Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12617000036314
Ethics application status
Approved
Date submitted
16/12/2016
Date registered
10/01/2017
Date last updated
18/09/2023
Date data sharing statement initially provided
24/03/2021
Date results provided
18/09/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
A phase III multi-centre randomised controlled trial to evaluate the ability of slightly higher than normal carbon dioxide levels, compared to normal carbon dioxide levels, to reduce brain damage in resuscitated cardiac arrest patients admitted to the intensive care unit.
Scientific title
Targeted therapeutic mild hypercapnia after resuscitated cardiac arrest: A phase III multi-centre randomised controlled trial
Secondary ID [1] 290781 0
None
Universal Trial Number (UTN)
Trial acronym
The TAME Cardiac Arrest trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Out-of-hospital cardiac arrest 301394 0
Condition category
Condition code
Cardiovascular 301139 301139 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients allocated to the targeted therapeutic mild hypercapnia protocol will be sedated as per unit gudelines and at the clinical discretion of the treating intensive care doctors to achieve moderate to deep sedation (a target Richmond Agitation Scale Score of –4). Arterial blood gases and end-tidal carbon dioxide levels will be measured at baseline and then used to guide respiratory rate adjustments of minute ventilation to remain within the target PaCO2 range of 50-55 mmHg for 24 hours following randomisation.. Arterial blood gases will be repeated every 4 hours for 24 hours following randomisation or if end-tidal carbon dioxide values change >5 mmHg. Adjustments to be made to the minute ventilation in order to stay within the target PaCO2 range will be made at the clinical discretion of the treating intensive care doctors. Strategies to monitor adherence to the target PaCO2 range will be via respiratory rate monitoring that displays a continuous record of PaCo2 values and as recorded on the participant's physiological observation chart while in the intensive care unit.
Intervention code [1] 296693 0
Treatment: Other
Comparator / control treatment
Patients allocated to the standard care (targeted normocapnia) protocol will be sedated to achieve moderate to deep sedation (a target Richmond Agitation Scale Score of – 4). Arterial blood gases and end-tidal carbon dioxide levels will be measured at baseline and then used to guide respiratory rate adjustments of minute ventilation to remain within the target PaCO2 range of 35-45 mmHg for 24 hours following randomisation.. Arterial blood gases will be repeated every 4 hours for 24 hours following randomisation or if end-tidal carbon dioxide values change >5 mmHg.
Control group
Active

Outcomes
Primary outcome [1] 300542 0
The proportion of patients with a favourable neurological outcome as assessed by the Glasgow Outcomes Scale Extended (GOSE) method. The GOSE uses an 8-level scale from death (1) to upper good recovery (8) and can be administered by proxy or direct patient interview.. A GOSE outcome is deemed to be favourable if a patient scores greater or equal to 5.
Timepoint [1] 300542 0
Assessed at 6 months following enrolment administered by proxy or direct patient interview.
Secondary outcome [1] 330273 0
Mortality status at intensive care unit (ICU) discharge
Timepoint [1] 330273 0
A review of hospital records will be performed to determine this outcome at the time of intensive care unit (ICU) discharge.
Secondary outcome [2] 330274 0
Mortality status at hospital discharge
Timepoint [2] 330274 0
A review of hospital records will be performed to determine this outcome at the time of hospital discharge.
Secondary outcome [3] 330275 0
Mortality status at 6 months
Timepoint [3] 330275 0
Assessed at 6 months from enrolment.assessed via hospital record review or direct contact with the participant or their next of kin
Secondary outcome [4] 330276 0
Functional recovery as measured by the modified Rankin scale
Timepoint [4] 330276 0
Assessed at 6 months following enrolment administered by proxy or direct patient interview.
Secondary outcome [5] 330278 0
Cognitive recovery as assessed using the Montreal Cognitive Assessment (MoCA-blind) questionnaire.
Timepoint [5] 330278 0
Assessed at 6 months following enrolment administered by proxy or direct patient interview.
Secondary outcome [6] 330279 0
Quality of life assessed by the EuroQol5D5L scale
Timepoint [6] 330279 0
Assessed at 6 months following enrolment administered by proxy or direct patient interview.
Secondary outcome [7] 330280 0
Quality Adjusted Life Years (QALYs)
Timepoint [7] 330280 0
Assessed at 6 months from enrolment assessed comparing changes in EuroQoL5D on two occasions (before hospitalisation and at 6 months from enrolment).
Secondary outcome [8] 408968 0
Informant Questionnaire on Cognitive Decline in the Elderly-Cardiac Arrest (IQCODE)
Timepoint [8] 408968 0
Assessed at 6 months following enrolment administered by proxy or direct patient interview.
Secondary outcome [9] 408969 0
Neurological dysfunction of attention, perceptual speed, motor speed and visual scanning assessed by the Symbol Digit Modality Test
Timepoint [9] 408969 0
Assessed at 6 months from enrolment assessed by following written or verbal explanation
Secondary outcome [10] 408970 0
Health economic evaluation
Timepoint [10] 408970 0
Evaluation of hospital and post-discharge estimates of costs from enrolment to 6 months
Secondary outcome [11] 408971 0
Pneumonia as defined by the presence of increased or purulent trachael secretions, new or progressive radiographic infiltrate and a decreased arterial oxygen tension fraction of inspired oxygen ratio of less than 240 mmHg or less than 32 kPa.
Timepoint [11] 408971 0
Occurring from enrolment until Day 7 while the participant is in the intensive care unit as reported by treating clinicians.
Secondary outcome [12] 408972 0
Sepsis and septic shock according to the third international consensus definitions for sepsis and septic shock as published in the journal JAMA 2016;315:801-810.
Timepoint [12] 408972 0
Occurring from enrolment until Day 7 while the participant is in the intensive care unit as reported by treating clinicians.
Secondary outcome [13] 408973 0
Bradycardia requiring pacing
Timepoint [13] 408973 0
Occurring from enrolment until Day 7 while the participant is in the intensive care unit as reported by treating clinicians.
Secondary outcome [14] 408974 0
Moderate or severe bleeding according to the GUSTO criteria as reported in the journal N Engl J Med 1993;329:673-82.
Timepoint [14] 408974 0
Occurring from enrolment until Day 7 while the participant is in the intensive care unit as reported by treating clinicians.
Secondary outcome [15] 408975 0
Cooling device-related skin complications as defined as being blistering or skin necrosis in areas covered by surface device.
Timepoint [15] 408975 0
Occurring from enrolment until Day 7 while the participant is in the intensive care unit as reported by treating clinicians.
Secondary outcome [16] 408976 0
Arrhythmia that results in haemodynamic compromise (for example ventricular fibrillation and ventricular tachycardia).
Timepoint [16] 408976 0
Occurring from enrolment until Day 7 while the participant is in the intensive care unit as reported by treating clinicians.

Eligibility
Key inclusion criteria
Adult (greater than or equal to 18 years of age)
Out-of-hospital cardiac arrest of a presumed cardiac or unknown cause
Sustained return of spontaneous circulation - defined as 20 minutes with signs of circulation without the need for chest compressions
Unconscious (FOUR-score motor response of less than 4, not able to obey veral commands after sustained return of spontaenous circulation
Eligible for intensive care without restrictions or limitations
Within less than 180 minutes of return of spontaneous circulation
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Unwitnessed cardiac arrest with an initial rhythm of asystole
Temperature on admission of less than 30oC
On extracorporeal membrane oxygenation prior to return of spontaneous circiulation
Obvious or suspected pregnancy
Intracranial bleeding
Severe chronic obstructive pulmonary disorder (COPD) with long-term home oxygen therapy

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. Participants will be enrolled in the study by ICU doctors, nurses, and research staff and the assigned intervention will be communicated to the bedside nurse who will implement the study intervention.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A permuted block randomisation method will be used with variable block sizes, stratified by site. The allocation sequence will be generated by the study statistician using computer generated random numbers.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Independent statisticians at Monash University Department of Epidemiology and Preventive Medicine will perform data analysis on an intention-to-treat basis. Baseline and outcome variables will be compared using Chi-square tests for equal proportion, Student’s t-test for normally distributed outcomes and the Mann-Whitney test for any non-parametric data. Multivariate models adjusting for any baseline imbalances and known covariates will be performed using logistic regression. A p-value of 0.05 will be considered to be statistically significant.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/12/2017
Actual
4/03/2018
Date of last participant enrolment
Anticipated
30/06/2022
Actual
29/09/2021
Date of last data collection
Anticipated
30/04/2022
Actual
29/03/2022
Sample size
Target
1700
Accrual to date
Final
1700
Recruitment in Australia
Recruitment state(s)
NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 7167 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 14925 0
3084 - Heidelberg
Recruitment outside Australia
Country [1] 24604 0
Belgium
State/province [1] 24604 0
Erasme
Country [2] 24605 0
Canada
State/province [2] 24605 0
Edmonton
Country [3] 24606 0
Denmark
State/province [3] 24606 0
Aarhus
Country [4] 24607 0
Finland
State/province [4] 24607 0
Helsinki
Country [5] 24608 0
France
State/province [5] 24608 0
Belfort
Country [6] 24609 0
Ireland
State/province [6] 24609 0
Dublin
Country [7] 24610 0
Italy
State/province [7] 24610 0
Milan
Country [8] 24611 0
Netherlands
State/province [8] 24611 0
Amsterdam
Country [9] 24612 0
New Zealand
State/province [9] 24612 0
North & South Island
Country [10] 24613 0
Norway
State/province [10] 24613 0
Oslo
Country [11] 24614 0
Saudi Arabia
State/province [11] 24614 0
Riyadh
Country [12] 24615 0
Singapore
State/province [12] 24615 0
Singapore
Country [13] 24616 0
Slovenia
State/province [13] 24616 0
Maribor
Country [14] 24617 0
Sweden
State/province [14] 24617 0
Malmo
Country [15] 24618 0
Switzerland
State/province [15] 24618 0
Zurich
Country [16] 24619 0
United Kingdom
State/province [16] 24619 0
England, Wales and Northern Ireland

Funding & Sponsors
Funding source category [1] 295200 0
Government body
Name [1] 295200 0
National Health and Medical Research Council
Country [1] 295200 0
Australia
Funding source category [2] 297062 0
Government body
Name [2] 297062 0
Irish Health Research Board
Country [2] 297062 0
Ireland
Primary sponsor type
Individual
Name
A/Prof Glenn Eastwood
Address
Department of Intensive Care
Austin Hospital
145 Studley Road
Heidelberg
Victoria 3084
Country
Australia
Secondary sponsor category [1] 294032 0
None
Name [1] 294032 0
Address [1] 294032 0
Country [1] 294032 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296550 0
Austin Health Human Research Ethics Committee
Ethics committee address [1] 296550 0
Ethics committee country [1] 296550 0
Australia
Date submitted for ethics approval [1] 296550 0
01/05/2017
Approval date [1] 296550 0
13/07/2017
Ethics approval number [1] 296550 0
HREC/17/Austin/209

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes
Attachments [1] 1902 1902 0 0
/AnzctrAttachments/372051-20170713 LETTER HREC17Austin209 Jul17 (Ethics approval - new study).pdf (Ethics approval)

Contacts
Principal investigator
Name 71262 0
Dr Glenn Eastwood
Address 71262 0
Department of Intensive Care
Austin Hospital
145 Studley Road
Heidelberg
Victoria 3084
Country 71262 0
Australia
Phone 71262 0
+61 3 9496 4835
Fax 71262 0
+61 3 9496 3932
Email 71262 0
[email protected]
Contact person for public queries
Name 71263 0
Glenn Eastwood
Address 71263 0
Department of Intensive Care
Austin Hospital
145 Studley Road
Heidelberg
Victoria 3084
Country 71263 0
Australia
Phone 71263 0
+ 61 3 9496 4835
Fax 71263 0
+61 3 9496 3932
Email 71263 0
[email protected]
Contact person for scientific queries
Name 71264 0
Glenn Eastwood
Address 71264 0
Department of Intensive Care
Austin Hospital
145 Studley Road
Heidelberg
Victoria 3084
Country 71264 0
Australia
Phone 71264 0
+61 3 9496 5992
Fax 71264 0
+61 3 9496 3932
Email 71264 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?
de-identified participant data that is agreed upon after request.
When will data be available (start and end dates)?
Beginning after 12-months and ending after 36-months after publication of the primary manuscript of the primary outcome of the trial in accordance with the policy of the Australian New Zealand Intensive Care Research Centre, Monash University.
Available to whom?
Clinician researchers
Available for what types of analyses?
As per approved statistical analyses following review by the Australian New Zealand Intensive Care Reserach Centre staff.
How or where can data be obtained?
The TAME project manager, via the email [email protected] of the Australian and New Zealand Intensive Care Research Centre (ANZIC-RC) will be contacted and help to coordinate the secure encrypted electronic transfer or similiar.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseTargeted hypothermia versus targeted normothermia after out-of-hospital cardiac arrest: A statistical analysis plan.2020https://dx.doi.org/10.1186/s13063-020-04654-y
N.B. These documents automatically identified may not have been verified by the study sponsor.