Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620000391976
Ethics application status
Approved
Date submitted
10/03/2020
Date registered
23/03/2020
Date last updated
30/05/2024
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 centralised monitoring according to the risk based monitoring plan. This approach will involve reviewing data entered by site staff into the eCRF. Data are reviewed using protocol compliance reporting and direct review of oxygen data entered and assessed according to pre-specified risk indicator thresholds. 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.
Secondary outcome [6] 410740 0
Duration of invasive mechanical ventilation assessed through data-linkage to medical records
Timepoint [6] 410740 0
Ascertained at hospital discharge or at 90 days (2160 hours) following enrolment of the last trial participant (whichever is sooner).

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
Sex
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
1/04/2020
Actual
11/05/2020
Date of last participant enrolment
Anticipated
1/06/2025
Actual
Date of last data collection
Anticipated
31/12/2025
Actual
Sample size
Target
40000
Accrual to date
23844
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] 22433 0
Saudi Arabia
State/province [2] 22433 0
Country [3] 23841 0
Japan
State/province [3] 23841 0
Tokyo 105-8461
Country [4] 23842 0
Canada
State/province [4] 23842 0
Country [5] 23843 0
Ireland
State/province [5] 23843 0
Country [6] 23844 0
Kuwait
State/province [6] 23844 0
Country [7] 23845 0
Malaysia
State/province [7] 23845 0
Country [8] 24830 0
Pakistan
State/province [8] 24830 0
Not applicable
Country [9] 24831 0
Nepal
State/province [9] 24831 0
Not applicable
Country [10] 25396 0
Brazil
State/province [10] 25396 0
Not applicable
Country [11] 25397 0
Oman
State/province [11] 25397 0
Not applicable
Country [12] 25398 0
India
State/province [12] 25398 0
Not applicable

Funding & Sponsors
Funding source category [1] 305210 0
Government body
Name [1] 305210 0
Health Research Council of 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
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
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
Ethics committee name [3] 308862 0
The Jikei University Ethics Committee
Ethics committee address [3] 308862 0
Ethics committee country [3] 308862 0
Japan
Date submitted for ethics approval [3] 308862 0
12/07/2020
Approval date [3] 308862 0
14/09/2020
Ethics approval number [3] 308862 0
32-163(10244)
Ethics committee name [4] 308863 0
Nepean Blue Mountains Local Health District HREC
Ethics committee address [4] 308863 0
Ethics committee country [4] 308863 0
Australia
Date submitted for ethics approval [4] 308863 0
26/06/2020
Approval date [4] 308863 0
26/08/2020
Ethics approval number [4] 308863 0
2020/ETH00961
Ethics committee name [5] 308864 0
Standing committee for coordination of health and medical research, Ministry of Health, Kuwait
Ethics committee address [5] 308864 0
Ethics committee country [5] 308864 0
Kuwait
Date submitted for ethics approval [5] 308864 0
Approval date [5] 308864 0
13/11/2020
Ethics approval number [5] 308864 0
1369/2020
Ethics committee name [6] 311061 0
Health Research Consent Declaration Committee
Ethics committee address [6] 311061 0
Ethics committee country [6] 311061 0
Ireland
Date submitted for ethics approval [6] 311061 0
Approval date [6] 311061 0
23/04/2021
Ethics approval number [6] 311061 0
21-002-AF1
Ethics committee name [7] 311062 0
Human Research Ethics Committee USM
Ethics committee address [7] 311062 0
Ethics committee country [7] 311062 0
Malaysia
Date submitted for ethics approval [7] 311062 0
Approval date [7] 311062 0
19/04/2021
Ethics approval number [7] 311062 0
USM/JEPeM/20120703
Ethics committee name [8] 311063 0
Medical Research Ethics Committee, University Malaya Medical Centre
Ethics committee address [8] 311063 0
Ethics committee country [8] 311063 0
Malaysia
Date submitted for ethics approval [8] 311063 0
Approval date [8] 311063 0
02/04/2021
Ethics approval number [8] 311063 0
20201114-9216
Ethics committee name [9] 311064 0
International Islamic University Malaysia Research Ethics Committee
Ethics committee address [9] 311064 0
Ethics committee country [9] 311064 0
Malaysia
Date submitted for ethics approval [9] 311064 0
Approval date [9] 311064 0
24/06/2021
Ethics approval number [9] 311064 0
IIUM/504/14/11/2/ IREC 2021-191
Ethics committee name [10] 311065 0
Lady Reading Hospital Medical Teaching Hospital Ethical Review Board
Ethics committee address [10] 311065 0
Ethics committee country [10] 311065 0
Pakistan
Date submitted for ethics approval [10] 311065 0
Approval date [10] 311065 0
23/02/2021
Ethics approval number [10] 311065 0
59/LRH/MTI
Ethics committee name [11] 311066 0
Northwest General Hospital and Research Centre Ethics Committee
Ethics committee address [11] 311066 0
Ethics committee country [11] 311066 0
Pakistan
Date submitted for ethics approval [11] 311066 0
Approval date [11] 311066 0
26/05/2021
Ethics approval number [11] 311066 0
NwGH/Res/Ethical approval/1421
Ethics committee name [12] 311067 0
National Institutes of Health Health Research Institutes National Bioethics Committee
Ethics committee address [12] 311067 0
Ethics committee country [12] 311067 0
Pakistan
Date submitted for ethics approval [12] 311067 0
Approval date [12] 311067 0
Ethics approval number [12] 311067 0
No.4-87/NBC-641/21/139
Ethics committee name [13] 311068 0
Ethical Review Board, Karahi Medical and Dental College, Abbassi Shaheed Hospital
Ethics committee address [13] 311068 0
Ethics committee country [13] 311068 0
Pakistan
Date submitted for ethics approval [13] 311068 0
28/09/2021
Approval date [13] 311068 0
Ethics approval number [13] 311068 0
03/21
Ethics committee name [14] 311069 0
Pakistan Kidney and Liver Institute and Research Center Ethical Review Board
Ethics committee address [14] 311069 0
Ethics committee country [14] 311069 0
Pakistan
Date submitted for ethics approval [14] 311069 0
10/02/2022
Approval date [14] 311069 0
Ethics approval number [14] 311069 0
PKLI-IRB/AP/53053
Ethics committee name [15] 311070 0
Pakistan (National Institute of Cardiovascular Diseases)
Ethics committee address [15] 311070 0
Ethics committee country [15] 311070 0
Pakistan
Date submitted for ethics approval [15] 311070 0
Approval date [15] 311070 0
07/04/2022
Ethics approval number [15] 311070 0
ERC-12/2022
Ethics committee name [16] 311071 0
Patel Hospital Ethics Committee
Ethics committee address [16] 311071 0
Ethics committee country [16] 311071 0
Pakistan
Date submitted for ethics approval [16] 311071 0
Approval date [16] 311071 0
20/04/2022
Ethics approval number [16] 311071 0
PH/ IRB/2022/005
Ethics committee name [17] 311072 0
Nepal Health Research Council
Ethics committee address [17] 311072 0
Ethics committee country [17] 311072 0
Nepal
Date submitted for ethics approval [17] 311072 0
Approval date [17] 311072 0
13/09/2021
Ethics approval number [17] 311072 0
89/2021 P
Ethics committee name [18] 311073 0
University of Alberta Health Research Ethics Board – Biomedical Panel
Ethics committee address [18] 311073 0
Ethics committee country [18] 311073 0
Canada
Date submitted for ethics approval [18] 311073 0
09/09/2020
Approval date [18] 311073 0
Ethics approval number [18] 311073 0
Pro00089179
Ethics committee name [19] 312813 0
National Committee of Ethics in Research. 60 - Hospital do Coração/Associação Beneficente Síria - HCOR
Ethics committee address [19] 312813 0
Ethics committee country [19] 312813 0
Brazil
Date submitted for ethics approval [19] 312813 0
28/06/2022
Approval date [19] 312813 0
20/10/2022
Ethics approval number [19] 312813 0
5.706.935
Ethics committee name [20] 313132 0
Comitato Ethico of IRCCS, Ospedale San Raffaele
Ethics committee address [20] 313132 0
Ethics committee country [20] 313132 0
Italy
Date submitted for ethics approval [20] 313132 0
10/05/2021
Approval date [20] 313132 0
19/01/2022
Ethics approval number [20] 313132 0
N/A
Ethics committee name [21] 313133 0
Darul Sehat Hospital, IRB Liaquat College of Medicine & Dentistry
Ethics committee address [21] 313133 0
Ethics committee country [21] 313133 0
Pakistan
Date submitted for ethics approval [21] 313133 0
01/07/2022
Approval date [21] 313133 0
05/01/2023
Ethics approval number [21] 313133 0
IRB/M-000050/23
Ethics committee name [22] 313134 0
Institutional Ethics Committee – Bio Medical Research
Ethics committee address [22] 313134 0
Ethics committee country [22] 313134 0
India
Date submitted for ethics approval [22] 313134 0
26/05/2022
Approval date [22] 313134 0
26/09/2022
Ethics approval number [22] 313134 0
AMH-C-S-023/06-21
Ethics committee name [23] 313135 0
Institutional Ethics Committee, Dr Kamakshi Memorial Hospital PVT. Ltd.
Ethics committee address [23] 313135 0
Ethics committee country [23] 313135 0
India
Date submitted for ethics approval [23] 313135 0
26/05/2022
Approval date [23] 313135 0
26/08/2022
Ethics approval number [23] 313135 0
IEC-CS 22 A/BC-127/2022

Summary
Brief summary
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
[email protected]
Contact person for public queries
Name 100787 0
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
[email protected]
Contact person for scientific queries
Name 100788 0
Paul Young
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
[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 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 [email protected]


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
7297Study protocol  [email protected]
7298Statistical analysis plan  [email protected]
7299Informed consent form  [email protected]
7301Ethical approval  [email protected]



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseOxygen targets.2022https://dx.doi.org/10.1007/s00134-022-06714-0
Dimensions AIProtocol and statistical analysis plan for the mega randomised registry trial comparing conservative vs. liberal oxygenation targets in adults with sepsis in the intensive care unit (Mega-ROX Sepsis)2023https://doi.org/10.1016/j.ccrj.2023.04.008
N.B. These documents automatically identified may not have been verified by the study sponsor.