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Trial registered on ANZCTR


Registration number
ACTRN12621001163897p
Ethics application status
Submitted, not yet approved
Date submitted
19/07/2021
Date registered
27/08/2021
Date last updated
27/08/2021
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] 304818 0
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 322883 0
Condition category
Condition code
Reproductive Health and Childbirth 320462 320462 0 0
Complications of newborn
Respiratory 320692 320692 0 0
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] 321185 0
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] 328296 0
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] 328296 0
A single plasma sample taken 2 to 4 hours after 4th or 5th maintenance dose.
Secondary outcome [1] 398429 0
Mechanical ventilation received (yes/no), determined from bedside chart.
Timepoint [1] 398429 0
First 5 days after randomisation
Secondary outcome [2] 398433 0
Death
Timepoint [2] 398433 0
First 14 days after randomisation
Secondary outcome [3] 398434 0
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] 398434 0
First 14 days after randomisation
Secondary outcome [4] 398435 0
Necrotising enterocolitis stage 2 or 3 as determined from the medical record
Timepoint [4] 398435 0
First 14 days after randomisation
Secondary outcome [5] 398436 0
Intestinal perforation as determined from the medical record
Timepoint [5] 398436 0
First 14 days after randomisation
Secondary outcome [6] 398437 0
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] 398437 0
First 14 days after randomisation
Secondary outcome [7] 398438 0
Duration of use of doxapram as determined from the medical record
Timepoint [7] 398438 0
From randomisation to primary hospital discharge
Secondary outcome [8] 398439 0
Mean Fi02 as determined from medical records
Timepoint [8] 398439 0
Day 2 post randomisation
Secondary outcome [9] 398440 0
PCO2 (kPa) by blood gas
Timepoint [9] 398440 0
Day2 post randomisation
Secondary outcome [10] 398441 0
Mean systolic blood pressure (mmHg) by oscillometric machine
Timepoint [10] 398441 0
Day 2 post randomisation
Secondary outcome [11] 398442 0
Mean heart rate by pulse oximetry
Timepoint [11] 398442 0
Day 2 post randomisation
Secondary outcome [12] 398443 0
Proportion of time Sp02 <90% by pulse oximetry
Timepoint [12] 398443 0
Day 2 post randomisation
Secondary outcome [13] 398444 0
Proportion of time Sp02 <80% by pulse oximetry
Timepoint [13] 398444 0
Day 2 post randomisation
Secondary outcome [14] 398445 0
Mean Sp02 by pulse oximetry
Timepoint [14] 398445 0
Day 2 post randomisation
Secondary outcome [15] 398446 0
Intermittent hypoxaemia rate/h by pulse oximetry
Timepoint [15] 398446 0
Day 2 post randomisation
Secondary outcome [16] 398447 0
Percentage change of maximal antral cross-sectional area (ACSA) by pulse oximetry
Timepoint [16] 398447 0
Day 2 post randomisation
Secondary outcome [17] 398448 0
Superior mesenteric artery peak systolic velocity by pulse oximetry
Timepoint [17] 398448 0
Day 2 post randomisation
Secondary outcome [18] 398449 0
Superior mesenteric artery pulsatility index by pulse oximetry
Timepoint [18] 398449 0
Day 2 post randomisation
Secondary outcome [19] 398450 0
Mean Fi02 as determined from medical records
Timepoint [19] 398450 0
Day 5 post randomisation
Secondary outcome [20] 398451 0
PCO2 (kPa) by blood gas
Timepoint [20] 398451 0
Day 5 post randomisation
Secondary outcome [21] 398452 0
Mean systolic blood pressure (mmHg) by oscillometric machine
Timepoint [21] 398452 0
Day 5 post randomisation
Secondary outcome [22] 398453 0
Mean heart rate by pulse oximetry
Timepoint [22] 398453 0
Day 5 post randomisation
Secondary outcome [23] 398454 0
Proportion of time Sp02 <90% by pulse oximetry
Timepoint [23] 398454 0
Day 5 post randomisation
Secondary outcome [24] 398455 0
Proportion of time Sp02 <80% by pulse oximetry
Timepoint [24] 398455 0
Day 5 post randomisation
Secondary outcome [25] 398456 0
Mean Sp02 by pulse oximetry
Timepoint [25] 398456 0
Day 5 post randomisation
Secondary outcome [26] 398457 0
Intermittent hypoxaemia rate/h by pulse oximetry
Timepoint [26] 398457 0
Day 5 post randomisation
Secondary outcome [27] 398458 0
Percentage change of maximal antral cross-sectional area by ultrasound
Timepoint [27] 398458 0
Day 5 post randomisation
Secondary outcome [28] 398459 0
Superior mesenteric artery peak systolic velocity by ultrasound
Timepoint [28] 398459 0
Day 5 post randomisation
Secondary outcome [29] 398460 0
Superior mesenteric artery pulsatility index by ultrasound
Timepoint [29] 398460 0
Day 5 post randomisation
Secondary outcome [30] 399319 0
Systolic hypertension by oscillometric machine greater than or equal to the 95th centile for post-menstrual age
Timepoint [30] 399319 0
Day 2 post randomisation
Secondary outcome [31] 399320 0
Systolic hypertension by oscillometric machine greater than or equal to the 95th centile for post-menstrual age
Timepoint [31] 399320 0
Day 5 post randomisation
Secondary outcome [32] 399321 0
Moderate-severe undisturbed tremors by Finnegan score
Timepoint [32] 399321 0
Day 2 post randomisation
Secondary outcome [33] 399322 0
Moderate-severe undisturbed tremors by Finnegan score
Timepoint [33] 399322 0
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
Gender
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
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] 23975 0
New Zealand
State/province [1] 23975 0
Auckland

Funding & Sponsors
Funding source category [1] 309189 0
University
Name [1] 309189 0
University of Auckland
Address [1] 309189 0
Private Bag 92019, Victoria Street West, Auckland 1142, New Zealand
Country [1] 309189 0
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] 310150 0
None
Name [1] 310150 0
Address [1] 310150 0
Country [1] 310150 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 309045 0
Health and Disability Ethics Committees New Zealand
Ethics committee address [1] 309045 0
133 Molesworth Street, Thorndon, Wellington 6011
Ethics committee country [1] 309045 0
New Zealand
Date submitted for ethics approval [1] 309045 0
26/07/2021
Approval date [1] 309045 0
Ethics approval number [1] 309045 0

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
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 112770 0
Dr Christopher JD McKinlay
Address 112770 0
Liggins Institute, University of Auckland, Building 503, Level 2, 85 Park Road, Auckland 1023,
Country 112770 0
New Zealand
Phone 112770 0
+64 274725099
Fax 112770 0
Email 112770 0
c.mckinlay@auckland.ac.nz
Contact person for public queries
Name 112771 0
Dr Christopher JD McKinlay
Address 112771 0
Liggins Institute, University of Auckland, Building 503, Level 2, 85 Park Road, Auckland 1023,
Country 112771 0
New Zealand
Phone 112771 0
+64 274725099
Fax 112771 0
Email 112771 0
c.mckinlay@auckland.ac.nz
Contact person for scientific queries
Name 112772 0
Dr Christopher JD McKinlay
Address 112772 0
Liggins Institute, University of Auckland, Building 503, Level 2, 85 Park Road, Auckland 1023,
Country 112772 0
New Zealand
Phone 112772 0
+64 274725099
Fax 112772 0
Email 112772 0
c.mckinlay@auckland.ac.nz

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
researchhub@auckland.ac.nz
What supporting documents are/will be available?
Study protocol
How or where can supporting documents be obtained?
Type [1] 12590 0
Study protocol
Citation [1] 12590 0
Link [1] 12590 0
Email [1] 12590 0
c.mckinlay@auckland.ac.nz
Other [1] 12590 0
Attachment [1] 12590 0
Summary results
No Results