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Trial registered on ANZCTR


Registration number
ACTRN12616001285448
Ethics application status
Approved
Date submitted
5/09/2016
Date registered
13/09/2016
Date last updated
26/02/2020
Date data sharing statement initially provided
23/04/2019
Date results provided
23/04/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Randomised Evaluation of Active Control of Temperature vs. Ordinary temperature management in mechanically ventilated adults in ICU with fever.
Scientific title
A multi-centre, phase II, randomized, open label, clinical trial comparing combined prophylactic intravenous paracetamol and early targeted physical cooling for fever with standard temperature management in mechanically ventilated adults without acute brain pathologies who are expected to be ventilated beyond the day after randomisation.
Secondary ID [1] 290019 0
None
Universal Trial Number (UTN)
U1111-1182-7938
Trial acronym
The REACTOR trial.
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Fever 300077 0
Mechanical ventilation 300247 0
Condition category
Condition code
Inflammatory and Immune System 299963 299963 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Where clinically appropriate, administer regular IV paracetamol 1 gm 6 hourly as ‘fever prophylaxis’. If the patient is deeply sedated with no response to voice, target a body temperature of no greater than 36.5-37 degrees Celsius using simple cooling measures (removal of clothing and sheets, using a sponge or wet towel, using a fan) plus a physical cooling device if necessary. Physical cooling devices are any device at the study site that the treating clinician considers appropriate such as cooling blankets, cooling pads and cooling helmets.
Shivering should be aggressively treated where possible using the following hierarchy of treatments:
1. Administration of an opioid bolus
2. Increasing of sedation
3. Administration of a bolus of neuromuscular paralysis
Decisions regarding choice of drugs, doses, frequency, and duration of administration will be at the discretion of the treating clinician.
Protocol-driven temperature control measures including IV paracetamol should be ceased at day 28 or ICU discharge (whichever is sooner). Physical cooling can be ceased to allow the patient to be desedated at any time at the discretion of the treating clinician but should be recommenced if further deep sedation is needed and body temperature is not within the target range of 36.5-37 degrees Celsius. If treatments to control shivering are clinically inappropriate or shivering cannot be controlled then physical cooling should be ceased.
Intervention code [1] 295758 0
Treatment: Devices
Intervention code [2] 295858 0
Treatment: Drugs
Comparator / control treatment
Patients allocated to the control group should receive standard care. There are no protocol-defined temperature targets. Administration of IV paracetamol in the standard care arm is discouraged unless there is a specific indication for its use.
Control group
Active

