A double-blind randomised trial to compare oral azacitidine (CC-486) with placebo in adults with acute myeloid leukaemia and myelodysplasia who are undergoing allogeneic stem cell transplantation
| ISRCTN | ISRCTN55111436 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN55111436 |
| EudraCT/CTIS number | 2018-001012-30 |
| ClinicalTrials.gov number | NCT04173533 |
| Secondary identifying numbers | 41275 |
- Submission date
- 25/02/2019
- Registration date
- 25/02/2019
- Last edited
- 23/05/2025
- Recruitment status
- No longer recruiting
- Overall study status
- Ongoing
- Condition category
- Cancer
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data
Record updated in last year
Plain English summary of protocol
Contact information
Ms Andrea Hodgkinson
Scientific
Scientific
Haematology Team
Room 13, Centre for Clinical Haematology
Queen Elizabeth Hospital
Edgbaston
Birmingham
B15 2TH
United Kingdom
| Phone | +44 (0)121 371 7858 |
|---|---|
| amadeus@trials.bham.ac.uk |
Study information
| Study design | Randomised; Interventional; Design type: Treatment, Drug |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a patient information sheet |
| Scientific title | A double-blind, phase III, randomised study to compare the efficacy and safety of oral azacitidine (CC-486) versus placebo in subjects with acute myeloid leukaemia or myelodysplastic syndromes as maintenance after allogeneic haematopoietic stem cell transplantation |
| Study acronym | AMADEUS |
| Study objectives | The aim of the study is to find out if there is a difference in the relapse free survival of patients with AML or high risk MDS treated with maintenance therapy of oral azacitidine versus placebo after stem cell transplantation. |
| Ethics approval(s) | Approved 02/05/2019, East Midlands - Leicester Central Research Ethics Committee (The Old Chapel, Royal Standard Place, Nottingham, NG1 6FS; Tel: +44 (0)207 1048098; Email: nrescommittee.eastmidlands-leicestercentral@nhs.net), ref: 19/EM/0063 |
| Health condition(s) or problem(s) studied | Acute myeloid leukaemia, myelodysplastic syndromes |
| Intervention | Patients will be randomised 1:1 to either treatment with oral azacitidine (CC-486) or matching placebo. Patients will take a dose of 200 mg once daily from days 1 – 14 of a 28-day cycle. Patients will commence therapy between days 42 and 84 post-transplant up to a maximum of 12 months from the date of transplant. Patients will be followed up for 2 years for survival information. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase III |
| Drug / device / biological / vaccine name(s) | Azacitidine (CC-486) |
| Primary outcome measure | Relapse free survival; Timepoint(s): Date of first relapse (including morphological, cytogenetic or molecular relapse) or death from any cause. Patients who are progression free and still alive at the end of the trial will be censored at their date of last follow-up |
| Secondary outcome measures | 1. Overall survival is defined as the time from date of randomisation to date of death, from any cause. Patients who are alive at the end of the trial will be censored at their date last seen. 2. Cumulative incidence of relapse is defined as the time from date of randomisation to date of relapse. Patients who die without relapse will be considered a competing risk, at their date of death. Patients who are alive and relapse free at the end of the trial will be censored at their date last seen. 3. Non-relapse mortality is defined as the time from date of randomisation to date of any death not following relapse. Patients who die post relapse will be considered a competing event at their date of death and patients who are alive at the end of the trial will be censored at their date last seen. 4. Incidence of acute and chronic GVHD of any grade reported throughout the trial. 5. Time to early treatment discontinuation is defined as the time from date of randomisation to date of treatment discontinuation, for any reason. Patients who take the full year of treatment will be censored at 12 months. 6. Safety will be collected in accordance with CTCAE criteria version 4.0 and defined as the number of patients who experience one or more adverse event. 7. Quality of life measured using the EORTC-QLQ-C30 and EQ-5D questionnaires at randomisation i.e. baseline and at 3, 6, 12 (end of treatment) and 24 months post randomisation 8. GVHD-free and relapse-free survival defined as time from date of randomisation to date of first event or death. An event is defined as GVHD or relapse (including molecular relapse and progression). Patients who are alive and event free at the end of the trials will be censored at their date last seen |
| Overall study start date | 07/07/2017 |
| Completion date | 31/03/2027 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Sex | Both |
| Target number of participants | Planned Sample Size: 324; UK Sample Size: 324 |
| Total final enrolment | 326 |
| Key inclusion criteria | Current participant inclusion criteria as of 24/02/2021: 1. Age ≥ 16 years at the time of signing the informed consent form 2. Patients with a diagnosis of any of the below and undergoing allo-SCT using MAC or RIC preparative regimens, and with either peripheral blood or bone marrow as the source of hematopoietic stem cells: 2.1. AML (CR1 or CR2) according to WHO classification 2.2. Secondary AML (defined as a previous history of MDS, antecedent hematological disease, or chemotherapy exposure; CR1 or CR2) 2.3. Advanced or high-risk MDS with an IPSS-R of ≥3.5 (intermediate 3.5 or higher) including intermediate or high-risk CMML (e.g. CPSS int-2 or high risk) 3. At the time of allo-SCT 3.1. No prior allo-SCT 3.2. No more than 1 antigen mismatch at HLA-A, -B, -C, -DRB1 or -DQB1 locus for either related or unrelated donor 3.3. No haplotype or cord blood donor 3.4. Bone marrow blast <5% for AML and <10% for MDS patients 4. Able to commence study therapy between 42 to 84 days following allo-SCT 5. Post-transplant bone marrow: 5.1. AML patients – blast count ≤5% confirmed within 28 days prior to starting study therapy 5.2. MDS patients – confirmation of CR post-transplant with blast count ≤5% in bone marrow 6. Adequate neutrophil and platelet engraftment within 14 days prior to starting study therapy defined as: 6.1. ANC ≥1.0 x 109/l on two consecutive testing without daily use of myeloid growth factor 6.2. Platelet ≥ 50 x 109/l on two consecutive testing without platelet transfusion within 1 week 7. Adequate organ function: 7.1. Serum AST or ALT <3 x upper limit of normal (ULN) 7.2. Serum bilirubin <2 x ULN. Higher levels are acceptable if these can be attributed to active red blood cell (RBC) precursor destruction within the bone marrow (i.e., ineffective erythropoiesis) or Gilbert’s syndrome. 7.3. Serum creatinine <2 x ULN 8. Adequate coagulation (PT ≤15 s and PTT ≤40 s) 9. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 10. Patients with adequately controlled GVHD (defined as GVHD grade <II with concurrent use of corticosteroids equivalent of prednisone at a dose ≤0.5 mg/kg) can be included 11. Females of childbearing potential may participate, providing they meet the following conditions: 11.1. Agree to use at least two effective contraceptive methods (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomised partner) or practice true abstinence throughout the study, and for 3 months following the last dose of study therapy 11.2. Have a negative serum or urine pregnancy test (sensitivity of at least 25 mIU/mL) at screening 11.3. Have a negative serum or urine (investigator’s discretion) pregnancy test (sensitivity of at least 25 mIU/ml) within 72 h prior to starting study therapy. This applies even if the subject practices complete abstinence from heterosexual contact. 12. Male patients with a female partner of childbearing potential must agree to the use of at least two physician-approved contraceptive methods throughout the course of the study and should avoid fathering a child during the course of the study and for 3 months following the last dose study therapy 13. Understand and voluntarily sign an informed consent form (ICF) prior to any study-related assessments or procedures being conducted 14. Able to adhere to the study visit schedule (i.e., clinic visits at the study sites are mandatory unless noted otherwise for study visits) and other protocol requirements Previous participant inclusion criteria: 1. Age > = 16 at the time of signing the informed consent form 2. Patients with a diagnosis of AML (CR1 or CR2) according to WHO classification or high risk MDS (as per IPSS-R) undergoing allo-SCT using MAC or RIC preparative regimens, and with either peripheral blood or bone marrow as the source of hematopoietic stem cells. 3. At the time of allo-SCT: 3.1. No prior allo-SCT; and 3.2. No more than 1 antigen mismatch at HLA-A, -B, -C, -DRB1 or -DQB1 locus for either related or unrelated donor; and 3.3. No haplotype or cord blood donor; and 3.4. Bone marrow blast < 5% for AML and < 10% for MDS patients 4. Able to commence study therapy between 42 to 84 days following allo-SCT 5. Post-transplant bone marrow 5.1. AML patients – blast count < = 5% confirmed within 28 days prior to starting study therapy 5.2. MDS patients – confirmation of CR post-transplant with blast count < = 5% in bone marrow 6. Adequate neutrophil and platelet engraftment within 14 days prior to starting study therapy defined as: 6.1. ANC > = 1.0 x 10^9/L on two consecutive testing without daily use of myeloid growth factor; and 6.2. Platelet > = 50 x 10^9/L on two consecutive testing without platelet transfusion within 1 week 7. Adequate organ function: 7.1. Serum AST and ALT < 3 x upper limit of normal (ULN) 7.2. Serum bilirubin < 2 x ULN. Higher levels are acceptable if these can be attributed to active red blood cell (RBC) precursor destruction within the bone marrow (i.e., ineffective erythropoiesis) or Gilbert’s syndrome 7.3. Serum creatinine < 2 x ULN 8. Adequate coagulation (PT < = 15 seconds, PTT < = 40 seconds, and/or INR < = 1.5) 9. Eastern Cooperative Oncology Group (ECOG) performance status of < = 2 10. Patients with adequately controlled GVHD (defined as GVHD grade < II with concurrent use of corticosteroids equivalent of prednisone at a dose < = 0.5 mg/kg) can be included 11. Females of childbearing potential (FCBP) may participate, providing they meet the following conditions: 11.1. Agree to use at least two effective contraceptive methods (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomised partner) throughout the study, and for 3 months following the last dose of study therapy and 11.2. Have a negative serum pregnancy test (sensitivity of at least 25 mIU/mL) at screening; and 11.3. Have a negative serum or urine (investigator’s discretion) pregnancy test (sensitivity of at least 25 mIU/mL) within 72 hours prior to starting study therapy. This applies even if the subject practices complete abstinence from heterosexual contact. 12. Male patients with a female partner of childbearing potential must agree to the use of at least two physician-approved contraceptive methods throughout the course of the study and should avoid fathering a child during the course of the study and for 3 months following the last dose study therapy 13. Understand and voluntarily sign an informed consent form (ICF) prior to any study related assessments or procedures being conducted 14. Able to adhere to the study visit schedule (i.e., clinic visits at the study sites are mandatory, unless noted otherwise for study visits) and other protocol requirements |
| Key exclusion criteria | Current participant exclusion criteria as of 24/02/2021: 1. Use of any of the following after transplantation and prior to starting study therapy: 1.1. Any agents (chemotherapy or targeted agents) used for adjuvant therapy (note that prophylactic use of these agents is allowed in this study, e.g., methotrexate for GVHD or rituximab for EBV reactivation) 1.2. Unlicensed investigational agents/therapies used within 28 days prior to starting study therapy 1.3. Azacitidine, decitabine or other hypomethylating agent (HMA) 1.4. Lenalidomide, thalidomide and pomalidomide used within 28 days prior to starting study therapy 1.5. Any chemotherapy used for adjuvant therapy 2. Subjects who have undergone a haploidentical or cord blood transplant 3. Active GVHD grade II or higher (acute GVHD Clinical Staging and Grading) 4. Concurrent use of corticosteroids equivalent of prednisone at a dose > 0.5 mg/kg 5. Known active viral infection with Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) 6. Active uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment) 7. History of inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis), celiac disease (i.e., sprue), prior gastrectomy or upper bowel removal, or any other GI disorder or defect that may interfere with the absorption, distribution, metabolism or excretion of the investigational medicinal products (IMPs) and/or predispose the subject to an increased risk of gastrointestinal toxicity prior to allo-SCT 8. Idiopathic thrombocytopenic purpura (ITP), disseminated intravascular coagulation, haemolytic uremic syndrome, thrombotic thrombocytopenic purpura (TTP) 9. History of prior malignancies. However, the following will be exceptions: 9.1. Fully resected basal cell or squamous cell carcinoma of skin 9.2. Treated cervical carcinoma in situ 9.3. Lobular breast carcinoma in situ, 9.4. Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, node, metastasis clinical staging system) 9.5. Previous Myelodysplastic Syndrome (MDS), Chronic Myelomonocytic Leukemia (CMML), Myeloproliferative Neoplasm (MPN) resulting in secondary acute myeloid leukaemia (AML) 9.6. Cancer treated with curative intent ≥5 years previously 10. Significant active cardiac disease within the previous 6 months, including: 10.1. New York Heart Association (NYHA) class III or IV congestive heart failure 10.2. Unstable angina or angina requiring surgical or medical intervention; and/or 10.3. Myocardial infarction 11. Known or suspected hypersensitivity to azacitidine or mannitol 12. Pregnant or lactating females 13. Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the patient from participating in the study. 14. Any condition including the presence of laboratory abnormalities, which places the patient at unacceptable risk if he/she were to participate in the study 15. Any condition that confounds the ability to interpret data from the study Previous participant exclusion criteria: 1. Use of any of the following after transplantation and prior to starting study therapy: 1.1. Any agents (chemotherapy or targeted agents) used for adjuvant therapy (note that prophylactic use of these agents is allowed in this study, e.g., methotrexate for GVHD or rituximab for EBV reactivation) 1.2. Unlicensed investigational agents/therapies used within 28 days prior to starting study therapy 1.3. Azacitidine, decitabine or other hypomethylating agent (HMA) 1.4. Lenalidomide, thalidomide and pomalidomide used within 28 days prior to starting study therapy 2. Subjects who have undergone a haploidentical or cord blood transplant 3. Active GVHD grade II or higher (acute GVHD Clinical Staging and Grading) 4. Concurrent use of corticosteroids equivalent of prednisone at a dose > 0.5 mg/kg 5. Known active viral infection with Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) 6. Active uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment) 7. History of inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis), celiac disease (i.e., sprue), prior gastrectomy or upper bowel removal, or any other GI disorder or defect that may interfere with the absorption, distribution, metabolism or excretion of the investigational medicinal products (IMPs) and/or predispose the subject to an increased risk of gastrointestinal toxicity prior to allo-SCT 8. Idiopathic thrombocytopenic purpura (ITP), disseminated intravascular coagulation, haemolytic uremic syndrome, thrombotic thrombocytopenic purpura (TTP) 9. Prior history of/concurrent malignancies (including CMML). However, subjects with the following history/concurrent conditions are allowed: 9.1. Basal or squamous cell carcinoma of the skin 9.2. Carcinoma in situ of the cervix 9.3. Carcinoma in situ of the breast 9.4. Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, node, metastasis (TNM) clinical staging system) 10. Significant active cardiac disease within the previous 6 months, including: 10.1. New York Heart Association (NYHA) class III or IV congestive heart failure 10.2. Unstable angina or angina requiring surgical or medical intervention; and/or 10.3. Myocardial infarction 11. Known or suspected hypersensitivity to azacitidine or mannitol 12. Pregnant or lactating females 13. Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the patient from participating in the study. 14. Any condition including the presence of laboratory abnormalities, which places the patient at unacceptable risk if he/she were to participate in the study 15. Any condition that confounds the ability to interpret data from the study |
| Date of first enrolment | 14/06/2019 |
| Date of final enrolment | 27/03/2023 |
Locations
Countries of recruitment
- England
- Scotland
- United Kingdom
- Wales
Study participating centres
Beatson West of Scotland Cancer Centre
Glasgow
G12 0YN
United Kingdom
G12 0YN
United Kingdom
King's College Hospital
London
SE5 9RS
United Kingdom
SE5 9RS
United Kingdom
St. James's University Hospital
Leeds
LS9 7TF
United Kingdom
LS9 7TF
United Kingdom
Manchester Royal Infirmary
Manchester
M13 9WL
United Kingdom
M13 9WL
United Kingdom
