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Trial registered on ANZCTR


Registration number
ACTRN12620000129987
Ethics application status
Approved
Date submitted
22/12/2019
Date registered
11/02/2020
Date last updated
11/02/2020
Date data sharing statement initially provided
11/02/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Diazoxide for babies with severe or recurrent low blood glucose: The Neonatal Glucose Care Optimisation (NeoGluCO) Study (I).
Scientific title
Oral diazoxide versus placebo to reduce time to succesful metabolic transition in neonates with severe or recurrent hypoglycaemia: The Neonatal Glucose Care Optimisation (NeoGluCO) Study (I).
Secondary ID [1] 300109 0
Nil known
Universal Trial Number (UTN)
U1111-1242-9558
Trial acronym
NeoGluCO Study-I
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Neonatal hypoglycaemia 315644 0
Condition category
Condition code
Metabolic and Endocrine 313933 313933 0 0
Other metabolic disorders
Reproductive Health and Childbirth 314144 314144 0 0
Complications of newborn

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Diazoxide 10 mg/ml as clear suspension. Babies will be loaded with 0.5 ml/kg (diazoxide 5 mg/kg) orally or by gastric tube and then commenced on a maintenance dose of 0.15 ml/kg (diazoxide 1.5 mg/kg) every 12 hours. The study intervention will be prescribed on hospital charts and administered by nurses or midwives. It will be weaned by protocol with the aim of maintaining glucose concentration from 2.6 to 5 mmol/L and weaning intravenous dextrose and commencing enteral feeding as soon as possible. If glucose concentration is <2.6, dose will increase to 0.25 ml/kg; if 5.1 to 6.9, dose will be withheld; if 7.0 or more the intervention will be stopped. Weekly dose adjustment for weight will be made, if required, once the baby returns to birthweight. The intervention will continue until the primary outcome is reached, up to a maximum of four weeks.
Intervention code [1] 316387 0
Treatment: Drugs
Comparator / control treatment
Identical volume of sterile water, weaned according to the same protocol.
Control group
Placebo

Outcomes
Primary outcome [1] 322325 0
The primary outcome is time to successful metabolic transition, defined as the first time point at which all of the following criteria are met: i) Glucose stability, defined as blood glucose concentration in the target range of 2.6 to 5.0 mmol/L for 24 hours, no intravenous fluids and achivement of full enteral bolus feeding; iib) full enteral bolus feeding, defined as a) 5 full breast feeds in 24 hours without supplements; or b) 5 breast feeds in 24 hours with supplements according to breastfeeding code at >=120 ml/kg/d of expressed breast milk or formula; or c) >=120 ml/kg/d of expressed breast milk or formula in 24 hours at a minimum interval of bolus feeds of three hours; and iii0 no intravenous fluids.
Timepoint [1] 322325 0
The primary outcome will be assessed daily following randomisation, for up to four weeks, at which point the outcome event will be censored. As this is a time to event analysis there is no primary assessment timepoint. The primary outcome will be determined from hospital observation and feeding charts and laboratory records.
Secondary outcome [1] 378092 0
Glucose Stabilisation, as defined in primary outcome (see above). It will be determined from laboratory records.
Timepoint [1] 378092 0
Assessed daily following randomisation, for up to four weeks.
Secondary outcome [2] 378212 0
Establishment of full enteral bolus feeds, as defined in primary outcome (see above). It will be determined from hospital observation and feeding charts.
Timepoint [2] 378212 0
Assessed daily following randomisation, for up to four weeks.
Secondary outcome [3] 378213 0
Time to establish full sucking feeds defined as 5 full breast feeds in 24 hours or >=120 ml/kg/d of expressed breast milk or formula by bottle, determined from hospital observation and feeding charts.
Timepoint [3] 378213 0
Assessed daily following randomisation, up to discharge to home.
Secondary outcome [4] 378214 0
Feeding at discharge from hospital to home,
Timepoint [4] 378214 0
At discharge from hospital and to home, determined from hospital feeding charts.
Secondary outcome [5] 378215 0
Duration of intravenous fluids, determined from hospital fluid charts. .
Timepoint [5] 378215 0
Up to discharge from hospital
Secondary outcome [6] 378216 0
Episodes of hypoglycaemia (<2.6 mmol/L), defined by blood glucose measurement, including frequency, duration, timing and treatment before, during and after the episode.
Timepoint [6] 378216 0
Up to discharge from hospital.
Secondary outcome [7] 378217 0
Number of blood glucose tests performed during study intervention and hospital admission, determined from laboratory records.
Timepoint [7] 378217 0
Up to discharge from hospital.
Secondary outcome [8] 378218 0
Duration of admission, determined from hospital electronic record: neonatal care, postnatal ward, community birthing unit
Timepoint [8] 378218 0
Hospital admission and at discharge to home.
Secondary outcome [9] 378219 0
totoal duration of study intervention, determined from hospital drug chart. .
Timepoint [9] 378219 0
Up to discharge from hospital.
Secondary outcome [10] 378220 0
Plasma insulin concentration.
Timepoint [10] 378220 0
>=36 hours after commencing the intervention.
Secondary outcome [11] 378221 0
Death
Timepoint [11] 378221 0
Up to discharge from hospital.
Secondary outcome [12] 378222 0
Clinical seizures as recorded in hospital records.
Timepoint [12] 378222 0
Up to discharge from hospital.
Secondary outcome [13] 378223 0
Discontinuation of study intervention due to elevated blood glucose concentration or hyperglycaemia, determined from drug chart and hospital record.
Timepoint [13] 378223 0
Up to discharge from hospital.
Secondary outcome [14] 378224 0
Discontinuation of study intervention due to other adverse event (serious; non-serious), as determined by attending clinician and recorded on study adverse events form.
Timepoint [14] 378224 0
Up to discharge from hospital.
Secondary outcome [15] 378225 0
Congestive heart failure, defined as respiratory distress (tachypnoea, recession, or use of oxygen or positive pressure support) with consistent CXR findings (cardiomegaly, plethora, interstitial fluid or effusions)
Timepoint [15] 378225 0
Up to discharge from hospital.
Secondary outcome [16] 378226 0
Commencement of low flow oxygen, as determined from hospital observation charts.
Timepoint [16] 378226 0
Up to discharge from hospital.
Secondary outcome [17] 378227 0
Impaired cardiac function, defined as one or more that following: echocardiographic findings: a) patent ductus arteriosus (>=1.5 mm with growing, pulsatile or bidirectional pattern); b) pulmonary hypertension (pulmonary artery pressure = systemic pressure, as estimated by tricuspid regurgitant jet [RV-RA gradient +5 mmHg] or ductal shunt right to left (>20%) with characteristic pulmonary Doppler envelope [TPV/ RVET <20%]; c) left ventricular dilatation and/or decreased systolic contraction (left ventricular internal diameter diastole z-score >2 and reduced systolic function [FS% <25 or MPI >0.41]).
Timepoint [17] 378227 0
>=72 hours after commencing the study intervention.
Secondary outcome [18] 378273 0
Inborn error of metabolism on Guthrie metabolic screen.
Timepoint [18] 378273 0
>=48 hours.
Secondary outcome [19] 378847 0
Episodes of elevated glucose concentration (5.1 to 6.9 mmol/L), defined by blood glucose measurement, including frequency, duration, timing and treatment before, during and after the episode.
Timepoint [19] 378847 0
Up to discharge from hospital
Secondary outcome [20] 378848 0
Episodes of hyperglycaemia (>=7 mmol/L), defined by blood glucose measurement, including frequency, duration, timing and treatment before, during and after the episode
Timepoint [20] 378848 0
Up to hospital discharge
Secondary outcome [21] 378850 0
Plasma creatinine concentration
Timepoint [21] 378850 0
>=36 hours after commencing the intervention.
Secondary outcome [22] 378851 0
Plasma diazoxide concentration
Timepoint [22] 378851 0
>=36 hours after commencing the intervention.
Secondary outcome [23] 378852 0
Commencement of positive pressure respiratory support, as determined from hospital observation charts.
Timepoint [23] 378852 0
Up to hospital discharge.

