Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622001297718p
Ethics application status
Submitted, not yet approved
Date submitted
27/09/2022
Date registered
6/10/2022
Date last updated
6/10/2022
Date data sharing statement initially provided
6/10/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Does delaying starting protein benefit late preterm and term surgical newborns?
Scientific title
The effect of late versus early initiation of amino acids on length of Neonatal Intensive Care Unit (NICU) stay in late preterm and term surgical newborns
Secondary ID [1] 307997 0
Nil known
Universal Trial Number (UTN)
U1111-1282-9923
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
NICU Dependency 327666 0
Condition category
Condition code
Reproductive Health and Childbirth 324749 324749 0 0
Complications of newborn
Diet and Nutrition 324750 324750 0 0
Other diet and nutrition disorders
Inflammatory and Immune System 324804 324804 0 0
Other inflammatory or immune system disorders
Infection 324805 324805 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
10% Glucose + Heparin (days 1 and 2) then 10% Glucose + Heparin with electrolytes (days 3-7) plus 17% SMOFlipid® (Fish Oil-Rich in OMEGA-3 Acids, Medium Chain Triglycerides, Olive Oil, Soya Oil)/vitalipid fat emulsion will be provided to infants randomised to the intervention arm. The initial 10% Glucose + Heparin will contain 1U Heparin/ml. The total dose of heparin administered will be dependent on the volume of glucose required to maintain normoglycemia and appropriate electrolyte balance. The 10% Glucose + Heparin and electrolytes will also contain 1U Heparin/ml in addition to Potassium 1mmol/50ml and 0.225% sodium chloride. Again, the total dose of heparin, potassium and sodium chloride administered will be dependent on the volume of glucose required to maintain normoglycemia and appropriate electrolyte balance.
The 17% SMOFlipid®/Vitalipid will commence at 0.5 g/kg/day on day 1, increasing daily up to 3 g/kg/day. The 17% SMOFlipid® solution contains SMOFlipid 20% 36ml, Vitalipid N Infant 11.2ml and Soluvit N 2.8ml per 50 ml.

For both groups the total fluid intake will commence at 45 mL/kg/day, increasing up to 150 mL/kg/day to maintain appropriate glucose and electrolyte balance. Each infant will receive their allocated nutritional intervention until postoperative day 7. Enteral feeds may commence at any time with the initiation and increase in volume as per centre practice with corresponding reduction in the administration of the 10% Glucose + Heparin with electrolytes solution as per normal nursery practice.

The 10% Glucose + Heparin (days 1 and 2) then 10% Glucose + Heparin with electrolytes (days 3-7) plus 17% SMOFlipid® will be prescribed by the attending Neonatologist. Administration will be via peripheral central venous catheter as per normal clinical practice at the study site. Adherence to the allocated intervention will be achieved through daily audit of the participants medical records.

From post-operative day 8 following the completion of the intervention period any participants still requiring parenteral nutrition will be prescribed standard total parenteral nutrition comprising 23g Amino Acid (as Primene) / 1000ml (Baxter 34 weeks to term parenteral nutrition as per 2022 Australia and New Zealand Neonatal Consensus Group PN Solutions) plus 17% SMOFlipid®/vitalipid fat emulsion. The Baxter 34 weeks to term parenteral nutrition solution contains Amino acid (as primene) 23g/l, Glucose 100g/l, Nitrogen 3.5g/l, Sodium 25 mmol/l, Potassium 20 mmmol/l, Magnesium 1.5 mmol/l, Calcium 9 mmol/l, Chloride 22.9 mmol/l, Phosphate 9 mmol/l, Acetate 8.5 mmol/l, Zinc 395.83 microgram/l, Heparin 500U/l, Paediatric Trace Elements 0.9 Units/l.
Intervention code [1] 324451 0
Treatment: Other
Comparator / control treatment
Parenteral nutrition (Baxter® 34 weeks to term parenteral nutrition as per 2022 Australia and New Zealand Neonatal Consensus Group PN Solutions) plus 17% SMOFlipid® /vitalipid fat emulsion. The Baxter 34 weeks to term parenteral nutrition solution contains Amino acid (as primene) 23g/l, Glucose 100g/l, Nitrogen 3.5g/l, Sodium 25 mmol/l, Potassium 20 mmmol/l, Magnesium 1.5 mmol/l, Calcium 9 mmol/l, Chloride 22.9 mmol/l, Phosphate 9 mmol/l, Acetate 8.5 mmol/l, Zinc 395.83 microgram/l, Heparin 500U/l, Paediatric Trace Elements 0.9 Units/l..
17% SMOFlipid®/Vitalipid will commence at 0.5 g/kg/day on day 1, increasing daily up to 3 g/kg/day. Total fluid intake will commence at 45 mL/kg/day, increasing up to 150 mL/kg/day to maintain appropriate glucose and electrolyte balance. Each infant will receive their allocated nutritional intervention until postoperative day 7. Enteral feeds may commence at any time with the initiation and increase in volume as per centre practice.

