Protocol and statistical analysis plan for the mega randomised registry trial comparing conservative vs. liberal oxygenation targets in adults in the intensive care unit with suspected hypoxic ischaemic encephalopathy following a cardiac arrest (Mega-ROX HIE)

Paul J Young^{1

2

3

4}, Abdulrahman Al-Fares^{5

6}, Diptesh Aryal⁷, Yaseen M Arabi⁸, Muhammad Sheharyar Ashraf⁹, Sean M Bagshaw¹⁰, Abigail Beane^{11

12}, Airton L de Oliveira Manoel¹³, Layoni Dullawe¹², Fathima Fazla¹², Tomoko Fujii^{3

14

15}, Rashan Haniffa^{11

12

16

17}, Mohd Shahnaz Hasan¹⁸, Carol L Hodgson^{3

4

19

20}, Anna Hunt², Cassie Lawrence², Israel Silva Maia^{21

22}, Diane Mackle², Giacomo Monti^{23

24}, Alistair D Nichol^{3

20

25

26}, Shaanti Olatunji², Sristi Patodia²⁷, Aasiyah Rashan^{12

28}, Sumayyah Rashan^{12

29}, Jessica Kasza³⁰; Mega-ROX management committee; Australian and New Zealand Intensive Care Society Clinical Trials Group; Brazilian Research in Intensive Care Network; Critical Care Asia and Africa Network, and; Irish Critical Care-Clinical Trials Group

Affiliations

¹ Intensive Care Unit, Wellington Hospital, Wellington, New Zealand.
² Medical Research Institute of New Zealand, Wellington, New Zealand.
³ Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Victoria, Australia.
⁴ Department of Critical Care, University of Melbourne, Melbourne, Victoria, Australia.
⁵ Department of Anesthesia, Critical Care Medicine, and Pain Medicine, Al-Amiri Hospital, Ministry of Health, Kuwait.
⁶ Kuwait Extracorporeal Life Support Program, Al-Amiri Center for Respiratory and Cardiac Failure, Ministry of Health, Kuwait.
⁷ Nepal Intensive Care Research Foundation, Kathmandu, Nepal.
⁸ College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, and Intensive Care Department, King Abdulaziz Medical City, Ministry of National-Guard Health Affairs, Riyadh, Saudi Arabia.
⁹ Department of Anesthesia and Critical Care Unit, Lady Reading Hospital, Peshawar, Pakistan.
¹⁰ Department of Critical Care Medicine, Faculty of Medicine and Dentistry, University of Alberta, and the Critical Care Strategic Clinical Network, Alberta Health Services, Edmonton, Alberta, Canada.
¹¹ Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.
¹² National Intensive Care Surveillance - MORU (NICS-MORU), Colombo, Sri Lanka.
¹³ Department of Critical Care Medicine, Sultan Qaboos Comprehensive Cancer Care and Research Center, Muscat, Oman.
¹⁴ Intensive Care Unit, Jikei University Hospital, Tokyo, Japan.
¹⁵ Department of Health Promotion and Human Behavior, Kyoto University School of Public Health, Kyoto, Japan.
¹⁶ Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
¹⁷ University College Hospital, London, United Kingdom.
¹⁸ Department of Anaesthesiology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia.
¹⁹ The Intensive Care Unit, Alfred Health, Melbourne, Victoria, Australia.
²⁰ The George Institute for Global Health, Sydney, New South Wales, Australia.
²¹ HCor Research Institute, São Paulo, Brazil.
²² Brazilian Research in Intensive Care Network - BricNet, Brazil.
²³ Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy.
²⁴ Faculty of Medicine, Vita-Salute San Raffaele University, Milan, Italy.
²⁵ School of Medicine and Medical Sciences, University College Dublin, Ireland.
²⁶ Department of Anaesthesia and Intensive Care, St Vincent's Hospital, Dublin, Ireland.
²⁷ Department of Critical Care Medicine, Apollo Hospitals, Chennai, India.
²⁸ University College London, Institute of Health Informatics, London, United Kingdom.
²⁹ Division of Surgery and Interventional Science, University College London, London, United Kingdom.
³⁰ School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.

PMID: 39072241
PMCID: PMC11282325
DOI: 10.1016/j.ccrj.2024.03.004

Protocol and statistical analysis plan for the mega randomised registry trial comparing conservative vs. liberal oxygenation targets in adults in the intensive care unit with suspected hypoxic ischaemic encephalopathy following a cardiac arrest (Mega-ROX HIE)

Paul J Young et al. Crit Care Resusc. 2024.

. 2024 Jun 21;26(2):87-94.

doi: 10.1016/j.ccrj.2024.03.004. eCollection 2024 Jun.

Authors

Affiliations

¹ Intensive Care Unit, Wellington Hospital, Wellington, New Zealand.
² Medical Research Institute of New Zealand, Wellington, New Zealand.
³ Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Victoria, Australia.
⁴ Department of Critical Care, University of Melbourne, Melbourne, Victoria, Australia.
⁵ Department of Anesthesia, Critical Care Medicine, and Pain Medicine, Al-Amiri Hospital, Ministry of Health, Kuwait.
⁶ Kuwait Extracorporeal Life Support Program, Al-Amiri Center for Respiratory and Cardiac Failure, Ministry of Health, Kuwait.
⁷ Nepal Intensive Care Research Foundation, Kathmandu, Nepal.
⁸ College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, and Intensive Care Department, King Abdulaziz Medical City, Ministry of National-Guard Health Affairs, Riyadh, Saudi Arabia.
⁹ Department of Anesthesia and Critical Care Unit, Lady Reading Hospital, Peshawar, Pakistan.
¹⁰ Department of Critical Care Medicine, Faculty of Medicine and Dentistry, University of Alberta, and the Critical Care Strategic Clinical Network, Alberta Health Services, Edmonton, Alberta, Canada.
¹¹ Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.
¹² National Intensive Care Surveillance - MORU (NICS-MORU), Colombo, Sri Lanka.
¹³ Department of Critical Care Medicine, Sultan Qaboos Comprehensive Cancer Care and Research Center, Muscat, Oman.
¹⁴ Intensive Care Unit, Jikei University Hospital, Tokyo, Japan.
¹⁵ Department of Health Promotion and Human Behavior, Kyoto University School of Public Health, Kyoto, Japan.
¹⁶ Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
¹⁷ University College Hospital, London, United Kingdom.
¹⁸ Department of Anaesthesiology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia.
¹⁹ The Intensive Care Unit, Alfred Health, Melbourne, Victoria, Australia.
²⁰ The George Institute for Global Health, Sydney, New South Wales, Australia.
²¹ HCor Research Institute, São Paulo, Brazil.
²² Brazilian Research in Intensive Care Network - BricNet, Brazil.
²³ Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy.
²⁴ Faculty of Medicine, Vita-Salute San Raffaele University, Milan, Italy.
²⁵ School of Medicine and Medical Sciences, University College Dublin, Ireland.
²⁶ Department of Anaesthesia and Intensive Care, St Vincent's Hospital, Dublin, Ireland.
²⁷ Department of Critical Care Medicine, Apollo Hospitals, Chennai, India.
²⁸ University College London, Institute of Health Informatics, London, United Kingdom.
²⁹ Division of Surgery and Interventional Science, University College London, London, United Kingdom.
³⁰ School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.

PMID: 39072241
PMCID: PMC11282325
DOI: 10.1016/j.ccrj.2024.03.004

Abstract

Background: The effect of conservative vs. liberal oxygen therapy on 90-day in-hospital mortality in adults with hypoxic ischaemic encephalopathy (HIE) following a cardiac arrest who are receiving invasive mechanical ventilation in the intensive care unit (ICU) is uncertain.

Objective: To summarise the protocol and statistical analysis plan for the Mega-ROX HIE trial.

Design setting and participants: Mega-ROX HIE is an international randomised clinical trial that will be conducted within an overarching 40,000-participant registry-embedded clinical trial comparing conservative and liberal ICU oxygen therapy regimens. We expect to enrol approximately 4000 participants with suspected HIE following a cardiac arrest who are receiving invasive mechanical ventilation in the ICU.

Main outcome measures: The primary outcome is in-hospital all-cause mortality up to 90 days from the date of randomisation. Secondary outcomes include duration of survival, duration of mechanical ventilation, ICU length of stay, hospital length of stay, and the proportion of participants discharged home.

Results and conclusions: Mega-ROX HIE will compare the effect of conservative vs. liberal oxygen therapy regimens on day-90 in-hospital mortality in adults in the ICU with suspected HIE following a cardiac arrest. The protocol and planned analyses are reported here to mitigate analysis bias.

Trial registration: Australian and New Zealand Clinical Trials Registry (ACTRN 12620000391976).

Keywords: Cardiac arrest; Oxygen; Protocol; Randomised clinical trial.

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Figures

**Fig. 1**
Overview of steps undertaken by the data monitoring committee at interim analyses. Abbreviations: HIE: hypoxic ischaemic encephalopathy; Mega-ROX: Mega randomised registry trial comparing two approaches to oxygen therapy in the intensive care unit.

See this image and copyright information in PMC

References

1. Sekhon M.S., Ainslie P.N., Griesdale D.E. Clinical pathophysiology of hypoxic ischemic brain injury after cardiac arrest: a "two-hit" model. Crit Care. 2017;21:90. - PMC - PubMed
1. Young P.J., Bailey M., Bellomo R., Bernard S., Bray J., Jakkula P., et al. Conservative or liberal oxygen therapy in adults after cardiac arrest: an individual-level patient data meta-analysis of randomised controlled trials. Resuscitation. 2020;157:15–22. - PubMed
1. Young P., Mackle D., Bellomo R., Bailey M., Beasley R., Deane A., et al. Conservative oxygen therapy for mechanically ventilated adults with suspected hypoxic ischaemic encephalopathy. Intensive Care Med. 2020;46:2411–2422. - PMC - PubMed
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Protocol and statistical analysis plan for the mega randomised registry trial comparing conservative vs. liberal oxygenation targets in adults in the intensive care unit with suspected hypoxic ischaemic encephalopathy following a cardiac arrest (Mega-ROX HIE)

Affiliations

Protocol and statistical analysis plan for the mega randomised registry trial comparing conservative vs. liberal oxygenation targets in adults in the intensive care unit with suspected hypoxic ischaemic encephalopathy following a cardiac arrest (Mega-ROX HIE)

Authors

Affiliations

Abstract

Figures

References

LinkOut - more resources

Full Text Sources