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Trial registered on ANZCTR


Registration number
ACTRN12614000492651
Ethics application status
Approved
Date submitted
15/04/2014
Date registered
12/05/2014
Date last updated
1/08/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
Hyperglycaemia in Neonates Trial:
Computer determined insulin dosage in the management of neonatal hyperglycaemia
Scientific title
In preterm babies with neonatal hyperglycaemia is a computer determined insulin dosage more effective than standard medical care in reducing episodes of insulin-induced hypoglycaemia.
Secondary ID [1] 284446 0
Nil
Universal Trial Number (UTN)
U1111-1153-9365
Trial acronym
HINT 2
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Neonatal Hyperglycaemia 291657 0
Premature birth 291685 0
Condition category
Condition code
Reproductive Health and Childbirth 292044 292044 0 0
Complications of newborn

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm 1: Computer Determined Insulin Dosage, insulin dose calculation by computer model, timing of blood glucose measurements determined by computer model.

The computer model is available on a computer tablet at the cot side. Medical staff will input the following data parameters: Gestational age, weight, current nutrition (IV dextrose and enteral feeds) and current blood glucose concentration. Using this data the model calculates current insulin sensitivity for the individual baby. Further calculations by the model will produce a suggested insulin dose which will most likely result in achieving a blood glucose concentration within the appropriate target range of 5-8 mmol / L. The model will also advise the staff when to measure the next blood glucose concentration.
Duration of intervention: for the time period the baby is receiving an insulin infusion.

Arm 2: Bedside Titration, insulin dose calculation by medical staff, timing of blood glucose measurements determined by computer model.

Medical staff will use the current standard practice for prescribing insulin. Standard practice is supported with local protocols and clinical experience. The clinicians will decide a suitable dose of insulin to be prescribed. The computer model will only be used to advise when the next blood glucose concentration should be measured.
Duration of intervention: for the time period the baby is receiving an insulin infusion.


Arm 3: Standard Care, insulin dose and timing of blood glucose measurements determined by medical staff.

Medical staff will use the current standard practice for prescribing insulin. Standard practice is supported with local protocols and clinical experience. The medical staff will also decide when the next blood glucose concentration should be measured.
Duration of intervention: for the time period the baby is receiving an insulin infusion.
Intervention code [1] 289198 0
Treatment: Other
Comparator / control treatment
Standard Medical Care
Control group
Active

Outcomes
Primary outcome [1] 291922 0
Hypoglycaemia (any blood glucose concentration < 2.6 mmol / L), detected by intermittent blood glucose monitoring.
Timepoint [1] 291922 0
While receiving an intravenous insulin infusion
Secondary outcome [1] 307830 0
Hypoglycaemia, detected by both intermittent glucose monitoring and Continuous Glucose Monitoring (CGM) (two consecutive measures < 2.6 mmol /L), and area under the glucose x time curve < 2.6 mmol.L-1min-1
Timepoint [1] 307830 0
While receiving an insulin infusion
Secondary outcome [2] 307831 0
Proportion of time blood glucose concentration is in the target range (5-8 mmol/L) detected by intermittent glucose monitoring and continuous glucose monitoring (CGM)
Timepoint [2] 307831 0
While receiving an insulin infusion
Secondary outcome [3] 307832 0
Frequency, duration and severity of hypoglycaemia detected by intermittent glucose monitoring and Continuous Glucose Monitoring (CGM)
Timepoint [3] 307832 0
While receiving an insulin infusion
Secondary outcome [4] 307833 0
Number and volume of blood transfusions
Timepoint [4] 307833 0
40 weeks’ post-menstrual age
Secondary outcome [5] 307834 0
Glycosuria (number of days on which at least one urinalysis shows greater than or equal to 2+ glucose)
Timepoint [5] 307834 0
From birth to 36 weeks’ post-menstrual age
Secondary outcome [6] 307835 0
GLP-1 plasma concentrations
Timepoint [6] 307835 0
At enrolment, 7, 14 days post enrolment and 36 weeks’ post-menstrual age.
Secondary outcome [7] 307836 0
Body composition (fat mass and fat-free mass), as assessed by air displacement plethysmography using PeaPod.
Timepoint [7] 307836 0
Measured at 36 weeks’ post-menstrual age.
Secondary outcome [8] 307837 0
Growth to 36 weeks’ post-menstrual age: weight, length, head circumference, knemometry.
Timepoint [8] 307837 0
Twice weekly until 36 weeks’ post-menstrual age
Secondary outcome [9] 307838 0
Intraventricular Haemorrhage IVH - Worst grade of periventricular haemorrhage seen on the left or right side of the head by imaging or post mortem examination during the first 14 days of life. Assessed on ultrasound by Papile classification. (ANZNN 2013)
Timepoint [9] 307838 0
First 14 days of life
Secondary outcome [10] 307839 0
Periventricular leukomalacia - Worst cystic change in left or right cerebral hemispheres measured by the ultrasound scan closest to six weeks of age. (ANZNN 2013)
Timepoint [10] 307839 0
At 6 weeks’ post-menstrual age.
Secondary outcome [11] 307840 0
Worst documented stage of retinopathy of prematurity, as determined through ophthalmological screening by International Classification of Retinopathy of Prematurity (ICROP)
Timepoint [11] 307840 0
By point of discharge home
Secondary outcome [12] 307841 0
Sepsis - a positive bacterial or fungal culture of blood and/or cerebrospinal fluid, or a positive urine culture by sterile collection AND after consideration of clinical and laboratory evidence, a decision is made to give the patient antibiotics with therapeutic intent against this organism for greater than or equal to 5 days
Timepoint [12] 307841 0
By point of discharge home
Secondary outcome [13] 307842 0
Chronic lung disease - baby received any respiratory support (supplemental oxygen or intermittent positive pressure ventilation (IPPV) or continuous positive airways pressure (CPAP) or high flow) for a chronic pulmonary disorder on the day the baby reached 36 weeks’ post-menstrual age. (ANZNN 2013.)
Timepoint [13] 307842 0
at 36 weeks’ post-menstrual age
Secondary outcome [14] 307843 0
Necrotising enterocolitis - Proven NEC
Definition (ANZNN 2013):
1) Diagnosis at surgery or post mortem, or
2) Radiological diagnosis, a clinical history plus
pneumatosis intestinalis, or portal vein gas, or a persistent dilated loop on serial X-rays, or
3) Clinical diagnosis, a clinical history plus abdominal wall cellulitis and palpable abdominal mass.
Timepoint [14] 307843 0
by point of discharge home
Secondary outcome [15] 307844 0
Neurodevelopment delay as defined by any developmental delay defined as a standardised score more than 1 SD below the mean (<-1SD)). Score used will be Bayley Scales of Infant Development Third Edition.
Timepoint [15] 307844 0
At 2 years’ corrected age

Eligibility
Key inclusion criteria
Preterm babies < 30 weeks’ gestation or <1,500 g at birth who develop hyperglycaemia (2 consecutive blood glucose concentrations greater than or equal to 10 mmol / L at least 4 h apart) whose parents give written informed consent.
Minimum age
23 Weeks
Maximum age
37 Weeks
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Congenital abnormalities likely to affect life expectancy or neurological development; previous insulin treatment; judged to be at risk of imminent death.

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)
Babies will be randomised by contacting the central website randomisation service. Assignment will be to one of three groups:
- Computer Determined Dosage (CDD)
- Bedside titration with computer tablet (Tablet Only)
- Standard Care (Control)
Randomisation will be stratified by collaborating centre and gestational age (less than 26 weeks, greater than or equal to 26 weeks).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation by using a randomisation table created by computer software.
Randomisation will be stratified by collaborating centre, weight for gestational age (small or appropriate for gestational age) and gestational age (<26 weeks, Greater than or equal to 26 weeks)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
3 Arm trial design to determine if the intervention is effective or acts as a surrogate marker for detection of hypoglycaemia due to the potential increased frequency of blood glucose measurements.
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The primary outcome of hypoglycaemia will be analysed initially by chi square test. This will be followed by a logistic regression analysis, including potentially confounding variables such as sex, birth weight z score and gestational age. Continuous data will be compared by Student’s t test or the Mann-Whitney U test if the data are not normally distributed and cannot be converted to near-normality by simple transformation. Data with repeated points, such as continuous glucose monitoring data will be compared by repeated measures ANOVA. Significance will be set at the 5% level. The data will be analysed on an intention to treat basis.

Sample size calculation:
In our previous study, 58% of babies in the tight glycaemic group with a target BGC of 4-6 mmol/L experienced hypoglycaemia, compared with 38% of babies receiving insulin with a target BGC 8-10 mmol/L21. We estimate that 50% of babies receiving insulin with a target of 5-8 mmol/L will experience hypoglycaemia. Previous work with CDD has shown an incidence of hypoglycaemia of 22% in preterm babies on insulin. To reduce the incidence of hypoglycaemia from 50% to 22% with 80% power, alpha 0.05, two tailed testing requires 46 babies in each group x 3 groups = 138 babies.
National Women’s Health has 150 potentially eligible babies a year, of whom approximately 50 will become hyperglycaemic; assuming 60% recruitment based on our previous trial = 30 babies/year. We estimate that our four collaborating centres: Middlemore Hospital, Wellington Hospital, Dunedin Hospital and Waikato Hospital, will each recruit 5-10 babies/year= 30 + 30 = 60 babies per year; this will require 2.5 years of recruitment

