Clinical trial NCT01757535
Conditions: Leukemia, Myeloid, Acute
Keywords: Maintenance therapy AML Acute Myeloid Leukemia Oral Azacitidine Best supportive care Complete remission
Sponsor: Celgene
Start date: 2013-04-24; Completion date: 2024-06-18
Enrollment: 472 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study enrolled 472 participants, aged 55 or older, with a diagnosis of de novo acute myeloid leukemia (AML) or AML secondary to prior myelodysplastic disease or chronic myelomonocytic leukemia (CMML), and who have achieved first complete remission (CR)/ complete remission with incomplete blood count recovery (CRi) following induction with or without consolidation chemotherapy.

The study is amended to include an extension phase (EP). The EP allows participants who are currently receiving oral azacitidine and who are demonstrating clinical benefit as assessed by the investigator, to continue receiving oral azacitidine after unblinding by sponsor until the participant meets the criteria for study discontinuation or until oral azacitidine becomes commercially available and reimbursed. In addition, all participants in the placebo arm and participants who had been discontinued from the treatment phase (irrespective of randomization arm) and continuing in the follow-up phase will be followed for survival in the EP.

Detailed description:
This is an international, multicenter, placebo-controlled, Phase 3 study with a double-blind, randomized, parallel-group design in subjects with de novo AML or AML secondary to prior diagnosis of myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) aged ≥ 55 years, who are in first CR/CRi following induction therapy with or without consolidation chemotherapy. The study consists of 3 phases; the pre-randomization phase (screening phase), the treatment phase, and the follow-up phase.

The study is amended to include an extension phase (EP). The EP allows participants who are currently receiving oral azacitidine and who are demonstrating clinical benefit as assessed by the Investigator, to continue receiving oral azacitidine after unblinding by sponsor until they meet the criteria for study discontinuation or until oral azacitidine becomes commercially available and reimbursed. In addition, all participants in the placebo arm and participants who had been discontinued from the treatment phase (irrespective of randomization arm) and continuing in the follow-up phase will be followed for survival in the EP.

Arms: arm 1: 300 mg oral azacitidine on days 1 to 14 of each 28-day treatment cycle. arm 2: Identically matching placebo tablets on days 1 to 14 of each 28-day treatment cycle.
Interventions: intervention 1: Oral Azacitidine intervention 2: Placebo
Intervention descriptions: intervention 1: 300 mg oral azacitidine on days 1 to 14 of each 28-day treatment cycle. intervention 2: Identically matching placebo tablets on days 1 to 14 of each 28-day treatment cycle.

Protocol documents:
Prot_000.pdf: 
EDMS Doc. Number: 23107036 - 17852850
Oral Azacitidine (CC-486)
Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
1
CC-486-AML-001 Amendment 2.0 Final: 08 Nov 2018
TITLE PAGE
A PHASE 3, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY TO COMPARE 
EFFICACY AND SAFETY OF ORAL AZACITIDINE 
PLUS BEST SUPPORTIVE CARE VERSUS BEST 
SUPPORTIVE CARE AS MAINTENANCE THERAPY IN 
SUBJECTS WITH ACUTE MYELOID LEUKEMIA IN 
COMPLETE REMISSION
INVESTIGATIONAL PRODUCT (IP):
Oral Azacitidine (CC-486)
PROTOCOL NUMBER:
CC-486-AML-001 
DATE FINAL:
15 Aug 2012
AMENDMENT 1.0 DATE FINAL:
29 Dec 2015
AMENDMENT 2.0 DATE FINAL:
08 Nov 2018
EudraCT NUMBER:
2012-003457-28
IND NUMBER:
074618
SPONSOR NAME / ADDRESS:
Celgene Corporation
CONFIDENTIAL
This protocol is provided to you as an Investigator, potential Investigator, or 
consultant for review by you, your staff, and ethics committee/institutional 
review board.  The information contained in this document is regarded as 
confidential and, except to the extent necessary to obtain informed consent, 
may not be disclosed to another party unless such disclosure is required by 
law or regulations.  Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further 
disclosed by them.


EDMS Doc. Number: 23107036 - 17852850
Oral Azacitidine (CC-486)
Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
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CC-486-AML-001 Amendment 2.0 Final: 08 Nov 2018
MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
Contact Information:
Name:
Ignazia La Torre, MD.
Title:
 Address:
 
Phone:
E-mail:
Note: The back-up 24-hour global emergency contact call center should only be used if you are 
not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls.
Back-up 24 Hour Global Emergency Contact Call Center: 


EDMS Doc. Number: 23107036 - 17852850
Oral Azacitidine (CC-486)
Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
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CC-486-AML-001 Amendment 2.0 Final: 08 Nov 2018
CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
Printed Name of Celgene Therapeutic Area Head and Title
By my signature, I indicate I have reviewed this protocol and find its content to be 
acceptable.  


EDMS Doc. Number: 23107036 - 17852850
Oral Azacitidine (CC-486)
Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
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CC-486-AML-001 Amendment 2.0 Final: 08 Nov 2018
SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Site Principal Investigator
dd mmm yyyy
Printed Name of Site Principal Investigator
Institution Name: _______________________________________
By my signature, I agree to personally supervise the conduct of this study at my study 
site and to ensure its conduct is in compliance with the protocol, informed consent, 
Institutional Review Board (IRB)/Ethics Committee (EC) procedures, instructions from 
Celgene representatives, the Declaration of Helsinki, ICH Good Clinical Practices 
Guidelines, and local regulations governing the conduct of clinical studies.


EDMS Doc. Number: 23107036 - 17852850
Oral Azacitidine (CC-486)
Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
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CC-486-AML-001 Amendment 2.0 Final: 08 Nov 2018
COORDINATING PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Coordinating Principal Investigator
dd mmm yyyy
Printed Name of Coordinating Principal Investigator
Institution Name: _______________________________________
By my signature, I agree the protocol has been written to comply with ICH Good 
Clinical Practices guidelines and agree to offer guidance throughout the study as 
needed.


EDMS Doc. Number: 23107036 - 17852850
Oral Azacitidine (CC-486)
Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
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CC-486-AML-001 Amendment 2.0 Final: 08 Nov 2018
PROTOCOL SUMMARY
A Phase 3, randomized, double-blind, placebo-controlled study to compare efficacy and safety of 
oral azacitidine plus best supportive care versus best supportive care as maintenance therapy in 
subjects with acute myeloid leukemia in complete remission.
Indication
Maintenance therapy for acute myeloid leukemia (AML) in subjects aged 55 years and over, who 
are in first complete remission.
Objectives
Primary Objective
The primary objective of the study is to evaluate whether maintenance therapy with oral 
azacitidine improves overall survival (OS) compared with placebo in subjects with AML, age ≥ 
55 years, who have achieved first complete remission (CR) or complete remission with 
incomplete blood count recovery (CRi) after induction with intensive chemotherapy with or 
without consolidation chemotherapy.
Secondary Objectives
The secondary objectives of the study are:

To determine relapse-free survival (RFS); 

To determine safety, tolerability; and

To determine the effect of oral azacitidine compared with placebo on health-related 
quality-of-life (HRQoL) and healthcare resource utilization.
Exploratory objectives
 
 
 
Study Design
This is an international, multicenter, placebo-controlled, Phase 3 study with a double-blind, 
randomized, parallel-group design in subjects with de novo AML or AML secondary to prior 
diagnosis of myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML)
aged ≥ 55 years, who are in first CR/CRi following induction therapy with or without 
consolidation chemotherapy.  
The study consists of 3 phases; Pre-randomization Phase, Treatment Phase, and Follow-up Phase 
(Figure 1).


EDMS Doc. Number: 23107036 - 17852850
Oral Azacitidine (CC-486)
Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
7
CC-486-AML-001 Amendment 2.0 Final: 08 Nov 2018
Pre-Randomization Phase (Screening Phase)
Screening procedures are to occur during the Pre-randomization Phase.  Screening procedures 
are to take place within 28 days prior to randomization.  Subject eligibility for randomization 
will be based on the documentation of achieving and maintaining CR/CRi following diagnosis 
and induction/consolidation treatment of AML, as verified by central pathology and cytogenetics 
review.
Newly diagnosed subjects, ≥55 years of age, who have a confirmed diagnosis of AML according 
to the criteria set by the World Health Organization (WHO) 2008 classification 
 
, who have achieved first CR/CRi status after induction therapy and with/without 
consolidation therapy will be eligible for randomization (within 4 months [± 7 days] of achieving 
first CR/CRi).  The definitions of response criteria for CR or CRi are primarily those defined by 
the International Working Group (IWG) on AML 
 and are described 
below:
Complete Remission (CR)
Complete Remission with Incomplete Blood 
Count Recovery (CRi)

< 5% of blasts in bone marrow  

absence of blasts with Auer rods

absence of extramedullary disease

independent of blood transfusions

neutrophil counts > 1.0 x 109/L

platelet counts ≥ 100 x 109/L

< 5% of blasts in bone marrow  

absence of blasts with Auer rods

absence of extramedullary disease

independent of blood transfusions

neutrophil counts < 1.0 x 109/L
or platelet counts < 100 x 109/L
A screening bone marrow aspirate, bone marrow biopsy and peripheral blood smear will be sent 
to the central pathology reviewer for analysis and confirmation of CR/CRi.  A standard 
cytogenetic metaphase preparation will be made from the bone marrow aspirate at the central
laboratory for cytogenetic analysis. 
Additional screening assessments include demographics and medical history, prior treatments for 
AML (and other malignancy, if applicable), prior medications, Eastern Cooperative Oncology 
Group (ECOG) performance status (Appendix B), physical examination, vital signs, weight and 
height measurements, complete blood count (CBC) with differential count, blood chemistry, 
serum erythropoietin (EPO) level, urinalysis, coagulation screening, serum ferritin level, 
pregnancy testing (females of childbearing potential [FCBP] only), electrocardiogram (ECG), 
chest x-ray, transplant eligibility, documentation of induction and consolidation therapies, 
healthcare resource utilization and bone marrow and peripheral blood sampling for biomarker 
analysis.  Adverse events (AEs), including second primary malignancies (SPMs) will be 
collected beginning on the date of signed informed consent document (ICD).
Randomization and Double-blind Treatment Phase
Following confirmation of eligibility at screening, subjects will be randomized 1:1 to receive 
300 mg oral azacitidine once a day (QD) or placebo, for 14 days of each 28 day cycle.  
Randomization will occur by a central randomization procedure using an Interactive Voice 
Response System (IVRS).  Randomization must occur within 4 months (± 7 days) of achieving 
CR/CRi.


EDMS Doc. Number: 23107036 - 17852850
Oral Azacitidine (CC-486)
Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
8
CC-486-AML-001 Amendment 2.0 Final: 08 Nov 2018
After randomization, no crossover between the treatment arms will be permitted at any point 
during the study.  During the double-blind treatment phase, subjects will ingest investigational 
product (IP) (azacitidine tablets or placebo tablets) a once a day in a fed or fasted state on the 
first 14 days of each 28-day cycle (Section 8.2.3 for details).  Dose modifications may occur for 
managing toxicity or disease progression if necessary during treatment (Section 8.2.5).
During the double-blind treatment phase, subjects will be assessed for safety, tolerability and 
efficacy.  Assessments during the double-blind treatment phase will include monitoring for AEs, 
monitoring for relapse of AML and SPMs, physical examination, vital signs and weight 
measurement, ECOG performance status, hematology and serum chemistry, serum ferritin level, 
pregnancy testing (FCBP only), concomitant medications, therapies and procedures, review of 
bone marrow aspirate (or biopsy if adequate aspirate is not attainable) and peripheral blood 
smear slides, cytogenetic analysis, assessing hematological response/improvement, CR/CRi 
status assessment, bone marrow and peripheral blood sampling for biomarker analysis, 
peripheral blood sampling for pharmacokinetics (PK) analysis, IP administration and 
accountability, HRQoL, and healthcare resource utilization.
A separate central review of all bone marrow aspirates, bone marrow biopsies, and peripheral 
blood smears will be conducted by a pathologist blinded to subject treatment.  The central 
reviewer’s assessments will be used to confirm the CR/CRi status at screening and during 
treatment for maintenance assessment.  If the central reviewer and local pathologist disagree on 
the CR/CRi status of a subject, a third party reviewer will adjudicate and make the final 
assessment.  
The central cytogenetic review will provide standardized analysis and reporting for all subjects, 
regardless of the laboratory performing the initial analysis (local or central).  
 
 
 
  
 
 


EDMS Doc. Number: 23107036 - 17852850
Oral Azacitidine (CC-486)
Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
9
CC-486-AML-001 Amendment 2.0 Final: 08 Nov 2018
CR/CRi Status Assessment
First status assessment for maintenance of CR/CRi will occur at Cycle 3. If CR/CRi status is 
maintained, subjects can continue on to Cycle 4 and beyond. Subjects will be further assessed for 
CR/CRi status at Cycles 6, 9, 12, 15, 18, 21, 24, 30, 36 and the Treatment Discontinuation visit.  
After Cycle 36, bone marrow evaluation for the assessment of maintenance of CR/CRi will occur 
only if clinically indicated at the discretion of the Investigator. Subjects may be discontinued 
from treatment at the Investigator’s discretion for any of the reasons detailed in Section 12.  
Dose and Schedule Adjustment in Subjects with Disease Relapse/Progression
In subjects on study who have subsequent evidence of disease relapse with blasts > 5% either in 
the peripheral blood count or bone marrow, and provided the blasts are no greater than 15% in 
the blood or bone marrow, escalation of the dosing regimen (dose and/or schedule) can be 
implemented as follows (provided it is in the subject’s best interest to do so as judged by the 
Investigator):

Subject currently on blinded treatment with oral azacitidine 300 mg or placebo QD for 14 
days - escalate schedule to oral azacitidine 300 mg or placebo QD for 21 days

In the event that dose had previously been reduced, subject currently on blinded treatment 
of oral azacitidine 200 mg or placebo QD for 14 days - escalate schedule as a first step, to 
21 days QD and then escalate dose to oral azacitidine or placebo to 300 mg QD for 21 
days

Subject currently on blinded treatment with oral azacitidine 200 mg or placebo QD for 7
days - escalate schedule as a first step, to oral azacitidine 200 mg or placebo QD for 14 
days and then escalate dose to oral azacitidine 300 mg or placebo QD for 14 days
Subject Discontinuation from Treatment following AML Relapse
Subjects will be discontinued from treatment when they meet the following criteria:

Appearance of > 15% blasts in the bone marrow or peripheral blood; and

The above occurrence should be attributed to relapse following CR/CRi, and not 
attributable to any other cause (eg, bone marrow regeneration after consolidation 
therapy).
Prior to discontinuing a subject from treatment due to AML relapse or for any other cause, the 
Investigator should contact the sponsor or its designee and forward appropriate supporting 
documents for review and discussion.
Follow-up Phase
All discontinued subjects, regardless of reason for discontinuation, should undergo Treatment 
Discontinuation visit procedures at the time of study discontinuation.  Subjects will have a 
follow-up visit for the collection of AEs up to 28 days after last dose of IP or up to the end-of-
treatment visit, whichever is longer.  After this follow-up visit, subjects will be followed for 
survival, by telephone, every month for the first year and then every 3 months until death, 
withdrawal of consent for further follow-up, study end, or until a subject is lost to follow-up.


EDMS Doc. Number: 23107036 - 17852850
Oral Azacitidine (CC-486)
Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
10
CC-486-AML-001 Amendment 2.0 Final: 08 Nov 2018
Extension Phase (EP)
Upon a site’s IRB/IEC approval of Protocol Amendment 2 which allows for an EP, after study 
unblinding by Celgene, any subject randomized to the oral azacitidine arm, who continues to 
receive oral azacitidine, who demonstrates clinical benefit as assessed by their Investigator, and 
consents to participate in Extension Phase, may continue to receive oral azacitidine in the EP (at 
their current dose) at the start of their next cycle.  To receive oral azacitidine in the EP, the 
subject must not have been discontinued from receiving IP prior to entering this EP of the study. 
Subjects randomized into the placebo arm will discontinue treatment and will not receive oral 
azacitidine in the EP.  However, upon consent, these subjects may be transitioned into the EP 
and followed for survival.
In addition, any subject who was discontinued from the treatment phase (irrespective of 
randomization arm), upon providing additional consent, may enter the EP, where they will be 
followed for survival (without receiving oral azacitidine) for at least another 12 months, until 
death, withdrawal of consent or study closure, or lost to follow-up.  Details for the EP are 
provided in Appendix K.
Study Population
This study will enroll approximately 460 subjects, aged 55 or older, with a diagnosis of de novo
AML or AML secondary to prior myelodysplastic disease or CMML, and who have achieved 
first CR/CRi following induction with or without consolidation chemotherapy.  Subjects who 
have previously achieved CR/CRi with a hypomethylating agent will be excluded from the study. 
The study will be conducted at approximately 180 clinical sites worldwide.
Length of Study
The study will close once the total number of events (n=330 deaths) required for a fully powered 
analysis of OS have occurred.  The expected duration of the study is 91 months, including a 53-
month subject accrual period, followed by an additional 24-month period of treatment and/or 
observation. At the investigator’s discretion, subjects can continue beyond 24 months of 
treatment or until the study closes.  
The sponsor may consider closing this trial when data supporting key endpoints and objectives of 
the study have been analyzed. In a case where there are subjects still being administered the
investigational product, and it is the opinion of the investigator(s) that those subjects would
continue to receive benefit from treatment, the sponsor has chosen to initiate an extension phase 
(EP) to ensure drug access for patients benefiting from oral azacitidine but as well continued 
collection of survival information for patients on placebo and patients in Follow-up Phase at the 
time of unblinding.
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
post-treatment follow-up, or the date of receipt of the last data point from the last subject that is 
required for primary and/or secondary analysis, as pre-specified in the protocol, whichever is the 
later date.


EDMS Doc. Number: 23107036 - 17852850
Oral Azacitidine (CC-486)
Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
11
CC-486-AML-001 Amendment 2.0 Final: 08 Nov 2018
Study Treatments
Oral Azacitidine/Placebo
Subjects will be randomized 1:1 basis to receive 300 mg oral azacitidine or placebo for the first 
14 days of each 28-day treatment cycle until no longer receiving the benefit or until the end of 
the study.  
Best Supportive Care
Best supportive care (BSC) is not a treatment regimen in this study.  However, it may be used in 
combination with the study treatment (oral azacitidine or placebo) as deemed necessary.  Best 
supportive care includes, but is not limited to, treatment with red blood cell (RBC) transfusions 
(packed red blood cell [pRBC] or whole blood), single donor or pooled donor platelet 
transfusions, use of erythropoiesis stimulating agent (ESAs) and other RBC hematopoietic 
growth factors, antibiotic, antiviral and/or antifungal therapy, granulocyte colony stimulating 
factors (G-CSFs) and nutritional support (Section 8.1.2)
Overview of Efficacy Assessments
The primary efficacy endpoint is OS. 
The secondary efficacy endpoints include RFS, and time to relapse from CR/CRi, time to 
discontinuation from treatment, safety/tolerability, patient-reported outcomes utilizing the
Functional Assessment of Chronic Illness Therapy – Fatigue Scale (FACIT-Fatigue Scale) and 
the EQ-5D and measures of healthcare resource utilization.  Response will be independently 
assessed by a collection of hematology laboratory parameters, peripheral blood smear, bone 
marrow aspirates or biopsies along with cytogenetic information (if applicable). 
Overview of Safety Assessments
Safety assessments include adverse events, monitoring of SPM, hematology [complete blood 
count (CBC) with differential] and serum blood chemistry analyses, body weight measurement, 
physical exam, vital signs, pregnancy testing (for FCBP subjects) and concomitant 
medication/therapy.  Urinalysis, ECG and coagulation will be repeated whenever clinically 
indicated during the double-blind treatment phase.
Overview of Health-Related Quality of Life and Healthcare Resource Utilization 
Assessments
 
 
 
  
  
 
 
 
 
 


EDMS Doc. Number: 23107036 - 17852850
Oral Azacitidine (CC-486)
Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
12
CC-486-AML-001 Amendment 2.0 Final: 08 Nov 2018
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


EDMS Doc. Number: 23107036 - 17852850
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Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
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CC-486-AML-001 Amendment 2.0 Final: 08 Nov 2018
 
Data Monitoring Committee
An external independent Data Monitoring Committee (DMC) with multi-disciplinary 
representation will evaluate safety, futility and compliance prospectively.  The DMC will be 
comprised of medical hematologists/oncologists with experience in treating subjects with AML 
and a statistician, all of whom are not otherwise involved in the study as Investigators.  The 
DMC responsibilities, authorities, and procedures will be documented in the DMC charter, 
which will be endorsed by the DMC prior to the first DMC data review meeting.  An 
external/independent statistician will generate critical safety reports on an unblinded basis for the 
DMC to review periodically.  The DMC chairman may convene formal DMC meetings if there 
are safety concerns.  The sponsor can also request additional DMC review of safety data in case 
of emerging safety concerns.  The DMC responsibilities, authorities, and procedures will be 
detailed in the DMC charter which will be signed by DMC members before the first DMC data 
review meeting.  


EDMS Doc. Number: 23107036 - 17852850
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TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
PROTOCOL SUMMARY ..........................................................................................................6
2.
STUDY OBJECTIVES...........................................................................................28
2.1.
Primary Objective...................................................................................................28
2.2.
Secondary Objectives .............................................................................................28
3.
STUDY ENDPOINTS............................................................................................29
3.1.
Primary Endpoint(s) ...............................................................................................29
3.2.
Secondary Endpoint(s)............................................................................................29
4.
OVERALL STUDY DESIGN ................................................................................30
4.1.
Study Design ..........................................................................................................30
4.3.
Study Duration .......................................................................................................36
5.
TABLE OF EVENTS.............................................................................................38
6.
PROCEDURES......................................................................................................44
6.1.
Screening................................................................................................................44
6.2.
Information to be Collected on Screening Failures..................................................46
6.3.
Entering a Subject Into the Study............................................................................47
6.4.
Baseline..................................................................................................................47
6.5.
Treatments..............................................................................................................47
6.6.
Safety.....................................................................................................................48
6.6.1.
Adverse Events.......................................................................................................48
6.6.2.
Second Primary Malignancies.................................................................................48
6.6.3.
Physical Examination .............................................................................................49
6.6.4.
Vital Signs Measurement........................................................................................49


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6.6.5.
Weight....................................................................................................................49
6.6.6.
Hematology and Serum Chemistry Laboratory Evaluations ....................................49
6.6.7.
Pregnancy Testing (FCBP only)..............................................................................49
6.6.8.
Concomitant medications/significant non-drug therapies/concomitant 
procedures..............................................................................................................50
6.7.
Efficacy..................................................................................................................50
6.9.
Health-related Quality of Life.................................................................................51
6.10.
Health Resource Utilization....................................................................................51
6.12.
Unscheduled Visits.................................................................................................52
6.13.
Discontinuation ......................................................................................................52
6.14.
Follow-up...............................................................................................................53
6.15.
Extension Phase......................................................................................................53
7.
STUDY POPULATION.........................................................................................54
7.1.
Number of Subjects and Sites .................................................................................54
7.2.
Inclusion Criteria....................................................................................................54
7.3.
Exclusion Criteria...................................................................................................55
7.4.
Inclusion and Exclusion Criteria for EP ..................................................................56
8.
DESCRIPTION OF STUDY TREATMENTS........................................................57
8.1.
Description of Investigational Product(s)................................................................57
8.1.1.
Azacitidine and Placebo..........................................................................................57
8.1.2.
Best Supportive Care ..............................................................................................57
8.2.
Treatment Administration and Schedule .................................................................57
8.2.1.
Investigational Product Treatment Schedule ...........................................................57
8.2.2.
Investigational Product Dispensation ......................................................................57
8.2.3.
Investigational Product Administration...................................................................58
8.2.4.
Missing Doses ........................................................................................................58
8.2.5.
Dose Modifications for Toxicity.............................................................................58
8.2.6.
Dose and Schedule Adjustment in Subjects with AML Relapse/Progression...........61
8.2.7.
Re-treatment Criteria ..............................................................................................62
8.3.
Method of Treatment Assignment...........................................................................62
8.4.
Packaging and Labeling..........................................................................................63


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8.5.
Clinical Supplies.....................................................................................................63
8.6.
Investigational Product Accountability and Disposal ..............................................64
8.7.
Investigational Product Compliance........................................................................64
8.8.
Blinding..................................................................................................................65
8.9.
Emergency Unblinding...........................................................................................65
9.
CONCOMITANT MEDICATIONS AND PROCEDURES....................................66
9.1.
Permitted Concomitant Medications and Procedures...............................................66
9.2.
Prohibited Concomitant Medications and Procedures..............................................67
9.3.
Required Concomitant Medications and Procedures................................................67
10.
STATISTICAL ANALYSES..................................................................................68
10.1.
Overview................................................................................................................68
10.2.
Study Population Definitions ..................................................................................68
10.2.1.
Intent-to-Treat Population.......................................................................................68
10.2.2.
Modified Intent-to-Treat Population .......................................................................68
10.2.3.
Safety Population....................................................................................................68
10.3.
Sample Size and Power Considerations...................................................................68
10.4.
Background and Demographic Characteristics........................................................69
10.5.
Subject Disposition.................................................................................................69
10.6.
Efficacy Analysis....................................................................................................69
10.6.1.
Primary Efficacy Analysis ......................................................................................70
10.6.2.
Secondary Efficacy Analyses..................................................................................71
10.6.2.1.
Key Secondary Efficacy Analyses ..........................................................................71
10.6.2.2.
Additional Secondary Efficacy Analyses ................................................................71
10.7.
Safety Analysis.......................................................................................................73
10.8.
Interim Analysis .....................................................................................................73
10.9.
Other Topics...........................................................................................................73
10.9.1.
Health-Related Quality-of-Life ...............................................................................73
10.9.2.
Healthcare Resource Utilization..............................................................................74
11.
ADVERSE EVENTS..............................................................................................75
11.1.
Monitoring, Recording and Reporting of Adverse Events .......................................75


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CC-486-AML-001 Amendment 2.0 Final: 08 Nov 2018
11.2.
Evaluation of Adverse Events.................................................................................75
11.2.1.
Seriousness.............................................................................................................75
11.2.2.
Severity / Intensity..................................................................................................76
11.2.3.
Causality ................................................................................................................77
11.2.4.
Duration .................................................................................................................77
11.2.5.
Action Taken..........................................................................................................78
11.2.6.
Outcome.................................................................................................................78
11.3.
Abnormal Laboratory Values..................................................................................78
11.4.
Pregnancy...............................................................................................................78
11.4.1.
Females of Childbearing Potential: .........................................................................78
11.4.2.
Male Subjects.........................................................................................................79
11.5.
Reporting of Serious Adverse Events......................................................................79
11.5.1.
Safety Queries ........................................................................................................80
11.6.
Expedited Reporting of Adverse Events..................................................................80
12.
DISCONTINUATIONS .........................................................................................81
13.
EMERGENCY PROCEDURES.............................................................................82
13.1.
Emergency Contact.................................................................................................82
13.2.
Emergency Identification of Investigational Products .............................................82
14.
REGULATORY CONSIDERATIONS...................................................................83
14.1.
Good Clinical Practice............................................................................................83
14.2.
Investigator Responsibilities ...................................................................................83
14.3.
Subject Information and Informed Consent.............................................................83
14.4.
Confidentiality........................................................................................................84
14.5.
Protocol Amendments.............................................................................................84
14.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................................84
14.7.
Ongoing Information for Institutional Review Board / Ethics Committee................85
14.8.
Closure of the Study ...............................................................................................85
15.
DATA HANDLING AND RECORDKEEPING.....................................................86
15.1.
Data/Documents .....................................................................................................86
15.2.
Data Management...................................................................................................86
15.3.
Record Retention....................................................................................................86
16.
QUALITY CONTROL AND QUALITY ASSURANCE........................................88


EDMS Doc. Number: 23107036 - 17852850
Oral Azacitidine (CC-486)
Protocol CC-486-AML-001
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CC-486-AML-001 Amendment 2.0 Final: 08 Nov 2018
16.1.
Study Monitoring and Source Data Verification......................................................88
16.2.
Audits and Inspections............................................................................................88
17.
PUBLICATIONS ...................................................................................................89
19.
APPENDICES........................................................................................................94
Appendix A:
WHO Classification of Acute Myeloid Leukemia..............................................94
Appendix B:
Eastern Cooperative Oncology Group (ECOG) Performance Status...................95
Appendix C:
Risk Status Based on Cytogenetics.....................................................................96
Appendix D:
New York Heart Association Classification for Congestive Heart Failure..........97
Appendix E:
International Working Group AML Response Criteria .......................................98
Appendix F:
FACIT-Fatigue Scale (Version 4).......................................................................99
Appendix G:
EQ-5D Health Questionnaires (English Version for the US) ............................100
Appendix H:
Physical Impairment Numeric Rating Scale .....................................................102
Appendix I:
Recommendations for Management of Treatment-Induced Diarrhea .................103
Appendix J:
List of Abbreviations and Definitions of Terms.................................................104
Appendix K:
Extension Phase...............................................................................................107


EDMS Doc. Number: 23107036 - 17852850
Oral Azacitidine (CC-486)
Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
19
CC-486-AML-001 Amendment 2.0 Final: 08 Nov 2018
LIST OF TABLES
Table 1:
Table of Events.......................................................................................................38
Table 2:
Guidelines for Dose Modifications .........................................................................60


EDMS Doc. Number: 23107036 - 17852850
Oral Azacitidine (CC-486)
Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
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CC-486-AML-001 Amendment 2.0 Final: 08 Nov 2018
LIST OF FIGURES
Figure 1:
Overall Study Design..............................................................................................35
















EDMS Doc. Number: 23107036 - 17852850
Oral Azacitidine (CC-486)
Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
28
CC-486-AML-001 Amendment 2.0 Final: 08 Nov 2018
2.
STUDY OBJECTIVES
2.1.
Primary Objective
The primary objective of the study is to evaluate whether maintenance therapy with oral 
azacitidine improves OS compared with placebo in subjects with AML, age ≥55 years, who 
have achieved first CR or CRi after induction with intensive chemotherapy with or without 
consolidation chemotherapy.
2.2.
Secondary Objectives
The secondary objectives of the study are:  

To determine RFS; 

To determine safety, tolerability; and

To determine the effect of oral azacitidine compared with placebo on health-related 
quality-of-life (HRQoL) and healthcare resource utilization.
  
 
 


EDMS Doc. Number: 23107036 - 17852850
Oral Azacitidine (CC-486)
Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
29
CC-486-AML-001 Amendment 2.0 Final: 08 Nov 2018
3.
STUDY ENDPOINTS
3.1.
Primary Endpoint(s)
The primary endpoint of the study is OS.
3.2.
Secondary Endpoint(s)
The secondary endpoints of the study are:

RFS;

Time to relapse from CR/CRi;

Time to discontinuation from treatment;

Safety / tolerability (type, frequency, severity, and relationship of AEs to study 
treatments; physical examinations, vital signs; clinical laboratory evaluations, and 
concomitant medication/therapy); 

Patient-reported outcomes utilizing the FACIT-Fatigue Scale and the EQ-5D; and

Measures of healthcare resource utilization.
 
 
 


EDMS Doc. Number: 23107036 - 17852850
Oral Azacitidine (CC-486)
Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
30
CC-486-AML-001 Amendment 2.0 Final: 08 Nov 2018
4.
OVERALL STUDY DESIGN
4.1.
Study Design
This is an international, multicenter, placebo-controlled, Phase 3 study with a double-blind, 
randomized, parallel-group design in subjects with de novo AML or AML secondary to prior 
diagnosis of MDS or CMML, aged ≥ 55 years, who are in first CR/CRi following induction 
therapy with or without consolidation chemotherapy.  
The study consists of 3 phases; the Pre-randomization Phase (Screening Phase), the Treatment 
Phase, and the Follow-up Phase (Figure 1).
The study is amended to include an Extension Phase (EP).  The EP allows subjects who are 
currently receiving oral azacitidine and who are demonstrating clinical benefit as assessed by the 
Investigator, to continue receive oral azacitidine after unblinding by Sponsor (Celgene
Corporation) until they meet the criteria for study discontinuation or until oral azacitidine 
becomes commercially available and reimbursed.  In addition, all subjects in the placebo arm and 
subjects who had been discontinued from the treatment phase (irrespective of randomization 
arm) and continuing in the Follow-up Phase will be followed for survival in the EP.
Details for the EP are provided in Appendix K.
Pre-Randomization Phase (Screening Phase)
Subject screening procedures are to occur during the Pre-randomization Phase.  Screening 
procedures are to take place within 28 days prior to randomization.  Subject eligibility for 
randomization will be based on the documentation of achieving CR/CRi following diagnosis and 
induction/consolidation treatment of AML, as verified by central pathology and cytogenetics 
review.
Newly diagnosed subjects, ≥55 years of age, who have a confirmed diagnosis of AML 
according to criteria set by the WHO 2008 classification (
) and have achieved 
first CR/CRi status after induction with or without consolidation therapy, will be eligible for 
randomization (within 4 months [± 7 days] of achieving first CR/CRi).  The definitions of 
response criteria for CR or CRi are primarily defined by IWG on AML (
; 
Appendix E) and are described below:
Complete Remission (CR)
Complete Remission with Incomplete Blood 
Count Recovery (CRi)

< 5% blasts in bone marrow  

absence of blasts with Auer rods

absence of extramedullary disease

independent of blood transfusions

neutrophil count > 1.0 x 109/L

platelet count ≥ 100 x 109/L

< 5% blasts in bone marrow  

absence of blasts with Auer rods

absence of extramedullary disease

independent of blood transfusions

neutrophil count < 1.0 x 109/L or platelet 
count < 100 x 109/L
A screening bone marrow aspirate, bone marrow biopsy and peripheral blood smear will be sent 
to the central pathology reviewer for analysis and confirmation of CR/CRi.  A standard 


EDMS Doc. Number: 23107036 - 17852850
Oral Azacitidine (CC-486)
Protocol CC-486-AML-001
Celgene Corporation
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31
CC-486-AML-001 Amendment 2.0 Final: 08 Nov 2018
cytogenetic metaphase preparation will be made from the bone marrow aspirate at the central 
laboratory for standard cytogenetic analysis. 
Additional screening assessments include demographics and medical history, prior treatments for 
AML (and other malignancy, if applicable), prior medications, ECOG performance status 
(Appendix B), vital signs, weight and height measurements, physical examination, CBC with 
differential count, blood chemistry, serum EPO level, urinalysis, coagulation, ECG, serum 
ferritin level, pregnancy testing (FCBP only), chest x-ray, transplant eligibility, documentation of 
induction and consolidation therapies, healthcare resource utilization and bone marrow and 
peripheral blood sampling for biomarker analysis.  All laboratory analyses will be performed by 
a central laboratory.  Adverse Events, including SPMs, will be collected beginning on the date of 
signed ICD.
Randomization and Double-blind Treatment Phase
Following confirmation of eligibility at screening, subjects will be randomized 1:1 to receive   
300 mg oral azacitidine (QD) or placebo.  Treatment assignment will occur by a central 
randomization procedure using an Interactive Voice Response System (IVRS).  Randomization 
must occur within 4 months (± 7 days) of achieving the first CR/CRi.
After randomization, no crossover between the treatment arms will be permitted at any point 
during the study.  During the double-blind treatment phase, subjects will ingest IP (azacitidine 
tablets or placebo tablets) on the first 14 days of each 28-day cycle.  Dose modifications may 
occur for managing toxicity if necessary during treatment (Section 8.2.5).
During the double-blind treatment phase, subjects will be assessed for safety, tolerability and 
efficacy.  Assessments during the double-blind treatment phase will include monitoring for AEs, 
monitoring for relapse of AML and SPMs, physical examination, vital signs and weight 
measurement, ECOG performance status, hematology and serum chemistry, serum ferritin level, 
pregnancy testing (FCBP only), concomitant medications, therapies and procedures, review of 
bone marrow aspirate (or biopsy if adequate aspirate is not attainable) and peripheral blood 
smear slides, cytogenetic analysis, CR/CRi status assessment, bone marrow and peripheral blood 
sampling for biomarker analysis, blood sampling for PK analysis, IP administration and 
accountability, HRQoL, and healthcare resource utilization.
A separate central review of all bone marrow aspirates, bone marrow biopsies, and peripheral 
blood smears will be conducted by a pathologist blinded to subject treatment.  The central 
reviewer’s assessments will be used to confirm the CR/CRi status at screening and during 
treatment for maintenance assessment.  If the central reviewer and local pathologist disagree on 
the CR/CRi status of a subject, a third-party reviewer will adjudicate and make the final 
assessment.  
The central cytogenetic review will provide standardized analysis and reporting for all subjects, 
regardless of the laboratory performing the initial analysis (local or central).
 
