharge (discharge is on average 3 months after birth)
Amount of Protein Given to Participant in Grams Per Kilograms on Day 14 of Life
Calculated as the mean daily protein intake in grams per kilogram of body weight on Day 14 of life.
Measured: Day 14 of life
Amount of Carbohydrates Given to Participant in Grams Per Kilograms on Day 14 of Life
Calculated as the mean daily carbohydrates intake in grams per kilogram of body weight on Day 14 of life.
Measured: Day 14 of life
Amount of Fats Given to Participant in Grams Per Kilograms on Day 14 of Life
Calculated as the mean daily fats intake in grams per kilogram of body weight on Day 14 of life.
Measured: Day 14 of Life
Weight z Score
Weight Z-scores were calculated using the PediTools Fenton Growth Curves Calculator (2013 version), based on the Fenton Preterm Growth Charts.
The following thresholds were used for interpretation:
Z-score ≤ -2: Growth failure (worse outcome)
Z-score = 0: Population mean (appropriate outcome)
Z-score 0 to <2: Appropriate growth (better outcome)
Z-score ≥ 2: Excessive growth (worse outcome)
Measured: day 28
Weight
Measured: birth
Weight
Measured: 36 weeks postmenstrual age
Number of Patients With Bronchopulmonary Dysplasia
Measured: 36 weeks post menstrual age
Number of Patients With Perinatal and Hospital Acquired Sepsis Episodes
Measured: birth until discharge ( discharge will be about 3 months post birth)
Number of Patients Who Died
Measured: 24 months PMA
Number of Patients With Neurodevelopmental Impairment
Measured: 24 months PMA
Number of Patients With Hearing Loss
Measured: 24 months PMA
Number of Patients With Cerebral Palsy
Measured: 24 months PMA
Serial FiO2 (Fraction of Inspired Oxygen)
Measured: Day 1 of life through day 14 of life
Ventilator Setting
Measured: Day 1 of life through day 14 of life

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

11 Feb 202114 Jun 2026

First posted14 Oct 2020
Study start11 Feb 2021
Primary completion14 Mar 2024
Study completion14 Jun 2026 (estimated)

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (3)Papers the sponsor has linked to this study.
Other trials for Bilirubin EncephalopathyStudies of the same condition, open and under way.
More trials run by The University of Texas Health Science Center, HoustonThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 2
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: None (open label)
Enrolment: 134 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT04584983
Sponsor's protocol ID: HSC-MS-20-0916
Other IDs: KL2TR003168
Status last verified: Nov 2025
First submitted: 6 Oct 2020
Last updated: 28 Nov 2025
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: No

Publications

Holzapfel LF, Arnold C, Tyson JE, Shapiro SM, Reynolds EW, Pedroza C, Stephens EK, Kleinfeld A, Huber AH, Rysavy MA, Del Mar Romero Lopez M, Khan AM. Effect of reduced versus usual lipid emulsion dosing on bilirubin neurotoxicity and neurodevelopmental impairment in extremely preterm infants: study protocol for a randomized controlled trial. BMC Pediatr. 2023 Jul 10;23(1):347. doi: 10.1186/s12887-023-04149-0.
PubMed 37430233
Holzapfel LF, Tyson JE, Shapiro SM, Pedroza C, Reynolds E, Lee KH, Rysavy MA, Kleinfeld A, Huber AH, Romero Lopez M, Khan AM, Arnold C. Parenteral Lipid Dose and Bilirubin Neurotoxicity in Extremely Preterm Infants: A Factorial Randomized Trial. J Pediatr. 2026 Jul 4;297:115225. doi: 10.1016/j.jpeds.2026.115225. Online ahead of print.
PubMed 42401326
Holzapfel L, Arnold C, Tyson J, Shapiro S, Reynolds E, Pedroza C, Stephens E, Kleinfeld A, Huber A, Rysavy M, Khan A, Del Mar Romero Lopez M. Effect of Reduced Versus Usual Lipid Emulsion Dosing on Bilirubin Neurotoxicity and Neurodevelopmental Impairment in Extremely Preterm Infants: Study Protocol for a Randomized Controlled Trial. Res Sq [Preprint]. 2023 Mar 7:rs.3.rs-2566352. doi: 10.21203/rs.3.rs-2566352/v1.
PubMed 36945475

Study at a glance

From the registry record, last updated by the sponsor on 28 Nov 2025. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Bilirubin Neurotoxicity (BN) and Neurodevelopmental Impairment (NDI) in Extremely Preterm (EP) Infants: Avoidable by Reducing the Usual Intravenous Lipid (UL) Administration
ClinicalTrials.gov ID: NCT04584983
Acronym / sponsor ID: HSC-MS-20-0916
Conditions: Bilirubin Encephalopathy
Keywords: preterm, bilirubin, lipid emulsions, unbound bilirubin, unbound free fatty acids
Phase: Phase 2
Study type: Interventional
Recruitment status: Active, not recruiting
Enrolment: 134 participants (actual)
Lead sponsor: The University of Texas Health Science Center, HoustonUniversity, hospital or other
Collaborators: National Center for Advancing Translational Sciences (NCATS)
Study start: 11 Feb 2021 (actual)
Primary completion: 14 Mar 2024 (actual)
Study completion: 14 Jun 2026 (estimated)
First posted: 14 Oct 2020 (actual)
Results: Posted 28 Nov 2025

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: None (open label)
Number of arms: 2

Arm	Type	Receives
usual prescribed intralipid (UL) regimen	Active comparator	Drug: usual prescribed intralipid (UL) regimen
restricted prescribed intralipid (RL) regimen	Experimental	Drug: restricted prescribed intralipid (RL) regimen

Who may qualify

Ages: Up to 27 weeks
Sex: All
Healthy volunteers: Not accepted
Age groups: Child

Key inclusion criteria (2 listed)

no major congenital anomaly or overt nonbacterial infection
mother has consented to inclusion of the infant for the Neonatal Research Network (NRN) Cycled Phototherapy Trial

Key exclusion criteria (1 listed)

has received Intralipid

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
usual prescribed intralipid (UL) regimenIntralipid will be started at 1 g/kg/day and routinely advanced by 1 g/kg/day each day to a max of 3 g/kg/day as per usual clinical practice	Drug	usual prescribed intralipid (UL) regimen
restricted prescribed intralipid (RL) regimenIntralipid will be started at 0.5 g/kg/day and routinely advanced by 0.5 g/kg/day each day to a max of 1.5 g/kg/day (half rate of usual clinical practice).	Drug	restricted prescribed intralipid (RL) regimen

Primary outcome

Number of Patients With Unbound Bilirubin (UB) Concentration Greater Than 30 Nanomoles Per Liter (Nmol/L)
Time frame: within first 14 days of life
Average Unbound Bilirubin (UB) Concentration
Time frame: within first 14 days of life
6 UB measurements will be taken per participant .Average of the 6 readings will be reported
Brain Stem Auditory-evoked Response (BAER) V Latency
Time frame: 38 weeks post menstrual age(PMA)
Brainstem auditory evoked response (BAER) testing is a procedure used to assess the auditory pathways of the brainstem and evaluate hearing ability. Wave latency, measured in milliseconds, is the measure of electric transmission of sound. If the wave latency is prolonged, this means that something is in the way of electric sound wave transmission, such as bilirubin which has an affinity for depositing in a specific area of the brainstem that wave V measures.

19 secondary outcomes

Peak Free Fatty Acid Uptake (FFAU)
Time frame: within first 14 days of life
Peak UB Concentration
Time frame: within first 14 days of life
Total Unbound Free Fatty Acids (FFA)
Time frame: within first 14 days of life
Peak Total Serum Bilirubin
Time frame: within first 14 days of life
Number of Patients With Direct Bilirubin Greater Than 1.5 mg/dL
Time frame: Before discharge (discharge is on average 3 months after birth)
Amount of Protein Given to Participant in Grams Per Kilograms on Day 14 of Life
Time frame: Day 14 of life
Amount of Carbohydrates Given to Participant in Grams Per Kilograms on Day 14 of Life
Time frame: Day 14 of life
Amount of Fats Given to Participant in Grams Per Kilograms on Day 14 of Life
Time frame: Day 14 of Life
Weight z Score
Time frame: day 28
Weight
Time frame: birth
Weight
Time frame: 36 weeks postmenstrual age
Number of Patients With Bronchopulmonary Dysplasia
Time frame: 36 weeks post menstrual age
Number of Patients With Perinatal and Hospital Acquired Sepsis Episodes
Time frame: birth until discharge ( discharge will be about 3 months post birth)
Number of Patients Who Died
Time frame: 24 months PMA
Number of Patients With Neurodevelopmental Impairment
Time frame: 24 months PMA
Number of Patients With Hearing Loss
Time frame: 24 months PMA
Number of Patients With Cerebral Palsy
Time frame: 24 months PMA
Serial FiO2 (Fraction of Inspired Oxygen)
Time frame: Day 1 of life through day 14 of life
Ventilator Setting
Time frame: Day 1 of life through day 14 of life

Results and safety

Results posted to the registry on 28 Nov 2025, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Usual Prescribed Intralipid (UL) Regimen	67	65
Restricted Prescribed Intralipid (RL) Regimen	67	67

Primary outcome: Number of Patients With Unbound Bilirubin (UB) Concentration Greater Than 30 Nanomoles Per Liter (Nmol/L)

Time frame: within first 14 days of life. Count of participants. Unit: Participants

Measure	Usual Prescribed Intralipid (UL) Regimen n = 57	Restricted Prescribed Intralipid (RL) Regimen n = 63
Value	2	3

Population analysed: Data were not collected for 8 participants in the usual prescribed intralipid (UL regimen) arm because 1 died before sampling began, and 7 did not receive sampling because they never achieved the maximum dose of lipid and therefore did not trigger blood draws to begin. Data were not collected for 4 participants in the reduced prescribed intralipid (RL) regimen arm because 3 died before sampling began, and 1 did not achieve the maximum dose of lipid and therefore, did not trigger blood draws.

Primary outcome: Average Unbound Bilirubin (UB) Concentration

Time frame: within first 14 days of life. Mean (Standard Deviation). Unit: nanomolar (nM)

Measure	Usual Prescribed Intralipid (UL) Regimen n = 57	Restricted Prescribed Intralipid (RL) Regimen n = 63
Value	12.3 (7.8)	13.2 (7.8)

Primary outcome: Brain Stem Auditory-evoked Response (BAER) V Latency

Time frame: 38 weeks post menstrual age(PMA). Mean (Standard Deviation). Unit: milliseconds (ms)

Measure	Usual Prescribed Intralipid (UL) Regimen n = 58	Restricted Prescribed Intralipid (RL) Regimen n = 57
Value	7.25 (0.58)	7.34 (0.48)

Population analysed: Data were not collected from 7 participants in the usual prescribed intralipid (UL regimen) arm who received intervention because 7 infants died in the UL arm before BAER testing was performed at 36 weeks PMA . Data were not collected from 10 participants in the reduced prescribed intralipid (RL) regimen arm because 10 infants died in the UL arm before BAER testing was performed at 36 weeks PMA.

19 secondary outcomes are reported in the full results.

Adverse events

Time frame: up to 26 months. Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Usual Prescribed Intralipid (UL) Regimen	0 of 67 (0%)	0 of 67 (0%)	7 of 67
Restricted Prescribed Intralipid (RL) Regimen	0 of 67 (0%)	0 of 67 (0%)	10 of 67

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 28 Nov 2025.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Background: PubMed 37430233Holzapfel LF, Arnold C, Tyson JE, Shapiro SM, Reynolds EW, Pedroza C, Stephens EK, Kleinfeld A, Huber AH, Rysavy MA, Del Mar Romero Lopez M, Khan AM. Effect of reduced versus usual lipid emulsion dosing on bilirubin neurotoxicity and neurodevelopmental impairment in extremely preterm infants: study protocol for a randomized controlled trial. BMC Pediatr. 2023 Jul 10;23(1):347. doi: 10.1186/s12887-023-04149-0.
Derived from this study: PubMed 42401326Holzapfel LF, Tyson JE, Shapiro SM, Pedroza C, Reynolds E, Lee KH, Rysavy MA, Kleinfeld A, Huber AH, Romero Lopez M, Khan AM, Arnold C. Parenteral Lipid Dose and Bilirubin Neurotoxicity in Extremely Preterm Infants: A Factorial Randomized Trial. J Pediatr. 2026 Jul 4;297:115225. doi: 10.1016/j.jpeds.2026.115225. Online ahead of print.
Derived from this study: PubMed 36945475Holzapfel L, Arnold C, Tyson J, Shapiro S, Reynolds E, Pedroza C, Stephens E, Kleinfeld A, Huber A, Rysavy M, Khan A, Del Mar Romero Lopez M. Effect of Reduced Versus Usual Lipid Emulsion Dosing on Bilirubin Neurotoxicity and Neurodevelopmental Impairment in Extremely Preterm Infants: Study Protocol for a Randomized Controlled Trial. Res Sq [Preprint]. 2023 Mar 7:rs.3.rs-2566352. doi: 10.21203/rs.3.rs-2566352/v1.
Individual participant dataSharing planned: No

Related trials for Bilirubin Encephalopathy

Not yet recruitingObservational study
Reliability of Transcutaneous Bilirubin Measurement According to the Skin Colour of Newborns
Neonatal Jaundice

Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Lindsay F Holzapfel, MD, MS principal investigator

The University of Texas Health Science Center, Houston

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 2 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 28 Nov 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 28 Nov 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Patients With Unbound Bilirubin (UB) Concentration Greater Than 30 Nanomoles Per Liter (Nmol/L) (time frame: within first 14 days of life). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04584983, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Nov 2025.

Trial summary

Key requirements

Who may be able to join

Who cannot join

Trial locations and contacts

About this study

What participants receive

What is being measured

Timeline

Resources

More details

Publications

Study at a glance

Clinical summary

Study design

Who may qualify

Key inclusion criteria (2 listed)

Key exclusion criteria (1 listed)

Interventions

Primary outcome

Results and safety

Participant flow

Primary outcome: Number of Patients With Unbound Bilirubin (UB) Concentration Greater Than 30 Nanomoles Per Liter (Nmol/L)

Primary outcome: Average Unbound Bilirubin (UB) Concentration

Primary outcome: Brain Stem Auditory-evoked Response (BAER) V Latency

Adverse events

Research links

Related trials for Bilirubin Encephalopathy

Reliability of Transcutaneous Bilirubin Measurement According to the Skin Colour of Newborns

Referral and contact

Questions about this trial

Participant flow

Primary outcome: Number of Patients With Unbound Bilirubin (UB) Concentration Greater Than 30 Nanomoles Per Liter (Nmol/L)

Primary outcome: Average Unbound Bilirubin (UB) Concentration

Primary outcome: Brain Stem Auditory-evoked Response (BAER) V Latency

Adverse events