Eligibility
Key inclusion criteria
Babies are eligible for this study if they are born at >=35 weeks’ gestation and are admitted to a neonatal unit in the first week after birth with recurrent or severe hypoglycaemia, defined by one or more of the following:
•3 or more episodes of hypoglycaemia <2.6 mmol/L in 48 hours
•Blood glucose of 1.2 to <2.0 mmol/L persisting after 2 doses of dextrose gel and feeding
•Any episode of hypoglycaemia <1.2 mmol/L.
Minimum age
No limit
Maximum age
7 Days
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Confirmed major congenital malformation or chromosomal disorder
Suspected inborn error of metabolism
Suspected congenital hyperinsulinism or other endocrine disorder affecting
glucose and insulin metabolism
Gastrointestinal disorder likely to affect feed tolerance

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)
Participants will be assigned to study interventions using a web-based computer randomisation system. The randomisation system will assign a study medication bottle identified by a random number, which contains either diazoxide or placebo. Only the study statistician and data manager will have access to the allocation sequence during the course of the trial, and only the data manager and trial pharmacists will know the contents of study medication bottles.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A computer generated randomisation sequence with permuted blocks, stratified by centre and SGA status (<10th customised centile) will be used to assign study interventions.
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
Phase
Phase 2 / Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Intervention groups will be compared for the primary outcome using Cox’s proportional hazards regression analysis, with treatment effect expressed as hazards ratio with 95% confidence interval (CI). Secondary outcomes will be compared between groups using generalised linear models with treatment effect presented as odds ratio, count ratio, mean difference or ratio of geometric means (positively skewed data), as appropriate, with 95% CI. Regression models will be adjusted for gestation length and birthweight z-score (fixed effects), and non-independence of multiples (random effect). For significance tests, alpha level will be set at 0.05 (two tailed).

A trial of 74 babies randomised in 1:1 ratio (37 per group), will give 80% power to detect a relative hazard of 2.0 (2-tailed alpha 0.05), assuming 90% of infants in each group have a primary outcome event within the study period (PAS v.16). A hazard ratio of 2.0 indicates that the diazoxide group reaches the primary outcome at twice the rate (events per unit of time) of the control group.

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 outside Australia
Country [1] 22189 0
New Zealand
State/province [1] 22189 0
Auckland

Funding & Sponsors
Funding source category [1] 304553 0
University
Name [1] 304553 0
The University of Auckland
Address [1] 304553 0
Private Bag 92019, Auckland 1142
Country [1] 304553 0
New Zealand
Primary sponsor type
University
Name
Liggins Institute, University of Auckland
Address
85 Park Road, Grafton, Auckland 1023
Country
New Zealand
Secondary sponsor category [1] 304877 0
None
Name [1] 304877 0
Address [1] 304877 0
Country [1] 304877 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304980 0
Health and Disability Ethics Committee
Ethics committee address [1] 304980 0
133 Molesworth Street, Thorndon, Wellington 6011
Ethics committee country [1] 304980 0
New Zealand
Date submitted for ethics approval [1] 304980 0
Approval date [1] 304980 0
08/12/2019
Ethics approval number [1] 304980 0

Summary
Brief summary
The Neonatal Glucose Care Optimisation (NeoGluCO) Study is investigating if early treatment of severe or recurrent neonatal hypoglycaemia (low blood glucose) with oral diazoxide reduced to the time to successful neonatal metabolic transition. this is defined as achieving glucose stability (blood glucose in the target range of 2.6 to 5.0 mmol/L), full enteral bolus feeds, and stopping of intravenous fluids. We hypothesise that early diazoxide therapy will improve glycaemic stability, allowing earlier weaning of intravenous fluids and establishment of full feeds. If effective, such a treatment could have major benefits for neonates with severe or recurrent hypoglycaemia, including reduced length of admission and separation of mother and baby, reduced use of formula and facilitation of earlier establishment of breastfeeding, reduced number of heel pricks for blood glucose testing, and better long-term neurodevelopmental outcome.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 98846 0
Dr Chris McKinlay
Address 98846 0
Liggins Institute, University of Auckland
Private Bag 92019, Auckland 1142
Country 98846 0
New Zealand
Phone 98846 0
+64 274725099
Fax 98846 0
Email 98846 0
c.mckinlay@auckland.ac.nz
Contact person for public queries
Name 98847 0
Dr Chris McKinlay
Address 98847 0
Liggins Institute, University of Auckland
Private Bag 92019, Auckland 1142
Country 98847 0
New Zealand
Phone 98847 0
+64 274725099
Fax 98847 0
Email 98847 0
c.mckinlay@auckland.ac.nz
Contact person for scientific queries
Name 98848 0
Dr Chris McKinlay
Address 98848 0
Liggins Institute, University of Auckland
Private Bag 92019, Auckland 1142
Country 98848 0
New Zealand
Phone 98848 0
+64 274725099
Fax 98848 0
Email 98848 0
c.mckinlay@auckland.ac.nz

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