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Trial registered on ANZCTR


Registration number
ACTRN12619000115134
Ethics application status
Approved
Date submitted
17/01/2019
Date registered
25/01/2019
Date last updated
23/09/2022
Date data sharing statement initially provided
25/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Evaluating the effects of high and low oxygen therapy compared to standard oxygen therapy in patients undergoing major surgery under general anaesthesia
Scientific title
A multi-centre, patient and assessor-blinded, parallel groups, randomised controlled trial comparing restricted and liberal oxygen therapy with standard oxygen therapy in patients having major surgery
Secondary ID [1] 296830 0
None
Universal Trial Number (UTN)
U1111-1220-9961
Trial acronym
The HOT-ROX trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hyperoxia, hyperoxaemia 311085 0
Major non-cardiac surgery 311087 0
Surgical site infection 311163 0
Postoperative complications 311164 0
Condition category
Condition code
Anaesthesiology 309719 309719 0 0
Anaesthetics

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Following randomisation, participants will be allocated to restricted oxygen therapy (intervention 1), liberal oxygen therapy (intervention 2) or standard care oxygen therapy (control). In all three arms, the allocated oxygen therapy will be started after induction of anaesthesia, confirmation of artificial airway placement, and patient positioning are completed. The duration of the study will be until discharge from PACU or ICU, or 6 hours after transfer out of operating theatre, whichever occurs sooner.

In the restricted arm, the overarching aim is to avoid giving a greater FiO2 than is necessary to achieve an SpO2 greater than or equal to 93%. Intra-operatively, anaesthetists will use the lowest FiO2 that they consider safe to achieve the target SpO2, by titrating the inspired oxygen concentration delivered via the anaesthesia machine ventilator. Although anaesthetic machines are capable of delivering FiO2<0.21, use of such hypoxic gas mixtures will be prohibited. Following surgery, in the PACU or ICU, the FiO2 will be reduced as rapidly as possible while continuing to aim for an SpO2 of greater than or equal to 93% and supplemental oxygen will be ceased when possible.

In the liberal arm, the overarching aim will be to administer oxygen liberally in accordance with the current WHO recommendations on intraoperative and postoperative measures for surgical site infection prevention. Once the study intervention period starts, an FiO2 of =0.8 will be administered. Following surgery, this regimen will continue until extubation after which time oxygen will be administered at 15L/min via a non-rebreather mask. If a patient receives non-invasive ventilation or high flow oxygen therapy, an FiO2 of =0.8 will be used.
Intervention code [1] 313354 0
Treatment: Other
Comparator / control treatment
In the standard care arm, the clinical staff responsible for the participants’ care will be encouraged to administer an FiO2 between 0.4 and 0.6 whenever possible in the operating theatre, in accordance with their usual practice. There will be no restrictions placed on the use of oxygen in the PACU or ICU, and oxygen administration in accordance with the usual care of the practitioners responsible for the participants care will be encouraged.
Control group
Active

Outcomes
Primary outcome [1] 318685 0
The primary outcome measure is DAAH30, defined as the number of days spent alive and in the patient’s usual place of residence between randomisation and day 30. If a participant dies within 30 days of surgery, DAAH30 will zero even if intervening days were spent at home. The primary outcome will be assessed by a blinded outcome assessor, by contacting via telephone or in person the participant, participants next of kin or family or general practitioner, in addition to reviewing the participants medical record.
Timepoint [1] 318685 0
30 days following randomisation
Secondary outcome [1] 365697 0
Post-operative infection within 30 days of surgery. This secondary outcome will be assessed using the patients hospital records and verified with the participant, participants next of kin or family, of the participants general practitioner. Postoperative infection will be sub-classified as surgical site (superficial, deep or organ space) infection and non-surgical site infection (organ system involved) according to the current Centres for Disease Control and Prevention definitions.
Timepoint [1] 365697 0
30 days following randomisation
Secondary outcome [2] 365698 0
Requirement for re-operation due to infection within 30 days of initial surgery. This secondary outcome will be assessed using the patients hospital records and verified with the participant, participants next of kin or family, of the participants general practitioner.
Timepoint [2] 365698 0
30 days following randomisation
Secondary outcome [3] 365699 0
Days of in-hospital antibiotic therapy to day 30. This secondary outcome will be assessed using the patients hospital records.
Timepoint [3] 365699 0
30 days following randomisation
Secondary outcome [4] 365700 0
Major, non-infection-related post-operative complications within 30 days of surgery. This secondary outcome will be assessed using the patients hospital records and verified with the participant, participants next of kin or family, of the participants general practitioner.
Timepoint [4] 365700 0
30 days following randomisation
Secondary outcome [5] 365701 0
Day 90 all-cause mortality
Timepoint [5] 365701 0
90 days following randomisation. This outcome will be assessed by a blinded outcome assessor, by contacting via telephone or in person the participant, participants next of kin or family or general practitioner, in addition to reviewing the participants medical record.
Secondary outcome [6] 365865 0
Feasibility outcomes
Feasibility aim 1: Confirm correct patient selection:
The project manager will visit sites and review clinical records in order to verify that all participants fulfilled the eligibility criteria. Data will be collected on reasons for ineligibility in incorrectly enrolled patients to help guide information given to sites during enrolment for the full study. If fewer than 95% of the enrolled patients are eligible, we anticipate modification of the eligibility criteria would be required.
Timepoint [6] 365865 0
After recruitment of 210 participants
Secondary outcome [7] 366054 0
Feasibility aim 2: Confirm treatment separation and protocol compliance
Before undertaking a very large trial we consider it prudent to ensure that we can achieve clinically important separation between treatment groups in terms of FiO2 in the context of a clinical trial. Treatment separation and protocol compliance will be confirmed by a between group FiO2 separation of at least 5%
Timepoint [7] 366054 0
After recruitment of 210 participants
Secondary outcome [8] 366055 0
Feasibility aim 3: Confirm confounder minimisation
Given that higher levels of positive end expiratory pressure (PEEP) may help improve pulmonary oxygen transfer, it is possible that PEEP will be increased by anaesthetists to increase oxygenation in patients randomised to the restricted titrated arm of the study, introducing potential confounding. If a statistically significant and clinically important (i.e. >2cmH2O) difference in PEEP between groups was observed in the feasibility study, we would protocolise PEEP for HOT-ROX.
Timepoint [8] 366055 0
After recruitment of 210 participants
Secondary outcome [9] 366056 0
Feasibility aim 4: Establish recruitment rate feasibility
A recruitment rate of three patients per site per month will allow us to enrol 2640 participants in 20 sites over 44 months.
Timepoint [9] 366056 0
After recruitment of 210 participants
Secondary outcome [10] 366057 0
Feasibility aim 5: Maintenance of the blind
Because the study intervention will be delivered post-operatively in the PACU, it is possible some participants will correctly deduce which group they have been allocated to. We will determine how frequently this occurs by asking participants at follow-up if they know which group they were assigned to. Blinding of the surgeon or proceduralist will reduce the likelihood of treatment bias. The anaesthetist will ask the surgeon at the end of each operation whether they were aware of the the treatment allocation. Blinding of outcome assessors will require one research coordinator to collect oxygen-related data and another to collect outcome data. This study will allow us to assess whether this is logistically feasible.
Timepoint [10] 366057 0
After recruitment of 210 participants
Secondary outcome [11] 366059 0
Feasibility aim 6. Protocol safety
We do not anticipate safety concerns with our current protocol as the treatment strategies being investigated are similar to those used in previous studies. However, we consider it prudent to ensure there are no unexpected adverse consequences with protocol implementation before proceeding with the full study. All adverse events which are considered to be potentially causally related to the study intervention or are otherwise of concern in the investigator’s judgement will be reported. Episodes of severe hypercapnic respiratory failure with a documented arterial blood pH<7.20 in spontaneously breathing patients that occur during the study treatment period will be reported as adverse events.

Adverse events are required to be recorded by sites on case report forms and serious adverse events must be reported within 24 hours to the coordinating centre. Adverse events may additionally be reported by study participants and recorded on case report forms by the site investigator. Adverse events will be reviewed by an independent data monitoring and safety committee who will prepare a report on adverse events at the time of interim analysis.
Timepoint [11] 366059 0
After recruitment of 210 participants
Secondary outcome [12] 366060 0
Feasibility aim 7. Ease of protocol implementation
We will ask Principal Investigators and Research Coordinators to provide feedback on study protocols & tools, the case report from, and the data dictionary in order to refine these for the full study. This will be performed using an online anonymous study specific questionnaire.
Timepoint [12] 366060 0
After recruitment of 210 participants
Secondary outcome [13] 366061 0
Feasibility aim 8. Assess feasibility of registry embedded RCTs in New Zealand anaesthesia
We will assess the completeness and feasibility of collection of all specified data points of interest obtained from the electronic SAFERsleep anaesthesia record and the MoH NMDS in New Zealand participants. These will be compared with similar data points obtained from data collected by research coordinators as detailed above.
Timepoint [13] 366061 0
After recruitment of 210 participants
Secondary outcome [14] 369691 0
2. Postoperative pulmonary complications
Composite of respiratory diagnoses that share common pathophysiological mechanisms including pulmonary collapse and airway contamination:
a. Atelectasis detected on computed tomography or chest radiograph
b. Pneumonia using US Centres for Disease Control criteria
c. Acute Respiratory Distress Syndrome using Berlin Consensus definition
d. Pulmonary aspiration (clear clinical history AND radiological evidence
Timepoint [14] 369691 0
30 days

Eligibility
Key inclusion criteria
• Patients undergoing non-cardiac surgery under general anaesthesia with an expected duration of at least 2 hours and anticipated in-hospital stay of at least 1 post-operative night
• American Society of Anaesthesiologists Physical Status Classification (ASA) 3 or 4
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Current pregnancy
• The treating clinicians consider that there is a specific indication for either liberal or restricted oxygen therapy in the perioperative period
• Previously enrolled in the HOT-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 computerised system accessible 24 hours a day via the Internet to ensure allocation concealment. Participants will be enrolled by clinical staff at the study sites.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The allocation sequence will be randomly generated by computer by an independent statistician. A permuted block randomisation method with variable block sizes, stratified by site, will be used to allocate eligible patients in a 1:1:1 ratio to restricted oxygen therapy (intervention 1), liberal oxygen therapy (intervention 2), or standard care (control).
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
The first interim analysis is planned after recruitment of 210 participants and in addition to predefined early stopping criteria will assess feasibility outcomes for the purpose of:
1. Ensuring effective application of the proposed eligibility criteria across multiple study centers (correct patient selection)
2. Ensuring restricted oxygen therapy reduces inspired oxygen and systemic oxygen exposure compared with standard care, and that liberal oxygen therapy increases inspired oxygen and systemic oxygen exposure compared with standard care (treatment separation and compliance)
3. Ensuring positive end expiratory pressure (PEEP) is similar by treatment groups (confounder minimisation)
4. Ensuring a recruitment rate of at least three patients per site per month can be achieved (recruitment rate feasibility).
5. Ensuring patient, surgeon/proceduralist, and outcome assessor blinding can be achieved (maintenance of the blind)
6. Ensuring unforeseen adverse consequences with the protocol do not occur (protocol safety)
7. Ensuring study protocol and study tools are optimised (ease of protocol implementation)
8. Verifying feasibility of accurate data collection and calculation of baseline, exposure and outcome data from electronic SAFERsleep and MoH NMDS databases (exploring the feasibility of future registry-embedded RCTs)
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
The primary outcome, DAAH30, will be compared between liberal and control arms, and conservative and control arms, using median differences in medians with 95% confidence intervals (CI) calculated using quantile regression.

Binary outcomes will be compared across arms using relative risks with 95% confidence intervals. Continuous outcomes will be compared using linear regression, and skewed outcomes using quantile regression. Survival times will be compared using Cox regression models and presented as Kaplan–Meier curves. Sensitivity analyses adjusting for factors imbalanced at baseline will be performed with the use of quantile regression for the primary outcome variable, robust Poisson regression for binary secondary outcomes, and a Cox proportional hazards model for the survival analysis.

Recruitment
Recruitment status
Suspended
Date of first participant enrolment
Anticipated
29/01/2019
Actual
14/02/2019
Date of last participant enrolment
Anticipated
16/01/2020
Actual
29/01/2021
Date of last data collection
Anticipated
13/06/2026
Actual
Sample size
Target
2640
Accrual to date
210
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment outside Australia
Country [1] 21197 0
New Zealand
State/province [1] 21197 0
Wellington
Country [2] 21198 0
New Zealand
State/province [2] 21198 0
Auckland

Funding & Sponsors
Funding source category [1] 301403 0
Other
Name [1] 301403 0
Australian and New Zealand College of Anaesthetists
Country [1] 301403 0
Australia
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
Country
New Zealand
Secondary sponsor category [1] 301357 0
None
Name [1] 301357 0
Address [1] 301357 0
Country [1] 301357 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302140 0
New Zealand Central Health and Disability Ethics Committee
Ethics committee address [1] 302140 0
133 Molesworth Street
Thorndon
Wellington 6011
Ethics committee country [1] 302140 0
New Zealand
Date submitted for ethics approval [1] 302140 0
09/10/2018
Approval date [1] 302140 0
06/11/2018
Ethics approval number [1] 302140 0
18CEN199

Summary
Brief summary
The World Health Organisation (WHO) and Centre for Disease Control (CDC) guidelines recommend liberal provision of oxygen intraoperatively and in the early post-operative period to reduce the risk of post-operative infection. However, evidence from related specialties indicates that overall, liberal oxygen therapy may be increase mortality and non-infection-related complications compared with restricted oxygen therapy raising the possibility that any decreased infection risk might come at the cost of an increased risk of other complications. For adults having major surgery, it is biologically plausible that more restricted use of oxygen therapy than occurs in standard practice might improve patient outcomes; however, it is also biologically plausible that more liberal oxygen therapy might improve patient outcomes compared with standard care. Overall, the optimal approach to oxygen therapy in the setting of major surgery is uncertain.

HOT-ROX will be the first trial evaluating restricted oxygen therapy vs. standard care and liberal oxygen therapy vs. standard care in patients having major surgery that is powered to assess the effect of these treatments on days alive and at home at 30 days (DAAH30). DAAH30 is strongly associated with the occurrence of postoperative complications and encapsulates the patient-important effects of such complications because it effectively combines hospital length of stay, readmission episodes, discharge destination and early post-operative mortality into a single outcome measure.

The first interim analysis is planned after recruitment of 210 participants and in addition to predefined early stopping criteria will assess the listed feasibility outcomes.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 89254 0
Dr Daniel Frei
Address 89254 0
Department of Anaesthesia and Pain Medicine
Wellington Hospital
Riddiford Street
Newtown
Wellington 6021
Country 89254 0
New Zealand
Phone 89254 0
+64 4 3855999
Fax 89254 0
Email 89254 0
[email protected]
Contact person for public queries
Name 89255 0
Dr Daniel Frei
Address 89255 0
Department of Anaesthesia and Pain Medicine
Wellington Hospital
Riddiford Street
Newtown
Wellington 6021
Country 89255 0
New Zealand
Phone 89255 0
+64 4 3855999
Fax 89255 0
Email 89255 0
[email protected]
Contact person for scientific queries
Name 89256 0
Dr Daniel Frei
Address 89256 0
Department of Anaesthesia and Pain Medicine
Wellington Hospital
Riddiford Street
Newtown
Wellington 6021
Country 89256 0
New Zealand
Phone 89256 0
+64 4 3855999
Fax 89256 0
Email 89256 0
[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?
All individual participant data collected during the trial after de-identification
When will data be available (start and end dates)?
Beginning 3 months and ending 15 years following main results publication.
Available to whom?
Available on a case by case basis at the discretion of the primary sponsor
Available for what types of analyses?
For IPD meta-analyses
How or where can data be obtained?
Access subject to approvals by the primary sponsor and principal investigator


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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No documents have been uploaded by study researchers.

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