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Trial registered on ANZCTR


Registration number
ACTRN12616000301460p
Ethics application status
Not yet submitted
Date submitted
3/03/2016
Date registered
8/03/2016
Date last updated
8/03/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
Evaluation of automated control of oxygen therapy in extremely preterm infants: the SCION trial
Scientific title
Evaluation of automated control of oxygen therapy in extremely preterm infants: the SCION trial
Secondary ID [1] 288686 0
NHMRC APP1128104
Universal Trial Number (UTN)
U1111-1180-3867
Trial acronym
SCION Trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Extremely premature birth 297896 0
Respiratory insufficiency of prematurity 297897 0
Oxidative stress of prematurity 297898 0
Condition category
Condition code
Respiratory 298061 298061 0 0
Other respiratory disorders / diseases
Reproductive Health and Childbirth 298072 298072 0 0
Complications of newborn

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Automated control of inspired oxygen therapy will be administered using a custom-built device incorporating a novel, adaptive and intuitive control algorithm (VDL1.1.). This device receives SpO2 input from an oximeter, compares the value with the midpoint of the desired SpO2 range, and provides an output, which is an updated value for FiO2. In subjects randomised to automated control, this device will be applied before 48 hours of life (i.e. within 24 hours of randomisation) and used until 36 weeks post-menstrual age or until respiratory support has ceased. The SpO2 target range will be 90-94%. Compliance with automated control will be monitored by local research personnel.
Intervention code [1] 294110 0
Treatment: Devices
Comparator / control treatment
Manual control of inspired oxygen therapy will be by bedside clinical staff, aiming to keep SpO2 in the target range (90-94%). This is the usual approach to SpO2 targeting, and will continue until 36 weeks post-menstrual age, or for as long as respiratory support is required.
Control group
Active

Outcomes
Primary outcome [1] 297583 0
Eupoxia - proportion of time with oxygen saturation (SpO2) in the desired target range, or above the desired target range when no supplemental oxygen is being administered. This is assessed by analysis of data received from the pulse oximeter at a sampling frequency of 1 Hz.
Timepoint [1] 297583 0
Throughout the period from birth to 36 weeks post-menstrual age.
Secondary outcome [1] 321466 0
Proportion of time in various degrees of hypoxia (SpO2 <80%, 80-84%, 85-89%), assessed by analysis of data received from the pulse oximeter at a sampling frequency of 1 Hz.
Timepoint [1] 321466 0
Throughout the period from birth to 36 weeks post-menstrual age.
Secondary outcome [2] 321467 0
Proportion of time in degrees of hyperoxia when in oxygen (SpO2 >96%, >98%), assessed by analysis of data received from the pulse oximeter at a sampling frequency of 1 Hz.
Timepoint [2] 321467 0
Throughout the period from birth to 36 weeks post-menstrual age.
Secondary outcome [3] 321468 0
Number of episodes per hour of prolonged hypoxia and hyperoxia (>=30 and >=60 sec), assessed by analysis of data received from the pulse oximeter at a sampling frequency of 1 Hz.
Timepoint [3] 321468 0
Throughout the period from birth to 36 weeks post-menstrual age.
Secondary outcome [4] 321469 0
Number of manual FiO2 adjustments per 24 hours, assessed by analysis of data received from an oxygen analyser at a sampling frequency of 1 Hz.
Timepoint [4] 321469 0
Throughout the period from birth to 36 weeks post-menstrual age.
Secondary outcome [5] 321470 0
Proportion of overshoot episodes (hypoxic event followed by prolonged hyperoxia), assessed by analysis of data received from the pulse oximeter at a sampling frequency of 1 Hz.
Timepoint [5] 321470 0
Throughout the period from birth to 36 weeks post-menstrual age.
Secondary outcome [6] 321471 0
Frequency of hypoxia and bradycardia (HR <100) after respiratory pauses and apnoea, assessed by analysis of data received from the pulse oximeter and a cardiorespiratory monitor at a sampling frequency of 1 Hz.
Timepoint [6] 321471 0
Throughout the period from birth to 36 weeks post-menstrual age.
Secondary outcome [7] 321472 0
Markers of oxidative damage, measured by assay of 8-hydroxydeoxyguanosine, malondialdehyde, and protein carbonyl content in serum.
Timepoint [7] 321472 0
Days 1, 7, 28 and at 36 weeks post-menstrual age
Secondary outcome [8] 321473 0
Plasma VEGF concentration
Timepoint [8] 321473 0
Days 1, 7, 28 and at 36 weeks post-menstrual age
Secondary outcome [9] 321474 0
Survival to 40 weeks PMA free of bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC) and retinopathy of prematurity (ROP), assessed by review in patient records and intensive care charts.
Timepoint [9] 321474 0
40 weeks post-menstrual age.
Secondary outcome [10] 321475 0
In hospital mortality
Timepoint [10] 321475 0
28 days, 40 week post-menstrual age and throughout hospitalisation.
Secondary outcome [11] 321476 0
BPD (physiological and clinical definitions), assessed by review of intensive care charts including documentation of results of air trial if necessary.
Timepoint [11] 321476 0
36 weeks post-menstrual age
Secondary outcome [12] 321477 0
Necrotising enterocolitis Stage IIb or greater, assessed by review of medical records and operative notes.
Timepoint [12] 321477 0
Throughout hospitalisation
Secondary outcome [13] 321478 0
Retinopathy > stage 2 in at least one eye, assessed by trained ophthalmologist.
Timepoint [13] 321478 0
40 weeks post-menstrual age.
Secondary outcome [14] 321479 0
Retinopathy requiring laser therapy or bevacizumab, assessed by trained ophthalmologist.
Timepoint [14] 321479 0
40 weeks post-menstrual age.
Secondary outcome [15] 321480 0
Severe intraventricular haemorrhage (grades III and IV), assessed by serial cranial ultrasound examination.
Timepoint [15] 321480 0
Throughout hospitalisation
Secondary outcome [16] 321481 0
Other complications of prematurity, assessed by review of medical records.
Timepoint [16] 321481 0
Throughout hospitalisation
Secondary outcome [17] 321482 0
Disability free survival, assessed by medical examination and psychometric assessment using the Bayley III developmental assessment tool.
Timepoint [17] 321482 0
2 years post-menstrual age
Secondary outcome [18] 321483 0
Moderate-severe cerebral palsy, assessed by medical assessment with determination of the gross motor function classification system.
Timepoint [18] 321483 0
2 years post-menstrual age
Secondary outcome [19] 321484 0
Cognitive function (<2SD below mean), medical examination and psychometric assessment using the Bayley III developmental assessment tool.
Timepoint [19] 321484 0
2 years post-menstrual age
Secondary outcome [20] 321485 0
Visual disturbance, corrected vision worse than 6/60 in better eye, assessed by ophthalmologic and optometric examination.
Timepoint [20] 321485 0
2 years post-menstrual age

Eligibility
Key inclusion criteria
Gestation at birth 23 weeks 0 days to 27 weeks 6 days by best obstetric estimate.
Age <24 hours, and managed in room air or supplemental oxygen.
Signed parental consent.
Minimum age
No limit
Maximum age
24 Hours
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Withdrawal of active treatment being considered.
Congenital anomaly likely to adversely affect outcome.
Lack of availability of automated control device or study personnel.

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)
The randomisation procedure will be by central randomisation using a web-based randomisation server.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer generated randomisation sequence from randomly permuted blocks, stratified by study centre and by gestation (23-25 weeks and 26-27 weeks).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Statistical analysis will follow standard methods for randomised trials, with the primary analysis being by intention to treat. For continuous outcomes, including the primary outcome, comparison will be of differences between mean values, using linear regression models for stratification adjustments. For dichotomous outcomes, proportions will be compared using the odds ratio with 95% CI, obtained from a logistic regression analysis.

Sample size has been calculated in relation to the primary outcome of eupoxia time throughout the intervention period. In our recent study of automated control in 20 infants, mean eupoxia time during manual control was 56%, with standard deviation (SD) 11%. In other studies variability in eupoxia has been greater (SD up to 16%), and an SD of 16% will be assumed. An absolute increase in eupoxia time of 8% (as was achieved in the largest published study of automated control) would represent a clinically significant benefit, and one that could have the potential to alter outcomes for extremely preterm infants. Detecting an improvement of this magnitude with 90% power and a = 0.05 (two-sided) would require 86 infants per group, which will be increased to 90 per group (180 subjects in total) to account for withdrawals and incomplete data.

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 in Australia
Recruitment state(s)
TAS
Recruitment hospital [1] 5392 0
Royal Hobart Hospital - Hobart
Recruitment postcode(s) [1] 12845 0
7000 - Hobart

Funding & Sponsors
Funding source category [1] 293045 0
Government body
Name [1] 293045 0
National Health and Medical Research Council
Address [1] 293045 0
Level 1
16 Marcus Clarke Street
Canberra ACT 2601
Country [1] 293045 0
Australia
Primary sponsor type
University
Name
Menzies Institute for Medical Research, University of Tasmania
Address
Liverpool St
Hobart
TAS 7000
Country
Australia
Secondary sponsor category [1] 291823 0
None
Name [1] 291823 0
N/A
Address [1] 291823 0
N/A
Country [1] 291823 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 294554 0
University of Tasmania Health and Medical Human Research Ethics Committee
Ethics committee address [1] 294554 0
University of Tasmania
Private Bag 01
Hobart Tas 7001
Ethics committee country [1] 294554 0
Australia
Date submitted for ethics approval [1] 294554 0
01/07/2016
Approval date [1] 294554 0
Ethics approval number [1] 294554 0

Summary
Brief summary
This research proposal seeks funding to conduct a vanguard randomised controlled trial (RCT) of automated control of oxygen therapy in preterm infants <28 weeks gestation in Australian neonatal Units. Our hypothesis is that automated oxygen control using a control device developed by our research team can produce a sustained improvement in time in the desired oxygen saturation (SpO2) target range over many weeks of hospitalisation, reduce blood markers of oxygen toxicity and oxygen debt, and thus have the potential to improve outcome.

Background
Almost all extremely preterm infants <28 weeks gestation receive supplemental oxygen during their first hospitalisation, with fraction of inspired oxygen (FiO2) titrated to target a preferred SpO2 range. Both hypoxia and hyperoxia are known to be associated with adverse outcomes, including mortality, chronic lung disease, retinopathy and necrotizing enterocolitis. SpO2 targeting is, however, fraught with difficulty, with manual oxygen control targeting the desired SpO2 range less than 50% of the time. Automated oxygen control may offer a solution, and existing control algorithms increase time in target range by around 10% in short term studies. Whether automated control can produce sustained improvements in SpO2 targeting, and do so in all individuals, are unknown.

Research Proposal
Preterm infants 23+0 to 27+6 weeks gestation (N=180) will be randomly allocated to automated oxygen control, or standard manual control, from early life until 36 weeks post-menstrual age (PMA). Automated control will be applied for as much of the time as possible, and with all manner of respiratory support modalities. FiO2 and SpO2 will be logged continuously, and blood markers of oxygen toxicity and debt examined at days 1, 7, 28 and at 36 weeks PMA. Time in the SpO2 target range (primary outcome), blood markers of oxidation and hypoxia, survival and complications of prematurity will be compared between groups.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 64122 0
Prof Peter Dargaville
Address 64122 0
Dept. of Paediatrics
Royal Hobart Hospital
Liverpool St
Hobart
TAS 7000
Country 64122 0
Australia
Phone 64122 0
+61362227546
Fax 64122 0
+61362227381
Email 64122 0
peter.dargaville@dhhs.tas.gov.au
Contact person for public queries
Name 64123 0
Prof Peter Dargaville
Address 64123 0
Dept. of Paediatrics
Royal Hobart Hospital
Liverpool St
Hobart
TAS 7000
Country 64123 0
Australia
Phone 64123 0
+61362227546
Fax 64123 0
+61362227381
Email 64123 0
peter.dargaville@dhhs.tas.gov.au
Contact person for scientific queries
Name 64124 0
Prof Peter Dargaville
Address 64124 0
Dept. of Paediatrics
Royal Hobart Hospital
Liverpool St
Hobart
TAS 7000
Country 64124 0
Australia
Phone 64124 0
+61362227546
Fax 64124 0
+61362227381
Email 64124 0
peter.dargaville@dhhs.tas.gov.au

No information has been provided regarding IPD availability
Summary results
No Results