ASPIRE: An Exploratory Study of Arginine Supplementation and the Postoperative Immune REsponse

Sponsor

University of Liverpool (Other)

Overall Status

Recruiting

CT.gov ID

NCT05306925

Collaborator

(none)

Enrollment

Locations

Arms

31.6

Anticipated Duration (Months)

Patients Per Site

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

ASPIRE is a nutrition study focusing on the effect of arginine supplementation on immune function in postoperative infants.

The investigators will explore the effect of current intravenous feeding (parenteral nutrition (PN)) formulations on blood arginine levels and the genes that are involved in body nutrition and fighting infection in babies who have had major bowel surgery. The investigators will also investigate the effect of supplementing arginine on these genes. The investigators will undertake an exploratory physiological study across two sites under which are part of a single neonatal partnership. 32 infants will be recruited; 16 preterm infants and 16 term/near term infants. 16 of these infants (8 preterm and 8 term/near term) will be supplemented with arginine. The investigators will record nutritional intake and routine biochemical testing data (which includes amino acid levels) collected over the first 30 days post surgery. The investigators will take blood for analysis at prespecified intervals for RNA sequencing, ammonia and metabolomics. RNA sequencing findings will allow the investigators to describe the effect of arginine on gene activity in postoperative infants

The investigators hypothesise that arginine supplementation will result in changes in gene expression that are consistent with changes in T-cell function and associated inflammatory pathways.

Condition or Disease	Intervention/Treatment	Phase
Preterm Surgery Nutritional Deficiency Immune System and Related Disorders	Dietary Supplement: Arginine	N/A

Detailed Description

Title:

Arginine Supplementation and the Postoperative Immune REsponse (ASPIRE) in neonates

Population:

Preterm infants <30 weeks gestation requiring a laparotomy/major bowel surgery before discharge; Term and near term infants (born >35 weeks gestation) requiring a laparotomy/major bowel surgery in the first 3 days of life (gastroschisis; major bowel atresias expected to require at least 7 days PN).

Number of infants:

32 infants (completing the study) will be recruited over approximately 24 months: 16 in the preterm group and 16 in the term group.

Number of sites:

Two sites - Alder Hey Children's Hospital (AHCH) and Liverpool Women's Hospital (LWH) under the umbrella of the Neonatal Partnership. Eligible infants will undergo surgery at AHCH and will receive early postoperative care at either AHCH or LWH

Study duration:

Informed consent will take place preoperatively where possible, or within 72 hours of surgery. In the term group, antenatal recruitment will be attempted. The first study related blood sample will be taken on day 3 postoperatively with the last sample taken on day 30 post-operatively. Other study assessments reflect those routinely performed in preterm infants receiving parenteral nutrition (PN).

Study intervention:

All infants will receive standard clinical treatment. 8 preterm and 8 term infants will receive PN as determined by local clinical guidelines (6.3 or 8.4% arginine content). 8 preterm infants will receive PN with an additional arginine supplement aimed to achieve 18% arginine intake (allocated according to intervention PN stock availability). 8 term infants will receive arginine supplementation up to 18%.

Primary objective:

To examine the changes in gene expression present in arginine supplemented infants between day 3 and day 10 post-operatively. Thus will be done via illumina RNA sequencing and statistical pathway analysis. The changes in gene expression will be compared with those seen between day 3 and day 10 in unsupplemented preterm and term infants. The genes of interest are those involved in immune function and inflammatory pathways.

Secondary objectives:

To explore other biological pathways i) known to be involved in the pathogenesis of necrotising enterocolitis ii) involved in arginine metabolism iii) that are related to the insulin-IGF-I axis
To determine the changes in metabolomic profiles of these infants during the first 30 days postoperatively.
Growth and body composition data during study period.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

32 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

There will be parallel assignment of supplemented parenteral nutrition (PN) and standard parenteral nutrition dependent upon stock availability of intervention PN.There will be parallel assignment of supplemented parenteral nutrition (PN) and standard parenteral nutrition dependent upon stock availability of intervention PN.

Masking:

None (Open Label)

Masking Description:

This is not blinded or randomized.

Primary Purpose:

Other

Official Title:

An Exploratory Study of Arginine Supplementation and the Postoperative Immune REsponse (ASPIRE)

Actual Study Start Date :

Apr 14, 2022

Anticipated Primary Completion Date :

Mar 1, 2024

Anticipated Study Completion Date :

Dec 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
No Intervention: Standard parenteral nutrition These infants will form the control group and will receive standard parenteral nutrition. They will be sub-stratified into gestational brackets - preterm (born <30 weeks) and term/near term.
Experimental: Arginine supplementation These infants will form the intervention group and will receive parenteral nutrition with additional arginine (up to 18% of amino acid make-up) for up to 14 days post-op. They will be sub-stratified into gestational brackets - preterm (born <30 weeks) and term/near term.	Dietary Supplement: Arginine The intervention infants will receive either parenteral nutrition which contains additional arginine (up to 18% arginine content) or a separate arginine infusion to provide up to 18% arginine. This is in comparison to standard parenteral nutrition which has an arginine content of 6.3%.

Arm

Intervention/Treatment

No Intervention: Standard parenteral nutrition

These infants will form the control group and will receive standard parenteral nutrition. They will be sub-stratified into gestational brackets - preterm (born <30 weeks) and term/near term.

Experimental: Arginine supplementation

These infants will form the intervention group and will receive parenteral nutrition with additional arginine (up to 18% of amino acid make-up) for up to 14 days post-op. They will be sub-stratified into gestational brackets - preterm (born <30 weeks) and term/near term.

Dietary Supplement: Arginine

The intervention infants will receive either parenteral nutrition which contains additional arginine (up to 18% arginine content) or a separate arginine infusion to provide up to 18% arginine. This is in comparison to standard parenteral nutrition which has an arginine content of 6.3%.

Outcome Measures

Primary Outcome Measures

Gene expression via Illumina RNA sequencing [Day 3 and 10 post-surgery]
RNA will be extracted from whole blood and sent for Illumina RNA sequencing. These sequences are then mapped to reference gene sets for gene expression analysis. The pattern of alteration in gene expression between days 3 and 10 in arginine deficient postoperative infants after correction of their deficiency by supplementation with arginine will be analysed. The changes in gene expression will be compared with those seen in unsupplemented infants. The genes of interest are those involved in T-cell function and associated inflammatory pathways. Statistical pathway analysis will be used to identify these genes and their relationship with key biological pathways.

Secondary Outcome Measures

Gene expression via Illumina RNA sequencing [Days 3, 10 and 30 post-surgery]
RNA will be extracted from whole blood and sent for Illumina RNA sequencing. These sequences are then mapped to reference gene sets for gene expression analysis. The pattern of alteration in gene expression between days 3, 10 and 30 in arginine deficient postoperative infants after correction of their deficiency by supplementation with arginine will be analysed. The changes in gene expression will be compared with those seen in unsupplemented infants. The genes of interest are those involved in T-cell function and associated inflammatory pathways. Statistical pathway analysis will be used to identify these genes and their relationship with key biological pathways. Secondary analysis will include Day 30 measurements.
Gene expression via Illumina RNA sequencing [Days 3, 10 and 30 post-surgery]
RNA will be extracted from whole blood and sent for Illumina RNA sequencing. These sequences are then mapped to reference gene sets for gene expression analysis. The pattern of alteration in gene expression between days 3, 10 and 30 in arginine deficient postoperative infants after correction of their deficiency by supplementation with arginine will be analysed. The changes in gene expression will be compared with those seen in unsupplemented infants. The genes of interest are those known to be associated with necrotising enterocolitis (NEC). Statistical pathway analysis will be used to identify these genes and their relationship with key biological pathways.
Gene expression via Illumina RNA sequencing [Days 3, 10 and 30 post-surgery]
RNA will be extracted from whole blood and sent for Illumina RNA sequencing. These sequences are then mapped to reference gene sets for gene expression analysis. The pattern of alteration in gene expression between days 3, 10 and 30 in arginine deficient postoperative infants after correction of their deficiency by supplementation with arginine will be analysed. The changes in gene expression will be compared with those seen in unsupplemented infants. The genes of interest are those known to be involved with arginine metabolism. Statistical pathway analysis will be used to identify these genes and their relationship with key biological pathways.
Blood ammonia levels [Days 3, 10 and 30 post-surgery]
Blood ammonia levels will be measured at day 3, 10 and 30 post-surgery and levels in supplemented intervention infants will be compared to unsupplemented control infants.
Plasma arginine levels [Days 3, 10 and 30 post-surgery]
Plasma arginine levels will be measured at day 3, 10 and 30 post-surgery and levels in supplemented intervention infants will be compared to unsupplemented control infants.
Plasma proline levels [Days 3, 10 and 30 post-surgery]
Proline is a urea cycle intermediate involved in arginine metabolism. Plasma proline levels will be measured at day 3, 10 and 30 post-surgery. Metabolomics profiling and analysis will be used to compare supplemented intervention infants with unsupplemented control infants.
Body composition measuring total body fluid measured in litres [Days 3, 10 and 30 post-surgery]
Body composition measurements will be taken regularly via bioelectrical impedance measuring total body fluid (intracellular and extra cellular distribution) during the study period. Results from control and intervention infants will be compared.
Body composition measuring fat free mass in grams [Days 3, 10 and 30 post-surgery]
Body composition measurements will be taken regularly via bioelectrical impedance measuring fat free mass during the study period. Results from control and intervention infants will be compared.
Growth measuring body weight in grams [Days 3, 10 and 30 post-surgery]
Infants will be weighed regularly during the study period. Measurements from control and intervention infants will be compared.

Eligibility Criteria

Criteria

Ages Eligible for Study:

22 Weeks to 44 Weeks

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Preterm infants born <30 weeks gestation requiring laparotomy/major bowel surgery before discharge
Term and near term infants (born>35 weeks gestation) requiring laparotomy/major bowel surgery in the first 3 days of life (gastroschisis; major bowel atresias expected to require at least 7 days of PN)

Exclusion Criteria:

Infants who are unlikely to survive because of poor immediate postoperative condition
Infants known (or suspected to have) a diagnosis of inborn error of metabolism or serious liver dysfunction
Parents who are unable to give informed consent