Individualized Nutrition to Optimize Preterm Infant Growth and Neurodevelopment (THRIVE)

February 26, 2024 updated by: Children's National Research Institute

Transforming Health and Resilience Via Individualized Nutrition in Very Preterm Infants for Extrauterine Growth and Development

Human milk has several well-established benefits but does not adequately meet the increased nutritional demands of the growing preterm infant, necessitating additional nutrient supplementation in a process known as fortification. In U.S. neonatal intensive care units (NICUs), human milk is primarily supplemented using standardized fortification, in which a multicomponent fortifier is added to human milk to achieve assumed nutrient content based on standard milk reference values. However, this method does not account for the significant variability in human milk composition or in preterm infant metabolism, and up to half of all very premature infants experience poor growth and malnutrition using current nutritional practices. Poor postnatal growth has adverse implications for the developing preterm brain and long-term neurodevelopment.

Recent advances allow for individualized methods of human milk fortification, including adjustable and targeted fortification. Adjustable fortification uses laboratory markers of protein metabolism (BUN level) to estimate an infant's protein requirements. In targeted fortification, a milk sample is analyzed to determine its specific macronutrient and energy content, with additional macronutrient supplementation provided as needed to achieve goal values. Emerging data suggest that both methods are safe and effective for improving growth, however information on their comparable efficacy and neurodevelopmental implications are lacking, particularly using advanced quantitative brain MRI (qMRI) techniques.

Through this prospective, randomized-controlled trial, the investigators will compare the impact of individualized human milk fortification on somatic growth and neurodevelopment in preterm infants. Infants will be randomized to receive one of three nutritional interventions: standardized (control group), adjustable, or targeted human milk fortification. Infants will undergo their assigned nutritional intervention until term-equivalent age or discharge home, whichever is achieved first. Brain qMRI will be performed at term-corrected age, and neurodevelopmental follow-up will be performed through 5 years of age.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

150

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United States
    • District of Columbia
      • Washington, District of Columbia, United States, 20010

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Birth gestational age (GA) of ≤32 weeks
  • Postnatal age ≤4 weeks at time of enrollment
  • Maternal plan to provide human milk to infant, and consent to providing donor human milk if insufficient maternal milk supply
  • Maternal age > 18 years old

Exclusion Criteria:

  • Formula feeding prior to 36 weeks PMA or discharge home (whichever achieved first), either secondary to parental preference or medical necessity
  • Dysmorphic features or congenital anomalies suggestive of a genetic syndrome, metabolic disorder, chromosomal abnormality, or congenital infection
  • Dysgenetic or major destructive brain lesions detected by head ultrasound before enrollment

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Supportive Care
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Standardized Fortification

All study participants will undergo feed advancement and fortification with liquid, bovine-based human milk fortifier (HMF) to an assumed human milk content of 24kcal/oz per the Children's National Hospital NICU standardized clinical feeding protocol. The same milk fortification recipes are utilized for mother's own milk (MOM) and donor human milk (DHM). Each infant's growth trajectory is monitored (weight, length, and head circumference) with dietary modifications performed as needed based on growth parameters.

Growth failure is defined as a decline in weight-for-age z-score by greater than 1 standard deviation (>1 SD) beginning 1 week after reaching goal fortified feeds. For infants who demonstrate growth failure, Step 1 will be to add medium chain triglyceride (MCT) oil. If growth remains sub-optimal, Step 2 will be to add liquid protein.
Dietary supplement: Standardized Fortification
Fortification with liquid, bovine-based HMF to assumed human milk content of 24kcal/oz
Experimental: Adjustable

Adjustable fortification will begin 1 week after tolerating goal feeds of standardized fortification. Blood urea nitrogen (BUN) level as a marker of protein metabolism will be measured weekly, and supplementation with liquid protein will be adjusted as necessary to maintain a goal BUN level between 9-14mmol/dL, up to a maximum assumed protein intake of 4.5 g/kg/day. Liquid protein supplementation will be modified as follows:

  • BUN Level <9 mmol/dL: Increase by 0.5g/kg/day
  • BUN Level 9-14 mmol/dL: No change
  • BUN Level >14 mmol/dL: Decrease by 0.25g/kg/day
  • BUN Level >20 mmol/dL: Hold for 1 week and re-assess

Growth failure is defined as a decline in weight-for-age z-score by >1 SD beginning 1 week after achieving BUN within goal range from adjustable fortification. For infants who demonstrate growth failure, MCT oil will be added and increased weekly as needed.
Dietary supplement: Standardized Fortification
Fortification with liquid, bovine-based HMF to assumed human milk content of 24kcal/oz
Dietary supplement: Adjustable Fortification
Additional liquid protein supplementation to maintain serum BUN levels within goal range (9-14mmol/dL)
Dietary supplement: Adjustable Fortification
Additional liquid protein and/or MCT oil supplementation to maintain protein, fat, and energy intake within goal range based upon mid-infrared human milk analysis
Experimental: Targeted

Targeted fortification will begin 1 week after tolerating goal feeds of standardized fortification. Additional supplementation with liquid protein and/or MCT oil will be provided based on twice weekly milk analysis using a mid-infrared human milk analyzer in order to meet macronutrient (carbohydrate, protein, lipid) and energy intake goals per pediatric nutrition guidelines (protein 4-4.5g/kg/day, fat 6-8g/kg/day, energy 120-130kcal/kg/day).