 


EDMS Doc. Number: 23107036 - 17852850
Oral Azacitidine (CC-486)
Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
32
CC-486-AML-001 Amendment 2.0 Final: 08 Nov 2018
 
 
 
 
CR/CRi Status Assessment
The first status assessment for maintenance of CR/CRi will occur at Cycle 3. If CR/CRi status is 
maintained, subjects can continue on to Cycle 4 and beyond. Subjects will be further assessed for 
CR/CRi status at Cycles 6, 9, 12, 15, 18, 21, 24, 30, 36, and the Treatment Discontinuation visit.  
After Cycle 36, bone marrow evaluation for the assessment of maintenance of CR/CRi will occur 
only if clinically indicated at the discretion of the Investigator. Subjects may be discontinued 
from treatment at the Investigator’s discretion for any of the reasons detailed in Section 12.  
Dose and Schedule Adjustment in Subjects with AML Relapse/Progression
In subjects on study who have subsequent evidence of AML relapse with blasts > 5% either in 
the peripheral blood or bone marrow, and provided the blasts are no greater than 15% in the 
blood or bone marrow, escalation of the dosing regimen (dose and/or schedule) can be 
implemented as follows (provided it is in the best interest to do so as judged by the Investigator):

Subject currently on blinded treatment of oral azacitidine 300 mg or placebo QD for 14 
days - escalate schedule to oral azacitidine 300 mg or placebo QD for 21 days

In the event that dose had previously been reduced, subject currently on blinded treatment 
of oral azacitidine 200 mg or placebo QD for 14 days - escalate schedule as a first step, to 
21 days QD and then escalate dose to oral azacitidine or placebo to 300 mg QD for 21 
days

Subject currently on blinded treatment for oral azacitidine 200 mg or placebo QD for 7 
days - escalate dose, as a first step, to oral azacitidine 200 mg or placebo QD for 14 days 
and then escalate dose schedule to oral azacitidine 300 mg or placebo QD for 14 days
Subject Discontinuation from Treatment following AML Relapse
Subjects will be discontinued from treatment when they meet the following criteria. 

Appearance of > 15% blasts in the bone marrow or peripheral blood; and


EDMS Doc. Number: 23107036 - 17852850
Oral Azacitidine (CC-486)
Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
33
CC-486-AML-001 Amendment 2.0 Final: 08 Nov 2018

The above occurrence should be attributed to relapse following CR/CRi, and not 
attributable to any other cause (eg, bone marrow regeneration after consolidation 
therapy).
Prior to discontinuing a subject from treatment due to AML relapse or for any other cause, the 
Investigator should contact the sponsor or its designee and forward appropriate supporting 
documents for review and discussion.
Follow-up Phase
All discontinued subjects, regardless of reason for discontinuation, should undergo Treatment 
Discontinuation visit procedures at the time of study discontinuation.  Subjects will have a 
follow-up visit for the collection of AEs up to 28 days after last dose of IP or up to the Treatment 
Discontinuation visit, whichever is longer.  After this follow-up visit, subjects will be followed 
for survival every month for the first year and then every 3 months until death, withdrawal of 
consent for further follow-up, study end, or until a subject is lost to follow-up.
Extension Phase
Details for the EP are provided in Appendix K.
Study Population
This study will enroll approximately 460 subjects, aged 55 years or older, with a diagnosis of de 
novo AML or AML secondary to prior myelodysplastic disease or CMML, and who have 
achieved a first CR/CRi following induction with or without consolidation chemotherapy.  
Subjects who have previously achieved a CR/CRi with a hypomethylating agent will be excluded 
from the study.  
The study will be conducted at approximately 180 clinical sites worldwide.
Length of Study and Study Closure
The study will close once the total number of events (n=330 deaths) required for a fully powered 
analysis of OS have occurred.  The expected duration of the study is 91 months, including a 53-
month subject accrual period, followed by an additional 24 months of treatment and/or 
observation.  At the Investigator’s discretion, subjects can continue beyond 24 months of 
treatment or until the study closes.
The sponsor may consider closing this study when data supporting key endpoints and objectives 
of the study have been analyzed. In a case where there are subjects still being administered the
investigational product, and it is the opinion of the investigator(s) that those subjects would
continue to receive benefit from treatment, the sponsor may choose to initiate an extension phase 
under current protocol to allow those subjects to continue receiving oral azacitidine. This would 
occur after their participation in this study, CC-486-AML-001, and after the unblinding of those 
remaining subjects.
The EP of the study will close once oral azacitidine becomes commercially available and 
reimbursed in the participating countries for the indication that the subject is being treated for 
such that the subject’s access to oral azacitidine is neither interrupted nor discontinued.


EDMS Doc. Number: 23107036 - 17852850
Oral Azacitidine (CC-486)
Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
34
CC-486-AML-001 Amendment 2.0 Final: 08 Nov 2018
Data Monitoring Committee
An external independent Data Monitoring Committee (DMC) with multi-disciplinary 
representation will evaluate safety, futility and compliance prospectively.  The DMC will be 
comprised of medical hematologists/oncologists with experience in treating subjects with AML 
and a statistician, all of whom are not otherwise involved in the study as Investigators.  The 
DMC responsibilities, authorities, and procedures will be documented in the DMC charter, 
which will be endorsed by the DMC prior to the first data review meeting.  An 
external/independent statistician will generate critical safety reports for the DMC to review 
periodically.  The DMC chairman may convene formal DMC meetings if there are safety 
concerns.  The sponsor can also request a DMC review of safety data.  The DMC 
responsibilities, authorities, and procedures will be detailed in the DMC charter which will be 
signed by DMC members before the first DMC data review meeting.  
Figure 1 provides a schematic of the overall study design.


EDMS Doc. Number: 23107036 - 17852850
Oral Azacitidine (CC-486)
Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
35
CC-486-AML-001 Amendment 2.0 Final: 08 Nov 2018
Figure 1:
Overall Study Design
Pre-Randomization Phase
Double-Blind Treatment Phase
Follow-Up Phase
AML=acute myeloid leukemia; BSC=best supportive care; CR= complete remission; CRi=complete remission with incomplete neutrophil regeneration. 
1 Stratification factors:  
a Age (at time of induction therapy):  55-64 and ≥ 65
b Prior history of MDS:  Yes / No
c Cytogenetic Risk category (at time of induction therapy):  Intermediate risk / Poor risk
d Received consolidation therapy following induction therapy: Yes / No
2 IWG Response Assessment for CR/CRi or Disease Relapse at Cycles 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, and the Treatment Discontinuation visit.  Beyond Cycle 
36, IWG assessment will be performed at the discretion of the Investigator, if clinically indicated
3 Subjects with AML relapse (> 5% and ≤ 15% blasts in the bone marrow) may continue treatment with extended dose schedule to 300 mg QD for 21 days and 
discontinue treatment when the bone marrow blasts reach > 15% Section 4.1
4 The study will close once the total number of events (n=330 deaths) required for a fully powered analysis of OS have occurred.
 
                                                                             
                                                                                                                                                              
                                  
                                                                                                                                                   
                                                                                                                                                               
                   
                                                                                                            
Day -28 to Day -1
Subjects should meet 
following criteria
≥55 years of age
Diagnosed with 
AML
Induction therapy 
with or without 
consolidation 
therapy
Randomization
should occur 
within 4 months 
(±7 days) of 
achieving CR/CRi
R
E
S
P
O
N
S
E 
A
S
S
E
S
S
M
E
N
T2    
1:1   Blinded Treatment
Complete 
Remission
 AML Relapse3
R  
A  
N  
D  
O  
M  
I  
Z  
A  
T  
I  
O  
N1
Oral Azacitidine Treatment Arm
300 mg/day x 14 days every 
28 days ± BSC
Placebo Arm
Placebo treatment for 14 
days every 28 days ± BSC
Follow-Up 
until Death 
E
N
D
O
F
T
R
E
A
T
M
E
N
T4   
Off
Treatment
Follow-Up 
until Death 
Continue 
Treatment


EDMS Doc. Number: 23107036 - 17852850
Oral Azacitidine (CC-486)
Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
36
CC-486-AML-001 Amendment 2.0 Final: 08 Nov 2018
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.3.
Study Duration 
The study will conclude once the total number of events (n=330 deaths) required for a fully 
powered analysis of OS have occurred.  The expected duration of the study is 91 months, 
including a 53-month subject enrollment period, followed by an additional 24 months of subject 
treatment and/or observation. At the Investigator’s discretion, patients can continue beyond 24 
months of treatment or until the study closes.
The sponsor may consider closing this trial when data supporting key endpoints and objectives of 
the study have been analyzed. In a case where there are subjects still being administered the
investigational product, and it is the opinion of the investigator(s) that those subjects would
continue to receive benefit from treatment, the sponsor may choose to initiate an extension phase 
under current protocol to allow those subjects to continue receiving oral azacitidine. This would 
occur after their participation in this study, CC-486-AML-001, and after the unblinding of those 
remaining subjects.


EDMS Doc. Number: 23107036 - 17852850
Oral Azacitidine (CC-486)
Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
37
CC-486-AML-001 Amendment 2.0 Final: 08 Nov 2018
The EP of the study will close once oral azacitidine becomes commercially available and 
reimbursed in the participating countries for the indication that the subject is being treated such 
that the subject’s access to oral azacitidine is neither interrupted nor discontinued.


EDMS Doc. Number: 23107036 - 17852850
Oral Azacitidine (CC-486)
Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
38
CC-486-AML-001 Amendment 2.0 Final: 08 Nov 2018
5.
TABLE OF EVENTS
Table 1:
Table of Events
Procedure
Pre-
Randomization 
Phase
Double-blind Treatment Phase
Post-Treatment 
Follow-up Phase
Cycle 1
Cycle 2
Cycle 3 and 
Beyond
Visit 1/Screen
(Day -28 to -1)1
Random-
ization
Day 11
Day 8, 
15, 22
(± 3 
days)
Day 1 
(± 3 
days)
Day 8, 
15, 22
(± 3 
days)
Day 1
(± 3
days)
Day 
1530
(± 3
days)
Treat-
ment 
Discontin-
uation
Follow
-up28     
Study Entry Assessments
Informed Consent

--
--
--
--
--
--
--
--
--
Demographics & Medical History

--
--
--
--
--
--
--
--
--
AML Diagnosis History
2
--
--
--
--
--
--
--
--
--
Transplant Eligibility

--
--
--
--
--
--
--
--
--
Documentation of Induction ± 
Consolidation Therapies 

--
--
--
--
--
--
--
--
--
CR/CRi Status Confirmation

--
--
--
--
--
--
--
--
--
12-Lead ECG
3
--
--
--
--
--
--
--
--
--
Chest X-ray
4
--
--
--
--
--
--
--
--
--
Prior Medications
5
--
--
--
--
--
--
--
--
--
ECOG Performance Status

6

--

--

--
--
--
Coagulation7

--
--
--
--
--
--
--
--
--
Serum EPO Level

--
--
--
--
--
--
--
--
--
Urinalysis8

--
--
--
--
--
--
--
--
--
Inclusion/Exclusion Criteria

--
--
--
--
--
--
--
--
--


EDMS Doc. Number: 23107036 - 17852850
Oral Azacitidine (CC-486)
Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
39
CC-486-AML-001 Amendment 2.0 Final: 08 Nov 2018
Table 1:
Table of Events (Continued)
Procedure
Pre-
Randomization 
Phase
Double-blind Treatment Phase
Post-Treatment 
Follow-up Phase
Cycle 1
Cycle 2
Cycle 3 and 
Beyond
Visit 1/Screen
(Day -28 to -1)1
Random-
ization
Day 11
Day 8, 
15, 22
(± 3 
days)
Day 1 
(± 3 
days)
Day 8, 
15, 22
(± 3 
days)
Day 1
(± 3 
days)
Day 
1530
(± 3
days)
Treat-
ment 
Discontin-
uation
Follow
-up28
Randomization
--

--
--
--
--
--
--
--
--
Safety Assessments
Adverse Events
After signing ICD and until 28 days after the last IP dose or until the last study visit, whichever period is longer
Second Primary Malignancy9
After signing ICD and throughout the duration of the study including post treatment follow-up period
Physical Examination

--

--

--

--

--
Vital Signs and Body Weight10

--

--

--

--

--
Hematology11

--







--
Serum Ferritin12

--
12
--
--
--
--
--

--
Unstained Peripheral Blood Smear13

--







--
Serum Chemistry14

--

--

--

--

--
Pregnancy Testing (FCBP only)15

--

--

--

--

--
Concomitant Medications, Therapy & 
Procedures16
--
--







--
Efficacy Assessments
Bone Marrow Aspirate17

--
--
--
--
--

--

--
Bone Marrow Biopsy17, 18

--
--
--
--
--

--

--
Cytogenetic Testing19

--
--
--
--
--

--

--
Peripheral Blood Smear20

--
--
--
--
--

--

--


EDMS Doc. Number: 23107036 - 17852850
Oral Azacitidine (CC-486)
Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
40
CC-486-AML-001 Amendment 2.0 Final: 08 Nov 2018
Table 1:
Table of Events (Continued)
Procedure
Pre-
Randomization 
Phase
Double-blind Treatment Phase
Post-Treatment 
Follow-up Phase
Cycle 1
Cycle 2
Cycle 3 and 
Beyond
Visit 1/Screen
(Day -28 to -1)1
Random-
ization
Day 11
Day 8, 
15, 22
(± 3 
days)
Day 1 
(± 3 
days)
Day 8, 
15, 22
(± 3 
days)
Day 1
(± 3 
days)
Day 
1530
(± 3
days)
Treat-
ment 
Discontin-
uation
Follow-
up28
IWG Response Assessment21
--
--
--
--
--
--

--

--
Follow-up AML Relapse22
--
--
--
--
--
--
--
--
--

Follow-up AML Therapies22
--
--
--
--
--
--
--
--
--

Survival Follow-up22
--
--
--
--
--
--
--
--
--

Investigational Product (IP)
Dispense/Administer
23, 24
23, 24
23, 24
IP Accountability



Other Assessments
Pharmacokinetics27
--
--
x
--
--
--
X
Patient-reported HRQoL Outcomes 
(FACIT-Fatigue Scale and EQ-5D) 25
--
--

--

--

--

--
Healthcare Resource Utilization
After signing ICD and until 28 days after the last IP dose or until the date of last study visit, whichever is later (not collected during 
follow-up period).
Optional Biomarker Bone Marrow 
Sampling (from the same sample taken 
for central review; additional consent 
required)26

--
--
--
--
--

--
x
--
Pharmacogenomic Blood Sampling29

--
--
--
--
--

--
x
--
AE = adverse event; AML = acute myeloid leukemia; ANC = absolute neutrophil count; CR = complete response; CRF = case report form; CRi = complete response with 
incomplete blood count recovery; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EPO = erythropoietin; FACIT -Fatigue Scale = Functional 
Assessment of Chronic Illness Therapy – Fatigue Scale FCBP = female of childbearing potential; HRQoL = health-related quality of life; ICD = Informed Consent Document; IP 
= investigational product; IWG = international working group; SAE = serious adverse event; SPM = second primary malignancy


EDMS Doc. Number: 23107036 - 17852850
Oral Azacitidine (CC-486)
Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
41
CC-486-AML-001 Amendment 2.0 Final: 08 Nov 2018
1. Results obtained on Day 1 just prior to the first dose will serve as the Baseline values.  If not available, the most recent screening results prior to Day 1 will be considered the 
Baseline values.  Subjects who fail eligibility criteria due to low neutrophil count or platelet count or other laboratory abnormality can be re-screened as long as this occurs 
within 4 months (± 7 days) from the achievement of CR or CRi status.
2. Documentation of AML diagnosis will be assessed locally from bone marrow aspirate and/or biopsy sample slides.   
3. Electrocardiogram required during screening period and whenever clinically indicated during the double-blind treatment phase.  For subjects with an abnormal ECG, a cardiac 
consultation should be obtained as deemed necessary by the treating physician.
4. Chest x-ray not needed if a previous chest x-ray taken within 4 weeks prior to Cycle 1, Day 1 is available and not clinically significant.
5. Includes any prior chemotherapy, cytotoxic therapy, radiation therapy, and all medications used for the 4-week period prior to Day 1 of Cycle 1.
6. Subjects must satisfy the ECOG performance status of 0, 1, 2, or 3 to be enrolled in the study.  Can be performed at randomization or Day 1 of Cycle 1.
7. Coagulation testing is conducted at screening and whenever clinically indicated during the double-blind treatment phase
8. A standard urinalysis (including microscopic analysis if indicated) is required at screening and whenever clinically indicated during the double-blind treatment phase.
9. Second primary malignancies will be monitored as events of interest and should be included as part of the assessment of AEs throughout the duration of the study including 
follow-up period.  Investigators are to report any SPM regardless of causal relationship to IP, occurring at any time from subject signing of informed consent document and 
throughout the duration of the study including follow-up period as a serious adverse event (considered to be at least “an important medical event” even if no other seriousness 
criteria apply).  This information must also be documented on the appropriate pages of the CRF and in the subject’s source documents.  Documentation of the diagnosis of the 
SPM (eg, any confirmatory histology or cytology results, X-rays, CT scans, etc) must be provided at the time of reporting as an SAE.
10. Includes height (at screening only), blood pressure, pulse, and temperature.
11. Includes a complete blood count (RBC count, hemoglobin, hematocrit, mean corpuscular volume [MCV], mean corpuscular hemoglobin [MCH], mean corpuscular 
hemoglobin concentration [MCHC], WBC count with differential, ANC, and platelet count).  Any or all laboratory assessments may be repeated more frequently if clinically 
indicated.  The samples will be collected prior to study treatment dosing and will be analyzed by the central laboratory.  In the event that hematology laboratory results are 
needed to acutely manage the subject, local laboratory tests may be used.  In addition to the local laboratory sample, a second sample should always be sent to the central 
laboratory. 
12. Serum ferritin levels will be collected at screening, on Day 1 of Cycle 1, on Day 1 of every 3 cycles thereafter (ie, Day 1 of Cycles 4, 7, 10, 13, etc.) and at the Treatment 
Discontinuation visit.
13. Whenever a hematology sample is collected for a complete blood count, an unstained peripheral blood smear should be prepared and sent to the central laboratory.  This 
unstained peripheral blood smear will be used to assess a manual blood count differential.
14. Includes serum chemistry labs (sodium, potassium, chloride, bicarbonate, calcium, phosphorus, BUN, creatinine, glucose, albumin, total protein, alkaline phosphatase, 
direct/indirect total bilirubin, aspartate aminotransferase [AST], alanine aminotransferase [ALT], lactate deyhydrogenase [LDH], and uric acid).  The samples will be collected 
prior to study treatment dosing and will be analyzed by the central laboratory.  Any or all laboratory assessments may be repeated more frequently if clinically indicated.  In the 
event that chemistry laboratory results are needed to acutely manage the subject, local laboratory tests may be used.  In addition to the local laboratory sample, a second sample 
should be sent to the central laboratory. 
15. A medically supervised serum pregnancy test with sensitivity of at least 25mIU/mL is to be obtained in female subjects of childbearing potential (FCBP) at Screening (within 
72 hours prior to starting study therapy).  A serum or urine pregnancy test (per Investigator’s discretion) is to be done prior to Day 1 of every subsequent cycle (within 72 
hours), and at the End of the Treatment visit.  The subject may not receive investigational product until the Investigator has verified that the result of the pregnancy test is 
negative.
16. All concomitant over-the-counter medications, prescription medications, including anti-infectives for prophylaxis and/or treatment of an infection taken from Cycle 1, Day 1 up 
to 28 days after the last dose of IP or up to the Treatment Discontinuation visit, whichever period is longer, must be recorded on the appropriate page(s) of the CRF.
17. A bone marrow aspirate and biopsy should ideally be collected at Screening, no earlier than 14 days prior to randomization.  The screening bone marrow aspirate and biopsy 
are required to be repeated even if a bone marrow aspirate and biopsy was performed for disease diagnosis/status as part of the standard of care within 28 days of Cycle 1, Day 
1.  The bone marrow aspirate slide, bone marrow biopsy slide, bone marrow aspirate sample for cytogenetics testing/chromosome analysis, and unstained peripheral blood 
smear slides must be sent to the central laboratory for review by the central pathology reviewer.  


EDMS Doc. Number: 23107036 - 17852850
Oral Azacitidine (CC-486)
Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
42
CC-486-AML-001 Amendment 2.0 Final: 08 Nov 2018
In addition, bone marrow aspirates must be collected during double-blind treatment phase on Day 1 (± 7 days)  of  Cycles 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, and the Treatment 
Discontinuation visit, in order to confirm continued CR or CRi, relapse after CR or CRi (as assessed by the Investigator based on CBC with WBC differential results), or 
disease relapse. After Cycle 36 bone marrow assessment for disease relapse is performed only if clinically indicated. If disease relapse features are observed following a bone 
marrow aspirate, it is recommended that a repeat bone marrow aspirate be performed at least 3-4 weeks later to confirm disease relapse unless the blast count was greater than 
50% in the marrow or peripheral blood.  Additional aspirates may be collected if clinically indicated or required for toxicity assessment.  A bone marrow biopsy can be 
collected in conjunction with an aspirate if it is standard institutional practice.  A bone marrow biopsy may be needed to evaluate bone marrow cellularity.  Whenever a bone 
marrow aspirate sample is sent to the local laboratory, additional (differently prepared) bone marrow aspirate slides must be sent to the central laboratory for review by the 
central pathology reviewer.  Instructions for submission of bone marrow samples to the central (pathology) reviewer are provided in Study Reference and/or Study Central 
Laboratory Manual.  
18. Bone marrow biopsies may be needed to assess bone marrow status if an adequate bone marrow aspirate cannot be attained. 
19. Bone marrow aspirates sample tube for cytogenetics testing/chromosome analysis to be obtained at Screening for evaluation by central laboratory to obtain karyotype.  A 
minimum of 16 analyzable metaphases for standard banding cytogenetic analysis is recommended at Screening.  During the study, repeat of bone marrow cytogenetics testing 
is to be completed whenever a bone marrow aspirate is obtained and in order to confirm CR, CRi, or disease relapse.  
20. Whenever bone marrow aspirate (or biopsy) slides are sent to the central reviewer, a peripheral blood smear slide should also be submitted.
21. International Working Group (IWG) response assessment will be assessed at Cycles 3, 6, 9, 12, 15, and 18, 21, 24, 30, 36 and the Treatment Discontinuation visit. After Cycle 
36 bone marrow assessment for disease relapse is performed only if clinically indicated. Subjects should be assessed for CR/CRi status maintenance, relapse after CR/CRi, or 
disease relapse.  
22. All discontinued subjects, regardless of reason for discontinuation, should be followed for survival, AML relapse, AML therapies and SPM every month (± 3 days) for the first 
year and then every 3 months (± 14 days) until death, lost to follow-up, withdrawal of consent from further follow-up, or the end of the study.  Documentation such as 
laboratory or pathology reports, bone marrow and/or peripheral blood reports supporting the AML relapse should be requested and collected.  Subjects who are discontinued 
prematurely will also undergo End-of-Study procedures.  The monthly and the quarterly survival follow-up can be performed via a telephone interview.
23. Investigational product should be dispensed on Day 1 of each cycle only.  For Day 1 of Cycle 1, treatment should be administered within 3 days after randomization.  The first 
dose of IP on Day 1 of each cycle should be taken only after all other study Day 1 procedures have been completed.  Antiemetic medication should be administered 30 minutes 
prior to each IP dose.
24. Investigational product is scheduled to be taken on 1-14 days of each cycle, unless there has been a schedule modification from 14 days to 7 days of IP administration due to 
toxicity.
25. FACIT–Fatigue Scale (Appendix F), EQ-5D (Appendix G), and exploratory quality-of-life (QoL) (Physical Impairment Numeric Rating Scale, Appendix H)
questionnaires, should ideally be completed prior to dosing and when feasible, prior to interaction with study personnel on Day 1 of every cycle, beginning on Day 1 of Cycle 
1, and at study discontinuation.
26. Bone marrow samples for biomarker assessment are desired but optional and subject must consent to the collection of these samples.  Samples should be collected when bone 
marrow is collected at protocol specified time points and when bone marrow is collected to confirm a response (CR or CRi) or relapse.  Biomarker analysis will only be 
performed using these samples when sufficient bone marrow sample material remains (optimally 10-15 mL).  Sample collection, processing, storage, and shipment procedures 
will be provided in the Study Reference and/or Study Central Laboratory Manual. 
27. Mandatory sample collection for PK.  Subjects should consent to the collection of these samples by signing the ICD, mandatory sample collection section.  Two blood samples 
(3 mL/sample) for azacitidine PK assessment will be collected at least 2 hours apart on Day 1 of Cycles 1, 3, and 6 between 0.5 and 6.0 hours post IP administration (Section
6.11).  Blood samples must be processed and plasma harvested and stored according to the instructions in the Study Reference and/or Study Central Laboratory Manual.
28. The study visit window in the double-blind treatment phase is ± 3 days for Cycles 1, 2, 3 and beyond, unless noted otherwise for a particular assessment.  Study visits should 
also take into account the subject’s IP supply.  Only 1 cycle of IP will be dispensed to the subject on Day 1 of each cycle.  Day 1 of Cycles 2 and beyond may be delayed from 
Day 28 of the prior cycle in order for subjects to recover from toxicity and meet criteria for re-treatment (Section 8.2.6).  During follow-up, the study visit window is ± 7 days 
for visits scheduled monthly (including the follow-up visit 28 days after last dose if necessary) or ± 14 days for visits scheduled every 3 months.  One cycle (one month) is
considered as 28 days (ie, 4 weeks).
29. Peripheral blood sampling for pharmacogenomic analysis is desired but optional and subject must consent to the collection of these samples.  Samples should be collected 
when bone marrow is collected at protocol specified time points and must be collected on the same day as the bone marrow aspirate procedure. 


EDMS Doc. Number: 23107036 - 17852850
Oral Azacitidine (CC-486)
Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
43
CC-486-AML-001 Amendment 2.0 Final: 08 Nov 2018
30. Beginning with the Cycle 25, Day 15 visit, assessments are optional and occur only if clinically indicated at the discretion of the Investigator. 


EDMS Doc. Number: 23107036 - 17852850
Oral Azacitidine (CC-486)
Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
44
CC-486-AML-001 Amendment 2.0 Final: 08 Nov 2018
6.
PROCEDURES
All of the required assessments are indicated in Table 1 with an “x” on the visits to be 
performed.  All data obtained from these assessments must be present in the subject’s source 
documentation.  All routine assessments during the treatment period must be performed ± 3 days 
of the day indicated in the tables.  During follow-up, the study visit window is ± 7 days for visits 
scheduled monthly (including the follow-up visit 28 days after last dose if necessary) or ± 14 
days for visits scheduled every 3 months.  One cycle (one month) is considered as 28 days (ie, 4 
weeks). Procedures are described in details below and in the footnote of the Table 1.
6.1.
Screening
Written informed consent must be obtained before any study-specific medical procedures are 
performed.  Screening procedures are to occur during the screening phase (Table 1).  Screening 
assessments must take place within 28 days prior to randomization.  Samples for biomarker 
analyses will be collected at Screening if written informed consent is obtained.
Subject eligibility is to be established by confirming all eligibility criteria.  A relevant record (eg, 
checklist) must be stored with the source documentation at the study site.  Failure to meet any 
eligibility criterion excludes a subject from enrollment into the study.  Subjects who fail 
eligibility criteria due to low neutrophil count or platelet count or other laboratory abnormality 
can be re-screened as long as this occurs within 4 months (± 7 days) from the achievement of CR 
or CRi status.
Prior Medical History on AML Diagnosis
History of AML disease diagnosis determined on local pathology and cytogenetics review must 
be collected and documented in the CRF page.  Relevant medical history and current medical 
conditions, including those symptoms and CR/CRi status related to AML, must be recorded on 
the appropriate CRF at Screening.  History of prior malignancy and treatment(s) administered 
will also be recorded on the appropriate CRF.
Prior Medications and AML Treatments and CR/CRi Status
All medications taken in the 4 weeks prior to randomization should be recorded on the 
appropriate CRF.
All prior treatments for AML, including induction and consolidation therapies, investigational 
agents or any other agent(s), should be recorded on the appropriate CRF.
Also documented in the CRF page before screening is determination of CR/CRi status following 
induction therapy with or without consolidation therapy. 
CR/CRi Status 
Bone marrow aspirates and biopsies (in phosphate-buffered saline with formalin) must be 
collected in order to confirm CR/CRi at screening.  Whenever a bone marrow aspirate sample 
and stained peripheral blood smear slides are sent to the local laboratory, additional (separately 
prepared) bone marrow aspirate slides and stained peripheral blood smear slides must be sent to 
the central laboratory for review by the central pathology reviewer.  A bone marrow biopsy (in 
sodium heparin solution) must be collected if an adequate aspirate is not attainable.  The 


EDMS Doc. Number: 23107036 - 17852850
Oral Azacitidine (CC-486)
Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
45
CC-486-AML-001 Amendment 2.0 Final: 08 Nov 2018
Screening bone marrow aspirate (and biopsy) samples for central pathology and cytogenetics 
review and the screening hematology sample for central laboratory review should ideally be 
collected no earlier than 14 days prior to randomization in order to allow sufficient time for 
central review and a repeat bone marrow assessment, if necessary.  Instructions for submission of
bone marrow samples to the central (pathology) reviewer are provided in the Study Reference 
and /or Study Central Laboratory Manual.
Hematology
Hematology assessment includes a CBC, RBC count, hemoglobin, hematocrit, mean corpuscular 
volume [MCV], mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin 
concentration [MCHC], white blood count (WBC) with differential, absolute neutrophil count 
[ANC], and platelet count).  Any or all laboratory assessments may be repeated more frequently 
if clinically indicated.  The samples will be collected prior to dosing and analyzed by the central 
laboratory.  In the event that hematology laboratory results are needed to acutely manage the 
subject, local laboratory tests may be used.  In addition to the local laboratory sample, a second 
sample should always be collected and sent to the central laboratory.
Whenever a hematology sample is collected for a complete blood count, an unstained peripheral 
blood smear should be prepared and sent to the central laboratory.  This unstained peripheral 
blood smear will be used to assess a manual blood count differential.
Serum Chemistry
Serum chemistry labs include sodium, potassium, chloride, bicarbonate, calcium, phosphorus, 
blood urea nitrogen (BUN), creatinine, glucose, albumin, total protein, alkaline phosphatase, 
direct/indirect/total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
lactate dehydrogenase (LDH), and uric acid.  The samples will be collected prior to dosing and 
analyzed by the central laboratory.  Any or all laboratory assessments may be repeated more 
frequently if clinically indicated.  In the event that chemistry laboratory results are needed to 
acutely manage the subject, local laboratory tests may be used.  In addition to the local 
laboratory sample, a second sample should be sent to the central laboratory.
ECOG Performance Status
Performance status (0, 1, 2, or 3) will be recorded on the CRF according to Table 1, and as 
defined by the ECOG criteria in Appendix B.
Transplant Eligibility
Only subjects deemed ineligible for allogeneic bone marrow or stem cell transplant by the 
Investigator are to be included in the study.  The reason(s) for a subject’s ineligibility should be 
recorded on the appropriate CRF.
Physical Examination
Information about the screening physical examination must be present in the subject’s source 
documentation.  Significant findings that are present prior to the start of treatment with IP must 
be included on the appropriate CRF.


EDMS Doc. Number: 23107036 - 17852850
Oral Azacitidine (CC-486)
Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
46
CC-486-AML-001 Amendment 2.0 Final: 08 Nov 2018
Vital Signs, Body Weight and Height Measurements
Screening vital signs include blood pressure, pulse and temperature.  Height will be measured at 
screening only.
12-Lead ECG
The screening ECG will be a 12-lead assessment.  The Investigator will review the results and 
assess as normal, abnormal - not clinically significant, or abnormal - clinically significant, and 
report the abnormal finding(s) on the appropriate CRF.  It is the responsibility of the Investigator
to seek cardiological consultation if thought appropriate to obtain.
Urinalysis
A standard urinalysis (including microscopic analysis if indicated) is required at screening and 
whenever clinically indicated during the double-blind treatment phase.
Coagulation
Coagulation at screening is conducted by the central laboratory.  Coagulation includes
prothrombin time (PT), activated partial thromboplastin time (PTT) and international normalized 
ratio (INR).
Serum Ferritin
Serum ferritin levels will be collected at screening, on Day 1 of Cycle 1, on Day 1 of every 3 
cycles thereafter (ie, Day 1 of Cycles 4, 7, 10, 13, etc.) and at the Treatment Discontinuation 
visit.
Pregnancy Testing
This protocol defines FCBP as a sexually mature woman who:  1) has not undergone a 
hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal 
(amenorrhea following cancer therapy does not rule out childbearing potential) for at least 
24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months).  
All FCBP must have a medically supervised screening serum pregnancy test with a sensitivity of 
at least 25 mIU/mL.  The FCBP subjects may not receive IP until the Investigator has verified 
that the result of the screening pregnancy test, which must be performed within 72 hours of 
randomization, is negative.
Sample Collection for Biomarker Assessments
Subjects must consent to the collection of bone marrow and blood samples for biomarker 
analyses.  Pharmacogenomic blood samples at Screening must be collected on the same day as 
the bone marrow aspirate procedure.
6.2.
Information to be Collected on Screening Failures
The informed consent date, demographics, and reason subject did not qualify for the study will 
be collected for all subjects determined to be screen failures.  Adverse Events experienced by 
screen failure subjects will be collected from the date of signing consent to the day the subject is 
confirmed to be a screen failure.  This information will be captured in the subject’s source 
documents and appropriate CRF(s).  


EDMS Doc. Number: 23107036 - 17852850
Oral Azacitidine (CC-486)
Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
47
CC-486-AML-001 Amendment 2.0 Final: 08 Nov 2018
6.3.
Entering a Subject Into the Study
Written consent must be obtained, all the screening evaluations must be completed, and 
eligibility criteria must be reviewed by the sponsor prior to contacting the IVRS to randomize a 
subject.  Once redacted data is submitted to the sponsor, the sponsor (clinical research physician 
or designee) will review eligibility data and notify the Investigator that they agree with the 
eligibility criteria and site can proceed with the enrollment. Relevant information will also be 
recorded on the Screening Log.
Randomization will be stratified based on the following factors:  
a.
Age (at time of induction therapy):  55-64 and ≥ 65
b. Prior history of MDS or CMML:  Yes / No
c.
Cytogenetic Risk category (at time of induction therapy):  Intermediate risk / Poor 
risk
d. Received consolidation therapy following induction: Yes / No
Randomization will occur by a central randomization procedure.  Specific contact information 
and instructions will be provided individually to each study site.
Randomization of a subject in the IVRS can only be performed once the sponsor (clinical 
research physician or designee) has reviewed the subject’s screening data and has reviewed the 
subject’s entry into the study.
6.4.
Baseline
Results obtained on Day 1 of Cycle 1 (just prior to the first dose of IP) from the physical 
examination, vital sign measurement, weight measurement and body surface area (BSA) 
calculation, and hematology or serum chemistry laboratory assessment will serve as the baseline 
values.  If not available, the most recent screening results prior to Day 1 of Cycle 1 will be 
considered the baseline values.
FACIT-F, EQ-5D, and Physical Impairment Numeric Rating Scale should ideally be completed 
prior to dosing and prior to interaction with study personnel on Day 1 of Cycle 1.
6.5.
Treatments
The first dose of IP should be administered within 3 days after randomization and within 4 
months (± 7 days) of achieving CR/CRi status.  The subject may not receive IP for each 
treatment cycle until all Day 1 procedures specified in Table 1 have been completed, including 
physical examination, vital signs, weight, ECG, hematology, serum chemistry laboratory 
assessments and pregnancy test for FCBP.
IP dispensation
Investigational product should be dispensed on Day 1 of each cycle.  Subjects should not receive 
any IP until all Day 1 assessments have been performed and the subject is confirmed to have met 
all criteria for continued treatment.
IP administration
Antiemetic medication (not supplied by the sponsor) should be administered 30 minutes prior to 
each IP dose.  If there has been no nausea/vomiting, Investigator may choose to omit antiemetic 


EDMS Doc. Number: 23107036 - 17852850
Oral Azacitidine (CC-486)
Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
48
CC-486-AML-001 Amendment 2.0 Final: 08 Nov 2018
as required, provided this is clearly documented in the CRF.  Investigational product is scheduled 
to be taken on Days 1 through 14 of each 28-day cycle.  Refer to Section 8.2.3 for more 
information.  
IP accountability
Investigational product accountability will be assessed by site personnel using pill counts and 
information provided by the subject or caregiver.  Investigational product dosing information 
should be captured in the source documentation on Day 1 of each cycle beginning at Cycle 2 and 
at Treatment Discontinuation.  Investigational product dosing information must also be entered 
on the appropriate CRF.  Refer to Section 12 for more information.
Refer to Appendix K for Treatment Assignment, IP dispensation and IP accountability in the EP. 
6.6.
Safety 
Safety assessments will consist of evaluating AEs and serious adverse events (SAEs) and 
concomitant medication/therapies used to treat them, secondary primary malignancy, 
hematology and serum chemistry parameters, body weight measurement, vital signs, physical 
examinations, and pregnancy testing (for FCBP subjects).  Urinalysis and ECG will be repeated 
whenever clinically indicated during the double-blind treatment phase.
6.6.1.
Adverse Events
All subjects will be monitored for AEs during the study.  Assessments may include monitoring 
of the following parameters:  the subject’s clinical signs and symptoms, laboratory, pathological, 
radiological or surgical findings, physical examination findings, or results of any other 
appropriate test or procedure.
All AEs will be recorded by the Investigator from the time the subject signs the informed consent 
document (ICD) to 28 days after the last dose of IP or until the date of the last study visit, 
whichever is later.  Adverse events and SAEs must be recorded on the AE CRF and in the 
subject’s source documentation.  All SAEs must be reported to Celgene Drug Safety within 24 
hours of the Investigator’s knowledge of the event by facsimile or other appropriate method, 
using the serious adverse event (SAE) Report Form, or approved equivalent form.
Information about common AEs of azacitidine can be found in the Investigator’s Brochure (IB) 
or will be communicated between IB updates in the form of Investigator Notifications.  This 
information about common side effects will also be included in the subject ICD and should be 
discussed with the subject as needed during the study.
6.6.2.
Second Primary Malignancies
Second primary malignancies will be monitored as events of interest and should be included as 
part of the assessment of AEs throughout the duration of the study including post treatment 
follow-up period.  Investigators are to report any second primary malignancy, regardless of 
causal relationship to IP, occurring at any time from signing of informed consent and until the 
last study visit, whichever period is longer as a SAE (considered to be at least “an important 
medical event” even if no other seriousness criteria apply).  This information must also be 
documented on the appropriate pages of the CRF and in the subject’s source documents.  
Documentation on the diagnosis of the second primary malignancy (eg, any confirmatory 


EDMS Doc. Number: 23107036 - 17852850
Oral Azacitidine (CC-486)
Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
49
CC-486-AML-001 Amendment 2.0 Final: 08 Nov 2018
histology or cytology or pathology results, X-rays, CT scans, etc.) must be provided at the time 
of reporting as an SAE. Subjects will be followed for SPMs as described in Section 6.14
6.6.3.
Physical Examination
Physical examinations must be performed as indicated in Table 1.
6.6.4.
Vital Signs Measurement
Vital signs (blood pressure, pulse and temperature) measurements must be performed as 
indicated in Table 1.
6.6.5.
Weight
Weight measurements must be performed as indicated in Table 1.  No dose adjustment should be 
made for weight loss or gain alone; however, the reason for weight loss (eg, significant nausea, 
vomiting, anorexia, etc.) or weight gain (e.g. peripheral edema) should be investigated to 
determine if a dose modification is warranted.
6.6.6.
Hematology and Serum Chemistry Laboratory Evaluations
Hematology and serum chemistry laboratory analyses must be performed according to Table 1.  
The same parameters as required at screening should be evaluated.  All samples should be sent to 
the central laboratory.  In the event that an immediate laboratory assessment is required to 
acutely manage a subject, local laboratory tests may be used.  In addition to collecting the local 
laboratory sample, a second sample should be collected and sent to the central laboratory.
Whenever a hematology sample is collected for a complete blood count, an unstained peripheral 
blood smear should be prepared and sent to the central laboratory.  This unstained peripheral 
blood smear will be used to assess a manual blood count differential
When abnormal laboratory values or test results constitute an AE (ie, induce clinical 
signs/symptoms, require medical intervention, or result in IP dose reduction, interruption or 
discontinuation) they must be recorded on the AE CRF.  Abnormal laboratory values or test 
results constitute AEs only if they induce clinical signs or symptoms, are considered clinically 
significant (eg, cause IP treatment modification or discontinuation), meet the criteria for a 
Serious Adverse Event, or require medical intervention.  Any laboratory abnormality that meets 
one or more of these criteria should be recorded on the AE CRF using the appropriate term (ie, 
sign, symptom or diagnosis) associated with the event.
6.6.7.
Pregnancy Testing (FCBP only)
A serum or urine pregnancy test (per Investigator’s discretion) is to be done within 72 hours 
prior to starting study therapy in the double-blind treatment phase.  The screening serum 
pregnancy test can be used as the test prior to starting study therapy in the double-blind treatment 
phase if it is performed within the 72-hour timeframe.  A serum or urine pregnancy test (per 
Investigator’s discretion) is to be done within 72 hours prior to IP administration on Day 1 of 
Cycle 2 and every treatment cycle thereafter, and at the Treatment Discontinuation visit.  The 
subject may not receive IP until the Investigator has verified that the result of the pregnancy test 
is negative.  Pregnancy testing at screening is provided in Section 6.1.


EDMS Doc. Number: 23107036 - 17852850
Oral Azacitidine (CC-486)
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6.6.8.
Concomitant medications/significant non-drug therapies/concomitant 
procedures
All concomitant over-the-counter medications including vitamins/minerals and herbal 
supplements taken for general health and well-being and prescription medications including anti-
infectives for prophylaxis and/or treatment of an infection that are taken from Cycle 1, Day 1 up 
to 28 days after the last dose of IP or up to the Treatment Discontinuation visit, whichever period 
is longer, must be recorded on the appropriate page(s) of the CRF.
6.7.
Efficacy 
IWG Response
International Working Group response assessment will be assessed at Cycles 3, 6, 9, 12, 15, 18, 
21, 24, 30, 36, and the Treatment Discontinuation visit. After Cycle 36, IWG response 
assessment will be performed if clinically indicated at the discretion of the Investigator.  Subjects 
should be assessed for CR/CRi status maintenance or disease relapse.
Bone Marrow Aspirate, Biopsy and Peripheral Blood Smear
Bone marrow aspirate (or biopsy if adequate aspirate is not attainable) samples during the 
double-blind treatment phase should be collected on Day 1 (± 7 days) of Cycles 3, 6, 9, 12, 15, 
18, 21, 24, 30, 36, and the Treatment Discontinuation visit.  After Cycle 36, bone marrow 
aspiration collection and evaluation will occur if clinically indicated at the discretion of the 
Investigator.
Additional bone marrow samples should be collected as clinically indicated.  A bone marrow 
biopsy must be collected if adequate aspirate is not attainable.  Whenever a bone marrow sample 
is collected, a peripheral blood smear is to be prepared.
Instructions for submission of bone marrow samples are provided in Study Reference and/or 
Study Central Laboratory Manual.
Cytogenetics
Bone marrow cytogenetic testing is to be completed whenever a bone marrow aspirate (or biopsy 
if adequate aspirate is not attainable - note that specific handling of the biopsy is required if to be 
used for cytogenetics testing [see the Study Reference and/or study’s Central Laboratory Manual
for handling instructions]) is obtained for efficacy assessment.
Follow-Up AML Therapies
All discontinued subjects, regardless of reason for discontinuation, should be followed for 
subsequent AML therapies every month for the first year and every three months thereafter until 
death, loss to follow-up, withdrawal of consent from further follow-up, or study closure.  
Subsequent AML therapy follow-up can be performed via the telephone.
Survival Follow-Up
All discontinued subjects, regardless of reason for discontinuation, should be followed for 
survival every month for the first year and every three months thereafter until death, lost to 
follow-up, withdrawal of consent from further follow-up, or study closure.  The survival follow-
up can be performed via telephone.


EDMS Doc. Number: 23107036 - 17852850
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6.10.
Health Resource Utilization
Healthcare utilization data will also be collected.  Information on each hospitalization will be 
collected utilizing a CRF designed specifically for this purpose.  Information to be collected will 
include, but not be limited to, the reason for hospitalization (eg, disease relapse, AML-related 
illness, treatment-related AE), and days of hospitalization by treatment setting (inpatient, special 
care unit).  Other disease- and treatment-related forms of healthcare utilization will be collected 
through routine study activities.  These include diagnostic procedures and treatment interventions 
not requiring hospitalization such as those required for AML-related illness, or for treatment-


EDMS Doc. Number: 23107036 - 17852850
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related adverse events.  Additionally, information on all concomitant medications and resource 
use associated with treatment administration for AML will be collected.
Healthcare resource utilization information should be collected after a subject signs informed 
consent through 28 days after the last dose of IP or until the date of last study visit, whichever is 
later.
 
 
 
 
 
  
 
 
 
 
6.12.
Unscheduled Visits
Should it become necessary to repeat an evaluation (eg, laboratory tests, vital signs, etc.), the 
results of the repeat evaluation should be entered as appropriate in an additional unscheduled 
visit page of the CRF.
6.13.
Discontinuation
The investigator should contact the sponsor or its designee and forward appropriate supporting 
documents for review and discussion prior to discontinuing a subject.  All subjects who have 
received at least one dose of IP should undergo Treatment Discontinuation procedures when 
treatment is discontinued. The Treatment Discontinuation procedures include AEs, monitoring 
for progression of AML and SPM, physical examination, vital signs and weight measurements, 
ECOG performance status, hematology and serum blood chemistry, serum ferritin level, 
pregnancy test (FCBP only), concomitant medications, therapies and procedures, transfusions 
administered, disease status assessment, subsequent AML therapies, IP accountability, HRQoL, 
and healthcare resource utilization.
If a subject is discontinued during a regular scheduled visit, all Treatment Discontinuation 
procedures should be complete at that visit.  If a procedure had been performed within 7 days of 
the Treatment Discontinuation visit, it does not need to be repeated.  For bone marrow aspirate 
and bone marrow biopsy, if the procedures have been performed within 15 days of Treatment 
Discontinuation visit, these procedures do not need to be repeated.


EDMS Doc. Number: 23107036 - 17852850
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The reason for discontinuation will be recorded in the CRF and in the source document for all 
randomized subjects, regardless of whether they are dosed or not. Reasons for discontinuation 
are provided in Section 12.
6.14.
Follow-up
All subjects discontinued from protocol-prescribed therapy for any reason will be followed for a 
period of 28 days following the last dose of IP or until the date of the last study visit, whichever 
is later, for the collection of AEs, concomitant medications, therapies and procedures, and 
healthcare resource utilization.  Females of childbearing potential should avoid becoming 
pregnant for 3 months after the last dose of IP and male subjects should avoid fathering a child 
for 3 months after the last dose of IP.
All subjects discontinued from protocol-prescribed therapy for any reason will also be followed 
for survival, AML relapse, subsequent AML therapies, and SPM every month for the first year 
following Treatment Discontinuation and every three months thereafter until death, lost to 
follow-up, withdrawal of consent for further data collection, or study closure. Documentation 
such as laboratory or pathology reports, bone marrow and/or peripheral blood reports supporting 
the AML relapse should be requested and collected.  The investigator must make every effort to 
obtain information regarding the subject’s survival status before determining the subject is lost to 
follow-up.  Survival follow-up can be performed via the telephone.
6.15.
Extension Phase
Details for the EP are provided in Appendix K.


EDMS Doc. Number: 23107036 - 17852850
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7.
STUDY POPULATION
7.1.
Number of Subjects and Sites
This study will enroll approximately 460 subjects, aged 55 or older, diagnosed with AML or 
AML secondary to prior myelodysplastic disease or CMML, and who have achieved CR/CRi 
following induction with or without consolidation chemotherapy.  In addition, subjects should 
not be eligible for allogeneic bone marrow or stem cell transplantation.
The study will be conducted at approximately 180 clinical sites across the world.
7.2.
Inclusion Criteria
Subjects must satisfy the following criteria to be enrolled in the study:
1. Male or female subjects ≥55 years of age at the time of signing the ICD;
2. Newly diagnosed, histologically confirmed de novo AML or AML secondary to prior 
myelodysplastic disease or CMML;
3. Should have undergone induction therapy with intensive chemotherapy with or without 
consolidation therapy;
4. Must have achieved first CR/CRi status within 4 months (± 7 days) prior to 
randomization, as evidenced by the following: 
Complete Remission (CR)
Complete Remission with Incomplete Blood 
Count Recovery (CRi)

< 5% blasts in bone marrow  

absence of blasts with Auer rods

absence of extramedullary disease

independent of blood transfusions

peripheral neutrophil count > 1.0 x 109/L

platelet count ≥ 100 x 109/L

< 5% blasts in bone marrow  

absence of blasts with Auer rods

absence of extramedullary disease

independent of blood transfusions

peripheral neutrophil count < 1.0 x 109/L
or platelet count < 100 x 109/L
5. ECOG performance status of 0, 1, 2 or 3 (Appendix B);
6. Adequate bone marrow function based on ANCs ≥ 0.5 x 109/L and platelet counts
≥ 20 x 109/L
7. Adequate organ function, defined as:

Serum bilirubin ≤1.5 times the upper limit of normal (ULN);

Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 
times the ULN;

Serum creatinine ≤2.5 times the ULN;


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8. FCBP1 may participate, providing they meet the following conditions:

Agree to practice abstinence; or

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 vasectomized partner) throughout the study, and for 
3 months following the last dose of oral azacitidine; and

Have a negative serum pregnancy test (sensitivity of at least 25 mIU/mL) at 
screening; and

Have a negative serum or urine pregnancy test (Investigator’s discretion) within 72 
hours prior to starting study therapy in the double-blind treatment phase (note that the 
screening serum pregnancy test can be used as the test prior to starting study therapy 
in the double-blind treatment phase if it is performed within the 72-hour timeframe).
9. Male subjects with a female partner of childbearing potential must agree to practice 
abstinence or to the use of a physician-approved contraceptive method throughout the 
course of the study and avoid fathering a child during the course of the study and for 3 
months following the last dose of azacitidine; 
10. Understand and voluntarily sign an ICD prior to any study related 
assessments/procedures are conducted;
11. Able to adhere to the study visit schedule and other protocol requirements;
12. Ability to swallow study medication.
7.3.
Exclusion Criteria
The presence of any of the following will exclude a subject from enrollment:
1. Suspected or proven acute promyelocytic leukemia (FAB M3) based on morphology, 
immunophenotype, molecular assay, or karyotype; or AML with previous hematologic 
disorder such as chronic myeloid leukemia or myeloproliferative neoplasms, excluding 
MDS and CMML; 
2. AML associated with inv(16), t(8;21), t(16;16), t(15;17), or t(9;22) karyotypes or 
molecular evidence of such translocations;
3. Prior bone marrow or stem cell transplantation;
4. Have achieved CR/CRi following therapy with hypomethylating agents;
5. Received therapy with hypomethylating agents for MDS and went on to develop AML 
within four months of discontinuing the therapy with hypomethylating agents;
6. Proven central nervous system leukemia;
7. Candidate for allogeneic bone marrow or stem cell transplant at screening;
                                               
1 A woman of childbearing potential is a sexually mature woman who  1) has not undergone a hysterectomy (the surgical removal 
of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or 2) has not been naturally postmenopausal for at 
least 24 consecutive months (ie has had menses at any time during the preceding 24 consecutive months).


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8. Diagnosis of malignant disease within the previous 12 months (excluding basal cell 
carcinoma of the skin without complications, “in-situ” carcinoma of the cervix or breast, 
or other local malignancy excised or irradiated with a high probability of cure);
9. Unstable angina, significant cardiac arrhythmia, or New York Heart Association (NYHA) 
class 3 or 4 congestive heart failure (Appendix D);
10. Uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing 
signs/symptoms related to the infection without improvement despite appropriate 
antibiotics or other treatment);
11. Known active viral infection with known human immunodeficiency virus (HIV) or viral 
hepatitis type B (HBV) or C (HCV);
12. Known or suspected hypersensitivity to azacitidine or mannitol;
13. Use of any other experimental drug or therapy within 28 days prior to Day 1 of Cycle 1;
14. Unwilling or unable to complete patient reported outcome assessments without assistance 
or with minimal assistance from trained site personnel and/or caregiver;
15. Any condition, including the presence of laboratory abnormalities, which places the 
subject at unacceptable risk if he/she were to participate in the study;
16. Any significant medical condition, laboratory abnormality, or psychiatric illness that 
would interfere or prevent the subject from participating in the study;
17. Any condition that confounds the ability to interpret data from the study;
18. Any condition causing an inability to swallow tablets;
19. Any condition that would impair absorption of the study medication (i.e. short gut, 
malabsorption syndrome).
7.4.
Inclusion and Exclusion Criteria for EP
Refer to Appendix K for Inclusion and Exclusion Criteria in the EP of the study.


EDMS Doc. Number: 23107036 - 17852850
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8.
DESCRIPTION OF STUDY TREATMENTS
8.1.
Description of Investigational Product(s)
8.1.1.
Azacitidine and Placebo
Celgene Corporation will supply azacitidine 150- and/or 200-mg tablets and matching placebo 
tablets for oral administration.  Each tablet is formulated using excipients that are generally 
regarded as safe and are used in marketed drug products.
All tablets will be packaged in blister cards.  Only sufficient IP for one cycle of treatment will be 
provided to each subject at the start of each treatment cycle.  All tablets should be swallowed 
whole and should not be broken or chewed.
No modification of tablets is necessary to preserve blinding as both placebo and azacitidine 
tablets are identical in appearance.
Shelf-life evaluation of the intact blister card is ongoing.  Study drug will be monitored for 
stability for the duration of the study.
8.1.2.
Best Supportive Care
Best supportive care may be used in combination with study treatment as deemed necessary.  
Best supportive care in both treatment arms will include, but not limited to RBC and platelet 
transfusions, use of an ESA, antibiotic, antiviral, and antifungal therapy, nutritional support
(Section 9.1), and granulocyte colony stimulating factors (G-CSFs) for subjects experiencing 
neutropenic infections (Section 9.1), thus the risk of not providing subjects with appropriate care 
is minimized, while providing the potential benefit of maintaining CR/CRi status. 
8.2.
Treatment Administration and Schedule
8.2.1.
Investigational Product Treatment Schedule
Following screening, eligible subjects will be randomized to receive 300 mg oral azacitidine or 
matching placebo QD for 14 days of each 28-day treatment cycle as described in Section 8.2.3.  
In the event of toxicity, dose and schedule may be modified (see Section 8.2.5).  Subjects may 
continue to receive the protocol-prescribed therapy for as long as they benefit from the treatment
or until treatment is discontinued for reasons detailed in Section 12. The Investigator should 
contact the Medical Monitor and forward appropriate supporting documents for review and 
discussion prior to discontinuing a subject.
8.2.2.
Investigational Product Dispensation
Investigational product will be dispensed on Day 1 of each treatment cycle.  Only 1 cycle of IP 
will be dispensed to the subject on Day 1 of each treatment cycle.  
The subject may not receive IP for each treatment cycle until all Day 1 procedures have been 
completed and all IP from the previous cycle are to be accounted for (where applicable).
For FCBP subjects, a pregnancy test must be verified negative when performed within 72 hours 
prior to IP administration on Day 1 of Cycle 1.


EDMS Doc. Number: 23107036 - 17852850
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8.2.3.
Investigational Product Administration
Investigational product administration will be accurately recorded including, but not limited to, 
date of administration, dose and any changes in dose administration (eg, interruption or reduction 
in dose due to an adverse event).
Investigational product is scheduled to be taken on the first 14 days of each 28-day treatment 
cycle, unless there has been a schedule modification of IP administration due to disease relapse 
or toxicity.  On PK sampling days, IP will be administered by the study site personnel in the 
clinic.  Subject will self-administer all other IP doses in the treatment phase.  
Antiemetic medication (not supplied by the sponsor) may be taken 30 minutes prior to IP 
administration.  Subject will ingest IP with approximately 240 mL (8 ounces) of room 
temperature water.  Investigational product may be taken on an empty stomach or with food.  If 
IP is taken in the morning, subjects may consume their usual breakfast before or after 
administration.  The breakfast meal should not exceed approximately 600 calories; however, the 
actual calorie will not need to be measured or recorded.  If a meal other than breakfast is 
consumed, a light meal (not more than 25% of a subject’s usual daily calories) may be eaten 
before or after administration.
Refer to Section 8.6 for details regarding IP accountability.
8.2.4.
Missing Doses
All efforts should be made to administer IP on all of the scheduled days of each 28-day treatment 
cycle.  Any missed doses during that period should not be taken after the last scheduled day of 
administration but should be returned by the subject for IP accountability. Any vomited doses 
should not be repeated. Treatment should resume on the next scheduled day.
8.2.5.
Dose Modifications for Toxicity
Subjects should be monitored for toxicity using the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.0, as a guide for the grading 
of severity.  
If a certain level of toxicity is observed and considered by the investigator to be at least possibly 
related to treatment, IP dosing may be interrupted, delayed or modified.  The Investigator is 
encouraged to contact the Medical Monitor prior to any treatment adjustment.
A maximum of one dose reduction to a daily dose of 200 mg is permitted in the event of toxicity.  
If toxicity persists, a maximum of one treatment schedule modification from 14 to 7 days (21 
days to 14 days for those subjects whose dose schedule has been extended due to disease 
progression) is permitted in the event of continuing toxicity that does not respond to dose 
reduction.  The decision to modify a subject’s treatment schedule from 14 to 7 days (21 days to 
14 days for those subjects whose dose schedule has been extended due to disease progression)
should first be discussed with the Medical Monitor or designee.  Subjects should not receive less 
than 200 mg IP or be scheduled to receive treatment for less than 7 days.  
Subjects who have their IP dose reduced or treatment schedule modified may return to their 
original dose and/or schedule in a step-wise fashion upon discussion and agreement between the 
investigator and the Medical Monitor provided that the increased dose or treatment schedule is 


EDMS Doc. Number: 23107036 - 17852850
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tolerable and at least two additional treatment cycles have occurred since the dose reduction or 
treatment schedule modification.  The treatment schedule should first be increased from 7 to 14 
days, followed by a dose escalation step from 200 to 300 mg.
Dose Modification for Febrile Neutropenia ≥ Grade 3
Any subject who experiences febrile neutropenia (two consecutive readings of body temperature 
> 38.0°C for 2 h and an absolute neutrophil count < 0.5 × 109/L) can continue to receive IP 
uninterrupted at the discretion of the Investigator.  If the febrile neutropenia episode persists for 
≥4 days despite adequate/maximal antibiotic, antiviral and/or antifungal therapy, IP should be 
temporarily discontinued until the fever has resolved and the ANC has improved or stabilized as 
assessed by the Investigator.  Treatment with IP at the same dose should resume no earlier than 3 
days following the resolution of the fever.  If a subject experiences febrile neutropenia in 2 
consecutive cycles, the steps noted above should be followed, but the IP dose should be reduced 
to 200 mg upon resumption of treatment with IP.  A treatment schedule modification from 14 to 
7 days (21 days to 14 days for those subjects whose dose schedule has been extended due to 
disease progression) of treatment may be warranted if a subject experiences regular episode of 
febrile neutropenia that are deemed by the Investigator to be related to IP.  
Dose Modification for Diarrhea ≥ Grade 3
It is recommended that subjects experiencing diarrhea be managed according to the guidelines 
provided in Appendix I.  Antidiarrheal medication may be administered as prophylaxis against 
diarrhea and for treatment of any AEs of diarrhea.  Dose modifications for diarrhea are 
summarized in Section 8.2.5.  In patients not having problems during the first two cycles, the 
treating physician may discontinue use of antiemetic medications.
Dose Modification for Nausea and Vomiting ≥ Grade 3
A serotonin (5-HT3) receptor antagonist (eg, ondansetron) (or other comparable medication) 
should be administered as an antiemetic approximately 30 minutes prior to administration of IP.  
Antiemetic medication(s) should be administered for treatment of any AEs of nausea and/or 
vomiting.  If there has been no nausea and/or vomiting during the first two cycles, Investigator 
may choose to omit antiemetic as required, provided this is clearly documented in the CRF.  
Dose modifications for nausea and vomiting are summarized in Section 8.2.5.
Dose Modification for Renal Dysfunction and Abnormal Serum Electrolytes
If unexplained elevations of BUN and/or serum creatinine (> 20%) occur (per Investigator), the 
next cycle of treatment should be delayed until values return to baseline and the dose should be 
reduced to 200 mg in the next cycle of treatment.  A schedule modification from 14 to 7 days (21 
days to 14 days in those subjects whose dose schedule has been extended due to disease 
progression) can be made if the elevation in BUN and/or creatinine recurs in the subsequent 
cycle.  Should similar unexplained renal disturbances subsequently persist or recur during the 
next cycle of treatment, study treatment should be discontinued.
Dose Modification for Other Treatment-Related Non-Hematologic Toxicity ≥ Grade 3
Any subject who experiences a treatment-related non-hematologic toxicity Grade 3 or higher that 
is an escalation from baseline status (prior to first IP dose) should temporarily discontinue IP 
treatment until the toxicity returns to Grade 2 or lower.  Dose modifications for Grade 3 or 
higher non-hematologic toxicity are summarized in Section 8.2.5.


EDMS Doc. Number: 23107036 - 17852850
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Dose Modification for Weight Change
No dose adjustment should be made for weight loss or gain alone; however, the reason for 
weight loss (eg, significant nausea, vomiting, anorexia, etc.) or weight gain (eg, peripheral 
edema) should be investigated and may require a dose modification as specified in Section 8.2.5.  
Table 2:
Guidelines for Dose Modifications
NCI-CTCAE Toxicity Grade
Action
Febrile Neutropenia (≥Grade 3)

Continue IP at the discretion of the Investigator

If episode persists for ≥ 4 days despite adequate / 
maximal antibiotic, antiviral and/or antifungal therapy, 
IP should be temporarily discontinued until the fever 
has resolved.

Resume IP at the same dose after the fever has resolved 
and the ANC has improved or stabilized (as assessed by 
the Investigator).  IP should not be resumed for at least 
3 days following resolution of fever.

If a subject experiences febrile neutropenia in 2 consecutive 
cycles, the steps noted above should be followed, but the IP 
dose should be reduced to 200 mg upon resumption of 
treatment with IP.

If subject continues to experience febrile neutropenia 
episodes that are deemed to be related to IP by the 
Investigator, a treatment schedule modification from 14 to 7 
days (21 days to 14 days for those subjects whose dose 
schedule has been extended due to disease progression) of 
treatment may also be warranted.  (Treatment schedule 
modification requires prior discussion with Medical 
Monitor).
Diarrhea (≥Grade 3)

Interrupt IP and provide adequate/maximum medical 
intervention

Resume IP at same dose when toxicity resolves to Grade 1

If event reoccurs upon re-challenge or during next treatment 
cycle, reduce IP dose to 200 mg.

If event reoccurs at same intensity once dose is reduced to 
200 mg, follow the steps above and modify treatment 
schedule from 14 to 7 days (21 days to 14 days for those 
subjects whose dose schedule has been extended due to 
disease progression) of IP administration. (Treatment 
schedule modification requires prior discussion with 
Medical Monitor).


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Table 2:
Guidelines for Dose Modifications (Continued)
NCI-CTCAE Toxicity Grade
Action
Nausea and/or Vomiting  
(≥Grade 3)

Interrupt IP and provide adequate/maximal medical 
intervention

Resume IP at same dose when toxicity resolves to Grade 1

If event reoccurs upon re-challenge or at same intensity 
during next treatment cycle, reduce dose to 200 mg

(Treatment schedule modification requires prior discussion
with Medical Monitor).
Renal Dysfunction

For unexplained elevations of BUN and/or serum creatinine 
(> 20%), hold IP, if this is apparent during the IP 
administration phase and/or delay the start of the next cycle 
of treatment until values return to baseline (± 20%).  Reduce 
IP dose in the next cycle of treatment to 200 mg.

Discontinue IP if similar unexplained renal and/or 
electrolyte disturbances subsequently persist or recur during
the next cycle of treatment.

(Treatment schedule modification requires prior discussion 
with Medical Monitor).
Other Grade 3 non-
hematological treatment-related 
AEs

Interrupt IP dosing and provide medical intervention as 
appropriate

Resume IP at same dose when toxicity resolves to Grade 2

If event reoccurs upon re-challenge or at same intensity
during next treatment cycle, reduce IP dose to 200 mg

If event reoccurs at same intensity once dose is reduced to 
200 mg, follow the steps above and modify treatment 
schedule from 14 to 7 days (21 days to 14 days for those 
subjects whose dose schedule has been extended due to 
disease progression) of IP administration.  (Treatment 
schedule modification requires prior discussion with 
Medical Monitor).
AE=Adverse Event; ANC=Absolute Neutrophil Count; CTCAE=Common Terminology Criteria for Adverse 
Events; NCI=National Cancer Institute; IP=Investigational Product.
8.2.6.
Dose and Schedule Adjustment in Subjects with AML Relapse/Progression
In subjects on study who have subsequent evidence of AML relapse with blasts > 5% either in 
the peripheral blood count or bone marrow, and provided the blasts are no greater than 15% in 
the blood or bone marrow, escalation of the dosing regimen (dose and/or schedule) can be 
implemented as follows (provided it is in the best interest to do so as judged by the Investigator):


EDMS Doc. Number: 23107036 - 17852850
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
Subject currently on blinded treatment of oral azacitidine 300 mg or placebo QD for 14 
days - escalate schedule to oral azacitidine 300 mg or placebo QD for 21 days

Subject currently on blinded treatment of oral azacitidine 200 mg or placebo QD for 14 
days - escalate dose schedule, as a first step, to oral azacitidine 200 mg or placebo QD for 
21 days and then escalate dose to oral azacitidine 300 mg or placebo QD for 21 days

Subject currently on blinded treatment for oral azacitidine 200 mg or placebo QD for 7 
days - escalate dose schedule, as a first step, to oral azacitidine 200 mg or placebo QD for 
14 days and then escalate dose to oral azacitidine 300 mg or placebo QD for 14 days
In cases where relapse is noted within a week of starting the next cycle, and there is a desire to 
escalate the dose schedule during the cycle, contact the Medical Monitor to discuss this, in order 
to obtain the additional required IP.  
8.2.7.
Re-treatment Criteria
Prior to the start of each cycle, subjects will have laboratory assessments performed to evaluate 
organ function.  In order to proceed to the next cycle, subjects must continue to meet entry 
criteria regarding renal and hepatic function (see Section 7.2).  Thus, subjects will have 
laboratory assessments performed to evaluate organ function prior to starting each cycle 
(including Cycle 1).  Because of the time it takes to obtain results from the central laboratory, 
samples should be collected early enough prior to starting the next cycle in order to allow 
sufficient time for review.  In the event that immediate laboratory assessment is needed, local 
laboratory measurement is acceptable for starting the next cycle pending the outcome of the 
central laboratory assessment (ie, in addition to collecting the local laboratory sample, a second 
sample should be collected and sent to the central laboratory).
The start of the next cycle will be delayed if the subject does not meet entry criteria regarding 
renal and hepatic function.  If there is a delay of more than 42 days (6 weeks) in the start of the 
next cycle, the Medical Monitor must be consulted.  Study treatment should be discontinued if 
there is a delay of more than 56 days (8 weeks) in the start of the next cycle, unless, in the 
opinion of the investigator and the Medical Monitor, the subject is experiencing clinical benefit.  
Justification of the subject continuing in the study must be recorded in the source documents.
Prior to discontinuing a subject for reasons other than those listed in Section 8.2.5, the 
investigator should contact the Medical Monitor and forward appropriate supporting documents 
for review and discussion.
8.3.
Method of Treatment Assignment
Subjects approved for enrollment will be randomized to receive oral azacitidine or placebo in a 
1:1 ratio.  Randomization will be accomplished by an IVRS to ensure timely registration and 
randomization.  A stratified blocked randomization schedule will be implemented.
Investigator or designated site staff will be assigned password protected, coded identification 
numbers that give them authorization to call into the IVRS to enroll subjects.  At screening, the 
investigator or designated staff will call into the IVRS and provide the requested identifying 
information for the subject.  The IVRS will then confirm the assignment of a 2-part unique 
subject number.  The first part is the center number and the second part is one of a series of 


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numbers allocated to subjects at that center.  Once assigned to a subject, the subject number will 
not be reused.  If the subject is not randomized, the IVRS must be notified.
Randomization will be performed using the following procedure to ensure that treatment 
assignment is unbiased and concealed from subjects and investigators.  A subject randomization 
list will be produced by the IVRS provider using a validated system that automates the random 
assignment of subject numbers to randomization numbers.  These randomization numbers are 
linked to the different treatment groups.  The randomization scheme for subjects will be 
reviewed and approved by the Biostatistics Group of the sponsor, Celgene Corporation.  Written 
consent must be obtained, all the screening evaluations must be completed, and eligibility criteria 
must be verified by the sponsor prior to randomizing a subject. Then the investigator or 
designated staff will call the IVRS and confirm that the subject fulfills all the inclusion and 
exclusion criteria.  The IVRS will assign a randomization number to the subject, which will be 
used to link the subject to a treatment group.
A stratified randomization schedule will be implemented.  Subjects will be stratified by:  age at 
time of induction therapy (55-64 years and ≥ 65 years), prior history of MDS or CMML (Yes / 
No), cytogenetic risk category at time of induction therapy (Intermediate risk / Poor risk) and 
received consolidation therapy following induction (Yes / No).  The random treatment 
assignment will be concealed so that investigators and subjects will not know in advance the next 
treatment assignment. 
After randomization, no crossover between the treatment arms will be permitted.  Subjects may 
continue to receive randomized study treatment for as long as it is appropriate, provided that all 
protocol-specified re-treatment criteria are met.
8.4.
Packaging and Labeling
The label(s) for IP will include sponsor name, address and telephone number, the protocol 
number, IP name, dosage form and strength (where applicable), amount of IP per container, lot 
number, expiry date (where applicable), medication identification/kit number, dosing 
instructions, storage conditions, and required caution statements and/or regulatory statements as 
applicable.  Additional information may be included on the label as applicable per local 
regulations.
8.5.
Clinical Supplies
The investigator(s) or designee(s) is responsible for taking an inventory of each shipment of IP 
received, and comparing it with the accompanying study drug shipping order form.  The 
investigator(s) or designee(s) will verify the accuracy of the information on the form and call the 
IVRS to register the study medication received at the site.  
At the study site, all IPs will be stored according to the storage conditions described on the IP 
packaging label in a locked, safe area to prevent unauthorized access.  The IP must be stored as 
directed on package label at controlled temperature and a temperature log must be maintained in 
the source documents.


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8.6.
Investigational Product Accountability and Disposal 
Investigational Product accountability will be assessed by the investigator or designee.  
Applicable information such as lot number, tablet count and expiration date should be collected, 
as well as information provided by the subject or the caregiver (eg, subject dosing diary).  
Investigational Product accountability should be assessed before drug dispensing for each 
subsequent treatment cycle in the treatment phase, starting on Day 1 of Cycle 2, and at the 
Treatment Discontinuation visit.
The investigator(s) or designee(s) is responsible for accounting for all IP that is issued to and 
returned by the subject during the course of the study according to applicable regulatory 
requirements.  Any unused IP must be returned by a study subject and retained by the 
investigative site for accountability to be conducted by a Celgene representative (or designee).  If 
any IP is lost or damaged, its disposition should be documented.  At the periodic monitoring 
visits, a Celgene representative (or designee) will conduct IP accountability and address any 
discrepancies.  Upon satisfactory reconciliation of all IP, returned IP may be destroyed.  At the 
conclusion of the study, all remaining study drug will be counted, reconciled with dispensing 
records, documented, and destroyed at the clinic site or allocated drug destruction location after 
completion of drug accountability by a Celgene representative (or designee).  The Celgene 
representative (or designee) will ensure that a final report of drug accountability to the unit dose 
level (ie, tablet) is prepared and placed in both the investigator study file and the central clinical 
study file.
Celgene Corporation will instruct the investigator(s) on the return, disposal and destruction of IP.  
A copy of the site’s Standard Operating Procedure (SOP) for drug destruction may be collected 
by the sponsor (or designee).  Any revisions to a site’s destruction process must be provided and 
approved by the sponsor (or designee) prior to implementation on this protocol.  Any site without 
a sponsor (or designee) approved destruction SOP and process will be required to return IP to 
Celgene.
8.7.
Investigational Product Compliance
Investigational Product will be administered by the study site personnel in the clinic on PK 
sampling days.  Subjects will self-administer all other IP doses in the treatment phase.  
Documentation of dosing during treatment will be recorded in a study specific diary card.  
Investigational product administration diary cards will be provided by the sponsor to study site 
personnel, who will in turn distribute them to study subjects.  Study site personnel will enter the 
scheduled daily doses, the number of tablets to be taken each day and any other applicable 
information.  Study site personnel will review the dosing information with the subject (or legally 
authorized representative) on scheduled clinic visit days.  Subjects (or legally authorized 
representative) will be asked to record IP dosing information and anti-emetic medication taken at 
home in the diary card and to bring the diary card and unused tablets in the blister card (or the 
blister card packaging even if it is empty) with them to scheduled clinic visits (ie, prior to the 
start of the next treatment cycle).  A diary card and tablet compliance check will be performed by 
study personnel.  Diary cards must be saved and kept with the source documentation.  Study site 
personnel will perform an IP administration compliance check and record this information in the 
subject’s source documentation and on the appropriate CRF.


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Administration of all IP will be recorded including dispensing, dosing and any changes in dosage
administration such as interruption or reduction in dosing due to an AE. 
8.8.
Blinding
This is a double-blind study.  Subjects, investigators, site staff and Celgene Corporation clinical 
and medical personnel will be unaware of treatment assignments until study closure and database 
lock. 
8.9.
Emergency Unblinding
In order to maintain the integrity of the study design, the blind must not be broken during the 
course of the study unless, in the opinion of the investigator, it is absolutely required to safely 
treat the subject.  There should be only rare instances when breaking the blind would be required, 
such as the development of pregnancy, for example.  In most instances of treatment-related 
toxicity, interrupting treatment and/or dose reduction of IP is all that would be required.  For 
more information on the unblinding process, please refer to Section 13.2.


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10.
STATISTICAL ANALYSES
10.1.
Overview
This Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study is 
designed to compare the efficacy and safety of oral azacitidine plus best supportive care versus 
placebo plus best supportive care in subjects with AML who have achieved CR/CRi following 
induction, with or without consolidation, chemotherapy.
All data will be summarized by treatment group.  In addition, where appropriate, a total column 
will be included to summarize subjects across treatment groups.  Summaries of continuous 
variables will present the number of subjects included in the analysis (N), the mean and standard 
deviation (SD) of the mean, the median, the minimum, and the maximum statistics.  Counts and 
percentages will be presented in summaries of categorical variables.  The denominator for each 
percentage will be the number of subjects in the population treatment group unless otherwise 
specified.  In general, missing data will not be imputed unless otherwise specified.
10.2.
Study Population Definitions
10.2.1.
Intent-to-Treat Population
The intent-to-treat (ITT) population includes all subjects who are randomized to treatment, 
regardless of whether they received treatment or not.  All efficacy analyses will be conducted for 
the ITT population.  Subjects will be analyzed based on randomized treatment group.
10.2.2.
Modified Intent-to-Treat Population
The modified intent-to-treat (mITT) population includes all subjects who have met all 
inclusion/exclusion criteria and experienced no major protocol deviations during the study, and 
received a minimum of one cycle of treatment.  Subjects who are randomized without confirmed 
CR/CRi per central review will be excluded from the mITT population.  This definition will be 
further clarified and detailed in the final statistical analysis plan prior to database lock.  
Key efficacy analysis will be performed for the mITT population as supportive and/or 
exploratory analysis only.  Subjects will be analyzed based on randomized treatment group.
10.2.3.
Safety Population
The safety population includes all randomized subjects who received at least 1 dose of IP.  The 
safety population will be used for all safety analysis.  Subjects will be analyzed according to the 
treatment actually received.
10.3.
Sample Size and Power Considerations
The equality of OS curves will be compared between the azacitidine and placebo treatment 
groups using a stratified log-rank test.  Assuming a median OS of 16 months in the placebo 
treated group 
), a median OS of 22.9 months in the azacitidine treated 
group (43% improvement), and a study duration of 60 months with a drop-out rate of 5% from 
both treatment groups, over the duration of the study, this design requires 330 deaths and 
approximately 460 subjects (230 per treatment arm) to be randomized in order to achieve at least 


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90% power to detect a constant hazard ratio of 0.70 and demonstrate a statistically significant 
difference in OS.  It is assumed that the OS distribution is exponential with a constant failure 
(hazard) rate and that accrual is non-uniform during an accrual period of 36 months with 25% of 
the subjects accrued during each of the first 2 years of enrollment (50% accrued at 24 months) 
and the remaining 50% accrued during the last year of enrollment.  Sample size calculations are 
based on a one-sided alpha of 0.025 with one interim analysis for futility after 30% of the events 
have occurred.
Sample size was calculated using the East® Version 5.4 software system (
 
).
10.4.
Background and Demographic Characteristics
Demographic and baseline disease characteristics will be summarized by treatment group for the 
ITT, mITT, and safety populations.  Subjects’ age, height, weight, body mass index (BMI), and 
continuous baseline characteristics will be summarized using descriptive statistics (N, mean, SD, 
median, minimum, maximum), while age group, gender, race and other categorical variables will 
be provided using frequency tabulations (count, percent) by treatment group.  Summaries of 
baseline disease characteristics will include CR/CRi status following induction therapy, whether 
the subject received consolidation therapy following induction therapy, prior history of MDS, 
time since initial AML diagnosis, ECOG performance status, bone marrow blasts (%), ANC 
(109/L), hemoglobin (g/dL), platelet counts (109/L), and cytogenetic risk classification.  For 
laboratory and vital sign measures, the most recent assessment on or prior to the date of 
randomization will be used for baseline.  
Medical history data (coded by the Medical Dictionary for Regulatory Affairs [MedDRA]
dictionary) will be summarized using frequency tabulations by treatment group, system organ 
class and preferred term for the ITT, mITT, and safety populations.
10.5.
Subject Disposition
Subject disposition (analysis population allocation, discontinued, along with primary reason for 
discontinuation) will be summarized using frequency tabulations for both treatment and follow-
up phases.  A summary of subjects enrolled by site and by country will be provided. Major 
protocol violations will be summarized using frequency tabulations for the ITT population.  
Supportive corresponding subject listings will also be provided.
10.6.
Efficacy Analysis
All efficacy analysis will be performed on the ITT population.  Key efficacy analysis will be 
performed on the mITT population as supportive evidence and to assess the robustness of the 
efficacy findings.  Subjects will be analyzed according to randomized treatment group. Refer to 
Section 3.1 and Section 3.2 for the primary and secondary efficacy endpoints, respectively.
A sequential gate-keeping approach will be used to control the overall type I error rate in order to 
perform hypothesis testing on multiple endpoints. Two endpoints, the primary efficacy endpoint 
of OS and the key secondary endpoint of RFS, will be tested sequentially in the given, pre-
specified order.  The primary efficacy endpoint will be tested first at the two-sided 0.05 
significance level.  In order to preserve the overall alpha level at 0.05 across the OS and RFS 


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endpoints, formal statistical inference for the RFS analyses can only be made if superiority of 
azacitidine is demonstrated for the primary efficacy endpoint, OS, at the two-sided 0.05 
significance level.  
Other than the pre-specified sequential testing of OS and RFS, no additional alpha adjustments 
for multiplicity will be made.
10.6.1.
Primary Efficacy Analysis
The primary efficacy endpoint of OS is defined as the time from randomization to death from 
any cause and will be calculated using randomization date and date of death, or date of last 
follow-up for censored subjects.  All subjects will be followed until drop-out, death, or study 
termination.  Drop-out may be due to withdrawal of consent from further data collection or loss 
to follow-up.  Subjects who drop-out or are alive at study termination will have their OS times
censored at the time of last contact, as appropriate.  
The primary efficacy analysis will be conducted for the ITT population and will compare the OS 
distributions between the two treatment groups.  The null hypothesis for testing the primary 
efficacy endpoint, time to death from any cause, is that the overall survival distributions for the 
two treatment groups are equivalent. The OS curves will be estimated using Kaplan-Meier (KM) 
methods.  A stratified log-rank test, stratifying by age at time of induction therapy (55-64 years, 
≥ 65 years), prior history of MDS (Yes / No), whether consolidation therapy was administered 
(Yes / No), and cytogenetic risk category at time of induction therapy (intermediate-risk,  poor-
risk), at a two-sided alpha level of 0.05, will be used to compare the survival distributions 
between the two treatment groups.  The p-value from the stratified log-rank test will be the 
confirmatory p-value.  Kaplan-Meier estimates for median OS as well as the 25th and 75th
percentiles and associated two-sided 95% CIs will be summarized for each treatment group, 
unadjusted for the stratification variables.  In addition, both the numerical difference and the 
95% CI of the difference, in the median, 25th, and 75th percentiles between the two treatment 
groups will be presented for the un-stratified analysis.  Plots of the KM survival curves will be 
presented for the two treatment groups, without adjustment for the stratification variables.
A stratified Cox proportional hazards model will be used to estimate the corresponding hazard 
ratio and 95% CI for azacitidine relative to placebo.  Additionally, KM methods will be used to 
estimate the 1-year and 2-year survival probabilities for time to death from any cause.  Estimates 
of the 1-year (365 days) and 2-year (730 days) survival probabilities and corresponding 95% 
confidence intervals will be presented by treatment group.  
Median follow-up time, by treatment and overall, will be estimated using KM methods.  The 
analysis of the OS endpoint will be repeated for the mITT-population as a supportive/exploratory 
analysis.
In order to assess the potentially confounding effects of other cancer therapy received subsequent 
to the protocol therapy on the survival estimates, an exploratory analysis based on the 
ITT population, will be performed using modified censoring criteria.  For this analysis, subjects 
who received subsequent therapy for AML following discontinuation from their protocol therapy 
will be censored on the date that the subsequent therapy was started regardless of their survival 
status at the time of the final analysis.  This exploratory modified time-to-death endpoint will be 
analyzed using the same methods as described above for the primary efficacy analysis.


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10.6.2.
Secondary Efficacy Analyses
10.6.2.1.
Key Secondary Efficacy Analyses
Relapse-free survival (RFS) is defined as the interval from the date of randomization to the date 
of documented relapse after CR or CRi or death from any cause, whichever occurs first.  
Subjects who are still alive without documented relapse after CR or CRi, or who were lost to 
follow-up without documented relapse, will be censored at the date of their last response 
assessment.  Relapse after CR or CRi is defined according the IWG AML response criteria 
(Appendix E).
The analysis of RFS will be performed using the ITT population and will be analyzed using the 
same methods as those used for the primary efficacy analysis of OS.  The p-value from the 
stratified log-rank test will be the confirmatory p-value.
The analysis of the RFS endpoint will be repeated for the mITT-population as a 
supportive/exploratory analysis.  Additional sensitivity analyses, based on the ITT population, 
will be performed using modified RFS definitions.  For these analyses of RFS, subjects lost to 
follow-up without documented relapse or death will be 1) considered as having an event; and 2) 
considered as having an event if they were randomized to the azacitidine treatment group and 
censored if they were randomized to the placebo treatment group.  The event/censoring time will 
be the date of the last response assessment.
In order to assess and compare the modified definition of AML relapse being used in this 
protocol as criteria for discontinuation from treatment (ie, appearance of > 15% blasts in the 
bone marrow or peripheral blood) with respect to the IWG definition of relapse after CR or CRi 
(Appendix E), an exploratory analysis based on the ITT population, will be performed for RFS 
using this modified definition of relapse.  For this analysis of RFS, relapse after CR or CRi is 
defined as the appearance of > 15% blasts in the bone marrow or peripheral blood.  Subjects who 
are still alive without documented relapse after CR or CRi or who were lost to follow-up without 
documented relapse will be censored at the date of their last response assessment.  This 
exploratory modified RFS endpoint will be analyzed using the same methods as described above 
for the key secondary efficacy analysis.
10.6.2.2.
Additional Secondary Efficacy Analyses
The time-to-event secondary efficacy variables will be analyzed similarly to the primary efficacy 
variable without stratification.  Kaplan-Meier methods will be used to estimate time-to-event 
curves, unless otherwise specified.  Counts and percentages will be used to describe categorical 
secondary variables.  Secondary efficacy analyses will be performed on the ITT population 
unless otherwise specified.
Time to relapse from CR/CRi is defined as the interval from the date of randomization to the 
date of documented relapse after CR or CRi, as defined according to the IWG AML response 
criteria (Appendix E).  Time to relapse will be analyzed using a competing risk analysis where 
death without documented relapse is treated as a competing risk for relapse from CR/CRi.  
Subjects who are lost to follow-up without documented relapse or are alive at last follow-up 
without documented relapse will be censored at the date of their last response assessment.  The 
cumulative incidence function for time to relapse from CR/CRi will be summarized for each 
treatment group.  Summary statistics will include the cumulative incidence estimate of the 


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median time to relapse and the one-year cumulative incidence of relapse for each treatment 
group.
Time to discontinuation from treatment will be assessed as an estimate of treatment 
failure/tolerability and is defined as the interval from the date of randomization to the date of 
discontinuation from IP.  Subjects who are ongoing in treatment at the time of study closure will 
be censored at the date of last visit.  
Time to discontinuation from treatment will be analyzed using a competing risk model with 
reason for treatment discontinuation classified as:

Disease relapse

Adverse event(s)

Became eligible for bone marrow or stem cell transplant

Withdrawal of consent / lost to follow-up / protocol violation 

Death
Cumulative incidence curves will be estimated and summarized for each specific reason for 
discontinuation from treatment by treatment group.
Additionally, time to discontinuation from treatment will be analyzed using KM methods.
 
 
  


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10.7.
Safety Analysis
All safety analyses will be performed on the safety population.
Adverse Events will be coded using MedDRA.  Adverse event listings will include the verbatim 
term and the MedDRA preferred term.  Treatment-emergent AEs (TEAEs) will be summarized 
by worst severity grade, system organ class, and preferred term.  Treatment-emergent AEs 
leading to death or to discontinuation from treatment, AEs classified as CTCAE (Version 4.0) 
Grade 3 or Grade 4, AEs related to IP, and SAEs will be summarized separately.  Time to 
discontinuation from the study due to AE will be summarized using KM methods.  Listings of all 
deaths and all SAEs, regardless of when they occurred, will also be generated.  Development of a 
SPM will be documented as an SAE (considered to be at least an “important medical event” even 
if no other seriousness criteria apply) throughout a subject’s duration in the study (signing of 
ICD through the follow-up period of the study).
Clinical laboratory results will be summarized descriptively by treatment group, which will also 
include a display of change from baseline.  Laboratory values outside of the normal ranges will 
be identified.  Clinically significant hematologic and non-hematologic laboratory abnormalities 
that meet Grade 3 or Grade 4 criteria according to the CTCAE will be listed and summarized.  
Graphical display of select laboratory parameters over the course of the study will be provided.
Vital sign measurements and ECOG performance status will be listed for each subject at each 
visit.  Descriptive statistics for the vital signs and ECOG performance status, both observed 
values and changes from baseline, will be summarized by treatment group.
10.8.
Interim Analysis
One interim analysis to assess futility will be performed when approximately 30% of the total 
events (99 deaths) have occurred.  A beta-spending function was used to calculate a futility 
boundary of Z < -1.9796 using Gamma (-10) and corresponds to a conditional power level of 
approximately 18%.  Based on the study assumptions, the interim analysis is projected to occur 
approximately 28 months after the first subject is randomized and at least 60% of subjects have 
been accrued.  At the time of the interim analysis, based on blinded data, the death rate will be 
evaluated relative to the study assumptions and enrollment into the study may be increased to 
ensure that the required number of 330 deaths can be reached in approximately 60 months from 
the time of randomization of the first subject.
 
 
 
  
 
 


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11.
ADVERSE EVENTS
11.1.
Monitoring, Recording and Reporting of Adverse Events
An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen 
in a subject during the course of a study. It may be a new intercurrent illness, a worsening 
concomitant illness, an injury, or any concomitant impairment of the subject’s health, including 
laboratory test values (as specified by the criteria below), regardless of etiology.  Any worsening 
(ie, any clinically significant adverse change in the frequency or intensity of a pre-existing 
condition including AML relapse) should be considered an AE.  A diagnosis or syndrome should 
be recorded on the AE page of the CRF rather than the individual signs or symptoms of the 
diagnosis or syndrome.  
An overdose, accidental or intentional, whether or not it is associated with an AE, or abuse, 
withdrawal, sensitivity or toxicity to an IP should be reported as an AE.  If an overdose is 
associated with an AE, the overdose and AE should be reported as separate terms.
All subjects will be monitored for AEs during the study.  Assessments may include monitoring 
of any or all of the following parameters:  the subject’s clinical symptoms, laboratory, 
pathological, radiological or surgical findings, physical examination findings, or other 
appropriate tests and procedures.
All AEs will be recorded by the Investigator from the time the subject signs informed consent to 
28 days after the last dose of IP or until the last study visit, whichever period is longer.  Adverse 
events and SAEs will be recorded on the AE page of the CRF and in the subject’s source 
documents.  All SAEs must be reported to Celgene Drug Safety within 24 hours of the 
investigator’s knowledge of the event by facsimile, or other appropriate method, using the SAE 
Report Form, or approved equivalent form.  Please note that SPMs will be monitored as events 
of interest throughout the duration of the study including post treatment follow-up period and 
must be reported as SAEs regardless of the treatment arm the subject is in.
11.2.
Evaluation of Adverse Events
A qualified Investigator will evaluate all adverse events as to: 
11.2.1.
Seriousness 
A serious adverse event (SAE) is any AE occurring at any dose that:

Results in death;

Is life-threatening (ie, in the opinion of the Investigator, the subject is at immediate 
risk of death from the AE);

Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay);

Results in persistent or significant disability/incapacity (a substantial disruption of the 
subject’s ability to conduct normal life functions);

Is a congenital anomaly/birth defect;


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
Constitutes an important medical event.
Important medical events are defined as those occurrences that may not be immediately life 
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above.  
Medical and scientific judgment should be exercised in deciding whether such an AE should be 
considered serious.
Second primary malignancies will be monitored as events of interest and must be reported as 
SAEs regardless of the treatment arm the subject is in (see Section 11.5).
Events not considered to be SAEs are hospitalizations for:

A standard procedure for protocol therapy administration.  However, hospitalization 
or prolonged hospitalization for a complication of therapy administration will be 
reported as an SAE.

Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition.

The administration of blood or platelet transfusion as routine treatment of studied 
indication.  However, hospitalization or prolonged hospitalization for a complication 
of such transfusion remains a reportable SAE.

A procedure for protocol/disease-related investigations (e.g., surgery, scans, 
endoscopy, sampling for laboratory tests, bone marrow sampling).  However, 
hospitalization or prolonged hospitalization for a complication of such procedures 
remains a reportable SAE.

Hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE.

A procedure that is planned (ie, planned prior to starting of treatment on study); must 
be documented in the source document and the CRF.  Hospitalization or prolonged 
hospitalization for a complication remains a reportable SAE.

An elective treatment of a pre-existing condition unrelated to the studied indication. 

Emergency outpatient treatment or observation that does not result in admission, 
unless fulfilling other seriousness criteria above.
If an AE is considered serious, both the AE page/screen of the CRF and the SAE Report Form 
must be completed.
For each SAE, the Investigator will provide information on severity, start and stop dates, 
relationship to IP, action taken regarding IP, and outcome.
11.2.2.
Severity / Intensity
The severity / intensity of AEs will be graded based upon the subject’s symptoms according to 
the currently active minor version of Common Terminology Criteria for Adverse Events 
(CTCAE, Version 4.0); 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40


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AEs that are not defined in the CTCAE should be evaluated for severity according to the 
following scale:

Grade 1 = Mild – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required

Grade 2 = Moderate – mild to moderate limitation in activity, some assistance may be 
needed; no or minimal medical intervention/therapy required

Grade 3 = Severe – marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalization is possible

Grade 4 = Life threatening – extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, hospitalization or hospice 
care probable

Grade 5 = Death - the event results in death
The term “severe” is often used to describe the intensity of a specific event (as in mild, moderate 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache).  This criterion is not the same as “serious” which is 
based on subject/event outcome or action criteria associated with events that pose a threat to a 
subject’s life or functioning.  
Seriousness, not severity, serves as a guide for defining regulatory obligations.
11.2.3.
Causality 
The Investigator must determine the relationship between the administration of IP and the 
occurrence of an AE/SAE as Not Suspected or Suspected as defined below:
Not suspected:
The temporal relationship of the adverse event to IP
administration makes a causal relationship unlikely or 
remote, or other medications, therapeutic interventions, or 
underlying conditions provide a sufficient explanation for the 
observed event.
Suspected:
The temporal relationship of the adverse event to IP
administration makes a causal relationship possible, and other 
medications, therapeutic interventions, or underlying conditions 
do not provide a sufficient explanation for the observed event.
If an event is assessed as suspected of being related to a comparator, ancillary or additional IP
that has not been manufactured or provided by Celgene, please provide the name of the 
manufacturer when reporting the event.
11.2.4.
Duration
For both AEs and SAEs, the Investigator will provide a record of the start and stop dates of the 
event.


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11.2.5.
Action Taken
The Investigator will report the action taken with IP as a result of an AE or SAE, as applicable 
(e.g., discontinuation or reduction of IP, as appropriate) and report if concomitant and/or 
additional treatments were given for the event. 
11.2.6.
Outcome
All SAEs that have not resolved upon discontinuation of the subject’s participation in the study 
must be followed until recovered (return to baseline), recovered with sequelae, or death (due to 
the SAE). 
11.3.
Abnormal Laboratory Values
An abnormal laboratory value is considered to be an AE if the abnormality:

results in discontinuation from the study;

requires treatment, modification/ interruption of IP dose, or any other therapeutic 
intervention; or

is judged to be of significant clinical importance.
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 
need to be documented as a serious adverse event.  
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded on the AE page/screen of the CRF.  If the abnormality was not a 
part of a diagnosis or syndrome, then the laboratory abnormality should be recorded as the AE.
11.4.
Pregnancy
11.4.1.
Females of Childbearing Potential:
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female subject occurring while the subject is on IP, or within 3 months of the 
subject’s last dose of IP, are considered immediately reportable events.  Investigational product is
to be discontinued immediately and the subject instructed to return any unused portion of the IP 
to the investigator.  The pregnancy, suspected pregnancy, or positive pregnancy test must be 
reported to Celgene Drug Safety immediately by facsimile, or other appropriate method, using 
the Initial Pregnancy Report Form, or approved equivalent form.  
The female should be referred to an obstetrician-gynecologist, preferably one experienced in 
reproductive toxicity for further evaluation and counseling.
The investigator will follow the female subject until completion of the pregnancy and must 
notify Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or 
abnormal outcome) using the Follow-up Pregnancy Report Form or approved equivalent form.
If the outcome of the pregnancy was abnormal (eg, spontaneous or therapeutic abortion), the 
investigator should report the abnormal outcome as an AE.  If the abnormal outcome meets any 
of the serious criteria, it must be reported as an SAE to Celgene Drug Safety by facsimile, or 


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other appropriate method, within 24 hours of the investigator’s knowledge of the event using the 
SAE Report Form or approved equivalent form.
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 28 days that the investigator suspects is 
related to the in utero exposure to the IP should also be reported to Celgene Drug Safety by 
facsimile, or other appropriate method, within 24 hours of the investigator’s knowledge of the 
event using the SAE Report Form, or approved equivalent form.
11.4.2.
Male Subjects
If a female partner of a male subject taking IP becomes pregnant while the male subject is on IP, 
or within 3 months of the male subject’s last dose of IP, the male subject taking IP should notify 
the Investigator, and the pregnant female partner should be advised to call their healthcare 
provider immediately.  Where applicable, the IP may need to be discontinued in the male subject 
but may be resumed later at the discretion of the Investigator and Medical Monitor.
11.5.
Reporting of Serious Adverse Events
Any AE that meets any criterion for an SAE requires the completion of an SAE Report Form in 
addition to being recorded on the AE page/screen of the CRF.  All SAEs must be reported to 
Celgene Drug Safety within 24 hours of the investigator’s knowledge of the event by facsimile, 
or other appropriate method, using the SAE Report Form, or approved equivalent form.  This 
instruction pertains to initial SAE reports as well as any follow-up reports.
Development of SPMs will be monitored as events of interest throughout the duration of the 
study including the post treatment follow-up period and must be reported as SAEs regardless of 
the treatment arm the subject is in. This includes any SPM, regardless of causal relationship to 
IP (oral azacitidine or placebo), occurring at any time for the duration of the study, from the time 
of signing the ICD until death, lost to follow-up, withdrawal of consent for further data 
collection, or study closure. Events of SPM are to be reported using the SAE report form and 
must be considered an “Important Medical Event” even if no other serious criteria apply; these 
events must also be documented in the appropriate page(s) of the CRF, ie, AE and SPM and 
subject’s source documents.  Documentation on the diagnosis of progression to AML and/or the 
SPM must be provided at the time of reporting as an SAE (eg, any confirmatory histology or 
cytology results, X-rays, computed tomography [CT] scans, etc.).  
The investigator is required to ensure that the data on these forms are accurate and consistent.  
This requirement applies to all SAEs (regardless of relationship to IP) that occur during the study 
(from the time the subject signs informed consent to 28 days after the last dose of IP or until the 
last study visit, whichever period is longer), and those made known to the investigator at anytime 
thereafter that are suspected of being related to IP.  Serious AEs occurring prior to treatment but 
after informed consent will be collected.
The SAE report should provide a detailed description of the SAE and include a summary of 
hospital records and other relevant documents.  If a subject died and an autopsy has been 
performed, copies of the autopsy report and death certificate are to be sent to Celgene Drug 
Safety as soon as these become available.  Any follow-up data will be detailed in a subsequent 
SAE Report Form, or approved equivalent form, and sent to Celgene Drug Safety.  


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Where required by local legislation, the Investigator is responsible for informing the Institutional 
Review Board (IRB)/Ethics Committee (EC) of the SAE and providing them with all relevant 
initial and follow-up information about the event.  The investigator must keep copies of all SAE 
information on file including correspondence with Celgene and the IRB/EC.
11.5.1.
Safety Queries
Queries pertaining to SAEs will be communicated from Celgene Drug Safety to the site via 
facsimile or electronic mail.  The response time is expected to be no more than five (5) business 
days.  Urgent queries (eg, missing causality assessment) may be handled by phone.
11.6.
Expedited Reporting of Adverse Events
For the purpose of regulatory reporting, Celgene Drug Safety will determine the expectedness of 
events suspected of being related to oral azacitidine based on the Azacitidine IB.
For countries within the European Economic Area (EEA), Celgene or its authorized 
representative will report in an expedited manner to Regulatory Authorities and Ethics 
Committees concerned, suspected unexpected serious adverse reactions (SUSARs) in accordance 
with Directive 2001/20/EC and the Detailed Guidance on collection, verification and 
presentation of adverse reaction reports arising from clinical trials on medicinal products for 
human use (ENTR/CT3) and also in accordance with country-specific requirements.
Celgene or its authorized representative shall notify the investigator of the following information
(in Japan, Celgene KK shall notify the heads of the institutes in addition to the investigators):

Any AE suspected of being related to the use of IP in this study or in other studies 
that is both serious and unexpected (ie, SUSAR).

Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity.

In Japan, measures taken in foreign countries to ensure subject safety, study reports 
that indicate potential risk of cancer, etc, or biannual SAE report according to the 
local regulations.
Where required by local legislation, the investigator shall notify his/her IRB/EC promptly of 
these new serious and unexpected AE(s) or significant risks to subjects.
The investigator must keep copies of all pertinent safety information on file including 
correspondence with Celgene and the IRB/EC.  (See Section 15.3 for record retention 
information).
Celgene Drug Safety Contact Information:
For Local Drug Safety Affiliate Office contact information, please refer to the Serious Adverse 
Event Report Form/Completion Guidelines or to the Pregnancy Report Form/Completion 
Guidelines.


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12.
DISCONTINUATIONS
The following events are considered sufficient reasons for discontinuing a subject from the IP / 
treatment:

Disease relapse 
Subjects will be discontinued from treatment when they meet the following criteria. 

Appearance of > 15% blasts in the bone marrow or peripheral blood; and

The above occurrence should be attributed to relapse following CR/CRi, and not 
attributable to any other cause (eg, bone marrow regeneration after consolidation 
therapy or myeloid growth factor administration).

AE(s)

Subject withdraws from active treatment but continues follow-up

Subject becomes eligible (per Investigator) for allogeneic bone marrow or stem cell 
transplantation during treatment period

Death

Lost to follow up

Protocol violation
Prior to discontinuing IP treatment for a subject assessed to have disease relapse, the Investigator 
may contact the Medical Monitor and forward appropriate supporting documents for review and 
discussion.
The reason for discontinuation will be recorded in the CRF and in the source documents.
All subjects discontinued from protocol prescribed treatment for any reason should undergo 
Treatment Discontinuation procedures including pregnancy test for FCBP.  Additionally, all 
subjects discontinued from protocol prescribed treatment will be followed for a period of 28 days 
following the last dose of IP or until the date of the last study visit, whichever is later, for the 
collection of adverse events.  Discontinued subjects will not be replaced.
During the follow-up period, all subjects should be followed every month for the first year and 
then every 3 months thereafter until death for collection of information on survival, AML 
relapse, monitoring for SPM and subsequent AML therapies, unless the subject has specifically 
withdrawn consent from further follow-up.  Documentation such as laboratory or pathology 
reports, bone marrow and/or peripheral blood reports supporting the AML relapse will be 
requested and collected.  The Investigator must make every effort to obtain information 
regarding the subject’s survival status before determining the subject is lost to follow-up.


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13.
EMERGENCY PROCEDURES
13.1.
Emergency Contact
In emergency situations, the Investigator should contact the responsible Clinical Research
Physician/Medical Monitor or designee by telephone at the number(s) listed on the Emergency 
Contact Information page of the protocol (after title page).
In the unlikely event that the Clinical Research Physician/Medical Monitor or designee cannot be 
reached, please contact the global Emergency Call Center by telephone at the number listed on 
the Emergency Contact Information page of the protocol (after title page).This global Emergency 
Call Center is available 24 hours a day and 7 days a week. The representatives are responsible 
for obtaining your call-back information and contacting the on call Celgene/CRO Medical 
Monitor, who will then contact you promptly.
Note: The back-up 24 hour global emergency contact call center should only be used if you are 
not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls. 
13.2.
Emergency Identification of Investigational Products
The blind must not be broken during the course of the study unless in the opinion of the 
Investigator, it is absolutely necessary to safely treat the subject.  If it is medically imperative to 
know what IP the subject is receiving, IP should be temporarily discontinued.
The Investigator may contact the Medical Monitor prior to breaking the blind to discuss
unblinding, mainly in the interest of the subject. However, the decision to break the blind in
emergency situations remains the responsibility of the treating physician, which will not be
delayed or refused by the sponsor.  
The Investigator should ensure that the code is broken only in accordance with the protocol. The 
Investigator should promptly notify the Medical Monitor of the emergency unblinding and the 
reason for breaking the blind, which should be clearly documented by the Investigator in the 
subject’s source documentation.
Emergency unblinding should be performed only by the Investigator through the IVRS by using
an emergency unblinding personal identification number (PIN), and the Investigator should call 
IVRS for unblinded dose information.


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14.
REGULATORY CONSIDERATIONS
14.1.
Good Clinical Practice
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that Celgene, its authorized representative,
and Investigator abide by Good Clinical Practice (GCP), as described in International 
Conference on Harmonization (ICH) Guideline E6 and in accordance with the general ethical 
principles outlined in the Declaration of Helsinki. The study will receive approval from an 
IRB/EC prior to commencement. The Investigator will conduct all aspects of this study in 
accordance with applicable national, state, and local laws of the pertinent regulatory authorities.
14.2.
Investigator Responsibilities
Investigator responsibilities are set out in the ICH Guideline for Good Clinical Practice and in 
the local regulations.  Celgene staff or an authorized representative will evaluate and approve all 
Investigators who in turn will select their staff.
The Investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, amendments, study treatments, as well as study-related duties and functions. 
The Investigator should maintain a list of Sub-investigators and other appropriately qualified 
persons to whom he or she has delegated significant study-related duties.
The Investigator is responsible for keeping a record of all subjects who sign an informed consent 
document and are screened for entry into the study.  Subjects who fail screening must have the 
reason(s) recorded in the subject’s source documents.
The Investigator, or a designated member of the Investigator’s staff, must be available during 
monitoring visits to review data, resolve queries and allow direct access to subject records (e.g., 
medical records, office charts, hospital charts, and study-related charts) for source data 
verification.  The Investigator must ensure timely and accurate completion of CRFs and queries.
14.3.
Subject Information and Informed Consent
The Investigator must obtain informed consent of a legal representative prior to any study related 
procedures.
Documentation that informed consent occurred prior to the study subject’s entry into the study 
and of the informed consent process should be recorded in the study subject’s source documents 
including the date.  The original informed consent document signed and dated by the study 
subject and by the person consenting the study subject prior to the study subject’s entry into the 
study, must be maintained in the Investigator’s study files and a copy given to the study subject.  
In addition, if a protocol is amended and it impacts on the content of the informed consent, the 
informed consent document must be revised.  Study subjects participating in the study when the 
amended protocol is implemented must be re-consented with the revised version of the informed 
consent document.  The revised informed consent document signed and dated by the study 
subject and by the person consenting the study subject must be maintained in the Investigator’s 
study files and a copy given to the study subject.  


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14.4.
Confidentiality
Celgene affirms the subject's right to protection against invasion of privacy and to be in 
compliance with ICH and other local regulations (whichever is most stringent). Celgene requires 
the Investigator to permit Celgene's representatives and, when necessary, representatives from 
regulatory authorities, to review and/or copy any medical records relevant to the study in 
accordance with local laws.
Should direct access to medical records require a waiver or authorization separate from the 
subject’s signed informed consent document, it is the responsibility of the Investigator to obtain 
such permission in writing from the appropriate individual.
14.5.
Protocol Amendments
Any amendment to this protocol must be approved by the Celgene Clinical Research 
Physician/Medical Monitor.  Amendments will be submitted to the IRB/EC and any additional 
local authorities as appropriate, depending on local legislations for written approval.  Written 
approval must be obtained before implementation of the amended version occurs.  The written 
signed approval from the IRB/EC should specifically reference the Investigator name, protocol 
number, study title and amendment number(s) that is applicable. Amendments that are 
administrative in nature do not require IRB/IEC approval but will be submitted to the IRB/IEC 
for information purposes.
14.6.
Institutional Review Board/Independent Ethics Committee Review 
and Approval
Before the start of the study, the study protocol, informed consent document, and any other 
appropriate documents will be submitted to the IRB/EC with a cover letter or a form listing the 
documents submitted, their dates of issue, and the site (or region or area of jurisdiction, as 
applicable) for which approval is sought. If applicable, the documents will also be submitted to 
the authorities in accordance with local legal requirements.
IP can only be supplied to an Investigator by Celgene or its authorized representative after 
documentation on all ethical and legal requirements for starting the study has been received by 
Celgene or its authorized representative. This documentation must also include a list of the 
members of the IRB/EC and their occupation and qualifications. If the IRB/EC will not disclose 
the names, occupations and qualifications of the committee members, it should be asked to issue 
a statement confirming that the composition of the committee is in accordance with GCP. For 
example, the IRB General Assurance Number may be accepted as a substitute for this list. 
Formal approval by the IRB/EC should mention the protocol title, number, amendment number 
(if applicable), study site (or region or area of jurisdiction, as applicable), and any other 
documents reviewed. It must mention the date on which the decision was made and must be 
officially signed by a committee member. Before the first subject is enrolled in the study, all 
ethical and legal requirements must be met.
The IRB/EC and, if applicable, the authorities, must be informed of all subsequent protocol 
amendments in accordance with local legal requirements. Amendments must be evaluated to 
determine whether formal approval must be sought and whether the informed consent document 
should also be revised.


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The Investigator must keep a record of all communication with the IRB/EC and, if applicable, 
between a Coordinating Investigator and the IRB/EC. This statement also applies to any 
communication between the Investigator (or Coordinating Investigator, if applicable) and 
regulatory authorities.
Any advertisements used to recruit subjects for the study must be reviewed by Celgene and the 
IRB/EC prior to use.  
14.7.
Ongoing Information for Institutional Review Board / Ethics 
Committee
If required by legislation or the IRB/EC, the Investigator must submit to the IRB/EC:

Information on serious or unexpected adverse events as soon as possible; 

Periodic reports on the progress of the study;

Deviations from the protocol or anything that may involve added risk to subjects.
14.8.
Closure of the Study
Celgene reserves the right to terminate this study at any time for reasonable medical or 
administrative reasons. Any premature discontinuation will be appropriately documented 
according to local requirements (e.g., IRB/EC, regulatory authorities, etc).
In addition, the Investigator or Celgene has the right to discontinue a single site at any time 
during the study for medical or administrative reasons such as:

Unsatisfactory enrollment;

GCP noncompliance;

Inaccurate or incomplete data collection;

Falsification of records;

Failure to adhere to the study protocol.
The sponsor may consider closing this trial when data supporting key endpoints and objectives of
the study have been analyzed. In a case where there are subjects still being administered the 
investigational product, and it is the opinion of the investigator(s) that those subjects would 
continue to receive benefit from treatment, the sponsor may choose to initiate an open-label 
rollover study under a separate protocol to allow those subjects to continue receiving oral 
azacitidine. This would occur after their participation in this study, CC-486-AML-001, and after
the unblinding of those remaining subjects.
The EP of the study will close once oral azacitidine becomes commercially available and 
reimbursed in the participating countries for the indications that the subjects are being treated 
such that the subject’s access to oral azacitidine is neither interrupted nor discontinued.


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15.
DATA HANDLING AND RECORDKEEPING 
15.1.
Data/Documents
The Investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the investigational product are complete, accurate, filed and 
retained.  Examples of source documents include: hospital records; clinic and office charts; 
laboratory notes; memoranda; subject’s diaries or evaluation checklists; dispensing records; 
recorded data from automated instruments; copies or transcriptions certified after verification as 
being accurate copies; microfiche; x-ray film and reports; and records kept at the pharmacy, and 
the laboratories, as well as copies of CRFs or CD-ROM.
15.2.
Data Management
Data will be collected via CRF and entered into the clinical database per Celgene SOPs. This 
data will be electronically verified through use of programmed edit checks specified by the 
clinical team.  Discrepancies in the data will be brought to the attention of the clinical team, and 
investigational site personnel, if necessary.  Resolutions to these issues will be reflected in the 
database.  An audit trail within the system will track all changes made to the data.
15.3.
Record Retention
Essential documents must be retained by the Investigator for a minimum of 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the IP. The investigator must retain these 
documents for the time period described above or according to local laws or requirements, 
whichever is longer.  Essential documents include, but are not limited to, the following:

Signed informed consent documents for all subjects;

Subject identification code list, screening log (if applicable), and enrollment log;

Record of all communications between the Investigator and the IRB/EC;

Composition of the IRB/EC;

Record of all communications between the Investigator, Celgene, and their authorized 
representative(s);

List of Sub-investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant study-related duties, together with their roles in 
the study, curriculum vitae, and their signatures;

Copies of CRFs (if paper) and of documentation of corrections for all subjects;

IP accountability records;

Record of any body fluids or tissue samples retained;

All other source documents (subject records, hospital records, laboratory records, 
etc.); 


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
All other documents as listed in Section 8 of the ICH consolidated guideline on GCP 
(Essential Documents for the Conduct of a Clinical Trial).
The Investigator must notify Celgene if he/she wishes to assign the essential documents to 
someone else, remove them to another location or is unable to retain them for a specified period.  
The Investigator must obtain approval in writing from Celgene prior to destruction of any 
records. If the Investigator is unable to meet this obligation, the Investigator must ask Celgene 
for permission to make alternative arrangements. Details of these arrangements should be 
documented. 
All study documents should be made available if required by relevant health authorities. 
Investigator/Institution should take measures to prevent accidental or premature destruction of 
these documents.


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16.
QUALITY CONTROL AND QUALITY ASSURANCE
All aspects of the study will be carefully monitored by Celgene or its authorized representative
for compliance with applicable government regulations with respect to current GCP and standard 
operating procedures.
16.1.
Study Monitoring and Source Data Verification
Celgene ensures that appropriate monitoring procedures are performed before, during and after 
the study.  Before the study is initiated at a site visit or at an investigator meeting, all aspects of 
the study are reviewed with the Investigator and the staff.  Prior to enrolling subjects into the 
study, a Celgene representative will review the protocol, CRFs, procedures for obtaining 
informed consent, record keeping, and reporting of AEs/SAEs with the Investigator.  Monitoring 
will include on-site visits with the Investigator and his/her staff as well as any appropriate 
communications by mail, email, fax, or telephone.  At each monitoring visit, the facilities, 
investigational product storage area, CRFs, subject’s source documents, and all other study 
documentation will be inspected/reviewed by the Celgene representative for accuracy, adherence 
to the protocol and Good Clinical Practice.
Accuracy will be checked by performing source data verification that is a direct comparison of 
the entries made onto the CRFs against the appropriate source documentation.  Any resulting 
discrepancies will be reviewed with the Investigator and/or his/her staff.  Any necessary 
corrections will be made directly to the CRFs or via queries by the Investigator and/or his/her 
staff. Monitoring procedures require that informed consents, adherence to inclusion/exclusion 
criteria and documentation of SAEs and their proper recording be verified.  Additional 
monitoring activities may be outlined in a study-specific monitoring plan.
16.2.
Audits and Inspections
In addition to the routine monitoring procedures, a Good Clinical Practice Quality Assurance 
unit exists within Celgene.  Representatives of this unit will conduct audits of clinical research 
activities in accordance with Celgene SOPs to evaluate compliance with Good Clinical Practice 
guidelines and regulations.
The Investigator is required to permit direct access to the facilities where the study took place, 
source documents, CRFs and applicable supporting records of study subject participation for 
audits and inspections by IRB/IECs, regulatory authorities (e.g., FDA, EMA, Health Canada) 
and company authorized representatives.  The Investigator should make every effort to be 
available for the audits and/or inspections.  If the Investigator is contacted by any regulatory 
authority regarding an inspection, he/she should contact Celgene immediately.


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17.
PUBLICATIONS
The results of this study may be published in a medical publication, journal, or may be used for 
teaching purposes.  Additionally, this study and its results may be submitted for inclusion in all 
appropriate health authority study registries, as well as publication on health authority study 
registry websites, as required by local health authority regulations.  Selection of first authorship 
will be based on several considerations, including, but not limited to study participation, 
contribution to the protocol development, and analysis and input into the manuscript, related 
abstracts, and presentations in a study.










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19.
APPENDICES
Appendix A: WHO Classification of Acute Myeloid Leukemia
Acute myeloid leukemia with recurrent genetic abnormalities
Acute myeloid leukemia with t(8;21)(q22;q22); (RUNX1-RUNX1T1)
Acute myeloid leukemia with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); (CBFB-MYH11)
Acute promyelocytic leukemia with t(15;17)(q22;q12); (PML-RARA)
Acute myeloid leukemia with t(9;11)(p22;q23); MLLT3-MLL
Acute myeloid leukemia with t(6;9)(p23q34); DEK-NUP214
Acute myeloid leukemia with inv(3)(q21q26.2) or t(3;3)(q26.2); RPN1-EVI1
Acute myeloid leukemia (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL1
Acute myeloid leukemia with gene mutations
Acute myeloid leukemia with myelodysplasia-related changes
Therapy-related myeloid neoplasm
Acute myeloid leukemia, not otherwise categorized
Acute myeloid leukemia with minimal differentiation
Acute myeloid leukemia without maturation
Acute myeloid leukemia with maturation
Acute myelomonocytic leukemia
Acute monoblastic and monocytic leukemia
Acute erythroid leukemia (erythroid/myeloid and pure erythroleukemia)
Acute megakaryoblastic leukemia
Acute basophilic leukemia
Acute panmyelosis with myelofibrosis
Source: Swerdlow, SH, Campo, E, Harris, NL, Jaffe, ES, Pileri, SA, Stein, H, et al. editors.  WHO Classification of 
Tumors of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: IARC Press; 2008; 109-139.  


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Appendix B: Eastern Cooperative Oncology Group (ECOG) Performance 
Status
Grade
ECOG 
0
Fully active, able to carry on all predisease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all self care but unable to carry out any work activities.  
Up and about more than 50% of waking hours
3
Capable of only limited self care, confined to bed or chair more than 50% of waking 
hours
4
Completely disabled.  Cannot carry on any self care.  Totally confined to bed or chair
5
Dead
Source:
 


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Appendix C: Risk Status Based on Cytogenetics
Risk Status
Cytogenetics
Better-risk
inv(16)1
t(16;16)1
t(8;21)1
t(15;17)
Intermediate-
risk
Normal cytogenetics
+8
t(9;11)
Other non-defined
Poor-risk
Complex (≥ 3 abnormalities)
-5
5q-
-7
7q-
11q23 - non t(9;11)
inv(3)
t(3;3)
t(6;9)
t(9;22)2
1 Other abnormalities in addition to these finding do not alter risk status
2 Philadelphia+ AML t(9;22) consider managing as myeloid blast crisis in CML.  These subjects are excluded from 
study entry.  
Source: 
 
  


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Appendix D: New York Heart Association Classification for Congestive 
Heart Failure
Functional Capacity
Class I.  Subjects with cardiac disease but without resulting limitation of physical activity.  Ordinary 
physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain.
Class II.  Subjects with cardiac disease resulting in slight limitation of physical activity.  They are 
comfortable at rest.  Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain.
Class III.  Subjects with cardiac disease resulting in marked limitation of physical activity.  They are 
comfortable at rest.  Less than ordinary activity causes fatigue, palpitation, dyspnea, or anginal pain.
Class IV.  Subjects with cardiac disease resulting in inability to carry on any physical activity without 
discomfort.  Symptoms of heart failure or the anginal syndrome may be present even at rest.  If any 
physical activity is undertaken, discomfort is increased.
Source:
 
  


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Appendix E: International Working Group AML Response Criteria
Hematologic Response According to IWG Criteria for AML
Category
Definition
Morphologic Complete Remission (CR)
The following conditions should be met:

ANC > 1,000/μL;

Platelet count ≥ 100,000/μL; 

The bone marrow should contain less than 5% blast cells; 

Auer rods should not be detectable;

No evidence of extramedullary disease;

Independent of transfusions.
Morphologic Complete Remission with 
Incomplete Blood Count Recovery (CRi)
Defined as a morphologic complete remission but the ANC count may be            
< 1,000/μL or the platelet count may be < 100,000/μL.
Cytogenetic Complete Remission (CRc)
Defined as morphologic complete remission with a reversion to a normal 
karyotype.
Relapse Free Survival
Defined for patients who achieve CR/CRi, and is measured from the date of 
attaining leukemia free state until the date of AML relapse or death from any 
cause, whichever occurs first.
Disease Relapse
Relapse after CR/CRi is defined as reappearance of leukemic blasts in the 
peripheral blood or ≥ 5% blasts in the bone marrow not attributable to any 
other cause (eg, bone marrow regeneration after consolidation therapy).  In the 
setting of recent treatment, if there are no circulating blasts and the bone 
marrow contains 5% to 20% blasts, a repeat bone marrow performed at least a 
week later is necessary to distinguish relapse from regeneration.
Source:
 










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Appendix I:
Recommendations for Management of Treatment-Induced 
Diarrhea
The following published guidelines 
 were modified in order to be consistent with 
the clinical study protocol.


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Appendix J:
List of Abbreviations and Definitions of Terms
AE
Adverse event
ALT
Alanine transaminase (also known as SGPT)
AML
Acute myeloid leukemia
ANC
Absolute neutrophil count
AST
Aspartate transaminase (also known as SGOT)
BSA
Body surface area
BSC
Best supportive care
BID
Twice a day
BUN
Blood urea nitrogen
CBC
CC-486
Complete blood count
Oral azacitidine
CCR
Conventional care regimen
CMML
Chronic myelomonocytic leukemia
CR
Complete remission
CRc
Complete cytogenetic remission
Cri
Complete remission with incomplete blood count recovery
CRF/eCRF
Case report form/electronic case report form
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EP
Extension Phase
EPO
Erythropoietin
EORTC
European Organization for Research and Treatment of Cancer
ESA
Erythropoiesis stimulating agent
FAB
French-American-British
FACIT-F
Functional Assessment of Chronic Illness Therapy – Fatigue
FACIT-Fatigue Scale
Functional Assessment of Chronic Illness Therapy – Fatigue Scale
FCBP
Female of childbearing potential
FDA
Food and Drug Administration
G-CSF
Granulocyte colony-stimulating factor
GM-CSF
Granulocyte macrophage colony-stimulating factor
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
HR
Hazard ratio
HRQoL
Health-related Quality-of-Life
IB
Investigator’s Brochure
ICD
Informed Consent Document
INT-2
Intermediate-2
IP
Investigational Product


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Appendix J:
List of Abbreviations and Definitions of Terms (Continued)
IPSS
International Prognostic Scoring System
ITT
IV
Intent to Treat
Intravenous
IVRS
Interactive Voice Response System
IWG
International Working Group
LDH
Lactate dehydrogenase
KM
Kaplan-Meier
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCR
Marrow complete response
MCV
Mean corpuscular volume
MDS
Myelodysplastic syndromes
MedDRA
Medical Dictionary for Regulatory Affairs
mRNA
Messenger-ribonucleic acid
miRNA
Micro-ribonucleic acid
mITT
Modified intent-to-treat
MRC
Medical Research Council
NCI-CTCAE
National Cancer Institute-Common Terminology Criteria for Adverse Events
NYHA
New York Heart Association
OS
Overall survival
PFS
Progression-free survival
PR
Partial remission
pRBC
Packed red blood cell
QD
Once a day
QoL
Quality-of-life
RA
Refractory anemia
RAEB
Refractory anemia with excess blasts
RAEB-T
Refractory anemia with excess blasts in transformation
RARS
Refractory anemia with ringed sideroblasts
RBC
Red blood cell
RNA
Ribonucleic acid
RFS
Relapse-free survival
SAE
Serious adverse event
SC
Subcutaneous
SDev
Standard deviation
SGOT
Serum glutamic oxaloacetic transaminase (also known as AST)
SGPT
Serum glutamic pyruvate transaminase (also known as ALT)
SOP
Standard operating procedure
SPM
Second primary malignancy
SRC
Synopsis Review Committee
SNP
Single nucleotide polymorphism
TEAE
Treatment-emergent adverse event


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Appendix J:
List of Abbreviations and Definitions of Terms (Continued)
TSA
Thrombopoiesis-stimulating agent
ULN
Upper Limit of Normal
US
United States
WBC
White blood cell 
WHO
World Health Organization


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Appendix K: Extension Phase
Subject Eligibility
At the Investigator’s discretion and with approval of the sponsor, subjects meeting all of the 
following eligibility criteria are eligible to enter the extension phase:
1. All subjects randomized into the oral azacitidine or placebo arm and are continuing in 
either the Treatment Phase or Follow-up Phase of the CC-486-AML-001 study;

Subjects randomized to oral azacitidine treatment arm and continuing in the 
Treatment Phase demonstrating clinical benefit as assessed by the Investigator are 
eligible to receive oral azacitidine in the EP;

Subjects randomized into placebo arm of the study will not receive oral azacitidine in 
the EP, but will be followed for survival in the EP;

Subjects currently in the in the Follow-up Phase will continue to be followed for 
survival in the EP;
2. Subjects who have signed the informed consent for the EP of the study;
3. Subjects who do not meet any of the criteria for study discontinuation (see Section 12).
Treatment Assignment
Once the total number of events (n=330 deaths) required for a fully powered analysis of overall 
survival have occurred and the Amendment 2 of the protocol is approved at the respective sites, 
subjects will start the EP at the start of their next regularly scheduled dosing cycle for oral 
azacitidine and align Cycle 1 Day 1 with the Treatment Discontinuation visit for Protocol 
Amendment 1, so they occur on the same day.  The dose and schedule for the first treatment 
cycle in the EP should be administered at the identical dose and schedule as the final treatment 
cycle in the Protocol Amendment 1. If a dose modification was required in the last cycle of 
Amendment 1, the first treatment cycle should be administered at the identical (modified) dose 
and/or schedule.    
Cycles should be repeated every 28 days.  Subjects should be monitored locally for hematology 
and chemistry testing, pregnancy testing for FCBP and dose limiting toxicities before the dosing 
of the next cycle. Dosage delay or reduction as described below may be necessary.
Management of Toxicities and Dose Modifications
Subjects should be monitored for toxicity using the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.0, as a guide for the grading 
of severity.  If a certain level of toxicity is observed and considered by the investigator to be at 
least possibly related to treatment, IP dosing may be interrupted, delayed or modified.  In all 
cases, the reason for dose modification must be recorded in the subject’s medical record.  If the 
subject discontinues the protocol-prescribed therapy because of an AE, this event must be 
reported in accordance with the procedures outlined in Section 8.2.5.
Oral azacitidine dose modifications due to nonhematological and hematological toxicities during 
oral azacitidine treatment should be managed as described in Section 8.2.5 for dose modification 
guidelines due to toxicity.  


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Dose and schedule adjustment in patients with AML relapse/progression will be performed as 
described in Section 8.2.6
Adverse Events
Adverse events (non-serious and serious) will continue to be collected in the EP AE CRF.  Refer 
to Section 11 Adverse Events (AEs) for reporting requirements, responsibilities and procedures.
For subjects entering the EP, ongoing AEs at the time of the end of study visit from Protocol 
Amendment 1 should be left as ongoing and should not be recorded again in the EP AE CRF.  
Adverse events with an onset date equal to or after the EP informed consent date should be 
recorded in the AE CRF for Amendment 2. If a previously reported AE during Amendment 1
worsens during the EP, then the AE should be recorded as a new AE with a higher grade on the 
EP AE CRF. All subjects will be monitored for AEs for 28 days following the date of last dose 
of IP. SAEs that have not resolved upon discontinuation of the subject’s participation in the 
study must be followed until recovered (return to baseline), recovered with sequelae, or death 
(due to the SAE).  
Concomitant Medications
All concomitant medications that are necessary for the subject’s welfare may be given at the 
Investigator’s discretion during the EP.  However, treatment with any other investigational
medication is not permitted. Refer to Section 9 for prohibited concomitant medications/therapy 
for subjects on oral azacitidine.
Survival Follow-up
All subjects participating in the EP will be followed for overall survival for an additional 12 
months or more.  During the survival follow up, subjects will be followed for survival every 
month for the duration of the survival follow-up, until death, withdrawal of consent for further 
follow-up, study termination, or until a subject is lost to follow-up.  New anticancer therapies 
should be collected at the same time schedule.
Survival follow-up may be conducted via telephone contact with the subject, family, or the 
subject’s treating physician or via record review (including public records, if admissible by law 
in the participating countries). 
Recommended Monitoring of Subjects
1. Complete blood count with WBC differential and platelet count as needed, and at a 
minimum, prior to each dosing cycle.
2. For FCBP, pregnancy testing must be done prior to initiating new cycle
3. Bone marrow biopsy and aspirate as clinically indicated.
4. Additional tests or more frequent monitoring are at the Investigator’s discretion based on 
the subject’s clinical status.
Investigator’s Responsibility 
1. Complete Extension Phase Case Report Form pages. 
2. Document all adverse events (serious and non-serious) on the adverse event log page of 
the Extension Phase Case Report Form as required by the protocol (Section 8.2.5). 


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3. Report serious adverse events and other immediately reportable events, as required by the 
protocol (see Section 11).  A completed SAE form must be faxed to Celgene Drug 
Safety, as detailed in the Serious Adverse Event Report Form Completion Guidelines, 
immediately (ie, within 24 hours of the Investigator’s knowledge of the event).
4. Report to the Sponsor about/of drug accountability.
5. Report to the Sponsor and complete the case report form page for extension phase 
termination when the subject completes, discontinues, or terminates treatment with oral 
azacitidine.
6. The subject should stop treatment with oral azacitidine if any of the following occur:
a.
Additional investigational treatment is started;
b. Subject is no longer receiving clinical benefit, as per Investigator’s discretion;
c.
Subject withdraws consent;
d. A CTCAE toxicity Grade 3 or 4 that represents a worsening from baseline 
(prior to the first dose) persists for more than 21 days, despite the temporary 
interruption of oral azacitidine;
e.
A positive pregnancy test in a FCBP, at any time; or
f.
At the specific request of the Sponsor or its authorized representative.
4. The Investigator must be available for periodic monitoring visits and allow the Sponsor 
access to all medical records.
5. The Investigator will maintain source documents on the subject for all case report form 
data points, which include the following:
a.
Informed consent;
b. Adverse events;
c.
Dosing information (date of administration, dose, number of tablets used, and 
lot number); 
d. Concomitant medications
e.
Termination date and reason.
Statistical Methods  
Safety evaluation for the EP will include monitoring for adverse events and recording of 
concomitant medications. Although physical examinations, vital sign measurements and 
laboratory assessments will be performed in the EP, these assessments will not be captured in the 
CRF. However, clinically significant findings from these assessments which meet the definition 
of an adverse event (see Section 11) will be reported as adverse events. Adverse events will be 
summarized as per Protocol Section 11.3 on the subjects entering into the EP.  Exposure to oral 
azacitidine as well as concomitant medications taken during the EP will also be summarized.


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Celgene Signing Page
This is a representation of an electronic record that was signed electronically in Livelink.
This page is the manifestation of the electronic signature(s) used in compliance with
the organizations electronic signature policies and procedures.
UserName:
Title:  
Date: Friday, 09 November 2018, 03:41 AM   Eastern Daylight Time
Meaning: Approved, no changes necessary.
 ================================================


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CC-486-AML-001 Amendment 2.0 Final: 08 Nov 2018
TITLE PAGE
– SUMMARY OF CHANGES –
AMENDMENT NO. 2.0
A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED STUDY TO COMPARE EFFICACY AND
SAFETY OF ORAL AZACITIDINE PLUS BEST SUPPORTIVE
CARE VERSUS BEST SUPPORTIVE CARE AS MAINTENANCE 
THERAPY IN SUBJECTS WITH ACUTE MYELOID 
LEUKEMIA IN COMPLETE REMISSION
INVESTIGATIONAL PRODUCT (IP):
Oral Azacitidine (CC-486)
PROTOCOL NUMBER:
CC-486-AML-001
ORIGINAL DATE:
15 Aug 2012
AMENDMENT No. 1.0 DATE:
29 Dec 2015
AMENDMENT No. 2.0 DATE:
08 Nov 2018
EudraCT NUMBER:
2012-003457-28
IND NUMBER: 
074618
Contact Information: 
Name:
Ignazia La Torre, MD
Title:
Address: 
Phone:
E-mail:
CONFIDENTIAL
This protocol is provided to you as an Investigator, potential Investigator, or consultant for review by 
you, your staff, and ethics committee/institutional review board.  The information contained in this 
document is regarded as confidential and, except to the extent necessary to obtain informed consent, 
may not be disclosed to another party unless such disclosure is required by law or regulations.  
Persons to whom the information is disclosed must be informed that the information is confidential 
and may not be further disclosed by them.


EDMS Doc. Number: 23107036 - 20736229
Oral Azacitidine (CC-486)
Summary of Changes CC-486-AML-001
Celgene Corporation
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CC-486-AML-001 Amendment 2.0 Final: 08 Nov 2018
CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
Printed Name of Celgene Therapeutic Area Head and Title
By my signature, I indicate I have reviewed this summary of changes and find its content to 
be acceptable.  


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1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
The primary purpose of this protocol amendment is to add an extension phase (EP)
 
  
In addition, all subjects who were discontinued from the treatment phase (irrespective of 
randomization arm) and continuing in the Follow-up Phase, will be followed for survival for at 
least another 12 months, until death, withdrawal of consent, study closure or until the subject is 
lost to follow-up.
Revised Sections:  Protocol Summary, Sections 4.1 and Appendix K
Minor changes included in this amendment are summarized below:

Duration of the study and subject enrollment period was updated
Revised Section: Protocol Summary and Section 4.1

Revised language
 
 
 
Revised Sections:  Protocol Summary

Added language to the protocol that would define End of Trial or Closure of the Study.
 
 
Revised Sections:  Section 4.1, Section 4.3, Section 14.8

Revised language
 
.
Revised Sections:  Table 1, Section 6.4, Section 6.9, Section 10.9.1

Included a few minor editorial corrections and additions to Appendix J, List of 
Abbreviations and Definitions of Terms.
Revised Section:  Appendix J

On recommendations from Health Regulatory Authorities, deleted language that 
indicated ‘Adverse events such as disease progression, death related to disease 
progression (in the absence of serious IP-related events) and serious events due to the 
relapse of the studied indication will not be subject to expedited reporting by the sponsor 
to regulatory authorities…’.
Revised Section:  Section 11.6


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
Included an administrative change
 
.
Revised Section: Medical Monitor/Emergency Contact Information Page

Included an administrative change
 
Revised Section: Celgene Therapeutic Area Head Signature Page

A few minor editorial corrections were made globally.
Revised Section: Global


EDMS Doc. Number: 20735352 - 20736229
Oral Azacitidine (CC-486)
Summary of Changes CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
1
CC-486-AML-001 Amendment 1.0  Final: 29 Dec 2015
TITLE PAGE
– SUMMARY OF CHANGES –
AMENDMENT NO. 1.0
A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED STUDY TO COMPARE EFFICACY AND 
SAFETY OF ORAL AZACITIDINE PLUS BEST SUPPORTIVE 
CARE VERSUS BEST SUPPORTIVE CARE AS MAINTENANCE 
THERAPY IN SUBJECTS WITH ACUTE MYELOID 
LEUKEMIA IN COMPLETE REMISSION
INVESTIGATIONAL PRODUCT (IP):
CC-486 (Oral Azacitidine)
PROTOCOL NUMBER:
CC-486-AML-001
ORIGINAL DATE:
15 Aug 2012
AMENDMENT No. 1.0 DATE:
29 Dec 2015
EudraCT NUMBER:
2012-003457-28
IND NUMBER: 
074618
Contact Information: 
Name:
Barry Skikne, MD, FACP; FCP (SA)
Title:
Address: 
Phone:
E-mail:
CONFIDENTIAL
This protocol is provided to you as an Investigator, potential Investigator, or consultant for review by 
you, your staff, and ethics committee/institutional review board.  The information contained in this 
document is regarded as confidential and, except to the extent necessary to obtain informed consent, 
may not be disclosed to another party unless such disclosure is required by law or regulations.  
Persons to whom the information is disclosed must be informed that the information is confidential 
and may not be further disclosed by them.


EDMS Doc. Number: 20735352 - 20736229
Oral Azacitidine (CC-486)
Summary of Changes CC-486-AML-001
Celgene Corporation
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CC-486-AML-001 Amendment 1.0  Final: 29 Dec 2015
CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
Printed Name of Celgene Therapeutic Area Head and Title
By my signature, I indicate I have reviewed this summary of changes and find its content to 
be acceptable.  


EDMS Doc. Number: 20735352 - 20736229
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Summary of Changes CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
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CC-486-AML-001 Amendment 1.0  Final: 29 Dec 2015
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
1. Modification of Inclusion Criterion #2 to allow patients with AML secondary to 
chronic myelomonocytic leukemia (CMML) into the study
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Revised Sections:  Protocol Summary, Sections 4.1, 6.3, 7.1, 7.2, 7.3, 8.3, and 10.6.2.3
2. Modification of Inclusion Criterion #4 to amend the amount of time required for 
subjects to be in complete remission (CR) or in complete remission with incomplete 
blood count recovery (CRi) from 3 months to 4 months (± 7 days).
 
 
 
 
 
 
 
 
 
 


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provided no delays occur because of adverse events, such as infections leading to 
 
 
 
 
Revised Sections:  Global
3. Reduction of the number of bone marrow collections and analyses for CR/CRi 
assessment:
 
 
 
 
 
 
Revised Sections:  Protocol Summary, 4.1, Figure 1 (footnote 2), Table 1 (footnote 17), 
Section 6.7
4. Reduction in the number of clinical visits in a cycle beginning with Cycle 25:
 
 
Revised Section: Table 1 heading (including footnote 30)
Minor changes included in this amendment are summarized below:

Replaced the word “demonstrate” in the Primary Objective with  “evaluate” 
 
Revised Section:  Protocol Summary and Section 2.1

 
 

Updated the number of sites participating in the clinical trial from 150 to 180.
Revised Section: Protocol Summary, Sections 4.1, 7.1


EDMS Doc. Number: 20735352 - 20736229
Oral Azacitidine (CC-486)
Summary of Changes CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
5
CC-486-AML-001 Amendment 1.0  Final: 29 Dec 2015

Revised language
 
  
Revised Section:  Protocol Summary (deleted from Page 8) and Section 4.1 (deleted from 
Page 30)

Provided clarification on HRQoL assessments and added the assessment of Physical 
Impairment Numeric Rating Scale, which had been omitted.
Revised Sections:  Protocol Summary, Table 1 (footnote 25), Sections 6.4, 6.9

Added language 
 
 
  
Revised Section:  Section 1.2 

 

Additional clarification provided regarding the timing of ECOG assessments.
Revise Section: Table 1 (footnote 6)

Corrected a typographical error in the study title. 
Revised Section: Title (Page 1)

Corrected a typographical error to clarify that the Study Sponsor will review eligibility 
criteria prior to randomization.
Revised Section: Section 6.3

Clarification provided regarding the time that concomitant medications should be 
recorded.
Revised Section: Sections 6.6.8, 9

Removed a  duplicate reference for guidance related to ≥ Grade 3 nausea and/or vomiting 
Revised Section: Table 2

Added additional clarification for mid-cycle treatment schedule escalations.
Revised Section: Section 8.2.6

Corrected a typographical error for the spelling of pomalidomide.
Revised Section: Section 9.2


EDMS Doc. Number: 20735352 - 20736229
Oral Azacitidine (CC-486)
Summary of Changes CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
6
CC-486-AML-001 Amendment 1.0  Final: 29 Dec 2015

Added language to the protocol that would enable the implementation of a roll-over 
protocol.
 
 
 
Revised Sections:  Protocol Summary, Sections 4.1, 4.3, 14.8

Included a few minor editorial corrections and additions to Appendix J, List of 
Abbreviations and Definitions of Terms.
Revised Sections:  Appendix J

Modified the wording concerning the involvement of the Medical Monitor in the 
unblinding and discontinuation of trial subjects.  
 
 
Revised Section: Sections 8.9, 13.2

Clarified the wording concerning the blast percentage cut-off for study discontinuation 
from ≥ 16% to > 15%.
Revised Section: Global

Implemented a revision to the protocol language 
 
 
 
  
Revised Sections: Protocol Summary and Sections 4.1, 4.2

Corrected a typographical error in Section 7.2 to replace “Adequate bone marrow 
function based on ANCs ≥ 0.5 x 109/L and platelet counts ≥ 20,000 x 109/L” with 
“Adequate bone marrow function based on ANCs ≥ 0.5 x 109/L and platelet counts ≥ 20 
x 109/L.” 
Revised Section: Section 7.2

Revised language
 
 
Revised Section: Table 1 (footnote 17) and Section 6.1

Provided guidance on handling of vomited doses of IP.
Revised Section: Section 8.2.4


EDMS Doc. Number: 20735352 - 20736229
Oral Azacitidine (CC-486)
Summary of Changes CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
7
CC-486-AML-001 Amendment 1.0  Final: 29 Dec 2015

Provided further guidance on the modification of doses and dosing schedule for toxicity 
and during AML relapse/progression.
Revised Section: Sections 8.2.5, 8.2.6, and Table 2

Corrected a typographical error 
 
 
Revised Section: Section 11.5

Updated References Section with 2 additional references 
 
Revised Section: Section 18

Revised Appendix G (EQ-5D Health Questionnaires) 
 
 
Revised Section: Appendix G

Included an administrative change
 
Revised Section: Celgene Therapeutic Area Head Signature Page

A few minor editorial corrections were made globally.
Revised Section: Global

SAP_001.pdf: 
EDMS Doc. Number: 23961279 - 23960662
Oral Azacitidine (CC-486)
Statistical Analysis Plan. Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
1
STATISTICAL ANALYSIS PLAN
A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED STUDY TO COMPARE EFFICACY AND
SAFETY OF ORAL AZACITIDINE PLUS BEST SUPPORTIVE 
CARE VERSUS BEST SUPPORTIVE CARE AS MAINTENANCE 
THERAPY IN SUBJECTS WITH ACUTE MYELOID 
LEUKEMIA IN COMPLETE REMISSION
STUDY DRUG:
Oral Azacitidine (CC-486)
PROTOCOL NUMBER:
CC-486-AML-001
DATE FINAL:
25th-Jul-2019
Prepared by:
Celgene Corporation
CONFIDENTIAL
The information contained in this document is regarded as confidential 
and, except to the extent necessary to obtain informed consent, may not be 
disclosed to another party unless such disclosure is required by law or 
regulations.  Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further 
disclosed by them.


EDMS Doc. Number: 23961279 - 23960662
Oral Azacitidine (CC-486)
Statistical Analysis Plan. Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
2
TABLE OF CONTENTS
TABLE OF CONTENTS............................................................................................................2
LIST OF TABLES......................................................................................................................5
SIGNATURE PAGE...................................................................................................................6
1.
LIST OF ABBREVIATIONS...................................................................................7
3.
STUDY OBJECTIVES...........................................................................................11
3.1.
Primary Objective...................................................................................................11
3.2.
Secondary Objectives .............................................................................................11
4.
INVESTIGATIONAL PLAN .................................................................................12
4.1.
Overall Study Design and Plan ...............................................................................12
4.1.1.
Pre-randomization Phase ........................................................................................12
4.1.2.
Double-blind Treatment Phase................................................................................12
4.1.3.
Follow-up Phase .....................................................................................................12
4.1.4.
Extension Phase (EP)..............................................................................................13
4.2.
Study Endpoints .....................................................................................................13
4.2.1.
Primary Efficacy Endpoint......................................................................................13
4.2.2.
Key Secondary Efficacy Endpoint ..........................................................................13
4.2.3.
Additional Secondary Efficacy Endpoint(s) ............................................................13
4.2.4.
Safety Endpoints.....................................................................................................13
4.3.
Stratification, Randomization, and Blinding............................................................14
4.4.
Sample Size Determination.....................................................................................14
5.
GENERAL STATISTICAL CONSIDERATIONS .................................................16
5.1.
Reporting Conventions ...........................................................................................16
5.2.
Analysis Populations ..............................................................................................16
5.2.1.
Intent-to-Treat Population.......................................................................................16
5.2.2.
Modified Intent-to-Treat Population .......................................................................17
5.2.3.
Safety Population....................................................................................................17
6.
SUBJECT DISPOSITION......................................................................................18
7.
PROTOCOL DEVIATIONS/VIOLATIONS ..........................................................19


EDMS Doc. Number: 23961279 - 23960662
Oral Azacitidine (CC-486)
Statistical Analysis Plan. Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
3
8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS................................20
8.1.
Demographics.........................................................................................................20
8.2.
Baseline Characteristics..........................................................................................20
8.3.
Medical History......................................................................................................20
8.4.
Prior Therapy..........................................................................................................21
8.4.1.
Prior Induction Therapies and Consolidation Therapies for AML ...........................21
8.4.2.
Prior Cancer History and Related Procedures/Surgeries, Radiation and 
Regimen Therapies.................................................................................................21
8.5.
Prior Medications ...................................................................................................21
9.
STUDY TREATMENTS AND EXTENT OF EXPOSURE....................................22
9.1.
Treatment Duration.................................................................................................22
9.2.
Cumulative Dose and Dose Intensity ......................................................................22
9.3.
Dose Adjustments...................................................................................................23
9.4.
Treatment Compliance............................................................................................23
10.
CONCOMITANT MEDICATIONS, PROCEDURES/SURGERIES AND 
FOLLOW-UP THERAPIES...................................................................................24
10.1.
Concomitant Medications .......................................................................................24
10.2.
Concomitant Procedures and Surgeries...................................................................24
10.3.
Subsequent AML Therapies....................................................................................24
10.4.
Post-treatment Transplant Therapy .........................................................................24
11.
EFFICACY ANALYSIS ........................................................................................25
11.1.
General Statistical Methods ....................................................................................25
11.2.
Analysis of Primary Efficacy Endpoint...................................................................26
11.2.1.
Primary Efficacy Analysis ......................................................................................26
11.2.2.
Sensitivity Analysis ................................................................................................27
11.3.
Analyses of Secondary Efficacy Endpoints.............................................................29
11.3.1.
Key Secondary Endpoint – Relapse-free Survival (RFS).........................................29
11.3.2.
Additional Time-to-Event Secondary Efficacy Endpoints .......................................31
11.4.
Subgroup Analysis..................................................................................................32


EDMS Doc. Number: 23961279 - 23960662
Oral Azacitidine (CC-486)
Statistical Analysis Plan. Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
4
12.
SAFETY ANALYSIS ............................................................................................35
12.1.
Adverse Events.......................................................................................................35
12.2.
Adverse Events of Special Interest..........................................................................37
12.2.1.
Treatment-emergent Adverse Events of Special Interest..........................................37
12.2.2.
Second Primary Malignancies.................................................................................39
12.3.
Death......................................................................................................................39
12.4.
Clinical Laboratory Evaluations..............................................................................39
12.5.
Vital Sign Measurements........................................................................................40
12.6.
Electrocardiograms.................................................................................................40
12.7.
Chest X-Ray...........................................................................................................40
12.8.
Pregnancy Status ....................................................................................................40
13.
HEALTH-RELATED QUALITY OF LIFE (HRQOL) ANALYSIS.......................41
14.
INTERIM ANALYSIS...........................................................................................42
14.1.
General Information................................................................................................42
14.2.
Statistical Approaches for Control of Alpha............................................................42
14.3.
Data Monitoring .....................................................................................................42
15.
CHANGES TO THE STATISTICAL ANALYSES SECTION OF THE 
PROTOCOL...........................................................................................................43
17.
APPENDICES........................................................................................................45
17.1.
Handling of Dates...................................................................................................45
17.1.1.
Dates Handling.......................................................................................................45
17.1.2.
Calculation Using dates ..........................................................................................45
17.1.3.
Calculation of Cycles..............................................................................................46
17.2.
Date Imputation Guideline......................................................................................47
17.2.1.
Impute Missing Adverse Events/ Prior or Concomitant Medications.......................47
17.3.
Table of Events.......................................................................................................49
17.4.
WHO Classification of Acute Myeloid Leukemia ...................................................54
17.5.
Eastern Cooperative Oncology Group (ECOG) Performance Status........................55
17.6.
Risk Status Based on Cytogenetics .........................................................................56
17.7.
International Working Group AML Response Criteria............................................57
17.8.
Grades for select laboratory analytes based on CTCAE v4.0...................................58


EDMS Doc. Number: 23961279 - 23960662
Oral Azacitidine (CC-486)
Statistical Analysis Plan. Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
5
LIST OF TABLES
Table 1 Abbreviations and Specialist Terms................................................................................7
Table 2 Primary Censoring Rules for RFS.................................................................................30
Table 3 EMA Censoring Rules for RFS.....................................................................................31


EDMS Doc. Number: 23961279 - 23960662
Oral Azacitidine (CC-486)
Statistical Analysis Plan. Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
6
SIGNATURE PAGE
STATISTICAL ANALYSIS PLAN (SAP) APPROVAL SIGNATURE PAGE 
SAP TITLE
Statistical Analysis Plan for A Phase 3, Randomized, Double-Blinded, Placebo-
Controlled Study to Compare Efficacy and Safety of Oral Azacitidine Plus Best 
Supportive Care Versus Best Supportive Care as Maintenance Therapy in Subjects 
with Acute Myeloid Leukemia in Complete Remission
SAP VERSION, DATE
Final, 25-JUL-2019
SAP AUTHOR
 
{See appended electronic 
signature page}
Printed Name and Title
Signature and Date
PROTOCOL TITLE
A Phase 3, Randomized, Double-Blinded, Placebo-Controlled Study to Compare 
Efficacy and Safety of Oral Azacitidine Plus Best Supportive Care Versus Best 
Supportive Care as Maintenance Therapy in Subjects with Acute Myeloid 
Leukemia in Complete Remission
INVESTIGATIONAL 
PRODUCT
Oral Azacitidine (CC-486)
PROTOCOL NUMBER
CC-486-AML-001
PROTOCOL VERSION, 
DATE
Protocol Amendment 2.0, 08-NOV-2018
SIGNATURE 
STATEMENT
By my signature, I indicate I have reviewed this SAP and find its contents to be 
acceptable.
Statistical Therapeutic Area Head
Signature
{See appended electronic signature page}
Printed Name
Date
Lead Clinical Research Physician / Clinical Research Physician
Signature
{See appended electronic signature page}
Printed Name
Date
Lead Product Safety Physician
Signature
{See appended electronic signature page}
Printed Name
Date


EDMS Doc. Number: 23961279 - 23960662
Oral Azacitidine (CC-486)
Statistical Analysis Plan. Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
7
1.
LIST OF ABBREVIATIONS
Table 1 Abbreviations and Specialist Terms
AE
Adverse event
ALT
Alanine transaminase (also known as SGPT)
AML
Acute myeloid leukemia
ANC
Absolute neutrophil count
ANOVA
Analysis of variance
AST
Aspartate transaminase (also known as SGOT)
ATC
Anatomical therapeutical chemical
AZA
Azacitidine
BSC
Best supportive care
BUN
Blood urea nitrogen
CBC
Complete blood count
CI
Confidence interval
CMH
Cochran-Mantel-Haenszel
CMML
Chronic myelomonocytic leukemia
CR
Complete remission
CRc
Complete cytogenetic remission
CRi
Complete remission with incomplete blood count recovery
CRF
Case report form
CT
Computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data Monitoring Committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EOS
End of study
EPO
Erythropoietin
ESA
Erythropoiesis stimulating agent
FAB
French-American-British


EDMS Doc. Number: 23961279 - 23960662
Oral Azacitidine (CC-486)
Statistical Analysis Plan. Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
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FACIT-F
Functional Assessment of Chronic Illness Therapy – Fatigue 
FCBP
Female of childbearing potential
FDA
Food and Drug Administration
Hgb
Hemoglobin
HR
Hazard ratio
HRQoL
Health-related quality-of-life
IP
Investigational product
IPCW
Inverse probability of censoring weighted 
ITT
Intent-to-treat
IV
Intravenous
IVRS
Interactive Voice Response System
KM
Kaplan-Meier
LDH
Lactic dehydrogenase
MDS
Myelodysplastic syndrome
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Affairs
mITT
Modified intent-to-treat
MRD
Measurable/Minimal Residual Disease
MRI
Magnetic resonance imaging
NCI-CTCAE
National Cancer Institute-Common Terminology Criteria for Adverse Events
NA
Not applicable
ORR
Overall response rate
OS
Overall survival
PD
Progressive disease
PFS
Progression-free survival
PK
Pharmacokinetic
PR
Partial Remission


EDMS Doc. Number: 23961279 - 23960662
Oral Azacitidine (CC-486)
Statistical Analysis Plan. Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
9
QD
Once a day
RFS
Relapse-free survival
ROW
Rest of the world
SAE
Serious adverse event
SAP 
Statistical Analysis Plan
SD
Stable disease
SDev
Standard deviation
SE
Standard error 
SGOT
Serum glutamic oxaloacetic transaminase (also known as AST)
SGPT
Serum glutamic pyruvic transaminase (also known as ALT)
TEAE
Treatment-emergent adverse event
TTP
Time to progression
ULN
Upper limit of normal
US
United States
WBC
White blood cell 
WHO
World Health Organization


EDMS Doc. Number: 23961279 - 23960662
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Celgene Corporation
Confidential and Proprietary
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EDMS Doc. Number: 23961279 - 23960662
Oral Azacitidine (CC-486)
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Celgene Corporation
Confidential and Proprietary
11
3.
STUDY OBJECTIVES
3.1.
Primary Objective
The primary objective of the study is to demonstrate if maintenance therapy with oral azacitidine 
improves overall survival (OS) compared with placebo in subjects with AML, age ≥ 55 years, 
who have achieved first complete remission (CR) or complete remission with incomplete blood 
count recovery (CRi) after induction with intensive chemotherapy with or without consolidation 
chemotherapy.
3.2.
Secondary Objectives
The secondary objectives of the study are:

To determine relapse-free survival (RFS); 

To determine safety, tolerability; and

To determine the effect of oral azacitidine compared with placebo on health-related 
quality-of-life (HRQoL) and healthcare resource utilization.
 
 
 
 
 


EDMS Doc. Number: 23961279 - 23960662
Oral Azacitidine (CC-486)
Statistical Analysis Plan. Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
12
4.
INVESTIGATIONAL PLAN
4.1.
Overall Study Design and Plan
This is an international, multicenter, placebo-controlled, phase 3 study with a double-blind, 
randomized, parallel-group design in subjects with de novo AML or AML secondary to prior 
diagnosis of myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) 
aged ≥ 55 years, who are in first CR/CRi following induction therapy with or without 
consolidation chemotherapy.  
The study consists of 4 phases; Pre-randomization Phase, Treatment Phase, Follow-up Phase, 
and Extension Phase. 
4.1.1.
Pre-randomization Phase
Newly diagnosed subjects, ≥55 years of age, who have a confirmed diagnosis of AML according 
to the criteria set by the World Health Organization (WHO) 2008 classification (Swerdlow, 
2008), who have achieved first CR/CRi status after induction therapy with/without consolidation 
therapy will be eligible for randomization (within 4 months [± 7 days] of achieving first 
CR/CRi).  Screening procedures are to occur during the Pre-randomization Phase, within 28 days 
prior to randomization. Subjects will provide informed consent prior to undergoing any study 
related procedures.
4.1.2.
Double-blind Treatment Phase
Following confirmation of eligibility at screening, approximately 460 subjects will be 
randomized 1:1 to receive 300 mg oral azacitidine once a day (QD) or placebo, for 14 days of 
each 28 day cycle.  Randomization will occur by a central randomization procedure using an 
Interactive Voice Response System (IVRS).  Subjects are stratified by years of age at the time of 
induction therapy (55-64 versus ≥65), prior history of MDS (yes versus no), cytogenetic risk 
category (intermediate risk versus high risk), and received consolidation therapy following 
induction therapy (yes versus no). 
After randomization, no crossover between the treatment arms will be permitted at any point 
during the study.  
During the double-blind treatment phase, subjects will be assessed for safety, tolerability and 
efficacy.  
4.1.3.
Follow-up Phase
All treatment discontinued subjects, regardless of reason for discontinuation, should undergo 
end-of-study procedures at the time of treatment discontinuation visit.  Subjects will have a 
follow-up visit for the collection of AEs up to 28 days after last dose or up to the end-of-
treatment visit, whichever is longer.  After this follow-up visit, subjects will be followed for 
survival, by telephone, every month for the first year and then every 3 months until death, 
withdrawal of consent for further follow-up, study end, or until a subject is lost to follow-up.
Discontinued subjects will not be replaced. 


EDMS Doc. Number: 23961279 - 23960662
Oral Azacitidine (CC-486)
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Celgene Corporation
Confidential and Proprietary
13
4.1.4.
Extension Phase (EP)
Upon a site’s IRB/IEC approval of Protocol Amendment 2 which allows for an EP, after study
unblinding by Celgene, any subject randomized to the oral azacitidine arm, who continues to
receive oral azacitidine, who demonstrates clinical benefit as assessed by their Investigator, and
consents to participate in Extension Phase, may continue to receive oral azacitidine in the EP (at
their current dose) at the start of their next cycle. To receive oral azacitidine in the EP, the
subject must not have been discontinued from receiving IP prior to entering this EP of the study.
Subjects randomized into the placebo arm will discontinue treatment and will not receive oral
azacitidine in the EP. However, upon consent, these subjects may be transitioned into the EP
and followed for survival.
In addition, any subject who was discontinued from the treatment phase (irrespective of
randomization arm), upon providing additional consent, may enter the EP, where they will be
followed for survival (without receiving oral azacitidine) for at least another 12 months, until
death, withdrawal of consent or study closure, or lost to follow-up.
4.2.
Study Endpoints
4.2.1.
Primary Efficacy Endpoint
The primary efficacy endpoint of the study is OS, defined as time from randomization to death 
from any cause.  
4.2.2.
Key Secondary Efficacy Endpoint
The key secondary efficacy endpoint is Relapse-free survival (RFS) which is defined as time
from randomization to the date of documented relapse or death from any cause, whichever 
occurs first.  
4.2.3.
Additional Secondary Efficacy Endpoint(s)
The additional secondary efficacy endpoints are:

Time to relapse;

Time to discontinuation from treatment;

Patient-reported outcomes utilizing the FACIT-Fatigue Scale and the EQ-5D; and

Measures of healthcare resource utilization. 
4.2.4.
Safety Endpoints
The safety endpoints include:

Type, frequency, severity, and relationship of adverse events to study treatments;

Physical examinations; 


EDMS Doc. Number: 23961279 - 23960662
Oral Azacitidine (CC-486)
Statistical Analysis Plan. Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
14

Vital signs; 

Clinical laboratory evaluations; 

Concomitant medication/therapy.
 
 
 
 
 
The analysis methods and timing of analysis for the quality of life endpoints are described in a 
separate pharmacoeconomics SAP. 
 
4.3.
Stratification, Randomization, and Blinding
Randomization will be carried out using an Interactive Voice Response System (IVRS). 
Treatment assignment will follow a 1:1 ratio between two treatment arms. Randomization 
method was based on permutated-block randomization. Randomization was stratified by the 
following factors: age at time of induction therapy (55-64 versus ≥ 65 years); prior history of 
MDS (yes versus no); cytogenetic risk category at time of induction therapy (intermediate risk 
versus poor risk); received consolidation therapy following induction therapy (yes versus no).  
This is a double-blind study. Subjects, investigators, site staff and Celgene Corporation clinical 
and medical personnel will be blinded of treatment assignments until database lock. 
4.4.
Sample Size Determination
The equality of OS curves will be compared between the oral azacitidine and placebo treatment 
arms using a stratified log-rank test.  Assuming a median OS of 16 months in the placebo treated 
group (
), a median OS of 22.9 months in the oral azacitidine treated group 
(43% improvement), and a study duration of 60 months with a drop-out rate of 5% from both 
treatment arms, over the duration of the study, this design requires 330 deaths and approximately 
460 subjects (230 per treatment arm) to be randomized in order to achieve at least 90% power to 
detect a constant hazard ratio of 0.70 and demonstrate a statistically significant difference in OS.  
It is assumed that the OS distribution is exponential with a constant failure (hazard) rate and that 
accrual is non-uniform during an accrual period of 36 months with 25% of the subjects accrued 
during each of the first 2 years of enrollment (50% accrued at 24 months) and the remaining 50% 


EDMS Doc. Number: 23961279 - 23960662
Oral Azacitidine (CC-486)
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Celgene Corporation
Confidential and Proprietary
15
accrued during the last year of enrollment.  Sample size calculations are based on a one-sided 
alpha of 0.025 with one interim analysis for futility after 30% of the events have occurred.
Sample size was calculated using the East® Version 5.4 software system 
 
).


EDMS Doc. Number: 23961279 - 23960662
Oral Azacitidine (CC-486)
Statistical Analysis Plan. Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
16
5.
GENERAL STATISTICAL CONSIDERATIONS
5.1.
Reporting Conventions
Summary tables, listings, and any supportive SAS output will include a “footer” of explanatory 
notes that will indicate, at a minimum, the following: 
Program source (e.g., SAS program name, including the path that generates the output), source 
data (e.g. derived dataset, raw datasets, etc) and data extraction date (e.g., the database lock date, 
run date.)
The purpose of the data extraction date is to link the output to a final database, either active or 
archived, that is write-protected for replication and future reference.  An output date will also 
appear on each output page and will indicate the date the output was generated by the analysis 
program. Individual source listings will display all the relative values supporting the 
corresponding tables and/or figures.
Summary statistics for continuous variables include sample size (n), mean, standard deviation 
(SDev), median, minimum, the 25th (Q1), and 75th (Q3) percentiles, and maximum. All mean and 
median values will be formatted to one more decimal place than the measured value. SDev
values will be formatted to two more decimal places than the measured value. Minimum and 
maximum values will be presented to the same number of decimal places as the measured value. 
Frequency summary for categorical variables includes number and percentage. All percentages 
will be rounded to one decimal place. Number and percentage values will be presented as xx 
(xx.x%). All analysis and summary tables will have the population sample size for each 
treatment arm in the column heading. All p-values (2-sided) will be rounded to 4 decimal places. 
P-values that round to 0.0000 will be presented as ‘<0.0001’ and p-values that round to 1.000 
will be presented as ‘>0.9999’. Confidence intervals (CIs) will be presented as 2-sided 95% CIs 
unless specified differently in specific analysis. All laboratory data will be reported using 
standard international (SI) units, unless specified otherwise. 
All listings will be sorted for presentation in order of treatment arm, study center, subject, and 
date of procedure or event. 
The day of the first dose of any study drug will be defined as Study Day 1. 
Baseline value is defined as the last non-missing value on or before randomization date, unless 
specified otherwise. If multiple values are present for the same date, the average of these values 
will be used as the baseline, unless specified otherwise. 
5.2.
Analysis Populations
5.2.1.
Intent-to-Treat Population
The Intent-to-Treat (ITT) population includes all subjects who are randomized, regardless of 
whether they received study treatment or not. Subjects will be analyzed based on randomized 
treatment arm. The ITT population will be used for the analysis of the primary and secondary 
efficacy endpoints.  


EDMS Doc. Number: 23961279 - 23960662
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5.2.2.
Modified Intent-to-Treat Population
The modified Intent-to-Treat (mITT) population includes all subjects who have met 
inclusion/exclusion criteria and experienced no protocol violations (as defined below) and have 
received a minimum of 1 cycle of treatment. Subjects will be analyzed based on randomized 
treatment arm. 
Protocol violations leading to exclusion from the mITT population are defined as any of the 
following:

No presence of CR/CRi at baseline as programmatically determined by central laboratory 
data

Had at least one inclusion or exclusion criteria violation;
5.2.3.
Safety Population
The safety population includes all randomized subjects who have received at least 1 dose of 
study drug.
Drug exposure and all safety analyses will be based on the safety population, unless specified 
otherwise. 


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6.
SUBJECT DISPOSITION
All subjects screened/randomized will be included in these analyses.
The disposition of subjects will be summarized with counts and percentages.  Summaries will 
include the number of subjects screened and randomized.  
For subjects randomized, subject disposition will be summarized for analysis population by 
treatment arm and overall for:

ITT Population

mITT Population

Safety Population
A listing of reasons for exclusion from the mITT Population will be provided.  A separate listing 
will be provided for subjects not randomized (screen failures) with reasons for screening failure.
Listings will be provided for subjects randomized but not treated, and for discontinued subjects 
with reason for treatment discontinuation.
Reasons for discontinuation from the study treatment phase will be collected on the CRF and 
will be summarized for all randomized subjects with the following

Disease relapse

Adverse event

Subject withdrew consent

Physician decision (become eligible for allogeneic bone marrow or stem cell 
transplantation during treatment period)

Death

Subject lost to follow-up

Protocol violation

Other
Reasons for discontinuation from the study will be collected on the CRF and will be summarized 
for all randomized subjects with following:

Death

Adverse event

Pregnancy

Progressive disease

Lack of efficacy

Recovery 

Withdrew consent 

Non-compliance with study drug

Lost to follow-up

Study terminated by sponsor

Transition to commercially available treatment

Protocol violation 

Other


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7.
PROTOCOL DEVIATIONS/VIOLATIONS
The protocol deviations/violations will be identified and reported by site and assessed by clinical 
research physician or designee following company standard operational procedure. The protocol 
violations will be summarized by treatment arm for the ITT population. 
A by-subject listing of subjects with protocol deviation in the ITT population will be provided. A 
by-subject listing of subjects with protocol violations in the ITT population will also be 
provided. 


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8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS
Summaries for the demographics, baseline characteristics, medical history, prior therapy, and 
prior medications will be presented for the ITT and safety populations. Data summaries will be 
presented by treatment and overall.  Individual subject listings will be provided to support the 
tables.
8.1.
Demographics
Demographic characteristics consist of age, sex, race, ethnicity, geographic region, weight (kg), 
height (cm), and body mass index (BMI). 
Age, height, weight and BMI will be summarized using descriptive statistics. Sex, race, ethnicity, 
geographic region, and age categories will be summarized with counts and percentages.
Age is calculated as described in section 17.1.2. 
8.2.
Baseline Characteristics
Baseline clinical characteristics, including the initial WHO AML classification, type of AML 
(primary or secondary), cytogenetic risk status at time of induction therapy, MRD status at 
randomization, prior history of MDS/CMML and type (primary or secondary), Eastern 
Cooperative Oncology Group (ECOG) Performance Status at randomization, CR/CRi status after 
induction therapy, CR/CRi status at randomization, consolidation therapy received or not, cycles 
of conlidation therapy received and reasons of not eligible for transplantation will be 
summarized using frequency distributions (count and percent).
Baseline clinical characteristics, including percentage of bone marrow blasts (%), peripheral 
blood blasts (%), Hgb (g/dL), platelet count (x 109/L), ANC (x 109/L) and WBC (x 109/L) will be 
summarized using descriptive statistics. In general, the baseline value is the last non-missing 
assessment on or prior to the date of randomization, unless otherwise specified.
The following time intervals will be summarized using descriptive statistics:

time (months) from initial AML diagnosis to randomization;

time (months) from start of induction therapy to randomization;

time (days) from start of induction therapy to first achieving CR/CRi; 

time (days) from first achieving CR/CRi to randomization
Results of the baseline chest x-ray, ECG, pregnancy status will be provided in by-subject 
listings. 
8.3.
Medical History
A summary of medical history will be presented by system organ class (SOC) and preferred term 
(PT) according to the Medical Dictionary for Regulatory Affairs (MedDRA) Version 22 using 
frequency distributions (counts and percentages). 


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Individual subject listings will be provided to support the table.
8.4.
Prior Therapy
8.4.1.
Prior Induction Therapies and Consolidation Therapies for AML
All prior induction therapies for AML will be summarized in frequency tabulations (subject 
counts and percentages). The Anatomical Therapeutical Chemical (ATC) coding scheme of the 
World Health Organization (WHO) (March 2019 version) will be used to group prior induction 
therapies for AML into relevant categories for these tabulations.
Similar summary table will be provided for consolidation therapies for AML.
Individual subject listings will be provided to support the summary tables.
8.4.2.
Prior Cancer History and Related Procedures/Surgeries, Radiation and 
Regimen Therapies
By-subject listing of prior cancer history, type of therapy received, diagnostic exams for cancer 
prior to screening for the study and related prior procedures/surgeries, prior radiation treatment 
and prior regimen treatments for cancers not under study will be provided.  
8.5.
Prior Medications
Prior medications are defined as medications that were started on or prior to the date of   
randomization. Prior medications that continue past the date of randomization will also be 
reported as concomitant medications. The ATC coding scheme of the WHO (March 2019
version) will be used to group medications into relevant categories for these tabulations.
Individual subject listings will be provided to support the tables.


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9.
STUDY TREATMENTS AND EXTENT OF EXPOSURE
All analyses of treatment exposure will be conducted using the safety population, unless 
otherwise specified. 
Descriptive statistics of treatment duration, cumulative dose, dose intensity and average daily 
dose will be presented by treatment arm.  Individual subject listings of drug exposure as recorded 
in CRF will be provided to support the tables.
9.1.
Treatment Duration
Treatment duration and number of days dosed will be summarized by treatment arm. 
Treatment duration is defined as treatment end date – first dose date +1, where treatment end 
date is last dose date + 14 days (the prescribed rest period of each cycle), or the death date, 
whichever is earlier. 
Total Person-years of treatment duration will be calculated as the sum of treatment duration 
(days)/365.25 across all subjects.
Total number of days dosed is defined as the total number of days the subject took a non-zero 
dose of study drug.
See Section 17.1.3 for cycle length and cycle number calculations. Average cycle length (days), 
average number of days dosed per cycle, and number of treatment cycles will be summarized by 
treatment arm. The number of days dosed per cycle is defined as the number of days the subject 
received a non-zero dose within that cycle. Average cycle length for a subject is defined as 
treatment duration in days divided by the number of cycles. Number of days dosed per cycle is 
defined as the total number of days dosed during the entire treatment period /number of cycles. 
For average cycle length and average number of days dosed per cycle, a single average value 
will be computed for each subject and then the descriptive statistics will be computed for each 
treatment arm.  Additionally, the count and percent of subjects by number of cycles of treatment 
will be provided for each treatment arm.
9.2.
Cumulative Dose and Dose Intensity
Cumulative dose is defined as the sum of all doses taken across the entire treatment period (in
mg). Average daily dose (mg/day) is defined as the cumulative dose divided by the total number 
of days dosed. 
Actual dose intensity during the treatment is defined as the cumulative dose divided by the 
treatment duration, which is defined as in Section 9.1. 
Relative dose intensity (RDI) is defined as the ratio of actual dose intensity to the planned dose
intensity, which is 300mg/day × 14 days/28days=150mg/day for all subjects. 
The overall relative dose intensity will be categorized into < 75%, 75% to 85%, 85% to 100%, 
and > 100%, and frequency counts will be provided by treatment arm. 
In addition, treatment exposure as described in section 9.1 and 9.2 will also be analyzed for 
subjects with dose escalation, which is defined as subjects who have at least one assigned dose 


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regimen of 300mg × 21/28 days. In these analyses, the first dose date refers to the first dose date 
of the treatment period where the assigned dose regimen is 300mg × 21/28 days. 
9.3.
Dose Adjustments
Dose adjustments (including dose escalation and dose reduction), as reported in the dose 
exposure CRF page, will be summarized by treatment arm and include the following:

Any dose adjustments; 

Dose adjustment due to AE; 

Dose adjustment due to AML relapse/progression; 

One dose reduction; 

Two dose reductions; 

Dose escalation (to 300mg × 21 days). 
Dose adjustment is defined as subjects who have reported at least one dose adjustment in the 
dosing CRF page. One dose reduction is defined as subjects have reduced assigned dose from 
300mg × 14 days to 200mg × 14 days. Two dose reduction is defined as subjects have reduced 
assigned dose from 300mg × 14 days to 200mg × 14 days, and then from 200mg × 14 days to 
200mg × 7 days. Dose escalation is defined as subjects who have received at least one assigned 
dose of 300mg × 21 days.  
In addition, time to first dose adjustment due to AE, time to first dose adjustment due to AML 
relapse/progression, reason for first dose adjustment and reason for first dose escalation will also 
be summarized. 
9.4.
Treatment Compliance 
As part of the routine recording of the amount of IP taken by each subject, the dose start and end 
dates, dose assigned and actual dose administered will be recorded in the CRF. These records 
will be used to calculate compliance. 
The compliance rate (%) for each subject will be computed as 100 times the cumulative dose (in 
mg) taken over the period divided by the intended cumulative dose (in mg) that should have been 
taken over the same period. It will be calculated for each subject for each cycle of treatment and 
overall. 
Overall compliance will be summarized using descriptive statistics overall and by cycle.  
Additionally, the number and percentage of subjects will be summarized by category < 75%, ≥75 
to ≤120%, and > 120%.




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11.
EFFICACY ANALYSIS
All efficacy evaluations will be conducted using the ITT population. Supportive analysis of the 
primary and key secondary efficacy endpoints using the mITT population will be conducted. 
Statistical comparisons will be made between oral azacitidine and placebo.
11.1.
General Statistical Methods
All hypothesis testing will be carried out at the 5% (2-sided) significance level and designed to 
evaluate the superiority of oral azacitidine relative to Placebo. 
The study randomization scheme was stratified according to 4 prognostic features: age at time of 
induction therapy 55-64 versus ≥65 years; prior history of MDS: yes versus no; cytogenetic risk 
status at time of induction therapy:  intermediate risk versus poor risk; and received 
consolidation therapy following induction therapy: yes versus no, resulting in 16 strata. The 
statistical analyses conducted to compare treatment arms will include methods that are stratified 
according to the randomization scheme, using the stratification factors as collected in the clinical 
database (for subject with missing stratification factor, the missing stratification factor value will 
be imputed by the data entered via the IVRS). Additionally, for primary endpoint OS and key 
secondary endpoint RFS, the stratified analysis using IVRS data may also be conducted. It is 
possible that the number of subjects in an individual stratum may be very small. In order to 
facilitate inferential statistical analysis, if the minimum number of subjects in a stratum is less 
than 16 (irrespective of treatment arm), then only the 3 stratification variables that result in the 
largest minimum stratum size will be used for analysis purposes. Analyses will not be stratified 
by investigative center, as the recruitment for many centers is likely to be very small. 
The general procedure for the analysis of the time-to-event efficacy variables will be as follows. 
Time-to-event variables will be measured in days but presented in months on tables and figures. 
A Kaplan-Meier (KM) survival analysis will be performed (unadjusted for the stratification 
variables). The resulting survival estimates will be presented graphically for selected endpoints. 
The median, 25th and 75th percentile time-to-event data will be presented with 95% confidence 
intervals (CIs) (if they can be estimated). The numerical difference (and CI of the difference) in 
the median, 25th and 75th percentiles between oral azacitidine and placebo will be presented for 
the unstratified analysis.  Differences will be calculated as oral azacitidine - placebo.  The 95% 
CI for the difference will be derived using Kosorok’s method (
).  One-year and 
two-year survival rates with 95% CIs and the difference in survival rates between oral azacitidine
and placebo with 95% CI for the difference will also be presented for OS.  The CI for the 
difference between treatment arms in the 1-year proportions will be calculated using 
Greenwood’s variance estimate 
).
For the primary efficacy analysis of OS, oral azacitidine will be compared to placebo using the 
stratified log-rank test to assess superiority. The null hypothesis is that the survival curves are 
equivalent. The stratified Cox proportional hazard regression model will be used to estimate the 
hazard ratio (HR) and associated 95% CIs for the HR.  
The censoring distributions of the treatment arms will be assessed using KM methods.  Reverse 
KM estimates for OS will be calculated to assess the censoring distributions, where observations 


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in the original analysis that were events (i.e., deaths) will be censored and observations that were 
censored will be treated as events.  The median, 25th and 75th percentiles will be presented and 
KM curves will be displayed graphically by treatment arm.  Additionally, reasons for censoring 
(e.g., lost to follow-up, withdrew consent, alive at data cut-off) will be summarized (n, percent) 
for the OS endpoint.  The median of the reverse OS KM distribution will be used as the estimate 
of the median follow-up time 
In order to accommodate tied time-to-event data, the EXACT option within SAS PROC PHREG 
will be used.  This method assumes that there is a true but unknown ordering for the tied event 
times, and that the ties are merely the results of imprecise measurements of time.
For the categorical efficacy variables, comparison of treatment arms will be via Fisher’s exact 
test, ignoring strata.  
A sequential gate-keeping approach will be used to control the overall type I error rate in order to 
perform hypothesis testing on multiple endpoints. Two endpoints, the primary efficacy endpoint 
of OS and the key secondary endpoint of RFS, will be tested sequentially in the pre-specified 
order. The primary efficacy endpoint will be tested first at the two-sided 0.05 significant level. In
order to preserve the overall alpha level at 0.05 across the OS and RFS endpoints, formal 
statistical inference for the RFS analyses can only be made if superiority of oral azacitidine is 
demonstrated for the primary efficacy endpoint OS, at the two-sided 0.05 significance level. 
Other than the pre-specified sequential testing of OS and RFS, no additional alpha adjustments 
for multiplicity will be made. 
11.2.
Analysis of Primary Efficacy Endpoint
The primary efficacy variable, time from randomization to death from any cause will be defined 
as the number of days from the date of randomization until the date of death from any cause, and 
is calculated by the formula:  date of death - date of randomization + 1.  Subjects surviving at the 
end of the follow-up period, or who withdraw consent, or who are lost to follow up will be 
censored at the date last known alive. For subjects who have withdrawn consent during the 
study, the last date known alive will be the date of consent withdrawal from the study. For all 
other subjects, the last date known alive will be derived by searching through all valid 
assessment dates in all study datasets to identify the last valid subject assessment date available 
for each subject.
11.2.1.
Primary Efficacy Analysis
The primary efficacy analysis will be performed using the ITT population.  The null hypothesis 
for testing the primary efficacy endpoint, time to death from any cause, is that the overall 
survival distributions for the oral azacitidine and placebo groups are equivalent.  The analysis of 
the primary efficacy endpoint will be conducted using a stratified log-rank test, stratifying by age 
at time of induction therapy, prior history of MDS, cytogenetic risk category, received 
consolidation therapy following induction therapy.  The p-value from the stratified log-rank test 
will be the p-value for primary analysis. The p-value from unstratified log-rank test will also be 


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provided. The KM method will be used to estimate the survival distribution functions for each 
treatment arm.  KM estimates for median OS as well as the 25th and 75th percentiles and 
associated two-sided 95% CIs will be summarized for each treatment arm. In addition, the 
numerical difference, and 95% CI of the difference, in the median, 25th, and 75th percentiles 
between the two treatment arms will be presented.  Plots of the KM survival curves will be 
presented for the two treatment arms, unadjusted for the stratification variables.  A stratified Cox 
proportional hazards model will be used to estimate the hazard rate ratio and the corresponding 
95% CI for oral azacitidine relative to placebo.    
Additionally, KM methods will be used to estimate the 1-year and 2-year survival probabilities 
for time to death from any cause. Estimates of the 1-year (365 days) and 2-year (730 days) 
survival probabilities and corresponding 95% confidence intervals will be presented by treatment 
arm. Kaplan Meier methods will also be used to estimate the death probabilities at 30, 90 days, 6 
months and 1 year. The death rate (count and percent) at 30, 90 days, 6 months and 1 year will 
also be summarized.
11.2.2.
Sensitivity Analysis
The primary efficacy analysis, as described above, will be repeated using the mITT population as 
a sensitivity analysis.  
To assess the potentially confounding effects of other therapy received subsequent to the study 
treatment, the following additional sensitivity analysis will be performed. 
1. Censoring for the use of any subsequent therapy (including post-treatment transplant) for 
AML.  For this analysis, subjects who received any subsequent therapy for AML 
following discontinuation from their study drug will be censored on the earlier of first 
subsequent therapy date, or transplant date, regardless of their survival status at the time 
of the final analysis. 
2. Censoring for the use of disease modifying subsequent AML therapy, which is defined as 
any subsequent AML therapy that is not hydroxycarbamide. 
3. Censoring for post-treatment transplant. For this analysis, subjects who received post-
treatment transplant will be censored at the time of the transplant. 
These modified time to death endpoints will be based on the ITT population and analyzed using 
the same methods described previously for the primary efficacy endpoint. In addition, based on 
the 13 April 2018 Type C Guidance meeting with the Agency on the analysis issues with 
subsequent therapy, the following analyses will be performed to further investigate impacts of
subsequent AML therapy on the overall survival. The following methods are planned:

Cox proportional hazard model with covariates adjustment will include, but not limited 
to, subsequent AML therapy (time-varying (yes or no)); treatment-by-subsequent AML 
therapy interaction; baseline characteristics such as age, ECOG score, cytogenetic risk 
status, CR/CRi status at randomization, etc. The covariates included in the final Cox 
model will be selected using stepwise variable selection procedure. 

Inverse probability of censoring weighted (IPCW) method. The IPCW modeling 
approach was introduced by Robins et al and estimates hazard ratios that are valid in the 


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presence of informative censoring at start of subsequent therapy. The method adjusts for 
subsequent therapy by recreating the population that would have been evaluated in the 
absence of any subsequent therapy by weighting the follow-up for those subjects who did 
not receive additional therapy in order to account for the follow-up of subjects who did 
receive subsequent therapy that has been (informatively) censored. The weights are 
determined by matching demographic and baseline characteristics as well as post
randomization clinical factors for subjects who did and did not receive subsequent 
therapy. Baseline covariates include the following: age, sex, ECOG score, cytogenetic 
risk status at diagnosis, prior history of MDS, geographic region, CR/CRi first achieved 
after induction, time to first achieving CR/CRi, CR/CRi status at randomization, MRD 
status at randomization, with or without consolidation, # of consolidation cycles received, 
platelet and ANC counts. Post randomization factors include platelet count, ANC, binary 
indicator of history of grade 3 or 4 AE, binary indicator of occurrence of a grade 3 or 4 
since last visit, time since last visit (months), bone marrow blast %, and ECOG score.  
Each subject is weighted equal to the inverse probability of not receiving additional 
treatment. Adjusted HRs for the treatment effect are then estimated from Cox regression 
models with adjustment for subsequent therapy (i.e., censoring at time of subsequent 
therapy), both with and without further adjustment for baseline covariates.

Regression based imputation analysis method proposed by Luo, X. et el that allows for 
inferences about the treatment effect in the presence of confounding due to additional 
therapy received subsequent to the study treatment. This method provides adjusted 
estimates of the KM survival curves, which allows for comparisons using the log-rank 
test and the calculation of an adjusted HR and associated confidence intervals. 
At the final analysis, the assumption of proportional hazards will be tested by a time-dependent 
Cox model with interaction of treatment and time. A figure of hazard function over time will 
give an instinct idea of hazard trend over time.
If proportional hazard assumption is violated, the following sensitivity analyses will be 
conducted using ITT population: 
1. Restricted mean survival time will be generated and compared between oral azacitidine
and placebo arms;
2. Piecewise cox regression will provide hazard estimates at the following intervals, ≤ 3 
months, 3 - ≤ 6 months, 6 - ≤ 12 months and > 12 months; 
3. In the presence of non-proportional and early OS separation, a generalized Wilcoxon test 
will be utilized to compare survival curves. 
To evaluate the impact of censoring in the primary analysis due to subjects who withdrew 
consent from survival follow-up, a sensitivity analysis of the OS endpoint will be performed.  
For this analysis, subjects who withdrew consent from survival follow-up will be treated as 
an event rather than as a censored observation. This sensitivity analysis will be based on the 
ITT population.


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11.3.
Analyses of Secondary Efficacy Endpoints
The secondary efficacy endpoints will be analyzed based on ITT population. Supportive analysis 
for the secondary efficacy endpoints will be analyzed in mITT population. 
11.3.1.
Key Secondary Endpoint – Relapse-free Survival (RFS)
Primary analysis 
Relapse-free survival is defined as the time from the date of randomization to the date of 
documented relapse or death from any cause, whichever occurs first. Subjects who are still alive 
without documented relapse, or who were lost to follow-up or withdrew consent without 
documented relapse, will be censored at the date of their last bone marrow assessment. Relapse 
is defined according to the IWG AML response criteria. See Appendix 17.7 for definitions of 
response categories. Documented relapse is defined as, the earliest date of the following

≥ 5% bone marrow blasts (myeloblasts) from Central Pathology report, or 

appearance of > 0% blasts in the peripheral blood with a later bone marrow confirmation 
(bone marrow blast [myeloblasts] ≥ 5%) within 100 days, or 

at least 2 peripheral blasts ≥ 5% within 30 days. 
Peripheral blasts reported from both Central Pathology and Central lab will be considered. 
Subjects who withdrew for any reason or received another therapy for AML without documented 
relapse will be censored on the date of their last bone marrow assessment, prior to receiving any 
other therapy for AML. Subjects who are still on treatment at the time of study closure without 
documented relapse will be censored on the date of their last bone marrow assessment. These 
rules are based on FDA guidance for cancer trial endpoints 
 
, and 
table 2 specifies the application of the guidance for various common situations for the calculation 
of RFS.


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Table 2 Primary Censoring Rules for RFS
Situation
Derivation Rules
Situation Outcome
Either documented 
relapse or death 
Define event date is earliest of: 

Date of documented 
relapse

Date of death
Calculate interval between the 
event date and the previous bone 
marrow assessment date or the 
randomization date (if no post-
baseline bone marrow
assessment). 
Note: The cutoff of 200 day is 
selected based on the following 
protocol specified schedule 
procedure: the 28-day treatment 
cycle has +/- 3 days window; 
bone marrow is expected to be 
conducted every 3 cycles (with 
+/- 7 day window). Thus, 
31*3+7=100 days is considered 
within the window for any two 
consecutive scheduled 
assessments. 
If interval ≤ 200 days, then: 
Event, if no subsequent therapy for AML 
or subsequent therapy for AML is on or 
after event date.
Censor, if subsequent therapy for AML is 
before event date. 
Censor date is last bone marrow 
assessment on or before start of 
subsequent therapy for AML, or 
randomization date if no post-baseline 
bone marrow assessment prior to start of 
subsequent therapy for AML. 
If interval > 200 days, then: 
Censor, 
Censor date is last bone marrow
assessment date, or randomization date if 
no post-baseline bone marrow assessment 
prior to start of subsequent therapy for 
AML.
No documented 
relapse and no death
Censor,
Censor date is last bone marrow
assessment date, or randomization date if 
no post-baseline bone marrow assessment 
prior to start of subsequent therapy for 
AML. 
The analysis of RFS will be performed using the ITT population and will be analyzed using the 
same methods as those used for the primary efficacy analysis of OS. In order to preserve the 
overall alpha level at 0.05 across the OS and RFS endpoints, formal statistical inference for the 
RFS analyses can only be made if superiority of oral azacitidine is demonstrated for the primary 
efficacy endpoint, OS, at the two-sided 0.05 significance level. The p-value from the stratified 
log-rank test will be the confirmatory p-value. 
Sensitivity analysis 
The analysis of the RFS endpoint will be repeated for mITT population as a supportive analysis. 


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Additional sensitivity analysis, based on the ITT population, will be performed using the RFS 
definition where documented relapse is based on investigator assessed response.
In addition, sensitivity analysis of RFS using censoring rules based on EMA guidance
 
 will also be performed. Details of the EMA censoring rule are provided in Table 3 
below. 
Table 3 EMA Censoring Rules for RFS
Situation
Derivation Rules
Situation Outcome
Either documented 
relapse or death 
Define event date is earliest of: 

Date of documented 
relapse

Date of death
Event, 
Event date is earliest of documented 
relapsed date or death date. 
Without documented 
relapse or death
Censor
Censor date is date of last bone marrow
assessment or date of randomization if no 
post-baseline bone marrow assessment 
11.3.2.
Additional Time-to-Event Secondary Efficacy Endpoints
Other time-to-event secondary efficacy endpoints will be analyzed similarly to the primary 
efficacy endpoint without stratification. Kaplan-Meier methods will be used to estimate time-to-
event curves, unless otherwise specified. 
Time to relapse 
Time to relapse is defined as the time from the date of randomization to the date of documented 
relapse. Time to relapse will be analyzed using a competing risk analysis where death without 
documented relapse is treated as a competing risk for relapse. Similar censoring rules as in 
primary analysis of RFS will be applied. The cumulative incidence function (
 
) for time to relapse will be summarized and displayed graphically for each 
treatment arm. 


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Time to discontinuation from treatment
Time to discontinuation from treatment will be assessed and is defined as the interval from the 
date of randomization to the date of discontinuation from IP.  Subjects who are ongoing in 
treatment at the time of study closure will be censored at the date of last visit.  
Time to discontinuation from treatment will be analyzed using a competing risk model with 
reason for treatment discontinuation classified as:

Disease relapse

Adverse event(s)

Became eligible for bone marrow or stem cell transplant

Withdrawal of consent / lost to follow-up / protocol violation /Other

Death
Cumulative incidence curves will be estimated and summarized for each specific reason for 
discontinuation from treatment by treatment arm.
11.4.
Subgroup Analysis
In addition to analyses that include all ITT subjects, additional exploratory subgroup analyses 
will be performed where an adequate number of subjects are available in each subgroup to allow 
for meaningful interpretation of results.  Analyses will be performed within the following 
subgroups for the OS and RFS endpoints:

Age at induction therapy (< 65, ≥ 65, ≥ 75 years)

Sex (male, female)

Race (White, Asian, Black or Others)

CR/CRi status at randomization (CR, CRi)

CR/CRi status at first achieving response (CR, CRi)

CR/CRi status at randomization and use of consolidation (CR with consolidation, CR 
without consolidation, CRi with consolidation, and CRi without consolidation)

Prior history of MDS or CMML (yes, no)

Cytogenetic risk category at induction therapy (intermediate, poor)

MRD status at randomization (positive, negative)

CR/CRi status at randomization and MRD status at randomization (CR with MRD 
positive, CR with MRD negative, CRi with MRD positive, and CRi with MRD negative)

Consolidation therapy following induction (yes, no)

Consolidation therapy following induction (1 or 2 cycles, 3 or 4 cycles)     

Geographic region (North America, Europe, Asia and Australia)

ECOG performance status (0 or 1, 2 or 3)


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Oral Azacitidine (CC-486)
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
WHO AML classification (AML with myelodysplasia-related changes, AML with 
recurrent genetic abnormalities, AML not otherwise specified)

Types of first line subsequent therapy
o
high intensity, low intensity chemotherapy
o
hypomethylating agent (HMA) monotherapy, other non-HMA subsequent therapy
o
Azacitidine monotherapy, other subsequent therapy (excluding decitabine 
monotherapy)
Overall Survival and RFS will be analyzed separately within each subgroup that is of adequate 
size using KM and Cox proportional hazard methods as described in previous section, but 
without stratification. The HRs from the subgroup analyses will be displayed graphically in a 
Forest plot.
In addition, to explore the efficacy of oral azacitidine in subjects who have dose escalation to 
300mg x 21/28 days, OS and RFS from randomization will be analyzed in this subset of subjects. 
The overall response (CR+CRi+Partial Remission) and corresponding best response categories 
(CR, CRi and PR) achieved during the dose escalation period will also be summarized in this 
subset of subjects. The response will be derived programmatically based on the IWG AML 
response criterion using clinical data. 
 
 
 
 
 
  
 
 
 
 
 


EDMS Doc. Number: 23961279 - 23960662
Oral Azacitidine (CC-486)
Statistical Analysis Plan. Protocol CC-486-AML-001
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EDMS Doc. Number: 23961279 - 23960662
Oral Azacitidine (CC-486)
Statistical Analysis Plan. Protocol CC-486-AML-001
Celgene Corporation
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35
12.
SAFETY ANALYSIS
All analyses of safety data will be conducted using the safety population, which are subjects who 
received at least 1 dose of study drug. All safety summaries will be provided by treatment arms. 
For summaries of safety data, the on-treatment period is defined as the period from date of first 
dose of IP through the date of last dose of IP plus 28 days, inclusive. Post-treatment period is 
defined as the period beyond the 28 days after the date of the last dose of IP. 
By subject listings of all AEs, Treatment-emergent Adverse Events (TEAEs, as defined below in 
section 12.1), serious TEAEs, grade 3 or 4 TEAEs, TEAEs leading to study drug 
discontinuation, TEAEs leading to dose reduction, TEAEs leading to dose interruption, TEAEs 
leading to dose reduction and dose interruption, TEAEs leading to death, AEs during pre-
treatment period, and all deaths will be provided. 
12.1.
Adverse Events
Adverse events (AEs) will be coded according to MedDRA, version 22. The severity of AEs will 
be assessed by the investigator according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0. For any AE not listed in the CTCAE grading system, the severity
of these events will be assessed by the Investigator using a 5-point scale: “Grade 1/Mild,” 
“Grade 2/Moderate,” “Grade 3/Severe,” “Grade 4/Life-threatening,” or “Grade 5/Death.” TEAEs 
with a missing severity will be presented in the summary table as an severity category of 
“Missing.” Relationship of AEs to investigational product by the investigator is documented on 
the eCRF. Adverse events that are missing the relationship to study medication will be presented 
in the summary table as “treatment-related”. The imputed values for relationship to study drug 
will be used for incidence summaries while actual values will be presented in data listings.
Treatment-emergent adverse events (TEAEs) include adverse events that started between the 
first dose date and 28 days after the last dose date of study treatment. Alternative definition of 
TEAEs will also be defined from first dose date to 28 days after the last dose date of study 
treatment, or date of start of subsequent AML therapy, whichever is earlier. This definition is 
employed to better differentiate the incidence of TEAEs between oral azacitidine and placebo 
without potential attenuation of differences due to events that occur in both arms due to 
subsequent therapies (that may have initiated prior to 28 days post last dose of study treatment).
Adverse events will be summarized by system organ class, preferred term, and treatment arm.  
Adverse event summaries will include frequency tables of:

Summary of TEAEs;

TEAEs; 

TEAEs by decreasing order of frequency of PT;

TEAEs by decreasing order of frequency of system organ class; 

TEAEs with most frequent preferred terms (≥ 10% in the oral azacitidine group);

Any occurrence of TEAEs by cycle of onset;


EDMS Doc. Number: 23961279 - 23960662
Oral Azacitidine (CC-486)
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
Any occurrence of TEAEs by cycle day of onset; 

First occurrence of TEAEs by cycle of onset;

First occurrence of TEAEs by cycle day of onset;

TEAEs by maximum severity;

TEAEs with severity of grade 3 or 4;

TEAE with severity of grade 1 or 2; 

TEAEs leading to death;

TEAEs related to study medication;

TEAEs related to study medication with severity of grade 3 or 4;

TEAEs related to study medication leading to death; 

serious TEAES; 

serious TEAEs by decreasing order of frequency of PT; 

serious TEAEs related to study medication;

serious TEAEs with severity of grade 3 or 4;

serious TEAEs related to study medication with severity of grade 3 or 4; 

TEAEs leading to study medication discontinuation;

TEAEs leading to dose reduction of study medication;

TEAEs leading to dose interruption of study medication;

TEAEs leading to dose interruption and reduction of study medication;

TEAEs by sex; 

TEAEs by age group (< 65, ≥ 65 to 75, and ≥ 75years); 

TEAEs by race group (White, Asian, Black or Others); 

TEAEs by ECOG performance status (0 or 1, 2 or 3)
Additionally, the incidence rate per 100 person-years will be summarized for all TEAEs and 
Grade 3 or 4 TEAEs by system organ class, preferred term, and treatment arm. The incidence 
rate per 100 person-years is calculated as (100*n)/*T, where n is the number of subjects with the 
given AE at the system organ class or preferred term level, and T is total person-years of 
exposure. If a subject has multiple events with the same preferred term, then the time to the first 
event is used. For subject with no event, time to earlier of last dose + 28 days or death date is 
used.
Subjects with multiple events reported for the same preferred term will be counted only once per 
system organ class and preferred term level.  For summaries by severity (CTCAE grade), 
subjects with multiple events at the preferred term level will be counted once and for the highest 
reported severity.  For summaries by treatment cycle, subjects with multiple events reported with 


EDMS Doc. Number: 23961279 - 23960662
Oral Azacitidine (CC-486)
Statistical Analysis Plan. Protocol CC-486-AML-001
Celgene Corporation
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a start date within the same cycle for the same preferred term will be counted once per system 
organ class level and preferred term level within the cycle.
In summaries of TEAEs related to study medication, if a subject reports multiple occurrences of 
the same AE, only the related occurrence will be summarized. Adverse events with missing 
relationship to study medication will be imputed as related to study medication.
Additional safety analysis may be performed, displayed and summarized, when deemed 
necessary.
To assess the safety profile among subjects who have dose escalation, defined as subjects who 
have at least one assigned dose of 300mg × 21/28 days, the following summary tables will be 
provided in subjects with dose escalation:

First occurrence of TEAE by dose schedule period (300mg × 14/28days, 300mg ×
21/28days); 

Any occurrence of TEAE by dose schedule period (300mg × 14/28days, 300mg ×
21/28days); 

Exposure adjusted incidence rate of first occurrence of TEAE by dose schedule period 
(300mg × 14/28days, 300mg × 21/28days); 

Exposure adjusted incidence rate of any occurrence of TEAE by dose schedule period 
(300mg × 14/28days, 300mg × 21/28days); 

Any occurrence of TEAEs by cycle of onset
The first occurrence and any occurrence of Grade 3/4 TEAE by dose schedule period will also be 
summarized. 
12.2.
Adverse Events of Special Interest
12.2.1.
Treatment-emergent Adverse Events of Special Interest
The AEs of special interest or AESIs refers to a group of terms/PTs from one or more SOCs 
relating to a defined medical condition or area of interest. The AE of special interest phrase or 
term refers to the group of PTs, rather than the individual PTs. Treatment-emergent adverse 
events for categories of adverse events of special interest will be selected using Standardized 
MedDRA Query (SMQ) definitions or MedDRA SOC and/or PT definitions. TEAEs will be 
summarized for the following categories of AESIs PT and by treatment arm: 

Myelosuppression
o
Neutropenia
o
Thrombocytopenia
o
Anemia
o
General myelosuppression;

Hemorrhagic events

Infections,

Renal failure


EDMS Doc. Number: 23961279 - 23960662
Oral Azacitidine (CC-486)
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
Hepatic failure

Ischemic colitis

Cardiac events
o
Cardiac arrhythmias
o
Myocardial infarction
o
Cardiac failure

Psychiatric disorders

Tumour lysis syndrome

Interstitial lung disease

Gastrointestinal Events

Anxiety, confusional state, insomnia
Adverse events of special interest will include summary of the following: 

Summary of AESI;

AESI and exposure adjusted incidence rate; 

AESI related to study medication;

AESI with severity of grade 3 or 4;

AESI related to study drug with severity of grade 3 or 4;

AESI leading to death

AESI leading to death by cycle of onset

AESI related to study drug leading to death 

Serious AESI 

Serious AESI related to study drug

AESI leading to dose reduction

AESI related to study drug leading to dose reduction 

AESI leading to dose interruption

AESI related to study drug leading to dose interruption

AESI leading to dose interruption and dose reduction

ASEI related to study drug leading to dose interruption and dose reduction

AESI leading to study drug discontinuation;

AESI related to study drug leading to study drug discontinuation
Each category/subcategories of adverse events of special interest defined above, with the 
exception of the infection and tumour lysis syndrome categories, will be summarized by AESI 


EDMS Doc. Number: 23961279 - 23960662
Oral Azacitidine (CC-486)
Statistical Analysis Plan. Protocol CC-486-AML-001
Celgene Corporation
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category, preferred term, and treatment arm. Additionally, the incidence rate per 100 person-
years will also be summarized for each event of interested. 
12.2.2.
Second Primary Malignancies
Second primary malignancies (SPM) will be monitored as events of interest and reported in the 
CRF serious adverse event for SPM page throughout a subject’s duration in the study (signing of 
informed consent form through the follow-up period of study). 
By-subject listings will be provided for SPMs and related procedures/surgeries, radiation 
therapies and regimen therapies. 
12.3.
Death
The primary cause of death verbatim term as recorded on the CRF death form will be coded 
according to MedDRA, version 22. The CRF death form also collects the Primary Category of 
Death Cause, as selected by the investigator. A summary of all deaths will be provided by 
treatment period, primary category of death cause by investigator, and the coded primary cause
of death (by system organ class, preferred term). 
An additional summary of death will be provided for ITT population. 
Listings will be provided and will include all subjects who died after signing informed consent.
12.4.
Clinical Laboratory Evaluations
The laboratory assessments prior to and including the date of first dose of study medication will 
be considered pre-treatment. The baseline value is defined as the last (most recent) non-missing 
value during the pre-treatment period. The laboratory data collected after date of discontinuation 
from the treatment period (date of last dose of IP + 28 days or end of treatment visit, whichever 
is longer) will be considered post-treatment.  
Clinical laboratory values from the central laboratories will be graded according to CTCAE 
version 4.0 for selected tests (see Appendix 17.8 for list of tests).  Summary statistics (N, Mean, 
SDev, Median, Minimum, and Maximum) of observed and change from baseline values will be 
presented for each lab test at each scheduled visit.  Frequency distributions for shift from 
baseline to worst CTCAE grade observed across all cycles and within each cycle will be 
displayed by treatment arm for CTCAE graded tests. Clinical laboratory values with a CTCAE 
grade of 3 or 4, observed during treatment will be summarized (counts and percentages) by cycle 
for CTCAE graded tests.  Listings of clinical laboratory data with abnormal flags will be 
provided by subject and test.
Nadirs (minimum values) of selected hematology parameters (Hgb, platelets, ANC, WBC and 
RBC) across all cycles and within each cycle will be summarized by cycle onset day using 
frequency distributions (counts and percent).  Additionally, the average onset day of nadir will be 
summarized across all cycles using descriptive statistics.  The earliest cycle day on which the 
lowest value was observed will be used as the onset day of the nadir.  In addition, descriptive 


EDMS Doc. Number: 23961279 - 23960662
Oral Azacitidine (CC-486)
Statistical Analysis Plan. Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
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statistics of the analyte values at nadir and change from baseline to nadir value will be provided 
for each selected hematology test.
Graphical display of select laboratory parameters over the course of the study will be provided. 
12.5.
Vital Sign Measurements
For vital signs (systolic blood pressure, diastolic blood pressure, pulse rate, temperature and 
weight), summary statistics (N, Mean, SDev, Median, Minimum, and Maximum) of observed 
and change from baseline values will be presented by study visit.  The baseline value is defined 
as the last (most recent) non-missing value during the pre-treatment period.  Post-treatment vital 
sign values will not be included in summary tables but will be included in data listings.
12.6.
Electrocardiograms
A 12-lead electrocardiogram (ECG) is required for all subjects at Screening visit. Screening ECG 
results will be provided in a by-subject listing. 
12.7.
Chest X-Ray
A chest x-ray will be taken at the Screening Visit unless the subject has a previous chest x-ray 
taken within 4 weeks prior to Day 1 that was not clinically significant.  
Screening chest x-ray information will be provided in a by-subject listing. 
12.8.
Pregnancy Status
A by-subject listing of pregnancy tests and results will be provided for all female subjects of 
childbearing potential.




