Clinical trial NCT02268383
Conditions: Myelodysplastic Syndromes
Sponsor: Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
Start date: 2014-10-09; Completion date: 2020-03-19
Enrollment: 75 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is an open-label extension study for participants previously enrolled in study MK-6143-001 (formerly called A536-03, ClinicalTrials.gov Identifier NCT01749514), to evaluate the long-term safety and tolerability of luspatercept (MK-6143) in participants with low or intermediate-1 risk MDS.

Detailed description:
This study is an open-label extension study to evaluate the safety, tolerability, and pharmacodynamic effects of up to 24 months of luspatercept treatment in participants with low or intermediate-1 risk myelodysplastic syndromes previously treated with luspatercept for up to 3 months in MK-6143-001 study (NCT01749514). The starting dose level in this study will be 1.0 mg/kg by subcutaneous (SC) injection every 3 weeks. Dose titration/modification rules will be followed for individual participants and will be based upon safety and efficacy data collected during the course of treatment.

Arms: arm 1: Luspatercept 1.0 mg/kg once every 3 weeks by subcutaneous injection.
Interventions: intervention 1: Luspatercept
Intervention descriptions: intervention 1: Luspatercept 1.0 mg/kg once every 3 weeks by subcutaneous injection.

Protocol documents:
Prot_000.pdf: 
Official Protocol Title: 
NCT number: 
Document Date: 
An Open-Label Extension Study to Evaluate the Long-Term Effects 
of ACE-536 for the Treatment of Anemia in Patients with Low or 
Intermediate-1 Risk Myelodysplastic Syndromes (MDS) Previously 
Enrolled in Study A536-03
29-Mar-2019
NCT02268383






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COORDINATING PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature:
Date:
Name (print):
Prof. Dr. Uwe Platzbecker
DD/MMM/YYYY
Institution Name and Address:
Universitätsklinikum Carl Gustav Carus
Medical Clinic and Polyclinic I, 
Fetscherstrasse 74
01307 Dresden, Germany
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.
I agree to conduct the study as outlined in the protocol.  The study will be conducted in 
accordance to current United States Food and Drug Administration (FDA) regulations, 
International Council of Harmonization (ICH) Guidelines, Good Clinical Practices (GCP), the 
Declaration of Helsinki, and local ethical and legal requirements.


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SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature:
Date:
Name (print):
DD/MMM/YYYY
Institution Name and Address:
By my signature I have read the protocol and agree to personally supervise and conduct the study 
as outlined in the protocol.  The study will be conducted in accordance to current United States 
Food and Drug Administration (FDA) regulations, International Council of Harmonization (ICH) 
Guidelines, Good Clinical Practices (GCP), the Declaration of Helsinki, and local ethical and 
legal requirements.




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1.
PROTOCOL SYNOPSIS
Name of Sponsor/Company: 
Acceleron Pharma Inc.
128 Sidney Street
Cambridge, MA 02139 USA
Name of Investigational Product: ACE-536
Name of Active Ingredient: Luspatercept (ACE-536)
Title of Study: An Open-Label Extension Study to Evaluate the Long-Term Effects of ACE-536
for the Treatment of Anemia in Patients with Low or Intermediate-1 Risk Myelodysplastic 
Syndromes (MDS) Previously Enrolled in Study A536-03
Study Centers: Up to 20
Phase of development: 2
Objectives:
Primary: 
x
To evaluate the long-term safety and tolerability of ACE-536 in patients with low or 
intermediate-1 risk MDS who were previously enrolled in study A536-03.
Secondary:
x
To evaluate erythroid response (modified HI-E from International Working Group [IWG] 
2006 criteria1), defined as proportion of patients with:
o
A mean hemoglobin (Hgb) increase ≥ 1.5 g/dL over an 8-week period as 
compared to baseline, not influenced by red blood cell (RBC) transfusion, in 
non-transfusion dependent (NTD) patients.
o
A decrease of ≥ 4 units or ≥ 50% of units of RBCs transfused over a period of 
8 weeks, relative to the 8 weeks immediately prior to Day 1, in transfusion 
dependent (TD) patients.
x
To evaluate rates of erythroid, neutrophil and platelet (HI-E, HI-N and HI-P) responses 
(IWG 2006 criteria)
x
To evaluate the rate of RBC transfusion independence lasting ≥ 8 weeks in TD patients
x
To evaluate time to HI-E response and duration of HI-E response (modified and 
non-modified IWG 2006 criteria)
x
To evaluate the mean change in RBC transfusion burden in TD patients and mean change 
in hemoglobin levels in NTD patients
x
To evaluate the pharmacokinetic (PK) profile of ACE-536
x
To evaluate other pharmacodynamic (PD) effects (e.g., iron overload/metabolism, 
erythropoietin (EPO), and reticulocytes)


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Exploratory:
x
To examine biomarkers related to the transforming growth factor beta (TGF-β)
superfamily
x
To examine self-reported quality of life using tools including but not limited to the
Functional Assessment of Cancer Therapy-Anemia Scale (FACT-An) questionnaire
Study Design: 
This open-label extension study will evaluate the safety, tolerability, and PD effects of up to 60
months of ACE-536 treatment in patients with low or intermediate-1 risk MDS previously treated 
with ACE-536 for up to 3 months in study A536-03.
The base study A536-03 is a phase 2, open-label, ascending dose study to evaluate the effects of 
ACE-536 on anemia in patients with low or intermediate-1 risk MDS who are not currently 
receiving treatment with an erythropoiesis-stimulating agent (ESA).  A total of up to 153 patients 
may be enrolled in the base study A536-03 and may be eligible for study A536-05.
Consenting patients that meet the A536-05 eligibility criteria may immediately roll over from 
A536-03 to study A536-05.  These patients will forego the Post-treatment Follow-up (PTFU) and 
End of Study (EOS) visit of A536-03 to begin study A536-05. For these patients, C1D1 of 
A536-05 may take place 28 (± 7) days after the last dose administered in study A536-03, which 
may coincide with the patient’s A536-03 End of Treatment (EOT) visit. These patients will be 
considered “patients without treatment interruption.” Patients enrolled in expansion cohorts 
2 and 3 in Study A536-03 must meet the “patients without treatment interruption” criteria to be 
considered for the A536-05 study, unless otherwise prospectively approved by the sponsor. 
Patients who complete the EOS visit for the base study A536-03 prior to C1D1 of A536-05 are 
considered “patients with treatment interruption.” These patients will have a 28-day screening 
period to allow them to be re-assessed for eligibility by meeting additional inclusion criteria, as
defined in Section 9.2.
Patients who have completed the EOT visit for the base study A536-03 but have not reached the 
EOS visit (i.e., patients in the follow-up period for A536-03), may still participate, but should be 
treated as patients with treatment interruption and should not begin study A536-05 C1D1 until 
they have completed their A536-03 EOS visit so that new baseline assessments can be measured.
For patients without treatment interruption, transfusion status (NTD or TD) will carry-over from 
the base study A536-03. For patients with treatment interruption, transfusion status will be 
reassessed prior to C1D1 of study A536-05. Transfusion status for all patients is defined as 
follows for all patients:
x
NTD patients are defined as patients who require a transfusion of < 4 units of RBCs in 
the 8 weeks prior to C1D1
x
TD patients are defined as patients who require a transfusion of ≥ 4 units of RBCs in 
the 8 weeks prior to C1D1
Each TD patient will have a defined “pre-transfusion hemoglobin threshold” which will be 
calculated based on transfusion history and will be used for determining when to transfuse during 
the study. The baseline pre-transfusion hemoglobin threshold will be the mean of all documented 
pre-transfusion hemoglobin values during the 12 weeks prior to C1D1 of base study A536-03 for
patients without treatment interruption, or prior to C1D1 of study A536-05 for patients with 




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Individual Dose Modification:
The following dose modification rules include parameters which may indicate when a dose delay 
and/or dose reduction is required.  These rules should be assessed prior to each dosing.  If a dose 
delay is required, the patient should have visits every 1 - 3 weeks to assess hematology results 
and adverse events (AE) until the patient is eligible to receive the next dose of ACE-536.
Observation on Dosing Day
Action
ACE-536 Dose Modification
Hemoglobin ≥ 12 g/dL 
Hold dose and monitor patient 
until hemoglobin < 11 g/dL
Resume dosing once hemoglobin 
< 11 g/dL 
Hemoglobin ≥ 2 g/dL increase from 
the previous dosing day, not 
attributable to RBC transfusion  
Continue dosing 
Reduce the dose by 1 dose level 
Non-hematologic AE ≥Grade 3, at 
least possibly related to study drug
Hold dose and monitor patient 
until resolution of AE to 
≤Grade 1 or baseline
Resume dosing upon resolution of the AE 
to ≤Grade 1 or baseline, and reduce the 
dose by 1 dose levela
≥50% increase in white blood cell 
count (WBC) compared to pre-dose 
WBC of previous treatment cycle and 
above upper limit of normal in the 
absence of an associated condition 
(e.g., infection or concomitant 
corticosteroid use)b
Dose delay; recheck CBC, 
including WBC at least weekly 
during dose delay.
Treatment may be resumed if WBC 
values are below upper limit of normal 
within 2 weeks
If WBC remains above upper 
limit of normal for ≥ 2 
consecutive weeks in absence of 
an associated condition (e.g.,
infection or concomitant 
corticosteroid use); continue dose 
delay and collect bone 
marrow/peripheral blood samples 
to assess MDS disease status.
Treatment may be resumed if:
x
Absence of disease progression per 
IWG response criteria for altering 
natural history of MDS1
AND
x
WBC values return below upper 
limit of normal
Discontinue treatment if:
x
Disease progression per IWG 
response criteria for altering natural 
history of MDS1
OR
x
WBC remain above upper limit of 
normal
Presence of ≥ 1% blasts in peripheral 
blood 
Dose interruption; immediately 
prepare peripheral blood smear 
for cytomorphology assessment.
If cytomorphology assessment confirms ≥ 
1% blasts in the peripheral blood; 
discontinue treatment
If cytomorphology assessment determines 
< 1% peripheral blasts are present, repeat 
hematology assessment.
x
If presence of < 1% blasts in 
peripheral blood, treatment can be 
resumed at next scheduled dosing 
cycle.
x
If presence of ≥ 1% blasts in 
peripheral blood; discontinue 
treatment
    a Patients who require more than 2 dose reductions due to an AE should be discontinued from treatment and 
complete the EOT, PTFU, LTFU, and EOS visits.
b The investigator may contact the medical monitor and forward appropriate supporting documents for review and 
discussion prior to making decision regarding treatment discontinuation.


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Individual Dose Titration for NTD Patients:
For NTD patients (with or without interruption), after C1D1, the dose level will be assessed for 
titration every cycle starting at C3D1 (e.g., C3D1, C4D1, C5D1, etc.). The dose level should be 
titrated individually for each patient not to exceed the maximum dose level evaluated in the base 
study A536-03 as follows:
x
If hemoglobin increase from baseline is < 1.5 g/dL throughout the previous two cycles at 
the same dose level, the dose level will be increased by 1 dose level (unless dose 
modification is required).
x
If hemoglobin increase from baseline is ≥ 1.5 g/dL but not sustained for at least two 
consecutive study measurements during the previous two cycles at the same dose level,
the dose level will be increased by approximately 1 dose level (unless dose modification 
required).  
x
If hemoglobin increase from baseline is ≥ 1.5 g/dL (not influenced by RBC transfusion)
as measured by two or more consecutive study measurements during the previous two 
cycles at the same dose level, the dose level will be unchanged (unless dose modification 
is required).
Baseline hemoglobin to assess titration will be the average of two or more measurements 
performed during the screening period for base study A536-03 (for patients without treatment 
interruption) or study A536-05 (for patients with treatment interruption).
Individual Dose Titration for TD Patients:
For all TD patients (with and without treatment interruption), the dose level will be assessed for 
titration every cycle starting at Cycle 3 Day 1 (e.g., C3D1, C4D1, C5D1, etc.).  The dose level 
should be titrated individually for each patient not to exceed the maximum dose level evaluated 
in the base study A536-03 as follows: 
x
If patient has ≥ 1 transfusion event during the previous 2 cycles at the same dose level, the 
dose will be increased by 1 dose level (unless a dose modification is required).
Number of patients: A planned total of up to 153 patients who enrolled in the base study
A536-03 may be eligible for the extension study A536-05.
Inclusion Criteria:
All patients must meet the following criteria: 
1. Completion of the treatment period in the base study A536-03.
2. Females of child bearing potential (defined as sexually mature women who have not 
undergone hysterectomy or bilateral oophorectomy, or are not naturally postmenopausal 
≥24 consecutive months) must have negative urine or blood pregnancy test prior to 
enrollment and use adequate birth control methods (abstinence, oral contraceptives, 
barrier method with spermicide, or surgical sterilization) during study participation and 
for 12 weeks following the last dose of ACE-536.  Males must agree to use a latex 
condom during any sexual contact with females of child-bearing potential while 
participating in the study and for 12 weeks following the last dose of ACE-536, even if he 
has undergone a successful vasectomy.  Patients must be counseled concerning measures 
to be used to prevent pregnancy and potential toxicities prior to dosing with ACE-536.


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3. Patient is able to adhere to the study visit schedule, understand and comply with all 
protocol requirements.
4. Patient understands and is able to provide written informed consent.
Patients with treatment interruption (defined as patients who complete their A536-03 EOS 
visit) must also meet the following criteria:
5. Documented diagnosis of idiopathic/de novo MDS or non-proliferative chronic 
myelomonocytic leukemia (CMML) according to the World Health Organization (WHO)
criteria2 (white blood count [WBC] < 13,000/μL) that meets International Prognostic 
Scoring System (IPSS) classification (Appendix 2) of low or intermediate-1 risk disease 
as determined by microscopic and standard cytogenetic analyses of the bone marrow and 
peripheral complete blood count (CBC) obtained during screening; 
6. Anemia defined as:
x
Mean hemoglobin concentration < 10.0 g/dL of 2 measurements (one performed 
within one day prior to Cycle 1 Day 1 and the other performed 7-28 days prior to 
Cycle 1 Day 1), for NTD patients (defined as having received ˂ 4 units of RBCs 
within 8 weeks prior to Cycle 1 Day 1), OR
x
Transfusion Dependent (TD), defined as having received ≥ 4 units of RBCs within 
8 weeks prior to Cycle 1 Day 1.
7. Platelet count ≥ 30 x 109/L.
8. ECOG performance status of 0, 1, or 2 (if related to anemia).
9. Adequate renal (creatinine ≤ 2.0 x upper limit of normal [ULN]) and hepatic (total 
bilirubin < 2 x ULN and aspartate aminotransferase (AST) and alanine aminotransferase 
(ALT) < 3 x ULN) function.
Exclusion Criteria:
All patients must not meet any of the following criteria:
1. Discontinuation/withdrawal from the base study A536-03 (due to patient request, patient 
unwillingness or inability to comply with the protocol, pregnancy, use of prohibited 
medication [e.g. azacitidine], medical reason or AE, disease progression, persistent 
increase in white blood cell count (WBC), presence of ≥1% blasts in peripheral blood,
hypersensitivity reaction to the study drug, at the discretion of the sponsor, or loss to 
follow-up) prior to completion of the treatment period.
2. Prior treatment with azacitidine (injectable or oral) or decitabine.
3. Treatment within 28 days prior to Cycle 1 Day 1 with:

ESA,

Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage 
colony stimulating factor (GM-CSF),

Lenalidomide.
4. For patients with treatment interruption only: Iron chelation therapy if initiated within 56 
days prior to Cycle 1 Day 1.


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5. Treatment with another investigational drug (including sotatercept [ACE-011]) or device, 
or approved therapy for investigational use ≤28 days prior to Cycle 1 Day 1, or if the 
half-life of the previous investigational product is known, within 5 times the half-life prior 
to Cycle 1 Day 1, whichever is longer.
6. Major surgery within 28 days prior to Cycle 1 Day 1. Patients must have completely 
recovered from any previous surgery prior to Cycle 1 Day 1.
7. Known positive for human immunodeficiency virus (HIV), active infectious hepatitis B 
(HBV) or active infectious hepatitis C (HCV). 
8. Uncontrolled hypertension defined as systolic blood pressure (SBP) ≥ 150 mm Hg or 
diastolic blood pressure (DBP) ≥ 100 mm Hg.
9. Pregnant or lactating females.
10. History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant 
proteins or excipients in the investigational drug.
11. Any other condition not specifically noted above which, in the judgment of the 
investigator, would preclude the patient from participating in the study.
Investigational product, dosage and mode of administration: 
ACE-536 drug product will be provided as either a sterile, liquid formulation or a lyophilized 
powder formulation for reconstitution with water. Each single-use vial of the liquid formulation 
contains 25 mg of ACE-536 in a 0.5 mL Tris-buffered saline solution (50 mg/mL).
Each single-use vial of the lyophilic formulation may contain either 25 mg, 50 mg, or 75 mg
ACE-536 for reconstitution with 0.5 mL, 1 mL, or 1.5 mL water, respectively, to form a 
citrate-buffered solution (50 mg/mL) for injection.
ACE-536 will be administered by SC injection on Day 1 of each cycle.
Criteria for Evaluation:
Safety Assessments:
x
All patients will be assessed for safety by monitoring AEs, clinical laboratory tests, 
vital signs, ECG, anti-drug antibody (ADA) testing, ECOG status, and physical 
examination. 
Efficacy Assessments:
x
Patients will be assessed for erythroid response over approximately 63 months
following initiation of treatment.  Erythroid response endpoints will be determined by 
monitoring hematologic laboratory values and RBC transfusions.
x
Other secondary efficacy endpoints will be assessed by examining erythropoiesis, iron 
overload, and iron metabolism:
o
Erythropoiesis parameters include serum EPO levels, reticulocytes, nucleated 
RBCs and soluble transferrin receptor
o
Iron overload/metabolism parameters include serum iron, total iron binding 
capacity (TIBC), transferrin, soluble transferrin receptor, ferritin, and hepcidin
PK Assessments:


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x
Blood samples will be drawn to evaluate PK parameters.
Exploratory Assessments:
x
Biomarkers related to the TGF-β superfamily
Patient-reported quality of life in the expansion cohort using tools including but not limited to the
FACT-An questionnaire
Statistical Methods 
Sample Size Calculation:
There is no formal sample size calculation for the study although up to 153 patients may 
participate from the base study A536-03 study.
Analysis Populations:
The modified Intent-to-Treat (mITT) Population: All patients enrolled in the study who 
received at least one dose of ACE-536.
Efficacy Evaluable (EE) Population: All patients who received at least one dose of ACE-536
and have 1) at least four hemoglobin assessments over an 8-week period post-treatment in NTD 
patients OR, 2) at least 8 consecutive weeks of transfusion frequency data between Cycle 1 Day 1 
and EOT visit in TD patients. 
Pharmacokinetics Population: All patients who received at least 1 dose of ACE-536 during 
Study A536-05 and have sufficient serum ACE-536 values for PK analysis.
Primary Endpoint Analysis:
Safety analysis: To assess clinical safety, AEs, vital sign measurements and clinical laboratory 
information will be summarized.  AEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA).  Changes from baseline for clinical laboratory values and vital signs will 
be summarized over time.  Descriptive statistics and shift tables will be generated as appropriate.
Efficacy/Pharmacodynamic Effects Analysis of Secondary Endpoints:
All efficacy analyses will be performed for the EE and mITT populations.
Efficacy will be evaluated by determining the proportion of patients who have a modified HI-E
erythroid response rate based upon the IWG 2006 criteria (Appendix 5), defined as 1) A mean 
hemoglobin increase ≥ 1.5 g/dL over an 8-week period as compared to baseline, not influenced 
by RBC transfusion in NTD patients or 2) A decrease of ≥ 4 units or ≥50% of units of RBCs 
transfused over a period of 8 weeks, relative to the number of units of RBCs transfused in the 8 
weeks immediately prior to Cycle 1 Day 1 in TD patients.


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Baseline hemoglobin will be the average of two or more measures (not influenced by RBC 
transfusion) performed during the screening period for study A536-03 (for patients without
interruption) or study A536-05 (for patients with interruption).
Baseline units of RBCs transfused will be the 8-week period prior to study A536-03 (for patients 
without interruption) or study A536-05 (for patients with interruption).
The erythroid response will be summarized using both a point estimate and its exact 95% 
confidence interval based on binomial distribution.
No direct comparison testing with concurrent or historical controls will be performed.  
Analysis of other Secondary efficacy/pharmacodynamic endpoints will include:
x
Time to HI-E response and duration of HI-E response as per the IWG 2006 criteria and 
modified IWG 2006 criteria.
x
Mean RBC transfusion burden
x
Rate of RBC transfusion-free period lasting ≥ 8 weeks in TD patients.
x
Mean hemoglobin level change in NTD patients
x
Other PD endpoints including:
o
Biomarkers for iron overload/metabolism
o
Relationship of biomarkers to response
o
Rates of HI-N and HI-P
The exploratory endpoints will include:
x
Biomarkers related to the TGF-E superfamily.
x
Patient-reported quality of life using tools including but not limited to the FACT-An
questionnaire
All binary endpoints will be summarized using both a point estimate and its exact confidence 
interval based on the binomial distribution.  The time-to-event type secondary endpoints will be 
analyzed using Kaplan-Meier method to estimate the survival curve and median time to event and 
95% confidence interval.






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1
Screening procedures: Other than informed consent, procedures listed as part of the 28-day screening period are only applicable to patients with treatment 
interruption. Patients with treatment interruption will need to qualify per the additional inclusion criteria listed in Section 9.2.1.  For patients without 
treatment interruption, C1D1 may coincide with EOT visit of the base study A536-03.  Procedures that are required to confirm eligibility for patients 
without treatment interruption can be performed at the base study A536-03 EOT visit and used to confirm eligibility prior to dosing on C1D1 of study 
A536-05.  
2
Study procedures must be done prior to administration of study drug. For patients without treatment interruption, C1D1 procedures shaded grey may be 
conducted as part of the EOT visit for study A536-03 and may not need to be repeated for study A536-05. All screening and Cycle 1 Day 1 procedure results 
required to confirm eligibility must be obtained and reviewed prior to study drug administration in A536-05.
Visit schedule: Each dosing visit (cycles 1-87) will be 21 days (±5 days) from the previous dosing visit, unless a dose delay is required. If a dose delay is 
required per the dose modification rules (Section 10.8), the patient will not be dosed.  The patient will return every 1-3 weeks for assessment of hematology 
results and AEs until the patient is eligible to receive the next dose of ACE-536 and start the next cycle. The patient should resume the study at the planned 
dosing cycle (e.g. if the patient missed a dose at C4D1, then they would resume dosing at C4D1 and not skip to C5D1).
Dosing: The patient dose must be calculated based on the patient’s weight on the day of dosing.  Dose modification rules and titration rules must be 
reviewed and implemented prior to dosing as required per protocol (see Section 10.8 and Section 10.9). A dose titration cannot occur until C3D1.
3
Medical History: Medical history for patients with treatment interruption will include medical events occurring after EOS visit in study A536-03 and prior 
to C1D1 for study A536-05.  Medical history for patients without treatment interruption will be taken from study A536-03.   
4
Quality of life questionnaires are only required on C1D1, C5D1, C9D1, C13D1, C17D1, C25D1, C33D1, C41D1, C49D1, C57D1, C65D1, C73D1, 
C81D1, EOT, and EOS.
5
Vital signs will include weight, heart rate, and systolic and diastolic blood pressure.
6
ECG: May be collected within 28 days prior to C1D1.
7
Bone marrow aspirate: Patients with treatment interruption must have a bone marrow aspirate including cytogenetics performed ≤ 3 months prior to C1D1 
for evaluation of eligibility per inclusion criteria Section 9.2.1. A bone marrow aspirate will not be performed on C1D1 for patients without treatment 
interruption. A bone marrow aspirate must be performed within 21 days after C9D1, C17D1, C25D1, C41D1, C57D1, and C73D1 for all patients. At the 
EOT visit, a bone marrow aspirate is required for all patients, unless performed < 3 months following a previous bone marrow aspirate and not clinically 
indicated. Refer to the Laboratory Manual for processing and shipping instructions.
8
Serum Iron Studies: May include serum iron, TIBC, transferrin, soluble transferrin receptor, ferritin.
9
Hematology: RBC, WBC with differential, hemoglobin, hematocrit, nucleated red blood cells (nRBC), reticulocyte count, platelet count, peripheral blasts, 
mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and red blood cell 
distribution width (RDW). On dosing days, hemoglobin values may be drawn and resulted (up to 1 day) prior to dosing (see Section 10.8, Individual Dose
Modification Rules). 
10
Serum Chemistry: Sodium, potassium, AST, ALT, lactate dehydrogenase (LDH), total bilirubin, direct bilirubin, alkaline phosphatase, blood urea nitrogen 
(BUN)/urea, creatinine, gamma-glutamyl transpeptidase (GGT), calcium, phosphorus, glucose, amylase, lipase, total protein, albumin, and uric acid. 
11
Urinalysis by dipstick analysis (local lab): pH, specific gravity, protein, glucose, ketones, blood, leukocyte esterase, and nitrite, with microscopic 
examination if indicated. Urine Chemistry (central lab): urine chemistries include but are not limited to: microalbumin and creatinine.
12
If the patient has a positive ADA result at their last assessment, the patient may be asked to return approximately every three months for additional testing, 
until a negative result is obtained or the result is considered stabilized.
13
PD Biomarkers: May include hepcidin, GDF15, GDF8, GDF11, Activin A and others to be determined.
14
Pregnancy test: (urine or serum) is required for female patients of child bearing potential only.
15
Transfusion Frequency: Transfusion history will be collected from the EOS visit in the base study A536-03 through the C1D1 visit of A536-05 as 
available for patients with treatment interruption up to 24 weeks. TD patients will have a defined “pre-transfusion hemoglobin threshold” for requiring 
transfusion during the study which will be calculated based on transfusion history and will be used for determining when to transfuse during the study. The 
baseline pre-transfusion hemoglobin threshold will be the mean of all documented pre-transfusion hemoglobin values during the 12 weeks prior to C1D1 of 
base study A536-03 (for TD patients without treatment interruption) or study A536-05 (for TD patients with treatment interruption).  During treatment, if the 


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pre-transfusion hemoglobin level is increased by ≥ 1 g/dL compared to the baseline pre-transfusion hemoglobin threshold for that patient, transfusion should 
be delayed by a minimum of 7 days and/or the number of units transfused should be reduced by 1 or more RBC units.  Patients should not be transfused if 
hemoglobin is ≥ 9 g/dL unless indicated for symptoms related to anemia or other reasons at the investigator’s discretion.
16
Cycles 16 through 87: Patients may complete up to 87 Cycles.  The last dose of ACE-536 may not be administered after 87 cycles or 1825 calendar days 
from C1D1, whichever occurs first.
17
End of Treatment (EOT): Should be performed 28 days (± 7 days) after the last dose of ACE-536.  Patients who discontinue treatment early should 
complete the EOT visit at the time of discontinuation, followed by PTFU, LTFU, and EOS visits.
18
Post-Treatment Follow-Up (PTFU): Patients will complete the PTFU visit 2 months (± 7 days) after the last dose of ACE-536
19
Long-Term Follow-Up (LTFU): Patients will complete LTFU visits every 3 months (± 7 days) after the last dose of ACE-536 for 3 years after the last dose 
of ACE-536.
20
End of Study (EOS): Should be performed 3 years after the last dose of ACE-536.
21
Long-Term Post-Treatment Follow-Up for overall survival (OS), progression to AML, other malignancies/pre-malignancies (please refer to Section 14.1 for 
details) may be conducted by record review (including public records if allowed by local regulations) and/or telephone contact with the patient, family, or 
the patient’s treating physician. The investigator must make every effort to obtain information regarding the patient’s survival status before determining the 
patient is lost to follow-up. 


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3.
TABLE OF CONTENTS
PROCEDURES IN CASE OF EMERGENCY.............................................................. 5 
1.
PROTOCOL SYNOPSIS ............................................................................ 6 
2.
SCHEDULE OF EVENTS........................................................................ 15 
3.
TABLE OF CONTENTS .......................................................................... 19 
4.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS............ 23 
5.
ETHICS ..................................................................................................... 26 
5.1. 
Institutional Review Board........................................................................ 26 
5.2. 
Ethical Conduct of the Study..................................................................... 26 
5.3. 
Patient Information and Consent ............................................................... 26 
5.4. 
Patient Data Protection .............................................................................. 26 
6.
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 27
7.
INTRODUCTION ..................................................................................... 28
7.1. 
Overview of Target Indication................................................................... 28 
7.2. 
Summary of Nonclinical Studies............................................................... 30 
7.2.1. 
Pharmacology Studies ............................................................................... 30 
7.2.2. 
Toxicology Studies .................................................................................... 30 
7.3. 
Summary of Clinical Experience............................................................... 30 
7.4. 
Potential Risks of Human Use................................................................... 31 
8.
TRIAL OBJECTIVES............................................................................... 33 
8.1. 
Primary Objective...................................................................................... 33 
8.2. 
Secondary Objectives ................................................................................ 33 
8.3. 
Exploratory Objective................................................................................ 33 
9.
OVERALL STUDY DESIGN AND PLAN: DESCRIPTION ................. 34 
9.1. 
Study Design.............................................................................................. 34 
9.2. 
Selection of Study Population ................................................................... 35 
9.2.1. 
Inclusion Criteria ....................................................................................... 35 
9.2.2. 
Exclusion Criteria...................................................................................... 36 
9.3. 
Patient Treatment Discontinuation and Withdrawal Criteria .................... 37 
10.
TREATMENT OF PATIENTS................................................................. 39 
10.1. 
Selection and Timing of Dose for Each Patient......................................... 39 
10.2. 
Concomitant Medications.......................................................................... 39 
10.2.1. 
Other Treatments for MDS........................................................................ 39 


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10.2.2. 
RBC Transfusions...................................................................................... 39 
10.3. 
Treatment Compliance............................................................................... 40 
10.4. 
Randomization........................................................................................... 40 
10.5. 
Treatments Administered........................................................................... 40 
10.6. 
Safety Review Team.................................................................................. 40 
10.7. 
Starting Dose Level ................................................................................... 40 
10.8. 
Individual Dose Modification Rules.......................................................... 41 
10.9. 
Individual Dose Titration........................................................................... 43 
10.9.1. 
Individual Dose Titration for NTD Patients .............................................. 43 
10.9.2. 
Individual Dose Titration for TD Patients................................................. 43 
10.10. 
Other Considerations for Dose Modification, Delay or Discontinuation.. 44 
11.
STUDY PROCEDURES........................................................................... 45 
11.1. 
Written Informed Consent......................................................................... 45 
11.2. 
Clinical Laboratory Tests .......................................................................... 45 
11.3. 
Other Safety Assessments.......................................................................... 46 
11.4. 
Pharmacokinetic and Pharmacodynamic Assessments ............................. 46 
11.4.1. 
Pharmacokinetic Assessments................................................................... 46 
11.4.2. 
Pharmacodynamic Evaluations.................................................................. 46 
12.
STUDY SCHEDULE ................................................................................ 47 
12.1. 
Screening ................................................................................................... 47 
12.2. 
Dosing Days and Interim Visits................................................................. 47 
12.3. 
End of Treatment Visit .............................................................................. 48 
12.4. 
Post-Treatment Follow-Up Visit ............................................................... 48 
12.5. 
Long-Term Follow-Up Visits.................................................................... 48 
12.6. 
End of Study Visit ..................................................................................... 48 
12.7. 
Termination of Study................................................................................. 49 
13.
STUDY DRUG MATERIALS AND MANAGEMENT .......................... 50 
13.1. 
Study Drug................................................................................................. 50 
13.2. 
Study Drug Packaging and Labeling ......................................................... 50 
13.3. 
Study Drug Storage.................................................................................... 50 
13.4. 
Study Drug Preparation ............................................................................. 50 
13.5. 
Administration........................................................................................... 50 
13.6. 
Study Drug Accountability........................................................................ 50 
13.7. 
Study Drug Handling and Disposal ........................................................... 51 


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14.
ASSESSMENT OF SAFETY.................................................................... 52 
14.1. 
Adverse Event Definitions......................................................................... 52 
14.2. 
Pregnancy and In Utero Drug Exposure.................................................... 53 
14.3. 
Severity...................................................................................................... 54 
14.4. 
Relationship to Study Drug ....................................................................... 54 
14.5. 
Documentation and Methods of Reporting of Adverse Events by 
Investigator ................................................................................................ 54 
14.5.1. 
Documentation of Serious Adverse Events ............................................... 55 
14.6. 
Reporting Period and Monitoring of Patients with Adverse Events.......... 55 
14.7. 
Notification about Serious Adverse Events............................................... 56 
14.7.1. 
Safety Reporting to Health Authorities, Independent Ethics Committees 
Institutional Review Boards and Investigators.......................................... 56 
15.
STATISTICS ............................................................................................. 58 
15.1. 
Analysis Populations ................................................................................. 58 
15.2. 
Statistical Plan ........................................................................................... 58 
15.2.1. 
Patient Accountability and Demographics ................................................ 58 
15.2.2. 
Primary Endpoint Analysis........................................................................ 58 
15.2.3. 
Secondary Analysis ................................................................................... 58 
15.2.4. 
Pharmacokinetics Analysis........................................................................ 59 
15.2.5. 
Anti-drug Antibody Analysis .................................................................... 59 
15.3. 
Determination of Sample Size................................................................... 60 
15.4. 
Interim Analysis......................................................................................... 60 
15.5. 
Deviation from Original Analysis Plan ..................................................... 60 
16.
SOURCE DOCUMENTATION AND INVESTIGATOR FILES............ 61 
16.1. 
Study Monitoring....................................................................................... 61 
16.2. 
Audits and Inspections............................................................................... 61 
17.
QUALITY CONTROL AND QUALITY ASSURANCE ........................ 61 
17.1. 
Data Quality Control and Quality Assurance ............................................ 61 
17.1.1. 
Investigator Responsibility........................................................................ 61 
17.1.2. 
Protocol Modifications .............................................................................. 61 
18.
CONFIDENTIALITY ............................................................................... 62 
19.
PUBLICATION POLICY ......................................................................... 62 
20.
PROTOCOL AMENDMENTS................................................................. 62 
21.
DATA HANDLING AND RECORDKEEPING ...................................... 63 


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21.1. 
Case Report Form Completion.................................................................. 63 
21.2. 
Retention of Records ................................................................................. 63 
22.
STUDY FINANCE AND INSURANCE.................................................. 64 
22.1. 
Study Finance ............................................................................................ 64 
22.2. 
Insurance.................................................................................................... 64 
23.
REFERENCES .......................................................................................... 65 
24.
APPENDICES ........................................................................................... 67 
24.1. 
Appendix 1:  Who Classification and Criteria for the Myelodysplastic 
Syndromes ................................................................................................. 67 
24.2. 
Appendix 2:  International Prognostic Scoring System (IPSS) for 
Myelodysplastic Syndromes (MDS).......................................................... 68 
24.3. 
Appendix 3:  Revised International Prognostic Scoring System (IPSS-R) 
for Myelodysplastic Syndromes (MDS).................................................... 69 
24.4. 
Appendix 4:  ECOG Performance Status .................................................. 70 
24.5. 
Appendix 5:  International Working Group (IWG) Criteria - Erythroid 
Response Evaluation.................................................................................. 71 
24.6. 
Appendix 6:  National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) Version 4.0................................... 72 
24.7. 
Appendix 7:  International Working Group Response Criteria for 
Myelodysplastic Syndromes...................................................................... 73 


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4.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ActRIIB
Activin receptor IIB
ADA
Anti-drug antibody
AE
Adverse event
ALT
Alanine aminotransferase
AML
Acute myeloid leukemia
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
BMP
Bone morphogenetic protein
BSC
Best supportive care
BUN
Blood urea nitrogen
CXDY
Cycle X Day Y
CBC
Complete blood count
Cmax
Maximum concentration
CMML
Chronic myelomonocytic leukemia
CRF
Case report form
CRO
Contract research organization
DBP
Diastolic blood pressure
ECD
Extracellular domain
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EE
Efficacy Evaluable
ESA
Erythropoiesis stimulating agent
EOS 
End of study 
EPO
Erythropoietin
EOT
End of treatment 
FACT-An
Functional Assessment of Cancer Therapy-Anemia Scale
FDA
United States Food and Drug Administration
FSH
Follicle-stimulating hormone 
GCP
Good clinical practices
G-CSF
Granulocyte colony-stimulating factor
GDF
Growth and differentiation factor
GGT
Gamma-glutamyl transpeptidase


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Abbreviation
Definition
GM-CSF
Granulocyte-macrophage colony-stimulating factor
HBV
Hepatitis B virus
HCV
Hepatitis C virus
Hgb
Hemoglobin
HI-E
Erythroid response
HI-N
Neutrophil response
HI-P
Platelet response
HIV
Human immunodeficiency virus
IB
Investigator’s brochure
ICF
Informed consent form
ICH
International conference on harmonisation
IEC
Independent ethics committee
IgG1
Immunoglobulin G1
mITT
Modified Intent-to-Treat
IPSS
International Prognostic Scoring System
IWG
International Working Group 
IV
Intravenous
KD
Dissociation constant
LDH
Lactate dehydrogenase
LTFU
Long-term follow-up
MedDRA
Medical Dictionary for Regulatory Activities
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MDS
Myelodysplastic syndromes
NCI-CTCAE
National Cancer Institute-Common terminology criteria for adverse events
nRBC
Nucleated red blood cell
NTD
Non-transfusion dependent 
ORR
Overall response rate
PD
Pharmacodynamic
PFS
Progression free survival
PHI
Protected health information
PK
Pharmacokinetic


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Abbreviation
Definition
PTFU
Post-treatment follow-up
QoL
Quality of life
RBC
Red blood cell
RDW
Red blood cell distribution width
SAE
Serious adverse event
SAP
Statistical analysis plan
SBP
Systolic blood pressure
SC
Subcutaneous
SD
Standard deviation
SRT
Safety review team
SUSAR
Suspected unexpected serious adverse reaction
T1/2
Elimination half-life
TD
Transfusion dependent 
TGF-β
Transforming growth factor beta
TIBC
Total iron binding capacity
Tmax
Time to maximum concentration
ULN
Upper limit of normal
WBC
White blood cell
WHO
World Health Organization


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5.
ETHICS
5.1.
Institutional Review Board
The investigator will submit this protocol, any protocol modifications, and the patient Informed 
Consent Form (ICF) to be used in this study to the appropriate IEC for review and approval.  A 
letter confirming IEC approval of the protocol and ICF as well as a statement that the IEC is
organized and operates according to Good Clinical Practice (GCP) and the applicable laws and 
regulations, must be forwarded to the sponsor prior to the enrollment of patients into the study.  
A copy of the approved ICF will also be forwarded to the sponsor. Appropriate reports on the 
progress of the study will be made to the IEC and the sponsor by the principal investigator in 
accordance with applicable governmental regulations and in agreement with the policy 
established by the sponsor.
5.2.
Ethical Conduct of the Study
The sponsor and the investigator must comply with all instructions, regulations, and 
agreements in this protocol and in the applicable International Council on Harmonisation 
(ICH) and GCP guidelines, and must also conduct the study in accordance with local 
regulations.  
5.3.
Patient Information and Consent
Informed written consent is required from each patient prior to any testing under this protocol, 
including screening tests and evaluations. The ICF, as specified by the study center’s IEC,
must follow the Protection of Human Patients regulations listed in the Code of Federal 
Regulations, Title 21, Part 50.  The principles of informed consent in the Declaration of 
Helsinki should be implemented in this clinical study and should comply with local and 
national regulations. The consent forms must be in a language fully comprehensible to the 
prospective subject. Information should be given in both oral and written form whenever 
possible and deemed appropriate by the IEC.
The background of the proposed study and the benefits and risks of the procedures and study 
must be explained to the patients.  It is the responsibility of the investigator to obtain consent 
and to provide the patient with a copy of the signed and dated ICF.  Confirmation of a patient’s 
informed consent must also be documented in the patient’s medical record prior to any testing 
under this protocol, including screening tests and evaluations.
All ICFs used in this study must be approved by the appropriate IEC and by the Sponsor or 
designee.  The ICF must not be altered without the prior agreement of the relevant IEC and the 
Sponsor.  
5.4.
Patient Data Protection
Prior to any testing under this protocol, including screening tests and evaluations, patients must 
authorize the release and use of protected health information (PHI), as required by local law.
The patient will not be identified by name in the case report form (CRF) or in any study 
reports.  These reports will be used for research purposes only.  The Sponsor, its designee, and 


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various government health agencies may inspect the records of this study.  Every effort will be 
made to keep the patient’s personal medical data confidential.
6.
INVESTIGATORS AND STUDY ADMINISTRATIVE
STRUCTURE
Acceleron Pharma is the sponsor for this trial.  The sponsor will serve as the medical monitor 
for the study.  The sponsor or designee also will manage the conduct of the trial and provide 
for clinical monitoring, data management, biostatistics, and report writing.  Clinical monitors
will monitor each study center on a periodic basis and verify source documentation for each 
patient.  The sponsor’s pharmacovigilance representative will be responsible for timely 
reporting of serious adverse events (SAEs) to health authorities as required.


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7.
INTRODUCTION
ACE-536 is a recombinant fusion protein consisting of a modified form of the extracellular 
domain (ECD) of the human activin receptor type IIB (ActRIIB) linked to the human IgG1 Fc 
domain. The ActRIIB receptor and its ligands are members of the TGFβ 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 TGFβ family as the ligands and receptors are highly conserved across species.3 Thus,
observations from pharmacology studies of ACE-536 or its murine analog RAP-536 in animal 
models provide significant insight into the potential of ACE-536 to treat human disease.
Members of the TGFβ family are reported to play a role in red blood cell (RBC) development 
(erythropoiesis). In nonclinical experiments, ACE-536 has been shown to bind with high 
affinity to some TGFβ ligands (e.g., GDF8, GDF11, BMP6 and activin B) but substantially 
less, or not at all, to others (e.g., BMP10 and activin A). The emerging body of evidence on 
ACE-536 suggests that its mechanism of action is completely independent from that of 
erythropoietin (EPO), and involves stimulation of the later, maturation phase of erythroblast 
differentiation and maturation in the bone marrow.
7.1.
Overview of Target Indication
The target indication for ACE-536 is for the treatment of anemia in patients with 
myelodysplastic syndromes (MDS).  MDS are heterogeneous diseases characterized by 
abnormal proliferation and differentiation of erythropoietic precursor cells in the bone marrow, 
resulting in peripheral cytopenias; approximately 25-30% of patients with MDS have 
progression to acute myeloid leukemia (AML).4,5,6
MDS is a hematologic neoplasm primarily of the elderly, with 86% of MDS cases diagnosed in 
individuals age ≥ 60 years (median age at diagnosis, 76 years).  According to the SEERS data, 
approximately 12,000 patients are diagnosed with MDS per year in the United States and 
approximately 20,000 in Europe.7 The incidence rate of MDS in Germany is 4.1 per 100,000,8
with a median age between 68 and 73 years.9 Looking at a subset of patients in Düsseldorf, the 
incidence of MDS is higher in men than women with the incidence and prevalence increasing 
dramatically with age.10 With the number of people over the age of 65 expected to rise over 
the next four decades in developed countries such as Germany, there will likely be a correlated 
rise in the number of patients diagnosed with MDS.11
MDS classification systems have been established to address the heterogeneity of MDS.  The 
International Prognostic Scoring System (IPSS) (Appendix 2) categorizes the different types of 
MDS by the number of bone marrow blasts, the number of cytopenias, and bone marrow 
cytogenetics to predict survival and potential progression to AML.6 The IPSS has four risk 
categories: low, intermediate-1, intermediate-2, and high.  Standardized response criteria for 
clinical trials have been established to evaluate response to the treatment.  The International 
Working Group (IWG) criteria is an evaluation tool often used to quantify the quality of a 
response to treatment and for the consideration of risk based treatment goals.1
Therapy for MDS is based on patient age, IPSS risk category, and ECOG performance status
(Appendix 4).12 MDS can be cured by stem cell transplantation; however, most patients cannot 
receive the transplant due to age or limited availability of appropriate donors.  Therefore, 
supportive care is often provided for these patients.  The median survival rate for low risk 
MDS is 5.7 years and decreases to 3.5 years for patients with intermediate-1 risk MDS.6,13


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Anemia is the predominant cytopenia observed in MDS and is present in 85% of MDS patients 
at the time of diagnosis.14 Refractory anemia resulting from ineffective erythropoiesis is a 
major cause of morbidity and mortality in MDS patients.15 Supportive care with blood 
transfusions, erythropoiesis stimulating agents (ESAs), and other growth factors are used to 
treat anemia.
Clinical studies have demonstrated that ESAs can provide clinical benefit to MDS patients by 
reducing the need for RBC transfusions.  Only one third of unselected patients treated with 
ESAs have an erythroid response.16,17 A significant number of MDS patients have serum EPO 
levels in excess of 500 U/L, indicating the anemia in MDS is not a consequence of endogenous 
EPO deficiency and unlikely to respond to exogenous EPO.18 This observation suggests that 
impaired erythropoiesis in MDS patients occurs downstream of the steps that are regulated by
EPO.  Ineffective erythropoiesis leading to anemia in MDS patients appears to be associated 
with intramedullary apoptosis of cells during the later stages of erythrocyte development
beyond those regulated by EPO.19,20
The azanucleosides, azacitidine (Vidaza®) and decitabine (Dacogen®), and lenalidomide 
(Revlimid®) have demonstrated activity in patients with MDS.21,22 A randomized phase 3 trial 
comparing azacitidine with best supportive care (BSC) demonstrated hematologic 
improvement, delayed progression to AML or death and improved quality of life.23 A second 
phase 3 trial demonstrated improved 2-year overall survival.24 A phase 3 study comparing 
decitabine with BSC showed improved overall response rate (ORR) and progression-free 
survival (PFS).25
MDS represents a significant hematologic malignancy of the elderly population, contributing 
to serious comorbidities and increased health care use and cost.  Given the high prevalence of 
cardiac and other comorbidities in this patient population, and the strong association between 
comorbidities, transfusional support, and iron overload, strategies to improve anemia and 
maintain adequate iron balance are critical in managing patients with MDS.4


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7.2.
Summary of Nonclinical Studies
A brief summary of key findings from pharmacology and toxicology studies is provided below.  
A comprehensive review of ACE-536, as well as details regarding the information summarized 
below, is provided in the Investigator’s Brochure (IB). The ACE-536 IB should be reviewed 
prior to initating the study. 
7.2.1.
Pharmacology Studies
In vitro and in vivo pharmacology studies have been conducted with ACE-536 or its murine 
ortholog, RAP-536. The RAP-536 molecule has the same ECD as ACE-536, but contains a 
murine IgG Fc domain in place of the human IgG Fc.  The RAP-536 ortholog is substantially 
less immunogenic in rodent species and therefore permitted the conduct of longer term 
pharmacology studies in rodents without the confounding influence of immune reactivity.
ACE-536 has been shown to have significant effects on erythropoiesis.  Evidence suggests that 
it binds ligands that normally act to modulate the differentiation of late-stage erythroid 
precursors (normoblasts).  Because ACE-536 affects late-stage erythrocyte precursor 
populations, its action is distinct from that of EPO.  Unlike EPO, ACE-536 is not a 
growth-promoting cytokine.
Studies of ACE-536 in normal animals across several species (mice, rats, and cynomolgus 
monkeys) demonstrated an erythroid response that was rapid in onset, robust, and sustained.  
These effects were also demonstrated in a variety of animal models of anemia, including 
anemia associated with kidney failure, acute blood loss, and chemotherapy.  
RAP-536 was shown to significantly improve hematologic parameters, including increased 
hemoglobin concentrations, and to correct ineffective erythropoiesis and anemia in mouse 
models of MDS and E-thalassemia, both target indications for ACE-536.  This is consistent 
with its proposed mechanism of action of driving the late stages of erythroid differentiation 
that is downstream and distinct from EPO. 
Additional information regarding pharmacological effects of ACE-536 is summarized in the 
current version of the ACE-536 IB.
7.2.2.
Toxicology Studies
Repeat-dose toxicology studies of 1 and 3 month treatment duration have been conducted with 
ACE-536 in Sprague-Dawley rats and cynomolgus monkeys to evaluate the toxicity of 
ACE-536.  Recovery periods of up to 10 weeks were included as part of these studies. In 
addition, the main phase of a repeat-dose toxicology study of 6 months treatment duration in 
cynomolgus monkeys is complete. Findings from toxicology studies are described in more 
detail in the IB.
7.3.
Summary of Clinical Experience
The safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) effects of 
ACE-536 was evaluated in healthy postmenopausal women in a phase 1, randomized, double-
blind, placebo-controlled, multiple ascending dose study (Study A536-02).  The primary 
objective of the study was to evaluate the safety and tolerability of ACE-536 in this population.
Secondary objectives of the study are to examine the PK parameters and PD effects of
ACE-536.


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A total of 32 subjects were enrolled.  Eligible subjects were healthy, postmenopausal women, 
45-75 years old.  The anticipated PD effect was an increase in plasma hemoglobin level.
Screening and baseline hemoglobin values had to be between 11.0 and 14.5 g/dL, inclusive, to
mitigate the risk of substantial excursions above the normal range. Sequential cohorts of 8
subjects each were randomized to receive either ACE-536 (n=6) or placebo (n=2) administered
as a SC injection on Day 1 and Day 15.  Each subject was to be followed for 112 days
(16 weeks) after receiving their last dose of ACE-536 or placebo.  The following dose levels
were evaluated: 0.0625, 0.125, and 0.25 mg/kg.
ACE-536 administered every 2 weeks by subcutaneous (SC) injection for one or two doses at 
dose levels of 0.0625, 0.125 or 0.25 mg/kg was generally safe and well-tolerated in healthy 
postmenopausal female subjects.  No serious or severe adverse events (AE) were reported.  
The majority of AEs were considered mild in severity.  AEs that were considered at least
possibly drug-related across ACE-536 dose groups included injection site hemorrhage 
(3 subjects), injection site macule (2 subjects), and dry skin, macule, hyperesthesia, muscle 
spasms, myalgia, generalized pruritus, and papular rash (1 subject each). Injection site pain 
was reported in one placebo-treated subject.
PK results indicated mean area under the concentration-time curve (AUC) and maximum 
concentration (Cmax) values increased in a dose-proportional manner with ACE-536 dose level; 
mean time to maximum concentration (Tmax) ranged from 7.0 to 9.8 days, and mean T½ ranged 
from 14.9 to 16.2 days after the first dose.  These PK results support intermittent SC dosing of 
ACE-536 in future studies, e.g., every 3 weeks.
PD assessments for hematological markers showed increases in hemoglobin levels at the 
0.125 mg/kg dose level and more consistently at the 0.25 mg/kg dose level.  Small increases in 
reticulocyte count and EPO levels were also observed at the two higher dose levels of 
ACE-536 investigated.  A small decrease in serum follicle-stimulating hormone (FSH) levels 
was observed at 0.25 mg/kg. These data support further studies of ACE-536 in conditions 
associated with ineffective erythropoiesis and anemia.
Two phase 2 studies with ACE-536 are ongoing.  Study A536-03 is entitled, “A Phase 2, 
Open-Label, Ascending Dose Study of ACE-536 for the Treatment of Anemia in Patients with 
Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS)”.  Study A536-04 is entitled 
“A Phase 2, Open-Label, Ascending Dose Study to Evaluate the Effects of ACE-536 in 
Patients with ß-Thalassemia”.  Preliminary results from these studies and additional 
information regarding the completed Phase 1 study can be found in the current version of the 
IB.
7.4.
Potential Risks of Human Use
Increases in hematologic parameters (RBC, hemoglobin, hematocrit, reticulocytes) are 
expected pharmacologic effects of ACE-536 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 
modifications rules for individual patients and dose escalation/reduction rules will be utilized 
to minimize risks associated with increased RBC parameters.
AEs observed in the Phase 1 study in healthy volunteers and the ongoing phase 2 studies that
were considered probably or possibly related to study drug included injection site reactions


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(hemorrhage, pruritus, rash), skin rash, hyperesthesia, muscle spasms, myalgia, pruritus, and 
hyperkalemia
As with all biologics, there is the potential for anti-drug antibodies (ADA) that can be 
associated with increased drug clearance and hypersensitivity reactions.  ADA formation 
against ACE-536 as well as human ActRIIB protein will be monitored in the initial clinical 
studies.
Repeat dose toxicology studies of 1 and 3 month duration have been conducted with ACE-536
in Sprague-Dawley rats and cynomolgus monkeys to evaluate the toxicity of ACE-536.  In 
addition, a repeat-dose toxicology study of 6 months treatment duration in cynomolgus 
monkeys is ongoing.  Reproductive toxicity studies are currently ongoing and therefore 
ACE-536 should not be administered to pregnant or nursing women.  Male and female patients
of childbearing potential participating in studies of ACE-536 must be willing to abstain from 
sexual intercourse or use adequate contraception during study participation and for at least 
12 weeks following treatment discontinuation. Please refer to the IB for additional information 
regarding findings from toxicology studies.  It is unknown if humans will experience any of the 
effects of ACE-536 that were noted in the rat and monkey toxicology studies.  Safety effects 
will be monitored closely through AE reporting, clinical laboratory tests, vital signs, and 
physical examinations.
A comprehensive review of ACE-536, as well as details regarding the information summarized 
above, is provided in the IB. The ACE-536 IB should be reviewed prior to initating the study. 


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8.
TRIAL OBJECTIVES
8.1.
Primary Objective
x
To evaluate the long-term safety and tolerability of ACE-536 in patients with low
or intermediate-1 risk MDS who were previously enrolled in study A536-03.
8.2.
Secondary Objectives
x
To evaluate erythroid response (modified HI-E from IWG 2006 criteria), defined as
proportion of patients with:

A mean hemoglobin (Hgb) increase ≥ 1.5 g/dL over an 8-week period as
compared to baseline, not influenced by RBC transfusion, in non-transfusion 
dependent (NTD) patients.

A decrease of ≥ 4 units or ≥ 50% of units of RBCs transfused over a period of 8 
weeks, relative to the 8 weeks immediately prior to Day 1, in transfusion 
dependent (TD) patients.
x
To evaluate rates of erythroid, neutrophil and platelet (HI-E, HI-N and HI-P)
responses (IWG 2006 criteria)
x
To evaluate the rate of RBC transfusion independence lasting ≥ 8 weeks in TD
patients
x
To evaluate time to HI-E response and duration of HI-E response (modified and
non-modified IWG 2006 criteria)
x
To evaluate the mean change in RBC transfusion burden in TD patients and mean
change in hemoglobin levels in NTD patients
x
To evaluate the PK profile of ACE-536
x
To evaluate other PD effects (e.g., iron overload/metabolism, EPO, and
reticulocytes)
8.3.
Exploratory Objective
x
To examine biomarkers related to the TGF-β superfamily
x
To examine self-reported quality of life using tools including but not limited to the
FACT-An questionnaire


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9.
OVERALL STUDY DESIGN AND PLAN: DESCRIPTION
This is a phase 2, open-label, extension study to evaluate the safety, tolerability, and PD effects 
of up to 60 months of ACE-536 treatment and 3 years of follow-up in patients with low or 
intermediate-1 risk MDS previously treated with ACE-536 for up to 3 months in the base study 
A536-03.
9.1.
Study Design 
Patients in all cohorts will receive ACE-536, administered subcutaneously (SC), every 3 weeks 
for up to 87 cycles or up to 1825 days, whichever occurs first. Dose titration(s), delay(s) and 
dose reduction(s) may be required for individual patients as outlined in the Individual Dose 
Modification Rules (Section 10.8).
The base study A536-03 is a phase 2, open-label, ascending dose study to evaluate the effects 
of ACE-536 on anemia in patients with low or intermediate-1 risk MDS who are not currently 
receiving treatment with an ESA.  A total of up to 153 patients may be enrolled in the base 
study A536-03 and may be eligible for study A536-05.
Consenting patients that meet the A536-05 eligibility criteria may immediately roll over from 
A536-03 to study A536-05.  These patients will forego the Post-treatment Follow-up (PTFU) 
and End of Study (EOS) visit of A536-03 to begin study A536-05.  For these patients, C1D1 of 
A536-05 may take place 28 (± 7) days after the last dose administered in the base study 
A536-03, which may coincide with the patient’s A536-03 End of Treatment (EOT) visit. 
These patients will be considered “patients without treatment interruption.” Patients enrolled in 
expansion cohorts 2 and 3 in Study A536-03 must meet the “patients without treatment 
interruption” criteria to be considered for the A536-05 study, unless otherwise prospectively 
approved by the sponsor. 
Patients who complete the EOS visit for the base study A536-03 prior to C1D1 of A536-05 are 
considered “patients with treatment interruption.”  These patients will have a 28-day screening 
period to allow them to be re-assessed for eligibility by meeting additional inclusion criteria, as 
defined in Section 9.2.
Patients who have completed the EOT visit for the base study A536-03 but have not reached 
the EOS visit (i.e. patients in the follow-up period for A536-03), may still participate, but 
should be treated as patients with treatment interruption and should not begin study A536-05
C1D1 until they have completed their A536-03 EOS visit so that new baseline assessments can 
be measured.
For patients without treatment interruption, transfusion status (NTD or TD) will carry-over 
from the base study A536-03. For patients with treatment interruption, transfusion status will 
be reassessed prior to C1D1 of study A536-05. Transfusion status for all patients is defined as 
follows for all patients:
x
NTD patients are defined as patients who require a transfusion of < 4 units of RBCs
in the 8 weeks prior to C1D1
x
TD patients are defined as patients who require a transfusion of ≥ 4 units of RBCs
in the 8 weeks prior to C1D1
Each TD patient will have a “pre-transfusion hemoglobin threshold” for requiring transfusion, 
which will be calculated based on transfusion history and will be used for determining when to 


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transfuse during the study.  The baseline pre-transfusion hemoglobin threshold will be the 
mean of all documented pre-transfusion hemoglobin values during the 12 weeks prior to C1D1 
of base study A536-03 for patients without treatment interruption, or prior to C1D1 of study 
A536-05 for patients with treatment interruption.  During treatment, if the pre-transfusion 
hemoglobin level is increased by ≥ 1 g/dL compared to the baseline pre-transfusion 
hemoglobin threshold for that patient, transfusion should be delayed by a minimum of 7 days 
and/or the number of units transfused should be reduced by 1 or more RBC units. Patients
should not be transfused if hemoglobin is ≥ 9 g/dL unless indicated for symptoms related to 
anemia or other reasons at the investigator’s discretion.
Patients will participate in the extension study A536-05 for approximately 8 years, including a 
28-day screening period, a 60-month treatment period and a 3-year follow-up period.
The SRT established for study A536-03 will review safety and PD data periodically throughout 
study A536-05.
9.2.
Selection of Study Population
9.2.1.
Inclusion Criteria
All patients must meet the following criteria: 
1. Completion of the treatment period in the base study A536-03.
2. Females of child bearing potential (defined as sexually mature women who have not
undergone hysterectomy or bilateral oophorectomy, or are not naturally
postmenopausal ≥ 24 consecutive months) must have negative urine or blood
pregnancy test prior to enrollment and use adequate birth control methods (abstinence,
oral contraceptives, barrier method with spermicide, or surgical sterilization) during
study participation and for 12 weeks following the last dose of ACE-536.  Males must
agree to use a latex condom during any sexual contact with females of child-bearing
potential while participating in the study and for 12 weeks following the last dose of
ACE-536, even if he has undergone a successful vasectomy.  Patients must be
counseled concerning measures to be used to prevent pregnancy and potential toxicities
prior to dosing with ACE-536.
3. Patient is able to adhere to the study visit schedule, understand and comply with all
protocol requirements.
4. Patient understands and is able to provide written informed consent.
Patients with treatment interruption (defined as patients who completed the A536-03
EOS visit) must also meet the following criteria:
5. Documented diagnosis of idiopathic/de novo MDS or non-proliferative chronic
myelomonocytic leukemia (CMML) according to WHO criteria16 (white blood count
[WBC] < 13,000/μL) that meets International Prognostic Scoring System (IPSS)
classification (Appendix 2) of low or intermediate-1 risk disease as determined by
microscopic and standard cytogenetic analyses of the bone marrow and peripheral
complete blood count (CBC) obtained during screening;
6. Anemia defined as:


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x
Mean hemoglobin concentration < 10.0 g/dL of 2 measurements (one performed
within one day prior to Cycle 1 Day 1 and the other performed 7-28 days prior to
Cycle 1 Day 1) for NTD patients (defined as having received ˂ 4 units of RBCs
within 8 weeks prior to Cycle 1 Day 1), OR
x
Transfusion Dependent (TD), defined as having received ≥ 4 units of RBCs within
8 weeks prior to Cycle 1 Day 1.
7. Platelet count (≥ 30 x 109/L).
8. ECOG performance status of 0, 1, or 2 (if related to anemia).
9. Adequate renal (creatinine ≤ 2.0 x upper limit of normal [ULN]) and hepatic (total
bilirubin < 2 x ULN and aspartate aminotransferase (AST) and alanine
aminotransferase (ALT) < 3 x ULN) function.
9.2.2.
Exclusion Criteria
All patients must not meet the following criteria:
1. Discontinuation/withdrawal from the base study A536-03 (due to patient request,
patient unwillingness or inability to comply with the protocol, pregnancy, use of
prohibited medication [e.g. azacitidine], medical reason or AE, disease progression,
persistent increase in white blood cell (WBC) count, presence of ≥ 1% blasts in
peripheral blood, hypersensitivity reaction to the study drug, at the discretion of the
sponsor, or loss to follow-up) prior to completion of the treatment period.
2. Prior treatment with azacitidine (injectable or oral) or decitabine.
3. Treatment within 28 days prior to Cycle 1 Day 1 with:
x
Erythropoiesis stimulating agent (ESA),
x
Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage
colony stimulating factor (GM-CSF),
x
Lenalidomide.
4. For patients with treatment interruption only: Iron chelation therapy if initiated within
56 days prior to Cycle 1 Day 1.
5. Treatment with another investigational drug (including sotatercept [ACE-011]) or
device, or approved therapy for investigational use ≤ 28 days prior to Cycle 1 Day 1, or
if the half-life of the previous investigational product is known, within 5 times the
half-life prior to Cycle 1 Day 1, whichever is longer.
6. Major surgery within 28 days prior to Cycle 1 Day 1. Patients must have completely
recovered from any previous surgery prior to Cycle 1 Day 1.
7. Known positive for human immunodeficiency virus (HIV), active infectious hepatitis B
(HBV) or active infectious hepatitis C (HCV).
8. Uncontrolled hypertension defined as systolic blood pressure (SBP) ≥ 150 mm Hg or
diastolic blood pressure (DBP) ≥ 100 mm Hg.
9. Pregnant or lactating females.


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10. History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant
proteins or excipients in the investigational drug.
11. Any other condition not specifically noted above which, in the judgment of the
investigator, would preclude the patient from participating in the study.
9.3.
Patient Treatment Discontinuation and Withdrawal Criteria
Patients will be informed that they have the right to discontinue treatment and/or withdraw 
from the study at any time for any reason without prejudice to their medical care.  
A patient may be discontinued from treatment for any of the following reasons: 
x
Patient’s request
x
Patient’s unwillingness or inability to comply with the protocol
x
Pregnancy
x
Use of prohibited medication (e.g., ESA)
x
Medical reason or AE, at the discretion of the investigator and/or the medical
monitor
x
Lack of effect (e.g., worsening anemia for NTD patients as evidenced by sustained
reduction in Hgb by ≥ 2 g/dL over 8 weeks or transfusion dependence), to be discussed
with the medical monitor
x
Disease progression (per IWG criteria for altering natural history of MDS1):

For patients with 5-10% blasts, a second bone marrow sample should be
collected within 4 weeks for clinical assessment (e.g., cytomorphology, 
cytogenetics) to confirm progression before discontinuing patients from 
treatment.
x
Persistent increase in white blood cell (WBC) count as per Individual Dose
Modifications Section 10.8
x
Presence of ≥ 1% blasts in peripheral blood as per Individual Dose Modifications
Section 10.8
x
Hypersensitivity reaction to study drug
x
At the discretion of the sponsor (e.g., termination of the study or a dose level)
A patient may be withdrawn from the study for any of the following reasons:
x
Patient’s request
x
Patient’s unwillingness or inability to comply with the protocol
x
Death
x
Loss to follow-up
x
At the discretion of the sponsor (e.g., termination of the study)
The reasons for study withdrawal and/or treatment discontinuation must be recorded in the 
patient’s CRF.  The investigator must notify the sponsor, the medical monitor and the contract 


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research organization (CRO) immediately when a patient has been discontinued/withdrawn due 
to an AE.  Patients who discontinue treatment early should complete the EOT follow-up visit at 
the time of discontinuation, then complete the PTFU visit 2 months ± 7 days after the last dose 
of ACE-536, the LTFU visits every 3 months, and finally the EOS visit 3 years after the last 
dose of ACE-536.
The investigator must notify the sponsor and the CRO when a patient has been 
discontinued/withdrawn for reasons unrelated to the study or study drug (e.g., withdrawn 
consent, lost to follow-up).


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10.
TREATMENT OF PATIENTS
10.1.
Selection and Timing of Dose for Each Patient
Once a patient is enrolled, the appropriate dose of ACE-536 will be administered as a SC
injection on Cycle 1 Day 1.  Subsequent doses will be administered every 3 weeks on Day 1 of 
the cycle for up to 87 cycles. The last dose of ACE-536 may not be administered after 87
cycles or 1825 calendar days from C1D1, whichever occurs first. Dose reductions may be 
required for individual patients as outlined in the Individual Dose Modifications Rules 
(Section 10.8).  If a dose delay is required, the patient will return every 1-3 weeks for 
assessment of hematology results and AEs until the patient is eligible to receive the next dose 
of ACE-536.  Patients will be asked to return to the clinic for follow-up visits, the first 
occurring approximately 28 days after the last dose of ACE-536 and then approximately every 
3 months from then on, until 3 years after the last dose of ACE-536. If a patient has a positive 
ADA result at the last visit, the patient may be asked to return for additional ADA testing every 
three months, until a negative result is obtained or the result is considered to be stabilized.
10.2.
Concomitant Medications
During screening and throughout the study, patients may take stable doses of medications for 
chronic conditions that are not specifically excluded by the protocol (see Section 9.2). If a 
patient requires treatment with any new medications that are specifically excluded by the 
eligibility criteria, the patient will be discontinued from the study and should complete the 
EOT visit and enter the 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 patient to discontinue from the study. For patients with 
treatment interruption, concomitant medications will be collected beginning at study screening
and will include all medications taken within 28 days prior to Cycle 1 Day 1. For patients 
without treatment interruption, concomitant medication will be collected beginning at C1D1.
10.2.1.
Other Treatments for MDS
If treatment with azacitidine, decitabine, lenalidomide, ESA, or G-CSF is required during the 
ACE-536 treatment period, the patient should be discontinued from treatment with study drug
and complete the EOT visit and enter the follow-up period. Iron chelation therapy is allowed
for patients without treatment interruption.  For patients with treatment interruption, iron 
chelation therapy is allowed unless initiated within 56 days prior to C1D1. If iron chelation 
therapy is required during study treatment, patient should follow standard of care for 
management of iron chelation therapy.
10.2.2.
RBC Transfusions
Concurrent treatment for anemia with blood transfusions is allowed, at the discretion of the 
investigator, for low hemoglobin levels, symptoms associated with anemia (e.g., hemodynamic 
or pulmonary compromise requiring treatment) or comorbidity.
For any RBC transfusions (NTD or TD patients) received during the study, collect hemoglobin 
values just prior to transfusion.


