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Trial registered on ANZCTR


Registration number
ACTRN12624000782538
Ethics application status
Approved
Date submitted
5/06/2024
Date registered
25/06/2024
Date last updated
25/06/2024
Date data sharing statement initially provided
25/06/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Biomarkers for Sepsis in Children
Scientific title
Discovery, validation, and verification of novel biomarkers for early sepsis diagnosis and risk stratification in children
Secondary ID [1] 312288 0
Nil known
Universal Trial Number (UTN)
Trial acronym
BASIS
Linked study record
Participant data from the HAPPI KIDS study (Hoq et al. 2020; DOI 10.1093/jalm/jfaa045) will be used as a comparator group for the BASIS study.

Health condition
Health condition(s) or problem(s) studied:
sepsis 334020 0
Condition category
Condition code
Infection 330691 330691 0 0
Other infectious diseases

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
Children with suspected sepsis will be identified by screening through emergency department attendances. Participants will have no direct involvement, the study is collecting data retrospectively from the medical records and correlating biomarkers obtained from discard blood samples. Data that will be extracted from the medical record includes demographic data, severity of illness, and outcome. Only data from the index hospitalisation will be included.
Intervention code [1] 328751 0
Diagnosis / Prognosis
Comparator / control treatment
Healthy controls will be matched for sex and age with children from the HAPPI Kids study, which collected samples from May 2017-Oct 2017, and healthy controls. In addition, some children with suspected sepsis will be found to be sepsis negative, and wil also be included in the analysis.
Control group
Historical

Outcomes
Primary outcome [1] 338445 0
Novel biomarker for early sepsis diagnosis
Timepoint [1] 338445 0
Blood samples will be taken during routine initial investigations for children with suspected sepsis as per normal clinical care. Instead of the samples being discarded following laboratory analysis, they will be stored at -80 degrees celcius. Consent for biomarker analysis will be obtained, and once the patient diagnosis is known, the samples will be analysed for mRNA and protein signatures.
Secondary outcome [1] 435966 0
Novel biomarkers for risk stratification of children with sepsis
Timepoint [1] 435966 0
Blood samples will be taken during routine initial investigations for children with suspected sepsis as per normal clinical care. Instead of the samples being discarded following laboratory analysis, they will be stored at -80 degrees celcius. Consent for biomarker analysis will be obtained, and once the patients severity of illness is known, the samples will be analysed for mRNA and protein signatures.

Eligibility
Key inclusion criteria
• Aged <18 years; AND
• Admission to hospital; AND
• Treatment with intravenous (IV)/ intramuscular (IM)/ intraosseous (IO) antibiotics pre-hospital or in ED; AND
• Circulatory support (fluid bolus or inotropic support) pre-hospital or in ED
OR
Admission diagnosis of suspected sepsis, septicaemia or septic shock

Fluid bolus defined as equal to or greater than 5ml/kg or 500mls administered over less than or equal to 30 minutes to treat impaired perfusion (not dehydration)
Inotropic support defined as intravenous infusion of inotrope/vasopressor
Minimum age
No limit
Maximum age
17 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
a) Patients not initially seen in the Emergency Department (i.e. transferred to the ward including ICU)
b) Patients presenting with trauma who receive antibiotics for prophylaxis or circulatory support for blood loss
c) Patients transferred from another hospital if > 24 hours since presentation
d) Patients transferred from another hospital ward to ED

Study design
Purpose
Screening
Duration
Longitudinal
Selection
Case control
Timing
Both
Statistical methods / analysis
Sample size:
Proteomics
We propose obtaining samples from 10 participants (20 samples) for the discovery phase, and samples from the entire sepsis cohort (200 samples) for the verification and validation phases.

Transcriptomics
For the discovery phase, we will perform RNAseq on unstimulated and stimulated (PMA/Ionomycin) PBMCs on a cohort of 20 sepsis episodes to determine which method provides the highest quality data. Once this methodology has proved feasible and yields adequate data, we propose analysing samples from 200 sepsis episodes with 200 samples (1 samples per episode), which should provide adequate data for correlative analyses.

Statistical analysis plan:
Proteomics
Proteomics analysis will be undertaken on frozen blood samples left over from routine clinical testing (discard samples). These will be analysed based on severity of illness and clinical outcome. The initial discovery phase will analyse samples from a small cohort of children with severe outcomes (permanent disability or death), whilst the validation phase will analyse a larger cohort with the full spectrum of disease severity. The standard proteomics approach used to study disease mechanisms, consisting of three phases where the number of individuals increases from a few to many, whilst, concurrently, the number of proteins studied decreases from hundreds to a handful of proteins that can be translated into patient care.
1. Discovery phase: Data Independent Acquisition (DIA) Mass Spectrometry approach will be used to assess changes in expression of approximately 400 plasma proteins. This unbiased discovery of proteins not yet implicated in sepsis significantly adds to the proposal’s innovation and novelty.
a. Disease mechanisms – We will identify differentially expressed proteins in participants with sepsis confirmed (n=20) compared to healthy age and gender-matched controls (n=20, collected through ‘Happi Kids’ HREC 34183). Differentially expressed proteins will be examined in the context of biological data to identify the functions, pathways and respective networks represented by those proteins, which will, in turn, identify the specific mechanism of sepsis.
b. Outcome-based signature – Differentially expressed proteins within the sepsis group, n=20 (10 severe outcomes and 10 non-severe) will be used as candidates for the verification and validation. We envisage that 10 to 20 candidate proteins will be identified.
2. Verification phase: We will identify and validate a minimal viable protein signature of proteins in the whole sepsis cohort using a standard, commercially available ELISA based immunoassay approach or targeted mass spectrometry.
3. Validation phase: We will use samples from the whole sepsis cohort (n= 200), age and gender-matched healthy samples from the HAPPI KIDS study (n=40), as well as age and gender matched samples from children who are sepsis negative (n=40), to screen the proteins of interest (identified in discovery phase B) using targeted proteomics. We will use a targeted mass spectrometry approach known as multiple reaction monitoring (MRM) to verify the expression of up to 5 candidate proteins.

Transcriptomics
Bioinformatics analysis on RNAseq will be performed at the Walter and Eliza Hall Institute. The aim is to identify a transcriptome signature and profile at initial blood collection that correlates with clinical outcomes. In addition to PBMCs we will also collect plasma. When we identify a transcriptome signature that correlates with outcomes we will ascertain if that signature can be translated to detection of corresponding proteins in blood. For example, if a strong signature is obtained indicating transcriptional activity of pathways relevant for IL-8 or PCT expression or function, we can then measure these cytokines and putative chemokines / proteins in serum. Similarly, transcriptomic changes in specific metabolic pathways can be indicate the utility of proteins or metabolites from the respective pathways as putative biomarkers. A plasma test would be easier to translate to a point of care test. Nonetheless a highly targeted microarray identifying a transcriptional signature could also be translated to a clinical test. The purpose of performing an unbiased transcriptional analysis is to discover novel biomarker collections that cannot be discovered a priori using technically challenging proteomic analyses. When a transcriptional profile is discovered then a proteomic approach will be pursued.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
7/10/2024
Actual
Date of last participant enrolment
Anticipated
5/10/2026
Actual
Date of last data collection
Anticipated
6/12/2027
Actual
Sample size
Target
240
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 26643 0
The Royal Childrens Hospital - Parkville
Recruitment postcode(s) [1] 42683 0
3052 - Parkville

Funding & Sponsors
Funding source category [1] 316675 0
Government body
Name [1] 316675 0
National Health and Medical Research Council
Country [1] 316675 0
Australia
Primary sponsor type
Other
Name
Murdoch Children's Research Institute
Address
Country
Australia
Secondary sponsor category [1] 318865 0
None
Name [1] 318865 0
Address [1] 318865 0
Country [1] 318865 0
Other collaborator category [1] 283072 0
Other Collaborative groups
Name [1] 283072 0
Walter and Elisa Hall Institute
Address [1] 283072 0
Country [1] 283072 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 315453 0
The Royal Children’s Hospital Human Research Ethics Committee
Ethics committee address [1] 315453 0
http://www.rch.org.au/ethics
Ethics committee country [1] 315453 0
Australia
Date submitted for ethics approval [1] 315453 0
Approval date [1] 315453 0
21/05/2024
Ethics approval number [1] 315453 0
101005

Summary
Brief summary
Early sepsis diagnosis is challenging for clinicians due to the non-specific nature of symptoms and the cross-over between clinical signs and symptoms of sepsis and those of other mild self-limited infections. Current diagnostic criteria for sepsis in children perform poorly, causing clinicians to rely on their own experience and judgement to diagnose sepsis. They must balance the risk of over-treatment, un-necessary hospitalisation, and overuse of broad spectrum antibiotics with the risk of delayed treatment, which is a known contributor to poor outcome and death from sepsis. The lack of clear diagnostic criteria also results in variable estimates of sepsis prevalence, severity, outcomes, cost, difficulty benchmarking care, and inconsistent enrolment strategies for clinical trials. The Biomarkers in Sepsis (BASIS) study will identify novel biomarkers (protein and mRNA) for early sepsis diagnosis and risk stratification. These will have the potential to save lives through commercialisation into point-of-care tests.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 134754 0
A/Prof Elliot Long
Address 134754 0
Emergency Department, The Royal Children's Hospital, 52 Flemington Road, Parkville, VIC 3052
Country 134754 0
Australia
Phone 134754 0
+61425573585
Fax 134754 0
Email 134754 0
elliot.long@rch.org.au
Contact person for public queries
Name 134755 0
Elliot Long
Address 134755 0
Emergency Department, The Royal Children's Hospital, 52 Flemington Road, Parkville, VIC 3052
Country 134755 0
Australia
Phone 134755 0
+61425573585
Fax 134755 0
Email 134755 0
elliot.long@rch.org.au
Contact person for scientific queries
Name 134756 0
Elliot Long
Address 134756 0
Emergency Department, The Royal Children's Hospital, 52 Flemington Road, Parkville, VIC 3052
Country 134756 0
Australia
Phone 134756 0
+61 425573585
Fax 134756 0
Email 134756 0
elliot.long@rch.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Aggregate data will be shared upon request to the principal investigator


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
23851Study protocol    387924-(Uploaded-05-06-2024-11-00-41)-BASIS protocol v1.1 13 May 2024 clean.doc
23852Ethical approval    387924-(Uploaded-05-06-2024-11-00-54)-101005 Ethics 21.05.2024.pdf



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.