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Trial registered on ANZCTR


Registration number
ACTRN12615000957594
Ethics application status
Approved
Date submitted
1/09/2015
Date registered
11/09/2015
Date last updated
1/05/2019
Date data sharing statement initially provided
1/05/2019
Date results information initially provided
1/05/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Evaluating the effects of two approaches to oxygen therapy in Intensive Care Unit patients requiring life support (mechanical ventilation)
Scientific title
A multicentre, randomised, single-blinded clinical trial comparing the effect of conservative oxygen therapy with standard care on ventilator-free days in mechanically ventilated adults in the intensive care unit.
Secondary ID [1] 287388 0
None
Universal Trial Number (UTN)
1111-1167-0569
Trial acronym
The ICU -ROX trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Critical illness 296085 0
Mechanical ventilation 296128 0
Hyperoxaemia 296129 0
Respiratory failure 296130 0
Condition category
Condition code
Respiratory 296345 296345 0 0
Other respiratory disorders / diseases
Anaesthesiology 296346 296346 0 0
Other anaesthesiology

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The ‘intervention arm’ is a conservative approach to oxygen therapy, which aims to minimise unnecessary exposure to hyperoxaemia and reduce the exposure to higher than necessary inspired oxygen concentrations. When a participant is allocated to conservative oxygen therapy, the inspired oxygen concentration will be decreased to room air as rapidly as possible provided that the SpO2 measured by peripheral pulse oximetry is greater than the acceptable lower limit. SpO2 levels of greater than 96% will be strictly avoided and an upper SpO2 alarm limit of 97% will apply whenever supplemental oxygen is being administered in the ICU to minimise the risk of hyperoxaemia. After extubation, in the conservative oxygen group, the upper monitored alarm limit of acceptable SpO2 of 97% will still apply whenever supplemental oxygen is being administered. In the event that the SpO2 exceeds the acceptable upper limit, downward titration of supplemental oxygen will be undertaken as a high priority and supplemental oxygen will be discontinued as soon possible. The lower limit alarm for SpO2 will be set at 90% (or lower if clinically appropriate). If the PaO2 or the SaO2 is lower than the acceptable limit, inspired oxygen may be increased if clinically appropriate, irrespective of the SpO2 reading. The intervention will be applied whenever the patient is in the ICU (including any periods of ICU readmission). The duration of the intervention period is until 28 days or hospital discharge, whichever occurs first. The site principal investigators will take primary responsibility for training local staff and will use study tools provided by the coordinating centre including posters describing the intervention. On-site monitoring will be performed by a project manger from the coordinating centre to ensure compliance with the protocol.
Intervention code [1] 292741 0
Treatment: Other
Comparator / control treatment
Patients assigned to the ‘comparator arm’ will receive ‘standard care’ both while ventilated and after extubation with no specific measures taken to avoid high FiO2 or high SpO2. The use of upper alarm limits for SpO2 in the ‘comparator arm’ group will be prohibited as upper alarm limits for SpO2 are not used as part of standard care. The lower limit alarm for SpO2 will be set at 90% (or lower if clinically appropriate). If the PaO2 or the SaO2 is lower than the acceptable limit, inspired oxygen may be increased if clinically appropriate, irrespective of the SpO2 reading. The use of an FiO2 of less than 0.3 whilst ventilated is discouraged.
Control group
Active

Outcomes
Primary outcome [1] 295996 0
The primary outcome measure is Ventilator Free Days. VFDs is defined as the total number of days (or part days) of unassisted breathing between randomisation and day 28 (672 hours post-randomisation) with the exception that all patients who die by day 28 will be defined as having zero VFDs and any periods of assisted breathing lasting less than 24 hours for the purpose of a surgical procedure will not count against the VFD calculation. For the purposes of this definition, assisted breathing is defined as any form of invasive positive pressure ventilation via an endotracheal tube or tracheostomy tube or non-invasive ventilation provided via a face mask or nasal mask. Patients who are receiving extracorporeal membrane oxygenation (ECMO) will be defined as receiving assisted breathing irrespective of whether they are ventilated or not.

Unassisted breathing will be defined as any other form of breathing, including but not limited to patients who are:
1. Extubated and receiving supplemental oxygen (including high flow nasal prongs) or breathing room air; or
2. Breathing spontaneously through a tracheostomy tube.

Patients transferred to another hospital or health care facility while still receiving assisted breathing will be followed to day 28 to assess VFDs. In patients who are breathing unassisted at the time of transfer to another hospital or health care facility, VFDs will be counted from the end of the last period of unassisted breathing prior to transfer.

The outcome will be assessed by review of the hospital records
Timepoint [1] 295996 0
Day 28 post randomisation
Secondary outcome [1] 317131 0
all cause mortality
Timepoint [1] 317131 0
day 90 post randomisation
Secondary outcome [2] 317132 0
all cause mortality
Timepoint [2] 317132 0
day 180 post randomisation
Secondary outcome [3] 317133 0
duration of survival assessed hospital records or direct contact with next of kin or general practitioner to establish date of death.
Timepoint [3] 317133 0
day 180 post randomisation
Secondary outcome [4] 317134 0
quality of life assessed using the EuroQol5D5L
Timepoint [4] 317134 0
day 180 post randomisation
Secondary outcome [5] 317135 0
Functional outcome assessed by the Extended Glasgow Outcome Scale (for patients with acute brain pathologies at baseline only)
Timepoint [5] 317135 0
day 180 post randomisation
Secondary outcome [6] 317136 0
proportion of patients in paid employment at baseline who are unemployed at 180 days. Assessed by telephone interview.
Timepoint [6] 317136 0
day 180 post randomisation
Secondary outcome [7] 317152 0
Cognitive function assessed using the telephone interview for cognitive status
Timepoint [7] 317152 0
day 180 post randomisation

Eligibility
Key inclusion criteria
Patients at least 18 years of age who require invasive mechanical ventilation in the ICU and are expected to be receiving mechanical ventilation beyond the next calendar day.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
After enrollment of 100 participants, in response to feedback from site investigators and research coordinators, the exclusion criteria were amended to read as follows:
1. Greater than two hours of invasive mechanical ventilation and/ or non-invasive ventilation in an ICU during this hospital admission (includes time ventilated in another hospital’s ICU)
2. In the view of the treating clinician, hyperoxia is clinically indicated for reasons including (but not limited to) carbon monoxide poisoning or a requirement for hyperbaric oxygen therapy
3. In the view of the treating clinician, avoidance of hyperoxia is clinically indicated for reasons including (but not limited to) chronic obstructive airways disease (COPD), paraquat poisoning, previous exposure to bleomycin, or chronic hypercapnic respiratory failure
4. Pregnancy
5. Death is deemed to be inevitable as a result of the current acute illness and either the treating clinician, the patient, or the substitute decision maker are not committed to full active treatment
6. Patients with a life expectancy of less than 90 days due to a chronic or underlying medical condition
7. Admitted following a drug overdose (including alcohol intoxication)
8. Long-term dependence on invasive ventilation prior to this acute illness
9. Confirmed or suspected diagnosis of any of the following: Guillain-Barré syndrome, cervical cord injury above C5, muscular dystrophy, or motor neurone disease
10. Enrolment not considered in the patient’s best interests
11. Enrolled in any other trial of targeted oxygen therapy
12. Previously enrolled in the ICU-ROX study

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)
Central randomisation will be performed using a secure, web-based, randomisation interface. Randomisation will not be performed until participants fulfil all eligibility criteria and are ready to be assigned to study treatment. Participants will be enrolled in the study by ICU doctors, nurses, and research staff and the assigned intervention will be communicated to the bedside nurse who will implement the study intervention.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A permuted block randomisation method will be used with variable block sizes, stratified by site. The allocation sequence will be generated by the study statistician using computer generated random numbers.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
The study will commence with a pilot run-in phase of 100 participants. The purpose of the pilot run-in phase is:
1. to confirm that the recruitment rate is sufficient for the trial to be completed in a timely fashion.
2. to determine that the intervention increases the proportion of hours when the inspired oxygen concentration is 21%, increases the proportion of hours when the oxygen saturation measured by pulse oximetry is at least 97%, and does not increase the proportion of hours when the oxygen saturation measured by pulse oximetry is less than 88%.
3. to determine that the intervention does not result in a significant difference in PEEP levels applied between treatment groups.
4. to determine that at least 95% of enrolled patients are eligible.
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
The primary outcome (VFDs) will be analysed using both a Wilcoxon rank-sum test with results presented medians (interquartile range) and secondly using a boot-strapped t-test with results presented as mean difference (95% CI).
We consider a clinical difference of 2.6 VFDs to be a minimally important clinical difference. This effect size was used for sample size calculations in a recently published New England Journal of Medicine publication investigating simvastatin use in patients with Acute Respiratory Distress Syndrome which used VFDs as the primary outcome variable. Based on pilot work we anticipate that baseline VFDs will be 16.4 (SD 11.3). A sample size of 800 participants will provide 90% power to detect a difference of 2.6 VFDs using a two tailed hypothesis at an alpha of 0.05. We have set our minimum sample size at 1000 participants. This includes a 15% inflation in the sample size to account for the expected non-Gaussian distribution of VFDs, and an additional 80 participants to allow for drop-outs and an expected temporal trend of reducing day 90 mortality after ICU admission.

A complete statistical analysis plan was published in March 2018 (prior to completion of enrolment).

Recruitment
Recruitment status
Completed
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)
SA,WA,VIC
Recruitment outside Australia
Country [1] 7132 0
New Zealand
State/province [1] 7132 0

Funding & Sponsors
Funding source category [1] 291954 0
Government body
Name [1] 291954 0
Health Research Council of New Zealand Project Grant
Address [1] 291954 0
Physical Address: Level 3 - ProCARE Building, Grafton Mews, at 110 Stanley Street (GPS: 50 Grafton Road), Grafton, Auckland 1010
Postal Address: PO Box 5541, Wellesley Street, Auckland 1141
Country [1] 291954 0
New Zealand
Primary sponsor type
Other
Name
Medical Research Institute of New Zealand
Address
Private Bag 7902
Wellington 6242
Level 7, CSB Building
Wellington Hospital
Riddiford St, Newtown
Wellington 6021
New Zealand
Country
New Zealand
Secondary sponsor category [1] 290620 0
Hospital
Name [1] 290620 0
Austin Hospital
Address [1] 290620 0
145 Studley Rd,
Heidelberg,
VIC 3084,
Australia
Country [1] 290620 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293449 0
New Zealand Central Health and Disability Ethics Committee
Ethics committee address [1] 293449 0
Ministry of Health
Ethics Department
Freyberg Building
Reception – Ground Floor
20 Aitken Street
Wellington 6011
Ethics committee country [1] 293449 0
New Zealand
Date submitted for ethics approval [1] 293449 0
Approval date [1] 293449 0
06/03/2015
Ethics approval number [1] 293449 0
15CEN14

Summary
Brief summary
Adequate delivery of oxygen to the organs is essential for human life and all organs of the body require oxygen to function normally. Normally, oxygen makes up just under a quarter of the gas in the air we breathe. In patients who require life support, much higher amounts of oxygen (up to 100% oxygen) can be used. Sometimes it is necessary to provide higher than normal amounts of oxygen to patients on life support in order to achieve normal levels of oxygen in the blood. However, patients who require life support often receive more oxygen than is absolutely necessary to achieve normal oxygen levels in the blood. This commonly causes abnormally high levels of oxygen in the blood. The purpose of this study is to find out whether a conservative oxygen strategy, which avoids giving more oxygen than is necessary to maintain normal levels of oxygen in the blood, improves ventilator-free days (the number of days free from life support) compared to standard care.
Trial website
Trial related presentations / publications
1. Mackle DM, Bailey MJ, Beasley RW, Bellomo R, Bennett VL, Deane AM, Eastwood GM, Finfer S, Freebairn RC, Litton E, Linke NJ, McArthur CJ, McGuinness SP, Panwar R, Young PJ; Australian and New Zealand Intensive Care Society Clinical Trials Group. Protocol summary and statistical analysis plan for the intensive care unit randomised trial comparing two approaches to oxygen therapy (ICU-ROX). Crit Care Resusc. 2018 Mar;20(1):22-32.
The SAP is available to download at the following url: https://cicm.org.au/Resources/Publications/Journal/2010-2020
2. Young PJ, Mackle DM, Bailey MJ, Beasley RW, Bennett VL, Deane AM, Eastwood GM, Finfer S, Freebairn RC, Litton E, Linke NJ, McArthur CJ, McGuinness SP, Panwar R, Bellomo R; The ICU-ROX pilot investigators ; The Australian and New Zealand Intensive Care Society Clinical Trials Group . Intensive care unit randomised trial comparing two approaches to oxygen therapy (ICU-ROX): results of the pilot phase. Crit Care Resusc. 2017 Dec;19(4):344-354.
Public notes

Contacts
Principal investigator
Name 59974 0
Dr Paul Young
Address 59974 0
Wellington Hospital
Riddiford Street
Newtown
Wellington 6021
Country 59974 0
New Zealand
Phone 59974 0
+6443855999
Fax 59974 0
Email 59974 0
paul.young@ccdhb.org.nz
Contact person for public queries
Name 59975 0
Dr Paul Young
Address 59975 0
Wellington Hospital
Riddiford Street
Newtown
Wellington 6021
Country 59975 0
New Zealand
Phone 59975 0
+6443855999
Fax 59975 0
Email 59975 0
paul.young@ccdhb.org.nz
Contact person for scientific queries
Name 59976 0
Dr Paul Young
Address 59976 0
Wellington Hospital
Riddiford Street
Newtown
Wellington 6021
Country 59976 0
New Zealand
Phone 59976 0
+6443855999
Fax 59976 0
Email 59976 0
paul.young@ccdhb.org.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?
Deidentified individual participant data collected during the ICU-ROX trial (and the data dictionary) will be shared.
When will data be available (start and end dates)?
Beginning two years after article publication with no end date.
Available to whom?
These data will be available to researchers to who provide a methodologically sound proposal for the purposes of achieving specific aims outlined in that proposal. To gain access, data requesters will need to sign a data access agreement and to confirm that data will only be used for the agreed purpose for which access was granted.
Available for what types of analyses?
These data will be available to researchers to who provide a methodologically sound proposal for the purposes of achieving specific aims outlined in that proposal.
By what mechanism will data be made available?
Proposals should be directed to the corresponding author via email: paul.young@ccdhb.org.nz and will be reviewed by the ICU-ROX study management committee. Requests to access data to undertake hypothesis-driven research will not be unreasonably withheld.
What supporting documents are/will be available?
Study protocol
Statistical analysis plan
Informed consent form
Clinical study report
Ethical approval
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary