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Trial registered on ANZCTR


Registration number
ACTRN12620000324910
Ethics application status
Approved
Date submitted
20/02/2020
Date registered
9/03/2020
Date last updated
9/03/2020
Date data sharing statement initially provided
9/03/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Early versus late parenteral nutrition in term and late preterm infants: A Randomized Controlled Trial
Scientific title
Early versus late parenteral nutrition in term and late preterm infants: A Randomized Controlled Trial
Secondary ID [1] 300613 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
critical illness 316376 0
Condition category
Condition code
Diet and Nutrition 314634 314634 0 0
Other diet and nutrition disorders
Reproductive Health and Childbirth 314695 314695 0 0
Complications of newborn

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
‘Late Parenteral Nutrition (PN)’
Infants randomised to ‘Late PN’ will commence PN only after the completion of Day 5 (i.e.120 hours) of NICU admission.
If an infant randomised to ‘late PN’ does not require PN after Day 5, the infant will still be included as being in the ‘Late PN’ group and analysed as such.

PN will be defined as the administration of any amount of intravenous amino acids and/or lipid emulsion. Administration of PN is either via peripheral intravenous cannula or central venous access device. Prescription of PN (including type of PN, dosage and rate of administration) will be determined by the treating clinician on a daily basis, depending on the infant’s clinical progress and according to the KEMH/PCH Neonatology Guidelines (Nutrition: Volume and Nutritional Requirements AND Parenteral Nutrition.
All PN formulations will be prepared by the Pharmacy Department at PCH or an external compounding provider. PN may be ‘Standard PN’ or ‘Non- standard PN’. ‘Standard PN’ consists of predetermined amounts of glucose, amino acids and standard concentrations of electrolytes, trace elements, vitamins and heparin. If clinically indicated, ‘Non-standard PN’ may be ordered by the treating clinician to allow modifications. SMOF 17% consisting of soya oil (30%), medium chain triglyceride (30%), refined olive oil (25%) and fish oil (15%) will be used as the source of parenteral lipids. Both fat soluble (Soluvit N®) and water soluble vitamins (Vitalipid N®) will be added to the lipid emulsion (SMOF®).
Infants randomised to the ‘early PN’ group will receive PN formulation as prescribed by the treating doctor within the 48 hours of admission to NICU.
Infants randomised to the ‘late PN’ group, will receive glucose and sodium chloride solutions at a rate, as per infant’s needs up to Day 5 and then commence PN from Day 6 of admission to NICU.
PN will be prescribed by NICU registrar/senior registrar/consultant and administered by NICU nursing staff according to the KEMH/PCH Neonatology Guidelines: Volume and Nutritional Requirements. Administration of PN and glucose, sodium and other electrolytes will be titrated according to routine biochemical results (examples: blood glucose, serum sodium, potassium, magnesium, calcium) by the treating clinician.
All PN charts will be reviewed daily by the research team to ensure each prescription is ordered, prepared and administered correctly.
Intervention code [1] 316926 0
Treatment: Other
Comparator / control treatment
‘Early Parenteral Nutrition (PN)’
Infants randomised to ‘Early PN’ will be commenced PN within Day 2 (i.e. 48 hours) of admission to NICU.
Control group
Active

Outcomes
Primary outcome [1] 322960 0
Plasma phenylalanine levels
measured by performing amino acid analysis using ultra performance binary liquid chromatography
Timepoint [1] 322960 0
Day 4 and Day 8 of admission
Primary outcome [2] 322961 0
Plasma F2- isoprostanes levels
measured by GC coupled to electron-capture negative-mode chemical ionisation and MS (GC/MS)
Timepoint [2] 322961 0
Day 4 and Day 8 of admission
Secondary outcome [1] 380365 0
Total and individual plasma amino acid levels
composite endpoint
measured by performing amino acid analysis using ultra performance binary liquid chromatography
Timepoint [1] 380365 0
Day 4 and Day 8 of admission
Secondary outcome [2] 380366 0
Plasma fatty acid profiles
composite endpoint
measured by gas chromatography
Timepoint [2] 380366 0
Day 4 and Day 8 of admission
Secondary outcome [3] 380367 0
In-hospital all-cause mortality: defined as death from any cause during the initial hospital stay
measured by reviewing medical records.
Timepoint [3] 380367 0
During hospital stay
Secondary outcome [4] 380368 0
Healthcare-associated bloodstream infection (HABSI): defined as positive culture on a blood sample drawn 48 hours after admission to the ICU