Parenteral nutrition (Baxter® 34 weeks to term parenteral nutrition as per 2022 Australia and New Zealand Neonatal Consensus Group PN Solutions) plus 17% SMOFlipid® will be prescribed by the attending Neonatologist. Adminsitration will be via peripheral central venous catheter as per normal clinical practice at the study site. Adherence to the allocated intervention will be achieved through daily audit of the participants medical records.
Control group
Active

Outcomes
Primary outcome [1] 332569 0
Duration of NICU dependency. This data will be colected from the participants medical records and reported as the crude number of NICU-stay days and time to live discharge from NICU, to account for mortality as a competing risk. The ‘time to discharge’ will be defined as the ‘time to readiness for discharge from NICU’, defined as lack of need for mechanical ventilatory or hemodynamic support or invasive blood pressure monitoring.
Timepoint [1] 332569 0
NICU discharge
Secondary outcome [1] 413947 0
Time to (live) discharge from hospital including stay at the referral hospital (if applicable) recorded from the subjects medical record.
Timepoint [1] 413947 0
At primary hospital discharge
Secondary outcome [2] 413948 0
Time to final (live) weaning from mechanical respiratory support recorded from the subjects medical record.
Timepoint [2] 413948 0
At NICU discharge.
Secondary outcome [3] 413949 0
Time to (live) weaning from a composite of pharmacological or mechanical haemodynamic support during NICU stay from the subjects medical record
Timepoint [3] 413949 0
At NICU discharge.
Secondary outcome [4] 413951 0
Number of re-admissions to NICU (both readmission within 48 hours and beyond 48 hours during their primary hospital admission) from the subjects medical record.
Timepoint [4] 413951 0
At primary hospital discharge
Secondary outcome [5] 413952 0
Duration of antibiotic treatment (whenever given) within the intervention period recorded from the subjects medical record.
Timepoint [5] 413952 0
At NICU discharge
Secondary outcome [6] 413953 0
Nutrition received during NICU stay including macronutrients and calories administered during the intervention window as well as amounts administered parenterally and enterally recorded from the subjects medical record.
Timepoint [6] 413953 0
At NICU discharge.
Secondary outcome [7] 414019 0
Weight Z-score at first discharge home recorded from the subjects medical record.
Timepoint [7] 414019 0
At primary hospital discharge
Secondary outcome [8] 414020 0
Incidence of sepsis will be determined from review of the participants medical records.
Timepoint [8] 414020 0
At primary hospital discharge
Secondary outcome [9] 414021 0
All cause mortality after enrolment
Timepoint [9] 414021 0
Time of death following enrolment assessed up until primary hospital discharge
Secondary outcome [10] 414379 0
Duration of antibiotic treatment during total NICU stay recorded from the subjects medical record
Timepoint [10] 414379 0
At NICU discharge
Secondary outcome [11] 414380 0
Nutrition received during total NICU stay including macronutrients and calories administered during total NICU stay as well as amounts administered parenterally and enterally recorded from the subjects medical record.
Timepoint [11] 414380 0
At NICU discharge
Secondary outcome [12] 414381 0
length Z-score at first discharge home recorded from the subjects medical record.
Timepoint [12] 414381 0
At primary hospital discharge
Secondary outcome [13] 414382 0
Head circumference Z-score at first discharge home recorded from the subjects medical record.
Timepoint [13] 414382 0
At primary hospital discharge

Eligibility
Key inclusion criteria
Infants born >34 weeks gestation (inborn or outborn).
Confirmation of a surgical diagnosis requiring operative intervention.
The need for Parenteral nutrition.
Informed parental consent.
Minimum age
34 Weeks
Maximum age
42 Weeks
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Expected death within 24 hours.
Re-admission to NICU following previous randomisation.

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Participating centres pharmacy departments will provide both the intervention and standard care components with identical volume and packaging, labeled as study intervention A or B. As both trial arms receive SMOF/vitalipid fat emulsion allocation concelament can be maintained for parents, all nursery and research staff. The randomisation schedule will be concealed in opaque allocation envelopes provided by the data coordinating centre. Envelopes will list the site ID and randomisation code. Envelopes in each stratum will be sequentially assigned to infants. Treatment allocation will be listed as A or B to maintain allocation concealment but while allowing nursery staff to request study product A or B from pharmacy staff following randomisation and prescription. To ensure compliance to randomisation arm is maintained and safety is ensured, the hospital pharmacy will remain unblinded to study allocation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A computer generated randomisation schedule using balanced variable block design (block size 4 to 6), with an allocation ratio of 1:1 will be generated by an independent statistician not involved with trial participants of data analysis. Stratification will occur for surgical diagnosis (cardiac surgery or other) and study centre.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
A data safety monitoring committee (DSMC) will review the study data at 50 % recruitment to assess the safety of the intervention. A blinded sample size review will be performed at 33 % follow-up (coinciding with projected end recruitment) and the sample size increased if required. All deaths, irrespective of the cause will be required to be reported by trial sites as serious adverse events. The DSMC may stop the trial if there are concerns that the study intervention is harmful to the patient, as defined prospectively in the charter. All adverse events will be reported to the respective ethics Committee and the DSMC.
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
The sample size, based on the mean (SD) data for the duration of NICU admission (11.6 (5.56) days) for eligible neonates at the WCH Adelaide is comparable to data from the PEPaNIC trial. To detect a 30% reduction in NICU admission days, similar to the PEPaNIC trial sub-group analysis for newborns less than 28 days of age, with alpha =.05, beta =.2 and 90% power, a sample size of 106 (53 per arm) is required.

