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Trial registered on ANZCTR


Registration number
ACTRN12611000981921
Ethics application status
Approved
Date submitted
14/09/2011
Date registered
14/09/2011
Date last updated
18/09/2012
Type of registration
Prospectively registered

Titles & IDs
Public title
Permissive HyperthErmia Through Avoidance of Paracetamol in Known or Suspected Infection in the Intensive Care Unit (ICU) - pilot study
Scientific title
A Pilot randomised controlled trial investigating the safety and efficacy of a permissive temperature strategy against a paracetamol-based strategy in critically ill patients with known or suspected infection
Secondary ID [1] 263041 0
Nil known
Universal Trial Number (UTN)
Trial acronym
HEAT pilot
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Known or suspected infection in critically ill patients in ICU 270770 0
Condition category
Condition code
Infection 270953 270953 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
After randomisation, the patient will receive 1gm of IV paracetamol or placebo 6 hourly until one of the following occurs:
1. the patient ceases antimicrobial therapy
2. the patient is discharged from ICU
3. the patient is deemed to have completed the course of study medication (as described below)

Provided that the patient remains on antimicrobial therapy and remains in ICU, they will receive paracetamol or placebo until at least the morning of study day 2. On the morning of study day 2, the research co-ordinator will assess the patient. If the patient has not had a standardised body temperature of <37.5 degrees for the previous 24 hours, they will continue to receive paracetamol or placebo 6 hourly and will be assessed by the research co-ordinator on each subsequent morning to determine if they have had a standardised body temperature of <37.5 degrees for the previous 24 hours. If, at the time of assessment by the research co-ordinator, the patient has had a standardised body temperature of <37.5 degrees for the entire past 24 hours, further study treatment will be withheld. If the patient does not develop a fever of >37.9 degrees within 48 hours from the time of assessment by the research co-ordinator, they will be deemed to have completed the course of study medication. If the patient does develop another standardised body temperature of >37.9 degrees , the patient will restart study medication and, thereafter, they will be assessed each morning by the research co-ordinator to determine whether they a have had a standardised body temperature of <37.5 degrees for a period of 24 hours at which point medication will be withheld and then stopped as described above.

Once the patient has completed the course of study medication, they may receive open label paracetamol at the discretion of the treating clinician.
Intervention code [1] 269385 0
Treatment: Drugs
Comparator / control treatment
5% dextrose
Control group
Placebo

Outcomes
Primary outcome [1] 279623 0
The primary efficacy measure is the number of "alive ICU-free days" to study day 28. The number of ICU-free days will be calculated as 28 minus the number of days in ICU (excluding days of ICU readmission). Patients who die in ICU will be counted as having zero ICU free days.
Timepoint [1] 279623 0
ICU-free survival will be determined at 672 hours from the time of randomisation.
Secondary outcome [1] 294054 0
Mean daily temperature measured via axillary thermometer
Timepoint [1] 294054 0
Study day 0 to study day 7 (determined from six hourly temperature measurements at 00:00hr, 06:00hr, 12:00hr, 18:00hr)
Secondary outcome [2] 294055 0
Maximum daily temperature via axillary thermometer
Timepoint [2] 294055 0
Study day 0 to study day 28 (determined from six hourly temperature measurements at 00:00hr, 06:00hr, 12:00hr, 18:00hr)
Secondary outcome [3] 294056 0
Serum bilirubin levels (serum assay)
Timepoint [3] 294056 0
Daily study day 0 to study day 7
Secondary outcome [4] 294057 0
Either serum aspartate aminotransferase or serum alanine aminotransferase (depending on local hospital preference) (serum assays)
Timepoint [4] 294057 0
Daily study day 0 to study day 7
Secondary outcome [5] 294058 0
Prothrombin time (blood)
Timepoint [5] 294058 0
Daily study day 0 to study day 7
Secondary outcome [6] 294059 0
Incidence of CK>5000 (serum assay)
Timepoint [6] 294059 0
study day 0, study day 3, study day 5 and study day 7
Secondary outcome [7] 294061 0
Levels of acute kidney injury (based on RIFLE criteria)
Timepoint [7] 294061 0
daily study day 0 to day 7
Secondary outcome [8] 294062 0
ICU-support-free survival
Timepoint [8] 294062 0
day 28
Secondary outcome [9] 294063 0
Hospital-free hours
Timepoint [9] 294063 0
day 28
Secondary outcome [10] 294064 0
Mechanical ventilation-free hours
Timepoint [10] 294064 0
day 28
Secondary outcome [11] 294065 0
Duration of inotropic/vasopressor support
Timepoint [11] 294065 0
day 28
Secondary outcome [12] 294066 0
Mortality
Timepoint [12] 294066 0
day 28
Secondary outcome [13] 294067 0
Mortality
Timepoint [13] 294067 0
day 90
Secondary outcome [14] 294068 0
ICU length of stay
Timepoint [14] 294068 0
Censored at day 90
Secondary outcome [15] 294069 0
Hospital length of stay
Timepoint [15] 294069 0
Censored at day 90
Secondary outcome [16] 294070 0
CRP (serum assay)
Timepoint [16] 294070 0
study day 0, study day 3, study day 5 and study day 7
Secondary outcome [17] 296817 0
Monocyte HLA-DR levels (serum assay)
Timepoint [17] 296817 0
study day 0, study day 1
Secondary outcome [18] 296818 0
IL-1b (serum assay)
Timepoint [18] 296818 0
study day 0, study day 1
Secondary outcome [19] 296819 0
IL-8 (serum assay)
Timepoint [19] 296819 0
study day 0, study day 1
Secondary outcome [20] 296820 0
IL-12 p70 (serum assay)
Timepoint [20] 296820 0
study day 0, study day 1
Secondary outcome [21] 296821 0
IL-6 (serum assay)
Timepoint [21] 296821 0
study day 0, study day 1
Secondary outcome [22] 296822 0
IL-10 (serum assay)
Timepoint [22] 296822 0
study day 0, study day 1
Secondary outcome [23] 296823 0
Prostaglandin E2 (PGE2) (serum assay)
Timepoint [23] 296823 0
study day 0, study day 1
Secondary outcome [24] 296824 0
TNF alpha (serum assay)
Timepoint [24] 296824 0
study day 0, study day 1
Secondary outcome [25] 296825 0
IL-17 (serum assay)
Timepoint [25] 296825 0
study day 0, study day 1
Secondary outcome [26] 296826 0
IL-18 (serum assay)
Timepoint [26] 296826 0
study day 0, study day 1
Secondary outcome [27] 296827 0
IL-33 (serum assay)
Timepoint [27] 296827 0
study day 0, study day 1
Secondary outcome [28] 296828 0
Soluble CD40 ligand (sCD40L) (serum assay)
Timepoint [28] 296828 0
study day 0, study day 1

Eligibility
Key inclusion criteria
Patients are eligible to be included in the study only if they meet the following criteria at the time of randomisation:
1. Age greater than or equal to16 years
2. Standardised body temperature greater than or equal to 38.0 degrees within the previous 12 hours.
3. Receiving antimicrobial therapy for a known or suspected infection (this does NOT include post-operative patients who are receiving antibiotics for the purposes of prophylaxis rather than treatment)
Minimum age
16 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients will be excluded from the study if they meet ANY of the following criteria:
1. AST or ALT greater than five times the upper limit of normal OR bilirubin greater than twice the upper limit of normal OR any other contraindication to 4gm paracetamol per day
2. a requirement for ongoing NSAID use (in excess of low dose aspirin);
3. evidence of acute brain injury during the current hospital admission (defined as any acute traumatic brain injury, subarachnoid haemorrhage, acute ischaemic stroke, acute intracerebral haemorrhage, or acute intracranial infection); hyperthermic syndromes (including heat stroke; current biochemical evidence of thyrotoxicosis (thyroid function tests are not required prior to recruitment into the trial unless clinically indicated); malignant hyperthermia, neuroleptic malignant syndrome, or other drug-induced hyperthermia)
4. admission to ICU following a cardiac arrest which is currently being treated with therapeutic hypothermia;
5. there is a limitation of therapy order or aggressive treatment is deemed unsuitable
6. patients who are moribund and, in whom, death is perceived to be imminent (within 24 hours);
7. any patient with rhabdomyolysis that is deemed by the treating clinician to be clinically significant.
8. any patient transferred from another ICU who fulfilled all inclusion criteria in the other ICU and spent >12 hours in the other ICU prior to transfer
9. any patient who is pregnant;
10. previously randomised into the HEAT trial or previously eligible for enrolment during the current ICU admission but not enrolled in the study (i.e. patients who were not enrolled within 12 hours of onset of fever in association with satisfying other eligibility criteria may not be enrolled at a later point in the ICU admission)

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)
Randomisation and treatment allocation will be achieved by a web-based randomisation and drug allocation system via password-protected encrypted website interface.

All staff and patients will be blinded as to the treatment allocation. Treatment will be allocated in boxes of 12 bottles of study medication (maximum of 3 days supply) and resupply will be performed via a web-based system
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Block randomisation stratified by centre using computer generated random numbers, generated by the study statistician.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2 / Phase 3
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 3842 0
New Zealand
State/province [1] 3842 0

Funding & Sponsors
Funding source category [1] 269847 0
Government body
Name [1] 269847 0
Health Research Council of New Zealand
Address [1] 269847 0
The Health Research Council of New Zealand
Level 3, 110 Stanley Street
PO Box 5541
Auckland 1010
New Zealand
Country [1] 269847 0
New Zealand
Primary sponsor type
Charities/Societies/Foundations
Name
Medical Research Institute of New Zealand
Address
Private Bag 7902
Wellington 6242

Level 7, CSB Building
Wellington Hospital
Riddiford St, Newtown
Wellington 6021
New Zealand
Country
New Zealand
Secondary sponsor category [1] 268874 0
Other Collaborative groups
Name [1] 268874 0
Australian and New Zealand Intensive Care Society Clinical Trials Group
Address [1] 268874 0
PO Box 164
Carlton South
Victoria 3053
Country [1] 268874 0
Australia
Other collaborator category [1] 260677 0
Charities/Societies/Foundations
Name [1] 260677 0
The George Institute for Global Health
Address [1] 260677 0
Level 7, 341 George St | Sydney NSW 2000 Australia. Postal Address: PO Box M201 | Missenden Rd | NSW 2050 Australia. T +61 2 9657 0352
Country [1] 260677 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 271816 0
Multi-region Ethics Committee
Ethics committee address [1] 271816 0
c/- Ministry of Health
PO Box 5013
1 The Terrace
Wellington 6011
Ethics committee country [1] 271816 0
New Zealand
Date submitted for ethics approval [1] 271816 0
Approval date [1] 271816 0
26/05/2011
Ethics approval number [1] 271816 0
MEC/11/01/004

Summary
Brief summary
Fever is an adaptive response to infections which occurs widely in the animal kingdom. The suppression of fever increases the risk of mortality in animals, although the effect of antipyretics in critically ill patients is unknown. The objective of this study is to determine whether paracetamol influences the risk of mortality in critically ill patients with fever and known or suspected infection. A phase 2b double blind randomised placebo controlled trial of paracetamol will be undertaken in 700 patients with fever and known or suspected infection in New Zealand and Australia under the auspices of the Australian and New Zealand Intensive Care Society Clinical Trials Group (ANZICS CTG). If either the aggressive or permissive antipyretic regimes influence outcomes including survival in patients with fever and infection, the findings will have a major impact on the burden of infectious disease in New Zealand and internationally.
Trial website
www.heat-trial.org.nz
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 33156 0
Address 33156 0
Country 33156 0
Phone 33156 0
Fax 33156 0
Email 33156 0
Contact person for public queries
Name 16403 0
Paul Young
Address 16403 0
Intensive Care Unit
Wellington Regional Hospital
Private Bag 7902
Riddiford Street
Newtown 6021
Country 16403 0
New Zealand
Phone 16403 0
+ 64 27 455 2269
Fax 16403 0
Email 16403 0
paul.young@ccdhb.org.nz
Contact person for scientific queries
Name 7331 0
Paul Young
Address 7331 0
Intensive Care Unit
Wellington Regional Hospital
Private Bag 7902
Riddiford Street
Newtown 6021
Country 7331 0
New Zealand
Phone 7331 0
+ 64 27 455 2269
Fax 7331 0
Email 7331 0
paul.young@ccdhb.org.nz

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary