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Trial registered on ANZCTR


Registration number
ACTRN12620001122943
Ethics application status
Approved
Date submitted
12/08/2020
Date registered
30/10/2020
Date last updated
30/10/2020
Date data sharing statement initially provided
30/10/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Optimising treatment outcomes for children and adults through rapid genome sequencing of sepsis pathogens. A study protocol for a prospective, multi-centre trial (DIRECT)
Scientific title
Reducing time to appropriate antibiotics by integrating rapid pathogen genome sequencing with personalised antimicrobial dosing in children and adults with sepsis. A study protocol for a prospective, multi-centre trial (DIRECT)
Secondary ID [1] 302006 0
Nil known
Universal Trial Number (UTN)
Trial acronym
DIRECT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Sepsis 318565 0
Antimicrobial resistance 318597 0
Condition category
Condition code
Infection 316579 316579 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Design and setting:
The DIRECT study is a pilot prospective, non-randomised multicentre trial of an integrated diagnostic and therapeutic algorithm combining rapid direct pathogen sequencing and software-guided, personalised antibiotic dosing in children and adults with sepsis on ICU.

Participants and interventions:
DIRECT will collect microbiological and pharmacokinetic samples from approximately 50 children and adults with sepsis admitted to one of four ICUs in Brisbane. Consecutive patients with suspected sepsis (irrespective of culture results) will be recruited in whom MinION sequencing will be combined with Bayesian software-guided (ID-ODS) personalised antimicrobial dosing.

Intervention description:

Consecutive patients with suspected sepsis admitted to ICU will undergo MinION nanopore pathogen sequencing integrated with personalised antibiotic therapy using a combination of Bayesian dosing software (ID-ODSTM) and measured antibiotic plasma concentrations. A senior ICU pharmacist/clinician at each site will lead this software-guided intervention of antimicrobial dose optimisation. All dosing regimens will be checked by both the senior ICU pharmacist and attending ICU consultant prior to prescription. The final decision regarding the use of the optimised dosing of antibiotics will remain at the discretion of the attending ICU consultant.

Participants will be asked to provide the following blood samples. At the time of the suspected sepsis diagnosis, participants will provide a single additional EDTA blood sample. The volume of EDTA blood required is 1-2ml for infants and young children (<5y), 2-6ml for older children (5-12y), and 6–10ml for adolescents and adults. Participants will subsequently provide up to four plasma samples to measure antimicrobial levels at 24h, 48h, 72h, 96h after sepsis diagnosis. The volume of plasma samples required is 0.5ml for infants and young children (<5y), 1-2ml for older children (5-12y), and 3-5ml for adolescents and adults. The duration of patient participation in the study will be up to 5 days. Antimicrobial pharmacokinetic sampling will cease if the patient is discharged from ICU before 5 days.
Intervention code [1] 318291 0
Diagnosis / Prognosis
Intervention code [2] 318318 0
Treatment: Devices
Comparator / control treatment
A comparator group of patients with suspected sepsis admitted to ICU (n=100) who have had antibiotic concentrations measured daily but who have not undergone dosing adjustments. Similar to the intervention group, participants in the comparator group will provide up to four plasma samples to measure antimicrobial levels at 24h, 48h, 72h, 96h after sepsis diagnosis.
Control group
Active

Outcomes
Primary outcome [1] 324710 0
The primary outcome is time to effective antimicrobial therapy defined as trough drug concentrations above the MIC of the pathogen.
Timepoint [1] 324710 0
Time to effective antimicrobial therapy will be determined at the completion of the study, after all participant samples have been collected and analysed. It is calculated as the time required to achieve a trough drug concentrations above the MIC of the pathogen. Participant plasma samples to measure antimicrobial levels will be collected at 24h, 48h, 72h, 96h after antibiotic commencement.
Secondary outcome [1] 385483 0
Diagnostic accuracy of MinION nanopore pathogen sequencing direct from whole blood.

Conventional measures of diagnostic accuracy (sensitivity, specificity, predictive values and likelihood ratios) will be evaluated for MinION nanopore pathogen sequencing against a composite reference standard which will incorporate blood culture results, other significant microbiological samples taken at the discretion of the clinical team and clinical and epidemiological features. These composite features will be interpreted independently by two experts in microbiology and infectious disease. In the event of discordance a third expert opinion will adjudicate.
Timepoint [1] 385483 0
Diagnostic accuracy will be determined at the completion of the study after all participant samples have been collected and analysed.
Secondary outcome [2] 385485 0
Time to pathogen identification and susceptibility testing using MinION nanopore pathogen sequencing direct from whole blood.
Timepoint [2] 385485 0
Time from patient recruitment to pathogen identification and susceptibility susceptibility will be determined using electronic time-stamps documenting each step of analysis and interpretation. Time to pathogen identification will be calculated at the completion of the study after all participant samples have been collected and analysed.
Secondary outcome [3] 385486 0
Time to pathogen identification and susceptibility testing using MinION nanopore pathogen sequencing from positive blood culture broth.
Timepoint [3] 385486 0
Time to pathogen identification and susceptibility testing will be determined using electronic time-stamps documenting each step of analysis and interpretation.

Time to pathogen identification will be calculated at the completion of the study after all participant samples have been collected and analysed.

Eligibility
Key inclusion criteria
1. Admitted to paediatric or adult ICU at one of the participating centres
2. Decision to treat for suspected sepsis, defined as suspected or proven infection with suspected or proven organ dysfunction.
3. Commenced within 24h on intravenous broad-spectrum antibiotics, or within 24h of a change to new antibiotics consistent with treatment for a new episode of suspected sepsis.
4. Blood cultures are being obtained or were obtained within the past 12 hours
Minimum age
1 Months
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Inability to gain informed consent during the study period
2. Neonates
3. Death is likely imminent
4. Palliative care patient

Study design
Purpose of the study
Diagnosis
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
No randomisation of patients will occur. All patients in ICU who meet the selection criteria will be eligible for recruitment to the study.
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Statistical methods for primary and secondary outcomes
The primary outcome measure, time to optimal antimicrobial therapy will be reported by median and interquartile range. Comparison between projected time to optimal antimicrobial therapy using an integrated diagnostic sequencing and dosing algorithm will be compared with the observed time to optimal therapy using a suitable non-parametric test such as the Kruskal-Wallis test.

Diagnostic accuracy of MinION nanopore pathogen sequencing will be reported as sensitivity, specificity, positive and negative likelihood ratios against the composite reference standard reported above and illustrated by a 2x2 table.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
4/01/2021
Actual
Date of last participant enrolment
Anticipated
30/06/2021
Actual
Date of last data collection
Anticipated
30/09/2021
Actual
Sample size
Target
50
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 17238 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [2] 17239 0
Queensland Children's Hospital - South Brisbane
Recruitment hospital [3] 17240 0
The Prince Charles Hospital - Chermside
Recruitment hospital [4] 17241 0
Princess Alexandra Hospital - Woolloongabba
Recruitment postcode(s) [1] 30947 0
4029 - Herston
Recruitment postcode(s) [2] 30948 0
4101 - South Brisbane
Recruitment postcode(s) [3] 30949 0
4032 - Chermside
Recruitment postcode(s) [4] 30950 0
4102 - Woolloongabba

Funding & Sponsors
Funding source category [1] 306427 0
Other Collaborative groups
Name [1] 306427 0
Queensland Genomics Health Alliance
Country [1] 306427 0
Australia
Funding source category [2] 306429 0
Government body
Name [2] 306429 0
Medical Research Futures Fund
Country [2] 306429 0
Australia
Primary sponsor type
University
Name
The University of Queensland
Address
The University of Queensland
Brisbane QLD 4072
Country
Australia
Secondary sponsor category [1] 307656 0
None
Name [1] 307656 0
Address [1] 307656 0
Country [1] 307656 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306627 0
Children's Health Queensland Hospital and Health Service Human Ethics Committee
Ethics committee address [1] 306627 0
Ethics committee country [1] 306627 0
Australia
Date submitted for ethics approval [1] 306627 0
24/07/2019
Approval date [1] 306627 0
31/07/2019
Ethics approval number [1] 306627 0
HREC/19/QCHQ/55177

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

Contacts
Principal investigator
Name 104506 0
Dr Adam Irwin
Address 104506 0
UQ Centre for Clinical Research
Building 71 / 918
Royal Brisbane and Women's Hospital
Herston QLD 4029
Country 104506 0
Australia
Phone 104506 0
+61 07 3346 6075
Fax 104506 0
Email 104506 0
a.irwin@uq.edu.au
Contact person for public queries
Name 104507 0
Adam Irwin
Address 104507 0
UQ Centre for Clinical Research
Building 71 / 918
Royal Brisbane and Women's Hospital
Herston QLD 4029
Country 104507 0
Australia
Phone 104507 0
+61 07 3346 6075
Fax 104507 0
Email 104507 0
a.irwin@uq.edu.au
Contact person for scientific queries
Name 104508 0
Adam Irwin
Address 104508 0
UQ Centre for Clinical Research
Building 71 / 918
Royal Brisbane and Women's Hospital
Herston QLD 4029
Country 104508 0
Australia
Phone 104508 0
+61 07 3346 6075
Fax 104508 0
Email 104508 0
a.irwin@uq.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Individual participant data collected during the trial, after de-identification, and relating to published results will be made available.
When will data be available (start and end dates)?
Beginning 3 months from publication of study results. No end date determined.
Available to whom?
To researchers who provide a methodologically sound proposal at the discretion of Primary Sponsor
Available for what types of analyses?
To achieve the aims in the HREC approved proposal or for IPD meta-analyses
How or where can data be obtained?
Access subject to approval by Principal Investigator via email to
Dr Adam Irwin
UQ Centre for Clinical Research
The University of Queensland
Ph: 07 3346 6075
Email: a.irwin@uq.edu.au


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
8763Study protocol  a.irwin@uq.edu.au
8765Informed consent form  a.irwin@uq.edu.au
8767Ethical approval  a.irwin@uq.edu.au



Results publications and other study-related documents

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

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseOptimising Treatment Outcomes for Children and Adults Through Rapid Genome Sequencing of Sepsis Pathogens. A Study Protocol for a Prospective, Multi-Centre Trial (DIRECT).2021https://dx.doi.org/10.3389/fcimb.2021.667680
N.B. These documents automatically identified may not have been verified by the study sponsor.