Freeman Hospital
Newcastle-Upon-Tyne
NE7 7DN
United Kingdom
NE7 7DN
United Kingdom
Churchill Hospital
Oxford
OX3 7LE
United Kingdom
OX3 7LE
United Kingdom
Queen Elizabeth Hospital
Birmingham
B15 2TH
United Kingdom
B15 2TH
United Kingdom
St Bartholomew’s Hospital
London
EC1A 7BE
United Kingdom
EC1A 7BE
United Kingdom
Bristol Haematology and Oncology Centre
Bristol
BS2 8ED
United Kingdom
BS2 8ED
United Kingdom
University College London Hospitals
London
NW1 2BU
United Kingdom
NW1 2BU
United Kingdom
Addenbrookes Hospital
Cambridge
CB2 0QQ
United Kingdom
CB2 0QQ
United Kingdom
University Hospital of Wales
Cardiff
CF14 4XW
United Kingdom
CF14 4XW
United Kingdom
Christie Hospital
Manchester
M20 4BX
United Kingdom
M20 4BX
United Kingdom
Hammersmith Hospital
London
W12 0HS
United Kingdom
W12 0HS
United Kingdom
Leicester Royal Infirmary
Leicester
LE1 5WW
United Kingdom
LE1 5WW
United Kingdom
The Clatterbridge Cancer Centre
Liverpool
CH63 4JY
United Kingdom
CH63 4JY
United Kingdom
Nottingham City Hospital
Nottingham
NG5 1PB
United Kingdom
NG5 1PB
United Kingdom
Derriford Hospital
Plymouth
PL6 8DH
United Kingdom
PL6 8DH
United Kingdom
The Royal Marsden Hospital
London
SW3 6JJ
United Kingdom
SW3 6JJ
United Kingdom
Royal Hallamshire Hospital
Sheffield
S5 7AU
United Kingdom
S5 7AU
United Kingdom
Sponsor information
University of Birmingham
University/education
University/education
Research Support Group
Aston Webb Building
Edgbaston
Birmingham
B15 2TT
England
United Kingdom
| Phone | +44 (0)121 371 7858 |
|---|---|
| amadeus@trials.bham.ac.uk | |
"ROR" |
https://ror.org/03angcq70 |
Funders
Funder type
Charity
IMPACT (funded by NHS Blood & Transplant, Anthony Nolan and Leuka)
No information available
Celgene
Private sector organisation / For-profit companies (industry)
Private sector organisation / For-profit companies (industry)
- Alternative name(s)
- Celgene Corporation
- Location
- United States of America
Results and Publications
| Intention to publish date | 31/03/2027 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | Planned publication in a high-impact peer reviewed journal |
| IPD sharing plan | The data sharing plans for the current study are unknown and will be made available at a later date. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 28/06/2023 | No | No |
Editorial Notes
23/05/2025: The following changes were made to the trial record:
1. The overall end date was changed from 30/04/2025 to 31/03/2027.
2. Contact details updated.
14/04/2023: The recruitment end date was changed from 30/04/2023 to 27/03/2023. Total final enrolment added.
14/07/2022: Trial website added.
13/06/2022: The following changes have been made:
1. The recruitment end date has been changed from 14/06/2022 to 30/04/2023.
2. The overall trial end date has been changed from 14/06/2024 to 30/04/2025.
3. The intention to publish date has been changed from 01/04/2025 to 30/04/2026.
20/09/2021: Internal review.
24/02/2021: The following changes have been made:
1. The trial contact has been updated.
2. The ClinicalTrials.gov number has been added.
3. The participant inclusion criteria have been updated.
4. The participant exclusion criteria have been updated.
5. The trial participating cenrtres "Birmingham Heartlands Hospital" and "Southampton General Hospital" have been removed.
04/06/2020: Recruitment for this study is no longer paused.
20/04/2020: Due to current public health guidance, recruitment for this study has been paused.
18/03/2020: Link to plain English summary on CRUK added.
05/08/2019: Internal review.
08/07/2019: The funder name was updated from 'Leuka' to 'IMPACT (funded by NHS Blood & Transplant, Anthony Nolan and Leuka)'.
05/07/2019: Ethics approval information added.
21/06/2019: Internal review.
14/06/2019: The following changes were made to the trial record:
1. The recruitment start date was changed from 01/04/2019 to 14/06/2019.
2. The recruitment end date was changed from 01/04/2022 to 14/06/2022.
3. The overall trial end date was changed from 01/04/2024 to 14/06/2024.
05/04/2019: Internal review.
22/03/2019: The condition has been changed from "Specialty: Cancer, Primary sub-specialty: Haematological Oncology; Health Category: Cancer and neoplasms; Disease/Condition: Malignant neoplasms, stated or presumed to be primary, of lymphoid, haematopoietic and related tissue" to "Acute myeloid leukaemia, myelodysplastic syndromes" following a request from the NIHR.
