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Trial registered on ANZCTR


Registration number
ACTRN12609000173291
Ethics application status
Approved
Date submitted
26/03/2009
Date registered
15/04/2009
Date last updated
6/07/2012
Type of registration
Retrospectively registered

Titles & IDs
Public title
A Phase II Study of the Impact of Two Different Schedules of Thymoglobulin on the Incidence of Extensive Chronic Graft Verus Host Disease (GVHD) in Patients Undergoing Unrelated Donor or Mismatched Related Donor Stem Cell Transplantation
Scientific title
A Phase II Study of the Impact of Two Different Schedules of Thymoglobulin on the Incidence of Extensive Chronic Graft Versus Host Disease (GVHD) in Undergoing Unrelated Donor or Mismatched Related Donor Stem Cell Transplantation for Haematological Malignancy
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Graft versus Host Disease in Haematology Malignancy Patients receiving donor stem cell transplantation 4529 0
Condition category
Condition code
Cancer 4817 4817 0 0
Other cancer types

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Thymoglobulin - 2 different schedules:
Canadian patients will receive:
0.5mg/kg day -2
2mg/kg day -1
2mg/kg day 0 before graft infusion

Australian patients will receive the same dose and schedule of Thymoglobulin except the doses will be given on day -3, day -2 and day -1 respectively.
Thymoglobulin will be given as a continuous IV infusion over 4-8 hrs
Intervention code [1] 4288 0
Treatment: Drugs
Comparator / control treatment
The comparison group will consist of historical `controls' who had a peripheral blood stem cell (PBSC) unrelated donor transplant at Royal Melbourne Hospital (RMH) from 2000-2006. Historical controls of patients did not receive Thymoglobulin (or any form of T cell depletion), but are otherwise comparable for other transplant characteristics. At RMH we have an extensive data set on these patients including all information proposed to be collected in the prospective study group
Control group
Historical

Outcomes
Primary outcome [1] 5676 0
To compare the incidence of extensive chronic GVHD at one and two years in patients receiving Thymoglobulin prophylaxis, with historical controls of patients who did not receive Thymoglobulin (or any form of T cell depletion), but who are otherwise comparable for other transplant characteristics. For this purpose patients receiving the two different Thymoglobulin schedules will be analysed together. Grading of acute GVHD will be done according to Glucksberg/Seattle criteria. The scoring system from Filipovich (BBMT 2005) will be used to grade the severity of chronic GVHD.
Timepoint [1] 5676 0
1 and 2 years after study opening
Primary outcome [2] 5677 0
To evaluate the relationship between rabbit IgG levels at the time of stem cell infusion and GVHD outcome. This will be using an assay on a blood sample.
Timepoint [2] 5677 0
1 and 2 years after study opening
Secondary outcome [1] 241570 0
To compare the incidence between the two groups (thymoglobulin vs no thymoglobulin) of cytomegalovirus (CMV)reactivation and disease. Patients will undergo weekly molecular monitoring for CMV reactivation at least until day 100. Patients with histological evidence of organ infection with CMV will be regarded as having CMV disease
Timepoint [1] 241570 0
Weekly until at least day 100
Secondary outcome [2] 241572 0
To describe the effect of Thymoglobulin prophylaxis on various immunological parameters using blood tests. To determine the counts of the following mononuclear cell subsets:
B cells, CD4 T cells, CD8 T cells, Regulatory T cells, NKT cells, NK cells, Monocytes, Dendritic cells and HLADR high
Timepoint [2] 241572 0
1 and 2 years after study opening
Secondary outcome [3] 241641 0
To compare the incidence of extensive chronic GVHD between the two different thymoglobulin schedules. Grading of acute GVHD will be done according to Glucksberg/Seattle criteria. The scoring system from Filipovich (BBMT 2005) will be used to grade the severity of chronic GVHD.
Timepoint [3] 241641 0
1 and 2 years after study opening
Secondary outcome [4] 241642 0
To compare the incidence of acute GVHD grades II-IV and III-IV between the two groups (thymoglobulin vs no thymoglobulin). Grading of acute GVHD will be done according to Glucksberg/Seattle criteria.
Timepoint [4] 241642 0
1 and 2 years after study opening
Secondary outcome [5] 241643 0
To compare the incidence between the two groups (thymoglobulin vs no thymoglobulin) of Epstein-Barr Virus (EBV) reactivation (detectability in plasma by polymerase chain reaction (PCR)) and post-transplant lymphoproliferative disorder (PTLD). This will be measured by Computed tomography (CT) scan and or a biopsy and EBV PCR.
Timepoint [5] 241643 0
1 and 2 years after study opening
Secondary outcome [6] 241644 0
To compare the incidence between the two groups (thymoglobulin vs no thymoglobulin) of other infections including clinical (microbiologically undocumented) infections and definite (microbiologically documented) infections
Timepoint [6] 241644 0
1 and 2 years after study opening
Secondary outcome [7] 241645 0
To compare the incidence between the two groups (thymoglobulin vs no thymoglobulin) of relapse in patients with standard risk and advanced disease. Relapse will be diagnosed by blood tests, Bone Marrow biopsy or Computed tomography (CT) scans as appropriate.
Timepoint [7] 241645 0
1 and 2 years after study opening
Secondary outcome [8] 241646 0
To compare the incidence between the two groups (thymoglobulin vs no thymoglobulin) of treatment-related mortality (TRM) and overall and disease-free survival. Disease-free survival is defined as survival without recurrence of the underlying disease.
Timepoint [8] 241646 0
1 and 2 years after study opening
Secondary outcome [9] 241648 0
To compare the incidence of moderate/severe chronic GVHD between the two different thymoglobulin schedules. Moderate chronic GVHD involves (1) at least one organ or site with clinically significant but no major disability (maximum score of 2 in any affected organ or site) or (2) three or more organs or sites with no clinically significant functional impairment (maximum score of 1 in all affected organs or sites). A lung score of 1 will also be considered moderate chronic GVHD. Severe chronic GVHD indicates major disability caused by chronic GVHD (score of 3 in any organ or site). A lung score of 2 or greater will also be considered severe chronic GVHD
Timepoint [9] 241648 0
1 and 2 years after study opening

Eligibility
Key inclusion criteria
1.age > 18 years
2.undergoing an unrelated or mismatched related peripheral blood stem cell (PBSC) allograft
3.no contra-indication to receiving Thymoglobulin
4.life expectancy >3 months
5.absence of active invasive fungal infection at the time of transplant
6.myeloablative conditioning (including cy/TBI, VP16/TBI fludarabine-melphalan >120mg/m2, fludarabine-busulphan at a dose at least equivalent to 3.2mg/kg intravenous (IV) per day for 4 days and by-cy. IV busulphan will be used, given as a single daily dose of 3.2mg/kg at a rate of 80mg/hr. Monitoring, if available, will be done to conform with local guidelines
Minimum age
18 Years
Maximum age
80 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1.active invasive fungal infection at the time of transplant
2.contra-indication to receiving Thymoglobulin
3.Pregnancy

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
In Australia all patients will be on one scedule. In Canada patients will be on a different schedule
Phase
Phase 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
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)
Recruitment outside Australia
Country [1] 1699 0
Canada
State/province [1] 1699 0
Calgary

Funding & Sponsors
Funding source category [1] 4718 0
Commercial sector/Industry
Name [1] 4718 0
Genzyme
Address [1] 4718 0
PO Box 282 North Ryde B/C NSW 1670 AUSTRALIA
Country [1] 4718 0
Australia
Primary sponsor type
Hospital
Name
The Royal Melbourne Hospital
Address
Grattan St,
Parkville, 3050 VIC
Country
Australia
Secondary sponsor category [1] 4264 0
None
Name [1] 4264 0
Address [1] 4264 0
Country [1] 4264 0
Other collaborator category [1] 623 0
Hospital
Name [1] 623 0
Calgary
Address [1] 623 0
1331 - 29 Street NW
Calgary, Alberta T2N 4N2
Country [1] 623 0
Canada

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 6753 0
Ethics committee address [1] 6753 0
Ethics committee country [1] 6753 0
Date submitted for ethics approval [1] 6753 0
28/09/2008
Approval date [1] 6753 0
Ethics approval number [1] 6753 0
2008.172

Summary
Brief summary
This study is for patients with a condition in which it has been recommended that an unrelated or (less commonly) a mismatched related donor stem cell transplant be performed.

One of the major side-effects of receiving a peripheral blood stem cell transplant from an unrelated or mismatched related donor is graft vs host disease (GVHD), particularly extensive chronic GVHD which can occur in up to 80% of patients. Some forms of chronic GVHD, particularly of the skin, lung and liver, can be debilitating, respond poorly to therapy and result in significant impairment of quality of life and can lead to death.

The type of donor cells which are responsible for GVHD are called T cells. The number of T cells can be substantially reduced by giving the patient a drug, for three days prior to the transplant, called thymoglobulin. This drug is derived from rabbits and is an antibody which inactivates or “depletes” many of the T cells as they are infused. Evidence from various studies suggests that T cell depletion of this type can substantially reduce the risk of GVHD after a transplant, with major improvements in the quality of life in surviving patients.

There are, however, potential disadvantages from T cell depletion. The same T cells which cause GVHD may also be important for engraftment (the ability of the donor stem cells to grow successfully in the recipients bone marrow and restore blood counts), immunity against viral infections (particularly in the first 3-4 months post-transplant) and a graft vs leukaemia/lymphoma effect which is when the immune system of the donor attacks any residual tumour which has survived the chemotherapy and radiotherapy.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 29437 0
Address 29437 0
Country 29437 0
Phone 29437 0
Fax 29437 0
Email 29437 0
Contact person for public queries
Name 12684 0
Sarah Bascomb
Address 12684 0
St Andrews Place
East Melbourne, VIC 3002
Country 12684 0
Australia
Phone 12684 0
+61 3 9656 3720
Fax 12684 0
+61 3 9639 3745
Email 12684 0
s.bascomb@cancertrialsaustralia.com
Contact person for scientific queries
Name 3612 0
Andrew Grigg
Address 3612 0
The Royal Melbourne Hospital
Grattan St
Parkville, VIC 3050
Country 3612 0
Australia
Phone 3612 0
+61 3 9342 7690
Fax 3612 0
Email 3612 0
andrew.grigg@mh.org.au

No information has been provided regarding IPD availability
Summary results
No Results