ANZCTR - Registration

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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 information initially 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]

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

Mechanical ventilation

Condition category

Condition code

Inflammatory and Immune System

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]

Treatment: Devices

Intervention code [2]

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]

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]

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]

ICU-free days (the number of days alive and outside ICU) assessed by review of medical records.

Timepoint [1]

From randomisation until day 28

Secondary outcome [2]

In hospital mortality assessed by review of medical records.

Timepoint [2]

Censored at Day 90

Secondary outcome [3]

Survival time assessed by review of medical records.

Timepoint [3]

To day 90

Secondary outcome [4]

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]

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]

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]

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]

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]

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]

Heart rate using ECG monitoring

Timepoint [7]

Measured six hourly for seven days (168 hours) or until ICU discharge (whichever is sooner).

Secondary outcome [8]

Respiratory rate, measured by bedside nurse or by ventilator depending on whether patient is ventilated or not.

Timepoint [8]

Measured six hourly for seven days (168 hours) or until ICU discharge (whichever is sooner).

Secondary outcome [9]

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]

Measured six hourly for seven days (168 hours) or until ICU discharge (whichever is sooner).

Secondary outcome [10]

Highest recorded AST assessed by serum assay

Timepoint [10]

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]

Highest serum creatinine

Timepoint [11]

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]

Mean daily dose of paracetamol assessed by review of medical records.

Timepoint [12]

Until day 28 or ICU discharge.

Secondary outcome [13]

Proportion of paracetamol doses administered via the IV route assessed by review of medical records.

Timepoint [13]

Until day 28 or ICU discharge.

Secondary outcome [14]

ICU length of stay (overall and for survivors and non-survivors separately) assessed by review of medical records.

Timepoint [14]

Censored at day 28

Secondary outcome [15]

Hospital length of stay (overall and for survivors and non-survivors separately) assessed by review of medical records.

Timepoint [15]

Censored at day 28.

Secondary outcome [16]

Ventilator-free days assessed by review of medical records.

Timepoint [16]

To day 28.

Secondary outcome [17]

Vasopressor-free days assessed by review of medical records.

Timepoint [17]

To day 28.

Secondary outcome [18]

Proportion of patients receiving new post-randomisation renal replacement therapy in ICU assessed by review of medical records.

Timepoint [18]

Censored at day 28

Secondary outcome [19]

Days in receipt of IV antibiotics in ICU assessed by review of medical records.

Timepoint [19]

To day 28.

Secondary outcome [20]

Number of sets of blood cultures performed in ICU assessed by review of medical records.

Timepoint [20]

To day 28.

Secondary outcome [21]

Proportion of patients cooled with a physical cooling ‘device’ assessed by review of medical records.

Timepoint [21]

Until day 28 or ICU discharge.

Secondary outcome [22]

Duration of cooling therapy with a physical cooling ‘device’ assessed by review of medical records.

Timepoint [22]

Until day 28 or ICU discharge.

Secondary outcome [23]

Proportion of patients receiving paralysing drugs in ICU excluding for intubation assessed by review of medical records.

Timepoint [23]

Until day 28 or ICU discharge

Secondary outcome [24]

Proportion of patients receiving propofol and average daily dose received assessed by review of medical records.

Timepoint [24]

In the first 7 days (168 hours) in ICU following randomisation.

Secondary outcome [25]

Proportion of patients receiving morphine (or morphine equivalents of other opioids) and average daily dose received assessed by review of medical records.

Timepoint [25]

In the first 7 days (168 hours) in ICU following randomisation.

Secondary outcome [26]

Proportion of patients receiving midazolam (or midazolam equivalents of other benzodiazepines) and average daily dose received assessed by review of medical records.

Timepoint [26]

In the first 7 days (168 hours) in ICU following randomisation.

Secondary outcome [27]

Proportion of patients receiving dexmedetomidine and highest hourly rate of infusion (mcg/kg/hr) assessed by review of medical records.

Timepoint [27]

On each of the first 7 days in ICU following randomisation.

Secondary outcome [28]

Proportion of patients receiving noradrenaline and the highest hourly rate of noradrenaline administration (mcg/kg/min) assessed by review of medical records.

Timepoint [28]

On each of the first 7 days in ICU following randomisation

Secondary outcome [29]

Proportion of patients receiving adrenaline and the highest hourly rate of adrenaline administration (mcg/kg/min) assessed by review of medical records.

Timepoint [29]

On each of the first 7 days in ICU following randomisation.

Secondary outcome [30]

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]

On each of the first 7 days in ICU following randomisation

Secondary outcome [31]

Proportion of patients requiring discontinuation of physical cooling because of shivering assessed by review of medical records.

Timepoint [31]

Censored at Day 28

Secondary outcome [32]

In hospital cause-specific mortality assessed by review of medical records

Timepoint [32]

Censored at day 90

Secondary outcome [33]

Highest recorded ALT assessed by serum assay

Timepoint [33]

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]

Highest recorded ALP assessed by serum assay

Timepoint [34]

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]

Highest recorded GGT assessed by serum assay

Timepoint [35]

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]

Highest recorded bilirubin assessed by serum assay

Timepoint [36]

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?

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]

St George Hospital - Kogarah

Recruitment hospital [2]

Royal North Shore Hospital - St Leonards

Recruitment hospital [3]

Austin Health - Austin Hospital - Heidelberg

Recruitment hospital [4]

The Canberra Hospital - Garran

Recruitment postcode(s) [1]

2217 - Kogarah

Recruitment postcode(s) [2]

2065 - St Leonards

Recruitment postcode(s) [3]

3084 - Heidelberg

Recruitment postcode(s) [4]

2605 - Garran

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Wellington

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

Health Research Council of New Zealand

Address [1]

Level3, ProCare Building, 110 Stanley Street, Auckland 1010
P O Box 5541, Wellesley Street, Auckland 1141, New Zealand

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Northern A Health and Disability Ethics Committee

Ethics committee address [1]

Ministry of Health
Freyberg Building
20 Aitken street
P O Box 5013
Wellington 6011

Ethics committee country [1]

New Zealand

Date submitted for ethics approval [1]

25/07/2016

Approval date [1]

23/08/2016

Ethics approval number [1]

16/NTA/111

Summary

Brief summary

Background:
Intensive care doctors make decisions about prevention and treatment of fever every day but their decisions are currently made on the basis of very weak evidence. Although ICU patients often have limited physiological reserves so that their tolerance of the demands on the body created by fever may be limited, clinicians are generally tolerant of relatively high body temperatures in the absence of acute brain pathologies.
Study question:
Among adults in ICU without acute brain pathologies who are expected to life support (a breathing machine) beyond the day after randomisation, does systematic control of body temperature using regular IV paracetamol combined with physical cooling to treat fever alter mean body temperature compared to standard temperature management?
Why this study is being conducted:
Understanding whether or not an active approach to prevention and treatment of fever results in a lower mean body temperature than a standard care approach is a necessary prerequisite to evaluating the active approach in a phase 3 clinical trial. Obtaining high level evidence to inform clinical practice in relation to temperature management in patients without acute brain pathologies requiring invasive mechanical ventilation is a high priority because fever is common problem and the best approach to managing fever is uncertain.

Trial website

https://reactor.spinnakersoftware.com

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Dr Paul Young

Address

c/o Intensive Care Unit
Wellington Hospital
Private Bag 7902
Wellington 6021

Country

New Zealand

Phone

+64 4 806 0432

Fax

+64 4 806 0440

[email protected]

Contact person for public queries

Name

Mrs Anne Turner

Address

Medical Research Institute of New Zealand
Private Bag 7902
Wellington 6242

Country

New Zealand

Phone

+64 4 805 0268

Fax

+64 4 389 5707

[email protected]

Contact person for scientific queries

Name

Dr Paul Young

Address

c/o Intensive Care Unit
Wellington Hospital
Private Bag 7902
Wellington 6021

Country

New Zealand

Phone

+64 4 806 0432

Fax

+64 4 806 0440

[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 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.	Type	Email
7114	Study protocol	[email protected]
7115	Statistical analysis plan	[email protected]
7116	Informed consent form	[email protected]
7117	Clinical study report	[email protected]
7118	Ethical approval	[email protected]

Results publications and other study-related documents

Documents added manually

Type	Is Peer Reviewed?	DOI	Citations or Other Details	Attachment
Study results article	Yes		Paul J. Young, Michael J. Bailey, Frances Bass, Ri... [More Details]	371376-(Uploaded-13-02-2020-13-46-10)-Journal results publication.pdf
Plain language summary	No		Active temperature management reduced body tempera... [More Details]

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Randomised evaluation of active control of temperature versus ordinary temperature management (REACTOR) trial.	2019	https://dx.doi.org/10.1007/s00134-019-05729-4

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically