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Trial registered on ANZCTR


Registration number
ACTRN12619001042134
Ethics application status
Approved
Date submitted
21/06/2019
Date registered
23/07/2019
Date last updated
13/11/2019
Date data sharing statement initially provided
23/07/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Avatrombopag in untreated severe aplastic anaemia - a Bayesian optimal phase 2 study
Scientific title
Avatrombopag plus up Front ImmunosuppReSsive Therapy in treatment-naive severe aplastic anaemia (AA) – a Bayesian Optimal Phase II study
Secondary ID [1] 298657 0
Nil
Universal Trial Number (UTN)
Trial acronym
DIAAMOND-Ava FIRST
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Newly diagnosed severe aplastic anaemia 312995 0
Condition category
Condition code
Blood 311502 311502 0 0
Haematological diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Avatrombopag will be administered by an oral tablet, 20 mg per day for up to 180 days. Dose will be adjusted every 2 weeks guided by reticulocyte count, platelet count/platelet transfusion and neutrophil count.
Titration of avatrombopag will be based on FBE/reticulocyte counts which will be measured at every time point, day 1, 14, month 1,1.5, 2, 2.5, 3, 4, 5, 6, 9, 12, 15, 18, 21, 24.
Equine antithymocyte globulin (ATG) 40mg/kg/day intravenous days 1, 2, 3 and 4 of the 180 day period only.
Cyclosporin 5mg/kg/day oral tablet days 1-365 (dose adjusted based on blood levels). Concurrent with Avatrombopag from day 1 -180, and continuing from day 181 to day 365 as per standard therapy.
A patient diary will be issued to participants which will be required at each monthly visit with their clinical trial clinician/coordinator. Any unused tablets are to be returned at each participant visit.
Intervention code [1] 314598 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 320222 0
Primary endpoint - efficacy
Rate of complete response (CR), defined as meeting all of the following:
Haemoglobin >10 g/dL,
Absolute neutrophils >1.0 x 10^9/L and
Platelets >100 x 10^9/L
Haematological Response will be assessed on Full blood Examination and reticulocyte count
Timepoint [1] 320222 0
Haematological response will be assessed at the defined time points
day 1, 14, month 1,1.5, 2, 2.5, 3, 4, 5, 6
Primary outcome [2] 320224 0
Primary endpoint - safety
The primary safety endpoint will be Acquired Clonal Evolution (ACE) at 6 months.
Clonal evolution will be defined as a new clonal cytogenetic abnormality or bone marrow characteristics consistent with myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML) (as defined by the World Health Organization classification of haematological malignancies 2016).
This information will be assessed from bone marrow biopsy reports
Timepoint [2] 320224 0
ACE will be assessed at the 6 month visit after the treatment period
Secondary outcome [1] 370916 0
Time to first haematological response (complete or partial response) described by cumulative incidence curve.
Rate of complete response (CR), defined as meeting all of the following:
1 Haemoglobin >10 g/dL,
2 Absolute neutrophils >1.0 x 10^9/L and
3 Platelets >100 x 10^9/L
Rate of partial response (PR) defined as achieving all the following:
1 No longer meet criteria for diagnosis of sAA
2 Do not meet criteria for CR above
Haematological Response will beassessed on Full blood examination and reticulocyte count
Timepoint [1] 370916 0
The efficacy will be assessed based on FBE/reticulocyte counts and transfusion requirements at the defined time points
day 1, 14, month 1,1.5, 2, 2.5, 3, 4, 5, 6, 9, 12, 15, 18, 21, 24.
Secondary outcome [2] 370917 0
Time to best haematological response described by cumulative incidence curve. Outcome is assessed on Full Blood Examination and reticulocyte count
Timepoint [2] 370917 0
The efficacy will be assessed on Full Blood Examination and reticulocyte counts and transfusion requirements at the defined time points
day 1, 14, month 1,1.5, 2, 2.5, 3, 4, 5, 6, 9, 12, 15, 18, 21, 24.
Secondary outcome [3] 370918 0
Time to complete response assessed based on Full Blood Examination and reticulocyte count and transfusion requirements
Timepoint [3] 370918 0
The efficacy will be assessed based on FBE/reticulocyte counts and transfusion requirements at the defined time points
day 1, 14, month 1,1.5, 2, 2.5, 3, 4, 5, 6, 9, 12, 15, 18, 21, 24.
Secondary outcome [4] 370919 0
Composite secondary outcome
Rates of haematological response (overall, complete and partial)
The efficacy will be assessed on Full Blood Examination and reticulocyte counts and transfusion requirements
Timepoint [4] 370919 0
The efficacy will be assessed on Full Blood Examination and reticulocyte counts and transfusion requirements at the defined time points of 6, 12, 18 and 24 months.
Secondary outcome [5] 370920 0
Overall survival (OS) probability; OS is defined as time from day 1 of study treatment to death, or last follow-up for patients alive.
Participants will be followed up long term using the Aplastic Anaemia Registry (AAR)
Timepoint [5] 370920 0
Assessments will occur at the defined time points:
day 1, 14, month 1,1.5, 2, 2.5, 3, 4, 5, 6, 9, 12, 15, 18, 21, 24.
Secondary outcome [6] 370921 0
Event-free survival (EFS) probability; EFS is defined as time from day 1 of study treatment to either relapse, death, treatment failure or ACE (whichever occurs first), or last follow-up for patients alive in response
Timepoint [6] 370921 0
Assessments will occur at the defined time points:
day 1, 14, month 1,1.5, 2, 2.5, 3, 4, 5, 6, 9, 12, 15, 18, 21, 24.
Secondary outcome [7] 370922 0
Quality of life as measured by the EORTC QLQ-C30 questionaries
Timepoint [7] 370922 0
At baseline following diagnosis, at month 3 and 6 following trial treatment and at 12, 18 and 24 months following trial scheduled visits.
Secondary outcome [8] 370923 0
Cumulative incidence of paroxysmal nocturnal haemoglobinuria (PNH) population occurrence and clinical haemolytic PNH occurrence.
This information will be assessed from bone marrow biopsy reports
Timepoint [8] 370923 0
PNH assessment will be assessed at 3, 6, 12, 18 and 24 months
Secondary outcome [9] 370924 0
Need for and number of transfusions (red blood cell [RBC] and platelet units)
The outcome is assessed by access to medical records and transfusion history
Timepoint [9] 370924 0
Assessments will occur at the defined time points:
day 1, 14, month 1,1.5, 2, 2.5, 3, 4, 5, 6, 9, 12, 15, 18, 21, 24.
Secondary outcome [10] 370925 0
Composite secondary Outcome
Need for supportive care, including number and length of hospitalisations and intensive care admissions
The outcome is assessed by access to medical records
Timepoint [10] 370925 0
Assessments will occur at the defined time points:
day 1, 14, month 1,1.5, 2, 2.5, 3, 4, 5, 6, 9, 12, 15, 18, 21, 24.
Secondary outcome [11] 370927 0
Secondary Safety Outcome
Rate of acquired clonal evolution
This information will be assessed from bone marrow biopsy reports
Timepoint [11] 370927 0
ACE will be assessed at the 6 month visit, ACE will also be assessed, 12, 18 and 24 months
Secondary outcome [12] 370928 0
Secondary Safety Outcome
Rate of acquired somatic mutations detected on genomic testing
Timepoint [12] 370928 0
Rate of acquired somatic mutations will be assessed at the 6 month visit, post treatment,
and continued at 12, 18 and 24 months at trial completion
Secondary outcome [13] 370929 0
Secondary Safety Outcome
Safety and tolerability of the avatrombopag, including serious adverse events.
This will be assessed based on Full Blood Examination and reticulocyte counts and transfusion requirements

