Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000499785
Ethics application status
Approved
Date submitted
2/03/2022
Date registered
29/03/2022
Date last updated
16/04/2024
Date data sharing statement initially provided
29/03/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Preventing adverse events during paediatric cancer treatment: A multi-site hybrid randomised controlled trial of catheter lock solutions (The CLOCK trial)
Scientific title
Preventing adverse events during paediatric cancer treatment: A multi-site hybrid randomised controlled trial of catheter lock solutions (The CLOCK trial)
Secondary ID [1] 306380 0
Nil known
Universal Trial Number (UTN)
U1111-1273-3129
Trial acronym
The CLOCK trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Paediatric Cancer 325522 0
Central vascular access device (CVAD) related adverse events 325523 0
Condition category
Condition code
Cancer 322602 322602 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Intervention: KiteLock - 4% Tetrasodium-EDTA T-EDTA) Locking volumes will vary depending on the catheter type: 1-2 mL catheter lumen for PICC and tunnelled CVADs based on clinical discretion and 2mL for totally implanted CVADs.

The frequency of allocated lock solution will be administered depending on clinical requirement (i.e. if the CVAD is de-accessed for greater than 6 hours), or during routine CVAD management procedures (e.g., needleless connector changes, totally implanted device needling and flushing, administration set changes) with a maximum of one dose per 24 hours and a minimum of one dose every 8 weeks where the device is not in use. Clinicians (nursing and medical) will be administering the locking solution as per routine patient care, not research/trial staff.
The intervention will be administered from subject recruitment up until catheter removal or for a maximum of 3 months (whichever occurs first).
Intervention fidelity will be promoted through electronic medication ordering sets (where available), participant information cards, and twice-weekly monitoring by research staff.
Intervention code [1] 322811 0
Prevention
Comparator / control treatment
Comparator/control treatment: Comparator 1:
Normal Saline (0.9% Sodium Chloride) 10ml for all catheter types.


Comparator/control treatment: Comparator 2: Sodium Heparin 50units/5mL will be used for Peripherally Inserted Central Catheters (PICC) and Tunnelled CVADs, and for totally implanted CVADs either Sodium Heparin 50units/5mL or 100units/mL will be used. The concentration of the solution is determined by the specific guidelines set by the hospitals and their standard operating procedures.
Locking volumes will vary depending on the catheter type: 1-2 mL catheter lumen for PICC and tunnelled CVADs based on clinical discretion and 2mL for totally implanted CVADs.
Control group
Active

Outcomes
Primary outcome [1] 330395 0
The primary outcome is a serious CVAD complication. This is defined as a composite of CVAD-associated bloodstream infection (CABSI), CVAD-associated thrombosis or CVAD occlusion during CVAD dwell or at removal.

i CVAD-associated bloodstream infection (BSI): A laboratory confirmed BSI where an eligible BSI organism is identified with CVAD in place for >2 consecutive calendar days on the day of the BSI (day of CVAD placement being Day 1) and the CVAD in place on the date of the event or the day before (see Centers for Disease Control and Prevention Device-associated Module BSI for full criteria), in addition to single positive blood cultures (SPBC) for common commensals where there is clinical intent to treat as CABSI (i.e. commencement of antibiotics). To be assigned by a blinded infectious disease specialist.

ii. CVAD-associated thrombosis: A symptomatic thrombosed CVAD vessel or fibrin sheath occluding lumen diagnosed via ultrasound or venography. ‘Symptomatic’ is defined by pain and/or swelling of the area drained by the veins where the device is placed, an increasing clinically obvious collateral network superficially in the region of the catheter, or occluded CVAD. To be assigned by blinded radiologist.

iii. CVAD occlusion: Complete injection and/or aspiration catheter occlusion of at least 1 CVAD lumen (assessed using the Catheter Injection and Aspiration (CINAS) classification system), requiring administration of thrombolytic agent, and/or visible split in the CVAD structure related to occlusion event
Timepoint [1] 330395 0
From recruitment until 24 hours following study completion (device removed, patient withdrawn or up to a maximum of 3 months post-enrolment).
Secondary outcome [1] 406074 0
CABSI: A laboratory-confirmed bloodstream infection ( BSI) where an eligible BSI organism is identified with CVAD in place for >2 consecutive calendar days on the day of the BSI (day of CVAD placement being Day 1) and the CVAD in place on the date of the event or the day before (see Centers for Disease Control and Prevention Device-associated Module BSI for full criteria). This is in addition to single positive blood cultures (SPBC) for common commensals where there is clinical intent to treat as CABSI (i.e. commencement of antibiotics), Reported proportionally and per 1,000 catheter days.
Timepoint [1] 406074 0
From recruitment until 24 hours following study completion (device removed, patient withdrawn, or up to a maximum of 3 months post-enrolment).
Secondary outcome [2] 406075 0
Centres of Disease Control and Prevention (CDC)/National Healthcare Safety Network (NHSN) CABSI only: A laboratory confirmed BSI where an eligible BSI organism is identified with CVAD in place for >2 consecutive calendar days on the day of the BSI (day of CVAD placement being Day 1) and the CVAD in place on the date of the event or the day before (see Centers for Disease Control and Prevention Device-associated Module BSI for full criteria); excluding single positive blood cultures (SPBC) for common commensals.
Timepoint [2] 406075 0
From recruitment until 24 hours following study completion (device removed, patient withdrawn, or up to a maximum of 3 months post-enrolment).
Secondary outcome [3] 406076 0
CVAD-associated thrombosis: A symptomatic thrombosed CVAD vessel or fibrin sheath occluding lumen diagnosed via ultrasound or venography. ‘Symptomatic’ is defined by pain and/or swelling of the area drained by the veins where the device is placed, an increasing clinically obvious collateral network superficially in the region of the catheter, or occluded CVAD. To be assigned by blinded radiologist and hematologist.
Timepoint [3] 406076 0
From recruitment until 24 hours following study completion (device removed, patient withdrawn, or up to a maximum of 3 months post-enrolment).
Secondary outcome [4] 406077 0
CVAD occlusion: Complete injection and/or aspiration catheter occlusion of at least 1 CVAD lumen (assessed using the Catheter Injection and Aspiration (CINAS) classification system), requiring administration of the thrombolytic agent, and/or visible split in the CVAD structure related to occlusion event.
Timepoint [4] 406077 0
From recruitment until 24 hours following study completion (device removed, patient withdrawn, or up to a maximum of 3 months post-enrolment).
Secondary outcome [5] 406078 0
CVAD failure: Cessation of CVAD function prior to completion of treatment, resulting CVAD removal and replacement intravenous (IV) access. This will be determined through direct observation, patient self-report or from medical records.
Timepoint [5] 406078 0
From recruitment until 24 hours following study completion (device removed, patient withdrawn or up to a maximum of 3 months post-enrolment).
Secondary outcome [6] 406079 0
Adverse events: Infusion reactions (e.g., allergy), accidental administration of lock, thrombocytopenia, hypocalcemia, and mortality. This will be determined through direct observation, participant self-report, and from medical records.
Timepoint [6] 406079 0
From recruitment until 24 hours following study completion (device removed, patient withdrawn or up to a maximum of 3 months post-enrolment).
Secondary outcome [7] 406080 0
Health-related quality of life (HR QoL): will be measured using the EQ-5D-Y tool

Timepoint [7] 406080 0
EQ-5D-Y will be administered by study staff within 48 hours of recruitment and then again at study completion (device removed, patient withdrawn, or up to a maximum of 3 months post-enrolment).
Secondary outcome [8] 406081 0
Health-related quality of life (HR QoL): will be measured using the Australian Hospital Patient Experience Question Set (AHPEQS)
Timepoint [8] 406081 0
AHPEQS will be administered by study staff at study completion (device removed, patient withdrawn, or up to a maximum of 3 months post-enrolment).
Secondary outcome [9] 406082 0
Healthcare costs: Estimate of direct product costs, healthcare resource utilisation, and complication-associated resource use. This will be determined by observing clinical practice for the management of complications, review of medical records, and consolidated via approximation of direct costs (via hospital purchasing departments).
Timepoint [9] 406082 0
On an individual participant level, healthcare costs will be measured from recruitment until 24 hours following study completion (device removed, patient withdrawn, or up to a maximum of 3 months post-enrolment).
Secondary outcome [10] 407845 0
Mortality: will be assessed through a review of participants' medical records.
Timepoint [10] 407845 0
Outcome will be measured at 1 and again at 5 years following study completion (device removed, patient withdrawn, or up to a maximum of 3 months post-enrolment)
Secondary outcome [11] 408044 0
Serious CVAD complications: will be assessed through a review of the participant's medical record.
Timepoint [11] 408044 0
Outcome will be measured at 1 and again at 5 years following study completion (device removed, patient withdrawn, or up to a maximum of 3 months post-enrolment)
Secondary outcome [12] 434138 0
Incidental asymptomatic VTE: An asymptomatic non occlusive filling defect or occluded CVAD vessel diagnosed via ultrasound, CT, MRI or venography, which was performed for other reasons. i.e. not clinical suspicion of thrombosis or occlusion.
Timepoint [12] 434138 0
From recruitment until 24 hours following study completion (device removed, patient withdrawn or up to a maximum of 3 months post-enrolment).

Eligibility
Key inclusion criteria
Children (<18 years) with an oncological or malignant haematological condition who have a CVAD in situ (including peripherally inserted central catheters [PICCs], tunnelled (cuffed or non-cuffed) [e.g. Hickman®; Becton Dickinson, US] and totally implanted [e.g. PORT-A-CATH®; Smith Medical, US] will be eligible for inclusion.
Minimum age
0 Days
Maximum age
18 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- End-of-life pathway/measures at recruitment
- Pre-existing coagulopathic condition not related to current diagnosis or treatment (e.g. Haemophilia A and B or other factor deficiency; Immune Thrombocytopenic Purpura (ITP); Von Willebrand’s disease)
- Known allergy to heparin or T-EDTA

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)
Allocation will be concealed by central randomisation by computer.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be in a 1.5:1 ratio between the saline: T-EDTA groups, with randomly varied blocks of size 10 or 20 and stratification by: (i) health care facility; (ii) CVAD type (PICC, tunnelled CVAD, totally implanted CVAD) and (iii) duration of dwell since insertion (>= 8 weeks). Within the saline groups, there will be an even allocation to determine whether normal or heparin saline is allocated. The randomisation will be managed by Griffith Randomisation Service, which provides automated centralised randomisation for research studies, overseen by experienced statisticians, researchers, and with the support of Griffith Information Services. An automated 24-hour randomisation service will be available for investigators to use via a web portal.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Baseline characteristics for each of the groups will be descriptively presented using frequencies and percentages for categorical variables and means and standard deviations (or median and interquartile range if appropriate) for continuous variables. The primary analyses will compare between-group hazard rates of CVAD complications/100 devices and /1,000 CVAD days using Cox proportional hazards regression. Effect estimates will be presented for for T-EDTA vs combined normal and heparinised saline as hazard ratios with corresponding 95% confidence intervals. A secondary analysis will examine heparinised saline vs normal saline. Time-to-event data will be displayed graphically using Kaplan-Meier curves, and the differences between T-EDTA and Heparinised/ Normal saline compared using the log-rank test. The cause of any missing data will be assessed, and sensitivity analyses to investigate the potential impact of missingness will be undertaken using multiple imputation techniques if appropriate. Analysis will be ‘intention to treat’ with CVADs the unit of measurement. Sub-group analyses of the primary outcome will compare: totally implanted CVAD vs other CVAD; participant age (neonates/infants vs child/adolescent); past CABSI vs no past CABSI; first CVAD vs subsequent CVAD; and newly inserted CVAD vs >1 month dwell. A per-protocol analysis will assess the effect of protocol violations (i.e. administration of non-randomised catheter lock solution). For the primary outcome P-values =0.05 will be considered significant (to facilitate sequential comparisons). Analyses will be led by CI Ware (supported by statistician RA).

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/06/2022
Actual
5/09/2022
Date of last participant enrolment
Anticipated
30/04/2026
Actual
Date of last data collection
Anticipated
31/12/2030
Actual
Sample size
Target
756
Accrual to date
127
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,VIC
Recruitment hospital [1] 21679 0
Queensland Children's Hospital - South Brisbane
Recruitment hospital [2] 21680 0
Sydney Children's Hospital - Randwick
Recruitment hospital [3] 21681 0
The Royal Childrens Hospital - Parkville
Recruitment hospital [4] 21682 0
Gold Coast University Hospital - Southport
Recruitment hospital [5] 21683 0
Sunshine Coast University Hospital - Birtinya
Recruitment hospital [6] 23502 0
Monash Children’s Hospital - Clayton
Recruitment postcode(s) [1] 36722 0
4101 - South Brisbane
Recruitment postcode(s) [2] 36726 0
2031 - Randwick
Recruitment postcode(s) [3] 36727 0
3052 - Parkville
Recruitment postcode(s) [4] 36728 0
4215 - Southport
Recruitment postcode(s) [5] 36729 0
4575 - Birtinya
Recruitment postcode(s) [6] 38910 0
3168 - Clayton
Recruitment outside Australia
Country [1] 24560 0
New Zealand
State/province [1] 24560 0
Auckland

Funding & Sponsors
Funding source category [1] 310731 0
Charities/Societies/Foundations
Name [1] 310731 0
Cancer Council Queensland
Country [1] 310731 0
Australia
Primary sponsor type
University
Name
University of Queensland
Address
Cumbrae Stewart Building
72 Research Road
The University of Queensland
ST LUCIA QLD 4072
Country
Australia
Secondary sponsor category [1] 312412 0
None
Name [1] 312412 0
Address [1] 312412 0
Country [1] 312412 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310307 0
Children’s Health Queensland Hospital and Health Service Human Research Ethics Committee
Ethics committee address [1] 310307 0
Human Research Ethics Committee
Centre for Children’s Health Research
Queensland Children’s Hospital Precinct
Level 7, 62 Graham Street
South Brisbane QLD 4101
Ethics committee country [1] 310307 0
Australia
Date submitted for ethics approval [1] 310307 0
17/01/2022
Approval date [1] 310307 0
25/02/2022
Ethics approval number [1] 310307 0
HREC/22/QCHQ/81744
Ethics committee name [2] 310747 0
The University of Queensland Research Ethics and Integiry
Ethics committee address [2] 310747 0
St Lucia, QLD 4072 Australia
Ethics committee country [2] 310747 0
Australia
Date submitted for ethics approval [2] 310747 0
02/03/2022
Approval date [2] 310747 0
08/03/2022
Ethics approval number [2] 310747 0
2022/HE000196

Summary
Brief summary
Across Australia every year, children undergoing treatment for cancer experience more than 250 bloodstream infections, 70 deep vein thromboses, and 300 blockages - all caused from their central line. This central venous access device (CVAD) is vital as it administers treatments such as chemotherapy drugs and supportive therapies including blood transfusions and antibiotics, however we need to do more to prevent harm. When the CVAD is not in use, it is locked it with fluid. This fluid lock is an opportunity to prevent CVAD-associated complications. Therefore, the aim of this study is so compare the safety and effectiveness of the locking solutions KiteLock (Tetrasodium-EDTA (T-EDTA)) and heparinised saline with normal saline, which is routinely used in as part of standard care.

Who is it for?
You may be eligible for this study if you are aged younger than 18 years, have been diagnosed with an oncological or malignant haematological condition, and have a CVAD in place.

Study details
Participants will be randomised (i.e. allocated by chance) to receive either the normal saline (10ml of 0.9% sodium chloride), heparinised saline (1-2ml of sodium heparin 10units/ml or 100units/ml depending on the device and standard operating procedures), or KiteLock (1-2ml of 4% T-EDTA) administered into the lumen of the CVAD. The solution will be administered at a frequency based on clinical requirement (i.e. if the CVAD is de-accessed), plus during routine management procedures (e.g. needleless connector changes, totally implanted device needling, line cares) with a maximum of one dose per 24 hours. This will continue until the device is removed, the participant withdraws from the study, for up to a maximum of 3 months post-enrolment. Throughout this study period, participants may be assessed by their treating clinicians for bloodstream infections using blood cultures, for CVAD-associated thrombosis (i.e. blood clots) with ultrasound or venography, for blockages of the CVAD with a test of injection and/or aspiration catheter occlusion, and for CVAD failure requiring removal. Participants will also be monitored for any adverse events, with a research nurse contacting them twice weekly across the study period. A questionnaire assessing health-related quality of life will be given to participants at the trial commencement and completion. Participants will additionally be followed up at 1 and 5 years after study completion (using medical records only) to assess for any serious CVAD complications, and for any cause of death.

It is hoped that this study may help to identify the locking solution with the least complications and adverse effects, in order to prevent harm in children with a CVAD undergoing treatment for cancer.
Trial website
https://nmsw.uq.edu.au/research/paediatric-nursing-and-patient-safety/preventing-adverse-events-during-paediatric-cancer-treatment-multi-site-hybrid-randomised-controlled-trial
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 117202 0
Prof Amanda Ullman
Address 117202 0
Level 7, Centre for Children's Health Research, 62 Graham St, South Brisbane QLD 4101
Country 117202 0
Australia
Phone 117202 0
+61730697238
Fax 117202 0
Email 117202 0
[email protected]
Contact person for public queries
Name 117203 0
Prof Amanda Ullman
Address 117203 0
Level 7, Centre for Children's Health Research, 62 Graham St, South Brisbane QLD 4101
Country 117203 0
Australia
Phone 117203 0
+61730697238
Fax 117203 0
Email 117203 0
[email protected]
Contact person for scientific queries
Name 117204 0
Prof Amanda Ullman
Address 117204 0
Level 7, Centre for Children's Health Research, 62 Graham St, South Brisbane QLD 4101
Country 117204 0
Australia
Phone 117204 0
+61730697238
Fax 117204 0
Email 117204 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Data will only be available to the site staff and project manager unless required by legislative or regulatory agencies and the HRECs.


What supporting documents are/will be available?

No Supporting Document Provided



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.