EDMS Doc. Number: 23961279 - 23960662
Oral Azacitidine (CC-486)
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14.
INTERIM ANALYSIS
14.1.
General Information
One interim analysis to assess futility was planned in the protocol when approximately 30% of 
the total events (99 deaths) have occurred. A beta-spending function was used to calculate a 
futility boundary of Z < -1.9796 using Gamma(-10) and corresponds to a conditional power level 
of approximately 18%. The interim analysis was performed with a data cutoff date of 
31Dec2015, when 104 deaths occurred. The DMC meeting was held on 23 Mar 2016 where 
DMC members reviewed unblinded efficacy and safety data. The DMC concluded that the 
hazard ratio of the CC-486 over placebo remained within the protocol pre-specified futility
boundary, and the AE profile did not raise any unexpected safety concerns. Therefore, the DMC 
recommended that the study could continue as planned.
14.2.
Statistical Approaches for Control of Alpha
Because the interim analysis is for assessing futility purpose only, no alpha adjustment will be 
applied in the final analysis.  
14.3.
Data Monitoring
An independent DMC with multidisciplinary representation were established to evaluate the 
ongoing safety of the study subjects during the trial. The DMC comprised of medical oncologists 
with experience in treating subjects with AML and a statistician, all of whom are not otherwise 
involved in the study as investigators. The DMC met at least semi-annually after sufficient 
subject data has been collected.  The DMC responsibilities, authorities, and procedures were
documented in the DMC charter, which were endorsed by the DMC prior to the first data review 
meeting.


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15.
CHANGES TO THE STATISTICAL ANALYSES SECTION OF 
THE PROTOCOL
The planned sensitivity analysis of RFS using alternative definition of documented relapse, as 
specified in protocol 10.6.2.1, with 16% bone marrow blast cutoff value will not be performed. 
Because there is only one subject who lost to follow up from the study, the planned sensitivity 
analysis for RFS with modified definition as specified in protocol section 10.6.2.1 will not be 
performed. 


EDMS Doc. Number: 23961279 - 23960662
Oral Azacitidine (CC-486)
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EDMS Doc. Number: 23961279 - 23960662
Oral Azacitidine (CC-486)
Statistical Analysis Plan. Protocol CC-486-AML-001
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45
17.
APPENDICES
17.1.
Handling of Dates
17.1.1.
Dates Handling
Dates will be stored as numeric variables in the SAS analysis files and reported in 
DDMMMYYYY format (i.e., the Date9. datetime format in SAS).  Dates in the clinical database 
are classified into the categories of procedure dates, log dates, milestone dates, outcome dates, 
and special dates.

Procedure Dates are the dates on which given protocol-specified procedures are 
performed.  They include the dates of laboratory testing, physical examinations, bone 
marrow aspirate/biopsy, etc.  They should be present whenever data for a protocol-
specified procedure is present and should only be missing when a procedure is 
marked as NOT DONE in the database.  Procedure dates will not be imputed.

Log Dates are dates recorded in CRF data logs.  Specifically, they are the start and 
end dates for adverse events and concomitant medications/procedures.  They should 
not be missing unless an event or medication is marked as ongoing in the database.  
Otherwise, incomplete log dates will be imputed according to the rules in Appendix 
15.1 (e.g., for duration or cycle assignment etc). However, in listings, log dates will 
be shown as recorded without imputation.

Milestone Dates are dates of protocol milestones such as randomization, study drug 
start date, study termination, etc.  They should not be missing if the milestone occurs 
for a subject.  They will not be imputed.

Outcome Dates are dates corresponding to study endpoints such as survival, 
progression, etc.  In most cases they are derived either from a milestone (e.g., the 
survival date is derived from the death date), or a procedure date (e.g., the progression 
date is derived from the date of the bone marrow aspirate that was used to determine 
progression).  They may be subject to endpoint-specific censoring rules if the 
outcome did not occur, but are not otherwise subject to imputation.

Special Dates cannot be classified in any of the above categories and they include the 
date of birth.  They may be subject to variable-specific censoring and imputation rules 
(see section 5.1.2 below). 
Dates recorded in comment fields will not be imputed or reported in any specific format. 
17.1.2.
Calculation Using dates
Calculations using dates (e.g., subject’s age or relative day after the first dose of study 
medication) will adhere to the following conventions: 

Study days after the start day of study drug will be calculated as the difference 
between the date of interest and the first date of dosing of study medication (e.g, 


EDMS Doc. Number: 23961279 - 23960662
Oral Azacitidine (CC-486)
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azacitidine) plus 1 day. The generalized calculation algorithm for relative day if the 
following: 
- If TARGET DATE >= DSTART then STUDY DAY=(TARGET DATE-
        DSTART)+1;
- Else use STUDY DAY=TARGET DATE-DSTART.
Note that Study Day 1 is the first day of treatment of study drug.  Negative and zero 
study days are reflective of observations obtained during the baseline/screening 
period.  Note: Partial date for the first study drug is not imputed in general. All efforts 
should be made to avoid incomplete study drug start date. 

Age (expressed in days) is calculated: AGE = CONSENT – DATE of BIRTH + 1.  In 
practice, age will be converted to years by dividing the difference by 365.25 days, 
then truncating.
o
Partial birth date: impute missing day as 15th of the month; impute missing 
month as July; set missing age for missing year

Intervals that are presented in weeks will be transformed from days to weeks by using 
(without truncation) the following conversion formula:
WEEKS = DAYS /7.

Intervals that are presented in months will be transformed from days to months by 
using (without truncation) the following conversion formula:
MONTHS = DAYS /330.4375.
17.1.3.
Calculation of Cycles
The start date of each treatment cycle will be calculated based on study drug exposure records 
for each subject. The start date of the first cycle will be the earliest date the subject receives any 
study drug. 
Once the start dates, e.g., S1, S2, S3… are calculated, the end date of each cycle is calculated as 
the day before the start date of the following cycle, i.e., Ei = Si+1 -1. For the last cycle, the end 
date will be the same as the treatment end date, which is calculated as the last dose date +14 days 
(the prescribed rest period of each cycle), or the death date, whichever is earlier. 
The cycle number for each data of interest, e.g., AE or lab, will be calculated based on the cycle 
window set by their start and end dates. If a date is on or after Si and before Si+1, the 
corresponding cycle number will be i.


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Oral Azacitidine (CC-486)
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17.2.
Date Imputation Guideline
17.2.1.
Impute Missing Adverse Events/ Prior or Concomitant Medications 
Incomplete Start Date:
Missing day and month

If the year is the same as the year of the first dosing date, then the day and month of 
the first dosing date will be assigned to the missing fields.

If the year is prior to the year of first dosing date, then December 31 will be assigned 
to the missing fields.

If the year is after the year of first dosing, then January 1 will be assigned to the 
missing fields.
Missing day only 

If the month and year are the same as the year and month of first dosing date, then the 
first dosing date will be assigned to the missing day.

If either the year of the partial date is before the year of the first dosing date or the 
years of the partial date and the first dosing date are the same but the month of partial 
date is before the month of the first dosing date, then the last day of the month will be 
assigned to the missing day.

If either the year of the partial date is after the year of the first dosing date or the 
years of the partial date and the first dose date are the same but the month of partial 
date is after the month of the first dosing date, then the first day of the month will be 
assigned to the missing day.

If the stop date is not missing, and the imputed start date is after the stop date, the 
start date will be imputed by the stop date. 
Missing day, month, and year

No imputation is needed, the corresponding AE will be included as TEAE. 
Incomplete Stop Date: If the imputed stop date is before the start date, then the imputed stop 
date will be equal to the start date.
Missing day and month

If the year of the incomplete stop date is the same as the year of the last dosing date, 
then the day and month of the last dosing date will be assigned to the missing fields. 

If the year of the incomplete stop date is prior to the year of the last dosing date or 
prior to the year of the first dosing date, then December 31 will be assigned to the 
missing fields. 

If the year of the incomplete stop date is prior to the year of the last dosing date but 
is the same as the year of the first dosing date, then the first dosing date will be 
assigned to the missing date. 


EDMS Doc. Number: 23961279 - 23960662
Oral Azacitidine (CC-486)
Statistical Analysis Plan. Protocol CC-486-AML-001
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
If the year of the incomplete stop date is after the year of the last dosing date, then
January 1 will be assigned to the missing fields.
Missing day only 

If the month and year of the incomplete stop date are the same as the month and year 
of the last dosing date, then the day of the last dosing date will be assigned to the 
missing day. 

If either the year of the partial date is not equal to the year of the last dosing date or 
the years of the partial date and the last dosing date are the same but the month of 
partial date is not equal to the month of the last dosing date, then the last day of the 
month will be assigned to the missing day. 


EDMS Doc. Number: 23961279 - 23960662
Oral Azacitidine (CC-486)
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17.3.
Table of Events
Procedure
Pre-
Randomization 
Phase
Double-blind Treatment Phase
Post-Treatment 
Follow-up Phase
Cycle 1
Cycle 2
Cycle 3 and 
Beyond
Visit 1/Screen
(Day -28 to -1)1
Random-
ization
Day 11
Day 8, 
15, 22
(± 3 
days)
Day 1 
(± 3 
days)
Day 8, 
15, 22
(± 3 
days)
Day 1
(± 3
days)
Day 
1530
(± 3
days)
Treat-
ment 
Discontin-
uation
Follow
-up28     
Study Entry Assessments
Informed Consent

--
--
--
--
--
--
--
--
--
Demographics & Medical History

--
--
--
--
--
--
--
--
--
AML Diagnosis History
2
--
--
--
--
--
--
--
--
--
Transplant Eligibility

--
--
--
--
--
--
--
--
--
Documentation of Induction ± 
Consolidation Therapies 

--
--
--
--
--
--
--
--
--
CR/CRi Status Confirmation

--
--
--
--
--
--
--
--
--
12-Lead ECG
3
--
--
--
--
--
--
--
--
--
Chest X-ray
4
--
--
--
--
--
--
--
--
--
Prior Medications
5
--
--
--
--
--
--
--
--
--
ECOG Performance Status

6

--

--

--
--
--
Coagulation7

--
--
--
--
--
--
--
--
--
Serum EPO Level

--
--
--
--
--
--
--
--
--
Urinalysis8

--
--
--
--
--
--
--
--
--
Inclusion/Exclusion Criteria

--
--
--
--
--
--
--
--
--


EDMS Doc. Number: 23961279 - 23960662
Oral Azacitidine (CC-486)
Statistical Analysis Plan. Protocol CC-486-AML-001
Celgene Corporation
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Table 3:
Table of Events (Continued)
Procedure
Pre-
Randomization 
Phase
Double-blind Treatment Phase
Post-Treatment 
Follow-up Phase
Cycle 1
Cycle 2
Cycle 3 and 
Beyond
Visit 1/Screen
(Day -28 to -1)1
Random-
ization
Day 11
Day 8, 
15, 22
(± 3 
days)
Day 1 
(± 3 
days)
Day 8, 
15, 22
(± 3 
days)
Day 1
(± 3 
days)
Day 
1530
(± 3
days)
Treat-
ment 
Discontin-
uation
Follow
-up28
Randomization
--

--
--
--
--
--
--
--
--
Safety Assessments
Adverse Events
After signing ICD and until 28 days after the last IP dose or until the last study visit, whichever period is longer
Second Primary Malignancy9
After signing ICD and throughout the duration of the study including post treatment follow-up period
Physical Examination

--

--

--

--

--
Vital Signs and Body Weight10

--

--

--

--

--
Hematology11

--







--
Serum Ferritin12

--
12
--
--
--
--
--

--
Unstained Peripheral Blood Smear13

--







--
Serum Chemistry14

--

--

--

--

--
Pregnancy Testing (FCBP only)15

--

--

--

--

--
Concomitant Medications, Therapy & 
Procedures16
--
--







--
Efficacy Assessments
Bone Marrow Aspirate17

--
--
--
--
--

--

--
Bone Marrow Biopsy17, 18

--
--
--
--
--

--

--
Cytogenetic Testing19

--
--
--
--
--

--

--
Peripheral Blood Smear20

--
--
--
--
--

--

--


EDMS Doc. Number: 23961279 - 23960662
Oral Azacitidine (CC-486)
Statistical Analysis Plan. Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
51
Table 3:
Table of Events (Continued)
Procedure
Pre-
Randomization 
Phase
Double-blind Treatment Phase
Post-Treatment 
Follow-up Phase
Cycle 1
Cycle 2
Cycle 3 and 
Beyond
Visit 1/Screen
(Day -28 to -1)1
Random-
ization
Day 11
Day 8, 
15, 22
(± 3 
days)
Day 1 
(± 3 
days)
Day 8, 
15, 22
(± 3 
days)
Day 1
(± 3 
days)
Day 
1530
(± 3
days)
Treat-
ment 
Discontin-
uation
Follow-
up28
IWG Response Assessment21
--
--
--
--
--
--

--

--
Follow-up AML Relapse22
--
--
--
--
--
--
--
--
--

Follow-up AML Therapies22
--
--
--
--
--
--
--
--
--

Survival Follow-up22
--
--
--
--
--
--
--
--
--

Investigational Product (IP)
Dispense/Administer
23, 24
23, 24
23, 24
IP Accountability



Other Assessments
Patient-reported HRQoL Outcomes 
(FACIT-Fatigue Scale and EQ-5D) 25
--
--

--

--

--

--
Healthcare Resource Utilization
After signing ICD and until 28 days after the last IP dose or until the date of last study visit, whichever is later (not collected during 
follow-up period).
 
 
 
-
AE = adverse event; AML = acute myeloid leukemia; ANC = absolute neutrophil count; CR = complete response; CRF = case report form; CRi = complete response with 
incomplete blood count recovery; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EPO = erythropoietin; FACIT -Fatigue Scale = Functional 
Assessment of Chronic Illness Therapy – Fatigue Scale  FCBP = female of childbearing potential; HRQoL = health-related quality of life; ICD = Informed Consent Document; IP 
= investigational product; IWG = international working group; SAE = serious adverse event; SPM = second primary malignancy


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Oral Azacitidine (CC-486)
Statistical Analysis Plan. Protocol CC-486-AML-001
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1. Results obtained on Day 1 just prior to the first dose will serve as the Baseline values.  If not available, the most recent screening results prior to Day 1 will be considered the 
Baseline values.  Subjects who fail eligibility criteria due to low neutrophil count or platelet count or other laboratory abnormality can be re-screened as long as this occurs 
within 4 months (± 7 days) from the achievement of CR or CRi status.
2. Documentation of AML diagnosis will be assessed locally from bone marrow aspirate and/or biopsy sample slides.   
3. Electrocardiogram required during screening period and whenever clinically indicated during the double-blind treatment phase.  For subjects with an abnormal ECG, a cardiac 
consultation should be obtained as deemed necessary by the treating physician.
4. Chest x-ray not needed if a previous chest x-ray taken within 4 weeks prior to Cycle 1, Day 1 is available and not clinically significant.
5. Includes any prior chemotherapy, cytotoxic therapy, radiation therapy, and all medications used for the 4-week period prior to Day 1 of Cycle 1.
6. Subjects must satisfy the ECOG performance status of 0, 1, 2, or 3 to be enrolled in the study.  Can be performed at randomization or Day 1 of Cycle 1.
7. Coagulation testing is conducted at screening and whenever clinically indicated during the double-blind treatment phase
8. A standard urinalysis (including microscopic analysis if indicated) is required at screening and whenever clinically indicated during the double-blind treatment phase.
9. Second primary malignancies will be monitored as events of interest and should be included as part of the assessment of AEs throughout the duration of the study including 
follow-up period.  Investigators are to report any SPM regardless of causal relationship to IP, occurring at any time from subject signing of informed consent document and 
throughout the duration of the study including follow-up period as a serious adverse event (considered to be at least “an important medical event” even if no other seriousness 
criteria apply).  This information must also be documented on the appropriate pages of the CRF and in the subject’s source documents.  Documentation of the diagnosis of the 
SPM (eg, any confirmatory histology or cytology results, X-rays, CT scans, etc) must be provided at the time of reporting as an SAE.
10. Includes height (at screening only), blood pressure, pulse, and temperature.
11. Includes a complete blood count (RBC count, hemoglobin, hematocrit, mean corpuscular volume [MCV], mean corpuscular hemoglobin [MCH], mean corpuscular 
hemoglobin concentration [MCHC], WBC count with differential, ANC, and platelet count).  Any or all laboratory assessments may be repeated more frequently if clinically 
indicated.  The samples will be collected prior to study treatment dosing and will be analyzed by the central laboratory.  In the event that hematology laboratory results are 
needed to acutely manage the subject, local laboratory tests may be used.  In addition to the local laboratory sample, a second sample should always be sent to the central 
laboratory. 
12. Serum ferritin levels will be collected at screening, on Day 1 of Cycle 1, on Day 1 of every 3 cycles thereafter (ie, Day 1 of Cycles 4, 7, 10, 13, etc.) and at the Treatment 
Discontinuation visit.
13. Whenever a hematology sample is collected for a complete blood count, an unstained peripheral blood smear should be prepared and sent to the central laboratory.  This 
unstained peripheral blood smear will be used to assess a manual blood count differential.
14. Includes serum chemistry labs (sodium, potassium, chloride, bicarbonate, calcium, phosphorus, BUN, creatinine, glucose, albumin, total protein, alkaline phosphatase, 
direct/indirect total bilirubin, aspartate aminotransferase [AST], alanine aminotransferase [ALT], lactate deyhydrogenase [LDH], and uric acid).  The samples will be collected 
prior to study treatment dosing and will be analyzed by the central laboratory.  Any or all laboratory assessments may be repeated more frequently if clinically indicated.  In the 
event that chemistry laboratory results are needed to acutely manage the subject, local laboratory tests may be used.  In addition to the local laboratory sample, a second sample 
should be sent to the central laboratory. 
15. A medically supervised serum pregnancy test with sensitivity of at least 25mIU/mL is to be obtained in female subjects of childbearing potential (FCBP) at Screening (within 
72 hours prior to starting study therapy).  A serum or urine pregnancy test (per Investigator’s discretion) is to be done prior to Day 1 of every subsequent cycle (within 72 
hours), and at the End of the Treatment visit.  The subject may not receive investigational product until the Investigator has verified that the result of the pregnancy test is 
negative.
16. All concomitant over-the-counter medications, prescription medications, including anti-infectives for prophylaxis and/or treatment of an infection taken from Cycle 1, Day 1 up 
to 28 days after the last dose of IP or up to the Treatment Discontinuation visit, whichever period is longer, must be recorded on the appropriate page(s) of the CRF.
17. A bone marrow aspirate and biopsy should ideally be collected at Screening, no earlier than 14 days prior to randomization.  The screening bone marrow aspirate and biopsy 
are required to be repeated even if a bone marrow aspirate and biopsy was performed for disease diagnosis/status as part of the standard of care within 28 days of Cycle 1, Day 
1.  The bone marrow aspirate slide, bone marrow biopsy slide, bone marrow aspirate sample for cytogenetics testing/chromosome analysis, and unstained peripheral blood 
smear slides must be sent to the central laboratory for review by the central pathology reviewer.  


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Oral Azacitidine (CC-486)
Statistical Analysis Plan. Protocol CC-486-AML-001
Celgene Corporation
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In addition, bone marrow aspirates must be collected during double-blind treatment phase on Day 1 (± 7 days)  of  Cycles 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, and the Treatment 
Discontinuation visit, in order to confirm continued CR or CRi, relapse after CR or CRi (as assessed by the Investigator based on CBC with WBC differential results), or 
disease relapse.  After Cycle 36 bone marrow assessment for disease relapse is performed only if clinically indicated.  If disease relapse features are observed following a bone 
marrow aspirate, it is recommended that a repeat bone marrow aspirate be performed at least 3-4 weeks later to confirm disease relapse unless the blast count was greater than 
50% in the marrow or peripheral blood.  Additional aspirates may be collected if clinically indicated or required for toxicity assessment.  A bone marrow biopsy can be 
collected in conjunction with an aspirate if it is standard institutional practice.  A bone marrow biopsy may be needed to evaluate bone marrow cellularity.  Whenever a bone 
marrow aspirate sample is sent to the local laboratory, additional (differently prepared) bone marrow aspirate slides must be sent to the central laboratory for review by the 
central pathology reviewer.  Instructions for submission of bone marrow samples to the central (pathology) reviewer are provided in Study Reference and/or Study Central 
Laboratory Manual.  
18. Bone marrow biopsies may be needed to assess bone marrow status if an adequate bone marrow aspirate cannot be attained. 
19. Bone marrow aspirates sample tube for cytogenetics testing/chromosome analysis to be obtained at Screening for evaluation by central laboratory to obtain karyotype.  A 
minimum of 16 analyzable metaphases for standard banding cytogenetic analysis is recommended at Screening.  During the study, repeat of bone marrow cytogenetics testing 
is to be completed whenever a bone marrow aspirate is obtained and in order to confirm CR, CRi, or disease relapse.  
20. Whenever bone marrow aspirate (or biopsy) slides are sent to the central reviewer, a peripheral blood smear slide should also be submitted.
21. International Working Group (IWG) response assessment will be assessed at Cycles 3, 6, 9, 12, 15, and 18, 21, 24, 30, 36 and the Treatment Discontinuation visit.  After Cycle 
36 bone marrow assessment for disease relapse is performed only if clinically indicated. Subjects should be assessed for CR/CRi status maintenance, relapse after CR/CRi, or 
disease relapse.  
22. All discontinued subjects, regardless of reason for discontinuation, should be followed for survival, AML relapse, AML therapies and SPM every month (± 3 days)  for the first 
year and then every 3 months (± 14 days) until death, lost to follow-up, withdrawal of consent from further follow-up, or the end of the study.  Documentation such as 
laboratory or pathology reports, bone marrow and/or peripheral blood reports supporting the AML relapse should be requested and collected.  Subjects who are discontinued 
prematurely will also undergo End-of-Study procedures.  The monthly and the quarterly survival follow-up can be performed via a telephone interview.
23. Investigational product should be dispensed on Day 1 of each cycle only.  For Day 1 of Cycle 1, treatment should be administered within 3 days after randomization.  The first 
dose of IP on Day 1 of each cycle should be taken only after all other study Day 1 procedures have been completed.  Antiemetic medication should be administered 30 minutes 
prior to each IP dose.
24. Investigational product is scheduled to be taken on 1-14 days of each cycle, unless there has been a schedule modification from 14 days to 7 days of IP administration due to 
toxicity.
25. FACIT–Fatigue Scale, EQ-5D, and exploratory quality-of-life (QoL) (Physical Impairment Numeric Rating Scale) questionnaires, should ideally be completed prior to dosing 
and when feasible, prior to interaction with study personnel on Day 1 of every cycle, beginning on Day 1 of Cycle 1, and at study discontinuation.
26. Bone marrow samples for biomarker assessment are desired but optional and subject must consent to the collection of these samples.  Samples should be collected when bone 
marrow is collected at protocol specified time points and when bone marrow is collected to confirm a response (CR or CRi) or relapse.  Biomarker analysis will only be 
performed using these samples when sufficient bone marrow sample material remains (optimally 10-15 mL).  Sample collection, processing, storage, and shipment procedures 
will be provided in the Study Reference and/or Study Central Laboratory Manual. 
27. Mandatory sample collection for PK.  Subjects should consent to the collection of these samples by signing the ICD, mandatory sample collection section.  Two blood samples 
(3 mL/sample) for azacitidine PK assessment will be collected at least 2 hours apart on Day 1 of Cycles 1, 3, and 6 between 0.5 and 6.0 hours post IP administration.  Blood 
samples must be processed and plasma harvested and stored according to the instructions in the Study Reference and/or Study Central Laboratory Manual.
28. The study visit window in the double-blind treatment phase is ± 3 days for Cycles 1, 2, 3 and beyond, unless noted otherwise for a particular assessment.  Study visits should 
also take into account the subject’s IP supply.  Only 1 cycle of IP will be dispensed to the subject on Day 1 of each cycle.  Day 1 of Cycles 2 and beyond may be delayed from 
Day 28 of the prior cycle in order for subjects to recover from toxicity and meet criteria for re-treatment.  During follow-up, the study visit window is ± 7 days for visits 
scheduled monthly (including the follow-up visit 28 days after last dose if necessary) or ± 14 days for visits scheduled every 3 months.  One cycle (one month) is considered as 
28 days (ie, 4 weeks).
29. Peripheral blood sampling for pharmacogenomic analysis is desired but optional and subject must consent to the collection of these samples.  Samples should be collected 
when bone marrow is collected at protocol specified time points and must be collected on the same day as the bone marrow aspirate procedure. 
30. Beginning with the Cycle 25, Day 15 visit, assessments are optional and occur only if clinically indicated at the discretion of the Investigator. 


EDMS Doc. Number: 23961279 - 23960662
Oral Azacitidine (CC-486)
Statistical Analysis Plan. Protocol CC-486-AML-001
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54
17.4.
WHO Classification of Acute Myeloid Leukemia
Acute myeloid leukemia with recurrent genetic abnormalities
Acute myeloid leukemia with t(8;21)(q22;q22); (RUNX1-RUNX1T1)
Acute myeloid leukemia with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); (CBFB-MYH11)
Acute promyelocytic leukemia with t(15;17)(q22;q12); (PML-RARA)
Acute myeloid leukemia with t(9;11)(p22;q23); MLLT3-MLL
Acute myeloid leukemia with t(6;9)(p23q34); DEK-NUP214
Acute myeloid leukemia with inv(3)(q21q26.2) or t(3;3)(q26.2); RPN1-EVI1
Acute myeloid leukemia (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL1
Acute myeloid leukemia with gene mutations
Acute myeloid leukemia with myelodysplasia-related changes
Therapy-related myeloid neoplasma
Acute myeloid leukemia, not otherwise categorized
Acute myeloid leukemia with minimal differentiation
Acute myeloid leukemia without maturation
Acute myeloid leukemia with maturation
Acute myelomonocytic leukemia
Acute monoblastic and monocytic leukemia
Acute erythroid leukemia (erythroid/myeloid and pure erythroleukemia)
Acute megakaryoblastic leukemia
Acute basophilic leukemia
Acute panmyelosis with myelofibrosis
Source:
 
 


EDMS Doc. Number: 23961279 - 23960662
Oral Azacitidine (CC-486)
Statistical Analysis Plan. Protocol CC-486-AML-001
Celgene Corporation
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17.5.
Eastern Cooperative Oncology Group (ECOG) Performance Status
Grade
ECOG 
0
Fully active, able to carry on all predisease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all self care but unable to carry out any work activities.  
Up and about more than 50% of waking hours
3
Capable of only limited self care, confined to bed or chair more than 50% of waking 
hours
4
Completely disabled.  Cannot carry on any self care.  Totally confined to bed or chair
5
Dead
Source:
 
 


EDMS Doc. Number: 23961279 - 23960662
Oral Azacitidine (CC-486)
Statistical Analysis Plan. Protocol CC-486-AML-001
Celgene Corporation
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17.6.
Risk Status Based on Cytogenetics
Risk Status
Cytogenetics
Better-risk
inv(16)1
t(16;16)1
t(8;21)1
t(15;17)
Intermediate-
risk
Normal cytogenetics
+8
t(9;11)
Other non-defined
Poor-risk
Complex (≥ 3 abnormalities)
-5
5q-
-7
7q-
11q23 - non t(9;11)
inv(3)
t(3;3)
t(6;9)
t(9;22)2
1 Other abnormalities in addition to these finding do not alter risk status
2 Philadelphia+ AML t(9;22) consider managing as myeloid blast crisis in CML.  These subjects are excluded from 
study entry.  
Source: 
 
  


EDMS Doc. Number: 23961279 - 23960662
Oral Azacitidine (CC-486)
Statistical Analysis Plan. Protocol CC-486-AML-001
Celgene Corporation
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57
17.7.
International Working Group AML Response Criteria
Hematologic Response According to IWG Criteria for AML
Category
Definition
Morphologic Complete Remission (CR)
The following conditions should be met:

ANC > 1,000/μL;

Platelet count ≥ 100,000/μL; 

The bone marrow should contain less than 5% blast cells; 

Auer rods should not be detectable;

No evidence of extramedullary disease;

Independent of transfusions.
Morphologic Complete Remission with 
Incomplete Blood Count Recovery (CRi)
Defined as a morphologic complete remission but the ANC count may be            
< 1,000/μL or the platelet count may be < 100,000/μL.
Cytogenetic Complete Remission (CRc)
Defined as morphologic complete remission with a reversion to a normal 
karyotype.
Relapse Free Survival
Defined for patients who achieve CR/CRi, and is measured from the date of 
attaining leukemia free state until the date of AML relapse or death from any 
cause, whichever occurs first.
Disease Relapse
Relapse after CR/CRi is defined as reappearance of leukemic blasts in the 
peripheral blood or ≥ 5% blasts in the bone marrow not attributable to any 
other cause (eg, bone marrow regeneration after consolidation therapy).  In the 
setting of recent treatment, if there are no circulating blasts and the bone 
marrow contains 5% to 20% blasts, a repeat bone marrow performed at least a 
week later is necessary to distinguish relapse from regeneration.
Source:
 


EDMS Doc. Number: 23961279 - 23960662
Oral Azacitidine (CC-486)
Statistical Analysis Plan. Protocol CC-486-AML-001
Celgene Corporation
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58
17.8.
Grades for select laboratory analytes based on CTCAE v4.0 
The definitions in Tables 1 and 2 are based on the criteria specified in the CTCAE v4.0.  In cases where the criteria for a grade are 
based on signs and symptoms in conjunction with lab results, the grade is based only on observed lab values.  In cases where the same 
value of a lab result is used in defining more than one grade, the definition for the highest (worst) grade is implemented. 
Table 6.  Definitions for select Hematology analytes
Analyte
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Hgb (anemia)
>= LLN
100 g/L - < LLN
80 g/L - < 100 g/L
65 g/L - < 80 g/L
< 65 g/L
Platelets 
(decreased)
>= LLN
75.0 x 10^9/L - < 
LLN
50.0 - < 75.0 x 
10^9/L
25.0 - < 50.0 x 
10^9/L
< 25.0 x 10^9/L
ANC (decreased)
>=LLN
1.5 x 10^9/L - < LLN
1.0 - < 1.5 x 10^9/L
0.5 - < 1.0 x 10^9/L
< 0.5 x 10^9/L
WBC (decreased)
>=LLN
3.0 x 10^9/L - < LLN
2.0 - < 3.0 x 10^9/L
1.0 - < 2.0 x 10^9/L
< 1.0 x 10^9/L
All values given in SI units.  ND = Not defined in terms of laboratory values. 


EDMS Doc. Number: 23961279 - 23960662
Oral Azacitidine (CC-486)
Statistical Analysis Plan. Protocol CC-486-AML-001
Celgene Corporation
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Table 7.  Definitions for select Chemistry analytes
Analyte
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Hypoalbuminemia 
(decreased albumin)
>= LLN
30 g/L - < LLN
20 g/L - < 30 g/L
< 20 g/L
ND
Alkaline 
Phosphatase 
(increased)
<= ULN
> ULN - 2.5 x ULN
>2.5 – 5.0 x ULN
>5.0 - 20.0 x ULN
> 20.0 x ULN
Bilirubin, Total 
(increased)
<=ULN
> ULN - 1.5 x ULN
> 1.5 - 3.0 x ULN
>3.0 - 10.0 x ULN
>10.0 x ULN
SGPT* (AST) 
(increased)
<=ULN
> ULN - 3.0 x ULN
>3.0 - 5.0 x ULN
>5.0 - 20.0 x ULN
> 20.0 x ULN
SGOT *(ALT) 
(increased)
<=ULN
> ULN - 3.0 x ULN
>3.0 - 5.0 x ULN
>5.0 - 20.0 x ULN
> 20.0 x ULN
Creatinine 
(increased)
<=ULN
> ULN - 1.5 x ULN 
> 1.5 - 3.0 x ULN
>3.0 - 6.0 x ULN
> 6.0 x ULN
Hypercalcemia 
(increased calcium)
<=ULN
> ULN - 2.9 
mmol/L
> 2.9 - 3.1 mmol/L
> 3.1 - 3.4 mmol/L
> 3.4 mmol/L
Hypocalcemia 
(decreased calcium)
>= LLN
2.0 mmol/L - < 
LLN
1.75 - < 2.0 mmol/L
1.5 - < 1.75 mmol/L
< 1.5 mmol/L
Hyperglycemia 
(increased glucose)
<=ULN
> ULN - 8.9 
mmol/L
> 8.9 - 13.9 mmol/L
> 13.9 - 27.8 
mmol/L
> 27.8 mmol/L
Hypoglycemia 
(decreased glucose)
>= LLN
3.0 mmol/L - < 
LLN
2.2 - < 3.0 mmol/L
1.7 - < 2.2 mmol/L
< 1.7 mmol/L


EDMS Doc. Number: 23961279 - 23960662
Oral Azacitidine (CC-486)
Statistical Analysis Plan. Protocol CC-486-AML-001
Celgene Corporation
Confidential and Proprietary
60
Analyte
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Hypernatremia 
(increased sodium)
<=ULN
> ULN - 150 
mmol/L
> 150 - 155 mmol/L
> 155 - 160 mmol/L
> 160 mmol/L
Hyponatremia 
(decreased sodium)
>= LLN
130 mmol/L - < 
LLN
ND
120 - < 130 mmol/L
< 120 mmol/L
Hyperkalemia 
(increased 
potassium)
<=ULN
> ULN - 5.5 
mmol/L
> 5.5 - 6.0 mmol/L
> 6.0 - 7.0 mmol/L
> 7.0 mmol/L
Hypokalemia 
(decreased 
potassium)
>= LLN
ND
3.0 mmol/L - < 
LLN 
2.5 - < 3.0 mmol/L
< 2.5 mmol/L
Hypophosphatemia 
(decreased 
phosphates)
>= LLN
0.8 mmol/L - < 
LLN
0.6 - < 0.8 mmol/L
0.3 - < 0.6 mmol/L
< 0.3 mmol/L
Hyperuricemia 
(increased uric acid)
<=ULN
ND
> ULN - 0.59 
mmol/L
> 0.59 mmol/L
All values given in SI units.  ND = Not defined in terms of laboratory values.
*SGPT and SGOT grades based strictly on laboratory values without consideration for presence or absence of symptoms.


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UserName: 
Title:  
Date: Friday, 26 July 2019, 02:14 PM   Eastern Daylight Time
Meaning: Approved, no changes necessary.
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