Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000958684
Ethics application status
Approved
Date submitted
26/07/2023
Date registered
4/09/2023
Date last updated
23/06/2024
Date data sharing statement initially provided
4/09/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
A clinical trial to determine if antibiotics prevent chest infections in patients with brain injuries requiring life support in the intensive care unit
Scientific title
The Prophylaxis against Early Ventilator Associated Lower Respiratory Tract Infection (PREVENT LRTI) trial. A phase 2 multi-centre, randomized, double-blind, placebo-controlled parallel group clinical trial.
Secondary ID [1] 310186 0
Nil known
Universal Trial Number (UTN)
Trial acronym
PREVENT LRTI
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Lower respiratory tract infection 330854 0
Mechanical ventilation 330855 0
Acute brain injury 330856 0
Ventilator associated pneumonia 330857 0
Condition category
Condition code
Infection 327656 327656 0 0
Studies of infection and infectious agents
Injuries and Accidents 327657 327657 0 0
Other injuries and accidents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Study treatments will be commenced as soon as possible following randomisation. Patients allocated to the intervention group will receive four doses of 1 gram of ceftriaxone made up to a total of 100mL in 0.9% sodium chloride administered intravenously 12 hours apart.

Administration of each dose of study drug will be recorded. If is not given in adherence with the protocol, a protocol deviation will be logged. Auditing against the medication chart is not planned.
Intervention code [1] 326586 0
Prevention
Comparator / control treatment
Patients allocated to the comparator arm will receive four doses of a matched placebo (100mL of 0.9% sodium chloride) intravenously 12 hours apart.
Control group
Placebo

Outcomes
Primary outcome [1] 335455 0
The primary outcome will be administration of antibiotics to treat a presumed early lower respiratory tract infection in the ICU. This outcome will be met if:
(i) Antibiotics are commenced to treat a presumed infection during the index ICU admission within seven days (168 hours) of randomisation, determined from hospital records AND
(ii) The Principal Investigator (or a delegate) considers, at day seven post randomisation or at ICU discharge (whichever is sooner), that the patient had an infection while in the ICU, and that the lower respiratory tract was a probable source of that infection, ascertained from clinical records or confirmation from treating clinician.
Timepoint [1] 335455 0
7 days following randomisation or at ICU discharge, whichever is sooner.
Secondary outcome [1] 424708 0
Administration of antibiotics to treat a presumed late lower respiratory tract infection in the ICU within 28 days (672 hours) of randomisation. This definition will be considered to be met if:
(i) Antibiotics are commenced to treat a presumed infection in the ICU more than seven days (i.e. >168 hours) but less than 28 days (672 hours) after randomisation, as determined from clinical records AND
(ii) The Principal Investigator (or a delegate) considers, at day 28 post randomisation or at ICU discharge (whichever is sooner), that the patient had a late infection while in the ICU, and that the lower respiratory tract was a probable source of that infection, ascertained from hospital records or confirmation from treating clinician.
Timepoint [1] 424708 0
28 days following randomisation or at ICU discharge, whichever is sooner
Secondary outcome [2] 424710 0
Early ventilator associated pneumonia (VAP), defined as a new, progressive or persistent radiographic infiltrate on chest X-ray (without other obvious cause) occurring >48 hours after initiation of invasive mechanical ventilation and within 7 days (168 hours) of randomisation plus at least one of the following features of infection:
(i) Fever or hypothermia (temperature >38°C or <36°C)
(ii) Relative leukopenia or leukocytosis (white blood cell count<4.0 or >12 x 109/L)
(iii) Purulent sputum
as determined from clinical records
Timepoint [2] 424710 0
7 days post randomisation or at ICU discharge, whichever is sooner
Secondary outcome [3] 424711 0
Late ventilator associated pneumonia (VAP) within 28 days of randomisation, defined as a new, progressive or persistent radiographic infiltrate on chest X-ray (without other obvious cause) occurring >48 hours after initiation of invasive mechanical ventilation and more than seven days (i.e. >168 hours) but less than 28 days (672 hours) after randomisation plus at least one of the following features of infection:
(i) Fever or hypothermia (temperature >38°C or <36°C)
(ii) Relative leukopenia or leukocytosis (white blood cell count<4.0 or >12 x 109/L)
(iii) Purulent sputum
as determined from clinical records
Timepoint [3] 424711 0
28 days from randomisation or at ICU discharge, whichever is sooner
Secondary outcome [4] 424712 0
Ventilator-free days to day 28 defined as the number of days of unassisted breathing during the first 28 days after randomisation; deaths by day-28 will be assigned negative one ventilator-free days, assessed through data-linkage to medical records.
Timepoint [4] 424712 0
28 days following randomisation
Secondary outcome [5] 424713 0
ICU-free days to day 28, defined in an analogous fashion to ventilator-free days, assessed through data-linkage to medical records. Data will only be captured for the index hospitalisation episode.
Timepoint [5] 424713 0
28 days following randomisation
Secondary outcome [6] 424714 0
Hospital-free days to day 28, defined in an analogous fashion to ventilator-free days, assessed through data-linkage to medical records. Data will only be captured for the index hospitalisation episode.
Timepoint [6] 424714 0
28 days following randomisation
Secondary outcome [7] 424715 0
Unfavourable neurological outcomes at day 180 on the Extended Glasgow Outcome Scale (GOS-E), defined as a GOS-E of upper severe disability or worse (i.e. a GOS-E of 1-4).
Timepoint [7] 424715 0
Day 180 following randomisation
Secondary outcome [8] 426304 0
All-cause mortality at 90 days and 180 days post-randomisation, and survival time to day 180 ascertained from clinical records or by direct contact with the patient.
Timepoint [8] 426304 0
Day 90 and day 180 following randomisation

Eligibility
Key inclusion criteria
1. Aged greater than or equal to 18 years AND
2. Invasively mechanically ventilated with one or more of the following acute brain injuries/conditions:
(i) Ischaemic stroke
(ii) Intracerebral haemorrhage
(iii) Status epilepticus
(iv) Subarachnoid haemorrhage
(v) Suspected hypoxic ischaemic encephalopathy following resuscitation from cardiac arrest
(vi) Traumatic brain injury.
AND
3. Expected to be invasively ventilated (via endotracheal tube or tracheostomy) in the ICU until at least the day after tomorrow.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Being treated with antibiotics to treat a known or suspected infection
2. Has been treated with antibiotics for a known or suspected infection in the previous 7 days
3. On prophylactic antibiotics except for peri-operative prophylaxis with cephazolin (or the treating clinician intends administering prophylactic antibiotics apart from peri-operative prophylaxis with cephazolin.) (SDD is counted as prophylactic antibiotics for the purposes of this exclusion)
4. More than 12 hours since intubation (or tracheostomy insertion)
5. More than 72 hours since hospital admission
6. Documented allergy or other contraindication to ceftriaxone
7. 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.

Study design
Purpose of the study
Prevention
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)
A permuted block randomisation method will be used with variable block sizes, stratified by site.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
The proposed sample size for the phase 2 trial is 360-participants, which assumes 90% and a 5% alpha, and is based on a rate of early lower respiratory tract infection of 34% and 19% in the control and intervention groups respectively. These estimated event rates are likely to be conservative because of pragmatic primary outcome definition is expected to be more sensitive than a stringent VAP definition. If pooled estimates from the vanguard pilot phase are dramatically different from the estimates provided here, we may amend our sample size accordingly.

The analysis population is the intention to treat population defined as all study participants except for those who do not consent to use of data.

All baseline data will be assessed for normality and presented by treatment allocation. Categorical variables will be presented as frequency (%) and compared using chi-squared tests for equal proportion. Continuous variables will be presented as the mean (SD) or median (interquartile range [IQR]) and compared using a student t test for normally distributed variables, and a Wilcoxon rank-sum test otherwise.

Analysis of the primary outcome and other binary outcomes will be via log-binomial models. 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. The primary analysis will incorporate adjustment for site as a random effect.

Other outcomes
Free-day outcomes, which are expected to have a skewed distribution will be evaluated using quantile regression. Comparisons of peak daily temperature will be conducted using fitted mixed liner models including main effects for treatment and time and an interaction between the two to determine if treatments differed over time, with random intercepts for site and for individual.

Further details of planned analyses will be outlined in a statistical analysis plan that will be published in the public domain before treatment allocations are revealed to the investigators.

Recruitment
Recruitment status
Stopped early
Data analysis
No data analysis planned
Reason for early stopping/withdrawal
Other reasons/comments
Other reasons
A decision was taken to terminate this study on the 22nd of May as funding was awarded for a pivotal phase 3 trial
Date of first participant enrolment
Anticipated
11/09/2023
Actual
9/02/2024
Date of last participant enrolment
Anticipated
1/08/2025
Actual
31/05/2024
Date of last data collection
Anticipated
22/04/2024
Actual
Sample size
Target
360
Accrual to date
Final
5
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA,VIC
Recruitment hospital [1] 25258 0
The Alfred - Melbourne
Recruitment hospital [2] 25259 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [3] 25260 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [4] 25261 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [5] 25262 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [6] 25263 0
Royal Perth Hospital - Perth
Recruitment hospital [7] 25264 0
St George Hospital - Kogarah
Recruitment hospital [8] 25265 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [9] 25266 0
Queen Elizabeth II Jubilee Hospital - Coopers Plains
Recruitment hospital [10] 25267 0
Nepean Hospital - Kingswood
Recruitment postcode(s) [1] 40931 0
3004 - Melbourne
Recruitment postcode(s) [2] 40932 0
3050 - Parkville
Recruitment postcode(s) [3] 40933 0
2065 - St Leonards
Recruitment postcode(s) [4] 40934 0
6150 - Murdoch
Recruitment postcode(s) [5] 40935 0
3084 - Heidelberg
Recruitment postcode(s) [6] 40936 0
6000 - Perth
Recruitment postcode(s) [7] 40937 0
2217 - Kogarah
Recruitment postcode(s) [8] 40938 0
5000 - Adelaide
Recruitment postcode(s) [9] 40939 0
4108 - Coopers Plains
Recruitment postcode(s) [10] 40940 0
2747 - Kingswood
Recruitment outside Australia
Country [1] 25661 0
New Zealand
State/province [1] 25661 0
Wellington

Funding & Sponsors
Funding source category [1] 314356 0
Charities/Societies/Foundations
Name [1] 314356 0
Medical Research Institute of New Zealand
Country [1] 314356 0
New Zealand
Funding source category [2] 314357 0
Government body
Name [2] 314357 0
Australian Medical Research Future Fund
Country [2] 314357 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Medical Research Institute of New Zealand
Address
Medical Research Institute of New Zealand,
Private Bag 7902
Wellington 6242, NEW ZEALAND
Country
New Zealand
Secondary sponsor category [1] 316300 0
University
Name [1] 316300 0
The Australian and New Zealand Intensive Care Research Centre, Monash University
Address [1] 316300 0
The Australian and New Zealand Intensive Care Research Centre
Department of Epidemiology and Preventive Medicine
School of Public Health and Preventive Medicine, Monash University
Level 3, 553 St Kilda Road,
Melbourne, Victoria, 3004, AUSTRALIA
Country [1] 316300 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313449 0
Southern Health and Disability Ethics Committee
Ethics committee address [1] 313449 0
Ethics committee country [1] 313449 0
New Zealand
Date submitted for ethics approval [1] 313449 0
25/06/2023
Approval date [1] 313449 0
24/07/2023
Ethics approval number [1] 313449 0
2023 FULL 17890

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

Contacts
Principal investigator
Name 128202 0
Prof Paul Young
Address 128202 0
Medical Research Institute of New Zealand
Private Bag 7902
Wellington 6242
New Zealand
Country 128202 0
New Zealand
Phone 128202 0
+64 274552269
Fax 128202 0
Email 128202 0
[email protected]
Contact person for public queries
Name 128203 0
Paul Young
Address 128203 0
Medical Research Institute of New Zealand
Private Bag 7902
Wellington 6242
New Zealand
Country 128203 0
New Zealand
Phone 128203 0
+64 274552269
Fax 128203 0
Email 128203 0
[email protected]
Contact person for scientific queries
Name 128204 0
Paul Young
Address 128204 0
Medical Research Institute of New Zealand
Private Bag 7902
Wellington 6242
New Zealand
Country 128204 0
New Zealand
Phone 128204 0
+64 274552269
Fax 128204 0
Email 128204 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 from two years after article publication with no end date
Available to whom?
These data will be available to researchers to who provide a methodologically sound proposal for the purposes of achieving specific aims outlined in that proposal.
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?
Proposals should be directed to the corresponding author via email: [email protected] and will be reviewed by the study management committee. Requests to access data to undertake hypothesis-driven research will not be unreasonably withheld. To gain access, data requesters will need to sign a data access agreement and to confirm that data will only be used for the agreed purpose for which access was granted.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
19804Study protocol  [email protected]
19805Data dictionary  [email protected]
19806Other  [email protected] Case report forms



Results publications and other study-related documents

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

Documents added automatically
No additional documents have been identified.