Conditions: Myelodysplastic Syndrome
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 216
Healthy volunteers: no

Brief summary:
Evaluation of the Efficacy and Safety of Oral Azacitidine plus Best Supportive care versus Placebo and Best Supportive care in subjects with red blood cell (RBC) transfusion-dependent anemia and thrombocytopenia due to International Prognostic Scoring System (IPSS) lower risk myelodysplastic syndromes (MDS).

Detailed description:

Arms:
arm 1: Arm 1: Oral azacitidine tablets 300 mg daily (QD) + best supportive care (BSC) on days 1 through 21 of each 28-day treatment cycle. arm 2: Arm 2: Identically matching placebo tablets plus best supportive care on days 1 to 21 of each 28-day treatment cycle.

Interventions: intervention 1: Oral Azacitidine intervention 2: Placebo intervention 3: Best Supportiv Care (BSC)
Intervention descriptions: intervention 1: 300 mg daily, days 1 to 21 of each 28-day treatment cycle intervention 2: Identically matching placebo tablets on day 1 to 21 of each 28-day treatment cycle. intervention 3: BSC included and was not limited to packed RBC (packed red blood cell \[pRBC\] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections.

Protocol document:
Prot_002.pdf: 
Official Title of Study: 
A Phase 3, Multicenter, Randomized, Double-blind Study to Compare the Efficacy and Safety of Oral 
Azacitidine Plus Best Supportive Care Versus Placebo Plus Best Supportive Care in Subjects With Red 
Blood Cell Transfusion-dependent Anemia and Thrombocytopenia Due to IPSS Lower-risk 
Myelodysplastic Syndromes 
 
NCT Number: NCT01566695 
Document Date (Date in which document was last revised): 24 May 2022 
 
 
 


CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
A PHASE 3, MULTICENTER, RANDOMIZED, DOUBLE-BLIND STUDY TO 
COMPARE THE EFFICACY AND SAFETY OF ORAL AZACITIDINE PLUS BEST 
SUPPORTIVE CARE VERSUS PLACEBO PLUS BEST SUPPORTIVE CARE IN 
SUBJECTS WITH RED BLOOD CELL TRANSFUSION-DEPENDENT ANEMIA AND
THROMBOCYTOPENIA DUE TO IPSS LOWER-RISK MYELODYSPLASTIC
SYNDROMES
INVESTIGATIONAL PRODUCT (IP):
Oral Azacitidine
PROTOCOL NUMBER:
AZA-MDS-003
ORIGINAL DATE FINAL:
01 May 2012
AMENDMENT No. 1.0 DATE FINAL:
11 Apr 2014 
AMENDMENT No. 2.0 DATE FINAL:
08 Oct 2015
AMENDMENT No. 3.0 DATE FINAL:
21 Feb 2018
AMENDMENT No. 4.0 DATE FINAL
06 Aug 2018
AMENDMENT No. 5.0 DATE FINAL
28 Nov 2018
AMENDMENT No. 6.0 DATE FINAL
24 May 2022
EudraCT NUMBER:
2012-002471-34
IND NUMBER:
074618
SPONSOR NAME / ADDRESS:
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901
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.
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
Contact Information:
Name:
Title:
Address:
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901
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: 
 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
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.  
 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
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, International Council for 
Harmonization (ICH) Good Clinical Practices Guidelines, and local regulations 
governing the conduct of clinical studies.
 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
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.
 
 
 
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CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 6.0:
This protocol was amended to reduce the duration of survival follow-up for the patients in the 
Extension Phase (EP) from following up on regular basis until death, withdrawal of consent, lost 
to follow-up, or study termination, whichever is earlier, to 35 days ± 7 days after treatment 
discontinuation or until death, withdrawal of consent for further data collection, lost to follow-up, 
or study termination, whichever is earlier. This 35-day follow-up period includes a 28-day safety 
follow-up plus a 7-day window. 
As of 04-Feb-2020, the primary analysis Clinical Study Report (CSR) for this study, with data 
cut-off date of 25-Jan-2019, was finalized. At data cut-off, 216 analyzed patients had completed 
12 months of double-blind treatment or discontinued the study treatment, and after study 
unblinding by the Sponsor (Celgene), eligible patients had entered the Extension Phase. 
This Protocol Amendment 6.0 is to reduce data collection and the protocol burden for the patients 
in the Extension Phase.
The revision of this Protocol Amendment applies to all participants currently enrolled.
SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 6.0
Section 
Number & 
Title
Description of Change
Brief Rationale
Medical 
Monitor / 
Emergency 
Contact 
Information
Updated contact details for the 
Medical Monitor of the study.
Administrative change.
Celgene 
Therapeutic 
Area Head 
Signature
Page
Therapeutic Area Head and their
title were updated.
Administrative change.
Section 1.4: 
Risk/Benefit 
Assessment
New section added.
To incorporate the stand-alone risk 
benefit assessment information into the 
protocol.
Appendix J: 
Extension 
Phase
Survival follow-up (FU) was 
updated by reducing the duration of 
survival FU to 35 days (± 7 days)
after treatment discontinuation.
To reduce data collection and protocol 
burden for the patients in the Extension 
Phase.
 
 
 
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CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
PROTOCOL SUMMARY
Study Title
A Phase 3, Multicenter, Randomized, Double-blind Study to Compare the Efficacy and Safety of 
Oral Azacitidine Plus Best Supportive Care versus Placebo Plus Best Supportive Care in Subjects 
with Red Blood Cell Transfusion-dependent Anemia and Thrombocytopenia due to IPSS Lower-
risk Myelodysplastic Syndromes.  
Indication
Treatment of lower-risk (Low or Intermediate-1 [INT-1] risk) Myelodysplastic Syndromes (MDS)
according to the International Prognostic Scoring System (IPSS) with red blood cell (RBC) 
transfusion-dependent anemia and thrombocytopenia.
Objectives
Primary Objective

To evaluate RBC transfusion independence in the 2 treatment arms (oral azacitidine plus 
best supportive care versus placebo plus best supportive care) in subjects with RBC 
transfusion-dependent anemia and thrombocytopenia (platelet count ≤75 x 109/L) due to
IPSS lower-risk MDS.
Secondary Objectives

To evaluate in both treatment arms

overall survival (OS);

hematologic improvement-platelet response (HI-P);

duration of RBC transfusion independence and time to RBC transfusion 
independence;

progression to acute myeloid leukemia (AML), and time to AML progression;

hematologic improvement-erythroid response (HI-E);

platelet-transfusion independence, duration of platelet transfusion independence, and 
time to platelet transfusion independence;

hematologic response;

clinically significant bleeding events;

safety;

health-related quality-of-life (HRQoL); and

healthcare resource utilization.
 
 
 
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CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
 
 
Study Rationale
This clinical study will evaluate the efficacy and safety of oral azacitidine plus best supportive 
care versus placebo plus best supportive care in subjects with RBC transfusion-dependent anemia 
and thrombocytopenia (platelet count ≤ 75 x 109/L) due to IPSS lower-risk MDS.  
 
 
 
The study population represents a subset of IPSS lower-risk MDS patients who have both RBC 
transfusion-dependent anemia and thrombocytopenia. Lower-risk MDS patients often become 
dependent on frequent RBC transfusions, which leads to decreased HRQoL and increased 
morbidity and mortality (Hellstrom-Lindberg, 2003; Malcovati, 2005).  In addition, recent studies 
have shown that lower-risk MDS patients who are thrombocytopenic have a significantly worse 
prognosis compared to lower-risk MDS patients who are not thrombocytopenic.  Lower-risk MDS 
patients with significant thrombocytopenia have a median OS of approximately 14 to 16 months
(Garcia-Manero, 2008a; Cruz, 2010; Yong, 2010; Gonzalez-Porras, 2011).
In the United States (US), azacitidine (Vidaza®) is approved for the treatment of all 5 French-
American-British (FAB) classification subtypes of MDS: refractory anemia (RA) or refractory 
anemia with ringed sideroblasts (RARS) (if accompanied by neutropenia or thrombocytopenia or 
requiring transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with 
excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMML), but 
it is not routinely utilized in the lower-risk disease setting.  Azacitidine is approved in the European 
Union (EU) for the treatment of adult patients who are not eligible for hematopoietic stem cell 
transplantation with IPSS Intermediate-2 (INT-2) or High risk MDS, CMML with 10% to 29% 
marrow blasts without myeloproliferative disorder, and AML with 20% to 30% blasts and multi-
lineage dysplasia, according to World Health Organization (WHO) classification.  In addition to 
the US and EU, azacitidine is currently approved in 30 other countries, including Canada, 
Switzerland, Australia and Japan, for the treatment of MDS (approvals for specific subtypes vary 
by country).  Azacitidine is approved for subcutaneous (SC) and intravenous (IV) routes of 
administration (approvals vary by country).  Similarly, decitabine (Dacogen), another 
hypomethylating agent, is approved in the US for treatment of all FAB classification subtypes and 
IPSS INT-1, INT-2 and High risk MDS.  
While parenteral azacitidine and decitabine are approved for treatment of lower-risk MDS in some 
countries, these agents are not routinely administered and the mainstay therapy remains supportive 
treatment with erythropoiesis stimulating agents (ESAs) and RBC and/or platelet transfusions.  
While administration of ESAs may be beneficial for some RBC transfusion-dependent subjects, 
this therapy has no effect on thrombocytopenia.  Bone marrow transplantation is an option for only 
a subset of MDS patients that are good candidates for such an intensive procedure.  In addition, 
the outcomes of patients with lower-risk MDS are not improved by early introduction of allogeneic 
 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
stem cell transplantation (Cutler, 2004).  As a result, this treatment modality is recommended at 
the time of disease progression for lower-risk MDS patients.  No currently approved therapies have 
been shown to improve OS in lower-risk MDS patients with both RBC transfusion-dependent 
anemia and thrombocytopenia.
In addition to the absence of a demonstrated survival benefit in lower-risk MDS for currently 
approved therapies, other limitations include the association of clinically significant neutropenia 
and worsening thrombocytopenia in a high proportion of patients receiving parenteral azacitidine 
or decitabine, and the need for injections involving inconvenient drug product preparation and 
administration schedules for patients and health care providers.  The association of neutropenia 
with azacitidine is well established and dose-related, with the highest proportion of patients 
experiencing neutropenia in the first few cycles of treatment (Silverman, 2006; Lyons, 2009).  The 
requirement to receive SC or IV azacitidine for 7 consecutive days in a clinic or hospital setting 
often presents a challenge and may be a deterrent to patients who might otherwise benefit from 
treatment intervention before they develop higher-risk disease.  Even in higher-risk MDS or AML 
studies, clinical sites sometimes decline study participation due to the inconvenience of the 
preparation, administration, and treatment schedule requirements of azacitidine.  Injection and 
catheter site reactions for both azacitidine and decitabine can cause patient discomfort and 
morbidity.  In addition, SC administration of either agent can be problematic in subjects with 
thrombocytopenia.
An oral formulation of azacitidine provides an opportunity to deliver the drug at lower doses over 
a more prolonged schedule than can be practically achieved with parenteral therapy.  In addition, 
an oral formulation that can be taken at home rather than in the hospital/clinic setting represents 
an opportunity for subjects with lower-risk MDS disease to have a more convenient route of 
administration, thus alleviating the morbidity of injection and catheter-site reactions, and avoiding 
the inconvenience and resource utilization costs associated with frequent hospital/clinic visits.  In 
addition, intervention with azacitidine in lower-risk MDS subjects with both RBC transfusion-
dependent anemia and thrombocytopenia may offer better quality of life and possibly a survival 
advantage.
This study is randomized, double-blind, placebo-controlled, and parallel-group in order to 
eliminate bias in assignment of investigational product (IP) and data interpretation.  This will allow 
for a more accurate assessment of study endpoints and especially allow an improved assessment 
of OS according to blinded treatment assignment.  Placebo is the appropriate comparator, since 
the approved therapies available in some countries are not routinely used for treatment of lower-
risk disease.  Best supportive care in both treatment arms will include, but is not limited to RBC 
(packed red blood cell [pRBC] and whole blood) and platelet transfusions (single donor or pooled 
donor), antibiotic, antiviral and/or antifungal therapy, nutritional support as needed, and 
granulocyte colony stimulating factors for subjects experiencing neutropenic fever/infections.  
Best supportive care in this study excludes the use of ESAs and other hematopoietic growth factors
(granulocyte colony stimulating factors are allowed only for subjects experiencing neutropenic 
fever/infections as well as for secondary prophylaxis under certain conditions as described in 
Section 9.1) as these therapies are not approved for the treatment of MDS and do not increase 
 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
platelet counts in subjects with concomitant thrombocytopenia associated with their MDS.  ESAs 
are less effective for RBC transfusion-dependent anemia than for RBC transfusion-independent 
anemia (Hellstrom-Lindberg, 2003).  Thus the best supportive care for this study should minimize 
the risk of not providing subjects with appropriate care, while providing the potential benefit of 
achieving RBC transfusion independence and/or having improvement in platelet counts.  
Study Design
This is a phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study.  
The study consists of 3 phases: Screening, Double-blind treatment, and Follow-up.
Screening Phase
Subject screening procedures are to take place within 56 days prior to randomization.
Independent central review of bone marrow aspirate, biopsy and peripheral blood smear slides, 
central analysis of cytogenetics, central laboratory hematology result is used to confirm MDS 
disease and WHO classification (Appendix A) and to determine the IPSS risk classification 
(Appendix B).
RBC transfusion history must be available for the 56 days immediately preceding and including 
the date of randomization.  Transfusion data should include the type, number of units, reason and 
date of transfusion.  Transfusion data must include the hemoglobin (Hgb) value for which the 
transfusion was administered.  Hemoglobin (Hgb) levels at the time of or within 7 days prior to 
administration of an RBC transfusion must have been ≤ 10.0 g/dL in order for the transfusion to 
be counted towards RBC transfusion-dependent status.  Red blood cell transfusions administered 
when Hgb levels were > 10.0 g/dL will not qualify as a required transfusion for the purpose of 
providing evidence of RBC transfusion-dependent status.  In addition, any RBC transfusion 
administered for elective surgery will not qualify towards determination of RBC transfusion-
dependent status at baseline.  All RBC transfusion records for 56 days immediately preceding and 
including the date of randomization should be collected, regardless of Hgb levels.
RBC transfusion-dependent anemia at baseline is defined for this protocol as documentation of an 
average transfusion requirement of at least 2 units* of RBCs per 28 days during the 56 days 
immediately preceding and including the date of randomization.  There must not be any 
consecutive 28 days within the 56-day period during which no RBC transfusions were 
administered.
Platelet transfusion history, if applicable, must be available for the 56 days immediately preceding
and including the date of randomization.  Transfusion data should include the type, number of 
units, reason and date of transfusion. Transfusion data must include the platelet value for which 
the transfusion was administered.
Platelet transfusion dependence at baseline is defined for this protocol as at least 2 separate 
transfusion episodes during the 56 days immediately preceding and including the date of 
randomization.  There must not be any consecutive 28 days within the 56-day period during which 
                                                       
* As is consistent with medical practice in Japan, 1 unit RBC referenced in this protocol is equivalent to 2 units RBC in Japan.
 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
no platelet transfusion was administered.  In addition, any platelet transfusions administered for 
elective surgery will not qualify towards determination of platelet transfusion-dependent status at 
baseline.
Thrombocytopenia at baseline must be confirmed by two platelet counts that are ≤ 75 x 109/L and 
≥21 days apart.  The second confirmatory platelet count must be obtained ≤ 14 days prior to
randomization.  

At least one platelet count must be centrally analyzed within the 56 day screening 
period with results of ≤ 75 x 109/L; the second platelet count may be centrally or locally 
analyzed, with results that are also ≤ 75 x 109/L.  

Prior documented medical history of thrombocytopenia may be used to demonstrate 
eligibility for the study if at least one historical platelet count of ≤75 x 109/L was 
obtained within 56 days of randomization and ≥ 21 days apart from the centrally 
analyzed platelet count.

If additional platelet counts were obtained during the interim period, these must also 
have been ≤ 75 x 109/L. If platelet counts within the interim period are > 75 x 109/L, 
this would be acceptable only if directly associated with a platelet transfusion 
administered within 7 days prior to the date of the platelet count. 
Additional screening assessments include demographics and medical history, prior treatments for 
MDS (and other malignancy, if applicable), prior medications, physical examination, vital signs, 
weight and height measurements, Eastern Cooperative Oncology Group (ECOG) performance 
status (Appendix C), electrocardiogram (ECG), urinalysis, coagulation, Coombs’ test, reticulocyte 
count, serum erythropoietin (EPO) level, serum ferritin level, hematology, serum chemistry, 
pregnancy testing (females of childbearing potential [FCBP] only), 
 
  Adverse events (AEs) will be 
collected beginning on the date the informed consent is signed.
Randomization and Double-blind Treatment Phase
Following confirmation of eligibility at screening, subjects will be randomized 1:1 to receive oral 
azacitidine or placebo 300 mg once a day (QD) for 21 days.  Randomization will occur by a central 
randomization procedure using Interactive Response Technology (IRT).  Subjects will be stratified 
based on average baseline RBC transfusion requirement (≤4 units† versus > 4 units of RBC per 
28 days), baseline platelet transfusion status (dependent or independent), country of enrollment 
(ie, Japan versus Rest of World [ROW]) and ECOG performance status (0 to 1 versus 2).  The 
stratification on country of enrollment is due to the different transfusion treatment practices in 
Japan versus those in other countries.
The first dose of IP should be administered within 3 days of Randomization and can be on the 
same day of randomization.  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 (oral azacitidine or placebo) once a day on the first 21 days of each 28-day cycle (see 
                                                       
† As is consistent with medical practice in Japan, 1 unit RBC referenced in this protocol is equivalent to 2 units RBC in Japan.
 
 
 
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CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
Section 8.2.2 for details).  Dose modifications may occur for managing toxicity if necessary during 
treatment (see Section 8.2.4 for details).
During the double-blind treatment phase, subjects will be assessed continuously for safety and 
efficacy.  Assessments during the double-blind treatment phase will include AEs, monitoring for 
progression to AML and second primary malignancy, 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, transfusions 
administered, clinically significant bleeding events, central review of bone marrow aspirate (or 
biopsy if adequate aspirate is not attainable) and peripheral blood smear slides, cytogenetic
analysis, assessing hematologic response/improvement (International Working Group [IWG] 2006 
criteria; Cheson, 2006; Appendix D), disease status assessment, 
 
 
IP administration and accountability, HRQoL, and healthcare resource utilization.
Disease Status Assessment
Because a hematologic response to treatment with azacitidine may frequently be delayed, it is 
recommended that subjects receive at least 6 cycles of treatment with IP; however, subjects may 
be discontinued from treatment at the investigator’s discretion prior to reaching the recommended 
minimum number of cycles for any of the reasons detailed in Section 12.  Subjects will be assessed 
for disease status at the end of Cycle 6, prior to starting Cycle 7.

If subjects have met any of the following criteria, subjects can continue on to Cycle 7 
and beyond, and will be assessed for disease status at the end of every cycle:
o
RBC transfusion independence, or
o
platelet transfusion-independence for those subjects who were platelet 
transfusion dependent at baseline, or
o
Hematologic Improvement (HI; Cheson, 2006; Appendix D), or
o
≥ 50% reduction in average RBC transfusion requirement in the 56-day (8-
week) period immediately prior to disease status assessment as compared to the 
average baseline RBC transfusion requirement, or
o
any other clinical benefit, including no evidence of progressive disease (see 
Section 12 for definitions of progressive disease).
Thereafter, subjects may be discontinued from protocol-prescribed therapy for any of 
the reasons detailed in Section 12.

If subjects have failed to meet any of the above criteria at the end of Cycle 6, subjects
will be discontinued from protocol-prescribed therapy.
The decision to discontinue a subject, which will not be delayed or refused by the sponsor, remains 
the responsibility of the treating physician.  However, prior to discontinuing a subject, the 
investigator may contact the Medical Monitor and forward appropriate supporting documents for 
review and discussion.
All subjects who have received at least one dose of IP should undergo Treatment Discontinuation 
procedures (Section 6.13) when treatment is discontinued.
 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
The reason for discontinuation will be recorded in the case report form (CRF) and in the source 
document for all randomized subjects, regardless of whether they are dosed or not.
Follow-up Phase
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 
period is longer, for the collection of AEs, concomitant medications, therapies and procedures, 
transfusions administered 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, subsequent MDS therapies, progression to AML and second primary malignancy
every month for the first year following Treatment Discontinuation and every three months 
thereafter until death, lost to follow-up, or withdrawal of consent for further data collection.
Extension Phase
At the Investigator’s discretion and following confirmation of eligibility criteria below, subjects 
can enter the Extension Phase (EP):
Eligible Criteria:

Subjects who have signed the informed consent for the EP of the study;

Subjects randomized to the 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 the 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 Follow-up Phase, after permanent study treatment 
discontinuation, will continue to be followed for survival in the EP;

Subjects who do not meet any of the criteria for study discontinuation (see Section 12).
Details for the EP are provided in Appendix J.
Study Population
The study is closed to further enrollment, and at the time of this amendment, 216 subjects with 
IPSS lower-risk MDS and associated RBC transfusion-dependent anemia and thrombocytopenia 
(platelet count ≤ 75 x 109/L) have been enrolled.  Prior treatment with a hypomethylating agent or 
stem cell transplant is prohibited.  Subjects must have had ECOG performance status of 0, 1 or 2,
and adequate renal and liver function (Section 7).
Length of Study
The expected duration of the study is 134 months, including a 56-month enrollment followed by 
78 months of subject treatment and/or observation, including EP. The study is planned to conclude 
78 months after the last subject is randomized.
 
 
 
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CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
Study Treatments
Oral Azacitidine/Placebo
Subjects will be randomized 1:1 to receive 300 mg oral azacitidine or placebo QD for the first 21 
days of each 28-day treatment cycle.  Subjects can continue to receive additional cycles of 
protocol-prescribed therapy provided that all protocol-specified treatment criteria are met (see 
Section 8.2.5). As of Amendment 3.0, all subjects in Cycles 1 or 2 will receive CC-486 for 14 days 
of a 28-day cycle schedule.  Subjects may increase to a 21-day schedule at the conclusion of Cycle 
2 if there are no Grade 3 or 4 toxicities requiring dose delay or reductions and if there is no evidence 
of hematological improvement upon discussion and agreement between the investigator and the 
Medical Monitor.  Subjects remaining beyond Cycle 2 will continue to receive 300 mg oral 
azacitidine or matching placebo QD for 21 days of each 28-day treatment cycle.
Best Supportive Care may be used in combination with study treatment as deemed necessary.  Best 
supportive care includes, but is not limited to, treatment with RBC transfusions (pRBC or whole 
blood), single donor or pooled donor platelet transfusions, antibiotic, antiviral and/or antifungal 
therapy, nutritional support as needed, and granulocyte colony stimulating factors for subjects 
experiencing neutropenic fever/infections (Section 9.1).  Best supportive care for this study 
excludes the use of ESAs and other hematopoietic growth factors (granulocyte colony stimulating 
factors are allowed only for subjects experiencing neutropenic fever/infections as well as for 
secondary prophylaxis under certain conditions as described in Section 9.1).
Overview of Efficacy Assessments
The primary efficacy endpoint is the proportion of subjects in the overall population achieving 
RBC transfusion independence with a duration of ≥ 56 days (8 weeks). Red blood cell transfusions 
administered during the 56 days immediately preceding and including the date of randomization
will be used to establish baseline requirements. Red blood cell transfusions administered during 
the treatment period will be used in the efficacy analysis. Red blood cell transfusions administered 
for elective surgery will not be counted towards baseline requirements, efficacy analysis, or 
progressive disease status.
Secondary efficacy endpoints include OS, HI-P, proportion of subjects in the overall population 
achieving RBC transfusion independence with duration of ≥ 84 days (12 weeks), duration of RBC 
transfusion independence, [≥ 84 days (12 weeks) and ≥ 56 days (8 weeks)], time to RBC 
transfusion independence [≥ 84 days (12 weeks) and ≥ 56 days (8 weeks)], the proportion of 
subject progressing to AML, time to AML progression, HI-E (IWG 2006 criteria; Cheson, 2006; 
Appendix D), duration of RBC transfusion reduction, the proportion of platelet transfusion-
dependent subjects at baseline achieving platelet transfusion independence with duration ≥ 56 days 
(8 weeks), duration of platelet transfusion independence, time to platelet transfusion independence, 
hematologic response (IWG 2006 criteria; Cheson, 2006; Appendix D), and the proportion of 
subjects experiencing clinically significant bleeding events.
Platelet transfusions administered during the 56 days immediately preceding and including the 
date of randomization will be used to establish baseline requirements. Platelet transfusions 
administered during the treatment period will be used in the efficacy analysis. Platelet transfusions 
 
 
 
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administered for elective surgery will not be counted towards baseline requirements, efficacy 
analysis or progressive disease status.
Overview of Safety Assessments
Safety assessments include AEs, monitoring for progression to AML and second primary 
malignancy, physical examination, vital signs and body weight measurement, ECOG performance 
status, hematology (complete blood count [CBC] with white blood cell [WBC] differential and 
platelets) and serum chemistry, serum ferritin level, and concomitant medications, therapies and 
procedures, and pregnancy testing (for FCBP subjects only). Electrocardiogram, urinalysis and 
coagulation testing will be repeated as clinically indicated during the double-blind treatment phase.
Progression to AML and development of second primary malignancies will be monitored as events 
of interest and should be included as part of the assessment of AEs throughout the course of the 
study. Investigators are to report progression to AML and any second primary malignancies as 
serious adverse events (SAEs) 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 Informed Consent 
Document (ICD) until death, lost to follow-up, or withdrawal of consent for further data collection.
Overview of Health-Related Quality of Life and Healthcare Resource Utilization 
Assessments
Health-related quality of life assessment will be based on the Functional Assessment of Cancer 
Therapy-Anemia (FACT-An; Cella, 1997; Appendix E) and EuroQoL Group EQ-5D (EQ-5D-3L) 
instruments (Rabin, 2001; Appendix F). Healthcare resource utilization data, including, but not 
limited to hospitalization information, diagnostic procedures and treatment intervention not 
requiring hospitalization, or for treatment-related adverse events, and resource use associated with 
treatment administration for MDS will be collected through specially designed case report forms 
and/or through routine study activities.
 
 
 
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Analysis and Reporting
All efficacy analyses will be performed on the intent-to-treat (ITT) population. All safety analyses 
will be performed on the safety population.
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 RBC transfusion independence and the key secondary endpoint of OS, 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 
RBC transfusion independence and OS endpoints, formal statistical inference for the OS analyses 
can only be made if superiority of azacitidine is demonstrated for the primary efficacy endpoint, 
RBC transfusion independence, at the two-sided 0.05 significance level.  
The primary efficacy endpoint, RBC transfusion independence, will be analyzed and reported only 
once after all 100% of the information is available for RBC transfusion independence rates (ie, 
after all 216 subjects have completed 12 months (52 weeks [364 days]) of double-blind treatment 
or have been discontinued from treatment). An analysis of the OS endpoint will also be conducted 
at the time of the analysis of the primary efficacy endpoint. This analysis of the OS endpoint may 
be an interim analysis or it may be the final analysis, depending on the maturity of the survival 
data (e.g. the required 205 deaths have occurred) at the time of the final analysis for the RBC 
transfusion independence endpoint. An O’Brien-Fleming group sequential type boundary will be 
used to preserve the overall alpha level of 0.05 for the analysis of OS in the event that OS is 
analyzed twice.  
The remaining secondary efficacy variables, with the exception of the proportion of subjects 
progressing to AML and time to AML progression, will be analyzed and reported once at the time
of the analysis of RBC transfusion independence. Subjects will continue to be followed for 
progression to AML and survival until 205 deaths have been observed. Other than the pre-specified 
sequential testing of RBC transfusion independence and OS, no additional alpha adjustments for 
multiplicity will be made.  
Study Closure
The study will conclude once all subjects have completed or discontinued from the extension
phase. 
 
 
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Pathology Review
An independent central pathology reviewer will review slides of bone marrow aspirate, bone 
marrow biopsy and peripheral blood smear, and applicable central laboratory results prior to 
randomization to confirm MDS diagnosis and WHO classification. If the central pathology 
reviewer and local pathologist disagree on the diagnosis of a subject, a third party reviewer will 
adjudicate and make the final assessment. For these cases the third party reviewer’s assessment 
will be used for the statistical analyses.  
The independent central pathology reviewer will also assess bone marrow aspirates, biopsies (if 
adequate aspirate is not attainable), peripheral blood smears and applicable central laboratory 
results during the study.
Cytogenetics Review
An independent cytogeneticist will conduct cytogenetic analysis throughout the study. The 
independent central cytogenetic review will provide standardized analysis and reporting for all 
subjects. The independent central cytogenetic review results will be used for the statistical 
analyses.
Data Monitoring Committee
An independent Data Monitoring Committee (DMC) with multidisciplinary representation will 
evaluate safety during the course of the study in compliance with a prospective charter. The DMC 
will be comprised of medical oncologists/hematologists with experience treating MDS and a 
statistician, all of whom are not otherwise involved in the study as investigators. An independent 
statistician will generate critical safety reports for the DMC to review periodically. The DMC 
chairperson may convene formal DMC meetings if there are safety concerns. The sponsor can also 
request a DMC review of safety data. The sponsor will not have access to the unblinded data. The 
DMC responsibilities, authorities, and procedures will be detailed in the DMC charter which will 
be endorsed and signed by DMC members before the first data review meeting.
 
 
 
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 6.0: ........................... 
SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 6.0 ........................ 
PROTOCOL SUMMARY ............................................................................................ 
TABLE OF CONTENTS .............................................................................................. 
LIST OF TABLES ........................................................................................................ 
LIST OF FIGURES ...................................................................................................... 
1 INTRODUCTION ..................................................................................................... 
1.1 Myelodysplastic Syndromes ............................................................................. 
1.2 Azacitidine ........................................................................................................ 
1.3 Study Rationale ................................................................................................. 
1.4 Risk/Benefit Assessment .................................................................................. 
1.4.1 Risk Assessment ....................................................................................... 
1.4.2 Benefit Assessment ................................................................................... 
1.4.3 Overall Benefit Risk Conclusion .............................................................. 
2 STUDY OBJECTIVES .............................................................................................. 
2.1 Primary Objective ............................................................................................. 
2.2 Secondary Objectives........................................................................................ 
 
3 STUDY ENDPOINTS ............................................................................................... 
3.1 Primary Endpoint(s) .......................................................................................... 
3.2 Secondary Endpoint(s) ...................................................................................... 
 
4 OVERALL STUDY DESIGN ................................................................................... 
4.1 Study Design ..................................................................................................... 
4.1.1 Screening Phase ....................................................................................... 
4.1.2 Randomization and Double-blind Treatment Phase ................................ 
4.1.3 Follow-up Phase ...................................................................................... 
4.1.4 Extension Phase ....................................................................................... 
4.1.5 Study Closure ........................................................................................... 
4.1.6 Data Monitoring Committee .................................................................... 
4.2 Study Design Rationale ..................................................................................... 
4.3 Study Duration .................................................................................................. 
5 TABLE OF EVENTS ................................................................................................ 
6 PROCEDURES.......................................................................................................... 
6.1 Screening........................................................................................................... 
6.1.1 MDS Diagnosis, WHO Classification, and IPSS Risk Classification ...... 
6.1.2 RBC and Platelet Transfusion History .................................................... 
6.1.3 Thrombocytopenia History ...................................................................... 
6.1.4 Demographics and Medical History ........................................................ 
6.1.5 Prior Medications and MDS Treatments ................................................. 
6.1.6 Physical Examination .............................................................................. 
6.1.7 Vital Signs, Body Weight and Height Measurements .............................. 
6.1.8 Eastern Cooperative Oncology Group Performance Status .................... 
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6.1.9 Electrocardiogram ................................................................................... 
 
6.1.10 Urinalysis ............................................................................................... 
 
6.1.11 Coagulation............................................................................................ 
 
6.1.12 Coombs’ Test ......................................................................................... 
 
6.1.13 Reticulocyte Count ................................................................................. 
 
6.1.14 Serum EPO Level ................................................................................... 
 
6.1.15 Serum Ferritin ........................................................................................ 
 
6.1.16 Serum Transferrin Saturation ................................................................ 
 
6.1.17 Hematology ............................................................................................ 
 
6.1.18 Serum Chemistry .................................................................................... 
 
6.1.19 Pregnancy Testing ................................................................................. 
 
 
 
6.2 Information to be Collected on Screening Failures .......................................... 
 
6.3 Entering a Subject Into the Study ..................................................................... 
 
6.4 Baseline ............................................................................................................. 
 
6.5 Treatments ......................................................................................................... 
 
6.6 Safety ................................................................................................................ 
 
6.6.1 Adverse Events ......................................................................................... 
 
6.6.2 Progression to AML and Second Primary Malignancies ........................ 
 
6.6.3 Physical Examination, Vital Signs and Weight........................................ 
 
6.6.4 Urinalysis, 12-Lead Electrocardiogram or Coagulation ........................ 
 
6.6.5 Hematology and Serum Chemistry Laboratory Evaluations ................... 
 
6.6.6 Serum Ferritin .......................................................................................... 
 
6.6.7 Pregnancy Test......................................................................................... 
 
6.6.8 Concomitant Medications/Significant Non-drug Therapies/Concomitant 
Procedures .................................................................................................. 
 
6.6.9 Eastern Cooperative Oncology Group Performance Status .................... 
 
6.7 Efficacy ............................................................................................................. 
 
6.7.1 Transfusion Assessment ........................................................................... 
 
6.7.2 Assessment of Bleeding Events ................................................................ 
 
6.7.3 Bone Marrow Aspirate, Biopsy and Peripheral Blood Smear ................. 
 
6.7.4 Cytogenetics ............................................................................................. 
 
6.7.5 International Working Group Response/Improvement ............................ 
 
6.7.6 Disease Status Assessment ....................................................................... 
 
6.7.7 Serum EPO Level ..................................................................................... 
 
6.7.8 Progression to AML ................................................................................. 
 
6.7.9 Survival and Subsequent MDS Therapies ................................................ 
 
6.8 Health-related Quality of Life ........................................................................... 
 
6.9 Healthcare Resource Utilization ....................................................................... 
 
 
 
 
 
 
 
 
 
6.12 Unscheduled Visits ......................................................................................... 
 
6.13 Discontinuation ............................................................................................... 
 
6.14 Follow-up ........................................................................................................ 
 
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6.15 Extension Phase .............................................................................................. 
 
7 STUDY POPULATION ............................................................................................ 
 
7.1 Number of Subjects and Sites ........................................................................... 
 
7.2 Inclusion Criteria .............................................................................................. 
 
7.3 Exclusion Criteria ............................................................................................. 
 
8 DESCRIPTION OF STUDY TREATMENTS .......................................................... 
 
8.1 Description of Investigational Product(s) ......................................................... 
 
8.1.1 Azacitidine and Placebo .......................................................................... 
 
8.2 Treatment Administration and Schedule .......................................................... 
 
8.2.1 Investigational Product Dispensation...................................................... 
 
8.2.2 Investigational Product Administration ................................................... 
 
8.2.3 Missing Doses .......................................................................................... 
 
8.2.4 Dose Modifications .................................................................................. 
 
8.2.5 Re-treatment Criteria ............................................................................... 
 
8.3 Method of Treatment Assignment .................................................................... 
 
8.4 Packaging and Labeling .................................................................................... 
 
8.5 Clinical Supplies ............................................................................................... 
 
8.6 Investigational Product Accountability and Disposal ....................................... 
 
8.7 Investigational Product Compliance ................................................................. 
 
8.8 Blinding............................................................................................................. 
 
8.9 Emergency Unblinding ..................................................................................... 
 
9 CONCOMITANT MEDICATIONS AND PROCEDURES ..................................... 
 
9.1 Permitted Concomitant Medications and Procedures ....................................... 
 
9.2 Prohibited Concomitant Medications and Procedures ...................................... 
 
9.3 Required Concomitant Medications and Procedures ........................................ 
 
10 STATISTICAL ANALYSES .................................................................................. 
 
10.1 Overview ......................................................................................................... 
 
10.2 Study Population Definitions .......................................................................... 
 
10.2.1 Intent-to-Treat Population ..................................................................... 
 
10.2.2 Modified Intent-to-Treat Population...................................................... 
 
10.2.3 Safety Population ................................................................................... 
 
10.3 Sample Size and Power Considerations .......................................................... 
 
10.4 Background and Demographic Characteristics ............................................... 
 
10.5 Subject Disposition ......................................................................................... 
 
10.6 Efficacy Analysis ............................................................................................ 
 
10.6.1 Primary Efficacy Analysis...................................................................... 
 
10.6.2 Secondary Efficacy Analyses ................................................................. 
 
10.6.2.1 Key Secondary Efficacy Analyses ................................................. 
 
10.6.2.2 Additional Secondary Efficacy Analyses ...................................... 
 
10.6.2.3 Exploratory Efficacy Analyses ...................................................... 
 
10.7 Safety Analysis ............................................................................................... 
 
10.8 Interim Analysis .............................................................................................. 
 
10.9 Other Analyses ................................................................................................ 
 
10.9.1 Health-related Quality-of-life ................................................................ 
 
10.9.2 Healthcare Resource Utilization ............................................................ 
 
 
 
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10.10 Other Topics .................................................................................................. 
 
11 ADVERSE EVENTS ............................................................................................... 
 
11.1 Monitoring, Recording and Reporting of Adverse Events ............................. 
 
11.2 Evaluation of Adverse Events ......................................................................... 
 
11.2.1 Seriousness ............................................................................................. 
 
11.2.2 Severity / Intensity .................................................................................. 
 
11.2.3 Causality ................................................................................................ 
 
11.2.4 Duration ................................................................................................. 
 
11.2.5 Action Taken .......................................................................................... 
 
11.2.6 Outcome ................................................................................................. 
 
11.3 Abnormal Laboratory Values ......................................................................... 
 
11.4 Pregnancy ........................................................................................................ 
 
11.4.1 Females of Childbearing Potential ........................................................ 
 
11.4.2 Male Subjects ......................................................................................... 
 
11.5 Reporting of Serious Adverse Events ............................................................. 
 
11.5.1 Safety Queries ........................................................................................ 
 
11.6 Expedited Reporting of Adverse Events ......................................................... 
 
12 DISCONTINUATIONS .......................................................................................... 
 
13 EMERGENCY PROCEDURES .............................................................................. 
 
13.1 Emergency Contact ......................................................................................... 
 
13.2 Emergency Identification of Investigational Products .................................... 
 
14 REGULATORY CONSIDERATIONS ................................................................... 
 
14.1 Good Clinical Practice .................................................................................... 
 
14.2 Investigator Responsibilities ........................................................................... 
 
14.3 Subject Information and Informed Consent .................................................... 
 
14.4 Confidentiality ................................................................................................ 
 
14.5 Protocol Amendments ..................................................................................... 
 
14.6 Institutional Review Board/Independent Ethics Committee Review and 
Approval ........................................................................................................... 
 
14.7 Ongoing Information for Institutional Review Board / Ethics Committee ..... 
 
14.8 Closure of the Study........................................................................................ 
 
15 DATA HANDLING AND RECORDKEEPING .................................................... 
 
15.1 Data/Documents .............................................................................................. 
 
15.2 Data Management ........................................................................................... 
 
15.3 Record Retention ............................................................................................ 
 
16 QUALITY CONTROL AND QUALITY ASSURANCE ....................................... 
 
16.1 Study Monitoring and Source Data Verification ............................................ 
 
16.2 Audits and Inspections .................................................................................... 
 
17 PUBLICATIONS ..................................................................................................... 
 
18 REFERENCES ........................................................................................................ 
 
19 APPENDICES ......................................................................................................... 
 
APPENDIX A MYELODYSPLASTIC SYNDROMES WORLD HEALTH 
ORGANIZATION CLASSIFICATION SYSTEM ................................................ 
 
APPENDIX B INTERNATIONAL PROGNOSTIC SCORING SYSTEM SCORE .. 
 
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APPENDIX C EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS ................................................................................... 
 
APPENDIX D HEMATOLOGIC RESPONSE AND IMPROVEMENT 
ACCORDING TO THE INTERNATIONAL WORKING GROUP FOR 
MYELODYSPLASTIC SYNDROMES ................................................................ 
 
APPENDIX E FACT-AN (VERSION 4) ..................................................................... 
 
APPENDIX F EQ-5D HEALTH QUESTIONNAIRES (EQ-5D-3L; ENGLISH 
VERSION FOR THE US) ...................................................................................... 
 
APPENDIX G NEW YORK HEART ASSOCIATION CLASSIFICATION FOR 
CONGESTIVE HEART FAILURE ....................................................................... 
 
APPENDIX H RECOMMENDATIONS FOR MANAGEMENT OF TREATMENT-
INDUCED DIARRHEA ......................................................................................... 
 
APPENDIX I LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........ 
 
APPENDIX J EXTENSION PHASE ........................................................................... 
 
 
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LIST OF TABLES 
 
 
Table 1: Table of Events ............................................................................................... 
 
Table 2: Guidelines for Dose Modifications ................................................................. 
 
Table 3: Definitions of Progressive Disease for Clinical Decision on Discontinuing 
Subjects from the Investigational Product and/or from the Study .......................... 
 
 
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LIST OF FIGURES 
 
 
Figure 1: Overall Study Design .................................................................................... 
 
Figure 2: Decision Tree for Hematologic Recovery ..................................................... 
 
 
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1
INTRODUCTION 
1.1
Myelodysplastic Syndromes
Myelodysplastic syndromes (MDS) is an umbrella term that encompasses a heterogeneous 
collection of hematopoietic stem cell disorders primarily affecting older adults.  MDS is typically 
characterized by bone marrow hyperplasia and peripheral cytopenias that manifest clinically as 
anemia, neutropenia and/or thrombocytopenia of variable frequency and severity, with symptoms 
of anemia being the most frequent presenting manifestation.  Anemia is the most frequent 
laboratory finding and it often progresses to red blood cell (RBC) transfusion dependence.  Other 
less common presenting clinical features related to the cytopenias are an increased risk of infection 
and/or hemorrhage, and a potential to progress to acute myeloid leukemia (AML) (Catenacci, 
2005).  The latter clinical features will often evolve over the ensuing follow up of these patients.
MDS is classified according to World Health Organization (WHO) criteria by pathologic features 
on bone marrow examination (Brunning, 2008; Vardiman, 2009; Appendix A).  MDS is also 
categorized into one of 4 prognostic groups (Low, Intermediate-1 [INT-1], Intermediate-2 [INT-
2], and High risk) according to the International Prognostic Scoring System (IPSS) based on 
cytogenetic features, number of cytopenias and bone marrow blast percentages (Greenberg, 1997; 
Appendix B).  Overall survival and risk of progression to AML is significantly different in the 4 
risk groups (Greenberg, 1997).  The low and INT-1 groups tend to have a better prognosis than do 
subjects with INT-2 or High risk disease, with the median survival for patients in these risk groups 
being 5.7 years (low), 3.5 years (INT-1), 1.2 years (INT-2) and 0.4 years (High) (Greenberg, 1997).  
The median time for 25% of patients to progress to AML is 9.4, 3.3, 1.1, and 0.2 years, 
respectively, in the Low, INT-1, INT-2 and High risk groups (Greenberg, 1997).
For patients with lower-risk disease (IPSS low or INT-1), refractory anemia remains the primary 
clinical issue.  The development of RBC transfusion dependence significantly worsens the survival 
of patients with MDS and increases the propensity to develop AML (Malcovati, 2005).  In addition, 
long-term RBC transfusion dependence has other clinical and economic consequences, including 
a potentially negative impact on health-related quality of life (HRQoL) (Hellstrom-Lindberg, 
2003; Jansen, 2003; Thomas, 2007) and iron overload, as well as a number of immune related 
disorders and increased risks related to various infections.
Thrombocytopenia is an independent prognostic factor for survival in MDS and increased severity 
of thrombocytopenia correlates with shorter time to AML progression (Kantarjian, 2008; Kao, 
2008).  While thrombocytopenia is more prevalent in the INT-2 and High risk groups, at least one 
study has shown that as many as 50% of MDS patients classified as lower-risk are
thrombocytopenic (Garcia-Manero, 2008a).  In this study of 856 patients with lower-risk disease, 
thrombocytopenia significantly influenced survival.  Median OS was 
 
 22.4 months in those with platelet counts 50 to 99 x 109/L, 27.1 
months in those with platelet counts 100 to 199 x 109/L, and 48.1 months in patients with platelet 
counts ≥ 200 x 109/L.  
 
 
 
 
 
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These findings were confirmed in 2 additional retrospective studies that reported median overall 
survival rates between 0.9 and 
(Cruz, 2010; Yong, 2010).
 
 
  Thus, the presence of thrombocytopenia (ie, 
platelets 
in patients with lower-risk MDS has significant influence on survival.  
Furthermore, median survival would be further negatively influenced in this population, in that 
most patients have concurrent RBC transfusion dependence.  Age also plays a significant role in 
the prognosis of this patient population.  If age is ≥ 60 years and thrombocytopenia and anemia 
are both present, median survival would be expected to be 14 months, with only 9% surviving 
beyond 4 years (Garcia-Manero, 2008a).  
The mainstay of therapy in lower-risk MDS has been supportive care, which includes the use of 
RBC and/or platelet transfusions, treatment of infections, and the use of erythropoiesis stimulating 
agents (ESAs) such as epoetin alfa or darbepoietin, plus hematopoietic growth factors such as 
granulocyte colony-stimulating factor (G-CSF) when needed (National Comprehensive Cancer 
Network [NCCN], 2011; Silverman, 2000; Lübbert, 2000). Neither ESAs nor myeloid growth 
factors are approved for the treatment of MDS.  Furthermore, ESAs do not increase platelet counts 
in patients with concomitant thrombocytopenia associated with their MDS.  Lenalidomide is the 
standard of care in those countries where it is approved for the proportion of lower-risk MDS 
patients with deletion (5q) in patients with RBC transfusion dependence.  Therapy with 
lenalidomide is frequently associated with the development of thrombocytopenia, and it is thus not 
recommended for use in patients who have platelet counts below 50 x 109/L (Revlimid® US 
Prescribing Information).  There are limited available effective therapies for MDS patients with 
thrombocytopenia other than transfusion of platelets.  Platelet transfusions may not be effective in 
a number of patients, especially when transfusions are required frequently, as patients can become 
refractory (Hod, 2008).  Failure to respond to platelet transfusions may be related to immune and 
non-immune causes.  Common immune causes are development of alloimmune reactions to 
platelets, and thus transfused platelets are rapidly removed and destroyed by preformed antibodies 
to various platelet associated antigens.  A significant proportion of patients with thrombocytopenia 
do become refractory to platelet transfusions, often with development of more thrombocytopenia.  
Platelet transfusions are also associated with serious transfusion reactions, including Transfusion 
Related Lung Injury (TRALI) and transmission of a number of infectious agents that may lead to 
fatal outcomes (Silliman, 2009; Hillyer, 2003).
Allogeneic bone marrow transplantation has been effective, both in patients under the age of 
50 years and in those older than 50 years who are in good health and who have suitable human 
leukocyte antigen (HLA) matched donors.  However, this approach has limited value, since most 
patients with MDS are older than 65 years of age and have significant comorbidities that preclude 
the use of this modality as it is associated with a high morbidity and mortality rate (NCCN, 2011).  
In addition, the outcome of patients with lower-risk MDS is not improved by early introduction of 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
allogeneic stem cell transplantation (Cutler, 2004).  As a result, this treatment modality is 
recommended at the time of disease progression for lower-risk MDS patients.
1.2
Azacitidine
Azacitidine (Vidaza®) is an analog of the naturally occurring pyrimidine nucleoside cytidine and 
is classified as an antimetabolite.  In the United States (US), azacitidine (Vidaza®) is approved for 
the treatment of all 5 French-American-British (FAB) classification subtypes of MDS: refractory 
anemia (RA) or refractory anemia with ringed sideroblasts (RARS) (if accompanied by 
neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts 
(RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and chronic 
myelomonocytic leukemia (CMML), but it is not routinely utilized in the lower-risk disease 
setting.  Azacitidine is approved in the European Union (EU) for the treatment of adult patients 
who are not eligible for hematopoietic stem cell transplantation with IPSS INT-2 or High risk 
MDS, CMML with 10% to 29% marrow blasts without myeloproliferative disorder and AML with 
20% to 30% blasts and multi-lineage dysplasia, according to WHO classification.  In addition to 
the US and EU, azacitidine is currently approved in 30 other countries, including Canada, 
Switzerland, Australia and Japan, for the treatment of MDS (approvals for specific subtypes vary 
by country).  Current approved routes of administration include subcutaneous SC and intravenous 
IV (approvals vary by country).  Similarly, decitabine (Dacogen), another hypomethylating 
agent, is approved in the US for treatment of all FAB classification subtypes and IPSS INT-1, INT-
2 and High risk MDS.
Azacitidine has strong in vitro and in vivo anti-leukemic activity and the ability to induce 
differentiation at lower concentrations in hematopoietic and non-hematopoietic cell lines.  The 
effects of azacitidine may result from multiple mechanisms, including inhibition of
deoxyribonucleic acid (DNA), ribonucleic acid (RNA) and protein synthesis, incorporation into 
RNA and DNA, and activation of DNA damage pathways.  The ability of azacitidine to cause 
differentiation can be attributed to its activity as a hypomethylating agent.  The degree of 
methylation of cytosine residues in DNA has been demonstrated to play a role in gene expression.  
Indeed, hypermethylation of cytosine residues of genes critical to ensure orderly cell proliferation 
and maturation (differentiation) is frequently found in primary neoplasms and tumor cell lines 
(Zingg, 1997).  Therefore, use of an inhibitor of DNA methylation, such as azacitidine, would be 
a rational approach to revert these epigenetic aberrations in the malignant clone and to re-establish 
the antiproliferative signals that were extinguished by hypermethylation.  Preliminary data from 
the AZA-PH-GL-2003-CL-001 survival study with azacitidine in higher-risk MDS patients found, 
from analysis of pre-treatment bone marrow methylation density, that the overall survival benefit 
observed with azacitidine versus conventional care regimens (CCR) was independent of 
methylation status of the 5 genes analyzed (CDKN2B [p15], SOCS1, CDH1 [E-cadherin], TP73, 
and CTNNA1 [α-catenin]).  However, increasing methylation was associated with worse overall 
survival.  Patients with lower levels of methylation treated with azacitidine had the best overall 
survival, suggesting they may derive greater benefit from azacitidine.
Azacitidine has been extensively studied in MDS and has been shown in a large, randomized Phase 
3 trial of higher-risk MDS patients to provide a survival advantage of 9.4 months over CCR.  The 
 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
median overall survival of azacitidine-treated patients was 24.5 months compared with 15.0 
months for the CCR group, which included best supportive care, low-dose cytarabine, or intensive 
chemotherapy (Fenaux, 2009).  The clinical experience with azacitidine in AML is smaller, but 
positive efficacy results have been obtained.  In a subset of 113 patients with WHO-defined AML 
(mean age 70 years, 24% with unfavorable karyotype, median bone marrow blasts 23%) from the 
larger MDS study discussed above, the median overall survival was 24.5 months (n=55) in the 
azacitidine arm compared with 16.0 months (n=58) in the CCR arm (Fenaux, 2008).  Additionally, 
the outcome was not significantly different in patients with an unfavorable karyotype, although 
the sample size was small.  Silverman et al, using WHO-defined AML criteria for diagnosis, 
reported a median overall survival of 19.3 months (n=27) in azacitidine treated patients compared 
with 12.9 months (n=25) in patients who received best supportive care (Silverman, 2006).  
Additionally, Goldberg et al, reported on 33 patients who received azacitidine (n=11, median age 
74) or 7 +3 intensive chemotherapy (n=22, median age 67 years) (Goldberg, 2006).  Median blast 
count at baseline was 42% in the azacitidine group and 65% in the intensive chemotherapy group.  
The median overall survival was 13.2 months in azacitidine-treated patients compared with 9.2 
months in patients receiving intensive chemotherapy (Goldberg, 2006).  All of the above 
mentioned studies used the standard azacitidine dose of 75 mg/m2/day for 7 days.
Patients with lower-risk MDS have also been evaluated for response to therapy with azacitidine.  
In a retrospective study of 74 patients enrolled in an Italian named patient program, 77% of 
responses observed occurred within the first 6 cycles; most patients achieved their best response 
between the fourth and sixth cycle of treatment (Musto, 2010).  Most responses to azacitidine occur 
upon completion of 6 cycles of treatment, but responses may still occur beyond completion of 6 
courses (Silverman, 2006; Musto, 2010).  Elderly patients (>70 years of age) respond as well as 
younger patients, and failure to respond to prior ESA therapy does not preclude possible responses 
to azacitidine (Musto, 2010).
Overall response rates in lower-risk MDS subjects have been 
reported as approximately 50% in various studies (Silverman, 2002; Grinblatt, 2008; Lyons, 2009; 
Musto, 2010). 
There is minimal direct evidence available to indicate that treatment with 
azacitidine in the lower-risk disease setting improves survival.  However, in the study conducted 
by Musto et al, a favorable trend toward improved overall survival (OS) was observed in the lower-
risk MDS patients who responded to treatment with azacitidine (Musto, 2010).
An oral formulation of azacitidine has been evaluated in 3 clinical studies to date.  Results from a 
pilot study (AZA PH US 2007 PK 004) indicated that azacitidine in an oral formulation was 
bioavailable (Garcia-Manero, 2008b).  This was confirmed when evaluating several different 
formulations of the drug in a Phase 1 study (AZA PH US 2008 CL 008).  Results from another 
Phase 1 study of oral azacitidine in subjects with MDS, CMML, or AML (AZA PH US 2007 CL 
005) indicated that administration on different treatment schedules (7-, 14-, and 21-day once a day 
[QD], and 14- and 21-day twice a day [BID]) was feasible, generally well-tolerated, and exhibited 
biologic and clinical activity (Garcia-Manero, 2009; Garcia-Manero, 2010).
1.3
Study Rationale
This clinical study will evaluate the efficacy and safety of oral azacitidine plus best supportive 
care versus placebo and best supportive care in subjects with RBC transfusion-dependent anemia 
 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
and thrombocytopenia due to lower-risk MDS.  The primary endpoint is the proportion of subjects 
achieving RBC transfusion independence with duration ≥ 56 days (8 weeks).  The key secondary 
endpoint is overall survival.  Additional secondary endpoints include HI-P, proportion of subjects 
in the overall population achieving RBC transfusion independence with duration of ≥84 days (12
weeks), duration of RBC transfusion independence, [≥ 84 days (12 weeks) and ≥56 days (8 
weeks)], time to RBC transfusion independence [≥ 84 days (12 weeks) and ≥56 days (8 weeks)], 
the proportion of subjects progressing to AML, time to AML progression, HI-E (IWG 2006 
criteria; Cheson, 2006; Appendix D), duration of RBC transfusion reduction, the proportion of 
platelet transfusion-dependent subjects at baseline achieving platelet transfusion independence 
with duration ≥ 56 days (8 weeks), duration of platelet transfusion independence, time to platelet 
transfusion independence, hematologic response (IWG 2006 criteria; Cheson, 2006; Appendix D), 
and the proportion of subjects experiencing clinically significant bleeding events, safety, health-
related quality of life (HRQoL), and healthcare resource utilization.  
 
 
 
 
 
 
The study population represents a subset of IPSS lower-risk MDS patients who have both RBC 
transfusion-dependent anemia and thrombocytopenia.  Lower-risk MDS patients often become 
dependent on frequent RBC transfusions, which leads to decreased health-related quality of life 
and increased morbidity and mortality (Hellstrom-Lindberg, 2003; Malcovati, 2005).  In addition, 
recent studies have shown that lower-risk MDS patients who are thrombocytopenic have a 
significantly worse prognosis compared to
lower-risk
MDS patients who are not 
thrombocytopenic.  Lower-risk MDS patient with significant thrombocytopenia have a median OS 
of approximately 14 to 16 months (Garcia-Manero, 2008a; Cruz, 2010; Yong, 2010; Gonzalez-
Porras, 2011).
While azacitidine and decitabine are approved for treatment of lower-risk MDS in some countries, 
these agents are not routinely administered and the mainstay therapy remains supportive treatment 
with ESAs and RBC and/or platelet transfusions.  While administration of ESAs may be beneficial 
for some RBC transfusion-dependent subjects, this therapy has no effect on thrombocytopenia.  
Bone marrow transplant is an option for only a subset of MDS patients that are good candidates 
for such an intensive procedure.  In addition, the outcome of patients with lower-risk MDS is not 
improved by early introduction of allogeneic stem cell transplantation (Cutler, 2004).  As a result, 
this treatment modality is recommended at the time of disease progression for lower-risk MDS 
patients.  No currently approved therapies have been shown to improve OS in IPSS lower-risk
MDS patients with both RBC transfusion-dependent anemia and thrombocytopenia.
In addition to the absence of a demonstrated survival benefit in lower-risk MDS for currently 
approved therapies, other limitations include the association of clinically significant neutropenia 
and worsening thrombocytopenia in a high proportion of patients receiving parenteral azacitidine 
 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
or decitabine, and the need for injections involving inconvenient drug product preparation and 
administration schedules for patients and health care providers.  The association of neutropenia 
with azacitidine is well established and dose-related, with the highest proportion of patients 
experiencing neutropenia in the first few cycles of treatment (Silverman, 2006; Lyons, 2009).  The 
requirement to receive SC or IV azacitidine for 7 consecutive days in a clinic or hospital setting 
often presents a challenge and may be a deterrent to patients who might otherwise benefit from 
treatment intervention before they develop higher-risk disease.  Even in higher-risk MDS or AML 
studies, clinical sites sometimes decline study participation due to the inconvenience of the 
preparation, administration, and treatment schedule requirements of azacitidine.  Injection and 
catheter site reactions for both azacitidine and decitabine can cause patient discomfort and
morbidity.  In addition, SC administration of either agent can be problematic in subjects with 
thrombocytopenia.
An oral formulation of azacitidine provides an opportunity to deliver the drug at lower doses over 
a more prolonged schedule than can be practically achieved with parenteral therapy.  In addition, 
an oral formulation that can be taken at home rather than in the hospital/clinic setting represents 
an opportunity for subjects with lower-risk MDS disease to have a more convenient route of 
administration, thus alleviating the morbidity of injection and catheter-site reactions, and avoiding 
the inconvenience and resource utilization costs associated with frequent hospital/clinic visits.  In 
addition, intervention with azacitidine in IPSS lower-risk MDS subjects with both RBC 
transfusion-dependent anemia and thrombocytopenia may offer better quality of life and possibly 
a survival advantage.
 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Please refer to the Investigator’s Brochures (IB) for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies, and adverse event profile of the IP.  
The study will be conducted in compliance with the protocol, Good Clinical Practices (GCP) and 
the applicable regulatory requirements.
1.4
Risk/Benefit Assessment
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of Azacitidine may be found in the Investigator’s Brochure (IB),
and/or package insert.
1.4.1
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
Study Intervention - Azacitidine
Neutropenia and severe infections
In subjects randomized to oral 
azacitidine 300 mg at 21-day 
treatment schedule, the most 
frequent hematological AEs were 
neutropenia, febrile neutropenia, 
To mitigate risk of severe infections, 
during Cycles 1 and 2 (higher risk 
period for severe infections) the 
subjects will receive oral azacitidine 
for 14 days of a 28-day cycle 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
and associated infections. There 
was an imbalance in incidence of 
death between the drug and 
placebo treatment groups. Most 
of the death cases in the oral 
azacitidine-treated subjects 
occurred during the first 56 days 
on treatment with infections 
being the leading cause of death. 
Affected subjects showed lower 
median ANC at baseline, which 
could have made them more 
susceptible for severe infections.
schedule. The treatment can be 
extended to a 21-day schedule after
Cycle 2, if a subject did not 
experience Grade 3 or 4 toxicities 
requiring dose delay or reductions and 
if there is no evidence of 
hematological improvement on 14-day 
dosing schedule.
During the first 2 cycles on treatment 
subjects’ blood counts will be 
monitored on weekly basis, reducing 
to biweekly monitoring up to 
Cycle 12.
Guidance for IP dose modification due 
to toxicities including neutropenia and 
febrile neutropenia is provided in 
Section 8.2.4 and Table 2 of the 
Protocol.
A strong recommendation regarding 
administration of prophylactic 
fluoroquinolone antibiotics or other 
recognized prophylactic antibiotics
was provided for subjects who 
develop Grade 4 neutropenia (see 
Section 9.1).
Other known risks with oral 
azacitidine treatment observed in 
≥10% of subjects include:
thrombocytopenia; nausea;
vomiting, diarrhea; abdominal or 
upper abdominal pain; constipation; 
asthenia or fatigue; pyrexia; 
decreased appetite; weight 
decreased; and pain (arthralgia, 
back pain, pain in extremity).
These risks are consistent with 
the established safety profile of 
azacitidine.
The proposed exclusion criteria
(Section 7.3), safety monitoring, and 
dose adjustment (Section 8.2.4), will 
minimize the risks for the participants 
participating in this study.
An external independent Data 
Monitoring Committee (DMC) will 
monitor safety during the course of 
the study.
Study Procedures
Participants could be randomized to 
the placebo control arm.
This study is randomized, double 
blinded, and placebo controlled 
in order to eliminate bias in 
assignment of Investigational 
Product (IP) and data 
interpretation. This will allow for 
a more accurate assessment of 
study endpoints.
There is no current standard-of-care
for patients with the transfusion-
dependent anemia and 
thrombocytopenia due to International 
Prognostic Scoring System (IPSS)
Lower-risk Myelodysplastic 
Syndromes.
 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
The placebo arm is also
necessary to clearly recognize
the possible short- or long-term 
side effects of oral azacitidine.
1.4.2
Benefit Assessment
Azacitidine has demonstrated clinical benefit in myelodysplastic syndromes (MDS) with a 
decreased risk of progression to acute myeloid leukemia (AML) and a potential correction of the 
peripheral blood cytopenias, including the correction of red blood cell (RBC) or platelet 
transfusion dependence. While a benefit of overall survival has not been demonstrated by using 
oral azacitidine, it has shown that it can elicit packed red blood cell (pRBC) transfusion 
independence in heavily pre-transfused MDS patients. Therefore, the development of oral 
azacitidine offers an oral alternative to conventional hypomethylating agents (HMA), including 
injectable azacitidine, and provides a treatment option for patients who have exhausted 
symptomatic treatments (such as erythropoiesis stimulating agent [ESA] and Luspatercept) and 
are in need for a disease modifying treatment.
1.4.3
Overall Benefit Risk Conclusion
The study population represents a subset of subjects with RBC transfusion-dependent anemia and 
thrombocytopenia due to IPSS lower-risk MDS. The safety profile of azacitidine has been well 
characterized and is generally, taking into account the measures taken to minimize risk to 
participants in this study, manageable with appropriate monitoring and dosing adjustments as 
specified in the study protocol and the azacitidine Investigator’s Brochure.
In conclusion, it is considered safe and of potential therapeutic benefit to continue with the 
proposed study in the patient population at the dose regimen(s) as specified in the protocol.
 
 
 
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CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
2
STUDY OBJECTIVES
2.1
Primary Objective
The primary objective of the study is to evaluate RBC transfusion independence in the 2 treatment 
arms (oral azacitidine plus best supportive care versus placebo plus best supportive care) in 
subjects with RBC transfusion-dependent anemia and thrombocytopenia due to IPSS lower-risk 
MDS.
2.2
Secondary Objectives
The secondary objectives of the study are:

To evaluate in both treatment arms

overall survival (OS);

hematologic improvement-platelet response (HI-P);

duration of RBC transfusion independence and time to RBC transfusion 
independence;

progression to acute myeloid leukemia (AML), and time to AML progression;

hematologic improvement-erythroid response (HI-E);

platelet-transfusion independence, duration of platelet transfusion independence, 
and time to platelet transfusion independence;

hematologic response;

clinically significant bleeding events;

safety;

health-related quality-of-life (HRQoL); and

healthcare resource utilization.
 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
3
STUDY ENDPOINTS
3.1
Primary Endpoint(s)
The primary endpoint is the proportion of subjects in the overall population achieving RBC 
transfusion independence with duration ≥ 56 days (8 weeks).
3.2
Secondary Endpoint(s)
The secondary endpoints of the study are:

OS;

HI-P (IWG 2006 criteria; Cheson, 2006; Appendix D);

Proportion of subjects in the overall population achieving RBC transfusion 
independence with duration of ≥ 84 days (12 weeks);

Duration of RBC transfusion independence of ≥ 56 days (8 weeks);

Duration of RBC transfusion independence of ≥ 84 days (12 weeks);

Time to RBC transfusion independence of ≥ 56 days (8 weeks); 

Time to RBC transfusion independence of ≥ 84 days (12 weeks); 

Proportion of subjects progressing to AML and time to AML progression;

HI-E (IWG 2006 criteria; Cheson, 2006; Appendix D)

Duration of RBC transfusion reduction;

Proportion of platelet transfusion-dependent subjects at baseline achieving platelet 
transfusion independence with duration ≥56 days (8 weeks);

Duration of platelet transfusion-independence;

Time to platelet transfusion independence;

Hematologic response (IWG 2006 criteria; Cheson, 2006; Appendix D);

Proportion of subjects experiencing clinically significant bleeding events;

Safety (type, frequency, severity of AEs and relationship of AEs to oral 
azacitidine/placebo; monitoring for progression to AML and second primary 
malignancy);

HRQoL utilizing the Functional Assessment of Cancer Therapy-Anemia (FACT-An;
Appendix E) and EuroQoL Group EQ-5D (EQ-5D-3L; Appendix F) instruments; and

Measures of healthcare resource utilization.
 
 
 
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CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
 
 
 
 
 
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CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
4
OVERALL STUDY DESIGN
4.1
Study Design
This is a phase 3, multicenter, double-blind, randomized, placebo-controlled, parallel-group study 
that compares the efficacy and safety of oral azacitidine plus best supportive care therapy to that 
of placebo plus best supportive care in subjects with RBC transfusion-dependent anemia and 
thrombocytopenia (platelet count ≤ 75 x 109/L) due to IPSS lower-risk MDS.  The study enrolled
216 subjects at approximately 150 sites globally.
The study consists of 4 phases: Screening, Double-blind treatment, Follow-up and Extension.
4.1.1
Screening Phase
Subjects will provide informed consent prior to undergoing any study-related procedures.  
Screening assessments for protocol eligibility will be performed within 56 days prior to 
randomization as outlined in Table 1.
Confirmation of MDS disease, WHO classification (Appendix A), and IPSS risk classification 
(Appendix B) is based on independent central pathology review, independent central cytogenetic 
review, and central laboratory hematology result.  Thus bone marrow aspirate and bone marrow 
biopsy must be collected at screening. Slides with smears from the bone marrow aspirate and 
touch preps from the biopsy are sent together with slides with peripheral blood smear and a bone 
marrow biopsy to the central pathology reviewer for morphologic assessment. Samples of the 
bone marrow aspirate or biopsy (if adequate aspirate is not attainable) are sent to the central 
cytogenetic reviewer for processing and analysis.  Please refer to the study’s Central Laboratory 
Manual for details on the required samples and handling instructions.  The independent central 
cytogenetic review will provide standardized analysis and reporting for all subjects.  The results 
from independent central cytogenetic review will be used for the statistical analyses.
RBC transfusion history must be available for the 56 days immediately preceding and including 
the date of randomization.  Transfusion data should include the type, number of units, reason and 
date of transfusion.  Transfusion data must include the hemoglobin (Hgb) value for which the 
transfusion was administered.  Hemoglobin (Hgb) levels at the time of or within 7 days prior to
administration of an RBC transfusion must have been ≤ 10.0 g/dL in order for the transfusion to 
be counted towards RBC transfusion-dependent status.  Red blood cell transfusions administered 
when Hgb levels were > 10.0 g/dL will not qualify as a required transfusion for the purpose of 
providing evidence of RBC transfusion-dependent status.  In addition, any RBC transfusion 
administered for elective surgery will not qualify towards determination of RBC transfusion-
dependent status at baseline.  All RBC transfusion records for the 56 days immediately preceding 
and including the date of randomization should be collected, regardless of Hgb levels.
RBC transfusion-dependent anemia at baseline is defined for this protocol as documentation of an 
average transfusion requirement of at least 2 units‡ of RBCs per 28 days during the 56 days
                                                       
‡ As is consistent with medical practice in Japan, 1 unit RBC referenced in this protocol is equivalent to 2 units RBC in Japan.
 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
immediately preceding and including the date of randomization. There must also not be any 
consecutive 28 days within the 56-day period in which no RBC transfusions were administered.
Platelet transfusion history, if applicable, must be available for the 56 days immediately preceding
and including the date of randomization. Transfusion data should include the type, number of units, 
reason and date of transfusion. Transfusion data must include the platelet value for which the 
transfusion was administered. This data must be accurately and completely recorded. Platelet 
transfusions administered during the 56 days immediately preceding and including the date of 
randomization will be used to establish baseline requirements. Platelet transfusions administered 
during the treatment period will be used in the efficacy analysis.  
Platelet transfusion-dependence at baseline is defined for this protocol as at least 2 separate 
transfusion episodes during the 56 days immediately preceding and including the date of 
randomization. There must also not be any consecutive 28 days within the 56-day period in which 
no platelet transfusion was administered. In addition, any platelet transfusions administered for 
elective surgery will not qualify towards determination of platelet transfusion-dependent status at 
baseline.
Thrombocytopenia at baseline must be confirmed by two platelet counts that are ≤ 75 x 109/L and 
≥21 days apart. The second confirmatory platelet count must be obtained ≤ 14 days prior to
randomization.  

At least one platelet count must be centrally analyzed within the 56 day screening 
period with results of ≤ 75 x 109/L; the second platelet count may be centrally or locally 
analyzed, with results that are also ≤ 75 x 109/L.  

Prior documented medical history of thrombocytopenia may be used to demonstrate 
eligibility for the study if at least one historical platelet count of ≤75 x 109/L was 
obtained within 56 days of randomization and ≥ 21 days apart from the centrally 
analyzed platelet count.

If additional platelet counts were obtained during the interim period, these must also 
have been ≤ 75 x 109/L. If platelet counts within the interim period are > 75 x 109/L, 
this would be acceptable only if directly associated with a platelet transfusion 
administered within 7 days prior to the date of the platelet count. 
Additional screening assessments include demographics and medical history, prior treatments for 
MDS (and other malignancy, if applicable), prior medications, physical examination, vital signs, 
weight and height measurements, Eastern Cooperative Oncology Group (ECOG) performance 
status (Appendix C), electrocardiogram (ECG), urinalysis, coagulation, Coombs’ test, reticulocyte 
count, serum erythropoietin (EPO) level, serum ferritin level, hematology, serum chemistry, 
pregnancy testing (females of childbearing potential [FCBP] only), 
 
 Adverse events (AEs) will be 
collected beginning on the date the informed consent is signed.
4.1.2
Randomization and Double-blind Treatment Phase
Following confirmation of eligibility, subjects will be randomized in a 1:1 ratio to receive oral 
azacitidine or placebo 300 mg QD for 21 days. Randomization will occur by a central 
 
 
 
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CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
randomization procedure using Interactive Response Technology (IRT, including an Interactive 
Voice Response System [IVRS] and an Interactive Web Response System [IWRS]) with 
stratification as described in Section 8.3. As of Amendment 3.0, all subjects in Cycles 1 or 2 will 
receive CC-486 for 14 days of a 28-day cycle schedule. Subjects may increase to a 21-day schedule 
at the conclusion of Cycle 2 if there are no Grade 3 or 4 toxicities requiring dose delay or reductions 
and if there is no evidence of hematological improvement upon discussion and agreement between 
the investigator and the Medical Monitor.  Subjects remaining beyond Cycle 2 will continue to 
receive 300 mg oral azacitidine or matching placebo QD for 21 days of each 28-day treatment 
cycle.
The first dose of IP should be administered within 3 days of randomization and can be on the same 
day of randomization.  After randomization, no crossover between the treatment groups will be 
permitted during any point of the study.
During the double-blind treatment phase, subjects will ingest IP (oral azacitidine or placebo) once 
a day on the first 21 days of each 28-day cycle (see Section 8.2.2 for details). Dose modifications 
may occur for managing toxicity if necessary during treatment (Section 8.2.4).
Best supportive care may be used in combination with study treatment as deemed necessary.  Best 
supportive care includes, but is not limited to, treatment with RBC transfusions (packed red blood 
cell [pRBC] or whole blood), single donor or pooled donor platelet transfusions, antibiotic, 
antiviral and/or antifungal therapy, nutritional support as needed, and granulocyte colony 
stimulating factors for subjects experiencing neutropenic fever/infections (Section 9.1). Best 
supportive care for this study excludes the use of ESAs and other hematopoietic growth factors
(granulocyte colony stimulating factors are allowed only for subjects experiencing neutropenic 
fever/infections as well as for secondary prophylaxis under certain conditions as described in 
Section 9.1).
Visits during the double-blind treatment phase are scheduled weekly for the first 2 cycles, every 
other week for the next 10 cycles and then monthly once a subject has completed 12 cycles.
During the double-blind treatment, subjects will be assessed continuously for safety and efficacy.
Assessments include AEs, monitoring for progression to AML and second primary malignancy, 
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, transfusions administered, clinically 
significant bleeding events, central review of bone marrow aspirate (or biopsy if an adequate 
aspirate is not attainable) and peripheral blood smear, central review of cytogenetics, hematologic
response/improvement assessment (IWG 2006 criteria; Cheson, 2006; Appendix D), disease status 
assessment, 
 
 IP administration and accountability, HRQoL, and healthcare 
resource utilization.
Disease Status Assessment
Because a hematologic response to treatment with azacitidine may frequently be delayed, it is 
recommended that subjects receive at least 6 cycles of treatment with IP; however, subjects may 
 
 
 
40
1.0
Approved
930186922
1.0
v
Approved
1.0
v


CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
be discontinued from treatment at the investigator’s discretion prior to reaching the recommended 
minimum number of cycles for any of the reasons detailed in Section 12.  Subjects will be assessed 
for disease status at the end of Cycle 6, prior to starting Cycle 7.

If subjects have met any of the following criteria, subjects can continue on to Cycle 7 
and beyond, and will be assessed for disease status at the end of every cycle:
o
RBC transfusion independence, or
o
platelet transfusion-independence for those subjects who were platelet 
transfusion dependent at baseline, or
o
Hematologic Improvement (HI; Cheson, 2006; Appendix D), or
o
≥ 50% reduction in average RBC transfusion requirement in the 56-day 
(8-week) period immediately prior to disease status assessment as compared to 
the average baseline RBC transfusion requirement, or
o
any other clinical benefit, including no evidence of progressive disease (see 
Section 12 for definitions of progressive disease).
Thereafter, subjects may be discontinued from protocol-prescribed therapy for any of 
the reasons detailed in Section 12.

If subjects have failed to meet any of the above criteria at the end of Cycle 6, subjects 
will be discontinued from protocol-prescribed therapy.
The decision to discontinue a subject, which will not be delayed or refused by the sponsor, remains 
the responsibility of the treating physician.  However, prior to discontinuing a subject, the 
investigator may contact the Medical Monitor and forward appropriate supporting documents for 
review and discussion.
All subjects who have received at least one dose of IP should undergo Treatment Discontinuation 
procedures (Section 6.13) when treatment is discontinued.
The reason for discontinuation will be recorded in the case report form (CRF) and in the source 
document for all randomized subjects, regardless of whether they are dosed or not.
4.1.3
Follow-up Phase
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 
period is longer, for the collection of AEs, concomitant medications and procedures, transfusions 
administered 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, subsequent MDS therapies, progression to AML and second primary malignancy
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.
 
 
 
41
1.0
Approved
930186922
1.0
v
Approved
1.0
v


CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
4.1.4
Extension Phase
The Extension Phase (EP) allows subjects who are receiving oral azacitidine, at time of study 
unblinding, and who are demonstrating clinical benefit as assessed by the Investigator, to continue 
to receive oral azacitidine after unblinding by sponsor (Celgene Corporation) until they meet the 
criteria for study discontinuation.  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 upon their approval and 
eligibility of entering the EP.
Details for the EP are provided in Appendix J.
4.1.5
Study Closure
The study will conclude once all subjects have completed or discontinued from the extension
phase. 
4.1.6
Data Monitoring Committee
An independent Data Monitoring Committee (DMC) with multidisciplinary representation will 
evaluate safety during the course of the study in compliance with a prospective charter.  The DMC 
will be comprised of medical oncologists/hematologists with experience treating MDS and a 
statistician, all of whom are not otherwise involved in the study as investigators.  An independent 
statistician will generate critical safety reports for the DMC to review periodically.  The DMC 
chairperson may convene formal DMC meetings if there are safety concerns.  The sponsor can 
also request a DMC review of safety data.  The sponsor will not have access to the unblinded data.  
The DMC responsibilities, authorities, and procedures will be detailed in the DMC charter which 
will be endorsed and signed by DMC members before the first data review meeting.  
Figure 1 provides a schematic of the overall study design.
 
 
 
42
1.0
Approved
930186922
1.0
v
Approved
1.0
v


CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
Figure 1:
Overall Study Design
Disease Status Assessment at the End of Cycle 6
Has the subject experienced at least one of the following?

RBC transfusion independence

Or platelet transfusion independence for those subjects who were platelet 
transfusion dependent at baseline

Or Hematologic Improvement (Cheson, 2006; Appendix D)

Or ≥ 50% reduction in average RBC transfusion requirement in the 56-day 
(8 week) period immediately preceding disease status assessment as 
compared
to the average baseline RBC transfusion requirement

Or any clinical benefit, including no evidence of progressive disease (see 
Section 12 for definitions of progressive disease)
Screening Phase (Day -56 to Day -1)

IPSS lower-risk MDS

RBC transfusion-dependent (≥ 2 units1 RBC per 28 days for 56 days2 and no 
consecutive 28 days without an RBC transfusion)

Thrombocytopenia (ie, 2 platelet counts ≤ 75 x 109/L that are ≥21 days apart, 
with the second count ≤ 14 days2 prior to randomization)
Randomization3 and Double-blind 
Treatment Phase
1:1 randomization to blinded treatment 
(oral azacitidine or placebo)
Oral Azacitidine
300 mg QD
First 21 days of each 28-day cycle5
Placebo
First 21 days of each 28-day cycle
YES
Continue protocol-prescribed therapy until 
treatment discontinued4 for any of the 
reasons in Section 12, then enter Follow-up 
Phase
NO
Discontinue4 protocol-prescribed therapy 
and enter Follow-up Phase
Follow-up Phase
Follow-up for survival, subsequent MDS 
therapies, progression to AML, and second 
primary malignancies.
Extension Phase6
 
 
 
43
1.0
Approved
930186922
1.0
v
Approved
1.0
v


CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
1
As is consistent with medical practice in Japan, 1 unit RBC referenced in this protocol is equivalent to 2 units RBC in Japan.
2
Immediately preceding and including the date of randomization (see Section 7.2 for details).
3
Stratification factors: average baseline RBC transfusion requirement (≤4 units1 versus > 4 units of RBC per 28 days), baseline 
platelet transfusion status (dependent versus independent), country of enrollment (ie, Japan versus Rest of World) and ECOG 
performance status (0 to 1 versus 2).
4 The decision to discontinue a subject, which will not be delayed or refused by the sponsor, remains the responsibility 
of the treating physician.  However, prior to discontinuing a subject, the investigator may contact the Medical 
Monitor and forward appropriate supporting documents for review and discussion.
5 As of Amendment 3.0, all subjects in Cycles 1 or 2 will receive CC-486 for 14 days of a 28-day cycle schedule.  
Subjects may increase to a 21-day schedule at the conclusion of Cycle 2 if there are no Grade 3 or 4 toxicities 
requiring dose delay or reductions and if there is no evidence of hematological improvement upon discussion and 
agreement between the investigator and the Medical Monitor.  Subjects remaining beyond Cycle 2 will continue to 
receive 300 mg oral azacitidine or matching placebo QD for 21 days of each 28-day treatment cycle.  
6 Following unblinding, subjects could enter the Extension Phase to continue to receive oral azacitidine and/or be 
followed for survival.  See details for EP in Appendix J.
4.2
Study Design Rationale
This is a phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study 
that compares the efficacy and safety of oral azacitidine plus best supportive care versus placebo 
plus best supportive care in subjects with RBC transfusion-dependent anemia and 
thrombocytopenia (platelet count ≤ 75 x 109/L) due to lower-risk MDS.
The study population represents a subset of IPSS lower-risk MDS patients who have both RBC 
transfusion-dependent anemia and thrombocytopenia, and has a worse prognosis.  No currently 
approved therapies have been shown to improve OS in this population. So this study is designed 
to establish additional treatment options that could offer better quality of life and survival 
advantage for lower-risk MDS subjects who have both RBC transfusion-dependent anemia and 
thrombocytopenia.
This study is randomized, double-blinded, placebo-controlled, and parallel-group in order to 
eliminate bias in assignment of IP as well as data interpretation. This will allow for a more accurate 
assessment of study endpoints and especially allow an improved assessment of overall survival 
according to blinded treatment assignment. Best supportive care in both treatment arms will 
include, but is not limited to RBC (pRBC and whole blood) and platelet transfusions (single donor 
or pooled donor), antibiotic, antiviral and antifungal therapy, nutritional support as needed, and 
granulocyte colony stimulating factors for subjects experiencing neutropenic fever/infections (as 
detailed in Section 9.1). Best supportive care for this study excludes the use of ESAs and other 
hematopoietic growth factors as these therapies are not approved for the treatment of MDS and do 
not increase platelet counts in patients with concomitant thrombocytopenia associated with their 
MDS (granulocyte colony stimulating factors are allowed only for subjects experiencing 
neutropenic fever/infections as well as for secondary prophylaxis under certain conditions as 
described in Section 9.1). Furthermore, ESAs are less effective for RBC transfusion-dependent 
anemia than for RBC transfusion-independent anemia (Hellstrom-Lindberg, 2003). Thus, the best 
supportive care for this study should minimize the risk of not providing subjects with appropriate 
care, while providing the potential benefit of achieving RBC transfusion independence and/or 
having improvement in platelet counts. Further consideration of excluding the use of ESAs from 
best supportive care is the theoretical possibility that the combination of ESA with azacitidine may 
 
 
 
44
1.0
Approved
930186922
1.0
v
Approved
1.0
v


CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
have an additive effect on response and this could cloud the specific question relating to efficacy 
of oral azacitidine itself. Thus, excluding the use of ESAs from best supportive care would negate 
any possible bias in data interpretation, and allow accurate assessment of study endpoints.
Although parenteral azacitidine and decitabine are approved for treatment of lower-risk MDS in 
some countries, these agents are not routinely used.  The mainstay therapy remains supportive care 
with ESAs and RBC and/or platelet transfusions.  Also, in the EU azacitidine is only approved for 
treatment of patients with higher-risk MDS disease.  Placebo is therefore the appropriate 
comparator for this study.  The placebo arm is also necessary because should oral azacitidine have 
possible short or long term side effects, it would be difficult to clearly recognize these effects 
without a comparator arm, especially considering that the underlying MDS has a myriad of 
possible manifestations that could be misconstrued as secondary to the IP. The propensity to 
develop AML is a further reason for the inclusion of a placebo arm, because it is important to 
establish that AML occurrence is not induced more frequently and at an earlier time point than 
what would be expected from the underlying MDS.  Furthermore, the use of historical data is not 
regarded as an accurate and reliable comparator.
The starting dose and schedule for subjects is 300 mg oral azacitidine (or placebo) once a day for 
the first 21-days of each 28-day treatment cycle. This oral azacitidine dose and schedule has 
demonstrated tolerability and shown signs of clinical activity in a prior study 
(Garcia-Manero, 2010).  As of Amendment 3.0, all subjects in Cycles 1 or 2 will receive CC-486 
for 14 days of a 28-day cycle schedule.  Subjects may increase to a 21-day schedule at the 
conclusion of Cycle 2 if there are no Grade 3 or 4 toxicities requiring dose delay or reductions and 
if there is no evidence of hematological improvement upon discussion and agreement between the 
investigator and the Medical Monitor.  Subjects remaining beyond Cycle 2 will continue to receive 
300 mg oral azacitidine or matching placebo QD for 21 days of each 28-day treatment cycle. 
Subjects should continue to receive IP for at least 6 cycles of treatment before being assessed for 
disease status because, based on prior studies with parenteral azacitidine therapy, response to 
treatment may be significantly delayed (Silverman, 2006).  While on double-blinded treatment, 
subjects will continue to receive best supportive care, thus the requested 6-month minimum 
treatment period does not represent an undue risk to subjects.  In addition, because overall survival 
is one of the endpoints, the effect of extended therapy is being evaluated; suspension of therapy at 
an early time point may blunt any possible extended survival.  Crossover between the treatment 
groups is not allowed so as not to compromise the overall survival endpoint.
The primary endpoint, RBC transfusion independence, is defined as the absence of any RBC 
transfusion during any consecutive “rolling” 56 days during the treatment period compared with 
an average transfusion requirement of ≥ 2 units/28 days of RBCs confirmed for a minimum of 56
days immediately preceding and including the date of randomization.  Achieving RBC transfusion
independence is likely to be a substantial clinical benefit in a patient population with a median 
overall survival of approximately 14 to 16 months (Garcia-Manero, 2008a; Cruz, 2010; Yong, 
2010).
 
 
 
45
1.0
Approved
930186922
1.0
v
Approved
1.0
v


CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
Analysis of the primary endpoint will be conducted only once after full (100%) information is 
available for RBC transfusion independence rates (ie, after all subjects have completed 12 months 
of double-blind treatment or discontinued before reaching 12 months of double-blind treatment).  
Twelve months was selected as the duration of double-blind treatment based on the same reason 
mentioned above that a hematologic response to azacitidine treatment may frequently be delayed
(Silverman, 2006).
4.3
Study Duration 
The expected duration of the study is 134 months, including a 56-month enrollment followed by 
78 months of subject treatment and/or observation, including EP. The study is planned to conclude 
78 months after the last subject is randomized.
 
 
 
46
1.0
Approved
930186922
1.0
v
Approved
1.0
v


CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
5
TABLE OF EVENTS
Table 1 provides a detailed description of all study events or procedures by time point for each 28-day treatment cycle.
Table 1:
Table of Events
Procedure
Screening
  ≤ 56 days prior 
to 
Randomization
Random
-izationb
Double Blind Treatment Phase
a
Follow-
upa
Cycles 1 – 2
Cycles 3 – 12
Cycles 13 
and Beyond
Treatment 
Discon-
tinuationc
Day 1b
Days 8, 15, 22
Day 1
Day 15
Day 1
Informed Consent

--
--
--
--
--
--
--
--
Inclusion and Exclusion Criteria

--
--
--
--
--
--
--
--
MDS Diagnosis, WHO Classification 
and IPSS Score
d
--
--
--
--
--
--
--
--
RBC and Platelet Transfusion 
History
e
--
--
--
--
--
--
--
Thrombocytopenia History
f
--
--
--
--
--
--
--
Demographics and Medical History

--
--
--
--
--
--
--
--
Prior Treatment for MDS (and other 
malignancy, if applicable)
g
--
--
--
--
--
--
--
--
Prior Medications
h
--
--
--
--
--
--
--
--
Physical Examination

--
i
--

--


--
Vital Signs (blood pressure, pulse, 
temperature, respiratory rate)

--

--

--


--
Body Weight Measurement

--

--

--


--
Height

--
--
--
--
--
--
--
--
ECOG Performance Status

--
i
--

--


--
ECG – Local
j
--
--
--
--
--
--
--
--
Urinalysis
k
--
--
--
--
--
--
--
--
 
 
 
 
47
1.0
Approved
930186922
1.0
v
Approved
1.0
v


CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
Table 1:
Table of Events
Procedure
Screening
  ≤ 56 days prior 
to 
Randomization
Random
-izationb
Double Blind Treatment Phase
a
Follow-
upa
Cycles 1 – 2
Cycles 3 – 12
Cycles 13 
and Beyond
Treatment 
Discon-
tinuationc
Day 1b
Days 8, 15, 22
Day 1
Day 15
Day 1
Coagulation
l
--
--
--
--
--
--
--
--
Coombs’ Test (Direct/Indirect) -
Local
m
--
--
--
--
--
--
--
--
Reticulocyte Count - Local
n
--
--
--
--
--
--
--
--
Serum EPO Level
o
--
--
--
o
--
--
--
--
Serum Ferritinp

--

--

--


--
Serum Transferrin Saturation 
(Fe/TIBC)

--
--
--
--
--
--
--
--
Hematologyq

--
i





--
Serum Chemistryr

--
i


--


--
Pregnancy Testing (FCBP only)s

--

--

--


--
Assessing Adverse Events
After signing ICD and until 28 days after the last IP dose or until the last study visit, whichever period is longer.
Monitoring for Progression to AML 
and Second Primary Malignancy
After signing ICD and until death, lost to follow-up, withdrawal of consent for further data collection, or study 
closure.
Concomitant Medications, Therapy, 
and Procedures
--
From the date of randomization and until 28 days after the last dose of IP or until the last study 
visit, whichever period is longer
Bone Marrow Aspirate and/or Biopsy
(Biopsy mandatory at Screening)
d
--
--
--
t
--
t
--
--
Peripheral Blood Smear
Cytogenetic Testing
 
 
 
 
 
48
1.0
Approved
930186922
1.0
v
Approved
1.0
v


CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
Table 1:
Table of Events
Procedure
Screening
  ≤ 56 days prior 
to 
Randomization
Random
-izationb
Double Blind Treatment Phase
a
Follow-
upa
Cycles 1 – 2
Cycles 3 – 12
Cycles 13 
and Beyond
Treatment 
Discon-
tinuationc
Day 1b
Days 8, 15, 22
Day 1
Day 15
Day 1
FACT-An and EQ-5Dx
--
--

--

--


--
Healthcare Resource Utilization
After signing ICD and until 28 days after the last IP dose or until the last study visit, whichever period is longer
Randomization
--

--
--
--
--
--
--
--
IP Dispensationy
--
--

--

--

--
--
IP Administration
--
--
Day 1 to Day 21 of 28-day treatment cyclesz
--
--
IP Accountability
--
--
aa
--

--


--
Transfusion Assessmentcc
--
--
After the date of randomization and until 28 days after the last dose of IP or until the 
last study visit, whichever period is longer
Assessment of Bleeding Eventsdd
--
--






--
IWG Response/Improvementee
--
--
--
--
t
--
t
--
--
Disease Status Assessment
--
--
--
--
ff
--
ff

--
Subsequent MDS Therapies
--
--
--
--
--
--
--

gg, hh
Survival Follow-up
--
--
--
--
--
--
--
--
gg. hh
Key: AML=acute myeloid leukemia; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EPO=erythropoietin; EQ-5D=EuroQol Group 
EQ-5D-3L; FACT-An=Functional Assessment of Cancer Therapy-Anemia; FCBP=female of childbearing potential; ICD=informed consent document; 
IP=investigational product; IPSS=International Prognostic Scoring System; IWG= International Working Group; MDS=myelodysplastic syndromes; RBC=red 
blood cell; WHO=World Health Organization.
 
 
 
 
 
49
1.0
Approved
930186922
1.0
v
Approved
1.0
v


CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
a. The study visit window for visit related assessments in the double-blind treatment phase is ± 3 days for Cycles 1 and 2; ± 7 days for Cycle 3 and beyond, unless 
noted otherwise for a particular assessment.  However, please note that in all circumstances a drug holiday of 7 days needs to be maintained for the 
treatment schedules of 300 mg and 200 mg for 21 days /28-day-cycle (14 and 21 days, respectively, for modified treatment schedules of 200 mg for 
14 days/28-day-cycle and 7 days/28-day-cycle.  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 8.2.5).  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 month.  One cycle (one month) is considered as 28 days (ie, 4 weeks).
b. First dose of IP in Cycle 1 should be administered within 3 days of randomization and can be on the same day of randomization.
c. All subjects who have received at least one dose of IP should undergo Treatment Discontinuation procedures detailed in Section 6.13 when treatment is 
discontinued.  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.
d. MDS diagnosis, WHO classification (Appendix A), and IPSS risk classification (Appendix B) will be prospectively determined by independent central pathology 
and cytogenetics review, and applicable central laboratory results.  Thus bone marrow aspirate and biopsy samples together with peripheral blood samples must 
be collected at screening as detailed in Section 6.1.1.  At all later time points a biopsy is only needed if adequate aspirate is not attainable.  Blood samples at 
screening should be collected on the same day as the bone marrow aspirate/biopsy procedure.  Instructions for submission of bone marrow slides, sample 
collection, processing, storage, and shipment procedures are provided in the study’s Central Laboratory Manual.
e. Red blood cell transfusion history must be available for the 56 days immediately preceding and including the date of randomization and platelet transfusion 
history must be available for the 56 days immediately preceding and including the date of randomization.  Transfusion history data can be gathered during the 
56-day screening period as detailed in Section 6.1.2.
f. Thrombocytopenia at baseline must be confirmed by two platelet counts that are ≤ 75 x 109/L and ≥21 days apart.  The second confirmatory platelet count must 
be obtained ≤14 days prior to randomization.  At least one platelet count must be centrally analyzed within the 56 day screening period with results of ≤ 75 x 
109/L; the second platelet count may be centrally or locally analyzed, with results that are also ≤ 75 x 109/L . If additional platelet counts are obtained during the 
interim period, these must also have been ≤ 75 x 109/L.  If platelet counts within the interim period are > 75 x 109/L, this would be acceptable only if associated 
with a platelet transfusion administered within 7 days prior to the date of the platelet count (Section 6.1.3).
g. Prior Treatment for MDS includes all prior treatments for MDS regardless of discontinuation date of treatment as detailed in Section 6.1.5.
h. All medications taken in the 8 weeks (56 days) prior to randomization are to be collected on the appropriate Case Report Form (CRF).
i. The assessment does not need to be performed if the screening examination was performed within 7 days of the first dose of IP in the treatment phase.
j. Electrocardiogram will be performed locally at screening and whenever clinically indicated.  The investigator will review and assess the results as detailed in 
Section 6.1.9.
k. Urinalysis is conducted at the central laboratory at screening and whenever clinically indicated as detailed in Section 6.1.10.
l. Coagulation is conducted at the central laboratory at screening and whenever clinically indicated as detailed in Section 6.1.11.
m. A direct or indirect Coombs’ test at screening is performed at the local laboratory.
n. The screening reticulocyte count is performed at the local laboratory.
 
 
 
 
 
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CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
o. Ideally, the screening serum EPO level (Section 6.1.14) should be collected on the same day as a planned RBC transfusion, and should not be collected within 1 
week after any RBC transfusion due to possible reduction of the serum level related to the hemoglobin level achieved after the last transfusion.  Serum EPO level 
should also be tested on Day 1 of Cycle 6. However, if possible, the sample should not be collected within 1 week after any RBC transfusion due to possible 
reduction of the serum level related to the hemoglobin level achieved after the last transfusion. Therefore in the event that Day 1 of Cycle 6 would be scheduled 
within a week of a RBC transfusion, EPO sampling may be performed on Day 1 of the following cycle (Section 6.7.7).  Serum EPO level is tested at the central 
laboratory.
p. Serum ferritin level must be collected at screening, on Day 1 of Cycle 1, on Day 1 of every 3 cycles thereafter (eg, Day 1 of Cycles 4, 7, 10, 13, etc.)
(Section 6.6.6), and at Treatment Discontinuation.  Serum ferritin level is tested by the central laboratory.
q. Hematology includes a complete blood count as detailed in Section 6.1.17.  Any or all laboratory assessments may be repeated more frequently if clinically 
indicated.  All samples will be analyzed by the central laboratory.  The samples are to be collected at screening and prior to IP administration as detailed in 
Section 6.6.5, and at Treatment Discontinuation.
r. Serum chemistry parameters are detailed in Section 6.1.18.  All samples will be analyzed by the central laboratory.  Any or all laboratory assessments may be 
repeated more frequently if clinically indicated.  The samples are to be collected at screening and prior to IP administration as detailed in Section 6.6.5, and at 
Treatment Discontinuation.
s. For females of childbearing potential (FCBP, please refer to Section 6.1.19 for definition of FCBP) a medically supervised serum pregnancy test (conducted at 
the central laboratory or locally) is to be obtained and verified negative at screening (Section 6.1.19). During the treatment phase a serum or urine pregnancy 
test (investigator’s discretion; sensitivity of at least 25 mIU/mL) is to be done within 72 hours prior to Day 1 of every cycle and at the Treatment Discontinuation 
visit (Section 6.6.7). Note that the screening pregnancy test can be used as the test prior to starting study therapy in the treatment phase if it is performed within 
the 72-hour timeframe. The subject may not receive IP until the investigator has verified that the result of the pregnancy test is negative.
t. Day 1 of Cycles 3, 6, and 12 and every 6 months thereafter (eg, Day 1 of Cycles 18, 24, etc.).  See Section 6.7.3, Section 6.10.1 and Section 6.10.2 for detail.
 
x. FACT-An and EQ-5D questionnaires must be completed prior to interaction with study personnel (when feasible) and prior to IP administration at the start of 
every Cycle, and at Treatment Discontinuation (Section 6.8). If blood is drawn in advance of Day 1 of a particular cycle or in advance of the treatment 
discontinuation visit, the questionnaires will still be completed at the first visit with the site staff at that particular cycle or treatment discontinuation visit.
y. IP should only be dispensed on Day 1 of each treatment cycle after all Day 1 procedures have been completed and all IP from the previous cycle has been 
accounted for (where applicable).  Only 1 cycle of IP will be dispensed to the subject on Day 1 of each cycle (Section 8.2.1).  
z. IP is scheduled to be taken on Day 1 to Day 21 of each cycle, unless there has been a schedule modification of IP administration due to toxicity. As of Amendment 
3.0, all subjects in Cycles 1 or 2 will receive CC-486 for 14 days of a 28-day cycle schedule.  Subjects may increase to a 21-day schedule at the conclusion of 
Cycle 2 if there are no Grade 3 or 4 toxicities requiring dose delay or reductions and if there is no evidence of hematological improvement upon discussion and 
agreement between the investigator and the Medical Monitor.  Subjects remaining beyond Cycle 2 will continue to receive 300 mg oral azacitidine or matching 
placebo QD for 21 days of each 28-day treatment cycle. On 
 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 administered 30 
minutes prior to IP administration at the investigator´s discretion (Section 8.2.2).
aa. Day 1 of Cycle 2 only.
 
 
 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
 
cc. The type, number of units, reason and date of transfusions are to be collected after randomization and until 28 days after the last dose of IP or until the last study 
visit, whichever occurs later as detailed in Section 6.7.1.
dd.Assessment of all bleeding events should be performed during the treatment phase starting on Day 1 of Cycle 1, as detailed in Section 6.7.2, and at Treatment 
Discontinuation.  Information for each bleeding event should be recorded on the appropriate CRF.
ee. International Working Group Response/Improvement Assessment is scheduled to be performed on Day 1 of Cycles 3, 6, and 12, and every 6 cycles thereafter 
(eg, Day 1 of Cycles 18, 24, etc.), and could be done at any time prior to starting the next cycle (eg, prior to starting Cycles 4, 7, 13, etc., respectively) 
(Section 6.7.5).  
ff. An assessment of disease status must be performed at the end of Cycle 6, prior to starting Cycle 7.  

If subjects have met any of the following, subjects can continue on to Cycle 7 and beyond, and will be assessed for disease status at the end of every
cycle:

RBC transfusion independence, or

platelet transfusion-independence for those subjects who were platelet transfusion dependent at baseline, or

Hematologic Improvement (HI; Cheson, 2006; Appendix D), or

≥ 50% reduction in average RBC transfusion requirement in the 56-day (8-week) period immediately prior to disease status assessment as 
compared to the average baseline RBC transfusion requirement, or

any other clinical benefit, including no evidence of progressive disease (see Section 12 for definitions of progressive disease).
Thereafter, subjects may be discontinued from protocol-prescribed therapy for any of the reasons detailed in Section 12.

If subjects have failed to meet any of the above criteria at the end of Cycle 6, subjects will be discontinued from protocol-prescribed therapy
(Section 6.7.6).
The decision to discontinue a subject, which will not be delayed or refused by the sponsor, remains the responsibility of the treating physician.  However, prior 
to discontinuing a subject, the investigator may contact the Medical Monitor and forward appropriate supporting documents for review and discussion.
gg.All subjects discontinued from protocol-prescribed therapy for any reason should be followed for survival and subsequent MDS therapies (Section 6.7.9).
hh.Following unblinding, subjects could enter the Extension Phase to continue to receive oral azacitidine and/or be followed for survival.  See details for EP in
Appendix J.
 
 
 
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CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
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 of Cycles 1 and 2 must be performed ± 3 days of the scheduled day 
indicated in the table.  All routine assessments of Cycles 3 and beyond must be performed ± 7 days 
of the scheduled day indicated in the table.  However, please note that in all circumstances a drug 
holiday of 7 days needs to be maintained for the treatment schedules of 300 mg and 200 mg for 21 
days /28-day cycle (14 and 21 days, respectively, for modified treatment schedules of 200 mg for 
14 days/28-day cycle and 7 days/28 day-cycle.  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 month.  One cycle (one month) is considered as 28 days 
(ie, 4 weeks).  Procedures are described in detail below.
6.1
Screening
Written informed consents must be obtained before any study-specific procedures are performed
 during the course of 
the study.
Screening procedures are to occur during the screening phase (see Table 1).  Screening 
assessments to confirm eligibility must take place within 56 days prior to randomization, unless 
otherwise specified.  Subject eligibility is to be established by confirming all inclusion/exclusion 
criteria.  Failure to meet any entry criterion excludes a subject from enrolment into the study.  Refer 
to Section 6.2 for information to be collected on screen failures.
If a subject is screen failed and then re-screened, subject must be re-consented in writing.
6.1.1
MDS Diagnosis, WHO Classification, and IPSS Risk Classification
MDS diagnosis, WHO classification (Appendix A), and IPSS risk classification (Appendix B) will 
be prospectively determined by independent central pathology and cytogenetics review, and 
applicable central laboratory results.  Thus at screening bone marrow aspirate and biopsy samples
together with peripheral blood samples must be collected.  At all later time points a biopsy is only 
needed if adequate aspirate is not attainable.

Morphological assessment: Slides of the bone marrow aspirate (bone marrow aspirate 
smears, including one for iron stain) and biopsy (touch prep smears), and peripheral 
blood smear will be prepared locally and sent to the central pathology reviewer for 
assessment.  

Cytogenetic analysis:  Bone marrow aspirate (or biopsy if adequate aspirate is not 
attainable - note that specific handling of the biopsy is required if also to be used for 
cytogenetic testing [see the study’s Central Laboratory Manual for handling 
instructions]) will be sent to the central cytogenetic reviewer for processing and 
analysis prior to randomization. At least 20 analyzable metaphases are required for 
standard G-banding cytogenetic analyses.   If, after two bone marrow aspirate and/or 
biopsy procedures, 20 metaphases cannot be obtained, at least 10 analyzable 
metaphases are required for standard G-banding cytogenetic analysis at screening. 
 
 
 
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CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022

Peripheral blood sample:  A peripheral blood sample will be sent to the central 
laboratory for a complete blood count (CBC) with white blood cell (WBC) differential 
and platelet count.
The screening bone marrow aspirate and biopsy samples for central pathology and central 
cytogenetic review, and the screening hematology samples for central laboratory analysis should 
be collected no later than 14 days prior to randomization in order to allow sufficient time for central 
review and a repeat bone marrow assessment, if necessary.
Every attempt should be made to send the screening bone marrow aspirate and/or biopsy samples
(if adequate aspirate is not attainable) to the central cytogenetic reviewer for processing and 
analysis prior to randomization.  In the event that cytogenetic analysis cannot be performed by the 
central cytogenetic reviewer prior to randomization, a cytogenetic analysis by the local laboratory 
may suffice for randomization.  The sponsor must be consulted prior to randomizing a subject 
using cytogenetic results from a local laboratory.  A central “over read” of the cytogenetic report 
and photographs will be performed at a later date by the central cytogenetic reviewer.  If, in the 
case of a patient who undergoes 2 bone marrow procedures on 2 separate occasions (aspirate and/or 
biopsy), and the IPSS score is still not able to be determined due to a lack of metaphases (dividing 
cells), FISH analysis of bone marrow aspirate utilizing a sponsor-determined probe panel may be 
used for the determination of IPSS score at screening.  Additionally, if a definitive diagnosis of 
MDS is not determined via cytomorphologic analysis of the bone marrow aspirate or pathologic 
examination of bone marrow biopsies, local samples or prepared slides may be sent to the central 
reviewer to perform a potential “over read” of the samples.  These samples may be obtained outside 
of the 56 day screening period, but should not be from more than 3 months prior to the date of the 
first screening bone marrow procedure.
Instructions for submission of bone marrow slides and samples to central reviewers are provided
in the study’s Central Laboratory Manual.
6.1.2
RBC and Platelet Transfusion History
Red blood cell and platelet transfusion history should be recorded on the appropriate CRF at 
screening.  Transfusion history data can be gathered during the 56-day screening period.  All 
transfusion data should include the type, number of units, reason and date of transfusion.
Red Blood Cell Transfusion History
Red blood cell transfusion history must be available for the 56 days immediately preceding and 
including the date of randomization.  Data must include the Hgb value for which the RBC 
transfusion was administered.  The Hgb value can be from the central or a local laboratory.  
Hemoglobin levels at the time of or within 7 days prior to administration of an RBC transfusion 
must have been ≤ 10.0 g/dL in order for the transfusion to be counted towards RBC transfusion-
dependent status.  Red blood cell transfusions administered when Hgb levels were > 10.0 g/dL or 
RBC transfusions administered for elective surgery will not qualify as a required transfusion for 
the purpose of providing evidence of RBC transfusion-dependent status. All RBC transfusion 
records for the 56 days immediately preceding and including the date of randomization should be 
collected, regardless of Hgb levels (see Section 7.2).
 
 
 
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CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
Platelet Transfusion History
Platelet transfusion history must be available for the 56 days immediately preceding and including 
the date of randomization.  Data must include the platelet value for which the platelet transfusion 
was administered.  The platelet value can be from the central or a local laboratory.  Platelet 
transfusions administered for elective surgery will not qualify as a transfusion episode for the 
purpose of determining baseline platelet transfusion status.
6.1.3
Thrombocytopenia History
Thrombocytopenia must be confirmed by two platelet counts that are ≤ 75 x 109/L and ≥21 days 
apart.  The second confirmatory platelet count must be obtained within 14 days of randomization.

At least one platelet count must be centrally analyzed within the 56 day screening 
period with results of ≤ 75 x 109/L; the second platelet count may be centrally or locally 
analyzed, with results that are also ≤ 75 x 109/L.  

Prior documented medical history of thrombocytopenia may be used to demonstrate 
eligibility for the study if at least one historical platelet count of ≤75 x 109/L was 
obtained within 56 days of randomization and ≥ 21 days apart from the centrally 
analyzed platelet count.

If additional platelet counts were obtained during the interim period, these must also 
have been ≤ 75 x 109/L. If platelet counts within the interim period are > 75 x 109/L, 
this would be acceptable only if directly associated with a platelet transfusion 
administered within 7 days prior to the date of the platelet count. 
(See Section 7.2)
6.1.4
Demographics and Medical History
The subject’s date of birth, sex, race and ethnicity will be recorded on the appropriate CRF.  
Relevant medical history and current medical conditions, including those symptoms related to 
MDS, 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.
6.1.5
Prior Medications and MDS Treatments
All medications taken in the 8 weeks (56 days) prior to randomization will be recorded on the 
appropriate CRF.
All prior treatments for MDS (detailed in Section 9) will be recorded on the respective CRF(s) 
regardless of discontinuation date of treatment.
6.1.6
Physical Examination
Information about the screening physical examination must be present in the subject’s source 
documentation.  Significant findings must be included on the appropriate CRF.
6.1.7
Vital Signs, Body Weight and Height Measurements
Vital signs (blood pressure, pulse, temperature, and respiratory rate) and body weight will be 
assessed at screening.  Please refer to Section 6.6.3 for assessment schedule during the treatment 
phase.  Height is only collected once at screening.
 
 
 
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CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
6.1.8
Eastern Cooperative Oncology Group Performance Status
Performance status at screening will be assessed using ECOG criteria provided in Appendix C.  
Refer to Section 6.6.9 for timing of assessing ECOG performance status during the study.
6.1.9
Electrocardiogram
Electrocardiogram (ECG) at screening is conducted by the local laboratory.  ECG will be 
performed using the internationally recognized 12-leads.  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.  If the ECG is abnormal, the investigator 
should consult a cardiologist if deemed appropriate.
6.1.10
Urinalysis
Urinalysis at screening is conducted by the central laboratory.  Urinalysis includes examination by 
a standard stick test for specific gravity, glucose, ketones, blood, pH, and protein, and microscopic 
analysis if indicated.
6.1.11
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).
6.1.12
Coombs’ Test
A direct or indirect Coombs’ test at screening is performed at the local laboratory.
6.1.13
Reticulocyte Count
The screening reticulocyte count is performed at the local laboratory.
6.1.14
Serum EPO Level
If possible, the screening serum EPO level should be collected on the same day as a planned RBC 
transfusion, prior to the transfusion.  The screening serum EPO level should not be collected within 
1 week after any RBC transfusion due to possible reduction of the serum level related to the
hemoglobin level achieved after the last transfusion. Serum EPO level is tested by the central 
laboratory.  Refer to Section 6.7.7 for timing of serum EPO level testing during the study.
6.1.15
Serum Ferritin
Serum ferritin level at screening is to be tested by the central laboratory.  Refer to Section 6.6.6
for timing of serum ferritin testing during the study.
6.1.16
Serum Transferrin Saturation
Transferrin saturation is to be tested at screening only by the central laboratory as the percentage 
of serum iron/serum total iron binding capacity (Fe/TIBC).
6.1.17
Hematology
Hematology assessment includes a complete blood count (CBC, RBC count, hemoglobin, 
hematocrit, mean corpuscular volume [MCV], mean corpuscular hemoglobin [MCH], mean 
corpuscular hemoglobin concentration [MCHC], red cell distribution width [RDW], WBC count 
 
 
 
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CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
with differential, absolute neutrophil count [ANC], and platelet count).  The sample will be 
analyzed by the central laboratory.  Any or all laboratory assessments may be repeated more 
frequently if clinically indicated.  Refer to Section 6.6.5 for timing of hematology assessments 
during the study.
6.1.18
Serum Chemistry
The screening serum chemistry assessment includes sodium, potassium, chloride, bicarbonate (if 
available), calcium, magnesium, phosphorus, blood urea nitrogen (BUN), creatinine, glucose, 
albumin, total protein, alkaline phosphatase, direct/indirect/total bilirubin, Serum aspartate 
aminotransferase 
(AST)/serum 
glutamic-oxaloacetic 
transaminase 
(SGOT) or 
alanine 
transaminase (ALT)/serum glutamate pyruvate transaminase (SGPT), lactate deyhydrogenase 
(LDH), and uric acid.  The sample will be analyzed by the central laboratory.  Any or all laboratory 
assessments may be repeated more frequently if clinically indicated.  Refer to Section 6.6.5 for 
timing of serum chemistry assessments during the study.
6.1.19
Pregnancy Testing
This protocol defines a 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). The investigator 
will appraise a female subject as a FCBP according to this definition.  Justification must be 
recorded in the CRF and the source document.  Pregnancy testing is not required for non-FCBP 
subjects.  
A medically supervised serum pregnancy test (conducted at the central laboratory or locally) is to 
be obtained and verified negative in all female subjects of childbearing potential at screening.  
Refer to Section 6.6.7 for details regarding pregnancy tests during the study and to Section 7.2 for 
contraception information as required by the protocol.
6.2
Information to be Collected on Screening Failures
The informed consent date, 
 
 demographics, reason subject did not 
qualify for the study and the investigator’s signature will be collected for all subjects determined 
to be screen failures.  The 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 
 
 
 
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CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
information will be captured in the subject’s source documents and appropriate CRF(s).  Relevant 
information will also be recorded on the Screening Log.
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 verified by the investigator.  In addition the sponsor will review key eligibility 
criteria including central lab, pathology and cytogenetic reports prior to randomization of a 
subject. 
Randomization will occur by a central randomization procedure using IRT with 
stratification as described in Section 8.3.  Specific contact information and instructions will be 
provided individually to each study site.
Randomization should be as close to the planned first dose of IP in the treatment phase as possible 
to avoid randomizing subjects who ultimately do not participate in the study.
The first dose of IP should be administered within 3 days of Randomization and can be on the 
same day of randomization.
6.4
Baseline
Refer to Section 10.4 for baseline definitions of vital signs, weight and laboratory assessments, 
unless noted otherwise for a particular assessment.
Physical examination, ECOG performance status, hematology or serum chemistry does not need 
to be performed if the screening examination was performed within 7 days of the first dose of IP 
in the treatment phase.  Assessment of bleeding events, and the FACT-An and EQ-5D
questionnaires start on Day 1 of Cycle 1.  The FACT-An and EQ-5D questionnaires should always 
be completed prior to IP administration and, when feasible, prior to interaction with study 
personnel.
6.5
Treatments
Refer to Sections 8.2.1, 8.2.2, and 8.2.3 for details regarding IP dispensation, administration, and 
accountability.
6.6
Safety
Safety assessments include AEs, monitoring for progression to AML and second primary 
malignancy, physical examination, vital signs and body weight measurement, ECOG performance 
status, hematology (CBC with WBC differential and platelets) and serum chemistry, serum ferritin 
level, and concomitant medications, therapies and procedures, and pregnancy testing (for FCBP 
subjects).  
ECG, urinalysis and coagulation testing will be repeated as clinically indicated during the double-
blind treatment phase.
6.6.1
Adverse Events
All subjects will be monitored for AEs during the study.  Refer to Section 11.1 for details regarding 
monitoring, recording, and reporting of AEs, including SAEs.  
 
 
 
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CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
Information about common side effects already known about azacitidine will be included in the 
subject informed consent document and should be discussed with the subject as needed during the 
study.  This information can also be found in the IB or will be communicated between IB updates 
in the form of Investigator Notifications.
6.6.2
Progression to AML and Second Primary Malignancies
Progression to AML and second primary malignancies will be monitored as events of interest and 
should be included as part of the assessment of AEs throughout the course of the study.  
Investigators are to report progression to AML and any second primary malignancy, regardless of 
causal relationship to IP (oral azacitidine or placebo), occurring at any time from signing of 
informed consent until death, lost to follow-up, or withdrawal of consent for further data collection.  
Events of progression to AML and second primary malignancy are to be reported as a serious 
adverse event (SAEs; considered to be an adverse event of special interest (AESI) 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 progression 
to AML and/or the second primary malignancy (eg, any confirmatory histology or cytology results, 
X-rays, CT scans, etc.) must be provided at the time of reporting as an SAE.  Refer to Section 11.2
for evaluation of AEs.  
6.6.3
Physical Examination, Vital Signs and Weight
During the treatment phase physical examinations, vital signs (blood pressure, pulse, temperature 
and respiratory rate) and weight measurements are to be performed on Day 1 of each cycle and the 
Treatment Discontinuation visit.  Significant findings must be included on the appropriate CRF.
6.6.4
Urinalysis, 12-Lead Electrocardiogram or Coagulation
Urinalysis, ECG or coagulation should be performed as required by the protocol and whenever 
clinically indicated.
6.6.5
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 (see Section 6.1 for details 
regarding the parameters for hematology and serum chemistry, respectively).  
The hematology samples will be collected prior to IP administration and will be analyzed by the 
central laboratory.  The frequency of hematology assessment in the treatment phase is as such: 
weekly on Day 1, 8, 15 and 22 in Cycles 1-2, and biweekly on Day 1 and 15 in Cycles 3-12, and 
monthly on Day 1 thereafter and at Treatment Discontinuation.
The serum chemistry samples will be collected prior to IP administration and will be analyzed by 
the central laboratory.  The frequency of serum chemistry assessment in the treatment phase is as 
such: weekly in Cycles 1-2 and monthly on Day 1 thereafter, and at Treatment Discontinuation.
On a case-by-case basis and at the investigator’s discretion, the Day 8, 15, and 22 hematology and 
serum chemistry draws may be performed at the subject’s local/primary physician office and 
shipped to the central laboratory for analysis or obtained via an in-home nursing service (where 
 
 
 
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CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
available). In these specific cases, the sponsor needs to be consulted prior to performing these 
blood draws to assess logistics and obtain local laboratory details. In addition, to ensure the 
medical care of the individual study subject is maintained, the investigator remains responsible for 
all subject procedures performed during the study and communication with the subject must be 
continued. Proper documentation is required in the source documents at the investigative site in 
these cases.
Any or all laboratory assessments may be repeated more frequently if clinically indicated.  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.
Refer to Section 11.3 for guidance on abnormal laboratory values and test results.
6.6.6
Serum Ferritin
Samples for testing serum ferritin level are collected on Day 1 of Cycle 1, on Day 1 of every 3 
cycles thereafter (eg, Day 1 of Cycles 4, 7, 10, 13, etc.) and at Treatment Discontinuation.  The 
serum ferritin is tested by the central laboratory.
6.6.7
Pregnancy Test
For females of childbearing potential (FCBP, please refer to Section 6.1.19 for definition of FCBP) 
a serum or urine pregnancy test (investigator’s discretion; sensitivity of at least 25 mIU/mL) is to
be done within 72 hours prior to Day 1 of every cycle in the treatment phase and at the Treatment 
Discontinuation visit (note that the screening serum pregnancy test can be used as the test prior to 
starting study therapy in the treatment phase if it is performed within the 72-hour timeframe).
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 6.1.19.
6.6.8
Concomitant Medications/Significant Non-drug Therapies/Concomitant 
Procedures
All concomitant over-the-counter/prescription medications/procedures, taken from the date of 
randomization until 28 days after the last dose of the IP or until the last study visit, whichever 
period is longer, must be recorded on the appropriate CRF page.  See Section 9 for details 
regarding concomitant medications and procedures.
6.6.9
Eastern Cooperative Oncology Group Performance Status
Eastern Cooperative Oncology Group Performance status is to be assessed before IP 
administration on Day 1 of each cycle in the treatment phase and at Treatment Discontinuation.
6.7
Efficacy
6.7.1
Transfusion Assessment
The type, number of units, reason and date of transfusions are to be collected after the date of 
randomization and until 28 days after the last dose of IP or until the last study visit, whichever 
 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
occurs later.  The Hgb value for which any RBC transfusion is given, and the platelet value for 
which any platelet transfusion is given, must also be recorded on the CRF.  Red blood cell and/or 
platelet transfusions administered for elective surgery will not count toward baseline requirement, 
efficacy assessment, or progressive disease status.
6.7.2
Assessment of Bleeding Events
An assessment of all bleeding events during the treatment phase should be performed weekly on 
Day 1, 8, 15 and 22 of Cycles 1-2, biweekly on Day 1 and 15 of Cycles 3-12, and on Day 1 of each 
treatment cycle thereafter and at Treatment Discontinuation.  Information for each bleeding event 
should be recorded on the appropriate CRF.
The investigative site may inquire about signs and symptoms of bleeding events via a phone call 
made to the subject.  All phone calls made to the subject should be performed by a medically-
qualified person (eg, principal investigator or sub-investigator) at the investigative site and 
adequately documented in the subject’s medical record. 
6.7.3
Bone Marrow Aspirate, Biopsy and Peripheral Blood Smear
 
 
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 the study’s Central Laboratory 
Manual.
6.7.4
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’s Central Laboratory Manual for handling 
instructions]) is obtained for efficacy assessment.
6.7.5
International Working Group Response/Improvement
Response/improvement assessment according to the International Working Group (IWG) criteria 
(Cheson, 2006; Appendix D) is to be performed on Day 1 of Cycles 3, 6, and 12, and every 6 
cycles thereafter (eg, Day 1 of Cycles 18, 24, etc.) and recorded on the CRF.  Due to the turnaround 
time required to obtain results from the central review of bone marrow aspirate (or biopsy if 
adequate aspirate is not attainable), peripheral blood smear and cytogenetics, IWG 
response/improvement assessment could be done at any time prior to starting the next cycle (eg, 
prior to starting Cycles 4, 7, 13, etc., respectively).
6.7.6
Disease Status Assessment
An assessment of disease status must be performed at the end of Cycle 6, prior to starting Cycle 7.
 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022

If subjects have met any of the following criteria, subjects can continue on to Cycle 7 
and beyond, and will be assessed for disease status at the end of every cycle:
o
RBC transfusion independence, or
o
platelet transfusion-independence for those subjects who were platelet 
transfusion dependent at baseline, or
o
Hematologic Improvement (HI; Cheson, 2006; Appendix D), or
o
≥ 50% reduction in average RBC transfusion requirement in the 56-day (8-
week) period immediately prior to disease status assessment as compared to the 
average baseline RBC transfusion requirement, or
o
any other clinical benefit, including no evidence of progressive disease (see 
Section 12 for definitions of progressive disease).
Thereafter, subjects may be discontinued from protocol-prescribed therapy for any of 
the reasons detailed in Section 12.

If subjects have failed to meet any of the above criteria at the end of Cycle 6, subjects 
will be discontinued from protocol-prescribed therapy.
The decision to discontinue a subject, which will not be delayed or refused by the sponsor, remains 
the responsibility of the treating physician.  However, prior to discontinuing a subject, the 
investigator may contact the Medical Monitor and forward appropriate supporting documents for 
review and discussion.
Confirmation of response requires the investigator to document the Hgb and platelet levels in the 
subject’s medical records demonstrating the required increase from the baseline measurement
according to Appendix D; and the dates and units of the RBC/platelet transfusions that validate 
the erythroid/platelet response, respectively.  In the event that immediate laboratory assessment is 
needed for disease status assessment, local laboratory measurement is acceptable 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).
6.7.7
Serum EPO Level
Serum EPO level should be tested on Day 1 of Cycle 6.  However, if possible, the serum EPO 
level should not be collected within 1 week after any RBC transfusion (if applicable) due to 
possible reduction of the serum level related to the hemoglobin level achieved after the last 
transfusion.  Therefore in the event that Day 1 of Cycle 6 would be scheduled within a week of a 
RBC transfusion, EPO sampling may be performed on Day 1 of the following cycle. Refer to 
Section 6.1.14 for guidance on serum EPO level testing at screening.
6.7.8
Progression to AML
Refer to Section 6.6.2 for guidance on monitoring progression to AML.
6.7.9
Survival and Subsequent MDS Therapies
All subjects discontinued from protocol-prescribed therapy for any reason should undergo 
Treatment Discontinuation procedures (Section 6.13) and be followed for survival and subsequent 
MDS therapies (Section 6.14).
 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
6.8
Health-related Quality of Life
The FACT-An (Cella, 1997) is a validated HRQoL measure applicable to subjects with any cancer 
diagnosis.  In addition to general quality of life concerns, it provides specific information regarding 
fatigue and anemia.  It is composed of 47 questions that address physical, social/family, emotional, 
and functional well-being, as well as other concerns (Appendix E).  The FACT-An is available in 
many languages and it takes approximately 10 to 15 minutes to complete.
The EQ-5D (EQ-5D-3L) is a standardized instrument for use as a measure of health outcome.  It 
provides a simple descriptive profile and a single index value for health status, and is applicable 
to a wide range of health conditions and treatments (Appendix F).  The EQ-5D is available in many 
languages and it takes approximately 5 minutes to complete.
The FACT-An and EQ-5D questionnaires should be completed prior to interaction with study 
personnel (when feasible) and prior to IP administration on Day 1 of every Cycle and at the 
Treatment Discontinuation visit.  It is important that every subject completes all of the FACT-An 
and EQ-5D at every specified time point to minimize the amount of missing data.
6.9
Healthcare 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 progression, MDS-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 MDS-related illness (eg, RBC or platelet 
transfusions for anemia or thrombocytopenia, infection), or for treatment-related adverse events.  
Additionally, information on all concomitant medications (eg, G-CSF, anti-infective treatments, 
etc.) and resource use associated with treatment administration for MDS 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 
period is longer.
 
 
 
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CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
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 decision to discontinue a subject, which will not be delayed or refused by the sponsor, remains 
the responsibility of the treating physician.  However, prior to discontinuing a subject, the 
investigator may contact the Medical Monitor and forward appropriate supporting documents for 
review and discussion.
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 to AML and second primary malignancy, 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, clinically significant bleeding events, disease status 
assessment, subsequent MDS therapies, IP accountability, HRQoL, and healthcare resource 
utilization.
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
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.
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, transfusions 
administered 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, subsequent MDS therapies, progression to AML and second primary malignancy
every month for the first year following Treatment Discontinuation and every three months 
thereafter until death, lost to follow-up, or withdrawal of consent for further data collection.  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
Following unblinding, subjects could enter the Extension Phase to continue to receive oral 
azacitidine and/or be followed for survival. See details for EP in Appendix J.
 
 
 
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CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
7
STUDY POPULATION
7.1
Number of Subjects and Sites
The study population consists of 216 subjects who are ≥ 18 years old with RBC transfusion-
dependent anemia and thrombocytopenia (platelet count ≤ 75 x 109/L) due to IPSS lower-risk 
MDS.
The study will be conducted at approximately 150 clinical study sites worldwide.
7.2
Inclusion Criteria
Subjects must satisfy the following criteria to be enrolled in the study:
1. Age ≥ 18 years§ at the time of signing the informed consent document
2. Have a documented diagnosis of MDS according to WHO 2008 classification 
(Appendix A)
3. Be RBC transfusion-dependent as defined by:

Average transfusion requirement of ≥ 2 units** per 28 days of RBCs confirmed for a 
minimum of 56 days immediately preceding randomization (please note that the period 
covering the transfusion history overlaps with the screening phase)

Hemoglobin levels at the time of or within 7 days prior to administration of an RBC 
transfusion must have been ≤ 10.0 g/dL in order for the transfusion to be counted 
towards RBC transfusion-dependent status.  Red blood cell transfusions 
administered when Hgb levels were > 10.0 g/dL and/or RBC transfusions 
administered for elective surgery will not qualify as a required transfusion for the 
purpose of providing evidence of RBC transfusion-dependent status

No consecutive 28 days that are RBC-transfusion-free during the 56 days 

immediately preceding randomization
4. Have thrombocytopenia as defined by two platelet counts that are ≤ 75 x 109/L and
≥21 days apart. The second confirmatory platelet count must be obtained ≤ 14 days prior 
to randomization

At least one platelet count must be centrally analyzed within the 56 day screening 
period with results of ≤ 75 x 109/L; the second platelet count may be centrally or locally 
analyzed, with results that are also ≤ 75 x 109/L.  

Prior documented medical history of thrombocytopenia may be used to demonstrate 
eligibility for the study if at least one historical platelet count of ≤75 x 109/L was 
obtained within 56 days of randomization and ≥ 21 days apart from the centrally 
analyzed platelet count.

If additional platelet counts were obtained during the interim period, these must also 
have been ≤ 75 x 109/L. If platelet counts within the interim period are > 75 x 109/L, 
this would be acceptable only if directly associated with a platelet transfusion 
administered within 7 days prior to the date of the platelet count. 
                                                       
§
In Japan, both the subject and the subject’s legal representative must sign an informed consent document in case the age of 
the subject has not reached 20 years.
** As is consistent with medical practice in Japan, 1 unit RBC referenced in this protocol is equivalent to 2 units RBC in Japan.
 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
5. Have an ECOG performance status of 0, 1, or 2 (Appendix C)
6. Females of childbearing potential (FCBP) †† may participate, providing they meet the 
following conditions:

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 IP and

Have a negative serum pregnancy test at screening (Section 6.1.19); and

Have a negative serum or urine pregnancy test (investigator’s discretion; sensitivity of 
at least 25 mIU/mL) within 72 hours prior to starting IP in the treatment phase (note 
that the screening serum pregnancy test can be used as the test prior to starting study 
therapy in the treatment phase if it is performed within the 72-hour timeframe) (Section 
6.6.7)
7. Male subjects with a female partner of childbearing potential must agree to the use of at 
least two physician-approved contraceptive methods throughout the course of the study 
and should avoid fathering a child during the course of the study and for 3 months following 
the last dose of IP
8. Understand and voluntarily sign an informed consent document prior to any study related 
assessments/procedures being conducted
9. Able to adhere to the study visit schedule and other protocol requirements
7.3
Exclusion Criteria
The presence of any of the following will exclude a subject from enrollment:
1. IPSS higher-risk (INT-2 or High risk) MDS (Appendix B)
2. Secondary MDS, ie MDS that is known to have arisen as the result of chemical injury or 
treatment with chemotherapy and/or radiation for other diseases, unless subject received 
last dose from prior antineoplastic therapy ≥24 weeks prior to randomization
3. Hypoplastic MDS or other subtype with eligibility for treatment with immunotherapy
based on investigator’s judgment, unless subject received last dose from prior Chemo~ or 
Immunotherapy ≥24 weeks prior to randomization
4. CMML, atypical chronic myeloid leukemia (CML) and unclassifiable myeloproliferative 
disease (MPD)
5. Prior treatment with any of the following:

Azacitidine (any formulation), decitabine or other hypomethylating agent

Lenalidomide, unless the subject received the last dose ≥ 8 weeks prior to 
randomization
6. Prior allogeneic or autologous stem cell transplant
7. History of inflammatory bowel disease (eg, Crohn’s disease, ulcerative colitis), celiac 
disease (ie, sprue), prior gastrectomy or upper bowel removal, or any other gastrointestinal 
                                                       
†† 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 (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive 
months (ie, has had menses at any time during the preceding 24 consecutive months).
 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
disorder or defect that would interfere with the absorption, distribution, metabolism or 
excretion of the IP and/or predispose the subject to an increased risk of gastrointestinal 
toxicity
8. Thrombocytopenia secondary to other possible causes, including medication(s), congenital 
disorder(s), immune disorder(s) (eg, idiopathic thrombocytopenic purpura [ITP]), or 
microvascular disorder(s) (eg, disseminated intravascular coagulation, hemolytic uremic 
syndrome, thrombotic thrombocytopenic purpura)
9. Use of any of the following within 28 days prior to randomization:

cytotoxic, chemotherapeutic, targeted or investigational agents/therapies

thrombopoiesis-stimulating agents (TSAs; eg, Romiplostim, Eltrombopag, Interleukin-
11)

ESAs and other RBC hematopoietic growth factors (eg, Interleukin-3)

hydroxyurea
10. Ongoing medically significant adverse events from previous treatment, regardless of the 
time period
11. Concurrent use of any of the following:

iron-chelating agents, except for subjects on a stable or decreasing dose for at least 
8 weeks (56 days) prior to randomization

corticosteroid, except for subjects on a stable or decreasing dose for ≥ 1 week prior to 
randomization for medical conditions other than MDS
12. Prior history of malignancies, other than MDS, unless the subject has been free of the 
disease for ≥ 3 years.  However, subjects with the following history/concurrent conditions 
are allowed:

Basal or squamous cell carcinoma of the skin

Carcinoma in situ of the cervix

Carcinoma in situ of the breast

Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, 
metastasis [TNM] clinical staging system)
13. Significant active cardiac disease within the previous 6 months, including:

New York Heart Association (NYHA) class IV congestive heart failure (see Appendix 
G);

Unstable angina or angina requiring surgical or medical intervention; and/or

Myocardial infarction
14. Uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing 
signs/symptoms related to the infection without improvement despite appropriate
antibiotics, antiviral therapy, and/or other treatment)
15. Known Human Immunodeficiency Virus (HIV) or Hepatitis C (HCV) infection, or 
evidence of active Hepatitis B Virus (HBV) infection
16. Abnormal coagulation parameters (PT > 15 seconds, PTT > 40 seconds, and/or INR > 1.5).  
After consultation with the medical monitor, higher than normal range levels may be
acceptable if the subject is being treated with a stable dose of anticoagulants for thrombotic 
 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
prophylaxis (ie with atrial fibrillation, previous thromboembolic event, mechanical cardiac 
valve replacement or presence of lupus or antiphospholipid antibodies).  The decision to 
include such patients would be the responsibility of the investigator.   
17. Any of the following laboratory abnormalities:

Serum AST/SGOT or ALT/SGPT > 2.5 x upper limit of normal (ULN) unless these 
abnormal liver function test(s) can be attributed to iron overload as demonstrated by a 
serum transferrin saturation of > 65% and a serum ferritin of > 1000 µg/L

Serum bilirubin > 1.5 x ULN.  Higher levels are acceptable if these can be attributed to 
active red blood cell precursor destruction within the bone marrow (ie, ineffective 
erythropoiesis) or in the presence of known history of Gilbert Syndrome.  Subjects are 
excluded if there is evidence of autoimmune hemolytic anemia manifested as a 
corrected reticulocyte count of > 2% with either a positive Coombs’ test or over 50% 
of indirect bilirubin

Serum creatinine > 2.5 x ULN
18. Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or 
autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding.  Iron deficiency 
would be determined by a bone marrow aspirate stain for iron, the transferrin saturation 
(iron/total iron binding capacity [Fe/TIBC] ≤ 20%), or serum ferritin ≤ 15 ng/mL
19. Known or suspected hypersensitivity to azacitidine or mannitol
20. Pregnant or lactating females
21. Any significant medical condition, laboratory abnormality, or psychiatric illness that would 
prevent the subject from participating in the study
22. Any condition including the presence of laboratory abnormalities, which places the subject 
at unacceptable risk if he/she were to participate in the study
23. Any condition that confounds the ability to interpret data from the study
 
 
 
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CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
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.  Details of the specific formulations will 
be provided in the azacitidine IB.
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.  IP will be monitored for stability for the 
duration of the study.
8.2
Treatment Administration and Schedule
As of Amendment 3.0, all subjects in Cycles 1 or 2 will receive CC-486 for 14 days of a 28-day 
cycle schedule. Subjects may increase to a 21-day schedule at the conclusion of Cycle 2 if there 
are no Grade 3 or 4 toxicities requiring dose delay or reductions and if there is no evidence of 
hematological improvement upon discussion and agreement between investigator and the Medical 
Monitor. Subjects remaining beyond Cycle 2 will continue to receive 300 mg oral azacitidine or 
matching placebo QD for 21 days of each 28-day treatment cycle as described in Section 8.3.  In 
the event of toxicity, dose and schedule may be modified (see Section 8.2.4).  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 decision to discontinue 
a subject, which will not be delayed or refused by the sponsor, remains the responsibility of the 
treating physician.  However, prior to discontinuing a subject, the investigator may contact the 
Medical Monitor and forward appropriate supporting documents for review and discussion.
8.2.1
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.
 
 
 
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CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
8.2.2
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 21 days of each 28-day treatment cycle, 
unless there has been a schedule modification of IP administration due to toxicity.  On 
 
days, IP will be administered by the study site personnel in the clinic.  Subjects 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 at the investigator´s discretion (Section 9.1).  
The 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 (a light breakfast or meal 
of up to approximately 600 calories can be provided as a guidance).
Refer to Section 8.6 for details regarding IP accountability.
8.2.3
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.
8.2.4
Dose Modifications
All subjects in Cycle 1 or 2 will receive CC-486 for 14 days of a 28-day cycle schedule.  Subjects 
may increase to a 21-day schedule (Level +1) at the conclusion of Cycle 2 if no Grade 3 or 4 
toxicities requiring dose delay or reductions and if no evidence of hematological improvement 
upon discussion and agreement between the investigator and the Medical Monitor.
When the dose level is adjusted, weekly hematology monitoring is required for 2 cycles including 
the cycle in which the adjusted dose or dosing schedule was applied as well as the following cycle, 
see Section 8.2.5 Re-treatment Criteria.
The dose/treatment schedule modifications steps for 14 days schedule are:
Dose/schedule
300 mg/21d
Level +1
Dose escalation step
300 mg/14d
Level 1
Dose escalation step
200 mg/14d
Dose reduction step
Level -1
Dose escalation step
200 mg/7d
Dose reduction step
Level-2
 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
All efforts should be made to dose IP according to schedule without cycle delay, dose interruption 
and reduction.  Subjects will be monitored for hematologic toxicity and non-hematologic toxicity 
with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE, Version 4.0) used as a guide for the grading of severity.
If a certain level of toxicity is observed (eg, Table 2) and considered by the investigator to be at 
least possibly related to treatment, IP dosing may be interrupted, delayed or modified.  The 
investigator may contact the Medical Monitor prior to any treatment adjustment.  Please note that 
in the event neutropenia Grade 4 is observed, or any adverse event that would put a subject at 
unacceptable risk in the investigator´s opinion, IP dosing may be interrupted, delayed or modified 
even if not considered by the investigator to be at least possibly related to treatment.
A maximum of one dose reduction step to 200 mg is permitted in the event of toxicity.  A maximum 
of two treatment schedule modifications, stepwise first from 21 to 14 days and then from 14 days 
to 7 days, at a dose of 200 mg once a day are permitted in the event of continuing toxicity.  Subjects 
are not allowed to 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 
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 and then 14 to 21 days, followed by a dose escalation step from 200 to 300 mg.
The dose/treatment schedule modifications steps for 21 days schedule are:
Dose/schedule
300 mg/21d
Level 1
Dose escalation step
200 mg/21d
Dose reduction step
Level -1
Dose escalation step
200 mg/14d
Dose reduction step
Level -2
Dose escalation step
200 mg/7d
Dose reduction step
Level -3
Refer to Section 8.2.5 if, despite the temporary interruption, delay or modification of study 
treatment, the toxicity persists for more than 42 days and is considered by the investigator to be at 
least possibly related to study treatment.
Following any modification of study treatment or if a dose is missed, the subject should stay on 
the visit schedule as specified in Table 1.  Unscheduled visits may occur to monitor the subject’s 
toxicities if necessary.  
 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
Dose Modification for Febrile Neutropenia
Any subject who experiences febrile neutropenia ≥Grade 3 will have IP held until fever has 
resolved; must be afebrile for 3 days before re-starting IP, see Table 2.  Administration of 
antibiotic, antiviral and antifungal therapy is strongly recommended.
Dose Modification for Neutropenia Grade 4

Grade 4 ANC at Day 1 of a cycle:
Subjects with Grade 4 ANC at Day 1 of a cycle are going to be dosed for a maximum of 
14 days on the respective dose level 300 mg or 200 mg or a maximum of 7 days when 
already on a 14-day dosing schedule.  If a subject is stable or improving over several cycles, 
a discussion with the Medical Monitor is necessary to determine the dose schedule, see 
Table 2.

ANC change during a cycle:
Subjects who experience a drop in the ANC during a cycle (e.g. from Grade 3 to Grade 4 
or for > 50% drop for subject with Grade 4 at Day 15 or Day 8 [Day 8 during the 1st two 
cycles]) will hold the dose for the remaining cycle. If subject is stable or improving for 
several cycles, a discussion with the Medical Monitor is necessary to determine the dose 
schedule, see Table 2.

If dose was held, the start of next cycle is based on ANC recovery, see flow chart in Section 
8.2.5 Re-Treatment Criteria, and see dosing table above.
Dose Modification for Diarrhea
It is recommended that subjects experiencing diarrhea be managed according to the guidelines 
provided in Appendix H.  Anti-diarrhea medication may be administered as prophylaxis against 
diarrhea and for treatment of any adverse events of diarrhea.  Dose modifications for diarrhea 
(≥Grade 3) are summarized in Table 2.
Dose Modification for Nausea and Vomiting
A serotonin (5-HT3) receptor antagonist (eg, ondansetron) (or other comparable medication) may 
be administered as an antiemetic approximately 30 minutes prior to IP administration at the 
investigator´s discretion.  Antiemetic medication(s) may be administered for treatment of any 
adverse events of nausea and/or vomiting.  Dose modifications for nausea and vomiting 
(≥Grade 3) are summarized in Table 2.
Dose Modification for Renal Dysfunction and Abnormal Serum Electrolytes
If unexplained elevations of serum creatinine or electrolyte disturbances occur, dose or schedule 
modifications may be implemented as summarized in Table 2.
 
 
 
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CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
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 Table 2.  
Dose Modification for Other Treatment-Related Non-hematologic Toxicity
Any subject who experiences a treatment-related non-hematologic toxicity ≥Grade 3, that is an 
escalation from baseline status (see Section 10.4 for baseline definition), may have IP dosing 
temporarily interrupted until the toxicity returns to ≤ Grade 2.  Dose modifications for ≥Grade 3 
non-hematologic toxicity are summarized in Table 2.
Dose modification for hematologic or non-hematologic adverse events that would put a 
subject at unacceptable risk in the investigator´s opinion (independent of IP relationship)
Any subject who experiences any hematologic or non-hematologic adverse event ≥ Grade 2, that 
is an escalation from baseline status (see Section 10.4 for baseline definition) and would put a 
subject at unacceptable risk in the investigator´s opinion, may have IP dosing temporarily 
interrupted until the adverse event returns to ≤ Grade 1.  Dose modifications for ≥Grade 2 
hematologic or non-hematologic adverse events, that would put a subject at unacceptable risk in 
the investigator´s opinion (independent of IP relationship), are summarized in Table 2.
 
 
 
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CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
Table 2:
Guidelines for Dose Modifications
NCI CTCAE Toxicity Grade 
Action
Febrile Neutropenia 
(≥Grade 3)

Hold IP until fever has resolved. 

Antibiotic, antiviral and antifungal therapy is strongly 
recommended.

Resume IP at next lower dose level (see dosing table 
above) after the fever has resolved and ANC recovery.  
Contact Medical Monitor.  Must be afebrile for 3 days 
before re-starting IP.

Secondary prophylaxis with G-CSF is strongly recommended.
Neutropenia Grade 4
(related or unrelated to IP) 
Pre-existing Neutropenia Grade 4

Subjects with G4 ANC at D1 of a cycle are going to be dosed 
for a maximum of 14 days on the respective dose level 300 mg 
or 200 mg or a maximum of 7 days when already on a 14-day 
dosing schedule. 
If subjects are stable or improving for several cycles, a 
discussion with the Medical Monitor is necessary to determine 
the dose schedule. 

If dose was held, the start of next cycle is based on ANC 
recovery, see flow chart in Section 8.2.5 Re-Treatment Criteria

If the subject continues to experience neutropenia Grade 4 
during 2 consecutive cycles, the treatment schedule may be 
reduced one step. Secondary prophylaxis with G-CSF is 
strongly recommended.
Subjects experiencing worsening of Neutropenia to Grade 4 under 
IP treatment

Subjects that experience a drop in the ANC during a cycle (e.g.,
from G3 to G4 or for > 50% drop for subject with G4 at Day 15 
or Day 8 [Day 8 during the 1st two cycles]) will hold the dose 
for the remaining cycle. 
If subject is stable or improving for several cycles, a discussion 
with the Medical Monitor is necessary to determine the dose 
schedule.

If dose was held, the start of next cycle is based on ANC 
recovery, see flow chart in Section 8.2.5 Re-Treatment Criteria.

If the subject continues to experience neutropenia Grade 4 
during 2 consecutive cycles, the treatment may be reduced one 
step. Secondary prophylaxis with G-CSF is strongly 
recommended.
 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
Table 2:
Guidelines for Dose Modifications
NCI CTCAE Toxicity Grade 
Action
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 IP dose is reduced to 
200 mg, follow the steps above and modify the treatment 
schedule at a dose of 200 mg once a day. 
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

If event reoccurs at same intensity once IP dose is reduced to 
200 mg, follow the steps above and modify the treatment 
schedule at a dose of 200 mg once a day.  
Renal Dysfunction

For unexplained elevations of serum creatinine, delay the start 
of the next cycle of treatment until values return to baseline.  
Reduce IP dose in the next cycle of treatment to 200 mg.

The treatment schedule at a dose of 200 mg once a day can be 
modified if the elevation of serum creatinine recurs in the 
subsequent cycle.  

Discontinue IP if similar unexplained renal and/or electrolyte 
disturbances subsequently persist or recur during the next cycle 
of treatment.
Other Grade 3 
non-hematologic
treatment-
related toxicities

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, IP dose may be reduced to 200 mg once a 
day

If event reoccurs at same intensity once IP dose is reduced to 
200 mg once a day, follow the steps above and modify the 
treatment schedule at a dose of 200 mg once a day.  
Grade 2 
hematologic 
or 
non-
hematologic AEs putting
a 
subject at unacceptable risk in 
the investigator´s opinion

Interrupt IP dosing and provide medical intervention as 
appropriate

Resume IP at same dose when toxicity resolves to Grade 1
 
 
 
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CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
Table 2:
Guidelines for Dose Modifications
NCI CTCAE Toxicity Grade 
Action
(related or unrelated to IP)

If event reoccurs upon re-challenge or at same intensity during 
next treatment cycle, IP dose may be reduced to 200 mg once a 
day

If event reoccurs at same intensity once IP dose is reduced to 
200 mg, follow the steps above and consider modifying the 
treatment schedule at a dose of 200 mg once a day.  
Key: AE=Adverse Event; ANC=Absolute Neutrophil Count; D=Day; G=Grade; IP=Investigational Product; 
NCI=National Cancer Institute; CTCAE=Common Terminology Criteria for Adverse Events.
8.2.5
Re-treatment Criteria
In order to proceed to the next cycle, subjects must continue to meet entry criteria regarding renal 
and hepatic function (see Section 7.3).  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.
For subjects that experience hematotoxicity (ANC or platelet drop to Grade 4, or 50% drop within 
Grade 4) hematologic recovery is required before starting the next cycle at Day 28.  When this 
occurs later than Cycle 6, contact the Celgene Medical Monitor to discuss if the re-treatment 
criteria are met.
Hematologic recovery defined as:
ANC or platelets Day 1 ≥ ANC or platelets nadir from previous Cycle + (0.5 x [ANC or platelets Day 1
– ANC or platelets nadir from previous Cycle])
Note: Following dose adjustments, cycle duration should return to 28 days.
 
 
 
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CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
Figure 2:
Decision Tree for Hematologic Recovery
ANC=Absolute Neutrophil Count; IP=Investigational Product.
When the dose level is adjusted, weekly hematology monitoring is required for 2 cycles including 
the cycle in which the adjusted dose or dosing schedule was applied as well as the following cycle.  
During those 2 cycles, the following dose modification rule, based on ANC or platelets, is applied:

Subjects that experience a drop in the ANC or platelets during a cycle (drop to Grade 
4 or for > 50% drop for subject with Grade 4 at Day 15 or Day 8) will hold the dose for 
the remaining cycle.
Did ANC or platelets on Day 1 (ie Day 28 of previous 
cycle) recover?
Start Cycle at same 
dose schedule
Delay IP treatment 1 
week
YES
NO
Did ANC or platelets 1 week later (ie Day 35 of previous 
cycle) recover?
Start Cycle at same 
dose schedule
Contact Celgene Medical Monitor to discuss 
delaying IP treatment 1 week
YES
NO
Did ANC or platelets 1 week later (ie Day 42 of previous 
cycle) recover?
Start Cycle at next reduced dose schedule; see 
dosing table in Section 8.2.4 Dose 
Modifications
Contact Celgene Medical Monitor to discuss further 
delay, starting on a reduced dose level, or 
discontinuation of IP treatment
YES
NO
 
 
 
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CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022

If dose was held, the start of next cycle is based on ANC or platelet recovery, see flow 
chart in Section 8.2.5 Re-Treatment Criteria.
8.3
Method of Treatment Assignment
Subjects will be randomized to receive oral azacitidine or placebo in a 1:1 ratio.  Randomization 
will be accomplished by IRT to ensure timely registration and randomization.
Investigator or designated site staff will be assigned password protected, coded identification 
numbers that give them authorization to access the IRT system to enroll subjects.  At screening, 
the investigator or designated staff will access the IRT system and provide the requested 
identifying information for the subject. The IRT system 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 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 IRT system must be notified.
Randomization will be performed using the following procedure to insure that treatment 
assignment is unbiased and concealed from subjects and investigators. A subject randomization 
list will be produced by the IRT system 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 investigator.  In addition the sponsor will review key eligibility criteria 
including central lab, pathology and cytogenetic reports prior to randomization of a subject. Then
the investigator or designated staff will access the IRT system and confirm that the subject fulfills 
all the inclusion and exclusion criteria prior to randomization.  The IRT system 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 average 
baseline RBC transfusion requirement (≤ 4 units‡‡ versus > 4 units of RBC per 28 days), baseline 
platelet transfusion status (dependent or independent), country of enrollment (ie, Japan versus Rest 
of World [ROW]) and ECOG performance status (0 to 1 versus 2).  The stratification on country 
of enrollment is due to the different transfusion treatment practices in Japan versus those in other 
countries.  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 
                                                       
‡‡
As is consistent with medical practice in Japan, 1 unit RBC referenced in this protocol is equivalent to 2 units RBC in Japan.
 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
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 IP shipping order form.  The investigator(s) or 
designee(s) will verify the accuracy of the information on the form and access the IRT system to 
register the IP 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.
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 IP 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 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
IP will be administered by the study site personnel in the clinic on 
 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 
 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
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.
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 all subjects randomized 
have received at least 12 months of treatment, or have discontinued from the study, whichever 
occurs first.  At this point specific Celgene Corporation clinical and medical personnel may be 
unblinded to treatment assignment information in order to perform a final analysis on the primary 
efficacy endpoint and an interim analysis for the key secondary endpoint of OS.  The decision to 
unblind when all randomized subjects have completed 12 months of treatment or discontinued 
from the study, whichever occurs first, will depend upon the total number of deaths that have 
occurred at that time.  Refer to protocol Sections 10.3 and 10.8 for further details.
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 only be 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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CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
9
CONCOMITANT MEDICATIONS AND PROCEDURES
All prior and concomitant medications (prescription and non-prescription), treatments and 
therapies taken from the 8-week period (56 days) prior to randomization up to 28 days after the 
last dose of IP or up to the last study visit, whichever period is longer, must be recorded on the 
appropriate CRF.  
All prior treatments for MDS, including ESAs, TSAs, iron-chelating agents, chemotherapy, 
cytotoxic therapy, investigational agents or other medications considered supportive care for MDS 
should be recorded on the respective CRF(s) regardless of discontinuation date of treatment.
Concomitant medications should be kept to a minimum during the study.  However, if considered 
necessary for the subject’s welfare and are unlikely to interfere with the IP, they may be given at 
the discretion of the investigator.
9.1
Permitted Concomitant Medications and Procedures
Best supportive care may be used in combination with study therapy if deemed necessary.  Best 
supportive care in both treatment arms for this study includes, but is not limited to, treatment with 
RBC or whole blood transfusions, fresh frozen plasma transfusions, single donor or pooled donor 
platelet transfusions, antibiotic, antiviral and/or antifungal therapy, nutritional support as needed,
and granulocyte colony stimulating factors for subjects experiencing neutropenic fever/infections.  
The use of granulocyte colony stimulating factors is also allowed for secondary prophylaxis under 
certain conditions as described further below.  The use of these products will be considered as 
concomitant treatment and documented as concomitant medications, therapies or procedures.  
Additional details on the permitted treatments are detailed below.
Subjects who are currently using iron-chelating agents should be on a stable or decreasing dose 
for at least 8 weeks (56 days) prior to randomization.
Blood product support (RBCs and platelets) may be administered according to institutional 
standards.  Consider platelet transfusion if platelet counts are < 25 x 109/L. If appropriate 
administration of platelets does not correct the platelet counts, contact the Medical Monitors to 
consider IP dosing delay.  The use of these products will be considered as concomitant treatment, 
and should be collected on the appropriate CRF.
Subjects may be administered supportive and palliative care (eg, pain control) as clinically 
indicated throughout the study.
Nausea and vomiting are commonly reported adverse reactions associated with azacitidine 
treatment and subjects may be pre-medicated for nausea and vomiting prior to IP administration
at the investigator´s discretion.  Serotonin (5-HT3) receptor antagonists (eg, ondansetron) or other 
antiemetics may be administered approximately 30 minutes prior to IP administration.  Additional 
doses of serotonin (5-HT3) receptor antagonists or other antiemetics may be administered if 
required.  Pre-treatment or post-treatment with antiemetic medication will be considered as 
concomitant treatment and should be recorded on the appropriate CRF.
Treatment with antidiarrheal medications is recommended at the first sign of diarrhea as per the 
guidelines in Appendix H.  Pre-medication with antidiarrheal medication for subsequent doses of 
 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
azacitidine may be appropriate.  Pre- and post-treatment with an antidiarrheal must be recorded in 
the CRF as concomitant medication.
Myeloid growth factors (G-CSF and granulocyte macrophage colony-stimulating factor [GM-
CSF]) may be given per investigator’s discretion for the treatment of neutropenic fever/infections
as well as for secondary prophylaxis (ie, prophylactic use of myeloid growth factors if the subject 
had a previous event of neutropenic fever/infection or neutropenia Grade 4 during the treatment 
phase of the study) and the safety of the patient is considered jeopardized by subsequent episodes 
of neutropenic fever/infections or Grade 4 neutropenia.  
For subjects who develop an ANC < 0.5 x 109/L, administration of prophylactic fluoroquinolone 
antibiotics (eg, ciprofloxacin or levofloxacin or other recognized prophylactic antibiotics) is 
strongly recommended and should be documented as a concomitant medication on the appropriate 
CRF.  If neutropenic fever/infection occurs, treatment should consist of a broad spectrum 
antibiotic, and if the investigator deems the use of a myeloid growth factor to be medically 
important, myeloid growth factors may also be administered.  In case of use of secondary 
prophylaxis with myeloid growth factors, the dose modification guidelines detailed in Section 
8.2.4 remain applicable. Discontinuation of secondary prophylaxis with myeloid growth factors 
should be considered by the investigator as clinically appropriate.
Concurrent corticosteroids for medical conditions other than MDS is allowed provided subject is 
on a stable or decreasing dose for ≥ 1 week prior to randomization.
9.2
Prohibited Concomitant Medications and Procedures
Best supportive care for this study specifically excludes cancer surgery, immunotherapy, biologic 
therapy, radiotherapy, anticancer hormonal therapy, and systemic chemotherapy where the goal is 
to eradicate or slow the progression of the disease.
The following concomitant medications are specifically excluded during the course of the study:

Cytotoxic, chemotherapeutic, targeted or investigational agents/therapies

Azacitidine, decitabine or other demethylating agents

Lenalidomide, thalidomide and other immunomodulating drugs (IMiDs)

Erythropoietin stimulating agents and other RBC hematopoietic growth factors (eg,
Interleukin-3).

Romiplostim and other TSAs (eg, Interleukin-11, Eltrombopag)

Hydroxyurea

Androgens, unless to treat hypogonadism

Oral retinoids (topical retinoids are permitted)

Arsenic trioxide

Interferon
Refer to Section 7.3 for exclusion criteria pertaining to prohibited concomitant medications.
 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
9.3
Required Concomitant Medications and Procedures
Not applicable.
 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
10
STATISTICAL ANALYSES
The sections below provide an overview of the proposed statistical considerations and 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 RBC transfusion-dependent anemia and 
thrombocytopenia (platelet count ≤ 75 x 109/L) due to IPSS lower-risk MDS.
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 (SDev) 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.
All statistical analyses specified in this protocol will be conducted using SAS® Version 9.2 or 
higher 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, 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 ITT subjects who have at least one 
post-baseline efficacy assessment performed, met all inclusion/exclusion criteria, and received a 
minimum of one cycle of treatment.  
Key efficacy analysis will be performed for the mITT population as supportive evidence and/or 
sensitivity 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 one 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 basis for the power and sample size determination will be a test of the equality of the overall 
survival curves between the azacitidine and placebo treatment groups using a stratified log-rank 
test.  Assuming a median OS of 18 months in the placebo treated group (Garcia-Manero, 2008a), 
which takes into account possible cross-over outside of the protocol of placebo treated subjects to 
active treatment during the observation period, and a median OS of 25.7 months (43% 
 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
improvement) in the azacitidine treated group, 216 subjects (108 in each group) would have 
approximately 72% power to detect a constant hazard rate ratio of 0.70 using a two-sided log rank 
test with an overall significance level of 0.05.  It is assumed that the OS distribution is exponential
with a constant failure (hazard) rate and that accrual is uniform during the accrual period (56
months) with an overall drop-out rate of 5% from both treatment groups.  Full information 
necessary for a log rank test to have 72% power will be achieved when approximately 205 deaths 
have occurred in both treatment groups, which is expected approximately 134 months after 
randomization of the first subject into the study. 
An interim analysis of the OS endpoint may be performed and reported when all subjects have 
completed 12 months (52 weeks [364 days]) of double-blind treatment or have been discontinued 
from treatment (see Section 10.8).
While 56 days (8 weeks) is the standard duration a response must be maintained in order to meet 
the current IWG response criteria (IWG 2006 criteria; Cheson, 2006; Appendix D), limited 
information is available on the target population for estimating the response rate for RBC 
transfusion independence maintained for ≥ 84 days (12 weeks).  
 
 
 
 
  
For the primary efficacy endpoint RBC transfusion independence with a duration ≥56 days (8 
weeks), the response rate for oral azacitidine is assumed to be similar as the above findings.  A 
total sample size of 216 subjects (108 in the active treatment group and 108 in the placebo group) 
will have approximately 99% power to detect the difference between a response rate of 0.30 in the 
active treatment group and a response rate of 0.05 in the placebo group, and approximately 70% 
power to detect the difference between a response rate of 0.15 in the active treatment group and a 
response rate of 0.05 in the placebo group.  The power calculations for response rate are based on 
a two-sided alpha of 0.05 and test statistics on the difference of proportions using an un-pooled 
estimate of variance.
Sample size and power were calculated using the East® Version 5.3 software system (Cytel Inc., 
675 Massachusetts Avenue, Cambridge, MA 02139, http://www.cytel.com).
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, 
SDev, 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 WHO MDS diagnosis classification, 
IPSS risk classification, time since initial MDS diagnosis, ECOG performance status, bone marrow 
blasts (%), Hgb (g/dL), platelet counts (109/L), average baseline RBC transfusion requirement 
 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
(unit of RBC per 28 days), platelet transfusion status (dependent or independent), and IPSS 
cytogenetic classification.  For laboratory and vital sign measures, the most recent assessment on 
or prior to the date of randomization will be used for baseline.  Baseline transfusion history will 
include all transfusions up to and including the date of randomization.  
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 tabulation 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 RBC transfusion independence and the key secondary endpoint of OS, 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 RBC transfusion independence and OS endpoints, formal statistical inference for the OS 
analyses can only be made if superiority of azacitidine is demonstrated for the primary efficacy 
endpoint, RBC transfusion independence, at the two-sided 0.05 significance level.  
The primary efficacy endpoint, RBC transfusion independence, will be analyzed and reported only 
once after all 100% of the information is available for RBC transfusion independence rates (ie, 
after all 216 subjects have completed 12 months (52 weeks [364 days]) of double-blind treatment 
or have been discontinued from treatment).  An analysis of the OS endpoint will also be conducted 
at the time of the analysis of the primary efficacy endpoint.  This analysis of the OS endpoint may 
be an interim analysis or it may be the final analysis, depending on the maturity of the survival 
data (eg, the required 205 deaths have occurred) at the time of the final analysis for the RBC
transfusion independence endpoint.  An O’Brien-Fleming group sequential type boundary will be 
used to preserve the overall alpha level of 0.05 for the analysis of OS in the event that OS is 
analyzed twice.  
The remaining secondary efficacy variables, with the exception of the proportion of subjects 
progressing to AML and time to AML progression, will be analyzed and reported once at the time 
of the analysis of RBC transfusion independence.  Subjects will continue to be followed for 
 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
progression to AML and survival until 205 deaths have been observed.  Other than the pre-
specified sequential testing of RBC transfusion independence and OS, no additional alpha 
adjustments for multiplicity will be made.  
10.6.1
Primary Efficacy Analysis
The primary efficacy endpoint of RBC transfusion independence is defined as the absence of any 
RBC transfusion during any consecutive “rolling” 56 days during the treatment period, ie, Day 1 
to 56, Day 2 to 57, Day 3 to 58, etc.  Subjects with less than 56 days of assessment during the 
double-blind treatment period will be counted as non-responders.  The primary efficacy analysis 
will be performed on the ITT population and will compare the RBC transfusion independence rates 
in the two treatment groups.  The number and percentage of subjects achieving RBC transfusion 
independence and corresponding 95% confidence intervals (CI) will be tabulated and presented by 
treatment group.  A stratified Mantel-Haenszel (MH) chi-squared test, stratifying for average 
baseline RBC transfusion requirement (≤ 4 units§§ versus > 4 units of RBC per 28 days), baseline 
platelet transfusion status (dependent or independent), country of enrollment (ie, Japan versus 
ROW) and ECOG performance status (0 to 1 versus 2), at a two-sided alpha level of 0.05, will be 
used to compare the RBC transfusion independence rate between the two treatment groups.  The 
p-value from the stratified MH chi-square test will be the confirmatory p-value for the test of the 
null hypothesis that the proportion of subjects achieving RBC transfusion independence is equal 
between the two treatment groups.  Summaries will include the difference in proportions between 
the two treatment groups with corresponding 95% CI and the common odds ratio with 
corresponding 95% CI.  Subject listings with supporting data will be provided.
The analysis of the primary endpoint will be repeated for the mITT population as the supportive 
analysis. Additionally, the following sensitivity analyses will be conducted: 

In subjects considered baseline transfusion dependent based on transfusions given for a 
hemoglobin value ≤ 9.0 g/dL for 56 days;

In subjects considered baseline transfusion dependent based on transfusions given for a 
hemoglobin value ≤ 9.0 g/dL for 84 days.
10.6.2
Secondary Efficacy Analyses
10.6.2.1
Key Secondary Efficacy Analyses
Overall survival (OS), defined as the time from randomization to death from any cause, will be 
calculated using randomization date and date of death, or date of last follow-up for censored 
subjects.  Time to death from any cause is defined as the time between randomization and death 
from any cause.  All subjects will be followed until drop-out, death, or study closure.  Drop-out 
may be due to withdrawal of consent from further data collection or lost to follow-up.  Subjects 
who drop-out or are alive at study closure (or at the time of the interim analysis [Section 10.8]) 
will have their OS times censored at the time of last contact, as appropriate.  
The analysis of OS will be performed using the ITT population for the interim and final analysis.  
The null hypothesis for testing the key secondary efficacy endpoint, time to death from any cause, 
                                                       
§§
As is consistent with medical practice in Japan, 1 unit RBC referenced in this protocol is equivalent to 2 units RBC in Japan.
 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
is that the overall survival distributions for the two treatment groups are equivalent.  Overall 
survival curves will be estimated using Kaplan-Meier (KM) methods and will be compared using 
a stratified log-rank test, stratifying by average baseline RBC transfusion requirement (≤ 4 units§§
versus > 4 units of RBC per 28 days), baseline platelet transfusion status (dependent or 
independent), country of enrollment (ie, Japan versus ROW) and ECOG performance status (0 to 
1 versus 2).  The p-value from the stratified log-rank test will be the confirmatory p-value.  The p-
value from the final analysis of the OS endpoint will be adjusted for the interim analysis in order 
to preserve the overall alpha level at 0.05 (see Section 10.8 for further details regarding the interim 
analysis and methods for controlling the overall alpha level).  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.  
At the time of the final OS analysis, 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, will be estimated using KM methods.  The analysis of the 
OS endpoint will be repeated for the mITT-population as a supportive analysis.  
In order to assess the potentially confounding effects of other cancer therapy received subsequent 
to the protocol therapy on the survival estimates, a sensitivity analysis based on the ITT population, 
will be performed using modified censored criteria.  For this analysis, subjects who received 
subsequent therapy for MDS 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 modified time-to-death endpoint will be analyzed using the 
same methods as described above for the key secondary efficacy analysis.
The supportive and sensitivity analyses for the OS endpoint will be performed only at the time of 
the final analysis of OS.
The key secondary study endpoint of OS will be assessed as an interim analysis at the time of the 
primary analysis and in the final analysis at the time of study closure.
10.6.2.2
Additional Secondary Efficacy Analyses
For secondary efficacy analyses, KM methods will be used to estimate curves for time to event 
secondary variables.  Counts and percentages will be used to describe categorical secondary 
variables.  Secondary efficacy analyses will be performed on the ITT population unless otherwise 
specified.
 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
Platelet response (HI-P) is defined according to IWG 2006 criteria (Cheson, 2006; Appendix D).  
HI-P rates will be summarized and compared between the two treatment groups using the same 
methods as the primary endpoint (see Section 10.6.1).
RBC transfusion independence for 84 days is defined as the absence of any RBC transfusion 
during any consecutive “rolling” 84 days during the treatment period, ie, Day 1 to 84, Day 2 to 85, 
Days 3 to 86, etc. Frequency cross-tabulations of RBC transfusion dependency status for 84 days 
at baseline versus on-treatment will be presented by treatment group.
Duration of RBC transfusion independence for 56 days will be determined only for subjects 
who achieve RBC transfusion independence on treatment. Duration of RBC transfusion 
independence is defined as the time from the date transfusion independence is first observed (day 
1 of 56 or more days without a transfusion) until the date the subject has a subsequently 
documented transfusion of RBC. Subjects who maintain RBC transfusion independence through 
the end of the treatment period will be censored at the date of treatment discontinuation or death, 
whichever occurs first. Duration of RBC transfusion independence curves will be estimated using 
KM methods and treatment groups will be compared using a log-rank test.
Time to RBC transfusion independence for 56 days is defined as the time between 
randomization and the date onset of transfusion independence is first observed (ie, Day 1 of 56 
without any RBC transfusions). Subjects who do not achieve RBC transfusion independence 
during the treatment period will be censored at the date of treatment discontinuation or death, 
whichever occurs first. Time to RBC transfusion independence curves will be estimated using KM 
methods and treatment groups will be compared using a log-rank test. A Cox proportional hazards 
model will be used to estimate the corresponding hazard ratio and 95% CI.
Duration of RBC transfusion independence for 84 days will be determined only for subjects 
who achieve RBC transfusion independence on treatment.  Duration of RBC transfusion 
independence is defined as the time from the date transfusion independence is first observed (day 
1 of 84 or more days without a transfusion) until the date the subject has a subsequently 
documented transfusion of RBC.  Subjects who maintain RBC transfusion independence through 
the end of the treatment period will be censored at the date of treatment discontinuation or death, 
whichever occurs first.  Duration of RBC transfusion independence curves will be estimated using 
KM methods and treatment groups will be compared using a log-rank test.  
Time to RBC transfusion independence for 84 days is defined as the time between 
randomization and the date onset of transfusion independence is first observed (ie, Day 1 of 84 
without any RBC transfusions).  Subjects who do not achieve RBC transfusion independence 
during the treatment period will be censored at the date of treatment discontinuation or death, 
whichever occurs first.  Time to RBC transfusion independence curves will be estimated using 
KM methods and treatment groups will be compared using a log-rank test.  A Cox proportional 
hazards model will be used to estimate the corresponding hazard ratio and 95% CI.  
Progression to AML is defined as bone marrow blast count ≥ 20%.  Number and percentage of 
subjects progressing to AML will be presented by treatment group.
 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
Time to AML Progression is defined as the time from the date of randomization until the date 
the subject has documented progression to AML.  Subjects who do not progress to AML will be 
censored at the date of last follow-up or at date of death.  Time to AML progression curves will 
be estimated using KM methods and treatment groups will be compared using a log-rank test.  KM 
estimates for median time to AML progression and the 1-year and 2-year AML progression rate
will be summarized for each treatment group.  A Cox proportional hazards model will be used to 
estimate the corresponding hazard ratio and 95% CI.  
 
Erythroid response (HI-E) is defined according to IWG 2006 criteria (Cheson, 2006; 
Appendix D).  HI-E response will be presented descriptively, by treatment group, using counts and 
percents.
Duration of RBC transfusion reduction. A subject will be considered as a RBC transfusion 
reduction responder if the subject had at least 4 units reduction in transfusion units over a 
consecutive 56 days period compared to the baseline transfusion units in 56 days. The duration of 
response will be determined for RBC transfusion reduction responders. Subjects who maintain the 
response through the end of the treatment period will be censored at the date of treatment 
discontinuation or death, whichever occurs first. Duration of RBC transfusion reduction response 
will be analyzed descriptively using KM methods.
Platelet transfusion independence is defined as the absence of any platelet transfusion during 
any consecutive “rolling” 56 days during the treatment period, ie, Day 1 to 56, Day 2 to 57, Days 
3 to 58, etc.  Subjects will be considered platelet transfusion dependent at baseline if they have 
received ≥ 2 platelet transfusions during the 56 days immediately preceding randomization and 
had no consecutive 28-day period during which no platelet transfusions were administered.  
Frequency cross-tabulations of platelet transfusion status (dependent or independent) at baseline 
versus on-treatment will be presented by treatment group.
Duration of platelet transfusion independence will be determined only for subjects who are 
platelet transfusion dependent at baseline and achieve platelet transfusion independence on 
treatment.  Duration of platelet transfusion independence is defined as the time from the date 
transfusion independence is first documented (day 1 of 56 or more days without a transfusion) 
until the date the subject has a subsequently documented transfusion of platelets.  Subjects who 
maintain platelet transfusion independence through the end of the treatment period will be 
censored at the date of treatment discontinuation or death, whichever occurs first.  Duration of 
platelet transfusion independence will be analyzed descriptively using KM methods.
Time to platelet transfusion independence is defined as the time between randomization and the 
first documented date of onset of transfusion independence (ie, Day 1 of 56 without any platelet 
transfusions).  Subjects who were platelet transfusion dependent at baseline and who do not 
achieve platelet transfusion independence during the treatment period will be censored at the date 
of treatment discontinuation or death, whichever occurs first.  Subjects who are platelet transfusion 
independent at baseline will be excluded from the analysis.  Time to platelet transfusion 
independence will be analyzed descriptively using KM methods.
 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
Hematologic response (Complete Remission [CR], Partial Remission [PR], Marrow CR [mCR], 
Stable Disease [SD], Failure, Relapse after CR or PR, and Cytogenetic Response) is defined 
according to IWG 2006 criteria (Cheson, 2006; Appendix D).  Subjects will be classified according 
to their best response achieved during treatment for the response categories of CR, PR, mCR, SD, 
and failure.  Only subjects who achieve CR or PR will be included in the Relapse after CR or PR 
category.  Subjects will be evaluated for cytogenetic response regardless of their response status 
in other categories.  For cytogenetic response, subjects will be classified as having a complete or 
partial response based on the best response achieved during treatment.  Hematologic response will 
be presented descriptively, by treatment group, using counts and percents. 
Clinically significant bleeding event is defined as: any intracranial or retroperitoneal bleed; 
bleeding requiring transfusions of > 2 units of blood/blood products; bleeding associated with a 
decrease in hemoglobin of > 2 g/dL; or bleeding from any site requiring transfusions of > 2 units 
of blood.  Number and percentage of subjects experiencing a clinically significant bleeding event 
will be presented by treatment group.  Additionally, the number and percentage of subjects by the 
number of clinically significant bleeding events experienced during the treatment period will be 
summarized by treatment group.
10.6.2.3
Exploratory Efficacy Analyses
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 RBC transfusion independence and OS endpoints:

Age group (< 65 years, ≥ 65 years)

Sex (male, female)

Race (white, Asian, others)

WHO MDS diagnosis classification

baseline % of bone marrow blasts (< 5, ≥ 5)

Geographic region (North America, Europe, Japan, ROW)

Average baseline RBC transfusion requirements (≤ 4 units*** of RBC per 28 days, > 4 units
of RBC per 28 days)

Baseline platelet transfusion status (dependent, independent)

ECOG performance status (0 or 1, 2)

Baseline platelet count (≤ 50 x 109/L, > 50 x 109/L)

Prior lenalidomide use (yes, no)

Subject enrolled under Amendment 2 (yes, no)
                                                       
*** As is consistent with medical practice in Japan, 1 unit RBC referenced in this protocol is equivalent to 2 units RBC in Japan.
 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
RBC transfusion independence and OS will be analyzed separately within each subgroup using 
the appropriate analysis methods as described in Sections 10.6.1 and 10.6.2.1.  The odds ratios 
(ORs) for RBC transfusion independence and the hazard ratios (HRs) for OS will be presented 
graphically in Forest plots.  Exploratory analyses for the OS endpoint will be performed at the time 
of the final analysis of OS only.
10.7
Safety Analysis
All safety analyses will be performed on the safety population.
Adverse events (AEs) 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.  Listings of all 
deaths and all SAEs, regardless of when they occurred, will also be generated.  Progression to 
AML and development of a second primary malignancy will be documented as an SAE 
(considered to be at least an AESI even if no other seriousness criteria apply) throughout a subject’s 
duration in the study (from the time of signing ICD until death, lost to follow-up, or withdrawal of 
consent for further data collection).  AESIs , based on appropriate Standardized MedDRA Queries 
(SMQs), will also be summarized.
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 vital signs and ECOG performance status, both observed values and 
changes from baseline, will be summarized by treatment group.
10.8
Interim Analysis
An interim analysis of the OS endpoint may be performed when all 216 subjects have completed 
12 months of double-blind treatment or have discontinued before reaching 12 months of double-
blind treatment (100% information for the primary endpoint), whichever occurs first.  It is 
projected that approximately 68% of the expected total deaths will have occurred at the time of the
interim analysis.  In the event an interim analysis of OS is performed, an O’Brien-Fleming group 
sequential boundary with a Lan-Demets alpha spending function will be used to preserve the 
overall alpha level at 0.05 for testing the OS endpoint.  The required (two-sided) significance levels 
are estimated to be 0.013 at the interim and 0.037 at the final analysis for OS, but the actual levels 
used will depend on the actual number of events at the time of the interim analysis.
In order to preserve the overall alpha level at 0.05 across the RBC transfusion independence and 
OS endpoints, formal statistical inference for the OS analyses can only be made if superiority of 
 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
azacitidine is demonstrated for the primary efficacy endpoint, RBC transfusion independence, at 
the two-sided 0.05 significance level. 
10.9
Other Analyses
10.9.1
Health-related Quality-of-life
The primary objective of the HRQoL assessment is to evaluate the impact of oral azacitidine on 
HRQoL relative to placebo.  Analyses will address mean differences by treatment group on
HRQoL scale and subscale scores and treatment group differences in the proportion of subjects 
who achieve a minimal clinically important difference.
Scoring for the FACT-An and EQ-5D and methods to address missing values will be accomplished 
according to directions provided by each separate instrument developer.  
 
 
 
 
 
10.9.2
Healthcare Resource Utilization
The medical resource utilization and cost-effectiveness/cost utility analyses will be outlined in a 
separate Statistical Analysis Plan for health economic endpoints.
 
 
 
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Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
 
  
 
10.10
Other Topics
Data Monitoring Committee
An independent Data Monitoring Committee (DMC) with multi-disciplinary representation will 
evaluate safety during the course of the study in compliance with a prospective charter.  The DMC 
will be comprised of medical oncologists/hematologists with experience treating MDS and a 
statistician, all of whom are not otherwise involved in the study as investigators.  An independent 
statistician will generate critical safety reports for the DMC to review periodically.  The DMC 
chairperson 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 documented in the DMC charter, which will be endorsed and signed by the DMC prior to 
the first data review meeting.  
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
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) 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.
11.2
Evaluation of Adverse Events
A qualified Investigator will evaluate all AEs as to:
11.2.1
Seriousness 
An 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

Constitutes an AESI
AESI 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 
 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
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.
Progression to AML and development of 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).
For the purposes of this study, progressive disease (PD) from Int-1 MDS to Int-2 or high risk MDS 
will not require reporting as an SAE unless one or more of the above SAE criteria has been met.
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 (eg, 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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CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
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 AE 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 AE 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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CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
11.2.5
Action Taken
The investigator will report the action taken with IP as a result of an AE or SAE, as applicable (eg, 
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, recovered with sequelae, not recovered (death due to another 
cause) 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 an SAE.  
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 other 
 
 
 
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CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
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.
Progression to AML and development of 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.  This 
includes progression to AML or any second primary malignancy, 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, or withdrawal of consent for further data 
collection.  Events of progression to AML and second primary malignancy are to be reported using 
the SAE report form and must be considered an AESI even if no other serious criteria apply; these 
events must also be documented in the appropriate page(s) of the CRF and subject’s source 
documents.  Documentation on the diagnosis of progression to AML and/or the second primary 
malignancy 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 is 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 
 
 
 
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CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
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.  
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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CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
12
DISCONTINUATIONS
The following events are considered sufficient reasons for discontinuing a subject from the 
investigational product and/or from the study:

Lack of Efficacy

Progressive Disease (Table 3)

Adverse event(s)

Withdrawal of consent

Death

Lost to follow up

Protocol violation
Although lack of efficacy or progressive disease is considered a sufficient reason for discontinuing 
a subject from protocol-prescribed therapy, the investigator should continue to treat the subject 
until the investigator considers protocol-prescribed therapy to be no longer beneficial to the 
subject, or the change of disease state renders the subject unacceptable for further treatment in the 
judgment of the investigator. The decision to discontinue a subject, which will not be delayed or 
refused by the sponsor, remains the responsibility of the treating physician.  However, prior to 
discontinuing a subject, 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 document for all 
randomized subjects, regardless of whether they are dosed or not.
Subjects discontinued from the investigational product will not be replaced.
All subjects discontinued from protocol-prescribed therapy for any reason should undergo 
Treatment Discontinuation procedures (Section 6.13), and 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 period is longer as 
described in Section 6.14.
All subjects discontinued from protocol-prescribed therapy for any reason will also be followed 
for survival, subsequent MDS therapies, progression to AML and second primary malignancy as 
described in Section 6.14.
 
 
 
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CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
Table 3:
Definitions of Progressive Disease for Clinical Decision on 
Discontinuing Subjects from the Investigational Product and/or 
from the Study
Category 
Progression/Relapse††† Criteria 
Progression in Bone 
Marrow 
For subjects with:  
Less than 5% blasts at baseline:  > 50% increase in blasts to > 5% blasts 
5%-10% blasts at baseline:  ≥ 50% increase to > 10% blasts 
Note: A 2nd bone marrow sample should be collected within 4 weeks to confirm 
progression before discontinuing subjects from treatment.
Progression in RBC 
Transfusion 
Requirement
For subjects RBC transfusion-dependent at baseline:
Who do not achieve RBC transfusion independence ≥ 56 “rolling” days (8 weeks) 
during study treatment, a > 50% increase in the average RBC transfusion requirement 
during any 56-day (8-week) period during study treatment compared to the average 
RBC transfusion requirement in the 56 days (8 weeks) prior to randomization.
Relapse in RBC 
Transfusion 
Requirement
For subjects RBC transfusion-dependent at baseline:
Who achieve RBC transfusion independence ≥ 56 “rolling” days (8 weeks) during 
study treatment, a relapse to RBC transfusion-dependent status.  Relapse is defined as 
a return to baseline requirements.
Progression in Platelet 
Transfusion 
Requirement
For subjects platelet transfusion-dependent at baseline:
Who do not achieve platelet transfusion independence ≥ 56 days (8 weeks) during 
study treatment, a > 50 % increase in platelet transfusion requirement during any 56-
day (8-week) period during study treatment compared to the 56-day (8-week) period 
prior to randomization.
For subject not platelet transfusion-dependent at baseline:
Development of platelet transfusion dependence, ie ≥ 2 platelet transfusions in any 
56-day (8-week) period during study treatment.
Relapse in Platelet 
Transfusion 
Requirement
For subjects platelet transfusion-dependent at baseline:
Who achieve platelet transfusion independence ≥ 56 days (8 weeks) during study 
treatment, a relapse to platelet transfusion-dependent status.  Relapse is defined as a 
return to baseline requirements.
                                                       
††† RBC and/or platelet transfusions administered for elective surgery should not be counted toward determination of progressive 
disease or relapse status.
 
 
 
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CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
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/Clinical Research 
Organization (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 (Section 8.9). 
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 only be performed by the investigator through the IRT system by 
using an emergency unblinding personal identification number (PIN), and the investigator should 
access the IRT system for unblinded dose information.
 
 
 
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CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
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 GCP 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 ICD 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 (eg, 
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 ICD 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 ICD 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 ICD.  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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CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
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 ICD, 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 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, ICD, 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.
Investigational Product 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 ICD should also be revised.
 
 
 
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Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
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 AEs 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 (eg, 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 the case where there are subjects in the Extension Phase still 
being administered the investigational product, and it is the opinion of the investigator(s) that these 
subjects would continue to receive benefit from treatment, the sponsor may choose to initiate an 
open-label roll-over study under a separate protocol to allow these subjects to continue receiving 
oral azacitidine.  
 
 
 
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CC-486 (Oral Azacitidine)
Protocol AZA-MDS-003
Celgene Corporation
AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
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 IP 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 ICDs 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.); 

All other documents as listed in Section 8 of the ICH consolidated guideline on GCP 
(Essential Documents for the Conduct of a Clinical Trial).
 
 
 
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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, IP 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 GCP.
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 GCP 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/ECs, regulatory authorities (eg, Food and Drug Administration [FDA], 
European Medicines Agency [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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18
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Fenaux P, Mufti G, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, et al. Efficacy of 
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Garcia-Manero G, Shan J, Faderl S, Cortes J, Ravandi F, Borthakur G, et al. A prognostic score 
for patients with lower risk myelodysplastic syndrome. Leukemia 2008a;22(3):538-43.
Garcia-Manero G, Stoltz ML, Ward MR, Kantarjian H, Sharma S. A pilot pharmacokinetic study 
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label, dose-escalation study to evaluate the safety, pharmacokinetics, and pharmacodynamics of 
oral azacitidine in patients with myelodysplastic syndromes (MDS) or acute myelogenous (AML) 
leukemia. Blood 2009;114(22):Abstract 117.
Garcia-Manero G, Gore SD, Cogle CR, Jabbour EJ, Ward MR, MacBeth KJ, et al. Evaluation of 
oral azacitidine using extended treatment schedules. Blood 2010;116(21):Abstract 603.
Goldberg S, Hsu J, Orr A, Rowley SD, Donato ML, McKiernan P, et al.  5-azacitidine therapy in 
elderly subjects with Acute Myeloid Leukemia yields similar survival compared to 3 + 7 induction 
chemotherapy with less transfusional support, bacteremias, and hospital days. Blood 
2006;108(11):Abstract 4569.
 
 
Gonzalez-Porras JR, Cordoba I, Such E, Nomdedeu B, Vallespi T, Carbonell F, et al.  Prognostic 
impact of severe thrombocytopenia in low-risk myelodysplastic syndrome. Cancer 2011;epub 
ahead of print. http://dx.doi.org/10.1002/cncr.26173.
Greenberg, P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, et al.  International scoring system 
for evaluating prognosis in myelodysplastic syndromes. Blood 1997;89:2079-88.
Grinblatt D, Narang M, Malone J, Sweet D, Dunne T, Sullivan K.  Treatment of patients with low-
risk myelodysplastic syndromes receiving azacitidine who are enrolled in AVIDA, a longitudinal 
patient registry.  Blood 2008;112(11):Abstract 1646.
Hellstrom-Lindberg E, Gulbrandsen N, Lindberg G, Ahlgren T, Dahl IMS, Dybedal I, et al.  A 
validated decision model for treating the anaemia of myelodysplastic syndromes with 
erythropoietin + granulocyte colony-stimulating factor: Significant effects on quality of life. Br J 
Haematol 2003;120(6):1037-46.
Hod E, Schwartz J. Platelet transfusion refractoriness.  Br J Haematol 2008;142(3):348-60.
Hillyer CD, Josephson CD, Blajchman MA, Vostal JG, Epstein JS, Goodman JL. Bacterial 
contamination of blood components: risks, strategies, and regulation. Joint ASH and AABB 
educational session in transfusion medicine. Hematology 2003:575-89.
Jansen AJ, Essink-Bot ML, Beckers EA, Hop WC, Schipperus MR, Van Rhenen DJ. Quality of 
life measurement in patients with transfusion-dependent myelodysplastic syndromes. Brit J
Haematol 2003;121(2):270-4.
 
 
 
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Kantarjian H, O’Brien S, Ravandi F, Cortes J, Shan J, Bennett JM, et al. Proposal for a new risk 
model in myelodysplastic syndrome that accounts for events not considered in the original 
International Prognostic Scoring System. Cancer 2008;113(6):1351-61.
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reanalyzed: impact of cytopenias on clinical outcomes in myelodysplastic syndromes. Am J 
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List A, Dewald G, Bennett J, Giagounidis A, Raza A, Feldman E, et al. Lenalidomide in the 
myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med 2006;355:1456-65.
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Silliman CC, Fung YL, Ball JB, Khan SY. Transfusion-related acute lung injury (TRALI): current 
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of the World Health Organization (WHO) classification of myeloid neoplasms and acute myeloid 
leukemia: rationale and important changes. Blood 2009;114(5):937-51.
 
 
 
 
 
 
 
 
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and survival and disease progression in thrombocytopenic patients with myelodysplastic 
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evolution, mutation and carcinogenesis. Carcinogenesis 1997;18(5):869-82.
 
 
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19
APPENDICES
APPENDIX A
MYELODYSPLASTIC SYNDROMES WORLD HEALTH 
ORGANIZATION CLASSIFICATION SYSTEM
Myelodysplastic Syndromes World Health Organization Classification System
Category
Definition
Peripheral Blood Smear 
Evaluation
Bone Marrow Evaluation
Refractory cytopenia with unilineage 
dysplasia (RCUD): (refractory anemia 
[RA]; refractory neutropenia [RN]; 
refractory thrombocytopenia [RT])
Unicytopenia or bicytopenia
a
No or rare blasts (< 1%)
b
Unilineage dysplasia: ≥ 10% of the cells in 
one myeloid lineage
< 5% blasts
< 15% of erythroid precursors are ringed 
sideroblasts
Refractory anemia with ringed 
sideroblasts (RARS)
Anemia
No blasts
≥ 15% of erythroid precursors are ringed 
sideroblasts
Erythroid dysplasia only
< 5% blasts
Refractory cytopenia with
Multilineage dysplasia (RCMD)
Cytopenia(s)
No or rare blasts (< 1%)b
No Auer rods
< 1x109/L monocytes
Dysplasia in ≥ 10% of the cells in
≥ 2 myeloid lineages (neutrophil and/or 
erythroid precursors and/or 
megakaryocytes)
< 5% blasts in marrow
No Auer rods
± 15% ringed sideroblasts
Refractory anemia with excess
blasts-1 (RAEB-1)
Cytopenia(s)
< 5% blastsb
No Auer rods
< 1x109/L monocytes
Unilineage or multilineage dysplasia
5%-9% blastsb
No Auer rods
Refractory anemia with excess
blasts-2 (RAEB-2)
Cytopenia(s)
5%-19% blasts
c
Auer rodsc
< 1x109/L monocytes
Unilineage or multilineage dysplasia
10%-19% blastsc
Auer rods ±c
Myelodysplastic syndrome -
unclassified (MDS-U)
Cytopenias
< 1% blastsb
Unequivocal dysplasia in < 10% of cells in 
one or more myeloid lineages when 
accompanied by a cytogenetic abnormality 
considered as presumptive evidence for a 
diagnosis of MDS
d
< 5% blasts
MDS associated with isolated
del(5q)
Anemia
Usually normal or increased platelet 
count
No or rare blasts (< 1%)
Normal to increased megakaryocytes with
hypolobated nuclei
< 5% blasts
Isolated del(5q) cytogenetic abnormality
No Auer rods
a
Bicytopenia may occasionally be observed.  Cases with pancytopenia should be classified as MDS-U.
b
If the marrow myeloblast percentage is < 5% but there are 2% to 4% myeloblasts in the blood, the diagnostic classification is
RAEB-1.  Cases of RCUD and RCMD with 1% myeloblasts in the blood should be classified as MDS-U.
c
Cases with Auer rods and < 5% myeloblasts in the blood and less than 10% in the marrow should be classified as RAEB-2.  
Although the finding of 5% to 19% blasts in the blood is, in itself, diagnostic of RAEB-2, cases of RAEB-2 may have 5% blasts 
in the blood if they have Auer rods or 10% to 19% blasts in the marrow or both.  Similarly, cases of RAEB-2 may have < 10% 
blasts in the marrow but may be diagnosed by the other 2 findings, Auer rods + and/or 5% to 19% blasts in the blood.
 
 
 
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Appendix A: Myelodysplastic 
Syndromes 
World 
Health 
Organization 
Classification System (Continued)
d
Includes unbalanced abnormalities -7 or del(7q), -5 or del(5q), i(17q) or t(17p), -13 or del(13q), del(11q), del(12p) or t(12p), 
del(9q), idic(X)(q13), balanced abnormalities t(11;16)(q23;p13.3), t(3;21)(q26.2;q22.1), t(1;3)(p36.3;q21.1), T2;11)(p21;q23), 
inv(3)(q21q26.2), and t(6;9)(p23;q34), and complex karyotype (3 or more chromosomal abnormalities) involving one of more 
of the listed abnormalities.
Sources: Brunning RD, Bennett JM, Flandrin G, Matutes E, Head D, Vardiman JW, et al.  Pathology and genetics of tumors of 
hematopoietic and lymphoid tissues.  In: Jaffe ES, Harris NL, Stein H, Vardiman JW, editors.  World Health Organization 
Classification of Tumors.  Lyon (France).  IARC Press 2001:63-73.
Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, et al.  The 2008 revision of the World Health 
Organization (WHO) classification of myeloid neoplasms and acute myeloid leukemia: rationale and important changes.  Blood 
2009;114(5):937-51.
 
 
 
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APPENDIX B
INTERNATIONAL PROGNOSTIC SCORING SYSTEM SCORE
International Prognostic Scoring System for MDS
Prognostic Variable
Score Value
0
0.5
1.0
1.5
2.0
Bone Marrow Blasts (%)
< 5
5-10
-
11-20
21-30
Karyotype
a
Good
Intermediate
Poor
Cytopenias
b
0 or 1
2 or 3
a Good:  normal, -Y, del(5q), del(20q); Poor:  complex (3 abnormalities) or chromosome 7 anomalies; Intermediate:  
other abnormalities.
b Defined as:  Hemoglobin < 100 g/L, absolute neutrophil count < 1.8 x 109/L, and platelet count < 100 x 109/L.
Note:  Scores for risk groups are as follows:  Low = 0; INT-1 = 0.5-1.0; INT-2 = 1.5-2.0; and High:  2.5.
Sources:  Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, et al.  International scoring system for 
evaluating prognosis in myelodysplastic syndromes.  Blood 1997;89:2079-88.
 
 
 
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APPENDIX C
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS
Eastern Cooperative Oncology Group (ECOG) Performance Status
Grade
ECOG
0
Fully active, able to carry on all pre-disease 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 selfcare but unable to carry out any work activities.  Up and about 
more than 50% of waking hours.
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours.
4
Completely disabled.  Cannot carry on any selfcare.  Totally confined to bed or chair.
5
Dead.
Source:  Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al.  Toxicity and response criteria 
of the Eastern Cooperative Oncology Group.  Am J Clin Oncol 1982;5(6):649-55.
 
 
 
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APPENDIX D
HEMATOLOGIC RESPONSE AND IMPROVEMENT ACCORDING 
TO THE INTERNATIONAL WORKING GROUP FOR 
MYELODYSPLASTIC SYNDROMES
Hematologic Response According to IWG Criteria for MDS (Cheson, 2006)
Category 
Response criteria (responses must last at least 4 weeks) 
Complete Remission (CR)
Bone marrow:  ≤ 5% myeloblasts with normal maturation of all cell lines
a
Persistent dysplasia will be noteda,b
Peripheral blood
c
     Hgb ≥ 11 g/dL 
     Platelets ≥ 100 X 109/L 
     Neutrophils ≥ 1.0 X 109/Lb  
     Blasts 0% 
Partial Remission (PR) 
All CR criteria if abnormal before treatment except:  

Bone marrow blasts decreased by ≥ 50% over pre-treatment but still > 5% 

Cellularity and morphology not relevant 
Marrow CRb  
Bone marrow:  ≤5% myeloblasts and decrease by ≥ 50% over pre-treatmentb
Peripheral blood:  if HI responses, they will be noted in addition to marrow CRb.
Stable Disease (SD) 
Failure to achieve at least PR, but no evidence of progression for > 8 wks 
Failure 
Death during treatment or disease progression characterized by worsening of cytopenias, 
increase in percentage of bone marrow blasts, or progression to a more advanced MDS FAB 
subtype than pre-treatment.
Relapse After CR or PR 
At least 1 of the following:  

Return to pre-treatment bone marrow blast percentage

Decrement of ≥ 50% from maximum remission/response levels in granulocytes or 
platelets

Reduction in Hgb concentration by ≥ 1.5 g/dL or transfusion dependence 
Cytogenetic Response 
Complete:

Disappearance of the chromosomal abnormality without appearance of new ones 
Partial:

At least 50% reduction of the chromosomal abnormality 
Disease Progression 
For subjects with:

Less than 5% blasts: ≥50% increase in blasts to > 5% blasts

5%-10% blasts:        ≥50% increase to > 10% blasts

10%-20% blasts:      ≥50% increase to > 20% blasts

20%-30% blastsd:    ≥50% increase to > 30% blasts
Any of the following:

≥50% decrease from maximum remission/response in granulocytes or platelets

Reduction in Hgb by ≥2 g/dL

Transfusion dependence
Survival
Endpoints:

Overall: death from any cause

Event free: failure or death from any cause

PFS: disease progression or death from MDS

DFS: time to relapse

Cause-specific death: death related to MDS
KEY:  CR = complete remission; FAB = French-American-British; Hgb = hemoglobin; HI = hematologic improvement; IWG = 
International Working Group; MDS = myelodysplastic syndromes; PR = partial remission; PFS= progression-free survival; DFS= 
disease-free survival.
a
Dysplastic changes should consider the normal range of dysplastic changes (modification).
b
Modification to IWG (2000) response criteria.  
 
 
 
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Appendix D: Hematologic Response and Improvement According to the 
International Working Group for Myelodysplastic Syndromes
(Continued)
c
In some circumstances, protocol therapy may require the initiation of further treatment (eg, consolidation, maintenance) before 
the 4-week period.  Such subjects can be included in the response category into which they fit at the time the therapy is started. 
Transient cytopenias during repeated chemotherapy courses should not be considered as interrupting durability of response, as 
long as they recover to the improved counts of the previous course.
d
20 – 30% blasts is considered AML according to WHO classification (Vardiman, 2009).
Notes:  Deletions to IWG response criteria are not shown.  To convert hemoglobin from grams per deciliter to grams per liter, 
multiply grams per deciliter by 10.  
Source:  Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD et al.  Clinical application and proposal 
for modification of the International Working Group (IWG) response criteria in myelodysplasia.  Blood 2006; 108 (2): 419-25.
Hematologic Improvement According to IWG Criteria (Cheson, 2006)
Hematologic improvementa
Response criteria (responses must last at least 8 week)b
Erythroid Response (HI-E) (pre-
treatment, <11 g/dL) 

Hemoglobin increase by ≥ 1.5 g/dL

Relevant Reduction in units of RBC transfusions by an absolute number of at 
least 4 RBC transfusions/8 wk compared with the pretreatment transfusion 
number in the previous 8 wk
Note: Only RBC transfusions given for a hemoglobin of ≤ 9.0 g/dL on treatment will 
count in the RBC transfusion response evaluation.b
Platelet Response  (HI-P)
(pre-treatment, <100 X 109/L) 

Absolute increase of ≥ 30 X 109/L for subjects starting with > 20 X 109/L 
platelets 

Increase from < 20 X 109/L to > 20 X 109/L and by at least 100%b  
Neutrophil Response (HI-N)
(pre-treatment, <1.0 X 109/L) 

At least 100% increase and an absolute increase > 0.5 X 109/Lb  
Progression or Relapse After HI
c
At least 1 of the following:

At least 50% decrease from maximum response levels in granulocytes or 
platelets

Reduction in Hgb by ≥1.5 g/dL

Transfusion dependence
KEY:  HI-E, hematologic improvement erythroid response; HI-N, hematologic improvement neutrophil response; HI-P, 
hematologic improvement platelet response; IWG, International Working Group; RBC = red blood cell.
a
Pre-treatment counts averages of at least 2 measurements (not influenced by transfusions, ie, no RBC transfusions for 2 weeks
and no platelet transfusions for 1 week) ≥ 1 week apart (modification).  
b
Modification to IWG (2000) response criteria.
c In the absence of another explanation, such as acute infection, repeated courses of chemotherapy (modification), gastrointestinal 
bleeding, hemolysis, and so forth.  It is recommended that the 2 kinds of erythroid and platelet responses be reported overall as 
well as by the individual response pattern.  
Note:  Deletions to the IWG response criteria are not shown.  To convert hemoglobin levels from grams per deciliter to grams per 
liter, multiply grams per deciliter by 10.
Source:  Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD et al.  Clinical application and proposal 
for modification of the International Working Group (IWG) response criteria in myelodysplasia.  Blood 2006; 108 (2): 419-25.
 
 
 
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APPENDIX E
FACT-AN (VERSION 4)
 
 
 
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Appendix E:
FACT-An (Version 4) (Continued)
 
 
 
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Appendix E:
FACT-An (Version 4) (Continued)
 
 
 
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APPENDIX F
EQ-5D HEALTH QUESTIONNAIRES (EQ-5D-3L; ENGLISH 
VERSION FOR THE US)
 
 
 
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Appendix F: EQ-5D Health Questionnaires (EQ-5D-3L; English Version for 
the US) (Continued)
 
 
 
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APPENDIX G
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: 1994 Revisions to Classification of Functional Capacity and Objective Assessment of Patients With 
Diseases of the Heart.  American Heart Association website.  Available at: 
http://www.americanheart.org/presenter.jhtml?identifier=1712.  Accessed 02 Mar 2011.
 
 
 
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Final: 24 May 2022
APPENDIX H
RECOMMENDATIONS FOR MANAGEMENT OF TREATMENT-
INDUCED DIARRHEA
The following published guidelines (Benson, 2004) were modified in order to be consistent with 
the clinical study protocol.
 
 
 
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Final: 24 May 2022
APPENDIX I
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine transaminase (also SGPT)
AML
Acute myeloid leukemia
ANC
Absolute neutrophil count
AST
Aspartate transaminase (also SGOT)
BID
Twice a day
BUN
Blood urea nitrogen
CBC
Complete blood count
CCR
Conventional care regimen
CI
Confidence interval
CML
Chronic myeloid leukemia
CMML
Chronic myelomonocytic leukemia
CR
Complete remission
CRF
Case report form
CRO
Clinical research organization
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
EC
Ethics committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EEA
European Economic Area
EP
Extension Phase
EPO
Erythropoietin
EQ-5D
EuroQol Group 5D
EMA
European Medicines Agency
ESA
Erythropoiesis stimulating agent
EU
European Union
FAB
French-American-British
FACT-An
Functional Assessment Cancer Therapy-Anemia
FCBP
Female of childbearing potential
FDA
Food and Drug Administration
 
 
 
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Appendix I:List of Abbreviations and Definitions of Terms (Continued)
Fe/TIBC
Serum iron/serum total iron binding capacity
FISH
Florescent in situ hybridization
GCP
Good clinical practice
G-CSF
Granulocyte colony-stimulating factor
GM-CSF
Granulocyte macrophage colony-stimulating factor
Hgb
Hemoglobin
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HI
Hematologic improvement
HI-E
Hematologic improvement-erythroid response
HI-N
Hematologic improvement-neutrophil response
HI-P
Hematologic improvement-platelet response
HIV
Human immunodeficiency virus
HLA
Human leukocyte antigen
HR
Hazard ratio
HRQoL
Health-related Quality of Life
IB
Investigator’s Brochure
ICD
Informed Consent Document
ICH
International Conference on Harmonization
IMiD
Immunomodulating drugs
INR
International normalized ratio
INT-1
Intermediate-1
INT-2
Intermediate-2
IP
Investigational Product
IPSS
International Prognostic Scoring System
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITP
Idiopathic thrombocytopenic purpura
ITT
Intent-to-Treat
IV
Intravenous
IVRS
Interactive Voice Response System
IWG
International Working Group
IWRS
Interactive Web Response System
 
 
 
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Appendix I:List of Abbreviations and Definitions of Terms (Continued)
LDH
Lactic dehydrogenase
KM
Kaplan-Meier
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
mCR
Marrow complete response
MCV
Mean corpuscular volume
MDS
Myelodysplastic syndromes
MDS-U
Myelodysplastic syndrome -unclassified
MedDRA
Medical Dictionary for Regulatory Affairs
MH
Mantel-Haenszel
mITT
Modified intent-to-treat
MPD
Myeloidproliferative disease
NCI
National Cancer Institute
NYHA
New York Heart Association
OR
Odds ratio
OS
Overall survival
PIN
Personal Identification Number
PK
Pharmacokinetics
PR
Partial remission
pRBC
Packed red blood cells
PT
Prothrombin time 
PTT
Partial thromboplastin time
QD
Once a day
RA
Refractory anemia
RAEB
Refractory anemia with excess blasts
RAEB-T
Refractory anemia with excess blasts in transformation
RARS
Refractory anemia with ringed sideroblasts
RCMD
Refractory cytopenia with multilineage dysplasia
RCUD
Refractory cytopenia with unilineage dysplasia
RDW
Red cell distribution width
 
 
 
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Final: 24 May 2022
Appendix I:List of Abbreviations and Definitions of Terms (Continued)
RBC
Red blood cell
ROW
Rest of world
RN
Refractory neutropenia
RNA
Ribonucleic acid
RT
Refractory thrombocytopenia
SAE
Serious adverse event
SC
Subcutaneous
SD
Stable disease
SDev
Standard deviation
SGOT
Serum glutamic oxaloacetic transaminase (also AST)
SGPT
Serum glutamic pyruvate transaminase (also ALT)
SMQ
Standardized MedDRA Query
SOP
Standard operating procedure
SUSAR
Suspected unexpected serious adverse reactions
TEAE
Treatment-emergent adverse event
TNM
Tumor nodes metastasis
TRALI
Transfusion-related lung injury
TSA
Thrombopoiesis-stimulating agent
ULN
Upper limit of normal
US
United States
WBC
White blood cell 
WHO
World Health Organization
 
 
 
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Final: 24 May 2022
APPENDIX J
EXTENSION PHASE
Once all 216 subjects enrolled have completed 12 months of double-blind treatment or have 
discontinued before reaching 12 months of double-blind treatment and Amendment 5 of the 
protocol is approved at the respective sites, and after study unblinding by Celgene, eligible subjects
can enter the Extension Phase.
Subject Eligibility
At the Investigator’s discretion and following confirmation of eligibility criteria below, subjects 
can enter the extension phase:

Subjects who have signed the informed consent for the EP of the study;

Subjects randomized to the 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 the 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 Follow-up Phase, after permanent study treatment discontinuation, 
will continue to be followed for survival in the EP;

Subjects who do not meet any of the criteria for study discontinuation (see Section 12).
Treatment Assignment 
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, so they occur on the 
same day.  The dose and schedule will follow the study treatment administration and schedule
(Section 8.2).
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 (NCI) Common 
Terminology Criteria for Adverse Events (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 12.
Oral azacitidine dose modifications due to nonhematological and hematological toxicities during 
oral azacitidine treatment should be managed as described in Section 8.2.4 for dose modification 
guidelines due to toxicity.  
 
 
 
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AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022
Adverse Events
Adverse events (non-serious and serious) will continue to be collected in the EP AE CRF.  Refer 
to Section 11. Adverse Events for reporting requirements, responsibilities and procedures.
Concomitant Medications
All concomitant medications that are necessary for the subject’s welfare may be given at the 
Investigator’s discretion during the EP and recorded onto the CRF.  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 survival, subsequent MDS therapies,
progression to AML and secondary malignancy for 35 days ± 7 days, including 28-day safety 
follow-up (refer to Section 11.1: Monitoring, Recording, and Reporting of Adverse Events)
following Treatment Discontinuation or until death, withdrawal of consent for further data 
collection, lost to follow-up, or study termination, whichever is earlier. 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 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). 
Monitoring of Subjects
The monitoring of subjects is as per the local standard of care, and at least:

Complete blood count with WBC differential and platelet count as required, and at a minimum, 
prior to each dosing cycle

For FCBP, pregnancy testing must be done prior to initiating a new cycle

Bone marrow biopsy and aspirate as clinically indicated

Additional tests or more frequent monitoring are at the Investigator’s discretion based on the 
subject’s clinical status.
Investigator’s Responsibility 

Obtain subject’s signature of the informed consent form to enter the EP phase

Complete Extension Phase Case Report Form pages

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 8.2.4)

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)

Report drug accountability to the sponsor
 
 
 
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AZA-MDS-003 Amendment 6.0 
Final: 24 May 2022

Report to the sponsor and complete the case report form page for extension phase termination 
when the subject terminates treatment with oral azacitidine.

The subject should stop treatment with oral azacitidine if any of the following occur:

Additional investigational treatment is started;

Subject is no longer receiving clinical benefit, as per Investigator’s discretion;

Subject withdraws consent;

A positive pregnancy test in a FCBP, at any time; or

At the specific request of the sponsor or its authorized representative.

The Investigator must be available for periodic monitoring visits and allow the sponsor access 
to all medical records.

The Investigator will maintain source documents on the subject for all case report form data 
points, which include the following:

Informed consent;

Adverse events;

Dosing information (date of administration, dose, number of tablets used, and lot 
number); 

Concomitant-medications; and

Termination date and reason.
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 Section 10.7 on the subjects entering the EP.  Exposure to oral azacitidine as 
well as concomitant medications taken during the EP will also be summarized.
 
 
 
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CC-486 (Oral Azacitidine)
Summary of Changes AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
3
AZA-MDS-003 Amendment 5.0 Final: 28 Nov 2018
1.
JUSTIFICATION FOR AMENDMENT
This protocol is being amended to change the primary endpoint to RBC transfusion 
independence with duration ≥ 56 days (8 weeks) and to add an extension phase of CC-486 
treatment once the trial is unblinded.
Significant changes included in this amendment are summarized below:

The primary efficacy endpoint, “proportion of subjects in the overall population 
achieving RBC transfusion independence with duration ≥ 84 days (12 weeks)”, is 
switched with the secondary endpoint, “proportion of subjects in the overall population 
achieving RBC transfusion independence with duration ≥ 56 days (8 weeks).”
Revised sections:  Protocol Summary, Sections 3.1 Primary Endpoint(s), 3.2 Secondary 
Endpoint(s), 10.6.1 Primary Efficacy Analysis, and 12 Discontinuations.

A description of the Extension Phase is presented in Appendix J and mentioned 
throughout the protocol.  
Revised sections:  Protocol Summary, Sections 4.1.4 Extension Phase and 6.15 Extension 
Phase, and Appendix J: Extension Phase; and several minor editorial changes throughout 
the protocol to reflect the addition to the extension phase.

The following secondary endpoint was added: Duration of RBC transfusion reduction.
Revised sections: Protocol Summary, Sections 3.2 Secondary Endpoint(s) and 10.6.2.2 
Additional Secondary Efficacy Analyses

Deletion of Section 1.4 Protocol Amendment 4.0 Rationale
Revised sections: Section 1.4.

To reflect the switch in primary endpoint, the following paragraph was updated to (italic
- new text, strikethrough - deleted text):
“(…) The primary endpoint, RBC transfusion independence, is defined as the absence of 
any RBC transfusion during any consecutive “rolling” 84 56 days during the treatment 
period compared with an average transfusion requirement of ≥ 2 units/28 days of RBCs 
confirmed for a minimum of 56 days immediately preceding and including the date of 
randomization.  The longer RBC transfusion-independent interval (ie, ≥84 days) is more 
conservative than the IWG 2006 criteria (ie, ≥56 days; Appendix D) and is significant in 
a patient population with 2 or more cytopenias which is indicative of poor bone marrow 
function at the start of study treatment.  Achieving RBC transfusion independence of at 
least 84 days is likely to be a substantial clinical benefit in a patient population with a 
median overall survival of approximately 14 to 16 months (Garcia-Manero, 2008a; Cruz, 
2010; Yong, 2010). (…)”
Revised sections: Section 4.2 Study Design Rationale

For clarification, the text in italic below was added:
“(…) While 56 days (8 weeks) is the standard duration a response must be maintained in 
order to meet the current IWG response criteria (IWG 2006 criteria; Cheson, 2006; 
Appendix D), limited information is available on the target population for estimating the 
response rate for RBC transfusion independence maintained for ≥ 84 days (12 weeks).  
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EDMS Doc. Number: 23166916 - 19462446
CC-486 (Oral Azacitidine)
Summary of Changes AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
4
AZA-MDS-003 Amendment 5.0 Final: 28 Nov 2018
 
 
 
 
  For the primary efficacy 
endpoint RBC transfusion independence with a duration ≥56 days (8 weeks), the 
response rate for oral azacitidine is assumed to be similar as the above findings.  (…)”
Revised sections: Section 10.3 Sample Size and Power Considerations

To reflect the switch in endpoints, the following paragraph was updated to (italic - new 
text, strikethrough - deleted text):
“RBC transfusion independence for 56 84 days is defined as the absence of any RBC 
transfusion during any consecutive “rolling” 56 84 days during the treatment period, ie, 
Day 1 to 56 84, Day 2 to 57 85, Days 3 to 58 86, etc. Subjects who are RBC transfusion-
dependent at baseline and are discontinued from double-blind treatment for lack of 
therapeutic efficacy will be counted as non-responders. Frequency cross-tabulations of 
RBC transfusion dependency status for 56 84 days at baseline versus on-treatment will be 
presented by treatment group.”
Revised sections: Section 10.6.2.2 Additional Secondary Efficacy Analyses
The amendment also includes other minor clarifications and corrections:

Section 8.2.5, deletion of: “The decision to discontinue a subject, which will not be 
delayed or refused by the sponsor, remains the responsibility of the treating physician.  
However, prior to discontinuing a subject, the investigator may contact the Medical 
Monitor and forward appropriate supporting documents for review and discussion.” As 
already stated in Section 8.2.

“Important medical event” replaced by “adverse event of special interest (AESI)” in 
Sections 6.6.2 Progression to AML and Second Primary Malignancies, 10.7 Safety 
Analysis, 11.2.1 Seriousness, and 11.5 Reporting of Serious Adverse Events.

In Section 11.6 Expedited Reporting of Adverse Events, safety group recommended the 
deletion of: “Adverse events such as 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.  These events will be captured as AEs on the CRF, reported to Celgene Drug 
Safety meeting SAE reporting criteria (within 24 hours) and reported to regulatory 
authorities in the annual report.” 
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EDMS Doc. Number: 22883803 - 19462446
CC-486 (Oral Azacitidine)
Summary of Changes AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
3
AZA-MDS-003 Amendment 4.0 Final: 06 Aug 2018
1.
JUSTIFICATION FOR AMENDMENT
This protocol is being amended to address Celgene’s decision to close enrollment into the study
and revise sample size.
Significant changes included in this amendment are summarized below:

To reflect the change in sample size and the decision to close enrollment into the study, 
“386 subjects” is replaced by “216 subjects” throughout the protocol.

The following rationale for Amendment 4.0 was added:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Per protocol, the primary analysis will be 
conducted once all subjects enrolled have completed 12 months of double-blind treatment 
or have discontinued before reaching 12 months of double-blind treatment (100% 
information for the primary endpoint), whichever occurs first.
The current sample size of 216 randomized subjects is sufficient to allow analysis of the 
planned primary study objective of red blood cell (RBC) transfusion independence for 
CC-486 versus placebo with approximately 99% power. The key secondary study 
endpoint of overall survival (OS) will also be assessed as an interim analysis at the time 
of the primary analysis and in the final analysis at the time of study closure.”
Revised sections:  Addition to Section 1.4 Protocol Amendment 4.0 Rationale

Per protocol, the study will conclude once all subjects have completed the follow-up 
phase.
Revised sections: Protocol Summary and Section 4.1.4. Study Closure
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EDMS Doc. Number: 22883803 - 19462446
CC-486 (Oral Azacitidine)
Summary of Changes AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
4
AZA-MDS-003 Amendment 4.0 Final: 06 Aug 2018

To reflect the study closure update, the Follow-up sections were updated as follows. 
Original text: “All subjects discontinued from protocol-prescribed therapy for any reason
will also be followed for survival, subsequent MDS therapies, progression to AML and 
second primary malignancy 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.”
Updated text: “All subjects discontinued from protocol-prescribed therapy for any reason
will also be followed for survival, subsequent MDS therapies, progression to AML and 
second primary malignancy every month for the first year following Treatment 
Discontinuation and every three months thereafter until death, lost to follow-up, or 
withdrawal of consent for further data collection.”
Also, when appropriate, “or study closure” was deleted from “(…) withdrawal of consent 
for further data collection, or study closure.” to read “(…) or withdrawal of consent for 
further data collection.”
Revised sections: Protocol Summary and Sections 4.1.3. Follow-up Phase, 6.6.2. 
Progression to AML and Second Primary Malignancies, 6.14. Follow-up, 10.7. Safety 
Analysis, and 11.5 Reporting of Serious Adverse Events.

The duration of the study and enrollment period were updated based on the closure of 
enrollment and revised sample size.  Duration was changed from “122 months” to “134
months” and enrollment period from “81 months” to “56 months”.  
The protocol language will read as follows:
“The expected duration of the study is 134 months, including a 56-month enrollment 
followed by 78 months of subject treatment and/or observation. The study is planned to 
conclude 78 months after the last subject is randomized.”
Revised sections: Protocol Summary and Section 4.3 Study Duration.

To clarify the timing of the OS analysis, the following sentence was added: “The key 
secondary study endpoint of OS will be assessed as an interim analysis at the time of the 
primary analysis and in the final analysis at the time of study closure.”
Revised sections: Section 1.4 Protocol Amendment 4.0 Rationale and Section 10.6.2.1. 
Key Secondary Efficacy Analyses

To reflect the updated treatment administration and schedule, the following sentences 
were added in various sections: “As of Amendment 3.0, all subjects in Cycles 1 or 2 will 
receive CC-486 for 14 days of a 28-day cycle schedule.  Subjects may increase to a 21-
day schedule at the conclusion of Cycle 2 if there are no Grade 3 or 4 toxicities requiring 
dose delay or reductions and if there is no evidence of hematological improvement upon 
discussion and agreement between the investigator and the Medical Monitor.  Subjects 
remaining beyond Cycle 2 will continue to receive 300 mg oral azacitidine or matching 
placebo QD for 21 days of each 28-day treatment cycle.”
Revised sections: Protocol Summary, Section 4.1.2. Randomization and Double-blind 
Treatment Phase, Figure 1 Overall Study Design (footnote 5), Section 4.2. Study Design 
Rationale, Table 1 Table of Events (in footnote z), and Section 8.2. Treatment 
Administration and Schedule
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CC-486 (Oral Azacitidine)
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AZA-MDS-003 Amendment 4.0 Final: 06 Aug 2018

To reflect the change in power percentage and number of deaths based on the 216 
randomized subjects, Section 10.3. Sample Size and Power Considerations was updated 
to read:
“The basis for the power and sample size determination will be a test of the equality of 
the overall survival curves between the azacitidine and placebo treatment groups using a 
stratified log-rank test.  Assuming a median OS of 18 months in the placebo treated group 
(Garcia-Manero, 2008a), which takes into account possible cross-over outside of the 
protocol of placebo treated subjects to active treatment during the observation period, and 
a median OS of 25.7 months (43% improvement) in the azacitidine treated group, 216
subjects (108 in each group) would have approximately 72% power to detect a constant 
hazard rate ratio of 0.70 using a two-sided log rank test with an overall significance level 
of 0.05.  It is assumed that the OS distribution is exponential with a constant failure 
(hazard) rate and that accrual is uniform during the accrual period (56 months) with an 
overall drop-out rate of 5% from both treatment groups.  Full information necessary for a 
log rank test to have 72% power will be achieved when approximately 205 deaths have 
occurred in both treatment groups, which is expected approximately 134 months after 
randomization of the first subject into the study.
An interim analysis of the OS endpoint may be performed and reported when all subjects 
have completed 12 months (52 weeks [364 days]) of double-blind treatment or have been 
discontinued from treatment (see Section 10.8).
Limited information is available on the target population for estimating the response rate 
for the primary endpoint of RBC transfusion independence maintained for ≥ 84 days (12 
weeks).  
 
 
 
 
 
 
  A total sample size of 216 subjects (108 in the active treatment group and 
108 in the placebo group) will have approximately 99% power to detect the difference 
between a response rate of 0.30 in the active treatment group and a response rate of 0.05 
in the placebo group, and approximately 70% power to detect the difference between a 
response rate of 0.15 in the active treatment group and a response rate of 0.05 in the 
placebo group.  The power calculations for response rate are based on a two-sided alpha 
of 0.05 and test statistics on the difference of proportions using an un-pooled estimate of 
variance.
Sample size and power were calculated using the East® Version 5.3 software system 
(Cytel Inc., 675 Massachusetts Avenue, Cambridge, MA 02139, http://www.cytel.com).”
Revised section: Section 10.3. Sample Size and Power Considerations
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
To reflect the change in sample size, the Section 10.6. Efficacy Analysis was updated to 
read:
“(…) 
The primary efficacy endpoint, RBC transfusion independence, will be analyzed and 
reported only once after all 100% of the information is available for RBC transfusion 
independence rates (ie, after all 216 subjects have completed 12 months (52 weeks [364 
days]) of double-blind treatment or have been discontinued from treatment).  An analysis 
of the OS endpoint will also be conducted at the time of the analysis of the primary 
efficacy endpoint.  This analysis of the OS endpoint may be an interim analysis or it may 
be the final analysis, depending on the maturity of the survival data (eg, the required 205
deaths have occurred) at the time of the final analysis for the RBC transfusion 
independence endpoint.  An O’Brien-Fleming group sequential type boundary will be 
used to preserve the overall alpha level of 0.05 for the analysis of OS in the event that OS 
is analyzed twice.  
The remaining secondary efficacy variables, with the exception of the proportion of 
subjects progressing to AML and time to AML progression, will be analyzed and 
reported once at the time of the analysis of RBC transfusion independence.  Subjects will 
continue to be followed for progression to AML and survival until 205 deaths have been 
observed.  Other than the pre-specified sequential testing of RBC transfusion 
independence and OS, no additional alpha adjustments for multiplicity will be made.”
Revised section: Protocol Summary and Section 10.6. Efficacy Analysis

To reflect the change in sample size, the Section 10.8. Interim Analysis was updated to 
read:
“An interim analysis of the OS endpoint may be performed when all 216 subjects have 
completed 12 months of double-blind treatment or have discontinued before reaching 12 
months of double-blind treatment (100% information for the primary endpoint), 
whichever occurs first.  It is projected that approximately 68% of the expected total 
deaths will have occurred at the time of the interim analysis.  In the event an interim 
analysis of OS is performed, an O’Brien-Fleming group sequential boundary with a Lan-
Demets alpha spending function will be used to preserve the overall alpha level at 0.05 
for testing the OS endpoint.  The required (two-sided) significance levels are estimated to 
be 0.013 at the interim and 0.037 at the final analysis for OS, but the actual levels used 
will depend on the actual number of events at the time of the interim analysis.
In order to preserve the overall alpha level at 0.05 across the RBC transfusion 
independence and OS endpoints, formal statistical inference for the OS analyses can only 
be made if superiority of azacitidine is demonstrated for the primary efficacy endpoint, 
RBC transfusion independence, at the two-sided 0.05 significance level.”
Revised section: Section 10.8. Interim Analysis
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AZA-MDS-003 Amendment 4.0 Final: 06 Aug 2018
The amendment also includes other minor clarifications and corrections:

To clarify that the FACT-An and EQ-5D questionnaires can be completed following 
interaction with study personnel the following sentences were modified:
o
In Footnote x of Table 1. Table of Events, the words “when feasible” were added 
to read: “FACT-An and EQ-5D questionnaires must be completed prior to 
interaction with study personnel (when feasible) and prior to IP administration at 
the start of every Cycle, and at Treatment Discontinuation (Section 6.8). (…)”
o
In Section 6.4. Baseline, the last sentence now reads: “The FACT-An and EQ-5D 
questionnaires should always be completed prior to IP administration and, when 
feasible, prior to interaction with study personnel.”
o
In Section 6.8. Health-related Quality of life, first sentence of last paragraph 
reads: “The FACT-An and EQ-5D questionnaires should be completed prior to 
interaction with study personnel (when feasible) and prior to IP administration on 
Day 1 of every Cycle and at the Treatment Discontinuation visit.”
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EDMS Doc. Number: 22542661 - 19462446
CC-486 (Oral Azacitidine)
Summary of Changes AZA-MDS-003
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AZA-MDS-003 Amendment 3.0 Final: 21 Feb 2018
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:

The duration of the study and enrollment period was extended due to slow enrollment.  
Duration was extended from “60 months” to “122 months” and enrollment period from 
“26 months” to “81 months”.  
The protocol language will read as follows:
“The expected duration of the study is 122 months, including an 81-month enrollment 
followed by 41 months of subject treatment and/or observation. The study is planned to 
conclude 41 months after the last subject is randomized.”
Revised sections: Protocol Summary, Section 4.3 Study Duration, and Section 10.3 
Sample Size and Power Consideration.

 
 dose schedule was reduced to 14 days.  
Revised sections: Section 8.2.4. Dose Modifications

 to enhance hematotoxicity monitoring, the following 
information was added to Section 8.2.4. Dose Modifications: “Any subject who 
experiences febrile neutropenia ≥ Grade 3 will have IP held until fever has resolved; must 
be afebrile for 3 days before re-starting study drug.  Administration of antibiotic, antiviral 
and antifungal therapy is strongly recommended.”
Revised sections: Section 8.2.4. Dose Modifications and Table 2

, to enhance hematotoxicity monitoring, dose 
modification for neutropenia Grade 4 was updated.
Revised sections: Section 8.2.4. Dose Modifications and Table 2

, to enhance hematotoxicity monitoring for Febrile 
Neutropenia, the following wording “Secondary prophylaxis with G-CSF may be 
considered” was changed to “Secondary prophylaxis with G-CSF is strongly 
recommended”.
Revised sections: Table 2

, to enhance hematotoxicity monitoring, Section 8.2.5. 
Re-treatment Criteria was updated to reflect that for subjects that experience 
hematotoxicity (absolute neutrophil count [ANC] or platelet drop to Grade 4, or 50% 
drop within Grade 4), hematologic recovery is required before starting the next cycle at 
Day 28.  Hematology recovery is defined and a decision tree for hematologic recovery 
presents the rules in a friendly manner.
Revised sections: Section 8.2.5. Re-treatment Criteria

, to enhance hematotoxicity monitoring, the following 
sentences were added: “Consider platelet transfusion if platelet counts are < 25 x 109/L.  
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EDMS Doc. Number: 22542661 - 19462446
CC-486 (Oral Azacitidine)
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AZA-MDS-003 Amendment 3.0 Final: 21 Feb 2018
If appropriate administration of platelets does not correct the platelet counts, contact 
Medical Monitors to consider IP dosing delay.”
Revised sections: Section 9.1. Permitted Concomitant Medications and Procedures

, to enhance hematotoxicity monitoring, the following 
sentence: “For subjects who develop an ANC < 0.5 x 109/L, administration of 
prophylactic fluoroquinolone antibiotics (eg, ciprofloxacin or levofloxacin or other 
recognized prophylactic antibiotics) may be considered and documented as a concomitant 
medication on the appropriate case report form (CRF).“ was updated to: “For subjects 
who develop an ANC < 0.5 x 109/L, administration of prophylactic fluoroquinolone 
antibiotics (eg, ciprofloxacin or levofloxacin or other recognized prophylactic antibiotics) 
is strongly recommended and should be documented as a concomitant medication on 
the appropriate CRF.“
Revised sections: Section 9.1. Permitted Concomitant Medications and Procedures
The amendment also includes other minor clarifications and corrections:

Change of Medical Monitor 

Change of Celgene Therapeutic Area Head

In Section 6.1. Screening, the following sentence has been added for clarification: “If a 
subject is screen failed and then re-screened, subject must be re-consented in writing.”
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EDMS Doc. Number: 20600749 - 19462446
CC-486 (Oral Azacitidine) 
Summary of Changes AZA-MDS-003
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AZA-MDS-003 Amendment 2 Final: 08 Oct 2015
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
1. Modification of Inclusion Criterion #3 
Changed the definition of red blood cell (RBC) transfusion dependency for 
screening by increasing the maximum hemoglobin value threshold prior to 
transfusions when determining transfusion dependence from ≤9 g/dL to ≤10 
g/dL.
By increasing the maximum hemoglobin (Hgb) threshold to  ≤10 g/dL from ≤9 g/dL when 
evaluating subjects for the inclusion criterion of transfusion dependency, this may allow 
patients to be randomized earlier into the trial. The median age of diagnosis of 
myelodysplastic syndrome (MDS) is 71 to 76 years, and 72% of patients are age 70 or older.  
Along with this older demographic in MDS, patients often develop overlapping co-
morbidities.  When erythrocyte production is affected in MDS, patients frequently present 
with signs and symptoms of anemia including pallor, tachycardia, hypotension, fatigue, 
headache and exercise intolerance, or with signs and symptoms of worsening of an 
underlying condition such as angina pectoris, heart failure, or a pulmonary disorder.  Patients 
with such co-morbidities may have more symptoms at a higher baseline Hgb level than 
patient who do not have such co-morbidities.  Due to this fact, some practitioners choose to 
transfuse their older MDS patients with multiple co-morbidities at a higher Hgb level of 10 
g/dL than they would younger and/or more fit patients.
Increasing the Hgb threshold for the definition of transfusion dependence for eligibility does 
not change the overall survival (OS) of the target population of 17 months (Garcia-Manero, 
2008), which is still in the range of the median OS of 18 months assumed for the placebo 
treated group used for the sample size calculation in the current protocol.  Thus, no impact on 
the secondary endpoint of OS is expected. 
This change also does not affect the definition of transfusion independence as described in 
the primary objective of the study, nor would it be applicable to the International Working 
group (IWG) response criteria for hematologic improvement as described in the secondary 
objective of hematologic improvement-erythroid response (HI-E, which uses ≤9 g/dL as the 
maximum threshold of hemoglobin values for transfusions to count towards transfusion 
independence response evaluation).   However, to account for any potential impact a 
sensitivity analysis will be performed as specified in the modification of the Primary Efficacy 
Analysis (see further below).  
Changed the definition of RBC transfusion dependency for screening assessment 
by decreasing the time of observation of dependency from 84 to 56 days.
This modification has been made in order to change the definition of RBC transfusion 
dependence when evaluating a patient’s eligibility to enroll in the study. The change to this 
part of the inclusion criteria is proposed to address the fact that the targeted study population 
are patients with MDS who have significant thrombocytopenia and are required to wait an 
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EDMS Doc. Number: 20600749 - 19462446
CC-486 (Oral Azacitidine) 
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AZA-MDS-003 Amendment 2 Final: 08 Oct 2015
additional 28 days for the RBC transfusion definition to be met. This additional time required 
may result in some patients progressing to higher risk MDS or AML prior to randomization. 
Having a shorter observation time in which to define red blood cell transfusion dependence 
will shorten the time to enrollment in the study. This change is in line with the IWG 
Hematologic Response and Improvement Criteria for MDS (Cheson, 2006).  
Revised Sections: 3.2, 4.1.1, 4.2, 6.1.2, 7.2, and Figure 1
2. Modification of the primary efficacy analysis in accordance with the changes to the 
definition of red blood cell transfusion dependence at screening for the study.  
This includes the addition of a sensitivity analysis to account for any potential impact of 
increasing the RBC transfusion dependence requirement for the baseline hemoglobin (Hgb)
level from ≤9.0 g/dL to ≤10.0 g/dL, as well as for those subjects considered transfusion 
dependent at baseline based on transfusions given for a hemoglobin value ≤ 9.0 g/dL for both 
56 and 84 days
Revised Section:  10.6.1
3. Modification of Inclusion Criterion #4
Changed requirement for two centrally analyzed platelet counts that are 
≤75 x 109/L and ≥21 days apart to just one centrally analyzed platelet count if 
thrombocytopenia is already confirmed prior to screening or if locally analyzed 
platelet counts are ≤ 75 x 109/L and are ≥ 21 days apart
This modification has been made to potentially decrease the screening time for these patients 
who have both transfusion-dependent anemia and thrombocytopenia, as they are at risk to 
experience bleeding events, rapid progression of disease, as well as other complications.  By 
allowing the use of locally analyzed platelet counts within 56 days prior to randomization 
that are ≤ 75 x 109/L, in combination with a centrally analyzed platelet count, the screening 
period for a patient’s entry into the study may be reduced. The current protocol requirement 
of 2 centrally analyzed platelet counts at least 21 days apart extends the time required to 
complete screening and delays treatment for these patients who are at risk of complications 
and/or progression, and for whom there are very few alternative treatment options.
Revised Sections:  3.2, 4.1.1, 6.1.3, 7.2, and Table 1 (footnote f)
4. Modification of Exclusion Criterion #5
Changed the wash-out period for prior lenalidomide treatment from ≥ 24 weeks to 
≥8 weeks.
Under the current protocol, patients who have received lenalidomide previously have had to 
wait for 24 weeks since their last dose before being randomized into this study. Most of these 
patients have received other therapies in the interim, resulting in the loss of a population of 
patients due to this extended wash-out period.
 
 
 
 
 
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EDMS Doc. Number: 20600749 - 19462446
CC-486 (Oral Azacitidine) 
Summary of Changes AZA-MDS-003
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AZA-MDS-003 Amendment 2 Final: 08 Oct 2015
 
 
Based on the data examined and described above, amending the protocol to allow the 
inclusion of subjects with prior lenalidomide treatment after ≥ 8 week wash-out period is 
warranted because the average time to recovery of platelet counts to > 50 x 109/Lafter 
lenalidomide use is less than a month. Additionally, the platelet count at screening is unlikely 
to be affected by earlier treatment with lenalidomide. The overall study population would not 
be changed significantly. 
Revised Section:  7.3
5. Modification of Exclusion Criterion #16
Added language to allow for the participation in Study AZA-MDS-003 if a 
subject has abnormal coagulation parameters with the condition that they are 
being treated with a stable dose of anticoagulants for thrombotic prophylaxis.
The patients enrolled in study AZA-MDS-003 to date have a median age of 73 years, with 
43% being ≥ 75 years old or greater. The opportunity to include patients who have abnormal 
coagulation parameters due to anticoagulant therapy used for thrombotic prophylaxis reflects 
the real life occurrence of this combination of disorders (ie, atrial fibrillation, a previous 
thromboembolic event, mechanical heart valves, lupus or anti- phospholipid antibodies) in 
the population under study. The acceptance of such patients into the study would be only 
after consultation with the medical monitor so that reasonable precautions for the
combination of thrombocytopenia and anticoagulant use can be discussed with the 
investigator.   
Revised Section:  7.3
6. Modification of Exclusion Criterion #17
Added language to allow for the participation of subjects with > 2.5 x ULN of the 
ALT and/or AST values if accompanied by a serum transferrin saturation of 
> 65% and a serum ferritin level > 1000 µg/L.  
This population of low/intermediate-1 risk MDS patients is required to be RBC transfusion 
dependent in order to meet eligibility criteria for enrollment into Study AZA-MDS-003. As a 
consequence, transfusional iron overload is a very common complication. In addition to 
transfusional iron loading, MDS patients have increased intestinal absorption of iron, similar 
to patients with hemoglobinopathies and genetic hemaochromatosis. Hence, MDS patients 
may show evidence of iron loading even prior to initiation of transfusion therapy. In the 
presence of iron overload, the liver may be damaged which could result in increased AST, 
ALT, and/or serum bilirubin values.
Up to the present time, there is limited evidence to indicate that azacitidine is metabolized by 
liver-derived pathways
 
. It does not appear to be a substrate, an inducer, nor an inhibitor of cytochrome 
P450 isoenzymes (1A2, 2C19, 3A4/5) (Vidaza/CC-486 Investigator Brochure, v. 11, 2014).
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EDMS Doc. Number: 20600749 - 19462446
CC-486 (Oral Azacitidine) 
Summary of Changes AZA-MDS-003
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AZA-MDS-003 Amendment 2 Final: 08 Oct 2015
For these reasons the inclusion of patients with liver enzyme abnormalities secondary to iron 
overload with AST and/or ALT > 2.5 times ULN that is accompanied by a serum transferrin 
saturation of > 65%, and a serum ferritin of > 1000 µg/L, after consultation with the medical 
monitor, will be allowed.  The addition of oral azacitidine would not have further deleterious 
effects on their liver, and could potentially result in a decrease of iron overload by decreasing
RBC transfusion requirements.
Added language to allow for the participation of subjects with > 1.5 ULN serum 
bilirubin if in the presence of diagnosed or known Gilbert syndrome.
Gilbert syndrome, also known as Gilbert-Meulengracht syndrome, is a benign hereditary 
condition characterized by intermittent unconjugated hyperbilirubinemia in the absence of 
hepatocellular disease or hemolysis (Fretzayaz, 2012).  Patients with Gilbert syndrome are 
asymptomatic and typically have otherwise normal liver serum chemistries (VanWagner, 
2015).  This is a benign condition that does not otherwise affect normal liver function and 
should not exclude subjects from the trial.  
Revised Section:  7.3
7. Addition of secondary endpoints for RBC transfusion independence with duration 
of  ≥ 56 days (8 weeks) and time to RBC transfusion independence.
The following secondary endpoints were added:
Proportion of subjects in the overall population achieving RBC transfusion 
independence with duration of ≥ 56 days (8 weeks);
Duration of RBC transfusion independence of  ≥ 56 days (8 weeks);
Time to RBC transfusion independence of ≥ 56 days (8 weeks);
Adding secondary endpoints according to the definition of RBC transfusion independence by 
IWG criteria (i.e., a duration of 56 days) will allow for comparison of oral azacitidine
efficacy within comparable study populations and MDS subsets. The secondary endpoint 
definition for duration of RBC transfusion independence and time to RBC transfusion 
independence based on a duration of 84 days will not be changed.
Revised Sections:  1.3, 3.2, 10.6.2.2
8. Addition of language to section the titled “MDS Diagnosis, WHO Classification and
IPSS Risk classification” that could expand some of the allowable criteria used to 
determine the diagnosis and classification of MDS at screening.
Language has been added to allow for the use of historical cytomorphologic, 
histologic and/or cytogenetic bone marrow samples to support the screening central 
laboratory results, which may be samples that were obtained outside of the 56 day 
screening window, but must be from within 3 months of the first screening bone 
marrow procedure.  
Language has also been added to allow for the use of fewer than than 20 analyzable 
metaphases in standard G-banding cytogenetic analysis at screening.
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AZA-MDS-003 Amendment 2 Final: 08 Oct 2015
Language has been added to allow for the use of FISH analysis to rule out common 
chromosomal aberrations that occur in MDS if, after two bone marrow aspirate 
procedures as part of screening for this study, only few (<10), or no, metaphases are 
able to be rendered with which the karyotype can be characterized via standard G-
banding.
The to-date experience in AZA-MDS-003 has shown that 14% of subjects screened have an 
insufficient number of metaphase cells with which to analyze their cytogenetic status.  
Despite undergoing repeat bone marrow aspirates, and sometimes repeat biopsies, many 
patients do not have sufficient cells for adequate cytogenetic analysis in order to be evaluated 
for inclusion by IPSS criteria. 
In addition, while bone marrow chromosome banding analyses remain the gold standard of 
cytogenetics in MDS patients, in the case of repeated failure of standard G-banding (absent 
or poor quality metaphases) FISH analysis is recommended to detect targeted chromosomal 
abnormalities in interphase nuclei according to the European LeukemiaNet consensus 
regarding diagnostic procedures for MDS (Malcovati, 2013).   
Similar to the challenges in performing standard G-banding chromosomal analysis from 
patient samples with hypocellular /fibrotic bone marrow, clear confirmation of diagnosis of 
MDS by cytomorphological analysis is also limited due to the fact that MDS progresses;
issues of hypocellularity and reticulin fibrosis of the marrow can occur or increase in amount. 
In this circumstance, confirmation of a definitive MDS diagnosis on prior marrows could 
enable the central pathologist to have a clearer understanding for the presence of MDS in the 
screening samples for this study.  The 3 month window during which the historical bone 
marrow samples must have been obtained has been proposed to minimize the chance that the 
evolution of the MDS has occurred in this time period.    
Revised section:  6.1.1
9. The exploratory efficacy analyses has been amended to include a question of 
whether or not a subject was enrolled under Protocol Amendment #2.
This change has been made in order to carry out sensitivity analyses to compare the results 
obtained before versus after implementation of the protocol amendments.
Revised Section:  10.6.2.3
Minor changes included in this amendment are summarized below:
1. An administrative update was made to reflect the change of 
 
Revised Section: signature page (pg. 2)
2. Added language to emphasize the need for accurate and thorough documentation of 
platelet transfusion status since this information is used in the efficacy analysis.
This has been modified to provide clarity to the existing protocol language.
Revised Section:  4.1.1
3. Language has been added to the protocol that would enable the implementation of a 
roll-over protocol.
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AZA-MDS-003 Amendment 2 Final: 08 Oct 2015
This language has been added to allow for the closing of the study if the primary analysis has 
been completed (and been unblinded) in order to reconsent any remaining subjects into a roll-
over protocol without amending the original protocol.  This roll-over protocol will provide 
subjects who continue to benefit from treatment continuation via post-study treatment with 
this compound.  
Revised Sections:  4.1.4, 14.8
4. Added language to clarify the existing language regarding the study windows  and 
7-day drug holiday.
This has been modified to provide emphasis on the necessity of a study drug holiday.
Revised Sections:  6.0, Table 1 (footnote a)
5. Removed the time frame of “within 14 days of randomization” from the 
performance of a reticulocyte count in screening.
This has been modified to reflect the fact that analyzing the reticulocyte count earlier during 
the screening period allows for earlier testing for the presence of autoimmune hemolytic 
anemia in the case of a patient with an elevated indirect bilirubin level.  This would thus give 
the investigator the opportunity to avoid invasive bone marrow assessments for a patient who 
would ultimately be ineligible due to autoimmune hemolytic anemia.  
Revised Sections: Table 1 (footnote n), 6.1.13
6. Added language to clarify when the HRQoL questionnaire should be completed by 
the subjects.
This has been modified due to the scheduling by some sites of laboratory draws prior to the 
actual visit date, and the fact that laboratory personnel are not study specific and do not have 
access to the devices on which the subjects answer the questionnaire.  
Revised Sections:  Table 1 (footnote x)
7. Language was added to account for an in-home nursing service which may be 
utilized at the investigators discretion (if applicable in the respective country) to 
obtain hematology and serum chemistry laboratory samples on Days 8, 15, and 22.
This language has been added to the protocol as in-home nursing service will be rolled-out in 
some countries as applicable (depending on local regulations and demand) in the near future.  
This service is being initiated to address the concerns of some investigators regarding 
subjects who live a great distance from an investigative site and who may not be able to enter 
the study because the travel time for the frequency of visits would be prohibitive.
Revised Sections:  6.6.5
Supportive Literature Used in the SOC
Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, et al. Clinical 
application and proposal for modification of the International Working Group (IWG) response 
criteria in myelodysplasia. Blood 2006;108 (2):419-25.
Fretzayaz et al. Gilbert syndrome. Eur J Pediatric, 2012 Jan;171(1):11-5.
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CC-486 (Oral Azacitidine) 
Summary of Changes AZA-MDS-003
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AZA-MDS-003 Amendment 2 Final: 08 Oct 2015
Garcia-Manero G, Shan J, Faderl S, Cortes J, Ravandi F, Borthakur G, et al. A prognostic score 
for patients with lower risk myelodysplastic syndrome. Leukemia 2008a;22(3):538-43.
Malcovati, L, Cazzola, M. Refractory anemia with ring sideroblasts. Best Practice & Research 
Clinical Haematology 26 (2013) 377–385.
VanWagner, L, Green, R. Evaluating elevated bilirubin levels in asymptomatic adults. JAMA 
2015 February 3; 313(5): 516-517.
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CC-486 (Oral Azacitidine)
Summary of Changes AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
3
AZA-MDS-003 Amendment 1.0 Final: 11 Apr 2014
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
1.
 
 
One main purpose of this protocol amendment is to extend the targeted patient population by 
increasing the platelet count limit at screening from the current platelet counts of 
 
as entry criteria for enrollment into the 
protocol (Inclusion Criterion #4, Section 7.2).  
 
 
 
 
 
  
 
 
 
  As this increase is not considered to be significant enough to warrant any change to 
the current sample size calculation, the samples size of 386 subjects (193 in each group) 
remains the same as in the original AZA-MDS-003 protocol.
2. Extension of targeted patient population to allow subjects who had prior treatment 
with lenalidomide 
An additional reason for this protocol amendment is to allow subjects who had prior 
treatment with lenalidomide entering the study, provided that subjects had their last 
lenalidomide treatment ≥24 weeks prior to randomization (Exclusion Criterion #5, 
Section 7.3).  Lenalidomide (Revlimid®) is an immunomodulating agent with activity 
demonstrated in patients with lower risk MDS, particularly in lower risk transfusion 
dependent MDS patients with chromosome 5q deletion [del(5q)] who are RBC transfusion-
dependent.  The majority of these patients achieve transfusion independence with 
lenalidomide, however, patients frequently relapse and become dependent on transfusions 
again despite taking lenalidomide.  It is currently recommended that patients discontinue 
lenalidomide therapy at that point (NCCN Guidelines MDS, 2014), however, only very 
limited alternative treatment options are available for these patients to date.  
Based on publications by List (2006) and Raza (2008) lenalidomide shows significant 
activity in subjects with deletion of 5q as well as subjects without 5q deletion, respectively.  
Currently there is no evidence that no response or relapse to a prior response to lenalidomide 
treatment has any negative impact on subsequent azacitidine response.  Komrokji et al.
reported response to treatment with azacitidine in del(5q) MDS subjects after lenalidomide 
treatment failure (Komrokji, 2012).  Overall response rates (CR and PR) in these del(5q) 
patients previously treated with lenalidomide appear to be similar to those observed in the 
azacitidine registration trials for MDS (Vidaza® Prescribing Information), indicating that 
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CC-486 (Oral Azacitidine)
Summary of Changes AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
4
AZA-MDS-003 Amendment 1.0 Final: 11 Apr 2014
azacitidine may be an effective option for salvage treatment in patients previously failing 
lenalidomide.
The mandated window of at least 24 weeks between the last dose of lenalidomide 
administered and randomization in the AZA-MDS-003 study, will account for potential late-
responders to lenalidomide and also rule out any potential synergistic effects lenalidomide
and azacitidine might have.  In addition, this 24-week window allows subjects to recover 
from possible myelosuppression such as worsening of thrombocytopenia, that may be related 
to lenalidomide therapy before entering the AZA-MDS-003 study, thereby avoiding that a 
late hematologic recovery could be mistaken as a response to study treatment (CC-486 or 
placebo).
3. Inclusion of subjects with secondary MDS 
An additional reason for this protocol amendment is to allow subjects with secondary MDS 
(ie, MDS that is known to have arisen as the result of chemical injury or treatment with 
chemotherapy and/or radiation for other diseases) if subjects have been off-treatment from 
prior antineoplastic therapy ≥24 weeks prior to randomization. 
Generally secondary MDS has a worse prognosis than primary (de novo) MDS and this is 
thought for the most part, to be related to the fact that the karyotypic abnormalities are more 
complex in secondary MDS (Heim, 1992; Vanleeuwen, 1996; Larson, 1996; West, 2000).
As complex karyotypes are frequent in secondary MDS the majority of patients are classified 
as higher risk disease according to the IPSS risk classification.  However, a smaller fraction 
of secondary MDS with no chromosomal abnormalities, or better karyotypes, are classified 
as INT-1 according to IPSS displaying similar features as de novo MDS.  It is thought that 
the prognostic differences that are seen in these two patient groups (de novo MDS versus 
secondary MDS) relate primarily to the occurrence of their underlying cytogenetic changes 
and that survival is similar in de novo versus secondary MDS for equivalent chromosomal 
abnormalities (Estey, 1998; Tong, 2012). 
Based on the above observation, that karyotypic abnormalities appear to be one of the 
primary contributors on prognosis in both de novo MDS and secondary MDS, it is not 
expected that the inclusion of patients with secondary Int-1-risk MDS in the AZA-MDS-003 
study would affect the overall study population significantly with regards to the expected OS.  
However, azacitidine could potentially offer clinical benefit in this population with otherwise 
limited treatment options.
4. Further clarification on the inclusion of subjects with hypoplastic MDS or other 
subtypes 
The original protocol allows for inclusion of subjects with hypoplastic MDS or other subtype 
who are not eligible for treatment with immunotherapy.  The addition of “based on 
investigator’s judgment” further clarifies that it is solely at the treating investigator’s 
discretion to judge the patients’ suitability for treatment with immunotherapy. 
Based on several studies evaluating the use of immunosuppressive therapy with ATG with or 
without cyclosporine, it has been established that immunosuppressive therapy is most 
efficacious in MDS patients with a HLA-DR15 histocompatibility type (Jonasova, 1998; 
Molldrem, 1997; Saunthararajah, 2003).  Responses may also occur in subjects who have 
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CC-486 (Oral Azacitidine)
Summary of Changes AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
5
AZA-MDS-003 Amendment 1.0 Final: 11 Apr 2014
alternate HLA-DR typing, but responses occur less frequently (Saunthararajah, 2003).  
However, subjects with a higher age are at significant increased risk of developing serious 
life-threatening infections with this form of therapy, and this mode of treatment is not 
frequently prescribed for this older age group due to serious side effects that can transpire 
(Sloand, 2009).  Furthermore, from a global perspective, immunosuppressive therapy is not 
necessarily routinely used or available for this subtype of MDS.
Due to the fact that several patient specific parameters need to be considered when evaluating 
whether immunosuppressive therapy may be an adequate treatment option for an individual 
patient, Celgene has included the clarification “based on investigator’s judgment” to indicate 
that it is solely at the discretion of the treating investigator to determine whether 
immunosuppressive therapy may be a suitable treatment option for the patient. 
Furthermore, new emerging data specifically assessing response to azacitidine in patients 
with hypoplastic MDS indicates clinical efficacy in this specific patient population 
(Seymour, 2013).  Additionally, safety related to azacitidine treatment does not appear to be
compromised in this hypoplastic MDS population in comparison to that seen with alternative 
therapies including best supportive care, low dose Ara-C or more aggressive chemotherapy 
combinations including Ara-C plus anthracyclines (Seymour, 2013).  This new data further 
supports that patients with hypoplastic MDS should not be excluded from participation in 
this study unless considered suitable for immunosuppressive therapy by the investigator. 
5. Modification to study procedure at screening - addition of a mandatory bone 
marrow biopsy at screening 
Although the classification of MDS according to the WHO 2008 classification is primarily 
based on cytomorphologic and quantitative criteria derived from bone marrow aspirate and 
peripheral blood smear, the value of the bone marrow biopsy in MDS is well established and 
regarded mandatory by widely acknowledged diagnostic guidelines (Swerdlow, 2008; 
Malcovati, 2013; NCCN Guidelines MDS, 2014).
A bone marrow biopsy exam may aid in confirming a suspected diagnosis of MDS by 
excluding reactive and non-reactive conditions in which cytopenia and dyshematopoietic 
changes may also be observed.  A biopsy provides information on marrow cellularity, 
megakaryocyte component, blast compartment, bone marrow fibrosis, bone marrow tissue 
architecture such as granulomas and the presence of non-hematological cells, such as 
metastases.  The bone marrow in MDS is usually hyper- or normocellular, but in a minority 
of cases (approximately 10%), the bone marrow is hypocellular (hypoplastic MDS).  This 
group needs to be distinguished from both aplastic anemia and hypocellular AML.  The 
separation between these entities can be problematic as morphological differences may be 
subtle (Maschek, 1993; Huang, 2008; Sloand, 2009) and a bone marrow biopsy has been 
shown to be useful in distinguishing hypoplastic MDS from cases of aplastic anemia 
(Bennett, 2009).
In 10% to 20% of cases of MDS there is moderate to severe bone marrow fibrosis in which 
bone marrow aspiration often fails or delivers smears of inferior quality.  MDS with bone 
marrow fibrosis identifies a distinct subgroup of MDS with multilineage dysplasia and high 
transfusion requirement.  These cases need to be differentiated from other myeloid 
neoplasms with bone marrow fibrosis, such as chronic myelomonocytic leukemia, primary 
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CC-486 (Oral Azacitidine)
Summary of Changes AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
6
AZA-MDS-003 Amendment 1.0 Final: 11 Apr 2014
myelofibrosis, acute megakaryoblastic leukemia and acute panmyelosis with myelofibrosis.  
Most cases of MDS with fibrosis have an excess of blasts and an aggressive clinical course.  
Such cases may erroneously be considered low-grade MDS if only the blast count is 
determined from the BM aspirate, which in the presence of fibrosis is often diluted with 
peripheral blood.  In the fibrotic group, as in other cases of MDS with inadequate aspirates, 
an accurate blast determination requires a bone marrow biopsy and immunohistochemical 
studies for CD34.  Immunohistochemistry with anti-CD34 allows the identification and 
enumeration of CD34+ blast cells.  This is particularly useful in the case of an aspirate of 
suboptimal quality because of bone marrow fibrosis or hypocellularity (Buesche, 2008; Della 
Porta, 2009; Thiele, 2005).  
On the basis of these findings and given the target patient population for the AZA-MDS-003 
study with significant marrow dysfunction related to thrombocytopenia plus red blood cell 
transfusion dependency, it is possible that a proportion of the eligible subjects have 
hypoplastic marrows or marrows that have features of fibrosis.  In fact, it appears that bone 
marrow aspirates drawn from a considerable fraction of the patients screened for the AZA-
MDS-003 study thus far, presented with reduced marrow particles and cellularity.  Thus 
performing a bone marrow biopsy for central confirmation of the diagnosis of MDS at 
screening provides addition valuable information on the condition of the bone marrow and 
also helps to distinguish the fraction of hypoplastic MDS patients from patients with aplastic 
anemia.
6. Oral azacitidine may be taken on an empty stomach or with food
Currently Celgene is evaluating the pharmacokinetics and effect of food of a new tablet 
formulation of oral azacitidine (CC-486) in the ongoing Phase 1 study AZA-MDS-004 “A 
Phase 1, Multicenter, Open-label Study to Evaluate The Pharmacokinetics and Effect of Food 
of A New Tablet Formulation of Oral Azacitidine, and to Evaluate The Safety and Efficacy 
of Oral Azacitidine in Subjects with Myelodysplastic Syndromes, Chronic Myelomonocytic 
Leukemia or Acute Myeloid Leukemia”.  Part 1 of the AZA-MDS-004 study assessed the PK 
of oral azacitidine administered once daily as two 150-mg tablets (F8 formulation, the 
formulation being assessed in the AZA-MDS-003 study) and three 100-mg tablets (F6 
formulation) and evaluated the effect of food (600 calories) on oral azacitidine absorption 
from the two 150-mg tablets (F8).  Preliminary results showed that under fasted condition, 
the F6 and F8 PK profiles are comparable (N=17). Compared to fasted condition, the F8 PK 
profile under fed condition shifted ~1.0 hour to the right. Under fasted conditions, the PK 
parameters (AUCinf, Cmax, Tmax, terminal half-life elimination, apparent clearance, apparent 
volume of distribution) obtained following F6 and F8 administration are similar. Following 
F8 administration under fed and fasted conditions, the PK parameters are similar with the 
exception of the median Tmax, which is delayed by ~1.0 hour under fed condition.
In summary, following oral administration, azacitidine is rapidly absorbed. Little or no effect 
of food on azacitidine PK was observed with the F8 formulation, except Tmax delay of 
~1.0 hour under fed condition. Based on these results, oral azacitidine can be taken without 
regard to food (up to 600 calories) (Investigator’s Brochure) and this was reflected in the 
protocol.
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CC-486 (Oral Azacitidine)
Summary of Changes AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
7
AZA-MDS-003 Amendment 1.0 Final: 11 Apr 2014
7. Granulocyte colony stimulating factors may be administered as secondary 
prophylaxis during the study
The current protocol allows the administration of granulocyte colony stimulating factors 
(G-CSF and granulocyte macrophage colony-stimulating factor [GM-CSF]) for the treatment 
of neutropenic infections.  Celgene plans to amend the protocol to also allow administration 
of granulocyte colony stimulating factors as secondary prophylaxis as per the investigator’s 
discretion.
Febrile neutropenia is a serious and potentially life-threatening complication in patients 
undergoing systemic chemotherapy and an increase in frequency of febrile neutropenia may 
occur related to both the severity and duration of neutropenia.  Patients with MDS frequently 
succumb to infection, partly due to neutropenia and partly due to neutrophil dysfunction 
(Komrokji, 2003).  The use of secondary prophylaxis with Colony Stimulating Factors (CSF) 
in patients with a previous episode/episodes of severe febrile neutropenia may reduce the risk 
of developing recurrent febrile neutropenia/ neutropenia Grade 4 and in some cases may help 
sustain treatment intensity by enabling subsequent treatment cycles to occur on time.  
Currently there is no evidence to support the use of CSF as sole treatment in MDS patients, 
but it has been demonstrated that CSF can raise neutrophil counts in MDS patients receiving 
GM-CSF and G-CSF (Ganser, 1996).  However, in a randomized trial, G-CSF had no effect 
on survival, transformation to AML, or hemoglobin levels (Greenberg, 1993; Komrokji, 
2004). 
Based on the above background data, no impact on the primary and key secondary objective 
of the study (ie, RBC transfusion independence and Overall survival, respectively) is 
expected by allowing the administration of granulocyte colony stimulating factors as 
secondary prophylaxis.  Allowing a CSF depending on the discretion of the treating 
physician, is made primarily on a patient safety basis.
8. Modification of the wording concerning the involvement of the medical monitor in 
the unblinding and discontinuation of trial subjects 
The reason for the modification is to provide clearer wording, in accordance with the 
Declaration of Helsinki 3§ and ICH GCP (4.3, 5.13.4, and 4.7), in the respective sections of 
the protocol to clarify that the investigator is not required to discuss emergency unblinding or 
discontinuation if he/she feels that emergency unblinding or discontinuation of the subject is 
necessary.
The amendment also includes several other minor clarifications and corrections:

Addition of the EudraCT number to the cover page

Change of Medical Monitor / Emergency Contact Information

Change of Therapeutic Area Head

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CC-486 (Oral Azacitidine)
Summary of Changes AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
8
AZA-MDS-003 Amendment 1.0 Final: 11 Apr 2014

Clarification and implementation throughout the protocol that an Interactive Response 
Technology (IRT) system is used for central randomization which includes both an 
Interactive Voice and Web Response System(IVRS/IWRS)

Further clarification on the disease status assessment at the end of Cycle 6, to emphasize
that it is sufficient that any one of the criteria listed is met, in order for subjects to 
proceed to Cycle 7

Clarification that not a maximum of, but approximately 150 sites will be opened to enroll
approximately 386 subjects

Clarification and consistent implementation throughout the protocol, that the EQ-5D-3L 
(3 level version) of the EQ-5D questionnaire from the EuroQoL Group is used for the 
study

Clarification that immunophenotyping of bone marrow precursor cells at baseline will be
performed centrally and not at a subset of centers 

Clarification and consistent implementation throughout the protocol, that vital signs
cover blood pressure, pulse, temperature and the respiratory rate

Clarification and implementation throughout the protocol that serum pregnancy testing in 
female subjects of childbearing potential is mandatory at screening while both serum or 
urine pregnancy test (investigator’s discretion; sensitivity of at least 25 mIU/mL) is 
acceptable during treatment phase and at the Treatment Discontinuation visit

Clarification and consistent implementation of time points for the completion of the 
FACT-An and EQ-5D-3L questionnaires

Clarification that (prophylactic) antiemetic medication may be administered at the 
investigator´s discretion

Revision to remove the referenced “Study reference manual” as this document is not 
being used in the study

Clarification that it is the investigator´s accountability to verify all eligibility criteria, 
while the sponsor will only review key eligibility criteria including selected central lab
results as well as central pathology and cytogenetic reports required as per protocol

Modification of Section 6.6.5 to implement that Day 8, 15, and 22 hematology and serum 
chemistry draws may be performed at the subject’s local/primary physician office and 
shipped to the central laboratory for analysis on a case-by-case basis (at the investigator’s 
discretion and in consultation with Celgene)

Modification of Section 6.7.2 to implement that the investigative site may inquire about 
signs and symptoms of bleeding events via a phone call made to the subject  

Revision of Section 6.7.7 to provide further guidance on the timing of the serum EPO 
sample scheduled for Day 1 of Cycle 6, in order to accommodate that serum EPO level 
should not be collected within 1 week after any RBC transfusion (if applicable) due to 
possible reduction of the serum level related to the hemoglobin level achieved after the 
last transfusion
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CC-486 (Oral Azacitidine)
Summary of Changes AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
9
AZA-MDS-003 Amendment 1.0 Final: 11 Apr 2014

Minor clarification on Inclusion/Exclusion criteria (Section 7)

Inclusion criterion #3: clarification that the required RBC transfusion history of at 
least 84 days (with an average of ≥ 2 units** per 28 days) immediately preceding 
randomization overlaps with the screening phase

Inclusion criterion #4: clarification that both platelet counts required to prove 
thrombocytopenia (≤ 75 x 109/L and ≥21 days apart) must be analyzed by the 
central lab

Exclusion criterion #10: clarification that only ongoing medically significant
adverse events from previous treatments would exclude a subject from 
participation in the study 

Exclusion criterion #11: revision to allow for stable or decreasing doses of iron-
chelating agents for at least 8 weeks (56 days) prior to randomization

Additions to the dose modification guidelines (Section 8.2.4)

Dose modification guidelines for neutropenia Grade 4 (if deemed necessary by 
the investigator) have been added to account for the very low neutrophil counts 
frequently seen in the targeted patient population in the absence of fever and/or 
infection

Dose modification guidelines for hematologic or non-hematologic adverse events 
that would put a subject at unacceptable risk in the investigator´s opinion 
(independent of IP relationship) 

The possibility to use G-CSF as secondary prophylaxis has been added to the dose 
modification guidelines for neutropenic fever and neutropenia Grade 4 to match 
the modifications in Section 9.1 (Permitted Concomitant Medications and
Procedures)

Additional editorial revisions have been made to clarify that this is a guidance 
only and that it is at the investigator´s discretion to modify the IP dose to ensure 
the safety of the patient

Modification of the wording on the use of prophylactic fluoroquinolone antibiotics 
for subjects who develop very low ANC was modified to provide guidance that the 
use of prophylactic fluoroquinolone antibiotics may be considered with an ANC 
Grade 4 (ie, ANC < 0.5 x 109/L) 

Revision of Section 10.6.2.3 on additional exploratory subgroup analyses to allow for 
assessment of additional factors that may have a potential impact on the treatment 
outcome, such as the baseline platelet count, whether a subject received prior 
lenalidomide treatment and whether a subject has been diagnosed with secondary 
MDS or not 

Revision of Section 11 to clarify that there is no requirement to report progressive 
disease (PD) as a Serious Adverse Event (SAE) as this is part of the natural course of 
                                               
** As is consistent with medical practice in Japan, 1 unit RBC referenced in this protocol is equivalent to 2 units RBC in Japan.
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CC-486 (Oral Azacitidine)
Summary of Changes AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
10
AZA-MDS-003 Amendment 1.0 Final: 11 Apr 2014
the disease and does not warrant by itself criteria for seriousness (eg, PD from Int-1 
MDS to Int-2 or high risk MDS).

Revision of Appendix F (EQ-5D Health Questionnaires) to delete the third page 
referenced as EQ-5D by mistake.  This page is not part of the EQ-5D-3L 
questionnaire and is not used in the study 
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
1
STATISTICAL ANALYSIS PLAN
A PHASE 3, MULTICENTER, RANDOMIZED, DOUBLE-BLIND STUDY 
TO COMPARE THE EFFICACY AND SAFETY OF ORAL AZACITIDINE 
PLUS BEST SUPPORTIVE CARE VERSUS PLACEBO PLUS BEST 
SUPPORTIVE CARE IN SUBJECTS WITH RED BLOOD CELL 
TRANSFUSION-DEPENDENT ANEMIA AND THROMBOCYTOPENIA 
DUE TO IPSS LOWER-RISK MYELODYSPLASTIC SYNDROMES
STUDY DRUG:
Oral Azacitidine (CC-486)
PROTOCOL NUMBER:
AZA-MDS-003
DATE FINAL:
27MAR2019
Prepared by:
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901
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.
PENIA 
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
2
TABLE OF CONTENTS
SIGNATURE PAGE...................................................................................................................7
1.
LIST OF ABBREVIATIONS...................................................................................9
2.
INTRODUCTION..................................................................................................11
3.
OBJECTIVES ........................................................................................................12
4.
INVESTIGATIONAL PLAN .................................................................................13
4.1.
Overall Study Design and Plan ...............................................................................13
4.1.1.
Screening Phase......................................................................................................13
4.1.2.
Randomization and Double-blind Treatment Phase.................................................14
4.1.3.
Follow-up Phase .....................................................................................................15
4.1.4.
Extension Phase......................................................................................................15
4.1.5.
Study Closure .........................................................................................................15
4.2.
Study Endpoints .....................................................................................................15
4.3.
Stratification, Randomization and Blinding.............................................................16
4.4.
Sample Size............................................................................................................16
5.
GENERAL STATISTICAL CONSIDERATIONS .................................................18
5.1.
Reporting Conventions ...........................................................................................18
5.1.1.
Dates Handling.......................................................................................................18
5.1.2.
Calculation Using dates ..........................................................................................19
5.1.3.
Calculation of Cycles..............................................................................................19
5.2.
Analysis Populations ..............................................................................................20
5.2.1.
Intent-to-Treat Population.......................................................................................20
5.2.2.
Modified Intent-to-Treat Population .......................................................................20
5.2.3.
Safety Population....................................................................................................20
6.
SUBJECT DISPOSITION......................................................................................21
7.
PROTOCOL DEVIATIONS/VIOLATIONS ..........................................................23
8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS................................24
8.1.
Demographics.........................................................................................................24
8.2.
Baseline Disease Characteristics.............................................................................24
8.3.
Medical History......................................................................................................26
8.4.
Prior MDS Treatment .............................................................................................26
8.5.
Prior Cancer, Systemic Anti-cancer Therapy (Not for MDS) and Prior 
Radiation Therapy ..................................................................................................26
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
3
8.6.
Prior Thrombocytopenia Therapy ...........................................................................27
8.7.
Prior Medications ...................................................................................................27
8.8.
Coombs Test Results ..............................................................................................27
8.9.
Subsequent MDS Therapies....................................................................................27
8.10.
Concomitant Medications .......................................................................................27
9.
STUDY TREATMENTS AND EXTENT OF EXPOSURE....................................28
9.1.
Treatment Duration.................................................................................................28
9.2.
Number of Treatment Cycles..................................................................................28
9.3.
Duration of Exposure..............................................................................................28
9.4.
Average Length of Cycle........................................................................................28
9.5.
Average Number of Days Dosed per Cycle.............................................................28
9.6.
Cumulative Dose ....................................................................................................28
9.7.
Average Daily Dose................................................................................................28
9.8.
Dose Intensity.........................................................................................................29
9.9.
Dose Adjustment ....................................................................................................29
9.10.
Treatment Compliance............................................................................................29
10.
EFFICACY ANALYSIS ........................................................................................30
10.1.
Analysis of Primary Efficacy Endpoint...................................................................30
10.2.
Analyses of Secondary Efficacy Endpoints.............................................................32
10.2.1.
Key Secondary Endpoint ........................................................................................32
10.2.2.
Platelet response (HI-P)..........................................................................................33
10.2.3.
RBC transfusion independence for 84 days.............................................................33
10.2.4.
Duration of RBC transfusion independence of ≥ 56 days (8 weeks) ........................33
10.2.5.
Time to RBC transfusion independence of ≥ 56 days (8 weeks)..............................33
10.2.6.
Duration of RBC transfusion independence of ≥ 84 days (12 weeks) ......................34
10.2.7.
Time to RBC transfusion independence of ≥ 84 days (12 weeks) ............................34
10.2.8.
Progression to AML ...............................................................................................34
10.2.9.
Time to AML Progression ......................................................................................34
10.2.10.
Erythroid response (HI-E).......................................................................................35
10.2.11.
Duration of RBC transfusion reduction...................................................................35
10.2.12.
Platelet transfusion independence ...........................................................................35
10.2.13.
Duration of platelet transfusion independence.........................................................35
10.2.14.
Time to platelet transfusion independence...............................................................35
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.11


CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
4
10.2.15.
Hematologic response.............................................................................................36
10.2.16.
Clinically significant bleeding event .......................................................................36
10.2.17.
ECOG Performance Status......................................................................................36
10.3.
Subgroup Analysis..................................................................................................36
11.
SAFETY ANALYSIS ............................................................................................38
11.1.
Adverse Events.......................................................................................................38
11.1.1.
Adverse Events by Cycle........................................................................................39
11.1.2.
Adverse Events of Special Interest..........................................................................40
11.1.2.1.
Second Primary Malignancies.................................................................................42
11.1.2.2.
Progression to AML ...............................................................................................42
11.2.
Death......................................................................................................................42
11.3.
Clinical Laboratory Evaluations..............................................................................42
11.4.
Vital Sign Measurements........................................................................................43
11.5.
Bone Marrow Aspirate Differential and Peripheral Blood Smear ............................43
11.6.
Electrocardiogram ..................................................................................................43
11.7.
Pregnancy...............................................................................................................43
12.
HEALTH-RELATED QUALITY OF LIFE ANALYSIS........................................44
13.
HEALTHCARE RESOURCE UTILIZATION.......................................................45
15.
INTERIM ANALYSIS...........................................................................................47
15.1.
General Information................................................................................................47
15.2.
Statistical Approaches for Control of Alpha............................................................47
16.
CHANGES TO THE STATISTICAL ANALYSES SECTION OF THE 
PROTOCOL...........................................................................................................48
17.
REFERENCES.......................................................................................................49
18.
APPENDICES........................................................................................................50
18.1.
Appendix A: Date Imputation Guideline.................................................................50
18.1.1.
Impute Missing AE/ Prior or Concomitant Medications..........................................50
18.1.2.
Impute Missing Start Dates of Subsequent MDS Treatment....................................51
18.2.
Appendix B: Myelodysplastic Syndromes World Health Organization 
Classification System..............................................................................................52
18.3.
Appendix C: International Prognostic Scoring System Score ..................................54
18.4.
Appendix D: ECOG Performance Status.................................................................55
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
5
18.5.
Appendix E: Hematologic Response According to the IWG Criteria for 
MDS.......................................................................................................................56
18.6.
Appendix F: Derivation Rules for Hematologic Response and Hematologic 
Improvement According to the IWG Criteria for MDS ...........................................58
18.6.1.
Hematologic Response ...........................................................................................58
18.6.2.
Cytogenetic response (Complete or Partial) ............................................................60
18.6.3.
Hematologic Improvement .....................................................................................60
18.7.
Appendix G: Revised International Prognostic Scoring System (IPSS-R) for 
Myelodysplastic Syndromes ...................................................................................62
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6


CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
6
LIST OF TABLES
Table 1:
Abbreviations and Specialist Terms..........................................................................9
Table 2. 
IPSS-R Prognostic Score Values.............................................................................62
Table 3. 
IPSS-R Prognostic Risk Categories/Scores .............................................................62


CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
7
SIGNATURE PAGE
STATISTICAL ANALYSIS PLAN (SAP) AND SAP AMENDMENT APPROVAL SIGNATURE PAGE 
SAP TITLE
A Phase 3, Multicenter, Randomized, Double-blind Study to Compare the 
Efficacy and Safety of Oral Azacitidine Plus Best Supportive Care versus Placebo 
Plus Best Supportive Care in Subjects with Red Blood Cell Transfusion-
dependent Anemia and Thrombocytopenia due to IPSS Lower-risk 
l d
l
i
S
d
SAP VERSION, DATE
Final, 27 MAR 2019
SAP AUTHOR
{See appended electronic 
signature page}
Printed Name and Title
Signature and Date
PROTOCOL TITLE
A Phase 3, Multicenter, Randomized, Double-blind Study to Compare the 
Efficacy and Safety of Oral Azacitidine Plus Best Supportive Care versus Placebo 
Plus Best Supportive Care in Subjects with Red Blood Cell Transfusion-
dependent Anemia and Thrombocytopenia due to IPSS Lower-risk 
INVESTIGATIONAL 
PRODUCT
Oral Azacitidine
PROTOCOL NUMBER
AZA-MDS-003
PROTOCOL VERSION, 
DATE
Amendment 5, 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
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
8
Lead Product Safety Physician
Signature
{See appended electronic signature page}
Printed Name
Date
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
9
1.
LIST OF ABBREVIATIONS
Table 1:
Abbreviations and Specialist Terms
AE
Adverse event
AESI
Adverse event of special interest
AML
Acute myelogenous leukemia
ANC
Absolute neutrophil count
ATC
Anatomical therapeutic chemical
BMI
body mass index
AZA
Azacitidine
CI
Confidence interval
CR
Complete remission
CRF
Case report form
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data management committee
EAIR
Exposure-adjusted incidence rate
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EP
Extension phase
ESA
Erythropoiesis-stimulating agents
FCBP
Female of child-bearing potential
HI
Hematologic improvement
HI-E
Hematologic improvement erythroid
HI-N
Hematologic improvement neutrophil
HI-P
Hematologic improvement platelet
HLT
Higher level term
HRQoL
Health-related quality-of-life 
IC
Informed consent
INT-1
Intermediate-1
IP
Investigational Product
IPSS
International Prognostic Scoring System
IRT
Interactive Response Technology
ITT
Intent to treat
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
10
IVRS
Interactive Voice Response System
IWG
International Working Group
KM
Kaplan-Meier
mCR
Marrow CR
MDS
Myelodysplastic syndromes
MedDRA®
Medical Dictionary for Regulatory Activities
mITT
Modified intent to treat
NCI
National Cancer Institute
OS
Overall survival
PFS
Progression-free survival
PR
Partial remission
pRBC
Packed red blood cell
PT
Preferred term
QD
Once daily
RBC
Red blood cell 
RDI
Relative dose intensity
ROW
Rest of world
SAP
Statistical analysis plan
SAS
Statistical Analysis Software
SC
Subcutaneously/subcutaneous
SD
Stable disease
SMQ
Standardized MedDRA query
SOC
System organ class
TEAE
Treatment emergent adverse event
WBC
White blood cell 
WHO
World Health Organization
an
an
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
11
2.
INTRODUCTION
This statistical analysis plan (SAP) describes the analyses and data presentations for Celgene’s 
protocol [AZA-MDS-003] “A Phase 3, Multicenter, Randomized, Double-blind Study to 
Compare the Efficacy and Safety of Oral Azacitidine Plus Best Supportive Care versus Placebo 
Plus Best Supportive Care in Subjects with Red Blood Cell (RBC) Transfusion-dependent 
Anemia and Thrombocytopenia due to International Prognostic Scoring System (IPSS) Lower-
risk Myelodysplastic Syndromes (MDS)” Amendment 5, which was issued on 28 November
2018. It contains definitions of analysis populations, derived variables and statistical methods for 
the analysis of efficacy and safety.
These analyses include the final analysis for the primary study efficacy endpoint of RBC 
transfusion independence and the interim analysis for the key secondary endpoint of overall 
survival (OS). Throughout this SAP, the treatment arms will be referred to as oral azacitidine
(CC-486) or placebo. The purpose of the SAP is to ensure the credibility of the study findings by 
specifying the statistical approaches to the analysis of study data prior to database lock for the 
primary analysis (and the interim analysis for OS) when all randomized subjects have completed 
12 months of double-blind treatment or have discontinued the double-blind treatment. This SAP 
will be finalized and signed off prior to the clinical database lock for the primary analysis
including the final analysis for the primary efficacy endpoint and all secondary efficacy 
endpoints. The final analysis for OS and progression to acute myelogenous leukemia (AML) will 
be conducted separately in the future. The interim analysis for OS and progression to AML is 
included. The analysis plan 
 for Health-related 
quality of life will be provided separately and not included in this SAP. All statistical analyses 
detailed in this SAP will be conducted using Statistical Analysis Software (SAS)® Version 9.2
or higher.
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
12
3.
OBJECTIVES
The primary objective is to evaluate RBC transfusion independence in the 2 treatment arms (oral 
azacitidine plus best supportive care versus placebo plus best supportive care) in subjects with
RBC transfusion-dependent anemia and thrombocytopenia due to IPSS lower-risk MDS.
The secondary objectives of the study are:
!
To evaluate in both treatment arms
∀
Overall survival (OS);
∀
Hematologic improvement-platelet response (HI-P);
∀
Duration of RBC transfusion independence and time to RBC transfusion
independence;
∀
Progression to acute myeloid leukemia (AML), and time to AML progression;
∀
Hematologic improvement-erythroid response (HI-E);
∀
Platelet-transfusion independence, duration of platelet transfusion independence,
and time to platelet transfusion independence;
∀
Hematologic response;
∀
Clinically significant bleeding events;
∀
Safety;
∀
Health-related quality-of-life (HRQoL); and
∀
Healthcare resource utilization.
 
 
 
 
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
13
4.
INVESTIGATIONAL PLAN
4.1.
Overall Study Design and Plan
This is a phase 3, multicenter, double-blind, randomized, placebo-controlled, parallel-group 
study that compares the efficacy and safety of oral azacitidine plus best supportive care therapy 
to that of placebo plus best supportive care in subjects with RBC transfusion-dependent anemia 
and thrombocytopenia (platelet count ≤ 75 x 109/L) due to IPSS lower-risk MDS. The study 
enrolled 216 subjects at approximately 150 sites globally.
The study consists of 4 phases: Screening, Double-blind treatment, Follow-up, and Extension.
4.1.1.
Screening Phase
Subjects will provide informed consent prior to undergoing any study-related procedures. 
Screening assessments for protocol eligibility will be performed within 56 days prior to 
randomization as outlined in Table 1 of the protocol.
Confirmation of MDS disease, WHO classification (Appendix B), and IPSS risk classification 
(Appendix C) is based on independent central pathology review, independent central cytogenetic 
review, and central laboratory hematology result. Thus bone marrow aspirate and bone marrow 
biopsy must be collected at screening. The bone marrow aspirate and biopsy slides together with 
a peripheral blood smear slide are sent to the central pathology reviewer for morphologic 
assessment. Samples of the bone marrow aspirate or biopsy are sent to the central cytogenetic 
reviewer for processing and analysis. The independent central cytogenetic review will provide 
standardized analysis and reporting for all subjects. The results from independent central 
cytogenetic review will be used for the statistical analyses.
RBC transfusion history must be available for the 56 days immediately preceding and including 
the date of randomization. Transfusion data should include the type, number of units, reason and 
date of transfusion. Transfusion data must include the hemoglobin (Hgb) value for which the 
transfusion was administered. Hgb levels at the time of or within 7 days prior to administration 
of a RBC transfusion must have been ≤ 10.0 g/dL for the transfusion to be counted towards RBC 
transfusion-dependent status. Red blood cell transfusions administered when Hgb levels were > 
10.0 g/dL will not qualify as a required transfusion for the purpose of providing evidence of 
RBC transfusion-dependent status. In addition, any RBC transfusion administered for elective 
surgery will not qualify towards determination of RBC transfusion dependent status at baseline. 
All RBC transfusion records for the 56 days immediately preceding the date of randomization 
should be collected, regardless of Hgb levels. RBC transfusion-dependent anemia at baseline is 
defined for this protocol as documentation of an average transfusion requirement of at least 2 
units of RBCs per 28 days during the 56 days immediately preceding the date of randomization.
There must also not be any consecutive 28 days within the 56-day period in which no RBC 
transfusions were administered. Platelet transfusion history, if applicable, must be available for 
the 56 days immediately preceding and including the date of randomization. Transfusion data 
must include the platelet value for which the transfusion was administered.
Platelet transfusion-dependence at baseline is defined for this protocol as at least 2 separate 
transfusion episodes during the 56 days immediately preceding the date of randomization. There 
must also not be any consecutive 28 days within the 56-day period in which no platelet 
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
14
transfusion was administered. In addition, any platelet transfusions administered for elective 
surgery will not qualify towards determination of platelet transfusion dependent status at 
baseline.
Thrombocytopenia at baseline must be confirmed by two platelet counts that are ≤ 75 x 109/L 
and ≥ 21 days apart. The second confirmatory platelet count must be obtained ≤ 14 days prior to
randomization.
Other screening assessments will be also collected according to the protocol. 
4.1.2.
Randomization and Double-blind Treatment Phase
Following confirmation of eligibility, subjects will be randomized in a 1:1 ratio to receive oral
azacitidine or placebo 300 mg once daily (QD) for 21 days. Randomization will occur by a 
central randomization procedure using an Interactive Voice Response System (IVRS) with 
stratification as described in Section 4.3.
The first dose of IP should be administered within 3 days of Randomization and can be on the
same day of randomization. After randomization, no crossover between the treatment groups will 
be permitted during any point of the study.
During the double-blind treatment phase, subjects will ingest IP (oral azacitidine or placebo)
once a day on the first 21 days of each 28-day cycle (see Section 8.2.2 of the protocol for
details). Dose modifications may occur for managing toxicity if necessary during treatment
(Section 8.2.4 of the protocol).
Best supportive care may be used in combination with study treatment as deemed necessary.
Best supportive care includes, but is not limited to, treatment with RBC transfusions (packed red
blood cell [pRBC] or whole blood), single donor or pooled donor platelet transfusions, antibiotic,
antiviral and/or antifungal therapy, nutritional support as needed, and granulocyte colony
stimulating factors for subjects experiencing neutropenic infections (Section 9.1 of the protocol). 
Best supportive care for this study excludes the use of erythropoiesis-stimulating agents (ESAs)
and other hematopoietic growth factors (granulocyte colony stimulating factors are allowed in 
subjects experiencing neutropenic fever/infections as well as for secondary prophylaxis under 
certain conditions as described in Section 9.1 of the protocol).
Visits during the double-blind treatment phase are scheduled weekly for the first 2 cycles, every
other week for the next 10 cycles and then monthly once a subject has completed 12 cycles.
During the double-blind treatment, subjects will be assessed continuously for safety and efficacy.
Assessments include adverse events (AEs), monitoring for progression to AML and second 
primary malignancy, physical examination, vital signs and weight measurement, Eastern 
Cooperative Oncology Group (ECOG) performance status, hematology and serum chemistry, 
serum ferritin level, pregnancy testing (females of child-bearing potential [FCBP] only),
concomitant medications, therapies and procedures, transfusions administered, clinically
significant bleeding events, central review of bone marrow aspirate (or biopsy if an adequate
aspirate is not attainable) and peripheral blood smear, central review of cytogenetics,
hematologic response/improvement assessment (International Working Group [IWG] 2006 
criteria; Cheson, 2006; Appendix E), disease status assessment,
 
 IP administration and accountability, HRQoL, and healthcare resource utilization.
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
15
4.1.3.
Follow-up Phase
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
period is longer, for the collection of AEs, concomitant medications and procedures, transfusions
administered 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, subsequent MDS therapies, progression to AML and second primary malignancy
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.
4.1.4.
Extension Phase
The Extension Phase (EP) allows subjects who are receiving oral azacitidine, at time of study 
unblinding, and who are demonstrating clinical benefit as assessed by the Investigator, to 
continue to receive oral azacitidine after unblinding by Sponsor (Celgene Corporation) until they 
meet the criteria for study discontinuation. In addition, all subjects in the placebo arm and 
subjects who have 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 upon their 
approval and eligibility of entering the EP.
4.1.5.
Study Closure
The study will conclude once all subjects have completed or discontinued from the extension 
phase.
4.2.
Study Endpoints
The primary endpoint is the proportion of subjects in the overall population achieving RBC 
transfusion independence with duration ≥ 56 days (8 weeks).
The secondary endpoints are:
!
OS;
!
HI-P (IWG 2006 criteria; Cheson, 2006; Appendix E);
!
Proportion of subjects achieving RBC transfusion independence with duration ≥ 84 
days (12 weeks);
!
Duration of RBC transfusion independence of ≥ 56 days (8 weeks);
!
Duration of RBC transfusion independence of ≥ 84 days (12 weeks);
!
Time to RBC transfusion independence of ≥ 56 days (8 weeks); 
!
Time to RBC transfusion independence of ≥ 84 days (12 weeks);
!
Proportion of subjects progressing to AML and time to AML progression;
!
HI-E (IWG 2006 criteria; Cheson, 2006; Appendix E );
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
16
!
Duration of RBC transfusion reduction;
!
Proportion of platelet transfusion-dependent subjects at baseline achieving platelet
transfusion independence with duration ≥56 days (8 weeks);
!
Duration of platelet transfusion-independence;
!
Time to platelet transfusion independence;
!
Hematologic response (IWG 2006 criteria; Cheson, 2006; Appendix E);
!
Proportion of subjects experiencing clinically significant bleeding events;
!
Safety (type, frequency, severity of AEs and relationship of AEs to oral
azacitidine/placebo; monitoring for progression to AML and second primary
malignancy);
!
HRQoL utilizing the Functional Assessment of Cancer Therapy-Anemia (FACT-An) 
and EuroQoL Group EQ-5D (EQ-5D-3L) instruments; and
!
Measures of healthcare resource utilization.
4.3.
Stratification, Randomization and Blinding
Following confirmation of eligibility at screening, subjects will be randomized to receive oral 
azacitidine or matching placebo in a 1:1 ratio. Randomization will be accomplished by
Interactive Response Technology (IRT) to ensure timely registration and randomization. 
Subjects will be randomized according to the following stratification factors: average baseline 
RBC transfusion requirement (≤ 4 units versus > 4 units of RBC per 28 days), baseline platelet 
transfusion status (dependent or independent), country of enrollment (ie, Japan versus Rest of 
World [ROW]) and ECOG performance status (0 to 1 versus 2).
4.4.
Sample Size
The basis for the power and sample size determination will be a test of the equality of the overall 
survival curves between the oral azacitidine and placebo treatment groups using a stratified log-
rank test. Assuming a median OS of 18 months in the placebo treated group (Garcia-Manero, 
2008a), which takes into account possible cross-over outside of the protocol of placebo treated 
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
17
subjects to active treatment during the observation period, and a median OS of 25.7 months 
(43% improvement) in the oral azacitidine treated group, 216 subjects (108 in each group) would 
have approximately 72% power to detect a constant hazard rate ratio of 0.70 using a two-sided 
log rank test with overall significance level of 0.05. It is assumed that the OS distribution is 
exponential with a constant failure (hazard) rate and that accrual is uniform during the accrual 
period (56 months) with an overall drop-out rate of 5% from both treatment groups. Full 
information necessary for a log rank test to have 72% power will be achieved when 
approximately 205 deaths have occurred in both treatment groups, which is expected 
approximately 134 months after randomization of the first subject into the study.
An interim analysis of the OS endpoint will be performed and reported when all subjects have 
completed 12 months [52 weeks (364 days)] of double-blind treatment or have been discontinued 
from treatment (see Section 15).
While 56 days (8 weeks) is the standard response criteria for hematologic improvement (IWG 
2006 criteria; Cheson, 2006; Appendix E), limited information is available on the target 
population for estimating the response rate for the primary endpoint of RBC transfusion 
independence maintained for ≥ 84 days (12 weeks).
 
 
A 
total sample size of 216 subjects (108 in the active treatment group and 108 in the placebo 
group) will have approximately 99% power to detect the difference between a response rate of 
0.30 in the active treatment group and a response rate of 0.05 in the placebo group, and 
approximately 70% power to detect the difference between a response rate of 0.15 in the active 
treatment group and a response rate of 0.05 in the placebo group. The power calculations for 
response rate are based on a two-sided alpha of 0.05 and test statistics on the difference of 
proportions using an un-pooled estimate of variance.
Sample size and power were calculated using the East® Version 5.3 software system (Cytel Inc.,
675 Massachusetts Avenue, Cambridge, MA 02139, http://www.cytel.com).
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
18
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) 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 corresponding 
table and figure.
Descriptive summaries for continuous data will include the following statistics: N, mean, 
standard deviation, minimum, median, and maximum, unless specified otherwise. Categorical 
summaries for discrete data will include the frequency (count) and percentage at each discrete 
value (category), unless specified otherwise.
5.1.1.
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 a given protocol-specified procedure are 
performed. They include the dates of laboratory testing, physical examinations, tumor 
scans, 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 case report form (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 A. 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 tumor scan that was used to determine 
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Mile
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sta
st


CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
19
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). 
Dates recorded in comment fields will not be imputed or reported in any specific format. 
5.1.2.
Calculation Using dates
Calculations using dates (e.g., relative day after the date of randomization) will adhere to the 
following conventions: 
!
If not otherwise specified, study day will be calculated with respect to randomization 
date for efficacy measures and will be calculated with respect to first dose date for all 
other measures. Study days will be calculated as the difference between the date of 
interest and the date of randomization or first dose date plus 1 day. The generalized 
calculation algorithm for relative day: STUDY DAY = [(TARGET DATE – (RAND
or FDOSE)) + 1 where RAND = the date of randomization and FDOSE= the date of 
first dose] if the target data is on or after the randomization/ first dose date and 
STUDY DAY = [(TARGET DATE – (RAND or FDOSE)) if the target date is before 
the randomization/first dose date. Note that Study Day 1 is the date of 
randomization/first dose date. Negative study days are reflective of observations 
obtained during the baseline/screening period. Note: Partial dates for the date of 
randomization/first dose date are not imputed in general. All effort should be tried to 
avoid incomplete randomization/first dose date. 
!
Intervals that are presented in weeks, months, or years will be transformed from days 
to weeks by using (without truncation) the following conversion formula:
WEEKS = DAYS /7;
MONTHS = DAYS /30.4375;
YEARS = DAYS/365.25.
5.1.3.
Calculation of Cycles
The start date of each treatment cycle will be calculated based on study drug exposure records 
(with non-zero dosing) for each patient. The start date of the first cycle (S1) will be the date when 
the subject receives the first dose of 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, i=1, 2, …. For the last cycle, 
the end date will be calculated as the cycle start date plus prescribed cycle length (28 days), or 
the death date, whichever is earlier. The cycle number for each date 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. For AEs or lab results which 
meet the treatment-emergent criterion or reporting criterion, the events or results after the end 
date of the last cycle will be included in the summary of the last cycle.
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
20
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 treatment or not. All efficacy analyses will be conducted for the ITT
population and the subjects will be analyzed based on randomized treatment group.
5.2.2.
Modified Intent-to-Treat Population
The modified intent-to-treat (mITT) population includes all ITT subjects who have at least one 
post-baseline efficacy assessment performed, met all inclusion/exclusion criteria, and received a 
minimum of one cycle of treatment.
Key efficacy analysis will be performed for the mITT population as supportive evidence and/or 
sensitivity analysis only and the subjects will be analyzed based on randomized treatment group.
5.2.3.
Safety Population
The safety population includes all randomized subjects who received at least one dose of IP. The 
safety population will be used for all safety analysis and the subjects will be analyzed according 
to the treatment actually received.
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
21
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 group and overall for:
!
ITT Population
!
mITT Population
!
Safety Population
Reasons for excluding subjects from mITT population will be summarized and listed for each 
subject in the ITT population. A separate listing will be provided for subjects who were not 
randomized. A frequency table of enrollment by site and treatment will be provided. 
The reasons for excluding subjects from mITT population are:
1. Did not have at least one post-baseline efficacy assessment; 
2. Did not meet all inclusion/exclusion criteria;
3. Did not receive a minimum of one cycle of treatment.
The post-baseline efficacy assessments include any type of transfusions, local or central lab of 
Hgb and/or platelets count, disease status assessment (by investigator), IWG MDS Response 
assessment (by investigator), and assessment of bleeding events. 
Subjects who have been dosed in Cycle 2 will be considered as receiving a minimum of one 
cycle of treatment. For subjects who did not have Cycle 2 treatment, they will be considered as 
receiving a minimum of one cycle of treatment if: 1) they have been dosed (actual dose) for at 
least 21 days if they were assigned to “21 days” dose; or 2) they have been dosed (actual dose) 
for at least 14 days if they were assigned to “14 days” dose. Days with missing (or zero) dose 
due to any reason will not be included in the “21 days” or “14 days”.
Number of subjects who are ongoing in treatment and number of subjects who are ongoing in 
follow-up will be tabulated. Reasons for study drug discontinuation as collected on the CRF will 
be summarized for all ITT subjects with the following categories:
!
Adverse events
!
Lack of efficacy
!
Withdrew consent
!
Death
!
Lost to follow-up
!
Protocol violation
!
Progressive disease
!
Sponsor Decision
!
Other
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L
!


CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
22
Reasons for study discontinuation as collected on the CRF will be summarized for all 
randomized subjects with the following categories:
!
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
A by-subject listing of subject’s reason for discontinuation will be presented. 
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atatioion will b
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
23
7.
PROTOCOL DEVIATIONS/VIOLATIONS
The protocol deviations/violations will be identified and assessed by clinical research physician 
or designee following company standard operational procedure. The protocol 
deviations/violations will be summarized by treatment group for the ITT population. 
A by-subject listing of subjects with protocol deviations/violations in the ITT population will be 
provided. 
&(/*(1(35235,(7$5<,1)250$7,21


CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
24
8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS
Summaries for the demographics and baseline clinical characteristics will be summarized by 
treatment group for ITT, mITT and the Safety population. Baseline clinical characteristics are 
defined as the latest data collected on or before date of randomization, if not otherwise specified.
When there are retested values, the retest values will be used for the analysis. Individual subject 
listings will be provided to support the tables.
Summary statistics (mean, standard deviation, median, minimum, and maximum) will be 
provided for variables measured on a continuous scale. The frequency distribution (n, %) will be 
provided for those categorical variables measured on a nominal scale.
8.1.
Demographics
Demographic characteristics consist of age, gender, race, ethnicity, reproductive status, weight 
(kg), height (cm), and body mass index (BMI). 
Age, collected from Demographic CRF page, will be summarized both descriptively and 
categorically using the following age categories: (≤64, 65-74, and ≥75 years). 
Baseline BMI will be summarized both descriptively and categorically using the following 
categories (<20, 20-<25, 25-<30, #30 kg/m2) and calculated, using the formula:
BMI (kg/m2) = baseline weight (kg) / (height(m)²).
Gender, race, ethnicity and reproductive status will be summarized categorically with respect to 
the categories as specified in the CRF. A by-subject listing of demographic characteristics will 
be presented.
8.2.
Baseline Disease Characteristics
Baseline disease characteristics includes following variables: 
!
MDS World Health Organization (WHO) 2008 classification, 
!
Eastern Cooperative Oncology Group (ECOG) performance status (0 – 1, 2),
!
Time since initial diagnosis (defined as the number of months from the date of initial 
diagnosis to the date of randomization),
!
IPSS score classification (Greenberg, 1997, Appendix C),
!
Baseline platelet transfusion status (Dependent, Independent), 
!
Average baseline RBC transfusion requirements (units per 28 days) and category (≤ 4 
units per 28 days, > 4 units per 28 days), 
!
Bone marrow blasts baseline values and category (< 5%, ≥5%), 
!
Hgb (g/dL) values,
!
Platelet count (109/L) values, 
!
Absolute neutrophil count (109/L) values,
!
White blood cell count (109/L) values,
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!


CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
25
!
Transferrin saturation baseline values (%) values.
Subjects will be considered platelet transfusion dependent at baseline if they have received ≥2 
platelet transfusions during the 56 days immediately preceding randomization and had no 
consecutive 28-day period during which no platelet transfusions were administered.
The average number of units (in 28 days) of baseline RBC of transfusions is determined by the 
following rules: 
If the subject was randomized under the original protocol and protocol amendment 1, the average 
number of units per 28 days = sum of RBC transfusion units during the 84-day interval prior to 
the randomization date / 84 days * 28 days.
!
If the subject was randomized under protocol amendment 2, the average number of 
units per 28 days = sum of RBC transfusion units during the 56-day interval prior to 
the randomization date / 56 days * 28 days.
!
RBC transfusion and whole blood transfusion during the above specified period will 
be included. For whole blood transfusion, the number of units collected in the CRF 
will be used to calculate the RBC transfusions required units.
To eliminate the impact of transfusion, the baseline values for Hgb will be determined by
following steps:
Step 1: Apply the “7-day rule” on all Hgb values from the Central lab which are collected on 
or prior to Cycle 1 Day 1. Use the lowest value among the Hgb values which are collected 
after >7 days of a RBC/whole blood transfusion or collected on the same of the transfusion as 
the baseline value.
Step 2: For subjects who don’t have baseline value from Step 1, apply the “7/3-day 
rule”. Use the lowest value among the Hgb values from the Central lab which are collected 
within 7 days after a RBC/whole blood transfusion and within 3 days before another 
transfusion as the baseline value. The rationale is that the Hgb value within 7 days from the 
first transfusion was only somewhat influenced by that transfusion.
Step 3: For subjects who don’t have baseline values from Steps 1 and 2, use the lowest value 
among all Hgb values from the Central lab which are collected on or prior to Cycle 1 Day 1.
The baseline values for platelet count will be determined similarly to eliminate the impact of 
platelet transfusion.
For absolute neutrophil count, white blood cell count and bone marrow blasts, the baseline 
values will be determined by selecting the last non-missing value from the Central lab on or prior 
to Cycle 1 Day 1. In case that a randomized subject was not treated (no Cycle 1 Day 1 date), the 
date of randomization will be used. 
Baseline transferrin saturation will be derived using the serum samples collected at screening. 
The transferrin saturation result is derived as: iron (umol/L) / total iron binding capacity 
(umol/L). In case the result of total iron binding capacity is reported as “<xxx”, xxx-1 will be 
used as the total iron binding capacity to derive the transferrin saturation.
By-subject listings of the baseline disease characteristics will be provided.
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
26
In addition to the above baseline disease characteristics, the revised international prognostic 
scoring system for MDS (IPSS-R, Greenberg, 2012, Appendix G) 
 will 
be summarized for exploratory purpose. 
IPSS-R score will be classified and summarized as: very low, low, intermediate, high, very high. 
The derivation for the IPSS-R score is provided in Appendix G. The revised IPSS cytogenetic 
classification (from 
 central lab) will also by summarized (very good, good, intermediate, 
poor, very poor). 
 
 
 
By-subject listings of IPSS-R 
 will be provided.
8.3.
Medical History
A summary of medical and surgical history will be presented by treatment group and system 
organ class (SOC) Medical Dictionary for Regulatory Activities (MedDRA) version 21.0 or 
higher. A by-subject listing of medical and surgical history will also be presented.
8.4.
Prior MDS Treatment
A frequency table by Anatomical Therapeutic Chemical (ATC) coding scheme of the World 
Health Organization (WHO) (March 2018 version, or higher) and preferred name will be 
provided. A by-subject listing of all prior MDS treatments given will also be presented.
8.5.
Prior Cancer, Systemic Anti-cancer Therapy (Not for MDS) and 
Prior Radiation Therapy
A frequency tabulation of the number of subjects with prior cancer and prior systemic anti-
cancer therapy will be provided. A listing of types of prior cancer and all prior systemic anti-
cancer therapies documented on the CRF will also be presented.
A frequency tabulation of the number of subjects with prior radiation therapy, the types of 
radiation therapy used as well as descriptive statistics on the dose received will be given. A 
listing of all prior radiation therapies documented on the CRF will also be presented.
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
27
8.6.
Prior Thrombocytopenia Therapy
A frequency tabulation of the number of subjects with prior thrombocytopenia therapy and the 
types of therapy given. A listing of all prior thrombocytopenia therapies as well as the date the 
thrombocytopenia was first reported as documented on the CRF will also be presented.
8.7.
Prior Medications
Prior medications are defined as medications that were started before the date of first dose 
(whether or not ended before the date of first dose). Prior medications that continue into study 
treatment period will be also reported as concomitant medication.
Prior medications will be coded using WHO March 2018 version, or higher. Medication not in 
the WHO drug dictionary will be classified as “Not Coded” in the analysis. 
A frequency table by ATC class and preferred name will be provided. A listing of prior 
medications documented on the CRF will also be provided. 
8.8.
Coombs Test Results
A by-subject listing of baseline Coombs test results and reticulocyte count based on the data
collected on the CRF page will be provided. 
8.9.
Subsequent MDS Therapies
Subsequent MDS therapies will be summarized by ATC level 1 term and preferred name for the 
safety population, respectively. Details of subsequent MDS therapies will be presented in subject 
data listings.
8.10.
Concomitant Medications
Concomitant mediations are defined as non-study medications that are started after the initiation 
but before the end of the study treatment (last dose of study drug + 28 days, death, whichever 
earlier), or started before the initiation of the study treatment and ended or remain ongoing after 
the study treatment initiation. Concomitant medications will be coded in WHO drug dictionary 
(March 2018 version, or higher). Medication not in the WHO drug dictionary will be classified 
as “Not Coded” in the analysis. 
The ATC coding scheme of the WHO will be used to group medications into relevant categories. 
A frequency table by ATC class and preferred name will be provided. All concomitant 
medications documented on the CRF will be listed for the ITT population. 
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ent


CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
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9.
STUDY TREATMENTS AND EXTENT OF EXPOSURE
9.1.
Treatment Duration
See Section 5.1 for cycle start and end date as well as cycle number calculation. 
The treatment duration (months) is defined as: 
[(The treatment duration end date) – (the first study drug start date) + 1]/ 30.4375,
where treatment duration end data is defined as the last dose date + 7 days (the prescribed rest 
period of each cycle), or the death date, whichever is earlier.
Summary statistics will be provided for treatment duration by treatment group. 
By-subject listings of all exposure information collected on the CRF will be provided. 
9.2.
Number of Treatment Cycles
Number of cycles for each treatment group will be summarized both descriptively and 
categorically for the safety population by treatment group. 
9.3.
Duration of Exposure
Duration of exposure will be calculated for each treatment group. Duration of exposure (days) of 
a study drug is defined as the total number of days on the study drug during the treatment period 
(excluding the periods of dose break per protocol or dose interruptions). Duration of exposure 
will be summarized descriptively for the safety population.
9.4.
Average Length of Cycle 
The average length of cycle (days) is defined as the treatment duration (in days) divided by the 
number of cycles. The average length of cycle (days) will be summarized descriptively for the 
safety population by treatment group.
9.5.
Average Number of Days Dosed per Cycle
The average number of days dosed per cycle is defined as the number of days a subject is dosed 
divided by the number of cycles the subject had. The average number of days dosed per cycle 
will be summarized descriptively for the safety population by treatment group.
9.6.
Cumulative Dose 
The cumulative dose (mg) for a study drug is defined as the sum of all doses taken during the 
treatment period (in mg). Cumulative dose will be summarized for the safety population by 
treatment group.
9.7.
Average Daily Dose
Average daily dose (mg/day) of a study drug is defined as the cumulative dose of the study drug 
divided by the number of days dosed (received a non-zero dose). Average daily dose will be 
summarized for the safety population by treatment group.
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dose interru
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of cycle (d
of cycl
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days dosed 
days dose
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umulativ
mulativ
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9.7.
9.7.


CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
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9.8.
Dose Intensity 
Actual dose intensity (mg/day) during the treatment is defined as the cumulative dose divided by 
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 × 21 days/28days = 225 mg/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 group.
9.9.
Dose Adjustment
Dose adjustment (reduction/interruption), as reported in the Study Drug Record CRF page, will 
be summarized by treatment group and include the following:
!
Subjects with at least one dose adjustment
!
Reason for dose adjustment
!
Time to the first dose adjustment
!
Time to the first dose adjustment due to AE
!
Duration of the first dose adjustment due to AE
Subjects who have been assigned to 300 mg x 14 days dose during Cycle 1 or Cycle 2 and 
subjects who have not been assigned to 300 mg x 14 days dose during Cycle 1 or Cycle 2 will be 
identified and the number of subjects will be presented by treatment group.
For subjects who have not been assigned to 300 mg x 14 days dose during Cycle 1 or Cycle 2, 
the number of dose reductions will be identified and summarized by treatment group:
!
Subjects with only one dose reduction (from 300 mg x 21 days to 200 mg x 21 days);
!
Subjects with only two dose reductions (from 300 mg x 21 days to 200 mg x 21 days, 
then from 200 mg x 21 days to 200 mg x 14 days);
!
Subjects with three dose reductions (from 300 mg x 21 days to 200 mg x 21 days, 
then from 200 mg x 21 days to 200 mg x 14 days, then from 200 mg x 14 days to 200 
mg x 7 days).
9.10.
Treatment 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 treatment cycle and 
overall. 
Treatment compliance will be summarized using descriptive statistics by cycle and overall.  
Additionally, for overall treatment compliance, the number and percentage of subjects will be 
summarized by category < 75%, ≥75 to ≤ 120%, and > 120%.
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21 days to 
21 days to 
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
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10.
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. 
A sequential gate-keeping approach will be used to control the overall type I error rate and to
perform hypothesis testing on multiple endpoints. Two endpoints, the primary efficacy endpoint 
of RBC transfusion independence and the key secondary endpoint of OS, will be tested 
sequentially in the 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 
RBC transfusion independence and OS endpoints, formal statistical inference for the OS 
analyses can only be made if superiority of oral azacitidine is demonstrated for the primary 
efficacy endpoint, RBC transfusion independence, at the two-sided 0.05 significance level. 
The primary efficacy endpoint, RBC transfusion independence, will be analyzed and reported 
only once after all 100% of the information is available for RBC transfusion independence rates 
(ie, after all 216 subjects have completed 12 months (52 weeks [364 days]) of double-blind 
treatment or have been discontinued from treatment). An interim analysis of the OS endpoint 
will also be conducted at the time of the analysis of the primary efficacy endpoint as the number 
of required 205 death events will not be reached by the time of the final analysis for the RBC 
transfusion independence endpoint. An O’Brien-Fleming group sequential type boundary will be 
used to preserve the overall alpha level of 0.05 for the analysis of OS.
The remaining secondary efficacy variables, with the exception of the proportion of subjects
progressing to AML and time to AML progression, will be analyzed and reported once at the
time of the analysis of RBC transfusion independence. Subjects will continue to be followed for
progression to AML and survival until 205 deaths have been observed. Other than the pre-
specified sequential testing of RBC transfusion independence and OS, no additional alpha
adjustments for multiplicity will be made.
As there were no subjects enrolled from Japanese sites, the randomization stratification factor
“country of enrollment (ie, Japan versus ROW)” will not be used when the analysis is performed.
10.1.
Analysis of Primary Efficacy Endpoint
The primary efficacy endpoint of RBC transfusion independence is defined as the absence of any 
RBC transfusion during any consecutive “rolling” 56 days within the treatment period. A subject 
who did not receive any RBC transfusion during a consecutive rolling 56 days (i.e., day 1 to day 
56, day 2 to day 57) will be considered as a 56-day RBC transfusion independent responder. 
Subjects without achieving the response as defined above, subjects with less than 56 days of 
assessment during the double-blind treatment period, and subjects who had average baseline 
RBC transfusion units less than 2 units per 28 days (as defined in Section 8.2) will be counted as 
non-responders.
All RBC transfusion records on or after randomization within the evaluation period will be used 
to assess the response for each subject. In other words, the days after the end of the evaluation 
period will not contribute to a rolling period. The end date of the evaluation period is defined as:
!
For a subject who discontinues the treatment,
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
31
∀
If the subject doesn’t receive a subsequent MDS treatment, use the date of end of 
treatment visit;
∀
If the subject receives a subsequent MDS treatment, use the start date of the 
subsequent MDS treatment – 1 day, or the date of end of treatment visit, 
whichever is earlier;
!
For a subject who is still on-treatment at the time of the database lock for the primary 
analysis, the subject’s latest available assessment date in the database (from AE, vital 
sign, local and central lab, study drug records, efficacy assessments) will be used.
The 56-day rolling period for the RBS transfusion independent assessment starts on the date of 
randomization.
Note if the interval between the last RBC transfusion in the evaluation period (if there is at least 
one RBC transfusion during the evaluation period) and the end date of the evaluation period is 
less than 56 days, this rolling period, which is less than 56 days, won’t be considered as meeting 
the transfusion independence criteria even though there is no RBC transfusion in it. The day on 
which the transfusion is received will not contribute to the 56-day without receiving RBC
transfusion rolling period.
The primary efficacy analysis will be performed on the ITT population and will compare the 
RBC transfusion independence rates in the two treatment groups. The number and percentage of 
subjects achieving RBC transfusion independence and corresponding 95% confidence intervals 
(CI) will be tabulated and presented by treatment group. A stratified Mantel-Haenszel (MH) chi-
squared test, stratifying for average baseline RBC transfusion requirement (≤ 4 units versus > 4 
units of RBC per 28 days), baseline platelet transfusion status (dependent or independent) and 
ECOG performance status (0 to 1 versus 2), at a two-sided alpha level of 0.05, will be used to 
compare the RBC transfusion independence rate between the two treatment groups. The p-value 
from the stratified MH chi-square test will be the confirmatory p-value for the test of the null 
hypothesis that the proportion of subjects achieving RBC transfusion independence is equal 
between the two treatment groups. Summaries will include the unadjusted difference in 
proportions between the two treatment groups with corresponding 95% CI and the common odds 
ratio with corresponding 95% CI. Subject listings with supporting data will be provided.
The stratification variables, average baseline RBC transfusion requirement (≤ 4 units versus > 4 
units of RBC per 28 days), baseline platelet transfusion status (dependent or independent) and 
ECOG performance status (0 to 1 versus 2), will be derived from the corresponding CRF pages 
(see Section 8.2) and used in the stratified MH test.
The analysis of the primary endpoint will be repeated for the mITT population as the supportive 
analysis. Additionally, the following sensitivity analyses will be conducted after re-define the 
transfusion dependent subjects at baseline. Only the re-defined baseline RBC transfusion 
dependent subjects will be included in the sensitivity analyses:
!
Re-define baseline RBC transfusion dependent subjects using the RBC transfusion 
data during the 56 days immediately preceding randomization, and only including
RBC transfusion units that were given for a hemoglobin value ≤9.0 g/dL;
!
Re-define baseline RBC transfusion dependent subjects using the RBC transfusion 
data during the 84 days immediately preceding randomization, and only including 
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!


CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
32
RBC transfusion units that were given for a hemoglobin value ≤9.0 g/dL for 84 days, 
only subjects who were randomized under the original protocol and protocol 
amendment 1 are included;
For the sensitivity analyses, the pre-transfusion hemoglobin value collected on the Transfusion 
CRF will be used to assess the baseline transfusion dependency. 
10.2.
Analyses of Secondary Efficacy Endpoints
To control alpha, the Key Secondary Endpoint of Overall Survival (OS) will only be analyzed if 
the primary endpoint is statistically significant. The primary and key secondary endpoints are the 
only endpoints that will be controlled for alpha. 
10.2.1.
Key Secondary Endpoint 
Overall survival (OS), defined as the time from randomization to death from any cause, will be 
calculated using randomization date and date of death, or date of last follow-up for censored
subjects. Time to death is defined as the time between randomization and death from any cause. 
All subjects will be followed until drop-out, death, or study closure. Drop-out may be due to 
withdrawal of consent from further data collection or lost to follow-up. Subjects who drop-out or 
are alive at study closure (or at the time of the interim analysis [Section 15.2]) will have their OS 
times censored at the date of last known alive, as appropriate.
The analysis of OS will be performed using the ITT population for the interim and final analysis. 
The null hypothesis for testing the key secondary efficacy endpoint, time to death from any 
cause, is that the overall survival distributions for the two treatment groups are equivalent. 
Overall survival curves will be estimated using Kaplan-Meier (KM) methods and will be 
compared using a stratified log-rank test, stratifying by average baseline RBC transfusion 
requirement (≤ 4 units versus > 4 units of RBC per 28 days), baseline platelet transfusion status 
(dependent or independent) and ECOG performance status (0 to 1 versus 2). The p-value from 
the stratified log-rank test will be the confirmatory p-value. The p-value from the final analysis 
of the OS endpoint will be adjusted for the interim analysis to preserve the overall alpha level at 
0.05 (see Section 15.2 for further details regarding the interim analysis and methods for 
controlling the overall alpha level). 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 unstratified analysis. Plots of the KM survival curves 
will be presented for the two treatment groups, without adjustment for the stratification variables.
At the time of the final OS analysis, a stratified Cox proportional hazards model will be used to 
estimate the corresponding hazard ratio and 95% CI for oral azacitidine relative to placebo. The 
stratification variables average baseline RBC transfusion requirement (≤ 4 units versus > 4 units 
of RBC per 28 days), baseline platelet transfusion status (dependent or independent) and ECOG 
performance status (0 to 1 versus 2), will be derived from the corresponding CRF pages and used 
in the stratified log-rank test and the stratified Cox proportional hazards model.
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 
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
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group. Median follow-up time by treatment will be estimated using KM methods. The analysis of 
the OS endpoint will be repeated for the mITT population as a supportive analysis.
To assess the potentially confounding effects of other cancer therapy received subsequent to the 
protocol therapy on the survival estimates, a sensitivity analysis based on the ITT population, 
will be performed using modified censored criteria. For this analysis, subjects who received 
subsequent therapy for MDS 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 modified time-to-death endpoint will be analyzed using the 
same methods as described above for the key secondary efficacy analysis.
The supportive and sensitivity analyses for the OS endpoint will be performed only at the time of
the final analysis of OS.
10.2.2.
Platelet response (HI-P) 
HI-P is defined according to IWG 2006 criteria (Appendix E). HI-P rates will be summarized 
and compared between the two treatment groups using the same methods as the primary endpoint 
(see Section 10.1). The response collected in the IWG MDS Response Criteria CRF, and the 
response derived using central labs per IWG criteria will be summarized and analyzed 
separately. The detailed derivation is provided in Appendix F.
10.2.3.
RBC transfusion independence for 84 days
RBC transfusion independence for 84 days is defined as the absence of any RBC transfusion 
during any consecutive “rolling” 84 days during the treatment period, i.e., Day 1 to 84, Day 2 to 
85, Days 3 to 86, etc. The response is derived similarly as the derivation of the primary efficacy 
endpoint, except the rolling period is 84-day. The response of RBC transfusion independence for 
84 days will be analyzed similarly as the RBC transfusion independence for 56 days 
(Section 10.1).
10.2.4.
Duration of RBC transfusion independence of ≥ 56 days (8 weeks)  
Duration of RBC transfusion independence will be analyzed only for subjects who achieve RBC 
transfusion independence of ≥ 56 days on treatment. Duration of RBC transfusion independence 
is defined as the time from the date transfusion independence is first observed (day 1 of a ≥56
days period without a transfusion) until the date the subject has a subsequently documented RBC 
transfusion. In case a subject has more than one ≥56 days rolling periods which meet the RBC 
independence criteria, the duration with the longest rolling period will be used in the analysis. 
Subjects who maintain RBC transfusion independence through the end of the treatment period or 
who are still on-going with the treatment will be censored at the end date of evaluation period
which is defined in Section 10.1. Duration of RBC transfusion independence curves will be 
estimated using KM methods and treatment groups will be compared using an unstratified log-
rank test.
10.2.5.
Time to RBC transfusion independence of ≥ 56 days (8 weeks)
Time to RBC transfusion independence of ≥ 56 days is defined as the time between 
randomization and the date onset of transfusion independence is first observed (ie, Day 1 of 56 
without any RBC transfusions). Subjects who do not achieve RBC transfusion independence 
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2 5


CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
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34
during the treatment period will be censored at the end date of evaluation period which is defined 
in Section 10.1. In case a subject has more than one rolling periods which meet the independence 
criteria, the time to the first rolling period will be used in the analysis. Time to RBC transfusion 
independence curves will be estimated using KM methods and treatment groups will be 
compared using a stratified log-rank test. A stratified Cox proportional hazards model will be 
used to estimate the corresponding hazard ratio and 95% CI. Time to RBC transfusion 
independence (in month) for at least 56 days will also be summarized using descriptive statistics 
based on subjects who achieve the response.
10.2.6.
Duration of RBC transfusion independence of ≥ 84 days (12 weeks)
Duration of RBC transfusion independence will be analyzed only for subjects who achieve RBC 
transfusion independence of ≥ 84 days on treatment. The calculation and analysis are similar as 
for the duration of RBC transfusion independence of ≥ 56 days (Section 10.2.4).
10.2.7.
Time to RBC transfusion independence of ≥ 84 days (12 weeks)
Time to RBC transfusion independence of ≥ 84 days is defined as the time between 
randomization and the date onset of transfusion independence is first observed (ie, Day 1 of 84
without any RBC transfusions). The derivation and analysis are similar as for the time to RBC 
transfusion independence of ≥ 56 days (Section 10.2.5). Time to RBC transfusion independence
(in month) for at least 84 days will also be summarized using descriptive statistics based on 
subjects who achieve the response.
10.2.8.
Progression to AML
Progression to AML will be documented in central lab report or Follow-up Status CRF. Subjects 
who have a diagnosis of “s-AML arising from previous MDS” documented in 
 central lab 
report (in case multiple records are available for the bone marrow and/or peripheral blood 
samples collected on the same day, the records with the latest report date will be used), or
subjects with progression to AML documented in the Follow-up Status CRF will be identified.
Number and percentage of subjects progressing to AML will be presented by treatment group.
10.2.9.
Time to AML Progression 
Time to AML Progression is defined as the time from the date of randomization until the date the 
subject has documented progression to AML. For subjects who have progression to AML 
documented in 
 central lab report, the earliest sample collection date with the diagnosis of 
“s-AML arising from previous MDS” will be used as the date to AML progression (in case 
multiple records are available for the samples collected on the same day, the records with the 
latest report date will be used). For subjects who only have progression to AML documented in 
the Follow-up Status CRF, the date of progression from the CRF page will be used. Subjects who 
do not progress to AML will be censored at the date of last follow-up or at date of death. Time to 
AML progression curves will be estimated using KM methods and treatment groups will be 
compared using a log-rank test. KM estimates for median time to AML progression and the 1-
year and 2-year AML progression rate will be summarized for each treatment group. A Cox 
proportional hazards model will be used to estimate the corresponding hazard ratio and 95% CI. 
A competing risk analysis, treating death as a competing risk for AML progression, will be 
conducted for exploratory purposes.
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(1


CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
35
10.2.10.
Erythroid response (HI-E) 
HI-E is defined according to IWG 2006 criteria (Appendix E). HI-E response will be analyzed 
similarly as HI-P (Section 10.2.2). The response collected in the IWG MDS Response Criteria 
CRF, and the response derived using central labs per IWG criteria will be summarized
separately. The detailed derivation is provided in Appendix F.
10.2.11.
Duration of RBC transfusion reduction 
A subject will be considered as a RBC transfusion reduction responder if the subject has at least 
4 units reduction in transfusion units over any consecutive 56 days period compared to the 
baseline transfusion units in 56 days. Subjects with less than 4 units RBC transfusions during the 
56 days immediately preceding randomization will not be considered as a RBC transfusion 
reduction responder. The duration of response will only be determined for RBC transfusion 
reduction responders. Subjects who maintain the response through the end of the treatment 
period or who are still on-going with the treatment will be censored at the end date of evaluation 
period which is defined in Section 10.1. The derivation for responder and the calculation of the 
duration are similar as for the RBC transfusion independence described in Section 10.1 and 
Section 10.2.4. Duration of RBC transfusion reduction response will be analyzed descriptively 
using KM methods for the RBC transfusion reduction responders.
10.2.12.
Platelet transfusion independence 
Platelet transfusion independence is defined as the absence of any platelet transfusion during any 
consecutive “rolling” 56 days during the treatment period, (ie, Day 1 to 56, Day 2 to 57, Days 3 
to 58, etc.). Subjects will be considered platelet transfusion dependent at baseline if they have 
received ≥ 2 platelet transfusions during the 56 days immediately preceding randomization and 
had no consecutive 28-day period during which no platelet transfusions were administered. The 
response is derived similarly as the derivation of the primary efficacy endpoint, except using 
platelet transfusion. Frequency cross-tabulations of platelet transfusion status (dependent or 
independent) at baseline versus on treatment will be presented by treatment group.
10.2.13.
Duration of platelet transfusion independence 
Duration of platelet transfusion independence will be analyzed only for subjects who are platelet 
transfusion dependent at baseline and achieve platelet transfusion independence on treatment. 
The calculation of the duration is similar as for the duration of RBC transfusion independence of 
≥ 56 days (Section 10.2.4), except using platelet transfusion. Duration of platelet transfusion 
independence will be analyzed descriptively using KM methods.
10.2.14.
Time to platelet transfusion independence 
Time to platelet transfusion independence is defined as the time between randomization and the 
first documented date of onset of transfusion independence (ie, Day 1 of 56 without any platelet 
transfusions). The derivation is similar as for the time to RBC transfusion independence of ≥ 56 
days (Section 10.2.5), except using platelet transfusion. Subjects who are platelet transfusion 
independent at baseline will be excluded from the analysis. Time to platelet transfusion 
independence will be analyzed descriptively using KM methods. Time to platelet transfusion 
st
uring the
ing the
usio
sion n 
nsfusion
nsfusion
e treatment
e treatm
d date of ev
d date of 
the calcula
the calcula
d in
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be analyz
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nce of any 
nce of any
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hich no pla
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let transfu
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ays (
ays (


CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
36
independence (in month) for at least 56 days will also be summarized using descriptive statistics 
based on subjects who achieve the response.
10.2.15.
Hematologic response 
Hematologic response (Complete Remission [CR], Partial Remission [PR], Marrow CR [mCR], 
Stable Disease [SD], Disease Progression [PD], Failure, Relapse after CR or PR, and 
Cytogenetic Response) is defined according to IWG 2006 criteria (Appendix E). Subjects will be 
classified according to their best response achieved during treatment for the response categories 
of CR, PR, mCR, SD, PD, and failure. Only subjects who achieve CR or PR will be included in 
the Relapse after CR or PR category. Subjects will be evaluated for cytogenetic response 
regardless of their response status in other categories. For cytogenetic response, subjects will be 
classified as having a complete or partial response based on the best response achieved during 
treatment. Hematologic response will be presented descriptively, by treatment group, using 
counts and percent. All above responses collected in the IWG MDS Response Criteria CRF will 
be summarized. In addition, hematologic response CR, PR, SD, mCR, relapse after CR or PR, 
cytogenetic response, and hematologic improvement will be derived using central labs per IWG 
criteria and will be summarized separately. The detailed derivation is provided in Appendix F.
10.2.16.
Clinically significant bleeding event 
Clinically significant bleeding event is defined as: any intracranial or retroperitoneal bleed; 
bleeding requiring transfusions of > 2 units of blood/blood products; bleeding associated with a 
decrease in hemoglobin of > 2 g/dL; or bleeding from any site requiring transfusions of > 2 units 
of blood. Number and percentage of subjects experiencing a clinically significant bleeding event 
will be presented by treatment group. Additionally, the number and percentage of subjects by the 
number of clinically significant bleeding events experienced during the treatment period will be 
summarized by treatment group.
10.2.17.
ECOG Performance Status
ECOG performance will be summarized categorically with a shift from baseline to the worst 
post-baseline by cycle and for all cycles. Individual subject data will be listed. The ECOG 
performance score collected as Cycle 1 Day 1 will be used as the baseline value.
10.3.
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 RBC transfusion independence for at least 56 days and OS endpoints:
!
Age group (< 65, ≥ 65 years)
!
Sex (Male, Female)
!
Race (White, Asian, Others)
!
WHO MDS diagnosis classification (RCMD, RAEB-1, Others)
!
Baseline bone marrow blasts (< 5%, ≥ 5%)
d inin
ts will be
ts will be
ved during 
ed during
oup, using 
oup, using
 Criteria C
Criteria C
pse after CR
pse after C
ng central l
g centr
 provided i
provided i
cranial or r
ranial or r
od product
d produ
m any
any sisi
y
te re
te re
i
riencing a c
riencing a c
ally, the num
lly, the n
nts experie
nts experie
tus
tus
marized ca
marized ca
r all cycles
r all cycles
ed as Cycle
as Cycle
up Analy
up Anal
alyses that 
alyses that
med where
med where
ngful
gful il ntnterp
erp
ups for the R
ps for the 
!
Ag
Ag
!


CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
37
!
Geographic region (North America, Europe, ROW)
!
Average baseline RBC transfusion requirements prior to randomization (≤ 4 units of 
RBC per 28 days, > 4 units of RBC per 28 days)
!
Baseline platelet transfusion status (Dependent, Independent)
!
ECOG performance status (0 or 1, 2)
!
Baseline Platelet Count (≤50 x 109/L, >50 x 109/L- ≤ 75 x 109/L)
!
Prior lenalidomide use (Yes, No)
!
Subject enrolled under Amendment 2 (Yes, No)
!
IPSS-R risk category (Very low or low, Intermediate, High or very high)
RBC transfusion independence for 56 days and OS will be analyzed separately within each 
subgroup using the appropriate analysis methods as described in Section 10.1 and Section 10.2.1. 
The odds ratios (ORs) for RBC transfusion independence and the hazard ratios (HRs) for OS will 
be presented graphically in forest plots. 
The OS will also be explored by whether a subject achieves RBC transfusion independence for at 
least 56 days or not. 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 subgroup group 
(Responders and Non-responders), unadjusted for the stratification variables. This will be 
explored for all subjects in ITT population as well as for subjects within oral azacitidine arm and 
within Placebo arm.
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or subjects 


CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
38
11.
SAFETY ANALYSIS
The purpose of this section is to define the safety parameters for the study. All summaries of 
safety data will be conducted using the safety population. 
Besides the safety analysis described in this section, additional safety analysis may be 
performed, displayed and summarized, when deemed necessary.
11.1.
Adverse Events
Adverse events (AEs) will be coded according to the MedDRA version 21.0 or higher. 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 as 
described in Section 11.2.2. of the protocol. 
Treatment-emergent adverse events (TEAEs) are defined as any AE occurring or worsening with 
an onset date on or after the date of the first dose of the study medication and within 28 days 
after the date of the last dose. AEs will be summarized by SOC, preferred term (PT) and 
treatment group. The AE summarizes will include incidence tables of:
!
Summary of TEAEs.
!
TEAEs.
!
Treatment-related TEAEs. 
!
Serious TEAEs. 
!
Treatment-related serious TEAEs.
!
TEAEs with CTCAE toxicity grade of 3 or 4.
!
Treatment-related TEAEs with CTCAE toxicity grade of 3 or 4.
!
Serious TEAEs with severity of grade 3 or 4.
!
Treatment-related Serious TEAEs with severity of grade 3 or 4.
!
TEAE leading to death.
!
TEAEs leading to dose reduction.
!
TEAEs leading to dose interruption. 
!
TEAEs leading to dose interruption and reduction.
!
TEAEs leading to treatment discontinuation. 
!
Treatment-related TEAEs leading to death.
!
TEAEs by maximum severity.
!
TEAEs by age group (<65, 65 to 74, ≥75 years).
!
TEAEs by sex.
!
TEAEs by decreasing order of frequency of preferred term.
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TEAE
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Tr
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!


CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
39
!
TEAEs by decreasing order of frequency of system organ class.
!
Serious TEAEs by decreasing order of frequency of preferred term.
!
Serious TEAEs by decreasing order of frequency of system organ class
!
Pre-treatment AEs.
!
Non-serious TEAEs
Subjects with multiple events reported for the same preferred term will be counted only once per 
SOC and PT level. For summaries by severity (CTCAE grade), if a subject experience the same 
PT multiple events, then the subject will be counted only once and for the greatest severity.
In summaries of treatment-related TEAEs, if a subject reports multiple occurrences of the same 
AE, only the treatment-related occurrence will be summarized. Adverse events with missing 
relationship to study medication will be imputed as related to study medication.
Additionally, the exposure-adjusted incidence rate (EAIR) per 100 person-years will be 
summarized for all TEAEs and Grade 3 or 4 TEAEs by system organ class, preferred term, and 
treatment group. The EAIR per 100 person-years is defined as 100*(n/T), where n is the number 
of subjects with the specific AE at the SOC or PT level, and T is total exposure time (in years) 
among subjects included in the analysis. Subjects with multiple occurrences of the specific event 
will be counted only once in the numerator. The exposure time for a subject without the specific 
event is the treatment duration (calculated as Min [death date, last dose date + 28] – first dose 
date + 1 day), whereas the exposure time for a subject with the specific event is the treatment 
duration up to the start date (inclusive) of the first occurrence of the specific event. The total 
exposure time in years is calculated by dividing the sum of exposure time in days over all 
subjects included in the analysis by 365.25. The EAIR per 100 person-years is interpreted as the 
expected number of subjects with at least one occurrence of the specific event per 100 person-
years of exposure to the study drug.
Listings for the corresponding summary tables for TEAE, Serious TEAE, TEAEs leading to 
study drug discontinuation and TEAEs leading to death will be presented separately.
11.1.1.
Adverse Events by Cycle
The following TEAEs will be summarized by incidence tables, for the safety population by 
treatment group and cycle group:
!
All TEAEs 
!
Serious TEAEs
!
TEAEs with severity of grade 3 or 4;
!
TEAEs leading to death
!
Treatment-related TEAE leading to death 
!
TEAEs leading to study medication discontinuation
The following cycle group will be used:
!
Cycles 1-2 
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n/T), where
/T), where
otal
ta exposu
xpos
l
 occurrenc
occur
me for a sub
me for a su
date, last do
date, last do
with the sp
with the sp
ccurrence o
ccurrence
the sum
he sum of
of
m f
he EAIR pe
he EAIR p
one occurre
ne occurre
mary
ary tables
table
y
EAEs lead
AEs lead
s by C
by Cycle
ycle
will
will be sum
be sum
cy
cycle grou
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EAEs 
EAEs 
Seri
Serious TE
ous TE
!
TEAEs
TEAE
!
TE
TE
!


CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
40
!
Cycles 3-4 
!
Cycles 5-6 
!
Cycles 7-12 
!
Cycles 13-24 
!
Cycles > 24 
The analysis of TEAE by cycle of onset for any occurrence will be based on the onset date of AE 
to determine the cycle. AEs with a duration that overlaps multiple cycles will only be counted in 
the first overlapped cycle. Subjects with multiple occurrences reported with the onset date within 
the same cycle for the same SOC / PT will be counted once per SOC level / PT level within the 
cycle. 
TEAEs by cycle day of onset for any occurrence will also be summarized. The cycle day will be 
grouped as: cycle days 1-7, cycle days 8-14, cycle days 15-21, and cycle days >21.
The first occurrence of TEAEs by cycle of onset, and by cycle day of onset will be summarized 
by SOC and PT. Subjects with multiple occurrences reported for the same SOC / PT will be 
counted only once based on the earliest onset date (the first occurrence) per SOC level / PT level.
11.1.2.
Adverse Events of Special Interest
The AEs described in this section have been identified as treatment-emergent AEs of special 
interest (AESI) based on the known safety profile of azacitidine. These treatment-emergent AESI 
include those adverse events which Celgene is actively monitoring. 
AESIs refer to a group of terms/PTs from one or more SOCs relating to a defined medical 
condition or area of interest. The AESI category or term refers to the group of PTs, rather than 
the individual PT. Standardized MedDRA queries (SMQs) or company MedDRA queries based 
on specific SOC, higher level terms (HLT) or PTs were used to define the categories of AEs of 
special interest.
TEAEs will be summarized for the following categories of AESIs, by PT and treatment group:
!
Myelosuppression, 
∀
Neutropenia
∀
Thrombocytopenia
∀
Anemia
∀
General myelosuppression
!
Hemorrhagic events
!
Infection
!
Hepatic failure
!
Renal failure
!
Ischemic colitis
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AE
d in 
d in
e within
within
with
th
i in the
in the
cycle day
cycle day w
y
ys >21.
ys >21.
nset 
et will be 
will
same
ame SOC 
SOC
ence) per 
nce) per S
tre
treata me
ment
zaci
zac ti
i dine.
dine.
vely monit
vely monit
or more SO
r more SO
gory
gory or ter
or ter
y
A 
A queri
queries (
es (
HLT)
HLT) or PT
or PT
the fo
the follo
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on, , 
peni
enia
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!
Hem
Hem
!


CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
41
!
Gastrointestinal events
!
Interstitial lung disease
!
Tumour lysis syndrome
!
Cardiac events:
∀
Cardiac arrhythmias
∀
Myocardial infarction
∀
Cardiac failure
!
Anxiety, Confusional State, Insomnia
!
Psychiatric Disorders
Separate frequency tables will be provided for the AESIs identified above by AESI category, PT
and treatment group:
!
Summary of AESIs;
!
All AESIs;
!
Treatment-related AESIs;
!
Serious AESIs;
!
Treatment-related serious AESIs;
!
AESIs with severity of grade 3 or 4;
!
AESIs leading to death;
!
AESIs leading to death by cycle of onset;
!
Treatment-related AESIs leading to death;
!
AESIs leading to dose reduction;
!
AESI leading to dose interruption;
!
AESI leading to dose interruption and dose reduction;
!
AESIs leading to study medication discontinuation;
!
Treatment-related AESI leading to study drug discontinuation;
!
AESI with EAIR.
The summaries of all AESIs, serious AESIs, AESIs with severity of grade 3 or 4, AESIs leading 
to death, and AESIs leading to study medication discontinuation will also be presented by cycle 
group as defined in Section 11.1.1.
Additional safety analyses may be displayed by specific parameters, (e.g. time to occurrence, 
demographics, exposure/duration) if warranted. Similarly, other selected listings may be 
necessary to assist with analysis of the safety data.
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AESI categ
AESI cate
cle of onse
cle of on
s leading to
leading t
se reduction
se reductio
dose interr
dose inte
ng to dose i
ng to dose 
eading to s
eading to s
atment
atment-rela
re
AESI wi
AESI with
th
i
ummaries o
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group as de
Addit
Additioio


CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
42
11.1.2.1.
Second Primary Malignancies
Second primary malignancies (SPM) will be monitored as adverse 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. 
SPM identified as treatment-emergent AESI will be summarized by treatment group.
11.1.2.2.
Progression to AML
Progression to AML will be identified as treatment-emergent AESI and will be summarized by 
treatment group.
11.2.
Death 
Frequency tables of primary cause of death category (as selected by the investigator), and the
primary diagnosis (by SOC and PT) per the death CRF page will be provided by treatment period 
(on-treatment, or post-treatment) by treatment group for subjects in the safety population, as well 
as for subjects who are screen failures (pre-treatment period). A listing of deaths from the death 
CRF page, will be provided for all subjects who died after signing informed consent.
11.3.
Clinical Laboratory Evaluations
Clinical laboratory values will be presented using the reported units. Change in clinical 
laboratory results from baseline (last non-missing value on or prior to the date of first dose of the 
study drug) to each scheduled time point will be provided for the safety population. Clinical 
laboratory values will be graded according to CTCAE version 4.0 for applicable tests. Shift 
tables for change in maximum CTCAE grades of high and low lab values, separately, will be 
provided for the safety population by treatment for those labs that have CTCAE grades.  Separate 
shifts tables will be provided for lowest value by cycle and highest value by cycle. Clinically 
significant laboratory abnormalities that meet Grade of 3 or Grade 4 criteria according to the 
CTCAE will be listed and summarized (counts and percentages) by cycle. Laboratory data 
collected after the date of the end of treatment visit, last dose date + 28 days, whichever the 
latest, will not be used for summary. Nadirs, the minimum values, of selected hematology 
parameters, ie. Hgb, platelets, absolute neutrophil count (ANC), white blood cell counts, and 
RBC, across all cycles and within each cycle will be summarized. The day of nadir will be 
summarized categorically by frequency of the day of the cycle that the nadir observation occurs, 
by cycle and treatment. The categories for the days within a cycle are day 1-7, Day 8-14, Day 
15-21 and Day >21. The average onset day of nadir across all cycles, the analyte value at nadir 
by cycle, and the change from baseline to analyte value at nadir will be summarized descriptively 
by treatment for each selected hematology test.
A separate listing, including only values outside the normal range, if any, will also be provided. 
A listing of all clinical laboratory values will be provided. Separate listings will be provided for 
the hematology, blood chemistry, coagulation, urinalysis, erythropoietin, ferritin and serum 
tranferrin saturation laboratory values.
&(/*(1(35235,(7$5<,1)250$7,21
rized
rized by 
by 
vest
vestigator)
igator)
ovi
ovided
ded by tr
by
the safet
e safety p
sting of 
ing of de
de
ning inform
ning info
e reported u
e reported
g value on o
value on 
be provided
e provided
to CTC
o CTCAE
AE
grades of hi
grades of hi
treatment 
treatme
f
west value
est value
tities that m
es that m
mmarized (
mmarized (
he end of t
e end of t
for summar
for summa
platelets,
platelets,
ycles and w
ycles and w
ategorically
tegorical
d treatment
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list
listinin


CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol AZA-MDS-003
Celgene Corporation
Confidential and Proprietary
43
Graphical display of select laboratory parameters over the course of the study will be provided
(if needed).
11.4.
Vital Sign Measurements
Vital sign measurements (weight, systolic and diastolic blood pressure, pulse rate, respiration 
rate and temperature) as well as change from baseline will be summarized descriptively by 
scheduled time point. The last vital sign measurement on or prior to the date of first dose of 
study drug will be used as the baseline value. Frequency summaries (shift tables) of shifts from 
baseline to post-baseline by cycle and to the worst post-baseline value in terms of 
normal/abnormal will be provided for pulse, respiratory and blood pressure. The normal ranges 
are defined as: 60-100 beats/minute for pulse, 12 to 16 breaths/minutes for respiratory rate, 90-
140 mmHg for systolic blood pressure, and 60-90 mmHg for diastolic blood pressure). Vital sign 
data collected after the date of the end of treatment visit, last dose date + 28 days, whichever the 
latest, will not be used for summary. A listing of all vital signs will be provided.
11.5.
Bone Marrow Aspirate Differential and Peripheral Blood Smear
Bone marrow aspirate differential and peripheral blood smear differential, including erythroid 
precursors, Monocytic lineage, bone marrow blasts (%), ringed sideroblast (%), myeloid lineage, 
and peripheral blood blasts, as well as their changes from baseline, will be summarized 
descriptively by cycle and treatment for the Safety population.  For each variable, the last 
observed values on or prior to the date of the first dose date will be used as the baseline value.  
Bone marrow and peripheral blood data collected after the date of the end of treatment visit, last 
dose date + 28 days, whichever the latest, will not be used for summary. Individual subject 
information for bone marrow aspirate and bone marrow biopsy will be listed.
11.6.
Electrocardiogram
A 12-lead electrocardiogram (ECG) is required for all subjects at Screening visit. ECG results
will be provided in a by-subject listing. 
11.7.
Pregnancy
A by-subject listing of pregnancy tests and results will be provided for all female patients of 
childbearing potential. 
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12.
HEALTH-RELATED QUALITY OF LIFE ANALYSIS
The primary objective of the HRQoL assessment is to evaluate the impact of oral azacitidine on 
HRQoL relative to placebo. Analyses will address mean differences by treatment group on 
HRQoL scale and subscale scores and treatment group differences in the proportion of subjects 
who achieve a minimal clinically important difference. Complete analysis plans, including 
methods to assess responsiveness and minimally important differences will be described in a 
separate HRQoL statistical plan.
&(/*(1(35235,(7$5<,1)250$7,21


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13.
HEALTHCARE RESOURCE UTILIZATION
Healthcare resource utilization collected on the CRF healthcare utilization form will be 
summarized by treatment group and listed for individual subject. Summaries will include number 
of events, reasons for hospitalization, total number of days hospitalized, the rate of events and 
days of hospitalized per person-year of exposure and associated relative risk of hospitalization 
with the corresponding 95% CI. 
&(/*(1(35235,(7$5<,1)250$7,21


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&(/*(1(35235,(7$5<,1)250$7,21


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15.
INTERIM ANALYSIS
15.1.
General Information
An independent Data Monitoring Committee (DMC) with multi-disciplinary representation has
evaluated safety during the course of the study in compliance with a prospective charter. The 
DMC comprised of medical oncologists/hematologists with experience treating MDS and a 
statistician, all of whom were not otherwise involved in the study as investigators. An 
independent statistician generated critical safety reports for the DMC to review periodically. The 
DMC chairperson might convene formal DMC meetings if there were safety concerns. The
Sponsor can also request a DMC review of safety data. The DMC responsibilities, authorities, 
and procedures were documented in the DMC charter, which were endorsed and signed by the 
DMC prior to the first data review meeting.
15.2.
Statistical Approaches for Control of Alpha
An interim analysis of the OS endpoint will be performed when all 216 subjects have completed 
12 months of double-blind treatment or discontinued before reaching 12 months of double-blind 
treatment (100% information for the primary endpoint), whichever occurs first. It is projected 
that approximately 68% of the expected total deaths will have occurred at the time of the interim 
analysis. An O’Brien-Fleming group sequential boundary with a Lan-Demets alpha spending 
function will be used to preserve the overall alpha level at 0.05 for testing the OS endpoint. The 
required (two-sided) significance levels are estimated to be 0.013 at the interim and 0.037 at the 
final analysis for OS assuming 68% of the events have occurred, but the actual levels used will 
depend on the actual number of events at the time of the interim analysis.
In order to preserve the overall alpha level at 0.05 across the RBC transfusion independence and 
OS endpoints, formal statistical inference for the OS analyses can only be made if superiority of 
oral azacitidine is demonstrated for the primary efficacy endpoint, RBC transfusion 
independence, at the two-sided 0.05 significance level.
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16.
CHANGES TO THE STATISTICAL ANALYSES SECTION OF 
THE PROTOCOL
As there were no subjects enrolled from Japanese sites, the randomization stratification factor 
“country of enrollment (ie, Japan versus ROW)” will not be used when the analysis is performed.
Frequency cross-tabulations of RBC transfusion dependent status for 84 days at baseline versus 
on treatment will not be provided.
The end date of the evaluation period defined in Section 10.1 is used as the censoring date when 
calculating the duration of RBC transfusion independence ≥ 56 days and ≥ 84 days, duration of 
RBC transfusion reduction and duration of platelet transfusion independence. As defined in 
Section 10.1, the days after a subject started subsequent MDS treatment will not be included in
the response duration. The end date of the evaluation period defined in Section 10.1 is also used 
as the censoring date for subjects who do not achieve the corresponding response during the 
treatment period in the analysis of time to RBC transfusion independence ≥ 56 days and ≥ 84 
days, and time to platelet transfusion independence. 
Progression to AML will be identified based on documentations in central lab report or Follow-
up Status CRF, please see detail in Section 10.2.8.
No other changes to the statistical analyses section of the protocol are made in this SAP.
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17.
REFERENCES
Bejar R, Clinical and genetic predictors of prognosis in myelodysplastic syndromes. 
Haematologica 2014; 99: 956-964.
Bejar R, Papaemmanuil E, Haferlach T, Garcia-Manero G, Maciejewski JP, Sekeres MA, et al. 
Somatic Mutations in MDS Patients Are Associated with Clinical Features and Predict Prognosis 
Independent of the IPSS-R: Analysis of Combined Datasets from the International Working 
Group for Prognosis in MDS-Molecular Committee. Blood 2015 126.23: 907.
Brunning RD, Bennett JM, Flandrin G, Matutes E, Head D, Vardiman JW, et al. Pathology and 
genetics of tumors of hematopoietic and lympoid tissues. In: Jaffe ES, Harris NL, Stein H, 
Vardiman JW, editors. World Health Organization Classification of Tumors. Lyon (France). 
IARC Press, 2001:63-73.
Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD et al. Clinical 
application and proposal for modification of the International Working Group (IWG) response 
criteria in myelodysplasia. Blood 2006; 108 (2): 419-25.
Garcia-Manero G, Shan J, Faderl S, Cortes J, Ravandi F, Borthakur G, et al. A prognostic score 
for patients with lower risk myelodysplastic syndrome. Leukemia 2008a; 22(3):538-43.
Greenberg, P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, et al. International scoring 
system for evaluating prognosis in myelodysplastic syndromes. Blood 1997; 89:2079-88.
Nashza A, Bejar R. Molecular Data and the IPSS-R: How Mutational Burden Can Affect 
Prognostication in MDS. Curr Hematol Malig Rep 2017 Oct;12(5):461-467
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am. J. Clin. Oncol. 1982; 5(6): 
649-55.
Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, et al. The 2008 
revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute 
myeloid leukemia: rationale and important changes. Blood 2009;114(5):937-51.
&(/*(1(35235,(7$5<,1)250$7,21
and 
nd 
H, 
rance).
ance).
SD et al. C
SD et al
up (IWG) re
up (IWG) 
G, et al. A p
, et al. A 
2008a; 22(
2008a; 22
G, et al. Int
G, et al. 
mes. Blood
mes. Bloo
ow Mutatio
ow Mutati
2017 Oct;12
2017 Oct;
Davis TE, M
Davis TE
Onco
Oncology
logy G
y
running RD
running
nizat
za ion (W
n (W
d important
d important


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18.
APPENDICES 
18.1.
Appendix A: Date Imputation Guideline
18.1.1.
Impute Missing AE/ Prior or Concomitant Medications
Incomplete Start Date:
Missing day and month
!
If the year is same as the year of first day on study medication, then the day and 
month of the start date of study medication will be assigned to the missing fields
!
If the year is prior to the year of first day on study medication, then December 31 
will be assigned to the missing fields.
!
If the year is after the year of first day on study medication, then January 1 will be 
assigned to the missing fields.
Missing day only 
!
If the month and year are same as the year and month of first day on study 
medication, then the start date of study medication will be assigned to the missing 
day.
!
If the month and year are before the year and month of first day on study medication, 
then the last day of the month will be assigned to the missing day.
!
If the month and year are after the year and month of first day on study medication, 
then the first day of the month will be assigned to the missing day.
!
If the stop date is non-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 dose date of 
study medication, then the day and month of the last dose date will be assigned to the 
missing fields. 
!
If the year of the incomplete stop date is prior to the year of the last dose date of 
double-blind study medication, then December 31 will be assigned to the missing 
fields. 
!
If the year of the incomplete stop date is after the year of the last dose date of study 
medication, then January 1 will be assigned to the missing fields.
Missing day only 
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missing 
!
If th
If th
d


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!
If the month and year of the incomplete stop date are the same as the month and year 
of the last dose date of study medication, then the day of the last dose date will be 
assigned to the missing day. 
!
If the month and year of the incomplete stop date are before the month and year of 
the last dose date of the study medication, then the last day of the month will be 
assigned to the missing day. 
!
If the month and year of the incomplete stop date are after the month and year of the 
last dose date of study medication, then the first day of the month will be assigned to 
the missing day.
18.1.2.
Impute Missing Start Dates of Subsequent MDS Treatment
If the start date of the subsequent MDS treatment is unknown, it will be imputed as the earliest 
possible date after the last dose date (1 day after) which is collected in the treatment 
discontinuation CRF.
Missing day and month
!
If the year is same as the year of the last dose date, then the last dose date + 1 day
will be assigned to the missing date.
!
If the year is after the year of the last dose date, then January 1 will be assigned to the 
missing fields.
!
The year should not be prior to the year of the last dose date. In case that happens, 
December 31 will be assigned to the missing fields.
Missing day only 
!
If the month and year are same as the year and month of the last dose date, then the 
last dose date + 1 day will be assigned to the missing date.
!
If the month and year are after the year and month of the last dose date, then the first 
day of the month will be assigned to the missing day.
!
If the stop date is non-missing and the imputed start date is after the stop date, the 
start date will be imputed by the stop date. 
!
The month and year should not be prior to the year and month of the last dose date. 
In case that happens, the last day of the month will be assigned to the missing day.
Missing day, month, and year
!
The start date of the post MDS treatment should not be completely missing. In case 
that happens, the last dose date + 1 day will be assigned to the missing date.
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at


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18.2.
Appendix B: Myelodysplastic Syndromes World Health 
Organization Classification System
Myelodysplastic Syndromes WHO Classification System
Category
Definition
Peripheral Blood Smear 
Evaluation
Bone Marrow Evaluation
Refractory cytopenia with unilineage
dysplasia (RCUD): (refractory anemia
[RA]; refractory neutropenia [RN];
refractory thrombocytopenia [RT])
Unicytopenia or bicytopeniaa
No or rare blasts (< 1%)b
Unilineage dysplasia: ≥ 10% of the cells
in one myeloid lineage
< 5% blasts
< 15% of erythroid precursors are ringed
sideroblasts
Refractory Anemia With Ringed 
Sideroblasts (RARS)
Anemia
No blasts
≥ 15% of erythroid precursors are ringed
sideroblasts
Erythroid dysplasia only
< 5% blasts
Refractory Cytopenia With
Multilineage Dysplasia (RCMD)
Cytopenia(s)
No or rare blasts (< 1%)b
No Auer rods
< 1x109/L monocytes
Dysplasia in ≥ 10% of the cells in ≥ 2 
myeloid lineages (neutrophil and/or 
erythroid precursors and/or 
megakaryocytes)
< 5% blasts in marrow
No Auer rods
± 15% ringed sideroblasts
Refractory Anemia With Excess
Blasts-1 (RAEB-1)
Cytopenias
< 5% blastsb
No Auer rods
< 1x109/L monocytes
Unilineage or multilineage
dysplasia
5%-9% blastsb
No Auer rods
Refractory Anemia With Excess
Blasts-2 (RAEB-2)
Cytopenias
5%-19% blastsc
Auer rodsc
< 1x109/L monocytes
Unilineage or multilineage
dysplasia
10%-19% blastsc
Auer rods ±c
Myelodysplastic Syndrome -
Unclassified (MDS-U)
Cytopenias
< 1% blastsb
Unequivocal dysplasia in < 10% of cells
in one or more myeloid lineages when
accompanied by a cytogenetic
abnormality considered as presumptive
evidence for a diagnosis of MDSd
MDS Associated With Isolated
del(5q)
Anemia
Usually normal or increased platelet 
count
No or rare blasts (< 1%)
Normal to increased
megakaryocytes with
hypolobated nuclei
< 5% blasts
Isolated del(5q) cytogenetic
abnormality
No Auer rods
a Bicytopenia may occasionally be observed. Cases with pancytopenia should be classified as MDS-U.
b If the marrow myeloblast percentage is < 5% but there are 2% to 4% myeloblasts in the blood, the diagnostic 
classification is RAEB-1. Cases of RCUD and RCMD with 1% myeloblasts in the blood should be classified as
MDS-U.
c Cases with Auer rods and < 5% myeloblasts in the blood and less than 10% in the marrow should be classified as 
RAEB-2. Although the finding of 5% to 19% blasts in the blood is, in itself, diagnostic of RAEB-2, cases of 
RAEB-2 may have 5% blasts in the blood if they have Auer rods or 10% to 19% blasts in the marrow or both. 
Similarly, cases of RAEB-2 may have < 10% blasts in the marrow but may be diagnosed by the other 2 findings,
Auer rods + and/or 5% to 19% blasts in the blood.
d Includes unbalanced abnormalities -7 or del(7q), -5 or del(5q), i(17q) or t(17p), -13 or del(13q), del(11q), del(12p)
or t(12p), del(9q), idic(X)(q13), balanced abnormalities t(11;16)(q23;p13.3), t(3;21)(q26.2;q22.1),
t(1;3)(p36.3;q21.1), T2;11)(p21;q23), inv(3)(q21q26.2), and t(6;9)(p23;q34), and complex karyotype (3 or more
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RAEB


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chromosomal abnormalities) involving one of more of the listed abnormalities.
Sources: Brunning RD, Bennett JM, Flandrin G, Matutes E, Head D, Vardiman JW, et al. Pathology and genetics of
tumors of hematopoietic and lympoid tissues. In: Jaffe ES, Harris NL, Stein H, Vardiman JW, editors. World
Health Organization Classification of Tumors. Lyon (France). IARC Press, 2001:63-73.
Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, et al. The 2008 revision of the World 
Health Organization (WHO) classification of myeloid neoplasms and acute myeloid leukemia: rationale and 
important changes. Blood 2009; 114(5):937-51.
&(/*(1(35235,(7$5<,1)250$7,21


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18.3.
Appendix C: International Prognostic Scoring System Score
International Prognostic Scoring System for MDS
Prognostic Variable
Score Value
0
0.5
1.0
1.5
2.0
Bone Marrow Blasts (%)
< 5
5-10
-
11-20
21-30
Karyotypea
Good
Intermediate
Poor
Cytopeniasb
0 or 1
2 or 3
a Good: normal, -Y, del(5q), del(20q); Poor: complex (# 3 abnormalities) or chromosome 7 anomalies; 
Intermediate: other abnormalities.
b Defined as: Hemoglobin < 100 g/L, absolute neutrophil count < 1.5 x 109/L, and platelet count < 100 x 109/L.
Note: Scores for risk groups are as follows: Low = 0; INT-1 = 0.5-1.0; INT-2 = 1.5-2.0; and High: # 2.5
Source: Greenberg, P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, et al. International scoring system for 
evaluating prognosis in myelodysplastic syndromes. Blood 1997;89:2079-88.
&(/*(1(35235,(7$5<,1)250$7,21
/L.
/L
ystem for 
ystem for 


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18.4.
Appendix D: ECOG Performance Status
ECOG Performance Status
Grade
ECOG
0
Fully active, able to carry on all pre-disease 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 selfcare but unable to carry out any work activities. Up and about 
more than 50% of waking hours.
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours.
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair.
5
Dead.
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response 
criteria of the Eastern Cooperative Oncology Group. Am. J. Clin. Oncol. 1982;5(6):649-55.
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18.5.
Appendix E: Hematologic Response According to the IWG Criteria 
for MDS
Modified Hematologic Response According to IWG Criteria for MDS
Category 
Response criteria (responses must last at least 4 weeks) 
Complete Remission (CR)
Bone marrow: ≤5% myeloblasts with normal maturation of all cell linesa
Persistent dysplasia will be noteda,b
Peripheral bloodc
     Hgb ≥11 g/dL 
     Platelets ≥100 X 109/L 
     Neutrophils ≥1.0 X 109/Lb  
     Blasts 0% 
Partial Remission (PR) 
All CR criteria if abnormal before treatment except:
Bone marrow blasts decreased by ≥ 50% over pretreatment but still > 5% 
Cellularity and morphology not relevant 
Marrow CRb
Bone marrow:  ≤5% myeloblasts and decrease by ≥50% over pretreatmentb  
Peripheral blood:  if HI responses, they will be noted in addition to marrow CRb
Stable Disease (SD) 
Failure to achieve at least PR, but no evidence of progression for > 8 wks 
Failure 
Death during treatment or disease progression characterized by worsening of cytopenias, 
increase in percentage of bone marrow blasts, or progression to a more advanced MDS FAB 
subtype than pretreatment 
Relapse After CR or PR 
At least 1 of the following:  
     Return to pretreatment bone marrow blast percentage 
     Decrement of ≥ 50% from maximum remission/response levels in granulocytes or 
platelets 
     Reduction in Hgb concentration by ≥ 1.5 g/dL or transfusion dependence 
Cytogenetic Response 
Complete - Disappearance of the chromosomal abnormality without appearance of new ones 
Partial - At least 50% reduction of the chromosomal abnormality 
Disease Progression 
For subjects with:  
     Less than 5% blasts:  ≥50% increase in blasts to > 5% blasts 
     5%-10% blasts:  ≥50% increase to > 10% blasts 
     10%-20% blasts:  ≥50% increase to > 20% blasts 
     20%-30% blasts:  ≥50% increase to > 30% blasts 
Any of the following:  
     At least 50% decrement from maximum remission/response in granulocytes or platelets 
     Reduction in Hgb by ≥2 g/dL 
     Transfusion dependence 
KEY:  CR = complete remission; DFS = disease-free survival; FAB = French-American-British; Hgb = hemoglobin; HI = 
hematologic improvement; IWG = International Working Group; MDS = myelodysplastic syndromes; PFS = progression free 
survival; PR = partial remission  
a Dysplastic changes should consider the normal range of dysplastic changes (modification).
b Modification to IWG response criteria.  
d In some circumstances, protocol therapy may require the initiation of further treatment (eg, consolidation, maintenance) before 
the 4-week period.  Such subjects can be included in the response category into which they fit at the time the therapy is started.  
Transient cytopenias during repeated chemotherapy courses should not be considered as interrupting durability of response, as
long as they recover to the improved counts of the previous course.  
Notes:  Subjects with CMML will be assessed for response using the IWG criteria for MDS.  Deletions to IWG response criteria 
are not shown.  To convert hemoglobin from grams per deciliter to grams per liter, multiply grams per deciliter by 10.  
Source:  Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD et al.  Clinical application and 
proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia.  Blood 2006; 108 (2):
419-25.
&(/*(1(35235,(
: ≥50% incr
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 ≥50% incre
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Modified Hematologic Improvement According to IWG Criteria
Hematologic improvementa
Response criteria (responses must last at least 8 week)b
Erythroid Response (HI-E) 
(pretreatment, <11 g/dL) 
Hemoglobin increase by ≥1.5 g/dL 
Relevant reduction of units of RBC transfusions by an absolute number of at least 4 RBC 
transfusions/8 weeks compared with the pretreatment transfusion number in the previous 
8 weeks.  Only RBC transfusions given for a hemoglobin of ≤9.0 g/dL pretreatment will 
count in the RBC transfusion response evaluationb  
Platelet Response  (HI-P)
(pretreatment, <100 X 109/L) 
Absolute increase of ≥30 X 109/L for subjects starting with > 20 X 109/L platelets 
Increase from < 20 X 109/L to > 20 X 109/L and by at least 100%b  
Neutrophil Response (HI-N)
(pretreatment, <1.0 X 109/L) 
At least 100% increase and an absolute increase > 0.5 X 109/Lb  
Progression or Relapse After HIc
At least 1 of the following:  
     At least 50% decrement from maximum response levels in granulocytes or platelets 
     Reduction in hemoglobin by ≥1.5 g/dL 
     Transfusion dependence 
KEY:  HI = hematologic improvement; HI-E = hematologic improvement erythroid response; HI-N = hematologic 
improvement neutrophil response; HI-P = hematologic improvement platelet response; IWG = International 
Working Group; MDS = myelodysplastic syndromes; RBC = red blood cell
a Pretreatment counts averages of at least 2 measurements (not influenced by transfusions) ≥1 week apart 
(modification).  
b Modification to IWG response criteria.  
c In the absence of another explanation, such as acute infection, repeated courses of chemotherapy (modification), 
gastrointestinal bleeding, hemolysis, and so forth.  It is recommended that the 2 kinds of erythroid and platelet 
responses be reported overall as well as by the individual response pattern.  
Note:  Deletions to the IWG response criteria are not shown.  To convert hemoglobin levels from grams per deciliter 
to grams per liter, multiply grams per deciliter by 10.  
Source:  Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD et al.  Clinical 
application and proposal for modification of the International Working Group (IWG) response criteria in 
myelodysplasia.  Blood 2006; 108 (2): 419-25.
&(/*(1(35235,(7$5<,1)250$7,21
$7
$7
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)2
nse; HI
nse; HI-N = h
N = 
e; IWG = Int
IWG =
nsfusions)
nsfusions) ≥
ed courses of
d courses 
ded that the 2
ed that th
nse pattern. 
nse pattern. 
To convert he
To convert 
berg B, Wije
berg B, Wij
rnational Wo
rnational Wo


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18.6.
Appendix F: Derivation Rules for Hematologic Response and 
Hematologic Improvement According to the IWG Criteria for MDS
Following rules will be used to derive the hematologic response, cytogenic response, and 
hematologic improvement using central lab data, including 
 central lab data for bone 
marrow. Lab data collected after the date of the end of treatment visit, or last dose date + 28 
days, whichever occurs later, will not be used.
In the following derivations, if Hgb or platelet counts are used for evaluation, the Hgb values are 
only valid to use if there is no RBC/Whole blood transfusion within 7 days prior to the sample 
collection, the platelet count values are only valid to use if there is no platelet transfusion within 
7 days prior to the sample collection.
18.6.1.
Hematologic Response
!
Complete Remission (CR):
1. At each time point, check if the following criteria are all met:
a.
Bone marrow blast ≤5%,
b. Peripheral blood blast = 0%,  
c.
Hgb ≥11 g/dL,
d. Platelets ≥100 x 109 /L,
e.
Neutrophils ≥1.0 x 109/L;
2. The criteria in item 1 must be met for at least 4 weeks, ie., within 4 weeks there is no lab 
result showing any of the criteria (a to e) can’t be met. However, if the “4 weeks” 
assessment/confirmation is not available because the subject discontinued treatment 
within the 4 weeks following the previous assessment, these records will not contribute to 
CR.
To derive the responses at each time point, if the bone marrow blast assessment, Hgb, 
platelet, and/or Neutrophils, are not available, the results obtained from the latest available 
assessment will be used. For peripheral blood blast, if it is assessed by both 
 lab and 
lab at a time point, the higher value will be used; if it is assessed by either 
 
lab or 
(but not both) at a time point, then the result from the available lab 
 lab 
or 
) will be used; if at a time point, both results are missing, the latest result from either 
 lab or 
 (but not both) will be used.
CR (Yes) will only be available for subjects with baseline bone marrow blasts > 5%.
!
Partial Remission (PR):
For PR, all criteria for CR must be met except for 1(a). Replace 1(a) by: Bone marrow blasts 
decreased by ≥50% over pretreatment (baseline value) but still > 5%.
PR (Yes) will only be available for subjects with baseline bone marrow blasts > 5%.
!
Marrow CR (mCR):
1. At each time point, check if the following criteria are all met:
a.
Bone marrow <=5%;
b. Bone marrow reduction from baseline ≥ 50%.
e
lele
wi
w th
i in 
in 
4 weeks, i
weeks, i
an’t be met
an’t be met
e because th
because 
vious asses
vious asses
me po
me point
in , if
e not availa
e not availa
r peri
r periphera
phera
i
int, the
int, the hig
hig
oth) at a tim
oth) at a tim
ed; if at a t
ed; if at a t
 (but n
 (but n
ill only be
ill only be
Remission
Remission
PR, all cri
PR, all cri
decreased b
decreased b
PR
PR (Ye
(Ye
M
1(


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2. The criteria in item 1 must be met for at least 2 consecutive bone marrow assessments.
If a subject only has one post-baseline bone marrow result, the subject will not be considered 
as a responder for mCR.
mCR (Yes) will only be available for subjects with baseline bone marrow blasts > 5%.
!
Disease progression (modified from IWG):
A subject is considered having disease progress per the following rules:
For patients with: 
∀
< 5% blasts: >= 50% increase in blasts and has blasts > 5%
∀
>= 5% - < 10% blasts: >= 50% increase and has blasts > 10%  
∀
>= 10% - < 20% blasts: >= 50% increase and has blasts > 20%  
∀
>= 20% - < 30% blasts: >= 50% increase and has blasts > 30% 
Bone marrow blasts are used.
Or with any of the following: 
a.
At least 50% decrement from maximum remission / response levels in neutrophils
and < 1.0 x 109 /L;
b. At least 50% decrement from maximum remission / response levels in platelets and 
<100 x 109 /L;
c.
Reduction from maximum remission / response levels in Hgb by ≥ 2 g/dL and < 11 
g/dL;
To confirm a “disease progression”, any of the criteria (a, b and c) a subject met in a previous 
assessment must be kept for at least 4 weeks.  
!
Stable disease:
For at least 8 weeks, failure to achieve at least mCR, but no evidence of progression.
!
Failure due to death:
∀
Death during treatment; AND
∀
No post-baseline efficacy assessments are available; i.e., no bone marrow or 
hematology available.
!
Not evaluable:
∀
Subject withdrew consent or was lost to follow-up, AND
∀
Subject was alive at last contact, AND
∀
No post-baseline efficacy assessments are available; i.e., no bone marrow or 
hematology available.
!
Relapse after CR or PR:
A subject is considered having “Relapse after CR or PR” if any of the following is met:
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respon
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weeks. 
weeks. 
o achieve a
o achieve 
ring treatm
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ostst-baselin
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∀
Subj
Sub
∀


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∀
Return to pretreatment (baseline) bone marrow blast percentage; 
∀
At least 50% decrement from maximum remission / response levels in neutrophils
and < 1.0 x 109 /L;
∀
At least 50% decrement from maximum remission / response levels in platelets
and <100 x 109 /L;
∀
Reduction in Hgb concentration from maximum remission / response levels by >= 
1.5 g/dL and < 11 g/dL or transfusion dependence
To confirm a “relapse”, the criterion a subject met in a previous assessment must be met for 
at least at least 4 weeks. Subjects will not be evaluable for relapse after CR or PR if no 4 
weeks data available.
18.6.2.
Cytogenetic response (Complete or Partial)
1. At each time point, Abnormality Rate = (abnormal_metaphases / metaphases_analyzed) * 
100%;
2. The abnormality rate at the screening visit is considered as the baseline abnormality rate, 
in case there are multiple records, use the one with the larger “metaphases_analyzed”;
3. Only the subjects with non-zero baseline abnormality rate will be included in the 
analysis;
4. Cytogenetic Complete Response (CR) is “Yes” if the post-baseline abnormal rate is 
decreased to 0; in case the number of baseline “abnormal_metaphases” is ≤ 4, the post-
baseline responses from two consecutive time points will be needed to confirm a CR is 
“Yes” (this time point and the next time point both have 0 abnormality rate);
5. Cytogenetic Partial Response (PR) is “Yes” if the post-baseline abnormal rate is 
decreased by at least 50% from the baseline; in case the number of baseline 
“abnormal_metaphases” is ≤ 4, the post-baseline responses from two consecutive time 
points will be needed to confirm a PR is “Yes” (this time point and the next time point 
both have abnormality rate decrease by at least 50% from the baseline).
18.6.3.
Hematologic Improvement 
Following rules will be used to derive the hematologic improvement using the central lab data.
!
Platelet Response (HI-P): 
∀
Absolute increase of ≥ 30 x 109/L for subjects starting with > 20 x 109/L platelets, 
or
∀
Increase from ≤ 20 x 109/L to > 20 x 109/L and by at least 100%.
Platelet values within 7 days following a platelet transfusion will not be used.
!
Erythroid Response (HI-E): 
∀
Hgb increase by ≥ 1.5 g/dL, or
&(/*(1(35235,(7$5<,1)250$7,21
et for 
et for 
no 4
no 4
etaphases_
etaphases_
he baseline 
baseline 
ger “metap
er “metap
rate will b
rate will 
es” if the po
s” if the po
ne
ne “abnorm
“abnorm
e time point
ime point
me po
me point
int bo
bo
PR) is “Yes
PR) is “Yes
m the baseli
the baseli
m
≤ 4, the
, the po
po
confirm a P
confirm a P
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 rate decre
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c Improve
c Improv
be used to
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∀
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Platel
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∀
Relevant reduction of units of RBC transfusions by an absolute number of at least 
4 RBC transfusions/8 weeks compared with the pretreatment transfusion number 
in the previous 8 weeks. Only RBC transfusions given for a Hgb of ≤ 10.0 g/dL 
on treatment will count in the RBC transfusion response evaluation.
Hgb values within 7 days following a RBC/Whole blood transfusion will not be used.
!
Neutrophil Response (HI-N) (only derived for subjects with baseline ANC < 1.0 x 109/L): 
∀
At least 100% increase and an absolute increase > 0.5 x 109/L.
For HI-E, the relevant reduction of units of RBC transfusions is confirmed by checking whether 
a subject is a RBC transfusion reduction responder as defined in Section 10.2.11, ie., if the 
subject has at least 4 units reduction in transfusion units over a consecutive 56 days period 
compared to the baseline transfusion units in 56 days. 
For HI-P, HI-E and HI-N, the above criteria must be met for at least 8 weeks for a subject to be 
counted as a responder. If a subject doesn’t have the subsequent data which meet the response 
criteria, the subject will not be considered as a responder.
&(/*(1(35235,(7$5<,1)250$7,21
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18.7.
Appendix G: Revised International Prognostic Scoring System 
(IPSS-R) for Myelodysplastic Syndromes
The IPSS-R score will be derived per Greenberg, 2012. 
Table 2. 
IPSS-R Prognostic Score Values
Prognostic 
Variable
0
0.5
1.0
1.5
2.0
3
4
Cytogenetics
Very 
Good
Good
Intermediate
Poor
Very 
Poor
Bone Marrow 
Blast %
≤ 2
>2-<5%
5-10%
>10%
Hemoglobin 
(g/dL)
≥10
8-<10
<8
Platelets 
(x109/L)
≥100
50-<100
<50
Absolute 
Neutrophil 
Count (x109/L)
≥0.8
<0.8
Source:  Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G,  Solé F, et al. Revised International 
Prognostic Scoring System for Myelodysplastic Syndromes. Blood 2012; 120: 2454-2465. 
Table 3. 
IPSS-R Prognostic Risk Categories/Scores
RISK CATEGORY
RISK SCORE
Very Low
≤ 1.5
Low
> 1.5 – 3 
Intermediate
> 3 – 4.5
High
> 4.5 – 6
Very High
> 6
Source:  Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G,  Solé F, et al. Revised International 
Prognostic Scoring System for Myelodysplastic Syndromes. Blood 2012; 120: 2454-2465. 
The IPSS-R score will be the sum of the score values from the five prognostic variables. If at 
least one of the variables is missing, then the IPSS-R score is set to missing, unless the sum of 
the existing variables is >6 (in this case, the risk category is “Very High”).
For baseline IPSS-R score, the central data collected during the screening phase and/or on Cycle 
1 Day 1 (if available) will be used. The latest assessment for cytogenetics, bone marrow blast, 
and absolute neutrophil count, the worst values of hemoglobin, and platelets during the screening 
phase (including Cycle 1 Day 1) will be used. In case there are multiple results of cytogenetics 
and/or bone marrow blast from the same sample collection date, the record with the latest 
receiving date (XRDTC) will be used.
IPSS-R prognostic risk categories will be derived according to Table 3.
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