Trial Review

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Trial registered on ANZCTR


Registration number
Help: Registration number
ACTRN12626000610336
Ethics application status
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Approved
Date submitted
Help: Date submitted
3/04/2025
Date registered
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18/05/2026
Date last updated
Help: Date last updated
18/05/2026
Date data sharing statement initially provided
Help: Data sharing statement date
18/05/2026
Type of registration
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Prospectively registered

Titles & IDs
Public title
Precision Dosing of Busulfan in Children Undergoing haematopoietic stem-cell transplantation (HSCT)- A randomised controlled study to investigate the impact and feasibility of implementing pharmacogenomics into the busulfan dosing method for children undergoing haematopoietic stem-cell transplantation on target exposure attainment following dose 1.
Scientific title
Implementing pharmacogenetics in the busulfan dosing method for children undergoing hematopoietic stem-cell transplantation: a prospective, multicentric, randomized clinical trial investigating the impact on busulfan exposure attainment and feasibility of implementation of pharmacogenomic testing .
Additional trial identifiers [1] 314123 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Related trial records

Health condition
Health condition(s) studied:
Haematopoietic Stem Cell Transplant 336928 0
Condition category
Condition code
Cancer 333394 333394 0 0
Children's - Other
Blood 333395 333395 0 0
Haematological diseases

Intervention/exposure
Study type
Interventional
Description of the intervention or exposure
This study is designed as a prospective international multicentre randomised superiority clinical trial. Paediatric patients aged 0-18 years undergoing Haematopoietic Stem Cell Transplantation (HSCT) with a Busulfan (Bu)-based conditioning regimen will be randomly assigned to one of two groups. The experimental group will receive Bu dosing based on the pharmacogenetics (PG)-based personalised model. Participants will be randomly assigned (1:1 ratio, stratified by conditioning regimen - the presence of fludarabine) to receive their first dose of busulfan according to:

1) the most performing method based on age and weight - McCune's model (control arm)

2) a method that also considers a pharmacogenetic factor (variants occurring in the promoter region of the GSTA1 gene) in association with the co-administered chemotherapeutic agent fludarabine in the dose personalization (experimental arm) as per publication [Hassine K et al. 2024, Pharmacokinetic modeling and simulation with pharmacogenetic insights support the relevance of therapeutic drug monitoring for myeloablative busulfan dosing in adult HSCT, Transplantation and Cellular Therapy, Vol 30, Issue 3, P332, DOI: 10.1016/j.jtct.2023.12.003]

Busulfan will be given as an intravenous infusion over a 96hour time period and can be administered either every six hours for 16 doses, every 12 hours for 8 doses or every 24 hours for 4 doses.

A blood test or buccal swab is required a few weeks prior to the scheduled transplant for genotype testing which will be undertaken for Australian patients at Pathology Queensland. Sampling for busulfan plasma concentrations will be performed at several time points following the first dose and then according to standard clinical practice at the centre. Samples will be tested at local laboratories according to standard practice.

The pharmacogenomic test result will be sent to a centralised service for interpretation and randomisation will occur. The centralised service will then provide the dose for initial dosing calculated for the individual according to the arm of the study.

As the outcome linked to the main aim of this study is PK, the use of any drug with relevant drug-drug interaction with Bu during the days of administration of Bu up to 24h after the end of the last dose. Whenever those drugs can be stopped or replaced, a wash-out time is required prior to the first infusion of Bu. Appendix 6 contains the list of the drugs considered as presenting a relevant interaction with Bu in this study and the respective minimal wash-out time required.

The child receiving treatment will be in hospital during busulfan administration as per standard of care for a paediatric patient undergoing stem cell transplant.
Intervention code [1] 330703 0
Treatment: Other
Description of the comparator or control
The control group will receive busulfan dosing according
to the traditional McCune model (does not account for genetic factors).
McCune JS et al. 2014, Busulfan in infant to adult hematopoietic cell transplant recipients: a population pharmacokinetic model for initial and bayesian dose personalisation, Clin Cancer Res. 1;20(3):754-63, doi: 10.1158/1078-0432.CCR-13-1960.
Control group
Active

Outcomes
Primary outcome [1] 340972 0
The primary outcome measure will be the proportion of first doses that achieve the therapeutic target exposure as measured by area under the concentration vs time curve (AUC) from start of infusion until next dose is due.
Timepoint [1] 340972 0
Achieving target following dose 1 will be assessed only following dose 1 has been administered. The target is defined as +/-20% deviation based on the prescribed AUC.
Secondary outcome [1] 445651 0
Feasability of performing genotyping prior to transplant to deliver personalised doses within the optimal delivery time.
Timepoint [1] 445651 0
The assessment for the secondary aim will be at the time of transplant conditioning starting. Feasibility will be determined successful if the genotype testing results are available at the time required as per the study.
Secondary outcome [2] 445652 0
Transplant Related Toxicities including sinusoidal obstructive syndrome (SOS), acute graft vs host disease (aGVHD)
Timepoint [2] 445652 0
30 days, 100days and 365 days post transplant
Secondary outcome [3] 455512 0
Incidence of graft failure
Timepoint [3] 455512 0
30 days, 100days and 365 days post transplant
Secondary outcome [4] 459568 0
Incidence of relapse
Timepoint [4] 459568 0
30 days, 100days and 365 days post transplant
Secondary outcome [5] 459569 0
Incidence of death post transplant
Timepoint [5] 459569 0
Date of death reported.

Eligibility
Key inclusion criteria
Patients must be aged from 0–18 years old on entry to the study;
• Clinical indication of allogeneic or autologous hematopoietic stem cell transplantation;
• The conditioning protocol must include IV Bu formulations, Busulfex® (Otsuka Pharmaceutical), Busilvex® (Pierre Fabre Pharma) or other EMA or FDA approved generic formulations regardless of the administration schedule (q6h, q12h, or q24h)
• The expected length of time from recruitment to starting the conditioning regimen must be superior to 10 days;
• Informed written consent to participate in the study signed by the participant/parent
Minimum age
0 Years
Maximum age
18 Years
Sex
Both males and females
Healthy volunteers
No
Key exclusion criteria
- Inadequate access for blood sampling
- Confirmed pregnancy or refusal from the participant in guaranteeing an effective contraceptive method during the study.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation involves contacting the holder of the allocation schedule who is at central administration site.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomization will be done centrally and subjects will be randomly allocated to one of the intervention groups in a 1:1 ratio, using permuted block randomization. The randomization will be stratified by conditioning regimen into two categories based on the presence of Flu along with Bu.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Proportion of patients achieving the target AUC as well as those presenting a low or a high AUC after the first dose calculated by one of the arms of the study will be reported as percentages with the respective 95% CI. PG-based personalized doses will be compared with the results obtained with the control arm by using Pearson’s Chi-square test or Fisher’s exact test.
Dose adjustments will be expressed in percentage based on the first dose, as described above, with the respective 95% CI. Differences will be analyzed by using Student’s t-test or Mann-Whitney depending upon the distribution of the results.
Error indexes, AE% and ME%, will be expressed in percentage with the respective 95% CI. A graphical analysis of the AE% distribution will complement the evaluation of the prediction analysis.
Descriptive statistics will be used to assess the clinical applicability of the PG-based model by reporting the respective median delay in days between the collection of the DNA sample and the delivery of the personalized first dose of Bu. Respective interquartile range (IQR) will be reported as a non-normal distribution is expected. Following the determination of the optimal delay cut-off at 12 months of recruitment, the proportion of the “on-time” personalized first dose deliveries will be reported as a proportion with its respective 95% CI considering the binomial proportion distribution.
The clinical situations of interest will be analyzed as a time-to-event by using Kaplan Meier methods. Log rank tests will be used to compare their incidences between GSTA1-diplotype groups, Bu dosing schedule and method to determine de first dose. HRs and 95% CI will be derived. Relapse will be analyzed using cumulative incidence curves and the comparisons between categories of the dependent variables be made using Grey’s competitive risk test by using death as a competitive risk. Rate ratios and 95% CI will be presented. Chi-square tests will be used to assess the differences for all categorical variables and t-tests or Mann Whitney tests will be applied for continuous measures as appropriate. Multivariate analysis will be performed by including the factors revealing significant in univariate analysis through Cox regression or Grey’s test.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/07/2026
Actual
Date of last participant enrolment
Anticipated
1/07/2029
Actual
Date of last data collection
Anticipated
1/07/2030
Actual
Sample size
Target
25
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment outside Australia
Country [1] 26935 0
New Zealand
State/province [1] 26935 0
Country [2] 26936 0
Canada
State/province [2] 26936 0
Country [3] 26937 0
Denmark
State/province [3] 26937 0
Country [4] 26938 0
France
State/province [4] 26938 0
Country [5] 26939 0
Italy
State/province [5] 26939 0
Country [6] 26942 0
Saudi Arabia
State/province [6] 26942 0
Country [7] 26943 0
Switzerland
State/province [7] 26943 0
Country [8] 26944 0
United Kingdom
State/province [8] 26944 0

Funding & Sponsors
Funding source category [1] 318631 0
Charities/Societies/Foundations
Name [1] 318631 0
University Hospitals of Geneva (HUG)
Country [1] 318631 0
Switzerland
Primary sponsor type
Individual
Name
Prof. Marc Ansari, Geneva University Hospitals
Address
Country
Switzerland
Secondary sponsor category [1] 323353 0
None
Name [1] 323353 0
Address [1] 323353 0
Country [1] 323353 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 317236 0
Children’s Health Queensland Hospital and Health Service Human Research Ethics Committee
Ethics committee address [1] 317236 0
Ethics committee country [1] 317236 0
Australia
Date submitted for ethics approval [1] 317236 0
14/04/2025
Approval date [1] 317236 0
21/05/2025
Ethics approval number [1] 317236 0
HREC/25/QCHQ/111766

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

Contacts
Principal investigator
Name 140430 0
Dr Rachael Lawson
Address 140430 0
Queensland Childrens Hospital, 501 Stanley Street, South Brisbane 4101
Country 140430 0
Australia
Phone 140430 0
+617 3068 1924
Fax 140430 0
Email 140430 0
[email protected]
Contact person for public queries
Name 140431 0
Rachael Lawson
Address 140431 0
Queensland Childrens Hospital, 501 Stanley Street, South Brisbane 4101
Country 140431 0
Australia
Phone 140431 0
+617 3068 1924
Fax 140431 0
Email 140431 0
[email protected]
Contact person for scientific queries
Name 140432 0
Rachael Lawson
Address 140432 0
Queensland Childrens Hospital, 501 Stanley Street, South Brisbane 4101
Country 140432 0
Australia
Phone 140432 0
+617 3068 1924
Fax 140432 0
Email 140432 0
[email protected]

Data sharing statement
Will the study consider sharing individual participant data?
No


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.