Determined by reviewing medical records
Timepoint [4] 380368 0
During hospital stay
Secondary outcome [5] 380369 0
Length of hospital stay (days)
Length of hospital stay will be determined by reviewing medical records
Timepoint [5] 380369 0
During hospital stay
Secondary outcome [6] 380370 0
Weight at the time of discharge from the hospital (Z-scores)
Weight will be measured using a baby scale and then converted to Z-score by using Fenton 2013 growth charts (https://peditools.org/fenton2013/).
Timepoint [6] 380370 0
At discharge
Secondary outcome [7] 380371 0
Duration of respiratory support [defined as mechanical ventilation via endotracheal tube OR non-invasive positive-pressure ventilation (NIPPV) OR continuous positive airway pressure (CPAP) OR humidified high-flow nasal prong (HFNP) therapy in days]

Duration of respiratory support will be determined by reviewing medical records..
Timepoint [7] 380371 0
During hospital stay
Secondary outcome [8] 380372 0
Incidence of hypoglycaemia (plasma glucose < 45 mg/dL (2.6 mmol/L)

Determined by reviewing medical records.
Timepoint [8] 380372 0
During hospital stay
Secondary outcome [9] 380373 0
Liver function outcomes
Incidence of liver dysfunction [raised liver function tests including total bilirubin, alkaline phosphatase, gamma-glutamyltransferase , alanine transferase, and aspartate aminotransferase]
Determined by reviewing medical records.

