Clinical Trials Register

Summary
EudraCT Number:	2018-001012-30
Sponsor's Protocol Code Number:	RG_18-048
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2019-11-08
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2018-001012-30

A.3

Full title of the trial

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

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

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

A.3.2

Name or abbreviated title of the trial where available

AMADEUS

A.4.1

Sponsor's protocol code number

RG_18-048

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	University of Birmingham
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Leuka
B.4.2	Country	United Kingdom
B.4.1	Name of organisation providing support	Anthony Nolan
B.4.2	Country	United Kingdom
B.4.1	Name of organisation providing support	NHS Blood & Transplant
B.4.2	Country	United Kingdom
B.4.1	Name of organisation providing support	Celgene International II Sàrl
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	CRUK Clinical Trials Unit
B.5.2	Functional name of contact point	Professor Charles Craddock
B.5.3	Address:
B.5.3.1	Street Address	Centre for Clinical Haematology, Queen Elizabeth Hospital
B.5.3.2	Town/ city	Birmingham
B.5.3.3	Post code	B15 2TH
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	01213714374
B.5.6	E-mail	amadeus@trials.bham.ac.uk

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Oral azacitidine
D.3.2	Product code	CC-486
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Azacitidine
D.3.9.1	CAS number	320-67-2
D.3.9.2	Current sponsor code	CC-486
D.3.9.3	Other descriptive name	4-Amino-1-beta-D-ribofuranosyl-S-triazin-2(1H)-one
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Azacitidine
D.3.9.1	CAS number	320-67-2
D.3.9.2	Current sponsor code	CC-486
D.3.9.3	Other descriptive name	4-Amino-1-beta-D-ribofuranosyl-S-triazin-2(1H)-one
D.3.9.4	EV Substance Code	AS2
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Acute Myeloid Leukaemia (AML) and Myelodysplasia (MDS)

E.1.1.1

Medical condition in easily understood language

Blood cancer

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10000880
E.1.2	Term	Acute myeloid leukaemia
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10028532
E.1.2	Term	Myelodysplasia
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

The principle objective of the trial is to determine whether 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 post allo-SCT

E.2.2

Secondary objectives of the trial

The secondary objectives are to compare overall survival, cumulative incidence of relapse, non-relapse mortality, incidence of acute and chronic graft-versus-host-disease (GVHD), time to treatment discontinuation with oral azacitidine compared with placebo, safety, quality of life (QoL) and GVHD-free and relapse-free survival.

E.2.3

Trial contains a sub-study

E.3

Principal 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
• No prior allo-SCT; and
• No more than 1 antigen mismatch at HLA-A, -B, -C, -DRB1 or -DQB1 locus for either related or unrelated donor; and
• No haplotype or cord blood donor; and
• 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
• AML patients – blast count ≤ 5% confirmed within 28 days prior to starting study therapy
• 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:
• ANC ≥ 1.0 x 10^9/L on two consecutive testing without daily use of myeloid growth factor; and
• Platelet ≥ 50 x 10^9/L on two consecutive testing without platelet transfusion within 1 week
7. Adequate organ function:
• Serum AST and ALT < 3 x upper limit of normal (ULN)
• 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
• 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:
a. 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
b. Have a negative serum pregnancy test (sensitivity of at least 25 mIU/mL) at screening; and
c. 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

E.4

Principal exclusion criteria

1. Use of any of the following after transplantation and prior to starting study therapy:
• 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)
• Unlicensed investigational agents/therapies used within 28 days prior to starting study therapy
• Azacitidine, decitabine or other hypomethylating agent (HMA)
• 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:
• Basal or squamous cell carcinoma of the skin
• Carcinoma in situ of the cervix
• Carcinoma in situ of the breast
• 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:
• New York Heart Association (NYHA) class III or IV congestive heart failure
• Unstable angina or angina requiring surgical or medical intervention; and/or
• 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

E.5 End points

E.5.1

Primary end point(s)

To compare relapse free survival of patients with AML or high risk MDS treated with maintenance therapy of oral azacitidine versus placebo post allo-SCT

E.5.1.1

Timepoint(s) of evaluation of this end point

At 12 and 24 months from the date of randomisation.

E.5.2

Secondary end point(s)

To compare overall survival (OS), cumulative incidence of relapse (CIR), non-relapse mortality (NRM), incidence of acute and chronic graft-versus-host-disease (GVHD), time to treatment discontinuation with oral azacitidine compared with placebo, safety and tolerability, quality of life (QoL) and GvHD-free and relapse-free survival (GRFS).

E.5.2.1

Timepoint(s) of evaluation of this end point

OS and CIR are evaluated at 12 and 24 months from the date of randomisation.
NRM and time to treatment discontinuation are evaluated at day 100 and month 12 from the date of randomisation.
GRFS and incidence of acute and chronic GVHD are evaluated throughout the trial.
QoL is evaluated at baseline and then at 3, 6 and 24 months post randomisation as well as at 12 months post-transplant (end of treatment)

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

The end of the trial will be the last patients' last follow-up visit (i.e. month 24 visit)

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1