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Trial registered on ANZCTR


Registration number
ACTRN12619001043123
Ethics application status
Approved
Date submitted
20/06/2019
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 Relapsed or Refractory Severe Aplastic Anaemia – a Bayesian Optimal Phase II study
Scientific title
Avatrombopag iN Relapsed or Refractory severe Aplastic Anaemia as EXtra Therapy – a Bayesian Optimal Phase II study
Secondary ID [1] 298378 0
AVA2018-1
Universal Trial Number (UTN)
Trial acronym
The DIAAMOND-Ava NEXT Trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Refractory/relapsed severe aplastic anaemia 313049 0
Condition category
Condition code
Blood 311547 311547 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 180 days. Dose will be adjusted every 2 weeks guided by reticulocyte count, platelet count/platelet transfusion and neutrophil counts.
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.
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] 314620 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 320255 0
Primary endpoint - efficacy
Rate of overall response, including Partial Response (PR) and Complete Response (CR).
Patients will be considered as complete responders (CR) if achieving all the following:
o Haemoglobin >10 g/dL
o Absolute neutrophils >1.0 x 10^9/L
o Platelets >100 x 10^9/L

Patients will be considered as partial responders (PR) if achieving all the following:
• No longer meet criteria for diagnosis of sAA
• Does not meet criteria for CR above
• Transfusion independence (defined as no need for any RBC or platelet transfusion)
• Absolute neutrophils >0.5 x 10^9/L
• Platelets (unsupported with transfusion) >20 x 10^9/L
Haematological Response will be assessed on Full Blood Examination and reticulocyte counts
Timepoint [1] 320255 0
Overall 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] 320256 0
Primary endpoint - safety
The primary safety endpoint will be Aquired Clonal Evolution (ACE) 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] 320256 0
ACE will be assessed at the 6 month visit
Secondary outcome [1] 370995 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 be assessed on Full Blood Examination and reticulocyte count
Timepoint [1] 370995 0
The efficacy will be assessed based 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 [2] 370996 0
Time to best haematological response described by cumulative incidence curve. Outcome data will be assessed on Full Blood Examination and reticulocyte count
Timepoint [2] 370996 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 [3] 370997 0
Time to complete response assessed on Full Blood Examination and reticulocyte count
Timepoint [3] 370997 0
The efficacy will be assessed 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 [4] 370998 0
Composite secondary outcome
Rates of haematological response (overall, complete and partial)
The efficacy will be assessed on Full Blood Examination, reticulocyte counts and transfusion requirements
Timepoint [4] 370998 0
The efficacy will be assessed on Full Blood Examination and reticulocyte counts and transfusion requirements at the defined time points, 6, 12, 18 and 24 months
Secondary outcome [5] 370999 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] 370999 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] 371000 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.
Data will collected up to two years for the trial and ongoing, every 6 months, from the Aplastic Anaemia Registry.
Timepoint [6] 371000 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] 371001 0
Quality of life as measured by the EORTC QLQ-C30 questionaries
Timepoint [7] 371001 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] 371002 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] 371002 0
PNH assessment will be assessed at 3, 6, 12, 18 and 24 months
Secondary outcome [9] 371003 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] 371003 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] 371004 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] 371004 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. Refractory severe aplastic anaemia with an incomplete response following at least one course of horse or rabbit ATG given greater than 6 months ago. Incomplete response defined as any one of the following:
o Absolute neutrophil count <0.5 x10^9/L
o Platelet count <20 x 10^9/L
o Absolute reticulocyte count <60 x 10^9/L or ongoing requirement for red cell transfusion support (if not due to independent medical condition)

OR

Relapsed severe aplastic anaemia, defined as the occurrence of any of the following, after a haematological response to a prior course of horse or rabbit ATG given greater than 6 months ago:
• meeting again the criteria for SAA
• requirement for transfusion support (if not due to independent medical conditions)
• decrease in any of the peripheral blood counts as follows
• absolute neutrophils < 0.5 x 10^9/L
• platelets <20 x 10^9/L
2. Age >18
3. 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. Evidence of a myelodysplastic syndrome, defined according to the World Health Organization 2017 criteria. Patients with AA with cytogenetic abnormalities, which 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.
2. 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
3. History of cancer who are on active or previous chemo/radiotherapy within past 5 years
4. Pregnant or breast feeding patients
5. Participants with known hypersensitivity to avatrombopag
6. Severe renal impairment (defined as creatinine clearance less than 30ml/min)
7. Treatment with horse or rabbit ATG within 6 months of study entry. Concurrent treatment with Cyclosporine A is permitted.
8. 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, overall response rate (ORR) 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 ORR 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 ORR below 15% and the null hypothesis for safety is an ACE rate of more than 22%. The alternate hypothesis for efficacy is a ORR of greater than 40% and for safety an ACE rate of less than 11%. 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] 13862 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [2] 13863 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [3] 13865 0
Royal Hobart Hospital - Hobart
Recruitment hospital [4] 13866 0
Barwon Health - Geelong Hospital campus - Geelong
Recruitment hospital [5] 13867 0
The Alfred - Prahran
Recruitment hospital [6] 13868 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [7] 13869 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [8] 13870 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [9] 13871 0
Box Hill Hospital - Box Hill
Recruitment hospital [10] 13872 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [11] 13873 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [12] 13874 0
Concord Repatriation Hospital - Concord
Recruitment hospital [13] 13875 0
Westmead Hospital - Westmead
Recruitment hospital [14] 13877 0
Princess Alexandra Hospital - Woolloongabba
Recruitment postcode(s) [1] 26634 0
6150 - Murdoch
Recruitment postcode(s) [2] 26635 0
5000 - Adelaide
Recruitment postcode(s) [3] 26637 0
7000 - Hobart
Recruitment postcode(s) [4] 26638 0
3220 - Geelong
Recruitment postcode(s) [5] 26639 0
3004 - Prahran
Recruitment postcode(s) [6] 26640 0
3065 - Fitzroy
Recruitment postcode(s) [7] 26641 0
3168 - Clayton
Recruitment postcode(s) [8] 26642 0
3050 - Parkville
Recruitment postcode(s) [9] 26643 0
3128 - Box Hill
Recruitment postcode(s) [10] 26644 0
2065 - St Leonards
Recruitment postcode(s) [11] 26645 0
2050 - Camperdown
Recruitment postcode(s) [12] 26646 0
2139 - Concord
Recruitment postcode(s) [13] 26647 0
2145 - Westmead
Recruitment postcode(s) [14] 26649 0
4102 - Woolloongabba

Funding & Sponsors
Funding source category [1] 302914 0
Government body
Name [1] 302914 0
Medical Research Future Fund
Address [1] 302914 0
Australian Government
Department of Health
GPO Box 9848,
Canberra ACT 2601, Australia
Country [1] 302914 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, VIC 3004
Country
Australia
Secondary sponsor category [1] 302877 0
None
Name [1] 302877 0
Address [1] 302877 0
Country [1] 302877 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303485 0
Monash Health HREC
Ethics committee address [1] 303485 0
Research Support Services
Level 2, i Block,
Monash Medical Centre
246 Clayton Road
CLAYTON VIC 3168
Ethics committee country [1] 303485 0
Australia
Date submitted for ethics approval [1] 303485 0
29/11/2018
Approval date [1] 303485 0
04/03/2019
Ethics approval number [1] 303485 0
HREC/46798/MonH-2018-157278(v1)

Summary
Brief summary
Severe aplastic anaemia is a rare disease where current standard upfront treatment is immunosuppressive therapy (IST) in those ineligible for haematopoietic stem cell transplant (HSCT). Approximately 20% of patients with severe AA are refractory to IST and another third of patients will relapse within two 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 to severe AA patients relapsed or refractory to IST 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 93818 0
Prof Erica Wood
Address 93818 0
Monash University
School of Public Health and Preventive Medicine,
Level 1
553 St Kilda Road,
Melbourne, VIC 3004
Country 93818 0
Australia
Phone 93818 0
+61 03 9903 0051
Fax 93818 0
Email 93818 0
erica.wood@monash.edu
Contact person for public queries
Name 93819 0
Ms Vanessa Fox
Address 93819 0
Monash University
School of Public Health and Preventive Medicine,
Level 1
553 St Kilda Road,
Melbourne, VIC 3004
Country 93819 0
Australia
Phone 93819 0
+61 03 9903 0532
Fax 93819 0
Email 93819 0
vanessa.fox@monash.edu
Contact person for scientific queries
Name 93820 0
A/Prof Zoe McQuilten
Address 93820 0
Monash University
School of Public Health and Preventive Medicine,
Level 1
553 St Kilda Road,
Melbourne, VIC 3004
Country 93820 0
Australia
Phone 93820 0
+61 03 9903 0379
Fax 93820 0
Email 93820 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