Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000518864
Ethics application status
Approved
Date submitted
24/03/2021
Date registered
4/05/2021
Date last updated
23/06/2024
Date data sharing statement initially provided
4/05/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Low OxyGen Intervention for Cardiac Arrest injury Limitation (LOGICAL) trial
Scientific title
A multi-centre, randomised, single-blinded clinical trial comparing the effect of conservative vs. liberal oxygenation targets on survival with good neurological function in adults with suspected hypoxic ischaemic encephalopathy following a cardiac arrest who are invasively mechanical ventilated in the ICU
Secondary ID [1] 303780 0
None
Universal Trial Number (UTN)
Trial acronym
LOGICAL
Linked study record
LOGICAL is a substudy nested within Mega-ROX (ACTRN12620000391976)

Health condition
Health condition(s) or problem(s) studied:
hypoxic ischaemic encephalopathy 321281 0
cardiac arrest 321701 0
Condition category
Condition code
Neurological 319062 319062 0 0
Other neurological disorders
Cardiovascular 319440 319440 0 0
Other cardiovascular diseases

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.

Conservative oxygen therapy will be initiated immediately post randomisation (with randomisation required within 12 hours of unplanned invasive mechanical ventilation in an ICU). The duration of conservative oxygen 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 all participants via the study website. Participant oxygen levels will be reviewed by the project management team after they have been uploaded to the study website. 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] 320087 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.

Liberal oxygen therapy will be initiated immediately post randomisation (with randomisation required within 12 hours of unplanned invasive mechanical ventilation in an ICU). The duration of liberal oxygen 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 all participants via the study website. Participant oxygen levels will be reviewed by the project management team after they have been uploaded to the study website. Specific feedback will be provided to sites with high non-adherence rates and, if necessary such sites will be required to terminate enrolment
Control group
Active

Outcomes
Primary outcome [1] 326957 0
The primary outcome is good neurological outcome measured with the Extended Glasgow Outcome Scale (GOS-E). A good neurological outcome will be defined as a GOS-E of lower moderate disability or better (i.e. GOS-E 5-8). The GOS-E is a widely used outcome measure in patients with hypoxic brain injury. It categorises patients into one of the following eight categories: death, vegetative state, lower severe disability, upper severe disability, lower moderate disability, upper moderate disability, lower good recovery, and upper good recovery. In ascertaining the GOS-E, which will be assessed by a blinded, trained outcome assessor, we will use a structured interview to ensure consistency in ratings.
Timepoint [1] 326957 0
180 days post randomisation
Secondary outcome [1] 393286 0
All-cause mortality ascertained from clinical records or by direct contact with the patient
Timepoint [1] 393286 0
180 days post randomisation
Secondary outcome [2] 393287 0
Cause-specific mortality ascertained from clinical records or by direct contact with the patient with deaths categorised as neurological, arrhythmia-related, cardiogenic shock-related, distributive (septic) shock-related, hypovolaemic shock-related, hypoxic respiratory failure-related, metabolic, or other
Timepoint [2] 393287 0
180 days post randomisation
Secondary outcome [3] 393288 0
Duration of survival ascertained from clinical records or by direct contact with the patient
Timepoint [3] 393288 0
Until the time of last follow-up which is planned for 180 days post randomisation but may be performed up until the study database is locked for analysis (database lock is anticipated to occur six months after the final participant is enrolled)
Secondary outcome [4] 393290 0
Quality of life assessed using the EQ-5D-5L administered by a blinded central outcome assessor over the telephone
Timepoint [4] 393290 0
180 days post randomisation
Secondary outcome [5] 393291 0
Cognitive function assessed using the Montreal Cognitive Assessment (MoCA-blind) administered by a blinded centralised outcome assessor by telephone
Timepoint [5] 393291 0
180 days post randomisation
Secondary outcome [6] 393292 0
ICU length of stay assessed through data-linkage to medical records
Timepoint [6] 393292 0
Ascertained at hospital discharge or at 180 days (4320 hours) following enrolment of the last trial participant (whichever is sooner).
Secondary outcome [7] 393293 0
Hospital length of stay assessed through data-linkage to medical records
Timepoint [7] 393293 0
Ascertained at hospital discharge or at 180 days (4320 hours) following enrolment of the last trial participant (whichever is sooner).
Secondary outcome [8] 393294 0
Duration of invasive mechanical ventilation in the ICU assessed through data-linkage to medical records
Timepoint [8] 393294 0
Ascertained at hospital discharge or at 180 days (4320 hours) following enrolment of the last trial participant (whichever is sooner).
Secondary outcome [9] 393295 0
Proportion of patients discharged home assessed through data-linkage to medical records
Timepoint [9] 393295 0
Ascertained at hospital discharge or at 180 days (4320 hours) following enrolment of the last trial participant (whichever is sooner).

Eligibility
Key inclusion criteria
1. Aged greater than or equal to 18 years AND
2. Receiving invasive mechanical ventilation in the ICU following a cardiac arrest AND
3. Suspected of having hypoxic ischaemic encephalopathy (i.e. the patient has not obeyed commands following resuscitation from a cardiac arrest and there is clinical concern about possible brain damage)
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Enrolment is not considered in the patient’s best interests by the treating clinician (e.g. the patient is expected to die and is not being treated with curative intent or the treating clinician considers that one study treatment arm is either indicated or contraindicated) OR
2. Previously enrolled in the Mega-ROX trial OR
3. Greater than 12 hours have elapsed since the patient fulfilled the inclusion criteria

When a patient is not enrolled within 12 hours of fulfilling the eligibility criteria, he /she will be counted as “eligible but missed” rather than “excluded” for the purposes of describing participant flow.

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
The LOGICAL trial will be conducted nested within the Mega Randomised Registry Trial Comparing Liberal vs. Conservative OXygen Targets in Patients with Hypoxic Ischaemic Encephalopathy (Mega-ROX HIE). The Mega-ROX HIE trial is itself part of the larger Mega-ROX trials programme which includes a series of parallel randomised clinical trials conducted within a 40,000-participant sample size envelope. These trials are designed to determine the effect of conservative oxygen therapy vs. liberal oxygen therapy on in-hospital mortality overall and also specifically in patients with: hypoxic ischaemic encephalopathy; acute brain pathologies (excluding hypoxic ischaemic encephalopathy); and sepsis. The trials are two-sided superiority trials, which will preferentially allocate patients to intervention or control in a 1.05:1 ratio based on whichever of these treatments was better for the particular patient subgroup in the ICU-ROX trial. After the first and subsequent interim analyses the randomisation ratios may be altered (if required) to favour the treatment with the lower mortality rate for each patient subgroup based on accumulated Mega-ROX trial data. For each trial participant, three randomisation ratios are possible: 1.05:1 in favour of conservative oxygen; 1.05:1 in favour of liberal oxygen; and 1:1. Randomisation will be 1:1 if accumulated trial data show similar mortality rates by treatment group (i.e. if the point estimate for the relative risk of mortality with conservative vs. liberal oxygen incorporating adjustment for site is between 0.9 and 1.1). Otherwise, randomisation ratios will favour the treatment strategy associated with the lowest risk of death based on point estimates obtained from the accumulated trial data. Trial data for the Mega-ROX trials will be obtained from ICU registries. Data for the LOGICAL trial will be obtained using trial-specific case report forms and centralised follow-up conducted by trained blinded outcome assessors.
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Allowing for loss to follow-up of 4%, a sample of 1400 patients provides 90% power to detect an 8.5% absolute difference between treatment groups in the proportion of patients who survive with a favourable neurological outcome based on a control event rate of 32%. We inflated the sample size to 1540 after the interim analysis to account for losses to follow-up and for protocol deviations involving enrolment of ineligible patients. We further inflated the sample size to 1840 because evaluation of aggregate baseline data after recruitment of 1181 patients revealed a higher than expected proportion of patients with asystole and pulseless electrical activity. We reasoned that such patients might be less likely to benefit from conservative oxygen therapy than patients with other presenting rhythms and so inflated the sample size to account for this. Both adjustments to the sample size were supported by the DSMB.

Analysis of the primary outcome and other binary outcomes will be via log-binomial models incorporating adjustment for site. The numbers at risk in each group and the number and proportion of events observed will be reported, as well as the equivalent absolute risk difference and relative risk ratio and corresponding 95% confidence intervals. Sensitivity analyses accounting for differences across sites and any clinically meaningful baseline imbalances will be performed using log binomial regression. In addition we will incorporate adjustment for the independent covariates of age, gender, and APACHE-II score. Adjustment for baseline imbalances in the number of patients with hypoxic ischaemic encephalopathy, other acute brain pathologies, and sepsis which are expected due to adaptive randomisation will also be incorporated into all secondary analyses. Missing baseline characteristics will be imputed via single mean imputation using centre-specific means.

The effect of treatment allocation on the proportion of patients discharged home will be assessed in the same way as the primary outcomes. To account for the competing risk of death, ICU and hospital lengths of stay will be analysed using sub distribution hazard regression models and presented using cumulative incidence functions. As lengths of stay are typically well approximated by log-normal distributions, for increased transparency, they will also be reported as geometric means (95% CI), with additional stratification for survival and differences between groups reported as a ratio (95% CI). Survival time according to treatment group will be displayed as Kaplan-Meier curves and analysed using a log-rank test. Estimates of hazard ratios for survival, with corresponding 95% CI and P values, will be obtained from the Cox proportional hazards models incorporating treatment group alone, and additionally using independent covariates used in the multivariate logistic models described in relation to the primary outcome.

For analyses that compare differences in the median percentage of hours per participant and the median number of hours per participant above and below specific PaO2 thresholds, and those that compared the median percentage of hours per participant and the median number of hours spent breathing an FiO2 of 0.21 while in the ICU, we will calculate differences and medians and 95% CIs using quantile regression incorporating adjusting for site.

Analyses that compare the proportion of patients with at least one PaO2 recording less than 60mmHg and with at least one PaO2 recording greater than 100mmHg will be conducted via log-binomial models, adjusting for site The numbers at risk in each group and the number and proportion of events observed will be reported, as well as the relative risk and corresponding 95% confidence intervals.

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

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
2/08/2021
Actual
2/09/2021
Date of last participant enrolment
Anticipated
1/01/2024
Actual
1/06/2024
Date of last data collection
Anticipated
1/11/2024
Actual
Sample size
Target
1840
Accrual to date
Final
1840
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment outside Australia
Country [1] 23562 0
New Zealand
State/province [1] 23562 0

Funding & Sponsors
Funding source category [1] 308181 0
Government body
Name [1] 308181 0
Health Research Council of New Zealand
Country [1] 308181 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] 308960 0
None
Name [1] 308960 0
Address [1] 308960 0
Country [1] 308960 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308166 0
Northern B Health and Disability Ethics Committee
Ethics committee address [1] 308166 0
Ethics committee country [1] 308166 0
New Zealand
Date submitted for ethics approval [1] 308166 0
01/03/2021
Approval date [1] 308166 0
24/03/2021
Ethics approval number [1] 308166 0
19/NTB/195/AM06

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 109770 0
Dr Paul Young
Address 109770 0
Medical Research Institute of New Zealand
Private Bag 7902
Wellington 6242
New Zealand
Country 109770 0
New Zealand
Phone 109770 0
+64 274552269
Fax 109770 0
Email 109770 0
[email protected]
Contact person for public queries
Name 109771 0
Diane Mackle
Address 109771 0
Medical Research Institute of New Zealand
Private Bag 7902
Wellington 6242
New Zealand
Country 109771 0
New Zealand
Phone 109771 0
+64 273107429
Fax 109771 0
Email 109771 0
[email protected]
Contact person for scientific queries
Name 109772 0
Diane Mackle
Address 109772 0
Medical Research Institute of New Zealand
Private Bag 7902
Wellington 6242
New Zealand
Country 109772 0
New Zealand
Phone 109772 0
+64 273107429
Fax 109772 0
Email 109772 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)?
Data will be available two years following publication of the primary study results manuscript with no end date.
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
11157Study protocol  [email protected]
11158Statistical analysis plan  [email protected]
11159Informed consent form  [email protected]
11160Ethical approval  [email protected]



Results publications and other study-related documents

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