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/06/2014
Actual
11/10/2014
Date of last participant enrolment
Anticipated
31/03/2018
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
138
Accrual to date
Final
Recruitment outside Australia
Country [1] 6011 0
New Zealand
State/province [1] 6011 0

Funding & Sponsors
Funding source category [1] 289095 0
Charities/Societies/Foundations
Name [1] 289095 0
Cure Kids
Country [1] 289095 0
New Zealand
Funding source category [2] 289096 0
Government body
Name [2] 289096 0
Lotteries
Country [2] 289096 0
New Zealand
Primary sponsor type
University
Name
University of Auckland; Department of Paediatrics: Child and Youth Health
Address
Private Bag 92109, Auckland Mail Centre
Auckland, 1142
Country
New Zealand
Secondary sponsor category [1] 287756 0
None
Name [1] 287756 0
Address [1] 287756 0
Country [1] 287756 0
Other collaborator category [1] 277920 0
Individual
Name [1] 277920 0
Professor Geoffrey Chase
Address [1] 277920 0
Department of Mechanical Engineering, University of Canterbury, PO Box 4800 Christchurch 8140
Country [1] 277920 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290883 0
Health and Disability Ethics Committees (HDEC)
Ethics committee address [1] 290883 0
HDEC, C/- MEDSAFE, Level 6, Deloitte House, 10 Brandon Street, PO Box 5013, Wellington, New Zealand, 6145
Ethics committee country [1] 290883 0
New Zealand
Date submitted for ethics approval [1] 290883 0
Approval date [1] 290883 0
18/03/2014
Ethics approval number [1] 290883 0
14/STH/26

Summary
Brief summary
Neonatal hyperglycaemia is common in preterm babies and is associated with an increased incidence of mortality and major morbidity, which may lead to a poor neurodevelopmental outcome. Neonatal hyperglycaemia often is treated with an insulin infusion. However, there are limited data for this practice in the preterm population with no data on long-term outcomes. Furthermore, insulin increases the risk of hypoglycaemia, which is associated with poor neurodevelopmental outcome in preterm babies. Thus, on the one hand hyperglycaemia in preterm babies may be associated with adverse outcomes, but on the other hand the most common treatment for hyperglycaemia, insulin therapy, increases the risk of hypoglycaemia, which also may increase the risk of adverse neurodevelopmental outcomes.
A computer model that determines insulin dosing based on insulin sensitivity and nutritional intake in hyperglycaemic preterm babies has been developed by bioengineers at the University of Canterbury. This technique has been shown to reduce the risk of hypoglycaemia compared with historic controls and is now in routine use at Christchurch Women’s Hospital NICU. However, further testing is required to show the model is effective before it is incorporated into clinical practice throughout New Zealand and internationally.
We propose a randomised, controlled trial of computer determined insulin dosage in hyperglycaemic preterm babies to determine if this technique reduces the risk of hypoglycaemia, and improves neonatal growth and long-term outcome. If this technique is proven to be successful this could provide a safer way of administering insulin in vulnerable preterm babies, potentially improving neurodevelopmental outcome.
Trial website
Trial related presentations / publications
Williamson KA, Bloomfield FH, Chase G, Harding JE, Alsweiler JM. Computer determined insulin dosing in hyperglycaemic preterm babies. Proceedings of the Impact Workshop, Perinatal Society of Australia and New Zealand; 2014 April 5-9; Perth, Australia.
Public notes

Contacts
Principal investigator
Name 47762 0
Dr Jane Alsweiler
Address 47762 0
Department of Paediatrics: Child and Youth Health
University of Auckland
Private Bag 92109, Auckland Mail Centre
Auckland 1142
New Zealand
Country 47762 0
New Zealand
Phone 47762 0
+64 9 373 7599 ext 87766
Fax 47762 0
Email 47762 0
[email protected]
Contact person for public queries
Name 47763 0
Kathryn Williamson
Address 47763 0
Department of Paediatrics: Child and Youth Health, University of Auckland
Private Bag 92109 Auckland Mail centre
Auckland 1142
New Zealand
Country 47763 0
New Zealand
Phone 47763 0
+64 9 373 7599 ext 87766
Fax 47763 0
Email 47763 0
[email protected] or [email protected]
Contact person for scientific queries
Name 47764 0
Kathryn Williamson
Address 47764 0
Department of Paediatrics: Child and Youth Health, University of Auckland
Private Bag 92109 Auckland Mail centre
Auckland 1142
New Zealand
Country 47764 0
New Zealand
Phone 47764 0
+64 9 373 7599 ext 87766
Fax 47764 0
Email 47764 0
[email protected]

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