Growth failure is defined as a decline in weight-for-age z-score by >1 SD beginning 1 week after receiving macronutrient and energy intake within goal range from targeted fortification. For infants with growth failure, total energy intake will be increased with additional protein and/or MCT oil supplementation. Energy intake may be increased weekly as needed.
Dietary supplement: Standardized Fortification
Fortification with liquid, bovine-based HMF to assumed human milk content of 24kcal/oz
Dietary supplement: Adjustable Fortification
Additional liquid protein supplementation to maintain serum BUN levels within goal range (9-14mmol/dL)
Dietary supplement: Adjustable Fortification
Additional liquid protein and/or MCT oil supplementation to maintain protein, fat, and energy intake within goal range based upon mid-infrared human milk analysis

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Weight Gain Velocity
Time Frame: Study enrollment through nutritional intervention endpoint (term-equivalent age (40 weeks PMA [postmenstrual age]) or discharge home, whichever is achieved first)
Weight gain velocity (grams per kilogram per day)
Study enrollment through nutritional intervention endpoint (term-equivalent age (40 weeks PMA [postmenstrual age]) or discharge home, whichever is achieved first)
Length Growth Velocity
Time Frame: Study enrollment through nutritional intervention endpoint (term-equivalent age (40 weeks PMA [postmenstrual age]) or discharge home, whichever is achieved first)
Length growth velocity (centimeters per week)
Study enrollment through nutritional intervention endpoint (term-equivalent age (40 weeks PMA [postmenstrual age]) or discharge home, whichever is achieved first)
Head Circumference Growth Velocity
Time Frame: Study enrollment through nutritional intervention endpoint (term-equivalent age (40 weeks PMA [postmenstrual age]) or discharge home, whichever is achieved first)
Head circumference growth velocity (centimeters per week)
Study enrollment through nutritional intervention endpoint (term-equivalent age (40 weeks PMA [postmenstrual age]) or discharge home, whichever is achieved first)
Total and Regional Brain Volumes
Time Frame: Term-equivalent age (38 to 41 weeks postmenstrual age)
Total and regional (cortical and deep gray matter, white matter, amygdala-hippocampus, brainstem, cerebellum) brain volumes by MRI
Term-equivalent age (38 to 41 weeks postmenstrual age)
Neonatal Intensive Care Unit Network Neurobehavioral Scale (NNNS)
Time Frame: Term-equivalent age (38 to 41 weeks postmenstrual age)
Summary scores in 13 different domains (habituation, attention, handling, self-regulation, arousal, excitability, lethargy, hypertonicity, hypotonicity, non-optimal reflex, asymmetric reflex, quality of movement, stress)
Term-equivalent age (38 to 41 weeks postmenstrual age)
Wechsler Preschool and Primary Scale of Intelligence (4th edition) (WPPSI-IV)
Time Frame: 60 months (5 years) of age
Five primary indices: verbal comprehension, visual spatial, working memory, fluid reasoning, and processing speed (higher score indicates better performance, score range 40 to 160)
60 months (5 years) of age
Differential Abilities Scale (2nd edition)-(DAS-II)
Time Frame: 60 months (5 years) of age

*For children with significant delays who may be unable to reach basal scores on the WPPSI-IV

Early years core battery: verbal, nonverbal, and spatial reasoning subtests (higher score indicates better performance, score range 40-170)
60 months (5 years) of age
Mullen Scales of Early Learning (MSEL)
Time Frame: 18 months corrected age
Composite score as well as 5 subscores: gross motor, fine motor, visual reception, receptive language, and expressive language (reported as standardized t-scores, higher score indicates a better outcome, mean standardized t-score of 50 with standard deviation of 10)
18 months corrected age
Mullen Scales of Early Learning (MSEL)
Time Frame: 36 months (3 years) of age
Composite score as well as 5 subscores: gross motor, fine motor, visual reception, receptive language, and expressive language (reported as standardized t-scores, higher score indicates a better outcome, mean standardized t-score score of 50 with standard deviation of 10)
36 months (3 years) of age

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Children's National Research Institute

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

February 1, 2024

Primary Completion (Estimated)

January 1, 2034

Study Completion (Estimated)

January 1, 2034

Study Registration Dates

First Submitted

September 25, 2023

First Submitted That Met QC Criteria

February 12, 2024

First Posted (Actual)

February 20, 2024

Study Record Updates

Last Update Posted (Estimated)

February 28, 2024

Last Update Submitted That Met QC Criteria

February 26, 2024

Last Verified

February 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Pro00000615

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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