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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

1/08/2024

Date data sharing statement initially provided

11/02/2020

Date results provided

1/08/2024

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

Scientific title

Oral diazoxide versus placebo to reduce time to resolution of hypoglycaemia in neonates with severe or recurrent hypoglycaemia: The Neonatal Glucose Care Optimisation (NeoGluCO) Study

Secondary ID [1]

Nil known

Universal Trial Number (UTN)

U1111-1242-9558

Trial acronym

NeoGluCO Study

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Neonatal hypoglycaemia

Condition category

Condition code

Metabolic and Endocrine

Other metabolic disorders

Reproductive Health and Childbirth

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 5.4 mmol/L and weaning intravenous dextrose and commencing enteral feeding as soon as possible. If glucose concentration is =<2.5, dose will increase to 0.25 ml/kg; if 5.5 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]

Treatment: Drugs

Comparator / control treatment

Babies in the placebo group will receive an identical volume of clear, inert placebo suspension.

Control group

Placebo

Outcomes

Primary outcome [1]

The primary outcome is time to resolution of hypoglycaemia, defined as the first time point at which all of the following criteria are met concurrently:
i: No intravenous fluids for >= 24 hours (time recorded at the end of the 24-hour period).
ii: Enteral bolus feeding for >= 24 hours defined as a) breastfeeding without supplements; or b) breastfeeding with supplements at over 2 hourly intervals, or c) if not breastfeeding, gastric tube or bottle feeds at 3-4 hourly intervals (time recorded at the end of the 24-hour period).
iii: Normoglycaemia for >= 24 hours, defined as a minimum of four pre-feed BGC in the target range of 2.6 to 5.4 mmol/L (last BGC measured within 4 hours of primary outcome time point); four pre-feed BGC spanning over 20 hours; no BGC out of range for over or equal to 24 hours; time recorded at the end of the period).

Timepoint [1]

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]

Glucose Stabilisation, as defined in primary outcome (see above). It will be determined from laboratory records.

Timepoint [1]

Assessed daily following randomisation, for up to four weeks.

Secondary outcome [2]

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]

Assessed daily following randomisation, for up to four weeks.

Secondary outcome [3]

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]

Assessed daily following randomisation, up to discharge to home.

Secondary outcome [4]

Feeding at discharge from hospital to home,

Timepoint [4]

At discharge from hospital and to home, determined from hospital feeding charts.

Secondary outcome [5]

Duration of intravenous fluids, determined from hospital fluid charts. .

Timepoint [5]

Up to discharge from hospital

Secondary outcome [6]

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]

Up to discharge from hospital.

Secondary outcome [7]

Number of blood glucose tests performed during study intervention and hospital admission, determined from laboratory records.

Timepoint [7]

Up to discharge from hospital.

Secondary outcome [8]

Duration of admission, determined from hospital electronic record: neonatal care, postnatal ward, community birthing unit

Timepoint [8]

Hospital admission and at discharge to home.

Secondary outcome [9]

Total duration of study intervention, determined from hospital drug chart.

Timepoint [9]

Up to discharge from hospital.

Secondary outcome [10]

Plasma insulin concentration.

Timepoint [10]

>=36 hours after commencing the intervention.

Secondary outcome [11]

Death

Timepoint [11]

Up to discharge from hospital.

Secondary outcome [12]

Clinical seizures as recorded in hospital records.

Timepoint [12]

Up to discharge from hospital.

Secondary outcome [13]

Discontinuation of study intervention due to elevated blood glucose concentration or hyperglycaemia, determined from drug chart and hospital record.

Timepoint [13]

Up to discharge from hospital.

Secondary outcome [14]

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]

Up to discharge from hospital.

Secondary outcome [15]

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]

Up to discharge from hospital.

Secondary outcome [16]

Commencement of low flow oxygen, as determined from hospital observation charts.

Timepoint [16]

Up to discharge from hospital.

Secondary outcome [17]

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]

>=72 hours after commencing the study intervention.

Secondary outcome [18]

Inborn error of metabolism on Guthrie metabolic screen.

Timepoint [18]

>=48 hours.

Secondary outcome [19]

Episodes of elevated glucose concentration (5.5 to 6.9 mmol/L), defined by blood glucose measurement, including frequency, duration, timing and treatment before, during and after the episode.