Timepoint [13] 370929 0
Assessments will occur at the defined time points:
day 1, 14, month 1,1.5, 2, 2.5, 3, 4, 5, 6, 9, 12, 15, 18, 21, 24.

Eligibility
Key inclusion criteria
1. Severe or very severe aplastic anaemia characterised by bone marrow cellularity <30% (excluding lymphocytes) and at least two of the following:
a. Absolute neutrophil count <0.5 x10^9/L
b. Platelet count <20 x 10^9/L
c. Absolute reticulocyte count <60 x 10^9/L
2. No prior ATG-based immunosuppressive therapy
3. Age >18 years
4. Negative pregnancy test for women of child bearing potential
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Planned for a sibling allogeneic stem cell transplant
2. Evidence of a myelodysplastic syndrome, defined according to the World Health Organization 2017 criteria. Patients with AA with cytogenetic abnormalities that are recurrent in MDS, who do not meet the WHO diagnostic criteria for MDS, are also excluded. Patients with del(20q), +8 and –Y are not included in this category and are therefore eligible for this study.
3. Known diagnosis or clinical suspicion of inherited bone marrow failure syndrome (IBFS), including but not limited to Fanconi Anaemia, Dyskeratosis Congenita, Shwachman-Diamond Syndrome and Diamond-Blackfan Anaemia
4. Previous history of stem cell transplantation
5. History of cancer who are on active or previous chemo/radiotherapy within past 5 years
6. Pregnant or breast feeding patients
7. Active CMV disease
8. Participants with known hypersensitivity to any of the component medications (avatrombopag, cyclosporine, horse or rabbit ATG)
9. Concurrent hepatic, renal or cardiac disease of such severity that it would in the investigator’s opinion, preclude the patient’s ability to tolerate protocol therapy
10. Death anticipated within 14 days

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
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Two binary endpoints, CR rate up to 6 months (efficacy) and incidence of ACE during the 6-month follow-up period (safety) will be monitored jointly. Interim analyses will be performed after 10, 20, 30, 40 and 50 patients have been evaluated for co-primary outcomes. The trial will be terminated at each interim analysis if either the posterior probability of CR or ACE meet predefined thresholds for futility or safety, respectively. The maximum sample size of evaluable patients is 50. To allow for loss-to-follow up and withdrawal, up to 55 patients will be enrolled. The null hypothesis for efficacy is a CR below 15% and the null hypothesis for safety is an ACE rate of more than 16%. The alternate hypothesis for efficacy is a CR of greater than 45% and for safety an ACE rate of less than 8%. A target false positive rate of 10% was chosen under the global null as recommended in phase II studies.

The rate of CR and ACE will be reported as number (%) with 95% confidence interval. As the trial design is based on Bayesian statistics, a point estimate defined as the mode of the posterior distribution and a 95% credible interval will also be provided for the rates of CR and ACE.
Secondary outcome rates of overall response rate and partial response at 6, 12, 18 and 24 months and CR at other time points than 6 months will be reported as number (%) with 95% CI. Time to first haematological response (either complete or partial, whichever occurs first), time to best haematological response and time to CR will be described using cumulative incidence curves. Overall survival will be defined as time from day 1 of study treatment to death, or last follow-up for patients alive. A cumulative incidence curve of ACE will be displayed with death treated as a competing risk. Cumulative incidence of PNH occurrence will be calculated. EORTC-QLQC30 symptom and functional scales will be summarised using appropriate statistics and modelled using generalised linear models.

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)
NSW,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 14037 0
Concord Repatriation Hospital - Concord
Recruitment hospital [2] 14038 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [3] 14039 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [4] 14040 0
Westmead Hospital - Westmead
Recruitment hospital [5] 14041 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [6] 14042 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [7] 14043 0
Royal Hobart Hospital - Hobart
Recruitment hospital [8] 14044 0
The Alfred - Prahran
Recruitment hospital [9] 14045 0
Box Hill Hospital - Box Hill
Recruitment hospital [10] 14046 0
Barwon Health - Geelong Hospital campus - Geelong
Recruitment hospital [11] 14047 0
Royal Melbourne Hospital - Royal Park campus - Parkville
Recruitment hospital [12] 14049 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [13] 14050 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [14] 14051 0
Fiona Stanley Hospital - Murdoch
Recruitment postcode(s) [1] 26827 0
2139 - Concord
Recruitment postcode(s) [2] 26828 0
2065 - St Leonards
Recruitment postcode(s) [3] 26829 0
2050 - Camperdown
Recruitment postcode(s) [4] 26830 0
2145 - Westmead
Recruitment postcode(s) [5] 26831 0
4102 - Woolloongabba
Recruitment postcode(s) [6] 26832 0
5000 - Adelaide
Recruitment postcode(s) [7] 26833 0
7000 - Hobart
Recruitment postcode(s) [8] 26834 0
3004 - Prahran
Recruitment postcode(s) [9] 26835 0
3128 - Box Hill
Recruitment postcode(s) [10] 26836 0
3220 - Geelong
Recruitment postcode(s) [11] 26837 0
3052 - Parkville
Recruitment postcode(s) [12] 26839 0
3065 - Fitzroy
Recruitment postcode(s) [13] 26840 0
3168 - Clayton
Recruitment postcode(s) [14] 26841 0
6150 - Murdoch

Funding & Sponsors
Funding source category [1] 302894 0
Government body
Name [1] 302894 0
Medical Research Future Fund
Address [1] 302894 0
Australian Government
Department of Health
GPO Box 9848,
Canberra ACT 2601, Australia
Country [1] 302894 0
Australia
Primary sponsor type
University
Name
Monash University
Address
Monash University
School of Public Health and Preventive Medicine,
Level 1
553 St Kilda Road,
Melbourne 3004 Victoria
Country
Australia
Secondary sponsor category [1] 302874 0
None
Name [1] 302874 0
Address [1] 302874 0
Country [1] 302874 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303460 0
Monash Health HREC
Ethics committee address [1] 303460 0
Research Support Services
Level 2, i Block,
Monash Medical Centre
246 Clayton Road
CLAYTON VIC 3168
Ethics committee country [1] 303460 0
Australia
Date submitted for ethics approval [1] 303460 0
29/11/2018
Approval date [1] 303460 0
04/03/2019
Ethics approval number [1] 303460 0
HREC/46798/MonH-2018-157278(v1)

Summary
Brief summary
Severe aplastic anaemia is a rare disease where current standard upfront treatment for patients ineligible for haematopoietic stem cell transplant (HSCT) is immunosuppressive therapy (IST). Although patients with severe AA treated with IST (horse antithymocyte globulin [ATG] and CyA) have overall responses reported in 50-75%, the minority achieve complete responses, approximately 20% are refractory to IST and approximately 30% will relapse by 2 years. Partial or no response to IST leaves patients at ongoing risk of life-threatening complications of AA such as infections, haemorrhage and patients will require ongoing supportive treatments such as antibiotics, red blood cell and platelet transfusions, to combat these complications.
Eltrombopag is a thrombopoietin (TPO) mimetic and has shown promising efficacy for severe AA in phase II trials. Avatrombopag is a second generation TPO mimetic which has been studied in immune thrombocytopenia and thrombocytopenia due to chronic liver disease. It has several potential advantages over eltrombopag, including dosing, lack of toxicities, pharmacokinetics and potential increased potency. Avatrombopag has not been tested in AA to date.
In this study, avatrombopag will be given in addition to standard IST to treatment naive severe AA patients to determine if the rate of production of platelets, red blood cells and white blood cells is increased.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 93734 0
Prof Erica Wood
Address 93734 0
Monash University
School of Public Health and Preventive Medicine,
Level 1
553 St Kilda Road,
Melbourne 3004, Victoria
Country 93734 0
Australia
Phone 93734 0
+61 03 9903 0051
Fax 93734 0
Email 93734 0
erica.wood@monash.edu
Contact person for public queries
Name 93735 0
Ms Vanessa Fox
Address 93735 0
Monash University
School of Public Health and Preventive Medicine,
Level 1
553 St Kilda Road,
Melbourne 3004, Victoria
Country 93735 0
Australia
Phone 93735 0
+61 03 9903 0532
Fax 93735 0
Email 93735 0
sphpm.diaamond@monash.edu
Contact person for scientific queries
Name 93736 0
A/Prof Zoe McQuilten
Address 93736 0
Monash University
School of Public Health and Preventive Medicine,
Level 1
553 St Kilda Road,
Melbourne 3004, Victoria
Country 93736 0
Australia
Phone 93736 0
+61 03 9903 0379
Fax 93736 0
Email 93736 0
zoe.mcquilten@monash.edu

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
No, only aggregate participant data will be published
What supporting documents are/will be available?
No other documents available
Summary results
No Results