Analyses will be performed according to a pre-specified statistical analysis plan, written to conform with recent recommendations on the content of clinical trial analysis plans (Gamble C, Krishan A, Stocken D, Lewis S, Juszczak E, Dore C, et al. Guidelines for the Content of Statistical Analysis Plans in Clinical Trials. JAMA. 2017;318(23):2337-2343.). Analyses will follow the intention to treat principle, with all participants included in later analysis irrespective of protocol compliance. Primary and secondary outcomes will be analysed using linear, log-binomial and negative binomial regression models for continuous, binary and count outcomes, respectively. An adjustment will be made for variables used to stratify the randomisation strata (study centre, surgical diagnosis), with the difference between groups expressed as a relative risk with a confidence interval and two-sided p-value. Statistical significance will account for a single pre-specified interim analysis using the O’Brien Fleming approach.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
3/07/2023
Actual
Date of last participant enrolment
Anticipated
30/01/2026
Actual
Date of last data collection
Anticipated
27/02/2026
Actual
Sample size
Target
106
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC
Recruitment hospital [1] 23212 0
Womens and Childrens Hospital - North Adelaide
Recruitment hospital [2] 23213 0
Mater Mother's Hospital - South Brisbane
Recruitment hospital [3] 23214 0
Monash Children’s Hospital - Clayton
Recruitment hospital [4] 23215 0
The Children's Hospital at Westmead - Westmead
Recruitment postcode(s) [1] 38578 0
5006 - North Adelaide
Recruitment postcode(s) [2] 38579 0
4101 - South Brisbane
Recruitment postcode(s) [3] 38580 0
3168 - Clayton
Recruitment postcode(s) [4] 38581 0
2145 - Westmead

Funding & Sponsors
Funding source category [1] 312279 0
Hospital
Name [1] 312279 0
Women's and Children's Hospital - North Adelaide
Country [1] 312279 0
Australia
Primary sponsor type
University
Name
The University of Adelaide
Address
230 North Terrace
Adelaide,
South Australia,
5005
Country
Australia
Secondary sponsor category [1] 313803 0
None
Name [1] 313803 0
Address [1] 313803 0
Country [1] 313803 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 311636 0
Women's and Children's Health Network Human Research Ethics Committee
Ethics committee address [1] 311636 0
Ethics committee country [1] 311636 0
Australia
Date submitted for ethics approval [1] 311636 0
19/09/2022
Approval date [1] 311636 0
Ethics approval number [1] 311636 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 121802 0
A/Prof Michael Stark
Address 121802 0
The Robinson Research Institute,
55 King William Road
North Adelaide
South Australia
5006
Country 121802 0
Australia
Phone 121802 0
+61 8 83131325
Fax 121802 0
Email 121802 0
[email protected]
Contact person for public queries
Name 121803 0
Tara Crawford
Address 121803 0
The Robinson Research Institute,
55 King William Road
North Adelaide
South Australia
5006
Country 121803 0
Australia
Phone 121803 0
+61 8 83131418
Fax 121803 0
Email 121803 0
[email protected]
Contact person for scientific queries
Name 121804 0
Michael Stark
Address 121804 0
The Robinson Research Institute,
55 King William Road
North Adelaide
South Australia
5006
Country 121804 0
Australia
Phone 121804 0
+61 8 83131325
Fax 121804 0
Email 121804 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Clinical characteristics, study arm allocation, clinical outcomes
When will data be available (start and end dates)?
Completion of the primary outcome - projected February 2026. There will be no end date for data availability.
Available to whom?
Only researchers who provide a methodologically sound proposal, case-by-case basis at the discretion of the study chief investigators.
Available for what types of analyses?
IPD meta-analysis, systematic review
How or where can data be obtained?
Access will be subject to approvals by the principle investigator and study chief investigators following formal application. Initial contact with the principle investigator will be by email ([email protected]) with formal submission of the request reviewed by the trial steering committee.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.