Clinical Trial Results:
Evaluation of Treosulfan pharmacokinetics (PK) in children undergoing allogeneic haematopoietic stem cell transplantation (HSCT)
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Summary
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EudraCT number |
2013-003257-20 |
Trial protocol |
GB |
Global end of trial date |
15 Dec 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
01 Mar 2022
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First version publication date |
01 Mar 2022
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
10MI28
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02048800 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Great Ormond Street Hospital for Children
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Sponsor organisation address |
Great Ormond Street , London, United Kingdom, WC1 3JH
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Public contact |
research.governance@gosh.nhs.uk, Great Ormond Street Hospital for Children NHS FOundation Trust Bone Marrow Transplant Unit , 0044 02074059200 , research.governance@gosh.nhs.uk
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Scientific contact |
Dr. Robert Chiesa, Great Ormond Street Hospital for Children NHS FOundation Trust Bone Marrow Transplant Unit , 0044 02074059200 , robert.chiesa@gosh.nhs.uk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
06 May 2019
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
15 Dec 2017
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
This study aims to describe Treosulfan PK in children and infants undergoing allogeneic stem cell transplantation and to determine if this is a significant variable in determining transplant outcome.
The primary objective of the study is to assess PK parameters after Treosulfan infusion in children prior to allogeneic haematopoietic stem cell transplantation.
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Protection of trial subjects |
In conducting the trial, the Sponsor and sites shall comply with all laws and statutes, as amended from time to time, applicable to the performance of clinical trials including, but not limited to:
• the principles of ICH Harmonised Tripartite Guideline for Good Clinical Practice (CPMP/ICH/135/95) as set out in Schedule 1 (Conditions and Principles of Good Clinical Practice and for the Protection of Clinical Trial Subjects) of the Medicines for Human Use (Clinical Trials) Regulations 2004 and the GCP Directive 2005/28/EC, as set out in SI 2006/1928
• the Human Rights Act 1998
• the Data Protection Act 1998
• the Freedom of Information Act 2000
• the Human Tissue Act 2004
• the Medicines Act 1968
• the Medicines for Human Use (Clinical Trials) UK Regulations SI 2004/1031, and subsequent amendments
• Good Manufacturing Practice
• the Research Governance Framework for Health and Social Care, issued by the UK Department of Health (Second Edition 2005) or the Scottish Health Department Research Governance Framework for Health and Community Care (Second Edition 2006)
The trial will be conducted in accordance with the World Medical Association Declaration of Helsinki entitled ‘Ethical Principles for Medical Research Involving Human Subjects’ (1996 version), ICH Good Clinical Practice Guidelines and in accordance with the terms and conditions of the ethical approval given to the trial. The trial has received a favourable opinion from the Research Ethics Committee. CI has submitted Annual Progress Reports to the REC, which will commence one year from the date of ethical approval for the trial.
All subjects/guardians were provided informed consent prior to entering the study . The investigator was responsible for explaining the benefits and risk of the participation in the study to each subject's legal representative for obtaining informed consent.
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Background therapy |
Treosulfan is a busulfan analogue with a different mechanism of action and is widely used in the allo-HSCT setting. Whilst busulfan is a direct DNA alkylating agent, treosulfan is a prodrug with alkylating activity mediated by its main epoxybutane derivatives requiring a pH and temperature-dependent non-enzymatic two-step process to form first the mono and then diepoxide. Since the first report of treosulfan-based conditioning in paediatric allo-HSCT in 2002, this drug has been increasingly used off-label in children, largely due to a perceived wide therapeutic index and a lower propensity to cause hepatotoxicity (in particular veno-occlusive disease) than busulfan. The aim of this study was to characterise the PKPD profile of treosulfan in children undergoing allo-HSCT in an investigator-initiated, multicentre phase II clinical trial. | ||
Evidence for comparator |
N/A | ||
Actual start date of recruitment |
08 Sep 2014
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 60
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Worldwide total number of subjects |
60
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EEA total number of subjects |
60
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
34
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Children (2-11 years) |
21
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Adolescents (12-17 years) |
5
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
The study was conducted at 2 centres in the UK between September 2014 and December 2017. Children with an indication to HSCT and treatment with Treosulfan were screened for possible enrollment into this PK study. | ||||||||||||
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Pre-assignment
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Screening details |
There are total 60 subjects screened in this study however only 57 subjects enrolled in to this study. The total number comprise from two sites in the UK. | ||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||
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Arms
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Arm title
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Infusion of Treosulfan within condition regimen | ||||||||||||
Arm description |
Treosulfan is infused intravenously over 2 hours three days on day -7, -6 and -5 pre Hemopoietic Stem cell transplant. Also Fudarabine is administered 30mg/m2/day for 5 days on day -7 to -3 as part of conditioning regimen. | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Treosulfan
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Investigational medicinal product code |
l01AB02
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Other name |
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Pharmaceutical forms |
Injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Treosulfan given at a total dose of 30-42 gm/m2 over three days. The dosage is based on age. Infants <3 months was dosed at 10 gm/m2, children ag3-12 months were dosed at 12gm/m2 and children over 12 months dosed at 14 gm/m2.
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Baseline characteristics reporting groups
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Reporting group title |
Overall Study
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Reporting group description |
- | ||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Overall analysis
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||
Subject analysis set description |
The primary end point was to measure Treosulfan PK and the secondary endpoint was to assess its short term toxicity, graft failure and mortality.
Furthermore measures and models of efficacy (engraftment) and toxicity will be tested against PK parameters to ascertain dose/concentration-response relationships. These comparisons will be done by comparing the x2 distributed objective function value (OFV) between nested models, with the addition of one parameter giving a drop in OFV of 3.84 at a significance level of p <0.05.
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End points reporting groups
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Reporting group title |
Infusion of Treosulfan within condition regimen
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Reporting group description |
Treosulfan is infused intravenously over 2 hours three days on day -7, -6 and -5 pre Hemopoietic Stem cell transplant. Also Fudarabine is administered 30mg/m2/day for 5 days on day -7 to -3 as part of conditioning regimen. | ||
Subject analysis set title |
Overall analysis
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
The primary end point was to measure Treosulfan PK and the secondary endpoint was to assess its short term toxicity, graft failure and mortality.
Furthermore measures and models of efficacy (engraftment) and toxicity will be tested against PK parameters to ascertain dose/concentration-response relationships. These comparisons will be done by comparing the x2 distributed objective function value (OFV) between nested models, with the addition of one parameter giving a drop in OFV of 3.84 at a significance level of p <0.05.
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End point title |
Assess the Area Under the Curve (AUC) 0-∞, steady-state volume of distribution and clearance of Treosulfan [1] | ||||||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Assess the Area Under the Curve (AUC) 0-∞, steady-state volume of distribution and clearance of Treosulfan
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis of of end point is not mandatory field. This is a single arm study and no comparison group available. |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Assess the incidence of grade III-IV adverse events (NCI common toxicity criteria, version 4.0) within the first 30 days after transplant; | ||||||||||||||||||||||||||||||||||||
End point description |
Safety enpoints - Assess the incidence of grade III-IV adverse events (NCI common toxicity criteria, version 4.0) within the first 30 days after transplant;
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End point type |
Secondary
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End point timeframe |
30 days
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||
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End point title |
Assess transplant related mortality at 100 days after transplant | ||||||||||
End point description |
Safety endpoint - assess transplant related mortality at 100 days after transplant;
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End point type |
Secondary
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End point timeframe |
100 days after transplant
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| Notes [2] - One patient died after the conditioning regimen, but prior to the transplant. |
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| No statistical analyses for this end point | |||||||||||
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End point title |
Assess cumulative incidence and severity of acute GvHD. | ||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
End of study assessment of acute and chronic GVHD
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Assess the timing of neutrophil and platelet recovery; | ||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
First month post-BMT
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| No statistical analyses for this end point | |||||||||||
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End point title |
Assess donor engraftment after transplant | ||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Assess myeloid and T-cell engrfatment after transplant.
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| No statistical analyses for this end point | |||||||||||
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End point title |
Assess overall survival and disease-free survival at 1 year post transplant. | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
1 year post transplant
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| No statistical analyses for this end point | |||||||||
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End point title |
Overall | |||||||||
End point description |
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End point type |
Other pre-specified
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End point timeframe |
30 days
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| No statistical analyses for this end point | ||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
AEs and SAEs were recorded after Treosulfan administration (day – 7). Documentation started at the time of first Treosulfan administration and up to 100 days after last Treosulfan administration.
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Adverse event reporting additional description |
After the end of this documentation period, patients safety was monitored by the respective transplant treatment protocol. AEs are to be documented after each sampling period giving the highest CTCAE grade within the reporting period.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
19
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Reporting groups
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Reporting group title |
overall trial
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Reporting group description |
Single cohort of children and infants aged 28 days-16 years old receiving Treosulfan as part of their conditioning regimen prior to HSCT. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 4% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