Timepoint [9] 380373 0
During hospital stay
Secondary outcome [10] 380374 0
Highest blood urea nitrogen levels during hospital stay (Urea/2.14; mmol/L)
Determined by reviewing medical records.
Timepoint [10] 380374 0
During hospital stay
Secondary outcome [11] 380375 0
Highest C reactive protein (mg/L)
Determined by reviewing medical records
Timepoint [11] 380375 0
During hospital stay
Secondary outcome [12] 380552 0
Neonatal mortality (death in the first 28 days of birth from any cause)
Determined by reviewing medical records
Timepoint [12] 380552 0
28 days from birth
Secondary outcome [13] 380553 0
Incidence of hyperglycaemia (plasma glucose > 150 mg/dL (8.3 mmol/L)
determined by reviewing medical records
Timepoint [13] 380553 0
during hospital stay
Secondary outcome [14] 380554 0
Other types of hospital-acquired infection [e.g. ventilator-associated pneumonia, cerebrospinal fluid (CSF) infection, urinary tract infection (UTI), surgical site infection and fungal infection]: defined as positive growth on blood culture or CSF or sterile urine or wound swabs)
Determined by reviewing medical records.
Timepoint [14] 380554 0
during hospital stay
Secondary outcome [15] 380555 0
Duration of NICU stay (days)
Duration of NICU will be determined by reviewing medical records.
Timepoint [15] 380555 0
during hospital stay
Secondary outcome [16] 380556 0
Length at the time of discharge from the hospital (Z-scores)
Length will be measured by using a baby scale and then converted to Z-score by using Fenton 2013 growth charts (https://peditools.org/fenton2013/).
Timepoint [16] 380556 0
At discharge
Secondary outcome [17] 380557 0
Head circumference at the time of discharge from the hospital (Z-scores)
Head circumference will be measured by using a tape measure and then converted to Z-score by using Fenton 2013 growth charts (https://peditools.org/fenton2013/).
Timepoint [17] 380557 0
At discharge
Secondary outcome [18] 380558 0
Changes in length from baseline at discharge (Changes in Z scores)
Length will be measured by using a baby scale and then converted to Z-score by using Fenton 2013 growth charts (https://peditools.org/fenton2013/).
Timepoint [18] 380558 0
At discharge
Secondary outcome [19] 380559 0
Changes in head circumference from baseline at discharge (Changes in Z scores)
Head circumference will be measured by using a tape measure and then converted to Z-score by using Fenton 2013 growth charts (https://peditools.org/fenton2013/).
Timepoint [19] 380559 0
On admission and at discharge
Secondary outcome [20] 380560 0
Changes in weight from baseline at discharge (Changes in Z scores)
Weight will be measured by using a baby scale and then converted to Z-score by using Fenton 2013 growth charts (https://peditools.org/fenton2013/).
Timepoint [20] 380560 0
During hospital stay
Secondary outcome [21] 380672 0
Highest blood glucose level (mmol/L)
Determined by reviewing medical records.
Timepoint [21] 380672 0
During admission
Secondary outcome [22] 380673 0
Lowest blood glucose level (mmol/L)
Determined by reviewing medical records.
Timepoint [22] 380673 0
During hospital stay
Secondary outcome [23] 380674 0
Incidence of cholestasis: defined as serum level of direct bilirubin>20% of total serum bilirubin or serum level of direct bilirubin > 34 mmol/L
Determined by reviewing medical records.
Timepoint [23] 380674 0
During hospital stay
Secondary outcome [24] 380675 0
Highest plasma level of total bilirubin during hospital stay (mmol/L)
Determined by reviewing medical records.
Timepoint [24] 380675 0
During hospital stay
Secondary outcome [25] 380677 0
Highest plasma level of alkaline phosphatase during hospital stay (IU/L)
Determined by reviewing medical records,
Timepoint [25] 380677 0
During hospital stay
Secondary outcome [26] 380678 0
Highest plasma level of gamma-glutamyl-transferase during hospital stay (IU/L)
Determined by reviewing medical records.
Timepoint [26] 380678 0
During hospital stay
Secondary outcome [27] 380679 0
Highest plasma level of alanine transferase (IU/L)
Determined by reviewing medical records.
Timepoint [27] 380679 0
During hospital stay
Secondary outcome [28] 380680 0
Highest plasma level of aspartate aminotransferase (IU/L)
Determined by reviewing medical records.
Timepoint [28] 380680 0
During hospital stay
Secondary outcome [29] 380681 0
Duration of ventilation (days): defined as mechanical ventilation via endotracheal tube or NIPPIV
Duration of ventilation will be determined by reviewing medical records.
Timepoint [29] 380681 0
During hospital stay
Secondary outcome [30] 380682 0
Duration of inhaled nitric oxide therapy (hours)
Duration of inhaled nitric oxide therapy will be determined by reviewing medical records.
Timepoint [30] 380682 0
During hospital stay
Secondary outcome [31] 380683 0
Duration of inotrope support (hours)
Duration of inotrope support will be determined by reviewing medical records.
Timepoint [31] 380683 0
During hospital stay
Secondary outcome [32] 380684 0
Incidence of metabolic acidosis (pH< 7.25 or base excess <-5)
Incidence of metabolic acidosis will be determined by reviewing medical records.
Timepoint [32] 380684 0
During hospital stay
Secondary outcome [33] 380685 0
Red cell fatty acid profiles
Red cell fatty acid profiles will be measured by gas chromatography
Timepoint [33] 380685 0
Day 4 and Day 8 of admission