Outcomes
Primary outcome [1] 299509 0
The between group difference in mean body temperature using a core temperature monitoring device (eg bladder thermometer, oesophageal temperature probe or blood temperature probe) where possible. If core temperature monitoring is not possible tympanic temperature monitoring will be used in preference to other devices.
Timepoint [1] 299509 0
Censored at day 28. This outcome will be assessed using ALL temperatures recorded in ICU for clinical purposes (typically temperature is recorded hourly).
Secondary outcome [1] 327367 0
ICU-free days (the number of days alive and outside ICU) assessed by review of medical records.
Timepoint [1] 327367 0
From randomisation until day 28
Secondary outcome [2] 327375 0
In hospital mortality assessed by review of medical records.
Timepoint [2] 327375 0
Censored at Day 90
Secondary outcome [3] 327376 0
Survival time assessed by review of medical records.
Timepoint [3] 327376 0
To day 90
Secondary outcome [4] 327381 0
Highest daily temperature measured using a core temperature monitoring device (eg bladder thermometer, oesophageal temperature probe or blood temperature probe) where possible. If core temperature monitoring is not possible tympanic temperature monitoring will be used in preference to other devices.
Timepoint [4] 327381 0
Censored at day 28. This outcome will be assessed using ALL temperatures recorded in ICU for clinical purposes (typically temperature is recorded hourly) and the highest daily will be used to measure this outcome.
Secondary outcome [5] 327382 0
Proportion of patients with a post randomisation body temperature in ICU of greater than or equal 38.3 degrees Celsius. Temperature is measured using a core temperature monitoring device (eg bladder thermometer, oesophageal temperature probe or blood temperature probe) where possible. If core temperature monitoring is not possible tympanic temperature monitoring will be used in preference to other devices.
Timepoint [5] 327382 0
Censored at day 28. This outcome will be assessed using ALL temperatures recorded in ICU for clinical purposes (typically temperature is recorded hourly).
Secondary outcome [6] 327383 0
Proportion of patients with a post randomisation body temperature in ICU of greater than or equal to 39 degrees Celsius. Proportion of patients with a post randomisation body temperature in ICU of greater than or equal 38.3 degrees Celsius. Temperature is measured using a core temperature monitoring device (eg bladder thermometer, oesophageal temperature probe or blood temperature probe) where possible. If core temperature monitoring is not possible tympanic temperature monitoring will be used in preference to other devices.
Timepoint [6] 327383 0
Censored at day 28. This outcome will be assessed using ALL temperatures recorded in ICU for clinical purposes (typically temperature is recorded hourly).
Secondary outcome [7] 327384 0
Heart rate using ECG monitoring
Timepoint [7] 327384 0
Measured six hourly for seven days (168 hours) or until ICU discharge (whichever is sooner).
Secondary outcome [8] 327385 0
Respiratory rate, measured by bedside nurse or by ventilator depending on whether patient is ventilated or not.
Timepoint [8] 327385 0
Measured six hourly for seven days (168 hours) or until ICU discharge (whichever is sooner).
Secondary outcome [9] 327386 0
Mean arterial pressure based on invasive arterial blood pressure monitoring or sphygmomanometry (whichever is being used to monitor blood pressure for clinical purposes)
Timepoint [9] 327386 0
Measured six hourly for seven days (168 hours) or until ICU discharge (whichever is sooner).
Secondary outcome [10] 327387 0
Highest recorded AST assessed by serum assay
Timepoint [10] 327387 0
Censored at day 28, based on all tests performed routinely for clinical purposes between randomisation and ICU discharge (typically at least once daily).
Secondary outcome [11] 327388 0
Highest serum creatinine
Timepoint [11] 327388 0
Censored at day 28, based on all tests performed routinely for clinical purposes between randomisation and ICU discharge (typically at least once daily).
Secondary outcome [12] 327389 0
Mean daily dose of paracetamol assessed by review of medical records.
Timepoint [12] 327389 0
Until day 28 or ICU discharge.
Secondary outcome [13] 327390 0
Proportion of paracetamol doses administered via the IV route assessed by review of medical records.
Timepoint [13] 327390 0
Until day 28 or ICU discharge.
Secondary outcome [14] 327391 0
ICU length of stay (overall and for survivors and non-survivors separately) assessed by review of medical records.
Timepoint [14] 327391 0
Censored at day 28
Secondary outcome [15] 327392 0
Hospital length of stay (overall and for survivors and non-survivors separately) assessed by review of medical records.
Timepoint [15] 327392 0
Censored at day 28.
Secondary outcome [16] 327393 0
Ventilator-free days assessed by review of medical records.
Timepoint [16] 327393 0
To day 28.
Secondary outcome [17] 327394 0
Vasopressor-free days assessed by review of medical records.
Timepoint [17] 327394 0
To day 28.
Secondary outcome [18] 327395 0
Proportion of patients receiving new post-randomisation renal replacement therapy in ICU assessed by review of medical records.
Timepoint [18] 327395 0
Censored at day 28
Secondary outcome [19] 327396 0
Days in receipt of IV antibiotics in ICU assessed by review of medical records.
Timepoint [19] 327396 0
To day 28.
Secondary outcome [20] 327397 0
Number of sets of blood cultures performed in ICU assessed by review of medical records.
Timepoint [20] 327397 0
To day 28.
Secondary outcome [21] 327398 0
Proportion of patients cooled with a physical cooling ‘device’ assessed by review of medical records.
Timepoint [21] 327398 0
Until day 28 or ICU discharge.
Secondary outcome [22] 327399 0
Duration of cooling therapy with a physical cooling ‘device’ assessed by review of medical records.
Timepoint [22] 327399 0
Until day 28 or ICU discharge.
Secondary outcome [23] 327400 0
Proportion of patients receiving paralysing drugs in ICU excluding for intubation assessed by review of medical records.
Timepoint [23] 327400 0
Until day 28 or ICU discharge
Secondary outcome [24] 327401 0
Proportion of patients receiving propofol and average daily dose received assessed by review of medical records.
Timepoint [24] 327401 0
In the first 7 days (168 hours) in ICU following randomisation.
Secondary outcome [25] 327402 0
Proportion of patients receiving morphine (or morphine equivalents of other opioids) and average daily dose received assessed by review of medical records.
Timepoint [25] 327402 0
In the first 7 days (168 hours) in ICU following randomisation.
Secondary outcome [26] 327403 0
Proportion of patients receiving midazolam (or midazolam equivalents of other benzodiazepines) and average daily dose received assessed by review of medical records.
Timepoint [26] 327403 0
In the first 7 days (168 hours) in ICU following randomisation.
Secondary outcome [27] 327404 0
Proportion of patients receiving dexmedetomidine and highest hourly rate of infusion (mcg/kg/hr) assessed by review of medical records.
Timepoint [27] 327404 0
On each of the first 7 days in ICU following randomisation.
Secondary outcome [28] 327405 0
Proportion of patients receiving noradrenaline and the highest hourly rate of noradrenaline administration (mcg/kg/min) assessed by review of medical records.
Timepoint [28] 327405 0
On each of the first 7 days in ICU following randomisation
Secondary outcome [29] 327406 0
Proportion of patients receiving adrenaline and the highest hourly rate of adrenaline administration (mcg/kg/min) assessed by review of medical records.
Timepoint [29] 327406 0
On each of the first 7 days in ICU following randomisation.
Secondary outcome [30] 327407 0
Proportion of patients receiving each of the following drugs by infusion (dobutamine, milrinone, dopamine, metaraminol, phenylephrine, vasopressin, levosimendan) assessed by review of medical records. This is a composite secondary outcome.
Timepoint [30] 327407 0
On each of the first 7 days in ICU following randomisation
Secondary outcome [31] 327408 0
Proportion of patients requiring discontinuation of physical cooling because of shivering assessed by review of medical records.
Timepoint [31] 327408 0
Censored at Day 28
Secondary outcome [32] 327525 0
In hospital cause-specific mortality assessed by review of medical records
Timepoint [32] 327525 0
Censored at day 90
Secondary outcome [33] 327545 0
Highest recorded ALT assessed by serum assay
Timepoint [33] 327545 0
Censored at day 28, based on all tests performed routinely for clinical purposes between randomisation and ICU discharge (typically at least once daily).
Secondary outcome [34] 327546 0
Highest recorded ALP assessed by serum assay
Timepoint [34] 327546 0
Censored at day 28, based on all tests performed routinely for clinical purposes between randomisation and ICU discharge (typically at least once daily).
Secondary outcome [35] 327547 0
Highest recorded GGT assessed by serum assay
Timepoint [35] 327547 0
Censored at day 28, based on all tests performed routinely for clinical purposes between randomisation and ICU discharge (typically at least once daily).
Secondary outcome [36] 327548 0
Highest recorded bilirubin assessed by serum assay
Timepoint [36] 327548 0
Censored at day 28, based on all tests performed routinely for clinical purposes between randomisation and ICU discharge (typically at least once daily).

Eligibility
Key inclusion criteria
1. Patients requiring invasive mechanical ventilation in the ICU and expected to be receiving mechanical ventilation beyond the day after randomisation.
2. Fever (body temperature 37.8 degrees Celsius or more) in the previous 12 hours.
3. Deeply sedated with no response to voice
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Acute brain pathologies (traumatic brain injury, intracerebral haemorrhage, subarachnoid haemorrhage, or ischaemic stroke).
2. Confirmed or suspected hypoxic ischaemic encephalopathy (includes all patients who have had a recent cardiac arrest where there is clinical concern about possible brain damage as a result of the cardiac arrest).
3. Death is deemed to be inevitable as a result of the current acute illness and either the treating clinician, the patient, or the substitute decision maker are not committed to full active treatment.
4. Patients admitted to the intensive care unit with greater than or equal to 20% total body surface area burns.
5. Life expectancy of less than 90 days due to an underlying medical condition.
6 Fulfilled all other eligibility criteria >24 hours ago but was not enrolled in the study.
7. Previously enrolled in the REACTOR study.

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 web based randomisation
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation with variable block sizes, stratified by site.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
Sample size of 184 patients provides 90% power to detect an effect size of 0.3 degrees Celsius based on a standard deviation of 0.6 using two tailed hypothesis and an alpha of 0.05, allowing for 5% drop-out rate.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/12/2016
Actual
25/11/2016
Date of last participant enrolment
Anticipated
1/12/2018
Actual
12/03/2019
Date of last data collection
Anticipated
1/02/2019
Actual
12/04/2019
Sample size
Target
184
Accrual to date
Final
184
Recruitment in Australia
Recruitment state(s)
ACT,NSW,VIC
Recruitment hospital [1] 6603 0
St George Hospital - Kogarah
Recruitment hospital [2] 6604 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [3] 6606 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [4] 6607 0
The Canberra Hospital - Garran
Recruitment postcode(s) [1] 14210 0
2217 - Kogarah
Recruitment postcode(s) [2] 14211 0
2065 - St Leonards
Recruitment postcode(s) [3] 14213 0
3084 - Heidelberg
Recruitment postcode(s) [4] 14214 0
2605 - Garran
Recruitment outside Australia
Country [1] 8180 0
New Zealand
State/province [1] 8180 0
Wellington

Funding & Sponsors
Funding source category [1] 294442 0
Government body
Name [1] 294442 0
Health Research Council of New Zealand
Country [1] 294442 0
New Zealand
Primary sponsor type
Other Collaborative groups
Name
Medical Research Institute of New Zealand
Address
Level 7, CSB Building, Wellington Hospital, Riddiford Street, Newtown, Wellington 6021
Private Bag 7902. Wellington 6242, New Zealand.
Country
New Zealand
Secondary sponsor category [1] 293297 0
None
Name [1] 293297 0
Address [1] 293297 0
Country [1] 293297 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295873 0
Northern A Health and Disability Ethics Committee
Ethics committee address [1] 295873 0
Ethics committee country [1] 295873 0
New Zealand
Date submitted for ethics approval [1] 295873 0
25/07/2016
Approval date [1] 295873 0
23/08/2016
Ethics approval number [1] 295873 0
16/NTA/111

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

Contacts
Principal investigator
Name 68562 0
Dr Paul Young
Address 68562 0
c/o Intensive Care Unit
Wellington Hospital
Private Bag 7902
Wellington 6021
Country 68562 0
New Zealand
Phone 68562 0
+64 4 806 0432
Fax 68562 0
+64 4 806 0440
Email 68562 0
paul.young@ccdhb.org.nz
Contact person for public queries
Name 68563 0
Anne Turner
Address 68563 0
Medical Research Institute of New Zealand
Private Bag 7902
Wellington 6242
Country 68563 0
New Zealand
Phone 68563 0
+64 4 805 0268
Fax 68563 0
+64 4 389 5707
Email 68563 0
anne.turner@mrinz.ac.nz
Contact person for scientific queries
Name 68564 0
Paul Young
Address 68564 0
c/o Intensive Care Unit
Wellington Hospital
Private Bag 7902
Wellington 6021
Country 68564 0
New Zealand
Phone 68564 0
+64 4 806 0432
Fax 68564 0
+64 4 806 0440
Email 68564 0
paul.young@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 individual patient data contained in the study database along with the study data dictionary and an explanation of database fields
When will data be available (start and end dates)?
For 5 years from the date of publication
Available to whom?
Anyone who requests data access to undertake hypothesis-driven research
Available for what types of analyses?
Any hypothesis-driven research
How or where can data be obtained?
Data will be provided on request; requests should be sent to the corresponding author


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
7114Study protocol  Paul.young@ccdhb.org.nz
7115Statistical analysis plan  Paul.young@ccdhb.org.nz
7116Informed consent form  Paul.young@ccdhb.org.nz
7117Clinical study report  Paul.young@ccdhb.org.nz
7118Ethical approval  Paul.young@ccdhb.org.nz



Results publications and other study-related documents

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

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseRandomised evaluation of active control of temperature versus ordinary temperature management (REACTOR) trial.2019https://dx.doi.org/10.1007/s00134-019-05729-4
N.B. These documents automatically identified may not have been verified by the study sponsor.