Conditions: Pulmonary Arterial Hypertension
Keywords: Pulmonary Hypertension
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 324
Healthy volunteers: no

Brief summary:
The objectives of this study are to evaluate the efficacy and safety of sotatercept (MK-7962) treatment (plus background pulmonary arterial hypertension (PAH) therapy) versus placebo (plus background PAH therapy) at 24 weeks in adults with PAH. The primary hypothesis of the study is that the participants receiving sotatercept will have improved 6-minute walk distance (6MWD) at 24 weeks compared to participants receiving placebo.

Detailed description:
This is a Phase 3, randomized, double-blind, placebo-controlled, multicenter, parallel-group study in subjects with symptomatic PAH who present with idiopathic or heritable PAH, PAH associated with connective tissue diseases (CTD), drug or toxin induced, post shunt correction PAH, or PAH presenting at least 1 year following the correction of congenital heart defects (CHDs), and currently on background PAH therapy.

The primary efficacy endpoint of the study is exercise capacity, as measured by the 6-minute walk distance (6MWD) measured at 24 week following initiation of treatment.

Study duration will be approximately 2 years. A stratified Wilcoxon test will be used for analysis of the primary endpoint, with appropriate imputation for missing data, as detailed in the Statistical Analysis Plan. An unblinded, external, independent Data Monitoring Committee (DMC) will monitor participant safety throughout the course of the study. Participants completing this study will be eligible to receive sotatercept in a separate, open-label extension study.

Arms:
arm 1: Sotatercept at a starting dose of 0.3 mg/kg with a target dose of 0.7 mg/kg administered subcutaneously (SC) every 21 days plus background PAH therapy arm 2: Placebo administered (SC) every 21 days plus background PAH therapy

Interventions: intervention 1: Sotatercept intervention 2: Placebo intervention 3: Background PAH Therapy
Intervention descriptions: intervention 1: Sotatercept at a starting dose of 0.3 mg/kg with a target dose of 0.7 mg/kg administered subcutaneously (SC) every 21 days plus background PAH therapy. intervention 2: Placebo administered subcutaneously (SC) every 21 days plus background PAH therapy. intervention 3: Background PAH therapy may consist of the following drug classes: an endothelin-receptor antagonist (ERA), a phosphodiesterase 5 (PDE5) inhibitor, a soluble guanylate cyclase stimulator, and/or a prostacyclin analogue or receptor agonist.

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:
NCT04576988
Document Date:
A Phase 3, Randomized, Double-Blind, Placebo-
Controlled Study to Compare the Efficacy and 
Safety of Sotatercept Versus Placebo When Added 
to Background Pulmonary Arterial Hypertension 
(PAH) Therapy for the Treatment of PAH
06-Oct-2021


Clinical Study Protocol 
Sotatercept (ACE-011) 
Study No: A011-11 
Revision 1.0 
06 October 2021 
Acceleron Pharma Inc. 
Page 1 of 109 
CONFIDENTIAL 
Protocol A011-11 (STELLAR) 
PROTOCOL TITLE: 
A Phase 3, Randomized, Double-Blind, 
Placebo-Controlled Study to Compare the Efficacy 
and Safety of Sotatercept Versus Placebo When 
Added to Background Pulmonary Arterial 
Hypertension (PAH) Therapy for the Treatment of 
PAH 
SHORT TITLE: 
A Phase 3 Study of Sotatercept for the Treatment of 
PAH 
REGULATORY AGENCY 
IDENTIFYING NUMBERS: 
IND 136150 
EudraCT 2020-004142-11 
SPONSOR: 
Acceleron Pharma Inc. 
128 Sidney Street 
Cambridge, MA 02139 
USA 
ORIGINAL PROTOCOL DATE: 
PROTOCOL AMENDMENT 01: 
12 September 2020 
06 October 2021  
Confidentiality Statement 
This confidential information in this document is provided to you as an investigator or consultant 
for review by you, your staff, and the applicable Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC).  Your acceptance of this document constitutes agreement that you will 
not disclose the information contained herein to others without written authorization from 
Acceleron Pharma Inc. 
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PROCEDURES IN CASE OF EMERGENCY 
Table 1: 
Emergency Contact Information 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
Substantive changes from Revision 0.0 to Revision 1.0 are detailed below.  Minor edits are not 
included. 
Protocol Location 
Description of Change 
Brief Rationale 
Title Page 
Added “PROTOCOL 
AMENDMENT 01: 01 October 
2021” 
Updated protocol amendment 
identifier and release date 
Table 1 
Updated pharmacovigilance row 
Added new contact information 
Updated Medical Monitor row 
Changed phone number 
Section 2, Schedule of 
Events 
Changed the following in footnote 
d: “perform targeted 
cardiopulmonary and skin 
examinations.” 
Updated based on new information 
about the study treatment. 
Updated footnote j in Table 2 to 
indicate that RHC will be 
performed last “when possible.” 
Similar changes were made in 
Section 9.2.1 Screening Period (up 
to 4 weeks prior to Visit 1) and 
Section 9.3.2 Right Heart 
Catheterization. 
Clarified that sites have flexibility 
if it is not possible to schedule the 
RHC last  
Changed “CO2” in footnote i in 
Table 2 and footnote k in Table 3 to 
“HCO3” and added “albumin.” 
A similar change was made to 
Section 9.3.16, Serum Chemistry 
Correction 
Updated footnote n in Table 2 and 
footnote o in Table 3 to change 
“should be done prior to study drug 
administration” to “must be done 
prior to study drug administration.” 
Clarified the mandatory order of 
procedures 
Updated footnote m in Table 3 to 
remove the following: “If the 
PAH-SYMPACT cannot be 
completed at home on the 7 days 
prior to the EOS visit it should be 
completed once on-site at the EOT 
visit.” 
A similar change was made to 
Section 9.3.8.2, Pulmonary Arterial 
Hypertension – Symptoms and 
Impact 
Correction 
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Protocol Location 
Description of Change 
Brief Rationale 
Changed the row label “Serum 
Chemistry” to “Serum 
chemistry/FSH” in Table 3. 
Similar changes were made in 
Section 9.2 Study Procedures and 
Synopsis. 
Improved consistency of row labels 
across Section 2 
Removed “hematology (complete 
blood count)” assessment from 
Visits 10-12, 14-16, 18-20, 22-24, 
26-28, and 30-32 in Table 3.  
Similar changes were made in 
Section 9.2 Study Procedures. 
Updated study assessments 
Section 3.2, Risks and/or 
Benefits to Participants 
Aligned text with A011-14 
(ZENITH) Version 1.0 from 08 
April 2021, updated text regarding 
the detection of anti-drug 
antibodies, and added text 
regarding the risk of telangiectasia. 
Updated information for 
programmatic consistency and 
accuracy 
Section 5.3 Secondary 
Efficacy Endpoints and 
Rationale;  
Section 11.5.2 Secondary 
Endpoints; and Synopsis  
Changed Secondary Endpoints to 
clarify that the Physical Impacts, 
Cardiopulmonary Symptoms, and 
Cognitive/Emotional Impacts 
domains of the PAH-SYMPACT 
will be evaluated. Removed 
EQ-5D-5L (added to the 
Exploratory Endpoints below).  
Updates to endpoints 
Section 5.4 Exploratory 
Endpoints; Section 11.5.3 
Exploratory Endpoints; 
and Synopsis 
Added evaluation of the 
Cardiovascular Symptoms domain 
of the PAH-SYMPACT®, 
EQ-5D-5L, and EQ-5D-5L VAS to 
the Exploratory Endpoints.  
Updates to endpoints 
Section 6.5, Home Health 
Care Visits 
Removed the following: “For HHC 
visits, hematology results are not 
required to be evaluated prior to 
study drug administration.  
However, if results evaluated after 
dosing meet the criteria for dose 
modification, the following visit 
will be conducted on-site and the 
medical monitor consulted.” 
This text no longer applies because 
hematology will not be performed 
during the home health care visits 
Section 6.6, 
Randomization and 
Blinding 
Amended text starting in the middle 
of paragraph 2. 
Clarified that participants will be 
discontinued after emergency 
unblinding and aligned the wording 
across the program 
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Revision 1.0 
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Protocol Location 
Description of Change 
Brief Rationale 
Section 7.2, Background 
PAH Therapy 
Removed the word “diuretics” from 
the description of background PAH 
therapy.  
Added a definition of stable 
diuretic therapy.  
Correction and alignment with the 
Clarification letter sent 22 March 
2021 
Section 7.3, Inclusion 
Criteria and Synopsis 
Added the following to criterion 4: 
“and a pulmonary capillary wedge 
pressure (PCWP) or left ventricular 
end-diastolic pressure of 
≤ 15 mmHg.” 
To avoid redundancy, the following 
was removed from exclusion 
criterion 20: “or PCWP 
> 15 mmHg as determined in the 
Screening Period RHC.” 
Improved consistency of entry 
criteria 
Section 7.4, Exclusion 
Criteria and Synopsis 
Added the following new 
criterion 4: “Baseline platelet count 
< 50,000/mm3 (< 50.0 × 109/L) at 
screening” 
Improved consistency with the 
criteria for dose delay and 
modification 
Changed the following in criterion 
12: “If PFT is not available, a chest 
CT scan showing no more than 
mild interstitial lung disease (ILD) 
at the screening visit or 1 year prior 
to it” 
Correction 
Modified criterion 8 in the 
following way: “> 13 × ULN 
(bilirubin criterion waived if there 
is a documented history of Gilbert’s 
syndrome)” 
Correction 
Modified criterion 11 in the 
following way: “HaveHistory of 
full or partial pneumonectomy.”  
Correction 
Section 8.3.4, Dose 
Modifications Due to 
Adverse Events of 
Telangiectasia; 
Section  8.3.5, Dose 
Re-escalation following 
Dose Reduction; 
Section 10.9, Monitoring 
of Identified Risks, 
Potential Risks, and 
Adverse Events of Special 
Interest 
Added language to describe dose 
modifications required for adverse 
events of telangiectasia. 
Updated to provide guidance on 
dose modifications required for 
newly identified AESI of 
telangiectasia. 
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Protocol Location 
Description of Change 
Brief Rationale 
Section 9.2.1 Screening 
Period (up to 4 weeks 
prior to Visit 1) 
Added the following: “Upon 
discussion with the medical 
monitor, a historic RHC may be 
allowed as long as it was collected 
within 28 days prior to Visit 1.” 
Clarification of screening 
procedures 
Section 9.3.1 Six-minute 
Walk Test 
Added text describing the timing of 
6MWT evaluations, criteria for 
screen failure related to the 6MWT, 
and criteria for performing an 
additional 6MWT. 
Added a reference to the Guidelines 
for the Six-Minute Walk Test 
(2002). 
Provided additional guidance and 
aligned across the program 
Section 9.3.2 Right Heart 
Catheterization 
Removed “selected” as follows: 
“Right ventricle pressure data from 
the RHC with simultaneously 
recorded ECG recordings may be 
collected and digitally stored at the 
clinical selected sites.” 
Clarified the locations able to 
collect and store the specified data 
Section 9.3.5, Borg 
Dyspnea Scale 
(Borg CR10 Scale) 
Changed text to the following: 
“The Borg Dyspnea Scale (Borg 
CR10 Scale)…” 
Correction 
Section 9.3.9, Clinical 
Worsening Assessment 
Removed “therapy” in the  
following statement: 
“Deterioration of PAH therapy…” 
Clarified the meaning of clinical 
worsening 
Section 9.4.1, Participants 
Early Discontinuation  
Modified the criteria for 
discontinuation due to a clinical 
worsening event and altered the 
instructions for further study visits.  
Clarified that patients who 
experience clinical worsening that 
does not meet the criteria for 
discontinuation may continue on 
study drug up to the primary 
endpoint evaluation 
Modified the following text: “An 
increase in QTcF of > 60 ms that 
results in QTcF of > 500 ms (or 
> 550 ms if right bundle branch 
abnormality is present) during the 
treatment period.”  
Clarified the modified 
discontinuation criterion for 
patients with right bundle branch 
abnormality 
Section 9.8, Criteria for 
Study Termination; 
Section 12, Direct Access 
to Source 
Data/Documents; 
Section 13, Ethics and 
Responsibilities; 
Removed Appendix 3, Study 
Governance Considerations, and 
incorporated the information into 
the main body of the protocol. 
Aligned protocol text across the 
program 
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Protocol Location 
Description of Change 
Brief Rationale 
Section 14, Data 
Handling and Record 
Keeping;  
Section 16, 
Confidentiality; 
Section 18, Appendices 
Section 10, Safety 
Assessment, Reporting, 
and Monitoring  
Aligned text with A011-14 
(ZENITH) Version 1.0 from 08 
April 2021. Updated Table 5 and 
the surrounding text to indicate that 
telangiectasia is the only AESI and 
provide monitoring parameters.  
Updated information for 
programmatic consistency and 
accuracy 
Section 11.5.1.1, 
Handling of Missing Data 
Updated the 6MWD values to be 
used for participants with missing 
data.  
Corrections 
Abbreviations: 6MWD = six-minute walk distance; 6MWT = six-minute walk test; AESI = adverse event of special 
interest; CT = computed tomography; ECG = electrocardiogram; EOS = end of study; EOT = end of treatment; 
EQ-5D-5L = EuroQol - 5 Dimension - 5 Level; FSH = follicle-stimulating hormone; HCO3 = bicarbonate; 
PAH = pulmonary arterial hypertension; PAH SYMPACT = Pulmonary Arterial Hypertension – Symptoms and 
Impact; PCWP = pulmonary capillary wedge pressure; PFT = pulmonary function test; QTcF = Fridericia’s 
corrected QT interval; RHC = right heart catheterization; ULN = upper limit of normal; VAS = visual analog scale. 
 
 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................4 
1.
PROTOCOL SYNOPSIS ...........................................................................................15 
1.1. 
STUDY SCHEMATIC ...............................................................................................25 
2.
SCHEDULE OF EVENTS .........................................................................................26 
3.
INTRODUCTION: BACKGROUND AND STUDY RATIONALE ........................32 
3.1. 
Background .................................................................................................................32 
3.2. 
Risks and/or Benefits to Participants ..........................................................................33 
3.3. 
Study Rationale ...........................................................................................................34 
4.
STUDY OBJECTIVES ..............................................................................................35 
5.
STUDY ENDPOINTS AND RATIONALE ..............................................................36 
5.1. 
Endpoints Reported in Previous Pulmonary Arterial Hypertension Studies ..............36 
5.2. 
Primary Efficacy Endpoint and Rationale ..................................................................36 
5.2.1. 
6-Minute Walk Distance Rationale ............................................................................36 
5.3. 
Secondary Efficacy Endpoints and Rationale .............................................................37 
5.3.1. 
Multicomponent Improvement Endpoint Rationale ...................................................37 
5.3.2. 
Pulmonary Vascular Resistance Rationale .................................................................38 
5.3.3. 
N-Terminal Pro-Hormone B-type Natriuretic Peptide Rationale ...............................38 
5.3.4. 
World Health Organization Functional Class Rationale ............................................38 
5.3.5. 
Time to Clinical Worsening Rationale .......................................................................39 
5.3.6. 
Simplified French Risk Score Calculator Rationale ...................................................39 
5.3.7. 
Quality-of-Life Assessments Rationale ......................................................................39 
5.4. 
Exploratory Endpoints ................................................................................................39 
5.5. 
Safety Endpoints .........................................................................................................40 
6.
STUDY DESIGN .......................................................................................................41 
6.1. 
Study Description .......................................................................................................41 
6.2. 
Duration of Study .......................................................................................................41 
6.3. 
Rationale for Dose Selection ......................................................................................41 
6.4. 
Study Design, Stratification and Treatment Assignment ...........................................42 
6.5. 
Home Health Care Visits ............................................................................................43 
6.6. 
Randomization and Blinding ......................................................................................43 
7.
STUDY POPULATION .............................................................................................44 
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7.1. 
Rationale for Selected Population ..............................................................................44 
7.2. 
Background Pulmonary Arterial Hypertension Therapy ............................................44 
7.3. 
Inclusion Criteria ........................................................................................................44 
7.4. 
Exclusion Criteria .......................................................................................................45 
7.5. 
Screen Failures ............................................................................................................47 
8. 
STUDY DRUG TREATMENT .................................................................................48 
8.1. 
Study Drug Description ..............................................................................................48 
8.1.1. 
Clinical Drug Product .................................................................................................48 
8.1.2. 
Formulation .................................................................................................................48 
8.2. 
Study Drug Management ............................................................................................48 
8.2.1. 
Storage ........................................................................................................................48 
8.2.2. 
Packaging and Shipment .............................................................................................48 
8.2.3. 
Dose and Administration ............................................................................................49 
8.3. 
Dose Modification ......................................................................................................49 
8.3.1. 
Escalation to Target Dose (0.7 mg/kg) .......................................................................49 
8.3.2. 
Dose Modifications Due to Hemoglobin Increase ......................................................49 
8.3.3. 
Dose Modifications Due to Low Platelet Count .........................................................50 
8.3.4. 
Dose Modifications Due to Adverse Events of Telangiectasia ..................................50 
8.3.5. 
Dose Re-escalation Following Dose Reduction .........................................................50 
8.3.6. 
Accountability .............................................................................................................54 
9. 
STUDY CONDUCT ...................................................................................................55 
9.1. 
General Instructions ....................................................................................................55 
9.2. 
Study Procedures ........................................................................................................55 
9.2.1. 
Screening Period (up to 4 weeks prior to Visit 1) ......................................................55 
9.2.2. 
Double-Blind, Placebo-Controlled Treatment Period (Visits 1 to 9) .........................56 
9.2.3. 
Period 1 Follow-up Visits 1 and 2 ..............................................................................59 
9.2.4. 
Long-Term Double-Blind Treatment Period (Visit 10 up to Visit 33) .......................61 
9.2.5. 
End of Treatment Visit (± 3 days) ..............................................................................63 
9.2.6. 
End of Study (± 3 days) ..............................................................................................63 
9.3. 
Description of Study Procedures ................................................................................64 
9.3.1. 
Six-Minute Walk Test .................................................................................................64 
9.3.2. 
Right Heart Catheterization ........................................................................................65 
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9.3.3. 
12-Lead Electrocardiogram ........................................................................................65 
9.3.4. 
Echocardiogram Parameters .......................................................................................65 
9.3.5. 
Borg Dyspnea Scale (Borg CR10 Scale) ....................................................................65 
9.3.6. 
World Health Organization Functional Class Assessment for Pulmonary 
Hypertension ...............................................................................................................66 
9.3.7. 
N-Terminal pro-B-type Natriuretic Peptide ................................................................67 
9.3.8. 
Patient-Reported Outcomes (QoL Assessments) ........................................................67 
9.3.8.1. 
EuroQol – 5 Dimension – 5 Level Assessment ..........................................................67 
9.3.8.2. 
Pulmonary Arterial Hypertension – Symptoms and Impact .......................................68 
9.3.9. 
Clinical Worsening Assessment .................................................................................68 
9.3.10. 
Physical Examination .................................................................................................68 
9.3.11. 
Vital Signs ..................................................................................................................69 
9.3.12. 
Pharmacokinetics Measurements................................................................................69 
9.3.13. 
Anti-Drug Antibody (ADA) Assessments ..................................................................69 
9.3.14. 
Pharmacodynamics .....................................................................................................69 
9.3.15. 
Clinical Laboratory Tests ...........................................................................................70 
9.3.16. 
Serum Chemistry/Follicle-Stimulating Hormone .......................................................70 
9.3.17. 
Urinalysis (Dipstick) ...................................................................................................70 
9.3.18. 
Pregnancy Testing ......................................................................................................70 
9.3.19. 
Hematology .................................................................................................................70 
9.4. 
Discontinuation and Withdrawal Criteria ...................................................................71 
9.4.1. 
Participants Early Discontinuation .............................................................................71 
9.4.2. 
End of Study Definition ..............................................................................................72 
9.5. 
Participants Lost to Follow-up....................................................................................72 
9.6. 
Concomitant Medication and Therapy During Study Conduct ..................................73 
9.7. 
Treatment Compliance ................................................................................................73 
9.8. 
Criteria for Study Termination ...................................................................................73 
9.8.1. 
Study and Site Closure................................................................................................74 
10. 
SAFETY ASSESSMENT, REPORTING, AND MONITORING .............................75 
10.1. 
Adverse Events ...........................................................................................................75 
10.1.1. 
Definitions of Adverse Event .....................................................................................75 
10.1.1.1. 
Unexpected Adverse Events .......................................................................................75 
10.1.1.2. 
Events Not Considered as Adverse Events .................................................................75 
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10.2. 
Serious Adverse Events ..............................................................................................75 
10.2.1. 
Definition of Serious Adverse Events ........................................................................75 
10.2.2. 
Definition of Serious Adverse Event Terms ...............................................................76 
10.3. 
Assessment of Severity ...............................................................................................77 
10.4. 
Assessment of Causality .............................................................................................77 
10.5. 
Documenting Adverse Events ....................................................................................78 
10.6. 
Reporting Serious Adverse Events .............................................................................78 
10.6.1. 
Reporting Period and Monitoring of Participants with Adverse Events ....................79 
10.6.2. 
Safety Reporting to Health Authorities, Independent Ethics Committees, 
Institutional Review Boards, and Investigators ..........................................................79 
10.7. 
Overdose .....................................................................................................................80 
10.8. 
Pregnancy ...................................................................................................................80 
10.9. 
Monitoring of Identified Risks, Potential Risks, and Adverse Events of 
Special Interest ............................................................................................................81 
10.9.1. 
Adverse Events of Special Interest .............................................................................81 
11. 
STATISTICAL ANALYSES .....................................................................................83 
11.1. 
Overview .....................................................................................................................83 
11.2. 
Sample Size Determination ........................................................................................83 
11.3. 
Populations for Analysis .............................................................................................83 
11.4. 
Statistical Methods ......................................................................................................84 
11.5. 
Study Endpoints ..........................................................................................................84 
11.5.1. 
Primary Endpoint ........................................................................................................84 
11.5.1.1. 
Handling of Missing Data ...........................................................................................84 
11.5.2. 
Secondary Endpoints ..................................................................................................85 
11.5.3. 
Exploratory Endpoints ................................................................................................87 
11.6. 
Analysis of Safety .......................................................................................................87 
11.7. 
Pharmacokinetic Analysis ..........................................................................................88 
11.8. 
Interim Analysis ..........................................................................................................88 
11.9. 
Subgroup Analysis ......................................................................................................88 
11.10. 
Critical-Event Adjudication Committee and Data Monitoring Committee ................88 
12. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................89 
12.1. 
Study Monitoring ........................................................................................................89 
12.2. 
Audits and Inspections ................................................................................................89 
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13. 
ETHICS AND RESPONSIBILITIES .........................................................................90 
13.1. 
Good Clinical Practice ................................................................................................90 
13.2. 
Regulatory and Ethical Considerations ......................................................................90 
13.3. 
Institutional Review Board/Independent Ethics Committee ......................................90 
13.4. 
Informed Consent .......................................................................................................91 
14. 
DATA HANDLING AND RECORD KEEPING ......................................................92 
14.1. 
Source Documentation ................................................................................................92 
14.2. 
Data Quality Assurance ..............................................................................................92 
15. 
STUDY REPORT AND PUBLICATIONS ...............................................................93 
16. 
CONFIDENTIALITY ................................................................................................94 
16.1. 
Data Protection ...........................................................................................................94 
17. 
REFERENCES ...........................................................................................................95 
18. 
APPENDICES ............................................................................................................99 
APPENDIX 1. ABBREVIATIONS AND SPECIALIST TERMS ...........................................100 
APPENDIX 2. SIX-MINUTE WALK TEST ...........................................................................103 
APPENDIX 3. CONTRACEPTIVE GUIDANCE AND COLLECTION OF 
PREGNANCY INFORMATION .............................................................................106 
 
 
 
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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Schedule of Events Period 1 – Double-Blind Placebo-Controlled Treatment 
Period and Follow-Up .................................................................................................27 
Table 3: 
Schedule of Events Period 2 – Long-Term Double-Blind Treatment Period 
and Follow-Up ............................................................................................................30 
Table 4: 
World Health Organization Functional Class Assessment for Pulmonary 
Arterial Hypertensiona ................................................................................................67 
Table 5: 
Monitoring of Adverse Events of Special Interest .....................................................82 
Table 6: 
Highly Effective Contraceptive Methods .................................................................108 
 
LIST OF FIGURES 
Figure 1: 
Schematic of Study Periods for Study A011-11 .........................................................25 
Figure 2: 
Guidelines for Target Dose Escalation (0.7 mg/kg) ...................................................51 
Figure 3: 
Guidelines for Dose Modification Due to Hemoglobin Increase From Visit 3 
Onward .......................................................................................................................52 
Figure 4: 
Guidelines for Dose Modification Due to Low Platelet Count ..................................53 
 
 
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1. 
PROTOCOL SYNOPSIS 
Protocol Title  
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to 
Compare the Efficacy and Safety of Sotatercept Versus Placebo When 
Added to Background Pulmonary Arterial Hypertension (PAH) 
Therapy for the Treatment of PAH 
Short Title 
A Phase 3 Study of Sotatercept for the Treatment of PAH. 
Protocol Number 
A011-11 (STELLAR) 
Study Type 
Phase 3, randomized, double-blind, placebo-controlled, multicenter, 
parallel-group study. 
Rationale  
Pulmonary arterial hypertension is a progressive, fatal disease that 
causes marked limitations in physical activity and quality of life, even 
when treated with approved therapies.  This Phase 3 study is supported 
by data from the PULSAR study (Phase 2, NCT03496207), in which 
participants taking any approved single or combination therapy for 
PAH were randomized to receive additional sotatercept or placebo for 
24 weeks.  The PULSAR study demonstrated a statistically significant 
improvement in its primary endpoint, pulmonary vascular resistance 
(PVR).  Additionally, improvement was observed in 6-Minute Walk 
Distance (6MWD), N-terminal pro-B-type natriuretic peptide 
(NT-proBNP), and other endpoints. 
Study Objective 
The objective of this study is to evaluate the efficacy and safety of 
sotatercept treatment (plus background PAH therapy) versus placebo 
(plus background PAH therapy) at 24 weeks in adults with PAH. 
Study Population 
Participants diagnosed with symptomatic PAH (World Health 
Organization [WHO] functional class [FC] II or III) who present with 
idiopathic or heritable PAH, PAH associated with connective tissue 
diseases (CTD), drug or toxin induced, post shunt correction PAH, or 
PAH presenting at least 1 year following the correction of congenital 
heart defects, and currently on background PAH therapy. 
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Number of 
Participants 
Approximately 284 participants will be randomly assigned in a 1:1 
ratio to the two study treatment groups (142 participants per arm). 
Study Design 
The study is divided into a Screening Period (up to 4 weeks), 
Double-Blind Placebo-Controlled (DBPC) Treatment Period 
(24 weeks), a Long-Term Double-Blind (LTDB) Treatment Period 
(until last participant completes the DBPC treatment period, up to 
approximately 72 weeks), and a Follow-Up Period (at least 8 weeks) 
(Figure 1).  
Each study eligible participant will be randomly assigned in a 1:1 ratio 
to 1 of the 2 treatment arms for the duration of the DBPC and LTDB 
Treatment Periods.  
•
Arm 1: Placebo administered subcutaneously (SC) every
21 days plus background PAH therapy
•
Arm 2: Sotatercept at a starting dose of 0.3 mg/kg with a
target dose of 0.7 mg/kg administered SC every 21 days
plus background PAH therapy
The LTDB treatment period will last until the last participant 
randomized completes the DBPC Treatment Period and the study is 
unblinded.  During this period, select study visits may be performed as 
home health care (HHC) visits as described in Section 6.5.  After the 
study is unblinded, participants who complete the DBPC Treatment 
Period and are currently on treatment (sotatercept or placebo) in the 
LTDB Treatment Period may be eligible to participate in a separate 
open-label long-term follow-up (LTFU) study. 
Participants who complete the DBPC and LTDB treatment periods and 
do not wish to participate in the LTFU study will complete the Follow-
up Period as described in Section 6.2. 
Participants who discontinue the DBPC Treatment Period early will 
complete the end of treatment (EOT) visit at the time of 
discontinuation.  These participants will be invited to come for limited 
study assessments at selected visits (Period 1 Follow-up Visits 1 and 2) 
depending on the timing of their discontinuation.  In addition, they will 
complete the end of study (EOS) visit (described in Section 9.2.6), 
provided that consent is not withdrawn. 
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Estimated 
Duration of the 
Study 
Study duration for a given participant in A011-11 will be up to 
approximately 108 weeks as follows: 
• Screening Period (for up to 4 weeks) 
• DBPC Treatment Period (Period 1) (24 weeks, which 
includes 9 study visits [Visit 1 to Visit 9]) 
• LTDB Treatment Period (Period 2) (up to approximately 
72 weeks, [Visit 10 up to Visit 33], depending on when the 
last participant randomized into the study completes the 
DBPC Treatment Period) 
• Follow-up Period (at least 8 weeks, which may include 
Period 1 Follow-up Visits 1 and 2 and EOT and EOS visits) 
Inclusion Criteria 
Eligible participants must meet all of the following inclusion criteria to 
be enrolled in the study: 
1. Age ≥ 18 years 
2. Documented diagnostic right heart catheterization (RHC) at any 
time prior to screening confirming the diagnosis of WHO PAH 
Group 1 in any of the following subtypes: 
• Idiopathic PAH  
• Heritable PAH 
• Drug/toxin-induced PAH 
• PAH associated with CTD 
• PAH associated with simple, congenital 
systemic-to-pulmonary shunts at least 1 year following 
repair 
3. Symptomatic PAH classified as WHO FC II or III 
4. Baseline RHC performed during the Screening Period 
documenting a minimum PVR of ≥ 5 Wood units (WU) and a 
pulmonary capillary wedge pressure (PCWP) or left ventricular 
end-diastolic pressure of ≤ 15 mmHg  
5. On stable doses of background PAH therapy and diuretics (i.e., 
patient-specific dose goal for each therapy already achieved) 
for at least 90 days prior to screening; for infusion 
prostacyclins, dose adjustment within 10% of optimal dose is 
allowed per medical practice.  Background PAH therapy is 
defined in Section 7.2  
6. 6MWD ≥ 150 and ≤ 500 m repeated twice at screening 
(measured at least 4 hours apart, but no longer than 1 week), 
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and both values are within 15% of each other (calculated from 
the highest value) 
7. Females of childbearing potential must:  
• Have 2 negative urine or serum pregnancy tests as verified 
by the investigator prior to starting study therapy; she must 
agree to ongoing urine or serum pregnancy testing during 
the study and until 8 weeks after the last dose of the study 
drug 
• If sexually active, have used, and agree to use, highly 
effective contraception without interruption, for at least 
28 days prior to starting the investigational product, during 
the study (including dose interruptions), and for 16 weeks 
(112 days) after discontinuation of study treatment 
• Refrain from breastfeeding a child or donating blood, eggs, 
or ovum for the duration of the study and for at least 
16 weeks (112 days) after the last dose of study treatment 
8. Male participants must:  
• Agree to use a condom, defined as a male latex condom or 
nonlatex condom NOT made out of natural (animal) 
membrane (e.g., polyurethane), during sexual contact with a 
pregnant female or a female of childbearing potential while 
participating in the study, during dose interruptions and for 
at least 16 weeks (112 days) following investigational 
product discontinuation, even if he has undergone a 
successful vasectomy 
• Refrain from donating blood or sperm for the duration of 
the study and for 16 weeks (112 days) after the last dose of 
study treatment 
9. Ability to adhere to study visit schedule and understand and 
comply with all protocol requirements 
10. Ability to understand and provide written informed consent 
Exclusion Criteria 
1. Diagnosis of pulmonary hypertension WHO Groups 2, 3, 4, or 
5 
2. Diagnosis of the following PAH Group 1 subtypes: human 
immunodeficiency virus (HIV)-associated PAH and PAH 
associated with portal hypertension.  Exclusions in PAH 
Group 1 should also include schistosomiasis-associated PAH 
and pulmonary veno-occlusive disease 
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3. Hemoglobin (Hgb) at screening above gender-specific upper 
limit of normal (ULN), per local laboratory test  
4. Baseline platelet count < 50,000/mm3 (< 50.0 × 109/L) at 
screening 
5. Uncontrolled systemic hypertension as evidenced by sitting 
systolic blood pressure > 160 mmHg or sitting diastolic blood 
pressure > 100 mmHg during screening visit after a period of 
rest  
6. Baseline systolic blood pressure < 90 mmHg at screening 
7. Pregnant or breastfeeding women 
8. Any of the following clinical laboratory values at the screening 
visit: 
• Estimated glomerular filtration rate 
(eGFR) < 30 mL/min/m2 (as defined by the Modification of 
Diet in Renal Disease [MDRD] equation) 
• Serum alanine aminotransferase, aspartate 
aminotransferase, or total bilirubin levels > 3 × ULN 
(bilirubin criterion waived if there is a documented history 
of Gilbert’s syndrome) 
9. Currently enrolled in or have completed any other 
investigational product study within 30 days for small-molecule 
drugs or within 5 half-lives for biologics prior to the date of 
signed informed consent 
10. Prior exposure to sotatercept (ACE-011) or luspatercept 
(ACE-536) and/or excipients or known allergic reaction to 
either one 
11. History of full pneumonectomy 
12. Pulmonary function test (PFT) values of forced vital capacity 
(FVC) < 60% predicted at the screening visit or within 
6 months prior to the screening visit.  If PFT is not available, a 
chest CT scan showing more than mild interstitial lung disease 
at the screening visit or 1 year prior to it. 
13. Initiation of an exercise program for cardiopulmonary 
rehabilitation within 90 days prior to the screening visit or 
planned initiation during the study (participants who are stable 
in the maintenance phase of a program and who will continue 
for the duration of the study are eligible). 
14. History of more than mild obstructive sleep apnea that is 
untreated 
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15. Known history of portal hypertension or chronic liver disease, 
including hepatitis B and/or hepatitis C (with evidence of recent 
infection and/or active virus replication), defined as mild to 
severe hepatic impairment (Child-Pugh Class A-C) 
16. History of restrictive, constrictive, or congestive 
cardiomyopathy 
17. History of atrial septostomy within 180 days prior to the 
screening visit 
18. Electrocardiogram (ECG) with Fridericia’s corrected QT 
interval (QTcF) > 500 ms during the Screening Period  
19. Personal or family history of long QT syndrome (LQTS) or 
sudden cardiac death 
20. Left ventricular ejection fraction < 45% on historical 
echocardiogram within 6 months prior to the screening visit  
21. Any symptomatic coronary disease events (prior myocardial 
infarction, percutaneous coronary intervention, coronary artery 
bypass graft surgery, or cardiac anginal chest pain) within 6 
months prior to the screening visit.  Note: Anginal pain can be 
ignored as an exclusion criterion if coronary angiography 
shows no obstructions. 
22. Cerebrovascular accident within 3 months prior to the screening 
visit 
23. Acutely decompensated heart failure within 30 days prior to the 
screening visit, as per investigator assessment 
24. Significant (≥ 2+ regurgitation) mitral regurgitation or aortic 
regurgitation valvular disease 
25. Received intravenous inotropes (e.g., dobutamine, dopamine, 
norepinephrine, vasopressin) within 30 days prior to the 
screening visit 
Efficacy Endpoints 
Primary Efficacy Endpoints  
The primary efficacy endpoint is the change in 6MWD at Week 24 
versus baseline. 
Secondary Efficacy Endpoints 
Ranked as below: 
1. Multicomponent improvement endpoint measured by the 
proportion of participants achieving all of the following at 
Week 24 relative to baseline: 
• Improvement in 6MWD (increase ≥ 30 m) 
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• Improvement in NT-proBNP (decrease in NT-proBNP 
≥ 30%) or maintenance/achievement of NT-proBNP level 
< 300 ng/L 
• Improvement in WHO FC or maintenance of WHO FC II 
2. Change from baseline in PVR at Week 24 
3. Change from baseline in NT-proBNP levels at Week 24 
4. Proportion of participants who improve in WHO FC at Week 
24 from baseline 
5. Time to death or the first occurrence of any of the following 
clinical worsening events: 
• Worsening-related listing for lung and/or heart transplant 
• Need to initiate rescue therapy with an approved 
background PAH therapy or the need to increase the dose of 
infusion prostacyclin by 10% or more 
• Need for atrial septostomy 
• Hospitalization for worsening of PAH (≥ 24 hours) 
• Deterioration of PAH defined by both of the following 
events occurring at any time, even if they began at different 
times, as compared to their baseline values: 
− Worsened WHO FC 
− Decrease in 6MWD by ≥ 15% confirmed by 2 tests at 
least 4 hours apart, but no more than 1 week 
6. Proportion of participants who maintain or achieve a low risk 
score at Week 24 versus baseline using the simplified French 
Risk score calculator 
7. Change from baseline in the Physical Impacts domain score of 
Pulmonary Arterial Hypertension-Symptoms and Impact 
(PAH-SYMPACT®) at Week 24 
8. Change from baseline in the Cardiopulmonary Symptoms 
domain score of PAH-SYMPACT® at Week 24 
9. Change from baseline in the Cognitive/Emotional Impacts 
domain score of PAH-SYMPACT® at Week 24 
Exploratory Endpoints 
The following indices will also be evaluated: 
• Change in echocardiogram parameters at Week 24 versus 
baseline 
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• Change in dyspnea score (assessed by Borg CR10 scale®) at 
Week 24 versus baseline 
• Proportion of participants who achieve PVR < 3 WU at 
Week 24 
• Proportion of participants who achieve mean pulmonary 
arterial pressure (mPAP) < 25 mmHg at Week 24 
• Change from baseline in mPAP at Week 24 
• Change from baseline in the Cardiovascular Symptoms 
domain score of PAH-SYMPACT® at Week 24 
• Change from baseline in the 
EuroQoL – 5 Dimension  – 5 Level (EQ-5D-5L) index 
score at Week 24 
• Change from baseline in the EQ-5D-5L visual analog scale 
(VAS) at Week 24 
Safety Endpoints 
Safety will be evaluated by collecting the following information: 
• Adverse events  
• Anti-drug antibodies  
• Laboratory assessments (hematology, 
serum chemistry/FSH, urinalysis) 
• Vital signs  
• Physical examination  
• 12-Lead ECG  
Sample Size 
Determination and 
Power Calculations 
The sample size determination is based on the primary efficacy 
endpoint and the secondary endpoint of improvement in WHO FC.  
Assumptions for the desired treatment effect and estimate of variability 
(6MWD endpoint) are based on data from the PULSAR study (Phase 
2, NCT03496207) and from a published clinical trial in PAH 
participants.1 
For 6MWD, assuming a 1:1 randomization, a 2-sided 0.05 Type I error 
rate, a 25-m improvement in sotatercept treatment compared to 
placebo, a common standard deviation (SD) of 50 m, and 121 
participants per arm, the statistical power is approximately 96%, under 
the Wilcoxon rank sum test using N-Query®. 
For the secondary endpoint, “proportion of participants who improve in 
WHO FC at Week 24,” assuming the proportion of participants treated 
with placebo and sotatercept is 0.11 and 0.25, respectively, 1:1 
randomization, a 2-sided 0.05 Type I error rate, and 121 participants 
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per arm, the statistical power is approximately 80% based on the 
2-sample chi-square test. 
Assuming a 15% dropout rate, the total sample size will be n = 284 
(n = 142 participants per arm). 
Stratified 
Randomization 
Factors 
Randomization will be stratified by:  
• Baseline WHO FC (Class II or III)  
• Background PAH therapy (mono/double or triple therapy) 
Statistical Methods 
Efficacy Analyses: All efficacy analyses will be based on the Full 
Analysis Set (FAS), which is defined as all randomized participants.  
All participants will be analyzed according to the treatment arm to 
which the participant is randomized.  Efficacy analyses will also be 
performed on the Per-Protocol Set (PPS), which is defined as all 
participants randomized who receive at least 1 dose of study treatment 
with no data or study procedural-related issues that would otherwise 
impact the interpretation of the efficacy data.  Analyses on the FAS 
will be considered primary for reporting purposes. 
Safety Analyses: All safety analyses are based on the Safety Set, 
which is defined as all participants who receive at least 1 dose of study 
medication. All participants will be analyzed according to the treatment 
they are administered. 
Pharmacokinetic Analyses: The Pharmacokinetic (PK) Population is 
defined as all participants who receive at least 1 dose of study drug and 
have sufficient PK samples collected and assayed for PK analysis. 
Primary Endpoint: 
The change in 6MWD at Week 24 from baseline will be analyzed 
using the stratified Wilcoxon test with the randomization factors as 
strata.  The Hodges-Lehmann location-shift estimate of the treatment 
group difference with 95% confidence interval (CI) will be provided. 
Secondary Endpoints: 
The multicomponent improvement endpoint will be analyzed using the 
Cochran-Mantel-Haenszel test, stratified by the randomization factors. 
The change in NT-proBNP and PVR at Week 24 versus baseline will 
be analyzed using an analysis of covariance (ANCOVA) model with 
randomization factors and baseline values as covariates. 
The proportion of participants who improve in WHO FC at Week 24 
from baseline will be analyzed using the Cochran-Mantel-Haenszel 
test, stratified by the randomization factors. 
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Time to first clinical worsening event or death will be analyzed using 
log-rank test with randomization factors as strata. 
The proportion of participants who maintain or achieve a low risk score 
using the simplified French Risk score calculator at Week 24 versus 
baseline will be analyzed using the Cochran-Mantel-Haenszel test 
stratified by the randomization factors. 
The change from baseline at Week 24 in the Physical Impacts domain 
score of PAH-SYMPACT® will be analyzed using an ANCOVA model 
with randomization factors and baseline value as covariates. 
The change from baseline at Week 24 in the Cardiopulmonary 
Symptoms domain score of PAH-SYMPACT® will be analyzed using 
an ANCOVA model with randomization factors and baseline value as 
covariates. 
The change from baseline at Week 24 in the Cognitive/Emotional 
Impacts domain score of PAH-SYMPACT® will be analyzed using an 
ANCOVA model with randomization factors and baseline value as 
covariates. 
A gatekeeping method will be used to control the Type I error rate in 
secondary endpoints by testing in the order of the secondary endpoints 
listed above, after successful testing for the primary endpoint.  
Secondary endpoint testing will be performed using a 2-sided 
alpha = 0.05 level proceeding successively in the order of the 
secondary endpoints listed above after each of the preceding endpoints 
is tested to be statistically significant. 
Exploratory Endpoints: 
For continuous variables, ANCOVA will be used with the 
randomization factors and baseline as covariates.  For dichotomous 
variables, the Cochran-Mantel-Haenszel test will be used, stratified by 
the randomization factors.  No adjustments for multiplicity will be 
performed.  
Safety Endpoints 
Safety data will be summarized descriptively by treatment arm. 
Safety and 
Pharmacovigilance 
An unblinded, external, independent Data Monitoring Committee 
(DMC) will monitor participant safety throughout the course of the 
study. 
A detailed charter will outline all activities of the DMC (including but 
not limited to the composition of the DMC, the type of data to be 
reviewed, the DMC responsibilities, and the frequency of meetings). 
Internal data review of safety-related data will occur in a blinded 
manner at a preplanned frequency throughout the study duration. 
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1.1. 
STUDY SCHEMATIC 
Figure 1: 
Schematic of Study Periods for Study A011-11 
Participants who sign the 
informed consent form 
and meet eligibility criteria
Randomization
1:1
Participants who 
discontinue early or do 
not wish to participate 
in the long-term 
follow-up (LTFU) study  
Screening
Double Blind Placebo-Controlled (DBPC) 
Treatment Period (Visits 1-9) 
Long-Term Double Blind (LTDB) 
Treatment PeriodA (Visit 10 up to Visit 33)B 
Up to ~72 weeksC
24 weeks
Up to 4 weeks
Follow-Up Period 
(EOT & EOS)
At least 8 weeks
Placebo + background PAH therapyD
(mono, double, or triple)
N = 142
SotaterceptE + background PAH therapyD
(mono, double, or triple)
N = 142
Primary Endpoint AnalysisF: 
6MWD at 24 weeks
A During the LTDB treatment period, select study visits may be performed as home health care (HHC) visits. 
B LTDB treatment period will last until the last participant randomized completes the DBPC treatment period, at which point the study will be unblinded and participants may rollover 
into the LTFU study 
C LTDB treatment period duration is estimated based on projected enrollment duration and time required for the last participant to complete the DBPC treatment period.
D Background PAH therapy refers to approved PAH-specific medications and may consist of monotherapy or combination therapy with ERA, PDE5 inhibitors, soluble guanylate cyclase 
stimulators, and/or prostacyclin analogues or receptor agonists.
E Sotatercept at a starting dose of 0.3 mg/kg SC with a target dose of 0.7 mg/kg SC
F Primary endpoint analysis will be completed after the last participant randomized completes the DBPC treatment period.
6MWD = 6-minute walk distance; EOS = end of study; EOT = end of treatment; PAH = pulmonary arterial hypertension. 
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2.
SCHEDULE OF EVENTS
The schedule of events (SoE), which provides an overview of the study periods and procedures, 
is presented in Table 2 and Table 3. 
Specific information on visits and assessments during the Screening Period, Double-Blind 
Placebo-Controlled (DBPC) Treatment Period, and Follow-up Period is discussed in Section 9. 
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Table 2: 
Schedule of Events Period 1 – Double-Blind Placebo-Controlled Treatment Period and Follow-Up 
Study Procedure/ Assessment 
Screening 
Period 
(up to 
4 weeks 
prior to 
Visit 1) 
Double-Blind Placebo-Controlled (DBPC) 
Treatment Perioda (24 weeks) 
Period 1 Follow-Up Visitsb 
(early discontinuation during DBPC 
period only) 
Visit 1 
±3 days 
Visit 2 
±3 days 
Visits 3, 4 
±3 days 
Visit 5 
±3 days 
Visits 6, 7, 8 
±3 days 
Visit 9 
(1°EP 
Evaluation) 
±3 days 
Follow-Up Visit 1 
(12 weeks after 
Visit 1) 
±3 days 
Follow-Up Visit 2 
(24 weeks after 
Visit 1) 
±3 days 
Informed consent 
X 
Inclusion/exclusion criteria 
X 
Medical history reviewc 
X 
Physical examinationd
X 
X 
X 
X 
X 
X 
12-lead ECG
X 
X 
X 
Pulmonary function test or Chest 
CT scane
X 
Vital signs including weightf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test (urine or serum)g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology (complete blood 
count)h
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistry/FSHi 
X 
X 
X 
X 
X 
Urinalysis (dipstick) 
X 
X 
Right heart catheterizationj 
X 
X 
X 
6MWTk 
X 
X 
X 
X 
X 
X 
Borg Dyspnea Scale (pre- and 
post-6MWT) 
X 
X 
X 
X 
X 
X 
WHO FC assessment 
X 
X 
X 
X 
X 
X 
Clinical worsening assessment 
X 
X 
X 
X 
X 
QoL assessmentsl
X 
X 
X 
NT-proBNP sample collection 
X 
X 
X 
X 
X 
X 
X 
X 
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Study Procedure/ Assessment 
Screening 
Period 
(up to 
4 weeks 
prior to 
Visit 1) 
Double-Blind Placebo-Controlled (DBPC) 
Treatment Perioda (24 weeks) 
Period 1 Follow-Up Visitsb 
(early discontinuation during DBPC 
period only) 
Visit 1 
±3 days 
Visit 2 
±3 days 
Visits 3, 4 
±3 days 
Visit 5 
±3 days 
Visits 6, 7, 8 
±3 days 
Visit 9 
(1°EP 
Evaluation) 
±3 days 
Follow-Up Visit 1 
(12 weeks after 
Visit 1) 
±3 days 
Follow-Up Visit 2 
(24 weeks after 
Visit 1) 
±3 days 
ADA sample collection 
X 
X 
X 
X 
X 
X 
X 
X 
PK sample collection 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
X 
Echocardiogramm
X 
X 
X 
X 
Study drug administrationn
X 
X 
X 
X 
X 
X 
AE/SAE review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: 6MWT = 6-Minute Walk Test; ADA = anti-drug antibody; AE = adverse event; ALT = alanine transaminase; AST = aspartate transaminase; 
DBPC = double-blind placebo-controlled; ECG = electrocardiogram; EOS = end of study; EOT = end of treatment; EQ-5D-5L = EuroQoL - 5 Dimension - 
5 Level; FC = functional class; FSH = follicle-stimulating hormone; Hgb = hemoglobin; NT-proBNP = N-terminal pro-hormone B-type natriuretic peptide; 
PAH = pulmonary arterial hypertension; PAH-SYMPACT = Pulmonary Arterial Hypertension - Symptoms and Impact; PFT = pulmonary function test; 
PK = pharmacokinetic(s); QoL = quality of life; RHC = right heart catheterization; SAE = serious adverse event; WHO = World Health Organization. 
a Each dosing visit will be 21 days (± 3 days) from the previous dosing visit unless a dose delay is required.  If a dose delay is required per the dose modification 
guidelines (Section 8.3), the participant will not be dosed and will return every 3 weeks for assessment of hematology results and AEs until eligible to receive the 
next dose of study drug.  The participant should resume treatment at the next planned dosing visit (e.g., if the participant missed a dose at Visit 4, then they 
would resume dosing at Visit 5). 
b Participants discontinuing study treatment prior to Visit 5 are asked to complete EOT (Table 3), Follow-up Visits 1 and 2, and EOS (Table 3) visits (and in that 
order).  Participants discontinuing study treatment after Visit 5 but before Visit 9 are asked to complete only EOT (Table 3), Follow-up Visit 2, and EOS (Table 3) 
visits (and in that order). 
c Medical history review includes confirmation of disease history associated with PAH. 
d Perform full physical examination at the screening visit only.  For all other visits, perform targeted cardiopulmonary and skin examinations. 
e A PFT will be done if the most recent test was performed more than 6 months prior to the screening visit.  If a PFT is not possible, a chest computed 
tomography scan at the screening visit or a scan result within 1 year prior should be assessed for exclusion of interstitial lung disease.  
f Height measurement will be required for the collection of vital signs at screening. 
g Two serum or urine pregnancy tests are required for female participants of childbearing potential at the screening visit.  One urine or serum pregnancy test is 
required prior to study drug administration at all other visits. 
h Complete blood (cell) count includes red blood cells, absolute white blood cells, Hgb, hematocrit, and platelet count.  Results are evaluated at the screening 
visit and then prior to study drug administration (or up to 3 days prior if available) for each visit except for Visit 1.  Refer to Section 8.3 for dose modification 
guidelines based on Hgb levels and platelet count  
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i Blood urea, creatinine, total bilirubin, direct bilirubin, AST, ALT, alkaline phosphatase, sodium, potassium, chloride, calcium, phosphorus, glucose, 
magnesium, HCO3, albumin, and FSH will be measured. 
j In order to reduce invasive procedures for participants prior to confirming eligibility, RHC during the Screening Period should be performed last and after all 
screening clinical laboratory tests are done for eligibility, when possible.  The RHC performed after screening may be performed on the day of study visit or 
within 1 week prior to study drug administration.  If other assessments are performed on the same day, RHC should be performed last, when possible. 
k 6MWT during the Screening Period must be performed twice, at least 4 hours but no longer than 1 week apart.  6MWT can be performed on the day of the 
study visit and has to be performed before study drug administration. 
l QoL assessments include EQ-5D-5L and PAH-SYMPACT®.  EQ-5D-5L should be completed before performing other study assessments (6MWT, blood
draws, AE discussions, and RHC).  PAH-SYMPACT should be completed at home daily on the 7 days prior to the study visit.
m Echocardiogram can be performed on the day of the study visit or up to 1 week prior to study drug administration.
n All study procedures must be done prior to study drug administration.  Dose must be calculated based on the participant’s weight on the day of dosing during
the DBPC treatment period.  Dose modification guidelines based on Hgb levels and platelet count must be reviewed and implemented prior to dosing
(Section 8.3).
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Table 3: 
Schedule of Events Period 2 – Long-Term Double-Blind Treatment Period and Follow-Up 
Study Procedure/ Assessment 
Long-Term Double-Blind (LTDB)a Treatment Periodb (Up to ~ 72 weeks)c 
Follow-Up Period 
Visits 10-12, 14-16, 18-20, 
22-24, 26-28, and 30-32d 
±3 days 
Visit 13, 21, and 29 
±3 days
Visit 17, 25, and 33 
±3 days 
EOTe 
±3 days 
EOSe, f 
(At least 56 ±7 
days after EOT)
Physical examinationg 
X 
X 
X 
X 
12-lead ECG
X 
X 
X 
Weighth 
X 
X 
Vital signs 
X 
X 
X 
X 
Pregnancy test (urine or serum)i 
X 
X 
X 
X 
Hematology (complete blood count)j 
X 
X 
X 
Serum chemistry/FSHk 
X 
X 
X 
Urinalysis (dipstick) 
X 
X 
6MWTl 
X 
X 
X 
X 
Borg Dyspnea Scale (pre- and post-6MWT) 
X 
X 
X 
X 
WHO FC assessment 
X 
X 
X 
X 
Clinical worsening assessment 
X 
X 
X 
X 
QoL assessmentsm 
X 
NT-proBNP sample collection 
X 
X 
X 
X 
ADA sample collection 
X 
X 
X 
X 
PK sample collection 
X 
X 
X 
X 
Echocardiogramn 
X 
X 
Study drug administrationo 
X 
X 
X 
AE/SAE review 
X 
X 
X 
X 
X 
Concomitant medication review 
X 
X 
X 
X 
X 
Abbreviations: 6MWT = 6-Minute Walk Test; ADA = anti-drug antibody; AE = adverse event; ALT = alanine transaminase; AST = aspartate transaminase; DBPC = double-blind 
placebo-controlled; ECG = electrocardiogram; EOS = end of study; EOT = end of treatment; EQ-5D-5L = EuroQoL - 5 Dimension - 5 Level; FC = functional class; 
FSH = follicle-stimulating hormone; Hct = hematocrit; Hgb = hemoglobin; HHC = Home health care; LTDB = long-term double-blind; LTFU = long-term follow-up; NT-proBNP 
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= N-terminal proB-type natriuretic peptide; PAH-SYMPACT® = Pulmonary Arterial Hypertension - Symptoms and Impact; PK = pharmacokinetic(s); QoL = quality of life; RHC 
= right heart catheterization; SAE = serious adverse event; WHO = World Health Organization. 
a The LTDB treatment period is applicable until the last randomized participant completes Visit 9 in the DBPC treatment period and the study is unblinded, at which point 
participants can rollover into a separate open label LTFU study. 
b Each dosing visit will be 21 days (± 3 days) from the previous dosing visit unless a dose delay is required.  If a dose delay is required per the dose modification rules 
(Section 8.3), the participant will not be dosed and will return every 3 weeks for assessment of hematology results and AEs until eligible to receive the next dose of study drug.  
The participant should resume treatment at the next planned dosing visit (e.g., if the participant missed a dose at Visit 4, then he/she would resume dosing at Visit 5) if eligible per 
dose modification rules.  
c Estimate is based on projected enrollment duration and time required for the last participant to complete the DBPC treatment period. 
d These select visits may be conducted as HHC visits for eligible participants.  See Section 6.5 for further details. 
e Once the study is unblinded, participants who complete the DBPC treatment period and are currently on treatment in the LTDB treatment period may roll over from this study 
into a separate open-label LTFU study.  For these participants, the EOS visit can be waived and Visit 1 of the LTFU study will take place 21 (± 7) days after the last dose 
administered in this study, which may coincide with this study’s EOT visit.  Participants who discontinue treatment early for reasons other than clinical worsening should complete 
the EOT visit at the time of discontinuation and complete the EOS visit at least 56 days (± 7 days) after the EOT visit. 
f EOS visit is applicable to participants who do not wish to participate in the LTFU study and for participants who discontinue treatment early for reasons other than clinical 
worsening. 
g Perform targeted cardiopulmonary and skin examinations. 
h For dosing visits at which weight is not collected, the most recently collected weight should be utilized for dose calculation. 
i Two serum or urine pregnancy tests are required for female participants of childbearing potential at the screening visit.  One urine or serum pregnancy test is required prior to 
study drug administration at all other visits. 
j Complete blood (cell) count includes red blood cells, absolute white blood cells, Hgb, Hct, and platelet count.  Results are evaluated prior to study drug administration (or up to 
3 days prior if available) for each visit conducted on-site.  For HHC visits, results are not required to be evaluated prior to study drug administration.  Refer to Section 8.3 below 
for dose modification guidelines based on Hgb levels and platelet count. 
k Blood urea, creatinine, total bilirubin, direct bilirubin, AST, ALT, alkaline phosphatase, sodium, potassium, chloride, calcium, phosphorous, glucose, magnesium, HCO3, 
albumin, and FSH will be measured. 
l 6MWT can be performed on the day of the study visit and has to be performed before study drug administration.
m QoL assessments include EQ-5D-5L and PAH-SYMPACT®.  EQ-5D-5L should be completed before performing other study assessments (6MWT, blood draws, AE discussions,
and RHC).  PAH-SYMPACT® should be completed at home daily on the 7 days prior to the study visit.
n Echocardiogram can be performed on the day of the study visit or up to 1 week prior to study drug administration.
o All study procedures must be done prior to study drug administration.
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3.
INTRODUCTION: BACKGROUND AND STUDY RATIONALE
3.1. 
Background 
Pulmonary arterial hypertension (PAH) applies to a group of diseases causing a progressive 
increase in pulmonary vascular resistance (PVR), resulting in right ventricular dysfunction and 
ultimately failure as well as premature death.2,3  The PAH pathophysiology involves pulmonary 
endothelial dysfunction, resulting in impaired production of vasodilators, such as nitric oxide and 
prostacyclin, and overexpression of vasoconstrictors, such as endothelin-1.  The pathophysiology 
of PAH also entails the abnormal proliferation of pulmonary vascular smooth muscle cells 
(VSMCs) in pulmonary arterioles, which results in progressive pulmonary vascular remodeling, 
increased PVR and, eventually, right-sided heart failure.4  In the absence of treatment, the 
majority of patients succumb to heart failure within a few years of diagnosis.5  There is currently 
no pharmacological cure for PAH.  Current background PAH therapy involves increasing blood 
flow through the pulmonary vasculature via pharmacologic manipulation of various pathways to 
relieve symptoms and slow clinical worsening of the disease.  In addition to general supportive 
care agents (e.g., anticoagulants, diuretics, digoxin), current disease-specific treatments for PAH 
include vasodilator-type agents such as endothelin-receptor antagonists (ERAs), 
phosphodiesterase 5 (PDE5) inhibitors, and prostanoids. 
Genetic mutations in the bone morphogenetic protein (BMP) type II receptor (BMPR2) are 
associated with the majority of the familial form of PAH6,7 and approximately 25% of idiopathic 
PAH.  Specifically, impairment of the BMPR2-associated signal pathway appears to lead to 
uncontrolled proliferation of pulmonary VSMCs, the principal cause of PAH.  These data 
strongly suggest a key role of transforming growth factor (TGF)-β family members in the 
pathogenesis of PAH.  Sotatercept acts to block activin ligands and growth and differentiation 
factors (GDFs), may attenuate BMPs, and improve pulmonary vascular remodeling by restoring 
balance to Smad signaling.8 
Sotatercept is a novel first-in-class fusion protein comprising the extracellular domain of human 
activin receptor type IIA linked to the Fc domain of human immunoglobulin G1.9  It has 
previously been tested in chemotherapy-induced anemia,10 multiple myeloma,11 bone loss,9 
myelodysplastic syndromes,12 β-thalassemia,13 end-stage kidney disease,14 and as an 
erythropoietic agent,15 and has been well tolerated in more than 350 participants exposed to the 
drug.  Sotatercept binds select ligands in the TGF-β superfamily, such as activins A and B and 
GDF-8 and -11, to suppress their signaling and restore balance between the opposing 
growth-promoting activin/GDF and growth-inhibiting BMP pathways.16,17 
Recent preclinical data suggest that sotatercept (murine analogue, RAP-011) may positively 
affect vascular remodeling in animal models of PAH. RAP-011 was evaluated in both 
preventative and therapeutic disease models.  Affected animals treated with RAP-011 showed 
substantial improvements in pulmonary vascular and cardiac hemodynamic measurements that 
were either comparable or superior to agents approved for treatment of PAH.  Importantly, a 
substantial reduction in the proliferation of pulmonary VSMCs was observed in RAP-011-treated 
animals as assessed by histologic evaluation in both preventative and therapeutic disease models. 
Taken together, these data indicate that RAP-011 can attenuate the development and progression 
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of PAH, even when administered to animals with established disease.  These preclinical data 
suggest that sotatercept is a mechanism-targeted nonvasodilator therapy that may positively 
affect vascular remodeling associated with PAH.8  Detailed descriptions of the chemistry, 
pharmacology, efficacy, and safety of sotatercept are provided in the Investigator’s Brochure 
(IB). 
3.2. 
Risks and/or Benefits to Participants 
The evidence for potential benefits of sotatercept is supported by data observed in preclinical 
studies in rodent models of PAH and clinical results from the PULSAR study (Phase 2, 
NCT03496207). 
Preclinical studies in rodent models of PAH have shown reduced muscularization and thickness 
of pulmonary vessel walls, reduced right-sided heart pressures, and reduced right-to-left ventricle 
weight ratios.  These improvements observed in rodent models are thought to be associated with 
reductions in PVR as well as increases in functional capacity and quality of life (QoL) in 
humans, which have been assessed in the PULSAR study, a Phase 2 Study of Sotatercept for the 
Treatment of PAH (NCT03496207), in which participants taking any approved single or 
combination therapy for PAH were randomized to receive additional sotatercept or placebo for 
24 weeks. 
Results from the PULSAR study demonstrated a statistically significant improvement in PVR at 
24 weeks when compared to baseline (the study’s primary endpoint).18  Pulmonary vascular 
resistance was reduced in both sotatercept dose groups versus placebo (least squares mean 
difference [standard error1]) (sotatercept 0.3 mg/kg: −145.8 [48.6] dyn·s/cm5, p = 0.0027; 
sotatercept 0.7 mg/kg: −239.5 [45.8] dyn·s/cm5, p < 0.0001). 
Six-Minute Walk Distance (6MWD) was the key secondary endpoint at 24 weeks.  The 
least squares mean increase from baseline in 6MWD was 58.1 m for sotatercept 0.3 mg/kg, 
50.1 m for sotatercept 0.7 mg/kg, and 28.7 m for placebo.  Combined, sotatercept produced a 
least squares mean difference versus placebo of 24.9 m (95% confidence interval [CI]: 3.1, 
46.6 m).  Sotatercept also improved N-terminal proB-type natriuretic peptide (NT-proBNP) 
levels. 
In addition, a greater proportion of participants in the sotatercept treatment groups improved in 
World Health Organization (WHO) functional class (FC) compared with placebo. 
Risks of sotatercept to participants that were observed in previous clinical studies included 
increases in hemoglobin (Hgb), hematocrit (Hct), red blood cell (RBC) count, and blood pressure 
(BP).  Leukopenia, neutropenia (including febrile neutropenia), granulocytopenia, and 
thrombocytopenia have been described as treatment-emergent adverse events (TEAEs) in clinical 
oncology studies in chemotherapy-induced anemia and osteolytic bone disease in multiple 
myeloma.  Infection may be a consequence of the decrease in white blood cells, and bleeding 
may be a consequence of the decrease in platelets.  As of the preplanned interim data cutoff of 
14 January 2020, increased Hgb and thrombocytopenia were the most common drug-related 
adverse effects.  By Week 24 of the PULSAR study, Hgb levels had not changed from baseline 
in the placebo group (0.0 ± 1.1 g/dL) but had increased in the sotatercept 0.3 mg/kg 
(1.2 ± 1.2 g/dL) and sotatercept 0.7 mg/kg (1.5 ± 1.1 g/dL) groups.  Change from baseline in 
platelet counts at Week 24 were −6.3 ± 29.1, 12.1 ± 47.7, and −12.1 ± 49.8 × 109/L in the 
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placebo, sotatercept 0.3 mg/kg, and sotatercept 0.7 mg/kg groups, respectively.  No events of 
bleeding were deemed related to a treatment-emergent reduction in platelet counts, and no 
participant presented with platelet counts below 50 × 109/L. 
Each of the risks of sotatercept was monitored during the PULSAR study, and dosing 
adjustments were made as necessary to mitigate these risks.  Potential risks of reproductive 
effects and renal injury were also monitored, and no clinically meaningful changes were 
observed.  Anti-drug antibodies (ADAs) were detected but without associated adverse effects. 
Cutaneous telangiectasia emerged as a late-onset adverse event in the open-label extension 
period of PULSAR. 
More detailed information about the known and expected benefits and risks and possible AEs of 
sotatercept may be found in the IB. 
3.3. 
Study Rationale 
This is a Phase 3, randomized, double-blinded, placebo-controlled study to compare the efficacy 
and safety of sotatercept versus placebo when added to background PAH therapy for the 
treatment of PAH. 
This Phase 3 study is supported by data from the PULSAR study (Phase 2, NCT03496207) as 
described in Section 3.2. 
In the PULSAR study, more than 90% of patients at baseline were receiving double or triple 
background PAH therapy, targeting multiple existing therapeutic pathways.  Sotatercept was able 
to demonstrate hemodynamic and functional improvements in these patients, including those 
receiving maximal PAH therapy with double/triple drug combinations and intravenous (IV) 
prostacyclin. 
Treatment with sotatercept in addition to background PAH therapies was well tolerated, with 
thrombocytopenia and increased Hgb levels being the most commonly reported drug-related side 
effects.  The treatment-induced increases in Hgb levels and decrease in platelet count observed in 
the PULSAR study are consistent with effects of sotatercept in previous clinical studies 
described in Section 3.1.9-15 
There is an unmet need for additional PAH therapies because, despite available therapeutic 
options, the disease continues to progress in most patients.  Through a novel mechanism of 
action, sotatercept targets an imbalance in activin/GDF and BMP pathway signaling, opening a 
new treatment paradigm for PAH.  This Phase 3 study is being conducted to definitively assess 
the risk:benefit profile of sotatercept in PAH. 
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4.
STUDY OBJECTIVES
The objectives of this study are to evaluate the efficacy and safety of sotatercept treatment (plus 
background PAH therapy) versus placebo (plus background PAH therapy) at 24 weeks in adults 
with PAH. 
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5.
STUDY ENDPOINTS AND RATIONALE
5.1. 
Endpoints Reported in Previous Pulmonary Arterial Hypertension 
Studies 
Pivotal clinical trials for many drugs approved for PAH used 6MWD as a primary endpoint to 
assess exercise capacity.  Secondary endpoints commonly measured include invasive 
hemodynamics to demonstrate improvement in PVR, WHO FC to assess symptoms, and 
NT-proBNP to assess cardiac function. 
However, these endpoints did not consistently correlate with indicators of disease progression 
such as hospitalization and death.  This led to the preference toward morbidity and mortality as 
primary endpoints, which were used in the more recent clinical trials for PAH.19-22  Despite the 
limitations of 6MWD and improvement in WHO FC as standalone endpoints, it is noteworthy 
that all 4 trials utilizing morbidity and mortality as endpoints include 6MWD and FC in the 
definition of clinical worsening. 
While the use of clinical worsening or disease progression had been endorsed by the World 
Symposium on Pulmonary Hypertension (PH) in previous meetings, at their last meeting in 
2018, the Task Force on Endpoints in Clinical Trial Design recommended identifying endpoints 
that reflect “improvement of patients’ ability to live more functional and fulfilled lives,” such as 
time to clinical improvement instead of worsening and utilization of change in risk as marker of 
efficacy.23-26 
Assessment of risk in PAH has been proposed using variables that are routinely measured in 
PAH, with a recommendation first issued by the European Society for Cardiology and European 
Respiratory Society, followed by validation and simplified versions using registry data.21  The 
indices that consistently show the most significant predictive effect across the different risk 
scores are 6MWD, WHO FC, and NT-proBNP. 
Please refer to Section 11 for details on study endpoints calculations. 
5.2. 
Primary Efficacy Endpoint and Rationale 
The primary efficacy endpoint is the change from baseline in 6MWD at Week 24. 
5.2.1. 
6-Minute Walk Distance Rationale
The 6MWD has been the most commonly used primary endpoint in clinical trials of PH 
therapies, beginning with the first randomized controlled trial (RCT) for regulatory approval of 
epoprostenol.27  However, the utility of improvement in 6MWD as a primary outcome measure 
in clinical trials became limited particularly in more contemporary trials involving sequential, 
add-on therapies, in which the change from baseline in 6MWD was smaller than the clinically 
relevant thresholds of around 30 m,28 despite the significance achieved by morbidity and 
mortality outcomes.19-21  The 6MWD remains an important prognostic factor in the risk scores 
but as absolute thresholds (< 165 m, 165 to 440 m, and > 440 m)23 instead of changes from 
baseline.  Based on these scores, patients who walk > 440 m have a low (< 5%) risk of mortality 
in 1 year. 
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5.3. 
Secondary Efficacy Endpoints and Rationale 
The secondary endpoints will be assessed as ranked below: 
1. Multicomponent improvement endpoint measured by the proportion of participants
achieving all of the following at Week 24 relative to baseline:
•
Improvement in 6MWD (increase ≥ 30 m)
•
Improvement in NT-proBNP (decrease in NT-proBNP ≥ 30%) or
maintenance/achievement of NT-proBNP level < 300 ng/L
•
Improvement in WHO FC or maintenance of WHO FC II
2. Change from baseline in PVR at Week 24
3. Change from baseline in NT-proBNP levels at Week 24
4. Proportion of participants who improve in WHO FC at Week 24 from baseline
5. Time to death or the first occurrence of any of the following clinical worsening events
(time to clinical worsening [TTCW])
•
Worsening-related listing for lung and/or heart transplant
•
Need to initiate rescue therapy with an approved background PAH therapy or the
need to increase the dose of infusion prostacyclin by 10% or more
•
Need for atrial septostomy
•
Hospitalization for worsening of PAH (≥ 24 hours)
•
Deterioration of PAH defined by both of the following events occurring at any time,
even if they began at different times, as compared to their baseline values:
−
Worsened WHO FC
−
Decrease in 6MWD by ≥ 15% confirmed by 2 tests at least 4 hours apart, but no 
more than 1 week
6. Proportion of participants who maintain or achieve a low risk score (Section 5.3.6) at
Week 24 versus baseline using the simplified French Risk score calculator
7. Change from baseline in the Physical Impacts domain score of Pulmonary Arterial
Hypertension-Symptoms and Impact (PAH-SYMPACT®) at Week 24
8. Change from baseline in the Cardiopulmonary Symptoms domain score of
PAH-SYMPACT® at Week 24
9. Change from baseline in the Cognitive/Emotional Impacts domain score of
PAH-SYMPACT® at Week 24
5.3.1. 
Multicomponent Improvement Endpoint Rationale 
The components of the endpoint are considered important and relevant to the medical 
management of patients with PAH in that they encompass functional assessments (6MWD and 
WHO FC) and a prognostic biomarker and indicator of cardiac strain (NT-proBNP). 
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The justification for the proposed multicomponent secondary endpoint takes into consideration 
the following: 
•
Assessment of risk in PAH is currently based upon recommendations initially issued
by the European Society of Cardiology and the European Respiratory Society, with
subsequent validation and simplified versions using robust registry data.  The
variables that have consistently been the most significant prognostic indicators of
disease progression and survival are NT-proBNP, 6MWD, and WHO FC.
•
Four of the most recent clinical trials in PAH that relied upon morbidity and mortality
events as a primary endpoint nevertheless utilized 6MWD and WHO FC in the
composite endpoint of “clinical worsening.”
•
NT-proBNP, as described in Section 5.3.3, has been consistently shown to be an
independent predictor of survival in PAH
5.3.2. 
Pulmonary Vascular Resistance Rationale 
The term PAH describes a group of PH patients characterized hemodynamically by the presence 
of precapillary PH, defined by a pulmonary artery wedge pressure ≤ 15 mmHg and a 
PVR > 3 WU.29  Generally, PVR values < 5 WU are considered to be of good prognostic value.  
This parameter is in fact part of the calculation of the REVEAL risk score.26 
Earlier trials have used PVR as part of their endpoints, mostly as the key secondary endpoint, or 
in substudies, as in the pivotal trials of the more recently approved PAH therapies. 
Decreases in PVR in response to treatment have been associated with long-term transplant-free 
survival.29 
5.3.3. 
N-Terminal Pro-Hormone B-type Natriuretic Peptide Rationale
N-Terminal pro-hormone B-type natriuretic peptide (NT-proBNP) is secreted by cardiomyocytes
in response to ventricular stretch and is an established noninvasive marker of ventricular
dysfunction in patients with PAH.  Plasma NT-proBNP levels correlate with functional capacity,
right ventricular function, and echocardiographic and hemodynamic variables, and it has been
consistently shown to be an independent predictor of survival in PAH.29-31  In addition, the
2 largest studies of investigational new therapies in PAH to date, which used an outcomes-based
primary endpoint, have shown that improvement in NT-proBNP correlated with lower risk of
morbidity/mortality.32,33
5.3.4. 
World Health Organization Functional Class Rationale 
The WHO FC, despite its interobserver variability,34 remains one of the most powerful predictors 
of survival, not only at diagnosis but also during follow-up.35-37  A worsening FC is one of the 
most alarming indicators of disease progression, which should trigger further diagnostic studies 
to identify the causes of clinical deterioration.36-38 
The WHO FC is also a powerful predictor of survival, as the WHO FC categories (I to IV) 
represent a scale to measure the severity of PAH.  Studies have shown that a poor WHO FC 
status at presentation is associated with a lower 5-year survival rate and is therefore an important 
prognostic factor in the risk scores. 
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5.3.5. 
Time to Clinical Worsening Rationale 
Time to clinical worsening can be used to assess disease progression associated with PAH and 
therefore presents a relevant measurement to patients, clinicians, and regulatory agencies.  The 
majority of clinical trials in PAH have included TTCW as a secondary endpoint.  Some of the 
more recent clinical trials have demonstrated a treatment-related delay in TTCW, and while 
others have not,39 recent results suggest that TTCW shows promise in detecting disease 
progression.19-22 
5.3.6. 
Simplified French Risk Score Calculator Rationale 
The simplified French risk scoring system is based on the 2015 ESC/ERS Guidelines for the 
diagnosis and treatment of PH.  In this study, the noninvasive parameters will be used to 
determine the score.  “Low risk” is defined as attaining or maintaining all 3 low-risk criteria: 
WHO FC I or II, 6MWD > 440 m, and NT-proBNP < 300 ng/L.32 
5.3.7. 
Quality-of-Life Assessments Rationale 
Disease-specific patient-reported outcome (PRO) instruments are essential tools to evaluate 
disease, treatment and the QoL.  QoL for PAH participants in this study will be assessed using 2 
PRO measures: the EuroQoL – 5 Dimension – 5 Level (EQ-5D-5L) index score and the 
PAH-SYMPACT®. 
The EQ-5D-5L is a standardized measure of health status that provides a simple, generic 
measure of health for clinical and economic appraisal.  It is designed for self-completion and 
therefore captures information directly from the respondent, thereby generating data that 
conforms to the general requirement of all PRO measures. 
The PAH-SYMPACT draft consists of 16 symptom and 25 impact items within 4 domains.  It 
was developed based on interviews with patients with PAH.  It is the only PAH-specific 
instrument developed and validated in accordance with the United States Food and Drug 
Administration guidance on PRO development process therefore providing a validated insight of 
disease impact in PAH patients. 
5.4. 
Exploratory Endpoints 
In addition to the primary and secondary endpoints, the following will be analyzed: 
•
Change in echocardiogram (ECHO) parameters at Week 24 versus baseline
•
Change in dyspnea score (assessed by Borg CR10 scale) at Week 24 versus baseline
•
Proportion of participants who achieve PVR < 3 wood units (WU) at Week 24
•
Proportion of participants who achieve mean pulmonary arterial pressure (mPAP)
< 25 mmHg at Week 24
•
Change from baseline in mPAP at Week 24
•
Change from baseline in the Cardiovascular Symptoms domain score of
PAH-SYMPACT® at Week 24
•
Change from baseline in the EQ-5D-5L index score at Week 24
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•
Change from baseline in the EQ-5D-5L visual analog scale (VAS) at Week 24
5.5. 
Safety Endpoints 
Safety will be evaluated by collecting the following: 
•
AEs
•
ADAs
•
Laboratory assessments (hematology, serum chemistry/follicle-stimulating hormone
(FSH), urinalysis)
•
Vital signs
•
Physical examination
•
12-Lead electrocardiogram (ECG)
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6.
STUDY DESIGN
6.1. 
Study Description
This is a Phase 3, randomized, double-blind, placebo-controlled study to compare the efficacy 
and safety of sotatercept versus placebo when added to background PAH therapy for the 
treatment of PAH. 
Participants enrolled in the study will have a diagnosis of PAH (Pulmonary Hypertension WHO 
Group 1) associated with idiopathic/heritable, drug-induced, connective tissue diseases (CTD), 
or post shunt correction PAH, within WHO FC II or III. 
6.2. 
Duration of Study 
Each participant will be enrolled in the study for up to approximately 108 weeks as follows: 
•
The Screening Period is up to 4 weeks (28 days).
•
The DBPC Treatment Period (Period 1) (24 weeks, which includes 9 study visits
[Visit 1 to Visit 9]).
•
The Long-Term Double Blind (LTDB) Treatment Period (Period 2) (up to
approximately 72 weeks, [Visit 10 up to Visit 33], depending on when the last
participant randomized into the study completes the DBPC Treatment Period).
•
The Follow-up Period will be at least 8 weeks, which may include Period 1
Follow-up Visits 1 and 2 and end of treatment (EOT) and end of study (EOS) visits.
6.3. 
Rationale for Dose Selection
The PULSAR study demonstrated that both the 0.3 and 0.7 mg/kg sotatercept doses are 
pharmacologically active and that both resulted in statistically significant improvements across a 
number of study endpoints compared to placebo.  However, comprehensive exposure-response 
(E-R) analyses demonstrated that a concentration-effect relationship exists for PVR, 6MWD, and 
NT-proBNP for efficacy and Hgb for safety.  Simulations based on these E-R models suggest a 
higher probability of achieving clinically meaningful targets for 6MWD, PVR, and NT-proBNP 
with the 0.7 mg/kg dose level compared to 0.3 mg/kg.  Consistent with these, in PULSAR data, 
55% of patients in the 0.7 mg/kg group achieved a ≥ 30% reduction in PVR (PULSAR primary 
endpoint) compared to 25% in the 0.3 mg/kg dose group. 
Acceleron Pharma Inc.’s interpretation of the PULSAR safety data is that both dose levels are 
generally safe and well tolerated in patients with PAH, which is consistent with previous 
experience with sotatercept in other indications.  While a concentration-effect relationship was 
also demonstrated for Hgb increases, no significant difference at steady state was observed 
between sotatercept dose levels in the PULSAR study; mean change from baseline in Hgb at 
Week 24 was 1.2 and 1.5 g/dL in the 0.3 and 0.7 mg/kg groups, respectively.  The PULSAR 
study demonstrated that excursions in Hgb concentration above the upper limit of normal (ULN) 
can be effectively managed by sotatercept dose modification guidelines.  Simulations based on 
the E-R model for Hgb suggest a very low probability (< 10%) of crossing Hgb safety thresholds 
defined in the PULSAR study. 
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Clinical trial simulations from the pharmacokinetic (PK)/pharmacodynamic (PD) model for Hgb 
suggested that the probability of having Hgb ≥ 18 g/dL and an increase in Hgb ≥ 2 g/dL is higher 
during the first 21 days after a dose of 0.7 mg/kg than after a dose of 0.3 mg/kg.  Therefore, for 
this study, a starting dose of 0.3 mg/kg was selected and will be administered at Visit 1 and a 
target dose of 0.7 mg/kg will be administered at Visit 2 and for the remainder of the treatment 
period.  All doses will be administered subcutaneously (SC) every 3 weeks with appropriate dose 
modification guidelines (see Section 8.3). 
6.4. 
Study Design, Stratification and Treatment Assignment 
This is a Phase 3, randomized, double-blind, placebo-controlled, multicenter, parallel-group 
study.  Participants who have provided signed informed consent and meet all eligibility criteria 
will be stratified by: 
•
WHO Functional Class (FC) (Class II or III)
•
Background PAH therapy (mono/double or triple therapy)
Approximately 284 participants will be randomly assigned in a 1:1 ratio to receive SC injections 
of either placebo or sotatercept at a starting dose of 0.3 mg/kg SC at Visit 1.  Participants will 
then be escalated to the target dose level of 0.7 mg/kg SC at Visit 2 and at will remain at this 
target dose level for all subsequent DBPC Treatment Period and LTDB Treatment Period visits 
(Visits 2 to 9 and Visits 10 to 33).  Randomization is described below (see Section 6.5). 
Dosing will be once every 21 days for a total consecutive period of 24 weeks during the DBPC 
Treatment Period and up to 72 weeks during the LTDB Treatment Period.  During all study 
periods, all participants will remain on background PAH therapy. 
The study is divided into a screening period (up to 4 weeks), a DBPC Treatment Period 
(24 weeks), a LTDB Treatment Period (until the last participant randomized completes the 
DBPC Treatment Period [up to approximately 72 weeks]), and a Follow-up Period (at least 
8 weeks). 
The LTDB Treatment Period will last until the last participant randomized completes the DBPC 
Treatment Period and the study is unblinded.  During this period, selected study visits may be 
performed as home health care (HHC) visits as described in Section 6.5.  After the study is 
unblinded, participants who complete the DBPC Treatment Period and are currently on treatment 
(sotatercept or placebo) in the LTDB Treatment Period may be eligible to participate in the 
separate open-label long-term follow-up (LTFU) study.  For these participants, the EOS visit can 
be waived and Visit 1 of the LTFU study will take place 21 (± 7) days after the last dose 
administered in this study, which may coincide with this study’s EOT visit. 
Participants who complete the DBPC and LTDB treatment periods and do not wish to participate 
in the LTFU study will complete the EOT and EOS visits of the Follow-up Period as described 
in Section 6.2. 
Participants who discontinue the DBPC Treatment Period early will complete the EOT visit at 
the time of discontinuation.  These participants will be invited to come for limited study 
assessments at selected visits (Period 1 Follow-up Visits 1 and 2) depending on the timing of 
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their discontinuation.  In addition, they will complete the EOS visit (described in Section 9.2.6) 
provided that consent is not withdrawn. 
6.5. 
Home Health Care Visits 
Select study visits (Visits 10, 11, 12, 14, 15, 16, 18, 19, 20, 22, 23, 24, 26, 27, 28, 30, 31, and 32) 
may be performed at the participant’s home during the LTDB treatment period by a qualified 
health care professional if permitted by local and institutional regulations requested by study 
participant. 
Participants are eligible for HHC visits if dose modification/delays did not occur in the previous 
2 consecutive visits.  Participants can opt to start HHC at Visit 10, provided that dose 
modification was not performed at Visits 8 and 9.  Guidelines for dose modification are 
described in Section 8.3. 
If a dose modification is required, at any time during the LTDB treatment period, the following 2 
visits will be performed on-site.  The participant will be eligible for HHC visits again once 2 
consecutive visits without dose modification have occurred. 
For example, if a dose modification is required at Visit 13, then Visits 14 and 15 must be 
performed on-site.  If no further dose modifications are required at Visits 14 and 15, then Visit 
16 may be performed as a HHC visit. 
6.6. 
Randomization and Blinding 
Participants who have signed the informed consent and meet all eligibility criteria will be 
stratified by baseline WHO FC and background PAH therapy and then randomized to receive 
placebo plus background PAH therapy or sotatercept plus background PAH therapy.  
Randomization assignments will be generated through a computerized system, provided by an 
Interactive Response Technology (IRT) (see IRT Manual for details).  Recruitment will be 
controlled to ensure that at least 50% of enrolled participants are PAH in WHO FC III. 
In the event of a medical emergency for an individual participant in which knowledge of the 
study drug is critical to the participant’s medical management, the investigator may break the 
blind for that participant via the IRT (see IRT user Manual for further instruction).  If the nature 
of the emergency does not permit time to consult with the medical monitor prior to breaking the 
blind, the investigator must inform the medical monitor that the blind has been broken at the 
earliest opportunity. 
In non-urgent situations, the investigator must consult with the study medical monitor prior to 
breaking the blind.  Only if knowledge of the participant’s treatment assignment is necessary for 
the medical management of that participant should the blind be broken.  If the blind is broken, 
the participant will be discontinued from the study and will not be eligible to enroll in the LTFU 
study.  The investigator should not inform the participant of their treatment assignment under 
any circumstances. 
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7.
STUDY POPULATION
7.1. 
Rationale for Selected Population
Participants diagnosed with symptomatic PAH (WHO FC II or III) who present with idiopathic 
or heritable PAH, PAH associated with CTD, drug/toxin induced, post shunt correction PAH, or 
