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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

10/04/2024

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]

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

Condition category

Condition code

Blood

Haematological diseases

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Avatrombopag will be administered by an oral tablet, maximum dose of 60 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.
Eligibility for extended therapy is based on hematological response at 6 months (180 days):
• Avatrombopag will be continued up to 12 months, at the same dose, in participants achieving partial response (PR) at 6 months;
• Avatrombopag will be discontinued in all patients achieving complete response (CR) at 6 months
• Avatrombopag will be discontinued in all patients achieving no response (NR) at 6 months
The extended duration of avatrombopag will be for a further 6 months. Participants who achieve a CR at the completion of 180 days and subsequently relapse within 6 months of discontinuation (defined as no longer meeting criteria of CR) will be able to request extended duration for a further 6 months. The local PI or delegate will be responsible for identifying qualifying participants
Titration of avatrombopag will be based on FBE/reticulocyte counts which will be measured at time point, day 14, month 1,1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

No control group

Control group

Uncontrolled

Outcomes

Primary outcome [1]

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]

Overall haematological response at month 6.

Primary outcome [2]

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]

ACE will be assessed at the 6 month visit

Secondary outcome [1]

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]

The efficacy will be assessed based on Full blood Examination and reticulocyte counts and transfusion requirements at the defined time points day 14, month 1,1.5, 2, 2.5, 3, 4, 5, 6, 9, 12, 15, 18, 21, 24.

Secondary outcome [2]

Time to best haematological response described by cumulative incidence curve. Outcome data will be assessed on Full Blood Examination and reticulocyte count

Timepoint [2]

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]

Time to complete response assessed on Full Blood Examination and reticulocyte count

Timepoint [3]

The efficacy will be assessed assessed on Full Blood Examination and reticulocyte counts and transfusion requirements at the defined time points day 14, month 1,1.5, 2, 2.5, 3, 4, 5, 6, 9, 12, 15, 18, 21, 24.

Secondary outcome [4]

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]

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]

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]

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]

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]

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]

Quality of life as measured by the EORTC QLQ-C30 questionaries

Timepoint [7]

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]

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]

PNH assessment will be assessed at baseline, 3, 6, 12, 18 and 24 months

Secondary outcome [9]

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]

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]

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]

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

Sex

Both males and females

Can healthy volunteers participate?

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 trial.
2. Known diagnosis or clinical suspicion of inherited bone marrow failure syndrome (IBMFS), including but not limited to Fanconi Anaemia, Dyskeratosis Congenita, Shwachman-Diamond Syndrome and Diamond-Blackfan Anaemia
3. Cancer diagnosis within the last 5 years (except for patients with resected basal cell carcinoma or squamous cell carcinoma of the skin)
4. Previous history of melanoma
5. Pregnant or breast feeding patients2
6. Participants with known hypersensitivity to avatrombopag
7. Severe renal impairment (defined as creatinine clearance =30m/min)
8. Treatment with horse or rabbit ATG within 6 months of trial entry. Concurrent treatment with Cyclosporine A is permitted.
9. 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) at 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

Active, not recruiting

Date of first participant enrolment

Anticipated

5/08/2019

Actual

22/10/2019

Date of last participant enrolment

Anticipated

1/12/2023

Actual

20/11/2023

Date of last data collection

Anticipated

1/12/2025

Actual

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

NSW,QLD,SA,TAS,WA,VIC

Recruitment hospital [1]

Fiona Stanley Hospital - Murdoch

Recruitment hospital [2]

The Royal Adelaide Hospital - Adelaide

Recruitment hospital [3]

Royal Hobart Hospital - Hobart

Recruitment hospital [4]

The Alfred - Prahran

Recruitment hospital [5]

St Vincent's Hospital (Melbourne) Ltd - Fitzroy

Recruitment hospital [6]

Monash Medical Centre - Clayton campus - Clayton

Recruitment hospital [7]

Royal Melbourne Hospital - City campus - Parkville

Recruitment hospital [8]

Box Hill Hospital - Box Hill

Recruitment hospital [9]

Royal North Shore Hospital - St Leonards

Recruitment hospital [10]

Concord Repatriation Hospital - Concord

Recruitment hospital [11]

Westmead Hospital - Westmead

Recruitment hospital [12]

Princess Alexandra Hospital - Woolloongabba

Recruitment postcode(s) [1]

6150 - Murdoch

Recruitment postcode(s) [2]

5000 - Adelaide

Recruitment postcode(s) [3]

7000 - Hobart

Recruitment postcode(s) [4]

3004 - Prahran

Recruitment postcode(s) [5]

3065 - Fitzroy

Recruitment postcode(s) [6]

3168 - Clayton

Recruitment postcode(s) [7]

3050 - Parkville

Recruitment postcode(s) [8]

3128 - Box Hill

Recruitment postcode(s) [9]

2065 - St Leonards

Recruitment postcode(s) [10]

2139 - Concord

Recruitment postcode(s) [11]

2145 - Westmead

Recruitment postcode(s) [12]

4102 - Woolloongabba

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

Medical Research Future Fund

Address [1]

Australian Government
Department of Health
GPO Box 9848,
Canberra ACT 2601, Australia

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Monash Health HREC

Ethics committee address [1]

Research Support Services
Level 2, i Block,
Monash Medical Centre
246 Clayton Road
CLAYTON VIC 3168

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

29/11/2018

Approval date [1]

04/03/2019

Ethics approval number [1]

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

https://aaregistry.org.au/

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Prof Erica Wood

Address

Monash University
School of Public Health and Preventive Medicine,
Level 1
553 St Kilda Road,
Melbourne, VIC 3004

Country

Australia

Phone

+61 03 9903 0051

Fax

[email protected]

Contact person for public queries

Name

Vanessa Fox

Address

Monash University
School of Public Health and Preventive Medicine,
Level 1
553 St Kilda Road,
Melbourne, VIC 3004

Country

Australia

Phone

+61 03 9903 0532

Fax

[email protected]

Contact person for scientific queries

Name

Zoe McQuilten

Address

Monash University
School of Public Health and Preventive Medicine,
Level 1
553 St Kilda Road,
Melbourne, VIC 3004

Country

Australia

Phone

+61 03 9903 0379

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

No, only aggregate participant data will be published

What supporting documents are/will be available?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
22153	Study protocol	McQuilten Z, Heritier S, Fox L, et al Efficacy and safety of avatrombopag in combination with immunosuppressive therapy in treatment-naïve and relapsed/refractory severe aplastic anaemia: protocol for the DIAAMOND-Ava-FIRST and DIAAMOND-Ava-NEXT Bayesian Optimal Phase II trials BMJ Open 2024;14:e076246. doi: 10.1136/bmjopen-2023-076246	https://bmjopen.bmj.com/content/14/1/e076246

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Dimensions AI	The Australian Aplastic Anaemia and other Bone Marrow Failure Syndromes Registry	2023	https://doi.org/10.1016/j.beha.2023.101516
Dimensions AI	Efficacy and safety of avatrombopag in combination with immunosuppressive therapy in treatment-naïve and relapsed/refractory severe aplastic anaemia: protocol for the DIAAMOND-Ava-FIRST and DIAAMOND-Ava-NEXT Bayesian Optimal Phase II trials	2024	https://doi.org/10.1136/bmjopen-2023-076246

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically