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Trial registered on ANZCTR


Registration number
ACTRN12616001440415
Ethics application status
Approved
Date submitted
5/10/2016
Date registered
14/10/2016
Date last updated
19/11/2018
Date data sharing statement initially provided
19/11/2018
Date results information initially provided
19/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
The Australian Predicting Infectious Complications in Children with Cancer (PICNICC) Project
Scientific title
The Australian Predicting Infectious Complications in Children with Cancer (PICNICC) Project: validation of international clinical decision rule and identification of novel biomarkers.
Secondary ID [1] 289580 0
None
Universal Trial Number (UTN)
N/A
Trial acronym
PICNICC
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Paediatric Cancer 299320 0
Febrile Neutropenia 299322 0
Microbiologically Documented Infection 299323 0
Sepsis 299324 0
Condition category
Condition code
Cancer 299311 299311 0 0
Children's - Brain
Cancer 299312 299312 0 0
Children's - Leukaemia & Lymphoma
Cancer 299313 299313 0 0
Children's - Other

Intervention/exposure
Study type
Observational
Patient registry
True
Target follow-up duration
30
Target follow-up type
Days
Description of intervention(s) / exposure
The aim of this project is to prospectively validate the European-based PICNICC clinical decision rule (CDR) that reliably stratifies children with cancer and febrile neutropenia into low and high risk for microbiologically documented infection (MDI), so as to optimise their management and quality of life and improve resource allocation. The CDR is based on six simple clinical variables including (i) tumour type (ii) maximum temperature, (iii) total white cell count, (iv) monocyte count, (v) haemoglobin and (vi) severity of illness. It provides the opportunity for a world first external validation of this globally derived rule and is a critical step before the rule can be safely implemented into practice.

Patient demographic, FN episode and outcome data will be collected prospectively by the study-site research assistant (RA) and will follow international consensus definitions. Patients that develop FN outside of RA working hours will have relevant data collected retrospectively within 72 hours. Data will be entered into an electronic password protected study database (REDCap). Accuracy of data collection will be verified by project manager (first ten records for each site then periodically throughout recruitment) as well as chief investigator and site associate investigator.

To identify novel biomarkers that predict outcomes we will perform RNA sequencing (RNAseq) analysis on peripheral blood mononuclear cells (PBMC) collected from participants at Royal Children's Hospital Melbourne at two time points. Blood will be collected in EDTA tubes (5ml if <40kg and 12ml if >40kg). Peripheral blood samples will be processed by the Children’s Cancer Centre Tissue Bank. Within two hours of sample collection, plasma will be harvested following centrifugation and stored at -80 degrees celsius. PBMCs will be isolated by Ficoll density gradient centrifugation. PBMC will be cryopreserved and stored in the vapor phase of liquid nitrogen for in vitro assays and pelleted and resuspended in RNAlater for nucleic acid extraction. Samples will be batched and distributed by the CCC Tissue Bank.

RNAseq will be performed at MCRI (25-30 M coverage) on unstimulated and stimulated samples. Additionally PBMCs will be analysed by flow cytometry to determine the frequency of T cells, and monocytes. This latter data set will allow bioinformatic deconvolution to dissect the transcriptome of relevant cell types. When we have established which method (stimulated or unstimulated) provides that most robust data we will proceed to collect and analyses 100-200 samples . Flow cytometry and stimulation of PBMCs will be performed in the Pellegrini laboratory at the Walter and Eliza Hall Institute of Medical Research. The cell samples sent to WEHI will be thawed and placed in culture medium. During the pilot study these samples will be unstimulated or stimulated with agents that are known to amplify immune responses for a few hours. The medium the cells were kept in will then be collected, to be analysed upon completion of transcriptome analysis for secreted immunogenic factors. The cells themselves will be labelled with specific antibodies which will distinguish the individual cells into subtypes of immune cells and their activation status. During this process all the cells will be run on a machine to analyse composition. Therefore no cells will remain after the analysis has taken place. However, the culture medium these cells were kept in will be stored indefinitely at -80 degrees celsius in the secure Pellegrini laboratory freezer. RNA sequencing is being carried out to identify biomarkers that can predict the outcome of FN episodes only. The transcriptome analysis performed as part of this study is purely exploratory. None of the tests being performed are validated or accredited as diagnostics. Therefore no information will be revealed about disease-predisposing germline traits, heritable disorders or parental identity.

Each enrolled patient that experiences a febrile neutropenia episode will be followed at presentation (i.e. Day 1), Day 2, Day 7 and Day 30. Cost information will be obtained using hospital costs records for inpatient data and outpatient costs via the Medicare consent form, completed at patient recruitment by the RA.

The optional quality of life surveys have been replicated into an electronic format for parents/guardians and patients older than three years, The age ranges for the CHU-9D assessment (7 to 18 years and a proxy version for patients aged 3 to 6 years) have been stipulated by the University of Sheffield and will be adhered to when implementing the questionnaire. The RA will implement each tool electronically prior to discharge, providing education on how to complete the surveys. To provide a comprehensive overview of the true impact of FN and unplanned hospital admission on the child. For patients that have been discharged home, the surveys will be distributed electronically, via RedCAP, to valid email address.
Intervention code [1] 295184 0
Diagnosis / Prognosis
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 298800 0
Prospectively validate the internationally derived PICNICC clinical decision rule that predicts microbiologically documented infection in children with cancer and febrile neutropenia. Patient demographic, FN episode and outcome data will be collected prospectively by the study-site research assistant (RA) and will follow international consensus definitions.
Timepoint [1] 298800 0
Each FN episode will include data from presentation until 30 days after the FN occurence, The study will take place over two years, allowing FN episodes that occur during this time to be captured.
Primary outcome [2] 298801 0
To identify novel biomarkers that predict outcomes we will perform RNA sequencing (RNAseq) analysis on peripheral blood mononuclear cells (PBMC) collected from participants at RCH Melbourne at two time points.
Timepoint [2] 298801 0
Sample collection: at presentation (Day 1, hour 0-4) and 24hrs later (Day 2). Pilot data analysis post collection of first 20 samples, approximately one month. Exploratory analysis once all data collected, approximately 18 months post study commencement.
Secondary outcome [1] 325238 0
Costs will be measured for outpatient and inpatient health care service use. The site RA will collect actual inpatient costs of each FN episode including bed-days, medications and investigations. This information is accessible from hospital health information systems. Costs for outpatient service use, where relevant, will be captured by accessing Medicare records for medical and pharmaceutical services. 3 months prior to 9 months post FN episode.
Timepoint [1] 325238 0
Require 12 months of data relevant to the FN episode, three months prior and nine months post. This will be collected for the entire participant cohort and information extracted for the twelve months relevant to each participants episode. Therefore Medicare data has been requested for the period of 01/07/2016 to 01/12/2019.
Secondary outcome [2] 328208 0
All patients greater than three years of age enrolled in the validation study will be given the option to participate in the quality of life (QOL) assessment. To test patient QOL the Child Health Utility 9D (CHU9D, University of Sheffield) will be used. This tool is validated for use in children aged 7 to 18 years and will allow this age group to self-report. A proxy completion version will be used for children aged 3 to 6 years.
Timepoint [2] 328208 0
QoL surveys will be administered to Participants at Day 1, Day 7 and Day 30. A reminder email will be sent for those who are yet to complete the survey at Day 3, Day 10 and Day 35.
Secondary outcome [3] 328388 0
All parents/guardians of participants enrolled in the validation study will be given the option to participate in the QOL assessment. Parent/guardian QOL will be assessed using the Assessment for Quality of Life 6D (AQoL-6D) and the CarerQOL.
Timepoint [3] 328388 0
QoL surveys will be administered to Parents/Guardians at Day 1, Day 7 and Day 30. A reminder email will be sent for those who are yet to complete the survey at Day 3, Day 10 and Day 35.

Eligibility
Key inclusion criteria
1. Children (age less than or equal to 18 years)
2. Diagnosis of cancer or leukaemia and on active treatment
3. Diagnosis of fever (greater than or equal to 38 degrees celsius) in the setting of neutropenia (absolute neutrophil count less than 1.0 cells/microlitre)
Minimum age
No limit
Maximum age
18 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Febrile neutropenia treatment commenced at a non-participating site
2. Allogeneic haematopoietic stem cell transplant within preceding 3 months
3. Febrile neutropenia episode occurred while patient was receiving concurrent intravenous or oral antibiotics (excluding prophylaxis)


Study design
Purpose
Screening
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
International data indicate that microbiologically documented infection occurs in between 18 and 25% of episodes of febrile neutropenia. This is supported by local pilot data at Monash Children’s Hospital and Royal Children’s Hospital. For validation of the PICNICC clinical decision rule (Objective 1), 780 episodes of febrile neutropenia, with an estimated event rate of 18%, are required for 80% power to show AUC-ROC of the PICNICC model is greater than or equal to 0.7. Accounting for a 10% dropout the target for recruitment is 848 across the 8 study sites.

The sample size for the biomarker study (Objective 2) will be calculated from an exploratory study. The bioinformatics department at the Walter and Eliza Hall Institute (WEHI) will perform power calculations in the preliminary data to ascertain a sufficient sample size. Based on their experience 100-200 participants with 200-400 samples should provide adequate data for correlative analyses.

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)
NSW,QLD,SA,WA,VIC
Recruitment hospital [1] 6056 0
The Royal Childrens Hospital - Parkville
Recruitment hospital [2] 6057 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [3] 6059 0
John Hunter Children's Hospital - New Lambton
Recruitment hospital [4] 6060 0
Womens and Childrens Hospital - North Adelaide
Recruitment hospital [5] 6061 0
Lady Cilento Children's Hospital - South Brisbane
Recruitment hospital [6] 6062 0
Sydney Children's Hospital - Randwick
Recruitment hospital [7] 6063 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [8] 6064 0
Princess Margaret Hospital - Subiaco
Recruitment postcode(s) [1] 13505 0
3052 - Parkville
Recruitment postcode(s) [2] 13506 0
3168 - Clayton
Recruitment postcode(s) [3] 13507 0
2145 - Westmead
Recruitment postcode(s) [4] 13508 0
2031 - Randwick
Recruitment postcode(s) [5] 13510 0
2305 - New Lambton Heights
Recruitment postcode(s) [6] 13511 0
4101 - South Brisbane
Recruitment postcode(s) [7] 13512 0
5006 - North Adelaide
Recruitment postcode(s) [8] 13513 0
6008 - Subiaco

Funding & Sponsors
Funding source category [1] 293970 0
Government body
Name [1] 293970 0
National Health and Medical Research Council
Address [1] 293970 0
Level 1
16 Marcus Clarke Street
Canberra ACT 2601
Country [1] 293970 0
Australia
Primary sponsor type
Hospital
Name
Peter MacCallum Cancer Centre
Address
305 Grattan Street
Melbourne VIC 3000
Country
Australia
Secondary sponsor category [1] 292783 0
Hospital
Name [1] 292783 0
The Royal Children's Hospital
Address [1] 292783 0
50 Flemington Road
Parkville VIC 3052
Country [1] 292783 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295385 0
The Royal Children's Hospital Human Research Ethics Committee
Ethics committee address [1] 295385 0
Research Ethics & Governance
The Royal Children's Hospital
Level 4, South Building
50 Flemington Road
Parkville Vic 3052
Ethics committee country [1] 295385 0
Australia
Date submitted for ethics approval [1] 295385 0
11/07/2016
Approval date [1] 295385 0
29/09/2016
Ethics approval number [1] 295385 0
HREC / 16 / RCHM / 108

Summary
Brief summary
The aim of this study is to validate the PICNICC clinical decision rule and explore potential biomarkers that will assist in prediction of microbiologically documented infection in children undergoing treatment for cancer or leukaemia presenting with febrile neutropenia (FN).

Who is it for?
You may be eligible to join this study if you are aged less than 18 years and have are undergoing active treatment for cancer or leukaemia with a diagnosis of fever and with absolute neutrophil count less than 1.0 cells/ microlitre.

Study details
The study involves obtaining routinely documented information from medical records related to the FN episode. In addition requesting permission to access Medicare data over a 12 month period, to analyse costs that may have occurred due to the FN episode for the participant and their family. Participants (aged 3 to 18 years) and their parent/guardian will be asked to complete an electronic survey at presentation to hospital, seven days thereafter and a follow up survey at 30 days. At one site participants will be asked to provide two small blood samples at routine blood sampling times to assist in analysing markers in the blood that may be able to diagnose and predict the severity of an infection.

FN is the most frequent complication of the treatment of childhood cancer. Throughout Australia and the rest of the world, management usually involves hospital admission for intravenous antibiotics until resolution of fever and recovery of neutrophil count. International and local data indicate these unplanned FN admissions negatively impact quality of life (QOL), increase the risk of hospital-acquired infection and pose a significant economic burden on the healthcare system.

In collaboration with the European-based PICNICC group, this project will test an established clinical decision rule (CDR) that predicts severe infection in children with cancer presenting with FN. This rule will enable emergency department, oncology and other paediatric doctors to reliably identify patients at low-risk of severe infection who will benefit from reduced intensity antibiotic treatment and early hospital discharge. This study will also identify novel biomarkers in blood that may be used in the future to improve our prediction of exactly which children with FN have a severe infection. Finally, we will also explore the cost of treatment of FN in Australia as well as the impact of this common condition on patient and family quality of life. This information will be used to inform future research and identify areas for cost savings and improvements in quality of life.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 67066 0
Dr Gabrielle M Haeusler
Address 67066 0
Peter MacCallum Cancer Institute
Department of Infectious Diseases
305 Grattan Street
Melbourne VIC 3000
Country 67066 0
Australia
Phone 67066 0
+61409237348
Fax 67066 0
Email 67066 0
Gabrielle.Haeusler@petermac.org
Contact person for public queries
Name 67067 0
Ms Zoe Allaway
Address 67067 0
Peter MacCallum Cancer Institute
Department of Infectious Diseases
305 Grattan Street
Melbourne VIC 3000
Country 67067 0
Australia
Phone 67067 0
+61 401 051 243
Fax 67067 0
Email 67067 0
Zoe.Allaway@rch.org.au
Contact person for scientific queries
Name 67068 0
Dr Gabrielle M Haeusler
Address 67068 0
Peter MacCallum Cancer Institute
Department of Infectious Diseases
305 Grattan Street
Melbourne VIC 3000
Country 67068 0
Australia
Phone 67068 0
+61409237348
Fax 67068 0
Email 67068 0
Gabrielle.Haeusler@petermac.org

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
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