PAH presenting at least 1 year following the correction of congenital heart defects, and currently 
on background PAH therapy will be eligible for this study. 
PAH is considered a relatively rare condition, with approximately 80% of PAH patients 
presenting as WHO FC II-III.  Typically, WHO FC I PAH patients are excluded from 
interventional studies due to the relatively low rate of identification, low prevalence, and mild 
symptomatology.  Similarly, there is a low prevalence of PAH patients with WHO FC IV, and 
given their severe disease burden, these patients have a limited ability to participate in longer 
interventional studies.  Eligibility criteria (Section 7.3 and Section 7.4) for this study are 
consistent with those of other studies in this population. 
7.2. 
Background Pulmonary Arterial Hypertension Therapy 
Background PAH therapy refers to approved PAH-specific medications and may consist of 
monotherapy or combination therapy with ERA, PDE5 inhibitors, soluble guanylate cyclase 
stimulators, and/or prostacyclin analogues or receptor agonists.  Background PAH therapy 
should be stable at least 90 days prior to screening and remain stable throughout the study. 
Stable diuretic therapy is defined as no addition of a new diuretic and no switching of a 
pre-existent oral diuretic to parenteral administration; however, dose adjustments (up or down) in 
pre-existent oral diuretics are acceptable. 
7.3. 
Inclusion Criteria 
Eligible participants must meet these criteria (and others) to be enrolled in the study: 
1. Age ≥ 18 years
2. Documented diagnostic right heart catheterization (RHC) at any time prior to screening
confirming the diagnosis of WHO PAH Group 1 in any of the following subtypes:
•
Idiopathic PAH
•
Heritable PAH
•
Drug/toxin-induced PAH
•
PAH associated with CTD
•
PAH associated with simple, congenital systemic-to-pulmonary shunts at least 1 year
following repair
3. Symptomatic PH classified as WHO FC II or III
4. Baseline RHC performed during the Screening Period documenting a minimum PVR of
≥ 5 WU and a pulmonary capillary wedge pressure (PCWP) or left ventricular
end-diastolic pressure of ≤ 15 mmHg
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5. On stable doses of background PAH therapy and diuretics (i.e., patient-specific dose goal
for each therapy already achieved) for at least 90 days prior to screening; for infusion
prostacyclins, dose adjustment within 10% of optimal dose is allowed per medical
practice.  Background PAH therapy is defined in Section 7.2.
6. 6MWD ≥ 150 and ≤ 500 m repeated twice at screening (measured at least 4 hours apart,
but no longer than 1 week), and both values are within 15% of each other (calculated
from the highest value).
7. Females of childbearing potential (as defined in Appendix 3) must:
•
Have 2 negative urine or serum pregnancy tests as verified by the investigator prior to
starting study drug administration; she must agree to ongoing pregnancy testing
during the course of the study and until 8 weeks after the last dose of the study drug
•
If sexually active, have used, and agree to use, highly effective contraception without
interruption, for at least 28 days prior to starting the investigational product, during
the study (including dose interruptions), and for 16 weeks (112 days) after
discontinuation of study treatment
•
Refrain from breastfeeding a child or donating blood, eggs, or ovum for the duration
of the study and for at least 16 weeks (112 days) after the last dose of study treatment
8. Male participants must:
•
Agree to use a condom, defined as a male latex condom or non-latex condom NOT
made out of natural (animal) membrane (e.g., polyurethane), during sexual contact
with a pregnant female or a female of childbearing potential while participating in the
study, during dose interruptions and for at least 16 weeks (112 days) following
investigational product discontinuation, even if he has undergone a successful
vasectomy
•
Refrain from donating blood or sperm for the duration of the study and for 16 weeks
(112 days) after the last dose of study treatment
9. Ability to adhere to study visit schedule and understand and comply with all protocol
requirements
10. Ability to understand and provide written informed consent
7.4. 
Exclusion Criteria 
Participants will be excluded from the study if any of the following criteria are met: 
1. Diagnosis of PH WHO Groups 2, 3, 4, or 5
2. Diagnosis of the following PAH Group 1 subtypes: human immunodeficiency virus
(HIV)-associated PAH and PAH associated with portal hypertension.  Exclusions in PAH
Group 1 should also include schistosomiasis-associated PAH and pulmonary
veno-occlusive disease
3. Hemoglobin at screening above gender-specific ULN, per local laboratory test
4. Baseline platelet count < 50,000/mm3 (< 50.0 × 109/L) at screening
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5. Uncontrolled systemic hypertension as evidenced by sitting systolic BP > 160 mmHg or
sitting diastolic BP > 100 mmHg during screening visit after a period of rest
6. Baseline systolic BP < 90 mmHg at screening
7. Pregnant or breastfeeding women
8. Any of the following clinical laboratory values at the screening visit:
•
Estimated glomerular filtration rate (eGFR) < 30 mL/min/m2 (as defined by the
Modification of Diet in Renal Disease [MDRD] equation)
•
Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total
bilirubin levels > 3 × ULN (bilirubin criterion waived if there is a documented history
of Gilbert’s syndrome)
9. Currently enrolled in or have completed any other investigational product study within
30 days for small-molecule drugs or within 5 half-lives for biologics prior to the date of
signed informed consent
10. Prior exposure to sotatercept (ACE-011) or luspatercept (ACE-536) or known allergic
reaction to either one
11. History of full pneumonectomy
12. Pulmonary function test (PFT) values of forced vital capacity (FVC) < 60% predicted at
the screening visit or within 6 months prior to the screening visit.  If PFT is not available,
a chest CT scan showing more than mild interstitial lung disease at the screening visit or
1 year prior to it.
13. Initiation of an exercise program for cardiopulmonary rehabilitation within 90 days prior
to the screening visit or planned initiation during the study (participants who are stable in
the maintenance phase of a program and who will continue for the duration of the study
are eligible).
14. History of more than mild obstructive sleep apnea that is untreated
15. Known history of portal hypertension or chronic liver disease, including hepatitis B
and/or hepatitis C (with evidence of recent infection and/or active virus replication),
defined as mild to severe hepatic impairment (Child-Pugh Class A-C).
16. History of restrictive, constrictive, or congestive cardiomyopathy
17. History of atrial septostomy within 180 days prior to the screening visit
18. Electrocardiogram (ECG) with Fridericia’s corrected QT interval (QTcF) > 500 ms
during the Screening Period
19. Personal or family history of long QT syndrome (LQTS) or sudden cardiac death
20. Left ventricular ejection fraction (LVEF) < 45% on historical ECHO within 6 months
prior to the screening visit
21. Any symptomatic coronary disease events (prior myocardial infarction, percutaneous
coronary intervention, coronary artery bypass graft surgery, or cardiac anginal chest pain)
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within 6 months prior to the screening visit.  Note: Anginal pain can be ignored as an 
exclusion criterion if coronary angiography shows no obstructions 
22. Cerebrovascular accident within 3 months prior to the screening visit
23. Acutely decompensated heart failure within 30 days prior to the screening visit, as per
investigator assessment
24. Significant (≥ 2+ regurgitation) mitral regurgitation or aortic regurgitation valvular
disease.
25. Received intravenous inotropes (e.g., dobutamine, dopamine, norepinephrine,
vasopressin) within 30 days prior to the screening visit
7.5. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized to receive study treatment.  Electronic case report forms (eCRFs) 
must be completed for all participants who sign the informed consent form (ICF).  A minimal set 
of screen failure information is required to ensure transparent reporting of screen failure 
participants to meet the Consolidated Standards of Reporting Trials publishing requirements and 
to respond to queries from regulatory authorities.  Minimal information includes demography, 
reason for screen failure, and AEs. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once with the approval of the study medical monitor.  Rescreened participants will be 
assigned a new participant number. 
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8.
STUDY DRUG TREATMENT
8.1. 
Study Drug Description
Sotatercept is a homodimeric recombinant fusion protein consisting of the extracellular domain 
of the human activin receptor type IIA (ActRIIA) linked to the human IgG1 Fc domain. 
Sotatercept is the generic name assigned to ActRIIA-IgG1Fc.  The laboratory code is ACE-011.  
The Chemical Abstracts Service (CAS) Registry number for sotatercept is 1001080-50-7; the 
United States Adopted Name (USAN) and the International Nonproprietary Name (INN) is 
sotatercept. 
8.1.1. 
Clinical Drug Product 
The clinical drug product consists of sotatercept (60 mg/vial) in 10 mM citrate buffer, pH 5.8, 
8% w/v sucrose, and 0.02% w/v polysorbate 80.  The matching placebo consists of 10 mM 
citrate buffer, pH 5.8, 2% w/v sucrose, 3% w/v mannitol, and 0.02% w/v polysorbate 80. Both 
the clinical drug product containing sotatercept and its matching placebo are supplied as a 
lyophilized powder in labeled, rubber-stoppered, type I glass vials.  Both the investigator and the 
participant will be blinded as described in Section 6.5. 
PAH background therapy will not be provided as study medication during the study.  To be 
enrolled in the study, participants must be on stable PAH background therapy according to local 
practice.  Participants must remain on the same PAH background therapy during the course of 
the study.  More details on PAH background therapy are provided in Section 7.2. 
8.1.2. 
Formulation 
Sotatercept (60 mg/vial) clinical drug product and placebo will be provided by Acceleron 
Pharma Inc. as a lyophilized powder. 
8.2. 
Study Drug Management 
8.2.1. 
Storage 
The recommended storage temperature for sotatercept lyophilized drug product and matching 
placebo is 2°C to 8°C.  Refer to the Pharmacy Manual for additional details. 
8.2.2. 
Packaging and Shipment 
Sotatercept or its matching placebo will be packaged in single-use kits.  Each kit will contain 
1 vial of sotatercept (60 mg/vial) or its matching placebo product and 1 prefilled syringe of 
sterile water for injection (sWFI) for reconstituting the lyophilized sotatercept or its matching 
placebo.  Each kit also contains ancillary components as follows: 
•
A swabbable vial adapter to aid reconstitution and withdrawal of required drug or
placebo solution from the vial
•
A syringe and needle for SC injection
•
Alcohol swabs
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Each vial, prefilled syringe, and kit will be labeled for clinical trial use only, with 
country-specific required label text.  Each kit will be assigned a serialized Medication ID number 
for identification.  The kit will be tamper sealed.  Kits will be stored at a depot and shipped under 
refrigerated conditions until the time of dispensation. 
8.2.3. 
Dose and Administration 
Each eligible participant will be randomly assigned in a 1:1 ratio to one of the two treatment 
arms: 
•
Arm 1: Placebo administered subcutaneously (SC) every 21 days plus background
PAH therapy
•
Arm 2: Sotatercept at a starting dose of 0.3 mg/kg SC with a target dose of 0.7 mg/kg
administered subcutaneously (SC) every 21 days plus background PAH therapy
Prior to administration, the lyophilized sotatercept drug product (60 mg/vial) or matching 
placebo will be reconstituted with 1.3 mL of sWFI.  Reconstituted sotatercept yields a 50-mg/mL 
solution of sotatercept. 
8.3. 
Dose Modification 
Dose delay, reduction, or discontinuation may be performed in any treatment arm (sotatercept or 
placebo).  Dose delays should always precede dose reductions, as summarized in Figure 2, 
Figure 3 and Figure 4.  While guidance for dose modifications and dose delay are summarized in 
Figure 3 and Figure 4, dose delays or reductions can be implemented for safety reasons at any 
time per the investigator’s assessment and are not limited to the dose modification guidance 
provided.  
Blood samples must be taken and assessed for Hgb and platelet count levels on the same day of 
study drug administration or up to 3 days prior to that day if available. 
8.3.1. 
Escalation to Target Dose (0.7 mg/kg) 
All participants will begin treatment at a starting dose of 0.3 mg/kg at Visit 1. At Visit 2, the 
dose will be escalated to the target dose of 0.7 mg/kg and remain at 0.7 mg/kg for the duration of 
the treatment period, unless dose reduction criteria as described in Section 8.3.2 and 
Section 8.3.3 are met.  However, if at Visit 2 Hgb increases by more than 2.0 g/dL from baseline 
and this value is above the gender-specific ULN per local laboratory test, dosing should be 
delayed.  All other study procedures, with the exception of study drug administration, should be 
performed.  At Visit 3, if Hgb has increased by less than 2.0 g/dL from baseline or Hgb value is 
below the gender-specific ULN per local laboratory test, dosing should be restarted at 0.3 mg/kg.  
At Visit 4, if Hgb has increased by less than 2.0 g/dL from baseline or Hgb value is below the 
gender-specific ULN per local laboratory test, the dose will be escalated to the target dose of 
0.7 mg/kg.  Refer to Figure 3 for additional details. 
8.3.2. 
Dose Modifications Due to Hemoglobin Increase 
From Visit 3 onward, if Hgb level increases by more than 2 g/dL from the previous dosing visit, 
and this value is above the gender-specific ULN per local laboratory test, then a maximum of 3 
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consecutive dose delays are allowed during the study treatment period.  After the third dose 
delay, if Hgb level persists at more than 2 g/dL above the previous dosing visit, and this value is 
above the gender-specific ULN per local laboratory test then the dose should be reduced to 
0.3 mg/kg.  If the participant is already at a dose of 0.3 mg/kg, the study medical monitor should 
be consulted, and study drug discontinuation should be considered. 
If Hgb level increases more than 4 g/dL above the participant’s baseline value, the study medical 
monitor should be consulted, and study drug discontinuation should be considered. 
8.3.3. 
Dose Modifications Due to Low Platelet Count 
If platelet count is less than 50,000/mm3, dose delay is allowed for up to 3 visits.  If platelet 
count remains less than 50,000/mm3 after 3 consecutive dose delays, then study drug treatment 
should be discontinued/not restarted.  At the visit following each dose delay, if platelet count is 
more than 50,000/mm3, then the dose should be reduced to 0.3 mg/kg and study drug treatment 
should be restarted.  If the participant is already at a dose of 0.3 mg/kg, study treatment should 
be restarted at 0.3 mg/kg.  Refer to Figure 4 for additional details. 
8.3.4. 
Dose Modifications Due to Adverse Events of Telangiectasia 
In cases of the identification of new events of telangiectasia that are of moderate or greater 
severity/intensity, or for the progression of a telangiectasia event from mild to moderate, the dose 
of study drug should be delayed for one visit if the participant was receiving 0.7 mg/kg study 
drug, or for three visits if the participant was receiving 0.3 mg/kg at the time of the event.  If, 
following the dose hold(s), there has been no progression in the severity of the event of 
telangiectasia, dosing of study drug may be resumed at a dose level of 0.3 mg/kg.  If the event of 
telangiectasia progresses during the time in which study drug dosing has been delayed, the 
investigator should consult the medical monitor and consider discontinuation from study drug.  
8.3.5. 
Dose Re-escalation Following Dose Reduction 
In cases of dose reduction due to an AE not related to study drug, the dose can be re-escalated 
when the AE is resolved.  In cases of dose reduction due to increases in Hgb, the dose will be 
re-escalated to 0.7 mg/kg after 2 consecutive visits at which Hgb values are stable and equal or 
lower than the ULN normal (refer to Figure 3).  Similarly, in cases of dose reduction due to 
decrease in platelet count, the dose will be re-escalated to 0.7 mg/kg after 2 consecutive visits at 
which platelet counts are stable and more than 50,000/mm3, with no association with AEs of 
bleeding (refer to Figure 4).  In cases of dose reduction due to events of telangiectasia, the dose 
may be re-escalated to 0.7 mg/kg only if the event has completely resolved. 
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Figure 2: 
Guidelines for Target Dose Escalation (0.7 mg/kg) 
Hgb increase > 2.0 g/dL 
from last dosing visitA
AND 
Hgb above gender-specific 
upper limit of normal per 
local laboratory test?
Escalate dose to target 
dose of 0.7 mg/kg
Dose delay for one 
visit (3 weeks)B
No
Yes
Hgb increase > 2.0 g/dL 
from last dosing visitA
AND 
Hgb above gender-specific 
upper limit of normal per 
local laboratory test?
Check 
Hgb
Restart dosing 
at 0.3 mg/kg
Dose delay for one 
visit (3 weeks)B
Yes
No
Hgb increase > 2.0 g/dL 
from last dosing visitA 
AND 
Hgb above gender-specific 
upper limit of normal per 
local laboratory test?
Check 
Hgb
Dose delay for one 
visit (3 weeks)B
Restart dosing at 
0.3 mg/kg
No
Yes
Hgb increase > 2.0 g/dL 
from last dosing visitA
AND 
Hgb above gender-specific 
upper limit of normal per 
local laboratory test?
Restart dosing at 
0.3 mg/kg
Consult medical 
monitor and 
consider treatment 
discontinuation
Check 
Hgb
Yes
No
A If Hgb increases > 4 g/dL above participant baseline 
value, consult medical monitor and consider treatment 
discontinuation
B If a dose delay is required, the participant will not be 
dosed. All other study procedures should be performed as 
scheduled. The participant will return every 3 weeks for 
assessment of hematology results and AEs until the 
participant is eligible to receive the next dose of study 
drug. The participant should resume treatment at the next 
planned dosing visit (e.g. if the participant missed a dose 
at Visit 4, then they would resume dosing at Visit 5).
Check 
Hgb
Hgb increase > 2.0 g/dL 
from last dosing visitA
AND 
Hgb above gender-specific 
upper limit of normal per 
local laboratory test?
No
Escalate dose to target 
dose of 0.7 mg/kg
Yes
Follow Figure 3 for dose 
delay, reduction, and 
discontinuation for 
hemoglobin increase
Guidelines for Target Dose Escalation
Visit 2
Visit 3
Visit 4
Visit 5
Abbreviations: AE = adverse event; Hgb = hemoglobin. 
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Figure 3: 
Guidelines for Dose Modification Due to Hemoglobin Increase From Visit 3 Onward 
Abbreviations: AE = adverse event; Hgb = hemoglobin. 
Hgb increase > 2.0 g/dL 
from last dosing visitA
AND 
Hgb above gender-specific 
upper limit of normal per 
local laboratory test?
Continue dosing at 
previous dose level
Dose delay for one 
visit (3 weeks)B
No
Yes
Hgb increase > 2.0 g/dL 
from last dosing visitA
AND 
Hgb above gender-specific 
upper limit of normal per 
local laboratory test?
Check Hgb
Restart dosing at 
previous dose level
Dose delay for one 
visit (3 weeks)B
Yes
No
Hgb increase > 2.0 g/dL 
from last dosing visitA
AND  
Hgb above gender-specific 
upper limit of normal per 
local laboratory test?
Check Hgb
Dose delay for one 
visit (3 weeks)B
Restart dosing at 
previous dose level
No
Yes
Hgb increase > 2.0 g/dL 
from last dosing visitA
AND 
Hgb above gender-specific 
upper limit of normal per 
local laboratory test?
Restart dosing at 
previous dose level
Reduce dose to 
0.3 mg/kgC. 
Check Hgb
Yes
No
A  If Hgb increases > 4 g/dL above participant baseline value, consult medical monitor and 
consider treatment discontinuation
B If a dose delay is required, the participant will not be dosed. All other study procedures 
should be performed as scheduled. The participant will return every 3 weeks for assessment of 
hematology results and AEs until the participant is eligible to receive the next dose of study 
drug. The participant should resume treatment at the next planned dosing visit (e.g. if the 
participant missed a dose at Visit 4, then they would resume dosing at Visit 5).
C If participant is already on 0.3 mg/kg, consult medical monitor and consider treatment 
discontinuation
Dose modification due Hemoglobin (Hgb) increase from Visit 3 onward
Re-escalate dose to 
0.7 mg/kg
2 consecutive visits at 
which Hgb is stable and 
below the gender-specific 
upper limit of normal
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Figure 4: 
Guidelines for Dose Modification Due to Low Platelet Count 
Abbreviations: AE = adverse event; PLT = platelet. 
PLT count < 50,000/mm3 
(< 50.0 x 109/L)?
Continue dosing at 
0.7 mg/kg
Dose delay for one 
visit (3 weeks)A
No
Yes
PLT count < 50,000/mm3 
(< 50.0 x 109/L)?
Check PLT count
Reduce dose to 
0.3 mg/kgB
Dose delay for one 
visit (3 weeks)A
Yes
No
PLT count < 50,000/mm3 
(< 50.0 x 109/L)?
Check PLT count
Reduce dose to  
0.3 mg/kgB
No
Yes
A If a dose delay is required, the participant will not be dosed. All other study procedures should be performed as scheduled. The 
participant will return every 3 weeks for assessment of hematology results and AEs until the participant is eligible to receive the next 
dose of study drug. The participant should resume treatment at the next planned dosing visit (e.g. if the participant missed a dose at 
Visit 4, then they would resume dosing at Visit 5).
B If the participant is already at a dose of 0.3 mg/kg, study treatment should be restarted at 0.3 mg/kg.
Guidelines for Dose Modification due to Low Platelet (PLT) Count
Discontinue study 
drug treatment
Dose delay for one 
visit (3 weeks)A
PLT count < 50,000/mm3 
(< 50.0 x 109/L)?
Reduce dose to 
0.3 mg/kgB
No
Check PLT count
Yes
2 consecutive visits at 
which PLT counts are 
stable and > 50,000/mm3 
(< 50.0 x 109/L) with no 
association with adverse 
events of bleeding
Re-escalate dose 
to 0.7 mg/kg
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8.3.6. 
Accountability 
Accountability for study drug during the study is the responsibility of the investigator or 
designee.  Investigational clinical supplies must be received by a designated person at the clinical 
site and kept in a secure and temperature-controlled location.  The investigational site must 
maintain accurate records with dates and amounts of study drug received, to whom it was 
administered (participant-by-participant accounting), and accounts of any study drug accidentally 
or deliberately damaged, destroyed, or returned.  Accurate recording of all study drug 
administration must be made in the appropriate section of the participant’s eCRF and source 
documents.  Unless otherwise notified, all vials of study drug, both used and unused, must be 
saved for drug accountability.  The used vials may be discarded, per the institution’s standard 
practice, after drug accountability has been completed by the monitor.  The investigator must 
return all unused vials of study drug to Acceleron Pharma Inc. at the end of the study, or the 
study drug may be destroyed at the clinical site after Acceleron Pharma Inc. approval.  Either 
method must be documented on the drug accountability log. 
Acceleron Pharma Inc. (or designee) will review with the investigator and relevant site personnel 
the process for investigational product return, disposal, and/or destruction including 
responsibilities for the site versus Acceleron Pharma Inc. (or designee). 
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9.
STUDY CONDUCT
9.1. 
General Instructions
•
Study procedures and their timing are summarized in the Schedule of Events (SoE)
(Section 2).
•
Prospective approval of protocol deviations to recruitment and eligibility criteria, also
known as protocol waivers or exemptions, are not permitted.
•
Assessments performed outside of their defined windows must be handled as protocol
deviations.
•
Immediate safety concerns must be discussed with the medical monitor immediately
upon occurrence or awareness to determine whether the participant should continue
or discontinue study treatment.
•
Adherence to the study design requirements, including those specified in the SoE, is
essential and required for study conduct.
•
All protocol assessment data must be recorded in the participant’s source
documentation.
9.2. 
Study Procedures
9.2.1. 
Screening Period (up to 4 weeks prior to Visit 1)
Potential participants must sign an ICF before any study-specific screening tests are conducted.  
Informed consent must be provided before any screening procedures are undertaken. 
All screening procedures must be performed per the SoE (Section 2) and are to be completed and 
reviewed by the investigator to confirm participant eligibility prior to dosing. 
The investigator will maintain a screening log to record details of all participants screened to 
confirm eligibility and record reasons for screening failure, as applicable. 
Any screening clinical laboratory values considered abnormal may be repeated once during the 
screening period but prior to the RHC (RHC should be performed last and after all other 
screening procedures are done, when possible, as described below and in the SoE).  Upon 
discussion with the medical monitor, a historic RHC may be allowed as long as it was collected 
within 28 days prior to Visit 1.  
Screening procedures may be performed and completed over more than 1 screening visit as long 
as all screening procedures are completed within the 28 days immediately preceding Visit 1. 
Screening will include a review of the participant’s medical, surgical, and family history, 
collecting of demographics, race, ethnicity, and medical record requests for relevant external 
procedures. 
Screening procedures include: 
•
Informed consent
•
Inclusion/ exclusion criteria
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•
Medical history review
•
Physical examination
•
12-Lead ECG
•
Vital signs including weight
•
A serum or urine pregnancy test (where applicable)
•
Hematology (complete blood cell [CBC] count)
•
Serum chemistry/FSH
•
Urinalysis (dipstick)
•
Pulmonary function test if the last test results are done over 6 months prior to the
screening visit (or if PFT is not available, a chest CT scan at the screening visit or a
scan result within 1 year prior)
•
RHC
•
6MWT
•
Borg Dyspnea Scale (pre- and post-6MWT)
•
WHO FC Assessment
•
NT-proBNP sample collection
•
ADA sample collection
•
PK sample collection
•
ECHO
•
AE/SAE review
•
Concomitant medication review
Measurements/assessments taken during Screening Period will be recorded as the baseline values 
for study assessment of endpoints unless described otherwise.  The RHC should be performed 
last and after all other screening procedures are performed, when possible. 
9.2.2. 
Double-Blind, Placebo-Controlled Treatment Period (Visits 1 to 9) 
Study procedures for Visits 1 to 9 vary dependent on the visit number.  All study 
procedures/assessments should be performed prior to the administration of the study drug. 
Visit 1 (± 3 days) 
Visit 1 procedures include: 
•
Targeted cardiopulmonary and skin physical examinations
•
Vital signs including weight
•
A serum or urine pregnancy test (where applicable)
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•
QoL assessments
•
NT-proBNP sample collection
•
ADA sample collection
•
PK sample collection
•
Randomization
•
Study drug administration
•
AE/SAE review
•
Concomitant medication review
Visit 2 (± 3 days) 
Visit day windows are relative to the date of the previous dose of study drug: every 21 days 
(± 3 days).  Visit 2 procedures include: 
•
Vital signs including weight
•
A serum or urine pregnancy test (where applicable)
•
Hematology (CBC)
•
6MWT
•
Borg Dyspnea Scale (pre- and post- 6MWT)
•
WHO FC assessment
•
Clinical worsening assessment
•
NT-proBNP sample collection
•
ADA sample collection
•
PK sample collection
•
Study drug administration
•
AE/SAE review
•
Concomitant medication review
Visit 3 and Visit 4 (± 3 days) 
Visit 3 and Visit 4 procedures include: 
•
Vital signs including weight
•
A serum or urine pregnancy test (where applicable)
•
Hematology (CBC)
•
NT-proBNP sample collection
•
ADA sample collection
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•
PK sample collection
•
Study drug administration
•
AE/SAE review
•
Concomitant medication review
Visit 5 (± 3 days) 
Visit 5 procedures include: 
•
Targeted cardiopulmonary and skin physical examinations
•
12-Lead ECG
•
Vital signs including weight
•
A serum or urine pregnancy test (where applicable)
•
Hematology (CBC)
•
Serum chemistry/FSH
•
6MWT
•
Borg Dyspnea Scale (pre- and post-6MWT)
•
WHO FC assessment
•
Clinical worsening assessment
•
NT-proBNP sample collection
•
ADA sample collection
•
PK sample collection
•
ECHO
•
Study drug administration
•
AE/SAE review
•
Concomitant medication review
Visits 6, 7, and 8 (± 3 days) 
The procedures at Visits 6, 7, and 8 include: 
•
Vital signs including weight
•
A serum or urine pregnancy test (where applicable)
•
Hematology (CBC)
•
Study drug administration
•
AE/SAE review
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•
Concomitant medication review
Visit 9 (± 3 days) 
The first primary endpoint evaluation occurs at Visit 9.  The procedures include the following: 
•
Targeted cardiopulmonary and skin physical examinations
•
12-Lead ECG
•
Vital signs including weight
•
A serum or urine pregnancy test (where applicable)
•
Hematology (CBC)
•
Serum chemistry/FSH
•
Urinalysis (dipstick)
•
RHC
•
6MWT
•
Borg Dyspnea Scale (pre- and post- 6MWT)
•
WHO FC assessment
•
Clinical worsening assessment
•
QoL assessments
•
NT-proBNP sample collection
•
ADA sample collection
•
PK sample collection
•
ECHO
•
Study drug administration
•
AE/SAE review
•
Concomitant medication review
9.2.3. 
Period 1 Follow-up Visits 1 and 2
Period 1 Follow-up Visits are applicable for participants who discontinue study early during the 
DBPC Treatment Period.  For participants discontinuing prior to Visit 5, Follow-up Visits 1 and 
2 should be performed.  For participants discontinuing after Visit 5 and prior to Visit 9, only 
Follow-up Visit 2 should be performed.  Please refer to the SoE (Section 2) for details on 
assessments during these visits. 
Follow-up Visit 1 (12 weeks After Visit 1, ± 3 days) 
Follow-up Visit 1 procedures include: 
•
Targeted cardiopulmonary and skin physical examinations
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•
Vital signs including weight
•
A serum or urine pregnancy test (where applicable)
•
Hematology (CBC)
•
Serum chemistry/FSH
•
6MWT
•
Borg Dyspnea Scale (pre- and post-6MWT)
•
WHO FC assessment
•
Clinical worsening assessment
•
NT-proBNP sample collection
•
ADA sample collection
•
PK sample collection
•
AE/SAE review
•
Concomitant medication review
Follow-up Visit 2 (24 weeks After Visit 1, ± 3 days) 
Follow-up Visit 2 procedures include: 
•
Targeted cardiopulmonary and skin physical examinations
•
Vital signs including weight
•
A serum or urine pregnancy test (where applicable)
•
Hematology (CBC)
•
Serum chemistry/FSH
•
RHC
•
6MWT
•
Borg Dyspnea Scale (pre- and post-6MWT)
•
WHO FC assessment
•
Clinical worsening assessment
•
QoL assessments
•
NT-proBNP sample collection
•
ADA sample collection
•
PK sample collection
•
ECHO
•
AE/SAE review
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•
Concomitant medication review
9.2.4. 
Long-Term Double-Blind Treatment Period (Visit 10 up to Visit 33)
The LTDB period can last up to approximately 72 weeks depending on enrollment duration for 
study participants and the time required for the last participant to complete the DBPC Treatment 
Period.  During this period, select study visits may be performed as HHC visits as described in 
Section 6.5. 
Once the last randomized participant completes the last visit in DBPC Treatment Period, the 
study will be unblinded and eligible participants can rollover to the LTFU study.  These 
participants will forgo the EOS visit to begin the LTFU study.  For these participants, Visit 1 of 
the LTFU study will take place 21 (± 7) days after the last dose administered in this study, which 
may coincide with this study’s EOT visit. 
Participants who discontinue during the LTDB Treatment Period for reasons other than clinical 
worsening will complete EOT and EOS visits as described in Section 9.2.6. 
Visits 10, 11, 12, 14, 15, 16, 18, 19, 20, 22, 23, 24, 26, 27, 28, 30, 31, and 32 (± 3 days) 
These visits may be performed as HHC visits for eligible participants.  The procedures include 
the following: 
•
Vital signs
•
A serum or urine pregnancy test (where applicable)
•
Study drug administration
•
AE/SAE review
•
Concomitant medication review
Visits 13, 21, and 29 (± 3 days) 
When possible, participants are required to be on-site for these visits.  Procedures/assessments 
include the following: 
•
Targeted cardiopulmonary and skin physical examinations
•
12-Lead ECG
•
Weight
•
Vital signs
•
A serum or urine pregnancy test (where applicable)
•
Hematology (CBC)
•
Serum chemistry/FSH
•
6MWT
•
Borg Dyspnea Scale (pre- and post-6MWT)
•
WHO FC assessment
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•
Clinical worsening assessment
•
NT-proBNP sample collection
•
ADA sample collection
•
PK sample collection
•
Study drug administration
•
AE/SAE review
•
Concomitant medication review
Visits 17, 25, and 33 (± 3 days) 
When possible, participants are required to be on-site for these visits.  Procedures/assessments 
include the following: 
•
Targeted cardiopulmonary and skin physical examinations
•
12-Lead ECG
•
Weight
•
Vital signs
•
A serum or urine pregnancy test (where applicable)
•
Hematology (CBC)
•
Serum chemistry/FSH
•
Urinalysis (dipstick)
•
6MWT
•
Borg Dyspnea Scale (pre- and post-6MWT)
•
WHO FC assessment
•
Clinical worsening assessment
•
NT-proBNP sample collection
•
ADA sample collection
•
PK sample collection
•
ECHO
•
Study drug administration
•
AE/SAE review
•
Concomitant medication review
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9.2.5. 
End of Treatment Visit (± 3 days) 
The EOT visit should occur 21 days (± 3 days) after the last study drug administration. 
Participants who discontinue early should complete the EOT visit at the time of discontinuation.  
Discontinuation of study drug administration can occur at any visit during the DBPC Treatment 
Period or the LTDB period.  Reasons for early discontinuation are described in Section 9.4.1.  
The procedures at the EOT visit include the following: 
•
Targeted cardiopulmonary and skin physical examinations
•
12-Lead ECG
•
Vital signs
•
A serum or urine pregnancy test (where applicable)
•
Hematology (CBC)
•
Serum chemistry/FSH
•
Urinalysis (dipstick)
•
6MWT
•
Borg Dyspnea Scale (pre- and post-6MWT)
•
WHO FC assessment
•
Clinical worsening assessment
•
QoL assessments
•
NT-proBNP sample collection
•
ADA sample collection
•
PK sample collection
•
ECHO
•
AE/SAE review
•
Concomitant medication review
9.2.6. 
End of Study (± 3 days)
The EOS visit will be completed by participants who do not wish to participate in the LTFU 
study and for participants who discontinue treatment early for reasons other than clinical 
worsening.  These participants should also complete their EOT visit assessments as described in 
Section 9.2.5 as long as consent is not withdrawn.  Details on EOS assessments are in Section 2. 
The procedures include the following: 
•
Targeted cardiopulmonary and skin physical examinations
•
6MWT
•
Borg Dyspnea Scale (pre- and post-6MWT)
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•
WHO FC assessment
•
Clinical worsening assessment
•
NT-proBNP sample collection
•
ADA sample collection
•
PK sample collection
•
AE/SAE review
•
Concomitant medication review
9.3. 
Description of Study Procedures 
9.3.1. 
Six-Minute Walk Test 
The 6MWD will be measured by the 6MWT during the Screening Period and at multiple 
timepoints throughout the study as per the SoE.  During Screening, the 6MWT is to be 
performed twice-at least 4 hours and no more than 1 week apart; the distances must be within 
15% of each other, based on the longer distance.  If the difference between the first and second 
tests is > 15%, the test may be repeated once more, provided that the repeat test is within 1 week 
of the previous test.  If the difference between the distances remains > 15%, the participant will 
be considered a screen failure. 
The 6MWT should be performed indoors, along a long, flat, straight, enclosed corridor with a 
hard surface that is seldom traveled.  The walking course should be 30 m in length (or at least 
15 m) and should be at the same location that is used for all study visits40,41.  The length of the 
corridor should be marked every 3 m.  The turnaround points should be marked (e.g., with a 
cone).  A starting line, which marks the beginning and end of each 60-m lap, should be marked 
on the floor (e.g., using brightly colored tape).  
The distance walked in 6 minutes (the 6MWD) will be calculated and recorded.  If the 
participant discontinues the test prematurely, the time (mm:ss) and distance walked will be 
recorded.  Requirement of acute supportive rescue medication (e.g., oxygen therapy) and any 
adverse events occurring during the 6MWT must be recorded.  If a participant is on chronic 
oxygen therapy, oxygen should be administered at their standard rate, or as directed by the 
investigator.  During the study, the 6MWT should be performed at approximately the same time 
of day to avoid diurnal variation.  The 6MWT should be performed under the same conditions at 
least between Screening and Visit 9, including chronic oxygen therapy, use of walking aids or 
face coverings (the latter as required by local regulations).  All 6MWTs performed from Visit 1 
onward can be performed at the study visit day or within 10 days prior to study drug 
administration.  Refer to Appendix 2 for additional details. 
For evaluation of clinical worsening as indicated by the 6MWT, a decrease of ≥ 15% in 6MWD 
at any timepoint, as compared to screening, must be confirmed by a second 6MWT performed at 
least 4 hours and no more than 1 week apart from the first. 
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9.3.2. 
Right Heart Catheterization 
Right heart catheterization will be performed according to the RHC manual and will assess 
several prognostic hemodynamic variables in addition to PVR, including right atrial pressure, 
mPAP, mean PCWP, mixed venous saturation of oxygen (SvO2), and cardiac output.  The 
following hemodynamic parameters will be assessed when the participant is in a stable 
hemodynamic rest state (as demonstrated by 3 consecutive cardiac output measurements within 
10% of each other) while the participant is breathing ambient air or oxygen: 
•
Right atrial pressure, mPAP, mean PCWP, systolic PAP, diastolic PAP, SvO2, and
heart rate (HR)
•
Cardiac output measured in triplicate by the thermodilution technique or by the Fick
method (the same method must be used for all RHC assessments for each participant)
The PVR will be calculated and populated in the eCRF.  Right ventricle pressure data from the 
RHC with simultaneously recorded ECG recordings may be collected and digitally stored at the 
clinical sites. 
In order to reduce invasive procedures for participants prior to confirming eligibility, RHC in the 
Screening Period should be performed last and after all screening tests are done for eligibility, 
when possible.  The RHC performed after screening may be performed on the day of study visit 
or within 1 week prior to study drug administration.  If other assessments are performed on the 
same day, RHC should be performed last, when possible. 
9.3.3. 
12-Lead Electrocardiogram
A single 12-lead ECG will be obtained at each study visit as outlined in the SoE (Section 2) and 
will be transferred to a central laboratory for reading and interpretations.  Parameters obtained 
will be HR, QRS, and QT:QTcF. 
•
Clinically significant abnormal findings will be reported as AEs
•
ECGs should be performed prior to 6MWT
9.3.4. 
Echocardiogram Parameters
Two-dimensional echocardiogram (2-D ECHO) parameters will include but not limited to 
tricuspid annular plane systolic excursion (TAPSE), PAP, right ventricular fractional area change 
(RVFAC), and right ventricular end diastolic area (RVEDA).  The ECHO performed during the 
Screening Period is used as the baseline for this study.  All ECHOs performed after screening 
can be performed on the day of study visit or within 1 week prior to study drug administration.  
The ECHO parameters review process will be performed by a central vendor, according to the 
study manual. 
9.3.5. 
Borg Dyspnea Scale (Borg CR10 Scale) 
The Borg Dyspnea Scale (Borg CR10 Scale) will be used pre- and post-6MWT. 
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9.3.6. 
World Health Organization Functional Class Assessment for Pulmonary 
Hypertension 
The WHO class system is used to provide information about how affected an individual is by 
their disease.  The 4 FCs that are used to rate how ill a PAH participant is are detailed in Table 4. 
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Table 4: 
World Health Organization Functional Class Assessment for Pulmonary 
Arterial Hypertensiona 
WHO Class 
Description 
Class I 
Patients with PAH but without resulting limitation of physical activity.  Ordinary physical 
activity does not cause undue dyspnea or fatigue, chest pain, or near syncope. 
Class II 
Patients with PAH resulting in a slight limitation of physical activity.  They are comfortable 
at rest.  Ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near 
syncope. 
Class III 
Patients with PAH resulting in marked limitation of physical activity.  They are comfortable 
at rest.  Less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near 
syncope. 
Class IV 
Patients with PAH with inability to carry out any physical activity without symptoms.  These 
patients manifest signs of right heart failure.  Dyspnea and/or fatigue may even be present at 
rest.  Any physical activity leads to increased discomfort. 
Abbreviations: PAH = pulmonary arterial hypertension; WHO = World Health Organization. 
a Modified after New York Heart Association (NYHA) functional assessment. 
9.3.7. 
N-Terminal pro-B-type Natriuretic Peptide
B-type natriuretic peptide (BNP) is a hormone produced by the heart.  NT-proBNP is a
non-active prohormone that is released from the same molecule that produces BNP.  Both BNP
and NT-proBNP are released in response to changes in pressure inside the heart.  NT-proBNP
levels are primarily used to help detect, support diagnosis, and, in some instances, evaluate the
severity of heart failure.  Samples for NT-proBNP analysis will be collected as described in the
SoE and will be shipped and analyzed by a central laboratory.
9.3.8. 
Patient-Reported Outcomes (QoL Assessments) 
9.3.8.1. 
EuroQol – 5 Dimension – 5 Level Assessment 
The EQ-5D-5L scale is a standardized measure of health status developed to provide a simple 
generic measure of health for clinical and economic appraisal.  EQ-5D-5L is designed for 
self-completion and, as such, captures information directly from the respondent, thereby 
generating data that conform to the general requirement of all PRO measures. 
The EQ-5D questionnaire has 2 components: health state description and evaluation. 
In the description part, health status is measured in terms of 5 dimensions (5D): mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression.  The “mobility” dimension 
asks about the person’s walking ability.  The “self-care” dimension asks about the ability to wash 
or dress by oneself, and “usual activities” dimension measures performance in “work, study, 
housework, family or leisure activities.”  The “pain/discomfort” dimension asks how much pain 
or discomfort an individual has, while the “anxiety/depression” dimension asks how anxious or 
depressed the individual is.  Respondents self-rate their level of severity for each dimension 
using the 5-level (EQ-5D-5L) scale. 
In the evaluation part, the respondents evaluate their overall health status using the visual 
analogue scale (EQ-VAS). 
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Participants will complete the EQ-5D-5L questionnaire prior to study drug administration during 
the study visits outlined in the SoE.  Refer to the study manual for more details. 
9.3.8.2. 
Pulmonary Arterial Hypertension – Symptoms and Impact 
PAH-SYMPACT® is a PRO instrument; the draft consists of 16 symptom and 25 impact items 
within 4 domains.  The PRO was developed based on interviews with patients with PAH 
following the process outlined in the FDA’s PRO guidance. 
Participants will complete the PAH-SYMPACT® questionnaire at home, once daily on the 7 days 
prior to the study visits outlined in the SoE.  Refer to the study manual for more details. 
9.3.9. 
Clinical Worsening Assessment 
Clinical worsening must be assessed by the investigator and recorded on the CRF. 
Clinical worsening must be assessed using the following criteria: 
•
Death
•
Worsening-related listing for lung and/or heart transplant
•
Need to initiate rescue therapy with an approved PAH therapy or the need to increase
the dose of infusion prostacyclin by 10% or more
•
Need for atrial septostomy
•
Hospitalization for worsening of PAH (≥ 24 hours)
•
Deterioration of PAH defined by both of the following events occurring at any time,
even if they began at different times, as compared to their baseline values:
−
Worsened WHO FC (II to III, III to IV, II to IV, etc.)
and
−
Decrease in 6MWD by ≥ 15% (confirmed by two 6MWTs at least 4 hours apart,
but no more than 1 week)
An independent blinded adjudication committee will adjudicate all clinical worsening events up 
to the end of the study, including death, to determine whether these events are due to PAH. 
All other clinically significant abnormal findings that do not meet the above criteria will be 
reported as AEs. 
9.3.10. 
Physical Examination 
•
A full physical examination will include, at a minimum, assessments of the
cardiovascular, respiratory, gastrointestinal, skin, and neurological systems.  A full
physical examination will be completed at the Screening Visit only.
•
A targeted physical examination will include, at a minimum, assessments of the
cardiovascular and pulmonary systems, as well as the skin, and will be completed at
all other visits after screening.
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•
Investigators should pay special attention to clinical signs related to previous serious
illnesses.
9.3.11. 
Vital Signs
Vitals signs to be collected before blood collection and study treatment administration include 
the following: 
9.3.12. 
•
Temperature, pulse rate (PR), respiratory rate, and BP will be assessed at every visit.
Height will be measured once during the Screening Period.  Weight will be measured
(in indoor clothing but without shoes) and recorded at each dosing visit during the
DBPC treatment period.  Weight will be measured on selected visits during the LTDB
treatment period.  Dose will be calculated based on the participant’s most recently
recorded weight.
•
Blood pressure and pulse measurements will be assessed while seated after a period of
rest in a quiet setting with no distractions (e.g., television, cell phones).  The same
method of collection (manual or automated) should be used throughout the study.
Manual techniques will be used only if an automated device is not available.
•
Clinically significant abnormal findings will be reported as AEs (Section 10.1).
Pharmacokinetics Measurements
Serum samples will be collected for measurement of serum concentrations of sotatercept as 
specified in the SoE (Section 2).  Samples may be collected at additional timepoints during the 
study if warranted and agreed upon between the investigator and Acceleron Pharma Inc.  
Instructions for the collection and handling of biological samples will be provided by the 
Acceleron Pharma Inc.  The actual date and time (24-hour clock time) of each sample will be 
recorded.  Samples will be used to evaluate the PK of sotatercept.  Samples collected for 
analyses of sotatercept serum concentration may also be used to evaluate the safety or efficacy 
aspects related to concerns arising during or after the study. 
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded.  Samples collected for analyses of 
sotatercept serum concentration may also be used to determine concentrations of concomitant 
medications in the background PAH therapy. 
9.3.13. 
Anti-Drug Antibody (ADA) Assessments 
The ADA samples will be collected as outlined in the SoE and will be analyzed by a central lab.  
Participants who have a new or higher titer-positive ADA result at their last visit may be asked to 
return for additional ADA testing approximately every 3 months until response is negative or 
titer is stable. 
9.3.14. 
Pharmacodynamics  
Venous blood samples will be collected for the measurement of PD biomarkers including 
N-terminal prohormone of brain natriuretic peptide (NT-proBNP) at timepoints listed in the SoE.
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Samples collected for NT-proBNP analyses will be used to evaluate the study drug safety and/or 
efficacy aspects during the study. 
9.3.15. 
Clinical Laboratory Tests 
The investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study in the AE section of the CRF. 
The laboratory reports must be filed with the source documents.  Clinically significant abnormal 
laboratory findings are those not associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
All laboratory tests with values considered clinically significantly and/or abnormal during 
participation in the study or within 6 weeks after the last dose of study treatment should be 
repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or medical monitor. 
If such values do not return to normal/baseline within a period of time judged reasonable by the 
investigator, the etiology should be identified, and Acceleron Pharma Inc. notified. 
All protocol-required laboratory assessments must be conducted in accordance with the SoE. 
Please refer to the SoE (Section 2) for the timing and frequency of clinical laboratory tests. 
9.3.16. 
Serum Chemistry/Follicle-Stimulating Hormone 
A central laboratory will be used for the analysis of all chemistry laboratory specimens collected. 
Blood samples for laboratory evaluations will be collected per the SoE table and should be 
drawn prior to dosing.  Blood urea, creatinine, total bilirubin, direct bilirubin, AST, ALT, 
alkaline phosphatase, sodium, potassium, chloride, calcium, phosphorus, glucose, magnesium, 
HCO3, albumin, and FSH will be measured.  Investigators must review the results to monitor the 
participant’s safety. 
9.3.17. 
Urinalysis (Dipstick) 
Urinalysis will be performed per the SoE using dipsticks provided to sites by the central 
laboratory to evaluate pH, specific gravity, protein, glucose, bilirubin, ketones, blood, 
leukocytes, urobilinogen, and nitrite. 
9.3.18. 
Pregnancy Testing 
Pregnancy testing (urine or serum) will be performed per the SoE for all females of childbearing 
potential prior to each dose administration.  See Appendix 3 for further information. 
9.3.19. 
Hematology 
Hematology (CBC) laboratory assessments will be collected and analyzed locally at the 
investigator sites and will be measured at the visits specified in the SoE.  Hematology (CBC) 
includes RBCs, absolute white blood cells, Hgb, Hct, and platelet count. 
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9.4. 
Discontinuation and Withdrawal Criteria 
9.4.1. 
Participants Early Discontinuation 
The reason for early discontinuation must be recorded in the corresponding participant’s eCRF.  
The investigator must notify Acceleron Pharma Inc. and medical monitor when a participant has 
discontinued treatment or has withdrawn from the study.  All participants who are discontinued 
from the study prior to the EOT visit should complete the assessments scheduled for the EOT 
visit at the time of discontinuation and will be asked to return to the clinic to complete the 
remaining follow-up EOS visit. 
Early discontinuation of study treatment refers to permanently stopping study drug 
administration before completing the DBPC or before the trial has been unblinded for 
participants to rollover into the LTFU study.  Reasons that may lead to discontinuation from the 
study drug include the following: 
•
AE: If a participant discontinues due to a drug-related serious adverse event (SAE) or
other medical reason(s), the participant should be followed at regular intervals until
the AE normalizes or the participant returns to their baseline condition, as per
Section 10.6.
•
Participant request (withdrawal of consent): If the participant withdraws from the
study and withdraws consent for disclosure of future information, no further
evaluations are to be performed and no additional data are to be collected and this
will be recorded as the EOS visit; Acceleron Pharma Inc. may retain and continue to
use any data collected before such withdrawal of consent.
•
Participant’s unwillingness or inability to comply with the protocol
•
A clinical worsening event that occurs prior to Visit 9 and is accompanied by
initiation of rescue therapy with an approved PAH therapy or the need to increase the
dose of infusion prostacyclin by 10% or more.
•
An increase in QTcF of > 60 ms that results in QTcF of > 500 ms (or > 550 ms if
right bundle branch abnormality is present) during the treatment period.
•
More than 3 dose delays required per dose adjustment guidelines (Section 8.3)
•
Pregnancy
•
Women of childbearing potential not using adequate combination of effective
contraception methods throughout the study
•
Men with a partner of childbearing potential not accepting to use contraceptive
methods throughout the study
•
Study terminated by Acceleron Pharma Inc.
•
Lost to follow-up
Participants who discontinue study treatment during the DBPC Treatment Period prior to Visit 5 
will be asked to return to complete limited study assessments (specified in the SOE, Section 2) at 
Follow-up Visit 1 and Follow-up Visit 2.  Participants who discontinue study treatment during 
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the DBPC Treatment Period after Visit 5 will be asked to return to complete limited study 
assessments (specified in the SOE, Section 2) at Follow-up Visit 2.  These participants will 
complete the relevant EOT visit assessments in addition to the EOS visit assessments described 
in Section 9.2.6.  Details on EOT and EOS assessments are in Section 2. 
Participants who discontinue study treatment during the LTDB Treatment Period will complete 
the EOT and EOS visits as specified in the SoE (Section 2). 
Participants who experience an event of clinical worsening prior to Visit 9 (during the DBPC 
treatment period) that is accompanied by the initiation of rescue therapy with an approved PAH 
therapy or the need to increase the dose of infusion prostacyclin by 10% or more will discontinue 
immediately.  These participants will complete the EOT visit at the time of discontinuation as 
specified in the SoE (Section 2).  They will be asked to return to complete the EOS visit, 
provided that consent is not withdrawn.  These participants will not be eligible to enroll in the 
LTFU study.  
Participants who experience a clinical worsening event prior to Visit 9 (during the DBPC 
treatment period) that does not meet the criteria for study treatment discontinuation (ie, is NOT 
accompanied by the initiation of rescue therapy with an approved PAH therapy or the need to 
increase the dose of infusion prostacyclin by 10% or more) will continue to receive study 
treatment and complete study visits up to Visit 9.  Thereafter, they will be eligible to roll over 
into the open-label LTFU study.  These participants will complete the EOT visit, which may 
coincide with the first dosing visit in the LTFU study. 
Participants who discontinue study treatment due to any clinical worsening event during the 
LTDB Treatment Period may roll over directly into the LTFU study after completing the EOT 
visit, which may coincide with the first dosing visit in the LTFU study. 
Acceleron Pharma Inc. may terminate the study after consultation with the investigator and the 
DMC at any time for safety or administrative reasons.  Acceleron Pharma Inc. will terminate the 
study if the occurrence of SAEs or other findings suggests unacceptable risk to the health of the 
participants. 
9.4.2. 
End of Study Definition 
A participant is considered to have completed the study if he/she has completed all phases of the 
study, including the EOT and/or EOS visits. 
The EOS visits are only required for participants who discontinue the study early or decline 
transition to a future sotatercept LTFU study.  The EOS is defined as when the last participant 
completes the last visit. 
9.5. 
Participants Lost to Follow-up 
A participant will be considered lost to follow-up if he/she stops attending scheduled visits and is 
unable to be contacted by the study site. 
The following actions must be taken if a participant stops attending study visits: 
•
The site must attempt to contact the participant and reschedule the missed visit as
soon as possible and counsel the participant on the importance of maintaining the
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assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study. 
•
Before a participant is deemed lost to follow-up, the investigator or designee must
make every effort to regain contact with the participant (where possible, 3 telephone
calls and, if necessary, a certified letter to the participant’s last known mailing
address or local equivalent methods).  Each attempt at contact must be documented in
the participant’s study record.
•
If the participant continues to be unreachable after the mentioned attempts, he/she
will be considered to have withdrawn from the study with a primary reason of lost to
follow-up, which should be noted on the participant’s eCRF.
9.6. 
Concomitant Medication and Therapy During Study Conduct 
During screening and throughout the study, participants may take stable doses of medications for 
chronic conditions.  If there is an immediate clinical need during the study to prescribe a new 
medication or a new dosage of an existing medication for either a new or worsening preexisting 
condition, concurrent therapy may be administered at the discretion of the investigator.  The 
investigator may consult the medical monitor regarding what constitutes a stable dose or a 
chronic condition.  Information regarding concomitant medications will be collected in the eCRF 
beginning after signing the ICF and will include all medications taken during Screening Period to 
EOS. 
9.7. 
Treatment Compliance 
Each dose of study treatment will be administered by SC injection(s) and must be documented in 
the study record.  Accurate recording of all study drug administration must be made in the 
appropriate section of the participant’s eCRF and source documents. 
Background PAH therapy compliance will be the responsibility of each participant and his/her 
treating physician.  The investigator should promote compliance by instructing the participant to 
take their background PAH therapy exactly as prescribed and by stating that compliance is 
necessary for the participant’s safety and the validity of the study.  The participant is expected to 
adhere to their background PAH therapy throughout the study and should be instructed to contact 
the investigator if he/she is unable for any reason to take their background PAH therapy as 
prescribed. 
9.8. 
Criteria for Study Termination 
Both Acceleron Pharma Inc. and the Principal Investigator reserve the right to terminate the 
study at any time.  Should this be necessary, Acceleron Pharma Inc. or a specified designee will 
inform the appropriate regulatory authorities of the termination of the study and the reasons for 
its termination, and the Principal Investigator will inform the Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) of the same.  In terminating the study, Acceleron 
Pharma Inc. and the Principal Investigator will assure that adequate consideration is given to the 
protection of the participants’ interests. 
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9.8.1. 
Study and Site Closure 
Acceleron Pharma Inc. or its designee reserves the right to close the study site or terminate the 
study at any time for any reason at the sole discretion of Acceleron Pharma Inc.  Study sites will 
be closed upon study completion.  A study site is considered closed when all required documents 
and study supplies have been collected and a study site closure visit has been performed. 
The investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by Acceleron Pharma Inc. or investigator may 
include but are not limited to the following: 
•
Failure of the investigator to comply with the protocol, the requirements of the
IRB/IEC or local health authorities, Acceleron Pharma Inc.’s procedures, or Good
Clinical Practice (GCP) guidelines
•
Inadequate recruitment of participants by the investigator
•
Discontinuation of further study treatment development
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10.
SAFETY ASSESSMENT, REPORTING, AND MONITORING
10.1. 
Adverse Events
10.1.1. 
Definitions of Adverse Event
An AE is any untoward medical occurrence in a clinical investigation participant 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 examination, 
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. 
10.1.1.1. Unexpected Adverse Events 
An unexpected AE is an event the nature, severity, or outcome of which is not consistent with 
the Reference Safety Information in the current IB. 
10.1.1.2. Events Not Considered as Adverse Events 
Preexisting medical conditions/signs/symptoms present 30 days prior to the initial study drug 
administration (Visit 1) 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 preexisting conditions, including the disease under study, that do not represent a 
clinically significant exacerbation or worsening need not be considered AEs. 
10.2. 
Serious Adverse Events 
10.2.1. 
Definition of Serious Adverse Events 
An SAE is any event that meets any of the following criteria: 
•
Results in death
•
Life threatening
•
Inpatient hospitalization or prolongation of existing hospitalization
•
Results in persistent or significant disability/incapacity
•
Congenital anomaly/birth defect
•
Other: Important medical events that may not result in death, be life threatening, or
require hospitalization may be considered an SAE when, based upon appropriate
medical judgment, they may jeopardize the participant and may require medical or
surgical intervention to prevent one of the outcomes listed in this definition
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10.2.2. 
Definition of Serious Adverse Event Terms 
Death: An AE that results in death. 
Life threatening: An AE in which the participant was at risk of death at the time of the event; it 
does not refer to an event that, hypothetically, might have caused death if it were more severe. 
Hospitalization: An AE that requires inpatient hospitalization or prolongation of existing 
hospitalization; however, a hospitalization for an elective procedure will not be considered an 
SAE. 
Hospitalization for planned surgery prior to signing the ICF or routine clinical procedures that 
are not the result of an AE are not to be considered SAEs.  If anything untoward is reported 
during the procedure, that occurrence must be reported as an AE, either “serious” or 
“nonserious” according to the usual criteria. 
In general, hospitalization signifies that the participant has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment that 
would not have been appropriate in the physician’s office or outpatient setting.  When in doubt 
as to whether “hospitalization” occurred or was necessary, the AE should be considered serious. 
Events not to be considered as SAEs are hospitalizations related to any of the following: 
•
A standard procedure for protocol therapy administration.  However, hospitalization
or prolonged hospitalization for a complication of therapy administration will be
reported as an SAE.
•
Routine treatment or monitoring of the studied indication not associated with any
deterioration in condition.
•
A procedure for protocol/disease-related investigations (e.g., surgery, scans,
endoscopy, sampling for laboratory tests, bone marrow sampling).  However,
hospitalization or prolonged hospitalization for a complication of such procedures
remains a reportable SAE.
•
Hospitalization or prolongation of hospitalization for technical, practical, or social
reasons, in absence of an AE.
•
An elective treatment of a preexisting condition unrelated to the studied indication.
•
Emergency outpatient treatment or observation that does not result in admission,
unless fulfilling other seriousness criteria above.
Disability/incapacitating: An AE is incapacitating or disabling if the experience results in a 
substantial and/or permanent disruption of the participant’s ability to carry out normal life 
functions. 
Congenital anomaly/birth defect: Congenital anomaly/birth defect in a child of a participant or 
its partner that was exposed to study drug prior to conception or during pregnancy. 
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 participant and may require medical or 
surgical intervention to prevent one of the outcomes listed in the definitions for SAEs.  Examples 
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of such medical events include 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. 
10.3. 
Assessment of Severity 
Investigators must evaluate the severity/intensity of AEs and SAEs.  If there is a change in 
severity of an AE, it must be recorded as a separate event. 
Mild: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.  Usually transient in nature and generally not 
interfering with normal activities. 
Moderate: 
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.); sufficiently 
discomforting to interfere with normal activities. 
Severe: 
Severe or medically significant but not immediately life threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; prevents 
normal activities limiting self-care activities of daily living (bathing, dressing and 
undressing, feeding self, using the toilet, taking medications, and not bedridden). 
The term “severe” is often used to describe the intensity of a specific event (as in mild, moderate, 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache).  This criterion is not the same as “serious,” which is 
based on participant/event outcome or action criteria associated with events that pose a threat to 
a participant’s life or functioning. 
10.4. 
Assessment of Causality 
The investigator must determine the relationship between the administration of study drug and 
the occurrence of an AE/SAE as “not suspected” or “suspected” as defined below.  Factors for 
the assessment of causal relationship include, but are not limited to, temporal relationship 
between the AE and the administration of study drug including PK properties of sotatercept, 
known side effects of study drug, medical history, concomitant therapy, course of the underlying 
disease, and pertinent study procedures.  Median time to reach maximum sotatercept (Tmax) 
ranged from 5 to 8 days since first dose.  After every 21-day dosing, sotatercept concentrations 
are expected to reach 95% steady state by Week 15 and tmax at steady state can occur relatively 
early in the first few days after dose. 
Not-suspected: Means a causal relationship of the AE to study drug administration is unlikely 
or remote, or other medications, therapeutic interventions, or underlying 
conditions provide a sufficient explanation for the observed event. 
Suspected: 
Means there is a reasonable possibility that the administration of study drug 
caused the AE.  “Reasonable possibility” means there is evidence to suggest a 
causal relationship between the study drug and the AE. 
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10.5. 
Documenting Adverse Events 
It is the responsibility of the investigator to document all AEs that occur during the study. 
Participants will be evaluated and questioned generally for AEs during the course of the study, 
starting at the signing of the informed consent.  Care will be taken not to introduce bias when 
detecting AEs and/or SAEs.  Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrences.  The investigator must report in detail all 
adverse signs and symptoms that are either volunteered by participants or observed during or 
following the course of investigational product administration on the appropriate CRF page.  All 
clearly related signs, symptoms, and abnormal results from diagnostic procedures should be 
recorded under 1 diagnosis.  All AEs and SAEs reported from the signing of the ICF to the EOS 
visit are to be reported and documented on the AE eCRF.  Any AE related to a protocol 
procedure should be marked as such on the eCRF.  
All AEs spontaneously reported by the participant 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 are considered AEs and must be recorded on the AE eCRF. 
It is important that each AE report includes a description of the event, duration (onset and 
resolution dates), severity, relationship with study drug, any other potential causal factors, any 
treatment given or other action taken (including dose modification or discontinuation of study 
drug), and outcome.  In addition, SAEs should be identified and the appropriate seriousness 
criteria should be documented. 
Specific guidance can be found in the eCRF Completion Guidelines provided by Acceleron 
Pharma Inc. or designee. 
For all SAEs, an SAE form must be completed with as much information as possible and 
submitted within the timeframe described in Section 10.6. 
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 participant was 
hospitalized, a summary from the investigator should be included as part of the participant 
medical file.  In all instances, the investigator should follow up with participants until the 
outcome of the SAE is known. 
10.6. 
Reporting 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 Acceleron Pharma Inc. via the 
contract research organization (CRO) by entry on the eCRF or, if not available, by telephone or 
email. 
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, 
email addresses, telephone, for SAE reporting are located on the SAE Report Form, and in the 
completion, instructions are 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 
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email.  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 Acceleron Pharma Inc. or designee may have on the (S)AE within the same timelines as 
described for initial reports.  This is necessary to permit a prompt assessment of the event by 
Acceleron Pharma Inc. and (as applicable) to allow Acceleron Pharma Inc. to meet regulatory 
timelines associated with expedited reporting obligations. 
Requests for follow-up will usually be made by the responsible clinical research associate, 
medical monitor, or an Acceleron Pharma Inc. pharmacovigilance representative who may 
contact the investigator directly to obtain clarification on a particularly critical event. 
For all SAEs, an SAE form must be completed with as much information as possible and 
submitted within the timeframe described in Section 10.6. 
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 participant was 
hospitalized, a summary from the investigator should be included as part of the participant 
medical file.  In all instances, the investigator should follow up with participants until the 
outcome of the SAE is known. 
10.6.1. 
Reporting Period and Monitoring of Participants with Adverse Events 
All AEs must be recorded in the eCRF from the signing of the ICF up until the EOS Visit.  All 
participants who took at least 1 dose of study drug, whether they completed the DBPC Treatment 
Period or not, should complete the EOS Visit unless they are transitioning into the LTFU Study, 
provided that consent is not withdrawn. 
All AEs will be followed until return to screening baseline, resolution, or clinical database lock. 
All SAEs will undergo active follow-up until resolved or the event becomes chronic or stable.  
Follow-up data for SAEs obtained after clinical database lock will be incorporated into the 
sotatercept safety database. 
10.6.2. 
Safety Reporting to Health Authorities, Independent Ethics Committees, 
Institutional Review Boards, and Investigators 
Acceleron Pharma Inc. 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 safety events involving his/her participants to the IEC that approved the study. 
In accordance with International Council for Harmonisation (ICH) GCP guidelines, Acceleron 
Pharma Inc. will inform the investigator of findings that could adversely affect the safety of 
participants, impact the conduct of the study, or alter the IEC’s approval/favorable opinion to 
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Acceleron Pharma Inc. will inform the investigator of AEs that are both serious and unexpected 
and are considered to be related to study drug (suspected unexpected serious adverse reactions 
[SUSARs]).  The investigator should place copies of these Safety Reports in the Investigator Site 
File, if applicable.  National regulations with regard to Safety Report notifications to 
investigators will be followed. 
When specifically required by regulations and guidelines, Acceleron Pharma Inc. will provide 
appropriate Safety Reports directly to the concerned lead IEC and will maintain records of these 
notifications.  When direct reporting by Acceleron Pharma Inc. is not clearly defined by national 
or 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, Acceleron 
Pharma Inc.’s responsibilities regarding the reporting of SAEs/SUSARs will be carried out in 
accordance with that Directive and with the related Detailed Guidances. 
10.7. 
Overdose 
An overdose is defined as the administration of a quantity of a medicinal product given per 
administration or cumulatively which is above the maximum recommended dose according to 
the authorized product information. 
Sotatercept dosing is weight-based.  Therefore, for the purpose of this trial, an overdose is 
defined as any dose that has exposures in excess of the monkey no-observed-adverse-event level 
dose of 1 mg/kg (see current IB), which was also the highest dose tested in the human volunteers 
study (A011-02) with resolvable AEs. 
Any instance of overdose (suspected or confirmed and irrespective of whether or not it involved 
sotatercept) as defined in the protocol, with or without an AE, must be communicated to 
Acceleron Pharma Inc. or a specified designee within 24 hours and be fully documented as an 
AE in the CRF. 
There is no antidote for sotatercept and it is not dialyzable from blood.  Therefore, in case of 
overdose, participants should be monitored/treated as per clinical practice based on symptoms of 
potential risks as described in the IB. 
10.8. 
Pregnancy 
The investigator will attempt to collect pregnancy information if a female participant or a male 
participant’s female partner becomes pregnant while the participant is participating in this study 
and up to 16 weeks (112 days) after last dose of study drug treatment.  The pregnancy 
information will be recorded on the appropriate form and must be submitted to Acceleron 
Pharma Inc. within 24 hours of learning of the pregnancy.  The participant or partner will be 
followed for the outcome of the pregnancy.  Information on the status of the mother and child 
will be forwarded to Acceleron Pharma Inc. or designee.  Generally, follow-up will be no longer 
than 6 to 8 weeks following the estimated delivery date.  Any premature termination of the 
pregnancy will be reported as an AE.  Abnormal pregnancy outcomes (e.g., spontaneous abortion 
[includes miscarriage and missed abortion], fetal death, stillbirth, congenital anomalies, ectopic 
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pregnancy, neonatal death) are considered SAEs.  Any neonatal death that occurs within 1 month 
of birth should be reported, without regard to causality, as an SAE.  Details of all pregnancies in 
female participants and female partners of male participants will be collected after the start of 
study treatment and until 16 weeks (112 days) after the last dose. 
If a pregnancy is reported, the investigator must inform Acceleron Pharma Inc. within 24 hours 
of learning of the pregnancy.  If pregnancy is reported, the participant will be discontinued from 
the study treatment. 
10.9. 
Monitoring of Identified Risks, Potential Risks, and Adverse Events 
of Special Interest 
The adverse events of special interest (AESIs) are considered important parameters to be 
monitored in order to assess the overall safety of the PAH population and therefore be added for 
safety monitoring in the sotatercept clinical trial.  For further information, consult the IB. 
Laboratory data and vital signs are monitored on an ongoing basis by the investigator and 
medical monitor in the study.  Laboratory data and AEs are measured as per study schedule or 
upon an unscheduled visit if applicable.  Details regarding dose modifications due to decreases in 
platelets, increases in Hgb, and events of moderate or severe telangiectasia are provided in 
Section 8.3. 
Additional reviews will be performed periodically as part of standard safety signal detection and 
medical monitoring.  Finally, an independent DMC will be convened to monitor the safety of the 
study participants.  An independent blinded adjudication committee will adjudicate clinical 
events up to the end of the study, including death, to determine whether these events are due to 
PAH. 
10.9.1. 
Adverse Events of Special Interest 
The monitoring of AESIs is detailed in Table 5. 
Based on review of safety data from the PULSAR study, and the adequacy of routine safety 
monitoring described above, hepatic toxicity, leukopenia, and neutropenia are no longer 
considered as AESIs and will be followed as events of medical interest in routine medical 
monitoring and signal detection activities.  Thrombocytopenia, suppression of FSH, and 
thromboembolic events, formerly designated as AESIs, are now considered as potential risks. 
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Table 5: 
Monitoring of Adverse Events of Special Interest 
Description 
Monitoring Parameters 
Telangiectasia 
Any investigator who reports a patient with an AE of telangiectasia 
(spider veins, spider naevi) must complete a customized page in the 
eCRF 
Abbreviations: AE = adverse event; eCRF = electronic case report form. 
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11.
STATISTICAL ANALYSES
11.1. 
Overview
This is a Phase 3, randomized, double-blind, placebo-controlled, multicenter, parallel-group 
study to determine the efficacy and safety of sotatercept versus placebo. 
Planned statistical analyses to be conducted are outlined in the sections that follow.  Additional 
detail will be described in the statistical analysis plan (SAP) and will include but not necessarily 
be limited to the analysis populations to be used in the analyses as well as additional details of 
procedures for accounting for missing data as needed.  Modifications and/or clarifications to 
protocol-specified statistical analyses as well as any other additional statistical analyses will be 
added to the SAP.  The SAP will be developed and finalized before the study is unblinded and 
the database is locked. 
11.2. 
Sample Size Determination 
Sample size determination is based on the primary efficacy endpoint and the secondary endpoint 
of improvement in WHO FC (see Section 5.2).  Assumptions for the desired treatment effect and 
estimate of variability (6MWD endpoint) are based on data from the PULSAR study (Phase 2, 
NCT03496207) and from a published clinical trial in PAH participants. 
For 6MWD, assuming a 1:1 randomization, a 2-sided 0.05 type I error rate, a 25-m improvement 
in sotatercept treatment compared to placebo, a common standard deviation (SD) of 50 m, and 
121 participants per arm, the statistical power is approximately 96% under the Wilcoxon 
rank-sum test using N-Query®. 
For the secondary endpoint, “proportion of participants who improve in WHO FC at Week 24,” 
assuming the proportion of participants treated with placebo and sotatercept is 0.11 and 0.25, 
respectively, 1:1 randomization, a 2-sided 0.05 type I error rate, and 121 participants per arm, the 
statistical power is approximately 80% based on the 2-sample chi-square test. 
Assuming a 15% dropout rate, the total sample size will be n = 284 (n = 142 participants per 
arm) (see Section 5.2). 
11.3. 
Populations for Analysis 
The populations to be used for statistical analyses are listed below. 
•
Full Analysis Set (FAS): All participants will be analyzed according to the treatment
arm to which the participant is randomized.
•
Safety Set: All participants who receive at least 1 dose of study treatment.  All
participants will be analyzed according to the treatment they actually received.
•
Per-Protocol Set (PPS): All participants randomized who receive at least 1 dose of
study treatment with no data or study procedural-related issues that would otherwise
impact the interpretation of the efficacy data.
•
Pharmacokinetic Population: All participants who receive at least 1 dose of study
drug and have sufficient PK samples collected and assayed for PK analysis.
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11.4. 
Statistical Methods 
The SAP will be developed and finalized before database lock and will describe the populations 
to be used in the analyses, and additional details of procedures for accounting for missing, 
unused, and spurious data as needed.  In general, analysis of covariance (ANCOVA) or the 
stratified Wilcoxon test will be used for continuous variables; Cochran-Mantel-Haenszel test will 
be used for dichotomous variables; log-rank test and Kaplan-Meier method will be used for time 
to event variables.  Statistical analyses of efficacy data will be performed on the FAS and PPS.  
Analyses with the FAS will be considered primary for reporting purposes. 
11.5. 
Study Endpoints 
11.5.1. 
Primary Endpoint 
The change in 6MWD at Week 24 from baseline will be analyzed using the stratified Wilcoxon 
test with the randomization factors as strata.  The Hodges-Lehmann location-shift estimate of the 
treatment group difference with 95% CI will be provided. 
11.5.1.1. Handling of Missing Data 
For the analysis of change in 6MWD at Week 24 from baseline, the following primary method 
will be used in the event that a participant’s Week 24 assessment is missing: 
For participants who missed the 6MWT at Week 24 for reasons other than death or a clinical 
worsening event (other than death), a standard multiple imputation method will be used to 
impute missing data.  For participants who die, the worst-rank score will be used to impute the 
missing data.  For participants who experience a clinical worsening event (other than death), the 
next worst-rank score will be used to impute the missing data.42 
The following additional sensitivity analyses will be performed: 
a.
Use the same standard multiple imputation method as described above for
participants who missed the 6MWT at Week 24 for reasons other than death or a
clinical worsening event (other than death) for missing data.  For participants who
missed the 6MWT at Week 24 due to death, the worst-rank score will be used to
impute the missing data under the untied worst-rank score approach with the
participant's baseline 6MWD being used to break ties for deaths.42  In this case,
participants who die will be considered to have a 6MWD at Week 24 of -2000 meters.
Ties will be broken by subtracting the individual participant's baseline 6MWD value
from the imputed Week 24 6MWD value.  In this case, participants with higher
baseline 6MWD values will have larger negative imputed Week 24 changes from
baseline resulting in lower ranks among those who die.  For participants who missed
the 6MWT at Week 24 due to a clinical worsening event (other than death), the
participant will be considered to have a 6MWD at Week 24 of -1000 meters.  Ties
will be broken by subtracting the individual participant's baseline 6MWD from the
imputed Week 24 6MWD value.  In this case, participants with higher baseline
6MWD values will have larger negative imputed Week 24 changes from baseline
resulting in lower ranks among those who experience a clinical worsening event
(other than death).
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b. Use the same standard multiple imputation method as described above for
participants who missed the 6MWT at Week 24 for reasons other than death or a
clinical worsening event (other than death) for missing data.  For participants who
missed the 6MWT at Week 24 due to death or a clinical worsening event (other than
death), the worst rank score will be used to impute the missing data under the tied
worst rank score approach42.  In this case, participants who die or experience a
clinical worsening event (other than death) will receive the same worst rank value.
c.
Use the same standard multiple imputation method as described above for
participants who missed the 6MWT at Week 24 for reasons other than death or a
clinical worsening event (other than death) for missing data.  For participants who
missed the 6MWT at Week 24 due to death or a clinical worsening event (other than
death), the worst rank score will be used to impute the missing data.  In this case,
participants will be considered to have a 6MWD at Week 24 of -2000 meters.  Ties
will be broken by subtracting the individual participant's baseline 6MWD from the
imputed Week 24 6MWD value.  Participants with higher baseline 6MWD values
will have larger negative imputed Week 24 changes from baseline resulting in lower
ranks among those who die or have a clinical worsening event (other than death).
d. The primary analysis described in Section 11.5.1 will be repeated with participants
who have non-missing change in 6MWD at Week 24 from baseline data.
e.
An ANCOVA model with randomization factors and baseline 6MWD as covariates.
The least squares mean of the treatment effect with corresponding 95% CI will be
provided.  The least squares mean and standard error of the mean (SEM) for each
treatment arm will also be provided.  Standard multiple imputation will be used for
participants who missed the 6MWT at Week 24 for reasons other than death or a
clinical worsening event (other than death) for missing data.  For participants who
missed the 6MWT at Week 24 due to death or a clinical worsening event, the worst
change from baseline will be used to impute the missing data.
f.
A tipping point analysis will be performed in the event that the p-value for the
treatment effect is highly significant at a 2-sided 0.05 significance level.
Additional sensitivity analyses may be performed.  These will be described in the SAP. 
11.5.2. 
Secondary Endpoints 
There are 8 secondary endpoints ranked as below: 
1. Multicomponent improvement endpoint measured by the proportion of participants
achieving all of the following at Week 24 relative to baseline:
•
Improvement in 6MWD (increase ≥ 30 m)
•
Improvement in NT-proBNP (decrease in NT-proBNP ≥ 30%) or
maintenance/achievement of NT-proBNP level < 300 ng/L
•
Improvement in WHO FC or maintenance of WHO FC II
2. Change from baseline in PVR at Week 24
3. Change from baseline in NT-proBNP levels at Week 24
4. Proportion of participants who improve in WHO FC at Week 24 from baseline
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5. Time to the first occurrence of any of the following clinical worsening events or death
(TTCW):
•
Worsening-related listing for lung and/or heart transplant
•
Need to initiate rescue therapy with an approved background PAH therapy or the
need to increase the dose of infusion prostacyclin by 10% or more
•
Need for atrial septostomy
•
PAH-specific hospitalization (≥ 24 hours)
•
Deterioration of PAH defined by both of the following events occurring at any time,
even if they began at different times, as compared to their baseline values:
−
Worsened WHO FC
−
Decrease in 6MWD by ≥ 15% confirmed by 2 tests at least 4 hours apart, but no
more than 1 week apart
6. Proportion of participants who achieve a low-risk score (Section 5.3.6) at Week 24 using
the simplified French Risk score calculator
7. Change from baseline in the Physical Impacts domain score of PAH-SYMPACT® at
Week 24
8. Change from baseline in the Cardiopulmonary Symptoms domain score of
PAH-SYMPACT® at Week 24
9. Change from baseline in the Cognitive/Emotional Impacts domain score of
PAH-SYMPACT® at Week 24
The multicomponent improvement endpoint will be analyzed using Cochran-Mantel-Haenszel 
test, stratified by the randomization factors. 
The change from baseline in PVR and NT-proBNP at Week 24 will be analyzed using an 
ANCOVA model with randomization factors and baseline values as covariates. 
The proportion of participants who improve in WHO FC at Week 24 from baseline will be 
analyzed using the Cochran-Mantel-Haenszel test, stratified by the randomization factors. 
Time to first clinical worsening event or death will be analyzed using the log-rank test with 
randomization factors as strata.  In addition, Kaplan-Meier curves will be generated for each arm 
with randomization factors as strata. 
The proportion of participants who maintain or achieve a low-risk score (Section 5.3.6) using the 
simplified French Risk score calculator at Week 24 versus baseline will be analyzed using the 
Cochran-Mantel-Haenszel test stratified by the randomization factors. 
The change from baseline in the Physical Impacts domain score of PAH-SYMPACT® at Week 
24 will be analyzed using an ANCOVA model with randomization factors and baseline value as 
covariates. 
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The change from baseline in the Cardiopulmonary Symptoms domain score of 
PAH-SYMPACT® at Week 24 will be analyzed using an ANCOVA model with randomization 
factors and baseline value as covariates. 
The change from baseline in the Cognitive/Emotional Impacts domain score of 
PAH-SYMPACT® at Week 24 will be analyzed using an ANCOVA model with randomization 
factors and baseline value as covariates. 
A gatekeeping method will be used to control the Type I error rate in secondary endpoints by 
testing in the order of the secondary endpoints listed above, after successful testing for the 
primary endpoint.  Secondary endpoint testing will be performed using a 2-sided alpha = 0.05 
level by proceeding successively in the order of the secondary endpoints listed above only after 
each of the preceding endpoints is tested to be statistically significant. 
The handling of missing data for missing secondary endpoints will be described in the SAP. 
11.5.3. 
Exploratory Endpoints 
Other endpoints of interest are the following: 
•
Change in ECHO parameters at Week 24 versus baseline
•
Change in dyspnea score (assessed by Borg CR10 scale) at Week 24 versus baseline
•
Proportion of participants that achieve PVR < 3 WU at Weeks 24 and 48
•
Proportion of participants that achieve mPAP < 25 mmHg at Week 24
•
Change from baseline in mPAP at Week 24
•
Change from baseline in the Cardiovascular Symptoms domain score of PAH-
SYMPACT® at Week 24
•
Change from baseline in the EQ-5D-5L index score at Week 24
•
Change from baseline in the EQ-5D-5L VAS at Week 24
They will be analyzed using appropriate statistical methods as mentioned in Section 11.4.  The 
SAP will provide more details. 
11.6. 
Analysis of Safety 
All safety analyses will be performed on the Safety Set. 
Adverse events will be coded using MedDRA.  Adverse event listings will include the verbatim 
term and the MedDRA preferred term.  Treatment-emergent adverse events are defined as an AE 
that starts after the first administration of study drug up to 8 weeks after the last dose and 
summarized by worst severity grade, system organ class, and preferred term.  
Treatment-emergent adverse events leading to death or discontinuation from treatment, TEAEs 
related to investigational product, and serious TEAEs will be summarized separately. 
Clinical laboratory results will be summarized descriptively by treatment arm.  Clinically 
significant laboratory abnormalities will be listed and summarized by treatment arm.  Chemistry 
and hematology laboratory tests will be collected regularly and reviewed periodically. 
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Descriptive statistics (mean, SD, SEM, median, min, max) will be provided for each timepoint of 
the collection by treatment arm for each timepoint analyzed. 
Vital sign measurements will be listed for each participant at each visit.  Descriptive statistics for 
vital signs, both observed values and changes from baseline, will be summarized by treatment 
group. 
Immunogenicity (incidence/titer of ADA) will also be analyzed. 
11.7. 
Pharmacokinetic Analysis 
Population PK analysis will be performed using nonlinear mixed effect modeling.  Concentration 
data obtained from this study and other studies will be combined to develop a population PK 
model that describes the PK exposure data and the associated variability.  Participant-specific 
factors (demographics, baseline characteristics, markers for organ function, ADAs against 
sotatercept, etc.) will be explored as covariates for their potential to influence sotatercept PK 
parameters.  Empiric individual Bayesian estimates of PK parameters will be generated, and 
using the final population PK model, appropriate measures of sotatercept exposure (area under 
the curve [AUC], maximum plasma concentration [Cmax], or other exposure metrics of interest) 
will be computed for each participant.  The relationship between serum sotatercept exposure and 
the primary efficacy endpoint, AEs of interest, or other selected secondary endpoints will be 
explored as appropriate. 
Full details will be included in a separate PK/PD Data Analysis Plan. 
11.8. 
Interim Analysis 
No interim analyses are planned. 
11.9. 
Subgroup Analysis 
Appropriate subgroup analyses by randomization factors and other baseline characteristics for 
clinical activity may be conducted as exploratory analyses.  Full details will be included in the 
SAP. 
11.10. 
Critical-Event Adjudication Committee and Data Monitoring 
Committee  
An independent blinded critical-event external adjudication committee will adjudicate all clinical 
worsening events up to the end of the study, including death, to determine whether these are due 
to PAH.  An external, independent Data Monitoring Committee (DMC) will review unblinded 
safety data after at least 15 participants have been enrolled and have completed Visit 2, and at 
approximately 3-month intervals thereafter.  A detailed charter will outline all activities of the 
DMC (including, but not limited to, DMC responsibilities, frequency of meetings, and type of 
data to be reviewed). 
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12. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
12.1. 
Study Monitoring 
Acceleron Pharma Inc. personnel (or designee) will monitor each site throughout the study at 
predetermined intervals to check for study progress, to identify any problems, and to ensure 
compliance with the protocol, GCP, and other regulations. 
Source document verification will be performed against entries on the eCRFs according to the 
study monitoring plan (see Section 14.1 for additional details on source documentation). 
12.2. 
Audits and Inspections 
Acceleron Pharma Inc., the CRO, and/or the IRB may audit the investigator’s records both 
during and after the study.  The purpose of the audit is to ensure that ethics, regulatory, and 
quality requirements are fulfilled in all studies performed by the Acceleron Pharma Inc. See 
Section 14.2 for additional information about audits and inspections. 
 