Eligibility
Key inclusion criteria
Infants will be eligible for study inclusion it they meet all of the following inclusion criteria: (1) All term or late preterm infants, born >=34 weeks of gestation at birth until day 28 of life admitted to NICU who have high likelihood of being unable to tolerate full enteral feeds for at least three to five days and hence require parenteral nutrition (PN) (2) Informed parental/legal guardian consent
Minimum age
0 Days
Maximum age
28 Days
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Infants will be excluded from participation in the trial if they meet any one or more of the following exclusion criteria: (1) Infants > 28 days of life; (2) Preterm infants (born at <34 weeks of gestation); (3) Infants who received PN from a referring hospital; (4) Infants with suspected inborn error of metabolism.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation concealment will be achieved by using opaque sealed envelopes. Once consent is provided, the CPI will open the next opaque sealed envelope to allocate the infant to either ‘Early PN’ or ‘Late PN’ group.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Group assignment will be allocated by the Clinical Trial Pharmacist at Perth Children's Hospital using a computer-generated randomisation sequence in a 1:1 ratio in block sizes of 2 and 4 and stratified according to the primary diagnostic category (medical or surgical) in order to minimise selection bias.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Data will be analysed by the trial biostatistician. The primary ANCOVA analyses will assess differences between the two PN groups in log-transformed F2 isoprostane and phenylalanine levels at Days 4 and 8. Covariate adjustment will be made for baseline F2 isoprostane/phenylalanine, sex, gestational age, medical/surgical group, term/late term group, daily PN doses, and severity of illness scores (SNAPPE-II).
Linear regression will be used for analysis of the secondary continuous outcomes (amino acid and fatty acid profiles; growth outcomes; highest BUN/CRP/ LFTs/blood glucose). Trajectories of F2 isoprostane, plasma amino acids and fatty acids will be examined within a mixed effects regression framework to take account of the multiple measures per child. Logistic regression will be used to derive odds ratios for binary outcomes (mortality, incidence of infection/elevated LFTs/metabolic acidosis). Morbidity and respiratory outcomes (duration of hospital/NICU stay, duration of respiratory support/mechanical ventilation) will be analysed as time-to-event data using Cox regression, with data censored at 90 days for non-survivors and survivors not reaching the endpoint within that time. Regression analyses will assess PN group differences in an uncorrected manner, as well as (jointly) adjusted for risk factors including sex, gestational age, medical/surgical group, term/late term group, daily PN doses, and severity of illness scores (SNAPPE-II). Associations of the biochemical markers (F2 isoprostane, plasma amino acids and fatty acids) with the main clinical outcomes will also be explored by appropriate regression analyses.
Summary statistics for main outcome measures will include 95% confidence intervals, and for all endpoints differences between PN groups will be considered statistically significant whenever the p-value is lower than 0.05 without correction for multiple testing. Baseline characteristics of study participants will be reported as percentages for categorical outcomes, and mean (standard deviation) for normally distributed continuous outcomes or median (interquartile range) for skewed continuous outcomes.

Cost analysis

The results of this RCT will be used to perform a cost analysis from an Australian public hospital perspective. We will estimate and compare the total direct medical costs associated with early versus late PN by using a micro-costing method. Medical cost types will include 1) NICU hospitalisation; 2) Total duration of hospitalisation; 3) Mechanical ventilation support; 4) Respiratory support; 5) Renal replacement therapy; 6) Haemodynamic support; 7) Surgery; 8) Medications; 9) PN; 10) Consultations from another specialist; 11) HABSI. The primary endpoint is the difference in total direct medical costs between early and late PN. Actual medical costs will be calculated by multiplying the volumes of health care use with the corresponding unit prices, obtained from a Senior Data Analyst of the Business Intelligence Unit, Child Adolescent Health Service. We will perform subgroup analysis for medical and surgical infants and for each major condition within the subgroups.
The cost analyses will be based on the Australian guidelines for performing economic evaluations79. Consolidated Health Economic Reporting Standards (CHEERS) statements will be followed for reporting the results in a peer reviewed journal.


Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 15934 0
Perth Children's Hospital - Nedlands
Recruitment postcode(s) [1] 29416 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 305032 0
University
Name [1] 305032 0
University of Western Australia
Address [1] 305032 0
35 Stirling Hwy, Crawley, Western Australia, 6009
Country [1] 305032 0
Australia
Funding source category [2] 305034 0
Hospital
Name [2] 305034 0
Perth Children's Hopsital
Address [2] 305034 0
15 Hospital Ave, Nedlands, WA, 6009
Country [2] 305034 0
Australia
Primary sponsor type
Hospital
Name
Perth Children's Hospital
Address
15 Hospital Ave, Nedlands, 6009
Country
Australia
Secondary sponsor category [1] 305394 0
University
Name [1] 305394 0
University of Western Australia
Address [1] 305394 0
35 Stirling Hwy, Crawley, WA, 6009
Country [1] 305394 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305428 0
Child and Adolescent Health Service HREC
Ethics committee address [1] 305428 0
15 Hospital Ave, Nedlands, WA, 6009
Ethics committee country [1] 305428 0
Australia
Date submitted for ethics approval [1] 305428 0
17/09/2019
Approval date [1] 305428 0
01/11/2019
Ethics approval number [1] 305428 0
RGS3537

Summary
Brief summary
During periods of acute illness in term (= 37 weeks’ gestation) and late preterm infants (between 34 to 37 weeks’ gestation), provision of sufficient enteral nutrition is unachievable, which necessitates the use of parenteral nutrition (PN). PN involves the administration of glucose, amino acids, lipids and various micronutrients. More than 200 babies receive PN in the Neonatal Intensive Care Unit (NICU) at Perth Children’s Hospital (PCH) each year, accounting for up to 1400 PNs annually.
In very preterm infants (< 32 weeks’ gestation), nutrition has been extensively researched and hence there is adequate evidence recommending early commencement of PN. However, there is a lack of evidence regarding the optimal time to commence PN therapy in term and late preterm infants. Hence, there are no clinical guidelines for this population. Moreover, nutritional reserve, requirements and morbidity of very preterm infants are different to that of term and late preterm infants. Therefore, it is inappropriate to extrapolate the nutritional recommendations of very preterm infants to term and late preterm infants.
The potential benefits of early amino acids include the prevention of catabolism, reduction in hypoglycaemia, improved growth and neurodevelopmental outcomes. Potential harms associated with early amino acids include hyperammonaemia, azotaemia, and metabolic acidosis.
The potential benefits of early lipids include the prevention of essential fatty acid (EFA) deficiency, improve nutrition, increase long chain polyunsaturated fatty acids (LCPUFA) and improved neurodevelopmental outcomes. Potential harms associated with early lipids include increased risk of sepsis, worsening of pulmonary hypertension and respiratory function.
Therefore, we plan to conduct a randomised controlled trial (RCT) that evaluates the benefits and risks of early versus late PN in term and late preterm infants by comparing relevant biochemical and clinical outcomes. We will also conduct a cost analysis of early versus late PN from a Western Australian (WA) public hospital perspective.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 100346 0
Ms Kwi Moon
Address 100346 0
Pharmacy Department
Perth Children's Hospital
15 Hospital Ave, Nedlands, WA, 6009
Country 100346 0
Australia
Phone 100346 0
+61 8 6456 2222
Fax 100346 0
Email 100346 0
Kwi.Moon@health.wa.gov.au
Contact person for public queries
Name 100347 0
Ms Kwi Moon
Address 100347 0
Pharmacy Department
Perth Children's Hospital
15 Hospital Ave, Nedlands, WA, 6009
Country 100347 0
Australia
Phone 100347 0
+61 8 6456 2222
Fax 100347 0
Email 100347 0
Kwi.Moon@health.wa.gov.au
Contact person for scientific queries
Name 100348 0
Ms Kwi Moon
Address 100348 0
Pharmacy Department
Perth Children's Hospital
15 Hospital Ave, Nedlands, WA, 6009
Country 100348 0
Australia
Phone 100348 0
+61 8 6456 2222
Fax 100348 0
Email 100348 0
Kwi.Moon@health.wa.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
No Results