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Trial registered on ANZCTR


Registration number
ACTRN12616000300471
Ethics application status
Approved
Date submitted
3/03/2016
Date registered
8/03/2016
Date last updated
27/09/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Safety and efficacy of automated targeting of oxygen therapy in premature infants
Scientific title
Safety and efficacy of automated targeting of oxygen therapy in premature infants
Secondary ID [1] 288684 0
RHHRF 15203
Universal Trial Number (UTN)
U1111-1180-3710
Trial acronym
SANTO-B
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Premature birth 297893 0
Respiratory insufficiency of prematurity 297894 0
Condition category
Condition code
Respiratory 298059 298059 0 0
Other respiratory disorders / diseases
Reproductive Health and Childbirth 298071 298071 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. Automated control using this device will be used for a 24 hour period in all study subjects, and will be compared with two flanking periods of manual control. The schedule of interventions is thus 12 hours manual control, 24 hours automated control and 12 hours manual control. The SpO2 target range will be 90-94% for both manual and automated control. In a sub-study within the 24 hour period of automated control, the effectiveness of activating an apnoea responsive feature in the algorithm will be compared with no apnoea response in two 12 hour periods in random order. When this feature is activated, the algorithm will make a pre-emptive response when respiratory pauses (5-14 sec) or apnoea (15 sec or more) are detected, potentially in advance of a deviation in SpO2.
Intervention code [1] 294108 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% for manual control). This is the usual approach to SpO2 targeting, which continues up until oxygen therapy is no longer required. For the purposes of the study two 12 hours periods of manual control are being "observed" as a comparator to the period of automated control.
Control group
Active

Outcomes
Primary outcome [1] 297581 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] 297581 0
Continuous monitoring second by second throughout the 24 hour study period
Secondary outcome [1] 321458 0
Proportion of time in various degrees of hypoxia (SpO2 <80%, 80-84%, 85-88%), assessed by analysis of data received from the pulse oximeter at a sampling frequency of 1 Hz.
Timepoint [1] 321458 0
Continuous monitoring second by second throughout the 24 hour study period
Secondary outcome [2] 321459 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] 321459 0
Continuous monitoring second by second throughout the 24 hour study period
Secondary outcome [3] 321460 0
Number of episodes per hour of prolonged hypoxia (SpO2 <80% and SpO2 <85%), lasting 30 sec or more, assessed by analysis of data received from the pulse oximeter at a sampling frequency of 1 Hz.
Timepoint [3] 321460 0
Continuous monitoring second by second throughout the 24 hour study period
Secondary outcome [4] 321461 0
Number of episodes per hour of prolonged hyperoxia in oxygen (SpO2 >96% and SpO2 >98%), lasting 30 sec or more, assessed by analysis of data received from the pulse oximeter at a sampling frequency of 1 Hz.
Timepoint [4] 321461 0
Continuous monitoring second by second throughout the 24 hour study period
Secondary outcome [5] 321462 0
Number of manual FiO2 adjustments made per 24 hours, assessed by analysis of data received from an oxygen analyser at a sampling frequency of 1 Hz.
Timepoint [5] 321462 0
Continuous monitoring second by second throughout the 24 hour study period
Secondary outcome [6] 321463 0
Proportion of apnoea events followed by hypoxia (SpO2 <85% and <80%) and/or by bradycardia (heart rate < 100 bpm), assessed by analysis of data received from an oximeter and a cardiorespiratory monitor at a sampling frequency of 1 Hz.
Timepoint [6] 321463 0
Within 24 hour study period, and compared by continuous monitoring throughout the 12 hour sub-study periods during automated control (apnoea response active and inactive)

Eligibility
Key inclusion criteria
i) Preterm birth at <32 weeks gestation
ii) Requirement for non-invasive respiratory support, including continuous positive airway pressure (CPAP), or high flow via nasal cannula (HF).
iii ) Either a) requirement for supplemental oxygen at the time of commencing the study, or b) in room air but showing a propensity to hypoxic events with or without apnoea.
iv) Research team available to commence recording.
Minimum age
No limit
Maximum age
4 Months
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Currently ventilated or in imminent need of intubation and ventilation

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
This is a non-blinded study of automated vs manual control of oxygen therapy in preterm infants.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
N/A
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
The study design is as follows:
The main study is a non-randomised crossover evaluation of oxygen saturation targeting during a 24 hour period of automated oxygen control compared with two flanking 12 hour periods of manual oxygen control (24 hours in total).
A sub-study of controller response to apnoea (active vs inactive) will be conducted during the 24 hour automated control period, with a randomised crossover design (two 12 hour periods).
Phase
Not Applicable
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Comparison of the automated and manual control epochs will be performed using paired statistical tests (paired t-test or Wilcoxon test, as appropriate), as will the comparison of the apnoea responsive and non-responsive epochs within the automated control period. Statistical significance will be assumed where P<0.05. Analysis of covariance will be used to determine whether the results are influenced by covariates such as gestation at birth, age at time of study, frequency and severity of hypoxic episodes and severity of lung disease at the time of study. Data will be reported for sub-groups by gestation, age at time of study, frequency of hypoxic episodes and FiO2 at time of study entry.

