COVID-19 studies are our top priority. For all other trials, there is a 4-week delay in processing a trial submitted/resubmitted to the ANZCTR and additional delays for updates of registered trials. We appreciate your patience.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12620000391976
Ethics application status
Approved
Date submitted
10/03/2020
Date registered
23/03/2020
Date last updated
29/09/2020
Date data sharing statement initially provided
23/03/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
The Mega Randomised Registry Trial Comparing Conservative vs. Liberal OXygenation Targets
Scientific title
A randomised, registry-embedded, single blinded clinical trial comparing conservative oxygen therapy to liberal oxygen therapy in mechanically ventilated adults in the intensive care unit.
Secondary ID [1] 300754 0
None
Universal Trial Number (UTN)
U1111-1242-3705
Trial acronym
Mega-ROX
Linked study record

Health condition
Health condition(s) or problem(s) studied:
critical illness 316603 0
Condition category
Condition code
Emergency medicine 314831 314831 0 0
Other emergency care

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Conservative oxygen therapy: the FiO2 will be decreased to 0.21 (room air) as rapidly as possible provided that the SpO2 measured by peripheral pulse oximetry is greater than the acceptable lower limit (the default lower limit will be 90% but this default lower SpO2 alarm can be reduced to a lower level than 90% at the discretion of the treating clinician). SpO2 levels of greater than 94% will be strictly avoided and an upper SpO2 alarm limit of 95% will apply whenever supplemental oxygen is being administered in the ICU to minimise the risk of hyperoxaemia. After extubation, the upper monitored alarm limit of acceptable SpO2 of 95% will 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 duration of therapy is until discharge from the study ICU, or 90 days from randomisation, whichever is sooner.

We will seek to ensure adherence by providing staff with an online study learning package, and through directly monitoring adherence in a random in at least 1 in 40 participants. Specific feedback will be provided to sites with high non-adherence rates and, if necessary such sites will be required to terminate enrolment
Intervention code [1] 317085 0
Treatment: Other
Comparator / control treatment
Liberal oxygen therapy (usual care): no specific measures will be taken to avoid high FIO2 or high SpO2 (including no upper alarm limit for SpO2). To minimise the risk of contamination the minimum acceptable FIO2 during episodes of mechanically ventilation in the ICU will be 0.3.
Control group
Active

Outcomes
Primary outcome [1] 323184 0
In-hospital all-cause mortality
Timepoint [1] 323184 0
Up to 90 days from the date of randomisation. Note, all patients who survive the index hospital admission and are discharged from hospital within 90 days of randomisation will be defined as alive.
Secondary outcome [1] 381102 0
Duration of survival
Timepoint [1] 381102 0
Ascertained at hospital discharge or at 90 days (2160 hours) following enrolment of the last trial participant (whichever is sooner).
Secondary outcome [2] 381103 0
ICU length of stay assessed through data-linkage to medical records
Timepoint [2] 381103 0
Ascertained at hospital discharge or at 90 days (2160 hours) following enrolment of the last trial participant (whichever is sooner).
Secondary outcome [3] 381104 0
Hospital length of stay assessed through data-linkage to medical records
Timepoint [3] 381104 0
Ascertained at hospital discharge or at 90 days (2160 hours) following enrolment of the last trial participant (whichever is sooner).
Secondary outcome [4] 381105 0
Proportion of patients discharged home assessed through data-linkage to medical records
Timepoint [4] 381105 0
Ascertained at hospital discharge or at 90 days (2160 hours) following enrolment of the last trial participant (whichever is sooner).
Secondary outcome [5] 381106 0
All-cause mortality (includes any deaths that occur after hospital discharge but only where these data can by obtained from registry data sources.)
Timepoint [5] 381106 0
Day 90 post randomisation with assessment through data-linkage to existing registry data sources such as national death registers.

Eligibility
Key inclusion criteria
Patients 18 years or older who require invasive mechanical ventilation in the ICU following an emergency (unplanned) ICU admission AND those starting mechanical ventilation in the ICU (i.e. intubated in the ICU) will be eligible for inclusion.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Where enrolment is not considered in a particular patient’s best interests by the treating clinician, that patient will be excluded. This exclusion criterion will be modified in jurisdictions where a best interest’s standard does not operate as part of ethics / regulatory requirements. In such jurisdictions this exclusion criterion which will be expressed as “the treating clinician considers that one study treatment arm is either indicated or contraindicated.
2. Previously enrolled in Mega-ROX.

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.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will occur using computer generated random numbers. No stratification or blocking of randomisation is planned
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
• This 40,000 participant trial will be conducted in multiple countries and includes innovative trial design features:
i. Linkage to identify enrolled patients in national ICU registries so that outcome data do not need to be collected specifically for the trial;
ii. Response adaptive randomisation giving trial participants an increased chance of being assigned to the oxygen regimen associated with the lowest mortality risk while the trial is ongoing.
• In the event that a zero percentage point absolute mortality difference between treatment groups is observed in our trial, 95% CIs would be expected to exclude the possibility of an absolute increase or decrease in mortality of well under one percentage point. In this situation, in the absence of heterogeneity of treatment effect, we submit that our trial would effectively exclude the possibility of a clinically important effect of conservative oxygen therapy on in-hospital mortality in this patient population.
• Because we consider that there is a distinct possibility that conservative oxygen therapy will be best for patients with some diagnoses while liberal oxygen will be best for patients with other diagnoses (i.e. that there will be heterogeneity of treatment effect), we are conducting a number of parallel nested trials within the overall 40,000 participant trial sample. Each of these nested trials will evaluate a pre-specified hypothesis in a specific cohort of critically ill patients and is accompanied by an appropriate power calculation.
Phase
Phase 3
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Assuming a control group mortality rate of 29.7%, a sample size of 38,420 provides 90% power to detect an absolute mortality difference of 1.5% using a two tailed hypothesis at an alpha of 0.05. We have inflated the sample size to 40,000 to account for losses to follow-up and to account for minor trial inefficiency that results from adaptive randomisation.. Our specified effect size is based on a number of considerations. Firstly, we have updated our Lancet SR/MA with the ICU-ROX data. The updated relative risk for in-hospital mortality with conservative vs. liberal oxygen therapy was 0.89 (95% CI (0.79 to 1.01) (manuscript in preparation). We have also performed a SR/MA in critically ill adults which yielded similar treatment effect estimates, relative risk 0.91 (95% CI 0.75 to 1.09) (manuscript in preparation). Based on a baseline mortality rate of 29.7%, a relative risk of 0.91 for conservative oxygen therapy vs. usual (liberal) oxygen corresponds to a 9% relative risk reduction in mortality with a conservative approach. We have powered our study conservatively so that we can detect an effect of just over half of this magnitude (a 5% relative risk reduction). Secondly, with our specified size, in the event that there is a zero percentage point absolute mortality difference between treatment groups is observed in the Mega-ROX trial, 95% CIs would be expected to exclude the possibility of an absolute increase or decrease in mortality of well under one percentage point. We submit that this would effectively exclude the possibility of a clinically important effect of conservative oxygen therapy on in-hospital mortality in this patient population overall. Finally, one common criticism of prior multicentre RCTs in ICU patients has been failure to account sufficiently for potential heterogeneity of treatment responses. Whether or not conservative oxygen therapy affects mortality overall, it is plausible that it benefits some patient groups and harms others. As outlined below, one of the factors involved in determining our sample size was providing power to detect effects in the planned nested trials.

Based on the number of patients with hypoxic ischaemic encephalopathy enrolled in the ICU-ROX trial, we would expect to recruit 6,880 patients with hypoxic ischaemic encephalopathy in the Mega-ROX HIE trial. Assuming a baseline in-hospital mortality rate of 54.4% in patients with hypoxic ischaemic encephalopathy, this sample size will provide >90% power to detect an absolute mortality difference of 4 percentage points using a two tailed hypothesis at an alpha of 0.05. This effect size is smaller than the treatment effect suggested by observed point estimates in the ICU-ROX trial and is, thus, appropriately conservative.

Based on the number of patients with acute brain pathology patients without hypoxic ischaemic encephalopathy enrolled in the ICU-ROX trial, we would expect to recruit 8,994 of these patients in the Mega-ROX ABI trial. Assuming a baseline in-hospital mortality rate of 24.8% in patients with acute brain pathologies without hypoxic ischaemic encephalopathy, this sample size will provide >90% power to detect an absolute mortality difference of 3 percentage points using a two tailed hypothesis at an alpha of 0.05. This effect size is smaller than that the treatment effect suggested by observed point estimates the ICU-ROX trial and is, thus, appropriately conservative.

Based on the number of patients with sepsis enrolled in the ICU-ROX trial, we would expect to recruit 10,362 patients with sepsis in the Mega-ROX Sepsis trial. Assuming a baseline in-hospital mortality rate of 25.6% in patients assigned to usual oxygen therapy, this sample size will provide >90% power to detect an absolute mortality difference of 2.8 percentage points using a two tailed hypothesis at an alpha of 0.05. This effect size is smaller than that the treatment effect suggested by observed point estimates the ICU-ROX trial and is, thus, appropriately conservative.

A detailed statistical analysis plan will be published in the public domain in advance of the study database lock.


Recruitment
Recruitment status
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)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment outside Australia
Country [1] 22431 0
New Zealand
State/province [1] 22431 0
Country [2] 22432 0
Sweden
State/province [2] 22432 0
Country [3] 22433 0
Saudi Arabia
State/province [3] 22433 0

Funding & Sponsors
Funding source category [1] 305210 0
Government body
Name [1] 305210 0
Health Research Council of New Zealand
Address [1] 305210 0
Physical address:Level 3 - ProCARE Building, Grafton Mews, at 110 Stanley Street (GPS: 50 Grafton Road), Grafton, Auckland 1010, New Zealand
Postal address:PO Box 5541, Wellesley Street, Auckland 1141, New Zealand
Country [1] 305210 0
New Zealand
Primary sponsor type
Charities/Societies/Foundations
Name
Medical Research Institute of New Zealand
Address
Physical Address: Level 7, CSB Building, Wellington Hospital, Riddiford St, Newtown, Wellington 6021, New Zealand

Postal Address, Private Bag 7902, Wellington 6242, New Zealand
Country
New Zealand
Secondary sponsor category [1] 305570 0
None
Name [1] 305570 0
Address [1] 305570 0
Country [1] 305570 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305562 0
Northern B Health and Disability Ethics Committee
Ethics committee address [1] 305562 0
Ministry of Health, 133 Molesworth Street, PO Box 5013, Wellington 6011, New Zealand
Ethics committee country [1] 305562 0
New Zealand
Date submitted for ethics approval [1] 305562 0
Approval date [1] 305562 0
07/01/2020
Ethics approval number [1] 305562 0
19/NTB/195
Ethics committee name [2] 305563 0
institutional review board / independent ethics committee, Ministriy of National Guard - health affairs
Ethics committee address [2] 305563 0
King Abdullah International Medical Research Center
P.O. Box 3660, Riyadh 11481, Saudi Arabia
Ethics committee country [2] 305563 0
Saudi Arabia
Date submitted for ethics approval [2] 305563 0
Approval date [2] 305563 0
03/02/2020
Ethics approval number [2] 305563 0
CT19/036/R

Summary
Brief summary
The purpose of the Mega-ROX study is to determine the effect of two approaches to oxygen therapy on the risk of death in patients who need emergency life support (a breathing machine) in the ICU.

Oxygen is essential for life and is given to all patients on life support. Often these patients receive more oxygen than they need to make their body oxygen levels normal.

Some research suggests that giving more oxygen than is needed to achieve normal oxygen levels in the body may be harmful while other research suggests that it is not, and it may even be beneficial.

This study compares two ways of giving oxygen to patients on life support. The first is to give a little more oxygen and the second is to give a little less. Both approaches are safe but is not clear which approach is the most effective.

All patients in this study can be allocated to either of the approaches to oxygen therapy being tested. However, the study is designed so that as the chances that one approach is better for patients with particular problems increases, the number of new patients given oxygen using that approach also increases. In a sense this means that every patient in this study benefits from the information gained from previous patients and every patient helps future patients.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 100786 0
Dr Paul Young
Address 100786 0
Medical Research Institute of New Zealand
Private Bag 7902
Wellington 6242
New Zealand
Country 100786 0
New Zealand
Phone 100786 0
+64 274552269
Fax 100786 0
Email 100786 0
paul.young@ccdhb.org.nz
Contact person for public queries
Name 100787 0
Ms Diane Mackle
Address 100787 0
Medical Research Institute of New Zealand
Private Bag 7902
Wellington 6242
New Zealand
Country 100787 0
New Zealand
Phone 100787 0
+64 273107429
Fax 100787 0
Email 100787 0
diane.mackle@ccdhb.org.nz
Contact person for scientific queries
Name 100788 0
Ms Diane Mackle
Address 100788 0
Medical Research Institute of New Zealand
Private Bag 7902
Wellington 6242
New Zealand
Country 100788 0
New Zealand
Phone 100788 0
+64 273107429
Fax 100788 0
Email 100788 0
diane.mackle@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?
All deidentified individual participant data collected during the trial will be shared
When will data be available (start and end dates)?
Two years following publication of the primary study results manuscript
Available to whom?
Researchers whose proposed use of the data has been approved.
Available for what types of analyses?
For a specified purpose after approval of a proposal by the study management committee.
How or where can data be obtained?
By sending a request to the Paul Young (the Chief Investigator) at paul.young@ccdhb.org.nz
What supporting documents are/will be available?
Study protocol
Statistical analysis plan
Informed consent form
Ethical approval
How or where can supporting documents be obtained?
Type [1] 7297 0
Study protocol
Citation [1] 7297 0
Link [1] 7297 0
Email [1] 7297 0
paul.young@ccdhb.org.nz
Other [1] 7297 0
Attachment [1] 7297 0
Type [2] 7298 0
Statistical analysis plan
Citation [2] 7298 0
Link [2] 7298 0
Email [2] 7298 0
paul.young@ccdhb.org.nz
Other [2] 7298 0
Attachment [2] 7298 0
Type [3] 7299 0
Informed consent form
Citation [3] 7299 0
Link [3] 7299 0
Email [3] 7299 0
paul.young@ccdhb.org.nz
Other [3] 7299 0
Attachment [3] 7299 0
Type [4] 7301 0
Ethical approval
Citation [4] 7301 0
Link [4] 7301 0
Email [4] 7301 0
paul.young@ccdhb.org.nz
Other [4] 7301 0
Attachment [4] 7301 0
Summary results
No Results