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
Introduction Immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and ciclosporin is standard of care for patients with severe aplastic anaemia (sAA) not eligible or suitable for allogeneic stem cell transplant. While patients respond to IST, few achieve complete responses and a signifi...
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2024-01-01
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| author | Stephane Heritier Alisa Higgins Piers Blombery Robin Filshie Paul Lacaze Kate Wilson William Stevenson Lauren Young Zoe McQuilten Jennifer Curnow Lucy Fox Vanessa Fox Ilona Cunningham Devendra K Hiwase Frank Firkin Kylie Mason Anthony K Mills Dominic Pepperell Sushrut Patil Jeff Szer Neil Waters Stephen Ting Erica Wood |
| author_facet | Stephane Heritier Alisa Higgins Piers Blombery Robin Filshie Paul Lacaze Kate Wilson William Stevenson Lauren Young Zoe McQuilten Jennifer Curnow Lucy Fox Vanessa Fox Ilona Cunningham Devendra K Hiwase Frank Firkin Kylie Mason Anthony K Mills Dominic Pepperell Sushrut Patil Jeff Szer Neil Waters Stephen Ting Erica Wood |
| author_sort | Stephane Heritier |
| collection | DOAJ |
| description | Introduction Immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and ciclosporin is standard of care for patients with severe aplastic anaemia (sAA) not eligible or suitable for allogeneic stem cell transplant. While patients respond to IST, few achieve complete responses and a significant proportion are refractory or relapse. The addition of eltrombopag, a thrombopoietin-receptor agonist (TPO-A), to IST has been shown to improve haematological responses in sAA. Avatrombopag is a second-generation TPO-A with potential advantages over eltrombopag. However, to date avatrombopag has not been studied in sAA.Methods and analysis Investigator-initiated, single-arm registry-based Bayesian Optimal Phase II trial of avatrombopag conducted in two cohorts, patients with untreated sAA (FIRST cohort) and in patients with sAA that has relapsed or is refractory to IST (NEXT cohort). In the FIRST cohort, participants receive IST (equine ATG and ciclosporin) plus avatrombopag from day 1 until day 180 at 60 mg oral daily, with dose adjusted according to platelet count. Participants in the NEXT cohort receive avatrombopag at 60 mg oral daily from day 1 until day 180, with or without additional IST at the discretion of the treating clinician.For each cohort, two primary endpoints (haematological response and acquired clonal evolution) are jointly monitored and the trial reviewed at each interim analysis where a ‘go/no-go’ decision is made by evaluating the posterior probability of the events of interests.Ethics and dissemination The trial has received ethics approval (Monash Health RES-18-0000707A). The trial conduct will comply with ICH-GCP and all applicable regulatory requirements. The results of the trial will be submitted to a peer-review journal for publication.Trial registration number ACTRN12619001042134, ACTRN12619001043123. |
| format | Article |
| id | doaj-art-23c90461090d45a8a6bc30f41730882d |
| institution | DOAJ |
| issn | 2044-6055 |
| language | English |
| publishDate | 2024-01-01 |
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| spelling | doaj-art-23c90461090d45a8a6bc30f41730882d2025-08-20T03:11:33ZengBMJ Publishing GroupBMJ Open2044-60552024-01-0114110.1136/bmjopen-2023-076246Efficacy 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 trialsStephane Heritier0Alisa Higgins1Piers Blombery2Robin Filshie3Paul Lacaze4Kate Wilson5William Stevenson6Lauren Young7Zoe McQuilten8Jennifer Curnow9Lucy Fox10Vanessa Fox11Ilona Cunningham12Devendra K Hiwase13Frank Firkin14Kylie Mason15Anthony K Mills16Dominic Pepperell17Sushrut Patil18Jeff Szer19Neil Waters20Stephen Ting21Erica Wood22School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, AustraliaSchool of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, AustraliaUniversity of Melbourne, Melbourne, Victoria, AustraliaHaematology Department, St Vincent’s Hospital, Melbourne, Victoria, AustraliaSchool of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, AustraliaCentral Clinical School, The University of Sydney Faculty of Medicine and Health, Sydney, New South Wales, AustraliaDepartment of Haematology, Royal North Shore Hospital, St Leonards, Sydney, AustraliaDepartment of Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, New York, New York, USADepartment of Haematology, Monash Health, Melbourne, Victoria, AustraliaDepartment of Haematology, Westmead Hospital, Sydney, New South Wales, AustraliaSchool of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, AustraliaSchool of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, AustraliaUniversity of Sydney, Sydney, New South Wales, AustraliaDepartment of Haematology, Royal Adelaide Hospital, Adelaide, South Australia, AustraliaHaematology Department, St Vincent’s Hospital, Melbourne, Victoria, AustraliaDepartment of Clinical Haematology, Peter MacCallum Cancer Centre & The Royal Melbourne Hospital, Parkville, Victoria, AustraliaUniversity of Queensland, Brisbane, Queensland, AustraliaDepartment of Haematology, Fiona Stanley Hospital, Murdoch, Perth, AustraliaDepartment of Haematology, Alfred Hospital, Melbourne, Victoria, AustraliaDepartment of Clinical Haematology, Peter MacCallum Cancer Centre & The Royal Melbourne Hospital, Parkville, Victoria, AustraliaSchool of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, AustraliaSchool of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, AustraliaDepartment of Haematology, Monash Health, Melbourne, Victoria, AustraliaIntroduction Immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and ciclosporin is standard of care for patients with severe aplastic anaemia (sAA) not eligible or suitable for allogeneic stem cell transplant. While patients respond to IST, few achieve complete responses and a significant proportion are refractory or relapse. The addition of eltrombopag, a thrombopoietin-receptor agonist (TPO-A), to IST has been shown to improve haematological responses in sAA. Avatrombopag is a second-generation TPO-A with potential advantages over eltrombopag. However, to date avatrombopag has not been studied in sAA.Methods and analysis Investigator-initiated, single-arm registry-based Bayesian Optimal Phase II trial of avatrombopag conducted in two cohorts, patients with untreated sAA (FIRST cohort) and in patients with sAA that has relapsed or is refractory to IST (NEXT cohort). In the FIRST cohort, participants receive IST (equine ATG and ciclosporin) plus avatrombopag from day 1 until day 180 at 60 mg oral daily, with dose adjusted according to platelet count. Participants in the NEXT cohort receive avatrombopag at 60 mg oral daily from day 1 until day 180, with or without additional IST at the discretion of the treating clinician.For each cohort, two primary endpoints (haematological response and acquired clonal evolution) are jointly monitored and the trial reviewed at each interim analysis where a ‘go/no-go’ decision is made by evaluating the posterior probability of the events of interests.Ethics and dissemination The trial has received ethics approval (Monash Health RES-18-0000707A). The trial conduct will comply with ICH-GCP and all applicable regulatory requirements. The results of the trial will be submitted to a peer-review journal for publication.Trial registration number ACTRN12619001042134, ACTRN12619001043123.https://bmjopen.bmj.com/content/14/1/e076246.full |
| spellingShingle | Stephane Heritier Alisa Higgins Piers Blombery Robin Filshie Paul Lacaze Kate Wilson William Stevenson Lauren Young Zoe McQuilten Jennifer Curnow Lucy Fox Vanessa Fox Ilona Cunningham Devendra K Hiwase Frank Firkin Kylie Mason Anthony K Mills Dominic Pepperell Sushrut Patil Jeff Szer Neil Waters Stephen Ting Erica Wood 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 |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | efficacy and safety of avatrombopag in combination with immunosuppressive therapy in treatment naive and relapsed refractory severe aplastic anaemia protocol for the diaamond ava first and diaamond ava next bayesian optimal phase ii trials |
| url | https://bmjopen.bmj.com/content/14/1/e076246.full |
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