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13.
ETHICS AND RESPONSIBILITIES
13.1. 
Good Clinical Practice
This study will be conducted in accordance with the standard of ICH GCP, an international 
ethical and scientific quality standard for designing, conducting, recording, and reporting studies 
that involve human patients.  All applicable country and local regulations will also be observed.  
Compliance with these standards provides assurance that the rights, safety, and well-being of 
study patients are protected, consistent with the principles in the Declaration of Helsinki, and that 
the clinical study data are credible. 
13.2. 
Regulatory and Ethical Considerations 
The following regulatory and ethical considerations will be applied: 
•
This study will be conducted in accordance with the protocol and with the following:
−
Consensus ethical principles derived from international guidelines including the
Declaration of Helsinki and Council for International Organizations of Medical
Sciences International Ethical Guidelines
−
ICH GCP guidance and regulations
−
Applicable laws and regulations
•
The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g.,
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed
and approved by the IRB/IEC before the study is initiated.
•
Any amendments to the protocol will require IRB/IEC approval before
implementation of changes made to the study design, except for changes necessary to
eliminate an immediate hazard to study participants.
•
The investigator will be responsible for the following:
−
Providing written summaries of the status of the study to the IRB/IEC annually or
more frequently in accordance with the requirements, policies, and procedures
established by the IRB/IEC
−
Notifying the IRB/IEC of SAEs or other significant safety findings as required by
IRB/IEC procedures
−
Providing oversight of the conduct of the study at the site and adherence to
requirements of 21 Code of Federal Regulations Part 312, ICH guidelines,
IRB/IEC, European Regulation 536/2014 for clinical studies (when applicable),
European Union Clinical Trials Directive 2001/20/EC (when applicable), and all
other applicable local regulations
13.3. 
Institutional Review Board/Independent Ethics Committee 
It is the responsibility of the investigator to ensure that the appropriate IRB/IEC has reviewed 
and approved this protocol prior to initiating the study.  The investigator must provide Acceleron 
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Pharma Inc. or Acceleron Pharma Inc.’s representative with current and revised IRB/IEC 
membership rosters that include the members’ occupations and qualifications.  Sites within the 
US may provide a copy of the US Department of Health and Human Services Assurance 
Number. 
The IRB/IEC must also review and approve the clinical site’s ICF, other written information 
provided to the participant, and all advertisements that may be used for study recruitment.  The 
investigator will provide the study monitor with copies of these documents and of dated IRB/IEC 
approval(s) prior to the start of the study. 
If the protocol or the ICF is amended during the study, the investigator is responsible for 
ensuring that the IRB/IEC has reviewed and approved these amended documents.  Approval of 
the amended documents must be obtained from the IRB/IEC before implementation and before 
new participants are consented to participate in the study using the amended version of the ICF. 
The investigator must provide Acceleron Pharma Inc. with the dated IRB/IEC approval of the 
amended documents as soon as available. 
13.4. 
Informed Consent 
Prior to study entry, the investigator or designee will explain the nature, purpose, benefits, and 
risks of participation in the study to each participant, participant’s legally acceptable 
representative, or impartial witness.  Participants must be informed that their participation is 
voluntary.  Written and signed informed consent must be obtained prior to the participant 
entering the study (before initiation of any study-related screening procedure).  Sufficient time 
will be allowed to discuss any questions raised by the participant.  The ICF, which will contain 
all US federally required elements, all ICH-required elements, and Health Insurance Portability 
and Accountability Act authorization information in a language that is understandable to the 
participant, must be signed by all participants.  The authorized person obtaining the informed 
consent must also sign and date the ICF.  A copy of the ICF(s) must be provided to the 
participant or the participant’s legally authorized representative, and such action must be 
documented according to local requirements.  The process of obtaining consent will be in 
compliance with all applicable local and country regulations and ICH requirements. 
If the ICF is amended during the study, the investigator must follow all applicable regulatory 
requirements pertaining to IRB/IEC approval of the amended form.  The clinical site must use 
the amended ICF for all new participants and must reconsent any ongoing participants with the 
amended ICF, if instructed to do so by the IRB/IEC. 
The consent and reconsent process must be properly documented in the source documentation.  
The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study as well as the time and date the written consent was 
obtained. 
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14.
DATA HANDLING AND RECORD KEEPING
14.1. 
Source Documentation 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected.  Source documents are filed at the investigator’s site. 
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained.  The 
investigator may need to request previous medical records or transfer records, depending on the 
study.  Also, current medical records must be available for source data verification. 
14.2. 
Data Quality Assurance 
The following data quality assurance considerations will be applied: 
•
All participant data relating to the study will be recorded on an eCRF unless
transmitted to Acceleron Pharma Inc. or designee electronically (e.g., laboratory
data).  The investigator is responsible for verifying that data entries are accurate and
correct by electronically signing the eCRF.
•
The investigator must maintain accurate documentation (source data) that supports
the information entered in the eCRF.
•
The investigator must permit study-related monitoring, audits, IRB/IEC review, and
regulatory agency inspections and provide direct access to source data documents.
•
Acceleron Pharma Inc. or designee is responsible for the data management of this
study including quality checking of the data.
•
Study monitors will perform ongoing source data verification as indicated to confirm
that data entered into the eCRF by authorized site personnel are accurate, complete,
and verifiable from source documents; that the safety and rights of participants are
being protected; and that the study is being conducted in accordance with the
currently approved protocol and any other study agreements, ICH GCP, and all
applicable regulatory requirements.
•
Records and documents, including signed ICFs, pertaining to the conduct of this
study must be retained by the investigator for 2 years after the last marketing
application approval or 2 years after formal discontinuation of the clinical
development of the investigational product, unless local regulations or institutional
policies require a longer retention period.  No records may be destroyed during the
retention period without the written approval of Acceleron Pharma Inc.  No records
may be transferred to another location or party without written notification to
Acceleron Pharma Inc.
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15.
STUDY REPORT AND PUBLICATIONS
Acceleron Pharma Inc. is responsible for preparing and providing the appropriate regulatory 
authorities with clinical study reports according to the applicable regulatory requirements. 
The publication policy of Acceleron Pharma Inc. is discussed in the investigator’s Clinical 
Research Agreement. 
All information concerning sotatercept is considered confidential and shall remain the sole 
property of Acceleron Pharma Inc.  The investigator agrees to use this information only in 
conducting the study and shall not use it for any other purposes without the written approval of 
Acceleron Pharma Inc.  The investigator agrees not to disclose 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 that the information developed from this clinical study will be 
used by Acceleron Pharma Inc. in connection with the development of sotatercept, 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 
Acceleron Pharma Inc. 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 Acceleron Pharma Inc. and the investigator. 
Acceleron Pharma Inc. will comply with the requirements for publication of study results.  In 
accordance with standard editorial and ethical practice, Acceleron Pharma Inc. will generally 
support the publication of multicenter studies only in their entirety and not as individual site data. 
In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
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16.
CONFIDENTIALITY
All information generated in this study is considered highly confidential and must not be 
disclosed to any person or entity not directly involved with the study unless prior written consent 
is gained from Acceleron Pharma Inc.  However, authorized regulatory officials, IRB/IEC 
personnel, Acceleron Pharma Inc., and its authorized representatives are allowed full access to 
the study records. 
Identification of participants and CRFs shall be by initials and screening and treatment numbers 
only.  If required, the participant’s full name may be made known to an authorized regulatory 
agency or other authorized official. 
16.1. 
Data Protection 
The following data protection considerations will be applied: 
•
Participants will be assigned a unique identifier by Acceleron Pharma Inc.  Any
participant records or datasets that are transferred to Acceleron Pharma Inc. will
contain the identifier only; participant names or any information that would make the
participant identifiable will not be transferred.
•
The participant must be informed that his/her personal study-related data will be used
by Acceleron Pharma Inc. in accordance with local data protection law.  The level of
disclosure must also be explained to the participant.
•
The participant must be informed that his/her medical records may be examined by
Clinical Quality Assurance auditors or other authorized personnel appointed by
Acceleron Pharma Inc., by appropriate IRB/IEC members, and by inspectors from
regulatory authorities.
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17.
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Abdulkadyrov KM, Salogub GN, Khuazheva NK, et al. Sotatercept in patients with
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Komrokji R, Garcia-Manero G, Ades L, et al. Sotatercept with long-term extension for
the treatment of anaemia in patients with lower-risk myelodysplastic syndromes: a phase
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Cappellini MD, Porter J, Origa R, et al. Sotatercept, a novel transforming growth factor
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Coyne DW, Singh HN, Smith WT, et al. Sotatercept Safety and Effects on Hemoglobin,
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Sherman ML, Borgstein NG, Mook L, et al. Multiple-dose, safety, pharmacokinetic, and
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Yung LM, Pearsall S, Bocobo G, Sako D, Dinter T, Kumar R, Yu Paul. ACTRIIA-Fc
rebalances BMP and activin/TGF-beta signaling to attenuate experimental pulmonary
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L-M Y, P Y, Bocobo G ea. Abstract A7399: ACTRIIA-Fc rebalances BMP and
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Badesch D. Sotatercept for the Treatment of Pulmonary Arterial Hypertension. ATS 2020
Virtual American Thoracic Society International Conference; 5 August-10 November,
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Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in
pulmonary arterial hypertension. N Engl J Med 2013;369(9):809-18. DOI:
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Galie N, Barbera JA, Frost AE, et al. Initial Use of Ambrisentan plus Tadalafil in
Pulmonary Arterial Hypertension. N Engl J Med 2015;373(9):834-44. DOI:
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Sitbon O, Channick R, Chin KM, et al. Selexipag for the Treatment of Pulmonary
Arterial Hypertension. N Engl J Med 2015;373(26):2522-33. DOI:
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Tapson VF SDC, Bohns Meyer GM, et al. . Treatment with oral treprostinil delays time
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Galie N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and
treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and
Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and
the European Respiratory Society (ERS): Endorsed by: Association for European
Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung
Transplantation (ISHLT). Eur Heart J 2016;37(1):67-119. DOI:
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Boucly A, Weatherald J, Savale L, et al. Risk assessment, prognosis and guideline
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Hoeper MM, Kramer T, Pan Z, et al. Mortality in pulmonary arterial hypertension:
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26.
Benza RL, Gomberg-Maitland M, Elliott CG, et al. Predicting Survival in Patients With
Pulmonary Arterial Hypertension: The REVEAL Risk Score Calculator 2.0 and
Comparison With ESC/ERS-Based Risk Assessment Strategies. Chest 2019;156(2):323-
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Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous
epoprostenol (prostacyclin) with conventional therapy for primary pulmonary
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Mathai SC, Puhan MA, Lam D, Wise RA. The minimal important difference in the 6-
minute walk test for patients with pulmonary arterial hypertension. Am J Respir Crit Care
Med 2012;186(5):428-33. (In eng). DOI: 10.1164/rccm.201203-0480OC.
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Tiede H, Sommer N, Milger K, et al. Short-term improvement in pulmonary
hemodynamics is strongly predictive of long-term survival in patients with pulmonary
arterial hypertension. Pulm Circ 2013;3(3):523-32. DOI: 10.1086/674338.
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Souza R, Jardim C, Julio Cesar Fernandes C, Silveira Lapa M, Rabelo R, Humbert M.
NT-proBNP as a tool to stratify disease severity in pulmonary arterial hypertension.
Respir Med 2007;101(1):69-75. DOI: 10.1016/j.rmed.2006.04.014.
31.
souza Rb, HB. Humbert, M. Short-term improvement in pulmonary hemodynamics is
strongly predictive of long-term survival in patients with pulmonary arterial
hypertension. Eur Respir J 2005;25:509-513.
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Galie N, Jansa P, Pulido T, et al. SERAPHIN haemodynamic substudy: the effect of the
dual endothelin receptor antagonist macitentan on haemodynamic parameters and NT-
proBNP levels and their association with disease progression in patients with pulmonary
arterial hypertension. Eur Heart J 2017;38(15):1147-1155. DOI:
10.1093/eurheartj/ehx025.
33.
Chin KM, Rubin LJ, Channick R, et al. Association of N-Terminal Pro Brain Natriuretic
Peptide and Long-Term Outcome in Patients With Pulmonary Arterial Hypertension.
Circulation 2019;139(21):2440-2450. DOI: 10.1161/CIRCULATIONAHA.118.039360.
34.
Taichman DB, McGoon MD, Harhay MO, et al. Wide variation in clinicians' assessment
of New York Heart Association/World Health Organization functional class in patients
with pulmonary arterial hypertension. Mayo Clin Proc 2009;84(7):586-92. DOI:
10.1016/S0025-6196(11)60747-7.
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35.
Sitbon O, Humbert M, Nunes H, et al. Long-term intravenous epoprostenol infusion in
primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol
2002;40(4):780-8. DOI: 10.1016/s0735-1097(02)02012-0.
36.
Nickel N, Golpon H, Greer M, et al. The prognostic impact of follow-up assessments in
patients with idiopathic pulmonary arterial hypertension. Eur Respir J 2012;39(3):589-96.
DOI: 10.1183/09031936.00092311.
37.
Barst RJ, Chung L, Zamanian RT, Turner M, McGoon MD. Functional class
improvement and 3-year survival outcomes in patients with pulmonary arterial
hypertension in the REVEAL Registry. Chest 2013;144(1):160-168. DOI:
10.1378/chest.12-2417.
38.
Benza RL, Miller DP, Gomberg-Maitland M, et al. Predicting survival in pulmonary
arterial hypertension: insights from the Registry to Evaluate Early and Long-Term
Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation
2010;122(2):164-72. DOI: 10.1161/CIRCULATIONAHA.109.898122.
39.
Galie N, Simonneau G, Barst RJ, Badesch D, Rubin L. Clinical worsening in trials of
pulmonary arterial hypertension: results and implications. Curr Opin Pulm Med 2010;16
Suppl 1:S11-9. DOI: 10.1097/01.mcp.0000370206.61003.7e.
40.
Singh S, Puhan, MA, Andrianopoulos, V. An official systematic review of theEuropean
Respiratory Society/AmericanThoracic Society: measurement propertiesof field walking
tests in chronicrespiratory disease. Eur Respir J 2014;44:1447-1478.
41.
A. T. S. Committee on Proficiency Standards for Clinical Pulmonary Function
Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit
Care Med 2002;166(1):111-7. DOI: 10.1164/ajrccm.166.1.at1102.
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Lachin J. Worst-rank score analysis with informatively missing observations in clinical
trials. Controlled Clin Trials 1999;20:408-422.
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18.
APPENDICES
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APPENDIX 1. ABBREVIATIONS AND SPECIALIST TERMS 
6MWD 
6-Minute Walk Distance 
6MWT 
6-Minute Walk Test 
ADA 
Anti-drug antibody 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BP 
Blood pressure 
CBC 
Complete blood cell (count) 
CI 
Confidence interval 
Cmax 
Maximum plasma concentration 
(e)CRF 
(Electronic) case report form 
CRO 
Contract research organization 
CTD 
Connective tissue disease 
DBPC 
Double-Blind Placebo-Controlled 
DMC 
Data monitoring committee 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
EOS 
End of study 
EOT 
End of treatment 
E-R 
Exposure-response 
ERAs 
Endothelin-receptor antagonists 
EQ-5D-5L 
EuroQoL – 5 Dimension – 5 Level 
FAS 
Full Analysis Set 
FC 
Functional class 
FSH 
Follicle-stimulating hormone 
GCP 
Good clinical practice 
GDF 
Growth and differentiation factor(s) 
Hct 
Hematocrit 
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Hgb 
Hemoglobin 
HHC 
Home health care 
HR 
Heart rate 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IV 
Intravenous 
LTDB 
Long-Term Double-Blind 
LTFU 
Long-term follow-up 
mPAP 
Mean pulmonary arterial pressure 
NT-proBNP 
N-terminal pro-B-type natriuretic peptide
PAH 
Pulmonary arterial hypertension 
PAH-SYMPACT 
Pulmonary Arterial Hypertension-Symptoms and Impact 
PAP 
Pulmonary artery pressure 
PCWP 
Pulmonary capillary wedge pressure 
PD 
Pharmacodynamic 
PDE5 
Phosphodiesterase 5 
PH 
Pulmonary hypertension 
PK 
Pharmacokinetic 
PPS 
Per-Protocol Set 
PR 
Pulse rate 
PRO 
Patient-reported outcome 
PVR 
Pulmonary vascular resistance 
QoL 
Quality of life 
QTcF 
Frederica's corrected QT interval 
RBC 
Red blood cell 
RCT 
Randomized controlled trial 
RHC 
Right heart catheterization 
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SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SD 
Standard deviation 
SoE 
Schedule of Events 
sWFI 
Sterile water for injection 
TAPSE 
Tricuspid annular plane systolic excursion 
TEAE 
Treatment-emergent adverse event 
TGF 
Transforming growth factor 
TTCW 
Time to clinical worsening 
ULN 
Upper limit of normal 
VSMC 
Vascular smooth muscle cell 
WHO 
World Health Organization 
WU 
Wood unit 
 
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APPENDIX 2. SIX-MINUTE WALK TEST 
The 6MWT should be performed indoors, along a long, flat, straight, enclosed corridor with a 
hard surface that is seldom traveled.  The walking course must be 30 m in length (or at least 
15 m) and should be at the same location that is used for all study visits.  The length of the 
corridor should be marked every 3 m.  The turnaround points should be marked (e.g., with a 
cone).  A starting line, which marks the beginning and end of each 60-m lap, should be marked 
on the floor (e.g., using brightly colored tape). 
REQUIRED EQUIPMENT 
1. Countdown timer (or stopwatch)
2. Mechanical lap counter
3. Two small cones to mark the turnaround points
4. A chair that can be easily moved along the walking course
5. Worksheets on a clipboard
6. A source of oxygen
7. Sphygmomanometer
8. Telephone
9. Automated electronic defibrillator
10. Portable pulse oximeter
PARTICIPANT PREPARATION 
1. Comfortable clothing should be worn.
2. Appropriate shoes for walking should be worn.
3. Participants should use their usual walking aids during the test (cane, walker, etc.).
4. The participant’s usual medical regimen should be continued.
5. A light meal is acceptable before early morning or early afternoon tests.
6. Participants should not have exercised vigorously within 2 hours of beginning the test.
MEASUREMENTS 
1. Repeat testing should be performed about the same time of day to minimize intraday
variability.
2. A “warm-up” period before the test should not be performed.
3. The participant should sit at rest in a chair, located near the starting position, for at least
10 minutes before the test starts.  During this time, check for contraindications, measure
pulse and blood pressure, and make sure that clothing and shoes are appropriate.  Record
in the source documents.
4. Measure and record baseline heart rate and oxygen saturation (SpO2) and follow the
manufacturer’s instructions to maximize the signal and to minimize motion artifact.
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Make sure the readings are stable before recording.  Note pulse regularity and whether 
the oximeter signal quality is acceptable. 
5. Have the participant stand and rate their baseline dyspnea using the Borg dyspnea scale 
(Borg CR10 Scale). 
a. Show the scale to the participant and ask the participant this: “Please grade your level 
of shortness of breath using this scale.”  Record the pre-walk Borg dyspnea level. 
b. At the end of the exercise, remind the participant of the breathing number that they 
chose before the exercise and ask the participant to grade their breathing level again. 
Instruct the Participant as Follows: 
“The object of this test is to walk as far as possible for 6 minutes.  You will walk back and forth 
in this hallway.  Six minutes is a long time to walk, so you will be exerting yourself.  You will 
probably get out of breath or become exhausted.  You are permitted to slow down, to stop, and to 
rest as necessary.  You may lean against the wall while resting but resume walking as soon as 
you are able. 
You will be walking back and forth around the cones.  You should pivot briskly around the cones 
and continue back the other way without hesitation.  Now I’m going to show you.  Please watch 
the way I turn without hesitation.” 
Demonstrate by walking 1 lap yourself.  Walk and pivot around a cone briskly. 
“Are you ready to do that?  I am going to use this counter to keep track of the number of laps you 
complete.  I will click it each time you turn around at this starting line.  Remember that the 
object is to walk AS FAR AS POSSIBLE for 6 minutes, but don't run or jog.  Start now, or 
whenever you are ready.” 
1. Position the participant at the starting line.  You should also stand near the starting line 
during the test.  Do not walk with the participant.  As soon as the participant starts to 
walk, start the timer. 
2. Do not talk to anyone during the walk.  Use an even tone of voice when using the 
standard phrases of encouragement.  Watch the participant.  Do not get distracted and 
lose count of the laps.  Each time the participant returns to the starting line, click the lap 
counter once (or mark the lap on the worksheet).  Let the participant see you do it.  
Exaggerate the click using body language, like using a stopwatch at a race. 
After the first minute, tell the participant the following (in even tones): “You are doing well.  
You have 5 minutes to go.” 
When the timer shows 4 minutes remaining, tell the participant the following: “Keep up the good 
work.  You have 4 minutes to go.” 
When the timer shows 3 minutes remaining, tell the participant the following: “You are doing 
well.  You are halfway done.” 
When the timer shows 2 minutes remaining, tell the participant the following: “Keep up the good 
work.  You have only 2 minutes left.” 
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When the timer shows only 1-minute remaining, tell the participant: “You are doing well.  You 
have only 1 minute to go.” 
Do not use other words of encouragement (or body language to speed up). 
If the participant stops walking during the test and needs a rest, say this: “You can lean against 
the wall if you would like; then continue walking whenever you feel able.”  Do not stop the 
timer. 
If the participant stops before the 6 minutes are up and refuses to continue (or you decide that 
they should not continue), wheel the chair over for the participant to sit on, discontinue the walk, 
and note on the worksheet the distance, the time stopped, and the reason for stopping 
prematurely. 
When the timer is 15 seconds from completion, say this: “In a moment I’m going to tell you to 
stop.  When I do, just stop right where you are, and I will come to you.” 
When the timer rings (or buzzes), say this: “Stop!”  Walk over to the participant.  Consider 
taking the chair if they look exhausted.  Mark the spot where they stopped by placing a bean bag 
or a piece of tape on the floor. 
Post-Test: 
1. Remind the participant of their breathing number pretest and ask the participant to rate
their level of shortness of breath again.  Record the post-walk Borg dyspnea level.
2. Measure SpO2 and pulse rate from the oximeter and then remove the sensor.
3. Record the number of laps from the counter.
4. Record the additional distance covered (the number of meters in the final partial lap)
using the markers on the wall as distance guides.
5. Calculate the total distance walked, rounding to the nearest meter, and record it on the
worksheet.
6. Congratulate the participant on good effort and offer a drink of water.
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APPENDIX 3. CONTRACEPTIVE GUIDANCE AND COLLECTION OF 
PREGNANCY INFORMATION 
DEFINITIONS 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  A high follicle-stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormone replacement therapy (HRT).  However, in 
the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. 
• Females on HRT and whose menopausal status is in doubt will be required to use 1 of 
the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study.  Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
CONTRACEPTION GUIDANCE 
Male Participants 
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to 1 of the following (during the protocol-defined time frame in Section 6.1): 
• Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent 
• Agree to use a male condom when having penile-vaginal intercourse with a WOCBP 
who is not currently pregnant 
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Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal 
intercourse or use a male condom during each episode of penile penetration while participating 
in the study and for 112 days after the last dose of study treatment.  Refrain from donating blood 
or sperm for the duration of the study and for 112 days after the last dose of study treatment. 
Female Participants 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 6.  
Females who are exclusively in same-sex relationships are exempt for contraception guidelines. 
Female participants must agree to use highly effective forms of birth control for at least 28 days 
prior to starting the study, while participating in the study, and for at least 112 days after the last 
dose of study treatment. 
Participants should refrain from breastfeeding a child, donating blood, eggs, or ovum for the 
duration of the study and for at least 112 days after the last dose of study treatment. 
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Table 6: 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependenta 
Failure rate of < 1% per year when used consistently and correctly 
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of 
ovulationb 
• 
Oral 
• 
Intravaginal 
• 
Transdermal 
Progestogen only hormonal contraception associated with inhibition of ovulation 
• 
Oral 
• 
Injectable 
Highly Effective Methods That Are User Independenta 
Implantable progestogen only hormonal contraception associated with inhibition of ovulationb 
• 
IUD 
• 
Intrauterine hormone-releasing system 
• 
Bilateral tubal occlusion 
Vasectomized Partner 
A vasectomized partner is a highly effective contraception method provided that the partner is the sole male 
sexual partner of the WOCBP and the absence of sperm has been confirmed.  If not, an additional highly effective 
method of contraception should be used. 
Sexual Abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study treatment.  The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the 
participant. 
Abbreviations: IUD = intrauterine device; WOCBP = woman of childbearing potential. 
a Typical use failure rates may differ from those when used consistently and correctly.  Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the efficacy 
of the contraceptive method.  In this case, 2 highly effective methods of contraception should be utilized during the 
study and for at least 112 days after the last dose of study treatment. 
Pregnancy Testing 
• A Woman of Childbearing Potential should only be included in the study after 
2 confirmed negative pregnancy tests. 
• Additional pregnancy testing should be performed prior to study treatment 
administration at each dosing visit during the study and as required locally. 
• Pregnancy testing will also be performed whenever a menstrual cycle is missed or 
when pregnancy is otherwise suspected. 
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Clinical Study Protocol  
Sotatercept (ACE-011) 
Study No: A011-11 
Revision 1.0 
06 October 2021 
Acceleron Pharma Inc. 
Page 109 of 109 
CONFIDENTIAL 
Collection of Pregnancy Information 
Male Participants with Partners Who Become Pregnant 
•
The investigator will attempt to collect pregnancy information on any male
participant’s female partner who becomes pregnant while the male participant is in
this study.
•
After obtaining the necessary signed informed consent from the pregnant female
partner directly, the investigator will record pregnancy information on the appropriate
form and submit it to the sponsor within 24 hours of learning of the partner’s
pregnancy.  The female partner will also be followed to determine the outcome of the
pregnancy.  Information on the status of the mother and child will be forwarded to the
sponsor.  Generally, the follow-up will be no longer than 6 to 8 weeks following the
estimated delivery date.  Any termination of the pregnancy will be reported regardless
of fetal status (presence or absence of anomalies) or indication for the procedure.
Female Participants Who Become Pregnant 
•
The investigator will collect pregnancy information on any female participant who
becomes pregnant while participating in this study.  Information will be recorded on
the appropriate form and submitted to the sponsor within 24 hours of learning of a
participant's pregnancy.  The participant will be followed to determine the outcome of
the pregnancy.  The investigator will collect follow-up information on the participant
and the neonate and the information will be forwarded to the sponsor.  Generally,
follow-up will not be required for longer than 6 to 8 weeks beyond the estimated
delivery date.  Any termination of pregnancy will be reported, regardless of fetal
status (presence or absence of anomalies) or indication for the procedure.
•
While pregnancy itself is not considered to be an AE or SAE, any pregnancy
complication or elective termination of a pregnancy will be reported as an AE or
SAE.  A spontaneous abortion is always considered to be an SAE and will be reported
as such.  Any post-study pregnancy related SAE considered reasonably related to the
study treatment by the investigator will be reported to the sponsor as described in
Section 10.8.  While the investigator is not obligated to actively seek this information
in former study participants, he or she may learn of an SAE through spontaneous
reporting.
•
Any female participant who becomes pregnant while participating in the study will
discontinue study treatment.
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