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Each TD patient will have a “pre-transfusion hemoglobin threshold” for requiring transfusion, 
which will be calculated based on transfusion history and will be used for determining when to 
transfuse during the study.  The baseline pre-transfusion hemoglobin threshold will be the
mean of all documented pre-transfusion hemoglobin values during the 12 weeks prior to C1D1 
of base study A536-03 for patients without treatment interruption, or prior to C1D1 of study 
A536-05 for patients with treatment interruption.  During treatment, if the pre-transfusion 
hemoglobin level is increased by ≥1 g/dL compared to the baseline pre-transfusion 
hemoglobin threshold for that patient, transfusion should be delayed by a minimum of 7 days 
and/or the number of units transfused should be reduced by 1 or more RBC units. Patients
should not be transfused if hemoglobin is ≥ 9 g/dL unless indicated for symptoms related to 
anemia or other reasons at the investigator’s discretion.
10.3.
Treatment Compliance
ACE-536 will be administered as a SC injection at the clinical site by the study staff and will 
be documented in the study record.  Monitoring for patient compliance with the treatment 
regimen is therefore unnecessary. 
10.4.
Randomization 
This is an open-label study and a randomization scheme is not needed for this study.
10.5.
Treatments Administered
A patient participating in the extension Study A536-05 without treatment interruption may 
continue to be dosed with ACE-536 at the same dose level administered at their last dose in the
base study A536-03 (see Section 10.7, Starting Dose Level). All patients with treatment 
interruption (defined as patients who have completed their EOS visit for study A536-03) will 
be initially treated with ACE-536 at an assigned starting dose level of 1.0 mg/kg, which has 
been determined to be safe and well tolerated by the Safety Review Team (SRT) based on data
from the base study A536-03.
10.6.
Safety Review Team
Safety will be evaluated by the SRT, which is comprised at minimum of the coordinating 
investigator, medical monitor, and an independent hematologist.  The role of the SRT will be 
described in greater detail in the SRT Charter.  The SRT will review safety data periodically 
throughout the trial, including AEs, SAEs, laboratory results (including hematology and 
chemistry), vital signs, and erythroid response data. 
10.7.
Starting Dose Level
A patient without treatment interruption may continue to be dosed with ACE-536 at the same 
dose level administered at their last dose in study A536-03, unless a dose reduction is required 
based upon patient dose modification rules from study A536-05. All patients with treatment 
interruption will be initially treated with ACE-536 at an assigned starting dose level of
1.0 mg/kg which has been deemed to be safe, well tolerated, and at least minimally effective
by the SRT based on data from study A536-03. Examples of possible starting dose levels with 
respective dose levels for modification (reductions and titrations) are shown in the table below 
for reference.  




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Observation on Dosing Day
Action
ACE-536 Dose Modification
Hemoglobin ≥ 12 g/dL 
Hold dose and monitor patient until 
hemoglobin < 11 g/dL
Resume dosing once hemoglobin 
< 11 g/dL 
Hemoglobin ≥ 2 g/dL increase from 
the previous dosing day, not 
attributable to RBC transfusion  
Continue dosing 
Reduce the dose by 1 dose level 
Non-hematologic AE ≥Grade 3, at 
least possibly related to study drug
Hold dose and monitor patient until 
resolution of AE to ≤Grade 1 or 
baseline
Resume dosing upon resolution of 
the AE to ≤Grade 1 or baseline, 
and reduce the dose by 1 dose 
level a
≥50% increase in white blood cell 
count (WBC) compared to pre-dose 
WBC of previous treatment cycle and 
above upper limit of normal in the 
absence of an associated condition 
(e.g., infection or concomitant 
corticosteroid use)b
Dose delay; recheck CBC, 
including WBC at least weekly 
during dose delay.
Treatment may be resumed if
WBC values are below upper limit 
of normal within 2 weeks
If WBC remains above upper limit 
of normal 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:
x
Absence of disease
progression per IWG response
criteria for altering natural
history of MDS1
AND
x
WBC values return below
upper limit of normal
Discontinue treatment if:
x
Disease progression per IWG
response criteria for altering
natural history of MDS1
OR
x
WBC remain above upper
limit of normal
Presence of ≥ 1% blasts in peripheral 
blood (based on local laboratory 
hematology sample)
Dose interruption; immediately 
prepare peripheral blood smear for 
cytomorphology assessment.
If cytomorphology assessment 
confirms ≥ 1% blasts in the 
peripheral blood; discontinue 
treatment
If cytomorphology assessment 
determines < 1% peripheral blasts 


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Observation on Dosing Day
Action
ACE-536 Dose Modification
are present, repeat hematology 
assessment.
x
If presence of < 1% blasts in
peripheral blood, treatment
can be resumed at next
scheduled dosing cycle.
x
If presence of ≥ 1% blasts in
peripheral blood; discontinue
treatment
a Patients who require more than 2 dose reductions due to an AE should be discontinued from treatment and 
complete the EOT, PTFU, LTFU, and EOS visits.
b The investigator may contact the medical monitor and forward appropriate supporting documents for review and 
discussion prior to making decision regarding treatment discontinuation.
10.9.
Individual Dose Titration
10.9.1.
Individual Dose Titration for NTD Patients 
For NTD patients (with or without interruption), after C1D1, the dose level will be assessed for 
titration every cycle starting at C3D1) (e.g., C3D1, C4D1, C5D1, etc.). The dose level should 
be titrated individually for each patient not to exceed the maximum dose level evaluated in the 
base study A536-03 as follows:  
x
If hemoglobin increase from baseline is < 1.5 g/dL throughout the previous two
cycles at the same dose level, the dose level will be increased by 1 dose level
(unless dose modification is required).
x
If hemoglobin increase from baseline is ≥ 1.5 g/dL but not sustained for at least two
consecutive study measurements during the previous two cycles at the same dose
level, the dose level will be increased by approximately 1 dose level (unless dose
modification required).
x
If hemoglobin increase from baseline is ≥ 1.5 g/dL (not influenced by RBC
transfusion) as measured by two or more consecutive study measurements during
the previous two cycles at the same dose level, the dose level will be unchanged
(unless dose modification is required).
Baseline hemoglobin to assess titration will be the average of two or more measurements 
performed during the screening period for base study A536-03 (for patients without treatment 
interruption) or study A536-05 (for patients with treatment interruption).
10.9.2.
Individual Dose Titration for TD Patients
For all TD patients (with and without treatment interruption), the dose level will be assessed 
for titration every cycle starting at Cycle 3 Day 1 (e.g., C3D1, C4D1, C5D1, etc.).  The dose 
level should be titrated individually for each patient not to exceed the maximum dose level 
evaluated in the base study A536-03 as follows:
x
If patient has ≥ 1 transfusion event during the previous 2 cycles at the same dose
level, the dose will be increased by 1 dose level (unless a dose modification is
required).


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10.10.
Other Considerations for Dose Modification, Delay or 
Discontinuation
For individual patients judged by the investigator to be at an unacceptable risk, but who do not 
meet the protocol-defined conditions for a dose modification or interruption, the investigator 
should consult with the medical monitor to decide whether to continue dosing at the same dose 
level, reduce the dose level, delay the patient’s dose, or discontinue the patient’s treatment with 
ACE-536.
Patient treatment interruption for site administrative reasons will be allowed between Cycles
17 and 18 and between Cycles 35 and 36 upon discussion with the sponsor.


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11.
STUDY PROCEDURES
Please refer to Section 2, Schedule of Events for the schedule of procedures required for each 
visit.
11.1.
Written Informed Consent
Patients will be required to sign an IEC approved ICF prior to any study related procedures, 
including screening evaluations.
11.2.
Clinical Laboratory Tests
The following laboratory assessments will be performed at the clinical site’s local laboratory 
according to the laboratory collection recommendations.  The sponsor may request additional 
safety tests be performed based on ongoing data review during the study. 
x
Hematology: RBC, WBC with differential, hemoglobin, hematocrit, reticulocyte
count, platelet count, peripheral blasts, mean corpuscular volume (MCV), mean
corpuscular hemoglobin (MCH), Mean corpuscular hemoglobin concentration
(MCHC), and red blood cell width (RDW).
x
Serum chemistry: Sodium, potassium, AST, ALT, lactate dehydrogenase (LDH),
total bilirubin, direct bilirubin, alkaline phosphatase, blood urea nitrogen
(BUN)/urea, creatinine, gamma- glutamyl transpeptidase (GGT), calcium,
phosphorus, glucose, amylase, lipase, total protein, albumin, and uric acid.
x
Urinalysis by dipstick analysis: pH, specific gravity, protein, glucose, ketones,
blood, leukocyte esterase, and nitrite, with microscopic examination if indicated.
x
Pregnancy test for women of child bearing potential only
The following laboratory assessments will be performed at the central laboratory according to 
the laboratory collection recommendations.  The sponsor may request additional safety tests be 
performed based on ongoing data review during the study. 
x
Iron studies: Serum iron, TIBC, transferrin, soluble transferrin receptor, ferritin, and
hepcidin.
x
nRBC
x
EPO levels
x
Peripheral blood smear
x
Urine Chemistry: Microalbumin and creatinine.


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11.3.
Other Safety Assessments
x
Physical examination
x
Vital signs: weight, heart rate, systolic and diastolic blood pressure
x
ECOG Status
x
12-lead ECG
x
ADA testing
x
The occurrence of a new malignancy or premalignant lesion will be monitored as an
event of interest and should be included as part of the assessment of adverse events
throughout the course of the study. Investigators are to report the development of
any new malignancy or premalignant lesion as a serious adverse event, regardless
of causal relationship to study drug, occurring at any time for the duration of the
study, from the time of signing the ICF up to and including 3 years of follow-up.
11.4.
Pharmacokinetic and Pharmacodynamic Assessments
11.4.1.
Pharmacokinetic Assessments
PK assessment of ACE-536 concentrations will be performed periodically as outlined in 
Section 2, (Schedule of Events).  Blood samples should be drawn and processed on-site for 
serum collection at the time points specified.  Additional details regarding PK collection and 
processing can be found in the relevant Laboratory Manual.
11.4.2.
Pharmacodynamic Evaluations
x
PD assessments including hematologic laboratory assessments and transfusion
information will be used to determine erythroid response to ACE-536.
x
Bone marrow aspirates will be performed for histology, cytogenetics, and
morphology. Additional analyses may be included, such as flow cytometry and/or
molecular testing.
x
Blood biomarkers for iron metabolism will include serum iron, TIBC, transferrin,
soluble transferrin receptor, ferritin, and hepcidin.
x
Biomarkers related to the TGFE superfamily and/or iron metabolism, such as
GDF15, GDF8, GDF11, and others may be tested in blood and/or bone marrow
samples, to be determined.
x
The relationship of biomarkers to erythroid response may be investigated.
x
The sponsor may request additional biomarkers for exploratory research purposes
only.


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12.
STUDY SCHEDULE
Please refer to Section 2, Schedule of Events for the schedule of procedures required for each 
visit.  Note that all windows on visits should be determined relative to the date of the previous 
dose of ACE-536.
12.1.
Screening 
x
The screening period is only applicable to patients with treatment interruption
(defined as patients who completed the EOS visit for the base study A536-03).
x
Signature of the current IEC approved ICF should occur prior to initiation of any
study-specific screening procedures.
x
All screening procedures, except for a bone marrow aspirate, should occur within
28 days prior to Cycle 1 Day 1.
x
Patients with treatment interruption must have a bone marrow aspirate including
cytogenetics within 3 months prior to Cycle 1 Day 1 for evaluation of patient
eligibility per the additional inclusion criteria listed in Section 9.2.1.
x
Qualification is required per the additional inclusion criteria listed in Section 9.2.1.
x
Historical hemoglobin and transfusion history will be collected for up to 24 weeks,
where available, prior to Cycle 1 Day 1 of A536-05. Patients without treatment
interruption will be evaluated for secondary endpoints based on historical
hemoglobin and transfusion history collected for up to 24 weeks, where available,
prior to Cycle 1 Day 1 of A536-03.
x
Pregnancy test (urine or serum) is required of female patients of child bearing
potential during the screening period.
x
Concomitant medications taken within 28 days prior to Cycle 1 Day 1 will be
documented in the CRF.
x
A medical history will be collected at screening and will include medical events
occurring after EOS visit in study A536-03 and prior to C1D1 for study A536-05.
Medical history for patients without treatment interruption will be taken from study
A536-03.
x
Screen failure information will be maintained to document specific information,
including but not limited to, reason for failure.
12.2.
Dosing Days and Interim Visits
x
All screening and Cycle 1 Day 1 procedure results required to confirm eligibility
must be obtained and reviewed prior to study drug administration in A536-05.
Patient eligibility must be confirmed from these results.
x
For any RBC transfusions received during the study, the hemoglobin value just
prior to transfusion should be collected.
x
Note that the patient dose must be calculated based on the patient’s weight on the
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x
All study procedures on each dosing day must be done prior to administration of
study drug.
x
If a dose delay is required per the dose modification rules (Section 10.8), the patient
will not be dosed. The patient will return every 1-3 weeks for assessment of
hematology results and AEs until the patient is eligible to receive the next dose of
ACE-536. The patient should resume the study at the planned dosing cycle (e.g. if
the patient missed a dose at C4D1, then they would resume dosing at C4D1 and not
skip to C5D1).
x
The hematology results can be collected up to 24 hours prior to the dosing day.  For
patients with treatment interruption, the hemoglobin should be available to confirm
eligibility within one day prior.
x
A bone marrow aspirate must be performed within 21 days after C9D1, C17D1,
C25D1, C41D1, C57D1, and C73D1.
x
A pregnancy test (urine or serum) is required prior to ACE-536 administration on
all dosing days for female patients of childbearing potential.
x
For patients with treatment interruption, any non-serious AEs that occur prior to
dosing in cycle 1 should be recorded in the Medical History section of the CRF.
x
All AEs that occur after dosing in Cycle 1 should be recorded in the AE page of the
CRF.
x
On subsequent dosing days, all AEs and abnormal findings that might require
modification of dosing (see Section 10.8) should be reviewed prior to dosing to
ensure that the patient is still eligible to receive additional doses of ACE-536.
12.3.
End of Treatment Visit
x
The EOT visit should occur approximately 28 days after the last dose of ACE-536.
x
Patients who discontinue treatment early should complete the EOT visit at the time
of discontinuation.
x
A bone marrow aspirate is required at the EOT visit unless performed < 3 months
following a previous bone marrow aspirate and not clinically indicated.
12.4.
Post-Treatment Follow-Up Visit
x
The PTFU visit should occur approximately 2 months after the last dose of ACE-
536.
12.5.
Long-Term Follow-Up Visits
x
LTFU visits should occur approximately every 3 months for 3 years after the last
dose of ACE-536.
12.6.
End of Study Visit
x
The EOS visit should occur approximately 3 years after the last dose of ACE-536.


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x
Patients who discontinue treatment early should complete the EOS visit
approximately 3 years after the EOT visit.
x
If a patient has a positive ADA result at the last visit, the patient may be asked to
return for additional ADA testing every three months, until a negative result is
obtained or the result is considered to be stabilized.
12.7.
Termination of Study
The sponsor may terminate this study or discontinue a cohort, after consultation with the 
investigator(s), or at any time, for safety or administrative reasons.  The sponsor will terminate 
the study if the occurrence of SAEs or other findings suggests unacceptable risk to the health 
of the patients.  


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13.
STUDY DRUG MATERIALS AND MANAGEMENT
13.1.
Study Drug
ACE-536 is a recombinant fusion protein consisting of a modified form of the ECD of the 
human activin receptor IIB (ActRIIB) linked to the human IgG1 Fc domain.
13.2.
Study Drug Packaging and Labeling
ACE-536 drug product will be provided as either a sterile, liquid formulation or a lyophilized 
powder formulation for reconstitution with water. Each single-use vial of the liquid 
formulation contains 25 mg of ACE-536 in a 0.5 mL Tris-buffered saline solution (50 mg/mL).
Each single-use vial of the lyophilic formulation may contain either 25 mg, 50 mg, or 75 mg 
ACE-536 for reconstitution with 0.5 mL, 1 mL, or 1.5 mL water, respectively, to form a 
citrate-buffered solution (50 mg/mL) for injection.
13.3.
Study Drug Storage
ACE-536 liquid formulation is stored frozen at d -65˚C until use.
ACE-536 lyophilized powder formulation is stored between 2 - 8˚C until use.
13.4.
Study Drug Preparation
Please refer to the study drug handling guideline provided under separate cover, for detailed 
ACE-536 drug handling, administration, and storage instructions.  
13.5.
Administration
ACE-536 will be administered by SC injection. Multiple injections may be required to
administer the appropriate dose at higher dose levels; however, no more than 4 injections will 
be administered per dose.
13.6.
Study Drug Accountability
Accountability for ACE-536 is the responsibility of the investigator.  Investigational clinical 
supplies must be received by a designated person at the clinical site and kept in a secured 
location.  The clinical site must maintain accurate records demonstrating dates and amounts of 
ACE-536 received, to whom it was dispensed (patient-by-patient accounting), and accounts of 
any ACE-536 accidentally or deliberately destroyed or returned.
Unless otherwise notified, all vials of ACE-536, both used and unused, must be saved for drug 
accountability purposes.  The used vials may be discarded, per the institution’s standard 
practice, after drug accountability assessment has been completed by the clinical monitor.  At 
the end of the study, the sponsor will provide direction for the outcome of all unused vials.  
Following the sponsor’s instructions, the investigator must either return all unused vials of 
ACE-536 to the sponsor or destroy them at the clinical site.  In either case, the outcome must 
be documented on the drug accountability log. 


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13.7.
Study Drug Handling and Disposal
Please refer to the study drug handling guideline provided under separate cover, for detailed 
ACE-536 drug handling, administration, storage, and disposal instructions. 


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14.
ASSESSMENT OF SAFETY
14.1.
Adverse Event Definitions
Adverse Event
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a study drug, which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of the study drug
whether or not it is considered related to the study drug. 
Abnormal laboratory and other abnormal investigational findings (e.g. physical exam, ECG) 
should not be reported as AEs unless they are associated with clinical signs and symptoms, lead 
to treatment discontinuation or are otherwise considered clinically relevant by the investigator.  
In cases of surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself.  In case of a fatality, the cause of death is 
considered as the AE, and the death is considered as its outcome.
Unexpected Adverse Events
An unexpected AE is an AE that is not described in nature or severity in the IB.
Events Not to Be Considered as Adverse Events
Pre-existing medical conditions/signs/symptoms present before the Screening period (from study 
A536-03 for patients without treatment interruption; from study A536-05 for patients with 
treatment interruption) that do not worsen in severity or frequency during the study are defined 
as Baseline Medical Conditions, and are not to be considered AEs. Anticipated day-to-day 
fluctuations of pre-existing conditions, including the disease under study, that do not represent a 
clinically significant exacerbation or worsening need not be considered adverse events.
Serious Adverse Event
A SAE is any AE, occurring at any dose level/regimen and regardless of causality that:
x
Results in death.
x
Is life-threatening:  Life-threatening means that the patient was at immediate risk of
death from the reaction as it occurred (i.e., it does not include a reaction which
hypothetically might have caused death had it occurred in a more severe form).
x
Requires inpatient hospitalization or prolongation of existing hospitalization;
however, a hospitalization for an elective procedure will not be considered a SAE.
x
Results in persistent or significant disability/incapacity.
x
Is a congenital anomaly/birth defect.
x
Is an important medical event: an important medical event is an event that may not
result in death, be life-threatening, or require hospitalization but may be considered
an SAE when, based upon appropriate medical judgment, it may jeopardize the
patient and may require medical or surgical intervention to prevent one of the
outcomes listed in the definitions for SAEs.  Examples of such medical events include


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allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse.  
For the purposes of reporting per regulations, any suspected transmission of an infectious agent
via a medical product is by default a suspected, unexpected serious adverse reaction (SUSAR) 
and should be reported in an expedited manner as described in Section 14.7.
Events Not to Be Considered as Serious Adverse Events
Elective hospitalizations to administer or to simplify study treatment or procedures are not 
considered SAEs. 
Adverse Events of Special Interest
Events of new malignancy and premalignant lesions (excluding benign tumors or benign 
neoplasia) are to be reported as described in Section 14.7 within 24 hours of the investigator’s 
knowledge of the event by fax, or other appropriate method, using the SAE Report Form, and 
must be considered an “Important Medical Event” even if no other serious criteria apply; these 
events must also be documented in the appropriate page(s) of the CRF and subject’s source 
documents. Documentation of the diagnosed malignancy must be provided at the time of
reporting as a serious adverse event (e.g., any confirmatory histology or cytology results, X-rays, 
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 MDS 
studies, these also include progression to high/very high risk of MDS
(per IPSS-R26, Appendix 3), myeloproliferation (e.g., 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.
14.2.
Pregnancy and In Utero Drug Exposure
The investigator will attempt to collect pregnancy information if a female patient or a male 
patient’s female partner becomes pregnant while the patient is participating in this study.  The 
pregnancy information will be recorded on the appropriate form and must be submitted to the 
Sponsor within 2 weeks of learning of the pregnancy. The patient or partner will be followed for 
the outcome of the pregnancy. Information on the status of the mother and child will be 
forwarded to the Sponsor or designee. Generally, follow-up will be no longer than 6 to 8 weeks 


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following the estimated delivery date. Any premature termination of the pregnancy will be 
reported.
14.3.
Severity
Investigators must evaluate the severity/intensity of AEs according to the current active minor 
version of the National Cancer Institute Common Toxicity Criteria for Adverse Events, version 
4.0 (NCI-CTCAE v4.0), preferentially using the graded scales.  If there is a change in severity of 
an AE, it must be recorded as a separate event. If a particular AE’s severity/intensity is not 
specifically graded, the investigator should apply the general guidelines for determination of 
Grade 1 through Grade 5 as listed in the NCI-CTCAE v4.0 cover page (as shown below), using 
their best medical judgment:
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (preparing meals, shopping for 
groceries or clothes, using the telephone, managing money, etc.).
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of 
daily living (bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden).
Grade 4: Life-threatening consequences; urgent intervention indicated.
Grade 5: Death related to AE.
14.4.
Relationship to Study Drug
Investigators must also assess the causal relationship of each AE to ACE-536. Factors for the 
assessment of causal relationship include, but are not limited to, temporal relationship between 
the AE and the administration of ACE-536, known side effects of ACE-536, medical history, 
concomitant therapy, course of the underlying disease and pertinent study procedures.
Probable: A causal relationship is clinically/biologically highly plausible and there is a 
plausible time sequence between onset of the AE and administration of ACE-536 and 
there is a reasonable response on withdrawal.
Possible:
A causal relationship is clinically/biologically plausible and there is a plausible time 
sequence between onset of the AE and administration of ACE-536.
Unlikely: A causal relationship is improbable and another documented cause of the AE is most 
plausible.
Unrelated:A causal relationship can be definitively excluded and another documented cause of 
the AE is most plausible.
14.5.
Documentation and Methods of Reporting of Adverse Events by 
Investigator
It is the responsibility of the Investigator to document all AEs that occur during the study. 
Patients will be evaluated and questioned generally for AEs during the course of the study, 


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starting at the signing of the informed consent.  The Investigator must report in detail all adverse 
signs and symptoms which are either volunteered by patients or observed during or following the 
course of investigational product administration on the appropriate CRF page. For patients 
without treatment interruption, any AE ongoing at the time of EOT in A536-03 needs to be re-
entered as an AE in A536-05. For patients with treatment interruption, all non-serious AEs 
occurring after signing of the ICF until a patient is dosed on C1D1 are to be documented on the 
medical history CRF. All AEs and SAEs occurring after the Cycle 1 Day 1 dose until 
approximately 2 months after the last study drug administration (PTFU visit) are to be reported 
and documented on the AE CRF.
All AEs spontaneously reported by the patient and/or in response to an open question from study 
personnel or revealed by observation, physical examination or other diagnostic procedures will 
be recorded on the AE CRF.  Any clinically relevant changes in laboratory assessments, or other 
clinical findings as described in Section 14.1, are considered AEs and must be recorded on the 
AE CRF.  AEs are to be followed for resolution as described in Section 14.6.
It is important that each AE report include a description of the event, duration (onset and 
resolution dates), severity, relationship with ACE-536, any other potential causal factors, any 
treatment given or other action taken (including dose modification or discontinuation of 
ACE-536) and outcome.  In addition, serious AEs (SAEs) should be identified and the 
appropriate seriousness criteria documented. AEs categorized as SAEs must also be documented 
using an SAE Report Form as described in Section 14.5.1.
Specific guidance can be found in the CRF Completion Guidelines provided by the Sponsor or 
designee. 
14.5.1.
Documentation of Serious Adverse Events
All SAEs that occur after the first study drug administration on Cycle 1 Day 1 until 
approximately 2 months after the last study drug administration (PTFUS visit) are to be 
documented on the AE CRF. SAEs should not be reported for patients who are considered 
screen failures unless the event is deemed due to a protocol required procedure.
For all SAEs, an SAE form must be completed with as much information as possible and 
submitted within the time frame described in Section 14.7 (Notification about Serious Adverse 
Events).  
When new significant information is obtained as well as when the outcome of an event is known, 
the investigator should record the information on a new SAE form.  If the patient was 
hospitalized, a copy of the discharge summary must be included as part of the patient medical 
file.  In all instances, the investigator should follow up with patients until the outcome of the 
SAE is known.
14.6.
Reporting Period and Monitoring of Patients with Adverse Events
As described in Section 14.5, all AEs must be recorded in the CRF up until approximately 2 
months after the last study drug administration (PTFU visit). All patients who took at least one 
dose of study drug, whether they completed the treatment period or not, should complete the 
EOT, PTFU, LTFU, and EOS visits.
All unresolved AEs will be followed until clinical database lock (or resolution if it occurs before 
database lock).  All unresolved SAEs will undergo active follow-up until resolved or the event 


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becomes chronic or stable.  Follow-up data for SAEs obtained after clinical database lock will be 
incorporated into the ACE-536 safety database.
14.7.
Notification about Serious Adverse Events
If an SAE occurs during the reporting period, the investigator must immediately, within a 
maximum 24 hours after becoming aware of the event, inform the sponsor via the CRO by 
telephone, fax, or e-mail.
All written reports should be transmitted using the study specific SAE Report Form, which must 
be completed by the investigator following specific completion instructions.  Names, addresses, 
telephone and fax numbers for SAE reporting are located on the SAE Report Form and in the 
completion instructions provided for the Investigator Site File. When an SAE (or follow-up
information) is reported by telephone, a written report must be sent immediately thereafter by fax 
or e-mail.  Reporting procedures and timelines for follow-up information are the same as for the 
initially reported SAE. 
Relevant pages from the CRF may be provided in parallel (e.g., medical history, concomitant 
therapy).  In all cases, the information provided in the SAE Report Form must be consistent with 
the data that are recorded in the corresponding sections of the CRF.
The investigator/reporter must respond to any request for follow-up information or to any 
question the Sponsor or designee may have on the AE within the same timelines as described for 
initial reports.  This is necessary to permit a prompt assessment of the event by the Sponsor and 
(as applicable) to allow the Sponsor to meet regulatory timelines associated with expedited 
reporting obligations.
Requests for follow-up will usually be made by the responsible clinical research associate or 
Medical Monitor, or an Acceleron pharmacovigilance representative who may contact the 
investigator directly to obtain clarification on a particularly critical event.
14.7.1.
Safety Reporting to Health Authorities, Independent Ethics Committees 
Institutional Review Boards and Investigators
The Sponsor will send appropriate safety notifications to Health Authorities in accordance with 
applicable laws and regulations.
The investigator must comply with any applicable site-specific requirements related to the 
reporting of SAEs involving his/her patients to the IEC that approved the study.
In accordance with International Conference on Harmonization (ICH) Good Clinical Practice 
(GCP) guidelines, the Sponsor will inform the investigator of “findings that could adversely 
affect the safety of patients, impact the conduct of the study, or alter the IEC’s
approval/favorable opinion to continue the study.” 
The Sponsor will inform the investigator of AEs that are both serious and unexpected and are 
considered to be related to ACE-536 (SUSARs). The investigator should place copies of these 
Safety Reports in the Investigator Site File.  National regulations with regard to Safety Report 
notifications to investigators will be followed.
When specifically required by regulations and guidelines, the Sponsor will provide appropriate 
Safety Reports directly to the concerned lead IEC and will maintain records of these 
notifications. When direct reporting by the Sponsor is not clearly defined by national or 


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site-specific regulations, the investigator will be responsible for promptly notifying the 
concerned IEC of any Safety Reports and for filing copies of all related correspondence in the 
Investigator Site File.
For studies covered by the European Union Clinical Trials Directive 2001/20/EC, the Sponsor’s 
responsibilities regarding the reporting of SAEs/SUSARs will be carried out in accordance with 
that Directive and with the related Detailed Guidances.


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15.
STATISTICS
15.1.
Analysis Populations
For all analysis populations, patients will be analyzed according to assigned treatment groups.
The modified Intent-to-Treat Population (mITT): All patients enrolled in the study who
received at least one dose of ACE-536.
Efficacy Evaluable (EE) Population: All patients who received at least one dose of ACE-536
and have 1) at least four hemoglobin assessments over an 8-week period post-treatment in NTD 
patients OR, 2) at least 8 consecutive weeks of transfusion frequency data between Cycle 1 Day 
1 and EOT visit in TD patients. 
Pharmacokinetics Population: All patients who received at least 1 dose of ACE-536 during 
Study A536-05 and have sufficient serum ACE-536 values for PK analysis.
15.2.
Statistical Plan
Summary statistics will be presented for continuous/quantitative variables, by way of number of 
patients (n), mean, standard deviation (SD), median, minimum and maximum and by way of 
group frequencies and percentages for categories of qualitative variables.  Percentages will be 
calculated using the total patients per treatment / subgroup. 95% confidence intervals (CIs) will 
be presented as applicable.
All patient data will be presented in separate data listings.
15.2.1.
Patient Accountability and Demographics
Exposure to study drug and reasons for discontinuation of study will be tabulated, and 
demographics will be presented using descriptive statistics (i.e., mean, SD, median, and range).  
15.2.2.
Primary Endpoint Analysis
Safety analysis: To assess clinical safety, AEs, vital sign measurements and clinical laboratory 
information will be summarized.  AEs will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA).  Changes from baseline for clinical laboratory values and vital 
signs will be summarized over time.  Descriptive statistics and shift tables will be generated as 
appropriate.
15.2.3.
Secondary Analysis
Efficacy/Pharmacodynamic Effects Analysis of Secondary Endpoints: 
All efficacy analyses will be performed for the EE and mITT populations.
Efficacy will be evaluated by determining the proportion of patients who have a modified HI-E
erythroid response rate based upon the IWG 2006 criteria (Appendix 5), defined as 1) A mean 
hemoglobin increase ≥ 1.5 g/dL over an 8-week period as compared to baseline, not influenced 
by RBC transfusion in NTD patients or 2) A decrease of ≥ 4 units or ≥50% of units of RBCs 
transfused over a period of 8 weeks, relative to the number of units of RBCs transfused in the 8 
weeks immediately prior to Cycle 1 Day 1 in TD patients.


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Baseline hemoglobin will be the average of two or more measures (not influenced by RBC 
transfusion) performed during the screening period for study A536-03 (for patients without 
interruption) or study A536-05 (for patients with interruption).
Baseline units of RBCs transfused will be the 8-week period prior to study A536-03 (for patients 
without interruption) or study A536-05 (for patients with interruption).
The erythroid response will be summarized using both a point estimate and its exact 95%
confidence interval based on binomial distribution.
No direct comparison testing with concurrent or historical controls will be performed.
Analysis of other secondary efficacy/pharmacodynamic endpoints will include:
x
Time to HI-E response and duration of HI-E response as per the IWG 2006 criteria
and modified IWG criteria.
x
Mean RBC transfusion burden
x
Rate of RBC transfusion-free period lasting ≥ 8 weeks in TD patients.
x
Mean hemoglobin level change in NTD patients
x
Other PD endpoints including:
o
Biomarkers for iron overload/metabolism
o
Relationship of biomarkers to response
o
Rates of HI-E, HI-N and HI-P
Exploratory endpoints will include:
x
Biomarkers related to the TGFE superfamily.
x
Patient-reported quality of life using tools including but not limited to the FACT-An
questionnaire.
All binary endpoints will be summarized using both a point estimate and its exact confidence 
interval based on the binomial distribution.  The time-to-event type secondary endpoints will be 
analyzed using Kaplan-Meier method to estimate the survival curve and median time to event 
and 95% confidence interval.
15.2.4.
Pharmacokinetics Analysis
Pharmacokinetics analysis: Non-compartmental PK parameters for ACE-536, such as Cmax,
Tmax, and AUC, will be estimated.  Dose proportionality may be assessed using the exposure data 
(e.g. Cmax, AUC) after the first dose if sufficient dose levels are studied.  Descriptive statistics 
will be provided for serum concentrations and PK parameters.  The relationship between 
ACE-536 exposure and response (i.e., safety, efficacy, and biomarkers) may be explored, if 
appropriate.
15.2.5.
Anti-drug Antibody Analysis
Anti-drug antibody analysis: The results of anti-drug and neutralizing antibody testing for 
ACE-536 and human ActRIIB protein versus time will be presented.  Exploratory analysis will 


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be performed on the potential effect of ADAs on ACE-536 PK and drug exposure if ADA tests
are deemed positive.
15.3.
Determination of Sample Size
There is no formal sample size calculation for the study although up to 153 patients may 
participate from the A536-03 study.
15.4.
Interim Analysis
Safety and erythroid response data will be reviewed periodically throughout the study. A formal 
interim analysis of the safety and efficacy data will be performed to support registration filings,
as needed throughout the study conduct.
15.5.
Deviation from Original Analysis Plan
A formal Statistical Analysis Plan (SAP) for the analysis and presentation of data from this study 
will be prepared before the database lock.  Deviations from the statistical analyses outlined in 
this protocol will be indicated in this plan; any further modifications will be noted in the final 
clinical study report.


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16.
SOURCE DOCUMENTATION AND INVESTIGATOR FILES
16.1.
Study Monitoring
The clinical monitor will arrange to visit the clinical sites at regular intervals during the study.  
The monitoring visits must be conducted according to the applicable ICH and GCP guidelines to 
ensure protocol adherence, quality of data, drug accountability, compliance with regulatory 
requirements, and continued adequacy of the clinical sites and their facilities.  During these 
visits, CRFs and other data related to the study will be reviewed and any discrepancies or 
omissions will be resolved.  The clinical monitor will be given access to study–relevant source 
documents (including medical records) for purposes of source data verification.
16.2.
Audits and Inspections
The investigators and clinical sites will permit trial-related monitoring, audits, IEC review, and 
regulatory inspections as requested by FDA or other health authorities and the sponsor or 
designee.  In addition to CRFs, the clinical site will permit direct access to source 
data/documents (i.e., original medical records, laboratory reports, hospital documents, progress 
reports, signed ICFs, etc.).  During and/or after completion of the study, quality assurance 
officers named by the sponsor or the regulatory authorities may wish to perform on-site audits.  
The investigator is expected to cooperate with any audit and provide assistance and 
documentation (including source data) as requested.
17.
QUALITY CONTROL AND QUALITY ASSURANCE
17.1.
Data Quality Control and Quality Assurance
17.1.1.
Investigator Responsibility
The investigator is responsible for ensuring the study is conducted according to the protocol, 
Code of Federal Regulations, GCP, and applicable regulatory requirements. The investigator’s 
responsibilities are outlined in these documents and must include the responsibility to obtain a 
signed informed consent prior to patient participation in the study.
17.1.2.
Protocol Modifications
The investigator should not modify the protocol without agreement from the sponsor and prior 
review or approval by the IEC, unless an emergency situation requires protocol modification to 
ensure the safety of patients.  Any deviations from the protocol should be documented by the 
investigator or designee. 


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18.
CONFIDENTIALITY
To maintain patient privacy, all CRFs, study drug accountability records, study reports and 
communications will identify the patient by the assigned patient identification number.  The 
investigator will grant clinical monitor(s) and auditor(s) from the sponsor or designee and 
regulatory authorities’ access to the patient’s original medical records for verification of data 
gathered on the CRFs and to audit the data collection process.  The patient’s confidentiality will 
be maintained and will not be made publicly available.  The patient’s medical information will 
only be released to the extent permitted by the applicable laws and regulations.
All information regarding the investigational product supplied by the sponsor to the investigator 
is privileged and confidential information.  The investigator agrees to use this information to 
accomplish the study and will not use it for other purposes without consent from the sponsor.  It 
is understood that there is an obligation to provide the sponsor with complete data obtained 
during the study.  The information obtained from the clinical study will be used towards the 
development of the investigational product and may be disclosed to regulatory authorities, other 
investigators, corporate partners, or consultants as required.
19.
PUBLICATION POLICY
All information concerning ACE-536 is considered confidential and shall remain the sole 
property of the sponsor.  The investigator(s) agree to use this information only in conducting the 
study and shall not use it for any other purposes without the sponsor’s written approval.  The 
investigator(s) agree not to disclose the sponsor’s confidential information to anyone except to 
persons involved in the study that need such information to assist in conducting the study, and 
then only on like terms of confidentiality and non-use.
It is understood by the investigator(s) that the information developed from this clinical study will 
be used by the sponsor in connection with the development of ACE-536, and therefore may be 
disclosed as required to regulatory agencies.  To allow for the use of the information derived 
from clinical studies, it is understood that there is an obligation to provide the sponsor with 
complete test results and all data developed in the study.
No publication or disclosure of study results will be permitted except as specified in a separate, 
written, agreement between the sponsor and the investigator(s).
20.
PROTOCOL AMENDMENTS
Protocol amendments that impact patient safety change the scope of the investigation, or affect 
the scientific quality of the study must be approved by the IEC and submitted to the appropriate 
regulatory authorities before implementation.
In the event that the protocol needs to be modified immediately to eliminate an apparent hazard 
to a patient, the sponsor will implement the protocol change and subsequently amend the 
protocol and notify the regulatory authorities and/or the IEC, as appropriate.


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21.
DATA HANDLING AND RECORDKEEPING
21.1.
Case Report Form Completion
CRFs will be completed for each enrolled patient.  It is the investigator’s responsibility to ensure 
the accuracy, completeness, and timeliness of the data reported in the patient’s CRF.  Source 
documentation supporting the CRF data should indicate the patient’s participation in the study 
and should document the dates and details of study procedures, AEs, and patient status.
Investigators will maintain copies of the CRFs at the clinical site.  For patients who discontinue 
or terminate from the study, the CRFs will be completed as much as possible, and the reason for 
the discontinuation or termination clearly and concisely specified on the appropriate CRF.
21.2.
Retention of Records
The investigator will maintain all study records according to ICH-GCP and applicable regulatory 
requirements.  Records will be retained for at least 2 years after the last marketing application 
approval or 2 years after formal discontinuation of the clinical development of the investigational 
product, or according to applicable regulatory requirements.  If the investigator withdraws from 
the responsibility of keeping the study records, custody must be transferred to a person willing to 
accept the responsibility. The sponsor must be notified in writing if a custodial change occurs.


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22.
STUDY FINANCE AND INSURANCE
22.1.
Study Finance
The costs necessary to perform the study will be agreed with each Investigator and will be 
documented in a separate financial agreement that will be signed by the Investigator and 
Acceleron Pharma Inc. or designee, prior to the study commencing. 
Participants may be reimbursed for study-related travel. 
22.2.
Insurance
The Sponsor has insurance coverage for study related ACE-536 induced injury and other 
liabilities incurred during clinical studies which will provide compensation for any study related 
injury according to the guidelines set out by the Association of the British Pharmaceutical 
Industry (ABPI), namely “Clinical Studies Compensation for Medicine Induced Injury.


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23.
REFERENCES
1. Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for
modification of the International Working Group (IWG) response criteria in myelodysplasia.
Blood 2006;108:419-25.
2. Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health
Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and
important changes. Blood 2009;114:937-51.
3. Massague J. TGF-beta signal transduction. Annu Rev Biochem 1998;67:753-91.
4. Goldberg SL, Chen E, Corral M, et al. Incidence and Clinical Complications of
Myelodysplastic Syndromes Among United States Medicare Beneficiaries. J Clin Oncol 2010.
5. Hofmann W-K, Lubbert, M., Hoelzer, D., Koeffler, HP. Myelodysplastic syndromes.
Hematol J 2004;5:1-8.
6. Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating
prognosis in myelodysplastic syndromes. Blood 1997;89:2079-88.
7. Germing U, Aul C, Niemeyer CM, Haas R, Bennett JM. Epidemiology, classification and
prognosis of adults and children with myelodysplastic syndromes. Ann Hematol 2008;87:691-9.
8. Williamson PJ, Kruger AR, Reynolds PJ, Hamblin TJ, Oscier DG. Establishing the incidence
of myelodysplastic syndrome. Br J Haematol 1994;87:743-5.
9. Matsuda A, Germing U, Jinnai I, et al. Difference in clinical features between Japanese and
German patients with refractory anemia in myelodysplastic syndromes. Blood 2005;106:2633-
40.
10. Neukirchen J, Schoonen WM, Strupp C, et al. Incidence and prevalence of myelodysplastic
syndromes: data from the Dusseldorf MDS-registry. Leuk Res 2011;35:1591-6.
11. Aul C, Gattermann N, Schneider W. Age-related incidence and other epidemiological aspects
of myelodysplastic syndromes. Br J Haematol 1992;82:358-67.
12. Clinical Practice Guidelines in Oncology: Myelodysplastic Syndromes. V.1.2012. 2012.
(Accessed at www.nccn.org.)
13. Casadevall N, Durieux P, Dubois S, et al. Health, economic, and quality-of-life effects of
erythropoietin and granulocyte colony-stimulating factor for the treatment of myelodysplastic
syndromes: a randomized, controlled trial. Blood 2004;104:321-7.
14. Noel P, Solberg LA, Jr. Myelodysplastic syndromes. Pathogenesis, diagnosis and treatment.
Crit Rev Oncol Hematol 1992;12:193-215.
15. Platzbecker U, Hofbauer LC, Ehninger G, Holig K. The clinical, quality of life, and
economic consequences of chronic anemia and transfusion support in patients with
myelodysplastic syndromes. Leuk Res 2012;36:525-36.
16. Jadersten M, Montgomery SM, Dybedal I, Porwit-MacDonald A, Hellstrom-Lindberg E.
Long-term outcome of treatment of anemia in MDS with erythropoietin and G-CSF. Blood
2005;106:803-11.


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17. Moyo V, Lefebvre P, Duh MS, Yektashenas B, Mundle S. Erythropoiesis-stimulating agents
in the treatment of anemia in myelodysplastic syndromes: a meta-analysis. Ann Hematol
2008;87:527-36.
18. Aul C, Arning M, Runde V, Schneider W. Serum erythropoietin concentrations in patients
with myelodysplastic syndromes. Leuk Res 1991;15:571-5.
19. Claessens YE, Bouscary D, Dupont JM, et al. In vitro proliferation and differentiation of
erythroid progenitors from patients with myelodysplastic syndromes: evidence for Fas-dependent
apoptosis. Blood 2002;99:1594-601.
20. Parker JE, Mufti GJ. The role of apoptosis in the pathogenesis of the myelodysplastic
syndromes. Int J Hematol 2001;73:416-28.
21. Quintas-Cardama A, Santos FP, Garcia-Manero G. Therapy with azanucleosides for
myelodysplastic syndromes. Nat Rev Clin Oncol 2010;7:433-44.
22. Komrokji RS, List AF. Role of lenalidomide in the treatment of myelodysplastic syndromes.
Semin Oncol 2011;38:648-57.
23. Kornblith AB, Herndon JE, 2nd, Silverman LR, et al. Impact of azacytidine on the quality of
life of patients with myelodysplastic syndrome treated in a randomized phase III trial: a Cancer
and Leukemia Group B study. J Clin Oncol 2002;20:2441-52.
24. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that
of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a
randomised, open-label, phase III study. Lancet Oncol 2009;10:223-32.
25. Lubbert M, Suciu S, Baila L, et al. Low-Dose Decitabine Versus Best Supportive Care in
Elderly Patients With Intermediate- or High-Risk Myelodysplastic Syndrome (MDS) Ineligible
for Intensive Chemotherapy: Final Results of the Randomized Phase III Study of the European
Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS
Study Group. J Clin Oncol 2011.
26. Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system
for myelodysplastic syndromes. Blood 2012;120:2454-65.
27. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern
Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-55.
28. Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for
modification of the International Working Group (IWG) response criteria in myelodysplasia.
Blood 2006;108:419-25.


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24.
APPENDICES
24.1.
Appendix 1: 
Who Classification and Criteria for the 
Myelodysplastic Syndromes2
a Bicytopenia may occasionally be observed.  Cases with pancytopenia should be classified as MDS-U. 
b If the marrow myeloblast percentage is < 5% but there are 2% to 4% myeloblasts in the blood, the diagnostic classification is RAEB-1.  Cases of 
RCUD and RCMD with 1% myeloblasts in the blood should be classified as MDS-U. 
c Cases with Auer rods and < 5% myeloblasts in the blood and less than 10% in the marrow should be classified as RAEB-2.  Although the 
finding of 5% to 19% blasts in the blood is, in itself, diagnostic of RAEB-2, cases of RAEB-2 may have < 5% blasts in the blood if they have 
Auer rods or 10% to 19% blasts in the marrow or both.  Similarly, cases of RAEB-2 may have < 10% blasts in the marrow but may be diagnosed 
by the other 2 findings, Auer rod+ and/or 5% to 19% blasts in the blood.
Disease
Blood findings
Bone marrow findings
Refractory cytopenia with unilineage 
dysplasia (RCUD): (refractory anemia 
[RA]; refractory neutropenia [RN]; 
refractory thrombocytopenia [RT])
Unicytopenia or bicytopeniaa
No or rare blasts 
(< 1%)b
Unilineage dysplasia: ≥ 10% of the cells in 
one myeloid lineage
< 5% blasts
< 15% of erythroid precursors are ring 
sideroblasts
Refractory anemia with ring 
sideroblasts (RARS)
Anemia
No blasts
≥ 15% of erythroid precursors are ring 
sideroblasts
Erythroid dysplasia only
< 5% blasts
Refractory cytopenia with multilineage 
dysplasia (RCMD)
Cytopenia(s)
No or rare blasts 
(< 1%)b
No Auer rods
< 1 x109/L monocytes
Dysplasia in ≥ 10% of the cells in ≥ 2 
myeloid lineages (neutrophil and/or 
erythroid precursors and/or 
megakaryocytes)
< 5% blasts in marrow
No Auer rods
± 15% ring sideroblasts
Refractory anemia with excess blasts-1
(RAEB-1)
Cytopenia(s)
< 5% blastsb
No Auer rods
< 1 x109/L monocytes
Unilineage or multilineage dysplasia
5%-9% blastsb
No Auer rods
Refractory anemia with excess blasts-2
(RAEB-2)
Cytopenia(s)
5%-19% blastsc
Auer rods ±c
< 1 x109/L monocytes
Unilineage or multilineage dysplasia
10%-19% blastsc
Auer rods ±c
Myelodysplastic syndrome-unclassified 
(MDS-U)
Cytopenias
< 1% blastsb
Unequivocal dysplasia in < 10% of cells in 
one or more myeloid lineages when 
accompanied by a cytogenetic abnormality 
considered as presumptive evidence for a 
diagnosis of MDS 
< 5% blasts
MDS associated with isolated del(5q)
Anemia
Usually normal or increased 
platelet count
No or rare blasts 
(< 1%)
Normal to increased megakaryocytes with 
hypolobated nuclei
< 5% blasts
Isolated del(5q) cytogenetic abnormality
No Auer rods


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24.2.
Appendix 2:
International Prognostic Scoring System (IPSS) for 
Myelodysplastic Syndromes (MDS)6
a Good = normal, –Y, del(5q), del(20q); Intermediate = other abnormalities;
Poor = complex (≥3 abnormalities) or chromosome 7 anomalies
b Neutrophils < 1800/μL, hemoglobin < 10 g/dL, platelets < 100,000/μL.
IPSS Scoring Value
Prognostic Variable
0
0.5
1.0
1.5
2.0
Bone Marrow Blasts (%)
< 5
5-10
—
11-20
21-30
Karyotypea
Good
Intermediate
Poor
Cytopeniasb
0-1
2-3
IPSS Classification
Risk Group
Low
Int-1
Int-2
High
Score
0
0.5 - 1.0
1.5 - 2.0
≥ 2.5


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24.3.
Appendix 3: 
Revised International Prognostic Scoring System 
(IPSS-R) for Myelodysplastic Syndromes (MDS)26
— indicates not applicable
a 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
Risk Category
Risk Score
Very low
≤ 1.5
Low
> 1.5 - 3
Intermediate
> 3 - 4.5
High
> 4.5 - 6
Very high
> 6
IPSS-R Scoring Value
Prognostic Variable
0
0.5
1
1.5
2
3
4
Cytogeneticsa
Very 
good
—
Good
—
Intermediate
Poor
Very 
poor
Bone Marrow Blasts 
(%)
≤ 2
—
> 2 - < 5
—
5 - 10
> 10
—
Hemoglobin (g/dL)
≥ 10
—
8 - <10
< 8
—
—
—
Platelets (x 109/L)
≥ 100
50 - <100
< 50
—
—
—
—
Absolute Neutrophil 
Count (ANC; x 
109/L)
≥ 0.8
< 0.8
—
—
—
—
—


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24.4.
Appendix 4:
ECOG Performance Status27
The ECOG scale is used to assess a patient’s quality of life in an evaluation by a health 
professional of the daily activities and how the activities are affected by the disease of the
patient.
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, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities.
Up and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours
4
Completely disabled. Cannot carry on any self-care.  Totally confined to bed or chair
5
Dead


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24.5.
Appendix 5:
International Working Group (IWG) Criteria -
Erythroid Response Evaluation1
Hematologic
Improvement (HI)a
Response Criteria
(Responses must last at least 8 weeks)
Erythroid response (Hi-E)
(pretreatment Hgb < 11 g/dL) 
Hgb increase of ≥ 1.5 g/dL for patients not transfused; or, as 
defined by having received less than 4 units of RBCs within 
8 weeks of Cycle 1 Day 1
Reduction by ≥4 units of RBCs transfused (for a Hgb 
≤9.0 g/dL) during any 8-week period on study, compared 
with the 8-week period prior to study day 1
Platelet response (HI-P)
(pretreatment, < 100 x109/L) 
Absolute increase of ≥ 30 x 109/L for patients starting with 
> 20 x 109/L platelets
Increase from < 20 x 109/L to > 20 x 109/L and by at least 
100%
Neutrophil response (HI-N)
(pretreatment, < 1.0 x109/L) 
At least 100% increase and an absolute increase > 0.5 x
109/L
a Pre-treatment counts are averages of at least 2 measurements (not influenced by transfusions) ≥ 1 week apart 
within 28 days prior to Day 1. 
Hgb: indicates hemoglobin; RBC: red blood cell; HI: hematologic improvement.


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24.6.
Appendix 6:
National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.0
See http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE


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24.7.
Appendix 7: 
International Working Group Response Criteria for 
Myelodysplastic Syndromes28

SAP_001.pdf: 
Official Protocol Title: 
NCT number: 
Document Date: 
An Open-Label Extension Study to Evaluate the Long-Term Effects 
of ACE-536 for the Treatment of Anemia in Patients with Low or 
Intermediate-1 Risk Myelodysplastic Syndromes (MDS) Previously 
Enrolled in Study A536-03
08-May-2020
NCT02268383


 
 
 
Statistical Analysis Plan 
 
An Open-Label Extension Study to Evaluate the Long-Term 
Effects of ACE-536 for the Treatment of Anemia in Patients 
with Low or Intermediate-1 Risk Myelodysplastic 
Syndromes (MDS) Previously Enrolled in Study A536-03   
 
 
Sponsor:  
Acceleron Pharma Inc. 
128 Sidney Street 
Cambridge, MA 02139 USA 
Tel: 
 
Fax: 
 
Investigational Product: 
Luspatercept (ACE-536) 
Protocol Number:  
A536-05 
EudraCT Number:  
2014-001280-13 
Version Number:  
2 (Final) 
Date: 
08 May 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
The information contained in this document, especially unpublished data, is the property of 
Acceleron Pharma Inc. (or under its control), and therefore provided to you in confidence for 
review by you and/or your staff.  It is understood that this information will not be disclosed to 
others without written authorization from Acceleron. 
PPD
PPD




 
A536-05 
 
Statistical Analysis Plan 
 
Confidential and Proprietary  
3 
Acceleron Pharma Inc. 
TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................3 
1. 
INTRODUCTION ........................................................................................................5 
2. 
STUDY OBJECTIVES ................................................................................................5 
3. 
OVERALL STUDY DESIGN ......................................................................................6 
3.1. 
Study Design .................................................................................................................6 
3.2. 
Treatment Discontinuation ...........................................................................................7 
3.3. 
Sample Size ..................................................................................................................8 
4. 
ANALYSIS POPULATIONS ......................................................................................9 
4.1. 
Intent-to-Treat (ITT) Population ...................................................................................9 
4.2. 
Safety Population ..........................................................................................................9 
4.3. 
Pharmacokinetics (PK) Population ...............................................................................9 
5. 
STATISTICAL METHODOLOGY .............................................................................9 
5.1. 
Definitions ....................................................................................................................9 
5.2. 
General Considerations ...............................................................................................10 
5.3. 
Disposition of Patients ................................................................................................11 
5.4. 
Demographic, Baseline Characteristics, and Disease History ....................................11 
5.5. 
Medical History ..........................................................................................................11 
5.6. 
Study Drug Exposure ..................................................................................................11 
5.7. 
Prior and Concomitant Medication and Procedures ...................................................12 
5.7.1. 
Prior and Concomitant Medication .............................................................................12 
5.7.2. 
Non-Medication Procedures .......................................................................................12 
5.8. 
Efficacy and Safety Analyses .....................................................................................12 
5.8.1. 
Primary Efficacy Endpoint .........................................................................................12 
5.8.2. 
Secondary Efficacy Endpoints ....................................................................................13 
5.8.2.1. 
Erythroid Response (modified HI-E from IWG 2006 criteria) ..................................13 
5.8.2.2. 
RBC Transfusion Independence .................................................................................13 
5.8.2.3. 
HI-E Response Rate ....................................................................................................13 
5.8.2.4. 
HI-P and HI-N Response Rate ....................................................................................14 
5.8.2.5. 
Time to and Duration of HI-E Response ....................................................................14 
5.8.2.6. 
Iron-Related Parameters .............................................................................................15 
5.8.2.7. 
Erythropoietin and Immature RBC Parameters ..........................................................15 


 
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Statistical Analysis Plan 
 
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5.8.2.8. 
Bone Metabolism Parameters .....................................................................................15 
5.8.2.9. 
Hemolysis-Related Parameters ...................................................................................15 
5.8.2.10. 
Other Analysis ............................................................................................................16 
5.8.3. 
Exploratory Endpoints ................................................................................................16 
5.8.3.1. 
FACT-An Questionnaire ............................................................................................16 
5.8.4. 
Subgroup Analyses .....................................................................................................17 
5.8.5. 
Safety Analyses ..........................................................................................................18 
5.8.6. 
Adverse Events ...........................................................................................................18 
5.8.7. 
Laboratory Evaluations ...............................................................................................19 
5.8.8. 
Vital Signs ..................................................................................................................19 
5.8.9. 
ECG Results................................................................................................................20 
5.8.10. 
Physical Examination .................................................................................................20 
5.8.11. 
Long-term Follow-up ..................................................................................................20 
5.9. 
Pharmacokinetics Analysis .........................................................................................20 
5.9.1. 
Pharmacokinetic Sampling Schedule .........................................................................20 
5.9.2. 
Data Handling .............................................................................................................20 
5.9.3. 
Pharmacokinetic Analysis ..........................................................................................21 
5.10. 
Interim Analysis ..........................................................................................................21 
5.11. 
Protocol Violations or Deviations ..............................................................................21 
5.11.1. 
Violation Criteria ........................................................................................................21 
5.11.2. 
Protocol Deviations ....................................................................................................21 
5.12. 
Handling of Missing Data and Visit Window ............................................................22 
5.12.1. 
Missing Data ...............................................................................................................22 
5.12.2. 
Missing Dates for Adverse Event ...............................................................................22 
5.12.3. 
Missing Dates for Concomitant Medication ...............................................................22 
5.12.4. 
Missing Dates for Disease Diagnosis Date .................................................................23 
5.13. 
Changes in Conduct or Planned Analyses from the Protocol .....................................23 
6. 
REFERENCES ...........................................................................................................24 
7. 
APPENDICES ............................................................................................................25 
7.1. 
Appendix 1: List of Abbreviations .............................................................................25 
7.2. 
Appendix 2: Schedule of Events for Study 03 ............................................................27 
7.3. 
Appendix 3: Schedule of Events for Study 05 ............................................................30 


 
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Statistical Analysis Plan 
 
Confidential and Proprietary  
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1. 
INTRODUCTION 
This statistical analysis plan (SAP) describes the statistical methods to be used for the analysis of 
Acceleron Protocol A536-05.  This SAP should be read in conjunction with the study protocol 
and electronic case report form (eCRF).  This version of the plan is intended for the final CSR 
based on the protocol amendment 04 dated 06 March 2018.  Any further changes to the protocol 
may necessitate updates to the SAP. 
The SAP will be signed off before the study database lock.  Any deviations from the SAP will be 
described and justified in the final clinical study report (CSR). 
2. 
STUDY OBJECTIVES 
Primary Objective: 
 To evaluate the long-term safety and tolerability of ACE-536 in patients with low or 
intermediate-1 risk MDS who were previously enrolled in study A536-03.  
Secondary Objectives: 
 To evaluate erythroid response (modified HI-E from International Working Group 
[IWG] 2006 criteria), defined as proportion of patients with:  
 A mean hemoglobin (Hgb) increase ≥ 1.5 g/dL over an 8-week period as 
compared to baseline, not influenced by red blood cell (RBC) transfusion, in non-
transfusion dependent (LTB) patients (refer to Section 5.1 for definitions of LTB 
and HTB).  
 A decrease of ≥ 4 units or ≥ 50% of units of RBCs transfused over a period of 8 
weeks, relative to the 8 weeks immediately prior to Day 1, in transfusion 
dependent (HTB) patients.  
 To evaluate rates of erythroid, neutrophil and platelet (HI-E, HI-N and HI-P) 
responses (IWG 2006 criteria)  
 To evaluate the rate of RBC transfusion independence lasting ≥ 8 weeks in HTB 
patients  
 To evaluate time to HI-E response and duration of HI-E response (modified and non-
modified IWG 2006 criteria)  
 To evaluate the mean change in RBC transfusion burden in HTB patients and mean 
change in hemoglobin levels in LTB patients  
 To evaluate the pharmacokinetic (PK) profile of ACE-536  
 To evaluate other pharmacodynamic (PD) effects (e.g., iron overload/metabolism, 
erythropoietin [EPO], and reticulocytes)  
 
Exploratory Objectives: 
 To examine biomarkers related to the TGF-β superfamily  


 
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Statistical Analysis Plan 
 
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 To examine self-reported quality of life using tools including but not limited to the 
FACT-An questionnaire  
3. 
OVERALL STUDY DESIGN 
This open-label extension study will evaluate the safety, tolerability, and PD effects of up to 60 
months of ACE-536 treatment in patients with low or intermediate-1 risk MDS previously 
treated with ACE-536 for up to 3 months in study A536-03.  
3.1. 
Study Design 
Patients in all cohorts will receive ACE-536, administered subcutaneously (SC), every 3 weeks 
for up to 87 cycles or up to 1825 days, whichever occurs first.  Dose titration(s), delay(s) and 
dose reduction(s) may be required for individual patients as outlined in the Individual Dose 
Modification Rules (protocol Section 10.8).   
The base study A536-03 is a phase 2, open-label, ascending dose study to evaluate the effects of 
ACE-536 on anemia in patients with low or intermediate-1 risk MDS who are not currently 
receiving treatment with an erythropoiesis-stimulating agent (ESA).  A total of up to 153 patients 
may be enrolled in the base study A536-03 and may be eligible for study A536-05.  
Consenting patients that meet the A536-05 eligibility criteria may immediately roll over from 
A536-03 to study A536-05.  These patients will forego the Post-Treatment Follow-up (PTFU) 
and End of Study (EOS) visits of A536-03 to begin study A536-05.  For these patients, C1D1 of 
A536-05 may take place 28 (± 7) days after the last dose administered in the base study 
A536-03, which may coincide with the patient’s A536-03 End of Treatment (EOT) visit.  These 
patients will be considered “patients without treatment interruption.”  Patients enrolled in 
expansion cohorts 2 and 3 in Study A536-03 must meet the “patients without treatment 
interruption” criteria to be considered for the A536-05 study, unless otherwise prospectively 
approved by the sponsor. 
Patients who complete the EOS visit for the base study A536-03 prior to C1D1 of A536-05 are 
considered “patients with treatment interruption.”  These patients will have a 28-day screening 
period to allow them to be re-assessed for eligibility by meeting additional inclusion criteria, as 
defined in protocol Section 9.2.  
Patients who have completed the EOT visit for the base study A536-03 but have not reached the 
EOS visit (i.e., patients in the follow-up period for A536-03), may still participate, but should be 
treated as patients with treatment interruption and should not begin study A536-05 C1D1 until 
they have completed their A536-03 EOS visit so that new baseline assessments can be measured.  
Patients transfusion status (LTB or HTB) are defined in Section 5.1.  Each HTB patient will have 
a “pre-transfusion hemoglobin threshold” for requiring transfusion, which will be calculated 
based on transfusion history and will be used for determining when to transfuse during the study.  
The baseline pre-transfusion hemoglobin threshold will be the mean of all documented 
pre-transfusion hemoglobin values during the 12 weeks prior to C1D1 of base study A536-03 for 
patients without treatment interruption, or prior to C1D1 of study A536-05 for patients with 
treatment interruption.  During treatment, if the pre-transfusion hemoglobin level is increased by 
≥ 1 g/dL compared to the baseline pre-transfusion hemoglobin threshold for that patient, 




 
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 Patient’s unwillingness or inability to comply with the protocol 
 Pregnancy 
 Use of prohibited medication (e.g., ESA) 
 Medical reason or adverse event, at the discretion of the investigator and/or the 
medical monitor  
 Lack of effect (e.g., worsening anemia for LTB patients as evidenced by sustained 
reduction in Hgb by ≥ 2 g/dL over 8 weeks or transfusion dependence), to be 
discussed with the medical monitor  
 Disease progression (per IWG criteria for altering natural history of MDS [Cheson et 
al, 2006]): 
  For patients with 5-10% blasts, a 2nd bone marrow sample should be collected 
within 4 weeks for clinical assessment (e.g., cytomorphology, cytogenetics) to 
confirm progression before discontinuing patients from treatment)  
 Persistent increase in white blood cell (WBC) count as per Individual Dose 
Modifications in protocol Section 10.8 
 Presence of ≥ 1% blasts in peripheral blood as per Individual Dose Modifications in 
protocol Section 10.8 
 Hypersensitivity reaction to study drug  
 At the discretion of the sponsor (e.g., termination of the study or a dose level) 
A patient may be withdrawn from the study for any of the following reasons: 
 Patient’s request 
 Patient’s unwillingness or inability to comply with the protocol 
 Death 
 Loss to follow-up 
 At the discretion of the sponsor (e.g., termination of the study) 
The reasons for study withdrawal and/or treatment discontinuation must be recorded in the 
patient’s CRF.  The investigator must notify the sponsor, the medical monitor and the contract 
research organization (CRO) immediately when a patient has been discontinued/withdrawn due to 
an AE.  Patients who discontinue treatment early should complete the EOT follow-up visit at the 
time of discontinuation, then complete the Post-Treatment Follow-up (PTFU) visit 2 months ± 7 
days after the last dose of ACE-536, the LTFU visits every 3 months, and finally the EOS visit 3 
years after the last dose of ACE-536.  
3.3. 
Sample Size 
There is no formal sample size calculation for the study although up to 153 patients may 
participate from the A536-03 study. 


 
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4. 
ANALYSIS POPULATIONS 
4.1. 
Intent-to-Treat (ITT) Population 
The intent-to-treat (ITT) population will consist of all patients who have received at least 1 dose 
of ACE-536 in A536-05 study.  This population will be used for all efficacy analyses.  
For patients who directly rolled over from A536-03 study, both A536-03 study and A536-05 
study data will be included for the analysis. 
For interrupted patients, only A536-05 study data will be included for the analysis. 
4.2. 
Safety Population 
Same as ITT population. 
4.3. 
Pharmacokinetics (PK) Population 
The pharmacokinetics population will include all patients who have received at least 1 dose of 
ACE-536 during Study A536-05 and have sufficient serum ACE-536 values for PK analysis.  
5. 
STATISTICAL METHODOLOGY 
5.1. 
Definitions 
Transfusion Status 
For patients without treatment interruption, transfusion status (LTB or HTB) will carry-over 
from the base study A536-03.  For patients with treatment interruption, transfusion status will be 
reassessed prior to C1D1 of study A536-05.  Transfusion status for all patients is defined as 
follows for all patients: 
 LTB patients are defined as patients who require a transfusion of < 4 units of RBCs in 
the 8 weeks prior to C1D1 
 HTB patients are defined as patients who require a transfusion of ≥ 4 units of RBCs 
in the 8 weeks prior to C1D1 
Baseline  
For patients who roll over to Study A536-05 without interruption, the baseline for Study A536-03 
will be used as the baseline for Study A536-05.  
For patients who enter Study A536-05 with interruption, the last value on or before the first dose 
of Study A536-05 will be considered as the baseline unless otherwise specified.  For baseline 
assessments that are not scheduled in A536-05 study or data collection is inadequate at the baseline 
of Study A536-05, the baseline value for Study A536-03 will be used as the baseline for Study 
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Baseline Hemoglobin  
Baseline hemoglobin will be an average of hemoglobin measurements within 28 days of Cycle 1 
Day 1, excluding measurements within 7 days following RBC transfusion. 
Baseline Transfusion Burden   
Baseline transfusion burden will be calculated as the total amount of RBC transfusion during the 
8 weeks prior to Cycle 1 Day 1.  
Baseline EPO and Other Lab Parameters   
Baseline erythropoietin (EPO) is defined as the maximum test value within 28 days of Cycle 1 
Day 1.  
For all other lab parameters, baseline is defined as the last observation on or prior to Cycle 1 Day 
1.  
End of Treatment (EOT) 
Procedures and evaluations for the end of treatment visit should be performed 28 days (±7 days) 
after the last dose of ACE-536.   
Post Treatment Follow-Up (PTFU)   
Procedures and evaluations for the post treatment follow-up visit should be performed 2 months 
(± 7 days) after the last dose of ACE-536.   
Long-Term Follow-Up (LTFU)   
LTFU visits should occur every 3 months (± 7 days) for 3 years after the last dose of ACE-536.   
End of Study (EOS)   
Procedures and evaluations for the end of study visit should be performed approximately 3 years 
after the last dose of ACE-536). 
 Patients who discontinue treatment early should complete the EOS visit approximately 3 
years after the EOT visit. 
 If a patient has a positive ADA result at the last visit, the patient may be asked to return 
for additional ADA testing every three months until a negative result is obtained or the 
result is considered to be stabilized. 
5.2. 
General Considerations   
Unless otherwise noted, continuous data will be summarized with the following descriptive 
statistics: number of observations (n), mean, standard deviation (STD), median, minimum and 
maximum.  Categorical data will be summarized with frequencies (n) and percentages (%).  In 
cases where missing data cause percentages not to sum to 100, a missing data row will be 
provided.  Percentages will use column totals as the denominator unless otherwise indicated. For 
time to event variables, the Kaplan-Meier curves will be presented if the number of patients is 
more than 5. 
All study data will be included in study data listings.  Missing data will generally not be imputed, 
unless otherwise stated. 


 
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Data summaries may also be presented for LTB and HTB patients separately as specified.  All 
summaries will be descriptive.  No formal hypothesis testing is planned. 
5.3. 
Disposition of Patients 
The number and percentage of patients receiving study treatment who completed the treatment 
period and study period along with the associated reasons for discontinuation from treatment 
and/or withdrawal from study will be presented.  
5.4. 
Demographic, Baseline Characteristics, and Disease History 
The following baseline and demographic characteristics will be summarized by descriptive 
statistics for the ITT population:  
 Race, ethnicity, age, sex, height, weight  
 Prior MDS Therapies, time from diagnosis; Prior erythropoiesis stimulating agents 
(ESA); IPSS and IPSS-R risk group; WHO Subtypes; ICT use 
 Baseline ECOG performance status  
 Baseline transfusion status (LTB or HTB) 
 Baseline hemoglobin and baseline transfusion burden  
 Baseline erythropoietin (EPO) and baseline serum ferritin  
 RS and SF3B1 mutation status; any splicing factor (yes or no) 
 Baseline bone marrow blasts  
Demographic and baseline data, medical history, and disease history data will also be listed for 
each patient. 
5.5. 
Medical History 
Medical history will be coded using MedDRA Version 20.0. Summary of medical history will be 
tabulated by system organ class (SOC) alone and by both SOC and the preferred term (PT).  
5.6. 
Study Drug Exposure 
Study drug exposure will be descriptively summarized for the safety population and will present 
the duration of exposure, the number of treatment cycles, the total dose administered, the number 
of patients with dose delay and reduction, and the number of patients with dose increase.  
The duration of exposure will be calculated as (last dose date – first dose date) + 21. 
The total number of cycles will be summarized by presenting the number and percentage of 
patients in each category. 
The total dose administered is the total amount of study drug in mg a patient received during the 
treatment period. 
Study drug administration details will be listed for each patient. 


 
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5.7. 
Prior and Concomitant Medication and Procedures 
5.7.1. 
Prior and Concomitant Medication 
The prior and concomitant medications are coded with WhoDrugDDEB2 201209.  The 
medications will be presented for the safety population.  
Medications will be assigned as prior or concomitant based on the following rules: 
 If both the start and stop date exist and are before the first dose date of study drug, the 
medication will be counted as prior. 
 If the start date is on or after the first dose date of study drug, the medication will be 
counted as concomitant. 
 If the start date is before the first dose date of study drug and the stop date is after the 
first dose date of study drug or the medication is ongoing, the medication will be 
counted as prior and concomitant. 
 If the start date is missing and the stop date is before the first dose of study drug, the 
medication will be counted as prior. 
 If the start date is missing and the stop date is after the first dose of study drug or the 
medication is ongoing, the medication will be counted as concomitant. 
 If the start and stop dates are missing, the medication will be counted as concomitant. 
Prior and concomitant medications will be summarized separately.  
5.7.2. 
Non-Medication Procedures  
All non-medication procedures will be listed for each patient. 
5.8. 
Efficacy and Safety Analyses 
No formal hypothesis testing is planned. All efficacy analyses will be performed using the ITT 
population. 
In general, the below rules apply to the derivations of efficacy endpoints related to hemoglobin 
and RBC transfusion data unless specified otherwise: 
 Hemoglobin measurements within 7 days following RBC transfusion will be 
excluded from the efficacy analysis 
 For each patient, all efficacy endpoints will be derived based on an analysis cutoff 
day, defined as the last dose + 56 days or the last date from transfusion record data, 
whichever is earlier.  
5.8.1. 
Primary Efficacy Endpoint 
Since the primary objective of this study is to evaluate the long-term safety and tolerability of 
ACE-536 in patients with low or intermediate-1 risk MDS who were previously enrolled in study 
A536-03, there is no primary efficacy endpoint specified for this study.  


 
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5.8.2. 
Secondary Efficacy Endpoints 
5.8.2.1. 
Erythroid Response (modified HI-E from IWG 2006 criteria) 
Erythroid response (modified HI-E from IWG 2006 criteria) is defined as the proportion of 
patients with:  
 A mean hemoglobin (Hgb) increase ≥ 1.5 g/dL over an 8-week period as compared to 
baseline, not influenced by RBC transfusion, in LTB patients. 
 A decrease of ≥ 4 units or ≥ 50% of units of RBCs transfused over a period of 8 
weeks, relative to the 8 weeks immediately prior to Day 1, in HTB patients. 
A point estimate of the proportion of patients achieving a modified erythroid response will be 
presented along with its associated exact 95% confidence interval based on binomial distribution.   
The complete hemoglobin measurements and RBC transfusion records will be listed for each 
patient. 
5.8.2.2. 
RBC Transfusion Independence 
For patients with ≥ 2 units of RBC transfusion at baseline, RBC transfusion independence (RBC-
TI) response is defined as not requiring RBC transfusion for 8 or more weeks while on treatment.  
The proportion of RBC-TI responders will be estimated by a point estimate along with the exact 
95% confidence interval based on binomial distribution.  The denominator is the number of 
patients with ≥ 2 units of RBC transfusion at baseline. 
Time to RBC-TI will be defined as the time from the first dose date to the starting date of the 
first consecutive 8-week interval not requiring RBC transfusion.  Duration of RBC-TI will be 
calculated as the longest period of time not requiring RBC transfusion during treatment and will 
be censored at the analysis cutoff date for ongoing responses. 
Both time to and duration of RBC-TI will be analyzed as continuous variables and summarized 
by descriptive statistics for RBC-TI responders only.  Duration of RBC-TI will also be analyzed 
as a time to event variable using Kaplan-Meier method.  
The derivations of RBC-TI response, time to and duration of RBC-TI will be listed for each 
patient. 
RBC-TI responders may experience multiple periods of ≥8 weeks of RBC-TI response.  For all 
RBC-TI responders, the number of episodes and cumulative duration will be summarized.  As an 
exploratory analysis, the cumulative duration of the multiple responses will be analyzed using 
Kaplan-Meier method. 
5.8.2.3. 
HI-E Response Rate  
Erythroid (HI-E) response will be defined following IWG 2006 criteria.  
 For low transfusion burden (LTB) patients, a hemoglobin increase of ≥ 1.5 g/dL from 
baseline during any rolling 8-week period in the absence of transfusion.  The rolling 
8-week period starts and ends at a hemoglobin measurement date with duration ≥ 8 
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 For high transfusion burden (HTB) patients, a reduction by ≥ 4 RBC units transfused 
during any rolling 8-week interval on treatment compared to baseline.  
A point estimate of the proportion of HI-E responders will be presented along with its associated 
exact 95% confidence interval based on binomial distribution.  HI-E response will also be listed 
for each patient.  
There are two versions of a HI-E response for LTB patients. 
 All hemoglobin values increase of ≥ 1.5 g/dL from baseline during any rolling 
8-week period in the absence of transfusion. 
 Mean hemoglobin value increase of ≥ 1.5 g/dL from baseline during any rolling 8-
week period in the absence of transfusion. 
5.8.2.4. 
HI-P and HI-N Response Rate  
Platelet (HI-P) and neutrophil (HI-N) response will be defined for patients with abnormal 
baseline values, following IWG 2006 criteria. 
HI-P response will be defined for patients with baseline platelet count < 100 × 109/L: 
 For patients with baseline ≥ 20 × 109/L, an absolute mean increase of ≥ 30 × 109/L 
during any rolling 8-week interval on treatment; 
 For patients with baseline < 20 × 109/L, mean value of > 20 × 109/L and mean 
percentage increase ≥ 100% during any rolling 8-week interval on treatment. 
HI-N response will be defined for patients with baseline neutrophil count (ANC) < 1.0 × 109/L: 
 Mean percentage increase ≥ 100% and an absolute mean increase > 0.5 × 109/L 
during any rolling 8-week interval on treatment compared with baseline.  
The number and percentage of HI-N/HI-P responders will be presented.  The HI-N and HI-P 
response will also be listed for each patient. 
5.8.2.5. 
Time to and Duration of HI-E Response  
Time to and duration of HI-E response will be analyzed for HI-E responders only. 
Time to HI-E response will be defined as the time from the first dose date to the first date of any 
rolling 8-week interval achieving HI-E response.  
Duration of HI-E response will be defined as below for LTB and HTB patients, respectively:   
 For LTB patients, duration of HI-E response will be calculated as the longest interval 
during which all hemoglobin measurements have an increase of ≥ 1.5 g/dL from 
baseline.  
 For HTB patients, duration of HI-E response will be calculated for the longest such 
interval as the time from the start date of the first rolling 8-week interval achieving 
hematologic response to the end date of the last consecutive rolling 8-week interval 
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When there are multiple disjoint intervals with response, the longest interval will be used. 
Patients with response ongoing by the analysis cutoff day will be censored at that date. 
Both time to and duration of HI-E response will be analyzed as continuous variables and 
summarized by descriptive statistics.  In addition, duration of HI-E response will also be 
analyzed as a time to event endpoint.  The survival curves will be estimated using Kaplan-Meier 
method if the number of patients is more than 5.  
HI-E responders may experience multiple periods of ≥ 8 weeks of HI-E response.  For all HI-E 
responders, the number of episodes and cumulative duration will be summarized.  As an 
exploratory analysis, the cumulative duration of the multiple responses will be analyzed using 
Kaplan-Meier method. 
5.8.2.6. 
Iron-Related Parameters 
Iron metabolism parameters including serum iron, total iron binding capacity (TIBC), transferrin, 
soluble transferrin receptor, ferritin, and hepcidin will be taken at Day 1 of Cycle 1 and every 4 
subsequent cycles, EOT, PTFU and EOS visits.  Descriptive statistics of observed values, 
absolute and percentage change from baseline values at each postbaseline visit will be presented.  
Shift analyses will also be performed to summarize serum ferritin EOT change from baseline. 
Serum ferritin will be grouped into three categories: < 300, ≥ 300 and < 1000, ≥ 1000 (µg/L). 
Plots of iron parameters for both mean observed values and mean absolute change from baseline 
over time will be presented. 
5.8.2.7. 
Erythropoietin and Immature RBC Parameters 
Blood samples relating to erythropoietin parameters including serum erythropoietin levels, 
reticulocytes and nucleated RBCs will be taken at Day 1 of Cycle 1 and every 4 subsequent 
cycles, EOT, PTFU and EOS visits.  Descriptive statistics of observed values, absolute and 
percentage change from baseline values at each postbaseline visit will be presented.  Plots of 
erythropoietin parameters for mean observed values, mean change and mean percentage change 
from baseline over time will be presented. 
5.8.2.8. 
Bone Metabolism Parameters 
Bone metabolism parameters including bone specific alkaline phosphatase (BSAP) and serum 
C-telopeptide of type I collagen (CTX) will be taken at Cycle 1 Day 1, Cycle 4 Day 1, and EOT 
visits.  Descriptive statistics of observed values, absolute and percentage change from baseline 
values at each postbaseline visit will be presented.  
5.8.2.9. 
Hemolysis-Related Parameters 
Hemolysis-related parameters include direct bilirubin, total bilirubin, and lactate dehydrogenase 
(LDH).  Descriptive statistics of observed values, absolute and percentage change from baseline 
values at each postbaseline visit will be presented.  Plots of hemolysis-related parameters for 
both mean observed values, mean change and mean percentage change from baseline over time 
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5.8.2.10. Other Analysis 
For the following continuous variables, the descriptive statistics including mean, standard 
deviation, median and range will be presented:  
 Maximum reduction over rolling 8-week intervals (absolute and percentage) in 
transfusion burden from baseline in HTB patients 
 Maximum increase in hemoglobin level from baseline in LTB patients 
 Maximum hemoglobin mean change from baseline during any rolling 8-week period 
in LTB patients 
 Maximum decrease/percentage decrease in serum ferritin  
 Change in absolute reticulocytes 
 Change in pre-transfusion hemoglobin level in HTB patients 
 Frequency of RBC transfusions in HTB patients 
5.8.3. 
Exploratory Endpoints 
5.8.3.1. 
FACT-An Questionnaire 
The FACT-An Questionnaire will be completed at Day 1 of Cycle 1 and every 4 subsequent 
cycles, End of Treatment, and End of Study visit.  The FACT-An questionnaire contains 
47 questions which are divided into the following subscales: 
 Physical Well-Being (PWB) (7 questions: Item Score range 0 - 28) 
 Social/Family Well-Being (SWB) (7 questions: Item Score range 0 - 28) 
 Emotional Well-Being (EWB) (6 questions: Item Score range 0 - 24) 
 Functional Well-Being (FWB) (7 questions: Item Score range 0 - 28)  
 Anemia subscale (AnS) (20 questions: Item Score range 0 - 80) 
Patients give individual responses to each question on a scale of 0 to 4 (0=Not at all; 1=A little 
bit; 2=Somewhat; 3=Quite a bit; 4=Very much). Item scores in the PWB and EWB subscales 
will be derived by subtracting the response value from 4.  Similarly, all item scores in the AnS 
subscale except Item Codes An5, An7, BL4 and An133 will be derived by subtracting the 
response value from 4.  Thus, a higher Item Score indicates a better quality of life.  Subscale 
totals will be derived as follows: 
Sum of Item Scores x Number of Items in Subscale 
Number of Items Answered 
For example, if 6 questions are answered in the Physical Well-Being subscale and the Item 
scores sum to a total score of 18, then the subscale score will be (18 x 7)/6 = 21. 
If 50% or more of responses in any subscale are missing, the subscale score will be set to 
missing. 
The following total scores will also be derived: 


 
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FACT-An Total Outcome Index (TOI) derived as: PWB + FWB + AnS 
(Score range 0 – 136) 
FACT-G Total Score (FACT-G) derived as: PWB + SWB + EWB + FWB 
(Score range 0 – 108) 
FACT-An Total Score (FACT-An) derived as: PWB + SWB + EWB + FWB + AnS 
(Score range 0 – 188) 
If 20% or more of the responses that contribute to the FACT-G score are missing, the FACT-G 
score will be set to missing, i.e., at least 22 of the 27 items contributing to FACT-G must be 
present.  Furthermore, FACT-An TOI, FACT-G and FACT-An scores should only be calculated 
if all component subscales have valid scores.  If any subscale total is missing, the respective total 
scores to which the subscale contributes will also be set to missing.   
Individual subscale scores and total scores will be summarized by visit.  All derived subscale and 
total scores and all individual responses will be listed.  
The association between FACT-An improvement and RBC-TI response will also be explored. 
5.8.4. 
Subgroup Analyses 
Subgroup analyses of the efficacy endpoints will be performed for the following baseline 
parameters: 
 RS status (positive or negative),  
 SF3B1 mutation status (mutated or wild type) 
 Splicing factor mutation status (mutated or wild type) 
 Baseline EPO level (≤ or >100, ≤ or > 200; ≤ or >500) 
 Baseline bone marrow blasts (< 5% or ≥ 5%) 
 IPSS risk group (low, Int-1, Int-2, or high) 
 IPSS-R risk group (very low, low, intermediate, high, very high) 
Logistic regression analysis will be performed to evaluate the effect of following prognostic 
factors on the IWG HI-E response and RBC-TI individually.   
 IPSS risk group (low vs Int-1/Int-2/high) 
 Baseline EPO (continuous) 
 Baseline EPO level (≤ 100 vs. > 100 IU/L) 
 Baseline EPO level (≤ 200 vs. > 200 IU/L) 
 Prior ICT (Yes vs. No) 
 Prior ESA (Yes vs. No) 
 RS status (positive vs. negative),  
 SF3B1 mutation status (mutated vs wild type) 


 
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Multivariable logistic regression analysis with backward selection will be performed to evaluate 
the association of association between baseline factors and IWG HI-E and RBC-TI response.  
5.8.5. 
Safety Analyses 
The safety endpoints will be summarized based on the Safety Population.  The safety endpoints 
include the incidence of treatment emergent adverse events, changes in laboratory tests, vital 
signs and ECG’s. 
Adverse events (AEs) will be coded using MedDRA Version 20.0.  Severity of AEs will be 
coded using National Cancer Institute Common Toxicity Criteria for Adverse Events version 4.0 
(NCI-CTCAE v4.0). 
5.8.6. 
Adverse Events 
All AEs and SAEs occurring after the Study A536-03 (for patients without interruption) or Study 
A536-05 (for patients with interruption) Cycle 1 Day 1 until approximately 2 months after the 
last study drug administration (PTFU visit) are to be reported and documented on the AE CRF. 
Treatment emergent adverse events (TEAE) are defined as: 
 AE starting or worsening from the first date of study drug; 
 AE occurs on the first date of study drug and the onset check box is marked “Onset 
after first dose of study drug”; 
 AE with a missing start date and a non-missing stop date on or after the first dose of 
study drug; 
 AE with both a missing start and stop date.  
A drug-related TEAE is defined as any TEAE related to the study medication as assessed by the 
investigator or with missing assessment of the causal relationship. 
The following summaries will also be presented: 
 Number and percentage of patients reporting each AE, categorized by SOC and PT 
 Number and percentage of patients reporting each AE experienced by ≥ 5% of 
patients in all patients by PT 
 Number and percentage of patients reporting SAE, categorized by SOC and PT 
 Number and percentage of patients reporting Grade ≥ 3 AE, categorized by SOC and 
PT 
 Number and percentage of patients reporting related AE, categorized by SOC and PT 
 Number and percentage of patients reporting AE leading to drug withdrawal, 
categorized by SOC and PT 
 Number and percentage of patients reporting AEs of interest by cycle 
Note that counting will be by patient, not event, and patients are only counted once within each 
SOC or preferred term.  If a patient has the same AE at more than one severity, or with more 


 
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than one relationship to study drug, the most severe rating or the stronger causal relationship to 
study drug will be given precedence.  Any missing severity, causality, or outcome will not be 
imputed and classed as unknown. 
All AEs will be listed. The following listings will also be provided: 1) patients with SAEs; 
2) patients with Grade ≥ 3 AEs; 3) patients with AEs leading to discontinuation.; and 4) death. 
5.8.7. 
Laboratory Evaluations 
Results from the following laboratory parameters, recorded at their respective time points will be 
summarized by time point:  
Hematology (Screening, Day 1 of each cycle, End of Treatment, Post Treatment Follow Up and 
End of Study): RBC, white blood cell (WBC) with differential, hemoglobin, hematocrit, 
reticulocyte count, platelet count, mean corpuscular volume (MCV), mean corpuscular 
hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), red blood cell 
distribution width (RDW), and nucleated RBCs (nRBCs)   
Chemistry (Screening, Day 1 of Cycle 1 and Day 1 of every other subsequent cycles, End of 
Treatment and End of Study): Sodium, potassium, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), lactate dehydrogenase (LDH), total bilirubin, direct bilirubin, alkaline 
phosphatase, blood urea nitrogen (BUN)/urea, creatinine, gamma-glutamyl transpeptidase 
(GGT), calcium, phosphorus, glucose, amylase, lipase, total protein, albumin, and uric acid 
Urine Analysis (Day 1 of Cycle 1 and every 4 subsequent cycles, End of Treatment and End of 
Study): pH, specific gravity, protein, glucose, ketones, blood, leukocyte esterase, nitrite, 
microscopic examination (if performed) 
Urine Chemistry (Day 1 of Cycle 1 and every 4 subsequent cycles, End of Treatment and End 
of Study): Microalbumin and creatinine; albumin/creatinine ratio 
Categorical and numeric variables will be presented separately.  Actual values and changes in 
hematology and biochemistry laboratory values from baseline will be summarized by time point.  
Shift tables for the hematology and biochemistry laboratory parameters comparing values above, 
within and below the normal reference range at baseline to the end of treatment visit will be 
presented using standard reference ranges.  
Peripheral blood smears are taken at Screening, Day 1 of Cycle 1 and every 4 subsequent cycles, 
and at the end of treatment visit.  These data will be listed only.   
All laboratory values will be listed for all patients. 
5.8.8. 
Vital Signs 
Vital signs parameters include weight (kg), heart rate, systolic and diastolic blood pressure, 
respiratory rate, and temperature (°C).  Vital signs are recorded at Screening and on Days 1 of 
each cycle and End of Treatment.  For each parameter at each time point, the observed values 
and change from baseline will be summarized.  Vital sign data will also be listed for all patients. 


 
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5.8.9. 
ECG Results 
12-lead ECG results are recorded at Cycle 1 Day 1 and at the end of treatment visit.  The 
quantitative ECG assessments (Ventricular rate, QRS width, PR interval, and QTcF interval) will 
be summarized at each time point. 
ECG overall interpretation (normal, abnormal/not clinically significant [NCS] and 
abnormal/clinically significant [CS]) will be presented for actual values and changes from 
baseline (Screening observation) to each post-baseline visit, expressed as Improvement, No 
Change, and Deterioration, defined as follow: 
 Improvement = CS to Abnormal NCS, Abnormal NCS to Normal  
 Deterioration = Normal to Abnormal NCS or CS, Abnormal NCS to Abnormal CS  
 No change = Normal to Normal, Abnormal NCS to Abnormal NCS, Abnormal CS to 
Abnormal CS 
If a result is missing for any patient, then an ‘Unknown’ category will be presented.  ECG results 
will be listed for all patients. 
5.8.10. 
Physical Examination 
A physical examination is conducted at Screening, Cycle 1 Day 1 and Day 1 of every 4 cycles 
and at the end of treatment and end of study visits. Physical exam details will be listed only. 
5.8.11. 
Long-term Follow-up 
A listing of Long-term Follow-up data including the visit date, malignancy status, and survival 
status will be provided. 
5.9. 
Pharmacokinetics Analysis 
5.9.1. 
Pharmacokinetic Sampling Schedule  
Blood samples for determination of ACE-536 serum concentrations are collected at Cycle 1 Day 
1, Day 1 of every 4 subsequent cycles, EOT, and EOS.  
Acceptable time windows for pharmacokinetic blood draws are ± 1 day in Cycle 1 and ± 7 days 
for the other cycles with PK sampling scheduled. 
5.9.2. 
Data Handling  
Concentrations that are below the limit of quantitation (BLQ) prior to the first dose will be 
assigned a numerical value of zero.  Post-treatment concentrations that are BLQ will be treated 
as missing.    
Concentrations assigned a value of missing will be omitted from the descriptive statistics.  A 
concentration value of zero will be excluded from the computation of the geometric mean 
(geometric CV%).  If any patients are found to be noncompliant with respect to dosing, have 
incomplete data, or encounter other circumstances that would affect the evaluation of 
pharmacokinetics, a decision will be made on a case-by-case basis as to their inclusion in the 


 
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pharmacokinetic analysis.  Data excluded from pharmacokinetic analysis will be included in the 
data listings, but not in the summaries. 
In tables and listings for the derived pharmacokinetic data, there should be four decimal places 
for numerical values below 1, three decimal places for numeric values below 10 but above 1, and 
two decimal places for numeric values above 10.  However, the listings of raw data should not 
have more decimal places than the actual data. 
5.9.3. 
Pharmacokinetic Analysis  
All ACE-536 serum concentrations will be listed by patient and scheduled time (visit and study).  
Actual dosing/sampling time, sample time relative to first dosing time, visit, and concentration as 
done for the 03 study will be presented in the listing.  
The ACE-536 serum concentrations will be summarized by scheduled time, including N (number 
of observations), arithmetic mean, arithmetic standard deviation (SD), arithmetic coefficient of 
variation (CV%), geometric mean, geometric CV%, minimum, median, and maximum.  Mean 
(SD) serum concentration-time profiles will be presented on linear scales.   
5.10. 
Interim Analysis 
There are no planned interim analyses.  However, safety and erythroid response data may be 
reviewed periodically throughout the study. 
5.11. 
Protocol Violations or Deviations 
Protocol violations and deviations will be reviewed and may result in a patient and/or patient 
visit data being excluded from the statistical summaries.  All decisions regarding exclusion of 
any patient data will be made and recorded during the final data review. 
5.11.1. 
Violation Criteria 
Patients who meet any of the following criteria will be listed: 
 Non-compliance with inclusion criteria 
 Non-compliance with exclusion criteria 
 Unauthorized concomitant therapy 
 Less than 8 weeks historical hemoglobin data 
 Dose not modified according to Dose Modification Criteria 
 Study assessment outside of visit window  
5.11.2. 
Protocol Deviations 
Deviations from the protocol, as defined in the protocol, will be documented on an ongoing basis 
by the study monitors and project manager throughout the study period.  
At the time of database lock and while the protocol violations are being reviewed, the project 
manager will forward all relevant documentation highlighting protocol deviations to the study 


 
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statistician.  These deviations will be included in the protocol violation document for agreement 
and will be listed with the protocol violations in the CSR. 
5.12. 
Handling of Missing Data and Visit Window 
5.12.1. 
Missing Data 
As a general principle, no imputation of missing data for other variables will be done. Exceptions 
are the start and stop dates of AEs and concomitant medication.  The imputed dates will be used 
to allocate the medication as prior or concomitant medications and to determine whether an AE 
is/is not treatment emergent.  Listings of the AEs and concomitant medications will present the 
actual partial dates; imputed dates will not be shown. 
5.12.2. 
Missing Dates for Adverse Event 
Imputing partial AE start dates: 
 If the year is unknown, the date will not be imputed and will be assigned a missing 
value. 
 If the month is unknown, then: 
 If the year matches the first dose date, then impute the month and day of the first 
dose date. 
 Otherwise, assign January. 
 If the day is unknown, then: 
 If the month and year match the first dose date, then impute the day of the first 
dose date. 
 Otherwise, assign ‘01’. 
Imputing partial AE stop dates: 
 If the year is unknown, the date will not be imputed and will be assigned a missing 
value. 
 If the month is unknown, then assign December. 
 If the day is unknown, then assign the last day of the month. 
5.12.3. 
Missing Dates for Concomitant Medication  
If start date is missing or partial: 
 if month is missing, use January  
 if day is missing, use the first day of the month under consideration 
 if year is missing, use year of the informed consent date  
 if entire date is missing, use informed consent date  
If stop date is missing or partial: 


 
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 if month is missing, use December  
 if day is missing, use the last day of the month under consideration 
 if year or the entire date is missing, set to December 31st, 2099 
If the imputed start date is after the stop date, then the imputed start date will be one day prior to 
the stop date. 
5.12.4. 
Missing Dates for Disease Diagnosis Date  
For disease diagnosis dates, the imputation rules are  
 if day is missing, use 15th of the month 
 if both day and month are missing, impute as January 1st 
 if month is missing, impute as January 
 if year is missing, set to missing 
5.13. 
Changes in Conduct or Planned Analyses from the Protocol 
Major changes between SAP and the planned analysis in Protocol are described below: 
Item 
Difference Between Protocol and SAP 
NTD/TD 
In SAP, the terms LTB/HTB are used in place of NTD/TD in protocol. 
mITT 
In the SAP, ITT is used in place of mITT in the protocol. 
Secondary objectives: 
time to and duration of 
mHI-E 
The secondary endpoints time to and duration of mHI-E will not be analyzed.  
Efficacy Evaluable 
Population (EE) 
Analysis on Efficacy Evaluable population will not be performed.  All 
analyses are on ITT population 
Definition of baseline 
hemoglobin 
Protocol definition: Baseline hemoglobin will be the average of at least two 
measures (not influenced by transfusion within 7 days of measurement); one 
measure performed within one day prior to Cycle 1 Day 1 and the other 
performed 7-28 days prior to Cycle 1 Day 1.  This definition is revised in 
this SAP to reflect the derivation rule implemented for this study. 


 
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6. 
REFERENCES 
Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for modification 
of the International Working Group (IWG) response criteria in myelodysplasia. Blood 
2006;108:419-25. 
National Cancer Institute Common Toxicity Criteria for Adverse Events, version 4.0 
(NCI-CTCAE v4.0) 
 
 


 
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7. 
APPENDICES 
7.1. 
Appendix 1: List of Abbreviations 
Abbreviation 
Definition 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BSAP 
Bone specific alkaline phosphatase 
BUN 
Blood urea nitrogen 
CRF 
Case report form 
CTX 
C-telopeptide of type I collagen 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EE 
Efficacy Evaluable 
ESA 
Erythropoiesis stimulating agent 
EOS 
End of Study 
EPO 
Erythropoietin 
EOT 
End of Treatment 
FACT-An 
Functional Assessment of Cancer Therapy-Anemia Scale 
HI-E 
Erythroid response 
HI-N 
Neutrophil response 
HI-P 
Platelet response 
HTB 
High Transfusion Burden 
ICT 
Iron Chelation Therapy 
IPSS 
International Prognostic Scoring System 
IPSS-R 
Revised International Prognostic Scoring System 
ITT 
Intent-to-Treat 
IWG 
International Working Group  
LDH 
Lactate dehydrogenase 
LTB 
Low Transfusion Burden 
LTFU 
Long-Term Follow-Up 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCH 
Mean corpuscular hemoglobin 


 
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Abbreviation 
Definition 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MDS 
Myelodysplastic syndromes 
NCI-CTCAE 
National Cancer Institute-Common terminology criteria for adverse events 
nRBC 
Nucleated red blood cells 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PTFU 
Post-treatment Follow-up 
QoL 
Quality of life 
RBC 
Red blood cell 
RDW 
Red blood cell distribution width 
RS 
Ring Sideroblasts 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SF3B1 
Splicing factor 3B subunit 1 
SRT 
Safety Review Team 
TGF-β 
Transforming growth factor beta 
TIBC 
Total iron binding capacity 
WBC 
White blood cell 
WHO 
World Health Organization 


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7.2. 
Appendix 2: Schedule of Events for Study 03 
 
 


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Screen 
Treatment Period 
Follow up period 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
EOT12 
Post-
Treatment 
Follow Up 
EOS13 
C1D12 C1D8 
C1D1
1 
C1D1
5 
C2D12,15 
C2D8 
C2D1
5 
C3D12,15 
C3D8 
C3D15 C4D12,15 
C4D8 
C4D15 
C5D12,15 
C5D8 
C5D15 
Day 
113 
(± 7d) 
Day 
141 
(± 7d) 
Day 
169 
(± 7d) 
Day 
-28 
Da
y 
1 
Day 
8 
(± 1d) 
Day 
11 
(± 1d) 
Day 
15 
(± 1d) 
Day14 
22 
(± 2d) 
Day 
29 
(± 2d) 
Day 
36 
(± 2d) 
Day14 
43 
(± 2d) 
Day 
50 
(± 2d) 
Day 
57 
(± 2d) 
Day14 
64 
(± 2d) 
Day 
71 
(± 2d) 
Day 
78 
(± 
2d) 
Day14 
85 
(± 2d) 
Day 
92 
(± 2d) 
Day 
99 
(± 2d) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FACT-An Questionnaire 18 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X19 
 
X 
Physical examination  
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
Vital signs1  
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ECOG Status 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
X 
ECG (12 lead) 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Bone marrow aspirate/biopsy3  
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Serum iron studies4 
X 
X 
 
 
 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Serum folate and B12 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Erythropoietin levels  
X 
X 
X 
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
Hematology5 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Peripheral blood smear 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
Serum chemistry6 
X 
X 
 
 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
X 
Urinalysis and Urine Chemistry7  
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
Anti-drug antibody16 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X16 
PK collection 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
PD biomarkers8 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
Bone biomarkers9 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Pregnancy test10 
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
Evaluate transfusion frequency11 
X 
X 
 
 
 
X 
 
 
X 
 
 
X2 
 
 
X 
 
 
X 
 
X 
Concomitant medications and AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Administer ACE-53617 
 
X 
 
 
 
X14 
 
 
X14 
 
 
X14 
 
 
X14 
 
 
 
 
 


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1 Vital signs: Weight, heart rate, systolic and diastolic blood pressure, respiration rate and temperature (measured in degrees Celsius).  Height is measured only at Screening.   
2 Study procedures must be done prior to administration of study drug.    
3 Bone marrow aspirate/biopsy including cytogenetics at screening must be performed ≤ 3 months prior to C1D1 for evaluation of patient eligibility and other PD biomarkers 
to be determined (e.g., GDF15, GDF8, and GDF11).  A bone marrow aspirate must be performed within 21 days after C3D1 (a bone marrow biopsy is not required).  If 
hemoglobin increases ≥ 2 g/dL, an optional bone marrow aspirate can be performed within 7 days of the result.  At the end of treatment visit, a bone marrow aspirate must 
be performed (a bone marrow biopsy is optional). 
4 Iron Studies: Serum iron, TIBC, transferrin, soluble transferrin receptor, ferritin. 
5 Hematology: RBC, WBC with differential, hemoglobin, hematocrit, nRBC, reticulocyte count, platelet count, MCV, MCH, MCHC, and RDW. On dosing days, hemoglobin 
values are to be drawn and resulted (up to 1 day) prior to dosing (see protocol Section 10.8.1, Patient Dose Modification Rules).  Historical hemoglobin data will be 
collected for 24 weeks, where available, prior to C1D1.  During the screening period, hemoglobin will be measured twice; one measure performed within one day prior to 
Cycle 1 Day 1 and the other performed 7-28 days prior to Cycle 1 Day 1.  Neither hemoglobin measure should be influenced by transfusion within 7 days of measurement. 
6 Chemistry: Sodium, potassium, AST, ALT, lactate dehydrogenase (LDH), total bilirubin, direct bilirubin, alkaline phosphatase, blood urea nitrogen (BUN)/urea, creatinine, 
GGT, calcium, phosphorus, glucose, amylase, lipase, total protein, albumin, and uric acid.  
7 Urinalysis by dipstick analysis (local lab): pH, specific gravity, protein, glucose, ketones, blood, leukocyte esterase, and nitrite, with microscopic examination if indicated.  Urine 
Chemistry (central lab): Microalbumin and creatinine. 
8 PD Biomarkers: Hepcidin, GDF15, GDF8, GDF11, and others to be determined. 
9 Bone Biomarkers: BSAP and CTX. 
10 Pregnancy test: (urine or serum) is required for female patients of child bearing potential at screening and prior to each dose of ACE-536. 
11 Transfusion history will be collected for 24 weeks, where available, prior to C1D1. 
12 End of Treatment (EOT): Should be performed 28 days (± 7 days) after the last dose of ACE-536.  Patients who discontinue treatment early should complete the end of 
treatment visit at the time of discontinuation and complete the post-treatment follow-up (PTFU) and EOS follow-up visits 28 days (± 7 days) and 56 days (± 7 days) after 
the EOT visit. 
13  End of Study (EOS): Should be performed 56 days (± 7 days) after the Day 113/EOT visit.  
14 Day 85 ± 2 days is the last possible study day that ACE-536 may be administered, regardless of the cycle. 
15 If a dose delay is required per the dose modification rules the patient will not be dosed.  The patient will return weekly to assess hematology results and adverse events until the 
patient is eligible to administer the next dose of ACE-536. 
16 If the patient has a positive ADA result at their last assessment, the patient may be asked to return approximately every three months for additional testing, until a negative result is 
obtained or the result is considered stabilized. 
17 For the first dose of ACE-536, dosing should occur after a minimum of 7 days post-transfusion and a minimum of 24 hours prior to a scheduled transfusion. 
18 Expansion cohort patients only, administration of FACT-An quality of life questionnaire. 
19 FACT-An should be completed at the EOT visit only for patients that discontinue treatment early. 
 






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1 
Screening procedures: Other than informed consent, procedures listed as part of the 28-day screening period are only applicable to patients with treatment 
interruption.  Patients with treatment interruption will need to qualify per the additional inclusion criteria listed in Section 9.2.1.  For patients without treatment 
interruption, C1D1 may coincide with EOT visit of the base study A536-03.  Procedures that are required to confirm eligibility for patients without treatment 
interruption can be performed at the base study A536-03 EOT visit and used to confirm eligibility prior to dosing on C1D1 of study A536-05.   
2 
Study procedures must be done prior to administration of study drug.  For patients without treatment interruption, C1D1 procedures shaded grey may be 
conducted as part of the EOT visit for study A536-03 and may not need to be repeated for study A536-05. All screening and Cycle 1 Day 1 procedure results 
required to confirm eligibility must be obtained and reviewed prior to study drug administration in A536-05.    
Visit schedule: Each dosing visit (cycles 1-87) will be 21 days (±5 days) from the previous dosing visit, unless a dose delay is required.  If a dose delay is 
required per the dose modification rules (Section 10.8), the patient will not be dosed.  The patient will return every 1-3 weeks for assessment of hematology 
results and AEs until the patient is eligible to receive the next dose of ACE-536 and start the next cycle.  The patient should resume the study at the planned 
dosing cycle (e.g. if the patient missed a dose at C4D1, then they would resume dosing at C4D1 and not skip to C5D1).    
Dosing: The patient dose must be calculated based on the patient’s weight on the day of dosing.  Dose modification rules and titration rules must be reviewed 
and implemented prior to dosing as required per protocol (see Section 10.8 and Section 10.9).  A dose titration cannot occur until C3D1.  
3 
Medical History: Medical history for patients with treatment interruption will include medical events occurring after EOS visit in study A536-03 and prior to 
C1D1 for study A536-05.  Medical history for patients without treatment interruption will be taken from study A536-03.    
4 
Quality of life questionnaires are only required on C1D1, C5D1, C9D1, C13D1, C17D1, C25D1, C33D1, C41D1, C49D1, C57D1, C65D1, C73D1, C81D1, 
EOT, and EOS. 
5 
Vital signs will include weight, heart rate, and systolic and diastolic blood pressure. 
6 
ECG: May be collected within 28 days prior to C1D1. 
7 
Bone marrow aspirate: Patients with treatment interruption must have a bone marrow aspirate including cytogenetics performed ≤ 3 months prior to C1D1 for 
evaluation of eligibility per inclusion criteria Section 9.2.1.  A bone marrow aspirate will not be performed on C1D1 for patients without treatment interruption. 
A bone marrow aspirate must be performed within 21 days after C9D1, C17D1, C25D1, C41D1, C57D1, and C73D1 for all patients.  At the EOT visit, a bone 
marrow aspirate is required for all patients, unless performed < 3 months following a previous bone marrow aspirate and not clinically indicated. Refer to the 
Laboratory Manual for processing and shipping instructions. 
8 
Serum Iron Studies: May include serum iron, TIBC, transferrin, soluble transferrin receptor, ferritin.   
9 
Hematology: RBC, WBC with differential, hemoglobin, hematocrit, nucleated red blood cells (nRBC), reticulocyte count, platelet count, peripheral blasts, 
mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and red blood cell distribution 
width (RDW). On dosing days, hemoglobin values may be drawn and resulted (up to 1 day) prior to dosing (see Section 10.8, Individual Dose Modification 
Rules).  
10 
Serum Chemistry: Sodium, potassium, AST, ALT, lactate dehydrogenase (LDH), total bilirubin, direct bilirubin, alkaline phosphatase, blood urea nitrogen 
(BUN)/urea, creatinine, gamma-glutamyl transpeptidase (GGT), calcium, phosphorus, glucose, amylase, lipase, total protein, albumin, and uric acid.  
11 
Urinalysis by dipstick analysis (local lab): pH, specific gravity, protein, glucose, ketones, blood, leukocyte esterase, and nitrite, with microscopic examination 
if indicated.  Urine Chemistry (central lab): urine chemistries include but are not limited to: microalbumin and creatinine.  
12 
If the patient has a positive ADA result at their last assessment, the patient may be asked to return approximately every three months for additional testing, until 
a negative result is obtained or the result is considered stabilized. 
13 
PD Biomarkers: May include hepcidin, GDF15, GDF8, GDF11, Activin A and others to be determined. 
14 
Pregnancy test: (urine or serum) is required for female patients of child bearing potential only. 
15 
Transfusion Frequency: Transfusion history will be collected from the EOS visit in the base study A536-03 through the C1D1 visit of A536-05 as available 
for patients with treatment interruption up to 24 weeks.  TD patients will have a defined “pre-transfusion hemoglobin threshold” for requiring transfusion during 
the study which will be calculated based on transfusion history and will be used for determining when to transfuse during the study. The baseline pre-transfusion 
hemoglobin threshold will be the mean of all documented pre-transfusion hemoglobin values during the 12 weeks prior to C1D1 of base study A536-03 (for TD 
patients without treatment interruption) or study A536-05 (for TD patients with treatment interruption).  During treatment, if the pre-transfusion hemoglobin 
level is increased by ≥ 1 g/dL compared to the baseline pre-transfusion hemoglobin threshold for that patient, transfusion should be delayed by a minimum of 7 


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days and/or the number of units transfused should be reduced by 1 or more RBC units.  Patients should not be transfused if hemoglobin is ≥ 9 g/dL unless 
indicated for symptoms related to anemia or other reasons at the investigator’s discretion.   
16 
Cycles 16 through 87: Patients may complete up to 87 Cycles.  The last dose of ACE-536 may not be administered after 87 cycles or 1825 calendar days from 
C1D1, whichever occurs first.   
17 
End of Treatment (EOT): Should be performed 28 days (± 7 days) after the last dose of ACE-536.  Patients who discontinue treatment early should complete 
the EOT visit at the time of discontinuation, followed by PTFU, LTFU, and EOS visits.   
18 
Post-Treatment Follow-Up (PTFU): Patients will complete the PTFU visit 2 months  (± 7 days) after the last dose of ACE-536  
19 
Long-Term Follow-Up (LTFU): Patients will complete LTFU visits every 3 months (± 7 days) after the last dose of ACE-536 for 3 years after the last dose of 
ACE-536.  
20 
End of Study (EOS): Should be performed 3 years after the last dose of ACE-536. 
21 
Long-Term Post-Treatment Follow-Up for overall survival (OS), progression to AML, other malignancies/pre-malignancies (please refer to Section 14.1 for 
details) may be conducted by record review (including public records if allowed by local regulations) and/or telephone contact with the patient, family, or the 
patient’s treating physician.  The investigator must make every effort to obtain information regarding the patient’s survival status before determining the patient 
is lost to follow-up.