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Trial registered on ANZCTR


Registration number
ACTRN12616000709448
Ethics application status
Approved
Date submitted
17/05/2016
Date registered
27/05/2016
Date last updated
16/05/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Investigation of endothelial toxicity after allogeneic haematopoietic stem cell transplantation
Scientific title
Investigation of endothelial toxicity after allogeneic haematopoietic stem cell transplantation
Secondary ID [1] 289241 0
nil
Universal Trial Number (UTN)
Trial acronym
Endotox
Linked study record

Health condition
Health condition(s) or problem(s) studied:
toxicity of allogeneic haemopoietic cell transplant regimens 298813 0
Condition category
Condition code
Blood 298868 298868 0 0
Haematological diseases

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
Blood samples will be taken from recipients immediately prior to commencement of the conditioning regimen, on the day of transplantation, and on post-transplant days 7, 14 and 21. In addition, for the subset of patients receiving busulphan, a total of 8 additional samples will be taken on days 1 (6 samples), 3 (1 sample) and 4(1 sample) of busulphan dosing.
Myeloablative allogeneic stem cell transplantation will be performed according to standard institutional care and will include the following:
1. Conditioning regimen. Either cyclophosphamide (60mg/kg IV for 2 days) and busuphan (1mg/kg PO for 4 days); cyclophosphamide (60mg/kg IV for 2 days) and total body irradiation (total 12 Gray over 3 days); or fludarabine (30mg/m^2 IV for 5 days) and melphalan (140mg/m^2 for 1 day).
2. Infusion of allogeneic stem cells (matched sibling donor, matched unrelated donor, mismatched unrelated adult or cord blood donor)
3. Graft versus host disease prophylaxis (methotrexate 15mg/m^2 IV on day +1, 10mg/m^2 IV on days +3, +6 and +11) and cyclopsporine (commence day -1 at 1.5mg/kg IV twice daily).
4. Antimicrobial prophylaxis per institutional guideline
Intervention code [1] 294780 0
Diagnosis / Prognosis
Comparator / control treatment
Pre-treatment clinical status and blood samples will be the control
Control group
Uncontrolled

Outcomes
Primary outcome [1] 298338 0
To characterise, by serum assay, the changes occurring in the fibrinolytic systems associated with endothelial toxicity occurring after allogeneic HSCT
Timepoint [1] 298338 0
day of transplant and post transplant days 7, 14, and 21
Secondary outcome [1] 323894 0
To determine, via the prospective collection of clinical information, the incidences of clinical syndromes involving endothelial toxicity after allogeneic HSCT, including TA-TMA, SOS, IPS and early aGVHD.
Timepoint [1] 323894 0
Participants will be monitored daily for the development of these complications from the start of conditioning regimen until day 28 post transplantation
Secondary outcome [2] 324010 0
To determine, using serum assays, whether pre-existing laboratory evidence of complement abnormalities or hypofibrinolysis exists in individuals about to undergo allogeneic HSCT, and whether these correlate with the development of clinical complications (TA-TMA, SOS, IPS and early aGVHD).
Timepoint [2] 324010 0
At hospital admission (prior to commencing conditioning regimen) and daily until post-transplant day 28.
Secondary outcome [3] 324011 0
To determine whether complement activation occuring after allogeneic HSCT, as assessed by serum assay, differs significantly between recipients of TBI-based, busulphan-based, and reduced intensity conditioning regimens.
Timepoint [3] 324011 0
Day of transplant and post-transplant days 7, 14 and 21.
Secondary outcome [4] 324012 0
In recipients of conditioning regimens which include busulphan, to determine whether busulfan exposure is associated with laboratory markers of endothelial toxicity (von Willebrand factor, plasminogen activator inhibitor-1 [PAI-1], schistocytes, platelet microparticles), .
Timepoint [4] 324012 0
Day of transplant and post-transplant days 7, 14 and 21.
Secondary outcome [5] 324097 0
To determine whether hypofibrinolysis occuring after allogeneic HSCT, as assessed by serum assay, differs significantly between recipients of TBI-based, busulphan-based, and reduced intensity conditioning regimens.
Timepoint [5] 324097 0
Day of transplant and post-transplant days 7, 14 and 21.
Secondary outcome [6] 324099 0
In recipients of conditioning regimens which include busulphan, to determine whether busulfan exposure is associated with laboratory markers of hypercoagulability (overall haemostatic potential [OHP] assay, thrombin activatable fibrinolysis inhibitor [TAFI], callibrated antithrombin time [CAT]).
Timepoint [6] 324099 0
Day of transplant and post-transplant days 7, 14 and 21.

Eligibility
Key inclusion criteria
1. Completed work-up and planned to proceed with allogeneic HSCT at Fiona Stanley Hospital
2. Has had sufficient work-up to enable haematopoietic cell transplantation-specific comorbidity index (HCT-CI) to be calculated (minimum: history and examination, lung function studies, assessment of cardiac ejection fraction)
3. Will receive one of the following conditioning regimens: busulfan + cyclophosphamide, TBI + cyclophosphamide or fludarabine + melphalan
4. Will receive GVHD prophylaxis with a calcineurin inhibitor (cyclosporine or tacrolimus) and short course methotrexate, with or without ATG
5. Provides informed consent to participate in the study
Minimum age
16 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Incomplete pre-transplant work-up (see inclusion criteria 2 above)
2. Will receive a conditioning regimen or GVHD prophylaxis regimen other than those specified in the inclusion criteria

Study design
Purpose
Natural history
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
Formal sample size calculation was not performed for this observational, non-intervention study..

Baseline and longitudinal laboratory assays of endothelial toxicity, coagulation and fibrinolysis will be summarised using standard descriptive statistics. The association between markers of endothelial toxicity and coagulation and fibrinolysis over time will be investigated separately using simple regression analysis.

The cumulative incidences of TMA, SOS, IPS and early aGVHD at post-transplant day 28 will be calculated using death prior to day 60 (without TMA/SOS) as a competing risk. The influence of pre-transplant markers of endothelial toxicity and hypercoagulability on the clinical endpoints above will be measured using the method of Fine and Grey (univariate analysis). Recipient characteristics including liver function, pulmonary function, age, disease status and conditioning regimen will be also be examined on univariate analysis. Multivariate analysis will be performed by Cox regression and will include variables with p = 0.1 on univariate analysis.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
30/06/2016
Actual
4/07/2016
Date of last participant enrolment
Anticipated
31/12/2017
Actual
6/12/2016
Date of last data collection
Anticipated
Actual
2/02/2017
Sample size
Target
30
Accrual to date
Final
31
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 5807 0
Fiona Stanley Hospital - Murdoch
Recruitment postcode(s) [1] 13249 0
6150 - Murdoch

Funding & Sponsors
Funding source category [1] 293617 0
Charities/Societies/Foundations
Name [1] 293617 0
WA Cancer and Palliative Care Network
Country [1] 293617 0
Australia
Primary sponsor type
Hospital
Name
Fiona Stanley Hospital
Address
11 Robin Warren Drive, Murdoch WA 6150
Country
Australia
Secondary sponsor category [1] 292438 0
University
Name [1] 292438 0
University of Western Australia
Address [1] 292438 0
35 Stirling Hwy, Nedlands, Western Australia 6009
Country [1] 292438 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295057 0
Royal Perth Hospital
Ethics committee address [1] 295057 0
Royal Perth Hospital
Wellington St, Perth, WA 6000
Ethics committee country [1] 295057 0
Australia
Date submitted for ethics approval [1] 295057 0
25/11/2015
Approval date [1] 295057 0
11/02/2016
Ethics approval number [1] 295057 0
15-187

Summary
Brief summary
The application of allogeneic haematopoietic stem cell transplantation (HSCT) is hampered by procedure-related morbidity and mortality, including transplant-associated thrombotic microangiopathy (TA-TMA), sinusoidal obstructive syndrome of the liver (SOS), idiopathic pneumonia syndrome (IPS) and acute graft vs host disease (aGVHD). While the aetiology of many of these conditions is not known, it has been postulated that endothelial toxicity related to the chemotherapy conditioning is an early event common to all of them. We hypothesise that endothelial toxicity is associated with complement dysregulation, and leads to a prothrombotic state with impaired fibrinolysis, which manifest as the clinical complications listed above.

In this study, we aim to document laboratory evidence of changes in coagulation and fibrinolytic potential occurring after allogeneic HSCT, and to correlate this with prospectively identified clinical and laboratory manifestations of endothelial toxicity. A total of 30 participants will be recruited, of which a minimum of 15 will have received the busulfan / cyclophosphamide regimen. Blood samples will be taken from recipients immediately prior to commencement of the conditioning regimen, on the day of transplantation, and on post-transplant days 7, 14 and 21. Additional blood samples will be taken for therapeutic dose monitoring from recipients of busulfan conditioning. Diagnoses of TA-TMA, SOS, IPS and aGVHD occurring up to post-transplant day 28 will be made according to specified criteria using diagnostic information collected as part of standard care.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 65934 0
Dr Duncan Purtill
Address 65934 0
Fiona Stanley Hospital, 11 Robin Warren Drive, Murdoch, WA 6150
Country 65934 0
Australia
Phone 65934 0
+61 8 6152 3788
Fax 65934 0
+61 8 6152 8049
Email 65934 0
[email protected]
Contact person for public queries
Name 65935 0
Duncan Purtill
Address 65935 0
Fiona Stanley Hospital, 11 Robin Warren Drive, Murdoch, WA 6150
Country 65935 0
Australia
Phone 65935 0
+61 8 6152 3788
Fax 65935 0
+61 8 6152 8049
Email 65935 0
[email protected]
Contact person for scientific queries
Name 65936 0
Duncan Purtill
Address 65936 0
Fiona Stanley Hospital, 11 Robin Warren Drive, Murdoch, WA 6150
Country 65936 0
Australia
Phone 65936 0
+61 8 6152 3788
Fax 65936 0
+61 8 6152 8049
Email 65936 0
[email protected]

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