Amino Acid Requirements in TPN for Neonates

Overseen By Mahroukh Rafii

Age: < 18

Sex: Any

Trial Phase: Academic

Sponsor: The Hospital for Sick Children

Must not be taking: Protein metabolism drugs

Disqualifiers: Mechanical ventilation, Infection, Enteral feeding, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 2 days per amino acid

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines the needs of three key amino acids in newborns fed through Total Parenteral Nutrition (TPN), a feeding method that bypasses traditional eating and digestion. Researchers aim to determine the actual requirements for phenylalanine, methionine, and histidine, as current solutions may provide more than necessary. The study collects breath and urine samples to measure how these amino acids are utilized by the body. Babies at least 28 weeks into gestation, who are stable, growing, and receiving most of their nutrition via TPN, might be suitable for this trial. As an unphased trial, this study offers a unique opportunity to contribute to essential research that could enhance nutritional care for newborns.

Will I have to stop taking my current medications?

The trial requires that participants are not on medications known to affect protein and amino acid metabolism. If your current medications affect these, you may need to stop them to participate.

What prior data suggests that this method is safe for neonates?

Research shows that the amino acids phenylalanine, methionine, and histidine are crucial for the growth and development of newborns receiving nutrition through TPN (total parenteral nutrition). Although current TPN solutions rely on older data, new studies suggest that newborns might require less of these amino acids than previously thought.

Regarding safety, phenylalanine and methionine are naturally occurring amino acids already used in TPN solutions for newborns, and histidine is also included. Ongoing research focuses on determining the right amounts needed, rather than introducing new substances, indicating a good safety profile.

Earlier studies have not reported specific side effects for these amino acids. However, adjusting the levels to better match actual needs could improve outcomes and reduce any risks from excessive amounts. Since this study is in a phase called "Not Applicable," researchers are still determining the exact requirements rather than testing a new treatment. Overall, using these amino acids in TPN is generally well-tolerated based on past clinical use. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about studying the amino acid requirements in total parenteral nutrition (TPN) for neonates because it could lead to better-tailored nutrition for these vulnerable patients. Unlike the standard TPN formulations that provide a general mix of nutrients, this study focuses on the precise needs for histidine, methionine, and phenylalanine, which are essential amino acids crucial for growth and development. By understanding the specific requirements of these amino acids, healthcare providers could optimize TPN to enhance growth outcomes and reduce the risk of complications in newborns who cannot be fed orally. This approach aims to provide more personalized nutrition, potentially improving recovery and growth rates in neonates.

What evidence suggests that this trial's treatments could be effective for determining amino acid requirements in TPN-fed neonates?

Research has shown that certain building blocks of protein, called amino acids—specifically histidine, methionine, and phenylalanine—are crucial for newborns fed through a vein, a method known as total parenteral nutrition (TPN). This trial will specifically assess the requirements for these amino acids in neonates. Studies have found that the amounts needed can differ significantly from those in commercial TPN solutions. For instance, methionine levels might be higher because newborns have immature enzymes that process it differently. Previous research suggests that newborns might require much less of these amino acids than typically provided. Achieving the right balance is essential to avoid problems and support healthy growth and development in newborns. ^{2 3 5 6 7}

Are You a Good Fit for This Trial?

This trial is for stable newborns who are the right size for their age, born at or after 28 weeks of pregnancy, and are under 28 days old. They must be mostly fed through a vein (at least 90% of calories and protein) and not have any infections or serious health issues.

Inclusion Criteria

Birth weight and length appropriate for gestational age

My baby was born at or after 28 weeks of pregnancy.

My baby is stable, growing, and mostly fed through IV nutrition.

Exclusion Criteria

My baby is on a breathing machine or needs extra oxygen.

Receiving enteral feeding providing > 10% of protein intake

Small for gestational age

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Each baby receives one or two levels of either phenylalanine, methionine, or histidine over a two-day period. Day 1 involves a standard pediatric amino acid solution, and Day 2 involves a TPN Test Solution with the amino acid being investigated.

2 days per amino acid

Daily visits for sample collection

Follow-up

Participants are monitored for safety and effectiveness after treatment

1-2 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Histidine
• Methionine
• Phenylalanine

Trial Overview The study is testing how much of three amino acids - Phenylalanine, Methionine, Histidine - neonates need when they're getting all their nutrition through a vein. Researchers will use special methods to measure these needs in about 18-20 babies per amino acid.

How Is the Trial Designed?

Group I: Phenylalanine, methionine, histidine requirement Experimental Treatment 1 Intervention

Histidine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as L-Histidine for:

• Nutritional supplement in parenteral nutrition

Approved in United States as L-Histidine for:

• Nutritional supplement in parenteral nutrition

Approved in Canada as L-Histidine for:

• Nutritional supplement in parenteral nutrition

Approved in Japan as L-Histidine for:

• Nutritional supplement in parenteral nutrition

Who Is Running the Clinical Trial?

The Hospital for Sick Children

Lead Sponsor

Trials

724

Recruited

6,969,000+

Published Research Related to This Trial

In a study involving 26 TPN-fed piglets, the indicator amino acid oxidation (IAAO) technique revealed that adding limiting amino acids significantly reduced lysine oxidation, indicating improved amino acid utilization.

Specifically, the addition of aromatic amino acids (AAA) to one diet and sulfur amino acids (SAA) to another both led to a 30% decrease in lysine oxidation, demonstrating the effectiveness of this method in identifying and addressing amino acid deficiencies in parenteral nutrition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The indicator amino acid oxidation method identified limiting amino acids in two parenteral nutrition solutions in neonatal piglets. Brunton, JA., Shoveller, AK., Pencharz, PB., et al.[2023]

Infants receiving total parenteral nutrition (TPN) often have low levels of tyrosine (Tyr) and high levels of phenylalanine (Phe), which can limit their ability to synthesize important biomolecules like proteins and catecholamines.

The study found that substituting half of the Phe in TPN with the soluble peptide gamma-glutamyl-tyrosine (Glu(Tyr)) resulted in normal plasma Tyr concentrations and improved Phe/Tyr ratios, suggesting that Glu(Tyr) could enhance Tyr availability for brain function in TPN formulations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of the soluble peptide gamma-L-glutamyl-L-tyrosine to provide tyrosine in total parenteral nutrition in rats. Radmacher, PG., Hilton, MA., Hilton, FK., et al.[2017]

A new amino acid solution (AF) designed for infants on total parenteral nutrition (TPN) resulted in more balanced plasma amino acid levels compared to a commercially prepared solution (CF), which caused imbalances in certain amino acids.

Infants receiving the AF solution had a better nitrogen balance (+170 mg/kg/day) compared to those on CF (+112 mg/kg/day), suggesting that AF may be a more effective nutritional option for infants requiring TPN.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Total parenteral nutrition with a new amino acid solution for infants. Kanaya, S., Nose, O., Harada, T., et al.[2019]

In a study involving 25 male Yorkshire piglets, the parenteral threonine requirement for neonates receiving total parenteral nutrition (TPN) was found to be significantly lower than that for those fed orally, with a mean requirement of 0.19 g/(kg.d) for TPN compared to 0.42 g/(kg.d) for oral feeding.

The research indicates that neonates on TPN need about 45% of the threonine that orally fed neonates require, highlighting the importance of adjusting amino acid intake based on feeding method to ensure proper nutrition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Threonine requirement of neonatal piglets receiving total parenteral nutrition is considerably lower than that of piglets receiving an identical diet intragastrically. Bertolo, RF., Chen, CZ., Law, G., et al.[2018]

In a study involving 18 neonatal piglets over 8 days, the control group receiving phenylalanine (Phe) showed significantly better nitrogen balance and utilization compared to those receiving N-acetyltyrosine (N-AcTyr) or glycyltyrosine (GlyTyr).

N-AcTyr was found to have low bioavailability, with 65% excreted in urine, indicating that current methods for supplying aromatic amino acids in total parenteral nutrition (TPN) for infants may need improvement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aromatic amino acid metabolism of neonatal piglets receiving TPN: effect of tyrosine precursors. Wykes, LJ., House, JD., Ball, RO., et al.[2017]

This study determined that neonatal piglets require approximately 0.45 g of phenylalanine per kg of body weight per day when receiving total parenteral nutrition (TPN), with a safe intake level of 0.48 g/kg/d, which is crucial for optimizing TPN formulations.

The research utilized phenylalanine oxidation techniques to assess amino acid requirements, revealing that higher intakes above 0.8 g/kg/d do not lead to a proportional increase in oxidation, indicating a limit to how much phenylalanine can be effectively utilized.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phenylalanine requirements determined by using L-[1-14C]phenylalanine in neonatal piglets receiving total parenteral nutrition supplemented with tyrosine. House, JD., Pencharz, PB., Ball, RO.[2018]

This study determined that the total sulfur amino acid (TSAA) requirement for postsurgical neonates receiving parenteral nutrition is approximately 47.4 to 49.0 mg/kg/day, using a method that measures amino acid oxidation.

The findings suggest that current commercial pediatric parenteral nutrition solutions provide about 90% of the estimated methionine requirement, indicating that these solutions may need adjustments to meet the specific needs of these vulnerable patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Total sulfur amino acid requirement and metabolism in parenterally fed postsurgical human neonates. Courtney-Martin, G., Chapman, KP., Moore, AM., et al.[2023]

Citations

1. pm.amegroups.org pm.amegroups.org/article/view/6123/html

Amino acid requirements of total parenteral nutrition (TPN) fed ... The requirement for four amino acids in the TPN fed human neonate have been estimated and are up to 90% lower or higher than what is present in current ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/6429311/

Total parenteral nutrition with a new amino acid solution for ... In comparison with controls, the plasma concentrations of threonine, glycine, methionine, phenylalanine, tryptophan, and lysine were higher in infants in group ...

3. withpower.com withpower.com/trial/phase-receiving-total-parenteral-nutrition-tpn-9-2022-1dd52

Amino Acid Requirements in TPN for Neonates ... Histidine, Methionine and Phenylalanine will have tolerable side effects & efficacy for patients with Overeating, Stable Neonates and Total Parenteral Nutrition

4. cdn.amegroups.cn cdn.amegroups.cn/journals/jrh/files/journals/34/articles/6123/public/6123-PB5-6228-R4.pdf?filename=pm-05-29.pdf&t=1749183178

Amino acid requirements of total parenteral nutrition (TPN) ... In TPN fed neonates, it was shown that when sufficient methionine is given to meet the needs for protein synthesis, additional cysteine did not ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC2795370/

Neonatology/Paediatrics – Guidelines on Parenteral Nutrition ... Other amino acids like methionine quickly reach high levels because key enzymes are immature. Amino acid imbalances develop quicker in newborns than in adults ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05562310

Phenylalanine, Methionine and Histidine Requirements in ... This is a single center project assessing the requirements for three essential amino acids in TPN fed neonates. Using the Carbon Oxidation method (indicator ...

7. hopkinsmedicine.org hopkinsmedicine.org/-/media/files/allchildrens/clinical-pathways/nicu_tpn-clinical-pathway-final_1_7_2025.pdf

Parenteral Nutrition for the Preterm Neonate Clinical Pathway Parenteral nutrition (PN) is the standard of care for preterm neonates due to minimal nutrient stores and GI immaturity, aiming to improve ...