Timepoint [19]

Up to discharge from hospital

Secondary outcome [20]

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]

Up to hospital discharge

Secondary outcome [21]

Plasma creatinine concentration

Timepoint [21]

>=36 hours after commencing the intervention.

Secondary outcome [22]

Plasma diazoxide concentration

Timepoint [22]

>=36 hours after commencing the intervention.

Secondary outcome [23]

Commencement of positive pressure respiratory support, as determined from hospital observation charts.

Timepoint [23]

Up to hospital discharge.

Secondary outcome [24]

Use of intravenous fluids and type, as determined from hospital observation charts

Timepoint [24]

Up to discharge from hospital

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 in a single episode
•Any episode of hypoglycaemia <1.2 mmol/L.

Minimum age

No limit

Maximum age

7 Days

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

Confirmed major congenital malformation or chromosomal disorder
Suspected genetic syndrome associated with hypoglycaemia, e.g., Beckwith Wiedemann Syndrome
Gastrointestinal disorder likely to affect feed tolerance
Planned or likely neonatal surgery
Confirmed sepsis (culture of pathogenic organism from blood, CSF or urine)
Hypoxic ischaemic encephalopathy
Family history of congenital hyperinsulinism
Suspected inborn error of metabolism
Triplets

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

Completed

Date of first participant enrolment

Anticipated

2/03/2020

Actual

14/05/2020

Date of last participant enrolment

Anticipated

30/08/2021

Actual

15/02/2023

Date of last data collection

Anticipated

1/11/2021

Actual

15/04/2023

Sample size

Target

Accrual to date

Final

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Auckland

Funding & Sponsors

Funding source category [1]

University

Name [1]

The University of Auckland

Address [1]

Private Bag 92019, Auckland 1142

Country [1]

New Zealand

Funding source category [2]

Government body

Name [2]

Health Research Council of New Zealand

Address [2]

Country [2]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Health and Disability Ethics Committee

Ethics committee address [1]

133 Molesworth Street, Thorndon, Wellington 6011

Ethics committee country [1]

New Zealand

Date submitted for ethics approval [1]

Approval date [1]

08/12/2019

Ethics approval number [1]

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 reduces the time to resolution of hypoglycaemia, this is defined as achieving glucose stability (blood glucose in the target range of 2.6 to 5.4 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

Laing D, Walsh EPG, Alsweiler JM, et al. Diazoxide for Severe or Recurrent Neonatal Hypoglycemia: A Randomized Clinical Trial. JAMA Netw Open. 2024;7(6):e2415764. doi:10.1001/jamanetworkopen.2024.15764

Public notes

Contacts

Principal investigator

Name

Dr Chris McKinlay

Address

Department of Paediatrics: Child and Youth Health, University of Auckland Private Bag 92019, Auckland 1142

Country

New Zealand

Phone

+64 274725099

Fax

[email protected]

Contact person for public queries

Name

Chris McKinlay

Address

Department of Paediatrics: Child and Youth Health, University of Auckland Private Bag 92019, Auckland 1142

Country

New Zealand

Phone

+64 274725099

Fax

[email protected]

Contact person for scientific queries

Name

Chris McKinlay

Address

Department of Paediatrics: Child and Youth Health, University of Auckland Private Bag 92019, Auckland 1142

Country

New Zealand

Phone

+64 274725099

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

What supporting documents are/will be available?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
23741	Study protocol	14. Laing D, Walsh E, Alsweiler JM, Hanning SM, Meyer MP, Ardern J, Cutfield WS, Rogers J, Gamble GD, Chase JG, Harding JE, McKinlay CJD. Oral diazoxide versus placebo for severe or recurrent neonatal hypoglycaemia: Neonatal Glucose Care Optimisation (NeoGluCO) Study; a randomised controlled trial. BMJ Open. 2022; DOI:10.1136/ bmjopen-2021-059452.
23742	Statistical analysis plan				It will be included with the primary study report

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Diazoxide for the Treatment of Transitional Neonatal Hypoglycemia: A Systematic Review.	2021	https://dx.doi.org/10.1177/09732179211059607
Embase	Oral diazoxide versus placebo for severe or recurrent neonatal hypoglycaemia: Neonatal Glucose Care Optimisation (NeoGluCO) study - a randomised controlled trial.	2022	https://dx.doi.org/10.1136/bmjopen-2021-059452

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically