A Phase 3, Open-label, Randomized Study to Compare the Efficacy and Safety of Luspatercept (ACE-536) Versus Epoetin Alpha for the Treatment of Anemia Due to IPSS-R Very Low, Low or Intermediate Risk Due to Myelodysplastic Syndrome (MDS) in ESA Naïve Subjects Who Require Red Blood Cell Transfusions
Phase: PHASE3
Conditions: Myelodysplastic Syndromes
Sponsor: Celgene

Official Title of Study: 
A Phase 3, Open-label, Randomized Study to Compare the Efficacy and Safety of Luspatercept (ACE-536) 
versus Epoetin Alfa for the Treatment of Anemia Due to IPSS-R Very Low, Low or Intermediate Risk 
Myelodysplastic Syndromes (MDS) in ESA Naïve Subjects Who Require Red Blood Cell Transfusions 
 
PROTOCOL(S) ACE-536-MDS-002 
 
NCT Number: NCT03682536 
  
Document Date (Date in which document was last revised): March 31, 2022 

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
1
A PHASE 3, OPEN-LABEL, RANDOMIZED STUDY TO COMPARE THE EFFICACY 
AND SAFETY OF LUSPATERCEPT (ACE-536) VERSUS EPOETIN ALFA FOR THE 
TREATMENT OF ANEMIA DUE TO IPSS-R VERY LOW, LOW OR INTERMEDIATE 
RISK MYELODYSPLASTIC SYNDROMES (MDS) IN ESA NAÏVE SUBJECTS WHO 
REQUIRE RED BLOOD CELL TRANSFUSIONS
The “COMMANDS” Trial
PROTOCOL NUMBER:
ACE-536-MDS-002
ORIGINAL PROTOCOL DATE:
03 May 2018
AMENDMENT No. 1.0 DATE
26 Feb 2019
AMENDMENT No. 2.0 DATE
01 Aug 2019
AMENDMENT No. 3.0 DATE
23 Feb 2021
AMENDMENT No. 4.0 DATE
31 Mar 2022
EudraCT NUMBER:
2017-003190-34
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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MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
Contact Information:
Name:
Title: Clinical Development Lead
Address: Route de Perreux, 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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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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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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COORDINATING PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Coordinating Principal Investigator
dd mmm yyyy
Printed Name of Coordinating Principal Investigator
Institution Name:_______________________________________
By my signature, I agree the protocol has been written to comply with ICH Good Clinical 
Practices guidelines and agree to offer guidance throughout the study as needed.
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OVERALL RATIONALE FOR PROTOCOL AMENDMENT 4.0:
The primary purpose of this amendment is to add a second interim analysis to test the superiority 
of the luspatercept arm as well as to remove the requirement to enroll at least 25% of subjects with 
an endogenous sEPO level of >200 U/L.
The rationale for the inclusion of the second interim analysis for efficacy is to mitigate the negative 
impact of the coronavirus disease 2019 (COVID-19) pandemic on enrollment and to mitigate the 
impact of the political crisis in Eastern Europe on  future study enrollment. In the event the primary 
efficacy endpoint at the time of the efficacy IA shows statistical significance (see Section 9.9) this 
could potentially allow for earlier access to the drug for patients in need.
The rationale for the removal of the requirement to enroll at least 25% of subjects with an 
endogenous sEPO level of > 200 U/L stems from the observation of subject recruitment in this 
study and current review of published clinical trials in subjects with lower risk Myelodysplastic 
Syndromes (MDS). The percentage of the subjects with sEPO level of >200 U/L is lower than 
25% in a number of published trials (Fenaux, 2018; Park, 2008; Santini, 2013; Suzuki, 2015). The 
number of subjects with an EPO level of >200 U/L recruited so far in this study shows a similar 
pattern, in line with previous publications. The change in proportion of subjects with sEPO level 
of >200 U/L should not affect the conclusions made between different sEPO populations and 
therefore the cap originally included for subjects with sEPO level of >200 U/L is now removed.
The protocol summary has been updated to align with the changes in the protocol body. 
This protocol amendment applies to all participants.
References
Fenaux P, Santini V, Aloe Spiriti MA, Giagounidis A, Schlag R, Radinoff A, et al. A phase 3 
randomized, placebo-controlled study assessing the efficacy and safety of epoetin-α in anemic 
patients with low-risk MDS. Leukemia. 2018 Mar 30;32(12):2648-58. Available from: 
https://doi.org/10.1038/s41375-018-0118-9.
Park S, Grabar S, Kelaidi C, Beyne-Rauzy O, Picard F, Bardet V, et al. Predictive factors of 
response and survival in myelodysplastic syndrome treated with erythropoietin and G-CSF: the 
GFM experience. Blood. 2008 Jan;111(2):574-582.
Santini V., Schemenau J, Levis A, Balleari E, Sapena R, Ades L, et al. Can the revised IPSS predict 
response to erythropoietic-stimulating agents in patients with classical IPSS low or intermediate-
1 MDS? Blood. 2013 Sep;122(13): 2286-2288
Suzuki T, Iekuni O, Ohmine K, Meguro A, Mori M, Fujiwara S, et al. Distribution of serum 
erythropoietin levels in Japanese patients with myelodysplastic syndromes. Int J Hematol. 
2015;101:32-36.
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 4.0
Section Number & 
Title
Description of Change
Brief Rationale
Protocol Summary
Match the PK secondary objective stated in 
Section 2 of the main protocol.
For consistency and 
alignment between the 
protocol summary and 
Section 2 of the protocol.
Medical Monitor / 
Emergency Contact 
Information
Update the Medical Monitor and contact 
information.
To provide the current 
Medical Monitor and 
Emergency Contact 
information.
Protocol Summary;
Section 1.3.2.2: 
Rationale for 
Stratification 
Factors;
Section 3.1: Study 
Design; 
Section 9.4: 
Randomization and 
Stratification
Remove the requirement to enroll at least 
25% of subjects with an endogenous sEPO 
level of >200 U/L.
The observation of 
subject recruitment in 
this study and current 
review of published 
clinical trials in subjects 
with lower risk 
Myelodysplastic 
Syndromes (MDS) 
supports the removal of 
the requirement.
Protocol Summary; 
Section 9.3: Sample 
Size and Power 
Considerations; 
Section 9.7.1: 
Primary Efficacy 
Analysis; Section 
9.9: Interim 
Analysis
Add the second interim analysis to test the 
superiority of the luspatercept arm.
To mitigate the negative 
impact of the COVID-19
pandemic on enrollment 
and to mitigate the 
impact of the political 
crisis in Eastern Europe 
on future study 
enrollment. In the event 
the primary efficacy 
endpoint at the time of 
the efficacy IA shows 
statistical significance 
this could potentially 
allow for earlier access to 
the drug for patients in 
need.
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 4.0
Section Number & 
Title
Description of Change
Brief Rationale
Section 1.2.3: 
Overall Benefit 
Risk Assessment; 
Section 1.4: Risk/ 
Benefit Assessment
Extend the Risk Benefit Section.
Section 1.2.3: Overall Benefit Risk 
Assessment was replaced with the new 
Section 1.4: Risk/ Benefit Assessment.
To incorporate risk 
benefit information into 
the protocol that was 
originally in a separate 
document, and to be in 
compliance with the 
BMS protocol template.
Section 3.1: Overall 
Study Design
Figure 2: correct a typographical error. The 
duration of the Long-Term Follow-Up 
phase from 5 years from the date of last 
dose of IP to first dose of IP to align with 
the rest of the protocol.
Correction
Section 6.1.1: Bone 
Marrow and 
Peripheral Blood 
Samples 
Clarify that in the event an adjudication by a 
third reviewer at the central lab is made in 
case of disagreement between the local 
pathologist and the central reviewer, the 
result of the adjudication will be considered 
the final result and only slides of the most 
recent BM sample should be used for 
adjudication. 
Clarify that central over-read of local bone 
marrow samples is also allowed during the 
treatment period of the study in the event 
the central analysis is technical failing.
Clarification
Section 6.1.6: Vital 
Signs, Height, and 
Weight 
Clarify that the weight of subjects on the 
epoetin alfa arm will be assessed at every 
third dosing visit only, to align with 
Section 5 Table 3 (Table of Events) and 
Section 7.2.2.
Clarification and 
alignment to other 
protocol sections.
Section 9.2: Study 
Population 
Definitions 
Include the PK population definition.
To include all study 
populations into the 
section of the protocol.
All
Minor formatting and typographical 
corrections.
Minor, therefore have not 
been summarized.
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PROTOCOL SUMMARY
Study Title
A Phase 3, Open-label, Randomized Study to Compare the Efficacy and Safety of Luspatercept 
(ACE-536) versus Epoetin Alfa for the Treatment of Anemia Due to IPSS-R Very Low, Low or 
Intermediate Risk Myelodysplastic Syndromes (MDS) in ESA Naïve Subjects Who Require Red 
Blood Cell Transfusions
Indication
Treatment of anemia due to very low, low, or intermediate risk myelodysplastic syndromes (MDS) 
according to the International Prognostic Scoring System - Revised (IPSS-R) in erythropoiesis 
stimulating agent (ESA) naïve subjects who require red blood cell (RBC) transfusions (ie, 2 to 6 
packed red blood cell (pRBC) units in the 8 weeks before randomization).
Myelodysplastic syndromes, primarily affecting older adults, 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) (Ades, 2014; Brunning, 2008; 
Catenacci, 2005; Fenaux, 2009; Steensma, 2013; Visconte, 2014; Zeidan, 2013).
Lower hemoglobin (Hgb) levels and RBC transfusion dependence (RBC-TD) 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 patients (Zeidan, 2013). In 
addition, long-term RBC-TD has 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).
Luspatercept (ACE-536), an erythroid maturation agent, 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 Fc portion of human immunoglobulin G1 (IgG1-Fc). Luspatercept acts 
on endogenous inhibitors of late-stage erythropoiesis (eg, growth differentiation factor 11 
[GDF11]) to increase release of mature erythrocytes into circulation. Nonclinical data have 
demonstrated that luspatercept binds to negative regulators governing late-stage erythroid 
development to inhibit their action, thereby promoting the maturation of erythrocytes in the bone 
marrow. These findings suggest that luspatercept may represent a novel therapeutic approach to 
anemia, particularly in diseases in which ineffective erythropoiesis is a contributing factor, as in 
β-thalassemia and MDS.
Objectives
Primary objective:
•
To evaluate the efficacy of luspatercept on RBC transfusion independence (RBC-TI; for 12
weeks [84 days] with an associated concurrent mean hemoglobin increase ≥1.5 g/dL)
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compared with epoetin alfa for the treatment of anemia due to IPSS-R very low, low, or 
intermediate risk MDS in ESA naïve subjects who require RBC transfusions
Secondary objectives:
•
To assess the safety and efficacy of luspatercept compared to epoetin alfa
•
To assess health-related quality-of-life (HRQoL) and anemia outcome measures (ie, 
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire [EORTC QLQ-C30] and the Functional Assessment of Cancer Therapy 
- Anemia [FACT-An] questionnaire) for subjects treated with luspatercept compared 
to epoetin alfa
•
To evaluate pharmacokinetics for luspatercept in MDS subjects
Study Design
ACE-536-MDS-002 is a Phase 3, multicenter, randomized, open-label, active controlled study.  
The primary objective of the study is to evaluate RBC-TI in the two treatment arms, luspatercept 
compared with epoetin alfa, for the treatment of anemia due to IPSS-R very low, low, or 
intermediate risk MDS in ESA naïve subjects who require RBC transfusions.
The study is divided into a Screening Period, a Treatment Period and a Post-treatment Follow-up 
Period.
Screening Period:
Subject screening procedures are to take place within 35 days prior to randomization (after the 
subject has given written informed consent). 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, peripheral blood smear and cytogenetics will be
used to confirm MDS diagnosis according to the World Health Organization (WHO) 2016
classification (Arber, 2016) and to determine the baseline IPSS-R riskclassification (Greenberg, 
2012).  A bone marrow biopsy will be collected only when adequate aspirate is not attainable.
Transfusion history must be available for at least 16 weeks immediately preceding and including 
the date of randomization.
Randomization:
Eligible subjects will be randomized by a central randomization procedure using integrated 
response technology (IRT) at a 1:1 ratio to either the luspatercept or the epoetin alfa arm.  
Randomization will be stratified based on RBC transfusion burden at baseline, ring sideroblast 
status (RS) at baseline and endogenous serum erythropoietin (sEPO) level at baseline.
Treatment Period:
The first dose of investigational product (IP) should be administered within 3 days of 
randomization at the latest.
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 
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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 outside 
of the study treatment.
Subjects should receive IP through to a minimum of the 24-Week MDS Disease Assessment Visit
scheduled for Day 169, unless the subject experiences unacceptable toxicities, withdrawsconsent, 
or meets any other treatment discontinuation criteria.
The MDS Disease Assessment (Section 6.4.2) on Day 169 (and every 24 weeks thereafter [ie, Day 
337, Day 505, etc.]) consists of the investigator’s assessment of clinical benefit from IP and status 
of underlying disease.  For subjects to remain on treatment beyond this timepoint both of the 
following criteria must be confirmed in each subject:
•
Evidence of clinical benefit defined as a transfusion reduction of ≥ 2 pRBC 
units/8 weeks compared to the baseline (for any consecutive 8-week period within the 
12 weeks immediately preceding Day 169 and every 24 weeks thereafter [ie, Day 337, 
Day 505, etc.]).
•
Absence of disease progression per International Working Group (IWG) criteria for 
altering natural history of MDS (Cheson, 2006) based on central morphological 
assessment of bone marrow, peripheral blood and cytogenetics results.
Based on the outcome of these assessments, subjects will either be discontinued from treatment 
with IP, undergo End of Treatment (EOT) Visit evaluations and enter the Post-treatment Follow-
up Period or continue open-label treatment with their assigned IP as long as the above criteria 
continue to be met or until the subject experiences unacceptable toxicities, withdraws consent, or 
meets any other discontinuation criteria.
Post-treatment Follow-up Period:
All subjects who have received at least one dose of IP should undergo EOT and 42-Day Follow-
up evaluations.
This includes (but is not limited to) the collection of adverse events (AEs), concomitant drugs and 
RBC-transfusion data (until 8 weeks after last dose of IP or the EOT Visit, whichever occurs later).
In addition, subjects will continue to be followed for 5 years from the date of the first dose of IP, 
or 3 years from the last dose (whichever occurs later), for monitoring for other malignancies/pre-
malignances and progression to AML along with data collection of subsequent MDS therapies, 
and overall survival unless the subject withdraws consent from the study, dies or is lost to follow-
up.  For that purpose, subjects will be followed after treatment every 12 weeks for 3 years from 
the date of last dose of IP and every 6 months thereafter, if applicable. 
An antidrug antibodies (ADA) sample(s) may be required in the Post-treatment Follow-up Period 
for subjects assigned to the luspatercept arm, who terminate the Treatment Period with less than 1
year of ADA monitoring if a subject is ADA positive at the time of treatment discontinuation.
The study will be conducted in compliance with International Council for Harmonisation (ICH) 
Good Clinical Practices (GCPs).
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Study Population
Adult subjects (≥ 18 years) with anemia due to a IPSS-R very low, low, or intermediate risk MDS 
according to the WHO 2016 classification and a bone marrow blast count of < 5% (Arber, 2016; 
Greenberg, 2012), who are ESA naïve with endogenous sEPO levels of < 500 U/L and who require 
RBC transfusions (ie, 2 to 6 units/8 weeks of pRBCs confirmed for a minimum of 8 weeks 
immediately preceding randomization).
Length of Study
The expected duration of the study is approximately 8 years, which consists of approximately 
2 years of enrollment, approximately 1 additional year of luspatercept or epoetin alfa treatment 
after the last subject is randomized, and 5 years of follow up from first dose of IP, or 3 years from 
last dose (whichever occurs later), to complete the Post-treatment 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 and/or exploratory analysis, as prespecified in the protocol, 
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 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.
Study Treatments
Eligible subjects will be randomized by a central randomization procedure using integrated 
response technology (IRT) at a 1:1 ratio to one of the below treatment arms:
•
Experimental Arm: luspatercept (ACE-536): starting dose of 1.0 mg/kg subcutaneous 
injection every 3 weeks (21 days; Q3W). Dose levels can be increased in a stepwise 
manner beyond the starting dose to 1.33 mg/kg, and up to a maximum of 1.75 mg/kg .
•
Control Arm: epoetin alfa (EPREX®/ERYPO® or PROCRIT®): starting dose of 450 
IU/kg (maximum total starting dose is 40,000 IU) subcutaneous injection once every 
week (7 days; QW).  Dose levels can be increased in a stepwise manner beyond the 
starting dose to 787.5 IU/kg, and up to a maximum of 1,050 IU/kg (with a maximum 
total dose of 80,000 IU).  Individual epoetin alfa doses according to body weight will 
be rounded: up to the next 2,000 IU dose level for Starting Dose Level and Dose 
Level -1; and up to the next 4,000 IU for Dose Level +1 and Dose Level +2 for doses 
exceeding a calculated dosing of 56,000 IU according to body weight.
Crossover between the treatment arms is not permitted during the Study Treatment Period. For a 
detailed description of study treatments please refer to Section 7.
Overview of Key Efficacy Assessments
Efficacy assessments include the collection of transfusion data (eg, RBC transfusions), assessment 
of hematological parameters (eg, hemoglobin, platelet count, neutrophils) and central 
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cytomorphology and cytogenetics review of bone marrow aspirate and peripheral blood for MDS 
disease assessment. 
Response assessment according to the IWG criteria (Cheson, 2006) is to be performed at the 24-
Week MDS Disease Assessment Visit (ie, Day 169) and every 24 weeks  thereafter (ie, Day 337, 
Day 505, etc.).
For a detailed description of efficacy assessments please refer to Section 6.4.
Overview of Key Safety Assessments
Safety assessments include hematology (complete blood count [CBC] with differential) and serum 
chemistry analyses, recording of adverse events, physical exam, vital signs and electrocardiograms 
(ECGs) (if clinically indicated).  In addition, subjects will be monitored for progression to AML 
and other malignancies/pre-malignancies.
Statistical Methods
A total sample size of approximately 350 subjects (175 subjects in the experimental arm 
[luspatercept (ACE-536)], 175 subjects in the control arm [epoetin alfa]) will have 90% power to 
detect the difference between a red blood cell transfusion independence (RBC-TI) for any 12-week 
period associated with a concurrent mean hemoglobin increase of 1.5 g/dL response rate of 36% 
in the experimental arm (luspatercept [ACE-536]) and a response rate of 20 % in the control arm 
(epoetin alfa), with one interim analysis on futility only when about 105 subjects have completed 
24 weeks of treatment, or discontinued before reaching 24 weeks of treatment (30% information 
for the primary endpoint). The sample size calculation is based on one-sided alpha of 0.025, test 
statistics on odds ratio of proportions.
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 is defined as the 
absence of any RBC transfusion of ≥ 12 weeks with a mean hemoglobin increase ≥1.5 g/dL during 
the same time period over the first 24 weeks from baseline (Week 1 through Week 24) during 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 first interim analysis to assess futility will be performed when approximately 105 subjects 
have completed 24 weeks of treatment or discontinued before reaching 24 weeks of treatment (30% 
information for primary endpoint).
A second interim analysis for superiority will be performed when approximately 300 subjects have 
completed 24 weeks of treatment or discontinued before reaching 24 weeks of treatment (85% 
information for primary endpoint). 
The addition of the second interim analysis does not alter the original sample size calculation. The 
study power remains at 90% for the final analysis with 350 subjects. The Lan-DeMets spending 
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function of the O’Brien-Fleming type will be used to control the overall one-sided Type I error 
rate at 0.025. The following significance level will be used:
•
Superiority interim analysis (85% information for primary endpoint): one-sided alpha 
of 0.015
•
Final analysis (100% information for primary endpoint): one-sided alpha of 0.021
Analyses will be performed to compare treatment within the stratification subgroups. 
The final analysis will be performed when all randomized subjects have completed 24 weeks of 
treatment or discontinued before 24 weeks. 
Additional follow-up analysis for efficacy and safety will be performed when all subjects have 
been followed for 5 years from the date of the first dose of IP, or 3 years from last dose (whichever 
occurs later) during the Post-treatment Follow-up Period of the study. 
For more details on statistical considerations please refer to Section 9 of the protocol.
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TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 4.0:............................................7
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 4.0 ................................8
PROTOCOL SUMMARY ........................................................................................................10
TABLE OF CONTENTS..........................................................................................................16
LIST OF TABLES....................................................................................................................21
LIST OF FIGURES ..................................................................................................................22
1
INTRODUCTION..................................................................................................23
1.1
Myelodysplastic Syndromes (MDS) .......................................................................23
1.1.1
Current Treatment Options for Lower-Risk MDS....................................................23
1.1.1.1
Erythropoiesis Stimulating Agents (ESAs)...............................................................24
1.1.1.2
Red Blood Cell Transfusions...................................................................................25
1.1.1.3
Lenalidomide..........................................................................................................25
1.1.1.4
Hypomethylating Agents.........................................................................................26
1.1.1.5
Iron Chelation Therapy ..........................................................................................26
1.2
Luspatercept Background .......................................................................................27
1.2.1
Mechanism of Action ..............................................................................................27
1.2.2
Summary of Clinical Experience.............................................................................28
1.3
Rationale ................................................................................................................29
1.3.1
Study Rationale and Purpose..................................................................................29
1.3.2
Rationale for the Study Design................................................................................30
1.3.2.1
Rationale for the Study Population .........................................................................30
1.3.2.2
Rationale for Stratification Factors ........................................................................31
1.3.2.3
Rationale for Study Endpoints.................................................................................31
1.3.2.4
Rationale for Open-label Design ............................................................................32
1.3.3
Rationale for Dose, Schedule and Regimen Selection..............................................32
1.3.4
Rationale for Choice of Comparator Compound.....................................................33
1.3.5
Rationale for Exploratory Biomarkers ....................................................................33
1.4
Risk/ Benefit Assessment .......................................................................................34
1.4.1
Risk Assessment......................................................................................................34
1.4.1.1
Study Intervention: Luspatercept ............................................................................34
1.4.1.2
Study Procedures....................................................................................................36
1.4.1.3
Other: Comparator Epoetin alfa (EPREX®/ERYPO® or PROCRIT®)......................37
1.4.2
Benefit Assessment..................................................................................................38
1.4.3
Overall Benefit Risk Conclusion .............................................................................38
2
STUDY OBJECTIVES AND ENDPOINTS...........................................................39
3
OVERALL STUDY DESIGN ................................................................................42
3.1
Study Design ..........................................................................................................42
3.2
Study Duration for Subjects....................................................................................47
3.3
End of Trial ............................................................................................................47
4
STUDY POPULATION.........................................................................................48
4.1
Number of Subjects ................................................................................................48
4.2
Inclusion Criteria....................................................................................................48
4.3
Exclusion Criteria...................................................................................................49
5
TABLE OF EVENTS.............................................................................................53
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ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
17
6
PROCEDURES......................................................................................................61
6.1
Screening Period.....................................................................................................61
6.1.1
Bone Marrow and Peripheral Blood Samples .........................................................61
6.1.2
Prior Transfusion History.......................................................................................63
6.1.3
Demographics ........................................................................................................63
6.1.4
Medical History......................................................................................................63
6.1.4.1
Assessment of HIV/Hepatitis B/Hepatitis C status...................................................63
6.1.5
Physical Examination .............................................................................................63
6.1.6
Vital Signs, Height, and Weight ..............................................................................63
6.1.7
Eastern Cooperative Oncology Group Performance Status.....................................64
6.1.8
Electrocardiogram..................................................................................................64
6.1.9
Hematology ............................................................................................................64
6.1.10
Serum Chemistry ....................................................................................................65
6.1.11
Serum EPO Level ...................................................................................................65
6.1.12
Serum Ferritin and Other Iron-Related Markers.....................................................65
6.1.13
Urinalysis...............................................................................................................65
6.1.14
Pregnancy Testing and Counseling.........................................................................65
6.1.15
Sample Collection for Exploratory Biomarker Assessments ....................................66
6.1.16
Subject Reported Quality-of-life and Healthcare Resource Utilization....................66
6.1.17
Concomitant Medications and Procedures..............................................................66
6.1.18
Adverse Event Evaluation.......................................................................................66
6.1.19
Monitoring for Progression to AML and Other Malignancies/Pre-
malignancies ..........................................................................................................66
6.1.20
Information to be Collected on Screening Failures .................................................67
6.2
Treatment Period ....................................................................................................67
6.2.1
Unscheduled Visits .................................................................................................68
6.2.2
End of Treatment....................................................................................................68
6.3
Post-treatment Follow-up Period.............................................................................69
6.3.1
Safety Follow-up (42-Day Follow-up).....................................................................69
6.3.2
Long-term Follow-up..............................................................................................69
6.4
Efficacy Assessment...............................................................................................70
6.4.1
Transfusion Assessment ..........................................................................................70
6.4.2
MDS Disease Assessment .......................................................................................71
6.5
Pharmacokinetics....................................................................................................72
6.6
Antidrug Antibody (ADA)......................................................................................72
6.7
Biomarkers, Pharmacodynamics, Pharmacogenomics.............................................73
6.8
Patient Reported Outcomes.....................................................................................73
6.9
Healthcare Resource Utilization..............................................................................74
7
DESCRIPTION OF STUDY TREATMENTS........................................................76
7.1
Description of Investigational Products...................................................................76
7.1.1
Luspatercept...........................................................................................................76
7.1.2
Epoetin Alfa............................................................................................................76
7.2
Treatment Administration and Schedule .................................................................76
7.2.1
Luspatercept Treatment ..........................................................................................76
7.2.1.1
Luspatercept Administration and Schedule .............................................................76
7.2.1.2
Luspatercept Dose Adjustment and Dose Modification ...........................................77
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Celgene Corporation
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Final: 31 Mar 2022
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7.2.2
Epoetin Alfa Treatment...........................................................................................80
7.2.2.1
Epoetin Alfa Administration and Schedule..............................................................80
7.2.2.2
Epoetin Alfa Dose Adjustment and Modification.....................................................81
7.2.3
Overdose ................................................................................................................83
7.2.3.1
Luspatercept Overdose ...........................................................................................83
7.2.3.2
Epoetin Alfa Overdose............................................................................................83
7.3
Method of Treatment Assignment...........................................................................83
7.4
Packaging and Labeling..........................................................................................84
7.5
Investigational Product Accountability and Disposal ..............................................84
7.5.1
Accountability Procedures......................................................................................84
7.5.2
Drug Disposal and Destruction ..............................................................................84
7.6
Investigational Product Compliance........................................................................85
8
CONCOMITANT MEDICATIONS AND PROCEDURES....................................86
8.1
Permitted Concomitant Medications and Procedures...............................................86
8.1.1
RBC Transfusions...................................................................................................86
8.1.2
Iron Chelation Therapy ..........................................................................................86
8.1.3
Corticosteroids .......................................................................................................87
8.1.4
Attenuated Vaccines ...............................................................................................87
8.1.5
Phlebotomy.............................................................................................................87
8.2
Prohibited Concomitant Medications and Procedures..............................................87
8.3
Required Concomitant Medications and Procedures................................................87
9
STATISTICAL CONSIDERATIONS ....................................................................88
9.1
Overview................................................................................................................88
9.2
Study Population Definitions ..................................................................................88
9.3
Sample Size and Power Considerations...................................................................88
9.4
Randomization and Stratification............................................................................89
9.5
Background and Demographic Characteristics........................................................89
9.6
Subject Disposition.................................................................................................89
9.7
Efficacy Analysis....................................................................................................90
9.7.1
Primary Efficacy Analysis.......................................................................................90
9.7.2
Secondary Efficacy Analyses...................................................................................90
9.8
Safety Analysis.......................................................................................................92
9.9
Interim Analysis .....................................................................................................92
9.10
Other Topics...........................................................................................................94
9.10.1
Health-related Quality-of-life Assessment...............................................................94
9.10.2
Healthcare Resource Utilization.............................................................................95
9.10.3
Pharmacokinetic Analysis.......................................................................................95
9.10.4
Data Monitoring Committee ...................................................................................95
9.10.5
Steering Committee.................................................................................................96
9.10.6
Exploratory Analysis ..............................................................................................96
9.10.7
Subgroup Analysis..................................................................................................96
10
ADVERSE EVENTS..............................................................................................97
10.1
Monitoring, Recording and Reporting of Adverse Events .......................................97
10.2
Evaluation of Adverse Events.................................................................................98
10.2.1
Seriousness.............................................................................................................98
10.2.2
Severity/Intensity ....................................................................................................99
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Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
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10.2.3
Causality ..............................................................................................................100
10.2.4
Duration...............................................................................................................100
10.2.5
Action Taken.........................................................................................................100
10.2.6
Outcome ...............................................................................................................100
10.3
Abnormal Laboratory Values................................................................................100
10.4
Pregnancy.............................................................................................................101
10.4.1
Females of Childbearing Potential .......................................................................101
10.4.2
Male Subjects .......................................................................................................102
10.5
Other Malignancies/Pre-malignancies...................................................................102
10.6
Reporting of Serious Adverse Events....................................................................102
10.6.1
Safety Queries ......................................................................................................103
10.7
Expedited Reporting of Adverse Events................................................................103
10.8
COVID-19 Reporting ...........................................................................................104
11
DISCONTINUATIONS .......................................................................................105
11.1
Treatment Discontinuation....................................................................................105
11.2
Study Discontinuation ..........................................................................................105
12
EMERGENCY PROCEDURES...........................................................................107
12.1
Emergency Contact...............................................................................................107
12.2
Emergency Identification of Investigational Products ...........................................107
13
REGULATORY CONSIDERATIONS.................................................................108
13.1
Good Clinical Practice..........................................................................................108
13.2
Investigator Responsibilities .................................................................................108
13.3
Subject Information and Informed Consent...........................................................109
13.4
Confidentiality......................................................................................................109
13.5
Protocol Amendments...........................................................................................109
13.6
Institutional Review Board/Independent Ethics Committee Review and 
Approval ..............................................................................................................109
13.7
Ongoing Information for Institutional Review Board/ Ethics Committee ..............110
13.8
Termination of the Study ......................................................................................110
14
DATA HANDLING AND RECORDKEEPING...................................................112
14.1
Data/Documents ...................................................................................................112
14.2
Data Management.................................................................................................112
14.3
Record Retention..................................................................................................112
15
QUALITY CONTROL AND QUALITY ASSURANCE......................................114
15.1
Study Monitoring and Source Data Verification....................................................114
15.2
Audits and Inspections..........................................................................................114
15.3
Product Quality Complaint ...................................................................................114
16
PUBLICATIONS .................................................................................................116
17
REFERENCES.....................................................................................................117
18
APPENDICES......................................................................................................122
APPENDIX A
TABLE OF ABBREVIATIONS...........................................................122
APPENDIX B
MYELODYSPLASTIC SYNDROMES WORLD HEALTH
ORGANIZATION CLASSIFICATION SYSTEM (2016) ....................127
APPENDIX C
INTERNATIONAL PROGNOSTIC SCORING SYSTEM SCORE 
- REVISED ..........................................................................................129
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Final: 31 Mar 2022
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APPENDIX D
INTERNATIONAL WORKING GROUP RESPONSE CRITERIA 
FOR MYELODYSPLASTICSYNDROMES .......................................131
APPENDIX E
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS.................................................................133
APPENDIX F
FOUR-VARIABLE MDRD GFR EQUATION ....................................134
APPENDIX G
EUROPEAN ORGANIZATION FOR RESEARCH AND 
TREATMENT OF CANCER QUALITY-OF-LIFE 
QUESTIONNAIRE (VERSION 3.0)....................................................135
APPENDIX H
FUNCTIONAL ASSESSMENT OF CANCER THERAPY-
ANEMIA (FACT-AN) QUESTIONNAIRE (VERSION 4.0) ...............137
APPENDIX I
QUALITY-OF-LIFE IN MYELODYSPLASIA SCALE -
PHYSICAL BURDEN (QUALMS-P)..................................................140
APPENDIX J
PATIENT TREATMENT SATISFACTION SURVEY........................141
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Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
21
LIST OF TABLES
Table 1:
Study Objectives ....................................................................................39
Table 2:
Study Endpoints .....................................................................................40
Table 3:
Table of Events ......................................................................................53
Table 4:
Luspatercept Starting Dose Level with Dose Reductions and Dose 
Titration .................................................................................................78
Table 5:
Luspatercept Dose Modification: Dose Delay, Dose Reduction, 
and Discontinuation Guidelines ..............................................................78
Table 6:
Epoetin Alfa Starting Dose Level with Dose Reductions and Dose 
Titration .................................................................................................81
Table 7:
Epoetin Alfa Dose Modification: Dose Delay, Dose Reduction, and 
Discontinuation Guidelines.....................................................................81
Table 8:
Futility Interim Boundaries for the first IA .............................................93
Table 9:
Summary of Alpha Spending..................................................................94
Table 10:
Abbreviations and Specialist Terms......................................................122
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Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
22
LIST OF FIGURES
Figure 1:
Luspatercept Schematic Representation and Mechanism of Action.........28
Figure 2:
Overall Study Design..............................................................................46
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Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
23
1
INTRODUCTION
1.1
Myelodysplastic Syndromes (MDS)
Myelodysplastic syndromes, primarily affecting older adults, 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 red blood cell (RBC) transfusion dependent anemia, increased risk of infection, and/or 
hemorrhage, as well as a potential to progress to acute myeloid leukemia (AML) (Ades, 2014; 
Brunning, 2008; Catenacci, 2005; Fenaux, 2009; Steensma, 2013; Visconte, 2014; Zeidan, 2013). 
Lower hemoglobin (Hgb) levels and 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 patients (Zeidan, 2013).
In 
addition, long-term RBC transfusion dependence has 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).
For most patients with MDS, anemia and associated transfusion dependency are the most 
prominent clinical problems and the main determinants of QoL (Balducci, 2010; Chan, 2014; 
Hellstrom-Lindberg, 2013; Kao, 2008; Malcovati, 2005; Platzbecker, 2012).
Patients with MDS can be categorized into 1 of 5 risk groups according to the International 
Prognostic Scoring System - Revised (IPSS-R) (very low, low, intermediate, high, and very high) 
based on cytogenetics, Hgb, platelets and absolute neutrophil count (ANC) levels and bone marrow 
(BM) blast percentages obtained at diagnosis.  The 5 risk groups showed significantly different 
risk of progression to AML and overall survival (OS). The median survival rate is 8.8 years for 
patients with low-risk MDS and is as short as 0.8 years for very high-risk MDS (Greenberg, 2012).
In lower-risk MDS, the risk of progression to AML 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 (Germing, 2012). In these patients, the main priorities are the treatment of 
cytopenias, primarily anemia, and the improvement in quality-of-life (QoL) (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.
1.1.1
Current Treatment Options for Lower-Risk MDS
The standard of care for lower-risk MDS remains supportive treatment with erythropoiesis 
stimulating agents (ESAs) such as epoetin alfa or darbepoetin (DAR), 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 (National Comprehensive Cancer Network [NCCN], 2017; European Society for 
Medical Oncology [ESMO], 2014 [Fenaux, 2014]; European LeukemiaNet [ELN], 2014 
[Malcovati, 2013]).
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Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
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1.1.1.1
Erythropoiesis Stimulating Agents (ESAs)
The use of ESAs (ie, recombinant erythropoietin [EPO] or darbepoetin [DAR]) is the standard of 
care for low and intermediate IPSS risk patients with symptomatic anemia and an endogenous 
serum erythropoietin (sEPO) level < 500 U/L, and is recommended by European and United States 
(US) treatment guidelines. The use of granulocyte-colony stimulating factor (G-CSF) may be 
employed as needed but is not required, although in some cases it may further improve the efficacy 
of the ESA (NCCN, 2017; ESMO, 2014 [Fenaux, 2014]; ELN, 2014 [Malcovati, 2013]).
The European guidance also recommends the use of ESAs for patients who have a low RBC 
transfusion burden (< 2 units/month) and/or an endogenous sEPO levels ≤500 U/L (ESMO, 2014 
[Fenaux, 2014]; ELN, 2014 [Malcovati, 2013]). However, major favorable prognostic factors for 
response to ESAs are a low or no RBC transfusion requirement (< 2 units/month) and an 
endogenous sEPO level < 500 U/L (Fenaux, 2013).  Responses to ESAs are best in patients with 
low endogenous levels (eg, < 500 U/L) of sEPO, normal blast counts and lower IPSS/World Health 
Organization (WHO) Prognostic Scoring System (WPSS) scores (Hellstrom-Lindberg, 2003; 
Santini, 2011).
Efficacy of ESAs in lower-risk MDS patients have recently been demonstrated in two Phase 3 
studies:
In the EPOANE3021 Phase 3 study, a total of 130 subjects with IPSS low or intermediate-1 risk 
MDS and Hgb ≤10 g/dL with a requirement of RBC transfusion ≤ 4 units/8 weeks and an 
endogenous sEPO level < 500 U/L, were randomized 2:1 to receive either epoetin alfa 450 
IU/kg/week or matching placebo for 24 weeks, followed by treatment extension in responders.  
Subjects were stratified by endogenous sEPO level (sEPO < 200 U/L versus sEPO ≥ 200 U/L) and 
prior transfusion status at screening (yes versus no).
In the modified intent-to-treat (ITT) analysis 2/45 (4.4%) subjects in the placebo group achieved 
the primary endpoint of International Working Group (IWG) 2006 erythroid response versus 27/85 
(31.8%) in the epoetin alfa group (p < 0.001). All of the responding subjects were in the stratum 
with endogenous sEPO < 200 U/L during screening. In that stratum, 20/40 (50%) subjects without 
prior transfusions demonstrated erythroid response during the first 24 weeks, compared with 7/31 
(22.6%) subjects with prior transfusions (two subjects with prior transfusion reached primary 
endpoint based on reduction of RBC units transfused by an absolute number of at least 4 units 
every 8 weeks compared to the 8 weeks prior to baseline) (Fenaux, 2017; Fenaux, 2018a).  The 
median duration of erythroid response in the epoetin alfa group was 197 days.  The percentage of 
subjects who were transfused in the epoetin alfa group decreased from 51.8% in the 8 weeks prior 
to baseline to 24.7% between weeks 16 and 24, compared to the placebo group which had an 
increase in transfusion rate from 48.9% to 54.1% over the same time periods (Fenaux, 2016).  In 
an additional post-hoc analysis conducted by the response review committee with modified IWG 
2006 criteria an erythroid response rate of 39/85 (45.9%) in the epoetin alfa group was 
estimated (Fenaux, 2017; Fenaux, 2018a).
In the ARCADE Phase 3 study, a total of 146 subject with IPSS low or intermediate-1 risk MDS 
and anemia ≤ 10 g/dL, requirement of RBC transfusion < 4 units/8 weeks, and an endogenous
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Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
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sEPO level ≤500 U/L were randomized 2:1 to receive either darbepoetin alfa (DAR) or matching 
placebo (PBO). In the ITT analysis, 29 (59.2%) subjects in the PBO group achieved the primary 
endpoint (percentage of participants with at least 1 RBC transfusion during the double-blind 
treatment period: Weeks 5 to 24) versus 35 (36.1%) subjects in the DAR group (p = 0.008). 
Transfusion rates were less with lower baseline sEPO for darbepoetin alfa (≤100 U/L: 23%, > 100 
U/L: 57%, 95% confidence interval non-overlapping) but not placebo. The proportion achieving 
hematologic improvement – erythroid response (HI-E) was significantly increased with DAR 
versus PBO; DAR:14.7% (11 of 75 evaluable) versus PBO:0% (0 of 35 evaluable), p = 0.016. All 
patients with HI-E (n=11) in the double-blind period had a baseline sEPO ≤100 U/L. The mean 
duration of response was 235 (21 days standard error) days. It should be noted, however, that the 
primary endpoint was switched during the course of the study.
Before unblinding and while 
enrollment was ongoing, transfusion incidence from weeks 5-24 became the primary endpoint and 
HI-E a secondary endpoint (Platzbecker, 2017c). 
EPREX®/ERYPO® (epoetin alfa, Janssen) has recently been authorized via mutual recognition 
procedure (MRP) by a number of European Union (EU) member states for the treatment of 
symptomatic anemia (hemoglobin concentration of ≤10 g/dL) in adults with low- or intermediate-
1-risk primary myelodysplastic syndromes (MDS) who have low serum erythropoietin (< 200 
U/L).
1.1.1.2
Red Blood Cell Transfusions 
Lower-risk MDS are characterized mainly by anemia and supportive care, primarily RBC cell 
transfusions, remain an important component of their treatment, but exposes patients to insufficient 
correction of anemia, alloimmunization, and organ iron overload. Treatment aimed at preventing 
anemia recurrence should therefore be used whenever possible (Fenaux, 2013).
In many patients with lower-risk MDS, anemia (ie, average hemoglobin levels < 10 g/dL) will 
eventually become resistant to all available drug treatments, even in the absence of evolution to 
higher-risk MDS, and will require repeated RBC transfusions. 
For those patients, it is 
recommended to administer transfusions at sufficiently high hemoglobin thresholds (ie, at least 
8 g/dL and 9 or 10 g/dL in cases of comorbidities worsened by anemia [eg, coronary artery disease, 
heart failure] or in cases of poor functional tolerance).  In addition, a sufficient number of RBC 
concentrates should be transfused each time, over 2 or 3 days if needed, to increase the hemoglobin 
level to > 10 g/dL and thereby limit the effects of chronic anemia such as cardiac failure, falls, 
fatigue and lower quality-of-life (Nordic Guideline, 2017; Fenaux, 2013; ESMO, 2014 [Fenaux, 
2014]).
However, the development of transfusion dependency significantly worsens the survival of 
patients with MDS (Malcovati, 2005).  In addition, long-term RBC transfusion dependency has 
several detrimental clinical effects including iron overload, economic consequences, and a 
negative impact on patients’ QoL (Hellstrom-Lindberg, 2003; Jansen, 2003; Thomas, 2007).
1.1.1.3
Lenalidomide
Lenalidomide (Revlimid®) is approved in the US for the treatment of patients with transfusion-
dependent anemia due to low- or intermediate (int-1)-risk MDS associated with a del(5q) 
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Celgene Corporation
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Final: 31 Mar 2022
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abnormality with or without additional cytogenetic abnormalities. Lenalidomide is the standard 
of care (in countries where lenalidomide is approved) for the small proportion of patients with 
lower-risk del(5q) MDS. In this population, lenalidomide led to RBC transfusion independence 
(8 weeks) for 67% of the patient population for a median duration of transfusion independence of 
44 weeks.
1.1.1.4
Hypomethylating Agents
There are two hypomethylating agents (HMAs) currently approved for the treatment of various 
subtypes of MDS, azacitidine and decitabine.
Azacitidine for injection (Vidaza®) is indicated for treatment of patients with the following 
French-American-British (FAB) classification subtypes of MDS in the US:  refractory anemia 
(RA) or refractory anemia with ringed sideroblasts (RARS) (if accompanied by neutropenia or 
thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB), 
refractory anemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic 
leukemia (CMML), but it is not routinely utilized in the lower-risk disease setting.
Azacitidine is approved in the 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 
multilineage dysplasia, and AML with > 30% marrow blasts 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).
Decitabine for injection (Dacogen®), 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 both 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, data supporting the use for these agents in the lower-risk MDS patient population is 
currently limited.
1.1.1.5
Iron Chelation Therapy
Iron accumulation in MDS patients is an ongoing process as ineffective erythropoiesis provides a 
signal that stimulates intestinal iron absorption. 
There is now evidence that ineffective 
erythropoiesis is associated with increased secretion of growth differentiation factor 15 (GDF15) 
and/or a molecule named twisted gastrulation 1 (TWSG1) (Tanno, 2007; Tanno, 2009) by 
maturing erythroblasts, leading to suppressed hepcidin production in the liver (Winder, 2008). 
Since hepcidin downregulates iron absorption in the duodenum, lack of hepcidin causes 
unrestrained intestinal iron uptake. Although this mechanism contributes to iron overload in MDS, 
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it is not the main cause, and rarely leads to serum ferritin levels above 1000 ng/ml at diagnosis.
The main cause of iron overload in MDS is chronic transfusion therapy (Gattermann, 2011).
Clinically significant iron overload associated with RBC transfusions is often observed in patients 
who have received 100 or more RBC units (Ades, 2014). Important sequelae of this increase in 
iron include iron-related cardiac, hepatic and endocrine toxicities. Therefore, iron chelation may 
be required in patients receiving frequent transfusions.
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 RA or 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).
Furthermore Sanz, et al reported that transfusion dependence (HR = 8.8; p < 0.0001) and iron 
overload (HR = 52.4; p < 0.0001) are independent risk factors for overall survival and leukemic 
progression (Sanz, 2008) demonstrating that the longer patients can remain transfusion 
independent, the better their overall survival.  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.
1.2
Luspatercept Background
1.2.1
Mechanism of Action
Luspatercept (ACE-536), an erythroid maturation agent, 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 IgG1 Fc domain (Figure 1A).  The ActRIIB receptor and its ligands are 
members of the transforming growth factor-β (TGF-β) superfamily, a group of proteins involved 
in the development, differentiation, and/or maturation of various tissues.  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 (Massague, 1998).  Thus, 
observations from pharmacology studies of luspatercept or its murine ortholog RAP-536 in animal 
models provide significant insight into the potential of luspatercept to treat human disease. 
Members of the TGF-β superfamily ligands, through their binding to activin receptors, are 
involved in modulating the differentiation of late-stage erythrocyte precursors (normoblasts) in the 
bone marrow.  Luspatercept acts as a ligand trap for growth differentiation factor 11 (GDF11) and 
other TGF-β superfamily ligands to suppress Smad2/3 signaling.  In nonclinical experiments, 
luspatercept has been shown to bind with high affinity to some TGF-β superfamily ligands (eg, 
GDF11, bone morphogenetic protein 6 [BMP6] and activin B) but substantially less to others (eg, 
bone morphogenetic protein 9 [BMP9] and activin A).  The mechanism of action of luspatercept 
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is independent from that of erythropoietin (EPO) (Suragani, 2014).  While EPO stimulates 
proliferation and differentiation of early erythroid progenitors, luspatercept as an erythroid 
maturation agent promotes stimulation of the later, maturation phase of erythroblast differentiation 
and maturation in the bone marrow (refer to Figure 1B).
During normal erythropoiesis, GDF11 appears to inhibit differentiation and maintain the survival 
of immature erythroid progenitors. In a mouse model of thalassemia, defects in erythroid 
differentiation led to an accumulation of GDF11 expressing cells that maintained their own 
survival (Dussiot, 2014).  Recent studies (Dussiot, 2014; Suragani, 2014) identified GDF11 as a 
regulator of erythropoiesis and showed that its inhibition in mouse models of anemia with 
ineffective erythropoiesis restores normal erythropoietic differentiation and improves anemia.
Figure 1:
Luspatercept Schematic Representation and Mechanism of Action
A
B
ActRIIB = activin receptor type IIB; ECD = extracellular domain; EPO = erythropoietin; GDF11 = growth 
differentiation factor 11; IgG1 = immunoglobulin G1; RBC = red blood cell; TGF-β = transforming growth factor-
beta.
Please refer to the current version of the Investigator’s Brochure (IB) for detailed information 
concerning the available pharmacology, toxicology, drug metabolism, clinical studies, and adverse 
event (AE) profile of luspatercept.
1.2.2
Summary of Clinical Experience
Luspatercept is currently in Phase 3 of clinical development in MDS and β-thalassemia. 
Across the Phase 2 program in MDS, responses to luspatercept treatment were observed in the 
majority of subjects at 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 HI-E in a substantial proportion of MDS subjects within the 
initial 3 months of treatment.
Luspatercept is currently being assessed in a Phase 2 study for subjects with lower-risk MDS and 
anemia.  Data is available for 88 subjects treated with doses of ≥ 0.75 mg/kg.  Subjects had HI-E 
response rates of 55% 11/20 (sEPO 200-500 U/L) and 63% (27/43) (sEPO < 200 U/L) and rates 
of red blood cell transfusion independence (RBC-TI, 8 weeks) of 46% (6/13) (sEPO 200-500 U/L) 
and 56% (14/25) (sEPO < 200 U/L).  The subgroup of subjects with no ring sideroblasts (RS-) and 
with sEPO ≤ 500 U/L had HI-E response rates of 50% (8/16) and rates of RBC-TI (8 weeks) of 
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44% (4/9) (Platzbecker, 2017a).  For subjects achieving RBC-TI (8 weeks) criteria, the median 
duration of treatment is 14.7 months (range 2.8-32.4 months, as of 13 April 2017); however, this 
figure is expected to increase as the current Phase 2 study is in progress.
Additionally, luspatercept is currently being assessed in two Phase 2 studies in β-thalassemia 
subjects (A536-04 and A536-06) in which luspatercept has demonstrated clinically significant 
efficacy in both RBC transfusion dependent and non-transfusion dependent subjects.  Further, a 
Phase 3, randomized, double-blind study to determine the efficacy and safety of luspatercept 
versus placebo in subjects with β-thalassemia who require regular red blood cell transfusions is 
ongoing.
Luspatercept was assessed in the Medalist trial (Fenaux, 2018b): A Phase 3, randomized, double-
blind study in subjects with very low- to intermediate-risk MDS (IPSS-R) with ring sideroblasts 
who require RBC transfusions and who were refractory, intolerant, or ineligible to receive an ESA.  
Subjects (N = 229) were randomized in a 2:1 ratio against placebo. Of 153 subjects receiving 
luspatercept, 58 (37.9%) achieved the primary endpoint of RBC-TI for ≥ 8 weeks compared with 
10 of 76 subjects (13.2%) receiving placebo (odds ratio [OR] 5.1, p < 0.0001). Of those receiving 
luspatercept, 43 of 153 (28.1%) achieved the key secondary endpoint of RBC-TI for ≥12 weeks 
(weeks 1 to 24) compared with 6 of 76 (7.9%) receiving placebo (OR 5.1, p = 0.0002). Subjects
receiving luspatercept were more likely to achieve a modified hematologic improvement –
erythroid response (mHI-E), defined as a reduction in transfusion of ≥ 4 RBC units/8 weeks or a 
mean hemoglobin increase of ≥ 1.5 g/dL/8 weeks in the absence of transfusions, compared with 
subjects receiving placebo (52.9% versus 11.8% during weeks 1 to 24; p < 0.0001). Luspatercept 
was well tolerated and resulted in a significantly reduced transfusion burden.
Additional information regarding clinical experience with luspatercept is summarized in the 
current version of the luspatercept IB.
1.3
Rationale
1.3.1
Study Rationale and Purpose
Anemia is the predominant cytopenia observed in adult MDS and is present in 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 transfusion support.  Of the approximately 80% to 
90% of patients with MDS that develop anemia, 40% of those patients become transfusion 
dependent (TD). Lower Hgb levels and RBC transfusion-dependence have been associated with 
inferior cardiovascular outcomes and increased mortality in patients with MDS, representing a 
strong rationale for the 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 quality-of-life (QoL), iron overload and its associated 
complications, immune-related disorders, and increased risk of infections (Hellstrom-Lindberg, 
2003; Jansen, 2003; Thomas, 2007).
The use of ESAs is standard of care in lower-risk MDS patients with endogenous sEPO ≤500 U/L
according to treatment guidelines (NCCN, 2017; ESMO, 2014 [Fenaux, 2014]; ELN, 2014 
[Malcovati, 2013]). Recent Phase 3 studies with Epoetin alfa and darbepoetin have demonstrated 
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efficacy, but limited in both magnitude and size of patient population in whom a clinically 
significant effect is seen (see Section 1.1.1.1).  Epoetin alfa has been recently been approved via 
the MRP in Europe in patients with low- or intermediate-1-risk primary MDS (according to IPSS) 
who have low serum erythropoietin (< 200 U/L).
Therefore, a new therapeutic option that would increase the frequency of response as well as the 
duration of RBC-TI for a sustained period of time in patients with lower-risk MDS for a sustained 
period of time would provide an important clinical benefit in this patient population.
Luspatercept has a novel mechanism of action distinct from ESAs which may be more beneficial 
in the treatment of anemia in IPSS-R lower-risk MDS patients who are ESA naïve and require 
RBC transfusions. Preliminary Phase 2 results for luspatercept demonstrate promising results for 
erythroid response (HI-E), transfusion independence and duration of response for subject with 
endogenous sEPO level up to 500 U/L and for subject with and without ring sideroblasts.
A direct comparison of epoetin alfa and luspatercept in a Phase 3 study in lower-risk MDS is 
therefore justified in subjects with endogenous sEPO ≤ 500 U/L.
1.3.2
Rationale for the Study Design
ACE-536-MDS-002 is a Phase 3, multicenter, randomized, open-label, active controlled study.  
The primary objective of the study is to evaluate RBC-TI in the two treatment arms, luspatercept 
compared with epoetin alfa, for the treatment of anemia due to IPSS-R very low, low, or 
intermediate risk MDS in subjects who require RBC transfusions.
The design of this study (ie, randomized, prospectively stratified [see stratification factors in 
Section 1.3.2.2 below], with an active-control arm, and parallel-group design) will control 
potential bias in assignment of the IP or in data interpretation.  The multicenter nature of the study 
will provide assurance that the results are likely to have general applicability.  In addition, to avoid 
bias and to ensure comparability of the frequency and units of RBC transfusions administered in 
both treatment arms, for each subject a “pre-transfusion hemoglobin threshold” for requiring 
transfusion during the study will be determined based on transfusion history in the 8 weeks prior 
to the first dose of IP.  This “pre-transfusion hemoglobin threshold” should be maintained 
throughout the Treatment Period when administering RBC transfusions (for details see 
Section 8.1.1).
1.3.2.1
Rationale for the Study Population
This study targets subjects who have received RBC transfusions (ie, 2 to 6 packed red blood cell 
[pRBC] units in the 8 weeks before randomization).  This subject population represents a subset 
of subjects with IPSS-R lower-risk MDS who have anemia, requiring RBC transfusions and have 
limited treatment options in managing their anemia.
The IPSS-R classification has been chosen to define this Phase 3 study population because this 
classification provides better discrimination of MDS progression risk factors compared with the 
original IPSS (Greenberg, 1997) for evaluating clinical outcomes (survival duration and time to 
progression of AML) for MDS subjects (Greenberg, 2012).  For the purpose of the study, subjects 
with IPSS-R very-low, low and intermediate risk will be referred to as lower-risk MDS.
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Subjects in the lower-risk groups often become dependent on frequent RBC transfusions, which 
leads to decreased HRQoL and increased morbidity and mortality (Hellstrom-Lindberg, 2003; 
Malcovati, 2005).  Thus, the therapeutic goal in this subject population is to reduce or eliminate 
transfusion dependence, which is evaluated in this study.
1.3.2.2
Rationale for Stratification Factors
A stratified randomization scheme will be used based on RBC transfusion burden at baseline, ring 
sideroblast (RS) status at baseline and endogenous sEPO at baseline to control heterogeneity and 
to balance key factors impacting study endpoints over the two treatment arms.
RBC transfusion burden at baseline:  < 4 pRBC units/ 8 weeks versus ≥ 4 pRBC units/ 8 weeks
Lower-risk MDS patients often become dependent on frequent RBC transfusions, which leads to 
increased morbidity and mortality and decreased HRQoL (Hellstrom-Lindberg, 2003; Malcovati, 
2005). In this proposed study, subjects who receive 2 to 3 pRBC units during the 8-week period 
prior to randomization will be balanced with subjects who receive 4 to 6 pRBC units during the 8-
week period prior to randomization. This RBC transfusion burden stratification is considered 
important due to the likelihood of transfusion independence being correlated with the degree of 
transfusion burden.
Ring sideroblast (RS) status at baseline:  RS+ versus RS- (with RS+ defined as Ring sideroblast 
≥15% of erythroid precursors in bone marrow or ≥5% (but < 15%) if SF3B1 mutation is present)
The ongoing Phase 3 study in lower risk MDS in ESA ineligible subjects (ACE-536-MDS-001) is 
restricted to subjects who are RS+. However, in the population of this proposed study both RS+ 
and RS- patients are included and will be stratified according to RS status (RS+/RS-) at baseline. 
Stratifying subjects based on RS status will balance the distribution of RS+ and RS- subjects 
between the two treatment arms as well as any associated potential prognostic differences between 
the two groups. Of note, IWG HI-E response rates have been shown to be similar in RS+ and RS-
subjects at endogenous sEPO levels ≤ 500 U/L in Phase 2 studies with luspatercept (A536-03, 
A536-05) (Platzbecker, 2017b), however, limited data is available, thus this stratification factor is 
a precautionary measure.
Endogenous serum erythropoietin (sEPO) level at baseline:  ≤ 200 U/L versus > 200 U/L
In this proposed study, subjects who have an endogenous sEPO level ≤200 U/L at randomization 
will be balanced with subjects who have an endogenous sEPO level of > 200 U/L at randomization. 
This stratification will balance the impact of endogenous sEPO levels on the study endpoints over 
the two treatment arms.
1.3.2.3
Rationale for Study Endpoints
The primary endpoint of RBC-TI for 12 weeks (84 days) with a mean hemoglobin increase 
≥1.5 g/dL is defined as proportion of subjects who are RBC transfusion-free for any 12-week 
period during the first 24-week period of study treatment associated with a concurrent mean 
hemoglobin increase ≥ 1.5 g/dL compared to baseline and reflects an important direct clinical 
benefit of the treatment.
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Lower Hgb levels and 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 HRQoL, iron overload and its associated complications, 
immunorelated disorders, and increased risk of infections (Hellstrom-Lindberg, 2003; Jansen, 
2003; Thomas, 2007).  Therefore, treatment of anemia leading to transfusion independency would 
benefit these patients. In this study, a prolonged period of 12 weeks of transfusion independence 
(instead of 8 weeks as per IWG criteria [Cheson, 2006]) would illustrate an important direct 
clinical benefit and therefore would be considered clinically relevant.  The additional requirement 
of a mean increase of Hgb of ≥1.5 g/dL compared to baseline represents a substantial and 
clinically meaningful Hgb increase and will increase the robustness and objectivity of the endpoint.
Preliminary data from the Phase 2 A536-03 and A536-05 studies in MDS show an RBC-TI over a 
24-week period of 78% (7/9) in subjects with baseline sEPO ≤500 U/L and 2 to 6 pRBC
units/8 weeks.
Secondary objectives include evaluation of efficacy (eg, RBC-TI for 24 weeks over the first 
24-week period of study treatment, RBC-TI for ≥ 12 weeks (84 days), duration and time to RBC-TI
for ≥ 12 weeks (84 days), HRQoL) as well as safety and tolerability.  Safety is assessed by
evaluating adverse events and laboratory data.  Adverse events and abnormal laboratory value
severity will be graded using version 4.03 of the National Cancer Institute Common Terminology
Criteria for Adverse Events (NCI CTCAE).
1.3.2.4
Rationale for Open-label Design
Epoetin alfa and luspatercept are two distinct treatment modalities and are not only different in the 
frequency of application (weekly versus 3-weekly) but also in terms of dose modification, dose 
delay and stopping rules, which have been established and need to be applied separately to allow 
for a fair comparison.  A double blind, double dummy design would increase patient burden 
significantly as the number of injections for subjects on the luspatercept arm would be tripled.  In 
addition, epoetin alfa (EPREX®/ERYPO®) is supplied in prefilled syringes of various sizes 
(depending on the number of units) in the majority to the participating countries rendering blinding 
operationally unfeasible.
1.3.3
Rationale for Dose, Schedule and Regimen Selection
For luspatercept, 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 (8 weeks), 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 clinically 
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significant increase in hemoglobin was maintained with the Q3W dosing schedule.  Additional 
information regarding these clinical studies is summarized in the current version of the luspatercept 
IB.
Epoetin alfa dosing is based on the label approved via the mutual recognition procedure in a 
number of EU member states for the treatment of symptomatic anemia (hemoglobin concentration 
of ≤ 10 g/dL) in adults with low- or intermediate-1-risk primary MDS who have low serum 
erythropoietin (< 200 U/L) and is based on the EPOANE3021 study.
1.3.4
Rationale for Choice of Comparator Compound
The choice of the active comparator epoetin alfa will ensure that all subjects on the control arm 
are treated according to standard of care as per international treatment guidelines (NCCN, 2017; 
ELN, 2014 [Malcovati, 2013]).  Epoetin alfa has been authorized via the MRP by a number of EU 
member states for the treatment of symptomatic anemia (hemoglobin concentration of ≤10 g/dL) 
in adults with low- or intermediate-1-risk primary MDS who have low serum erythropoietin (<
200 U/L).
While darbepoetin alfa is also part of the treatment guidelines, and efficacy in treatment of lower-
risk MDS has been demonstrated in a Phase 3 study (ARCADE), darbepoetin alfa is not expected 
to have received regulatory approval at the time ACE-536-MDS-002 study initiation. 
1.3.5
Rationale for Exploratory Biomarkers
ActRIIB ligands (eg, GDF11 and Activin B)
Luspatercept binds with high affinity to both GDF11 and Activin B and inhibits subsequent 
signaling downstream of Activin Receptor IIB.  Growth differentiation factor 11 (GDF11) and 
Activin B are present in serum and bone marrow and nonclinical studies have demonstrated 
increased circulating GDF11 levels in a murine model of MDS.  It is also possible that baseline 
levels of these proteins in patients may correlate with response.
MDS-associated molecular mutations (eg, SF3B1)
Emerging literature describes the prognostic impact of gene mutations in MDS patients.  For 
example, Haferlach, et al surveyed genetic aberrations in 944 patients and demonstrated that 90% 
of the population had at least one mutation.  Forty-seven (47) genes were significantly mutated 
and many of the mutations were linked to higher risk groups and/or blast elevation.  Of the 47 
genes, almost half affected survival, suggesting that molecular profiling of multiple target genes 
could be valuable for classification and prognosis in MDS patients (Haferlach, 2014).  In 
particular, SF3B1 and other genes involved in ribonucleic acid (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 (Malcovati, 2011; Papaemmanuil, 2011) and 
thought to be causally related to chromosome stability, deoxyribonucleic acid (DNA) repair and 
gene regulation that may result in anemia and thrombocytopenia (Pellagatti, 2015; Visconte, 
2014).  Preliminary results from ongoing Phase 2 studies of luspatercept in MDS indicate that
subjects harboring a SF3B1 mutation had increased HI- E response rates to luspatercept (A536-
03, A536-05) but similar rates of RBC-TI (8 weeks) (Platzbecker, 2017b).
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In this study, we will build on these data by evaluating the prognostic value of a discrete subset of 
MDS-related gene mutations in the study population, as well as evaluating the impact of these 
mutations on clinical benefit with luspatercept. Bone marrow aspirates will be collected from 
subjects at screening as the baseline for molecular biomarker analyses. Biomarker assessments 
will be performed on subjects in both the control arm (epoetin alfa) and the investigational arm
(luspatercept), thus a distinction between the prognostic (disease outcome in the absence of 
therapy) and/or predictive (disease outcome in the presence of therapy) nature of the marker(s) 
will be determined. While the IPSS-R prognostic classification system remains the gold standard 
for risk stratification of subjects with MDS at diagnosis, prognostic risk factors in addition to 
cytogenetics, blast count and cytopenias are being identified that will be important in 
understanding the study population. Finally, we also propose to collect and store an aliquot of 
bone marrow mononuclear cells for future analyses such as assessment of RNA expression to 
allow us to develop a gene signature that predicts response.
Terminal erythropoiesis
As previously mentioned, luspatercept acts on late stages of erythroid differentiation, through a 
mechanism unique from that of EPO.  We hypothesize that patients may respond differently to 
luspatercept depending on the stage at which erythropoiesis is affected in their bone marrow. For 
example, responders may have bone marrow that is “primed” and rich in late-stage erythroid 
precursors compared to non-responders.  As such, we propose to isolate bone marrow mononuclear 
cells from patients and using flow cytometry, measure the extent of terminal erythroid
differentiation in each patient (Hu, 2013) at baseline and after treatment.  Subsequently, we can 
compare this phenotypic profile to response and determine whether there is a correlation between 
erythroid differentiation state and response to luspatercept and/or EPO.  We can also evaluate the 
profile after treatment to determine which erythroid populations are modified following 
administration of luspatercept.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
Subjects who have evidence of a prior infection with SARS-CoV-2 may be at risk for potential 
long-term sequelae.  The sequelae could potentially affect the safety profile of luspatercept.  In 
addition, some health authorities may want to know coronavirus disease 2019 (COVID-19) status 
as prior infection with SARS-CoV-2 may increase toxicity or impact interpretation of study events 
or results.
1.4
Risk/ Benefit Assessment
1.4.1
Risk Assessment
1.4.1.1
Study Intervention: Luspatercept
1.4.1.1.1
Non-clinical Risks
Kidney findings:  In monkey studies kidney findings included glomerulonephritis, accumulation 
of tubular protein, mixed inflammatory cell infiltrates, and degeneration/atrophy of tubules.  
Although the presence of immunoglobulin is suggestive of immune complexes in renal tissue, 
presence of these immune complexes could not be demonstrated, and a direct drug effect on the 
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kidney could not be excluded.  However, clinical experience of luspatercept in subjects without 
severe renal dysfunction at baseline has not resulted in identification of a drug-related renal toxicity 
signal. Therefore, to exclude subjects with severe renal dysfunction in whom the safety has not yet 
been characterized, subjects with an estimated glomerular filtration rate (eGFR) of < 40 
mL/min/1.73m2 will be excluded from the study.
Maternal health and fetal development:  Luspatercept has exhibited toxicity both in terms of 
maternal health and fetal development in reproductive toxicity studies in preclinical species.  If 
luspatercept is taken during pregnancy, a teratogenic effect in humans cannot be ruled out.  If a 
woman becomes pregnant while taking luspatercept, the medication must be stopped immediately.  
In addition, since it is unknown if luspatercept is excreted in breast milk, breastfeeding is 
prohibited.  Male and female subjects of childbearing potential participating in studies of 
luspatercept must be willing to abstain from sexual intercourse or use adequate contraception 
during the treatment period of the study and for at least 12 weeks after discontinuation of study 
therapy.
Hematologic malignancies:  Hematologic malignancies were observed in rats in a nonclinical 
juvenile toxicity study at high doses not being used in humans.  No related tumors developed in 
adult rats and monkeys in similar studies.  Dose modification guidelines include monitoring of 
increased white blood cell (WBC) counts as well as the presence of blasts in peripheral blood.  In 
addition, participating subjects will be followed long term as specified in Section 6.3.2 for 
evidence of tumor formation. 
1.4.1.1.2
Clinical risks
Increases in hematologic parameters and blood pressure:  Increases in hematologic parameters (ie, 
RBC, Hgb, hematocrit, reticulocytes) are expected as 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 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 luspatercept:  Adverse events 
considered probably or possibly related to luspatercept 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 subjects regardless of causality in the open-
label Phase 2 studies in MDS include (in order of decreasing frequency in the extension study) 
nasopharyngitis, fatigue, cough, diarrhea, dyspnea, hypertension, arthralgia, edema peripheral, 
pneumonia, and headache.  Adverse events reported in at least 15% of subjects regardless of 
causality (in order of decreasing frequency) in the open-label Phase 2 studies in β-thalassemia 
included pyrexia, headache, diarrhea, asthenia, bone pain, myalgia, oropharyngeal pain, arthralgia, 
musculoskeletal pain, back pain, influenza, dizziness, rhinitis, abdominal pain, nausea, 
pharyngitis, and vomiting. 
1.0
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930183290
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v
Approved
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v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
36
Antidrug antibodies (ADA):  As with all biologics, there is the potential for ADA that can be 
associated with increased drug clearance and hypersensitivity reactions.  Data from current 
sponsored luspatercept studies in MDS indicate that 8.8% of subjects do develop treatment-
emergent ADAs 
.  However, analyses of the impact of these ADAs on 
safety and efficacy of luspatercept in these subjects have concluded that subjects who develop 
ADAs on treatment with luspatercept experience neither clinically significant allergic responses 
nor decrements in efficacy as assessed by hemoglobin increase and transfusion reduction 
compared with subjects who do not develop ADAs.  Nevertheless, antidrug antibody formation 
against luspatercept as well as human ActRIIB protein will be monitored.
Thromboembolic events:  Emerging data in β-thalassemia subjects treated with luspatercept from 
the Phase 3 study ACE-536-B-THAL-001 reveals an imbalance in the rate of thromboembolic 
events in the luspatercept arm versus the placebo arm (3.6% versus 0.9%, in the luspatercept and 
placebo arms, respectively.  All subjects with thromboembolic events had a least two pre-existing 
risk factors for thromboembolic events:  they were all splenectomized and had at least one other 
risk factor including hormonal replacement or contraception, thrombocytosis, smoking, obesity, 
cardiac disease, hypertension, previous thromboembolic event, or diabetes.  The incidence rate 
observed in the luspatercept arm is consistent with the expected event rate for β-thalassemia 
subjects, ranging from 3.3% and 6.3% (Taher, 2010; Borgna Pignatti, 1998; Moratelli, 1998; 
Michaeli, 1992). Of note, in the MDS population, no imbalance in thromboembolic events was 
observed in the Phase 3 study ACE-536-MDS-001, which evaluated the efficacy and safety of 
luspatercept versus placebo in subjects with IPSS-R very low, low or intermediate risk MDS with 
chronic anemia and refractory to, intolerant of, or ineligible for treatment with an erythropoietin-
stimulating agent (ESA), ring sideroblast-positive and require frequent RBC transfusions. 
Safety effects will be monitored closely through AE reporting, clinical laboratory tests, vital signs, 
and physical examinations.
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of luspatercept may be found in the Investigator’s Brochure.
1.4.1.2
Study Procedures
Blood drawing:  Needle sticks carry some risks such as fainting, bleeding, bruising, discomfort, 
dizziness, infection and/or pain at the puncture site. 
Bone marrow aspirate/ biopsy collection:  Bone marrow is collected using a needle under local 
anesthesia to aspirate (draw out) marrow tissue from the inside of the pelvic or hipbone. The risks 
on bone marrow biopsy and aspirate include pain, bleeding, bruising, and/or discomfort at the 
biopsy site. Infection is also possible, but rare. 
Trained medical personnel will perform the blood and bone marrow aspirate/bone marrow biopsy 
(BMA/BMB) collection procedures and will make every effort to minimize any discomforts. Risks 
from the needle sticks can be mitigated by applying adequate pressure to the puncture site for 
adequate time (10–20 min). 
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
37
Electrocardiogram (ECG):  The ECG involves placing adhesive patches on the skin. A slight 
redness or inflammation may appear due to an allergic reaction to the adhesive used to attach the 
patches. Those are minor and do not require any intervention.
1.4.1.3
Other: Comparator Epoetin alfa (EPREX®/ERYPO® or PROCRIT®)
Hypertension:  Hypertensive crisis with encephalopathy and seizures, requiring the immediate 
attention of a physician and intensive medical care, have occurred during epoetin alfa treatment in 
patients with previously normal or low blood pressure. Hypertension will be controlled prior to 
treatment initiation and during treatment.  
Increased mortality, myocardial infarction, stroke, and thromboembolism: Using ESAs to target 
a Hgb level of > 11 g/dL increases the risk of serious adverse cardiovascular reactions and has not 
been shown to provide additional benefit.  For subjects with a predose Hgb of ≥12.0 g/dL (7.5 
mmol/L), dosing of epoetin alfa will be delayed until Hgb < 11.0 g/dL (6.8 mmol/L). Patients with 
high risk of cardiovascular diseases, stroke, and thromboembolism are excluded from study 
participation.
Increased mortality and/ or increased risk of tumor progression or recurrence in patients with 
cancer: Subject with a prior history of malignancies other than MDS, unless the subject has been 
free of the disease for ≥ 5 years, are not eligible for study participation. During the study, subjects 
will be assessed for MDS disease progression every 24 weeks.
Seizures:  Epoetin alfa should be used with caution in patients with epilepsy, history of seizures, 
or medical conditions associated with a predisposition to seizure activity such as central nervous 
system infections and brain metastases. Patients with new-onset seizures or poorly controlled 
seizures within 12 weeks prior to randomization are excluded from study participation.
Rise in the platelet counts:  There may be a moderate dose-dependent rise in the platelet count 
within the normal range during treatment with epoetin alfa. This regresses during the course of 
continued therapy. In addition, thrombocythemia above the normal range has been reported. The 
platelet count will be monitored regularly.
Serious allergic reactions: Serious allergic reactions, including anaphylactic reactions, 
angioedema, bronchospasm, skin rash, and urticaria may occur. The needle cover on the 
EPREX®/ERYPO® pre-filled syringe contains dry natural rubber (a derivative of latex), which 
may cause severe allergic reactions in individuals sensitive to latex. Epoetin alfa will be 
discontinued immediately and permanently, and appropriate therapy will be administered.
Severe cutaneous reactions: Blistering and skin exfoliation reactions including erythema 
multiforme and Stevens-Johnson Syndrome /toxic epidermal necrolysis, have been reported. 
Epoetin alfa will be discontinued, and reactions will be managed.
Other frequently reported adverse reactions: Other frequently reported adverse reactions in ≥ 5% 
of epoetin alfa-treated patients in clinical studies are nausea, vomiting, myalgia, arthralgia, 
stomatitis, cough, weight decrease, leukopenia, bone pain, rash, hyperglycemia, insomnia, 
headache, depression, dysphagia, and hypokalemia. 
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
38
Safety effects will be monitored closely through AE reporting, clinical laboratory tests, vital signs, 
and physical examinations.
Information provided in this section is based on the UK Summary of Product Characteristics 
(SmPC) for EPREX® and the prescribing information for PROCRIT®.  For additional information 
please refer to the full documents, respectively.
1.4.2
Benefit Assessment
Luspatercept has a novel mechanism of action distinct from ESAs which may be more beneficial 
in the treatment of anemia in IPSS-R lower-risk MDS patients who are ESA naïve and require 
RBC transfusions. Preliminary Phase 2 results for luspatercept demonstrate promising results for 
erythroid response (HI-E), transfusion independence and duration of response for subjects with 
endogenous sEPO level up to 500 U/L and for subjects with and without ring sideroblasts. A direct 
comparison of epoetin alfa and luspatercept in a Phase 3 study in lower risk MDS is therefore 
justified in subjects with endogenous sEPO ≤ 500 U/L.
Overall, based on the assessment of available safety information collected during the overall 
cumulative experience to date, the benefit-risk balance for the use of luspatercept in the 
populations under study as well as in the currently approved indications remains favorable.
1.4.3
Overall Benefit Risk Conclusion
Current available information based on non-clinical and clinical data support an acceptable 
benefit-risk profile for luspatercept in subjects with very low, low or intermediate risk MDS who 
are ESA naïve and require red blood cell transfusions, when used in accordance with the 
precautions, dosing, and safety monitoring outlined in this study protocol and the routine 
pharmacovigilance practices.
Luspatercept may have the potential to provide hematologic improvement in erythroid response 
involving stimulation of the maturation phase of erythroblast differentiation and maturation in the 
bone marrow compared to epoetin alfa, which stimulates proliferation and differentiation of early 
erythroid progenitors.  Furthermore, luspatercept could have the potential therapeutic benefit to 
achieve transfusion independence for a sustained period of time and could be an important 
treatment option for an unmet medical need.
Considering the measures taken to minimize risk to participants participating in this study, the 
potential risks identified in association with luspatercept are justified by the anticipated benefits 
that may be afforded to participants with lower risk MDS.
1.0
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930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
39
2
STUDY OBJECTIVES AND ENDPOINTS
Table 1:
Study Objectives
Primary Objective
The primary objective of the study is to evaluate the efficacy of luspatercept on red blood cell transfusion 
independence (RBC-TI; for 12 weeks [84 days] with an associated concurrent mean hemoglobin increase ≥ 1.5 
g/dL) compared with epoetin alfa for the treatment of anemia due to very low, low, or intermediate risk 
myelodysplastic syndromes (MDS) according to the International Prognostic Scoring System - Revised (IPSS-R) 
in erythropoiesis stimulating agent (ESA) naïve subjects who require RBC transfusions. 
Secondary Objective(s)
The secondary objectives are:
•
To assess the safety and efficacy of luspatercept compared to epoetin alfa
•
To assess health-related quality of life (HRQoL) and anemia outcome measures (ie, the European
Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire [EORTC QLQ-C30]
and the Functional Assessment of Cancer Therapy - Anemia (FACT-An) questionnaire for subjects
treated with luspatercept compared to epoetin alfa
•
To evaluate pharmacokinetics for luspatercept in MDS subjects
Exploratory Objective(s)
The exploratory objectives are:
•
To evaluate the impact of luspatercept therapy on healthcare resource utilization and treatment
satisfaction in both treatment arms
•
To evaluate overall MDS treatment satisfaction in both treatment arms
•
To evaluate molecular and cellular markers in the bone marrow and/or in peripheral blood at baseline
and during therapy that may provide further prognostic classification of MDS subtypes and potentially
impact luspatercept efficacy
•
To evaluate molecular and cellular markers in the bone marrow and/or in peripheral blood at baseline
and during therapy that may provide information on luspatercept mechanism of action and on-therapy
markers predictive of response or relapse
•
To evaluate exposure-response relationships for luspatercept in MDS subjects
•
To evaluate the safety of luspatercept in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-
2) antibody positive subjects and to support potential health authority requests
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
40
Table 2:
Study Endpoints
Endpoint
Name
Description
Timeframe
Primary
Red blood cell transfusion 
independence (RBC-TI) for 
12 weeks (84 days) with a 
mean hemoglobin increase 
≥1.5 g/dL
Proportion of subjects who are RBC 
transfusion-free for any 12-week
period associated with a concurrent
mean hemoglobin increase ≥1.5 g/dL 
compared to baseline 
Week 1 through 
Week 24
Secondary
Red blood cell transfusion 
independence (RBC-TI) for 
24 weeks
Proportion of subjects who are RBC 
transfusion-free from Week 1 through 
Week 24
Week 1 through 
Week 24
Mean hemoglobin change 
over 24 weeks 
Mean hemoglobin change over the 24-
week period of Week 1 through 
Week 24 compared to baseline
Week 1 through 
Week 24
Hematologic improvement –
erythroid response (HI-E) 
per IWG (Cheson, 2006)
Proportion of subjects achieving HI-E 
over any consecutive 56-day period
Week 1 through 
Week 24
Time to HI-E
Time from first dose to first onset of 
achieving HI-E
Week 1 through 
Week 24
RBC-TI for ≥ 12 weeks (84 
days)
Proportion of subjects who are RBC 
transfusion-free over a consecutive 
84-day period
Week 1 through 
Week 24
Duration of RBC-TI
≥ 12 weeks (84 days)
Maximum duration of RBC 
transfusion independence for subjects 
who achieve RBC-TI ≥ 84 days
Week 1 through End of 
Treatment
Time to RBC-TI ≥12 weeks 
(84 days)
Time from first dose to first onset of 
transfusion independence ≥84 days
Week 1 through 
Week 24
Time to first RBC 
transfusion
Time from first dose to first 
transfusion on treatment
Week 1 through End of 
Treatment
RBC transfusion burden on 
treatment 
Total number of RBC units transfused 
on treatment 
Week 1 through 
Week 24
RBC-TI for ≥ 56 days (8 
weeks)
Proportion of subjects who are RBC 
transfusion-free over a consecutive 
56-day period
Week 1 through 
Week 24
RBC-TI for a consecutive 
24-week period
Proportion of subjects who are RBC 
transfusion-free for a consecutive 24-
week period in the first 48 weeks from 
first dose 
Week 1 through 
Week 48
Health-related quality-of-
life (HRQoL)
Evaluation of EORTC QLQ-C30 
score and FACT-An
Screening through 
Week 24
Safety
Type, frequency, severity of AEs and 
relationship of AEs to
luspatercept/epoetin alfa
Screening through 
42 days post last dose; 
Randomization through 
Week 48
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
41
Table 2:
Study Endpoints
Endpoint
Name
Description
Timeframe
Secondary 
(continued)
PK parameters
Serum luspatercept concentrations and 
PK parameters
Randomization through 
1 year post first dose
Antidrug antibodies (ADA) 
Frequency of antidrug antibodies 
Randomization through 
1 year post first dose
Progression to AML 
Number and percentage of subjects 
progressing to AML; time to AML 
progression 
Randomization through 
5 years from first dose 
or 3 years from last 
dose (whichever occurs 
later)
Overall survival
Time from date of randomization to 
death due to any cause
Randomization through 
5 years from first dose 
or 3 years from last 
dose (whichever occurs 
later) 
Exploratory
Molecular and cellular 
markers in the bone marrow 
and/or in peripheral blood 
Evaluation of biomarkers that may 
potentially impact luspatercept 
efficacy, predict response or relapse, 
help to better understand MOA and/or 
provide further prognostic 
classification of MDS subtypes.
Molecular markers (eg, SF3B1) 
include evaluation of MDS-associated 
gene mutations and their impact on 
drug efficacy, clinical response or 
relapse, drug MOA and 
prognostication of MDS. 
Baseline through End 
of Treatment
Healthcare resource 
utilization
Evaluation of healthcare resource use 
(eg, hospitalization) associated with 
investigational product (IP) during 
study
Screening through 
Week 24
Health-related quality-of-
life (HRQoL)
Description of QUALMS-P and 
Treatment Satisfaction
Screening through 
Week 24
Exposure-response 
relationship.
Exposure-response relationship for 
selected endpoints of efficacy and 
safety.
Randomization through 
1 year post first dose
SARS-CoV-2 serology
Exploratory measurements of SARS-
CoV-2 serology (anti-SARS-CoV-2 
IgG or total antibody), from serum 
samples collected at baseline, D169, 
D337 and EOT, and impact on safety 
profile of luspatercept.
Screening through 
42 days post last dose 
Abbreviations: ADA = antidrug antibodies; AE = adverse event; AML = acute myeloid leukemia; D = Day; EORTC QLQ-C30 = 
European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire; EOT = end of treatment; FACT-An 
= Functional Assessment of Cancer Therapy – Anemia; HI-E = hematologic improvement – erythroid response; IgG = 
immunoglobulin G; IWG = International Working Group; MDS = myelodysplastic syndromes; MOA = mechanism of action; 
PK = Pharmacokinetics; QUALMS-P = Quality of Life in Myelodysplasia Scale - Physical Burden; RBC = red blood cell; RBC-
TI =  red blood cell transfusion independence; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
42
3
OVERALL STUDY DESIGN
3.1
Study Design
The study will be conducted in compliance with the International Council for Harmonisation (ICH) 
of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good Clinical 
Practice (GCP) and applicable regulatory requirements.
This is an interventional active-controlled, open-label, randomized Phase 3 study to compare the 
efficacy and safety of luspatercept (ACE-536) versus epoetin alfa for the treatment of anemia due 
to IPSS-R very low, low or intermediate risk MDS in ESA naïve subjects who require RBC 
transfusions.
The study is divided into the Screening Period, a Treatment Period and a Post-treatment Follow-
up Period. 
See Figure 2 for more details and refer to Section 6 for a 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 35 days 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, peripheral blood smear and cytogenetics will be
used to confirm MDS diagnosis according to the WHO 2016 classification (APPENDIX B) and to 
determine the baseline IPSS-R riskclassification (Greenberg, 2012).  A bone marrow biopsy will 
be collected only when adequate aspirate is not attainable.
Transfusion history must be available for at least 16 weeks immediately preceding and including 
the date of randomization. Refer to Table 3 for a full list of study procedures/assessments.  
The sponsor may review key eligibility criteria as well as relevant data (eg, central laboratory 
reports and cytomorphology/cytogenetic reports) and communicate as necessary with the 
investigator prior to randomization of a subject.
Randomization 
Approximately 350 eligible subjects will be randomized by a central randomization procedure 
using integrated response technology (IRT) at a 1:1 ratio to one of the below treatment arms:
•
Experimental Arm: luspatercept (ACE-536): starting dose of 1.0 mg/kg subcutaneous
injection every 3 weeks (21 days; Q3W). Dose levels can be increased in a stepwise
manner beyond the starting dose to 1.33 mg/kg, and up to a maximum of 1.75 mg/kg.
See Section 7.2.1 for details.
•
Control Arm: epoetin alfa (EPREX®/ERYPO® or PROCRIT®): starting dose of 450
IU/kg (maximum total starting dose is 40,000 IU) subcutaneous injection once every
week (7 days; QW).  Dose levels can be increased in a stepwise manner beyond the
starting dose to 787.5 IU/kg, and up to a maximum of 1,050 IU/kg (with a maximum
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
43
total dose of 80,000 IU).  Individual epoetin alfa doses according to body weight will 
be rounded as described in Section 7.2.2 in more detail.
Randomization will be stratified based on the following factors:
•
RBC transfusion burden at baseline 
−
< 4 pRBC units/ 8 weeks 
−
≥ 4 pRBC units/ 8 weeks
•
Ring sideroblast (RS) status at baseline (with RS+ defined as Ring sideroblast ≥ 15% 
of erythroid precursors in bone marrow or ≥5% (but < 15%) if SF3B1 mutation is 
present).  
−
RS+
−
RS-
•
Endogenous Serum Erythropoietin (sEPO) level at baseline.
−
≤ 200 U/L
−
> 200 U/L
Crossover between treatment arms is not permitted during the Study Treatment Period.
Treatment Period
The first dose of investigational product (IP) should be administered on the same day after
randomization, but at the latest within 3 days of randomization.  More details will be provided in 
the IRT manual for additional information on randomization utilizing IRT.
Subjects on the luspatercept arm will receive IP every 3 weeks (21 days) (ie, at the Week 1 Day 1 
(W1D1) Visit, W4D1 Visit; W7D1 Visit, etc.).
Subjects on the epoetin alfa arm will receive IP every week (7 days) (ie, at the W1D1 Visit, W2D1 
Visit; W3D1 Visit, etc.).
Details on IP administration and intra-individual dose titration are outlined in Section 7.
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 outside 
of the study treatment.  Please refer to Section 8 for more details on permitted and prohibited 
concomitant medications and procedures.
Subjects should receive IP through to a minimum of the 24-Week MDS Disease Assessment Visit 
scheduled for Day 169, unless the subject experiences unacceptable toxicities, withdrawsconsent, 
or meets any other treatment discontinuation criteria.
The MDS Disease Assessment (Section 6.4.2) performed on Day 169 (and every 24 weeks 
thereafter [ie, Day 337, Day 505, etc.]); Section 6.4.2) consists of the investigator’s assessment of 
clinical benefit from IP and status of underlying disease.  For subjects to remain on treatment 
beyond this timepoint both of the following criteria must be confirmed:
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
44
•
Evidence of clinical benefit defined as a transfusion reduction of ≥ 2 pRBC 
units/8 weeks compared to the baseline (for any consecutive 8-week period within the 
12 weeks immediately preceding Day 169 and every 24 weeks thereafter [ie, Day 337, 
Day 505, etc.]).
•
Absence of disease progression per IWG criteria for altering natural history of 
MDS (Cheson, 2006) based on central morphological assessment of bone marrow, 
peripheral blood and cytogenetics results.
Based on the outcome of these assessments, subjects will either be discontinued from treatment 
with IP and enter the Post-treatment Follow-up Period or continue open-label treatment with their 
assigned IP as long as the above criteria continue to be met or until the subject experiences 
unacceptable toxicities, withdraws consent, or meets any other discontinuation criteria.
For subjects to continue open-label treatment with IP, scheduled MDS disease assessments will be 
repeated at the 48-Week MDS Disease Assessment Visit (ie. Day 337) and every 24 weeks 
thereafter (see Section 6.4.2 for details) to confirm continued clinical benefit and absence of
disease progression as per above criteria.
Serial measurements of safety and efficacy will occur at scheduled study visits as outlined in 
Table 3.  Laboratory analyses will be performed centrally.  Local laboratories are allowed in cases 
when timely results are needed (eg, pre-dose Hgb assessments, 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.  Where discrepancies 
are present, results of the central laboratory will be used to determine response assessments.
An End of Treatment (EOT) Visit 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 (Section 6.2.2). 
Post-treatment Follow-up Period
The Post-treatment Follow-up Period consist of the 42-Day Safety Follow-up (Section 6.3.1), 
which includes (but is not limited to) the collection of adverse events (AEs), concomitant drugs 
and RBC-transfusion data, and the Long-term Follow-up (Section 6.3.2). 
The transfusion data collection will continue until 8 weeks from the date of last dose of IP or from 
the date of the EOT Visit (whichever is later).
In addition, continuation of monitoring for other malignancies/pre-malignances and progression 
to AML will occur in the Long-term Post-treatment Follow-up Period along with data collection 
of subsequent MDS therapies, and overall survival for 5 years from the date of the first dose of IP,
or 3 years from the last dose (whichever occurs later), unless the subject withdraws consent from 
the study, dies or is lost to follow-up.  For that purpose, visits (which may consist of telephone 
contacts from the site) will be conducted every 12 weeks for the first 3 years from the date of last 
dose of IP and every 6 months thereafter, if applicable.
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
45
An antidrug antibodies (ADA) sample(s) may be required in the Post-treatment Follow-up Period 
for subjects assigned to the luspatercept arm, who terminate the Treatment Period with less than 
1-year of ADA monitoring if a subject is ADA positive at the time of treatment discontinuation.
Data Monitoring Committee (DMC)/Steering Committee (SC)
An external, independent DMC comprised of experts in MDS not involved in the ACE-536-MDS-
002 study as well as a SC comprised of study investigators and sponsor representatives will be 
established.  For details on composition and roles please refer to Section 9.10.4 and Section 9.10.5,
respectively.
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
46
Figure 2:
Overall Study Design
Abbreviations:  AE = adverse event; EOT = End of Treatment; IP = investigational product; MDS = Myelodysplastic syndromes; 
QW = once every week; Q3W = every 3 weeks; SC = subcutaneous.
1
Individual epoetin alfa doses according to body weight will be rounded: up to the next 2,000 IU dose level for Starting Dose 
Level and Dose Level -1, and up to the next 4,000 IU for Dose Level +1 and Dose Level +2 for doses exceeding a calculated 
dosing of 56,000 IU according to body weight.
2
Crossover between the treatment arms is not permitted during the Study Treatment Period.
Randomization 1:1
N=350
Study Discontinuation
Screening
Eligibility Check
Luspatercept2
(ACE-536)
1.0 mg/kg SC Q3W
titration up to max 1.75 mg/kg
Epoetin alfa2
450 IU/kg1 SC QW 
(max. total dose 40K IU)
titration up to 1050 IU/kg1
(max. total dose 80K IU)
Post-treatment Follow-up
42 Day Follow-up: AE Reporting until 42 days post last dose of IP
Collection of Transfusion data: for at least 8 weeks after last dose of IP or until EOT
(whichever is later)
Long Term Follow-up: Monitoring for other malignancies/pre-malignancies, progression to AML, 
subsequent MDS therapies and survival for 5 years from the date of the first dose of IP, or 3 years from 
the last dose (whichever occurs later), unless the subject withdraws consent from the study, dies or is 
lost to follow-up
Continuation of
Treatment
MDS Disease Status Assessment 
every 24 weeks
End of Treatment (EOT)
Continue treatment unless discontinued early for evidence 
of progression, death, unacceptable toxicity, 
subject/physician decision, or withdrawal of consent.
MDS Disease Status Assessment
24-Week MDS Disease Assessment Visit (Day 169, ie, 168 days after first dose of IP)
Treatment Period
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
47
3.2
Study Duration for Subjects
The duration of participation for subjects who complete the study will be approximately six years 
(and may be shorter or longer for individual subjects) consisting of the following phases: 
•
Screening Period: up to 35 days prior to randomization
•
Treatment Period: at least up to the 24-Week MDS Disease Assessment (ie, Day 169)
unless the subject experiences unacceptable toxicities, withdraws consent, or meets any
other treatment discontinuation criteria (eg, absence of clinical benefit, or disease
progression per IWG criteria for altering natural history of MDS (Cheson, 2006).
•
Post-treatment Follow-up Period:  5 years from the date of the first dose of IP, or 3 years
from the last dose (whichever occurs later), unless the subject withdraws consent from
the study, dies or is lost to follow-up.  Long-term Follow-up visits may be conducted
as telephone contacts from the site.
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 and/or exploratory analysis, as prespecified in the protocol, 
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 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.
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
48
4
STUDY POPULATION
4.1
Number of Subjects 
Approximately 350 subjects with anemia due to IPSS-R very low, low, or intermediate risk MDS 
who are ESA naïve with endogenous sEPO levels of < 500 U/L and who require RBC transfusions 
(ie, 2 to 6 pRBC units in the 8 weeks before randomization) will be randomized worldwide.
4.2
Inclusion Criteria
Subjects must satisfy the following criteria to be randomized 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) Subject is willing and able to adhere to the study visit schedule and other protocol
requirements.
4) Subject has a documented diagnosis of MDS according to WHO 2016 classification
(Section 6.1.1, APPENDIX B) that meets IPSS-R classification (Greenberg, 2012) of very
low, low, or intermediate risk disease, and:
•
< 5% blasts in bone marrow.
5) Subject has an endogenous serum erythropoietin (sEPO) level of < 500 U/L.
6) Subject requires RBC transfusions, as documented by
the following criteria
(Section 6.1.2):
•
A transfusion requirement of 2 to 6 pRBCs units/8 weeks confirmed for a minimum of
8 weeks immediately preceding randomization.
−
Hemoglobin levels at the time of or within 7 days prior to administration of a RBC
transfusion must have been ≤ 9.0 g/dL (5.6 mmol/L) with symptoms of anemia (or
≤7 g/dL [4.3 mmol/L] in the absence of symptoms) in order for the transfusion to
be counted towards meeting eligibility criteria.  Red blood cell transfusions
administered when Hgb levels were > 9.0 g/dL (or > 7 g/dL in the absence of
symptoms) and/or RBC transfusions administered for elective surgery, infections
or bleeding events will not qualify as a required transfusion for the purpose of
meeting eligibility criteria or stratification.
−
The hemoglobin level after the last RBC transfusion prior to randomization must
be < 11.0 g/dL (6.8 mmol/L) (centrally or locally analyzed).
7) Subject has Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2.
8) Females of childbearing potential (FCBP), defined as a sexually mature woman who:
1) has achieved menarche at some point, 2) not undergone a hysterectomy or bilateral
oophorectomy or 3) has not been naturallypostmenopausal (amenorrhea following cancer
therapy or amenorrhea due to other medical reasons 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 W1D1).
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
49
Refer to Section 6.1.14 for additional details.  She must agree to ongoing pregnancy 
testing during the course of the study, and after end of study treatment.
•
Either commit to true abstinence1 from heterosexual contact (which must be reviewed
on a monthly basis and source documented) or agree to use, and be able to comply with,
highly effective contraception 2 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.
9) Male subjects must:
•
Practice true abstinence1(which must be reviewed prior to each IP administration or on
a monthly basis [eg, in the event of dose delays]) or agree to use a condom (latex or
non-latex, but not made out of natural [animal] membrane) 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.
4.3
Exclusion Criteria
The presence of any of the following will exclude a subject from randomization (with the 
randomization date defined as the date in which the subject is randomized in IRT):
1) Subject with the any of the following prior treatments:
•
Erythropoiesis-stimulating agents (ESAs)
−
Subjects may be randomized at the investigator’s discretion contingent on the fact
that the subject received no more than 2 doses of epoetin alfa (prior treatment with
darbepoetin not acceptable for entry into the study). The last dose of epoetin alfa
must be ≥ 8 weeks from the date of randomization.  A blood sample to determine
the endogenous sEPO level (central laboratory) for stratification must be taken
within 5 days of randomization unless a prior screening sample analyzed by the
central laboratory demonstrated an endogenous sEPO level ≤ 500 U/L.
• Granulocyte
colony-stimulating factor (G-CSF), granulocyte-macrophage colony-
stimulating factor (GM-CSF), within 8 weeks prior to randomization, unless given for
treatment of febrile neutropenia
• Disease modifying agents (eg, immune-modulatory drug [IMiDs such as lenalidomide]
−
Except if the subject received ≤ 1 week of treatment with a disease modifying agent
≥ 8 weeks from randomization, at the investigator’s discretion.
• Hypomethylating agents
−
Subjects may be randomized at the investigator’s discretion contingent that the
subject received no more than 2 doses of HMA.  The last dose must be ≥ 8 weeks
from the date of randomization.
1 True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. [Periodic 
abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception].
2 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 successful vasectomy.
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
50
•
Luspatercept (ACE-536) or sotatercept (ACE-011)
•
Immunosuppressive therapy for MDS
•
Hematopoietic cell transplant
2) Subject with MDS associated with del(5q) cytogenetic abnormality or MDS unclassifiable 
(MDS-U) according to WHO 2016 classification.
3) Subject with myelodysplastic/myeloproliferative neoplasms (MDS/MPN) according to 
WHO 2016 classification (ie, Chronic myelomonocytic leukemia (CMML), Atypical 
chronic myeloid leukemia (aCML), BCR-ABL12, Juvenile myelomonocytic leukemia 
(JMML), MDS/MPN unclassifiable.
4) Subject with secondary MDS, ie, MDS that is known to have arisen as the result of 
chemical injury or treatment with chemotherapy and/or radiation for other diseases.
5) Subject with known clinically significant anemia due to iron, vitamin B12, or folate 
deficiencies, or autoimmune or hereditary hemolytic anemia, or hypothyroidism, or any 
type of known clinically significant bleeding or sequestration.  Subject with drug induced 
anemia (eg, mycophenolate).
•
Iron deficiency to be determined by serum ferritin < 100 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) Subject with known history of diagnosis of AML.
7) Subject receiving any of the following treatment within 8 weeks prior to randomization:
•
Anticancer cytotoxic chemotherapeutic agent or treatment 
•
Systemic 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)
•
Androgens, unless to treat hypogonadism
•
Hydroxyurea
•
Oral retinoids (except for topical retinoids)
•
Arsenic trioxide
•
Interferon and interleukins
•
Investigational drug or device, or approved therapy for investigational use (if 5 times 
the half-life of the previous investigational drug exceeds 8 weeks, then the time of 
exclusion should be extended up to 5 times the half-life of the investigational drug)
8) Subject with uncontrolled hypertension, defined as repeated elevations of systolic blood 
pressure (SBP) of ≥ 150 mmHg and/or diastolic blood pressure (DBP) ≥ 100 mmHg despite 
adequate treatment.  
9) Subject with any of the following laboratory abnormalities:
•
Absolute neutrophil count (ANC) < 500/μL (0.5 x 109/L)
•
Platelet count < 50,000/μL (50 x 109/L) 
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
51
•
Estimated glomerular filtration rate (eGFR) < 40 mL/min/1.73 m2 (APPENDIX F)
•
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)
•
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. 
10) Subject with prior history of malignancies, other than MDS, unless the subject has been 
free of the disease 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)
11) Subject with major surgery within 8 weeks prior to randomization.  Subjects must have 
completely recovered from any previous surgery prior to randomization.
12) Subject with history of cerebrovascular accident (including ischemic, embolic, and 
hemorrhagic cerebrovascular accident), transient ischemic attack, deep venous thrombosis 
(DVT; including proximal and distal), pulmonary or arterial embolism, arterial thrombosis 
or 
other 
venous 
thrombosis 
within 
6 
months 
prior 
to 
randomization
Note: prior superficial thrombophlebitis is not an exclusion criterion.
13) New-onset seizures or poorly controlled seizures within 12 weeks prior to randomization.
14) Subject with the following cardiac conditions within 6 months prior to randomization: 
myocardial infarction, uncontrolled angina, acute decompensated cardiac failure or New 
York Heart Association (NYHA) Class III-IV heart failure, or uncontrolled cardiac 
arrhythmia as determined by the investigator.  Subjects with a known ejection fraction 
˂ 35%, confirmed by a local echocardiogram (ECHO) or multi-gated acquisition (MUGA) 
scan performed within 6 months prior to randomization.
15) Subject with 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).
16) Subject with known human immunodeficiency virus (HIV), known evidence of active 
infectious Hepatitis B, and/or known evidence of active Hepatitis C.  Local laboratory
testing confirming HIV, Hepatitis B, and Hepatitis C status should not have been performed 
beyond 4 weeks prior to the date of ICF signature.
17) Subject with history of severe allergic or anaphylactic reactions or hypersensitivity to 
recombinant proteins or excipients in luspatercept (see Investigator’s Brochure).
18) Subject with known hypersensitivity to the active substance or to any of the excipients in 
epoetin alfa.
19) Subject with history of pure red cell aplasia (PRCA) and/or antibody against erythropoietin.
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
52
20) Female subject who is pregnant or breastfeeding.
21) 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.
22) 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.
23) Subject has any condition or receives concomitant medication that confounds the ability to 
interpret data from the study.
24) Subject has history of active SARS-CoV-2 infection within 4 weeks prior to screening, 
unless the subject has adequately recovered from COVID symptoms and related 
complications as per investigator’s discretion and following a discussion with the Medical 
Monitor.  Use of a live COVID-19 vaccine is prohibited within 4 weeks prior to 
randomization.
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
53
5
TABLE OF EVENTS
Table 3:
Table of Events
Screening
Treatment Period (open-label)
Post-treatment Follow-up
Efficacy Assessment
Independent of any 
dose delays
Section
Day -35
to 
Random
-ization
W1D1
Visitc
W2D1
Visit
W3D1
Visit
Add. 
Visits
EPO
W5/6D1
W8/9D1
etc.
3-wkly
Visits
W4D1
W7D1
W10D1
etc.
24-Wk
MDS 
Assess-
ment
Visit
D169
Every
24 wks
D337
D505
etc.
EOT
Visita
42-Day
Follow-
up
Long 
Term 
Follow-
up
End of 
Study
Section
6.4
6.4
6.2.2/11.1
6.3.1
6.3.2
11.2
Time window
±2 days
±2 days
±2 days
±2 days
±14 daysb
±14 daysb
+3 days
±7 days
Note: Weekly visits as displayed above represent visits as they are scheduled if dosing occurs without any dose delays.  In the event of dose delays (eg, due to adverse events) 
the next dosing visit (weekly for epoetin alfa and every three weeks for luspatercept) and associated assessments should be delayed accordingly.  Assessments to monitor the 
condition of the subject should be recorded as unscheduled visits.  Please note that efficacy assessments (MDS Disease assessments) always occur at the designated days after 
randomization as indicated above.  Dose delays do not affect the timing of these assessments.
Informed Consent
6.1
X
−
−
−
−
−
−
−
−
−
−
−
Inclusion/
Exclusion 
Evaluation
6.1
X
−
−
−
−
−
−
−
−
−
−
−
Physical 
Examination
6.1.5
X
−
−
−
−
−
X
X
X
−
−
−
Demographics
6.1.3
X
−
−
−
−
−
−
−
−
−
−
−
Medical History
6.1.4
X
−
−
−
−
−
−
−
−
−
−
−
HIV and Hep B/C 
Status
6.1.4.1
X
−
−
−
−
−
−
−
−
−
−
−
Prior RBC and 
Platelet 
Transfusions
6.1.2
X
−
−
−
−
−
−
−
−
−
−
−
Randomizationc
6.1/9.4
X
−
−
−
−
−
−
−
−
−
−
−
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
54
Table 3:
Table of Events
Screening
Treatment Period (open-label)
Post-treatment Follow-up
Efficacy Assessment
Independent of any 
dose delays
Section
Day -35
to 
Random
-ization
W1D1
Visitc
W2D1
Visit
W3D1
Visit
Add. 
Visits
EPO
W5/6D1
W8/9D1
etc.
3-wkly
Visits
W4D1
W7D1
W10D1
etc.
24-Wk
MDS 
Assess-
ment
Visit
D169
Every
24 wks
D337
D505
etc.
EOT
Visita
42-Day 
Follow-
up
Long 
Term 
Follow-
up
End of 
Study
Section
6.4
6.4
6.2.2/11.1
6.3.1
6.3.2
11.2
Time window
±2 days
±2 days
±2 days
±2 days
±14 daysb
±14 daysb
+3 days
±7 days
INVESTIGATIONAL PRODUCT (IP)
IP Administration 
and Accountability 
Luspatercept
7
−
X
−
−
−
X
−
−
−
−
−
−
IP Administration 
and Accountability 
Epoetin alfah
7
−
X
X
X
Xd
X
−
−
−
−
−
−
SAFETY ASSESSMENTS
ECOG 
Performance Status
6.1.7
X
X
−
−
−
X
X
X
X
−
−
−
Urinalysis
6.1.13
X
X
−
−
−
Every
12 weeks
ie,
W13D1
W25D1
etc.
−
−
−
−
−
−
ECG (12-lead)
6.1.8
X
−
−
−
−
−
−
−
−
−
−
−
Pregnancy Test 
and Counselingi
6.1.14
X
X
−
−
−
X
−
−
X
X
Xk
−
Adverse events
6.1.18
10
Continuous, after signing informed consent until 42 days after last IP administration
−
−
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
55
Table 3:
Table of Events
Screening
Treatment Period (open-label)
Post-treatment Follow-up
Efficacy Assessment
Independent of any 
dose delays
Section
Day -35
to 
Random
-ization
W1D1
Visitc
W2D1
Visit
W3D1
Visit
Add. 
Visits
EPO
W5/6D1
W8/9D1
etc.
3-wkly
Visits
W4D1
W7D1
W10D1
etc.
24-Wk
MDS 
Assess-
ment
Visit
D169
Every
24 wks
D337
D505
etc.
EOT
Visita
42-Day 
Follow-
up
Long 
Term 
Follow-
up
End of 
Study
Section
6.4
6.4
6.2.2/11.1
6.3.1
6.3.2
11.2
Time window
±2 days
±2 days
±2 days
±2 days
±14 daysb
±14 daysb
+3 days
±7 days
Prior and 
Concomitant 
medications/ 
procedures
6.1.17
8
Continuous, 8 weeks prior to randomization until 42 days after last IP administration or until the EOT visit, whichever 
occurs later
−
−
Vital Signs (Height 
to be measured 
only at screening)
6.1.6
X
X
X
X
Xd
blood 
pressure 
only
X
X
X
X
−
−
−
Serum Chemistry
6.1.10
X
X
−
−
−
X
X
X
X
−
−
−
EFFICACY ASSESSMENTS
Hematology
6.1.9
X
X
X
X
Xd
local Hgb 
only
X
X
X
X
−
−
−
Serum EPO
6.1.11
X
−
−
−
−
Every 
6 weeks,
ie,
W7D1
W13D1
etc.
X
X
X
−
−
−
Serum Ferritin and 
other iron-related 
markers
6.1.12
X
X
−
−
−
X
X
X
X
−
−
−
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
56
Table 3:
Table of Events
Screening
Treatment Period (open-label)
Post-treatment Follow-up
Efficacy Assessment
Independent of any 
dose delays
Section
Day -35
to 
Random
-ization
W1D1
Visitc
W2D1
Visit
W3D1
Visit
Add. 
Visits
EPO
W5/6D1
W8/9D1
etc.
3-wkly
Visits
W4D1
W7D1
W10D1
etc.
24-Wk
MDS 
Assess-
ment
Visit
D169
Every
24 wks
D337
D505
etc.
EOT
Visita
42-Day 
Follow-
up
Long 
Term 
Follow-
up
End of 
Study
Section
6.4
6.4
6.2.2/11.1
6.3.1
6.3.2
11.2
Time window
±2 days
±2 days
±2 days
±2 days
±14 daysb
±14 daysb
+3 days
±7 days
Transfusion Data 
Collection and 
Assessment
6.1.2
6.4.1
Assess and record on ongoing basis (prior to each dose of IP) until 8 weeks after last dose of IP or the EOT Visit, whichever occurs 
later.  Clinical site staff must confirm (and document in the subject’s source record) if any transfusions were received by the subject 
(including any transfusions received at institutions outside of the study site in between study visits) prior to each IP administration.
In addition to local procedures in place at the site to capture this information, a patient transfusion diary will be provided to subjects 
and will be reviewed by the site when/if returned by the patient. 
−
MDS Disease 
Assessment
6.4.2
−
−
−
−
−
−
X
X
−
−
−
BMA and PB for 
Cytomorphology 
and Cytogenetic 
testing (including 
RS status)e
6.1.1
X
−
−
−
−
−
X
X
X
−
−
−
EXPLORATORY/BIOMARKER ASSESSMENTS 
PB for 
Exploratory
Biomarkers 
(eg, TGF-ß 
superfamily, 
MDS-associated 
molecular 
mutations and 
other markers of 
drug MOA)
6.1.1
6.7
X
−
−
X
−
W10D1
W34D1
only
X
X
X
−
−
−
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
57
Table 3:
Table of Events
Screening
Treatment Period (open-label)
Post-treatment Follow-up
Efficacy Assessment
Independent of any 
dose delays
Section
Day -35
to 
Random
-ization
W1D1
Visitc
W2D1
Visit
W3D1
Visit
Add. 
Visits
EPO
W5/6D1
W8/9D1
etc.
3-wkly
Visits
W4D1
W7D1
W10D1
etc.
24-Wk
MDS 
Assess-
ment
Visit
D169
Every
24 wks
D337
D505
etc.
EOT
Visita
42-Day 
Follow-
up
Long 
Term 
Follow-
up
End of 
Study
Section
6.4
6.4
6.2.2/11.1
6.3.1
6.3.2
11.2
Time window
±2 days
±2 days
±2 days
±2 days
±14 daysb
±14 daysb
+3 days
±7 days
BMA for 
Exploratory 
Biomarkers 
(eg, soluble 
biomarkers, 
MDS-associated 
molecular 
mutations, 
erythroid 
differentiation 
and other markers 
of drug MOA)f
6.1.1
6.7
X
−
−
−
−
−
X
X
X
−
−
−
SARS-CoV-2
serology
6.7
X
−
−
−
−
−
X
D337 only
X
−
−
−
PK/ADA ASSESSMENTS
PK Sample 
Collection
(Luspatercept 
arm only)
Should be 
collected prior to 
IP dosing on a 
dosing day
6.5
−
X
X
X
−
W4D1
W10D1
W16D1
W22D1
only
X
And every 12 weeks (± 14 days) from the 24-
Week MDS Assessment visit for up to one 
year from the first dose.  Once a subject has 
been discontinued from treatment, PK 
samples may no longer be collected as long 
as ADA are not detectable.
−
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
58
Table 3:
Table of Events
Screening
Treatment Period (open-label)
Post-treatment Follow-up
Efficacy Assessment
Independent of any 
dose delays
Section
Day -35
to 
Random
-ization
W1D1
Visitc
W2D1
Visit
W3D1
Visit
Add. 
Visits
EPO
W5/6D1
W8/9D1
etc.
3-wkly
Visits
W4D1
W7D1
W10D1
etc.
24-Wk
MDS 
Assess-
ment
Visit
D169
Every
24 wks
D337
D505
etc.
EOT
Visita
42-Day 
Follow-
up
Long 
Term 
Follow-
up
End of 
Study
Section
6.4
6.4
6.2.2/11.1
6.3.1
6.3.2
11.2
Time window
±2 days
±2 days
±2 days
±2 days
±14 daysb
±14 daysb
+3 days
±7 days
ADA Sample 
Collection
(Luspatercept 
arm only)
Should be 
collected prior to 
IP dosing on a 
dosing day
6.6
−
X
−
−
−
W4D1
W10D1
W16D1
W22D1
only
X
And every 12 weeks (±14 days) from the 24-
Week MDS Assessment visit for up to one 
year from the first dose.  If the subject was 
discontinued from study treatment earlier 
than one year from the first dose, additional 
samples will be collected if last ADA is 
positive. 
−
QUALITY-OF-LIFE
EORTC QLQ-
C30g
6.8
X
X
−
−
−
X
6-wkly 
only
W7D1
W13D1
etc.
X
X
D337
only
X
−
−
−
FACT-Ang
6.8
X
X
X
X
−
X
X
X
D337
only
X
−
−
−
QUALMS-Pg
6.8
X
−
−
−
−
−
X
−
−
−
−
−
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
59
Table 3:
Table of Events
Screening
Treatment Period (open-label)
Post-treatment Follow-up
Efficacy Assessment
Independent of any 
dose delays
Section
Day -35
to 
Random
-ization
W1D1
Visitc
W2D1
Visit
W3D1
Visit
Add. 
Visits
EPO
W5/6D1
W8/9D1
etc.
3-wkly
Visits
W4D1
W7D1
W10D1
etc.
24-Wk
MDS 
Assess-
ment
Visit
D169
Every
24 wks
D337
D505
etc.
EOT
Visita
42-Day 
Follow-
up
Long 
Term 
Follow-
up
End of 
Study
Section
6.4
6.4
6.2.2/11.1
6.3.1
6.3.2
11.2
Time window
±2 days
±2 days
±2 days
±2 days
±14 daysb
±14 daysb
+3 days
±7 days
Patient Treatment 
Satisfaction 
Surveyg
6.8
X
X
−
−
−
6-wkly 
only
W7D1
W13D1
etc.
X
X
D337
only
X
−
−
−
Healthcare 
Resource 
Utilization
6.9
After signing ICF and until 42 days after the last IP dose or End of Treatment Visit, whichever period is longer
−
−
FOLLOW-UP
Monitoring for 
progression to 
AML and other 
malignancies/pre-
malignancies
6.1.19
6.3.2
10.5
After signing ICF and until 5 years from the first dose of IP, or 3 years from the last dose (whichever occurs later), or until death, lost to 
follow-up, withdrawal of consent for further data collection
Post-treatment 
MDS therapies
6.3.2
−
−
−
−
−
−
−
−
−
X
X
X
Survival Follow-
up
6.3.2
−
−
−
−
−
−
−
−
−
X
X
X
Abbreviations: ADA = antidrug antibodies; AML = acute myeloid leukemia; BMA = bone marrow aspirate; BMB = bone marrow biopsy; D = Day; ECG = electrocardiogram;
ECOG = Eastern Cooperative Oncology Group; EORTC QLQ-C30 = European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire; EOT = End of 
Treatment; EPO = erythropoietin; FACT-An = Functional Assessment of Cancer Therapy – Anemia; FCBP = female of childbearing potential; Hep = hepatitis; Hgb = hemoglobin; 
HIV = human immunodeficiency virus; ICF = informed consent form; IP = investigational product; IRT = integrated response technology; MDS = myelodysplastic syndromes; 
MOA = mechanism of action; PB = peripheral blood; PK = pharmacokinetics; QUALMS-P = Quality of Life in Myelodysplasia Scale - Physical Burden; RBC = red blood cell;
SARS-CoV-2 = Severe acute respiratory syndrome coronavirus 2; TGF-β = transforming growth factor-beta; W/wk = week; wkly = weekly.
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
60
a
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.
b
As central laboratory results from bone marrow and peripheral blood samples (ie, cytomorphology, cytogenetic analysis) are required as part of the MDS Disease Assessment, a 
14-day window is allowed for the 24-Week MDS Disease Assessment Visit (ie, Day 169 ±14 days) in order to account for sample collection and turnaround time of results.  Please 
see Section 6.4.2 for details. 
c
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.
d
On days where subject dosing occurs at home (if in line with local practice) and not at the site: blood pressure measurement and Hgb value collection are not applicable 
(Section 7.2.2).
e
Collection of a BMB is only required when adequate aspirate is not attainable.  To allow for cytomorphology assessment and cytogenetic analysis of the BMB please follow 
guidance for processing the sample provided in the study’s Central Laboratory Manual.
f
Remaining BMA (after quantity sufficient is allocated towards cytomorphology and cytogenetics analysis) will be used for exploratory biomarker studies.  An additional bone 
marrow procedure should not be performed for these samples.  Refer to the central laboratory manual for additional information related to sample collection.
g
Questionnaires should be completed by the subject prior to IP administration.
h
In the event epoetin alfa will be home-administered, compliance will be monitored using a medication diary card or other local procedures in place at the investigational site. 
i
In the event of dose delays, counseling about pregnancy precautions and the potential risks of fetal exposure must be conducted monthly.
k
An additional pregnancy test is to be performed 12 weeks (±7 days) from the date of last dose of IP for FCBP.
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
61
6
PROCEDURES
Questions regarding the protocol should be directed to the Celgene Medical Monitor or designee.
All of the protocol required assessments are listed in Table 3, 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.
Refer to the electronic case report form (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’s
Central Laboratory Manual.
6.1
Screening Period
Upon giving written informed consent, subjects enter the Screening Period to determine eligibility.  
Screening evaluations will be performed for all subjects to determine study eligibility. These 
evaluations must be completed within 35 days of randomization unless noted otherwise below. 
All eligibility criteria must be met in order for subjects to be randomized in the study. Waivers to 
the protocol will not be granted during the conduct of this trial.  Subjects who do not meet the 
eligibility criteria will be considered screening failures and will not be eligible for randomization.  
Subjects who fail screening may undergo rescreening.
Safety laboratory analyses and all laboratory assessments will be performed centrally unless noted 
otherwise. Screening laboratory values must demonstrate subject eligibility, but may be repeated 
within the screening window, if necessary.
The following assessments will be performed during screening as specified in the Table of Events
(Table 3), after informed consent has been obtained.
The sponsor may review key eligibility criteria as well as relevant data (eg, central laboratory 
reports and cytomorphology/cytogenetic reports) and communicate as necessary with the 
investigator prior to randomization of a subject.
6.1.1
Bone Marrow and Peripheral Blood Samples
Diagnosis of MDS, WHO classification (APPENDIX B), and IPSS risk classification 
(APPENDIX C) will be prospectively determined by independent central pathology and 
cytogenetics review, and applicable central laboratory results.  The screening bone marrow 
aspirate sample together with peripheral blood should be collected within the protocol screening 
window prior to randomization.  Samples should be collected, if possible, no later than 14 days 
prior to the planned randomization in order to allow sufficient time for central review and a repeat 
bone marrow assessment, if necessary.
The collection of a bone marrow biopsy is only required when an adequate aspirate is not 
attainable.  To allow for cytomorphology assessment and cytogenetic analysis of the bone marrow 
biopsy please follow the guidance for processing the sample provided in the study’s Central 
Laboratory Manual.
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
62
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 and were done within 8 weeks before ICF signature.
•
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 
classification (APPENDIX B) 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, which will be 
considered the final assessment. Only slides of the most recent BM sample should be 
used for adjudication.  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.
Every attempt should be made to send bone marrow and peripheral blood samples to the central 
laboratory for processing andanalysis prior to the first dose of investigational product. In the event 
that cytomorphology/cytogenetic analysis is technical failing at the central laboratory prior to 
randomization, local cytomorphology/cytogenetic analysis may suffice for randomization
purposes after consultation with the sponsor. This will require a central “over read” of the local 
cytomorphology/cytogenetics report, slides and/or photographs by the central laboratory prior to 
randomization.
Additionally, in the event a local BM assessment for MDS diagnosis was made no more than 
8 weeks before ICF signature, local BM samples/reports may be allowed for central “over read”
after consultation with the sponsor and provided the central lab can confirm the diagnosis using 
the local samples/reports.  The sponsor must be consulted prior to randomizing a subject using 
cytogenetic results from a local laboratory.
Results from central laboratory analysis should be used to determine the baseline IPSS-R 
category (Greenberg, 2012) (APPENDIX C).  In the event historical local BM samples/reports are 
being used for “over read”, local lab results obtained from the same date the BM was taken should 
be used to determine the baseline IPSS-R category, if possible.
The central laboratory will also assess bone marrow and peripheral blood samples during the 
Treatment Period of the study. During the course of the study, whenever a bone marrow sample 
is collected, a peripheral blood smear is to be prepared.  In the event analysis of the samples sent 
to the central lab is technical failing, local cytomorphology/cytogenetics report, slides and/or
photographs may be used for “over read” by the central lab. 
Bone marrow aspirate and/or blood collected at prespecified study time points will also be used 
for central laboratory exploratory/biomarker analysis (eg, MDS-associated molecular mutations 
[eg, SF3B1, etc.] and soluble biomarkers.
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
63
Sample collection, processing, storage, and shipment procedures will be provided in the study’s 
Central Laboratory Manual.
6.1.2
Prior Transfusion History
Transfusion history must be available for at least 16 weeks immediately preceding and including 
the date of randomization.
Red blood cell transfusion data during the 8 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) (including any transfusions received at institutions outside of the study 
site).
In the event a subject requires RBC transfusions during Screening, the Screening Hematology 
sample should be taken prior to the administration of the RBC transfusion or ≥ 7 days after the 
RBC transfusion to minimize risk of confounding the baseline IPSS-R score.  For details on the 
required information to be collected and reported in the eCRF for transfusions please refer to 
Section 6.4.1.
6.1.3
Demographics
The subject’s date of birth, sex, race, and ethnicity will be recorded on the appropriate eCRF as
allowed by local regulations. 
6.1.4
Medical History
All relevant medical conditions (including recent surgical history) diagnosed/ occurring prior to 
screening should be included and recorded in the 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.
6.1.4.1
Assessment of HIV/Hepatitis B/Hepatitis C status
If known, local testing confirming HIV, Hepatitis B, and Hepatitis C status should not have been 
performed beyond 4 weeks prior to the date of ICF signature.  If beyond this window or if 
information is not available in the medical history, additional local testing is required.
6.1.5
Physical Examination
Information about the physical examination must be present in the subject’ssource documentation.  
Significant findings must be reported as AE on the respective eCRF.
Refer to Table 3 for timing of physical examinations during the study.
6.1.6
Vital Signs, Height, and Weight
Vital signs including height (measured at screening only), weight, seated blood pressure 
(documented as mean of 2 readings obtained approximately 10 minutes apart with the subject 
seated for approximately 10 minutes prior to initial reading), temperature, and heart rate (HR) are 
to be reported in the subject’s source record and appropriate eCRF.
Subjects must have blood pressure and weight assessed prior to IP administration on days where 
dosing occurs at the site (for subjects on the epoetin alfa arm, weight will be assessed at every third 
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
64
dosing visit only).  For more details and exceptions please refer to Section 7.2.1.1 and 
Section 7.2.2.1 for luspatercept and epoetin alfa treatment, respectively.
Refer to Table 3 for timing of vital signs during the study.
6.1.7
Eastern Cooperative Oncology Group Performance Status
Performance status will be assessed by the investigator during Screening and at other timepoints
indicated on Table 3 using ECOG criteria provided in APPENDIX E.
6.1.8
Electrocardiogram
A 12-lead ECG is performed locally at the study site.  The following ECG parameters will be 
recorded on the respective eCRF(s): eg, HR, PR interval, QRS duration, QT. The investigator will 
review the results and assess as normal, abnormal - not clinically significant, or abnormal -
clinicallysignificant, and report the abnormal finding(s) on the appropriate eCRF.  If the ECG is 
abnormal, the investigator should consult a cardiologist if deemed appropriate.
Refer to Table 3 for timing of ECGs during the study.
6.1.9
Hematology
Hematology assessment (ie, RBC count, complete blood count [CBC], WBC with differential 
[including myeloblasts], hemoglobin, hematocrit, nucleated red blood cells [nRBC], reticulocytes, 
platelet count, mean corpuscular volume [MCV], mean corpuscular hemoglobin [MCH], mean 
corpuscular hemoglobin concentration [MCHC], and red blood cell distribution width [RDW]) 
will be performed by the central laboratory.  Sample collection, processing, storage, and shipment 
procedures are provided in the study’s Central Laboratory Manual.
Local laboratories are allowed in cases when timely results are needed (eg, pre-dose Hgb 
assessments, 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.  Where discrepancies are present, results of the central laboratory
will be used to determine response assessments (Section 6.4).
Please note that for subjects on the epoetin alfa arm, on visit days in-between 3-weekly visits (ie, 
W5D1, W6D1, W8D1, W9D1, W11D1, W12D1, etc.) only local pre-dosing Hgb values are 
required (when dosing occurs at the site; in the event of home dosing no Hgb assessment is 
performed).
In the event a subject requires RBC transfusions during Screening, the Screening Hematology 
sample should be taken prior to the administration of the RBC transfusion or ≥ 7 days after the 
RBC transfusion to minimize risk of confounding the baseline IPSS-R score. For details regarding 
assessment of Hgb levels prior to IP dosing to ensure dose modification rules are followed please 
refer to Section 7.2.1 and Section 7.2.2 for luspatercept and epoetin alfa, respectively.
Refer to Table 3 for timing of hematologyassessments during the study.
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
65
6.1.10
Serum Chemistry
Serum chemistry (ie, sodium, potassium, calcium, phosphorus, creatinine, creatinine clearance 
and/or eGFR, glucose, albumin, alkaline phosphatase, total bilirubin, direct/indirect bilirubin, 
AST/SGOT or ALT/SGPT, lactate dehydrogenase [LDH]) will be analyzed by the central 
laboratory.  Sample collection, processing, storage, and shipment procedures are provided in the 
study’s Central Laboratory Manual.
Local laboratories are allowed in cases when timely results are needed (eg, adverse events).  In 
these circumstances, a split sample should still be collected and sent to the central laboratory for 
analysis.
Refer to Table 3 for timing of serum chemistry assessments during the study.
6.1.11
Serum EPO Level
Serum EPO samples will be analyzed by the central laboratory.  Serum EPO collected during the 
Screening Period 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 serumlevel related 
to the hemoglobin level achieved after the last transfusion.  Sample collection, processing, storage, 
and shipment procedures are provided in the study’s Central Laboratory Manual.
Refer to Table 3 for timing of serum EPO level testing duringthe study.
6.1.12
Serum Ferritin and Other Iron-Related Markers
Analysis of serum ferritin and other iron-related markers (ie, total serum iron, iron saturation, total 
iron binding capacity, unsaturated iron binding capacity) will be performed/provided by the central 
laboratory.  Sample collection, processing, storage, and shipment procedures are provided in the 
study’s Central Laboratory Manual.
Refer to Table 3 for timing of serum ferritin testing during the study.
6.1.13
Urinalysis
Urinalysis will be conducted by the central laboratory and includes macroscopic, microscopic and 
quantitative analysis of urine (ie, albumin, protein, creatinine, albumin/creatinine ratio).
Sample collection, processing, storage, and shipment procedures are provided in the study’s 
Central Laboratory Manual.
Refer to Table 3 for timing of urinalysis sample collection during the study.
6.1.14
Pregnancy Testing and Counseling
For the definition of females of childbearing potential (FCBP) please refer to Section 4.2
(Inclusion criterion 8)).  The investigator will appraise a female subject of their FCBP status 
according to this definition.  Justification for the designation must be recorded in the eCRF and the 
source document.
A medically supervised serum pregnancy test (ie, a serum beta human chorionic gonadotropin 
[β-hCG] test with a minimum sensitivity of 25 mIU/mL [conducted at the central laboratory or 
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
66
locally]) is to be obtained and verified negative for a FCBP at screening.  Pregnancy testing is not 
required for non-FCBP subjects.
Additional urine (or serum) pregnancy testing, to confirm negative results and to assess subject 
eligibility, will be performed within 72 hours prior to the administration of the first dose of IP, 
unless the screening serum pregnancy test was already performed and verified negative during this 
time frame.
During the Treatment Period and in the Post-treatment Follow-up Period urine or serum pregnancy 
testing 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 Table 3 and Section 6.3.2 for timing of pregnancy testing and counseling during thestudy.
6.1.15
Sample Collection for Exploratory Biomarker Assessments
Refer to Section 6.7 for more information. 
6.1.16
Subject Reported Quality-of-life and Healthcare Resource Utilization
Refer to Section 6.8 and Section 6.9 for more information. 
6.1.17
Concomitant Medications and Procedures
Information on prior and concomitant medications and procedures are to be reported on the 
appropriate eCRF starting 8 weeks prior to randomization.  Any prior anticancer treatments should 
be recorded on the appropriate eCRF(s).
Refer to Section 8 for more information on permitted and prohibited medication.
6.1.18
Adverse Event Evaluation
Ongoing evaluation and reporting of adverse events begins when the subject signs the informed 
consent form and must be documented on the appropriate eCRF.
Refer to Section 10 for more information.
6.1.19
Monitoring for Progression to AML and Other Malignancies/Pre-
malignancies
Progression to AML as per WHO classification (Arber, 2016) 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 5 years after the first dose 
of IP, or 3 years from the last dose (whichever occurs later), or until death, lost to follow-up or 
withdrawal of consent from the study.  For that purpose, subjects will be followed post treatment 
every 12 weeks for 3 years from the date of last dose of IP and every 6 months thereafter, if 
applicable.
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 AEs throughout the course of the study 
(please refer to Section 10.5 for details).  Investigators are to report the development of any new 
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
67
malignancy or pre-malignant lesion as a serious adverse event (SAE), regardless of causal 
relationship to IP (luspatercept or epoetin alfa), occurring at any time for the duration of the study, 
from the time of signing the ICF for up to and including long-term follow-up (ie, 5 years from first 
dose of IP, or 3 years from last dose [whichever occurs later]), 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.
6.1.20
Information to be Collected on Screening 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 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.
6.2
Treatment Period
The subject must receive the first dose of investigational product (IP) within 3 days of 
randomization at the latest and can be on the same day as randomization.  For all subsequent visits, 
an administrative time window of ± 2 days is permitted if not indicated otherwise.  If screening 
assessments are performed within 72 hours of Week 1 Day 1 (W1D1), safety laboratory and 
physical examinations need not be repeated at W1D1.
Subjects on the luspatercept arm will receive IP every 3 weeks (21 days) (ie, at the W1D1 Visit, 
W4D1 Visit; W7D1 Visit, etc.). Subjects on the epoetin alfa arm will receive IP every week 
(7 days) (ie, at the W1D1 Visit, W2D1 Visit; W3D1 Visit, etc.).  For details regarding IP 
administration including dose adjustments and dose modifications please refer to Section 7.
The following evaluations will be performed at the frequency specified in the Table of Events 
(Table 3). The evaluations should be performed prior to dosing on the visit day, unless otherwise 
specified. 
•
Physical examination (as detailed in Section 6.1.5)
•
Administration and accountability of IP (as detailed in Section 7)
•
ECOG performance status (as detailed in Section 6.1.7)
•
Urinalysis (as detailed in Section 6.1.13)
•
Pregnancy testing and counseling (as detailed in Section 6.1.14)
•
Adverse event assessment and reporting on an ongoing basis (as detailed in Section 10)
•
Concomitant medications and procedures on an ongoing basis (refer to Section 8 for
more information on permitted and prohibited medications)
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
68
•
Vital signs and weight (as detailed in Section 6.1.6)
•
Serum chemistry (as detailed in Section 6.1.10)
•
Hematology assessments (as detailed in Section 6.1.9)
•
Serum EPO level (as detailed in Section 6.1.11)
•
Serum ferritin level (as detailed in Section 6.1.12)
•
Transfusion data collection and assessment (as detailed in Section 6.4.1)
•
Bone marrow aspirate and peripheral blood collection for cytomorphology and
cytogenetic testing (as detailed in Section 6.1.1)
•
MDS Disease assessment (as detailed in Section 6.4.2)
•
Exploratory Biomarker sample collection (as detailed in Section 6.7)
•
Pharmacokinetic (PK) and ADA sample collection (as detailed in Section 6.5 and
Section 6.6, respectively.
•
Subject reported quality-of-life and healthcare resource utilization (see Section 6.8 and
Section 6.9 for more details)
•
Monitoring for progression to AML and other malignancies/pre-malignancies (as
detailed in Section 6.1.19)
6.2.1
Unscheduled Visits
Should it become necessary to repeat an evaluation (eg, laboratory tests or vital signs), the results 
of the repeated 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.
6.2.2
End of Treatment
An 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 of Events (Table 3).
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 as per investigator’s discretion (with the exception of blood pressure 
assessment and sample collection for hematology, chemistry, and urinalysis). A bone marrow 
assessment procedure should only be performed at EOT if a prior bone marrow assessment has 
been performed > 90 days apart.
End of Treatment Visit procedures/ assessments may occur at the 42-Day Follow-up assessment 
if a subject is discontinued within ± 7 days of the 42-Day Follow-up assessment.
The reason for treatment discontinuation will be recorded in the subject’s eCRF and source 
document for all randomized subjects, regardless of whether they have been dosed or not. Reasons 
for treatment discontinuation are provided in Section 11.1. 
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Celgene Corporation
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Final: 31 Mar 2022
69
6.3
Post-treatment Follow-up Period
6.3.1
Safety Follow-up (42-Day Follow-up)
All subjects will be followed for 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, as 
described in Section 10.1.
Refer to Table 3 for additional assessments to be performed at the 42-Day Follow-up.  An 
administrative time window of +3 days is permitted.
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 10.4 for additional details.
6.3.2
Long-term Follow-up
Transfusion data collection will continue until 8 weeks from the date of last dose of IP or from the 
date of the EOT Visit (whichever is later) (Section 6.4.1).  Subjects should also be followed via 
telephone contact by the site to verify if transfusions were given outside of the investigative site.
Antidrug antibodies sample(s) may be required in the Post-treatment Follow-up Period for subjects 
assigned to the luspatercept arm, who terminate the Treatment Period with less than 1 year of ADA 
monitoring if a subject is ADA positive at the time of treatment discontinuation (Section 6.6).
An additional pregnancy test is to be performed 12 weeks (±7 days) from the date of last dose of 
IP for FCBP (Section 6.1.14).
All subjects discontinued from protocol-prescribed therapy for any reason should be followed for
the below events/therapies for 5 years after the first dose of IP, or 3 years from the last dose 
(whichever occurs later), or until death, lost to follow-up or withdrawal of consent from the study. 
•
Progression to AML and other malignancies/pre-malignancies (please refer to
Section 6.1.19 and Section 10.5 for details)
•
Survival (date and cause of death)
•
and subsequent MDS therapies
Subjects may be followed via telephone contact by the site for collection of the above data every 
12 weeks for the first 3 years from the date of last dose of IP and every 6 months thereafter (if 
applicable) until 5 years after the first dose of IP, or 3 years from the last dose (whichever occurs 
later), or until death, lost to follow-up or withdrawal of consent from the study. Refer to Table 3.
Data regarding subsequent MDS therapies, determination of AML progression and other 
malignancies/pre-malignancies, 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.
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.
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Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
70
6.4
Efficacy Assessment
Treatment response will be assessed locally by the investigator in accordance with IWG 2006 
criteria for MDS (Cheson, 2006) (APPENDIX D), through assessment of administered RBC 
transfusions, hematology parameters, peripheral blood smears, bone marrow aspirates and/or 
biopsies, and cytogenetics.  Central lab, cytomorphology and cytogenetics results will be used for 
response assessment. Please refer to Section 6.4.1 and Section 6.4.2 below for details.
Other efficacy assessments will include health-related quality-of-life, healthcare resource 
utilization.
The timing of efficacy assessments (MDS disease assessments, health-related quality-of-life, and 
healthcare resource utilization) as well as associated sampling and assessments (ie, bone marrow 
and peripheral blood samples, RBC transfusion assessment) are specified in the Table of Events 
(Table 3). Please refer to Section 6.1.1 for details on bone marrow aspirate samples for assessing 
treatment response.
6.4.1
Transfusion Assessment
The RBC transfusion data during the 8 weeks immediately preceding randomization will be used
to determine the baseline RBC transfusion requirement for an individual study subject.
During the Treatment Phase transfusions will be assessed and recorded in the eCRF on an ongoing 
basis (prior to each dose of IP) until 8 weeks after last dose of IP or the End of Treatment Visit, 
whichever occurs later.  Clinical site staff must confirm (and document in the subject’s source 
record) if any transfusions were received by the subject (including any transfusions received at 
institutions outside of the study site in between study visits) prior to each IP administration. In 
addition to local procedures in place at the site to capture this information, a patient transfusion 
diary will be provided to subjects and will be reviewed by the site when/if returned by the patient. 
Red blood cell transfusions administered for elective surgery, infections or bleeding events will 
not count toward baseline requirement, efficacy assessment, or progressive disease status but 
should still be recorded in the eCRF.
The following information will be collected for RBC transfusions (and platelet transfusions if 
applicable) and reported in the eCRF: 
•
Type, number of units, reason and date of transfusion
•
The Hgb value for which any RBC transfusion is given, and the platelet value for which
any platelet transfusion is given, (these Hgb and platelet values may be local or central
laboratory measurements)
Please find recommendations for adequate source documentation of transfusion history as well as 
transfusions given during the treatment phase below:
•
Signed original or copy of single transfusion record including number of units
administered and Hgb/platelet value prior to transfusion.
•
Signed record of multiple transfusions done at the same clinic.  For each transfusion,
the units and dates are specified along with Hgb/platelet value prior to each transfusion.
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Celgene Corporation
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Final: 31 Mar 2022
71
•
If electronic record: signed print-out of administration record(s), specifying unit(s) on 
specified date(s), plus signed additional documentation of Hgb/platelet values(s) prior 
to transfusion.
•
Signed referral letter(s) specifying date(s) and number(s) of units administered with 
Hgb/platelet value(s) prior to transfusion(s).
6.4.2
MDS Disease Assessment
The MDS Disease Assessment consists of the investigator’s assessment of clinical benefit from IP
and status of underlying disease.
The 24-Week MDS Disease Assessment Visit should be completed 24 calendar weeks (ie,
Day 169) after first dose of IP, regardless of dose delays.
As central laboratory results from bone marrow and peripheral blood samples (ie, cytomorphology, 
cytogenetic analysis) are required as part of the MDS Disease Assessment, a 14-day window is 
allowed for the 24-Week MDS Disease Assessment Visit (ie, Day 169 ± 14 days) in order to 
account for sample collection and turnaround time of results.
The MDS Disease Assessment by the investigator, associated with this visit to assess clinical 
benefit, should be completed no sooner than 24 calendar weeks (ie, 169 days) after first dose of IP
as it requires 24 weeks of transfusion information in addition to central laboratory results from 
bone marrow and peripheral blood samples (ie, cytomorphology, cytogenetic analysis).  Up to date 
information related to all transfusions received during the Treatment Period (including those 
received at institutions outside of the study site) must be available prior to completion of the 
clinical benefit component of the MDS Disease Assessment.
For subjects to remain on treatment beyond this timepoint both of the following criteria must be 
confirmed:
•
Evidence of clinical benefit defined as a transfusion reduction of ≥ 2 pRBC 
units/8 weeks compared to the baseline (for any consecutive 8-week period within the 
12 weeks immediately preceding Day 169 and every 24 weeks thereafter [ie, Day 337, 
Day 505, etc.]).
•
Absence of disease progression per IWG criteria for altering natural history of 
MDS (Cheson, 2006) based on central morphological assessment of bone marrow, 
peripheral blood and cytogenetics results.
Based on the outcome of these assessments, subjects will either be discontinued from treatment 
with IP and enter the Post-treatment Follow-up Period or continue open-label treatment with their 
assigned IP as long as above criteria continue to be met or until the subject experiences 
unacceptable toxicities, withdraws consent, or meets any other discontinuation criteria.
In circumstances where the next dose of IP is due to be scheduled prior to cytomorphology/
cytogenetics results being available, dosing should not be delayed for this reason contingent that 
the investigator has confirmed absence of signs of disease progression based on review of 
peripheral blood parameters.  However, the investigator must complete assessment of 
cytomorphology/cytogenetics results within 4 weeks of the MDS Disease Assessment Visit at the 
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Protocol ACE-536-MDS-002
Celgene Corporation
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Final: 31 Mar 2022
72
latest (ie, Day 169, Day 337, Day 505, etc. for the MDS disease assessments every 24 weeks 
thereafter) to continue dosing beyond these 4 weeks. 
For subjects to continue open-label treatment with IP, MDS disease assessments will be repeated 
at the 48-Week MDS Disease Assessment Visit and every 24 weeks thereafter (ie, Day 337, Day 
505 etc.; a ± 14-day time window to allowed for sample collection) to confirm continued clinical 
benefit and absence of disease progression as per above criteria.
6.5
Pharmacokinetics
Blood samples will be collected to analyze luspatercept concentrations in serum in subjects treated 
with luspatercept.  At each PK time point, approximately 3 mL of peripheral blood will be 
collected, and serum prepared as described in the in the study’s Central Laboratory Manual. Blood 
samples for PK will be taken at the following visits during the study (also see Table 3):
•
W1D1 (must be collected before the first dose), W2D1, W3D1, W4D1, W10D1,
W16D1, W22D1, 24-Week MDS Disease Assessment Visit, and every 12 weeks (± 14
days) from the 24-Week MDS Disease Assessment Visit
If a PK sample is drawn on a dosing day, the PK sample should be drawn prior to luspatercept 
dosing.  The maximum PK sampling period will not exceed one year from the first dose of 
luspatercept, unless justified by safety reasons. Pharmacokinetic sampling per investigator’s or 
sponsor’s discretion is allowed and should be recorded as an unscheduled visit.  Once a subject 
has been discontinued from treatment, PK samples may no longer be collected as long as ADA are
not detectable.
6.6
Antidrug Antibody (ADA)
Blood samples will be collected to assess ADAs against luspatercept in serum in subjects treated 
with luspatercept.  At each ADA sampling time point, approximately 3 mL of peripheral blood
will be collected, and serum prepared as described in the study’s Central Laboratory Manual.  
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 3):
•
W1D1 (must be collected before the first dose), W4D1, W10D1, W16D1, W22D1, 24-
Week MDS Disease Assessment Visit, and every 12 weeks (± 14 days) from the 24-
Week MDS Disease Assessment Visit
If an ADA sample is drawn on a dosing day, the ADA sample should be drawn prior to luspatercept 
dosing.  If the last available ADA result is positive at end of treatment, the subject may be asked 
to return to the clinical site for additional long-term follow up every 12 weeks (± 14 days) for up 
to one year after the first dose of luspatercept or until ADA are not detectable, whichever comes 
first.
The maximum ADA monitoring period will not exceed one year from the first luspatercept dose 
unless justified by safety reasons.  Antidrug antibodies sampling per investigator’s or sponsor’s 
discretion is allowed and should be recorded as an unscheduled visit.
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Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
73
6.7
Biomarkers, Pharmacodynamics, Pharmacogenomics
Bone marrow aspirate and/or blood samples for evaluation of exploratory biomarkers such as 
myeloid-associated molecular mutations and activin receptor IIB ligands and other exploratory 
biomarkers will be collected at specified timepoints as indicated in the Table of Events (Table 3).  
These measurements may include, but are not limited to, assessments of SARS-CoV-2 serologic 
status.  If required on study dosing days, samples should be taken prior to IP administration.
Bone marrow aspirate for evaluation of biomarkers will be collected at study time points when a 
bone marrow procedure is required for MDS disease assessment (eg, cytogenetics and 
cytomorphology analysis).  Please note that remaining bone marrow aspirate (after quantity 
sufficient is allocated towards cytomorphology and cytogenetics analysis) will be used for 
exploratory biomarker studies.  An additional bone marrow procedure should not be performed for 
these samples.  Refer to the study’s Central Laboratory Manual for additional information related 
to sample collection.
Activin Receptor IIB ligands and other exploratory biomarkers
Blood will be collected by the site and sent to central laboratories for analysis of soluble 
biomarkers.  Sample collection, storage and shipping procedures will be provided in the Central 
Laboratory Manual.  Refer to the Table of Events (Table 3) for timing of sample collection.
MDS-associated molecular mutations
Bone marrow aspirate will be collected by the site and sent to a central laboratory for analysis of 
molecular mutations such as SF3B1 and others.  If there is sufficient volume, an aliquot of bone 
marrow mononuclear cells will be stored frozen for future analysis, such as RNA expression 
profiling to allow us to develop a gene signature that predicts response.  Sample collection, storage 
and shipping procedures will be provided in the study’s Central Laboratory Manual.  Refer to the 
Table of Events (Table 3) for timing of sample collection.
Terminal erythropoiesis
Bone marrow aspirate will be collected by the site and sent to central laboratories for analysis of 
terminal erythroid differentiation by flow cytometry.  Sample collection, storage and shipping 
procedures will be provided in the Central Laboratory Manual.  Refer to the Table of Events
(Table 3) for timing of sample collection.
SARS-CoV-2 serology
Serum will be collected at baseline, D169, D337 and EOT for possible measurements of 
SARS-CoV-2 serology (anti-SARS-CoV-2 IgG or total antibody).
6.8
Patient Reported Outcomes
The European Organization for Research and Treatment of Cancer Quality-of-Life questionnaire 
(EORTC QLQ-C30) (Aaronson, 1993) (APPENDIX G) is a validated 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 
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Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
74
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.
The 
Functional 
Assessment 
of 
Cancer 
Therapy-Anemia 
Version 
4
(FACT-An) 
questionnaire (Yellen, 1997) (APPENDIX H) is a validated instrument specific in measuring 
HRQoL related anemia. The 47-item FACT-An scale measures cancer-related symptoms with 13 
items that measure fatigue (the FACIT-Fatigue subscale) and an additional 7 items that measure 
items pertinent to anemia. The 47-item FACT-An scale is formatted for self-administration on 
one page, and uses a 5-point Likert-type scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = 
Quite a bit; and 4 = Very Much). As each items of the FACT-An scale ranges from 0-4, and to 
obtain the score each negatively-worded item response is recoded so that 0 is consider worse 
quality of life and 4 is good response. The FACT-An is available in many languages and this 
instrument takes no more than 15 minutes to administer.
The Quality of Life in Myelodysplasia Scale (QUALMS) (Abel, 2016) is a novel QoL tool with a 
38-item assessment for patients with MDS (APPENDIX I). To score the QUALMS, each question 
(all have 5-point Likert-type answers) were assigned a value with a potential range of 0 (worst) to 
100 (best) as follows: Never = 100; Rarely = 75; Sometimes = 50; Often = 25 and Always = 0.
Four items were scored in the opposite direction such that Always = 100 and Never = 0. The 
QUALMS total score was calculated by averaging the scores, so the potential range of scores was 
0 (worst) to 100 (best). Higher scores mean better QoL. Recognizing the value of the QUALMS
and its limitation, QUALMS - Physical Burden (QUALMS-P), a 14-item subscale focused on 
physical factors (which had excellent internal consistency and performed well, distinguishing 
between clinical known groups), will be implemented on a limited basis as an exploratory 
endpoint. QUALMS-P will be measured at Screening and the 24-Week MDS Assessment Visit in 
countries where the tool has been linguistically and culturally validated.
The instrument is 
available in several languages and takes about 10 minutes to administer.
The Patient Treatment Satisfaction Survey (APPENDIX J) is designed to understand overall MDS 
treatment satisfaction. The survey composed of 3 questions that measure patients’ transfusion 
burden, treatment satisfaction and ease of administration. The survey will be analyzed by
descriptive statistics.
All eligible subjects will complete the EORTC QLQ-C30, FACT-An, QUALMS-P and the Patient 
Treatment Satisfaction Survey at the frequency noted in the Table of Events (Table 3).
Questionnaires should be completed by the subject prior to IP administration.
It is important that every subject completes all of the EORTC QLQ-C30, FACT-An, QUALMS-P
and Patient Treatment Satisfaction Survey assessments at every specified time point to minimize 
the amount of missing data.
6.9
Healthcare Resource Utilization
The economic objective of this study is to characterize certain aspects of medical resource 
utilization among subjects treated with luspatercept as compared to subjects receiving epoetin alfa 
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Protocol ACE-536-MDS-002
Celgene Corporation
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Final: 31 Mar 2022
75
treatment.  To facilitate this aim, certain medical resource utilization data will be collected. 
Information on hospitalizations will be collected utilizing a case report form designed for this 
purpose that collects information on reason for hospitalization (eg, disease progression, MDS-
related illness, treatment-related adverse event), and days of hospitalization by treatment setting 
(regular hospital ward versus intensive care unit).  Other disease- and treatment-related forms of 
healthcare utilization will be collected through routine study activities.  These may include RBC 
transfusions, emergency room visits, or significant diagnostic procedures.  Additionally, 
information on concomitant medications (eg, antibiotics, antiviral medications, iron chelation 
therapies) and resource use associated with treatment administration for MDS will be collected
(Table 3).
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Protocol ACE-536-MDS-002
Celgene Corporation
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Final: 31 Mar 2022
76
7
DESCRIPTION OF STUDY TREATMENTS
7.1
Description of Investigational Products
7.1.1
Luspatercept
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 25 mg and 
75 mg vials and when reconstituted with water for injection, each consists of 50 mg/mL 
luspatercept in a 
 mM citrate buffer-based solution (
 mM citrate, pH 
 sucrose, 
 
polysorbate 80).
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 24 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 24
hours.  Please refer to the pharmacy manual for more details.
Samples of luspatercept drug product, held at the recommended storage condition, have been 
shown to be stable through the labeled shelf-life.
7.1.2
Epoetin Alfa
Epoetin alfa (either EPREX®/ERYPO® [ex-US] or PROCRIT® [US]) will be centrally supplied or 
obtained according to local clinical study agreement and in accordance with local guidelines on a 
per country basis.  Please refer to local epoetin alfa prescribing information for more details on 
available formulations (pre-filled syringes or vials), preparation, storage conditions, the approved 
indications, known precautions, warnings, and adverse reactions of epoetin alfa (see current 
version of Prescribing Information).  The epoetin alfa dosing schedule and dose adjustments to be 
followed for this study are described in Section 7.2.2.
7.2
Treatment Administration and Schedule
7.2.1
Luspatercept Treatment
7.2.1.1
Luspatercept Administration and Schedule
Luspatercept will be administered as a subcutaneous injection every 3 weeks (21 days; Q3W), at 
an initial dose level of 1.0 mg/kg.  Doses may be titrated up starting at dosing visit W7D1 (ie, Dose 
3) as described in Section 7.2.1.2.
Luspatercept will be administered 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 (changes of body weight of ≤± 5% do not require a dose adjustment) 
prior to each IP administration.
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 
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Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
77
body (example left thigh and right thigh).  The maximum volume per subcutaneous injection 
should not exceed 1.2 mL.  
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.
The clinical site staff must also confirm (and document in the subject’s source record) if any 
transfusions were received by the subject (including any transfusions received at institutions 
outside of the study site in between study visits) prior to each IP administration.  In addition to 
local procedures in place at the site to capture this information, a patient transfusion diary will be 
provided to subjects and will be reviewed by the site when/if returned by the patient.
7.2.1.2
Luspatercept Dose Adjustment and Dose Modification
Appropriate dose adjustments should be made to maintain hemoglobin concentrations within the 
target range of 10 g/dL to 12 g/dL (6.2 mmol/L to 7.5 mmol/L) independent of transfusions.  
Starting as soon as with dosing visit W7D1 (ie, Dose 3) of luspatercept, and assessed by the 
investigator prior to every subsequent luspatercept dosing, 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 (Table 4), if all of the following criteria are met:
•
Subject Hgb levels are below the target range of 10 g/dL to 12 g/dL (6.2 mmol/L to 7.5 
mmol/L).  If the Hgb levels are within 10 g/dL to 12 g/dL (6.2 mmol/L to 7.5 mmol/L) 
due to the influence of transfusions, the dose may still be adjusted (please consider the 
other three criteria noted below).
•
Subject Hgb level increase compared to the Hgb sample taken prior to the previous 
luspatercept dose is ≤ 1 g/dL (0.6 mmol/L).  If the Hgb level increase is > 1 g/dL due 
to the influence of transfusions, the dose may still be adjusted.
•
The two most recent prior luspatercept administrations 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 luspatercept administrations (exception of dose delay required due to influence 
of RBC transfusions).  Refer to Table 5.
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 4).
Dose delay and/or reduction or discontinuation may be required due to increased hemoglobin or 
adverse events. For details on dose modification guidance for luspatercept please refer to Table 5.
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Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
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Table 4:
Luspatercept Starting Dose Level with Dose Reductions and Dose 
Titration
3rd Dose 
Reduction
2nd Dose 
Reduction
1st Dose 
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
Table 5:
Luspatercept Dose Modification: Dose Delay, Dose Reduction, and 
Discontinuation Guidelines
Event at the Day of Dosing
(Assessed prior to each IP administration at the 
respective visitk)
Action
Any suspected related AE ≥ Grade 3a,b
Dose delayc until resolved to ≤ Grade 1 or baseline, and 
then reduce dose by one dose level according to Table 4
> 2 dose reductions due to suspected related AEa
Discontinue treatment 
ΔHgb > 2.0 g/dL (1.2 mmol/L) (not influenced by 
RBC transfusionsd) compared to pre-dose Hgb of 
the previous luspatercept administration  
Reduce dose by one dose level according to Table 4
Predose Hgb ≥12.0 g/dL (7.5 mmol/L)
Dose delay until Hgb < 11.0 g/dL (6.8 mmol/L)d
≥ 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 complete blood count (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 normal
Discontinue treatment if: 
Disease progression per IWG response criteria for altering 
natural history of MDS (Cheson, 2006)
OR  WBC remain above upper limit of normale
1.0
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930183290
1.0
v
Approved
1.0
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Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
79
Table 5:
Luspatercept Dose Modification: Dose Delay, Dose Reduction, and 
Discontinuation Guidelines
Event at the Day of Dosing
(Assessed prior to each IP administration at the 
respective visitk)
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 
luspatercept administration.
-
If presence of ≥ 1% blasts in peripheral blood; 
discontinue treatmenth
Leukopenia, Neutropenia and/or 
Thrombocytopenia
A worsening by ≥ 2 gradesi leukopenia, 
neutropenia and/or thrombocytopenia to ≥Grade 3 
during treatment with luspatercept without any 
other likely cause (eg, infectious event, trauma,
etc.).
Worsening of Anemia
A ≥ 50% increase in transfusion burden from 
baseline in combination with an unexplained 
worsening from baseline of ≥2 gradesi leukopenia, 
neutropenia and/or thrombocytopenia.
Dose delayc and repeat WBC, neutrophils and platelet 
counts weekly for two consecutive weeks
•
If WBC, neutrophils and platelet counts improve to 
baseline or ≤Grade 1, resume treatment at the 
same/decreased dose.
•
If WBC, neutrophils and platelet counts do not 
improve as defined above, collect bone marrow and 
peripheral blood samples to assess MDS disease status.
-
If disease progression per IWG response criteria 
for altering natural history of MDS (Cheson, 
2006) is confirmed, discontinue treatment
-
If disease progression per IWG response criteria 
for altering natural history of MDS (Cheson, 
2006) is not confirmed, discuss future dosing 
with Medical Monitor
Abbreviations:  AE = adverse event; CBC = complete blood count; CTCAE = Common Terminology Criteria for 
Adverse Events; Hgb = hemoglobin; IP = investigational product; IWG = International Working Group; MDS = 
myelodysplastic syndromes; RBC = red blood cell; WBC = white blood cell count.
a Possibly, probably or definitely related to IP.
b Includes systolic blood pressure ≥160 mmHg and diastolic blood pressure ≥100 mmHg.
c If dose delay is > 12 consecutive weeks, treatment should be discontinued
d 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.
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.
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
80
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.
i
Thrombocytopenia, leukopenia, and neutropenia toxicity grades as defined by CTCAE criteria.
k Every attempt should be taken to assess the blasts count in peripheral blood prior to dosing, however, in 
circumstances where results are not readily available at the time of planned dosing, the investigator may proceed 
with dosing provided there are no signs of clinical progression. In this case, results must be evaluated as soon as 
they become available (but no later than 3 days post dosing).  If presence of ≥ 1% blasts in peripheral blood is 
observed, actions described in table above must be followed immediately.
7.2.2
Epoetin Alfa Treatment
7.2.2.1
Epoetin Alfa Administration and Schedule
Epoetin alfa (EPREX®/ERYPO® or PROCRIT®) will be administered as a subcutaneous injection 
once every week (7 days; QW) at a starting dose of 450 IU/kg (maximum total starting dose is 
40,000 IU).  Doses may be titrated up starting at dosing visit W7D1 (ie, Dose 7) as described in 
Section 7.2.2.2. Individual epoetin alfa doses according to body weight will be rounded: up to the 
next 2,000 IU dose level for Starting Dose Level and Dose Level -1; and up to the next 4,000 IU 
for Dose Level +1 and Dose Level +2 for doses exceeding a calculated dosing of 56,000 IU 
according to body weight (maximum total dose is 80,000 IU).
As epoetin alfa is dosed according to body weight, subject weight will be assessed at every third 
epoetin alfa dosing visit (ie, W1D1, W4D1, W7D1, etc.) and in the event of a dose delay at restart 
of treatment.  Changes of body weight of ≤ ± 5% do not require a dose adjustment.
Epoetin alfa will be administered as a subcutaneous injection by the site staff.  Starting with the 
W7D1 Visit, site visits for IP administration are only required every third dose (ie, W10D1, 
W13D1, W16D1, etc.) and self-administration or administration by a nursing service is permitted 
between dosing site visits at the discretion of the investigator (ie, W8D1 and W9D1; W11D1 and 
W12D1, etc.) if in line with local practice.  In the event dose adjustments of epoetin alfa are 
required, dosing should occur at the clinical site only until the dose adjustment process has been 
completed.
Administration of IP will be documented in the subject’s source record. Compliance of self-
administration of epoetin alfa will be monitored via the use of a medication diary card or other 
local procedures in place at the investigational site.
Subjects must have hemoglobin and blood pressure assessed prior to each IP administration when 
administered at the clinical site.
In addition, the clinical site staff must also confirm (and document in the subject’s source record) 
if any transfusions were received by the subject (including any transfusions received at institutions 
outside of the study site in between study visits) prior to each IP administration. In addition to 
local procedures in place at the site to capture this information, a patient transfusion diary will be 
provided to subjects and will be reviewed by the site when/if returned by the patient.
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
81
7.2.2.2
Epoetin Alfa Dose Adjustment and Modification
Appropriate dose adjustments should be made to maintain hemoglobin concentrations within the 
target range of 10 g/dL to 12 g/dL (6.2 mmol/L to 7.5 mmol/L) independent of transfusions.  
Starting as soon as the W7D1 dosing visit (ie, Dose 7) of epoetin alfa and assessed by the 
investigator, subjects may have the dose level increased in a stepwise manner beyond the starting 
dose of 450 IU/kg to 787.5 IU/kg and 1,050 IU/kg (total dose 80,000 IU).  Dose increases and 
decreases should be done one dosing level at a time Table 6).  A minimum of 4 weeks should 
elapse between dose increases.  
Dose delay and/or reduction or discontinuation may be required due to increased Hgb or adverse 
events. For details on dose modification guidance for epoetin alfa please refer to Table 7.
Table 6:
Epoetin Alfa Starting Dose Level with Dose Reductions and Dose 
Titration
Dose Level -1
Starting Dose Level
Dose Level +1
Dose Level +2
337.5 IU/kg
(maximum total dose 
40,000 IU)
450 IU/kg 
(maximum total dose 
40,000 IU)
787.5 IU/kg
(maximum total dose 
80,000 IU)
1,050 IU/kg
(maximum total dose 
80,000 IU)
Individual epoetin alfa doses according to body weight will be rounded: up to the next 2,000 IU dose level for Starting 
Dose Level and Dose Level -1; and up to the next 4,000 IU for Dose Level +1 and Dose Level +2 for doses exceeding 
a calculated dosing of 56,000 IU according to body weight.
Table 7:
Epoetin Alfa Dose Modification: Dose Delay, Dose Reduction, and 
Discontinuation Guidelines
Event at the Day of Dosing
(Assessed prior to each IP administration at the 
respective visitk)
Action
Any suspected related AE ≥ Grade 3a,b
Dose delayc until resolved to ≤ Grade 1 or baseline, and 
then reduce dose by one dose level according to Table 6.
> 2 dose reductions due to suspected related AEa
Discontinue treatment.
ΔHgb > 2.0 g/dL (1.2 mmol/L) over 4 weeks (not 
influenced by RBC transfusionsd) 
Consider dose decrease by one dose level according to 
Table 6.
Predose Hgb ≥ 12.0 g/dL (7.5 mmol/L)
Dose delay until Hgb < 11.0 g/dL (6.8 mmol/L)d.
Restart on same dose level or reduce by one dose level 
according to Table 6 (investigator judgement).
Loss of response or Hgb drop ≥ 1 g/dL (0.6 mmol/L) 
upon dose reduction 
Increase by one dose level according to Table 6.  
A minimum of 4 weeks should elapse between dose 
increases.
≥ 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)i
Dose delay; recheck complete blood count (CBC), 
including WBC, at least weekly during dose delay.
Treatment may be resumed if:
WBC values below upper limit of normale within 2 weeks
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
82
Table 7:
Epoetin Alfa Dose Modification: Dose Delay, Dose Reduction, and 
Discontinuation Guidelines
Event at the Day of Dosing
(Assessed prior to each IP administration at the 
respective visitk)
Action
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 normal
Discontinue treatment if: 
Disease progression per IWG response criteria for altering 
natural history of MDS (Cheson, 2006)
OR
WBC remain above upper limit of normale
Presence of ≥ 1% blasts in peripheral bloodi (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 
epoetin alfa administration.
-
If presence of ≥ 1% blasts in peripheral blood; 
discontinue treatmenth
Abbreviations:  AE = adverse event; CBC = complete blood count; Hgb = hemoglobin; IP = investigational product; 
IWG = International Working Group; MDS = myelodysplastic syndromes; RBC = red blood cell; WBC = white blood 
cell count.
a Possibly, probably or definitely related to IP.
b Includes systolic blood pressure ≥160 mmHg and diastolic blood pressure ≥100 mmHg.
c If dose delay is > 12 consecutive weeks, treatment should be discontinued.
d 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.
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.
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
83
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.
i Mandatory assessment only at 3-weekly visits (W4D1, W7D1, W10D1, etc.)
k Every attempt should be taken to assess the blasts count in peripheral blood prior to dosing, however, in 
circumstances where results are not readily available at the time of planned dosing, the investigator may proceed 
with dosing provided there are no signs of clinical progression. In this case, results must be evaluated as soon as 
they become available (but no later than 3 days post dosing).  If presence of ≥ 1% blasts in peripheral blood is 
observed, actions described in table above must be followed immediately.
7.2.3
Overdose
7.2.3.1
Luspatercept Overdose
On a per dose basis, an overdose for luspatercept 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 injection 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.
7.2.3.2
Epoetin Alfa Overdose
On a per dose basis, an overdose for epoetin alfa is defined as the following amount over the 
protocol-specified dose (applying the rounding rules as specified in Section 7.2.2.1) of epoetin alfa
assigned to a given subject, regardless of any associated adverse events or sequelae.
Subcutaneous injection 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.
7.3
Method of Treatment Assignment
The treatment assignment (randomization) will occur at the end of the Screening Period, once all 
required screening procedures have been completed and all inclusion and exclusion criteria have 
been assessed to determine eligibility of the subject.  Subjects deemed eligible for the study will 
be randomized bya central randomization procedure using IRT.
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 randomize 
subjects.
For drug assignment at dosing visits and in the event of any dose reduction or dose titration site 
staff must contact IRT to record the new dose level and obtain the new IP assignment.
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
84
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 as open-label 
study, stratified randomization with randomization ratio active versus comparator on a 1:1. 
Subjects will be placed into the appropriate stratum per the responses/data entered/collected for 
questions collecting stratification factors 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. The randomization number 
corresponds to a particular treatment arm within a stratum.
7.4
Packaging and Labeling
Where centrally supplied, the label(s) for IP will include sponsor name, address and telephone 
number, the protocol number, IP name, dosage form and strength (where applicable), amount of 
IP per container, lot number, expiry date (where applicable), medication identification/kit number, 
dosing instructions, storage conditions, and required caution statements and/or regulatory 
statements as applicable. Additional information may be included on the label as applicable per 
local regulations.
7.5
Investigational Product Accountability and Disposal 
7.5.1
Accountability Procedures
Accountability for IP 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 IP received, to whom it was administered 
(subject-by-subject accounting), and accounts of any IP 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.  
For luspatercept and epoetin alfa vials (PROCRIT® [US]), unless otherwise notified, all vials, both 
used and unused, should be saved for drug accountability purposes.  The used vials may be 
discarded, per the institution’s standard operating procedures, after drug accountability has been 
completed by the monitor.  For epoetin alfa prefilled syringes (EPREX®/ERYPO® [ex-US]), only 
unused IP must be saved for drug accountability purposes as used syringes must be discarded in 
sharp containers, unless otherwise notified.
7.5.2
Drug Disposal and Destruction
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).
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
85
7.6
Investigational Product Compliance
Luspatercept will be administered as a subcutaneous injection at the clinical site by the study staff.  
Monitoring for subject compliance with the treatment regimen on the luspatercept arm is therefore 
unnecessary.
Epoetin alfa may also be self-administered by the subject at certain timepoints if certain 
requirements are met as further detailed Section 7.2.2.1. Compliance of self-administration of 
epoetin alfa will be monitored via the use of a medication diary card or other local procedures in 
place at the investigational site.
The investigator or designee is responsible for accounting for all IP (luspatercept and epoetin alfa) 
that is administered during the course of the study.
Accurate recording of all IP administration will be made in the appropriate section of the subject’s 
eCRF and source documents.
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
86
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 may be administered at the discretion of the investigator.
All prior/ concomitant medications, used 8 weeks prior to randomization until 42 days after the 
last dose of IP, must be reported on the eCRF.  All prior procedures within the 8 weeks prior to 
randomization as well as concomitant procedures will be recorded on the appropriate eCRF. All 
transfusions will be reported on the eCRF for at least 16 weeks prior to randomization until 
8 weeks after last dose of IP or the EOT Visit, whichever occurs later.
Prior anticancer treatments should be recorded on the appropriate eCRF(s) regardless of treatment 
discontinuation/procedure date.
Prior iron chelation therapy should be recorded on the appropriate eCRF(s) regardless of treatment 
discontinuation 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 EOT visit 
and enter the Post-treatment 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 Investigator’s Brochure and/or local package insert.
8.1
Permitted Concomitant Medications and Procedures
8.1.1
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, shortness of breath, 
fatigue etc.) or comorbidity.
For any RBC transfusions received during the study, hemoglobin values just prior to transfusion 
will be collected.  Please refer to Section 6.4.1 for details on required data collection.
Each subject will have a “pre-transfusion hemoglobin threshold” for requiring a 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 8 weeks prior to the first dose of IP.  During treatment, if the pre-transfusion hemoglobin 
level is increased by ≥ 1 g/dL (0.6 mmol/L) (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.  Subjects may be transfused at the investigator’s discretion for 
symptoms related to anemia or other requirements (eg, infection).
8.1.2
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.  
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
87
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.
8.1.3
Corticosteroids
Concurrent systemic corticosteroids used for medical conditions other than MDS is allowed 
provided the subject is on a stable or decreasing dose for ≥ 1 week prior to randomization. Use of 
topical steroids is permitted.  Occasional use of corticosteroids before transfusions to prevent 
allergic reactions is permitted.  
8.1.4
Attenuated Vaccines
Administration of attenuated vaccines (eg, influenza vaccine) is allowed if clinically indicated, per 
investigator discretion with the exception of a live COVID-19 vaccine.  
Administration of a live COVID-19 vaccine is prohibited within 4 weeks prior to randomization. 
Live COVID-19 vaccines should not be used during the study, including the treatment period and 
until 42 days following the last dose of IP.  
8.1.5
Phlebotomy
Phlebotomy may be performed for emergency/urgency if excessively high Hgb levels occur.
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:
•
Erythropoietin stimulating agents (ESAs) other than assigned IP and other RBC
hematopoietic growth factors (eg, Interleukin-3)
•
Granulocyte colony stimulating factors (ie, G-CSF, GM-CSF), except in cases of
neutropenic fever.
•
Cytotoxic, chemotherapeutic, targeted or investigational agents/therapies
•
Azacitidine, decitabine or other hypomethylating agents
•
Lenalidomide, thalidomide and other immunomodulating drugs (IMiDs)
•
Hydroxyurea
•
Androgens, unless to treat hypogonadism
•
Oral retinoids (topical retinoids are permitted)
•
Arsenic trioxide
•
Interferon and interleukins
8.3
Required Concomitant Medications and Procedures
Not applicable.
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
88
9
STATISTICAL CONSIDERATIONS
9.1
Overview
This is a Phase 3, multicenter, randomized, open-label, active-controlled study.  The primary 
objective of the study is to evaluate efficacy in the two treatment arms, luspatercept compared with 
epoetin alfa, for the treatment of anemia due to IPSS-R very low, low, or intermediate risk MDS 
in ESA naïve subjects who require RBC transfusions.
The final analysis will be performed when all randomized subjects have completed 24 weeks of 
treatment or discontinued before 24 weeks. 
Additional follow-up analysis for efficacy and safety will be performed when all subjects have 
been followed for 5 years from the date of the first dose of IP, or 3 years from last dose (whichever 
occurs later) during the Post-treatment Follow-up Period of the study. 
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 follows:
Intent-to-treat (ITT): The 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.
HRQoL evaluable population:  The HRQoL evaluable population will consist of all subjects in 
the ITT population who completed the respective patient reported outcomes (PRO) assessment3 at 
baseline and at least one post-baseline assessment visit.
PK population: The PK population will consist of all subjects who received at least one dose of 
luspatercept and had measurable luspatercept serum concentrations.
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 approximately 350 subjects (175 in the experimental arm [luspatercept 
(ACE-536)], 175 in the control arm [epoetin alfa]) will have 90% power to detect the difference 
between a RBC-TI (for 12 weeks associated with a concurrent hemoglobin increase) response rate 
of 36% in the experimental arm (luspatercept [ACE-536]) and a response rate of 20% in the control 
arm (epoetin alfa), with the first interim analysis on futility only when about 105 subjects have 
completed 24 weeks of treatment, or discontinued before reaching 24 weeks of treatment (30% 
information for primary endpoint).  The Lan-DeMets (O’Brien-Fleming) spending function will 
3 Instrument-dependent.
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
89
be used as the futility boundary. The sample size calculation is based on one-sided alpha of 0.025, 
test statistics on odds ratio of proportions using the EAST® Version 6.4 software system.
A second interim analysis to test the superiority of the luspatercept arm does not alter the above 
sample size calculation. The study power remains at 90% for the final analysis with 350 subjects 
and the Lan-DeMets spending function of the O’Brien-Fleming type will be used to control the 
overall one-sided Type I error rate at 0.025.
9.4
Randomization and Stratification
Subjects will be randomized to receive luspatercept or epoetin alfa at a 1:1 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, RS status, and endogenous serum erythropoietin (sEPO) level 
at baseline:
•
RBC transfusion burden at baseline
−
< 4 pRBC units/8 weeks 
−
≥ 4 pRBC units/8 weeks
•
Ring sideroblast (RS) status at baseline (with RS+ defined as ring sideroblasts ≥15% 
of erythroid precursors in bone marrow or ≥5% (but < 15%) if SF3B1 mutation is 
present).  
−
RS+
−
RS-
•
Endogenous Serum Erythropoietin (sEPO) level at baseline.  
−
≤ 200 U/L
−
> 200 U/L
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 treatment arm.  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.
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
90
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 the ITT population. The primary efficacy endpoint of RBC transfusion independence for 
12 weeks with an associated concurrent mean increase of ≥ 1.5 g/dL Hgb increase, is defined as 
the absence of any RBC transfusion for any 12-week period from Week 1 to the end of Week 24 
associated with a concurrent mean increase of hemoglobin of at least ≥1.5 g/dL compared to 
baseline.
For the primary efficacy endpoint, 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 epoetin alfa arm 
will be calculated. In the primary efficacy analysis, the statistical hypothesis is
ܪ଴∶Pଵ൑Pଶ
ܪ௔∶ܲଵ൐ܲଶ
where
1
P denotes the true response rate in the luspatercept group, and 
2
P denotes the true response 
rate in the epoetin alfa group.  The number and percentage of subjects in the ITT population 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 two response rates with randomization 
factors as strata. The one-sided significance level at the final analysis will be 0.021 with one 
planned interim analysis for superiority.
Additional details will be outlined in the SAP.
9.7.2
Secondary Efficacy Analyses
The secondary efficacy endpoints will be analyzed and reported at the time of the analysis of the 
primary efficacy endpoints.
Secondary endpoints 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.  Count, percentages, and 95% confidence interval will be used to describe 
categorical secondary variables.
Gate-keeping method will be used to control the overall Type I error rate for the following 
secondary endpoints in the order of:
•
HI-E response (Week 1 to 24)
•
RBC-TI for 24 weeks (Week 1 to 24)
•
RBC-TI ≥ 12 weeks (Week 1 to 24)
After the result from the primary efficacy endpoint shows statistical significance, RBC-TI for 
24 weeks in Week 1 to 24 will be tested for significance at the one-sided significance level of 
0.021 only if both primary endpoint and HI-E response in Week 1 to 24 are significant. RBC-TI ≥ 
12 weeks in Week 1 to 24 will be tested for significance at the one-sided significance level of 
1.0
Approved
930183290
1.0
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Approved
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Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
91
0.021 only if the results for primary endpoint, HI-E in Week 1 to 24, and RBC-TI for 24 weeks in 
Week 1 to 24 are all significant. The testing procedure above will be implemented strictly in order 
to control the overall one-sided Type I error rate of 0.025 due to multiplicity.
Other secondary endpoints will be analyzed without employing methods for controlling the type 
one error rate. Any statistically significant treatment effect on these secondary endpoints cannot 
be interpreted as confirmatory, but rather informatory.
RBC transfusion independence (RBC-TI) for 24 weeks is defined as the absence of any RBC 
transfusion from Week 1 to the end of Week 24. Subjects discontinued from the Treatment Phase 
prior to finishing Week 24 will be counted as non-responders.
Mean hemoglobin change over 24 weeks is defined as the mean hemoglobin change over the 24-
week period of Week 1 through Week 24 compared to baseline
Hematologic improvement – erythroid response (HI-E) per IWG (Cheson, 2006) is defined as 
proportion of subjects meeting HI-E criteria sustained over any consecutive 56-day period over 
the first 24 weeks from Week 1.  Subjects discontinued from the Treatment Period without 
achieving HI-E will be counted as non-responders.
Time to HI-E will be summarized only for subjects who achieve HI-E response. It is defined as 
time from Week 1 to first onset of achieving HI-E. It will be summarized only for subjects who 
achieve HI-E within the first 24 weeks from Week 1.
RBC-TI for ≥ 12 weeks (84 days) is defined as the proportion of subjects achieving RBC-TI for 
≥ 84 days during any consecutive 84-day period from Week 1 through Week 24.
Duration of RBC-TI ≥12 weeks (84 days) is defined as the longest RBC-TI period for subjects 
who achieve RBC-TI ≥12 weeks from Week 1 through Week 24.  Subjects who maintain RBC-TI 
through the end of the Treatment Period or at the time of analysis will be censored at the date of 
treatment discontinuation, date of analysis or death, whichever occurs first.
Time to RBC-TI ≥ 12 weeks (84 days) will be summarized only for subjects who achieve RBC-
TI ≥84 days from Week 1 through Week 24. It is defined as the time between Week 1 and the 
date onset of TI is first observed (ie, Day 1 of 84 days without any RBC transfusions).
Time to first RBC transfusion is defined as time from Week 1 to first RBC transfusion on 
treatment. Subjects who maintain RBC-TI through the end of the Treatment Period or time of 
analysis will be censored at the date of treatment discontinuation/time of analysis or death, 
whichever occurs first. 
RBC transfusion burden on treatment is defined as total number of pRBC units transfused 
within the first 24 weeks of treatment since Week 1.
RBC-TI for ≥ 56 days (8 weeks) is defined as the proportion of subjects achieving RBC-TI for ≥ 
56 days during any consecutive 56-day period from Week 1 through Week 24.
RBC-TI for a consecutive 24-week period is defined as the proportion of subjects achieving 
RBC-TI for ≥ 168 days during any consecutive 168-day period from Week 1 through Week 48.
Progression to AML: time to AML progression is defined as the time between randomization 
and first diagnosis of AML as per WHO classification of ≥ 20% blasts in peripheral blood or bone 
1.0
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Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
92
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 
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
Interim Analysis
Two interim analyses are planned. The first interim analysis (IA) is for futility and the second IA 
is for efficacy.
For the first IA, the primary efficacy variable, RBC transfusion independence (12 weeks with a 
concurrent hemoglobin increase), will be compared between the two treatment arms using the 
CMH test at approximately 30% information (when approximately 105 subjects have completed
24 weeks of treatment, or discontinued before reaching 24 weeks of treatment). A non-binding β-
spending function of the O’Brien-Fleming type will be used to control the Type II error rate with 
overall one-sided β = 0.10.
At the first interim analysis, CMH statistic will be calculated and compared with the futility 
boundary.  If the value of the CMH statistics is below the futility boundary, a recommendation to 
stop the study due to futility can be considered.
1.0
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930183290
1.0
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Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
93
Equivalently, the p-value for the one-sided CMH test will be calculated and a recommendation to 
terminate will be made if the p-value is greater than the futility boundary. The table below gives 
the nominal p-value for rejecting the alternative hypothesis corresponding to the O’Brien-Fleming 
boundary.  (The interim bound is approximate and will be re-calculated based on the amount of 
information available when the interim analysis is actually performed.)
Table 8:
Futility Interim Boundaries for the first IA
Analysis
Futility Bound
(odds ratio)
Reject Alternative Hypothesis if p greater than
Interim (30%)
0.632
0.844
Note:  Nominal p-values for futility computed using the program East Version 6.4 (Cytel Statistical Software 
Company).
Thus, if at the first interim analysis, the p-value is greater than 0.844, then the DMC could consider 
stopping the trial due to futility.
A second interim analysis is planned to test the superiority of the primary endpoint at about 85% 
of the information (when approximately 300 subjects have completed 24 weeks of treatment or 
discontinued before reaching 24 weeks of treatment). 
At the second interim analysis, the p-value from the one-sided CMH test for the primary endpoint 
will be calculated. If the one-sided p-value is less than or equal to 0.015, DMC could recommend 
that luspatercept is superior to epoetin alfa in terms of the primary endpoint. If the one-sided p-
value is greater than 0.015, the study will continue as planned and the p-value from the one-sided 
CMH test at the final analysis will be compared against the significance level 0.021.  The Lan-
DeMets spending function of the O’Brien-Fleming type will be used to control the overall one-
sided alpha level at 0.025.
At the time of second interim analysis, gate-keeping method will be used to control the Type I 
error rate for the following secondary endpoints in the order of:
•
HI-E response (Week 1 to 24)
•
RBC-TI for 24 weeks (Week 1 to 24)
•
RBC-TI ≥ 12 weeks (Week 1 to 24)
After the result from the primary efficacy endpoint shows statistical significance at the level of 
0.015, RBC-TI for 24 weeks in Week 1 to 24 will be tested for significance at a one-sided 
significance level of 0.015 only if both the primary endpoint and HI-E response in Week 1 to 24 
are significant at the one-sided significance level of 0.015. RBC-TI ≥ 12 weeks in Week 1 to 24 
will be tested for significance only if the results for primary endpoint, HI-E in Week 1 to 24, and 
RBC-TI for 24 weeks in Week 1 to 24 are all significant at the one-sided significance level of 
0.015. The testing procedure above will be implemented strictly in order to control the overall one-
sided Type I error rate of 0.015 at the interim analysis due to multiplicity.
1.0
Approved
930183290
1.0
v
Approved
1.0
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Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
94
Other secondary endpoints will be analyzed without employing methods for controlling the Type 
I error rate. Any statistically significant treatment effect on these secondary endpoints cannot be 
interpreted as confirmatory, but rather informatory.
The table below summarizes alpha spent at each analysis. Note that the actual alpha level used at 
the second interim analysis will be determined based on the actual information fraction (percent 
of subjects who have completed 24 weeks of treatment or discontinued before reaching 24 weeks 
of treatment) at the second interim analysis.
Table 9:
Summary of Alpha Spending
Analysis
Enrollment
One-sided alpha
Endpoint Assessment
Futility Interim 
30% information for 
primary endpoint 
(105 subjects)
N/A 
Efficacy not tested
Superiority Interim 
85% information for 
primary endpoint (300 
subjects)
0.015
Testing in order of: 
Primary endpoint
HI-E response (Week 1 to 24)
RBC-TI for 24 weeks (Week 1 to 24)
RBC-TI ≥ 12 weeks (Week 1 to 24)
Superiority Final 
100% information for 
primary endpoint 
(350 subjects)
0.021
Testing in order of: 
Primary endpoint
HI-E response (Week 1 to 24)
RBC-TI for 24 weeks (Week 1 to 24)
RBC-TI ≥ 12 weeks (Week 1 to 24)
Abbreviations: HI-E = Hematologic improvement – erythroid response; N/A = not applicable: RBC-TI = Red blood 
cell transfusion independence
9.10
Other Topics
9.10.1
Health-related Quality-of-life Assessment
The effect of luspatercept and epoetin alfa on patients’ HRQoL based on EORTC QLQ-C30, 
FACT-An, QUALMS-P and the Patient Treatment Satisfaction Survey will be assessed. The intent 
is to summarize the descriptive statistics of observed score at each visit and change from baseline 
at each post-baseline visit for all domains of the QLQ-C30 and FACT-An, QUALMS-P for each 
treatment group. Within-treatment and between-treatment differences will be examined using a 
1-sample, 2-sided t-test and a pooled 2-sample, 2-sided t-test, respectively. However, these t-tests
will be descriptive (ie, non-inferential) in nature.
In addition, the least square (LS) mean (95% confidence interval [CI] and p-value) for change from 
baseline at each post-baseline visit for all domains within each treatment group, and the difference 
in the LS means (95% CI, p-value) between treatment groups at each post-baseline visit, will be 
1.0
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930183290
1.0
v
Approved
1.0
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Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
95
estimated using the analysis of covariance (ANCOVA) model adjusting for baseline domain scores 
and stratification factors (ie, transfusion burden, RS status and sEPO level) where appropriate.  
Various schemes will be assessed for missing data imputation. Full details will be included in an 
HRQoL SAP. 
9.10.2
Healthcare Resource Utilization
Characterization of certain medical resource utilization among subjects treated with luspatercept 
as compared to subjects receiving epoetin alfa. 
Examples of relevant healthcare resource 
utilization include hospitalizations, prior concomitant therapies and surgeries, as well as RBC 
transfusion utilization.  Data for the analysis of healthcare resource utilization will be sourced both 
from specific report forms or through routine study data collection.
Full details will be included in the SAP.
9.10.3
Pharmacokinetic Analysis
Population PK analysis will be performed using nonlinear mixed effect modeling. Concentration 
data obtained from this study and other studies may be combined to develop a population PK 
model that describes the PK exposure data and the associated variability.  Subject-specific factors 
(demographics, baseline characteristics, markers for organ function, ADA against luspatercept, 
etc.) will be explored as covariates for their potential to influence luspatercept PK parameters.  
Empiric individual Bayesian estimates of PK parameters will be generated using the final 
population PK model and appropriate measures of luspatercept exposure (area under the 
concentration-time curve [AUC], maximum plasma concentration of drug [Cmax], or other 
exposure metrics of interest) will be computed for each subject. The relationship between serum 
luspatercept exposure and the primary efficacy endpoint, AEs of interest, or other selected 
secondary endpoints will be explored as appropriate.
Full details will be included in the PK/Pharmacodynamic (PD) Data Analysis Plan.
9.10.4
Data Monitoring Committee
An external, independent DMC will be comprised of experts in MDS not involved in the ACE-536-
MDS-002 study, and an independent Statistician, and may include additional ad hoc members.  
Representatives of the sponsor may attend the open session of DMC meeting but will not be present 
during the closed sessions of DMC meetings. 
During the course of the study, the DMC will review the safety data regularly as well as safety and 
efficacy data in accordance with the guidelines for the preplanned analyses, including data 
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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930183290
1.0
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1.0
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Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
96
9.10.5
Steering Committee
A SC 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 SC 
will serve in an advisory capacity to the sponsor.  Operational details for the SC will be detailed 
in a separate SC charter.
Note: The SC is separate from the DMC.
9.10.6
Exploratory Analysis
Descriptive statistics will also be provided for exploratory parameters (eg, GDF11, SF3B1, 
c-reactive protein, SARS-CoV-2 antibody, and other molecular markers). Statistical test will be
applied for these parameters if applicable.  Full details will be included in the SAP.
9.10.7
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.
1.0
Approved
930183290
1.0
v
Approved
1.0
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Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
97
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 7.2.3 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.
•
Luspatercept: 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. Phlebotomy may be performed if excessively high
hemoglobin levels occur.
•
Epoetin alfa: The therapeutic margin of epoetin alfa is very wide. Overdosage of
epoetin alfa may produce effects that are extensions of the pharmacological effects of
the hormone. Phlebotomy may be performed if excessively high hemoglobin levels
occur. Additional supportive care should be provided as necessary.
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.
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930183290
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Approved
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Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
98
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;
•
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.
1.0
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930183290
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v
Approved
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Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
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•
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.
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
AEs 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.
1.0
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930183290
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Approved
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Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
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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.
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 unless the subject experiences progression 
of MDS or any other malignancy), 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
1.0
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930183290
1.0
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1.0
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Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
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•
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 female partner of a male subject are immediately reportable events.  For adequate 
measures of contraception please refer to Section 4.2.
10.4.1
Females of Childbearing Potential
Pregnancies and suspected pregnancies (including elevated β-hCG 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 and if applicable the subject 
instructed to return any unused portion of the IP to the investigator.  The pregnancy, suspected 
pregnancy, or positive pregnancy test must be reported to Celgene Drug Safety immediately by 
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 (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.
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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.  
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, 
computed tomography [CT] scans, etc.).
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 
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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.
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’s Brochure.
In the United States, expedited reports sent to the Food and Drug Administration (FDA) by the 
sponsor based on the reasonable possibility threshold are known as ‘Investigational New Drug 
(IND) safety reports’ and will be reported in accordance with 21 CFR 312.32.
For reporting to the FDA, events that are not suspected to be causally related to luspatercept by 
the sponsor will not be considered adverse reactions.  As per FDA regulations, events that are 
anticipated in the study population, as detailed in the IB, will not be considered adverse reactions 
on individual assessment and will be reviewed on an aggregate basis for assessment of frequency.
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. 
For the purpose of regulatory reporting in the EEA, Celgene Drug Safety will determine the 
expectedness of events suspected of being related to the other IP, epoetin alfa, based on the UK 
Summary of Product Characteristics (SmPC). 
In addition, if requested, any report of progression to high risk MDS or AML in both the 
luspatercept and epoetin alfa arm, regardless of causality, will be reported as an expedited safety 
report to individual health authorities. 
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Celgene or its authorized representative shall notify the investigator of the following information
(In Japan, Celgene KK shall notify the heads of the institutes in addition to the investigators):
•
Any AE suspected of being related to the use of IP in this study or in other studies that 
is both serious and unexpected (ie, SUSAR);
•
Any finding from tests in laboratory animals that suggests a significant risk for human 
subjects including reports of mutagenicity, teratogenicity, or carcinogenicity.
•
Other important safety information and periodic reports according to the local 
regulations.
Where required by local legislation, the investigator shall notify his/her IRB/EC promptly of these 
new serious and unexpected AE(s) or significant risks to subjects.
The investigator must keep copies of all pertinent safety information on file including 
correspondence with Celgene and the IRB/EC.  (See Section 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.
10.8
COVID-19 Reporting
The occurrence of a COVID-19 event will be monitored as part of the assessment of AEs 
throughout the course of the study.  Investigators are to report the occurrence of COVID-19 events, 
regardless of casual relationship to IP, occurring at any time for the duration of treatment up to 42 
days after the last dose.
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11
DISCONTINUATIONS
11.1
Treatment Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the 
investigational product(s):
•
Lack of Efficacy
•
Adverse Event
•
Withdrawal by subject
•
Death
•
Lost to follow-up
•
Pregnancy
•
Protocol violation
•
Study terminated by the sponsor
•
Other (to be specified on the eCRF)
−
Including treatment discontinuation guidance related to dose modification
Section 7.2.1.2 and Section 7.2.2.2 for luspatercept and epoetin alfa, respectively.
•
Disease Progression as per IWG criteria for altering natural history of MDS (Cheson,
2006) (APPENDIX D)
−
For subjects with 5-10% blasts, a second bone marrow sample should be collected
within 4 weeks for clinical assessment (eg, cytomorphology, cytogenetics) to
confirm progression before discontinuing subjects from treatment.
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.
An EOT evaluation will be performed for all subjects who are withdrawn from treatment with IP 
for any reason as soon as possible after the decision to permanently discontinue treatment has been 
made (Section 6.2.2).  Subjects who received at least one dose of IP will enter the Post-treatment
Follow-up Period (Section 6.3).
11.2
Study Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the study:
•
Screen failure
•
Withdrawal by subject
•
Death
•
Lost to follow-up
•
Protocol violation
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•
Study terminated by sponsor
•
Other (to be specified on the eCRF)
The reason for study discontinuation should be recorded in the End of Study eCRF and in the 
source documents.
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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
This is an open-label study; therefore, IP will be identified on the package labeling.
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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 five (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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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.
IP can only be supplied to an investigator by Celgene or its authorized representative after 
documentation on all ethical and legal requirements for starting the study has been received by 
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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 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 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.  
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;
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•
Inaccurate or incomplete data collection;
•
Falsification of records;
•
Failure to adhere to the study protocol.
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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).
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.  
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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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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, FDA, EMA, Health Canada) and 
company authorized representatives.  The investigator should make every effort to be available for 
the audits and/or inspections.  If the investigator is contacted by any regulatory authority regarding 
an inspection, he/she should contact Celgene immediately.
15.3
Product Quality Complaint
A Product Quality Complaint (PQC) is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, purity, or 
performance of any drug product manufactured by or on behalf of Celgene Corporation after it is 
released for distribution.  Product Quality Complaints may reduce the usability of the product for 
its intended function or affect performance of the product and therefore pose a significant risk to 
the patient.  Examples of PQCs include (but are not limited to): mixed product, mislabeling, lack 
of effect, seal/packaging breach, product missing/short/overage, contamination, suspected 
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falsified, tampered, diverted or stolen material, and general product/packaging damage.  If you 
become aware of a suspected PQC, you are obligated to report the issue immediately.  You can do 
so by emailing 
or by contacting the Celgene Customer Care 
Center 
.
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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.
Eligibility for external authorship, as well as selection of first authorship, will be based on several 
considerations, including, but not limited to, contribution to protocol development, study 
recruitment, data quality, participation in data analysis, participation in study steering committee 
(when applicable) and contribution to abstract, presentation and/or publication development.
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
117
17
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Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
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930183290
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Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
119
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Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
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Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
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1.0
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930183290
1.0
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Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
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18
APPENDICES
APPENDIX A
TABLE OF ABBREVIATIONS
Table 10:
Abbreviations and Specialist Terms
Abbreviation or Specialist 
Term
Explanation
aCML
Atypical chronic myeloid leukemia 
ActRIIB
Activin receptor type IIB
ADA
Antidrug antibodies
AE
Adverse event
ALT
Alanine aminotransferase (SGPT)
AML
Acute myeloid leukemia
ANC
Absolute neutrophil count
ANCOVA
Analysis of covariance
AST
Aspartate aminotransferase (SGOT)
AUC
Area under the concentration-time curve
β-hCG
β-subunit of human chorionic gonadotropin
BM
Bone marrow
BMA
Bone marrow aspirate
BMB
Bone marrow biopsy
BMP6
Bone morphogenetic protein 6
BMP9
Bone morphogenetic protein 9
BSC
Best supportive care
BUN
Blood urea nitrogen
CBC
Complete blood count
CFR
Code of Federal Regulation
CI
Confidence interval
Cmax
Maximum plasma concentration of drug
CMH
Cochran–Mantel–Haenszel
CMML
Chronic myelomonocytic leukemia
COVID-19
Coronavirus disease 2019
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DAR
Darbepoetin
DBP
Diastolic blood pressure
DMC
Data Monitoring Committee
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Luspatercept (ACE-536)
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Table 10:
Abbreviations and Specialist Terms
Abbreviation or Specialist 
Term
Explanation
DNA
Deoxyribonucleic acid
DVT
Deep venous thrombosis
EC
Ethics Committee
ECD
Extracellular domain
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EEA
European Economic Area
eGFR
Estimated glomerular filtration rate
ELN
European Leukemia Net
EMA
European Medicines Agency
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer Quality-of-Life 
Questionnaire
EOT
End of treatment
EPO
Erythropoietin
ESA
Erythropoiesis stimulating agent
ESMO
European Society for Medical Oncology
EU
European Union
FAB
French-American-British (FAB) classification
FACT-An
Functional Assessment of Cancer Therapy - Anemia
FCBP
Female of childbearing potential
FDA
Food and Drug Administration
GCP
Good clinical practice
G-CSF
Granulocyte-colony stimulating factor
GDF11
Growth differentiation factor 11
GDF15
Growth differentiation factor 15
GM-CSF
Granulocyte-macrophage colony-stimulating factor
Hep
Hepatitis
Hgb
Hemoglobin
HI-E
Hematologic improvement – erythroid response
HIV
Human immunodeficiency virus
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Table 10:
Abbreviations and Specialist Terms
Abbreviation or Specialist 
Term
Explanation
HMA
Hypomethylating agent
HR
Heart rate
HRQoL
Health-related quality-of-life
IA
Interim analysis
IB
Investigator’s brochure
ICF
Informed consent form
ICH
International Council for Harmonisation
ID
Subject identification 
IgG1-Fc
Immunoglobulin G1 - Fragment crystallizable
IMiD
Immune-modulatory drug
IND
Investigational new drug
Int-1
Intermediate-1
IP
Investigational product
IPSS
International prognostic scoring system
IPSS-R
Revised international prognostic scoring system
IRB
Institutional review board
IRT
Integrated response technology
ITT
Intent-to-treat
IU
International unit
IUD
Intrauterine device
IWG
International Working Group
JMML
Juvenile myelomonocytic leukemia
LDH
Lactatedehydrogenase
LS
Least square
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MedDRA
Medical dictionary for regulatory activities
MDRD
Modification of diet in renal disease
MDS
Myelodysplastic syndromes
MDS-U
Myelodysplastic syndromes - unclassifiable
MDS/MPN
Myelodysplastic/myeloproliferative neoplasms
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Celgene Corporation
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Table 10:
Abbreviations and Specialist Terms
Abbreviation or Specialist 
Term
Explanation
MOA
Mechanism of action 
MRP
Mutual recognition procedure
MUGA
Multi-gated acquisition
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
nRBC
Nucleated red blood cells
NYHA
New York Heart Association
OR
Odds ratio
OS
Overall survival
PBO
Placebo
PD
Pharmacodynamic
PK
Pharmacokinetics
PQC
Product Quality Complaint
pRBCs
Packed red blood cells
PRCA
Pure red cell aplasia
Q3W
Every 3 weeks 
QoL
Quality-of-life 
QUALMS
Quality of Life in Myelodysplasia Scale
QUALMS-P
Quality of Life in Myelodysplasia Scale - Physical Burden
QW
Once every week
RA
Refractory anemia
RAEB
Refractory anemia with excess blasts
RAEB-T
Refractory anemia with excess blasts in transformation
RARS
Refractory anemia with ringed sideroblasts
RBC
Red blood cell
RBC-TD
Red blood cell transfusion dependence
RBC-TI
Red blood cell transfusion independence
RDW
Red blood cell distribution width
RNA
Ribonucleic acid
RS
Ring sideroblast
SAE
Serious adverse event
SAP
Statistical analysis plan
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Celgene Corporation
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Table 10:
Abbreviations and Specialist Terms
Abbreviation or Specialist 
Term
Explanation
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SBP
Systolic blood pressure
sEPO
Endogenous serum erythropoietin
SC
Steering committee
SGOT
Serum glutamic oxaloacetic transaminase 
SGPT
Serum glutamic pyruvic transaminase
SmPC
Summary of Product Characteristics 
SOP
Standard operating procedure
SUSAR
Suspected unexpected serious adverse reaction
TEAE
Treatment-emergent adverse events
TD
Transfusion dependent/dependence
TGF-β 
Transforming growth factor-beta
TI
Transfusion independent/ independence
TNM 
Tumor nodes metastasis
TWSG1
Twisted gastrulation 1
UK
United Kingdom
ULN
Upper limit of normal
US
United States of America
W1D1
Week 1 Day 1
WBC
White blood cell
WHO
World Health Organization
WPSS
WHO prognostic scoring system
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APPENDIX B
MYELODYSPLASTIC SYNDROMES WORLD HEALTH
ORGANIZATION 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.
1.0
Approved
930183290
1.0
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Approved
1.0
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Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
128
Sources: Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz 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.
1.0
Approved
930183290
1.0
v
Approved
1.0
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Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
129
APPENDIX C
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
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
130
APPENDIX C.
INTERNATIONAL PROGNOSTIC SCORING SYSTEM SCORE –
REVISED (CONT.)
IPSS-R: Prognostic Risk Category Clinical Outcomesa
No. pts
Very Low
Low
Intermediate
High
Very High
Subjects (%)
7012
19%
38%
20%
13%
10%
Survivalb
-
8.8
5.3
3.0
1.6
0.8
AML/25%b,c
-
NR
10.8
3.2
1.4
0.7
a 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.
b Medians, years.
c 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.
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
131
APPENDIX D
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)c
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)c
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,c
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
Failurec
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 PRc
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 Responsec
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
Survivalc
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-002 subject population.
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
132
APPENDIX D.
INTERNATIONAL WORKING GROUP RESPONSE CRITERIA FOR 
MYELODYSPLASTIC SYNDROMES (CONT.)
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 Jul 15;108 (2):419-
25.
Hematologic Improvement According to IWG Criteria (Cheson,2006)
Hematologic Improvementa
Response criteria (responses must last at least 8 week)b
Erythroid Response (HI-E) (pre-
treatment, <11 g/dL)
- Hemoglobin increase by ≥ 1.5 g/dL
- Relevant Reduction in units of RBC transfusions by an absolute number of at least 
4 RBC transfusions/8 wk compared with the pretreatment transfusion number in the 
previous 8 wk
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
Hgb = hemoglobin; HI-E = hematologic improvement erythroid response; HI-N = hematologic improvement neutrophil response; 
HI-P = hematologic improvement platelet response; IWG = International Working Group; pRBC = packed red blood cells; RBC = 
red blood cell.; wk = week.
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.
Notes: 
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.
The following study-specific modifications will be applied: To accommodate the varying baseline transfusion burden of the ACE-
536-MDS-002 subject population HI-E will be defined as follows:
- Subjects with baseline transfusion burden of < 4 pRBC units/8 weeks preceding first dose of investigational product: Hgb 
increase of ≥ 1.5 g/dL in the absence of transfusions.
- Subjects with baseline transfusion burden of ≥ 4 pRBC units/8 weeks: a relevant reduction of pRBC units by an absolute number 
of at least 4 pRBC units/8 weeks compared to the baseline transfusion burden in the 8 weeks preceding first dose of 
investigational product.
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 Jul 15;108 (2):419-
25.
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
133
APPENDIX E
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.
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
134
APPENDIX F
FOUR-VARIABLE MDRD GFR EQUATION
For Serum Creatinine in mg/dL: 
GFR (mL/min/1.73 m²) = 175 × (Scr)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African American) 
(conventional units)
Creatinine levels in μmol/L can be converted to mg/dL by dividing them by 88.4
Source: 
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, 3rd, Feldman HI, et al. A new equation to estimate 
glomerular filtration rate. Ann Intern Med. 2009;150(9):604-12.
Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, Kusek JW, Van Lente F; Chronic Kidney 
Disease Epidemiology Collaboration. Using standardized serum creatinine values in the modification of diet in 
renal disease study equation for estimating glomerular filtration rate. Ann Intern Med. 2006 Aug 15;145(4):247-
54.
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
135
APPENDIX G
EUROPEAN ORGANIZATION FOR RESEARCH AND 
TREATMENT OF CANCER QUALITY-OF-LIFE QUESTIONNAIRE 
(VERSION 3.0)
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
136
APPENDIX G.
EUROPEAN ORGANIZATION FOR RESEARCH AND TREATMENT 
OF CANCER QUALITY-OF-LIFE QUESTIONNAIRE (VERSION 3.0) 
(CONTINUED)
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
137
APPENDIX H
FUNCTIONAL ASSESSMENT OF CANCER THERAPY-ANEMIA 
(FACT-AN) QUESTIONNAIRE (VERSION 4.0)
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
138
APPENDIX H.
FUNCTIONAL ASSESSMENT OF CANCER THERAPY-ANEMIA 
(FACT-AN) QUESTIONNAIRE (VERSION 4.0) (CONTINUED)
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
139
APPENDIX H.
FUNCTIONAL ASSESSMENT OF CANCER THERAPY-ANEMIA 
(FACT-AN) QUESTIONNAIRE (VERSION 4.0) (CONTINUED)
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
140
APPENDIX I
QUALITY-OF-LIFE IN MYELODYSPLASIA SCALE - PHYSICAL 
BURDEN (QUALMS-P)
1.0
Approved
930183290
1.0
v
Approved
1.0
v

Luspatercept (ACE-536)
Protocol ACE-536-MDS-002
Celgene Corporation
ACE-536-MDS-002 Amendment 4.0
Final: 31 Mar 2022
141
APPENDIX J
PATIENT TREATMENT SATISFACTION SURVEY
1.0
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