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Trial registered on ANZCTR


Registration number
ACTRN12620001339943p
Ethics application status
Submitted, not yet approved
Date submitted
26/10/2020
Date registered
11/12/2020
Date last updated
11/12/2020
Date data sharing statement initially provided
11/12/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
REscuing bone marrow function in patients with aplaStic anaEmia and bone marrow faiLure post allogEneiC Transplantation (RESELECT)
Phase I/II single arm with historical control study assessing the efficacy and safety of Atorvastatin and N-Acetyl Cysteine in the treatment of Poor Graft Function post allogeneic transplantation and relapsed/refractory aplastic anaemia
Scientific title
REscuing bone marrow function in patients with aplaStic anaEmia and bone marrow faiLure post allogEneiC Transplantation (RESELECT)
Phase I/II single arm with historical control study assessing the efficacy and safety of Atorvastatin and N-Acetyl Cysteine in the treatment of Poor Graft Function post allogeneic transplantation and relapsed/refractory aplastic anaemia
Secondary ID [1] 302626 0
Nil
Universal Trial Number (UTN)
U1111-1260-1760
Trial acronym
RESELECT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
One of the health conditions being studied in this trial will be Poor Graft Function
319522 0
One of the health conditions being studied in this trial will be Aplastic Anaemia 319523 0
Condition category
Condition code
Blood 317474 317474 0 0
Haematological diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a Phase I/II single arm, with historical cohort study assessing the efficacy and safety of:
Atorvastatin tablet
10mg daily orally
N-Acetyl Cysteine capsule
600mg twice a day orally
Both taken for 12 weeks in total
In the treatment of Poor Graft Function post allogeneic transplant and relapsed refractory Aplastic Anaemia. Adherence will be assessed by reviewing bottle returns
Intervention code [1] 318911 0
Treatment: Drugs
Comparator / control treatment
A historic control group will be used. This historical group is made up of patients who received allogeneic stem cell transplants performed at the Royal Melbourne Hospital between the years 2000-2016 and fulfilled the inclusion criteria for this study. This control group was only treated with best supportive care made up of transfusion support in the setting of thrombocytopenia and anaemia and filgrastim in the setting of neutropenia
Control group
Historical

Outcomes
Primary outcome [1] 325505 0
Complete Response (CR) defined as neutrophils greater than or equal to 1.5x10^9 and platelets greater than or equal to 100x10^9 without use of transfusions or cytokine support at 12 weeks
This outcome will be measured by a full blood examination performed on a blood sample at 12 weeks.

Timepoint [1] 325505 0
The primary timepoint will be measured at 12 weeks post trial enrollment
Primary outcome [2] 325506 0
Incidence of non haematological Adverse Events (AEs) of Grade 2 severity as measured by version 5 of the National Institute of Health common terminology criteria of adverse events (NIH-CTCAE) directly attributed to the trial medication as measured at 12 weeks.
Timepoint [2] 325506 0
12 weeks
Secondary outcome [1] 388229 0
Relapse free survival (RFS) in patients with PGF. This will be assessed by data collected from the participant's medical record as well as trial assessments.
Timepoint [1] 388229 0
The secondary outcome of RFS will be measured 12 months post trial enrollment
Secondary outcome [2] 388230 0
Overall Survival from time of enrolment. This will be assessed by data collected from the participant's medical record as well as trial assessments
Timepoint [2] 388230 0
This secondary outcome of OS will be measured 12 months post trial enrollment
Secondary outcome [3] 388231 0
Cumulative incidence of acute and chronic graft versus host disease (GVHD). This will be assessed by data collected from the participant's medical record as well as trial assessments
Timepoint [3] 388231 0
The cumulative incidence of acute and chronic GVHD will be assessed at mandated timepoints week 1,4,8,12, 6 months, 9, months and 12 months post trial enrollment
Secondary outcome [4] 388232 0
Cumulative incidence of recovery from PGF/AA. This will be assessed by data collected from full blood examination performed on blood samples taken at trial assessment points
Timepoint [4] 388232 0
The cumulative incidence of recovery from PGF/AA will be assessed at mandated timepoints: week 1,4,8,12, 6 months, 9, months and 12 months post trial enrollment
Secondary outcome [5] 388233 0
Cumulative incidence of non-relapse mortality (NRM). This will be assessed by data collected from the participant's medical record as well as trial assessments.
Timepoint [5] 388233 0
12 months post trial enrollment.

Eligibility
Key inclusion criteria
1. Poor Graft function OR Relapsed/refractory AA defined as the following
Poor Graft Function:
Two Lineage cytopenias defined as
-Thrombocytopenia
i)Less than or equal to 30x10^9 /L from D40-D60 OR
ii)Less than or equal to 50 x10 ^9/L from D60 onwards
-Neutropenia requiring filgrastim support at any time post D40
-Hb less than or equal to 80g/L
Relapsed /Refractory AA:
Relapse after stem cell transplant OR relapsed post/refractory to 1st line immunosuppression without an unrelated donor identified.
2. Age greater than or equal to 17 years
3. ECOG performance status 0-1
4. Life expectancy > 6 months
5. Patient’s written informed consent

Minimum age
17 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Active Grade 3-4 acute GVHD
2. Relapsed or progressive disease on screening bone marrow biopsy or most recent PET imaging.
3. Active second malignancy currently requiring treatment
4. Human Immuno-deficiency Virus (HIV) infection.
5. Any coexisting medical or psychological condition that would preclude participation in the required study procedures.
6. Female patients who are both lactating and breast-feeding or have a positive serum pregnancy test during the screening period or a positive pregnancy test on Day 1 before first dose of study drug
7. Prior history of statin induced myopathy
8. Prior history of severe asthma

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)
Not applicable
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not applicable
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
A historical comparator group will be used
Phase
Phase 1 / Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Toxicities will be described according to type and grade as frequencies. A list of all serious adverse events will be reported.
Efficacy outcomes will be reported using descriptive statistics of the efficacy endpoints. The primary outcome will be analysed using logistic regression. Overall survival (OS) will also be assessed, defined as the time from the data of the first dose of study medication to the date of death from any cause. OS will be estimated with the Kaplan-Meier method.

Recruitment
Recruitment status
Not yet 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)
NSW,WA,VIC

Funding & Sponsors
Funding source category [1] 307057 0
Charities/Societies/Foundations
Name [1] 307057 0
Maddie Riewoldt's Vision
Address [1] 307057 0
11 Hume St, Huntingdale VIC 3166
Country [1] 307057 0
Australia
Primary sponsor type
Hospital
Name
The Royal Melbourne Hospital
Address
300 Grattan Street
Parkville
VIC 3050
Country
Australia
Secondary sponsor category [1] 307623 0
None
Name [1] 307623 0
Address [1] 307623 0
Country [1] 307623 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 307181 0
The Royal Melbourne Hospital HREC
Ethics committee address [1] 307181 0
300
Grattan Street
Parkville
VIC 3050
Ethics committee country [1] 307181 0
Australia
Date submitted for ethics approval [1] 307181 0
27/10/2020
Approval date [1] 307181 0
Ethics approval number [1] 307181 0

Summary
Brief summary
Allogeneic Stem Cell transplant (alloSCT) is a curative procedure for many blood disorders and involves the transplantation of donor blood cells into a compatible recipient. Engraftment is a key milestone of success of alloSCT and is measured by standard blood tests to ensure normal levels of blood cells as well as a specialised blood test to confirm this blood is being produced by donor tissue. Poor graft function (PGF) is a significant complication of alloSCT and results in poor blood cell production by engrafted donor tissue. Aplastic anaemia(AA) is an autoimmune disease that results in the body's own immune cells attacking the bone marrow (the organ that produces blood cells) resulting in decreased production of blood cells. The mechanisms leading to PGF and AA are similar. There is evidence that the bone marrow microenvironment, the ecosystem in which blood cells reside, is abnormal in both PGF and AA. Atorvastatin is an old drug that has been used to treat high cholestrol and N-acetyl-cysteine (NAC) has been used as an antioxidant to treat paracetamol overdose. There is evidence that atorvastatin and NAC may be able to reverse this microenvironment dysfunction in PGF and AA. This study is aimed at testing the efficacy and safety of atorvastatin and NAC in the treatment of PGF and relapsed/refractory Aplastic anaemia.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 106310 0
Prof David Ritchie
Address 106310 0
Department of Clinical Haematology and BMT service
Peter MacCallum Cancer Centre/ The Royal Melbourne Hospital
300 Grattan Street
Parkville
VIC 3050
Country 106310 0
Australia
Phone 106310 0
+61 3 93427000
Fax 106310 0
Email 106310 0
david.ritchie@mh.org.au
Contact person for public queries
Name 106311 0
Dr Ashvind Prabahran
Address 106311 0
Department of Clinical Haematology and BMT service
Peter MacCallum Cancer Centre/ The Royal Melbourne Hospital
300 Grattan Street
Parkville
VIC 3050
Country 106311 0
Australia
Phone 106311 0
+61 3 93427000
Fax 106311 0
Email 106311 0
ashvind.prabahran@mh.org.au
Contact person for scientific queries
Name 106312 0
Dr Ashvind Prabahran
Address 106312 0
Department of Clinical Haematology and BMT service
Peter MacCallum Cancer Centre/ The Royal Melbourne Hospital
300 Grattan Street
Parkville
VIC 3050
Country 106312 0
Australia
Phone 106312 0
+61 3 93427000
Fax 106312 0
Email 106312 0
ashvind.prabahran@mh.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Individual patient data that underline the results reported in any future publication after de-identification
When will data be available (start and end dates)?
Beginning 3 months and ending 5 years following article publication
Available to whom?
Researchers who provide a methologically sound proposal with ethics approval
Available for what types of analyses?
Any purpose
How or where can data be obtained?
Proposal will need to be directed to Dr Ashvind Prabahran via ashvind.prabahran@mh.org.au. Requestors will need to sing a data access agreement.
What supporting documents are/will be available?
Study protocol
How or where can supporting documents be obtained?
Type [1] 9532 0
Study protocol
Citation [1] 9532 0
Link [1] 9532 0
Email [1] 9532 0
ashvind.prabahran@mh.org.au
Other [1] 9532 0
Attachment [1] 9532 0
Summary results
No Results