ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12621001163897

Ethics application status

Approved

Date submitted

19/07/2021

Date registered

27/08/2021

Date last updated

6/04/2022

Date data sharing statement initially provided

27/08/2021

Type of registration

Prospectively registered

Titles & IDs

Public title

Doxapram for Apnoea of Prematurity (DoxAPrem) Dosage Study

Scientific title

Oral Doxapram for Apnoea of Prematurity: Dosage Study in Preterm Infants

Secondary ID [1]

None

Universal Trial Number (UTN)

U1111-1267-6035

Trial acronym

DoxAPrem

Linked study record

Health condition

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

Apnoea of prematurity

Condition category

Condition code

Reproductive Health and Childbirth

Complications of newborn

Respiratory

Other respiratory disorders / diseases

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Oral doxapram as a single loading dose of 48 mg/kg followed by a maintenance dose of 24 mg/kg 6-hourly for 5 days (Treatment B). Compliance with dosing will be assessed from hospital drug charts.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Oral doxapram as a single loading dose of 24 mg/kg, followed by a maintenance dose of 12 mg/kg 6-hourly for 5 days (Treatment A).. Compliance with dosing will be assessed from hospital drug charts.

Control group

Dose comparison

Outcomes

Primary outcome [1]

Proportion of infants with steady state doxapram plasma concentration in the therapeutic range of 1.5 to 4.0 mg/L, assessed at 2 to 4 hours after 4th or 5th maintenance dose

Timepoint [1]

A single plasma sample taken 2 to 4 hours after 4th or 5th maintenance dose.

Secondary outcome [1]

Mechanical ventilation received (yes/no), determined from bedside chart.

Timepoint [1]

First 5 days after randomisation

Secondary outcome [2]

Death

Timepoint [2]

First 14 days after randomisation

Secondary outcome [3]

Confirmed or probable seizure: case 1 or 2 definition by standardised criteria
Determined from review of medical records and video-EEG, if available

Timepoint [3]

First 14 days after randomisation

Secondary outcome [4]

Necrotising enterocolitis stage 2 or 3 as determined from the medical record

Timepoint [4]

First 14 days after randomisation

Secondary outcome [5]

Intestinal perforation as determined from the medical record

Timepoint [5]

First 14 days after randomisation

Secondary outcome [6]

Discontinuation of study intervention due any other adverse event that is considered serious as reported to the PI or determined from the medical record

Timepoint [6]

First 14 days after randomisation

Secondary outcome [7]

Duration of use of doxapram as determined from the medical record

Timepoint [7]

From randomisation to primary hospital discharge

Secondary outcome [8]

Mean Fi02 as determined from medical records

Timepoint [8]

Day 2 post randomisation

Secondary outcome [9]

PCO2 (kPa) by blood gas

Timepoint [9]

Day2 post randomisation

Secondary outcome [10]

Mean systolic blood pressure (mmHg) by oscillometric machine

Timepoint [10]

Day 2 post randomisation

Secondary outcome [11]

Mean heart rate by pulse oximetry

Timepoint [11]

Day 2 post randomisation

Secondary outcome [12]

Proportion of time Sp02 <90% by pulse oximetry

Timepoint [12]

Day 2 post randomisation

Secondary outcome [13]

Proportion of time Sp02 <80% by pulse oximetry

Timepoint [13]

Day 2 post randomisation

Secondary outcome [14]

Mean Sp02 by pulse oximetry

Timepoint [14]

Day 2 post randomisation

Secondary outcome [15]

Intermittent hypoxaemia rate/h by pulse oximetry

Timepoint [15]

Day 2 post randomisation

Secondary outcome [16]

Percentage change of maximal antral cross-sectional area (ACSA) by pulse oximetry

Timepoint [16]

Day 2 post randomisation

Secondary outcome [17]

Superior mesenteric artery peak systolic velocity by pulse oximetry

Timepoint [17]

Day 2 post randomisation

Secondary outcome [18]

Superior mesenteric artery pulsatility index by pulse oximetry

Timepoint [18]

Day 2 post randomisation

Secondary outcome [19]

Mean Fi02 as determined from medical records

Timepoint [19]

Day 5 post randomisation

Secondary outcome [20]

PCO2 (kPa) by blood gas

Timepoint [20]

Day 5 post randomisation

Secondary outcome [21]

Mean systolic blood pressure (mmHg) by oscillometric machine

Timepoint [21]

Day 5 post randomisation

Secondary outcome [22]

Mean heart rate by pulse oximetry

Timepoint [22]

Day 5 post randomisation

Secondary outcome [23]

Proportion of time Sp02 <90% by pulse oximetry

Timepoint [23]

Day 5 post randomisation

Secondary outcome [24]

Proportion of time Sp02 <80% by pulse oximetry

Timepoint [24]

Day 5 post randomisation

Secondary outcome [25]

Mean Sp02 by pulse oximetry

Timepoint [25]

Day 5 post randomisation

Secondary outcome [26]

Intermittent hypoxaemia rate/h by pulse oximetry

Timepoint [26]

Day 5 post randomisation

Secondary outcome [27]

Percentage change of maximal antral cross-sectional area by ultrasound

Timepoint [27]

Day 5 post randomisation

Secondary outcome [28]

Superior mesenteric artery peak systolic velocity by ultrasound

Timepoint [28]

Day 5 post randomisation

Secondary outcome [29]

Superior mesenteric artery pulsatility index by ultrasound

Timepoint [29]

Day 5 post randomisation

Secondary outcome [30]

Systolic hypertension by oscillometric machine greater than or equal to the 95th centile for post-menstrual age

Timepoint [30]

Day 2 post randomisation

Secondary outcome [31]

Systolic hypertension by oscillometric machine greater than or equal to the 95th centile for post-menstrual age

Timepoint [31]

Day 5 post randomisation

Secondary outcome [32]

Moderate-severe undisturbed tremors by Finnegan score

Timepoint [32]

Day 2 post randomisation

Secondary outcome [33]

Moderate-severe undisturbed tremors by Finnegan score

Timepoint [33]

Day 5 post randomisation

Eligibility

Key inclusion criteria

Infants are eligible for this study if they are born at <32 weeks’ gestation, are admitted to neonatal intensive care and meet all of the following criteria:
a) Greater than or equal to 72 h old
b) Maximum non-invasive respiratory support (bubble nasal CPAP greater than or equal to 8 cmH20)
c) Optimised dose of caffeine citrate (greater than or equal to 15 mg/kg/day)
d) Evidence of significant apnoea/bradycardia/desaturation events in the past 48 hours, defined as one or more of the following: hypercapnia (PC02 greater than or equal to 8 kPa); hypoxaemia (peripheral oxygen saturation <90% for greater than or equal to 30% of time over greater than or equal to 6 hours; greater than or equal to 1 ABD event requiring positive pressure inflation; greater than or equal to 6 significant desaturations in 6 hours (peripheral oxygen saturation <80% associated with bradycardia <100/min and requiring nursing intervention).

Minimum age

3 Days

Maximum age

3 Months

Sex

Both males and females

Can healthy volunteers participate?

No

Key exclusion criteria

Current treatment for proven sepsis
Recent grade 3-4 intraventricular haemorrhage (<72 hours)
Confirmed major congenital malformation or chromosomal disorder
Previous use of doxapram
Use of respiratory stimulant other than caffeine citrate
Previous seizure

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)

Web based randomisation

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Computer generated random permuted blocks or 2 and 4

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Parallel

Other design features

Phase

Phase 2

Type of endpoint/s

Statistical methods / analysis

Statistical analysis will be performed with JMP v15 and SAS v9.4 (SAS Institute) or later.
Descriptive statistics: Categorical data will be presented as number and percent, and continuous data as mean and standard deviation or median and inter-quartile range, as appropriate. Count data will be presented as median and inter-quartile range or grouped into ordinal categories. Denominators will be given for all outcomes.
Primary analysis: Intervention groups will be compared for the primary outcome using generalised linear models with treatment effect expressed as odds ratio with a 95% confidence interval (CI). For significance tests, the alpha level will be set at 0.1 (two-tailed).
For continuous secondary outcomes, intervention groups will be compared at baseline and on day 2 and 5 in repeated measures analysis. Post hoc analysis will be performed to determine mean differences between groups if there are significant group and/or time-group interactions. Other secondary outcomes will be compared between intervention groups using generalised linear models with treatment effect expressed as odds ratio or mean difference, as appropriate, with 95% CI.
It is envisaged that the trial will be completed as planned with no interim analysis.

Recruitment

Recruitment status

Recruiting

Date of first participant enrolment

Anticipated

28/02/2022

Actual

28/02/2022

Date of last participant enrolment

Anticipated

28/02/2023

Actual

Date of last data collection

Anticipated

1/04/2023

Actual

Sample size

Target

32

Accrual to date

2

Final

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Auckland

Funding & Sponsors

Funding source category [1]

University

Name [1]

University of Auckland

Address [1]

Private Bag 92019, Victoria Street West, Auckland 1142, New Zealand

Country [1]

New Zealand

Primary sponsor type

University

Name

University of Auckland

Address

Private Bag 92019, Victoria Street West, Auckland 1142, New Zealand

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 Committees New Zealand

Ethics committee address [1]

133 Molesworth Street, Thorndon, Wellington 6011

Ethics committee country [1]

New Zealand

Date submitted for ethics approval [1]

26/07/2021

Approval date [1]

03/09/2021

Ethics approval number [1]

Summary

Brief summary

The aim of this study is to evaluate use of doxapram by the oral route for treatment of apnoea in very preterm infants (pauses in breathing with desaturation and/or bradycardia). Apnoea occurs in approximately 70% of infants born at 32 weeks' gestation and is associated with delayed feeding, increased mortality and increased risk of neurodevelopmental impairment and long-term respiratory morbidity. First line treatment of apnoea involves continuous positive airway pressure (CPAP) and caffeine treatment. Infants who are refractory to caffeine are usually trialled on doxapram, an alternative respiratory stimulant. Traditionally doxapram has been given by continuous intravenous infusion, but long-term intravenous access can be difficult to maintain and increases the risk of sepsis. Several studies have found that oral doxapram is equally effective but the optimal oral dose in preterm infants is unclear. This trial will compare two oral doses of doxapram (12 mg/kg vs. 24 mg/kg 6 hourly) to determine which is more likely to achieve therapeutic blood concentrations. Plasma concentrations will also be used to develop a pharmacokinetic model to optimise dosing based on gestation and postnatal age. Effect of oral doxapram on respiratory parameters and tolerance will also be assessed.

Trial website

https://wiki.auckland.ac.nz/display/CPR/Kidz+First+Neonatal+Research

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Dr Christopher JD McKinlay

Address

Liggins Institute, University of Auckland, Building 503, Level 2, 85 Park Road, Auckland 1023,

Country

New Zealand

Phone

+64 274725099

Fax

Email

[email protected]

Contact person for public queries

Name

Dr Christopher JD McKinlay

Address

Liggins Institute, University of Auckland, Building 503, Level 2, 85 Park Road, Auckland 1023,

Country

New Zealand

Phone

+64 274725099

Fax

Email

[email protected]

Contact person for scientific queries

Name

Dr Christopher JD McKinlay

Address

Liggins Institute, University of Auckland, Building 503, Level 2, 85 Park Road, Auckland 1023,

Country

New Zealand

Phone

+64 274725099

Fax

Email

[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?

Drug concentrations and secondary outcomes

When will data be available (start and end dates)?

January 1 2024, no end date

Available to whom?

Available to approved researchers who submit a suitable proposal to the Clinical Data Research Hub at the Liggins Institute

Available for what types of analyses?

Only to achieve the aims in the approved proposal

How or where can data be obtained?

Clinical Data Research Hub at the Liggins Institute
[email protected]

What supporting documents are/will be available?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
12590	Study protocol			[email protected]

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.