Sample size calculation is based in part on preliminary data generated in an initial clinical study of the automated control algorithm, and also takes into account the need to more extensively test the VDL1.1 algorithm under standard clinical conditions. In the initial clinical study during manual control the mean time proportion in the eupoxic range was 53%, with standard deviation 9.4%. Detecting an absolute increase of 10% in this proportion with 80% power and a=0.05 would require 26 infants overall if the groups were independent, and potentially fewer in view of the crossover design. Given the additional requirements of the study, in particular to test the VDL1.1 algorithm under a range of clinical conditions, 30 infants will be studied when receiving oxygen and 30 when in room air. This will result in 60 study episodes overall, with a maximum of 2 episodes per infant (one in oxygen, one in air).

Recruitment
Recruitment status
Active, not 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] 5391 0
Royal Hobart Hospital - Hobart
Recruitment postcode(s) [1] 12844 0
7000 - Hobart

Funding & Sponsors
Funding source category [1] 293042 0
Charities/Societies/Foundations
Name [1] 293042 0
Royal Hobart Hospital Research Foundation
Address [1] 293042 0
Royal Hobart Hospital
Liverpool St
Hobart TAS 7000
Country [1] 293042 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] 291820 0
None
Name [1] 291820 0
No secondary sponsor
Address [1] 291820 0
N/A
Country [1] 291820 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294551 0
University of Tasmania Health and Medical Human Research Ethics Committee
Ethics committee address [1] 294551 0
University of Tasmania
Private Bag 01
Hobart Tas 7001
Ethics committee country [1] 294551 0
Australia
Date submitted for ethics approval [1] 294551 0
25/01/2016
Approval date [1] 294551 0
16/03/2016
Ethics approval number [1] 294551 0
H0015111

Summary
Brief summary
Many preterm infants receive supplemental oxygen during their first hospitalisation, with fraction of inspired oxygen (FiO2) titrated to target a preferred oxygen saturation (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, with existing control algorithms increase time in target range by around 10% in short term studies. We have developed an adaptive and intuitive algorithm (VDL1.1) for automated control of inspired oxygen in the preterm infant, which is to be used in the study outlined in this proposal. A forerunner version of the algorithm (VDL1.0), has been found to be very effective in SpO2 targeting, both in pre-clinical studies using a simulation of oxygenation, and in a 4 hour crossover study in preterm infants.

We propose to evaluate the effectiveness of the VDL1.1 algorithm in a 24 hour crossover study under standard clinical conditions. Preterm infants <32 weeks gestation at birth will be eligible if less than 4 months of age, receiving non-invasive respiratory support and showing the need or potential need for supplemental oxygen. In a non-randomised crossover study, a 24 hour period of automated oxygen control will be compared with two flanking 12 hour periods of standard manual control of inspired oxygen (total 24 hours). Additionally, within the 24 hour automated control period the function of the VDL1.1 algorithm with an apnoea-responsive element active or inactive (12 hours each in random order) will be evaluated. Primary outcome for the main study is eupoxia - the proportion of time with oxygen saturation in the desired target range, or above the desired target range when no supplemental oxygen is being administered. Secondary outcomes include i) proportion of time, and episodes of, hypoxia (SpO2 <80%, 80-84%, 85-88%) and hyperoxia (SpO2 >96% and >98%) when in supplemental oxygen; and ii) number of manual FiO2 adjustments per 24 hours. A total of 60 crossover periods will be studied.
Trial website
N/A
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 64114 0
Prof Peter Dargaville
Address 64114 0
Dept of Paediatrics
Royal Hobart Hospital
Liverpool St
Hobart
TAS 7000
Country 64114 0
Australia
Phone 64114 0
+61 3 61667546
Fax 64114 0
+613 62227381
Email 64114 0
peter.dargaville@dhhs.tas.gov.au
Contact person for public queries
Name 64115 0
Prof Peter Dargaville
Address 64115 0
Dept of Paediatrics
Royal Hobart Hospital
Liverpool St
Hobart
TAS 7000
Country 64115 0
Australia
Phone 64115 0
+61 3 61667546
Fax 64115 0
+613 62227381
Email 64115 0
peter.dargaville@dhhs.tas.gov.au
Contact person for scientific queries
Name 64116 0
Prof Peter Dargaville
Address 64116 0
Dept of Paediatrics
Royal Hobart Hospital
Liverpool St
Hobart
TAS 7000
Country 64116 0
Australia
Phone 64116 0
+61 3 61667546
Fax 64116 0
+613 62227381
Email 64116 0
peter.dargaville@dhhs.tas.gov.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary