Conditions: Myelodysplastic Syndromes
Keywords: Luspatercept Transfusion dependent Lower risk Low risk Myelodysplastic Syndromes ESA refractory ESA intolerant ESA ineligible ACE-536 Anemia Ring Sideroblasts Require Red Blood Cell Transfusions MEDALIST MDS IPSS-R very low/IPSS-R low/IPSS-R intermediate
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 229
Healthy volunteers: no

Brief summary:
The study will be conducted in compliance with the International Council on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good Clinical Practice (GCP) and applicable regulatory requirements.

This is a Phase 3, double-blind, randomized, placebo-controlled, multicenter study to determine the efficacy and safety of luspatercept (ACE-536) versus placebo in participants with anemia due to the Revised International Prognostic Scoring System (IPSS-R) very low, low, or intermediate MDS with ring sideroblasts who require red blood cell (RBC) transfusions.

Detailed description:
Anemia is considered to be one of the most prevalent cytopenias in patients who have myelodysplastic syndromes, an umbrella term used to describe disorders relating to the ineffective production of red blood cells, white blood cells, and/or platelets. Ranging in severity from mild (asymptomatic) to severe, anemia can result in patients requiring regular red blood cell (RBC) transfusions, which can lead to further complications from iron overload. The goal of this study is to assess the safety and efficacy of luspatercept versus placebo in anemic patients who are categorized as International Prognostic Scoring System-Revised (IPSS-R) very low, low, or intermediate risk Myelodysplastic syndrome (MDS), have ring sideroblasts present, and require constant RBC transfusions. The design of the study will allow a period of initial randomization of patients into either the luspatercept or placebo arm, followed by a double-blind treatment period, and then an MDS disease assessment visit. For those patients that are determined to be experiencing clinical benefit as judged from the study Investigator by this disease assessment visit, they will be permitted to enter the double-blind Extension Phase of the study. Once patients are discontinued from study treatment, they will enter a post treatment follow-up period.

Arms:
arm 1: Starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks arm 2: Subcutaneous injection every 3 weeks

Interventions: intervention 1: Luspatercept intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_000.pdf: 
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
1
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
TITLE PAGE
A PHASE 3, DOUBLE-BLIND, RANDOMIZED STUDY
TO COMPARE THE EFFICACY AND SAFETY OF 
LUSPATERCEPT (ACE-536) VERSUS PLACEBO FOR
THE TREATMENT OF ANEMIA DUE TO IPSS-R VERY 
LOW, LOW, OR INTERMEDIATE RISK
MYELODYSPLASTIC SYNDROMES IN SUBJECTS 
WITH RING SIDEROBLASTS WHO REQUIRE RED 
BLOOD CELL TRANSFUSIONS
The “MEDALIST” Trial
PROTOCOL NUMBER:
ACE-536-MDS-001 
ORIGINAL PROTOCOL FINAL:
25 Sep 2015
AMENDMENT 1.0 DATE:
21 Sep 2016
AMENDMENT 2.0 DATE:
09 May 2017
EudraCT NUMBER:
2015-003454-41
IND NUMBER:
112,562
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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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
2
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
Contact Information:
Name:
Title:  
Address:  Route de Perreux 1 - 2017 Boudry – Switzerland
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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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
3
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
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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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
4
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
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
Harmonisation (ICH) Good Clinical Practices Guidelines, and local regulations 
governing the conduct of clinical studies.
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
5
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
PROTOCOL SUMMARY
Study Title
A Phase 3, Double-blind, Randomized Study to Compare the Efficacy and Safety of 
Luspatercept (ACE-536) Versus Placebo for the Treatment of Anemia Due to IPSS-R Very Low, 
Low, or Intermediate Risk Myelodysplastic Syndromes in Subjects with Ring Sideroblasts Who 
Require Red Blood CellTransfusions
Indication
Treatment of anemia due to very low, low, or intermediate risk myelodysplastic syndromes 
(MDS) according to the revised International Prognostic Scoring System (IPSS-R) in subjects 
with ring sideroblasts who require red blood cell (RBC) transfusions
Objectives
The primary objective is:
!
To evaluate RBC transfusion independence (RBC-TI) of luspatercept compared with 
placebo for the treatment of anemia due to IPSS-R very low, low, or intermediate risk 
MDS in subjects with ring sideroblasts who require RBC transfusions
The secondary objectives are:
!
To assess the safety and tolerability of luspatercept compared with placebo
!
To evaluate the effect of luspatercept on reduction in RBC transfusions, increase in 
hemoglobin, duration of RBC-TI, improvement in health-related quality of life (HRQoL)
(ie, European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire [EORTC QLQ-C30]), increase in neutrophils, increase in platelets, 
decrease in serum ferritin, decrease in iron chelation therapy use, and time to RBC-TI 
compared with placebo
!
To evaluate population pharmacokinetics and exposure-response relationships for 
luspatercept in MDS subjects
Study Design
This is a Phase 3, double-blind, randomized, placebo-controlled, multicenter study to determine 
the efficacy and safety of luspatercept (ACE-536) versus placebo for the treatment of anemia due 
to IPSS-R very low, low, or intermediate risk MDS in subjects with ring sideroblasts who require 
RBC transfusions. 
The study is divided into the Screening Period, a double-blind Treatment Period (Primary Phase 
and Extension Phase) and a Posttreatment Follow-up Period.  
The study design is described in detail in Section 3.
The study will be conducted in compliance with International Council for Harmonisation (ICH) 
Good Clinical Practices (GCPs).
Study Treatments
Eligible subjects will be randomized at a 2:1 ratio to either:
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
6
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
!
Experimental Arm - Luspatercept (ACE-536): Starting dose of 1.0 mg/kg subcutaneous 
injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle) 
OR 
!
Control Arm: Placebo (volume equivalent to experimental arm) subcutaneous injection 
every 3 weeks (administered on Day 1 of each 21-day treatment cycle). 
After randomization, no crossover between the treatment arms will be permitted at any point 
during the study.
Best supportive care may be used in combination with study treatment in both arms when 
clinically indicated per investigator discretion. See Section 8 for more details.  
Stratification will be based on the following factors:
1. RBC Transfusion burden at baseline 
!
≥ 6 RBC units/8 weeks (mean of the two consecutive 8-week periods immediately 
prior to randomization)
!
< 6 RBC units/8 weeks (mean of the two consecutive 8-week periods immediately 
prior to randomization)
2. IPSS-R at baseline 
!
Very low, low
!
Intermediate
Primary Phase of the Treatment Period: Weeks 1-24
Subjects should receive investigational product (IP) through at least the first 24 calendar weeks 
unless the subject experiences unacceptable toxicities, withdraws consent, or meets any other
discontinuation criteria (Section 11).
Refer to Section 6.2.1 for additional details related to study procedures and assessments during 
the Primary Phase of the Treatment Period.
MDS Disease Assessment: Week 25 Visit 
The Week 25 Visit should be completed 24 calendar weeks after the date of first dose, regardless 
of dose delays.  Because central laboratory results from bone marrow and peripheral blood 
samples are required as part of the MDS Disease Assessment, a 14-day window is allowed for 
the Week 25 Visit.  Please refer to Section 6.2.2 for details.  
In order for subjects to remain on double-blind treatment beyond the first 24 calendar weeks, the 
following criteria must be confirmed upon the completion of the MDS Disease Assessment by 
the investigator at the Week 25 Visit:
!
Evidence of clinical benefit (eg, decrease in RBC transfusion requirement compared 
to baseline requirement or hemoglobin increase compared to baseline)
AND
!
Absence of disease progression per IWG criteria for altering natural history of MDS 
(Cheson, 2006; Appendix E).
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
7
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
Based on the outcome of the Week 25 Visit MDS Disease Assessment, subjects will either be 
discontinued from treatment with IP and enter the Posttreatment Follow-up Period or continue 
double-blind treatment with IP in the Extension Phase of the Treatment Period. 
Refer to Section 6.2.2 for additional details related to procedures/assessments.
Extension Phase of the Treatment Period:  After Week 25 Visit
Subjects who meet the criteria for remaining on double-blind treatment with IP in the Extension 
Phase may continue dosing on Day 1 of each 21-day treatment cycle until the subject 
experiences unacceptable toxicities, disease progression per IWG criteria for altering natural 
history of MDS (Cheson, 2006; Appendix E) or withdrawsconsent, or meets any other
discontinuation criteria (Section 11).  
MDS Disease Assessment will be repeated by the investigator at Extension Cycle 8, Day 1 and 
Day 1 of every eighth Extension cycle thereafter (ie, Extension Cycle 8, 16, 24+, or every 24 
weeks in the event of dose delays) until the subject is discontinued from IP.
Refer to Section 6.2.3 for additional details related to procedures/assessments.
Posttreatment Follow-up Period:
All subjects discontinued from protocol-prescribed therapy for any reason will be followed for
adverse event (AE)/serious adverse event (SAE) reporting for a period of 42 days after the last 
dose of IP, as well as for SAEs made known to the Investigator at any time thereafter that are 
suspected of being related to IP, as described in Section 10.
For subjects who do not complete the Primary Treatment Phase or do not participate in the 
Extension Phase or subjects who terminate the Extension Phase with less than 1-year of ADA 
monitoring, ADA and PK samples will be collected at End of Treatment (EOT) and then every 
12 weeks for up to 1 year from the first dose in the Primary Treatment Phase (please refer to 
Section 6.4 and Section 6.5).
Transfusion data collection will continue up until 16 weeks from the date of last dose of IP or the 
EOT Visit (whichever is later).  
Continuation of monitoring for progression to AML and other malignancies/pre-malignancies
(please refer to Section 10.5 for details) will occur in the Posttreatment Follow-up Period along 
with collection of information related to subsequent MDS therapies, and overall survival for at 
least 3 years from the date of last dose of IP unless the subject withdraws consent from the study, 
dies, or is lost to follow-up.  
Refer to Section 6.8 for additional details.
Study Population
The study will enroll approximately 210 subjects with IPSS-R (Greenberg, 2012; Appendix D) 
very low, low, or intermediate MDS with ring sideroblasts who require RBC transfusions.
Length of Study
The expected duration ofthe study is approximately 5 years which consists of approximately 2
years of enrollment, approximately 1 additional year of blinded luspatercept or placebo treatment 
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
8
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
after the last subject is randomized, and at least an additional3 years to complete the 
posttreatment follow-up period.
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
post-treatment follow-up, or the date of receipt of the last data point from the last subject that is 
required for primary, secondary 
 analysis, as prespecified in the protocol
and/or SAP, whichever is the later date.  
The Sponsor may end the trial when all key endpoints and objectives of the study have been 
analyzed and the availability of a roll-over protocol exists into which any subjects remaining on 
study may be consented and continue to receive access to luspatercept and/or complete long-term 
follow-up. Such a protocol would be written for a compound that would not yet be commercially 
available.  
Overview of Key Efficacy Assessments
Efficacy assessments include:
!
Transfusions (eg, RBC);
!
Hematology (eg, hemoglobin, platelet count, neutrophils);
!
Bone marrow aspirate (or biopsy) for assessment of MDS disease (eg, cytomorphology, 
cytogenetics)
Refer to Section 6 for full list.  
Overview of Key Safety Assessments
Safety assessments will include:
!
Adverse event reporting;
!
Concomitant medication/procedures;
!
MDS disease assessment (eg, cytomorphology, cytogenetics) via bone marrow aspirate 
(or biopsy)
!
Hematology (eg, hemoglobin, hematocrit, complete blood count [CBC] with differential); 
!
Serum Chemistry; 
!
Urinalysis;
!
Electrocardiogram (ECG);
!
Vital signs and body weight;
!
Physical examinations; 
!
Eastern Cooperative Oncology Group (ECOG) performance status;
Refer to Section 6 for full list. 
Statistical Methods
A total sample size of 210 (140 in experimental arm [luspatercept (ACE-536)], 70 in control arm 
[placebo]) will have 90% power to detect the difference between a response rate of 0.30 in the 
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
9
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
experimental arm (luspatercept [ACE-536]) and a response rate of 0.10 in the control arm 
(placebo).  The sample size calculation is based on one-sided alpha of 0.025, test statistics on 
difference of proportions using pooled estimate of variance and 10% dropout rate. 
The primary efficacy analysis will be the comparison of the response rates in the two treatment 
arms in the intent-to-treat (ITT) population. The primary efficacy endpoint of transfusion 
independent response is defined as the absence of any RBC transfusion during any consecutive 
56 day period during the Primary Phase of the Treatment Period.
The Cochran–Mantel–Haenszel (CMH) test will be used to compare the response rates from 
treatment group and control group with randomization factors as strata. Kaplan–Meier methods 
will be used to characterize the duration of response and survival.
The primary efficacy endpoint will be tested first at the one-sided 0.025 significance level. If 
superiority of luspatercept is demonstrated for the primary efficacy endpoint, then the key 
secondary endpoint will be tested at a one-sided 0.025 significance level. The key secondary 
endpoint, proportion of subjects achieving RBC-TI with duration ≥ 12 weeks, will be tested in 
the same manner as primary efficacy endpoint using the CMH test.
The analyses for the key secondary endpoint will be based on the ITT population. In order to 
perform hypothesis testing on multiple endpoints while controlling the overall Type I error rate, 
a sequential testing approach will be employed where the order of the endpoints to be tested are 
prespecified.
An interim analysis to assess futility will be performed when approximately 105 subjects have 
completed the Primary Phase of the Treatment Period (first 24 weeks of double-blind treatment) 
or discontinued before reaching 24 weeks of double-blind treatment (50% information for 
primary endpoint). 
Conditional power for the primary endpoint will be calculated assuming the observed trend 
continues for the rest of the data. If it is 10% or less, with confirmative data for secondary and 
other efficacy endpoints, the Data Monitoring Committee (DMC) may recommend stopping the 
study for futility.
There is no plan to claim luspatercept superiority based on interim analysis efficacy results, thus
the type one error rate remains at 0.025 one-sided for the final analysis.
The final analysis will be performed when all 210 subjects have completed 48 weeks of 
treatment or discontinued before 48 weeks. 
Additional follow-up analysis for efficacy and safety will be performed when all subjects have 
been followed for at least 3 years from the last dose of IP.
Refer to Section 9 for additional details.
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Section
ction 9


EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
10
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
PROTOCOL SUMMARY ..........................................................................................................5
1.
INTRODUCTION..................................................................................................17
1.1.
Disease Background ...............................................................................................17
1.1.1.
Staging and Prognostic Factors...............................................................................17
1.1.1.1.
Revised International Prognostic Scoring System (IPSS-R) for MDS......................17
1.1.1.2.
Ring Sideroblasts....................................................................................................18
1.1.2.
Current Treatment Options for Lower Risk MDS....................................................19
1.1.2.1.
Revlimid.................................................................................................................19
1.1.2.2.
Erythropoiesis Stimulating Agents (ESAs) Therapy................................................19
1.1.2.3.
Red Blood Cell Transfusions ..................................................................................19
1.1.2.4.
Hypomethylating Agents ........................................................................................20
1.2.
Compound Background ..........................................................................................21
1.2.1.
Summary of Nonclinical Studies with Luspatercept................................................22
1.2.2.
Summary of Clinical Experience ............................................................................23
1.2.2.1.
Potential Risks of Human Use ................................................................................23
1.2.2.2.
Overall Benefit Risk Assessment ............................................................................24
1.3.
Rationale ................................................................................................................25
1.3.1.
Study Rationale and Purpose ..................................................................................25
1.3.2.
Rationale for the Study Design ...............................................................................26
1.3.3.
Rationale for Dose, Schedule and Regimen Selection .............................................27
1.3.4.
Rationale for Choice of Placebo Comparator ..........................................................28
2.
STUDY OBJECTIVES AND ENDPOINTS...........................................................30
3.
OVERALL STUDY DESIGN ................................................................................34
3.1.
Study Design ..........................................................................................................34
3.2.
Study Duration for Subjects....................................................................................39
3.3.
End of Trial ............................................................................................................39
4.
STUDY POPULATION.........................................................................................40
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
11
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
4.1.
Number of Subjects ................................................................................................40
4.2.
Inclusion Criteria....................................................................................................40
4.3.
Exclusion Criteria...................................................................................................42
5.
TABLE OF EVENTS.............................................................................................45
6.
PROCEDURES......................................................................................................53
6.1.
Screening Period.....................................................................................................53
6.2.
Treatment Period ....................................................................................................59
6.2.1.
Primary Phase of the Treatment Period: Weeks 1-24...............................................60
6.2.2.
MDS Disease Assessment: Week 25 Visit ..............................................................61
6.2.3.
Extension Phase of the Treatment Period:  After Week 25 Visit..............................63
6.3.
Dose Delays ...........................................................................................................63
6.4.
Pharmacokinetics....................................................................................................64
6.5.
Anti-Drug Antibody (ADA)....................................................................................64
6.6.
Unscheduled Visits.................................................................................................65
6.7.
End of Treatment Visit ...........................................................................................65
6.8.
Posttreatment Follow-up Period..............................................................................66
6.8.1.
Safety Follow-up ....................................................................................................66
6.8.2.
Long-Term Follow-up ............................................................................................66
6.9.
Efficacy Assessments .............................................................................................67
6.10.
Safety Assessments.................................................................................................67
6.12.
Subject Reported Outcomes or Quality of Life Measurements ................................68
6.14.
Screen Failures .......................................................................................................69
7.
DESCRIPTION OF STUDY TREATMENTS........................................................70
7.1.
Description of Investigational Products...................................................................70
7.2.
Treatment Administration and Schedule .................................................................70
7.2.1.
Dose Modifications: Dose Titration, Dose Reduction, and Dose Delay ...................71
7.2.1.1.
Dose Titration Increase...........................................................................................71
7.2.1.2.
Dose Delay and Dose Reduction.............................................................................72
7.2.1.3.
Overdose ................................................................................................................73
7.3.
Method of Treatment Assignment...........................................................................74
7.4.
Packaging and Labeling..........................................................................................74
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523
( 35


EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
12
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
7.4.1.
Blinding..................................................................................................................74
7.5.
Investigational Product Accountability and Disposal ..............................................75
7.6.
Investigational Product Compliance........................................................................75
8.
CONCOMITANT MEDICATIONS AND PROCEDURES....................................76
8.1.
Permitted Concomitant Medications and Procedures...............................................76
8.1.1.
Iron Chelation Therapy...........................................................................................76
8.1.2.
RBC Transfusions ..................................................................................................76
8.2.
Prohibited Concomitant Medications and Procedures..............................................77
8.3.
Required Concomitant Medications and Procedures................................................77
9.
STATISTICAL CONSIDERATIONS ....................................................................78
9.1.
Overview................................................................................................................78
9.2.
Study Population Definitions ..................................................................................78
9.3.
Sample Size and Power Considerations...................................................................78
9.4.
Randomization and Stratification............................................................................78
9.5.
Background and Demographic Characteristics........................................................79
9.6.
Subject Disposition.................................................................................................79
9.7.
Efficacy Analysis....................................................................................................79
9.7.1.
Primary Efficacy Analysis ......................................................................................79
9.7.2.
Secondary Efficacy Analyses..................................................................................80
9.7.2.1.
Key Secondary Efficacy Analyses ..........................................................................80
9.7.2.2.
Additional Secondary Efficacy Analyses ................................................................80
9.8.
Safety Analysis.......................................................................................................81
9.9.
Other Analysis........................................................................................................82
9.10.
Timing of Analyses ................................................................................................82
9.10.1.
Interim Analysis .....................................................................................................82
9.10.2.
Final Analysis.........................................................................................................83
9.11.
Other Topics...........................................................................................................83
9.11.2.
Data Monitoring Committee ...................................................................................83
9.11.3.
Steering Committee ................................................................................................84
9.11.5.
Subgroup Analysis..................................................................................................84
10.
ADVERSE EVENTS..............................................................................................85
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(/*


EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
13
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
10.1.
Monitoring, Recording and Reporting of Adverse Events .......................................85
10.2.
Evaluation of Adverse Events.................................................................................85
10.2.1.
Seriousness.............................................................................................................85
10.2.2.
Severity/Intensity....................................................................................................87
10.2.3.
Causality ................................................................................................................87
10.2.4.
Duration .................................................................................................................88
10.2.5.
Action Taken..........................................................................................................88
10.2.6.
Outcome.................................................................................................................88
10.3.
Abnormal Laboratory Values..................................................................................88
10.4.
Pregnancy...............................................................................................................88
10.4.1.
Females of Childbearing Potential: .........................................................................89
10.4.2.
Male Subjects.........................................................................................................89
10.5.
Other Malignancies/Pre-malignancies.....................................................................89
10.6.
Reporting of Serious Adverse Events......................................................................90
10.6.1.
Safety Queries ........................................................................................................90
10.7.
Expedited Reporting of Adverse Events..................................................................91
11.
DISCONTINUATIONS .........................................................................................92
11.1.
Treatment Discontinuation......................................................................................92
11.2.
Study Discontinuation ............................................................................................92
12.
EMERGENCY PROCEDURES.............................................................................94
12.1.
Emergency Contact.................................................................................................94
12.2.
Emergency Identification of Investigational Products .............................................94
13.
REGULATORY CONSIDERATIONS...................................................................95
13.1.
Good Clinical Practice............................................................................................95
13.2.
Investigator Responsibilities ...................................................................................95
13.3.
Subject Information and Informed Consent.............................................................96
13.4.
Confidentiality........................................................................................................96
13.5.
Protocol Amendments.............................................................................................96
13.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................................96
13.7.
Ongoing Information for Institutional Review Board/ Ethics Committee ................97
13.8.
Termination of the Study ........................................................................................97
14.
DATA HANDLING AND RECORDKEEPING.....................................................99
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7


EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
14
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
14.1.
Data/Documents.....................................................................................................99
14.2.
Data Management...................................................................................................99
14.3.
Record Retention....................................................................................................99
15.
QUALITY CONTROL AND QUALITY ASSURANCE......................................101
15.1.
Study Monitoring and Source Data Verification....................................................101
15.2.
Audits and Inspections..........................................................................................101
16.
PUBLICATIONS .................................................................................................102
17.
REFERENCES.....................................................................................................103
18.
APPENDICES......................................................................................................107
APPENDIX A:
Table of Abbreviations ................................................................................107
APPENDIX B: 
Myelodysplastic Syndromes World HealthOrganization Classification
System (2016) ......................................................................................................111
APPENDIX C:
French-American-British (FAB) Myelodysplastic Syndromes (MDS) 
Classification System............................................................................................113
APPENDIX D:
International Prognostic Scoring System Score - Revised ............................114
APPENDIX E:
International Working Group Response Criteria for Myelodysplastic
Syndromes............................................................................................................116
APPENDIX F:
European Organization for Research and Treatment of Cancer Quality-
of-Life Questionnaire (Version 3.0)......................................................................119
APPENDIX G:
Eastern Cooperative Oncology Group (ECOG) Performance Status.............121
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235


EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
15
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
LIST OF TABLES
Table 1:
Revised International Prognostic Scoring System for Myelodysplastic 
Syndromes (IPSS-R): Prognostic Score Values.......................................................18
Table 2:
Study Objectives.....................................................................................................30
Table 3:
Study Endpoints .....................................................................................................31
Table 4:
Table of Events.......................................................................................................45
Table 5:
Starting Dose Level with Dose Reductions and Dose Titration................................71
Table 6:
Dose Modification: Dose Delay, Dose Reduction, and Discontinuation 
Guidelines ..............................................................................................................72
Table 7:
Abbreviations and Specialist Terms......................................................................107
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
16
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
LIST OF FIGURES
Figure 1:
Luspatercept Schematic Representation and Mechanism of Action .........................22
Figure 2:
Overall Study Design..............................................................................................38
CCI
&(/*(1(35235,(7$5<,1)250$7,21


EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
17
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
1.
INTRODUCTION 
1.1.
Disease Background 
Anemia is the predominant cytopenia observed in adult myelodysplastic syndrome (MDS) and is 
present in approximately 85% of MDS patients at the time of diagnosis (Noel, 1992). Anemia in 
MDS can range in severity from mild (asymptomatic) to severe, requiring regular RBC 
transfusion support. Of the approximately 80% to 90% of patients with MDS who develop 
anemia, 40% become transfusion dependent (TD) (Zeidan, 2013).
Lower hemoglobin (Hgb) levels and red blood cell (RBC) transfusion-dependence have been 
associated with inferior cardiovascular outcomes and increased mortality in patients with MDS, 
representing a strong rationale for aggressive management of anemia in MDS (Zeidan, 2013). 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), iron overload, 
and its associated complications, immune-related disorders, and increased risk of infections 
(Hellstrom-Lindberg, 2003; Jansen, 2003; Thomas, 2007). Therefore, a therapeutic option that 
would achieve transfusion independence in patients with International Prognostic Scoring 
System-Revised (IPSS-R) lower-risk MDS for a sustained period of time is an important unmet 
medical need.
Myelodysplastic syndromes are a heterogeneous group of clonal disorders of hematopoietic stem 
cells characterized by ineffective hematopoiesis that manifest clinically as anemia, neutropenia, 
and/or thrombocytopenia of variable severity; these often result in RBC- transfusion dependent 
(TD) anemia, increased risk of infection, and/or hemorrhage, as well as a potential to progress to 
acute myeloid leukemia (AML) (Adès, 2014; Visconte, 2014; Zeidan, 2013; Brunning, 2008; 
Fenaux, 2009; Steensma, 2013; Catenacci, 2005).
For most patients with MDS, anemia and associated transfusion dependency are the most 
prominent clinical problems and the main determinants of quality-of-life (QoL) (Balducci, 2010; 
Chan, 2014; Kao, 2008; Malcovati, 2005; Platzbecker, 2012; Hellström-Lindberg, 2013).
1.1.1.
Staging and Prognostic Factors 
1.1.1.1.
Revised International Prognostic Scoring System (IPSS-R) for MDS
Patients with MDS can be categorized into 1 of 4 risk groups according to the IPSS (low,
intermediate [Int]-1, Int-2, and high) based on cytogenetics, number of peripheral blood cell 
lineages affected by cytopenia, and bone marrow (BM) blast percentages obtained at diagnosis. 
The 4 risk groups showed significantly different risk of progression to AML and overall survival 
(OS) (Greenberg, 1997). The median survival rate is 5.7 years for patients with low risk MDS is
as short as 0.4 years for high-risk MDS.
While providing insight into the prognostic significance of baseline variables such as percent 
bone marrow blasts and cytogenetics, one of the limitations of the International Prognostic 
Scoring System (IPSS) (Greenberg, 1997) is that it underestimates the impact of cytopenias on 
prognosis for patients with lower-risk disease. The IPSS also underestimates the impact that 
RBC transfusion dependency has on overall survival and does not adequately assess the impact 
of cytogenetic changes (Germing, 2012).
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
18
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
A recent revision of the IPSS (the IPSS-R) provides more discriminatory risk factor assessment 
than the original IPSS for evaluating clinical outcomes (survival duration and time to AML 
evolution) for MDS patients (Greenberg, 2012). Bone marrow cytogenetics, bone marrow blast 
percentage, and cytopenias remain the basis of the IPSS-R, but with further refinement of these 
categories (Table 1). Cytogenetic prognostic subgroups were split into 5 rather than 3 categories 
with the addition of new and specific classifications of a number of less common cytogenetic 
subsets. Low bone marrow blast percentage was split into 2 categories (ie, ≤ 2% versus > 2% to 
< 5%), and the depth of cytopenias was defined using precise cutpoints. The application of 
additional refinements and prognostic variables in IPSS-R were intended to provide more 
meaningful classifications upon which to assess clinical outcome in MDS patients.
Table 1:
Revised International Prognostic Scoring System for Myelodysplastic 
Syndromes (IPSS-R): Prognostic Score Values
Prognostic
Variable
0
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1
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3
4
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--
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--
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50 to <100
<50
--
--
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--
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--
--
--
Source: Greenberg, 2012.
1.1.1.2.
Ring Sideroblasts
Early investigators defined ring sideroblasts as having iron granules in a perinuclear distribution 
surrounding the entire nucleus. The definition of a ring sideroblast proposed by the International 
Working Group on Morphology of Myelodysplastic Syndromes (IWGMDS) (an erythroblast 
with at least 5 siderotic granules covering at least a third of the circumference of the nucleus) has 
been incorporated into the 2008 World Health Organization (WHO) classification of Tumors of 
Hematopoietic and Lymphoid Tissues and for the definition of refractory anemia with ring 
sideroblasts (RARS), the required number of ring sideroblasts is ≥15% (Mufti, 2008).  The 2016 
update to the WHO criteria further expanded on this definition of ring sideroblastic disease by 
also including cases with ring sideroblasts ≥ 5% if SF3B1 mutation is present (Arber, 2016).
It is estimated that approximately 30% of all MDS patients have > 15% of bone marrow 
erythroid precursors being ring sideroblasts. Recently, spliceosome mutations were shown to be 
prevalent in MDS with ring sideroblasts, particularly mutations involving splicing factor 3B 
subunit 1 (SF3B1). RNA splicing is the most commonly mutated pathway in MDS, and there is 
strong evidence that mutations in splicing factors occur early in disease evolution. These 
mutations play a major role in determining the clinical features of the disease, with differences in 
morphological features seen on bone marrow biopsy and in leukemia-free survival 
(Papaemmanuil, 2013).
Subjects with RS with splicing factor mutations have been shown to have ineffective 
erythropoiesis, possibly related to defects in iron utilization (Conte, 2015; del Rey, 2015; 
Dolatshad, 2015). Recently, a heterozygous conditional knock-in mouse model has been 
developed with the most frequent K700E mutation of SF3B1 (Obeng, 2014). Ineffective 
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
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ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
erythropoiesis developed in these mice, with a block in the maturation of late-stage erythroid 
precursors.
1.1.2.
Current Treatment Options for Lower Risk MDS
In lower risk MDS, the risk of AML progression is less and survival is longer, with 
approximately one-half of these elderly patients dying from a cause other than the consequences 
of MDS or AML (Greenberg, 2012). In those patients, the main priority is generally the 
treatment of cytopenias, primarily anemia (usually the predominant cytopenia), and the 
improvement in quality of life (Fenaux, 2013). A clinically prominent challenge in patients with 
lower-risk MDS is the management of preexisting conditions aggravated by anemia, such as 
cardiovascular diseases.
The standard of care for cytopenias remains supportive treatment with erythropoiesis-stimulating 
agents (ESAs) such as epoetin alfa or darbepoetin, administration of RBC and/or platelet 
transfusions, infection prophylaxis and/or treatment and use of hematopoietic growth factors 
such as granulocyte colony-stimulating factor (G-CSF) and nutritional supplements when needed 
(Greenberg, 1997; Casadevall, 2004). 
1.1.2.1.
Revlimid
Revlimid® (lenalidomide) is approved in the United States (US) for the treatment of patients with 
transfusion-dependent anemia due to low- or Int-1-risk MDS associated with a del (5q) 
abnormality with or without additional cytogenetic abnormalities. This is the standard of care (in 
those countries where it is approved) for the small proportion of patients with lower risk del-5q 
MDS. In this population, lenalidomide led to transfusion independence for 67% of the patient 
population and a median duration of transfusion independence of 44 weeks. 
1.1.2.2.
Erythropoiesis Stimulating Agents (ESAs) Therapy
Erythropoiesis stimulating agents (ie, recombinant erythropoietin [EPO] or darbepoetin [DAR]), 
although not currently approved in most countries, are commonly used for the treatment of 
anemia in lower-risk MDS without del(5q) cytogenetic abnormality. Major favorable prognostic 
factors for response to ESAs are low or no RBC transfusion requirement (< 2 U per month) and 
baseline serum EPO level < 500 U/L. (Fenaux, 2013) Responses to ESAs are best in subjects 
with low endogenous levels (eg < 500 U/L) of erythropoietin (EPO), normal blast counts and 
lower IPSS/WHO Prognostic Scoring System (WPSS) scores (Hellström-Lindberg, 2003; 
Santini, 2011).
More recently, the European ESA Scoring System was developed, using a serum EPO level of 
≤200 U/L as a prognostic factor for ESA responsiveness (Santini, 2013). Approximately 70% of 
the relapses of anemia after initial response to ESAs are not associated with progression to 
higher-risk MDS but simply to loss of sensitivity of erythroid progenitors to ESAs. Second-line 
treatments in those patients may be different from those required in patients showing 
concomitant progression to higher-risk MDS (Fenaux, 2013).
1.1.2.3.
Red Blood Cell Transfusions 
In many patients with lower-risk MDS, anemia will eventually become resistant to all available 
drug treatments, even in the absence of evolution to higher-risk MDS, and will require repeated 
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
20
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
RBC transfusions. Frequent RBC transfusions are associated with chronic anemia (ie, average 
hemoglobin levels < 10g/dL) which can lead to increased morbidity, especially as a result of 
cardiac failure, falls, fatigue and lower quality of life (Fenaux, 2013). The development of 
transfusion dependency significantly worsens the survival of patients with MDS (Malcovati, 
2005). Long-term RBC transfusion dependence has several detrimental clinical effects including 
iron overload, economic consequences, and a negative impact on patients’ QoL (Hellström-
Lindberg, 2003; Jansen, 2003; Thomas, 2007).
1.1.2.3.1. Iron Chelation Therapy (ICT)
Clinically significant iron overload associated with decreased cardiac function is often observed 
in patients who have received 100 or more RBC units (Adès, 2014). Therefore, iron chelation 
may be required in patients receiving frequent transfusions in order to avoid iron-related cardiac, 
hepatic and endocrine toxicities. Deferoxamine (intramuscular/subcutaneous/intravenous) or 
deferasirox (oral) have been used in MDS patients as a treatment for iron overload (Messa, 
2010). However, deferasirox is frequently associated with gastrointestinal side effects and cannot 
be used in patients with renal function impairment (Fenaux, 2013). 
Retrospective studies suggest that when serum ferritin levels exceed 1000 μg/L, in the absence of 
inflammatory or other causes for ferritin elevation, transfusion burden often exceeds the body’s 
capacity to maintain iron bound to transferrin (Dreyfus, 2008). Patients with lower-risk World 
Health Organization (WHO) morphologic categories of refractory anemia (RA) or refractory 
anemia and with ringed sideroblasts (RARS) who had ferritin levels above 1,000 μg/L 
experienced more cardiac complications and had a reduced overall survival (hazard ratio [HR] = 
1.51; p < 0.001) (List, 2010). 
Sanz, et al reported that transfusion dependence and iron overload are independent risk factors 
for overall survival and leukemic progression (Sanz, 2008). In their review of 2241 patients 
whose complete transfusion history was available, 835 were transfusion dependent at the time of 
diagnosis, 526 became transfusion dependent during follow-up, and 880 remained transfusion 
independent (Sanz, 2008). Median survival was significantly shorter in patients who were 
transfusion dependent at diagnosis (19 months) compared with 60 months for those who later 
became transfusion dependent and 96 months for those who remained transfusion free 
(p < 0.0001). Independent prognostic factors associated with OS in a multivariate analysis 
included iron overload (HR = 52.4; p < 0.0001) and transfusion dependency (HR = 8.8; 
p < 0.0001) (Sanz, 2008).
Hence, therapeutic options that would achieve transfusion independence (TI) or reduce 
transfusion intensity in patients with lower-risk MDS for a significant amount of time would be 
highly desirable in terms of reduced requirements for iron chelation therapy.
1.1.2.4.
Hypomethylating Agents
There are 2 hypomethylating agents currently approved for the treatment of various subtypes of 
MDS, azacitidine and decitabine.
Vidaza® (azacitidine for injection) is indicated for treatment of patients with the following 
French-American-British (FAB) classification subtypes of MDS (Appendix C) in the US:  RA or 
RARS (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), 
refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in 
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
21
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
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).
Dacogen® (decitabine for injection), another hypomethylating agent, is approved in the US for 
treatment of patients with MDS, including previously treated and untreated, de novo and 
secondary MDS of all FAB subtypes (RA, RARS, RAEB, RAEB-T, and CMML) and Int-1, 
Int-2, and high-risk IPSS groups.
While azacitidine and decitabine are approved for treatment of various subtypes of MDS 
including Int-1 risk MDS in some countries, these agents are not uniformly administered as 
standard of care. This is partly because clinicians are reluctant to treat asymptomatic or 
minimally symptomatic lower-risk MDS patients, especially those who are not yet transfusion-
dependent. In addition, extensive data for these agents in the lower-risk MDS patient population 
are not currently available.
1.2.
Compound Background 
Luspatercept (ACE-536) is a recombinant fusion protein consisting of a modified form of the 
extracellular domain (ECD) of the human activin receptor type IIB (ActRIIB) linked to the 
human IgG1 Fc domain. The ActRIIB receptor and its ligands are members of the transforming 
growth factor (TGF)-β superfamily, a group of proteins involved in the development, 
differentiation, and/or maturation of various organ systems. No species differences have been 
described in the ligand-receptor interactions among members of the TGF-β family as the ligands 
and receptors are highly conserved across species (Massagué, 1998).  Thus, observations from 
pharmacology studies of luspatercept or its murine analog RAP-536 in animal models provide 
significant insight into the potential of luspatercept to treat human disease. 
Members of the TGF-β family have been shown to play a role as negative regulators of red blood 
cell (RBC) development (erythropoiesis). In nonclinical experiments, luspatercept has been 
shown to bind with high affinity to some TGF-β ligands (eg, growth differentiation factor 
[GDF]8, GDF11, bone morphogenetic protein [BMP]6 and activin B) 
 
. The emerging body of evidence on 
luspatercept suggests that its mechanism of action is completely independent from that of EPO, 
and involves stimulation of the later, maturation phase of erythroblast differentiation and 
maturation in the bone marrow (Figure 1).
Across the Phase 2 program, responses to luspatercept treatment were observed in the majority 
of subjects at expected pharmacologic dose levels of approximately 0.75 up to 1.75 mg/kg, 
administered once every 3 weeks. In particular, as described in more detail in the following 
sections, luspatercept treatment led to hematologic improvement in erythroid response (HI-E) in 
a substantial proportion of MDS subjects within the initial 3 months of treatment. 
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
22
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
The preliminary Phase 2 data suggest luspatercept is likely to attenuate ineffective erythropoiesis 
and correct the anemia that characterizes MDS and could provide significant clinical benefit to 
patients by improving hemoglobin levels and reducing the need for regular RBC transfusions. 
The impact on these endpoints, as supported by the preliminary clinical evidence presented here, 
suggest that luspatercept may provide a sustained clinical benefit (eg, RBC transfusion 
independence) for the treatment of anemia in patients with IPSS lower risk MDS with ≥15% ring 
sideroblasts.
Figure 1:
Luspatercept Schematic Representation and Mechanism of Action
A 
B
Please refer to the Investigator’s Brochure for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies, and adverse event profile of the 
investigational product (IP).
1.2.1. Summary of Nonclinical Studies with Luspatercept
A brief summary of key findings from pharmacology and toxicology studies is provided below. 
Please refer to the Investigator’s Brochure (IB) for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies, and adverse event profile of the 
investigational product (IP). The most recent version of the luspatercept IB should be reviewed 
prior to initiating the study.
 
 
 
 
 
 
  
 
 
 
 
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
23
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.2.2.
Summary of Clinical Experience 
One Phase 1 trial with healthy postmenopausal women has been completed. Two Phase 2 studies 
with MDS patients are ongoing:
!
Study A536-03: A Phase 2, Open-label, Ascending Dose Study of ACE-536 for the 
Treatment of Anemia in Patients with Low or Intermediate-1 Risk Myelodysplastic 
Syndromes (MDS)
!
Study A536-05: An Open-label Extension Study to Evaluate the Long-Term Effects of 
ACE-536 for the Treatment of Anemia in Patients with Low or Intermediate-1 Risk 
Myelodysplastic Syndromes (MDS)
Preliminary results from ongoing Phase 2 studies of luspatercept in patients with MDS indicate 
that the dose levels up to 1.75 mg/kg have been generally safe and well-tolerated to date, with no 
dose-limiting toxicities observed as of 07 July 2015 in either study.  Efficacy parameters are still 
under evaluation.
Additional information regarding clinical experience with luspatercept is summarized in the
current version of the luspatercept IB.
1.2.2.1.
Potential Risks of Human Use 
Increases in hematologic parameters (RBC, hemoglobin, hematocrit, reticulocytes) are expected 
pharmacologic effects of luspatercept treatment. Increases in systolic and diastolic blood 
pressures may occur in concert with increases in hemoglobin values. Excessive or rapid increases 
in hemoglobin or blood pressure may occur and will be monitored. Dose modification rules for 
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
24
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
individual subjects, including dose delay and/or dose reduction, will be utilized to minimize risks 
associated with increased RBC parameters. 
Adverse events considered probably or possibly related to study drug that were reported in at 
least 5% of subjects in the Phase 1 study in healthy volunteers included injection site hemorrhage 
and injection site macule.  Adverse events reported in at least 10% of patients regardless of 
causality in the ongoing Phase 2 studies in MDS and β-thalassemia included bone pain, 
headache, asthenia, myalgia, arthralgia, pyrexia, musculoskeletal pain, oropharyngeal pain, 
diarrhea, nasopharyngitis, and cough. As with all biologics, there is the potential for antidrug 
antibodies (ADA) that can be associated with increased drug clearance and hypersensitivity 
reactions. 
 
 
Luspatercept has exhibited maternal and developmental toxicity in reproductive toxicity studies 
in preclinical species and therefore luspatercept should not be administered to pregnant or 
nursing women. Male and female subjects of childbearing potential participating in studies of 
luspatercept must be willing to use effective methods of contraception during the Treatment 
Period and up to 12 weeks from the last dose of IP. Females of childbearing potential (FCBP)
must agree to pregnancy testing prior to enrollment and prior to each treatment cycle for the 
duration of the Treatment Period. 
 The occurrence of new malignancies, pre-malignant 
or precancerous lesions will be monitored as events of interest and will be included as part of the
assessment of adverse events regardless of causality, throughout the course of the study. In 
addition, participating subjects should be followed long term as specified in the protocol for 
evidence of tumor formation.
 
Safety effects will be 
monitored closely through adverse event (AE) reporting, clinical laboratory tests, vital signs, 
physical examinations, and ongoing review of unblinded data by an external Data Monitoring 
Committee (DMC).  
Please refer to the most current version of the Investigator’s Brochure and subsequent safety 
correspondence for additional information regarding findings from toxicology and clinical
studies.
The most recent version of the luspatercept IB should be reviewed prior to initiating the study.
1.2.2.2.
Overall Benefit Risk Assessment
Current available information continues to support an acceptable benefit-risk profile for 
luspatercept when used in accordance with the precautions, dosing, and safety monitoring 
outlined in the study protocol and the routine pharmacovigilance practices.
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
25
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
1.3.
Rationale
1.3.1.
Study Rationale and Purpose
IPSS-R classification of MDS (very low, low, or intermediate risk) 
The IPSS-R classification has been chosen to define the Phase 3 patient population because as 
discussed in Section 1.1.1.1, the IPSS-R classification provides a more discriminatory risk factor 
assessment than the original IPSS (Greenberg, 1997) for evaluating clinical outcomes (survival 
duration and time to progression of AML) for MDS subjects (Greenberg, 2012). The Phase 3 
patient population has been defined as having IPSS-R very low, low or, intermediate risk MDS. 
This patient population represents a subset of subjects with IPSS-R lower-risk MDS who have 
anemia and have limited treatment options in managing the anemia. Subjects in the lower risk 
groups often become dependent on frequent RBC transfusions, which leads to decreased health-
related quality of life (HRQoL) and increased morbidity and mortality (Hellström-Lindberg, 
2003; Malcovati, 2005). Therefore, the clinically prominent challenge in subjects with lower risk 
MDS is the management and treatment of cytopenias, mainly anemia (the predominant 
cytopenia), and the improvement in QoL. The recent IPSS-R classified 39% of subjects with 
RARS as very low risk, 56% as low risk, and 5% as intermediate risk. The IPSS-R assigns 34% 
of subjects with refractory cytopenia with multilineage dysplasia with ringed sideroblasts 
(RCMD-RS) to the very low risk, 50% to the low, and 16% to the intermediate risk groups 
respectively (Malcovati, 2013). 
Ring sideroblasts ≥ 15% of erythroid precursors in bone marrow (or ≥ 5%, if SF3B1 
mutation is present)
According to WHO criteria, refractory anemia with ring sideroblasts (RARS) is characterized by 
isolated anemia, erythroid dysplasia only, less than 5% blasts and ≥ 15% ring sideroblasts in the 
bone marrow. The 2016 update to the WHO criteria further expanded on this definition of ring 
sideroblastic disease by also including cases with ring sideroblasts ≥ 5% if SF3B1 mutation is 
present (Arber, 2016). Anemia is macrocytic in the large majority of these subjects, while 
reticulocyte count is in the normal range, reflecting an inappropriately low RBC production 
leading to anemia. The natural history of RARS is characterized by an initial phase of erythroid 
hyperplasia and ineffective erythropoiesis (Malcovati, 2013).
Two recent phase 3 randomized controlled studies evaluated the use of erythropoiesis-
stimulating agents (ESAs) versus placebo. In these studies, subjects with lower-risk MDS 
without ring sideroblasts had a higher probability of response, compared to those with ring 
sideroblasts. In subjects with RARS, responses were less frequent and not significantly different 
between ESAs and placebo (Hellström-Lindberg, 2013). The mode of action of ESAs on early 
erythroid progenitors would not be expected to benefit subjects with defects in the later stages of 
erythropoiesis when erythropoietin receptors are absent (Hattangadi, 2011; Broudy, 1991).
Study A536-03 is a Phase 2, open-label, ascending dose study of luspatercept for the treatment of 
anemia in patients with low or intermediate-1 risk MDS.  
In patients (n = 49) receiving 0.75 to 1.75 mg/kg, 51% of patients responded per International 
Working Group (IWG) hematologic improvement, erythroid response (HI-E) hemoglobin 
increase ≥1.5 g/dL for low transfusion burden patients or reduction of ≥ 4 RBC units or ≥50% 
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
26
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
of units of RBCs transfused/8 weeks for high transfusion burden patients).  Higher response rates 
were observed in ring sideroblast positive patients.  Patients with splicing factor mutations 
present (primarily SF3B1) had a 58% response rate.  Of the patients in the higher-dose group 
who received RBC transfusions prior to luspatercept treatment (range 2 to 18 units/8 weeks), 14
out of 40 (35%) patients were transfusion-free for ≥8 weeks during the 12-week treatment 
period. Additional information is summarized in the current version of the luspatercept IB.
Refractory, intolerant, or ineligible (endogenous serum erythropoietin level > 200 U/L) for 
ESAs.
Erythropoiesis-stimulating agents (ESAs) are often used in many newly diagnosed IPSS-R lower
to intermediate (very low, low, intermediate) risk MDS subjects with early onset anemia, as 
many subjects respond well to ESAs. To be eligible for the ACE-536-MDS-001 Phase 3 study, 
subjects must be refractory to, intolerant, or ineligible for ESAs.
Treatment guidelines vary in regards to defining an adequate course of ESA treatment.  The 
National Comprehensive Cancer Network (NCCN) guidelines (NCCN 2015 guidelines)
recommends dose levels starting at 40,000 IU administered 1-3 times weekly for a duration 6-8 
weeks prior to assessment of hematological improvement. The European Society for Medical 
Oncology (ESMO) guidelines recommend dose levels starting at 30,000 IU weekly (Fenaux, 
2014).  However, a significant proportion of these subjects will be resistant to ESAs as 
monotherapy or experience short-lasting responses. (Hellström-Lindberg, 2013). Studies have 
shown that elevated endogenous serum erythropoietin levels and RBC transfusion requirements 
are negatively correlated with response to ESAs. (Hellström-Lindberg, 2013).
Meta-analyses of clinical trials with thousands of treated subjects have led to the following 
conclusions: 
!
RARS subjects with or without a need for transfusion but with a serum EPO level > 200 
U/L had a response rate of 0% to ESAs (Hellström-Lindberg, 1995; Santini, 2011).
!
MDS subjects without a need for transfusion, with a serum EPO level < 200 U/L, and a 
diagnosis other than RCMD-RS have a higher response rate to ESAs (Santini, 2011). 
In study A536-03, high response rates were also seen in subjects in the higher-dose group with 
EPO levels < 200U/L (68%) and 200-500 U/L (36%).
1.3.2.
Rationale for the Study Design
ACE-536-MDS-001 is a phase-3 multicenter randomized double-blind placebo controlled study.
The primary objective is to evaluate RBC transfusion independence (RBC-TI) in 2 treatment
arms (luspatercept versus placebo) for treatment of anemia due to very low, low, or intermediate
risk (IPSS-R) MDS in subjects with ring sideroblasts who require RBC transfusions. Secondary 
objectives include evaluation of efficacy (eg, hematological improvement, HRQoL, changes in 
serum ferritin and iron chelation therapy use) as well as safety and tolerability.
The multicenter nature of the study provides assurance that the results are likely to have general 
applicability.  The design of this study (ie, randomized, double-blinded, placebo-controlled, and 
parallel-group) will eliminate bias in assignment of the IP or in data interpretation.
A 2:1 randomization will be used as this is an orphan disease with a limited number of subjects 
available. Subjects will be randomized to receive luspatercept or placebo at a 2:1 ratio. A 2:1 
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
27
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
randomization scheme would enrich the number of participants exposed to the active treatment 
group (Dumville, 2006).
In order to mitigate the potential bias should subjects in the control arm drop out early due tothe
lack of a quick response, the primary efficacy analysis will be the proportion of subjects
achieving RBC-TI with a duration ≥8 weeks measured at 24 weeks.
After completion of the MDS Disease Assessment by the investigator at the Week 25 Visit, 
subjects who exhibit clinical benefit with no evidence of disease progression per IWG criteria for 
altering natural history of MDS (Cheson, 2006; Appendix E) will continue double-blind
treatment. The proportion of subjects achieving RBC-TI with a duration ≥8 weeks at 48 weeks
will be assessed as a secondary endpoint to capture potential late responders. In addition, the 
proportion of subjects achieving RBC-TI with a duration ≥ 12 weeks will be assessed as a 
secondary endpoint, representing extended duration of benefit achieved with therapy.
The study will be stratified by RBC transfusion burden and IPSS-R risk category (Greenberg, 
2012) at baseline. These factors are discussed below.
RBC transfusion burden at baseline
The primary endpoint for the study is the proportion of subjects who are RBC transfusion free 
over any consecutive 56-day period. In the phase 2 studies, achieving transfusion independence 
(TI) was shown to be dependent on baseline transfusion burden, Subjects who receive an average 
of ≥ 6 RBC units during each of two consecutive 8-week periods prior to randomization will be 
less likely to become transfusion independent than those subjects who receive < 6 RBC units/8 
weeks. Thus, stratification by RBC transfusion burden is considered useful due to its likely effect 
on the primary endpoint.
IPSS-R classification at baseline: Very low and low versus intermediate
Among the lower risk categories for IPSS-R, mortality risk is distinctively worse for 
intermediate risk than for very low and low risk. The intermediate classification may also be 
indicative of higher risk of progression to AML (Greenberg, 2012). Thus in consideration of the 
long-term safety analyses, stratification for IPSS-R will be used.
1.3.3.
Rationale for Dose, Schedule and Regimen Selection
The starting dose level of 1.0 mg/kg and the maximum dose level of 1.75 mg/kg are based on 
clinical data from the ongoing Phase 2 A536-03 and A536-05 studies in MDS. Preliminary 
results indicate that the dose levels up to 1.75 mg/kg have been generally safe and well-tolerated 
to date. A higher response rate, including HI-E and RBC-TI, was observed in the higher dose 
groups (0.75-to 1.75 mg/kg subcutaneous every 3 weeks [Q3W]) compared to the lower dose 
groups (0.125-0.5 mg/kg subcutaneous Q3W).
Selection of the dosing schedule (every 3 weeks, Q3W) was based on the duration of the 
luspatercept responses as well as pharmacokinetic parameters for luspatercept in MDS patients.  
The transfusion-reducing effect of luspatercept relies on its ability to increase hemoglobin; in the 
Phase 2 studies, the increase in hemoglobin was well maintained with the Q3W dosing schedule.
Additional information regarding these clinical studies is summarized in the current version of 
the luspatercept IB.
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
28
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
1.3.4.
Rationale for Choice of Placebo Comparator
Treatment algorithms such as those issued by NCCN (NCCN 2015 guidelines) suggest that 
lower risk MDS patients with symptomatic anemia be treated with ESAs ± G-CSF if the serum 
EPO level is ≤500 U/L. Those without a response or who have a higher EPO level and either 
have a poor probability to respond to immune suppressive therapy, or who are intolerant to or 
fail immune suppressive therapy, have three options proposed: hypomethylating agents (HMAs), 
lenalidomide, or entry on a clinical trial. 
Entry into a clinical trial of luspatercept rather than use of HMAs or lenalidomide may be 
preferred in order to avoid the risk of Grade 3-4 cytopenias, which occur with both azacitidine 
and decitabine. Since lower risk MDS patients with ring sideroblasts and low blast counts (< 5%) 
are unlikely to progress to AML, the predominant therapeutic objective is the management of 
anemia and the prevention of transfusion related complications. Since this might mean 5 or more 
years of primarily chronic anemia management before disease progression, the benefit/risk of 
early intervention with HMAs is questionable. Subjects who fail to benefit from study drug in 
this clinical trial may subsequently receive HMAs or lenalidomide.
The primary endpoint for this study, RBC-TI, is better assessed against the natural history of the 
disease (ie, in subjects previously untreated with disease modifying agents). Based on these 
considerations, placebo is the appropriate comparator for the proposed Phase 3 study. Standard 
of care for the management of acute anemia (ie, RBC transfusions) will be applied to both 
treatment groups.
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
29
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
SF3B1 and other genes involved in RNA splicing such as SRSF2, U2AF1 and ZRSR2 have been 
observed in MDS patients (Pellagatti, 2015).  SF3B1 mutations were found in greater than 70% 
of RS+ patients (Papaemmanuil, 2011; Malcovati, 2011) and thought to be causally related to 
chromosome stability, DNA repair and gene regulation that may result in anemia and 
thrombocytopenia (Visconte, 2014; and Pellagatti, 2015).  
 
  
 
 
 
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
30
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
2.
STUDY OBJECTIVES AND ENDPOINTS
Table 2:
Study Objectives
Primary Objective
The primary objective of the study is to evaluate RBC transfusion independence (RBC-TI) of 
luspatercept compared with placebo for the treatment of anemia due to IPSS-R very low, low, or 
intermediate risk MDS in subjects with ring sideroblasts who require red blood cell (RBC) 
transfusions.
Secondary Objectives
The secondary objectives are:
!
To assess the safety and tolerability of luspatercept compared with placebo
!
To evaluate the effect of luspatercept on reduction in RBC transfusions, increase in 
hemoglobin, duration of RBC-TI, improvement in health-related quality of life (HRQoL)
(ie, European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire [EORTC QLQ-C30]), increase in neutrophils, increase in platelets, 
decrease in serum ferritin, decrease in iron chelation therapy use, and time to RBC-TI 
compared with placebo
!
To evaluate population pharmacokinetics and exposure-response relationships for 
luspatercept in MDS subjects
 
 
 
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
31
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
Table 3:
Study Endpoints
Endpoint
Name
Description
Timeframe
Primary 
Red Blood Cell 
Transfusion 
Independence (RBC-TI)
≥ 8 weeks 
Proportion of subjects who 
are RBC transfusion free over 
any consecutive 56-day 
period
Week 1 through Week 24
Secondary
RBC-TI ≥ 12 weeks 
Proportion of subjects who 
are RBC transfusion free over 
any consecutive 84-day 
period
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24;
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Proportion of subjects who 
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any consecutive 56-day 
period
Week 1 through Week 48
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transfused over 16 
weeks
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units transfused over a fixed 
16-week period
Week 9 through 24;
Week 33 through 48 
Modified hematologic 
improvement - erythroid 
(mHI-E) per IWG 
(Cheson, 2006)
Proportion of subjects 
achieving modified HI-E over 
any consecutive 56-day 
period
Week 1 through Week 
24;
Week 1 through Week 48
Mean hemoglobin 
increase ≥ 1.0 g/dL
Proportion of subjects 
achieving hemoglobin (Hgb) 
increase from baseline ≥ 1.0 
g/dL over any consecutive 56-
day period in absence of RBC 
transfusions 
Week 1 through Week 24;
Week 1 through Week 48
Duration of RBC-TI
Maximum duration of RBC 
transfusion independence for 
subjects who achieve RBC TI 
≥ 8 weeks
Week 1 through Week 24;
Week 1 through end of 
treatment
Health-related quality of 
life (HRQoL)
Change in EORTC QLQ-C30 
score
Week 1 through Week 48; 
baseline through end of 
treatment
Hematologic 
improvement -
neutrophils (HI-N) per 
IWG (Cheson, 2006)
Proportion of subjects 
achieving HI-N over any 
consecutive 56-day period
Week 1 through Week 24;
Week 1 through Week 48
Hematologic 
improvement - platelets 
(HI-P) per IWG 
(Cheson, 2006)
Proportion of subjects 
achieving HI-P over any 
consecutive 56-day period
Week 1 through Week 24;
Week 1 through Week 48
Mean decrease in serum 
ferritin
Change in serum ferritin.
Week 9 through 24;
Week 33 through 48 
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
32
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
Table 3:
Study Endpoints (Continued)
Endpoint
Name
Description
Timeframe
Mean decrease in iron 
chelation therapy (ICT) 
use
Change in mean daily dose 
of ICT
Week 9 through 24;
Week 33 through 48
Time to RBC-TI
Time from first dose to first 
onset of transfusion 
independence ≥ 8 weeks
Week 1 through Week 24;
Week 1 through Week 48
Progression to AML 
Number and percentage of 
subjects progressing to 
AML; time to AML 
progression 
Randomization through at 
least 3 years post last dose; 
Week 1 through Week 48
Overall survival
Time from date of 
randomization to death due 
to any cause
Randomization through at 
least 3 years post last dose; 
Week 1 through Week 48
Safety
Type, frequency, severity of 
AEs and relationship of AEs 
to luspatercept/placebo
Screening through 42 days 
post last dose; 
Week 1 through Week 48
A population PK model.
Exposure-response 
relationship. 
A Population PK model that 
describes the PK exposure 
data of luspatercept and 
associated variability.
Exposure-response 
relationship for the primary 
efficacy endpoint, AEs of 
interest, and selected 
secondary endpoints.
Randomization through 1-
year post first dose.
Anti-drug antibodies 
(ADA) 
Frequency of anti-drug 
antibodies and effects on 
efficacy, or safety, or PK
Randomization through 1-
year post first dose.
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
33
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
Table 3:
Study Endpoints (Continued)
Endpoint
Name
Description
Timeframe
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
34
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
3.
OVERALL STUDY DESIGN
3.1.
Study Design
The study will be conducted in compliance with the International Council on Harmonisation 
(ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good 
Clinical Practice (GCP) and applicable regulatory requirements.
This is a Phase 3, double-blind, randomized, placebo-controlled, multicenter study to determine 
the efficacy and safety of luspatercept (ACE-536) versus placebo in subjects with anemia due to 
IPSS-R very low, low, or intermediate MDS with ring sideroblasts who require RBC 
transfusions. 
The study is divided into the Screening Period, a double-blind Treatment Period (Primary Phase 
and Extension Phase), and a Posttreatment Follow-up Period. See Figure 2 for more details and 
refer to Section 6 for full list of study procedures/assessments. 
Screening Period 
Upon giving written informed consent, subjects enter the Screening Period to determine 
eligibility. Subject screening procedures are to take place within 5 weeks prior to randomization. 
During the Screening Period, the subject will undergo safety and other assessments to determine 
eligibility for the randomized study.
Central review of bone marrow aspirate smear and biopsy, peripheral blood smear, cytogenetics,
will be used to confirm MDS diagnosis and WHO classification (Appendix B) and/or FAB
classification (Appendix C) and to determine the baseline IPSS-R riskclassification (Greenberg, 
2012; Appendix D).
Transfusion history must be available for at least the 16 weeks immediately preceding and 
including the date of randomization. Transfusion data should include the type of transfusion (eg, 
RBC, platelets), number of units, and date of transfusion.  Red blood cell (RBC) cell transfusion 
data should include the hemoglobin (Hgb) value for which the transfusion was administered (ie, 
pretransfusion Hgb value).
Refer to Section 6 for full list of study procedures/assessments.  
Randomization
Randomization will occur bya central randomization procedure using integrated response 
technology (IRT). Eligible subjects will be randomized at a 2:1 ratio to either:
o
Experimental Arm: Luspatercept (ACE-536): Starting dose of 1.0 mg/kg subcutaneous 
injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle)
OR 
o
Control Arm: Placebo (Volume equivalent to experimental arm) subcutaneous injection 
every 3 weeks (administered on Day 1 of each 21-day treatment cycle)
After randomization, no crossover between the treatment arms will be permitted at any point 
during the study.
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
35
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
Stratification will be based on the following factors:
!
RBC Transfusion burden at baseline
∀
≥ 6 RBC units/8 weeks (mean of the two consecutive 8 weeks periods 
immediately prior to randomization)
∀
< 6 RBC units/8 weeks (mean of the two consecutive 8 weeks periods 
immediately prior to randomization)
!
IPSS-R at baseline
∀
Very low, low
∀
Intermediate
Refer to Section 6 for additional details.
Primary Phase of the Treatment Period: Weeks 1-24 
The first dose of investigational product (IP) should be administered after, but within 3 days of 
randomization and can be on the same day as randomization. Refer to the IRT manual for 
additional information on randomization utilizing IRT.  
Subjects will receive IP (either luspatercept or matching placebo) on Day 1 of each 21-day 
treatment cycle.
In both treatment arms, best supportive care (BSC) may be used in combination with study 
treatment when clinically indicated per investigator. Best supportive care includes, but is not 
limited to, treatment with transfusions, antibiotic, antiviral and/or antifungal therapy, and 
nutritional support as needed.  Best supportive care forthis study excludes the use of ESAs.  
Refer to Section 8 for additional details.
Subjects should receive IP through at least the first 24 calendar weeks after the date of first dose
unless the subject experiences unacceptable toxicities, withdrawsconsent, or meets any other 
treatment discontinuation criteria (Section 11.1).
Week 25 Visit:  MDS Disease Assessment 
The Week 25 Visit should be completed 24 calendar weeks after the date of first dose, regardless 
of dose delays.  As central laboratory results from bone marrow and peripheral blood samples are 
required as part of the MDS Disease Assessment, a 14 day window is allowed for the Week 25 
Visit.  Please refer to Section 6.2.2 for more details related to assessments/procedures. 
In order for subjects to remain on double-blind treatment beyond the first 24 calendar weeks, the 
following criteria must be confirmed upon the completion of the MDS Disease Assessment by 
the investigator at the Week 25 Visit:
!
Evidence of clinical benefit (eg, decrease in RBC transfusion requirement compared to 
baseline requirement or hemoglobin increase compared to baseline)
AND
!
Absence of disease progression per IWG criteria for altering natural history of MDS 
(Cheson, 2006; Appendix E).
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
36
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
Based on the outcome of the Week 25 Visit MDS Disease Assessment, subjects will either be 
discontinued from treatment with IP and enter the Posttreatment Follow-up Period or continue 
double-blind treatment with IP in the Extension Phase of the Treatment Period. 
Extension Phase of the Treatment Period:  After Week 25 Visit
Subjects who meet criteria to remain on double-blind treatment after completion of the Week 25 
Visit MDS Disease Assessment may continue dosing on Day 1 of each 21-day treatment cycle in 
the Extension Phase of the Treatment Period until the subject experiences unacceptable 
toxicities, disease progression per IWG criteria for altering natural history of MDS (Cheson,
2006; Appendix E), withdrawsconsent, or meets any other discontinuation criteria (Section 11). 
MDS Disease Assessment will be repeated by the investigator at Extension Cycle 8, Day 1 and 
Day 1 of every eighth Extension Cycle thereafter (ie, Extension Cycle 8, 16, 24+, etc. or every 
24 weeks in the event of dose delays) until the subject is discontinued from treatment.  
For subjects to continue double-blind treatment in the Extension Phase of the Treatment Period, 
each MDS Disease Assessment (criteria detailed in Section 6.2.2) should confirm continued 
clinical benefit and absence of disease progression per IWG criteria for altering natural history of 
MDS (Cheson, 2006; Appendix E).
Serial measurements of safety and efficacy will continue on scheduled study visits (Day 1 of 
every treatment cycle) in the Extension Phase of the Treatment Period.  Refer to Section 6 for 
full list of study procedures/assessments.
Best supportive care (BSC) may continue to be used in combination with study treatment when 
clinically indicated per investigator. See Section 8 for more information on best supportive
care/concomitant medications.
The same dose titration, delay and/or reduction, and treatment discontinuation criteria will still 
apply in the Extension Phase of the Treatment Period.  See Section 7.2.1 for dose modification 
rules and Section 11.2 for discontinuation criteria.
All subjects who have received at least one dose of study treatment should undergo end of
treatment (EOT) evaluations when IP is discontinued.  The reason for discontinuation will be 
recorded in the electronic case report form (eCRF) pages and in the source document.
Posttreatment Follow-up Period
All AEs will be recorded by the Investigator from the time the subject signs informed consent 
until 42 days after the last dose of IP as well as those serious adverse events (SAEs) made known 
to the Investigator at any time thereafter that are suspected of being related to IP. 
Transfusion data collection will continue up until 16 weeks from the date of last dose of IP or the 
End of Treatment Visit (whichever is later).  
Females of childbearing potential (FCBPs) will be advised to avoid becoming pregnant during 
study and for 12 weeks after the last dose of IP.  Males will be advised to use a latex condom 
during any sexual contact with FCBP prior to starting investigational product and continue for 
12 weeks following the last dose of IP, even if he has undergone a successful vasectomy.  Refer 
to Section 10.
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
37
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
For subjects who do not complete the Primary Treatment Phase or do not participate in the 
Extension Phase or subjects who terminate the Extension Phase with less than 1-year of ADA 
monitoring, ADA and PK samples will be collected at EOT and then every 12 weeks for up to 
one year from the first dose in the Primary Treatment Phase (please refer to Section 6.4 and 
Section 6.5).
Long-Term Follow-up: Progression to AML, Other Malignancies/Pre-malignancies, 
Subsequent MDS Therapies, Overall Survival
For all subjects who receive at least one dose of IP, continuation of monitoring for progression to 
AML and other malignancies/pre-malignancies (please refer to Section 10.5 for details) will 
occur in the Posttreatment Follow-up Period along with data collection of subsequent MDS 
therapies, and overall survival for at least 3 years from the date of last dose of IP unless the 
subject withdraws consent from the study, dies or is lost to follow-up.  Refer to Section 6.1 for 
additional details.
Data Monitoring Committee (DMC)
An external, independent DMC will be comprised of experts in MDS not involved in the 
ACE-536-MDS-001 study, an independent Geriatrician/Hypertension Expert, and an 
independent Statistician, and may include additional ad hoc members. Representatives of the 
Sponsor may attend the blinded part of the DMC meetings. The Sponsor will not have access to 
unblinded data during DMC meetings. 
Operational details for the DMC will be detailed in the DMC charter.  Refer to Section 9.11.2 for 
additional details.
Steering Committee
A Steering Committee (SC) will be established by charter for this study.  The Steering 
Committee will be comprised of Study Investigators and Sponsor representatives, and may 
include additional ad hoc members.  The Steering Committee will review blinded data. The SC 
will serve in an advisory capacity to the Sponsor.  
Operational details for the SC will be detailed in a separate SC charter. Refer to Section 9.11.3
for additional details.  
Note: The SC is separate from the DMC.
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will be deta
will be det
te fro
e from th
the


EDMS Doc. Number
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
38
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
Figure 2:
Overall Study Design
SCREENING PERIOD
Posttreatment 
FOLLOW-UP 
PERIOD           
STUDY DISCON
a Historical documentation of RBC transfusion dependence should be available (RBC units transfused and pre-transfusion Hgb values) for at least 16 weeks prior to 
randomization.  Refer to Section 6 for additional details.
b Dose may be titrated up to a maximum of 1.75 mg/kg.  Refer to Section 7.2.1.1 for additional details.
c After completion of the Week 25 Visit MDS Disease Assessment by the investigator, subjects experiencing clinical benefit and have not experienced disease progression per 
IWG criteria for altering natural history of MDS (Cheson, 2006; Appendix E), may continue double-blind treatment with IP beyond the Week 25 Visit in the Extension Phase of 
the Treatment Period until meeting protocol discontinuation criteria.  Refer to Section 6 and Section 11 for additional details.
d MDS Disease Assessment will be repeated by the investigator at Extension Cycle 8, Day 1 and Day 1 of every eighth Extension Cycle thereafter (ie, Extension Cycle 8, 16, 24+, 
etc. or every 24 weeks in the event of dose delays) until the subject is discontinued from treatment.  For subjects to continue double-blind treatment in the Extension Phase of the 
Treatment Period, each MDS Disease Assessment (criteria detailed in Section 6.2.2) should confirm continued clinical benefit and absence of disease progression per IWG 
criteria for altering natural history of MDS (Cheson, 2006; Appendix E). Refer to Section 6 for additional details.
OR
Luspaterceptb
starting dose  
1.0mg/kgb
OR
Placebob
Subcutaneous 
injection on D1 of 
each 21-day 
Treatment Cycle
R
a
n
d
o
m
i
z
a
t
i
o
n
Subjects 
who 
provide 
signed 
informed 
consent 
and meet 
eligibility 
criteria 
End of Treatment
AE Reporting 
Window until 42 days 
after last dose of IP
Continue double-
blind treatment b, d 
MDS Disease Status 
Assessment every 
eighth Extension 
Cycle (24 weeks)
MDS Disease 
Assessment c  
Week 25 Visit
24 calendar 
weeks after first 
dose, regardless 
of dose delays
2:1 randomization
210 subjects
Collection of 
transfusion data for 
at least 16 weeks after
last dose of IP or until 
End of Treatment 
visit (whichever is 
later)
Monitor for Other 
Malignancies/Pre-
malignancies, 
progression to AML, 
OS, and subsequent 
MDS therapies for at 
least 3 years from last 
dose of IP unless the 
subject withdraws 
consent from the 
study, dies or is lost to 
follow-up
Double-Blind TREATMENT PERIOD
Primary Phase
(24 weeks)
Extension Phase
(After Week 25 Visit until Treatment Discon)
Study
Discontinuation 
5 weeks a
No Crossover
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
39
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
3.2.
Study Duration for Subjects 
After a Screening Period of up to 5 weeks, eligible subjects who are randomized to receive IP 
(either placebo or luspatercept) should continue double-blind treatment through at least the first 
24 calendar weeks of the study unless the subject experiences unacceptable toxicities, disease 
progression per IWG criteria for altering natural history of MDS (Cheson, 2006; Appendix E),
withdraws consent, or meets any other discontinuation criteria (Section 11).
Subjects who experience clinical benefit as determined by the Week 25 Visit MDS Disease 
Status Assessment (Section 6.2.2 ) may continue double-blind treatment beyond the Week 25 
Visit (ie, in the Extension Phase of the Treatment Period) until the subject experiences 
unacceptable toxicities, disease progression per IWG criteria for altering natural history of MDS 
(Cheson, 2006; Appendix E), withdraws consent, or meets any other discontinuation criteria 
(Section 11).
For all subjects who receive at least one dose of IP, continuation of monitoring for progression to 
AML and other malignancies/pre-malignancies (please refer to Section 10.5 for details) will 
occur in the Posttreatment Follow-up Period, along with subsequent MDS therapies, and overall 
survival for at least 3 years from the date of last dose of IP unless the subject withdraws consent 
from the study, dies or is lost to follow-up.
3.3.
End of Trial
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
post-treatment follow-up, or the date of receipt of the last data point from the last subject that is 
required for primary, secondary 
 analysis, as prespecified in the protocol
and/or SAP, whichever is the later date.
The Sponsor may end the trial when all key endpoints and objectives of the study have been 
analyzed, and the availability of a roll-over protocol exists into which any subjects remaining on 
study may be consented and continue to receive access to luspatercept and/or complete post-
treatment follow-up.  Such a protocol would be written for a compound that would not yet be 
commercially available.
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,(


EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
40
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
4.
STUDY POPULATION
4.1.
Number of Subjects 
Approximately 210 subjects with anemia due to IPSS-R very low, low, or intermediate MDS 
with ring sideroblasts who require RBC transfusions will be randomized worldwide.
4.2.
Inclusion Criteria
Subjects must satisfy the following criteria to be enrolled in the study:
1. Subject is ≥ 18 years of age the time of signing the informed consent form (ICF). 
2. Subject must understand and voluntarily sign an ICF prior to any study-related 
assessments/procedures being conducted. 
3. Documented diagnosis of MDS according to WHO/FAB classification that meets IPSS-R 
classification (Greenberg, 2012; Appendix D) of very low, low, or intermediate risk 
disease, and:
!
Ring sideroblast ≥ 15% of erythroid precursors in bone marrow or ≥5% (but < 15%) 
if SF3B1 mutation is present.
!
< 5% blasts in bone marrow
!
Peripheral blood WBC count < 13,000/μL 
4. Refractory or intolerant to, or ineligible for, prior ESA treatment, as defined by any one 
of the following:
!
Refractory to prior ESA treatment - documentation of non-response or response that 
is no longer maintained to prior ESA-containing regimen, either as single agent or 
combination (eg, with G-CSF); ESA regimen must have been either:
∀
recombinant human erythropoietin (rHu EPO) ≥ 40,000 IU/wk for at least 8 doses 
or equivalent; 
OR
∀
darbepoetin alpha ≥ 500 μg Q3W for at least 4 doses or equivalent; 
!
Intolerant to prior ESA treatment - documentation of discontinuation of prior ESA-
containing regimen, either as single agent or combination (eg, with G-CSF), at any 
time after introduction due to intolerance or an adverse event
!
ESA ineligible - Low chance of response to ESA based on endogenous serum 
erythropoietin level > 200 U/L for subjects not previously treated with ESAs 
5. If previously treated with ESAs or granulocyte colony-stimulating factor (G-CSF), 
granulocyte-macrophage colony-stimulating factor (GM-CSF), both agents must have 
been discontinued ≥ 4 weeks prior to date of randomization.
6. Requires RBC transfusions, as documented by the following criteria:
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or ESA
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or ESA
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or 
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aining regi
me after int
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ESA ine
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5.5. If pre
If pre
gr
gr


EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
41
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
!
average transfusion requirement of ≥ 2 units/8 weeks of pRBCs confirmed for a 
minimum of 16 weeks immediately preceding randomization.
!
Hemoglobin levels at the time of or within 7 days prior to administration of a RBC 
transfusion must have been ≤ 10.0 g/dL in order for the transfusion to be counted 
towards meeting eligibility criteria. 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 meeting eligibility 
criteria.  Refer to Section 8.1.2 for guidance on transfusions during the course of the 
study.  
!
no consecutive 56-day period that was RBC transfusion-free during the 16 weeks 
immediately preceding randomization
7. Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2 (Appendix G)
8. Females of childbearing potential (FCBP), defined 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), must:
!
Have two negative pregnancy tests as verified by the Investigator prior to starting 
study therapy (unless the screening pregnancy test was done within 72 hours of 
C1D1). Refer to Section 6.1 for additional details.  She must agree to ongoing 
pregnancy testing during the course of the study, and after end of study treatment. 
!
If sexually active, agree to use, and be able to comply with, highly effective 
contraception** without interruption, 5 weeks prior to starting investigational 
product, during the study therapy (including dose interruptions), and for 12 weeks
after discontinuation of study therapy. 
** Highly effective contraception is defined in this protocol as the following (information 
will also appear in the ICF): Hormonal contraception (for example, birth control pills, 
injection, implant, transdermal patch, vaginal ring); intrauterine device (IUD); tubal 
ligation (tying your tubes); or a partner with a vasectomy 
9. Male subjects must:
!
Agree to use a condom, defined as a male latex condom or nonlatex condom NOT 
made out of natural (animal) membrane (for example, polyurethane), during 
sexual contact with a pregnant female or a female of childbearing potential while 
participating in the study, during dose interruptions and for at least 12 weeks
following investigational product discontinuation, even if he has undergone a 
successful vasectomy. 
10. Subject is willing and able to adhere to the study visit schedule and other protocol 
requirements.
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10.0. Su
S


EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
42
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
4.3.
Exclusion Criteria
The presence of any of the following will exclude a subject from enrollment:
1. Prior therapy with disease modifying agents for underlying MDS disease (eg, immune-
modulatory drug [IMiDs such as lenalidomide], hypomethylating agents, or 
immunosuppressive therapy [IST]).
!
subjects who previously received hypomethylating agents (HMA) or lenalidomide 
may be enrolled at the investigator’s discretion contingent that the subject received no 
more than 2 doses of HMA or no more than 1 calendar week of treatment with 
lenalidomide.  The last dose must be ≥ 5 weeks from the date of randomization.  
2. Previously treated with either luspatercept (ACE-536) or sotatercept (ACE-011)
3. MDS associated with del 5q cytogenetic abnormality
4. 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.
5. Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or 
autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding
!
iron deficiency to be determined by serum ferritin ≤ 15 μg/L and additional testing if 
clinically indicated (eg, calculated transferrin saturation [iron/total iron binding 
capacity ≤ 20%] or bone marrow aspirate stain for iron). 
6. Prior allogeneic or autologous stem cell transplant
7. Known history of diagnosis of AML 
8. Use of any of the following within 5 weeks prior to randomization:
!
anticancer cytotoxic chemotherapeutic agent or treatment 
!
corticosteroid, except for subjects on a stable or decreasing dose for ≥ 1 week prior to 
randomization for medical conditions other than MDS
!
iron-chelating agents, except for subjects on a stable or decreasing dose for at least 8 
weeks prior to randomization
!
other RBC hematopoietic growth factors (eg, Interleukin-3)
!
investigational drug or device, or approved therapy for investigational use.  If the 
half-life of the previous investigational product is known, use within 5 times the half-
life prior to randomization or within 5 weeks, whichever is longer is excluded.
9. Uncontrolled hypertension, defined as repeated elevations of diastolic blood pressure 
(DBP) ≥ 100 mmHg despite adequate treatment.  
10. Absolute neutrophil count (ANC) < 500/μL (0.5 x 109/L)
11. Platelet count < 50,000/μL (50 x 109/L) 
12. Estimated glomerular filtration rate (eGFR) or creatinine clearance < 40 mL/min.
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i
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11
11


EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
43
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
13. Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT)
or alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT) ≥ 3.0 x 
upper limit of normal (ULN)
14. Total bilirubin ≥ 2.0 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% indirect bilirubin
15. Prior history of malignancies, other than MDS, unless the subject has been free of the 
disease (including completion of any active or adjuvant treatment for prior malignancy) 
for ≥ 5 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)
16. Major surgery within 8 weeks prior to randomization. Subjects must have completely 
recovered from any previous surgery prior to randomization
17. History of stroke, deep venous thrombosis (DVT), pulmonary or arterial embolism within 
6 months prior to randomization
18. Pregnant or breastfeeding females
19. Myocardial infarction, uncontrolled angina, uncontrolled heart failure, or uncontrolled 
cardiac arrhythmia as determined by the investigator within 6 months prior to 
randomization.  Subjects with a known ejection fraction ˂ 35%, confirmed by a local 
ECHO or MUGA performed within 6 months prior to randomization are excluded.
20. 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), known Human Immunodeficiency 
Virus (HIV), known evidence of active infectious Hepatitis B, and/or known evidence of 
active Hepatitis C.  Local testing confirming HIV, Hepatitis B, and Hepatitis C status 
should not have been performed earlier than 4 weeks from the date of ICF signature.
21. History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant 
proteins or excipients in the investigational product (see Investigator Brochure).
22. Subject has any significant medical condition, laboratory abnormality, psychiatric illness, 
or is considered vulnerable by local regulations (eg, imprisoned or institutionalized) that 
would prevent the subject from participating in the study.
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21.1. Hi
Hi


EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
44
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
23. Subject has any condition including the presence of laboratory abnormalities, which 
places the subject at unacceptable risk if he/she were to participate in the study.
24. Subject has any condition or concomitant medication that confounds the ability to 
interpret data from the study.
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
45
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
5.
TABLE OF EVENTS
Table 4:
Table of Events
Screening
Treatment Period1
Posttreatment Follow-up
! 42 Day Follow-up = Occurs 42 days 
after last dose of IP
! 12 Week Follow-up = Occurs 12 
Weeks after last dose of IP
! Long Term Follow-up = Occurs 
every 3 months after 12 Week 
Follow-Up until at least 3 years post 
last dose of IP
Primary Phase
First 24 weeks of double-blind 
treatment
Up to maximum of 8 Treatment 
Cycles 
(if no dose delays)
Week 251,2
Visit
24 calendar 
weeks after 
first dose 
regardless of 
dose delays.
Extension Phase
Continuation of double-
blind treatment beyond 
Week 25 Visit
EOT
Visit2
Day -35
Every 
Cycle
(ie,1,2,3
+ up to 
max 8 
cycles
Every 
Other 
Cycle
Only)
(ie, 1, 3,
5, 7)
Cycles
1 and 5
Only
Cycle 1
Only
Every 
Ext 
Cycle
12,2,3
+
Ext 
Cycle 4, 
8, 12+
Ext 
Cycle 8, 
16, 24+
42 Day 
Follow-
up2
12, 24, 
48
Week 
Follow-
up
Long Term 
Follow-up
End of 
Study 
to -1
Day 1
Day 1
Day 8
Day 15
Day 1
Day 1
Day 1
STUDY ENTRY AND GENERAL ASSESSMENTS
Informed Consent
X
--
--
--
--
--
--
--
--
--
--
--
--
--
Inclusion/Exclusion
evaluations
X
--
--
--
--
--
--
--
--
--
--
--
--
--
Physical Examination
X
X
X
X
X
Randomization3
X
--
--
--
--
--
--
--
--
--
--
--
--
--
Demographics 
X
--
--
--
--
--
--
--
--
--
--
--
--
--
Medical History
X
--
--
--
--
--
--
--
--
--
--
--
--
--
Prior ESA Therapies
X
--
--
--
--
--
--
--
--
--
--
--
--
--
Prior RBC and Platelet 
Transfusions4
X
--
--
--
--
--
--
--
--
--
--
--
--
--
INVESTIGATIONAL PRODUCT (IP)
IP Administration and 
Accountability15
--
X3
--
--
--
--
X
--
--
--
--
--
--
--
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42 Day Follo
42 Day Foll
after
after last
la
! 12 We
12 W
We
W
!
0$
ond 
nd 
t
EOT
EO
Vis
Vi
1 2
2,3,3
+
Ext 
Ext 
Cycle 4,
Cycl
8, 12
8, 12
,1
7$5< 1
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Da
Day 1
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7$
7$
--
(7
(7
(7
(
----
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3
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----
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52
--
-
--
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5
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( 35
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/


EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
46
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
Table 4:
Table of Events (Continued)
Screening
Treatment Period1
Posttreatment Follow-up
! 42 Day Follow-up = Occurs 42 days 
after last dose of IP
! 12 Week Follow-up = Occurs 12 
Weeks after last dose of IP
! Long Term Follow-up = Occurs 
every 3 months after 12 Week 
Follow-Up until at least 3 years post 
last dose of IP
Primary Phase
First 24 weeks of double-blind 
treatment
Up to maximum of 8 Treatment 
Cycles 
(if no dose delays)
Week 251,2
Visit
24 calendar 
weeks after 
first dose 
regardless of 
dose delays.
Extension Phase
Continuation of double-
blind treatment beyond 
Week 25 Visit
EOT
Visit2
Day -35
Every 
Cycle
(ie,1,2,3
+ up to 
max 8 
cycles
Every 
Other 
Cycle
Only)
(ie, 1, 3,
5, 7)
Cycles
1 and 5
Only
Cycle 1
Only
Every 
Ext 
Cycle
12,2,3
+
Ext 
Cycle 4, 
8, 12+
Ext 
Cycle 8, 
16, 24+
42 Day 
Follow-
up2
12, 24, 
48 
Week 
Follow-
up
Long Term 
Follow-up
End of 
Study 
to -1
Day 1
Day 1
Day 8
Day 15
Day 1
Day 1
Day 1
SAFETY ASSESSMENTS
ECOG Performance Status 
X
X
--
--
--
X
X
--
--
X
--
--
--
--
Urinalysis5
X
C1D1 and D1 of every fourth cycle in 
Primary Phase (eg, C1, C4, C8)
X
Ext C1D1, then D1 of 
every fourth Extension 
cycle until treatment 
discontinuation
X
--
--
--
--
Coombs’ test6
X
--
--
--
--
--
--
--
--
--
--
--
--
--
Assessment of 
HIV/HepB/HepC status6
X
--
--
--
--
--
--
--
--
--
--
--
--
--
ECG(12-lead)
X
--
--
C5D8 
only
--
--
--
--
--
X
--
--
--
--
Pregnancy Test and 
Counseling7
X
X
--
--
--
X
X
--
--
X
--
--
--
--
Adverse events 
Continuous, after signing informed consent until 42 days after last IP administration
--
--
--
Prior and Concomitant 
medications/procedures 
X
Continuous, until 42 days after last IP administration or until the EOT visit, whichever occurs later
--
--
--
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
47
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
Table 4:
Table of Events (Continued)
Screening
Treatment Period1
Posttreatment Follow-up
! 42 Day Follow-up = Occurs 42 days 
after last dose of IP
! 12 Week Follow-up = Occurs 12 
Weeks after last dose of IP
! Long Term Follow-up = Occurs 
every 3 months after 12 Week 
Follow-Up until at least 3 years post 
last dose of IP
Primary Phase
First 24 weeks of double-blind 
treatment
Up to maximum of 8 Treatment 
Cycles 
(if no dose delays)
Week 251,2
Visit
24 calendar 
weeks after 
first dose 
regardless 
of dose 
delays.
Extension Phase
Continuation of double-
blind treatment beyond 
Week 25 Visit
EOT
Visit2
Day -35
Every 
Cycle
(ie,1,2,3
+ up to 
max 8 
cycles
Every 
Other 
Cycle
Only)
(ie, 1, 3,
5, 7)
Cycles
1 and 5
Only
Cycle 1
Only
Every 
Ext 
Cycle
12,2,3+
Ext 
Cycle 4, 
8, 12+
Ext 
Cycle 8, 
16, 24+
42 Day 
Follow-
up2
12, 24, 
48 
Week 
Follow-
up
Long Term 
Follow-up
End of 
Study 
to -1
Day 1
Day 1
Day 8
Day 15
Day 1
Day 1
Day 1
Vital Signs (Height to be 
measured only at screening; 
Weight to be measured only 
at screening and prior to each 
IP administration)
X
X
--
X
X
X
X
--
--
X
--
--
--
--
Serum Chemistry8
X
X
--
--
--
X
X
--
--
X
--
--
--
--
EFFICACY ASSESSMENTS
Hematology9, 15
X
X
--
X
X
X
X
--
--
X
--
--
--
--
Serum EPO
X10
--
X
--
--
X
--
--
--
X
--
--
--
--
Serum Ferritin
X11
X11
--
--
--
X
--
X
--
X
--
--
--
--
Transfusion Data Collection 
and Assessment
Assess and record on ongoing basis (prior to each dose of IP) until 16 weeks after last dose of IP or the End of Treatment Visit, 
whichever occurs later. Clinical site staff should confirm if any transfusions were received by the subject (including any at outside local 
institutions in between study visits) prior to each IP administration via use of patient diary or other local procedure in place at the 
investigational site.
--
MDS Disease Assessment12
--
--
--
--
--
X
--
--
X
X
--
--
--
--
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
48
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
Table 4:
Table of Events (Continued)
Screening
Treatment Period1
Posttreatment Follow-up
! 42 Day Follow-up = Occurs 42 days 
after last dose of IP
! 12 Week Follow-up = Occurs 12 
Weeks after last dose of IP
! Long Term Follow-up = Occurs 
every 3 months after 12 Week 
Follow-Up until at least 3 years post 
last dose of IP
Primary Phase
First 24 weeks of double-blind 
treatment
Up to maximum of 8 Treatment 
Cycles 
(if no dose delays)
Week 251,2
Visit
24 calendar 
weeks after 
first dose 
regardless of 
dose delays.
Extension Phase
Continuation of double-
blind treatment beyond 
Week 25 Visit
EOT
Visit2
Day -35
Every 
Cycle
(ie,1,2,3
+ up to 
max 8 
cycles
Every 
Other 
Cycle
Only)
(ie, 1, 3,
5, 7)
Cycles
1 and 5
Only
Cycle 1
Only
Every 
Ext 
Cycle
12,2,3
+
Ext 
Cycle 4, 
8, 12+
Ext 
Cycle 8, 
16, 24+
42 Day 
Follow-
up2
12, 24, 
48 
Week 
Follow-
up
Long Term 
Follow-up
End of 
Study 
to -1
Day 1
Day 1
Day 8
Day 15
Day 1
Day 1
Day 1
Bone Marrow Aspirate
(BMA) and Peripheral Blood 
for cytomorphology and 
cytogenetic testing13
BM 
Biopsy 
and
Aspirate 
Required
--
--
--
--
X
--
--
X
X
--
--
--
--
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EDMS Doc. Number
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
49
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
Table 4:
Table of Events (Continued)
Screening
Treatment Period1
Posttreatment Follow-up
! 42 Day Follow-up = Occurs 42 days 
after last dose of IP
! 12 Week Follow-up = Occurs 12 
Weeks after last dose of IP
! Long Term Follow-up = Occurs 
every 3 months after 12 Week 
Follow-Up until at least 3 years post 
last dose of IP
Primary Phase
First 24 weeks of double-blind 
treatment
Up to maximum of 8 Treatment 
Cycles 
(if no dose delays)
Week 251,2
Visit
24 calendar 
weeks after 
first dose 
regardless of 
dose delays.
Extension Phase
Continuation of double-
blind treatment beyond 
Week 25 Visit
EOT
Visit2
Day -35
Every 
Cycle
(ie,1,2,3
+ up to 
max 8 
cycles
Every 
Other 
Cycle
Only)
(ie, 1, 3,
5, 7)
Cycles
1 and 5
Only
Cycle 1
Only
Every 
Ext 
Cycle
12,2,3
+
Ext 
Cycle 4, 
8, 12+
Ext 
Cycle 8, 
16, 24+
42 Day 
Follow-
up2
12, 24, 
48
Week 
Follow-
up
Long Term 
Follow-up 
End of 
Study 
to -1
Day 1
Day 1
Day 8
Day 15
Day 1
Day 1
Day 1
PK and ADA
PK Sample Collection 
Refer to Section 6.4
--
C1,2,4,
6,8 
Only
--
X
X
X
Extension C4D1 and D1 
of every 4th Extension 
Cycle thereafter (eg, Ext. 
C4, C8, etc.) for up to one 
year from the first dose in 
the Primary Treatment 
Phase.
X18
--
X18
--
--
ADA Sample Collection
Refer to Section 6.5
--
C1,2,4,
6,8 
Only
--
--
--
X
Extension C4D1 and D1 
of every 4th Extension 
Cycle thereafter (eg, Ext. 
C4, C8, C12 C16+, etc.) 
for up to one year from 
the first dose in the 
Primary Treatment Phase.
X18
--
X18
QUALITY OF LIFE 
EORTC QLQ-C30 
 Questionnaire Completion
X
--
X16
--
--
X
Day 1 of Every Other Ext. 
Cycle 
(Ext. C1,C3, C5+, etc.)
X
--
--
--
--
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
50
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
Table 4:
Table of Events (Continued)
Screening
Treatment Period1
Posttreatment Follow-up
! 42 Day Follow-up = Occurs 42 days 
after last dose of IP
! 12 Week Follow-up = Occurs 12 
Weeks after last dose of IP
! Long Term Follow-up = Occurs 
every 3 months after 12 Week 
Follow-Up until at least 3 years post 
last dose of IP
Primary Phase
First 24 weeks of double-blind 
treatment
Up to maximum of 8 Treatment 
Cycles 
(if no dose delays)
Week 251,2
Visit
24 calendar 
weeks after 
first dose 
regardless of 
dose delays.
Extension Phase
Continuation of double-
blind treatment beyond 
Week 25 Visit
EOT
Visit2
Day -35
Every 
Cycle
(ie,1,2,3
+ up to 
max 8 
cycles
Every 
Other 
Cycle
Only)
(ie, 1, 3,
5, 7)
Cycles
1 and 5
Only
Cycle 1
Only
Every 
Ext 
Cycle
12,2,3
+
Ext 
Cycle 4, 
8, 12+
Ext 
Cycle 8, 
16, 24+
42 Day 
Follow-
up2
12, 24, 
48 
Week 
Follow-
up
Long Term 
Follow-up
End of 
Study 
to -1
Day 1
Day 1
Day 8
Day 15
Day 1
Day 1
Day 1
FOLLOW UP 
Monitoring for progression to 
AML and other 
malignancies/pre-
malignancies 17
(Refer to Section 10.5 for 
details)
After signing ICF and until at least 3 years post last dose of IP or until death, lost to follow-up, withdrawal of consent for further data collection.
Posttreatment MDS 
therapies17
--
--
--
--
--
--
--
--
--
--
X
X
X
X
Survival Follow-up17
--
--
--
--
--
--
--
--
--
--
X
X
X
X
1 Window of +/- 3 days is allowed during Treatment Period.  A window of +/- 14 days is allowed for the Week 25 Visit (Section 6.2.2).  A window of +/- 14 days is allowed for 
Posttreatment Long-term Follow-up Assessments (ie, OS, Progression to AML, other malignancies/pre-malignancies (please refer to Section 10.5 for details), subsequent MDS 
therapies).
2 Week 25 Visit and Extension Cycle 1 Visit procedures/assessments may not need to be repeated if previously performed within +/-7 days of the scheduled visit.  End of 
Treatment (EOT) Visit procedures/assessments may not need to be repeated if previously performed within +/-7 days of EOT visit.  If a subject is discontinued during a regular 
scheduled visit, all EOT procedures should be completed at that visit. End of Treatment (EOT) Visit procedures/assessments may occur at 42 Day Follow-up assessment if 
subject is discontinued within +/- 7 days of 42 Day Follow-up assessment.
3 Randomization via IRT.  The first dose of IP should be administered after, but within 3 days of randomization and can be on the same day as randomization. Refer to the IRT 
manual for additional information on randomization utilizing IRT.  Documentation must be complete to confirm an average RBC transfusion requirement of at least 2 units of 
packed red blood cells (pRBCs) per 8 weeks during the 16 weeks immediately preceding randomization. Hemoglobin levels at the time of or within 7 days prior to 
administration of a RBC transfusion must have been ≤ 10.0 g/dL in order for the transfusion to be counted towards meeting eligibility criteria. 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 meeting 
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
51
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
eligibility criteria.  There must also not be any consecutive 56-day period that was RBC transfusion free during the 16 weeks immediately preceding randomization.  Refer to 
Section 4.2.
4 Subjects must have at least 16 weeks documented transfusion history prior to randomization. This transfusion data includes hemoglobin measured prior to transfusion 
(pretransfusion Hgb).  Refer to Section 6.1.
5 Urinalysis assessed centrally and to include microscopic, quantitative analysis of urine. (eg, microalbumin/albumin, protein, creatinine, microalbumin/creatinine ratio).
6 A local Coomb’s test is only performed if total bilirubin > 2 x ULN (see Section 4.3).  If positive, a local reticulocyte count may be requested.  Local test results confirming 
known Human Immunodeficiency Virus (HIV), Hepatitis B, Hepatitis C status should not have been performed earlier than 4 weeks from the date of ICF signature.  If beyond 
this window, additional local testing may be requested (see Section 4.3).
7 Pregnancy test is required for all female subjects of childbearing potential.  Serum beta human chorionic gonadotropin (β-hCG) will be performed at screening.  A urine (or 
serum) pregnancy test will be repeated prior to the first administration of IP on C1D1, unless the screening pregnancy test was done within 72 hours of C1D1. During the 
Treatment Period, urine or serum pregnancy test is allowed. For males and FCBP, counseling about pregnancy precautions and the potential risks of fetal exposure must be 
conducted prior to each IP administration or on a monthly basis (eg, in the event of dose delays). Refer to Section 6.1 for additional details.
8 Serum chemistry (eg, sodium, potassium, chloride, bicarbonate [if available], calcium, magnesium, phosphorus, blood urea nitrogen [BUN], creatinine, creatinine clearance 
and/or estimated glomerular filtration rate, glucose, albumin, total protein, alkaline phosphatase, direct/indirect total bilirubin, AST/SGOT or ALT/SGPT, lactate 
dehydrogenase [LDH], uric acid) will be analyzed by the central laboratory.  Refer to Section 6.1. 
9 Hematology assessment (eg, red blood cell [RBC] count, complete blood count [CBC], white blood cell [WBC] with differential, hemoglobin, hematocrit, nucleated red blood 
cells [nRBC], absolute reticulocyte count, platelet count, mean corpuscular volume [MCV], mean corpuscular hemoglobin [MCH], mean corpuscular hemoglobin concentration 
[MCHC], and red blood cell distribution width [RDW]) will be tested by the central laboratory.  Refer to Section 6.1.  
10EPO will be assessed centrally.  During the Screening Period, the serum EPO level should be collected on the same day as a planned RBC transfusion, prior to the transfusion 
or 7 days after any RBC transfusion due to possible reduction of the serum level related to the hemoglobin level achieved after the last transfusion. 
11Serum ferritin will be assessed centrally. Sample should be collected within 5 weeks prior to randomization. Sample should be collected prior to administration of IP.  
Additional serum ferritin results from previous local laboratory assessments (ie, within the 16 week window immediately prior to randomization date) should be collected, if 
available in the medical records, and entered into the eCRF.
12During the Treatment Period, MDS Disease Assessment (which includes investigator assessment of clinical benefit and MDS disease status) should be completed by the 
investigator in conjunction with bone marrow/peripheral blood sample collection for cytomorphology and cytogenetics collected at the Week 25 Visit.  For details related to the 
allowed time window related to procedures and assessments refer to Section 6.2.2.  Based on the outcome of the MDS Disease Assessment, subjects will either be discontinued
from treatment with IP and enter the Posttreatment Follow-Up Period or continue double-blind treatment with IP in the Extension Phase of the Treatment Period.  Refer to 
Section 6.2.3 for additional details.
13During the Screening Period, bone marrow biopsy AND bone marrow aspirate are required. The screening BMB should be performed within 5 weeks prior to randomization.  
The screening BMA should be collected within the protocol screening window.  After randomization, a bone marrow biopsy is collected only when adequate aspirate is not 
attainable.  During the Extension Phase of the Treatment Period: Bone marrow and peripheral blood samples to be collected at Extension Cycle 8, Day 1 and Day 1 of every 
eighth Extension Cycle thereafter (ie, Extension Cycle 8, 16, 24+, etc. or approximately every 24 weeks in the event of dose delays). Bone marrow samples at End of Treatment 
Visit: Perform only if visit is > 90 days from prior bone marrow procedure. Refer to central laboratory manual for additional information related to sample collection
 
 
  
 
.
15On dosing days, local laboratory sample should be collected and Hgb levels assessed prior to each IP administration to ensure dose modification rules are followed as outlined 
in Section 7.2.1.1, Table 6.  In these circumstances, a split sample should also be collected and sent to the central laboratory for analysis. Subjects must have blood pressure 
assessed (as detailed in Section 6.1) prior to each IP administration.
16If subject completed Screening EORTC QLQ-C30 
 questionnaires within 14 days prior to C1D1, it does not have to be repeated at C1D1. If performed on C1D1, 
both EORTC QLQ-C30 
 questionnaires should be completed by the subject prior to IP administration.
17Long-Term Posttreatment Follow-up for Overall Survival (OS), Progression to AML, other malignancies/pre-malignancies (please refer to Section 10.5 for details), and data
collection for subsequent MDS therapies may be conducted by record review (including public records if allowed by local regulations) and/or telephone contact with the 
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
52
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
subject, family, or the subject’s treating physician.  The investigator must make every effort to obtain information regarding the subject’s survival status before determining the 
subject is lost to follow-up.
18 Post-treatment Follow-up: For subjects who do not complete the Primary Treatment Phase or do not participate in the Extension Phase or subjects who terminate the Extension 
Phase with less than 1-year of ADA monitoring, ADA and PK samples will be collected at EOT and then every 12 weeks for up to one year from the first dose in the Primary 
Treatment Phase (please refer to Section 6.4 and Section 6.5 for details).
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
53
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
6.
PROCEDURES
Any questions regarding the protocol should be directed to the Celgene Medical Monitor or 
designee. 
All of the protocol required assessments are listed in Section 5, Table 4, with an “X” indicating 
at which visits the assessments are to be performed. All data obtained from these assessments 
must be recorded in the subject’s source documentation.  Except for the Week 25 Visit, all study
visits during the Treatment Period (both Primary and Extension Phases) must occur within 
± 3 days of the scheduled day.  A 14 day window is allowed for the Week 25 Visit (refer to 
Section 6.2.2 for details).  Week 25 Visit and Extension Cycle 1 Visit procedures/assessments 
may not need to be repeated if previously performed within ±7 days of the scheduled visit.  
End of Treatment Visit procedures/assessments may not need to be repeated if previously 
performed within ±7 days of EOT visit.  If a subject is discontinued during a regular scheduled 
visit, all EOT procedures should be completed at that visit.  End of Treatment Visit 
procedures/assessments may occur at 42 Day Follow-up assessment if subject is discontinued 
within ± 7 days of 42 Day Follow-up assessment.
A window of ± 14 days is allowed for Posttreatment Long-Term Follow-up assessments (ie, OS, 
progression to AML, other malignancies/pre-malignancies, subsequent MDS therapies).  
Procedures are described in detail below.
Subjects must have hemoglobin and blood pressure assessed prior to each IP administration. 
Blood pressure values should be confirmed by a mean of two readings obtained approximately 5
minutes apart with the subject seated for approximately 10 minutes prior to initial reading. 
Safety laboratory analyses and all laboratory assessments will be performed centrally (except 
otherwise stated in this section) during the Treatment Period.  
Local laboratories are allowed in cases when timely results are needed (eg, randomization, study 
treatment dosing decisions, hematology assessments between clinic visits, adverse event).  In 
these circumstances, a split sample should still be collected and sent to the central laboratory for 
analysis.  With prior sponsor consultation, local laboratories may also be used to determine study 
eligibility if central laboratory results are not available (eg, hemolyzed sample, etc.) or if there is 
a discrepancy between local and central laboratory results impacting study eligibility.  Local 
laboratory data should be collected in the eCRF if relevant to study eligibility determination, 
dose administration, dose modification, or an AE, significant discrepancy between local and 
central laboratory results (from samples collected at the same study time point), or when no 
central laboratory results were obtained.  
Refer to the eCRF completion guidelines for additional information related to data entry 
requirements of local laboratories.  
Sample collection, processing, storage, and shipment procedures will be provided in the Study 
Laboratory Manual.
6.1.
Screening Period
!
Signing of the ICF
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
54
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
!
Assessment of Inclusion/Exclusion Criteria For Study Eligibility
Screening evaluations will be performed for all subjects to determine study eligibility. These 
evaluations must be completed within 5 weeks of randomization (refer to Table of Events,
Section 5, Table 4 for further information). Screening laboratory values must demonstrate 
subject eligibility, but may be repeated within the screening window, if necessary.
Waivers to the protocol will not be granted during the conduct of this trial, under any 
circumstances.
The following assessments/procedures will be performed during the Screening Period as 
specified in the Table of Events, Table 4:
!
Bone Marrow and Peripheral Blood Samples
Screening MDS diagnosis confirmation requires both bone marrow biopsy (BMB), bone marrow 
aspirate (BMA), and peripheral blood samples. Samples may be reviewed locally, but must also
be sent to the central laboratory for analysis.
The screening BMB, BMA, and peripheral blood samples should be collected within the protocol 
screening window or 5 weeks prior to randomization.  If a subject is rescreened (eg, due to 
retesting of another lab), repeat bone marrow samples do not need to be collected contingent that 
initial samples were adequate for cytomorphology/cytogenetic assessment by the central 
laboratory. During the course of the study, whenever a bone marrow sample is collected, a 
peripheral blood smear is to be prepared.
Sample collection, processing, storage, and shipment procedures will be provided in the study’s 
Central Laboratory Manual.
!
Cytomorphology Assessment
Bone marrow and peripheral blood samples will be prepared locally and sent to the
central laboratory for analysis to confirm MDS diagnosis and baseline WHO
(Appendix B) and/or FAB classification (Appendix C) prior to randomization.  
If the central reviewer and local pathologist disagree on the diagnosis of a subject, a 
third reviewer at the central laboratory may be consulted to provide an adjudication 
assessment. The central laboratory may also request the site to send in samples 
reviewed by the local pathologist for further assessment.
!
Cytogenetics Analysis
The central laboratory will conduct cytogenetic analysis throughout the study. The 
central laboratory will provide standardized analysis and reporting for all subjects. 
Bone marrow samples will be sent to the central laboratory for processing and 
cytogenetic analysis prior to randomization.
In the event that cytomorphology/cytogenetic analysis cannot be performed by the central 
laboratory prior to randomization, local cytomorphology/cytogenetic analysis may suffice for
randomization purposes after consultation with the Sponsor. Every attempt should be made to
send bone marrow and peripheral blood samples to the central laboratory for processing and
analysis prior to the first dose of investigational product. If this does not occur, a central “over
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
55
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
read” of the cytomorphology/cytogenetics report and photographs will be performed (at a later
date) by the central laboratory.
Results from central laboratory analysis should be used to determine baseline IPSS-R category 
(Greenberg, 2012; Appendix D).  
The central laboratory will also assess bone marrow and peripheral blood samples during the 
Treatment Period of the study.
 
Refer to Section 6.11 for additional information and Table 4 for timing of sample collection 
during the study.
!
Prior Transfusion History
Transfusion history must be available for at least the 16 weeks immediately preceding and 
including the date of randomization. Transfusion data should include the type of transfusion (eg, 
RBC, platelets), number of units, reason and date of transfusion.  
Transfusion data should also include the pretransfusion Hgb levels that triggered the RBC 
transfusions. 
These Hgb levels can be from local or central laboratory measurements.  For platelet 
transfusions, data should include the platelet value for which theplatelet transfusion was 
administered. These platelet values can be from the central or a local laboratory. 
Documentation of the following criteria is required to meet protocol inclusion criteria and must 
be confirmed prior to randomization:
!
Average transfusion requirement of at least 2 units of packed red blood cells (pRBCs) 
per 8 weeks during the 16 weeks immediately preceding randomization.  Only RBC 
transfusions administered due to a pre-transfusion Hgb of ≤ 10 g/dL will counted to 
determine eligibility.
!
There must also not be any consecutive 56-day period that was RBC transfusion free 
during the 16 weeks immediately preceding randomization.
All RBC transfusion records for at least 16 weeks immediately preceding and including the date 
of randomization should be collected (including any transfusions at outside local institutions).  
Red blood cell (RBC) transfusions administered for elective surgery will not count towards 
meeting RBC transfusion inclusion criteria requirements, but should still be recorded in the 
eCRF.  
The RBC transfusion data during the 16 weeks immediately preceding randomization will be
used to determine the baseline RBC transfusion requirement for an individual study subject.  
Thus, this information must be collected during the Screening window (prior to randomization). 
!
Prior Erythropoiesis-stimulating agent (ESA) Therapies
Type of ESA, dose, frequency, duration, best response, and reason for discontinuation should be 
collected and entered into the eCRF regardless of date of discontinuation.  
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
56
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
Eligible subjects must also be refractory or intolerant to prior ESA treatment, or ineligible for, 
ESA treatment.  See Section 4.2 for additional details.
!
Demographics and Medical History
The subject’s date of birth, sex, race and ethnicity will be recorded on the appropriate eCRF.
Relevant medical history (including recent surgical history) and current medical conditions, 
including those symptoms related to MDS, must also be recorded on the appropriate eCRF at 
screening. 
History of MDS disease and other prior malignancies will also be recorded on the appropriate
eCRF. This may include relevant information related to original MDS diagnosis (eg, date of 
original diagnosis, WHO and/or FAB classification at original diagnosis, prior treatments 
administered) and/or other past malignancies. 
Historic serum ferritin results from previous local laboratory reports (ie, within the 16 week 
window immediately prior to randomization date) will be also collected, if available in the 
medical records, and entered on the appropriate eCRF.
!
Concomitant Medications and Procedures 
All prior/concomitant medications taken in the 5 weeks prior to randomization will be recorded 
onthe appropriate eCRF(s).
All prior/concomitant procedures within the 8 weeks prior to randomization will be recorded on 
the appropriate eCRF(s).
Prior G-CSF/GM-CSF and iron chelation therapy should be recorded on the appropriate eCRF(s) 
regardless of treatment discontinuation date.
Prior anti-cancer treatments should be recorded on the appropriate eCRF(s) regardless of 
treatment discontinuation/procedure date.
Record concomitant medications/procedures on ongoing basis until 42 days post last dose of IP
or End of Treatment (EOT), whichever occurs later.  Refer to Section 8 for additional details.
!
Physical Examination
Information about the physical examination must be present in the subject’ssource 
documentation.  Significant findings must be included on the appropriate eCRF.
Refer to Table 4 for timing of physical examinations during the study.
!
Eastern Cooperative Oncology Group Performance Status
Performance status will be assessed by the investigator during Screening and at other timepoints
indicated on Table 4 using ECOG criteria provided in Appendix G.
!
Electrocardiogram
Electrocardiogram (ECG) at screening is performed locally at the study site. ECG will be 
performed using the internationally recognized 12-leads. If available, the following ECG 
parameters will be recorded on the respective eCRF(s): eg, heart rate (HR), PR interval, QRS 
duration, QT, QTc. The investigator will review the results and assess as normal, abnormal - not 
clinically significant, or abnormal - clinicallysignificant, and report the abnormal finding(s) on 
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
57
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
the appropriate eCRF. If the ECG is abnormal, the investigator should consult a cardiologist if
deemed appropriate.
Refer to Table 4 for timing of ECGs during the Treatment Period of the study.
!
Urinalysis
Urinalysis to include microscopic, quantitative analysis of urine. (eg, microalbumin/albumin, 
protein, creatinine, microalbumin/creatinine ratio).  
Microscopic urinalysis will be tested by the central laboratory.  
Refer to Table 4 for timing of urinalysis sample collection during the Treatment Period of the 
study.
!
Coombs’ Test
A direct or indirect Coombs’ test at screening is performed at the locallaboratory if screening 
total bilirubin is ≥ 2.0 x ULN.  Refer to Section 4.3.  If positive, a local reticulocyte count may 
be requested.
!
Assessment of HIV/Hepatitis B/Hepatitis C status 
If known, local test results confirming HIV, Hepatitis B, Hepatitis C status should not have been 
performed earlier than 4 weeks from the date of ICF signature.  If beyond this window, 
additional local testing may be requested (see Section 4.3).
!
Serum Ferritin
Sample should be collected within 5 weeks prior to randomization. 
Serum ferritin analysis is to be performed by the central laboratory. 
Additional serum ferritin results from previous local laboratory assessments (ie, within the 16 
week window immediately prior to randomization date) should be collected, if available in the 
medical records, and entered into the eCRF.
Refer to Table 4 for timing of serum ferritin testing during the study.
!
Serum EPO Level
During the Screening Period, the serum EPO level should be collected on the same day as a
planned RBC transfusion, prior to the transfusion or 7 days after any RBC transfusion due to 
possible reduction of the serum level related to the hemoglobin level achieved after the last 
transfusion. 
Serum EPO analysis is to be performed by the central laboratory.  
Refer to Table 4 for timing of serum EPO level testing duringthe study.
!
Hematology Panel
Hematology assessment (eg, red blood cell [RBC] count, complete blood count [CBC], white 
blood cell [WBC] with differential, hemoglobin, hematocrit, nucleated red blood cells [nRBC], 
absolute reticulocyte count, platelet count, mean corpuscular volume [MCV], mean corpuscular 
hemoglobin [MCH], mean corpuscular hemoglobin concentration [MCHC], and red blood cell 
distribution width [RDW]) will be tested by the central laboratory.  
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
58
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
On dosing days, local laboratory sample should be collected and Hgb levels assessed prior to 
each IP administration to ensure dose modification rules are followed as outlined in Section 
7.2.1.1, Table 6.  In these circumstances, a split sample should also be collected and sent to the 
central laboratory for analysis.  
Refer to Table 4 for timing of hematologyassessments during the study.  
!
Serum Chemistry Panel
Serum chemistry (eg, sodium, potassium, chloride, bicarbonate [if available], calcium, 
magnesium, phosphorus, blood urea nitrogen [BUN], creatinine,creatinine clearance and/or 
estimated glomerular filtration rate, glucose, albumin, total protein, alkaline phosphatase,
direct/indirect total bilirubin, AST/SGOT or ALT/SGPT, lactatedehydrogenase [LDH], uric 
acid) will be analyzed by the central laboratory.  
Refer to Table 4 for timing of serum chemistry assessments during the study. 
!
Pregnancy Testing and Counseling 
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 naturallypostmenopausal
(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).
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.  
The investigator will appraise a female subject as a FCBP according to this definition.  
Justification must be recorded in the eCRF and the source document. Pregnancy testing is not 
required for non-FCBP subjects.
Serum beta human chorionic gonadotropin (β-hCG) pregnancy test (which must be negative) 
with a minimum sensitivity of 25 mIU/mL will be performed within 5 weeks prior to Dose 1 Day 
1. Urine (or serum) pregnancy test will be performed to assess subject eligibility within 72 hours 
prior to the first administration of IP, if the initial serum pregnancy test did not already occur 
with 72 hours of dosing (negative results required for IP administration). 
During the Treatment Period urine or serum pregnancy test is allowed. 
For males and FCBP, counseling about pregnancy precautions and the potential risks of fetal 
exposure must be conducted prior to each IP administration or monthly (eg, in the event of dose 
delays).  Refer to Section 10.4 for additional details.
Refer to Table 4 for timing of pregnancy testing and counseling during the study.
!
Vital Signs, Height, and Weight
Vital signs, including height (measured at Screening only), weight (at Screening and on study 
drug dosing days only), seated blood pressure, temperature, heart rate, and respiratory rate. 
On study drug dosing days, blood pressure must be assessed prior to each IP administration.  
Blood pressure values should be confirmed by mean of two readings obtained approximately 5 
minutes apart with the subject seated for approximately 10 minutes prior to initial reading. 
Refer to Table 4 for timing of vital signs during the study.
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
59
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
!
Adverse Event Assessment - record on ongoing basis
Refer to Section 10.1.
!
Subject Reported Outcomes or Quality of Life or Health Economics (EORTC
QLQ-C30 
Refer to Section 6.12.
!
!
Randomization in Integrated Response Technology (IRT)
In addition to demographic information, the following information should be readily available 
prior to performing the randomization transaction in the IRT system: 
!
Baseline IPSS-R risk category (Greenberg, 2012; Appendix D)
!
Average 8-week baseline RBC transfusion requirement.
The first dose of IP should be administered after, but within 3 days of randomization and can be 
on the same day as randomization.  Refer to the IRT manual for additional information on 
randomization utilizing IRT.
!
Monitoring for Progression to AML and Other Malignancies/Pre-malignancies
Progression to AML as per WHO classification (Vardiman, 2009) will be monitored and will be 
included as part of the safety assessment throughout the course of the study.  Progression to 
AML should be monitored from time of signing of informed consent through at least 3 years 
after last dose of IP or until death, lost to follow-up or withdrawal of consent from the study. 
The occurrence of a new malignancy or pre-malignant lesion will be monitored as an event of 
interest and should be included as part of the assessment of adverse events throughout the course 
of the study (please refer to Section 10.5 for details). Investigators are to report the development 
of any new malignancy or pre-malignant lesion as a serious adverse event, regardless of causal 
relationship to IP (study drug[s] or control), occurring at any time for the duration of the study, 
from the time of signing the ICF for up to and including at least 3 years of long-term follow-up, 
or until death, lost to follow-up, or withdrawal of consent for further data collection.
Documentation supporting the diagnosis of progression to AML and other malignancies/pre-
malignancies (eg, confirmatory histology or cytology results, etc.) may be requested.  
Appropriate information related diagnosis of AML and other malignancies/pre-malignancies 
should be captured on the eCRF and in the subject’s source documents.  
Refer to Section 10.5 and Section 10.6 for more information regarding reporting requirements.  
6.2.
Treatment Period
The subject will begin treatment upon confirmation of eligibility. The subject must start 
treatment within 5 weeks of signing the informed consent form (ICF).  If screening assessments 
are performed within 72 hours of Cycle 1 Day 1 (C1D1), safety laboratory and physical 
examinations need not be repeated at C1D1 with the exception of blood pressure measurement, 
hematology, serum ferritin, and serum EPO sample collection.  
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
60
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
If subject completed the Screening EORTC QLQ-C30 
 questionnaires within 2 
weeks of C1D1, it does not have to be repeated at C1D1. If performed on C1D1, both EORTC
QLQ-C30 
 questionnaires should be completed by the subject prior to IP 
administration.
On dosing days, local laboratory hgb levels should be assessed prior to each IP administration to 
ensure dose modification rules are followed as outlined in Section 7.  In these circumstances, a 
split sample should also be collected and sent to the central laboratory for analysis.  Subjects 
should also have blood pressure assessed (as detailed in Section 6.1) and the clinical site should 
confirm with the subject if any transfusions were received at outside local centers in between 
study visits, prior to each IP administration.
6.2.1.
Primary Phase of the Treatment Period: Weeks 1-24
Subjects will receive IP (either luspatercept or matching placebo) on Day 1 of each 21-day 
treatment cycle.
Treatment cycles are 21 days in duration, and will occur as described in Section 7.2.
The following procedures/evaluations will be performed at the frequency specified in the Table 
of Events (Table 4) during the Primary Phase of the Treatment Period. The 
procedures/evaluations should be performed prior to dosing on the visit day, unless otherwise 
specified:  
!
IP administration and accountability
!
Eastern Cooperative Oncology Group Performance Status (as detailed in Section 6.1)
!
Pregnancy Testing and Counseling (as detailed in Section 6.1)
!
PK and ADA sample collection (as detailed in Section 6.4 and Section 6.5)
!
ECG (as detailed in Section 6.1)
!
Physical Examination (as detailed in Section 6.1)
!
Vital Signs (as detailed in Section 6.1)
!
Hematology Panel (as detailed in Section 6.1)
!
Serum Chemistry Panel (as detailed in Section 6.1)
!
Urinalysis (as detailed in Section 6.1)
!
Serum EPO Level (as detailed in Section 6.1)
!
Serum Ferritin (as detailed in Section 6.1)
!
Transfusion Data Collection and Assessment
During the study, the following will be recorded for all transfusions (including any transfusions 
received at outside institutions in between study visits) the subject received within 16 weeks 
prior to randomization, until 16 weeks after the last dose of IP or the End of Treatment (EOT) 
visit, whichever occurs later:
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
61
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
∀
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!
Clinical site staff should confirm if any transfusions were received by the subject 
(including any at outside local institutions in between study visits) prior to each IP 
administration via use of patient diary or other local procedure in place at the 
investigational site.
!
Adverse Event Assessment to be assessed on an ongoing basis. Refer to Section 10.1.
!
Monitoring for Progression to AML and other malignancies/pre-malignancies on an 
ongoing basis.  Refer to Section 6.1.
!
Concomitant Medications and Procedures - record on ongoing basis. Refer to 
Section 8.  
!
Subject Reported Outcomes or Quality of Life (EORTC QLQ-C30 
). (as 
detailed in Section 6.12)
!
6.2.2.
MDS Disease Assessment: Week 25 Visit
Assessment of Transfusions, Bone Marrow, and Peripheral Blood
The MDS Disease Assessment consists of the investigator’s assessment of clinical benefit from 
study drug and status of underlying disease.
The first MDS Disease Assessment should be completed 24 calendar weeks after the date of 
first dose, regardless of dose delays. The calculated due date for the first MDS Disease 
Assessment is defined as C1D1 + 168 days (ie, 24 weeks). The MDS Disease Assessment by the 
investigator should be completed no sooner than 24 calendar weeks (ie, 168 days) after the day
of C1D1 and requires a minimum of 24-weeks of transfusion information for the assessment of 
clinical benefit.  Up to date information related to all transfusions received during the Treatment 
Period (including those received at outside institutions) must be available prior to completion of
the clinical benefit component of the MDS Disease Assessment.
As central laboratory results from bone marrow and peripheral blood samples (eg, 
cytomorphology, cytogenetics analysis) are required as part of the MDS Disease Assessment, a 
14-day window is allowed for the Week 25 Visit in order to account for sample collection and 
turnaround time of results.  
In order for subjects to remain on double-blind treatment beyond the first 24 calendar weeks, the 
following criteria must be confirmed upon the completion of the MDS Disease Assessment by 
the investigator:
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
62
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
!
Evidence of clinical benefit (eg, decrease in RBC transfusion requirement compared to 
baseline requirement or hemoglobin increase compared to baseline)
AND
!
Absence of disease progression per IWG criteria for altering natural history of MDS 
(Cheson, 2006; Appendix E).
Based on the outcome of the MDS Disease Assessment, subjects will either be discontinued from 
treatment with IP and enter the Posttreatment Follow-up Period or continue double-blind 
treatment with IP in the Extension Phase of the Treatment Period. 
For subjects that meet criteria to continue double-blind treatment in the Extension Phase, the 
duration between the last dose of IP in the Primary Phase and first Extension Phase dose should 
not be delayed beyond 21 days solely due to awaiting cytomorphology/cytogenetics results 
contingent that the investigator has confirmed absence of signs of disease progression based on 
review of peripheral blood parameters.  
In circumstances where the subject does receive the first Extension Phase dose prior to 
cytomorphology/cytogenetics results being available, the investigator must complete assessment 
of cytomorphology/cytogenetics results prior to the next IP administration.
A bone marrow biopsy is to be collected only when adequate aspirate is not attainable. Whenever 
a bone marrow sample is collected, a peripheral blood smear is to be prepared.  Refer to the
Central Laboratory Manual for additional information.
The following procedures/evaluations will also be performed at the Week 25 Visit:
!
!
Subject Reported Outcomes or Quality of Life (EORTC QLQ30 
) (as detailed 
in Section 6.12)
!
!
Transfusion Data Collection and Assessment (as detailed in Section 6.1)
!
Adverse Event Assessment - record on ongoing basis. Refer to Section 10.1.
!
Monitoring for Progression to AML and other malignancies/pre-malignancies on an 
ongoing basis.  Refer to Section 10.5.
!
Concomitant Medications and Procedures - record on ongoing basis.  Refer to Section 8.
!
Eastern Cooperative Oncology Group Performance Status (as detailed in Section 6.1)
!
Pregnancy Testing and Counseling (as detailed in Section 6.1)
!
PK and ADA Sample Collection (as detailed in Section 6.4 and Section 6.5)
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
63
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
!
Physical Examination (as detailed in Section 6.1)
!
Vital Signs (as detailed in Section 6.1)
!
Hematology Panel (as detailed in Section 6.1)
!
Serum Chemistry Panel (as detailed in Section 6.1)
!
Urinalysis (as detailed in Section 6.1)
!
Serum EPO Level (as detailed in Section 6.1)
!
Serum Ferritin (as detailed in Section 6.1)
6.2.3.
Extension Phase of the Treatment Period:  After Week 25 Visit
Subjects who meet criteria to remain on double-blind treatment after completion of the Week 25 
Visit MDS Disease Assessment may continue dosing on Day 1 of each 21-day treatment cycle in 
the Extension Phase of Treatment Period until the subject experiences unacceptable toxicities, 
disease progression per IWG criteria for altering natural history of MDS (Cheson, 2006; 
Appendix E), withdrawsconsent, or meets any other discontinuation criteria (Section 11).
Bone marrow aspirate and peripheral blood samples will be collected (eg, cytomorphology, 
cytogenetics analysis) and the MDS Disease Assessment will be repeated by the investigator at 
Extension Cycle 8, Day 1 and Day 1 of every eighth Extension Cycle thereafter (ie, Extension 
Cycle 8, 16, 24+, etc. or approximately every 24 weeks in the event of dose delays) until the 
subject is discontinued from treatment.  
A bone marrow biopsy is to be collected only when adequate aspirate is not attainable. Whenever 
a bone marrow sample is collected, a peripheral blood smear is to be prepared.  Refer to the
Central Laboratory Manual for additional information.
In addition, information related to all transfusions received during the Treatment Period 
(including those received at outside institutions) should be available prior to completion of each 
MDS Disease Assessment. Clinical site staff should continue to confirm if any transfusions were 
received by the subject (including any at outside local institutions in between study visits) prior 
to each IP administration via use of patient diary or other local procedure in place at the 
investigational site.
For subjects to continue double-blind treatment in the Extension Phase of the Treatment Period, 
each MDS Disease Assessment (criteria detailed in Section 6.2.2) should confirm continued 
clinical benefit and absence of disease progression per IWG criteria for altering natural history of 
MDS (Cheson, 2006; Appendix E).
Additional procedures/assessments as outlined in Section 6.2.1 will also continue in the 
Extension Phase.  The frequency of procedures/assessments in the Extension Phase may differ 
than the Primary Phase.  Refer to Table 4 for additional information related to required 
assessments/procedures and frequency in the Extension Phase.  
6.3.
Dose Delays
On days when subjects return to the investigational site for IP administration, but IP is not 
administered (eg, due to protocol dose modification, delay rules (Section 7.2.1), all required 
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
64
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
assessments and procedures should be performed, regardless if IP is administered. During the 
time period of dose delay, the following assessments/procedures should be performed:
!
If dose delay is due to a laboratory or vital signs abnormality, the assessment that was the 
reason for the dose delay should be repeated at least on weekly basis.
!
If dose delay is due to increased hemoglobin level, perform hematology at least weekly.
!
If dose delay is due to an AE, perform hematology, serum chemistry, and serum ferritin 
at least every 3 weeks thereafter and before next dose administration. 
!
Pharmacokinetic (PK)/ADA samples should be collected on first day of dose delay and 
prior to IP administration on day dosing resumes.
!
For males and FCBP, pregnancy counseling as detailed in Section 6.1.
Refer to the eCRF completion guidelines for detailed instructions related to eCRF data entry.
6.4.
Pharmacokinetics
Blood samples will be collected to analyze luspatercept concentrations in serum in all subjects.  
At each PK time point, approximately 3 mL of blood will be collected and serum prepared as 
described in the study reference guide. Blood samples for PK will be taken at the following visits 
during the study (also see Table 4): 
!
Primary Phase of Treatment Period: C1D1 (must be collected before the first dose), 
C1D8, C1D15, C2D1, C4D1, C5D8 and then Day 1 of every other treatment cycle 
thereafter in the Primary Phase (ie, C6D1 and C8D1, if no dose delays)
!
Week 25 Visit (Collect sample only if > 14 days from prior sample collection.)
!
Extension Phase of Treatment Period (if applicable): Extension Phase Cycle 4, Day 1 and 
Day 1 of every fourth Extension Phase treatment cycle thereafter (eg, Extension Phase 
Cycles 4, 8, etc.) for up to one year from the first dose in the Primary Treatment Phase. 
!
Posttreatment Follow-up: For subjects who do not complete Primary Treatment Phase or 
do not participate in Extension Phase or subjects who terminate the Extension Phase with 
less than 1-year ADA of monitoring, PK samples will be collected at EOT and then every 
12 weeks for up to one year from the first dose in the Primary Treatment Phase.
After the study is unblinded, PK samples may no longer be collected from subjects in the 
placebo arm. In addition, upon unblinding of the study, PK sampling at all Post-Treatment 
Follow-up visits may continue only if subjects’ last available ADA is positive and they have not 
reached the maximum of 1-year ADA monitoring. Pharmacokinetic (PK) sampling per 
investigator’s or sponsor’s discretion is allowed and should be recorded as an unscheduled visit.  
Detailed procedures of PK sample collection, processing, and shipping are provided in the study 
reference guide.
6.5.
Anti-Drug Antibody (ADA)
Blood samples will be collected for assessment of anti-drug antibodies (ADA) against 
luspatercept in serum in all subjects.  The maximum ADA monitoring period will be 1 year from 
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
65
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
the first dose of the Primary Treatment Phase unless justified by safety reasons.  At each ADA 
time point, approximately 3 mL blood will be collected and serum prepared as described in the 
study reference guide. However, during the first year of treatment, an additional blood draw is 
not needed for the ADA test, as the ADA test will be conducted utilizing the PK samples 
obtained at the same visit.  Blood samples for ADA will be taken at the following visits during 
the study (also see Table 4): 
!
Primary Phase of Treatment Period: C1D1 (must be collected before the first dose), 
C2D1, and then Day 1 of every other treatment cycle thereafter in the Primary Phase (ie, 
C4D1, C6D1, and C8D1 if no dose delays).
!
Week 25 Visit (Collect sample only if > 14 days from prior sample collection)
!
Extension Phase of Treatment Period (if applicable): Extension Phase Cycle 4, Day 1 and 
Day 1 of every fourth Extension Phase treatment cycle thereafter (eg, Extension Phase 
Cycles 4, 8, 12, 16+, etc.) for up to 1 year from the first dose in the Primary Treatment 
Phase.
!
Post-treatment Follow-up: For subjects who do not complete the Primary Treatment 
Phase or do not participate in the Extension Phase or subjects who terminate the 
Extension Phase with less than 1-year of ADA monitoring, ADA samples will be 
collected at EOT and then every 12 weeks for up to one year from the first dose in the 
Primary Treatment Phase.
After the study is unblinded, ADA samples may no longer be collected from subjects in the 
placebo arm. In addition, upon unblinding of the study, ADA sampling at all Post-Treatment 
Follow-up visits may continue only if the subject’s last available ADA sample is positive and the 
subject has not reached the maximum of 1-year ADA monitoring.  Antidrug antibodies (ADA)
sampling per investigator’s or sponsor’s discretion is allowed and should be recorded as an 
unscheduled visit.
Detailed procedures of ADA sample collection, processing, and shipping are provided in the 
study reference guide.
6.6.
Unscheduled Visits
Should it become necessary to repeat an evaluation (eg, laboratory tests or vital signs), the results 
of the repeat evaluation should be entered as an additional unscheduled visit in the eCRF.  
Refer to the eCRF completion guidelines for detailed instructions related to eCRF data entry.
6.7.
End of Treatment Visit
An end of treatment (EOT) evaluation will be performed for subjects who are withdrawn from 
treatment for any reason as soon as possible after the decision to permanently discontinue 
treatment has been made. Evaluations will be performed as specified in the Table 4.
If a subject is discontinued during a regular scheduled visit, all EOT procedures should be 
completed at that visit. If a procedure had been performed within 7 days of the EOT visit, it does 
not need to be repeated unless clinically indicated per investigator discretion (with the exception 
of blood pressure assessment and sample collection for hematology, chemistry, and urinalysis).  
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
66
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
Bone marrow procedure should only be performed at EOT visit if > 90 days from prior bone 
marrow procedure.  End of Treatment (EOT) Visit procedures/assessments may occur at 42 Day 
Follow-up assessment if subject is discontinued within +/- 7 days of 42 Day Follow-up 
assessment.
The reason for discontinuation will be recorded in the eCRF and in the source document for all 
randomized subjects, regardless of whether they are dosed or not. Reasons for treatment 
discontinuation are provided in Section 11.1.
6.8.
Posttreatment Follow-up Period 
6.8.1.
Safety Follow-up
All subjects discontinued from protocol-prescribed therapy for any reason will be followed for a 
period of 42 days after the last dose of IP for AE reporting, as well as SAEs made known to the 
Investigator at any time thereafter that are suspected of being related to IP.
Females of childbearing potential should avoid becoming pregnant for 12 weeks after the last 
dose of IP and male subjects should avoid fathering a child for 12 weeks after the last dose of IP. 
Refer to Section 10 for additional details.
6.8.2.
Long-Term Follow-up
Transfusion data collection will continue up until 16 weeks from the date of last dose of IP or 16 
weeks after the End of Treatment Visit (whichever is later).  
For subjects who do not complete the Primary Treatment Phase or do not participate in the 
Extension Phase or subjects who terminate the Extension Phase with less than 1-year of ADA 
monitoring, ADA and PK samples will be collected at EOT and then every 12 weeks for up to 
one year from the first dose in the Primary Treatment Phase (please refer to Section 6.4 and 
Section 6.5).
All subjects discontinued from protocol-prescribed therapy for any reason should be followed for 
progression to AML, other malignancies/pre-malignancies, survival and subsequent MDS 
therapies.
Subjects who discontinue from treatment for any reason will be followed via telephone contact 
by the site for collection of data on survival, cause(s) of death, progression to AML, other 
malignancies/pre-malignancies (please refer to Section 10.5 for details), post-treatment therapy 
(ies) for MDS at the 42-Day and 12-Week Follow-up assessments and then every 3 months after 
the 12 Week Follow-up assessment for at least 3 years after last dose of IP or until death, lost to 
follow-up or withdrawal of consent from the study. Refer to Table of Events, Section 5, Table 4.
Data regarding subsequent MDS therapies, determination of AML progression and other 
malignancies/pre-malignancies, (refer to Section 6.1 and Section 10.5 for additional details), and 
date and cause of death will be recorded in the eCRF.  The investigator must make every effort 
to obtain information regarding the subject’s survival status before determining the subject is lost 
to follow-up. If the subject is discontinued from Long-Term Follow-up, the reason for 
discontinuation should be recorded on the End of Study eCRF.
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
67
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
Long-term follow-up may be conducted by record review (including public records if allowed by 
local regulations) and/or telephone contact with the subject, family, or the subject’s treating 
physician.
6.9.
Efficacy Assessments
Treatment response will be assessed locally by the investigator in accordance with IWG 2006 
criteria for MDS (Cheson, 2006; Appendix E) with modifications for the erythroid response 
criteria through transfusion assessments, hematology laboratory parameters, peripheral blood 
smear, bone marrow aspirates and/or biopsies, and cytogenetics.
Other efficacy assessments will include serum ferritin, concomitant iron chelation therapy use, 
health-related quality of life, 
.  
Efficacy data will also be reviewed by an external unblinded DMC and/or external blinded 
Steering Committee as specified time points detailed in each committees’ respective charters.  
Bone marrow aspirate (or biopsy, if adequate aspirate is not attainable) samples for assessing 
treatment response will be collected at the frequency specified in the Table of Events, Section 5, 
Table 4.  Whenever a bone marrow sample is collected, a stained peripheral blood smear is to be 
prepared.
Cytogenetic testing is to be completed whenever a bone marrow aspirate is obtained for 
assessment of cytogenetic response in accordance with IWG 2006 criteria for MDS (Cheson,
2006; Appendix E).  Bone marrow biopsy can be used for cytogenetics testing if adequate 
aspirate is not attainable (note that specific handling of the biopsy is required for cytogenetics 
testing).
6.10.
Safety Assessments
The safety measures assessed are routinely used in clinical studies evaluating the safety of 
investigational product for hematologic malignancies. Safety assessments, including (but not 
limited to) physical examination, vital signs, ECG, urinalysis, hematology, serum chemistry, 
pregnancy testing (for FCBP subjects only), AEs, concomitant medications and procedures, and 
transfusion data collection and assessment, will be performed at the frequency specified in 
Table 4 or more frequently if clinically indicated.
 
 
 
 
 
 
 
  
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
68
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
 
 
 
 
 
 
.
6.12.
Subject Reported Outcomes or Quality of Life Measurements
The European Organization for Research and Treatment of Cancer Quality-of-Life questionnaire 
(EORTC QLQ-C30) (Aaronson, 1993; Appendix F) is a validated health-related quality of life
(HRQoL) measure applicable to subjects with any cancer diagnosis. It is composed of 30 items 
that address general physical symptoms, physical functioning, fatigue and malaise, and social 
and emotional functioning. Subscale scores are transformed to a 0 to 100 scale, with higher 
scores on functional scales indicating better function and higher score on symptom scales 
indicating worse symptoms. The EORTC QLQ-C30 is available in many languages. This 
instrument takes 10 to 15 minutes to administer. 
  
 
 
  All eligible subjects will complete the EORTC QLQ-C30 
 at the frequency 
noted in the Table of Events, Section 5, Table 4.
For the C1D1 visit, if the subject completed the Screening Visit EORTC QLQ-C30 
 
questionnaires within 14 days prior to C1D1, they do not have to be repeated at C1D1. If 
performed on C1D1, both EORTC QLQ-C30 
 questionnaires should be completed by 
the subject prior to IP administration.
It is important that every subject complete all of the EORTC QLQ-C30 
assessments 
at every specified time point to minimize the amount of missing data.
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
69
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
 
 
 
 
 
 
.
6.14.
Screen Failures 
For all subjects determined as screen failures the following information is to be captured in the 
subject’s source documents and eCRF page(s): the date informed consent form (ICF) was signed, 
demographics, the reason subject did not qualify for the study, and the investigator’s signature 
for the eCRF pages. The adverse events experienced by screen failure subjects will be collected 
from the date of signing consent to the day the subject is confirmed as a screen failure. Relevant 
information will also be recorded on the Screening Log.
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
70
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
7.
DESCRIPTION OF STUDY TREATMENTS
7.1.
Description of Investigational Products
Luspatercept will be provided by the Sponsor. Luspatercept for injection is formulated as a 
sterile, preservative-free, lyophilized cake/powder.  Luspatercept for injection is available in 2 
fill sizes, and when reconstituted, each consists of 50 mg/mL luspatercept in a 10 mM citrate 
buffer-based solution (10 mM citrate, pH 6.5, 9% sucrose, 0.02% polysorbate 80).  The drug 
product is packaged in a 3 mL glass vial in the following fill sizes:  
!
25 mg/vial:  The 25 mg/vial presentation contains 37.5 mg of luspatercept protein.  
After reconstitution with 0.68 mL water for injection (WFI), each single-use vial will 
deliver at least 0.5 mL of 50 mg/mL luspatercept (25 mg)
!
75 mg/vial:  The 75 mg/vial presentation contains 87.5 mg of luspatercept protein. 
After reconstitution with 1.6 mL WFI, each single-use vial will deliver at least 1.5 mL 
of 50 mg/mL luspatercept (75 mg)
The recommended storage condition for Luspatercept for Injection (25 mg/vial and 75 mg/vial; 
lyophilized powder formulation) is 2°C to 8°C. It is recommended that the reconstituted 
luspatercept for injection, at room temperature, be administered immediately.  However, it may 
be held for up to 10 hours at 2°C to 8°C.  If not used immediately, the total in-use time of the 
reconstituted luspatercept for injection, from reconstitution to administration, must not exceed 10 
hours.
Samples of luspatercept drug product, held at the recommended storage condition, have been 
shown to be stable through the labeled shelf-life.
Placebo to be used in the study will be sterile normal saline (0.9% sodium chloride for injection) 
subcutaneous.  Sterile, normal saline should be supplied by the site. The investigational site’s 
designated individuals will prepare the placebo syringes to match the active syringes. The 
investigator and subject will be blinded. The manufacturer’s directions for storage and handling 
are to be followed, as are standard clinical practices for ensuring sterility of the placebo.
7.2.
Treatment Administration and Schedule
There will be unblinded designated site personnel at each site responsible for preparing the 
investigational product.  Luspatercept or placebo will be administered as a subcutaneous 
injection to subjects by the study staff at the clinical site and administration will be documented 
in the subject’s source record.  Subjects must have Hgb, blood pressure and weight assessed 
prior to each IP administration. Clinical site staff should also confirm if any transfusions were 
received by the subject (including any at outside local institutions in between study visits) prior 
to each IP administration via use of patient diary or other local procedure in place at the 
investigational site.
Subcutaneous injections will be given in the upper arm, thigh, and/or abdomen. Calculated doses 
requiring reconstituted volume greater than 1.2 mL should be divided into separate similar 
volume injections across separate sites using the same anatomical location but on opposite sides 
of the body (example left thigh and right thigh).  The maximum volume per SC injection should 
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
71
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
not exceed 1.2 mL.  The maximum total dose per administration should not exceed 168 mg, 
which results in 3.36 mL maximum total volume after reconstitution.
The injection sites can be rotated according to Investigator judgment, and the injections can be 
given in the following order as needed, for example: 1) right upper arm, 2) left upper arm, 3) 
right upper thigh, 4) left upper thigh.
Eligible subjects will be randomized at a 2:1 ratio to either:
!
Experimental Arm: Luspatercept (ACE-536): Starting dose 1.0 mg/kg subcutaneously 
injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle).  
Luspatercept clinical drug product will be provided by the Sponsor as a lyophilized 
powder.  Luspatercept will be administered after reconstitution as a subcutaneous 
injection to subjects by the study staff at the clinical site.
OR
!
Control Arm: Placebo (Volume equivalent to experimental arm) subcutaneously 
injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle).  
Placebo (normal saline) product will be provided by the local investigational site.
7.2.1.
Dose Modifications: Dose Titration, Dose Reduction, and Dose Delay
7.2.1.1.
Dose Titration Increase
Starting as soon as Cycle 3 Day 1 and assessed by the investigator prior to every subsequent 
treatment cycle, subjects may have the dose level increased in a stepwise manner beyond the 
starting dose of 1.0 mg/kg to 1.33 mg/kg, and up to a maximum of 1.75 mg/kg, but the maximum 
total dose should not exceed 168 mg, during both the Primary and Extension Phases of the 
Treatment Period if all the following criteria are met:
!
Subject has ≥ 1 RBC transfusion event (for pretransfusion Hgb of < 9.0 g/dL) during the 
2 most recent prior treatment cycles (~6-weeks).
!
The two most recent prior treatment cycles assessed must be at the same dose level.
!
Subject must not have met protocol dose delay and/or reduction criteria in the two most 
recent treatment cycles (exception of dose delay required due to influence of RBC 
transfusions).  Refer to Table 6, footnote b.
If all criteria above are met, the dose may be increased by 1 dose level.
The dose level should be titrated individually for each subject and must not exceed 1.75 mg/kg.
Starting dose with dose increases and reductions are presented below for reference (Table 5).
Table 5:
Starting Dose Level with Dose Reductions and Dose Titration
3rd Dose 
Reduction
(~25% 
reduction)
2nd Dose 
Reduction
(~25% 
reduction)
1st Dose 
Reduction
(~25% 
reduction)
Starting Dose 
Level
1st Dose 
Titration 
Increase
2nd Dose 
Titration 
Increase
0.45 mg/kg
0.6 mg/kg
0.8 mg/kg
1.0 mg/kg
1.33 mg/kg
1.75 mg/kg
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
72
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
7.2.1.2.
Dose Delay and Dose Reduction 
Dose delay and/or reduction or discontinuation may be required due to increased hemoglobin or 
adverse events in either treatment arm (luspatercept or placebo). Table 6 below provides 
guidelines for dose modifications and dose delay.
Celgene or its authorized representative should be notified of dose modification or interruption 
within 24 hours. Dose reduction and dose delays guidelines are detailed in Table 6 below.
Table 6:
Dose Modification: Dose Delay, Dose Reduction, and Discontinuation 
Guidelines
Event at the Day of Dosing
(Assessed prior to each IP administration)
Action
Any suspected related AE ≥ Grade 3a,d 
Dose delayc until resolved to ≤Grade 1 or 
baseline, and then reduce dose by 25%
≥ 2 dose reductions suspected related AE a
Discontinue treatment
ΔHgb ≥ 2.0 g/dL compared to pre-dose Hgb of 
previous treatment cycle 
Reduce dose by 25%b if ΔHgb not influenced by 
RBC transfusions
Predose Hgb ≥11.5 g/dL 
Dose delay until Hgb ≤11.0 g/dL 
≥ 50% increase in white blood cell count (WBC) 
compared to pre-dose WBC of previous treatment 
cycle and above upper limit of normal in the 
absence of an associated condition (eg, infection 
or concomitant corticosteroid use)
Dose delay; recheck CBC, including WBC, at least 
weekly during dose delay.
Treatment may be resumed if:
WBC values below upper limit of normale within 2 
weeks
If WBC remains above upper limit of normale for 
≥ 2 consecutive weeks in absence of an associated 
condition (eg, infection or concomitant 
corticosteroid use); continue dose delay and collect 
bone marrow/peripheral blood samples to assess 
MDS disease status. 
Treatment may be resumed if:
Absence of disease progression per IWG response 
criteria for altering natural history of MDS 
(Cheson, 2006)
AND
WBC values return below upper limit of normale
Discontinue treatmentf if: 
Disease progression per IWG response criteria for 
altering natural history of MDS (Cheson, 2006)
OR
WBC remain above upper limit of normale
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
73
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
Table 6:
Dose Modification: Dose Delay, Dose Reduction, and Discontinuation 
Guidelines (Continued)
a Possibly, probably or definitely related to IP.
b Predose Hgb value not being influenced by RBC transfusion (ie, Hgb result > 14 days after last RBC transfusion 
or within 3 days from next RBC transfusion); Hgb should be rechecked weekly during dose delay.
c If dose delay is > 12 consecutive weeks, treatment should be discontinued.
d Includes systolic blood pressure ≥160 mmHg and diastolic blood pressure ≥100 mmHg.
e Upper limit of normal >10,000 total WBC/μL or as defined by institutional standards
f Peripheral blood smear should be prepared for central pathology lab assessment. 
g At the investigator’s discretion, bone marrow samples may also be collected and analyzed centrally to assess MDS 
disease status (eg, cytomorphology) prior to making decision regarding treatment discontinuation.  The central 
laboratory must also confirm <5% bone marrow blasts prior to resumption of treatment. 
h The investigator may contact the Medical Monitor prior to making decision regarding treatment discontinuation.
7.2.1.3.
Overdose 
Overdose, as defined for this protocol, refers to luspatercept dosing only.  On a per dose basis, an
overdose is defined as the following amount over the protocol-specified dose of luspatercept 
assigned to a given subject, regardless of any associated adverse events or sequelae.  
Subcutaneous 10% over the protocol-specified dose
On a schedule or frequency basis, an overdose is defined as anything more frequent than the 
protocol required schedule or frequency.  Complete data about drug administration, including 
any overdose, regardless of whether the overdose was accidental or intentional, should be 
reported in the eCRF.  See Section 10.1 for the reporting of adverse events associated with 
overdose.
Event at the Day of Dosing
(Assessed prior to each IP administration)
Action
Presence of ≥ 1% blasts in peripheral blood 
(based on either local or central laboratory 
hematology sample)
Dose interruption; immediately prepare peripheral 
blood smearf,g for cytomorphology assessment by 
central pathology laboratory. 
!
If central pathology laboratory 
cytomorphology assessment confirms 
≥1% blasts in the peripheral blood; 
discontinue treatmenth
!
If central pathology laboratory 
cytomorphology assessment determines 
< 1% peripheral blasts are present, repeat 
hematology assessment.  
-
If presence of < 1% blasts in 
peripheral blood, treatment can be 
resumed at next scheduled dosing 
cycle.
-
If presence of ≥ 1% blasts in 
peripheral blood; discontinue 
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
74
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
7.3.
Method of Treatment Assignment
The treatment assignment (randomization) will occur at the end of the Screening Period, once all 
the required screening procedures have been completed and subject is deemed eligible to 
participate in the study based on assessment of all protocol inclusion and exclusion criteria.  This 
study will utilize the IRT for enrollment. 
Designated research personnel at each investigational site will be assigned password protected, 
coded identification numbers which gives them the authorization to call into IRT to enroll 
subjects.  For drug assignment at each dose start and in the event of any dose reduction, dose 
titration site staff must contact IRT to record the new dose level and obtain the new study 
treatment assignment.
The relationship of the randomization number to the subject identification (ID) number will be 
described by a randomization algorithm. The randomization algorithm will be employed by the 
IRT system to assign a subject to a treatment based on the prespecified rules, such us double 
blind study, stratified randomization with randomization ratio active versus placebo on a 2:1; 
subjects will be placed into the appropriate stratum per the responses/data entered/collected for 
questions collecting stratification and based on the combination of these data points, the IRT will 
place the subject in the next available slot within the appropriate stratum for that subject.  The
IRT will be utilized to ensure an equal weight central randomization based on randomization 
method according to stratification factors defined in Section 3.1, Study Design. The 
randomization number corresponds to a particular treatment arm within a stratum. The 
randomization number, by itself, will not unblind a user to the subject’s treatment. The 
randomization number should be coupled with all the unblinded code information, in order the 
subject to become unblinded.
7.4.
Packaging and Labeling
The IP will be labeled per local requirements.
7.4.1.
Blinding
For this trial, all subjects, study site staff and Celgene Corporation representatives with the 
exception of designated individuals (eg, the pharmacist at the investigational site, the 
bioanalytical laboratory), will remain blinded to all treatment assignments until all subjects have 
completed the study, or at the time the study is unblinded (per DMC recommendation) and the 
database is locked.
Placebo will not be supplied for luspatercept. The designated site individual (for example the 
pharmacist) at the investigational site will use a syringe (that exactly matches the syringe used 
for reconstituted luspatercept) and sterile normal saline (0.9% sodium chloride for injection) to 
prepare a matching placebo. Thus, the designated site individual at the Investigational site will be 
unblinded and will give Investigators and their staff luspatercept and placebo in a blinded 
manner.
Randomization, drug dispensing, dose reduction/titration, and drug discontinuation will be 
accomplished by an IRT system. Authorized site personnel must contact the IRT for 
randomization, study drug assignment at the beginning of each cycle, to register dose reductions 
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
75
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
or titrations, and treatment discontinuation. Confirmation of each call will be sent to the 
investigational site and Celgene.
For emergency unblinding refer to Section 12.2.
If applicable, include information in this section regarding the physical aspect of blinding related 
to the packaging and labeling.
7.5.
Investigational Product Accountability and Disposal 
Accountability for study drug that is administrated during the course of the study is the 
responsibility of the Investigator or designee.  Investigational clinical supplies must be received 
by a designated person at the clinical site and kept in a secure and temperature-controlled 
location.  The investigational site must maintain accurate records demonstrating dates and 
amounts of study drug received, to whom it was administered (subject-by-subject accounting), 
and accounts of any luspatercept accidentally or deliberately destroyed or returned.  Accurate 
recording of all IP administration will be made in the appropriate section of the subject’s eCRF 
and source documents.  Unless otherwise notified, all vials of study drug, both used and unused, 
must be saved for drug accountability.  The used vials may be discarded, per the institution’s 
standard practice, after drug accountability has been completed by the monitor.  The Investigator 
must return all unused vials of study drug to the Sponsor at the end of the study, or the study 
drug may be destroyed at the clinical site with the permission of the Sponsor.  For either 
scenario, the outcome must be documented on the drug accountability log.  The Sponsor will 
provide direction for the outcome of all unused vials.
Celgene (or designee) will review with the Investigator and relevant site personnel the process 
for investigational product return, disposal, and/or destruction including responsibilities for the 
site versus Celgene (or designee).
7.6.
Investigational Product Compliance
Study drug will be administered as a subcutaneous injection at the clinical site by the study staff.  
Monitoring for subject compliance with the treatment regimen is therefore unnecessary.
Accurate recording of all IP administration will be made in the appropriate section of the 
subject’s eCRF and source documents.
The Investigator or designee is responsible for accounting for all IP that is administered during 
the course of the study.
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
76
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
8.
CONCOMITANT MEDICATIONS AND PROCEDURES
Over the course of this study, additional medications may be required to manage aspects of the 
disease state of the subjects, including side effects from trial treatments or disease progression. 
Supportive care, including but not limited to anti-emetic medications, may be administered at the 
discretion of the Investigator. 
All prior/concomitant treatments used from 5 weeks prior to first dose of IP until 42 days after 
the last dose of IP (or the End of Treatment (EOT) Visit, whichever occurs later) must be 
reported on the eCRF. 
All prior procedures within the 8 weeks prior to randomization will be recorded on the 
appropriate eCRF(s).
Prior G-CSF/GM-CSF and iron chelation therapy should be recorded on the appropriate eCRF(s) 
regardless of treatment discontinuation date.
Prior anti-cancer treatments should be recorded on the appropriate eCRF(s) regardless of 
treatment discontinuation/procedure date.
If a subject requires treatment with any new medications that are specifically excluded in 
Section 8.2, the subject will be discontinued from treatment and should complete the end of 
treatment visit and enter the posttreatment follow-up period of the study. The Investigator should 
consult the medical monitor regarding any questions about whether a new medication or dosage 
of existing medication would require the subject to discontinue from the study. 
For information regarding other drugs that may interact with IP and affect its metabolism, 
pharmacokinetics, or excretion, please see the Investigators Brochure and/or local package insert.
8.1.
Permitted Concomitant Medications and Procedures
Granulocyte colony stimulating factors (ie, G-CSF, GM-CSF) are allowed only in cases of 
neutropenic fever or as clinically indicated per product label.
Concurrent corticosteroids used for medical conditions other than MDS is allowed provided 
subject is on a stable or decreasing dose for ≥ 1 week prior to randomization.
Administration of attenuated vaccines (eg, influenza vaccine) is allowed if clinically indicated,
per investigator discretion.  
8.1.1.
Iron Chelation Therapy
Subjects who are using iron-chelating therapies at time of randomization should be on a stable or 
decreasing dose for at least 8 weeks.  
Concurrent treatment with iron chelation therapies during the Treatment Period is allowed at the 
discretion of the investigator and is recommended to be used per product label.
8.1.2.
RBC Transfusions
Concurrent treatment for anemia with blood transfusions is allowed, at the discretion of the 
Investigator, for low hemoglobin levels, symptoms associated with anemia (eg, hemodynamic or 
pulmonary compromise requiring treatment) or comorbidity.
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.1.2.


EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
77
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
For any RBC transfusions received during the study, collect hemoglobin value just prior to 
transfusion.
Each subject will have a “pre-transfusion hemoglobin threshold” for requiring transfusion during 
the study which will be determined based on transfusion history. Baseline pre-transfusion 
hemoglobin threshold will be the mean of all documented pre-transfusion hemoglobin values 
during the 16 weeks prior to Dose 1 Day 1. During treatment, if the pre-transfusion hemoglobin 
level is increased by ≥ 1 g/dL (at the time of a next anticipated transfusion event) compared to 
the pre-transfusion hemoglobin threshold for that subject, transfusion should be delayed by a 
minimum of 7 days and/or the number of units transfused should be reduced by 1 or more RBC 
units. Subjects may be transfused at the Investigator’s discretion for symptoms related to anemia 
or other requirements (eg, infection).
8.2.
Prohibited Concomitant Medications and Procedures
Best supportive care for this study specifically excludes cancer surgery, immunotherapy, 
biologic therapy, radiotherapy, 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 hypomethylating agents
!
Lenalidomide, thalidomide and other immunomodulating drugs (IMiDs)
!
Erythropoietin stimulating agents (ESAs) and other RBC hematopoietic growth factors 
(eg, Interleukin-3).
!
Granulocyte colony stimulating factors (ie, G-CSF, GM-CSF), except in cases of 
neutropenic fever in cases of neutropenic fever or as clinically indicated per product 
label.
!
Hydroxyurea
!
Androgens, unless to treat hypogonadism
!
Oral retinoids (topical retinoids are permitted)
!
Arsenic trioxide
!
Interferon
8.3.
Required Concomitant Medications and Procedures
Not applicable.
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applicable


EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
78
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
9.
STATISTICAL CONSIDERATIONS
9.1.
Overview
This is a Phase 3, double-blind, randomized, placebo-controlled, multicenter study to determine 
the efficacy and safety of luspatercept (ACE-536) versus placebo in subjects with anemia due to 
very low, low, or intermediate MDS with ring sideroblasts who require RBC transfusions. 
The design of the study, including the proposed targeted subject population, study endpoints, and 
statistical plan, is discussed below.
9.2.
Study Population Definitions
Study populations to be analyzed are defined as follow: 
Intent-to-treat (ITT): The intent-to-treat (ITT) population will consist of all randomized 
subjects regardless of whether or not the subject received IP. 
Safety: The Safety Population will consist of all subjects who were randomized and received at 
least one dose of IP.  Subjects will be included in the treatment group corresponding to the IP 
they actually received.
Statistical methods to handle missing data will be described in the statistical analysis plan (SAP).
The SAP will describe any predefined rules for including/excluding any subjects with data from 
any analyses (eg, time windows, visit by visit analysis, endpoint analysis, protocol violation).
9.3.
Sample Size and Power Considerations
A total sample size of 210 (140 in experimental arm [luspatercept (ACE-536)], 70 in control arm 
[placebo]) will have 90% power to detect the difference between a response rate of 0.30 in the 
experimental arm (luspatercept [ACE-536]) and a response rate of 0.10 in the control arm 
(placebo).  The sample size calculation is based on one-sided alpha of 0.025, test statistics on 
difference of proportions using pooled estimate of variance and 10% dropout rate. 
9.4.
Randomization and Stratification
A 2:1 randomization will be used as this is an orphan disease with a limited number of subjects 
available. Subjects will be randomized to receive luspatercept or placebo at a 2:1 ratio. A 2:1 
randomization scheme would enrich the number of participants exposed to the active treatment 
group (Dumville, 2006). 
Subjects will be randomized to receive luspatercept or placebo at a 2:1 ratio. Randomization will 
be accomplished by an IRT to ensure timely registration and randomization. A stratified 
randomization schedule will be implemented. Randomization will be stratified by baseline RBC 
transfusion burden and baseline IPSS-R risk category (Greenberg, 2012; Appendix D). 
Stratification will be based on the following factors:
!
RBC transfusion burden at baseline
∀
≥ 6 RBC units/8 weeks (mean of the two consecutive 8 weeks periods 
immediately prior to randomization)
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Stratific
tratifi


EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
79
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
∀
< 6 RBC units/8 weeks (mean of the two consecutive 8 weeks periods 
immediately prior to randomization)
!
IPSS-R at baseline 
∀
Very low, low
∀
Intermediate
9.5.
Background and Demographic Characteristics
Subjects’ age, height, weight, and baseline characteristics will be summarized using descriptive 
statistics, while gender, race and other categorical variables will be provided using frequency 
tabulations by dose cohort.  Prior transfusion history will be summarized.  Medical history data 
will be summarized using frequency tabulations by the Medical Dictionary for Regulatory 
Activities (MedDRA) system organ class and preferred term.  Myelodysplastic syndrome (MDS)
diagnoses as well as RBC transfusion dependence will be summarized using frequency 
tabulations.
9.6.
Subject Disposition
Subject disposition (analysis population allocation, entered, discontinued, along with primary 
reason for discontinuation) will be summarized using frequency and percent for both treatment 
and follow-up phases.  A summary of subjects enrolled by site will be provided. Protocol 
deviations will be summarized using frequency tabulations.
9.7.
Efficacy Analysis
9.7.1.
Primary Efficacy Analysis
The primary efficacy analysis will be the comparison of the response rates in the two treatment 
arms in ITT population. The primary efficacy endpoint of transfusion independent response is 
defined as the absence of any RBC transfusion during any consecutive 56 day period during the 
Primary Phase of the Treatment Period (first 24 weeks of double-blind treatment) ie, days 1 to 
56, days 2 to 57, days 3 to 58, etc.
Subjects discontinued from the Primary Phase of the Treatment Period without achieving at least 
56 days consecutive of RBC transfusion independence will be counted as non-responders. 
For the primary efficacy endpoint, 56-day RBC transfusion independence, the response rate will 
be calculated using the number of responders divided by number of subjects in the ITT 
population (responders plus non-responders). The response rates of the subjects who were 
randomized to luspatercept and the placebo will be calculated. In the primary efficacy analysis, 
the statistical hypothesis is
2
1
2
1
0
:
:
P
P
H
P
P
H
a
#
∃
where
1
P denotes the true response rate in the luspatercept group, and 
2
P denotes the true 
response rate in the placebo group. The number and percentage of subjects in the ITT population 
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
80
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
who achieve the response will be presented by treatment group. The Cochran–Mantel–Haenszel 
(CMH) test will be used to test the difference between the 2 response rates at a 1-sided 
significance level of 0.025 with randomization factors as strata. 
Additional details will be outlined in the SAP.
9.7.2.
Secondary Efficacy Analyses
9.7.2.1.
Key Secondary Efficacy Analyses
The key secondary endpoint, proportion of subjects achieving RBC-TI with duration ≥ 12 weeks, 
will be tested in the same manner as primary efficacy endpoint using the CMH test.
The analyses for the key secondary endpoint will be based on the ITT population. In order to 
perform hypothesis testing on multiple endpoints while controlling the overall Type I error rate, 
a sequential testing approach will be employed where the order of the endpoints to be tested are 
pre-specified. The primary efficacy endpoint will be tested first at the one-sided 0.025 
significance level. If superiority of luspatercept is demonstrated for the primary efficacy 
endpoint then the key secondary endpoint will be tested, at a one-sided 0.025 significance level.
Proportion of subjects achieving RBC-TI with duration ≥ 12 weeks is the absence of any 
RBC transfusion during any consecutive 84 day period during the Treatment Period (Weeks 1-
24; Weeks 1-48), ie, days 1 to 84, days 2 to 85, days 3 to 86, etc. Subjects discontinued from the 
Treatment Period without achieving at least 84 consecutive days of RBC transfusion 
independence will be counted as non-responders. 
Full details will be included in the SAP.
9.7.2.2.
Additional Secondary Efficacy Analyses
Other secondary variables will be analyzed descriptively, unless otherwise specified, and will be 
based on the ITT population. Kaplan-Meier methods will be used to estimate curves for time to 
event secondary variables. Counts and percentages will be used to describe categorical secondary 
variables. 
Hemoglobin (Hgb) increase ≥ 1.0 g/dL is defined as proportion of subjects with ≥ 1.0 g/dL Hgb 
increase compared to baseline that is sustained over any consecutive 56-day period in the 
absence of RBC transfusions.
Total RBC units transfused over 16 weeks is defined as the total number of RBC units 
transfused over a fixed period of 16 weeks (weeks 9-24; weeks 32-48) compared to the total 
number of RBC units transfused in the 16 weeks immediately prior to randomization.
Proportion of subjects achieving RBC-TI with duration ≥ 8 weeks (Weeks 1-48) is the 
absence of any RBC transfusion during any consecutive 56-day period during the Treatment 
Period (Weeks 1-48).
Proportion of subjects achieving modified erythroid response (mHI-E) is defined as 
proportion of subjects meeting modified HI-E criteria (Cheson, 2006; Appendix E) sustained 
over any consecutive 56-day period during the Treatment Period. Red blood cell (RBC)
transfusions administered for a pre-transfusion Hgb of > 9.0 g/dL will count in the RBC 
transfusion response evaluation.
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
81
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
Duration of RBC-TI will be determined only for subjects who achieve RBC TI ≥ 8 weeks on 
treatment. Duration of RBC-TI is defined as the longest RBC-TI period during the Treatment 
Period.  Subjects who maintain RBC-TI through the end of the Treatment Period will be 
censored at the date of treatment discontinuation or death, whichever occurs first. 
Time to RBC-TI will be summarized only for subjects who achieve RBC TI ≥ 8 weeks on 
treatment. It is defined as the time between randomization and the date onset of TI is first 
observed (ie, Day 1 of 56 days without any RBC transfusions). 
Proportion of subjects achieving hematological response to neutrophils (HI-N) is defined as 
proportion of subjects meeting HI-N criteria (Cheson, 2006; Appendix E) sustained over any 
consecutive 56-day period during the Treatment Period.
Proportion of subjects achieving hematological response to platelets (HI-P) is defined as 
proportion of subjects meeting HI-P criteria (Cheson, 2006; Appendix E) sustained over any 
consecutive 56-day period during the Treatment Period.
Mean Change in Mean Daily Dose of Iron Chelation Therapy (ICT)
The change in daily dose for each subject is calculated as the difference of post-baseline mean 
daily dose and baseline mean daily dose. Analysis of covariance (ANCOVA) will be used to 
compare the treatment difference between groups, with the stratification factors and baseline ICT 
value as covariates.
Mean Serum Ferritin Decrease
The change is calculated as the difference of post-baseline mean serum ferritin and baseline 
mean serum ferritin. Analysis of covariance (ANCOVA) will be used to compare the treatment
difference between groups, with the stratification factors and baseline serum ferritin value as
covariates.
Time to progression to AML is defined as the time between randomization and first diagnosis 
of AML as per WHO classification of ≥ 20% blasts in peripheral blood or bone marrow.  
Subjects with diagnosis of AML will be considered to have had an event.  Subjects who have not 
progressed to AML at the time of analysis will be censored at the last assessment date which 
does not indicate progression to AML.
Overall survival (OS) is defined as the time between randomization and death/censored date.  
Subjects who die, regardless of the cause of death, will be considered to have had an event.  
Subjects who are alive at the time of analysis will be censored at the last assessment date at 
which the subject was known to be alive. All subjects who were lost to follow-up will also be 
censored at the time of last contact.
Full analysis details will be included in the SAP.
9.8.
Safety Analysis
All safety analyses will be performed on the safety population. Full details will be included in 
the SAP. Planned data presentations and analyses include the following:
Adverse events will be coded using MedDRA. Adverse event listings will include the verbatim 
term and the MedDRA preferred term. Treatment-emergent adverse events will be summarized 
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
82
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
by system organ class and preferred term. Treatment-emergent adverse events leading to death or 
to discontinuation from treatment, treatment-emergent adverse events (TEAEs) classified as 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)
(version 4.03) all grades or grade 3/4 TEAEs, related to investigational product, and serious 
TEAEs will be summarized separately.
Clinical laboratory results will be summarized descriptively by treatment group. Clinically 
significant hematologic and non-hematologic laboratory abnormalities will be listed and 
summarized according to the NCI CTCAE (version 4.03) by treatment group.
Physical examination data and vital sign measurements, including body weight, will be listed for 
each subject at each visit. Descriptive statistics for vital signs, both observed values and changes 
from baseline, will be summarized by treatment group.
9.9.
Other Analysis
Change in health related quality of life questionnaires utilizing EORTC QLQ-C30 
, changes from baseline in overall score and sub-scores will be analyzed and compared between 
treatment groups using repeated measures of Analysis of Variance (ANOVA)/ANCOVA using 
the screening scores as covariates where appropriate.  Various schemes will be assessed for 
missing data imputation.
 
 
 
 
 
9.10.
Timing of Analyses
9.10.1.
Interim Analysis 
An interim analysis to assess futility will be performed when approximately 105 subjects have 
completed the Primary Phase of the Treatment Period (first 24 weeks of double-blind treatment) 
or discontinued before reaching 24 weeks of double-blind treatment (50% information for 
primary endpoint). There will be no plan to claim luspatercept superiority based on efficacy 
results so the type one error rate remains at 0.025 one-sided for the final analysis. 
Conditional power for primary endpoint will be calculated assuming the observed trend 
continues for the rest of the data. If it is 10% (corresponding to a futility boundary of p-value 
≥0.201 using beta-spending function) or less, with confirmative data for secondary and other 
efficacy endpoints, the DMC may recommend stopping the study for futility.
This interim analysis will be performed by an independent statistician not affiliated with the 
study. The sponsor will remain blinded throughout the study. 
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
83
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
9.10.2.
Final Analysis 
Final analysis will be performed when all 210 subjects have completed 48 weeks of treatment or 
discontinued before 48 weeks. 
There is no plan to claim luspatercept superiority based on interim analysis efficacy results, thus 
the type one error rate remains at 0.025 one-sided for the final analysis. 
Additional follow-up analysis for efficacy and safety will be performed when all subjects have 
been followed for at least 3 years from the last dose of IP.
Full details will be included in the SAP.
9.11.
Other Topics
 
 
 
 
 
 
 
9.11.2.
Data Monitoring Committee 
An external, independent, unblinded DMC will be comprised of experts in MDS not involved in 
ACE-536-MDS-001 protocol, an independent Geriatrician/Hypertension Expert, an independent 
Statistician, and may include additional ad hoc members. Representatives of the Sponsor will be 
attending the blinded part of the DMC meetings. The Sponsor will not have access to the 
unblinded data during DMC meetings. 
During the course of the study, the DMC will review the unblinded safety data regularly as well 
as safety and efficacy data in accordance with the guidelines for the preplanned analyses and the
procedure pertaining to monitoring of AML progression outlined in the DMC charter.  An 
independent third party will prepare the reports of aggregate data summaries and individual
subject data listings, as appropriate, to the DMC members for each scheduled meeting.
The DMC responsibilities, authorities, and procedures will be detailed in the DMC charter, 
which will be endorsed by the DMC prior to the first data review meeting.
Operational details for the DMC will be detailed in the DMC charter.
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
84
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
9.11.3.
Steering Committee 
A Steering Committee will be established by charter for this study.  The Steering Committee will
be comprised of Study Investigators, Sponsor representatives, and may include additional ad hoc 
members.  The Steering Committee will review blinded data. The SC will serve in an advisory 
capacity to the Sponsor.  The SC may advise and recommend to the Sponsor the following (but 
not limited to):
!
Changes to the protocol or conduct of the study based upon emerging clinical or 
scientific data from this and/or other studies.
!
Procedures to ensure the safety of subjects and integrity of study data.
!
Procedures to meet the overall goals and objectives of the study.
The SC responsibilities, authorities, and procedures will be detailed in the SC charter, which will 
be endorsed by the SC prior to the first data review meeting.
Operational details for the SC will be detailed in a separate SC charter. 
Note: The SC is separate from the DMC.
 
 
 
9.11.5.
Subgroup Analysis
Appropriate subgroup analyses by stratification factors and other baseline characteristics for 
clinical activity may be conducted as exploratory analyses.  Full details will be included in the 
SAP.
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
85
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
10.
ADVERSE EVENTS
10.1.
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 in Section 10.3), 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 eCRF rather than the individual signs or symptoms of the diagnosis or 
syndrome. 
Abuse, withdrawal, sensitivity or toxicity to an investigational product should be reported as an 
AE. Overdose, accidental or intentional, whether or not it is associated with an AE should be 
reported on the overdose eCRF. (See Section 7.2.1.2 for the definition of overdose.) Any 
sequela of an accidental or intentional overdose of an investigational product should be reported 
as an AE on the AE eCRF. If the sequela of an overdose is an SAE, then the sequela must be 
reported on an SAE report form and on the AE eCRF. The overdose resulting in the SAE should 
be identified as the cause of the event on the SAE report form and eCRF but should not be 
reported as an SAE itself.
In the event of overdose, the subject should be monitored as appropriate and should receive 
supportive measures as necessary. There is no known specific antidote for luspatercept overdose. 
Actual treatment should depend on the severity of the clinical situation and the judgment and 
experience of the treating physician.
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 findings from 
other tests and/or procedures.
All AEs will be recorded by the Investigator from the time the subject signs informed consent 
until 42 days after the last dose of IP as well as those SAEs made known to the Investigator at 
any time thereafter that are suspected of being related to IP.  Adverse events (AEs) and SAEs 
will be recorded on the AE page of the eCRF 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.  
10.2.
Evaluation of Adverse Events
A qualified Investigator will evaluate all adverse events as to: 
10.2.1.
Seriousness 
An SAE is any AE occurring at any dose that:
!
Results in death;
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S


EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
86
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
!
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 important medical event.
Important medical events are defined as those occurrences that may not be immediately life-
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above.  
Medical and scientific judgment should be exercised in deciding whether such an AE should be 
considered serious.
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 start of treatment on study); must be 
documented in the source document and the eCRF.  Hospitalization or prolonged 
hospitalization for a complication remains a reportable SAE.
!
an elective treatment of or an elective procedure for a pre-existing condition, unrelated to 
the studied indication, that has not worsened from baseline. 
!
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 eCRF and the SAE Report Form 
must be completed.
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
87
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
For each SAE, the Investigator will provide information on severity, start and stop dates, 
relationship to the IP, action taken regarding the IP, and outcome.
10.2.2.
Severity/Intensity
For both AEs and SAEs, the Investigator must assess the severity/ intensity of the event. 
The severity/intensity of AEs will be graded based upon the subject’s symptoms according to the 
current active minor version of the Common Terminology Criteria for Adverse Events (CTCAE, 
Version 4.0); 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40
Adverse events that are not defined in the CTCAE should be evaluated for severity/intensity 
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.
10.2.3.
Causality
The Investigator must determine the relationship between the administration of the IP and the 
occurrence of an AE/SAE as Not Suspected or Suspected as defined below:
Not suspected:
a causal relationship of the adverse event to IP administration is 
unlikely or remote, or other medications, therapeutic 
interventions, or underlying conditions provide a sufficient 
explanation for the observed event.
Suspected:
there is a reasonable possibility that the administration of IP 
caused the adverse event.  ‘Reasonable possibility’ means there 
is evidence to suggest a causal relationship between the IP and 
the adverse event.
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
88
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
Causality should be assessed and provided for every AE/SAE based on currently available 
information.  Causality is to be reassessed and provided as additional information becomes 
available.
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.
10.2.4.
Duration
For both AEs and SAEs, the Investigator will provide a record of the start and stop dates of the 
event.
10.2.5.
Action Taken
The Investigator will report the action taken with IP as a result of an AE or SAE, as applicable 
(eg, discontinuation, interruption, or dose reduction of IP, as appropriate) and report if 
concomitant and/or additional treatments were given for the event. 
10.2.6.
Outcome
The Investigator will report the outcome of the event for both AEs and SAEs.
All SAEs that have not resolved upon discontinuation of the subject’s participation in the study 
must be followed until recovered (returned to baseline), recovered with sequelae, or death (due to 
the SAE).
10.3.
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, eg, one that indicates a new disease 
process and/or organ toxicity, or is an exacerbation or worsening of an existing 
condition.
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 
need to be documented as a serious adverse event.
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded on the AE page/screen of the eCRF.  If the abnormality was not 
a part of a diagnosis or syndrome, then the laboratory abnormality should be recorded as the AE. 
If possible, the laboratory abnormality should be recorded as a medical term and not simply as an 
abnormal laboratory result (eg, record thrombocytopenia rather than decreased platelets).
10.4.
Pregnancy
All pregnancies or suspected pregnancies occurring in either a female subject of childbearing 
potential or partner of childbearing potential of a male subject are immediately reportable events.  
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
89
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
10.4.1.
Females of Childbearing Potential:
Pregnancies and suspected pregnancies (including elevated βhCG or positive pregnancy test in a 
female subject of childbearing potential regardless of disease state) occurring while the subject is 
on IP, or within 12 weeks of the subject’s last dose of IP, are considered immediately reportable 
events.  Investigational product is to be discontinued immediately. The pregnancy, suspected 
pregnancy, or positive pregnancy test must be reported to Celgene Drug Safety immediately by 
email, phone or facsimile, or other appropriate method, using the Pregnancy Initial Report Form, 
or approved equivalent form.  
The female subject may be referred to an obstetrician-gynecologist or another appropriate 
healthcare professional for further evaluation.
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 Pregnancy Follow-up Report Form, or approved equivalent form.
If the outcome of the pregnancy was abnormal (eg, spontaneous 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 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.
10.4.2.
Male Subjects
If a female partner of a male subject taking IP becomes pregnant, the male subject taking IP 
should notify the Investigator, and the pregnant female partner should be advised to call their 
healthcare provider immediately.  
Males will be advised to use a male latex condom or nonlatex condom NOT made out of natural 
(animal) membrane (for example, polyurethane), during any sexual contact with FCBP prior to 
starting investigational product and continue for 12 weeks following the last dose of IP, even if 
he has undergone a successful vasectomy.
10.5.
Other Malignancies/Pre-malignancies
Events of new malignancy, pre-malignant lesions (excluding benign tumors or benign neoplasia) 
are to 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. All SAE criteria (eg, hospitalization) should be marked if applicable, and all 
events must be marked as an “Important Medical Event” even if no other serious criteria apply; 
these events must also be documented in the appropriate page(s) of the CRF and subject’s source 
documents.  Documentation related to the diagnosis of malignancy must be provided at the time 
of reporting as a serious adverse event (eg, any confirmatory histology or cytology results, X-
rays, CT scans, etc.).
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
90
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
Malignancies or cancerous tumors are lesions capable of invading into adjacent tissues, and may 
be capable of spreading to distant tissues. A benign tumor has none of those properties.
Malignancy or cancer is characterized by anaplasia, invasiveness, and metastasis.  For the 
Myelodysplastic Syndrome (MDS) studies, these also include progression to high/very high risk 
of MDS (per IPSS-R; Greenberg, 2012); myeloproliferation (eg, clinically significant increases 
in blasts), progression to AML, etc.
Premalignant or precancerous lesions refer to a state of disordered morphology of cells that is 
associated with an increased risk of cancer. If left untreated, these conditions may lead to cancer. 
Such conditions are usually either dysplasia or benign neoplasia (and the dividing line between 
those is sometimes blurry). Sometimes the term "precancer" is used to describe carcinoma in 
situ, which is a noninvasive cancer that has not progressed to an aggressive, invasive stage. Not 
all carcinoma in situ will progress to invasive disease.
Premalignant lesions are morphologically atypical tissue which appears abnormal under 
microscopic examination, and in which cancer is more likely to occur than in its apparently 
normal counterpart.
10.6.
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 eCRF.  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 (eg, via email), using the SAE Report Form, or approved equivalent 
form.  This instruction pertains to initial SAE reports as well as any follow-up reports.
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 until 42 days after the last dose of IP) or any 
SAE made known to the Investigator at any time thereafter that are suspected of being related to 
IP.  Serious adverse events occurring prior to treatment (after signing the ICF) will be captured.
The SAE report should provide a detailed description of the SAE and include a concise summary 
of hospital records and other relevant documents.  If a subject died and an autopsy has been 
performed, copies of the autopsy report and death certificate are to be sent to Celgene Drug 
Safety as soon as these become available.  Any follow-up data should 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/Ethics Committee (IRB/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.
10.6.1.
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.
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
91
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
10.7.
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 luspatercept based on the Investigator Brochure.
In the United States, all suspected unexpected serious adverse reactions (SUSARs) will be 
reported in an expedited manner in accordance with 21 CFR 312.32.
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 investigational products for 
human use (ENTR/CT3) and also in accordance with country-specific requirements.
In addition, any report of progression to high risk MDS or AML if the case is in the luspatercept 
arm, upon unblinding regardless of causality, will be reported as an expedited safety report to the 
regulatory authorities, as requested.
Celgene or its authorized representative shall notify the Investigator of the following 
information:
!
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.
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 14.3 for record retention 
information).
Celgene Drug Safety Contact Information:
For Celgene Drug Safety 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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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
92
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
11.
DISCONTINUATIONS
11.1.
Treatment Discontinuation
Subjects will have an End of Treatment (EOT) visit at the time of IP discontinuation.  All 
subjects who received at least one dose of IP will be followed for at least 3 years post last dose of 
IP. 
The following events are considered sufficient reasons for discontinuing a subject from the 
investigational products:
!
Lack of Efficacy 
!
Adverse Event
!
Withdrawal by subject
!
Death
!
Lost to follow-up
!
Pregnancy
!
Protocol violation
!
Study terminated by Sponsor
!
Disease Progression as per IWG criteria for altering natural history of MDS (Cheson, 
2006; Appendix E)
∀
For subjects with 5-10% blasts, a 2nd bone marrow sample should be collected 
within 4 weeks for clinical assessment (eg, cytomorphology, cytogenetics) to 
confirm progression before discontinuing subjects from treatment. 
!
Other (to be specified on the eCRF)
∀
Including treatment discontinuation guidance related to dose modification 
Table 6.
The reason for discontinuation of treatment should be recorded in the eCRF and in the source 
documents.
The decision to discontinue a subject from treatment remains the responsibility of the treating 
physician, which will not be delayed or refused by the Sponsor.  However, prior to discontinuing 
a subject, the Investigator may contact the Medical Monitor and forward appropriate supporting 
documents for review and discussion.
11.2.
Study Discontinuation
Subjects who discontinue from treatment for any reason will be followed via telephone contact 
by the site or subject site visit for collection of data on survival, cause(s) of death, progression to 
AML, other malignancies/pre-malignancies, post-treatment therapy(ies) for MDS at the 42-Day 
and 12-Week Follow-up assessments and then every 3 months after the 12-Week Follow-up 
assessment for at least 3 years after last dose of IP or until death, lost to follow-up or withdrawal 
of consent from the study.
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
93
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
Every attempt should be made to contact subjects during follow-up unless subjects discontinue
from the study. Every attempt should be made to collect all data on discontinued subjects.
The following events may be considered sufficient reasons for discontinuing a subject from the 
study:
!
Screen failure
!
Adverse event
!
Withdrawal by subject
!
Death
!
Lost to follow-up
!
Protocol deviation
!
Study terminated by Sponsor
!
Other (to be specified on the eCRF)
The reason for study discontinuation should be recorded on the End of Study eCRF and in the 
source documents.
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
94
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
12.
EMERGENCY PROCEDURES
12.1.
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/contract 
research organization 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. 
12.2.
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 if, in the opinion of 
the Investigator, continuing IP can negatively affect the outcome of the subject’s treatment.
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.  However, the Investigator may 
contact the Medical Monitor prior to breaking the blind to discuss unblinding, mainly in the 
interest of the subject. 
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 by using an 
emergency unblinding personal identification number (PIN), and the Investigator should call IRT
for unblinded dose information.
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
95
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
13.
REGULATORY CONSIDERATIONS
13.1.
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 Council for
Harmonisation (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.
13.2.
Investigator Responsibilities
Investigator responsibilities are set out in the ICH Guideline for Good Clinical Practice and in 
the local regulations.  Celgene staff or an authorized representative will evaluate and approve all 
Investigators who in turn will select their staff.
The Investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, amendments, study treatments, as well as study-related duties and functions, 
including obligations of confidentiality of Celgene information. The Investigator should maintain 
a list of Sub-investigators and other appropriately qualified persons to whom he or she has 
delegated significant study-related duties.
The Investigator is responsible for keeping a record of all subjects who sign an informed consent 
form (ICF) 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 eCRFs and queries.
The information contained in the protocol and amendments (with the exception of the 
information provided by Celgene on public registry websites) is considered Celgene confidential 
information.  Only information that is previously disclosed by Celgene on a public registry 
website may be freely disclosed by the Investigator or its institution, or as outlined in the Clinical 
Trial Agreement.  Celgene protocol, amendment and IB information is not to be made publicly 
available (for example on the Investigator’s or their institution’s website) without express written 
approval from Celgene.  Information proposed for posting on the Investigator’s or their 
institution’s website must be submitted to Celgene for review and approval, providing at least 5 
business days for review.
At the time results of this study are made available to the public, Celgene will provide 
Investigators with a summary of the results that is written for the lay person. The Investigator is 
responsible for sharing these results with the subject and/or their caregiver as agreed by the 
subject.
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
96
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
13.3.
Subject Information and Informed Consent
The Investigator must obtain informed consent of a subject and/or a subject’s 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 ICF 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 ICF 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 ICF.  The revised ICF 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.
13.4.
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 ICF, it is the responsibility of the Investigator to obtain such permission in 
writing from the appropriate individual.
13.5.
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.
13.6.
Institutional Review Board/Independent Ethics Committee Review 
and Approval
Before the start of the study, the study protocol, ICF, 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 (IP) product can only be supplied to an Investigator by Celgene or its 
authorized representative after documentation on all ethical and legal requirements for starting 
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
97
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
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 ICF should also be revised.
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.  
13.7.
Ongoing Information for Institutional Review Board/ Ethics 
Committee
If required by legislation or the IRB/EC, the Investigator must submit to the IRB/EC:
!
Information on serious or unexpected adverse events as soon as possible; 
!
Periodic reports on the progress of the study;
!
Deviations from the protocol or anything that may involve added risk to subjects.
13.8.
Termination of the Study
Celgene reserves the right to terminate this study prematurely 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).
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 still being administered the 
investigational product, and it is the opinion of the Investigator(s) that these subjects continue to 
receive benefit from treatment, the Sponsor may choose to initiate an open-label, roll-over or 
extension study under a separate protocol to allow these subjects continued access to luspatercept 
following their participation in this study ACE-536-MDS-001.
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
98
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
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.
CCI
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
99
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
14.
DATA HANDLING AND RECORDKEEPING 
14.1.
Data/Documents
The Investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the investigational product are complete, accurate, filed and 
retained.  Examples of source documents include: hospital records; clinic and office charts; 
laboratory notes; memoranda; subject’s diaries or evaluation checklists; dispensing records; 
recorded data from automated instruments; copies or transcriptions certified after verification as 
being accurate copies; microfiche; x-ray film and reports; and records kept at the pharmacy, and 
the laboratories, as well as copies of eCRFs or CD-ROM.
14.2.
Data Management
Data will be collected via eCRF and entered into the clinical database per Celgene standard 
operating procedures (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.
14.3.
Record Retention
Essential documents must be retained by the Investigator according to the period of time outlined 
in the clinical trial agreement. 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 ICFs 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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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
100
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
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 or institution should take measures to prevent accidental or premature destruction of 
these documents.
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
101
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
15.
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 SOPs.
15.1.
Study Monitoring and Source Data Verification
Celgene ensures that appropriate monitoring procedures are performed before, during and after 
the study.  All aspects of the study are reviewed with the Investigator and the staff at a study 
initiation visit and/or at an Investigators’ Meeting.  Prior to enrolling subjects into the study, a 
Celgene representative will review the protocol, eCRFs, 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.  During monitoring visits, the facilities, 
investigational product storage area, eCRFs, subject’s source documents, and all other study 
documentation will be inspected/reviewed by the Celgene representative in accordance with the 
Study Monitoring Plan.
Accuracy will be checked by performing source data verification that is a direct comparison of 
the entries made onto the eCRFs 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 eCRFs 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.
15.2.
Audits and Inspections
In addition to the routine monitoring procedures, a Good Clinical Practice Quality Assurance 
unit exists within Celgene.  Representatives of this unit will conduct audits of clinical research 
activities in accordance with Celgene SOPs to evaluate compliance with Good Clinical Practice 
guidelines and regulations.
The Investigator is required to permit direct access to the facilities where the study took place, 
source documents, eCRFs 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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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
102
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
16.
PUBLICATIONS
As described in Section 13.2, all protocol and amendment-related information, with the 
exception of the information provided by Celgene on public registry websites, is considered 
Celgene confidential information and is not to be used in any publications.  Celgene protocol-
related information proposed for use in a publication must be submitted to Celgene for review 
and approval, and should not be utilized in a publication without express written approval from 
Celgene, or as described in the Clinical Trial Agreement.  
Celgene will ensure Celgene-sponsored studies are considered for publication in the scientific 
literature in a peer-reviewed journal, irrespective of the results.  At a minimum, this applies to 
results from all Phase 3 clinical studies, and any other study results of significant medical 
importance.  This also includes results relating to investigational medicines whose development 
programs have been discontinued.
Study results may also be presented at one or more medical congresses, and may be used for 
scientific exchange and 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.  
 
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
103
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
17.
REFERENCES
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ol 2014; 
81.1.
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R, et al.
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
104
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
del Rey M, Benito R, Fontanillo C, Campos-Laborie FJ, Janusz K, et al. Deregulation of genes 
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clinical trials: a review. Contemp Clin Trials 2006;27(1):1-12.
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ion in 38
6):1286
):128 -92.
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Morel P, 
P, 
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dysplast
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J, Sanz G,
, Sanz G
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system f
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Wong P, Zha
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118
118(24)
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
105
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
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. Br J 
Haematol 2003;121(3):270-4.
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
106
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
Papaemmanuil E, Gertsung, M, Malcovati L, Tauro S, Gundem G, Van Loo P, et al. Clinical and 
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intermediate-1 MDS? Blood 2013;122(13):2286-8.
Schanz J, Tüchler H, Solé F, Mallo M, Luño E, Cervera J, et al. New comprehensive cytogenetic 
scoring system for primary myelodysplastic syndromes (MDS) and oligoblastic acute myeloid 
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2012;30(8):820-9.
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Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, et al. The 2008
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2013;27(5):243-59.
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
107
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
18.
APPENDICES
APPENDIX A:
Table of Abbreviations
Table 7:
Abbreviations and Specialist Terms
Abbreviation or 
Specialist Term
Explanation
ActRIIB
Activin receptor type IIB
ADA
Antidrug antibodies
AE
Adverse event
ALT
Alanine aminotransferase 
AML
Acute myeloid leukemia
ANCOVA
Analysis of covariance
ANOVA
Analysis of variance 
AST
Aspartate aminotransferase 
AUC
Area under the curve
β-hCG
β-subunit of human chorionic gonadotropin
BM
Bone marrow
BMA
Bone marrow aspirate
BMP
Bone morphogenetic protein 
BSC
Best supportive care
CBC
Complete blood count
CXDX
Cycle X Day X
Cmax
Maximum plasma concentration of drug
CMH
Cochran–Mantel–Haenszel
CMML
Chronic myelomonocytic leukemia
CRF
Case report form
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data Monitoring Committee
EC
Ethics Committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
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EDMS Doc. Number:
Luspatercept (ACE-536)
Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
108
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
Table 7:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
EEA
European Economic Area
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire 
EOT
End of treatment
EPO
Erythropoietin
ESA
Erythropoiesis- stimulating agents
FAB
French-American-British
FCBP
Female of childbearing potential
FDA
Food and Drug Administration
GCP
Good Clinical Practice
G-CSF
Granulocyte colony-stimulating factor
GDF
Growth Differentiation Factor 
GM-CSF
Granulocyte-macrophage colony-stimulating factor
Hgb
Hemoglobin
HI-E
Hematological improvement-erythroid
HI-N
Hematological improvement-neutrophils
HI-P
Hematological improvement-platelets
HIV
Human Immunodeficiency Virus 
HMA
Hypomethylating agents
HR
Hazard ratio
HRQoL
Health-related quality of life 
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Council for Harmonisation
ICT
Iron chelation therapy
IMiDs
Immune-modulatory drugs (a proprietary series of drugs with 
immunomodulatory and other properties)
IND
Investigational New Drug
Int
Intermediate
IP
Investigational Product
IPSS
International Prognostic Scoring System
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Table 7:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
IPSS-R
International Prognostic Scoring System-Revised
IRB
Institutional Review Board
IRT
Integrated Response Technology
ITT
Intent to treat
IWG
International Working Group
IWGMDS
International Working Group on Morphology of Myelodysplastic Syndrome
MDS
Myelodysplastic syndromes
MedDRA
Medical Dictionary for Regulatory Activities
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
OS
Overall survival
PK
Pharmacokinetics
pRBC
Packed red blood cell
Q3W
Every 3 weeks
QoL
Quality-of-life
RA
Refractory anemia
RAEB
Refractory anemia with excess blasts
RAEB-T
Refractory anemia with excess blasts in transformation
RARS
Refractory anemia with ring sideroblasts
RBC
Red blood cell 
RBC-TI
Red blood cell transfusion independence 
RCMD-RS
Refractory cytopenia with multilineage dysplasia with ringed sideroblasts
SAE
Serious adverse event
SAP
Statistical analysis plan
SC
Steering Committee
SF3B1
splicing factor 3B subunit 1
SGOT
Serum glutamic oxaloacetic transaminase 
SGPT
Serum glutamic pyruvic transaminase
SOP
Standard operating procedure
SUSAR
Suspected unexpected serious adverse reaction
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Table 7:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
TD
Transfusion dependent
TEAE
Treatment-emergent adverse event
TGF
Transforming growth factor
TI
Transfusion independence
ULN
Upper limit of normal
US
United States
USP
United States Pharmacopeia
WFI
Water for injection
WHO
World Health Organization
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APPENDIX B: Myelodysplastic Syndromes World HealthOrganization
Classification System (2016)
Peripheral blood and BM findings and cytogenetics of myelodysplastic syndromes (MDS)
Name
Dysplastic
lineages
Cytopeniasa
Ring sideroblasts as 
% of marrow 
erythroid elements
Bone marrow (BM)
and peripheral 
blood (PB) blasts
Cytogenetics by
Conventional karyotype 
analysis
MDS with single 
lineage dysplasia 
(MDS-SLD)
1
1 or 2
<15% / <5%b
BM <5%, PB <1%, 
no Auer rods
Any, unless fulfills all criteria 
for MDS with isolated del(5q)
MDS with 
multilineage dysplasia 
(MDS-MLD) 
2 or 3
1-3
<15% / <5% b
BM <5%, PB <1%, 
no Auer rods
Any, unless fulfills all criteria 
for MDS with isolated del(5q)
MDS with ring 
sideroblasts
(MDS-RS)
MDS-RS with 
single lineage 
dysplasia 
(MDS-RS-SLD) 
MDS-RS with
multilineage 
dysplasia
(MDS-RS-MLD)
1
2 or 3 
1 or 2
1-3
≥15% / ≥5% b
≥15% / ≥5% b
BM <5%, PB <1%, 
no Auer rods
BM <5%, PB <1%,
No Auer rods
Any, unless fulfills all criteria 
for MDS with isolated del(5q)
Any, unless fulfills all criteria 
for MDS with isolated del(5q)
MDS with isolated 
del(5q)
1-3
1-2
None or any
BM <5%, PB <1%, 
no Auer rods
del(5q) alone or with 1
additional abnormality except -
7 or del(7q)
MDS with excess 
blasts (MDSEB)
MDS-EB-1  
MDS-EB-2
0-3
0-3
1-3
1-3
None or any
None or any
BM 5-9% or PB 2-
4%, no Auer rods
BM 10-19% or PB 5-
19% or Auer rods
Any
Any
MDS, unclassifiable 
(MDS-U)
!
with 1% blood 
blasts
!
with single lineage
dysplasia and
pancytopenia
!
based on defining
cytogenetic
abnormality
1-3
1
0
1-3
3
1-3
None or any
None or any
<15%d
BM <5%, PB=1%c, 
no Auer rods
BM <5%, PB <1%, 
no Auer rods
BM <5%, PB <1%, 
no Auer rods
Any
Any
MDS-defining abnormality
Refractory cytopenia 
of childhood
1-3
1-3
None
BM <5%, PB <2%
Any
a Cytopenias defined as haemoglobin <10 g/dL, platelet count <100 x 109/L, and absolute neutrophil count <1.8 x 109/L; rarely, 
MDS may present with mild anaemia or thrombocytopenia above these levels. PB monocytes must be <1 x 109/L
b If SF3B1 mutation is present.
c 1% PB blasts must be recorded on at least two separate occasions.
d Cases with ≥15% ring sideroblasts by definition have significant erythroid dysplasia, and are classified as MDS-RS-SLD
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Sources: Arber DA, Orazi A, Hasserjian R, Thiele J, Borwitz MJ, Le Beau MM, et al.  The 2016 revision to the World Health 
Organization (WHO) classification of myeloid neoplasms and acute leukemia. Blood 2016;127(20):2391-405.
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APPENDIX C: French-American-British (FAB) Myelodysplastic Syndromes
(MDS) Classification System
MDS Subtype
Peripheral 
Blasts (%)
Bone 
Marrow 
Blasts (%)
AML 
Transformation
Median 
Survival 
(months)
MDS 
Diagnoses 
(%)
Refractory anemia (RA)
≤1
<5
10-20
30-65
10-40
Refractory anemia with 
ringed sideroblasts 
(RARS)
≤1
<5
10-35
34-83
10-35
Refractory anemia with 
excess blasts (RAEB)
<5
5-20
>50
8-18
25-30
Refractory anemia with 
excess blasts in 
transformation (RAEB-T)
≥5
21-29
60-100
4-11
10-30
Chronic myelomonocytic 
leukemia (CMML)
<5
≤20
>40
15-32
10-20
Key: AML = acute myelogenous leukemia; RA = refractory anemia; RARS = refractory anemia with ringed 
sideroblasts; RAEB = refractory anemia with excess blasts; RAEB-T = refractory anemia with excess blasts in 
transformation; CMML = chronic myelomonocytic leukemia.
Data from Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, et al. Proposals for the 
classification of the myelodysplastic syndromes. Br J Haematol 1982;51(2):189–99.
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J Haematol
J Haematol


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APPENDIX D:
International Prognostic Scoring System Score - Revised
IPSS-R Cytogenetic Risk Groups*,**
Cytogenetic Prognostic 
Subgroups
Cytogenetic Abnormalities
Very good
-Y, del(11q)
Good
Normal, del(5q), del(12p), del(20q), double including del(5q)
Intermediate
del(7q), +8, +19, i(17q), any other single or double independent clones
Poor
-7, inv(3)/t(3q)/del(3q), double including -7/del(7q), Complex: 3 abnormalities
Very poor
Complex: >3 abnormalities
IPSS-R Prognostic Score Values*
Prognostic Variable
0
0.5
1
1.5
2
3
4
Cytogenetics
Very 
Good
-
Good
-
Intermediate
Poor
Very Poor
BM Blasts (%)
≤2
-
>2 - <5
-
5 - 10
>10
-
Hemoglobin (g/dL)
≥10
-
8 - <10
<8
-
-
-
Platelets (x 109/L)
≥100
50 - <100
<50
-
-
-
-
ANC (x 109/L)
≥0.8
<0.8
-
-
-
-
-
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
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IPSS-R: Prognostic Risk Category Clinical Outcomes*
No. pts
Very Low
Low
Intermediate
High
Very High
Subjects (%)
7012
19%
38%
20%
13%
10%
Survival***
-
8.8
5.3
3.0
1.6
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AML/25%***,^
-
NR
10.8
3.2
1.4
0.7
*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(12):2454-65.
***Medians, years.
^ Median time to 25% AML evolution.
Schanz J, Tüchler H, Solé F, Mallo M, Luño E, Cervera J, et al. New comprehensive cytogenetic scoring system for 
primary myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia after MDS derived from an 
international database merge. J Clin Oncol 2012;30(8):820-9.
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APPENDIX E: International Working Group Response Criteria for 
MyelodysplasticSyndromes
Altering Natural History of MDS 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 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 pre-treatment but still > 5%
-
Cellularity and morphology not relevant
Marrow CR
b
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 thanpre-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 
plateletsc
-
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 plateletsc
-
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.
c Criteria not applicable for ACE-536-MDS-001 patient population.  
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d 20 – 30% blasts is considered AML according to WHO classification (Vardiman, 2009).
Notes: Deletions to IWG 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.
CCI
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Appendix E: International Working Group Response Criteria for 
MyelodysplasticSyndromes (Continued)
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
Platelet Response (HI-P)
(pre-treatment, <100 X 109/L)
-
Absolute increase of ≥ 30 X 109/L for subjects starting with > 20 X 109/Lplatelets
-
Increase from < 20 X 109/L to > 20 X 109/L and by at least100%b
Neutrophil Response (HI-N) (pre-
treatment, <1.0 X 109/L)
-
At least 100% increase and an absolute increase > 0.5 X109/Lb
Progression or Relapse After HIc
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 Pretreatment 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 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 F: European Organization for Research and Treatment of 
Cancer Quality-of-Life Questionnaire (Version 3.0)
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APPENDIX F: European Organization for Research and Treatment of 
Cancer Quality-of-Life Questionnaire (Version 3.0) 
(continued)
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APPENDIX G: 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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55


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EDMS Doc. Number:
Luspatercept (ACE-536)
Summary of Changes ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
3
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
!
Removal of “progression to acute myeloid leukemia (AML) or high/very high risk 
category MDS per IPSS-R” from the dose modification and treatment 
discontinuation criteria as per Steering Committee request 
Update to the protocol to remove “Progression to acute myeloid leukemia (AML) or high/very 
high risk category MDS per International Prognostic Scoring System – Revised (IPSS-R)” from 
the dose modification and treatment discontinuation criteria to avoid redundancy as “progression 
to AML and high/very high risk category MDS per IPSS-R” is covered by the criteria for disease 
progression per International Working Group (IWG) (Cheson, 2006) used in the protocol.
Revised sections: Protocol Summary; Section 1.3.2, Rationale for the Study; Figure 2: Overall 
Study Design (footnotes); Section 3, Overall Study Design; Section 6, Section 6.2.2; Section 
6.2.3; Procedures; Section 7.2.1.2, Table 6 Dose Modification: Dose Delay, Dose Reduction and 
Discontinuation Guidelines; Section 11.1, Treatment Discontinuation
!
Clarification on the anti-drug antibodies (ADA) and pharmacokinetic (PK) sample 
collection in the Follow-up period to maintain the blinding of the study 
Update to the protocol to include ADA sampling for all subjects in the Follow-up period rather 
than only when tested positive at the End of Treatment (EOT) visit as an available ADA 
antibody status for a subject potentially unblinds the Sponsor and/or the clinical site to a 
subject’s assigned treatment arm.
Revised sections: Protocol Summary; Table 3 Study Endpoints; Section 3; Table 4: Table of 
Events; Section 6.4; Section 6.5; Section 6.8.2
!
Clarification on the timing and allowed time window for the Week 25 Visit 
Update to the protocol to clarify the timing of the Week 25 visit procedures and myelodysplastic 
syndromes (MDS) disease assessments.
Revised sections: Protocol Summary; Table 3: Study Endpoints; Section 3; Section 6; Section 
6.2.2; Table 4: Table of Events
!
Modified protocol criteria related to dose modifications (Dose Delay, Dose 
Reduction and Discontinuation) measures related to potential cases of leukocytosis 
Updates to the protocol language 
 
to further strengthen dose modification and treatment stopping guidance
related to potential cases of leukocytosis as well as to monitor progression to high/very high risk 
MDS or AML as events of interest throughout the study and to report these events to regulatory 
agencies, as requested. 
Revised section: Protocol Summary; Section 3.1; Section 3.2; Section 6.1; Section 6.2.2; Section 
6.8.2; Table 6: Dose Modification: Dose Delay, Dose Reduction, and Discontinuation 
Guidelines; Section 9.11.2; Section 10.5; Section 10.7.
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EDMS Doc. Number:
Luspatercept (ACE-536)
Summary of Changes ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
4
ACE-536-MDS-001 Amendment 2.0 Final: 09 May 2017
!
Extended the Posttreatment Follow-up Period from “at least 2 years” to “at least 3 
years” from the date of last dose of investigational product (IP)
Updates to the protocol language based on feedback received from 
 
 to reflect the collection of all cases of cancers occurring in subjects for at least 3 years 
after the last investigational product is taken.
Revised section: Protocol Summary; Table 3: Study Endpoints; Section 3.1; Section 3.2; Figure
2: Overall Study Design; Table 4: Table of Events; Section 6.1; Section 6.2; Section 6.8.2; 
Section 9.10.2; Section 11.1; Section 11.2
The amendment also includes several other minor clarifications and corrections:
!
Administrative change to the Medical Monitor/ Emergency Contact Information 
(Cover page).
!
Correction in Table 3 (Study Endpoints) to reflect the correct timeframes 
corresponding with a 16-week period. 
!
Clarification in Section 4.2 (Inclusion criterion 5) regarding required wash out period 
for both prior erythropoiesis stimulating agents (ESA) and granulocyte colony 
stimulating factor (G-CSF) treatment.
!
Clarification in Section 4.2 (Inclusion criterion 8) regarding the requirement to use 
contraception in females of childbearing potential if they are sexually active.
!
Clarification in Section 4.3 (Exclusion criterion 5) regarding the sequence of 
assessments evaluated excluding iron deficiency.
!
Clarification in Section 4.3 (Exclusion criterion 20); Table 4 (Table of Events)
including footnotes; and Section 6.1 regarding timing of local testing confirming the 
Human Immunodeficiency Virus (HIV), Hepatitis B, and/or Hepatitis C status.
!
Clarification in Section 6 regarding the exceptional use of local laboratories to 
determine study eligibility after sponsor consultation (eg, hemolyzed sample etc.).  
!
Clarification in Section 7.2 regarding the IP administration of volumes greater than 
1.2 mL and the maximum total dose per administration that should not be exceeded.
!
Clarification in Section 8.1.1 that iron-chelating therapy at time of randomization 
should be on a stable or decreasing dose for at least 8 weeks.
!
  
!
Clarification in Appendix E regarding criteria related to the definition of disease 
progression not applicable for the ACE-536-MDS-001 patient population. 
!
Administrative changes (eg, consistency of acronym use throughout the document per 
Celgene Style Guide, spelling, grammatical error corrections, etc.) were also made 
throughout the document.
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EDMS Doc. Number:
Luspatercept (ACE-536)
Summary of Changes ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
3
ACE-536-MDS-001 Amendment 1.0 Final: 21 Sep 2016
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
!
Modified protocol criteria related to contraception measures to align with definition 
of “highly effective contraception measures” as per Clinical Trial Facilitation Group
(CTFG) guidelines
Updates to the protocol language regarding contraception and pregnancy testing for females of 
child bearing potential (FCBP) to align with definition of “highly effective contraception 
measures” as per Clinical Trial Facilitation Group (CTFG) guidelines were requested
 
 
 
Revised sections: Section 1.2.2.1, Potential Risks of Human Use; Section 4.2, Inclusion Criteria
8 and 9
!
Added monitoring of other malignancies/pre-malignancies as “important medical 
events”
 
 the Scientific 
Steering Committee (SSC) recommended monitoring of other malignancies/pre-malignancies
during the Treatment Period and for the duration of the Long-term Follow-up Period as 
“important medical events.” Designation as an “important medical event” will require sites to 
report events of other malignancies/pre-malignancies under the same guidelines as a serious 
adverse event.  These additional measures will further strengthen safety monitoring throughout 
the course of the study. 
New section: Section 10.5, Other Malignancies/Pre-malignancies
Revised sections: Protocol Summary; Section 3.2, Study Duration for Patients; Section 5, Table 
4 Table of Events; Section 6, Procedures; Section 6.1, Screening Period; Section 6.2.1, Primary 
Phase of Treatment Period: Weeks 1-24; Section 6.2.2, MDS Disease Assessment: Week 25 
Visit; Section 6.8.2, Long-term Follow-up; Section 11.2, Study Discontinuation
!
Added site guidance regarding collection of transfusion data
As additional assurance that all transfusion data is collected throughout the course of the study
(including transfusions that may have occurred in between study visits at local institutions), 
specific guidance for sites has been included in the protocol amendment.
 
 
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EDMS Doc. Number:
Luspatercept (ACE-536)
Summary of Changes ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
4
ACE-536-MDS-001 Amendment 1.0 Final: 21 Sep 2016
Revised sections: Section 5, Table 4 Table of Events; Section 6.1, Screening Period; Section 6.2, 
Treatment Period; Section 6.2.1, Primary Phase of Treatment Period: Weeks 1-24; Section 6.2.3, 
Extension Phase of the Treatment Period: After Week 25 Visit; Section 7.2, Treatment 
Administration and Schedule
!
 
 
!
Included dose modification and treatment discontinuation criteria regarding 
leukocyte increase and disease progression as per International Working Group
(IWG) criteria (Cheson, 2006)
Additional dose modification and treatment discontinuation rules to account for potential cases 
of leukocytosis and inclusion of disease progression per IWG criteria as treatment 
discontinuation criteria have been incorporated in the protocol amendment based upon 
 
.
Revised sections: Protocol Summary; Section 1.3.2, Rationale for the Study; Figure 2 
(footnotes); Section 3, Overall Study Design; Section 6, Procedures; Section 4.2, Inclusion 
Criterion 3; Section 7.2.1.2, Table 6 Dose Modification: Dose Delay, Dose Reduction and 
Discontinuation Guidelines; Section 11.1, Treatment Discontinuation
!
Accounted for update of World Health Organization (WHO) classification system
(Arber 2016) and included French-American-British (FAB) classification system for 
baseline MDS diagnosis 
As ring sideroblast positive disease is a key attribute of the study’s patient population additional 
language was added to the protocol taking into consideration the recent update to the WHO
classification criteria (Arber, 2016), which further expanded the definition of ring sideroblast 
positive disease to also include patients with ≥ 5% ring sideroblasts and confirmation of SF3B1 
mutation along with patients who solely meet the previously established ≥ 15% threshold.  In 
addition, the Scientific Steering Committee (SSC) agreed to this modification and also 
recommended use of the French-American-British (FAB) classification system in addition to the 
WHO classification system to determine eligibility related to baseline MDS diagnosis. 
Revised sections: Section 1.1.1.2, Ring Sideroblasts; Section 3.1, Study Design, Section 4.2, 
Inclusion Criterion 3; Section 6.1 Screening Period
!
Extended collection of transfusion data after treatment discontinuation
The duration of transfusion data collection has been extended to 16 weeks after last dose of IP or 
End of Treatment visit (whichever is later)
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EDMS Doc. Number:
Luspatercept (ACE-536)
Summary of Changes ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
5
ACE-536-MDS-001 Amendment 1.0 Final: 21 Sep 2016
 based on their assessment of another Celgene clinical study. This additional transfusion 
data  should aid in the characterization of the luspatercept risk-benefit profile.
Revised sections:  Protocol Summary; Section 3.1, Study Design and Figure 2: Overall Study 
Design; Section 5, Table 4 Table of Events; Section 6.2.1, Primary Phase of Treatment Period: 
Weeks 1-24; Section 6.8.2, Long-term Follow-up
!
Included upper pre-transfusion Hgb threshold of 10 g/dL to protocol eligibility 
criterion related to requirement of transfusions
With the older demographic in myelodysplastic syndromes (MDS), patients often develop 
overlapping comorbidities.  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.  This was discussed and agreed to with the Scientific Steering 
Committee (SSC).  
It is important to note that subjects may still receive transfusions at a lower Hgb threshold during 
the Treatment Period if clinically indicated at the investigators discretion as outlined in Protocol 
Section 8.1.2.  Additional language has been added to Section 8.1.2 as per SSC recommendation 
to provide further clarification on ensuring consistency in transfusion practices in regard to pre-
transfusion Hgb threshold after study entry.
Revised sections:  Section 4.2, Inclusion Criterion 6; Section 6.1, Screening Period; Section 
8.1.2, RBC Transfusions
!
Added language to allow for the participation of patients with > 2.0 upper limit of 
normal (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 patients from the trial.
Revised section: Section 4.3, Exclusion Criterion 14
!
Revised eligibility criteria to exclude patients with significant cardiac dysfunction 
based on known local ECHO/MUGA results
To further ensure patients with significant cardiac dysfunction are not enrolled into study, the 
Scientific Steering Committee (SSC) recommended that patients with known ejection fraction < 
35% be excluded (based upon local ECHO or MUGA performed within 6 months of 
randomization date).
Revised sections:  Section 4.3, Exclusion Criterion 19
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EDMS Doc. Number:
Luspatercept (ACE-536)
Summary of Changes ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
6
ACE-536-MDS-001 Amendment 1.0 Final: 21 Sep 2016
!
Revised eligibility criteria to allow use of experimental agents prior to 
randomization
As the MDS population is an older demographic, many patients have overlapping comorbidities 
that may require treatment, which may include investigational agents.  Contingent that the last 
dose of the investigational agent is at least 5 weeks from date of randomization (or 5 times the 
half-life, if half-life is known), these patients should not be excluded.
Revised sections: Section 4.3, Exclusion Criteria 1 and 8
!
Revised eligibility criteria to allow enrollment of patients who received a prior sub-
therapeutic course of hypomethylating agent or lenalidomide 
As the investigational use of active therapy (eg, hypomethylating agents, lenalidomide) is 
common in the clinical setting in certain countries (eg, US) for lower risk, non del5q, MDS 
patients who are erythropoiesis-stimulating agent (ESA) refractory; patients who may have 
received sub-therapeutic courses of these agents and discontinued due to intolerance should not 
be excluded from the protocol.  The Scientific Steering Committee recommended the following 
maximum durations of prior treatment with these agents to ensure only patients receiving sub-
therapeutic courses are enrolled.  
Lenalidomide = no more than 1 calendar week of treatment
Hypomethylating agents = no more than 2 doses 
Revised section: Section 4.3, Exclusion Criterion 1 
!
Decreased the ESA/G-CSF/GM-CSF washout window to 4 weeks from date of 
randomization
In order to ensure that the required ESA/growth factor washout period can be completed within 
protocol 5-week screening window, the Scientific Steering Committee (SSC) recommended 
decreasing the washout period to 4 weeks to avoid unnecessary screen failures.
Revised section: Section 4.2, Inclusion Criterion 5
!
Updated applicable protocol sections to align with Investigator’s Brochure (IB) 
Edition 8 (IB update occurring in parallel)
Revised sections: Section 1.2, Compound Background; Section 1.2.1.1, Toxicology Studies; 
1.2.2.1, Potential Risks of Human Use; Section 1.3.1, Study Rationale and Purpose
!
Added information related to benefit/risk and added section titled Overall Benefit 
Risk Assessment to the protocol
 information 
related to benefit/risk and an overall benefit risk assessment has been included in the protocol to 
allow the investigator to review the information and form his/her opinion of the benefit/risks to 
the patient in the current clinical trial.
New section:  Section 1.2.2.2, Overall Benefit Risk Assessment
Revised sections:  Section 1.2.2.1, Potential Risks of Human Use; 
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EDMS Doc. Number: 
Luspatercept (ACE-536)
Summary of Changes ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
7
ACE-536-MDS-001 Amendment 1.0 Final: 21 Sep 2016
The amendment also includes several other minor clarifications and corrections:
!
Update to sponsor medical monitor contact information on protocol page 2.
!
Update to sponsor therapeutic area head title on protocol page 3.Additional 
supportive information added to Section 1.3.1 Study Rationale  Clarification in 
Protocol Summary that bone marrow aspirate (or biopsy) for assessment of MDS 
disease is both efficacy and safety assessmentClarification in Section 4.3 regarding 
history of other malignancies (Exclusion criterion 15)Clarification in Section 4.3
(Exclusion criterion 20); Section 5, Table 4 Table of Events; and Section 6.1, 
Screening Period regarding assessment of known history of Human 
Immunodeficiency Virus (HIV), Hepatitis B, and/or Hepatitis C active infection.  
Clarification in Section 4.3 (Exclusion criterion 22) regarding exclusion of 
vulnerable patients.  
.Clarification in Section 6.1 regarding bone marrow sample collection
requirements to determine study eligibility
 
Update to Section 7.1 with 
current information regarding investigational product (IP) stability data Clarification 
in Section 7.1 regarding supply of placebo Clarification in Section 7.3 regarding 
randomization processUpdate to Section 7.4 to account for differences in local 
regulations between countries regarding packing and labeling of investigational 
product (IP)Clarification in Section 8.1 on allowance of attenuated vaccines (eg,
influenza vaccine) as concomitant medication if clinically indicatedClarification in 
Section 8.1.2 regarding pre-transfusion hemoglobin (Hgb) threshold recommendation 
during the Treatment PeriodSection 17 was updated to include additional citations 
added during this protocol amendment.Administrative changes (eg, consistency of 
acronym use throughout document per Celgene Style Guide, spelling, grammatical 
error corrections, etc.) were also made throughout document
Supportive Literature Used in the Summary of Changes 
Arber DA, Orazi A, Hasserjian R, Thiele J, Borwitz MJ, Le Beau MM, et al.  The 2016 revision 
to the World Health Organization (WHO) classification of myeloid neoplasms and acute 
leukemia. Blood 2016;127(20):2391-405. 
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 A, Moustaki M, Liapi O, Karpathios T. Gilbert syndrome. Eur J Pediatric 
2012;171(1):11-5.
VanWagner LB, Green RM. Evaluating elevated bilirubin levels in asymptomatic adults. JAMA 
2015;3; 313(5):516-7.
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
1
STATISTICAL ANALYSIS PLAN
A PHASE 3, DOUBLE-BLIND, RANDOMIZED STUDY TO COMPARE THE 
EFFICACY AND SAFETY OF LUSPATERCEPT (ACE-536) VERSUS PLACEBO FOR
THE TREATMENT OF ANEMIA DUE TO IPSS-R VERY LOW, LOW, OR 
INTERMEDIATE RISK MYELODYSPLASTIC SYNDROMES IN SUBJECTS WITH 
RING SIDEROBLASTS WHO REQUIRE RED BLOOD CELL TRANSFUSIONS
STUDY DRUG:
Luspatercept (ACE-536)
PROTOCOL NUMBER:
ACE-536-MDS-001
DATE FINAL:
May 31, 2018
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.
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
2
TABLE OF CONTENTS
SIGNATURE PAGE...................................................................................................................8
1.
LIST OF ABBREVIATIONS.................................................................................10
2.
INTRODUCTION..................................................................................................12
3.
STUDY OBJECTIVES...........................................................................................13
3.1.
Primary Objective...................................................................................................13
3.2.
Secondary Objectives .............................................................................................13
4.
INVESTIGATIONAL PLAN .................................................................................14
4.1.
Overall Study Design and Plan ...............................................................................14
4.1.1.
Screening Period.....................................................................................................14
4.1.2.
Randomization........................................................................................................14
4.1.3.
Double-Blind Treatment Period..............................................................................15
4.1.4.
Posttreatment Follow-up Period..............................................................................17
4.1.5.
Study Duration for Subjects....................................................................................17
4.1.6.
Unscheduled Visits.................................................................................................18
4.1.7.
End of Treatment Visits..........................................................................................18
4.1.8.
End of Trial ............................................................................................................18
4.1.9.
Visit Window .........................................................................................................19
4.2.
Treatment Administration and Schedule .................................................................19
4.2.1.
Dose Titration Increase...........................................................................................19
4.2.2.
Dose Delay and Dose Reduction.............................................................................20
4.2.3.
Overdose ................................................................................................................22
4.3.
Study Endpoints .....................................................................................................31
4.4.
Blinding..................................................................................................................33
4.5.
Sample Size Determination.....................................................................................33
5.
GENERAL STATISTICAL CONSIDERATIONS .................................................34
5.1.
Reporting Conventions ...........................................................................................34
5.2.
Analysis Populations ..............................................................................................37
5.2.1.
Intent-to-Treat Population.......................................................................................37
5.2.2.
Safety Population....................................................................................................37
5.2.3.
Health-related QoL Evaluable Population...............................................................37
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
3
6.
SUBJECT DISPOSITION......................................................................................38
7.
PROTOCOL DEVIATIONS/VIOLATIONS ..........................................................40
8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS................................41
8.1.
Demographics.........................................................................................................41
8.2.
Baseline Clinical Characteristics.............................................................................41
8.3.
Baseline Hematology Characteristics......................................................................42
8.4.
MDS Diagnosis History..........................................................................................42
8.5.
Prior Transfusion History .......................................................................................43
8.6.
Medical History......................................................................................................43
8.7.
Prior and Concomitant Medications........................................................................43
8.7.1.
Prior Medication.....................................................................................................43
8.7.2.
Concomitant Medication.........................................................................................43
8.8.
Concomitant Procedures and Surgeries...................................................................44
8.9.
Coombs’ Test .........................................................................................................44
8.10.
Pregnancy...............................................................................................................44
9.
STUDY TREATMENTS AND EXTENT OF EXPOSURE....................................45
9.4.
Cumulative Dose ....................................................................................................45
9.5.
Dose Modification..................................................................................................45
10.
PHARMACOKINETIC ANALYSIS......................................................................47
10.1.1.
Pharmacokinetic Analysis.......................................................................................47
10.1.2.
Anti-Drug Antibodies Analysis...............................................................................47
11.
EFFICACY ANALYSIS ........................................................................................49
11.1.
Determination of Week 24 and Week 48 cutoff date...............................................49
11.2.
Analysis of Primary Efficacy Endpoint...................................................................50
11.3.
Analyses of Secondary Efficacy Endpoints.............................................................51
11.3.1.
Key Secondary Efficacy Endpoint ..........................................................................51
11.3.2.
Mean Hemoglobin Increase ≥ 1.0 g/dL ...................................................................51
11.3.3.
Total RBC Units Transfused over 16 Weeks...........................................................52
11.3.4.
Proportion of Subjects Achieving RBC-TI with Duration ≥ 8 Weeks (Week 
1 -48)......................................................................................................................52
11.3.5.
Proportion of Subjects Achieving Modified Erythroid Response.............................52
11.3.6.
Duration of RBC-TI................................................................................................53
11.3.7.
Time to RBC-TI .....................................................................................................53
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3


EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
4
11.3.8.
Health-related QoL assessed by EORTC QLQ-C30................................................53
11.3.9.
Proportion of Subjects Achieving Hematological Improvement-Neutrophils...........54
11.3.10.
Proportion of Subjects Achieving Hematological Improvement-Platelets................54
11.3.11.
Mean Change in Mean Daily Dose of Iron Chelation Therapy ................................55
11.3.12.
Mean Serum Ferritin Decrease................................................................................55
11.3.13.
Time to Progression to Acute Myelogenous Leukemia ...........................................55
11.3.14.
Overall Survival .....................................................................................................56
11.4.
Subgroup Analysis..................................................................................................56
12.
SAFETY ANALYSIS ............................................................................................58
12.1.
Adverse Events.......................................................................................................58
12.1.1.
Adverse Events by Cycle and Maximum Dose Received ........................................59
12.1.2.
Adverse Events of Interest......................................................................................60
12.1.3.
Death......................................................................................................................60
12.2.
Clinical Laboratory Evaluations..............................................................................61
12.3.
Vital Sign Measurements........................................................................................61
12.4.
Electrocardiograms.................................................................................................61
12.5.
ECOG Performance Status......................................................................................62
15.
TIMING OF ANALYSES ......................................................................................65
15.1.
Interim analysis ......................................................................................................65
15.2.
Final analysis..........................................................................................................65
16.
REFERENCES.......................................................................................................66
17.
APPENDICES........................................................................................................68
17.1.
Appendix A: Date Imputation Guideline.................................................................68
17.1.1.
Impute Missing Adverse Events/ Prior or Concomitant Medications and 
Procedures/Medical History, End Date of Prior ESA treatment, Date of 
Original MDS Diagnosis.........................................................................................68
17.2.
Appendix B: Myelodysplastic Syndromes World HealthOrganization
Classification System  (2016)..................................................................................70
17.3.
Appendix C: French-American-British (FAB) Myelodysplastic Syndromes 
(MDS) Classification System..................................................................................72
17.4.
Appendix D:  International Prognostic Scoring System Score - Revised..................73
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235


EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
5
17.5
Appendix E:  International Working Group Response Criteria for 
MyelodysplasticSyndromes....................................................................................75
Appendix E:  International Working Group Response Criteria for Myelodysplastic
Syndromes (Continued) ..........................................................................................77
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
6
LIST OF TABLES
Table 1:
Abbreviations and Specialist Terms........................................................................10
Table 2:
Starting Dose Level with Dose Reductions and Dose Titration................................20
Table 3:
Dose Modification: Dose Delay, Dose Reduction, and Discontinuation 
Guidelines ..............................................................................................................20
Table 4:
Table of Events.......................................................................................................24
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
7
LIST OF FIGURES
Figure 1:
Overall Study Design..............................................................................................21
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
8
SIGNATURE PAGE
STATISTICAL ANALYSIS PLAN (SAP) AND SAP AMENDMENT APPROVAL SIGNATURE PAGE 
SAP TITLE
A Phase 3, Double-blind, Randomized Study to Compare the Efficacy and Safety of
Luspatercept (ACE-536) Versus Placebo for the Treatment of Anemia Due to IPSS-R 
Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes in Subjects with 
Ring Sideroblasts Who Require Red Blood Cell Transfusions
SAP VERSION, DATE
Final Draft, 30-May-2018
SAP AUTHOR
 
Printed Name and Title
Signature and Date
PROTOCOL TITLE
A Phase 3, Double-blind, Randomized Study to Compare the Efficacy and Safety of
Luspatercept (ACE-536) Versus Placebo for the Treatment of Anemia Due to IPSS-R 
Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes in Subjects with 
Ring Sideroblasts Who Require Red Blood Cell Transfusions
INVESTIGATIONAL 
PRODUCT
Luspatercept (ACE-536)
PROTOCOL NUMBER
ACE-536-MDS-001
PROTOCOL VERSION, 
DATE
Amendment 2.0, 09-May-2017
SIGNATURE 
STATEMENT
By my signature, I indicate I have reviewed this SAP and find its contents to be 
acceptable.
Statistical Therapeutic Area Head
Signature
   
Printed Name
 
Date
Lead Clinical Research Physician / Clinical Research Physician
Signature
Printed Name
Date
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
9
Lead Product Safety Physician
Signature
Printed Name
Date
CCI
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
10
1.
LIST OF ABBREVIATIONS
Table 1:
Abbreviations and Specialist Terms
ADA
Antidrug antibodies
AE
Adverse event
AML
Acute myelogenous leukemia
ANCOVA
Analysis of covariance
ATC
Anatomical therapeutic chemical
BMA
Bone marrow aspirate 
BMB
Bone marrow biopsy
BMI
Body mass index
BSC
Best supportive care
CI
Confidence interval
CTCAE
Common Terminology Criteria for Adverse Events
CMH
Cochran Mantel Haenszel
DMC
Data Monitoring Committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EPO
Erythropoietin
EOT
End of treatment
eCRF
Electronic case report form
ESA
Erythropoiesis-stimulating agents
FCBP
Female of childbearing potential
HI-E
Hematologic improvement-erythroid
HI-N
Hematologic improvement-neutrophils
HI-P
Hematologic improvement-platelets
HIV
Human Immunodeficiency Virus 
HRQoL
Health-related quality of life 
ICF
Informed consent form
ICT
Iron chelation therapy
IP
Investigational Product
IPSS-R
International Prognostic Scoring System-Revised
ITT
Intent to treat
IVRS
Interactive voice response system
IWG
International Working Group
KM
Kaplan-Meier
MDS
Myelodysplastic syndromes
MedDRA®
Medical Dictionary for Regulatory Activities
mHI-E
Modified hematologic improvement-erythroid
NCI
National Cancer Institute
OS
Overall survival
PK
Pharmacokinetics
PT
Preferred term
QTcF
Heart-rate corrected QT with Fredericia’s correction
RBC
Red blood cell 
RBC-TI
Red blood cell transfusion independence
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
11
RS
Ring Sideroblasts
SAE
Serious adverse event
SAP
Statistical analysis plan
SAS
Statistical analysis software
SF3B1
Splicing factor 3B subunit 1
SOC
System organ class
SD
Standard deviation
TEAE
Treatment-emergent adverse event
TGF
Transforming growth factor
WBC
White blood cell 
WHO
World Health Organization
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
12
2.
INTRODUCTION
This statistical analysis plan (SAP) describes the analyses and data presentations for Celgene’s 
protocol [ACE-536-MDS-001] “A Phase 3, Double-blind, Randomized Study to Compare the 
Efficacy and Safety of Luspatercept (ACE-536) Versus Placebo for the Treatment of Anemia 
Due to IPSS-R Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes in Subjects 
with Ring Sideroblasts Who Require Red Blood Cell Transfusions”. It contains definitions of 
analysis populations, derived variables and statistical methods for the analysis of efficacy and 
safety.
These analyses include one interim analysis and one final analysis. Throughout this SAP, the 
treatment arms will be referred to as luspatercept (ACE-536) and 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 interim/final analysis. This SAP will be 
finalized and signed prior to the clinical database lock. All statistical analyses detailed in this 
SAP will be conducted using Statistical Analysis Software (SAS)® Version 9.2 or higher.  
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
13
3.
STUDY OBJECTIVES
3.1.
Primary Objective
The primary objective is to evaluate red blood cell transfusion independence (RBC-TI) of 
luspatercept compared with placebo for the treatment of anemia due to the revised International 
Prognostic Scoring System (IPSS-R) very low, low, or intermediate risk Myelodysplastic 
Syndromes (MDS) in subjects with ring sideroblasts who require RBC transfusions.
3.2.
Secondary Objectives
The secondary objectives are as follows:
!
To assess the safety and tolerability of luspatercept compared to placebo
!
To evaluate the effect of luspatercept on reduction in RBC transfusions, increase in
                  hemoglobin, duration of RBC-TI, improvement in health-related quality of life
                 (HRQoL) (i.e. European Organization for Research and Treatment of Cancer Quality
                of Life Questionnaire [EORTC QLQ-C30]), increase in neutrophils, increase in
                 platelets, decrease in serum ferritin, decrease in iron chelation therapy use, and time
                 to RBC-TI compared with placebo
!
To evaluate population pharmacokinetics and exposure-response relationships for
                  luspatercept in MDS subjects
 
 
 
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
14
4.
INVESTIGATIONAL PLAN
4.1.
Overall Study Design and Plan
This is a Phase 3, double-blind, randomized, placebo-controlled, multicenter study to determine 
the efficacy and safety of luspatercept (ACE-536) versus placebo for the treatment of anemia due 
to IPSS-R very low, low, or intermediate risk MDS in subjects with ring sideroblasts who require 
RBC transfusions. The study will have approximately 210 subjects randomized worldwide (i.e.,
78 sites and 11 countries; US, Germany, France, Spain, Italy, UK, Sweden, Turkey, Belgium, 
Canada, Netherlands).
The study is divided into the Screening Period, a double-blind Treatment Period (Primary Phase 
and Extension Phase), and a Posttreatment Follow-up Period.
The study design is described in detail in Figure 1. 
4.1.1.
Screening Period
Upon giving written informed consent, subjects enter the Screening Period to determine
eligibility. Subject screening procedures are to take place within 5 weeks prior to randomization.
During the Screening Period, the subject will undergo safety and other assessments to determine
eligibility for the randomized study.
Central review of bone marrow aspirate smear and biopsy, peripheral blood smear, and
cytogenetics will be used to confirm MDS diagnosis and World Health Organization (WHO)
classification (Appendix B) and/or FAB classification (Appendix C) and to determine the 
baseline IPSS-R risk classification (Greenberg, 2012; Appendix D).
Transfusion history must be available for at least the 16 weeks immediately preceding and
including the date of randomization. Transfusion data should include the type of transfusion 
(e.g., RBC, platelets), number of units, and date of transfusion. Red blood cell (RBC) transfusion
data should include the hemoglobin (Hgb) value for which the transfusion was administered (i.e.,
pre-transfusion Hgb value).
4.1.2.
Randomization
Randomization will occur by a central randomization procedure using integrated response
technology (IRT). Eligible subjects will be randomized at a 2:1 ratio of Luspatercept (ACE-536)
versus Placebo:
!
Experimental Arm: Luspatercept (ACE-536): Starting dose of 1.0 mg/kg 
subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day 
treatment cycle)
OR
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versus Pl


EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
15
!
Control Arm: Placebo (Volume equivalent to experimental arm) subcutaneous 
injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle). 
After randomization, no crossover between the treatment arms will be permitted at any point
during the study.
Stratification will be based on the following factors:
!
RBC Transfusion burden at baseline
∀
≥6 RBC units/8 weeks (mean of the two consecutive 8 weeks periods
immediately prior to randomization)
∀
< 6 RBC units/8 weeks (mean of the two consecutive 8 weeks periods
immediately prior to randomization)
!
IPSS-R at baseline
∀
Very low, low
∀
Intermediate
4.1.3.
Double-Blind Treatment Period
Primary Phase: Weeks 1-24
The first dose of investigational product (IP) should be administered no later than 3 days after 
randomization, and can be on the same day as randomization. Subjects will receive IP (either 
luspatercept or matching placebo) on Day 1 of each 21-day treatment cycle.
In both treatment arms, best supportive care (BSC) may be used in combination with study 
treatment when clinically indicated per investigator. Best supportive care includes, but is not 
limited to, treatment with transfusions, antibiotic, antiviral and/or antifungal therapy, and
nutritional support as needed. Best supportive care for this study excludes the use of 
erythropoiesis-stimulating agents (ESAs).
Subjects should receive IP through at least the first 24 calendar weeks after the date of first dose
unless the subject experiences unacceptable toxicities, withdraws consent, or meets any other
treatment discontinuation criteria (Section 6).
Week 25 Visit: MDS Disease Assessment
The first MDS Disease Assessment should be completed 24 calendar weeks after the date of 
first dose, regardless of dose delays. The calculated due date for the first MDS Disease 
Assessment is defined as C1D1 + 168 days (i.e. 24 weeks).  The MDS Disease Assessment by 
the investigator should be completed no sooner than 24 calendar weeks (i.e. 168 days) after the 
day of C1D1 and requires a minimum of 24 weeks of transfusion information for the assessment 
of clinical benefit. Up to date information related to all transfusions received during the 
Treatment Period (including those received at outside institutions) must be available prior to 
completion of the clinical benefit component of the MDS Disease Assessment.
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
16
As central laboratory results from bone marrow and peripheral blood samples are required as part 
of the MDS Disease Assessment, a ±14 day window is allowed for the Week 25 Visit in order to 
account for sample collection and turnaround time of results.  
In order for subjects to remain on double-blind treatment beyond the first 24 calendar weeks, the
following criteria must be confirmed upon the completion of the MDS Disease Assessment by
the investigator:
!
Evidence of clinical benefit (e.g., decrease in RBC transfusion requirement compared 
to baseline requirement or hemoglobin increase compared to baseline) 
AND
!
Absence of disease progression per IWG criteria for altering natural history of MDS 
(Cheson, 2006; Appendix E).
Based on the outcome of the MDS Disease Assessment, subjects will either be discontinued from 
treatment with IP and enter the Posttreatment Follow-up Period or continue double-blind 
treatment with IP in the Extension Phase of the Treatment Period.
For subjects that meet criteria to continue double-blind treatment in the Extension Phase, the 
duration between the last dose of IP in the Primary Phase and first Extension Phase dose should 
not be delayed beyond 21 days solely due to awaiting cytomorphology/cytogenetics results 
contingent that the investigator has confirmed absence of signs of disease progression based on 
review of peripheral blood parameters.  
In circumstances where the subject does receive the first Extension Phase dose prior to 
cytomorphology/cytogenetics results being available, the investigator must complete assessment 
of cytomorphology/cytogenetics results prior to the next IP administration.
Extension Phase of the Treatment Period: After Week 25 Visit
Subjects who meet criteria to remain on double-blind treatment after completion of the Week 25 
Visit MDS Disease Assessment may continue dosing on Day 1 of each 21 day treatment cycle in 
the Extension Phase of the Treatment Period until the subject experiences unacceptable 
toxicities, disease progression per IWG criteria for altering natural history of MDS (Cheson, 
2006; Appendix E), withdraws consent, or meets any other discontinuation criteria (Section 6).
MDS Disease Assessment will be repeated by the investigator at Extension Cycle 8, Day 1 and
Day 1 of every eighth Extension Cycle thereafter (i.e., Extension Cycle 8, 16, 24+, etc. or every
24 weeks in the event of dose delays) until the subject is discontinued from treatment.
For subjects to continue double-blind treatment in the Extension Phase of the Treatment Period,
each MDS Disease Assessment should confirm continued clinical benefit and absence of disease 
progression per IWG criteria for altering natural history of MDS (Cheson, 2006; Appendix E). 
Serial measurements of safety and efficacy will continue on scheduled study visits (Day 1 of
every treatment cycle) in the Extension Phase of the Treatment Period. 
Best supportive care may continue to be used in combination with study treatment when
clinically indicated per investigator. 
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
17
The same dose titration, delay and/or reduction, and treatment discontinuation criteria will still
apply in the Extension Phase of the Treatment Period (Section 4.2). 
All subjects who have received at least one dose of study treatment should undergo end of
treatment (EOT) evaluations when IP is discontinued (Section 4.1.7).
4.1.4.
Posttreatment Follow-up Period
Safety Follow-up
All subjects discontinued from protocol-prescribed therapy for any reason will be followed for a 
period of 42 days after the last dose of IP for AE reporting, as well as SAEs made known to the 
Investigator at any time thereafter that are suspected of being related to IP. Females of 
childbearing potential should avoid becoming pregnant for 12 weeks after the last dose of IP and 
males will be advised to use a male latex condom or nonlatex condom NOT made out of natural 
(animal) membrane (for example, polyurethane), during any sexual contact with FCBP prior to 
starting investigational product and continue for 12 weeks following the last dose of IP, even if 
he has undergone a successful vasectomy.
Long-Term Follow-up  
Transfusion data collection will continue up until 16 weeks from the date of last dose of IP. 
For subjects who do not complete the Primary Treatment Phase or do not participate in the 
Extension Phase or subjects who terminate the Extension Phase with less than 1 year of ADA 
monitoring, ADA and PK samples will be collected at EOT and then every 12 weeks for up to 
one year from the first dose in the Primary Treatment Phase.
For all subjects who receive at least one dose of IP, continuation of monitoring for progression to 
AML and other malignancies/pre-malignancies will occur in the Posttreatment Follow-up Period 
along with data collection of subsequent MDS therapies, and overall survival for at least 3 years 
from the date of last dose of IP unless the subject withdraws consent from the study, dies or is 
lost to follow-up.  
4.1.5.
Study Duration for Subjects 
After a Screening Period of up to 5 weeks, eligible subjects who are randomized to receive IP 
(either placebo or luspatercept) should continue double-blind treatment through at least the first 
24 calendar weeks of the study unless the subject experiences unacceptable toxicities, disease 
progression per IWG response criteria for altering natural history of MDS (Cheson, 2006; 
Appendix E), withdraws consent, or meets any other discontinuation criteria (Section 6).
Subjects who meet protocol defined criteria as determined by the Week 25 Visit MDS Disease 
Assessment may continue double-blind treatment beyond the Week 25 Visit (i.e. in the 
Extension Phase of the Treatment Period) until the subject experiences unacceptable toxicities, 
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
18
disease progression per IWG criteria for altering natural history of MDS (Cheson, 2006; 
Appendix E), withdraws consent, or meets any other discontinuation criteria (Section 6).
For all subjects who receive at least one dose of IP, continuation of monitoring for progression to 
AML and other malignancies/pre-malignancies will occur in the Posttreatment Follow-up Period, 
along with subsequent MDS therapies, and overall survival for at least 3 years from the date of 
last dose of IP unless the subject withdraws consent from the study, dies or is lost to follow-up.  
Subject who receive at least one dose will also be followed for AEs up through 42 days post last 
dose.
4.1.6.
Unscheduled Visits
Should it become necessary to repeat an evaluation (e.g. laboratory tests or vital signs), the 
results of the repeat evaluation should be entered as an additional unscheduled visit in the
electronic case report form (eCRF).  
4.1.7.
End of Treatment Visits
An end of treatment (EOT) evaluation will be performed for subjects who are withdrawn from 
treatment for any reason as soon as possible after the decision to permanently discontinue 
treatment has been made.
If a subject is discontinued during a regular scheduled visit, all EOT procedures should be 
completed at that visit. If a procedure had been performed within 7 days of the EOT visit, it does 
not need to be repeated unless clinically indicated per investigator discretion (with the exception 
of blood pressure assessment and sample collection for hematology, chemistry, and urinalysis).  
Bone marrow procedure should only be performed at EOT visit if > 90 days from prior bone 
marrow procedure.  End of Treatment Visit procedures/assessments may occur at 42 Day 
Follow-up assessment if subject is discontinued within +/- 7 days of 42 Day Follow-up 
assessment.
4.1.8.
End of Trial 
The End of Trial is defined as either the date of the last visit of the last subject to complete the
post-treatment follow-up, or the date of receipt of the last data point from the last subject that is
required for primary, secondary 
 analysis, whichever is the later date.
The Sponsor may end the trial when all key endpoints and objectives of the study have been
analyzed, and the availability of a roll-over protocol exists into which any subjects remaining on
study may be consented and continue to receive access to luspatercept and/or complete post-
treatment follow-up. Such a protocol would be written for a compound that would not yet be
commercially available.
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
19
4.1.9.
Visit Window
Except for the Week 25 Visit, all study visits during the Treatment Period (both Primary and
Extension Phases) must occur within ± 3 days of the scheduled day. A ±14 day window is 
allowed for the Week 25 Visit. Week 25 Visit and Extension Cycle 1 Visit 
procedures/assessments may be combined and not need to be repeated if previously performed 
within ±7 days of the scheduled visit.  
End of Treatment Visit procedures/assessments may not need to be repeated if previously 
performed within ±7 days of EOT visit.  If a subject is discontinued during a regular scheduled 
visit, all EOT procedures should be completed at that visit.  End of Treatment Visit 
procedures/assessments may occur at 42 Day Follow-up assessment if subject is discontinued 
within ± 7 days of the 42 Day Follow-up assessment.
A window of ± 14 days is allowed for Posttreatment Long-Term Follow- up assessments (i.e.
OS, Progression to AML, other malignancies/pre-malignancies, subsequent MDS therapies).
4.2.
Treatment Administration and Schedule
4.2.1.
Dose Titration Increase
Starting as soon as Cycle 3 Day 1 and assessed by the investigator prior to every subsequent 
treatment cycle, subjects may have the dose level increased in a stepwise manner beyond the 
starting dose of 1.0 mg/kg to 1.33 mg/kg, and from 1.33 mg/kg to 1.75 mg/kg, but the maximum 
total dose should not exceed 168 mg, during both the Primary and Extension Phases of the 
Treatment Period if all of the following criteria are met:
!
Subject has ≥ 1 RBC transfusion event (for pre-transfusion Hgb of < 9.0 g/dL) during the 
2 most recent prior treatment cycles (~6 weeks).
!
The two most recent prior treatment cycles assessed must be at the same dose level.
!
Subject must not have met protocol dose delay and/or reduction criteria in the two most 
recent treatment cycles (exception of dose delay required due to influence of RBC 
transfusions).  Refer to Table 3, footnote b.
If all criteria above are met, the dose may be increased by 1 dose level. 
The dose level should be titrated individually for each subject and must not exceed 1.75 mg/kg.
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
20
Starting dose with dose increases and reductions are presented below for reference (Table 2).
Table 2:
Starting Dose Level with Dose Reductions and Dose Titration
3rd Dose 
Reduction
(~25% 
reduction)
2nd Dose 
Reduction
(~25% 
reduction)
1st Dose 
Reduction
(~25% 
reduction)
Starting 
Dose Level
1st Dose 
Titration 
Increase
2nd Dose 
Titration 
Increase
0.45 mg/kg
0.6 mg/kg
0.8 mg/kg
1.0 mg/kg
1.33 mg/kg
1.75 mg/kg
4.2.2.
Dose Delay and Dose Reduction
Dose delay and/or reduction or discontinuation may be required due to increased hemoglobin or 
adverse events in either treatment arm (luspatercept or placebo). Table 3 below provides 
guidelines for dose modifications and dose delay.
Celgene or its authorized representative should be notified of dose modification or interruption 
within 24 hours. 
Table 3:
Dose Modification: Dose Delay, Dose Reduction, and Discontinuation 
Guidelines
Event at the Day of Dosing
(Assessed prior to each IP administration)
Action
Any suspected related AE ≥ Grade 3a,d 
Dose delayc until resolved to ≤ Grade 1 or 
baseline, and then reduce dose by 25%
≥ 2 dose reductions suspected related AE a
Discontinue treatment
ΔHgb ≥ 2.0 g/dL compared to pre-dose Hgb of 
previous treatment cycle 
Reduce dose by 25%b if ΔHgb not influenced by 
RBC transfusions
Predose Hgb ≥11.5 g/dL 
Dose delay until Hgb ≤ 11.0 g/dL 
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
21
≥ 50% increase in white blood cell count (WBC) 
compared to pre-dose WBC of previous treatment 
cycle and above upper limit of normal in the 
absence of an associated condition (e.g. infection 
or concomitant corticosteroid use)
Dose delay; re-check CBC, including WBC, at 
least weekly during dose delay.
Treatment may be resumed if:
WBC values below upper limit of normale within 2 
weeks
If WBC remains above upper limit of normale for 
≥ 2 consecutive weeks in absence of an associated 
condition (e.g. infection or concomitant 
corticosteroid use); continue dose delay and collect 
bone marrow/peripheral blood samples to assess 
MDS disease status. 
Treatment may be resumed if:
Absence of disease progression per IWG response 
criteria for altering natural history of MDS 
(Cheson, 2006)
AND
WBC values return below upper limit of normale
Discontinue treatmentf if:
Disease progression per IWG response criteria for 
altering natural history of MDS (Cheson, 2006; 
Appendix E)
OR
WBC remain above upper limit of normale
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
22
Table 4:
Dose Modification: Dose Delay, Dose Reduction, and Discontinuation 
Guidelines (Continued)
a Possibly, probably or definitely related to IP.
b Predose Hgb value not being influenced by RBC transfusion (i.e. Hgb result > 14 days after last RBC transfusion 
or within 3 days from next RBC transfusion); Hgb should be rechecked weekly during dose delay.
c If dose delay is > 12 consecutive weeks, treatment should be discontinued.
d Includes systolic blood pressure ≥160 mmHg and diastolic blood pressure ≥100 mmHg.
e Upper limit of normal >10,000 total WBC/μL or as defined by institutional standards
f Peripheral blood smear should be prepared for central pathology lab assessment. 
g At the investigator’s discretion, bone marrow samples may also be collected and analyzed centrally to assess MDS 
disease status (e.g. cytomorphology) prior to making decision regarding treatment discontinuation. The central 
laboratory must also confirm <5% bone marrow blasts prior to resumption of treatment. 
h The investigator may contact the Medical Monitor prior to making decision regarding treatment discontinuation. 
4.2.3.
Overdose
Overdose refers to luspatercept dosing only. On a per dose basis, an overdose is defined as the 
following amount over the protocol-specified dose of luspatercept assigned to a given subject, 
regardless of any associated adverse events or sequelae.  
Subcutaneous 10% over the protocol-specified dose
Hemoglobin and Hematocrit measurements from both central and local lab within 3 weeks past 
the date of overdose will be listed in a separate listing. 
Event at the Day of Dosing
(Assessed prior to each IP administration)
Action
Presence of ≥ 1% blasts in peripheral blood (based 
on either local or central laboratory hematology 
sample)
Dose interruption; immediately prepare peripheral 
blood smearf,g for cytomorphology assessment by 
central pathology laboratory. 
! 
If central pathology laboratory 
cytomorphology assessment confirms ≥1% 
blasts in the peripheral blood; discontinue 
treatmenth
! 
If central pathology laboratory 
cytomorphology assessment determines 
< 1% peripheral blasts are present, repeat 
hematology assessment.  
-
If presence of < 1% blasts in 
peripheral blood, treatment can be 
resumed at next scheduled dosing 
cycle.
-
If presence of ≥ 1% blasts in 
peripheral blood; discontinue 
treatmenth
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
23
Figure 1:
Overall Study Design
SCREENING PERIOD
Post treatment 
FOLLOW-UP 
PERIOD             
STUDY DISCON
a Historical documentation of RBC transfusion dependence should be available (RBC units transfused and pre-transfusion Hgb values) for at least 16 weeks prior to 
randomization.  
b Dose may be titrated up to a maximum of 1.75 mg/kg.  
c After completion of the Week 25 Visit MDS Disease Assessment by the investigator, subjects experiencing clinical benefit and have not experienced disease progression per 
IWG criteria for altering natural history of MDS (Cheson, 2006; Appendix E), may continue double-blind treatment with IP beyond the Week 25 Visit in the Extension Phase of 
the Treatment Period until meeting protocol discontinuation criteria.  
d MDS Disease Assessment will be repeated by the investigator at Extension Cycle 8, Day 1 and Day 1 of every eighth Extension Cycle thereafter (i.e. Extension Cycle 8, 16, 24+, 
etc. or every 24 weeks in the event of dose delays) until the subject is discontinued from treatment. For subjects to continue double-blind treatment in the Extension Phase of the 
Treatment Period, each MDS Disease Assessment should confirm continued clinical benefit and absence of disease progression per IWG criteria for altering natural history of 
MDS (Cheson, 2006; Appendix E).
OR
Luspaterceptb
starting dose  
1.0mg/kgb
OR
Placebob
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injection on D1 of 
each 21-day 
Treatment Cycle
R
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who 
provide 
signed 
informed 
consent 
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eligibility 
criteria 
End of Treatment
AE Reporting 
Window until 42 days 
after last dose of IP
Continue double-
blind treatment b, d 
MDS Disease Status 
Assessment every 
eighth Extension 
Cycle (24 weeks)
MDS Disease 
Assessment c  
Week 25 Visit
24 calendar 
weeks after first 
dose, regardless 
of dose delays
2:1 randomization
Collection of 
transfusion data for 
at least 16 weeks after
last dose of IP or until 
End of Treatment 
visit (whichever is 
later)
Monitor for Other 
Malignancies/Pre-
malignancies, 
progression to AML, 
OS, and subsequent 
MDS therapies for at 
least 3 years from last 
dose of IP unless the 
subject withdraws 
consent from the 
study, dies or is lost 
to follow-up
Double-Blind TREATMENT PERIOD
Primary Phase
(24 weeks)
Extension Phase
Study
Discontinuation 
5 weeks a
No Crossover
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
24
Table 5:
Table of Events
Screening
Treatment Period1
Posttreatment Follow-up
! 42 Day Follow-up = Occurs 42 days 
after last dose of IP
! 12 Week Follow-up = Occurs 12 
Weeks after last dose of IP
! Long Term Follow-up = Occurs 
every 3 months after 12 Week 
Follow-Up until at least 3 years post 
last dose of IP
Primary Phase
First 24 weeks of double-blind 
treatment
Up to maximum of 8 Treatment 
Cycles 
(if no dose delays)
Week 251,2
Visit
24 calendar 
weeks after 
first dose 
regardless of 
dose delays.
Extension Phase
Continuation of double-
blind treatment beyond 
Week 25 Visit
EOT
Visit2
Day -35
Every 
Cycle
(ie,1,2,3
+ up to 
max 8 
cycles
Every 
Other 
Cycle
Only) 
(ie, 1, 3, 
5, 7)
Cycles 
1 and 5
Only
Cycle 1
Only
Every 
Ext 
Cycle
12,2,3
+
Ext 
Cycle 4, 
8, 12+
Ext 
Cycle 8, 
16, 24+
42 Day 
Follow-
up2
12, 24, 
48 
Week 
Follow-
up
Long Term 
Follow-up 
End of 
Study 
to -1
Day 1
Day 1
Day 8
Day 15
Day 1
Day 1
Day 1
STUDY ENTRY AND GENERAL ASSESSMENTS
Informed Consent
X
--
--
--
--
--
--
--
--
--
--
--
--
--
Inclusion/Exclusion 
evaluations
X
--
--
--
--
--
--
--
--
--
--
--
--
--
Physical Examination
X
X
X
X
X
Randomization3
X
--
--
--
--
--
--
--
--
--
--
--
--
--
Demographics 
X
--
--
--
--
--
--
--
--
--
--
--
--
--
Medical History
X
--
--
--
--
--
--
--
--
--
--
--
--
--
Prior ESA Therapies
X
--
--
--
--
--
--
--
--
--
--
--
--
--
Prior RBC and Platelet 
Transfusions4
X
--
--
--
--
--
--
--
--
--
--
--
--
--
INVESTIGATIONAL PRODUCT (IP)
IP Administration and 
Accountability15
--
X3
--
--
--
--
X
--
--
--
--
--
--
--
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12 Week
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
25
Table 4:
Table of Events (Continued)
Screening
Treatment Period1
Posttreatment Follow-up
! 42 Day Follow-up = Occurs 42 days 
after last dose of IP
! 12 Week Follow-up = Occurs 12 
Weeks after last dose of IP
! Long Term Follow-up = Occurs 
every 3 months after 12 Week 
Follow-Up until at least 3 years post 
last dose of IP
Primary Phase
First 24 weeks of double-blind 
treatment
Up to maximum of 8 Treatment 
Cycles 
(if no dose delays)
Week 251,2
Visit
24 calendar 
weeks after 
first dose 
regardless of 
dose delays.
Extension Phase
Continuation of double-
blind treatment beyond 
Week 25 Visit
EOT
Visit2
Day -35
Every 
Cycle
(ie,1,2,3
+ up to 
max 8 
cycles
Every 
Other 
Cycle
Only) 
(i.e. 1, 
3, 5, 7)
Cycles 
1 and 5
Only
Cycle 1
Only
Every 
Ext 
Cycle
12,2,3
+
Ext 
Cycle 4, 
8, 12+
Ext 
Cycle 8, 
16, 24+
42 Day 
Follow-
up2
12, 24, 
48 
Week 
Follow-
up
Long Term 
Follow-up 
End of 
Study 
to -1
Day 1
Day 1
Day 8
Day 15
Day 1
Day 1
Day 1
SAFETY ASSESSMENTS
ECOG Performance Status 
X
X
--
--
--
X
X
--
--
X
--
--
--
--
Urinalysis5
X
C1D1 and D1 of every fourth cycle in 
Primary Phase (e.g. C1, C4, C8)
X
Ext C1D1, then D1 of 
every fourth Extension 
cycle until treatment 
discontinuation 
X
--
--
--
--
Coombs’ test6
X
--
--
--
--
--
--
--
--
--
--
--
--
--
Assessment of 
HIV/HepB/HepC status6
X
--
--
--
--
--
--
--
--
--
--
--
--
--
ECG(12-lead)
X
--
--
C5D8 
only
--
--
--
--
--
X
--
--
--
--
Pregnancy Test and 
Counseling7
X
X
--
--
--
X
X
--
--
X
--
--
--
--
Adverse events 
Continuous, after signing informed consent until 42 days after last IP administration 
--
--
--
Prior and Concomitant 
medications/procedures 
X
Continuous, until 42 days after last IP administration or until the EOT visit, whichever occurs later
--
--
--
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EOT
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Visit
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cle 4,
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Ext
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Cycle 
16,
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Day 1
Day 1
$ <
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7$
7$
7$
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Ext
E
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C5D8 
C5D8 
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only
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
26
Table 4:
Table of Events (Continued)
Screening
Treatment Period1
Posttreatment Follow-up
! 42 Day Follow-up = Occurs 42 days 
after last dose of IP
! 12 Week Follow-up = Occurs 12 
Weeks after last dose of IP
! Long Term Follow-up = Occurs 
every 3 months after 12 Week 
Follow-Up until at least 3 years post 
last dose of IP
Primary Phase
First 24 weeks of double-blind 
treatment
Up to maximum of 8 Treatment 
Cycles 
(if no dose delays)
Week 251,2
Visit
24 calendar 
weeks after 
first dose 
regardless 
of dose 
delays.
Extension Phase
Continuation of double-blind 
treatment beyond Week 25 
Visit
EOT
Visit2
Day -35
Every 
Cycle
(ie,1,2,3
+ up to 
max 8 
cycles
Every 
Other 
Cycle
Only) 
(ie, 1, 3, 
5, 7)
Cycles 
1 and 5
Only
Cycle 1
Only
Every 
Ext 
Cycle
12,2,3+
Ext 
Cycle 4, 
8, 12+
Ext 
Cycle 8, 
16, 24+
42 Day 
Follow-
up2
12, 24, 
48 
Week 
Follow-
up
Long Term 
Follow-up 
End of 
Study 
to -1
Day 1
Day 1
Day 8
Day 15
Day 1
Day 1
Day 1
Vital Signs (Height to be 
measured only at screening; 
Weight to be measured only at 
screening and prior to each IP 
administration)
X
X
--
X
X
X
X
--
--
X
--
--
--
--
Serum Chemistry8
X
X
--
--
--
X
X
--
--
X
--
--
--
--
EFFICACY ASSESSMENTS
Hematology9, 15
X
X
--
X
X
X
X
--
--
X
--
--
--
--
Serum EPO
X10
--
X
--
--
X
--
--
--
X
--
--
--
--
Serum Ferritin
X11
X11
--
--
--
X
--
X
--
X
--
--
--
--
Transfusion Data Collection 
and Assessment
Assess and record on ongoing basis (prior to each dose of IP) until 16 weeks after last dose of IP or the End of Treatment Visit, 
whichever occurs later. Clinical site staff should confirm if any transfusions were received by the subject (including any at outside local 
institutions in between study visits) prior to each IP administration via use of patient diary or other local procedure in place at the 
investigational site.
--
MDS Disease Assessment12
--
--
--
--
--
X
--
--
X
X
--
--
--
--
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Visit
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cle 4,
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8, 12+
Ext
Cycle
C
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Day 1
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
27
Table 4:
Table of Events (Continued)
Screening
Treatment Period1
Posttreatment Follow-up
! 42 Day Follow-up = Occurs 42 days 
after last dose of IP
! 12 Week Follow-up = Occurs 12 
Weeks after last dose of IP
! Long Term Follow-up = Occurs 
every 3 months after 12 Week 
Follow-Up until at least 3 years post 
last dose of IP
Primary Phase
First 24 weeks of double-blind 
treatment
Up to maximum of 8 Treatment 
Cycles 
(if no dose delays)
Week 251,2
Visit
24 calendar 
weeks after 
first dose 
regardless of 
dose delays.
Extension Phase
Continuation of double-
blind treatment beyond 
Week 25 Visit
EOT
Visit2
Day -35
Every 
Cycle
(ie,1,2,3
+ up to 
max 8 
cycles
Every 
Other 
Cycle
Only) 
(ie, 1, 3, 
5, 7)
Cycles 
1 and 5
Only
Cycle 1
Only
Every 
Ext 
Cycle
12,2,3
+
Ext 
Cycle 4, 
8, 12+
Ext 
Cycle 8, 
16, 24+
42 Day 
Follow-
up2
12, 24, 
48 
Week 
Follow-
up
Long Term 
Follow-up 
End of 
Study 
to -1
Day 1
Day 1
Day 8
Day 15
Day 1
Day 1
Day 1
Bone Marrow Aspirate 
(BMA) and Peripheral Blood 
for cytomorphology and 
cytogenetic testing13
BM 
Biopsy 
and 
Aspirate 
Required
--
--
--
--
X
--
--
X
X
--
--
--
--
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12 Week Fol
12 Week Fol
Weeks 
Weeks aft
af
! Long T
Long
eve
ev
F
7,2
EOT
OT
Visit
Visit2
1)25
cle 4,
cle 4,
8, 12+
8, 12
Ext
xt
Cycle 
16,
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1)
1)
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
28
Table 4:
Table of Events (Continued)
Screening
Treatment Period1
Posttreatment Follow-up
! 42 Day Follow-up = Occurs 42 days 
after last dose of IP
! 12 Week Follow-up = Occurs 12 
Weeks after last dose of IP
! Long Term Follow-up = Occurs 
every 3 months after 12 Week 
Follow-Up until at least 3 years post 
last dose of IP
Primary Phase
First 24 weeks of double-blind 
treatment
Up to maximum of 8 Treatment 
Cycles 
(if no dose delays)
Week 251,2
Visit
24 calendar 
weeks after 
first dose 
regardless of 
dose delays.
Extension Phase
Continuation of double-
blind treatment beyond 
Week 25 Visit
EOT
Visit2
Day -35
Every 
Cycle
(ie,1,2,3
+ up to 
max 8 
cycles
Every 
Other 
Cycle
Only) 
(ie, 1, 3, 
5, 7)
Cycles 
1 and 5
Only
Cycle 1
Only
Every 
Ext 
Cycle
12,2,3
+
Ext 
Cycle 4, 
8, 12+
Ext 
Cycle 8, 
16, 24+
42 Day 
Follow-
up2
12, 24, 
48 
Week 
Follow-
up
Long Term 
Follow-up 
End of 
Study 
to -1
Day 1
Day 1
Day 8
Day 15
Day 1
Day 1
Day 1
PK and ADA
PK Sample Collection 
--
C1,2,4,
6,8 
Only
--
X
X
X
Extension C4D1 and D1 
of every 4th Extension 
Cycle thereafter (e.g. Ext. 
C4, C8, etc.) for up to one 
year from the first dose in 
the Primary Treatment 
Phase.
X18
--
X18
--
--
ADA Sample Collection
--
C1,2,4,
6,8 
Only
--
--
--
X
Extension C4D1 and D1 
of every 4th Extension 
Cycle thereafter (eg, Ext. 
C4, C8, C12 C16+, etc.) 
for up to one year from 
the first dose in the 
Primary Treatment Phase.
X18
--
X18
QUALITY OF LIFE 
EORTC QLQ-C30 
 Questionnaire Completion
X
--
X16
--
--
X
Day 1 of Every Other Ext. 
Cycle 
(Ext. C1,C3, C5+, etc.)
X
--
--
--
--
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Long
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OT
Visit
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ycle 4,
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8, 12
Ext
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Cycle 
16,
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
29
Table 4:
Table of Events (Continued)
Screening
Treatment Period1
Posttreatment Follow-up
! 42 Day Follow-up = Occurs 42 days 
after last dose of IP
! 12 Week Follow-up = Occurs 12 
Weeks after last dose of IP
! Long Term Follow-up = Occurs 
every 3 months after 12 Week 
Follow-Up until at least 3 years post 
last dose of IP
Primary Phase
First 24 weeks of double-blind 
treatment
Up to maximum of 8 Treatment 
Cycles 
(if no dose delays)
Week 251,2
Visit
24 calendar 
weeks after 
first dose 
regardless of 
dose delays.
Extension Phase
Continuation of double-
blind treatment beyond 
Week 25 Visit
EOT
Visit2
Day -35
Every 
Cycle
(ie,1,2,3
+ up to 
max 8 
cycles
Every 
Other 
Cycle
Only) 
(ie, 1, 3, 
5, 7)
Cycles 
1 and 5
Only
Cycle 1
Only
Every 
Ext 
Cycle
12,2,3
+
Ext 
Cycle 4, 
8, 12+
Ext 
Cycle 8, 
16, 24+
42 Day 
Follow-
up2
12, 24, 
48 
Week 
Follow-
up
Long Term 
Follow-up 
End of 
Study 
to -1
Day 1
Day 1
Day 8
Day 15
Day 1
Day 1
Day 1
FOLLOW UP 
Monitoring for progression to 
AML and other 
malignancies/pre-
malignancies 17
(Refer to Section 10.5 for 
details)
After signing ICF and until at least 3 years post last dose of IP or until death, lost to follow-up, withdrawal of consent for further data collection.
Posttreatment MDS 
therapies17
--
--
--
--
--
--
--
--
--
--
X
X
X
X
Survival Follow-up17
--
--
--
--
--
--
--
--
--
--
X
X
X
X
1 Window of +/- 3 days is allowed during Treatment Period.  A window of +/- 14 days is allowed for the Week 25 Visit.  A window of +/- 14 days is allowed for Posttreatment 
Long-term Follow-up Assessments (i.e. OS, Progression to AML, other malignancies/pre-malignancies, subsequent MDS therapies).
2 Week 25 Visit and Extension Cycle 1 Visit procedures/assessments may not need to be repeated if previously performed within +/-7 days of the scheduled visit.  End of 
Treatment (EOT) Visit procedures/assessments may not need to be repeated if previously performed within +/-7 days of EOT visit.  If a subject is discontinued during a regular 
scheduled visit, all EOT procedures should be completed at that visit.  End of Treatment (EOT) Visit procedures/assessments may occur at 42 Day Follow-up assessment if 
subject is discontinued within +/- 7 days of 42 Day Follow-up assessment.
3 Randomization via IRT.  The first dose of IP should be administered after, but within 3 days of randomization and can be on the same day as randomization. Refer to the IRT 
manual for additional information on randomization utilizing IRT.  Documentation must be complete to confirm an average RBC transfusion requirement of at least 2 units of 
packed red blood cells (pRBCs) per 8 weeks during the 16 weeks immediately preceding randomization. Hemoglobin levels at the time of or within 7 days prior to 
administration of a RBC transfusion must have been ≤ 10.0 g/dL in order for the transfusion to be counted towards meeting eligibility criteria. 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 meeting 
eligibility criteria.  There must also not be any consecutive 56-day period that was RBC transfusion free during the 16 weeks immediately preceding randomization.  4 Subjects 
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
30
must have at least 16 weeks documented transfusion history prior to randomization. This transfusion data includes hemoglobin measured prior to transfusion (pretransfusion 
Hgb).  5Urinalysis assessed centrally and to include microscopic, quantitative analysis of urine. (e.g. microalbumin/albumin, protein, creatinine, microalbumin/creatinine ratio).
6 A local Coomb’s test is only performed if total bilirubin > 2 x ULN.  If positive, a local reticulocyte count may be requested.  Local test results confirming known Human 
Immunodeficiency Virus (HIV), Hepatitis B, Hepatitis C status should not have been performed earlier than 4 weeks from the date of ICF signature.  If beyond this window, 
additional local testing may be requested.
7 Pregnancy test is required for all female subjects of childbearing potential.  Serum beta human chorionic gonadotropin (β-hCG) will be performed at screening.  A urine (or 
serum) pregnancy test will be repeated prior to the first administration of IP on C1D1, unless the screening pregnancy test was done within 72 hours of C1D1. During the 
Treatment Period, urine or serum pregnancy test is allowed. For males and FCBP, counseling about pregnancy precautions and the potential risks of fetal exposure must be 
conducted prior to each IP administration or on a monthly basis (e.g. in the event of dose delays).  8
Serum chemistry (eg, sodium, potassium, chloride, bicarbonate [if 
available], calcium, magnesium, phosphorus, blood urea nitrogen [BUN], creatinine, creatinine clearance and/or estimated glomerular filtration rate, glucose, albumin, total 
protein, alkaline phosphatase, direct/indirect total bilirubin, AST/SGOT or ALT/SGPT, lactate dehydrogenase [LDH], uric acid) will be analyzed by the central laboratory.  
9 Hematology assessment (eg, red blood cell [RBC] count, complete blood count [CBC], white blood cell [WBC] with differential, hemoglobin, hematocrit, nucleated red blood 
cells [nRBC], absolute reticulocyte count, platelet count, mean corpuscular volume [MCV], mean corpuscular hemoglobin [MCH], mean corpuscular hemoglobin concentration 
[MCHC], and red blood cell distribution width [RDW]) will be tested by the central laboratory.  10
EPO will be assessed centrally.  During the Screening Period, the serum 
EPO level should be collected on the same day as a planned RBC transfusion, prior to the transfusion or 7 days after any RBC transfusion due to possible reduction of the serum 
level related to the hemoglobin level achieved after the last transfusion. 
11Serum ferritin will be assessed centrally. Sample should be collected within 5 weeks prior to randomization. Sample should be collected prior to administration of IP.  Additional 
serum ferritin results from previous local laboratory assessments (ie, within the 16 week window immediately prior to randomization date) should be collected, if available in the 
medical records, and entered into the eCRF. 
12During the Treatment Period, MDS Disease Assessment (which includes investigator assessment of clinical benefit and MDS disease status) should be completed by the 
investigator in conjunction with bone marrow/peripheral blood sample collection for cytomorphology and cytogenetics collected at the Week 25 Visit. Based on the outcome of 
the MDS Disease Assessment, subjects will either be discontinued from treatment with IP and enter the Posttreatment Follow-Up Period or continue double-blind treatment with 
IP in the Extension Phase of the Treatment Period.  13
During the Screening Period, bone marrow biopsy AND bone marrow aspirate are required. The screening BMB 
should be performed within 5 weeks prior to randomization.  The screening BMA should be collected within the protocol screening window.  After randomization, a bone 
marrow biopsy is collected only when adequate aspirate is not attainable.  During the Extension Phase of the Treatment Period: Bone marrow and peripheral blood samples to be 
collected at Extension Cycle 8, Day 1 and Day 1 of every eighth Extension Cycle thereafter (ie, Extension Cycle 8, 16, 24+, etc. or approximately every 24 weeks in the event of 
dose delays). Bone marrow samples at End of Treatment Visit: Perform only if visit is > 90 days from prior bone marrow procedure. Refer to central laboratory manual for 
additional information related to sample collection
 
  
15On dosing days, local laboratory sample should be collected and Hgb levels assessed prior to each IP administration to ensure dose modification rules are followed as outlined in 
Section 4.2.2, Table 3.  In these circumstances, a split sample should also be collected and sent to the central laboratory for analysis.  Subjects must have blood pressure assessed 
prior to each IP administration.
16If subject completed Screening EORTC QLQ-C30 
 questionnaires within 14 days prior to C1D1, it does not have to be repeated at C1D1. If performed on C1D1, 
both EORTC QLQ-C30 
 questionnaires should be completed by the subject prior to IP administration.
17Long-Term Posttreatment Follow-up for Overall Survival (OS), Progression to AML, other malignancies/pre-malignancies, data collection for subsequent MDS therapies may be 
conducted by record review (including public records if allowed by local regulations) and/or telephone contact with the subject, family, or the subject’s treating physician.  The
investigator must make every effort to obtain information regarding the subject’s survival status before determining the subject is lost to follow-up.
18 Post-treatment Follow-up: For subjects who do not complete the Primary Treatment Phase or do not participate in the Extension Phase or subjects who terminate the Extension 
Phase with less than 1-year of ADA monitoring, ADA and PK samples will be collected at EOT and then every 12 weeks for up to one year from the first dose in the Primary 
Treatment Phase.
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EDMS Doc. Number:
Luspatercept
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Celgene Corporation
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31
4.3.
Study Endpoints
Endpoint
Name
Description
Timeframe
Primary 
Red Blood Cell 
Transfusion Independence 
(RBC-TI) ≥ 8 weeks 
Proportion of subjects who are 
RBC transfusion free over any 
consecutive 56 day period
Week 1 through Week 24
Secondary
RBC-TI ≥ 12 weeks 
Proportion of subjects who are 
RBC transfusion free over any 
consecutive 84 day period
Week 1 through Week 
24;
Week 1 through Week 48
RBC-TI ≥ 8 weeks 
Proportion of subjects who are 
RBC transfusion free over any 
consecutive 56 day period
Week 1 through Week 48
Reduction in RBC units 
transfused over 16 weeks
Mean change in total RBC 
units transfused over a fixed 
16 week period
Week 9 through 24;
Week 33 through 48 
Modified hematologic 
improvement - erythroid 
(mHI-E) per IWG 
(Cheson, 2006; Appendix 
E)
Proportion of subjects 
achieving modified HI-E over 
any consecutive 56 day period
Week 1 through Week 
24;
Week 1 through Week 48
Mean hemoglobin increase
≥ 1.0 g/dL
Proportion of subjects 
achieving hemoglobin (Hgb) 
increase from baseline ≥ 1.0 
g/dL over any consecutive 56
day period in absence of RBC 
transfusions 
Week 1 through Week 24;
Week 1 through Week 48
Duration of RBC-TI
Maximum duration of RBC 
transfusion independence for 
subjects who achieve RBC TI 
≥ 8 weeks
Week 1 through Week 24;
Week 1 through end of 
treatment
Health-related quality of 
life (HRQoL)
Change in EORTC QLQ-C30 
score
Week 1 through Week 24; 
Week 1 through Week 48; 
Week 1 baseline through 
end of treatment
Hematologic improvement 
- neutrophils (HI-N) per 
IWG (Cheson, 2006; 
Appendix E)
Proportion of subjects 
achieving HI-N over any 
consecutive 56 day period
Week 1 through Week 24;
Week 1 through Week 48
Hematologic improvement 
- platelets (HI-P) per IWG 
(Cheson, 2006; Appendix 
E)
Proportion of subjects 
achieving HI-P over any 
consecutive 56 day period
Week 1 through Week 24;
Week 1 through Week 48
Mean decrease in serum 
ferritin
Change in serum ferritin.
Week 9 through 24;
Week 33 through 48
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
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32
Endpoint
Name
Description
Timeframe
Mean decrease in iron 
chelation therapy (ICT) 
use
Change in mean daily dose 
of ICT
Week 9 through 24;
Week 33 through 48
Time to RBC-TI
Time from first dose to first 
onset of transfusion 
independence ≥ 8 weeks
Week 1 through Week 24;
Week 1 through Week 48
Progression to AML 
Number and percentage of 
subjects progressing to 
AML; time to AML 
progression 
Randomization through at 
least 3 years post last dose; 
Week 1 through Week 48
Overall survival
Time from date of 
randomization to death due 
to any cause
Randomization through at 
least 3 years post last dose; 
Week 1 through Week 48
Safety
Type, frequency, severity of 
AEs and relationship of AEs 
to luspatercept/placebo
Screening through 42 days 
post last dose; 
Week 1 through Week 48
A population PK model.
Exposure-response 
relationship. 
A Population PK model that 
describes the PK exposure 
data of luspatercept and 
associated variability.
Exposure-response 
relationship for the primary 
efficacy endpoint, AEs of 
interest, and selected 
secondary endpoints.
Randomization through 1
year post first dose.
Anti-drug antibodies 
(ADA) 
Frequency of anti-drug 
antibodies and effects on 
efficacy, or safety, or PK
Randomization through 1
year post first dose.
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
33
Endpoint
Name
Description
Timeframe
4.4.
Blinding
The study is a double blind study where all subjects, study site staff and Celgene Corporation 
representatives with the exception of designated individuals (e.g. the pharmacist at the 
investigational site, the bioanalytical laboratory), will remain blinded to all treatment
assignments until all subjects have completed the study, or at the time the study is unblinded (per 
DMC recommendation) and the database is locked.
4.5.
Sample Size Determination
A total sample size of 210 (140 in experimental arm [luspatercept (ACE-536)], 70 in control arm
[placebo]) will have 90% power to detect the difference between a response (RBC-TI ≥ 8 weeks 
Week 1 through Week 24) rate of 0.30 in the experimental arm (luspatercept [ACE-536]) and a 
response rate of 0.10 in the control arm (placebo). The sample size calculation is based on one-
sided alpha of 0.025, test statistics on difference of proportions using pooled estimate of variance 
and 10% dropout rate.
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
34
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 
tables and figures.
The day of the first dose of IP will be defined as Day 1. Baseline value will be defined as the last 
value measured on or before the date and time of the first dose of IP, unless otherwise specified;
if multiple values are present for the same date, but time values taken on that date are not 
recorded on the eCRF , the average of these values will be used as the baseline, unless otherwise 
specified below. For subjects who were not treated, the baseline will be the assessment value 
taken on the visit of Cycle 1 Day 1 if available; otherwise, the value on or prior to randomization 
date will be used. 
For efficacy analysis, the following definitions will be implemented for baseline Hgb, Epo, and
platelete: 
Since the Hgb value can be influenced by a RBC transfusion, the Hgb values used in efficacy 
analyses are required to satisfy the 14/3-day rule below:
!
14/3-day rule: Only Hgb values that are at least 14 days after a transfusion may be 
used unless there is another transfusion within 3 days after the Hgb assessment. If this 
occurs, the second Hgb value may be used (despite being < 14 days after the previous 
transfusion). The rationale is that the Hgb value < 14 days from the first transfusion 
was only somewhat influenced by that transfusion.
In efficacy analyses, after applying above 14/3-day rule, the baseline Hgb value is defined as the 
lowest Hgb value from the central, local laboratory, or pre-transfusion Hgb from transfusion 
records that is within 35 days on or prior to the first dose of IP if it is available. 
Erythropoietin value can also be influenced by a RBC transfusion. Baseline EPO is defined as 
the highest EPO value within 35 days of the first dose of IP. 
Baseline platelet is defined as the lowest platelet value within 35 days of the first dose of IP.
Summary statistics for continuous variables include sample size (n), mean, standard deviation 
(SD), median, minimum, the 25th (Q1) and 75th (Q3) percentiles, and maximum. All mean and 
median values will be formatted to one more decimal place than the measured value. SD values 
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
35
will be formatted to two more decimal places than the measured value. Minimum and maximum 
values will be presented to the same number of decimal places as the measured value. Frequency 
summary for categorical variables includes number and percentage. All percentages will be 
rounded to one decimal place. Number and percentage values will be presented as xx (xx.x).
Summary statistics for ANCOVA include sample size (n), mean, standard error of the mean, 
least square mean, standard error of the least square mean, two-sided 95% confidence interval
(CI) around least square mean, least square mean difference, standard error of the least square 
mean difference, two-sided 95% confidence interval (CI) around least square mean difference, 
and p-value. 
All analysis and summary tables will have the population sample size for each treatment group in 
the column heading.
P-values will be rounded to 4 decimal places. P-values that round to 0.0000 will be presented as 
‘<0.0001’ and p-values that round to 1.000 will be presented as ‘>0.9999’.
All laboratory data will be reported using standard international (SI) units except for 
hemoglobin. Hemoglobin data will be reported using g/dL. 
Subject data listings will be provided to support the tables. Graphs will be provided for the 
selected parameters. 
All subjects will be summarized using dummy treatments in the tables, listings, and figures until 
study is unblinded. After study is unblinded, they will be summarized by actual treatments.
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 given protocol-specified procedures are
performed. They include the dates of laboratory testing, physical examinations, 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 (e.g. for duration or cycle assignment etc). 
However, in listings, log dates will be shown as recorded without imputation.
!
Milestone Dates are dates of protocol milestones such as randomization, IP start date, 
study termination, etc. They should not be missing if the milestone occurs for a 
subject. They will not be imputed.
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
36
!
Outcome Dates are dates corresponding to study endpoints. In most cases they are 
derived either from a milestone, or a procedure date. 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. 
5.1.2.
Calculation Using Dates
Calculations using dates (e.g., subject’s age or relative day after the date of randomization) will 
adhere to the following conventions: 
!
Study days after the date of first dose of IP will be calculated as the difference 
between the date of interest and the date of first dose plus 1 day. The generalized 
calculation algorithm for relative day: Study Day = [(Target Date – Date of First 
Dose) + 1]. Note that Study Day 1 is the first dose date. Negative and zero study 
days are reflective of observations obtained during the baseline/screening period.
Note: Partial dates for the first dose are not imputed in general. All effort should be 
tried to avoid incomplete first dose date. 
!
Age (expressed in days) is calculated: AGE = Informed Consent Date– Date of Birth
+ 1. In practice, age will be converted to years by dividing the difference by 365.25 
days, then truncating to a whole number.
o
Prefer using calculated age from clinical database. When not available, may 
use calculated age from CRF or IVRS
o
Partial birth date: impute missing day as 15th of the month; impute missing 
month as July; set missing age for missing year
!
Intervals that are presented in weeks will be transformed from days to weeks by using 
(without truncation) the following conversion formula:
WEEKS = DAYS /7.
!
Intervals that are presented in months will be transformed from days to months by 
using (without truncation) the following conversion formula:
MONTHS = DAYS /30.4375.
5.1.3.
Calculation of Cycles
The start date of each treatment cycle will be calculated based on IP exposure records for each 
subject. The start date of the first cycle (C1) will be the date when the subject receives the first 
dose of IP.
Once the start dates, e.g., C1, C2, C3… are calculated, the end date of each cycle is calculated as 
the day before the start date of the following cycle, i.e., Ei = Ci+1 -1. For the last cycle, the end 
date will be calculated as the start date plus 20 days, study discontinuation date, or the death 
date, whichever is earlier. The cycle number for each date of interest, e.g., AE or laboratory test, 
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
37
will be calculated based on the cycle window set by their start and end dates. If a date is on or 
after Ci and before Ci+1, the corresponding cycle number will be i.
5.2.
Analysis Populations
5.2.1.
Intent-to-Treat Population
The intent-to-treat (ITT) population will include all subjects who were randomized, regardless of
whether or not the subject received IP, or regardless of whether or not the subject met the 
eligibility criteria. All efficacy analyses will be conducted for the ITT population. Subjects will 
be analyzed based on randomized treatment group.
5.2.2.
Safety Population
The Safety population will include all subjects who were randomized and received at least one 
dose of IP. The Safety population will be used for all safety analyses. Subjects will be analyzed 
according to the treatment they actually received.
5.2.3.
Health-related QoL Evaluable Population
The HRQoL evaluable population is defined as all subjects in ITT population who completed the 
EORTC QLQ-C30 assessment at baseline (ie, Cycle 1 Day 1 Visit or Screening Visit if 
assessment at the Cycle 1 Day 1 Visit was not completed, captured or available) and at least 1 
postbaseline assessment visit.
The completion of an HRQoL assessment for the EORTC QLQ-C30 at a given visit is defined as 
greater than or equal to half of the all items being answered (ie, ≥ 15 items of the 30 items within 
the EORTC QLQ-C30).
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
38
6.
SUBJECT DISPOSITION
The number of all screened subjects, the number and percentage of subjects who were 
randomized and not randomized, the failed inclusion/exclusion criteria for subjects who were 
screened but not randomized will be included in the summary of screened subjects status. 
Percentage will be based on all screened subjects.  
The number and percentage of analysis population allocation, the subjects who entered
(randomized), completed, ongoing, discontinued, and primary reasons for discontinuation will be 
included in the disposition summary. Percentage will be based on all randomized subjects, i.e. 
ITT population.
Reasons for treatment discontinuation will be summarized with the following categories:
!
Death
!
Adverse event
!
Pregnancy
!
Lack of efficacy
!
Withdrawal by subject
!
Lost to follow up
!
Study terminated by sponsor 
!
Protocol violation
!
Disease Progression as per IWG criteria for altering natural history of MDS (Cheson, 
2006; Appendix E). 
o
For subjects with 5-10% blasts, a 2nd bone marrow sample should be collected 
within 4 weeks for clinical assessment (e.g. cytomorphology, cytogenetics) to 
confirm progression before discontinuing subjects from treatment. 
! Other (to be specified on the eCRF) 
o
Including treatment discontinuation guidance related to dose modification 
Reasons for study discontinuation will be summarized with the following categories:
!
Screen failure
!
Death
!
Adverse event
!
Withdrawal by subject
!
Lost to follow up
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
39
!
Study terminated by sponsor
!
Protocol deviation
!
Other
Frequency tabulation of subjects enrolled by site, country, and treatment group will be 
summarized for the ITT population.
A separate listing will be provided for screen failures.
CCI
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
40
7.
PROTOCOL DEVIATIONS/VIOLATIONS
A protocol violation is defined as any departure from the approved protocol that: 1) impacts the 
safety, rights, and/or welfare of the subject; or 2) negatively impacts the quality or completeness 
of the data. A protocol deviation is an unplanned excursion from the approved protocol that does 
not result in harm to the study subjects or significantly affect the scientific validity of study data. 
The protocol deviations/violations will be identified and assessed by clinical research physician 
or designee throughout all study periods. 
Number and percentage of subjects with protocol violations will be summarized by protocol 
violation type and treatment group for the ITT population. 
All protocol violations and deviations will be listed for the ITT population. 
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
41
8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS
Summaries for the demographics and baseline clinical characteristics will be provided by 
treatment group for the ITT and Safety population.
8.1.
Demographics
Summary statistics will be provided descriptively by treatment group for the following 
continuous variables:
!
Age
!
Weight (kg)
!
Height (cm)
!
Body mass index (BMI; kg/m2)
Baseline BMI will be calculated as BMI (kg/m2) = baseline weight (kg) / (height (m))². Age will 
be calculated as discussed in Section 5.1.2. Age recorded from the CRF will be used when date 
of birth is not available. Other variables will be used as recorded from the CRF.
A frequency summary (number and percentage) will be provided by treatment group for the 
following categorical variables:
!
Age category (≤ 64, 65-74, and ≥75)
!
Gender (male, female)
!
Weight category (< 70, 70 to < 85, 85 to < 100, ≥ 100 kg)
!
BMI category (<20, 20 to <25, 25 to <30, #30 kg/m2)
8.2.
Baseline Clinical Characteristics
A frequency summary (number and percentage) will be provided by treatment group for the 
following categorical baseline characteristics variables:
!
ECOG performance status at baseline (Grade 0, 1, or 2, Missing)
!
Time since original MDS diagnosis (≤  2 , 2 to ≤  5, > 5 years). Time since original MDS 
diagnosis is defined as the number of months from the date of original diagnosis to the 
date of informed consent.
!
Average baseline RBC transfusion requirements (≥6 , < 6, < 4, ≥ 4 and < 6 units/8 
weeks)
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
42
!
Baseline transfusion burden (# of RBC transfusions/ last 8 weeks prior to first dose date;
< 4, ≥ 4 and < 6, < 6, ≥6 units)     
!
Baseline transfusion burden (# of RBC transfusions/ 9- 16 weeks prior to first dose date;
< 4, ≥ 4 and < 6, < 6, ≥6 units)     
!
Historic Serum Ferritin Results Available within 16 Weeks prior to first dose date
!
Splicing factor 3B subunit 1(SF3B1) mutation (mutated vs non-mutated)
!
Ring Sideroblasts status (>= 15-50% % vs > 50% ) 
!
Serum EPO (<100, 100-<200, 200-500 and >500 U/L)
!
Prior Erythropoiesis-Stimulating Agent 
o
Yes vs. No
o
Longest Duration of Prior ESA treatment (< 6, 6 - 12, > 12 - 24, > 24 months)
o
Refractory to prior ESA vs. Intolerant to prior ESA 
o
Time from end of prior ESA to start of study, defined as the number of months 
from the date of the end of prior ESA to the first dose date. 

< 6 months

6-12 months

> 12 – 24 months

> 24 months
!
Renal status: Creatinine Clearance (CrCL) (40 - <60 vs. ≥60 mL/min) 
!
Iron Chelation Therapy usage status (Yes vs. No)
!
Cardiovascular Comorbidities (MACE events)
!
Comorbidity score similar to Charlson Comorbidity Index
!
Platelets (<100, 100-400, > 400 (10^9/L))
!
ANC (0.5 to < 1.0, ≥ 1.0 (10^9/L))
!
Prior GCSF/GMCSF usage (Yes vs. No)
8.3.
Baseline Hematology Characteristics
Baseline hematology characteristics consist of Hemoglobin, Platelet, and ANC at baseline. All 
baseline hematology characteristics will be summarized desc riptively. 
8.4.
MDS Diagnosis History
A frequency summary of MDS diagnoses at original (first) diagnosis will be presented by 
treatment group for the following categorical variables:
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24 m
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CrCL
CrCL) (40 -
(40 
atus
atus (Yes v
(Yes
es (
s (MACE 
MACE
ar to
ar to Char
Char
400, > 40
400, > 4
1.0, 
1.0, ≥1.0 (
F/GMCSF 
F/GMCSF 
Baseli
Baseli
line hemato
line hema
seline hem
seline hem


EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
43
!
Baseline MDS World Health Organization (WHO) Classification 2008 from Central 
Reading (e.g. MDS RARS, MDS RCMD, Other)
!
IPSS-R risk at baseline (e.g. Very Low, Low, Intermediate, Missing)
8.5.
Prior Transfusion History
A frequency summary of prior transfusion types (i.e., RBC, Platelets, Other) and reasons (i.e.
Anemia, Thrombocytopenia, Internal bleeding, Surgery, Infection, Other) will be presented 
categorically by treatment group. 
8.6.
Medical History
Medical history will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA; Version TBD). A frequency summary of medical history will be presented by 
treatment group, system organ class (SOC), and preferred term (PT), with SOCs sorted in 
alphabetical order and PTs within each SOC in descending order of frequency. Summary table 
by SOC only will also be provided in descending order of Luspatercept group. 
8.7.
Prior and Concomitant Medications
8.7.1.
Prior Medication
Prior medications are defined as medications that were started before the date of first dose of IP
(whether or not ended before the date of first dose of IP). Prior medications that continue into 
study treatment period will be also reported as concomitant medication.
Prior medications will be coded in the WHO drug dictionary (WHODD; TBD). 
Prior medications will be summarized by Anatomical Therapeutic Chemical (ATC) 4 level and 
preferred term (PT), in alphabetical order for the ATC class, and within each ATC class, in 
alphabetical order for PTs.
8.7.2.
Concomitant Medication
Concomitant medication is defined as medications that were taken from the date of first dose of 
IP until 42 days after the last dose of IP or End of Treatment (EOT) Visit, whichever occurs 
later. If a medication is started before the date of first dose of IP and continues on or after the 
date of first dose of IP, then it will be considered both a prior medication and a concomitant 
medication.
Concomitant medications will be coded in the WHO drug dictionary (TBD). 
The ATC coding scheme of the WHO will be used to group medications into relevant categories.
A frequency table by Anatomical Therapeutic Chemical (ATC) class (level 4) and preferred term
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42 days afte
days af
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of fir
first d
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medicat
medicatioion
onco
onco


EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
44
will be provided, in alphabetical order for the ATC class, and within each ATC class, in 
alphabetical order for PTs.
8.8.
Concomitant Procedures and Surgeries
Concomitant procedures and surgeries are defined similarly to concomitant medications.
Concomitant procedures and surgeries will be coded according to the MedDRA (Version TBD)
and summarized by SOC and PT, with SOCs sorted in alphabetical order and PTs within each 
SOC in descending order of frequency. 
8.9.
Coombs’ Test
Coombs test results at screening will be provided in a data listing. 
8.10.
Pregnancy
Pregnancy test results will be provided in a data listing for all female subjects of childbearing 
potential. 
CCI
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all female
ll female


EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
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45
9.
STUDY TREATMENTS AND EXTENT OF EXPOSURE
Study treatment and extent of exposure summaries will be provided based on the Safety 
population.
9.1.
Treatment Duration
The treatment duration (weeks) is defined as: 
[(the treatment end date) – (the date of the first dose of IP) + 1]/7.
For subjects who discontinued treatment, the end date of the last cycle as defined in Section 5.1.3 
will be used as the treatment end date. It is calculated as  last IP date plus 20 days, study 
discontinuation date, or the death date, whichever is earlier. For subjects who are still on 
treatment at the time of data cutoff, the cutoff date will be used as the treatment end date. 
Descriptive statistics will be summarized for treatment duration by treatment group and overall.
9.2.
Number of  Doses Received
Total number of doses received by subjects will be summarized both descriptively and 
categorically (1, 2, 3, 4, 5, 6, 7, 8, 9-16, 17-24, 25-36, >36) for the Safety population by 
treatment group. 
Number of doses received at time of completion of Primary Treatment Phase (or discontinued 
earlier) will be summarized. 
9.3.
Average Length of Cycle between Doses
The average length of cycle between doses (days) is defined as [(the treatment end date) – (the 
date of the first dose of IP) + 1]/ the total number of doses received. The treatment end date is 
defined in Section 9.1.
The average length of cycle between doses (days) will be summarized descriptively by treatment 
group and overall.
9.4.
Cumulative Dose 
The cumulative dose (mg) for IP is defined as the sum of all actual dose given during the 
Treatment Period. Cumulative dose will be summarized descriptively by treatment group and 
overall.
9.5.
Dose Modification
Descriptive statistics will be summarized by treatment group and overall for the following 
variables:
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erall.
rall.


EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
46
!
Number of subjects who have at least one dose delay, 
!
Number of subjects with at least one dose reduction
!
Reasons for the dose delay (any suspected related AE ≥grade 3, pre-dose Hb≥11.5 g/dL, 
other, missing)
!
Reasons for the dose reduction (increase in Hgb ≥2.0 g/dL, any suspected related AE 
≥grade 3, other, missing)
!
Time to first dose delay (days)
!
Time to first dose reduction (days)
!
Time to first dose delay due to AE
!
Time to first dose reduction due to AE
!
Time of first dose delay due to Hgb increase
!
Time to first dose reduction due to Hgb
The subjects with dose titration will be summarized by maximum dose level (e.g. 1.0 mg/kg, 
1.33 mg/kg, 1.75 mg/kg). 
CCI
&(/*(1(35235,(7$5<,1)250$7,21
m dose l
o
ev


EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
47
10.
PHARMACOKINETIC ANALYSIS
10.1.1.
Pharmacokinetic Analysis
Blood samples for PK will be taken at the following visits during the study (see Table 4):
!
Primary Phase of Treatment Period: C1D1 (must be collected before the first dose), 
C1D8, C1D15, C2D1, C4D1, C5D8 and then Day 1 of every other treatment cycle 
thereafter in the Primary Phase (i.e. C6D1 and C8D1, if no dose delays)
! Week 25 Visit (Collect sample only if > 14 days from prior sample collection.)
! Extension Phase of Treatment Period (if applicable): Extension Phase Cycle 4, Day 1 and 
Day 1 of every fourth Extension Phase treatment cycle thereafter (e.g. Extension Phase 
Cycles 4, 8, etc.) for up to one year from the first dose in the Primary Treatment Phase. 
! Posttreatment Follow-up: For subjects who do not complete Primary Treatment Phase or 
do not participate in Extension Phase or subjects who terminate the Extension Phase with 
less than 1 year ADA of monitoring, PK samples will be collected at EOT and then every 
12 weeks for up to one year from the first dose in the Primary Treatment Phase.
After the study is unblinded, PK samples may no longer be collected from subjects in the 
placebo arm. In addition, upon unblinding of the study, PK sampling at all Post-Treatment 
Follow-up visits may continue only if subjects’ last available ADA is positive and they have not 
reached the maximum of 1 year ADA monitoring. Pharmacokinetic (PK) sampling per 
investigator’s or sponsor’s discretion is allowed and should be recorded as an unscheduled visit.  
Luspatercept concentration data will be listed by subject, including arm, treatment period, visit, 
dose level, dosing date/time, actual sample collection date/time, and actual sample time (day) 
relative to the first dose.
 
 
 
 
 
 
 
 
 
 
10.1.2.
Anti-Drug Antibodies Analysis
Blood samples will be collected for assessment of ADA against luspatercept in serum in all 
subjects at the following visits during the study (see Table 4). The maximum ADA monitoring 
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
48
period will be 1 year from the first dose of the Primary Treatment Phase unless justified by 
safety reasons: 
! Primary Phase of Treatment Period: C1D1 (must be collected before the first dose), 
C2D1, and then Day 1 of every other treatment cycle thereafter in the Primary Phase (i.e.
C4D1, C6D1, and C8D1 if no dose delays).
! Week 25 Visit (Collect sample only if > 14 days from prior sample collection)
! Extension Phase of Treatment Period (if applicable): Extension Phase Cycle 4, Day 1 and 
Day 1 of every fourth Extension Phase treatment cycle thereafter (e.g. Extension Phase 
Cycles 4, 8, 12, 16+, etc.) for up to 1 year from the first dose in the Primary Treatment 
Phase.
! Post-treatment Follow-up: For subjects who do not complete the Primary Treatment 
Phase or do not participate in the Extension Phase or subjects who terminate the 
Extension Phase with less than 1 year of ADA monitoring, ADA samples will be 
collected at EOT and then every 12 weeks for up to one year from the first dose in the 
Primary Treatment Phase.
After the study is unblinded, ADA samples may no longer be collected from subjects in 
the placebo arm.  In addition, upon unblinding of the study, ADA sampling at all Post-
Treatment Follow-up visits may continue only if the subject’s last available ADA sample 
is positive and the subject has not reached the maximum of 1 year ADA monitoring. 
Antidrug antibodies sampling per investigator’s or sponsor’s discretion is allowed and
should be recorded as an unscheduled visit.
The ADA results will be listed by subject, including arm, treatment period, visit, dose level, 
dosing date/time, actual sample collection date, and actual sample time (day) relative to the first 
dose. 
The number and percentage of the subjects for each ADA test will be presented by treatment 
group and ADA status.   The number and percentage of the subjects and median (range) titer for 
binding ADA to luspatercept will be presented by treatment group, visit, and ADA status.  The 
Box plot of ADA trend over time may be provided.   
The ADA status of a subject during treatment is determined based on the longitudinal ADA 
results as following:
!
Negative: All samples (baseline and post-baseline) are negative.
!
Positive to treatment-emergent ADA: 
-
At least one post-baseline sample is positive if the baseline sample is negative, or 
-
At least one post-baseline sample is positive with a titer ≥ 4-fold of the baseline titer 
if the baseline sample is positive
!
Positive to preexisting ADA: 
-
Baseline sample is positive and all post-baseline samples are negative, or
-
Both baseline and post-baseline samples are positive, but all positive post-
baseline sample have a titer < 4-fold of the baseline titer.
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!


EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
49
11.
EFFICACY ANALYSIS
All efficacy analyses will be performed on the ITT population, except the analysis of EORTC 
QLQ-C30 scores that will be performed on the HRQoL evaluable 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 (RBC-TI) ≥ 8 weeks and the key secondary endpoint of RBC-
TI ≥ 12 weeks (week 1-48 & week 1-24), will be tested sequentially in the pre-specified order. 
The primary efficacy endpoint will be tested first at the one-sided 0.025 significance level. In 
order to preserve the overall alpha level at 0.025 across the RBC transfusion independence 
endpoints, formal statistical inference for the RBC-TI ≥ 12 weeks analysis (first tested for week 
1-48, then week 1-24) can only be made if superiority of luspatercept is demonstrated for the 
primary efficacy endpoint, RBC-TI ≥ 8 weeks, at the one-sided 0.025 significance level. 
An interim analysis to assess futility on the primary and key secondary endpoint will be 
performed when approximately 105 subjects have completed the Primary Phase of the Treatment 
Period (first 24 weeks of double-blind treatment) or discontinued before reaching 24 weeks of 
double-blind treatment (50% information for primary endpoint). There will be no plan to claim 
luspatercept superiority based on efficacy results so the type I error rate remains at 0.025 one-
sided for the final analysis. 
The secondary efficacy variables will be analyzed and reported at the time of the analysis of the 
primary and key secondary efficacy endpoint.
Subjects will continue to be followed for progression to AML, other malignancies/pre-
malignancies, subsequent MDS therapies, and overall survival for at least 3 years from the date 
of IP last dose unless the subject withdraws consent from the study, dies or is lost to follow-up. 
Other than the pre-specified sequential testing of RBC-TI (≥ 8 weeks, then ≥12 weeks), no 
additional alpha adjustments for multiplicity will be made.
11.1.
Determination of Week 24 and Week 48 cutoff date 
Week 24: 
For subjects who are on treatment at the end of the Primary Phase of the Treatment, a cutoff of 
first dose of IP + 168 days is used to determine end of week 24. 
For subjects who are off treatment, off study, or died prior to the end of week 24, the earliest of 
the following 4 dates if applicable will be used to determine transfusion independence: 
!
Last dose date + 20 days
!
End of study date
!
Death date 
!
Final analysis cutoff date 
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re on treatm
+ 168 day
+ 168 days
s who are o
who are o
wing 4 date
ng 4 da
Last dos
Last do
!
End
End
!


EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
50
Week 48: 
For subjects who are on treatment, a cutoff of first dose of IP + 336 days is used to determine 
end of week 48. 
For subjects who are off treatment, off study, or died prior to the end of week 24, the earliest of 
the following 4 dates if applicable will be used to determine transfusion independence: 
!
Last dose date + 20 days
!
End of study date
!
Death date 
!
Final analysis cutoff date 
11.2.
Analysis of Primary Efficacy Endpoint
The primary efficacy analysis will be the comparison of the RBC transfusion independence
response rates in the two treatment groups. The primary efficacy endpoint of transfusion 
independence response is defined as the absence of any RBC transfusion during any consecutive 
56 day period during the Primary Phase of the Treatment Period (first 24 weeks of double-blind 
treatment) i.e. days 1 to 56, days 2 to 57, days 3 to 58, etc. 
Subjects have to have have at least 56 days of transfusion independence prior to  (and including) 
Week 24 cutoff date to quality as a responder. Subjects who failed to achieve at least 56 days 
prior to or on cutoff date will be counted as non responders. 
For the primary efficacy endpoint, 56-day RBC transfusion independence, the response rate will
be calculated using the number of responders divided by number of subjects (responders plus 
non-responders). Subjects discontinued from the Primary Phase of the Treatment Period without 
achieving at least 56 days consecutive of RBC transfusion independence will be counted as non-
responders. The response rates of the subjects who were randomized to luspatercept and the 
placebo will be calculated. In the primary efficacy analysis, the statistical hypothesis is
H0: P1= P2
Ha: P1> P2
where 
1
P denotes the true response rate in the luspatercept group, and 
2
P denotes the true 
response rate in the placebo group. 
The number and percentage of subjects who achieve RBC transfusion independence and 
corresponding 97.5% upper bound confidence intervals (CI) will be tabulated and presented by 
treatment group. The Cochran–Mantel–Haenszel(CMH) test will be used to test the difference 
between the two response rates at a one-sided significance level of 0.025, stratifying for average 
baseline RBC transfusion requirement ( ≥ 6 units versus < 6 units of RBC per 8 weeks), and 
baseline IPSS-R score (Very low, or low vs. Intermediate).
The p-value from the stratified Cochran-Mantel-Haenszel (CMH) 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. If the p-value is less 
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97
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etween the
baseline 
baseline 
selili


EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
51
than 0.025, the null hypothesis will be rejected, indicating that the true response rate in the 
luspatercept group is more than the true response rate in the placebo group. Summaries will 
include the difference in proportions between the two treatment groups with corresponding two-
sided 95% CI and the common odds ratio with corresponding two-sided 95% CI. Subject listings 
with supporting data will be provided.
11.3.
Analyses of Secondary Efficacy Endpoints
To control the overall Type I error rate (alpha), the key secondary endpoints will only be tested if 
superiority of luspatercept is demonstrated for the primary efficacy endpoint. The primary and 
key secondary endpoints are the only endpoints that will employ a sequential testing approach.
For other secondary variables, summary of descriptive statistics will be presented to describe 
continuous secondary variables. Kaplan-Meier methods will be used to estimate curves for time 
to event secondary variables. Counts and percentage will be used to describe categorical 
secondary variables.
11.3.1.
Key Secondary Efficacy Endpoint
The key secondary endpoint, proportion of subjects achieving RBC-TI with duration ≥12 weeks
is the absence of any RBC transfusion during any consecutive 84 day period during the 
Treatment Period (Week 1-48), i.e., days 1 to 84, days 2 to 85, days 3 to 86, etc. Subjects 
discontinued from the Treatment Period without achieving at least 84 consecutive days of RBC 
transfusion independence will be counted as non-responders.
Same approach as described in Section 11.1 will be used to assess RBC-TI with duration ≥ 12 
weeks. Subjects have to have have at least 84 days of transfusion independence prior to  (and 
including) Week 48 cutoff date  to quality as a responder.  Subjects who failed to achieve at least 
84 days prior to or on cutoff date will be counted as non responders. 
The key secondary endpoint will be tested in the same manner as primary efficacy endpoint, at a 
one-sided 0.025 significance level using the Cochran-Mantel-Haenszel (CMH) test.
11.3.2.
Mean Hemoglobin Increase ≥ 1.0 g/dL
Hemoglobin (Hgb) increase ≥ 1.0 g/dL is defined as proportion of subjects with ≥ 1.0 g/dL mean 
Hgb increase (after applying 14/3 day rule) from baseline that is sustained over any consecutive 
56-day period in the absence of RBC transfusions during the Treatment Period (Week 1-24, 
Week 1-48), in the time frames described in Section 11.1. The number and percentage of 
subjects achieving Mean Hgb increase ≥ 1.0 g/dL together with 95% CI will be presented by 
treatment group. The Cochran–Mantel–Haenszel(CMH) test will be used to compare 
Luspatercept treatment group to placebo group. 
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&
subjects
ubjects a
eatm
eatm


EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
Confidential and Proprietary
52
11.3.3.
Total RBC Units Transfused over 16 Weeks
Total RBC units transfused over 16 weeks is defined as the total number of RBC units transfused 
over a fixed period of 16 weeks (Week 9-24; Week 33-48) compared to the total number of RBC 
units transfused in the 16 weeks immediately on or prior to the first dose date. 
Total RBC units transfused from Week 9-24 is defined as sum of all transfused RBC units from 
first IP date + 56 days to first IP date + 168 days. Only subjects who are on treatment till end of 
week 24 will be included in this analysis. Total RBC units transfused from Week 33-48 is 
defined as sum of all transfused RBC units  from first IP date + 231 days to first IP date + 336 
days. This will only be calculated for subjects who are still on treatment at the end of 48 weeks.  
Mean change in total number of RBC units transfused over a fixed 16-week period (Week 9-24,
Week 33-48) from the total number of RBC units transfused in the 16 weeks immediately on or 
prior to first IP date will be summarized using descriptive statistics by treatment group.
Subgroup analysis might be done to assess transfusion reduction. 
    
11.3.4.
Proportion of Subjects Achieving RBC-TI with Duration ≥ 8 Weeks (Week 1 -
48)
Proportion of subjects achieving RBC-TI with duration ≥8 weeks is the absence of any RBC 
transfusion during any consecutive 56-day period during the Treatment Period (Week 1-48). The 
number and percentage of subjects who achieve RBC transfusion independence will be presented 
by treatment group.
Similar approach as described in Section 11.2 will be used. 
11.3.5.
Proportion of Subjects Achieving Modified Erythroid Response 
Proportion of subjects achieving the modified erythroid response (mHI-E) is defined as the 
proportion of subjects meeting the modified HI-E criteria per the International Working Group 
(IWG) (Cheson, 2006; Appendix E) sustained over any consecutive 56-day period during the 
Treatment Period (Week 1–24, Week 1-48). Subjects meeting the modified HI-E criteria are 
derived as below:  
     For subjects with < 4 units/8 weeks at baseline, a responder must satisfy the following 
conditions:
          i. there are no RBC transfusion within the response interval
          ii. mean of Hemoglobin increase >= 1.5 g/dL from baseline
For subjects with >=4 units at baseline, a responder must satisfy the following conditions:
          i. decrease of at least 4 units from baseline over any consecutive 56-day period
The number and percentage of subjects who achieve mHI-E together with 95% CI will be 
presented by treatment group. The Cochran–Mantel–Haenszel(CMH) test will be used to 
compare Luspatercept treatment group to placebo group.
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EDMS Doc. Number:
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11.3.6.
Duration of RBC-TI 
Duration of RBC-TI is defined as the longest duration of RBC-TI for subjects achieving RBC TI 
≥8 weeks during the Treatment Period (Week 1 - 24, Week 1 – 48, during entire study 
treatment) . Subjects who maintain RBC-TI at the time of the analysis will be censored. Wee 24 
and Week 48 cutoff dates as described in Section 11.1 will be used in the calculation. 
Duration of RBC transfusion independence curve will be estimated using Kaplan-Meier (KM) 
methods and treatment groups will be compared using a stratified log-rank test. KM estimates for 
median duration of RBC-TI as well as two-sided 95% CIs will be summarized for each treatment 
group, adjusted for the stratification variables. Hazard ratio will be calculated using Cox model 
stratified for the 2 strata. 
Plots of the KM survival curves will be presented for the two treatment groups, with adjustment 
for the stratification variables. 
11.3.7.
Time to RBC-TI  
Time to RBC-TI will be summarized only for subjects who achieve RBC TI ≥ 8 weeks on 
treatment. It is defined as the time between first dose date and the date onset of TI is first 
observed (i.e. Day 1 of 56 days without any RBC transfusions). 
Time to RBC-TI (in days) will be summarized using descriptive statistics by treatment group.
11.3.8.
Health-related QoL assessed by EORTC QLQ-C30
The European Organization for Research and Treatment of Cancer Quality-of-Life questionnaire 
(EORTC QLQ-C30) is a validated health-related quality of life (HRQoL) measure developped to 
subjectsmeasure the HRQoL of patients with cancer. It is commonly used in MDS research 
(Pinchon, 2009). It is composed of 30 items that address 15 domains, including one global health 
status, five functional domains (i.e., physical functioning, role functioning, emotional 
functioning, cognitive functioning, and social functioning), and nine symptom domains (i.e., 
fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, and 
financial difficulties). Domain scores are transformed to a 0 to 100 scale, with higher scores on 
functional scales indicating better function and higher score on symptom scales indicating worse 
symptoms.
To interpret the difference in change score from baseline between treatment groups and change 
score at the individual level, a ≥10-point change in any domain of the QLQ-C30 is commonly 
considered clinically-meaningful at an individual level (Osoba, 1998). Other cut-off values for 
clinically-meaningful change across different domains have also been reported (Cocks, 2012).
The primary EORTC QLQ-C30 domains of interest for the assessment are fatigue, dyspnea, 
global health status/QoL, physical functioning, and emotional functioning domains, as they are 
considered to be most clinically relevant to patients with MDS in the literature (Abel, 2014; 
Caocci, 2009; Williams, 2013) .  A ≥10-point change in any domain of the QLQ-C30 is 
commonly considered clinically-meaningful at an individual level.12 Other cut-off values for 
clinically-meaningful change across different domains have also been reported. 
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EDMS Doc. Number:
Luspatercept
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Celgene Corporation
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The EORTC QLQ-C30 scores will be calculated according to scoring algorithms defined by the 
authors (Appendix 16.1.9).
To assess the extent of missing data at each assessment visit by treatment group, the PRO 
compliance rate for the EORTC QLQ-C30 will be estimated per treatment group on the ITT 
population. Subjects are considered compliant with completion of the EORTC QLQ-C30 
assessment if at least half of the EORTC QLQ-C30 items are non-missing (i.e., ≥15 out of the 30 
items) at a given assessment visit.
To assess the effect of luspatercept versus placebo on HRQoL, the following key analyses will 
be performed based on the HRQoL evaluable population. To align the HRQoL analysis with 
analysis of key efficacity endpoints, the analysis of scores at Week 25 will be considered as 
primary.
 
11.3.8.1.
Main analysis
A cross-sectional analysis of changes from will be performed to compare the scores at Week 25, 
Week 48 and end of treatment between treatment groups using ANCOVA models adjusted for 
baseline domain scores and randomization stratification factors. The least squares (LS) means 
(95% confidence intervals [CI] and p-values) for changes from baseline at each postbaseline visit 
for all domains within each treatment group, and the difference in the LS means (95% CIs, p-
value) between treatment groups at each postbaseline visit, with the primary interest at the Week 
25 Visit, will be estimated.
To avoid bias when interpreting differences between groups in HRQoL score changes from 
baseline (screening) to end of treatment, the corresponding treatment duration will be described 
per treatment groups for patients analyzed.
 
 
 
11.3.9.
Proportion of Subjects Achieving Hematological Improvement-Neutrophils 
This is defined as the proportion of subjects meeting the HI-N criteria per the IWG (Cheson,
2006; Appendix E) sustained over any consecutive 56-day period during the Treatment Period 
(Week 1–24, Week 1-48). The number and percentage of subjects in the ITT population who 
achieve HI-N together with 95% CI will be presented by treatment group. The Cochran–Mantel–
Haenszel(CMH) test will be used to compare Luspatercept treatment group to placebo group. 
11.3.10.
Proportion of Subjects Achieving Hematological Improvement-Platelets 
This is defined as the proportion of subjects meeting the HI-P criteria per the IWG (Cheson,
2006; Appendix E) sustained over any consecutive 56-day period during the Treatment Period 
(Week 1–24, Week 1-48). The number and percentage of subjects in the ITT population who 
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
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achieve HI-P together with 95% CI will be presented by treatment group. The Cochran–Mantel–
Haenszel(CMH) test will be used to compare Luspatercept treatment group to placebo group.
11.3.11.
Mean Change in Mean Daily Dose of Iron Chelation Therapy 
The change in daily dose of ICT for each subject is calculated as the difference of post-baseline 
mean daily dose and baseline mean daily dose. There will be two comparisons between 
luspatercept group and placebo group; mean change from baseline for mean daily dose of Iron 
Chelation Therapy (ICT) averaged over Week 9 -24, and mean daily dose of ICT averaged over 
Week 33 - 48. 
Shift table of ICT status (receiveing ICT vs. not receiving ICT) at baseline and post baseline will 
be provided. 
11.3.12.
Mean Serum Ferritin Decrease   
The change is calculated as the difference of post-baseline mean serum ferritin (Week 9-24, 
Week 33-48) and baseline mean serum ferritin. There will be two comparisons between 
luspatercept group and placebo group; mean change from baseline for mean serum ferritin 
averaged over Week 9-24, and mean serum ferritin averaged over Week 33-48. 
11.3.13.
Time to Progression to Acute Myelogenous Leukemia 
Time to progression to AML is defined as the time between randomization and first diagnosis of 
AML as per WHO classification of ≥ 20% blasts in peripheral blood or bone marrow. Subjects 
with diagnosis of AML will be considered to have had an event. Subjects who have not
progressed to AML at the time of analysis will be censored at the last assessment date which
does not indicate progression to AML.
The number and percentage of subjects progressing to AML will be presented by treatment 
group during the Treatment Period (Week 1-48), and randomization through at least 3 years post 
last dose. Time to AML progression curves will be estimated using KM methods and treatment 
groups will be compared using a log-rank test. Kaplan-Meier estimates for median time to AML 
progression as well as the two-sided 95% CIs will be summarized for each treatment group, 
adjusted for the stratification variables. Plots of the KM survival curves will be presented for the 
two treatment groups, with adjustment for the stratification variables.
At the time of the final analysis, a Cox proportional hazards model will be used to estimate the 
corresponding hazard ratio and two-sided 95% CI.
Time to AML progression from initial MDS diagnosis is defined as the time between original 
diagnosis of MDS and first diagnosis of AML as per WHO classification of ≥ 20% blasts in 
peripheral blood or bone marrow. It will be summarized using descriptive statistics by treatment 
group.
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EDMS Doc. Number:
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11.3.14.
Overall Survival 
Overall survival (OS) is calculated as the time from randomization to death of any cause. OS will 
be censored at the last date that the subject was known to be alive for subjects who were alive at 
the time of analysis and for subjects who discontinued from the study or were lost to follow-up.  
The analysis of OS will be performed for the Treatment Period and Posttreatment Follow-up 
Period. 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 (≥6 units versus < 6 units of RBC per 8 weeks), baseline IPSS-R (very low or low 
versus intermediate). The p-value from the stratified log-rank test will be the confirmatory p-
value. The analysis of OS will be conducted at the time of the analysis of the primary and key 
secondary efficacy endpoint. 
Kaplan-Meier estimates for median OS and associated two-sided 95% CIs will be summarized 
for each treatment group, adjusted for the stratification variables. Plots of the KM survival curves 
will be presented for the two treatment groups, with 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 two-sided 95% CI for luspatercept relative to 
placebo. 
11.4.
Subgroup Analysis
In addition to analyses that include all ITT subject , additional exploratory subgroup analyses 
will be performed within the following subgroups for primary and key secondary efficacy 
endpoint, i.e., RBC-TI ≥ 8 weeks (Weeks 1-48) and ≥ 12 weeks (Weeks 1-24), and HI-E 
response:
!
Age group (≤ 64, 65-74, and ≥75)
!
Sex (Male, Female)
!
Race (White, non-White)
!
MDS WHO classification at baseline
!
Time since initial diagnosis at baseline (≤  2 , 2 to ≤  5, > 5 years)
!
ECOG performance status at baseline (0 or 1, 2)
!
Average baseline RBC transfusion requirement < 4, ≥ 4 and < 6, ≥6 units)
!
Baseline transfusion burden (# of RBC transfusions/ last 8 weeks; < 4, ≥ 4 and < 6, ≥
6 units)     
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
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!
Baseline IPSS-R risk (Very low or Low, Intermediate)
!
Longest Duration of Prior ESA treatment (< 6, 6 - 12, > 12 - 24, > 24 months)
!
Renal (CrCL > 40 - 60 vs. ≥60 mL/min)
!
SF3B1 (mutated vs non-mutated)
!
Baesline serum EPO (<100, 100-<200, 200-500 and >500 U/L)
!
Baseline Platelets (<100, 100-400, > 400 (10^9/L))
Primary and key secondary efficacy endpoint will be analyzed separately within each subgroup 
using the appropriate analysis methods as described in Sections 11.1 and 11.2.1, but formal 
hypothesis testing will not be performed in the subgroup analyses.
If the total number of subjects within one subgroup is less than 5% of the total sample size, that 
subgroup will be excluded in subgroup analysis. 
More subgroup analysis might be explored if applicable. 
 
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EDMS Doc. Number:
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12.
SAFETY ANALYSIS
All summaries of safety data will be conducted using the Safety population. 
12.1.
Adverse Events
Adverse events (AEs) will be coded according to the Medical Dictionary for Regulatory Affairs 
(MedDRA) Version TBD. The severity/intensity of AEs will be graded based upon the subject’s 
symptoms according to the current active minor version of the Common Terminology Criteria 
for Adverse Events (CTCAE, Version 4.0). Adverse events that are not defined in the CTCAE 
should be evaluated for severity/intensity 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
Adverse events will be classified as Not Suspected or Suspected depending on the relationship 
between IP administration and AE/SAE occurrence.
Not suspected:
a causal relationship of AE to IP administration is unlikely or 
remote, or other medications, therapeutic interventions, or 
underlying conditions provide a sufficient explanation for the 
observed event.
Suspected:
there is a reasonable possibility that the administration of IP 
caused AE. ‘Reasonable possibility’ means there is evidence to 
suggest a causal relationship between the IP and AE.
Treatment-emergent adverse events include adverse events that started on or after the date of first 
dose and on or before 42 days after the date of last dose of study treatment.   
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EDMS Doc. Number:
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The following summaries of AEs will include incidence tables by treatment group and overall:
!
All TEAEs regardless of causaulity 
!
TEAEs with CTCAE toxicity >= grade 3
!
TEAEs leading to death
!
TEAEs leading to permanent study drug discontinuation
!
All Suspected TEAEs
!
Serious TEAE 
!
Suspected Serious TEAEs
!
TEAEs with CTCAE toxicity grade 3 or 4
!
TEAEs leading to dose interruption
!
TEAE leading do dose reduction
!
TEAEs by age group (≤ 64, 65 to 74, >=75)
!
TEAEs by gender
!
TEAE by Crcl (40-<60, >=60)
!
TEAE by maximam Dose received (1.0 mg/kg, 1.33 mg/kg, 1.75 mg/kg)
!
TEAE in ADA positive subjects 
If a subject experiences multiple AEs under the same SOC and PT, then the subject will be 
counted only once for that SOC and PT.
All AEs will be summarized by maximum severity (mild, moderate, severe, life- threatening, 
death and, if needed, missing). If a subject reports multiple occurrences of a specific event, the 
subject will be counted only once by the maximum severity. If the severity is missing for one or 
more of the occurrences, the maximum severity of the remaining occurrences will be used. If the 
severity is missing for all of the occurrences, the subject will be counted only once in the
“missing” category of severity.
The relationship of an AE to IP is recorded on the AE CRF page as “Not suspected” and 
“Suspected.” Adverse events with missing relationship to IP will be assessed as drug-related.
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.
12.1.1.
Adverse Events by Cycle and Maximum Dose Received
The following summaries of TEAEs will include incidence tables by treatment and cycle group, 
dose level or maximum dose received:
!
All TEAEs 
!
Serious TEAEs
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EDMS Doc. Number:
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The following cycle group will be used:
!
Cycles 1-4 
!
Cycles 5-8 
!
Ext Cycles 1-4 
!
Ext Cycles 5-8 
!
Ext Cycles >=9 
The following maximum dose level group will be used:
!
1.0 mg/kg 
!
1.33 mg/kg
!
1.75 mg/kg
When summarizing TEAEs by maximum dose level, all AEs regardless of severity will be 
counted.
The analysis of TEAE by cycle 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. If an AE occurred multiple times in different cycle groups, it will be counted separately. If 
an AE occurred multiple times within the same cycle group, it will be counted only once.
12.1.2.
Adverse Events of Interest
Adverse event of interest including but no limited to premalignant disorders and malignancies
(including progression to AML or high risk MDS) will be summarized separately.   
12.1.3.
Death
A frequency table of the cause of death will be provided by treatment, including the number and 
percentage of subjects with deaths due to disease under investigation alone, subjects with deaths 
recorded as both disease under investigation and any TEAEs with an outcome of death, and 
subjects with an TEAEs with an outcome of death (but not due to disease under investigation).
Death during on-treatment period and post-treatment period will be summarized separately. On-
treatment death is defined as any death occurred on or after first dose of IP until 42 days after the 
last dose of IP. 
A listing of deaths will also be provided including deaths for all screened subjects during pre-
treatment, on-treatment, and post-treatment period.
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EDMS Doc. Number:
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12.2.
Clinical Laboratory Evaluations
Clinical laboratory values will be graded according to NCI CTCAE version 4.3 for applicable tests. 
Change in hematology, blood chemistry, urinalysis laboratory results from baseline to each scheduled 
time point will be provided for the safety population. Shift tables for change in maximum NCI CTCAE 
grades of laboratory values will be provided by treatment and scheduled time point for those laboratory 
parameters that have CTCAE grades. Separate shift tables will be provided with respect to normal ranges 
for all numeric laboratory parameters. 
Separate listings will be provided for laboratory values. 
12.3.
Vital Sign Measurements
Change from baseline will be summarized descriptively by scheduled time point and treatment 
groups for weight (kg), temperature (C), pulse rate (bpm), respiratory rate (bpm), systolic blood 
pressure, and diastolic blood pressure (mmHg).
Maximum post baseline increase in systolic blood pressure and diastolic blood pressure increase 
from baseline will also be summarized for the following categories: 
!
no increase, 
!
increased <20 mmHg,
!
increased >= 20 mmHg
o
(Systolic Blood Pressure ≥ 160 mmHg 
o
Diastolic Blood Pressure ≥ 100 mmHg
Maximum post baseline decrease of at least 10% in weight will be summarized using the number 
and percentage.
12.4.
Electrocardiograms
Electrocardiogram (ECG) parameters include heart rate, PR interval, QRS duration, RR interval, 
and QT are collected on the CRF page. The corrected value for QT interval will be derived based 
on Fridericia's formula as below:
Fridericia's formula: QTcF= QT/(RR)1/3, where RR is derived as:
Calculated RR (msec) = 60000 (msec)/heart rate (bpm)  
Recorded parameters, QTcFs and change from baseline values will be summarized at each time 
point by treatment group. 
In addition, at baseline and maximum QTcF from post-baseline visits, the proportion of subjects 
having absolute QTcF and intervals of the following categories will be presented:
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EDMS Doc. Number:
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!
> 450 ms
!
> 480 ms
!
> 500 ms 
At maximum QTcF from post-baseline visits, the proportion of subjects who have an increase 
from baseline in QTcF intervals of the following categories will be presented: 
!
>30 ms
!
> 60 ms
The overall electrocardiogram (ECG) interpretation will be summarized by presenting the 
number and percentage of subjects with ‘Normal’ ‘Abnormal, Not Clinically Significant’ and 
‘Abnormal, Clinically Significant’ by treatment group. Shift from baseline to worst during the 
treatment in the overall ECG interpretation will be displayed in cross–tabulations for each 
treatment.
12.5.
ECOG Performance Status 
ECOG performance will be summarized categorically with a shift from baseline to worst post-
baseline by scheduled time point and maximum shift by treatment.
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EDMS Doc. Number:
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EDMS Doc. Number:
Luspatercept
Statistical Analysis Plan. Protocol ACE-536-MDS-001
Celgene Corporation
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64
 
 
 
 
 
 
 
 
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15.
TIMING OF ANALYSES
15.1.
Interim analysis
An interim analysis to assess futility will be performed when approximately 105 subjects have 
completed the Primary Phase of the Treatment Period (first 24 weeks of double-blind treatment) 
or discontinued before reaching 24 weeks of double-blind treatment (50% information for 
primary endpoint). There will be no plan to claim luspatercept superiority based on efficacy 
results so the type I error rate remains at 0.025 one-sided for the final analysis. 
Conditional power for primary endpoint will be calculated assuming the observed trend 
continues for the rest of the data. If it is 10% (corresponding to a futility boundary of p-value 
≥0.201 using beta-spending function) or less, with confirmative data for secondary and other 
efficacy endpoints, the DMC may recommend stopping the study for futility.
The sponsor will remain blinded throughout the study.
15.2.
Final analysis
Final analysis will be performed when all 210 subjects have completed 48 weeks of treatment or                         
discontinued before 48 weeks. There is no plan to claim luspatercept superiority based on interim 
analysis efficacy results, thus the type I error rate remains at 0.025 one-sided for the final 
analysis. Additional follow-up analysis for efficacy and safety will be performed when all 
subjects have been followed for at least 3 years from the last dose of IP.
   
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EDMS Doc. Number:
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16.
REFERENCES
Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, et al. Proposals for 
the classification of the myelodysplastic syndromes. Br J Haematol 1982;51(2):189–99.
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.  
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(12):2454-65.
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.
DeMets DL, Lan KK, 1994, Interim analysis: The alpha spending function approach, Statistics in 
Medicine 13: 1341-1352.
Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significance of changes in 
health-related quality-of-life scores. J Clin Oncol. 1998;16(1):139-144.
Norman GR, Sloan JA, Wyrwich KW. The truly remarkable universality of half a standard 
deviation: confirmation through another look. Expert Rev Pharmacoecon Outcomes Res. 
2004;4(5):581-585.
Norman GR, Sloan JA, Wyrwich KW. Interpretation of changes in health-related quality of life: 
the remarkable universality of half a standard deviation. Med Care. 2003;41(5):582-592.
Bross I. How to Use Ridit Analysis. Biometrics. 1958;14(1):18-38.
Cancer LIAfRo. The Analysis of Case-Control Studies. Statistical Methods in Cancer Research, 
IARC Scientific Publications. Vol 11980.
Cancer LIAfRo. The Design and Analysis of Cohort Studies. Statistical Methods in Cancer 
Research, IARC Scientific Publications. Vol 21987.
Pinchon DJ, Stanworth SJ, Doree C, Brunskill S, Norfolk DR. Quality of life and use of red cell 
transfusion in patients with myelodysplastic syndromes. A systematic review. Am J Hematol. 
2009;84(10):671-7.
Cocks K, King MT, Velikova G, et al. Evidence-based guidelines for interpreting change scores 
for the European Organisation for the Research and Treatment of Cancer Quality of Life 
Questionnaire Core 30. Eur J Cancer. 2012;48(11):1713-21.
Abel GA, Klaassen R, Lee SJ, et al. Patient-reported outcomes for the myelodysplastic 
syndromes: a new MDS-specific measure of quality of life. Blood. 2014;123(3):451-2.
Caocci G, La Nasa G, Efficace F. Health-related quality of life and symptom assessment in 
patients with myelodysplastic syndromes. Expert Rev Hematol. 2009;2(1):69-80.
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2008
neopl
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-51.
ction appro
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e significan
signi
1):139
):139-144.
44
able univer
able univ
Rev Phar
Rev Pha m
etation of c
etation of c
ard deviatio
d deviati
ometri
metrics. 1
s
ase
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ol 11980.
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-7.
King MT, V
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European O
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Abel GA, K
Abel GA, K
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EDMS Doc. Number:
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Williams L, Ault P, Kantarjian H, et al. Symptom burden in acute myeloid leukemia (AML) and 
myelodysplastic syndrome (MDS). 55th ASH Annual Meeting and Exposition; 2013; New 
Orleans, LA.
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17.
APPENDICES
17.1.
Appendix A: Date Imputation Guideline
17.1.1.
Impute Missing Adverse Events/ Prior or Concomitant Medications and 
Procedures/Medical History, End Date of Prior ESA treatment, Date of Original 
MDS Diagnosis.
Incomplete Start Date:
Missing day and month
!
If the year is the same as the year of the first dosing date, then the day and month of 
the first doing date will be assigned to the missing fields.
!
If the year is prior to the year of first dosing date, then December 31 will be assigned 
to the missing fields.
!
If the year is after the year of first dosing, then January 1 will be assigned to the 
missing fields.
Missing day only 
!
If the month and year are the same as the year and month of first dosing date, then the 
first doing date will be assigned to the missing day.
!
If either the year of the partial date is before the year of the first dosing date or the 
years of the partial date and the first dosing date are the same but the month of partial 
date is before the month of the first dosing date, then the last day of the month will be 
assigned to the missing day.
!
If either the year of the partial date is after the year of the first dosing date or the 
years of the partial date and the first dose date are the same but the month of partial 
date is after the month of the first dosing date, then the first day of the month will be 
assigned to the missing day.
!
If the stop date is not missing, and the imputed start date is after the stop date, the 
start date will be imputed by the stop date. 
Missing day, month, and year
!
No imputation is needed. The corresponding AE will be included as TEAE. 
Incomplete Stop Date: If the imputed stop date is before the start date, then the imputed stop 
date will be equal to the start date.
Missing day and month
!
If the year of the incomplete stop date is the same as the year of the last dosing date, 
then the day and month of the last dosing date will be assigned to the missing fields. 
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EDMS Doc. Number:
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!
If the year of the incomplete stop date is prior to the year of the last dosing date or 
prior to the year of the first dosing date, then December 31 will be assigned to the 
missing fields. 
!
If the year of the incomplete stop date is prior to the year of the last dosing date but 
is the same as the year of the first dosing date, then the first dosing date will be 
assigned to the missing date. 
!
If the year of the incomplete stop date is after the year of the last dosing date, then 
January 1 will be assigned to the missing fields.
Missing day only 
!
If the month and year of the incomplete stop date are the same as the month and year 
of the last dosing date, then the day of the last dosing date will be assigned to the 
missing day. 
!
If either the year of the partial date is not equal to the year of the last dosing date or 
the years of the partial date and the last dosing date are the same but the month of 
partial date is not equal to the month of the last dosing date, then the last day of the 
month will be assigned to the missing day.
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EDMS Doc. Number:
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17.2.
Appendix B: Myelodysplastic Syndromes World HealthOrganization
Classification System  (2016)
Peripheral blood and BM findings and cytogenetics of myelodysplastic syndromes (MDS)
Name
Dysplastic
lineages
Cytopeniasa
Ring sideroblasts as 
% of marrow 
erythroid elements
Bone marrow (BM)
and peripheral 
blood (PB) blasts
Cytogenetics by Conventional
karyotype analysis
MDS with single 
lineage dysplasia 
(MDS-SLD)
1
1 or 2
<15% / <5%b
BM <5%, PB <1%, 
no Auer rods
Any, unless fulfills all criteria 
for MDS with isolated del(5q)
MDS with multilineage 
dysplasia (MDS-MLD) 
2 or 3
1-3
<15% / <5% b
BM <5%, PB <1%, 
no Auer rods
Any, unless fulfills all criteria 
for MDS with isolated del(5q)
MDS with ring 
sideroblasts
(MDS-RS)
MDS-RS with 
single lineage 
dysplasia 
(MDS-RS-SLD) 
MDS-RS with
multilineage 
dysplasia
(MDS-RS-MLD)
1
2 or 3 
1 or 2
1-3
≥15% / ≥5% b
≥15% / ≥5% b
BM <5%, PB <1%, 
no Auer rods
BM <5%, PB <1%,
No Auer rods
Any, unless fulfills all criteria 
for MDS with isolated del(5q)
Any, unless fulfills all criteria 
for MDS with isolated del(5q)
MDS with isolated 
del(5q)
1-3
1-2
None or any
BM <5%, PB <1%, 
no Auer rods
del(5q) alone or with 1
additional abnormality except -
7 or del(7q)
MDS with excess 
blasts (MDSEB)
MDS-EB-1  
MDS-EB-2
0-3
0-3
1-3
1-3
None or any
None or any
BM 5-9% or PB 2-
4%, no Auer rods
BM 10-19% or PB 5-
19% or Auer rods
Any
Any
MDS, unclassifiable 
(MDS-U)
!
with 1% blood 
blasts
!
with single lineage
dysplasia and
pancytopenia
!
based on defining
cytogenetic
abnormality
1-3
1
0
1-3
3
1-3
None or any
None or any
<15%d
BM <5%, PB=1%c, 
no Auer rods
BM <5%, PB <1%, 
no Auer rods
BM <5%, PB <1%, 
no Auer rods
Any
Any
MDS-defining abnormality
Refractory cytopenia 
of childhood
1-3
1-3
None
BM <5%, PB <2%
Any
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EDMS Doc. Number:
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a Cytopenias defined as haemoglobin <10 g/dL, platelet count <100 x 109/L, and absolute neutrophil count <1.8 x 109/L; rarely, 
MDS may present with mild anaemia or thrombocytopenia above these levels. PB monocytes must be <1 x 109/L
b If SF3B1 mutation is present.
c 1% PB blasts must be recorded on at least two separate occasions.
d Cases with ≥15% ring sideroblasts by definition have significant erythroid dysplasia, and are classified as MDSRS-SLD
Sources:
Arber DA, Orazi A, Hasserjian R, Thiele J, Borwitz MJ, Le Beau MM, et al.  The 2016 revision to the World Health 
Organization (WHO) classification of myeloid neoplasms and acute leukemia. Blood 2016;127(20):2391-405.
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17.3.
Appendix C: French-American-British (FAB) Myelodysplastic 
Syndromes (MDS) Classification System
MDS Subtype
Peripheral 
Blasts (%)
Bone 
Marrow 
Blasts (%)
AML 
Transformation
Median 
Survival 
(months)
MDS 
Diagnoses 
(%)
Refractory anemia (RA)
≤1
<5
10-20
30-65
10-40
Refractory anemia with 
ringed sideroblasts 
(RARS)
≤1
<5
10-35
34-83
10-35
Refractory anemia with 
excess blasts (RAEB)
<5
5-20
>50
8-18
25-30
Refractory anemia with 
excess blasts in 
transformation (RAEB-T)
≥5
21-29
60-100
4-11
10-30
Chronic myelomonocytic 
leukemia (CMML)
<5
≤20
>40
15-32
10-20
Key: AML = acute myelogenous leukemia; RA = refractory anemia; RARS = refractory anemia with ringed sideroblasts; RAEB 
= refractory anemia with excess blasts; RAEB-T = refractory anemia with excess blasts in transformation; CMML = chronic 
myelomonocytic leukemia.
Data from Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, et al. Proposals for the classification of 
the myelodysplastic syndromes. Br J Haematol 1982;51(2):189–99.
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99


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17.4.
Appendix D:  International Prognostic Scoring System Score -
Revised
IPSS-R Cytogenetic Risk Groups*,**
Cytogenetic Prognostic 
Subgroups
Cytogenetic Abnormalities
Very good
-Y, del(11q)
Good
Normal, del(5q), del(12p), del(20q), double including del(5q)
Intermediate
del(7q), +8, +19, i(17q), any other single or double independent clones
Poor
-7, inv(3)/t(3q)/del(3q), double including -7/del(7q), Complex: 3 abnormalities
Very poor
Complex: >3 abnormalities
IPSS-R Prognostic Score Values*
Prognostic Variable
0
0.5
1
1.5
2
3
4
Cytogenetics
Very 
Good
-
Good
-
Intermediate
Poor
Very Poor
BM Blasts (%)
≤2
-
>2 - <5
-
5 - 10
>10
-
Hemoglobin (g/dL)
≥10
-
8 - <10
<8
-
-
-
Platelets (x 109/L)
≥100
50 - <100
<50
-
-
-
-
ANC (x 109/L)
≥0.8
<0.8
-
-
-
-
-
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
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IPSS-R: Prognostic Risk Category Clinical Outcomes*
No. pts
Very Low
Low
Intermediate
High
Very High
Subjects (%)
7012
19%
38%
20%
13%
10%
Survival***
-
8.8
5.3
3.0
1.6
0.8
AML/25%***,^
-
NR
10.8
3.2
1.4
0.7
*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(12):2454-65.
***Medians, years.
^ Median time to 25% AML evolution.
Schanz J, Tüchler H, Solé F, Mallo M, Luño E, Cervera J, et al. New comprehensive cytogenetic scoring system for primary
myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia after MDS derived from an international database 
merge. J Clin Oncol 2012;30(8):820-9.
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17.5 Appendix E:  International Working Group Response Criteria for 
MyelodysplasticSyndromes
Altering Natural History of MDS 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 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 pre-treatment but still > 5%
-
Cellularity and morphology not relevant
Marrow CR
b
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 thanpre-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 
plateletsc
-
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 plateletsc
-
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.
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a Dysplastic changes should consider the normal range of dysplastic changes (modification).
b Modification to IWG (2000) response criteria.
c Criteria not applicable for ACE-536-MDS-001 patient population.  
d 20 – 30% blasts is considered AML according to WHO classification (Vardiman, 2009).
Notes: Deletions to IWG 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.
CCI
&(/*(1(35235,(7$5<,1)250$7,21


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Appendix E:  International Working Group Response Criteria for 
MyelodysplasticSyndromes (Continued)
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
Platelet Response (HI-P)
(pre-treatment, <100 X 109/L)
- Absolute increase of ≥ 30 X 109/L for subjects starting with > 20 X 109/Lplatelets
- Increase from < 20 X 109/L to > 20 X 109/L and by at least100%b
Neutrophil Response (HI-N) (pre-
treatment, <1.0 X 109/L)
- At least 100% increase and an absolute increase > 0.5 X109/Lb
Progression or Relapse After HIc
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 = hem
hematologic improvement neutrophil response; HI-P = 
hematologic impr
nternational Working Group; RBC = red blood cell.
a Pretreatment counts averages of at least 2 measurements (not influenced by transfusions, i.e. 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 criteria are not shown. To convert hemoglobin levels from grams per deciliter to grams per liter, 
multiply grams per decil
Source:  Cheson, B
nnett 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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