A Phase 2a Single-Arm, Open-Label, Multicenter Exploratory Study to Assess the Effects of Sotatercept (ACE-011) for the Treatment of Pulmonary Arterial Hypertension
Phase: PHASE2
Conditions: Pulmonary Arterial Hypertension
Sponsor: Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA

Official Protocol Title: 
NCT number: 
NCT03738150 
Document Date: 
12-Aug-2021
A Phase 2a Single-Arm, Open-Label, Multicenter Exploratory Study 
to Assess the Effects of Sotatercept (ACE-011) for the Treatment of 
Pulmonary Arterial Hypertension

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Clinical Study Protocol 
 
Sotatercept (ACE-011) 
Study No: A011-10
Revision: 05
12 August 2021 
Acceleron Pharma Inc. 
Page 2 of 93 
CONFIDENTIAL 
 
Signature Page 
 
Acceleron Pharma Approval 
 
Signature: 
 
Date: 
 
 
Name (print): 
 
 
 
 
 
 
Investigator Agreement: I have read the protocol and agree to conduct the study as outlined 
in the protocol.  The study will be conducted in accordance with current United States Food 
and Drug Administration (FDA) regulations, International Council for Harmonisation (ICH) 
Guidelines, Good Clinical Practices (GCP), the Declaration of Helsinki, and local ethical and 
legal requirements. 
 
Signature: 
 
Date: 
 
 
Name (print): 
 
 
 
 
 
 
 
 
 
Institution Name and Address: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PPD
:%/

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Clinical Study Protocol 
 
Sotatercept (ACE-011) 
Study No: A011-10 
Revision: 05 
12 August 2021 
Acceleron Pharma Inc. 
Page 4 of 93 
CONFIDENTIAL 
Protocol Amendment Summary of Changes Table 
Substantive changes from the Protocol Amendment 04 (18 June 2020) to Protocol Amendment 
05 (12 August 2021) are detailed below.  Minor edits are not included.  See Appendix 10 for the 
rest of the Protocol Amendment History.  
Protocol Location 
Description of Change 
Brief Rationale 
Cover Page 
Added: PROTOCOL 
AMENDMENT 05 
Dated 12 August 2021 
This is the protocol amendment 
identifier and release date. 
Section 1, Synopsis 
Participants will have the 
opportunity to transition into the 
sotatercept long-term follow-up 
study following completion of the 
third invasive cardiopulmonary 
exercise test (iCPET).   
To clarify that participants are 
eligible, upon completion of the 
third iCPET, to transition to the 
sotatercept long-term follow-up 
study. 
Section 2, Schedule of 
Events 
Added footnote to the Schedule of 
Events for the Extension Period 
(Table 4). 
To clarify that participants who 
complete the third iCPET and 
consent to the sotatercept long-term 
follow-up study will be asked to 
complete the End of Treatment Visit 
only. 
Section 4.7, Follow-Up 
Period 
Combined subsections 4.7.1. (End of 
Treatment or Discontinuation of 
Study Drug; End of Study) and 
4.7.2. (Extension Period) 
To simplify definition of Follow-Up 
Period. 
Section 4.9, End of Study 
Definition 
End of Study (EOS) visits are only 
required for participants who 
discontinue the study early or 
decline transition to the sotatercept 
long-term follow-up study. 
To clarify EOS requirement for early 
discontinuation or declining 
transition to the sotatercept long-
term follow-up study. 
Section 8.2.1, Efficacy 
Assessments, iCPET 
Updated iCPET being performed at 
Cycle 14 to Cycle 17 
Revised to correct Cycle timepoint 
EOS = End of Study; iCPET = Invasive Cardiopulmonary Exercise Test 
 
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Clinical Study Protocol 
 
Sotatercept (ACE-011) 
Study No: A011-10 
Revision: 05 
Page 5 of 93 
CONFIDENTIAL 
TABLE OF CONTENTS 
PROCEDURES IN CASE OF EMERGENCY ...............................................................................3 
Protocol Amendment Summary of Changes Table .........................................................................4 
TABLE OF CONTENTS .................................................................................................................5 
LIST OF TABLES ...........................................................................................................................9 
LIST OF FIGURES .........................................................................................................................9 
1. 
SYNOPSIS .................................................................................................................10 
2. 
SCHEDULE OF EVENTS .........................................................................................13 
3. 
INTRODUCTION ......................................................................................................18 
3.1. 
Study Rationale ...........................................................................................................18 
3.2. 
Rationale for Patient Population .................................................................................19 
3.3. 
Rationale for Study Endpoints ....................................................................................19 
3.4. 
Rationale for Dose Level and Frequency Selection ...................................................21 
3.4.1. 
Treatment Period ........................................................................................................21 
3.4.2. 
Extension Period .........................................................................................................21 
3.5. 
Background .................................................................................................................21 
3.6. 
Benefit/Risk Assessment ............................................................................................22 
4. 
STUDY DESIGN .......................................................................................................25 
4.1. 
Overall Design ............................................................................................................25 
4.2. 
Clinical Sites ...............................................................................................................25 
4.3. 
Standard of Care .........................................................................................................25 
4.4. 
Screening Period .........................................................................................................25 
4.5. 
Treatment Period ........................................................................................................25 
4.6. 
Extension Period .........................................................................................................25 
4.7. 
Follow-Up Period .......................................................................................................26 
4.8. 
Participant and Study Completion ..............................................................................28 
4.8.1. 
Extension Period .........................................................................................................28 
4.9. 
End of Study Definition ..............................................................................................28 
4.10. 
Justification for Dose ..................................................................................................28 
5. 
STUDY POPULATION .............................................................................................29 
5.1. 
Inclusion Criteria ........................................................................................................29 
5.2. 
Exclusion Criteria .......................................................................................................30 
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Clinical Study Protocol 
 
Sotatercept (ACE-011) 
Study No: A011-10 
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5.3. 
Screen Failures ............................................................................................................32 
6. 
TREATMENTS ..........................................................................................................33 
6.1. 
Treatments Administered ............................................................................................33 
6.2. 
Treatment Administration and Schedule ....................................................................33 
6.3. 
Dose Modification ......................................................................................................33 
6.4. 
Method of Treatment Assignment ..............................................................................37 
6.5. 
Randomization and Blinding ......................................................................................37 
6.6. 
Packaging and Labeling ..............................................................................................37 
6.7. 
Preparation/Handling/Storage/Accountability ............................................................37 
6.8. 
Treatment Compliance ................................................................................................38 
6.9. 
Concomitant Therapy .................................................................................................38 
7. 
DISCONTINUATION/WITHDRAWAL CRITERIA ...............................................39 
7.1. 
Discontinuation of Study Treatment ...........................................................................39 
7.2. 
Withdrawal from the Study ........................................................................................39 
7.3. 
Lost to Follow-Up.......................................................................................................40 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................41 
8.1. 
Screening Procedures ..................................................................................................41 
8.2. 
Efficacy Assessments .................................................................................................41 
8.2.1. 
iCPET .........................................................................................................................41 
8.2.2. 
Cardiac Magnetic Resonance Imaging .......................................................................42 
8.2.3. 
Pulmonary Vascular Resistance by Right Heart Catheterization ...............................43 
8.2.4. 
Six-Minute Walk Distance .........................................................................................43 
8.3. 
Adverse Events ...........................................................................................................44 
8.3.1. 
Adverse Event Definitions ..........................................................................................44 
8.3.1.1. 
Adverse Events ...........................................................................................................44 
8.3.1.2. 
Unexpected Adverse Events .......................................................................................44 
8.3.1.3. 
Events Not to Be Considered as Adverse Events .......................................................44 
8.3.1.4. 
Serious Adverse Event ................................................................................................44 
8.3.1.5. 
Events Not to Be Considered as Serious Adverse Events are Hospitalizations 
for: ...............................................................................................................................45 
8.3.1.6. 
Severity .......................................................................................................................46 
8.3.2. 
Relationship to Study Drug ........................................................................................46 
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Clinical Study Protocol 
 
Sotatercept (ACE-011) 
Study No: A011-10 
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8.3.3. 
Documentation and Methods of Detecting Adverse Events and Serious 
Adverse Events ...........................................................................................................47 
8.3.4. 
Documentation of Serious Adverse Events ................................................................47 
8.3.5. 
Reporting Period and Monitoring of Participants with AEs .......................................47 
8.3.6. 
Notification About Serious Adverse Events ...............................................................48 
8.3.7. 
Safety Reporting to Health Authorities, Independent Ethics Committees, 
Institutional Review Boards, and Investigators ..........................................................48 
8.3.8. 
Overdose .....................................................................................................................49 
8.3.9. 
Transmission of an Infectious Agent ..........................................................................49 
8.3.10. 
Pregnancy ...................................................................................................................49 
8.4. 
Monitoring of Identified, Potential and Adverse Events of Special Interest ..............50 
8.4.1. 
Identified Risk ............................................................................................................50 
8.4.2. 
Potential Risks ............................................................................................................51 
8.4.3. 
Adverse Events of Special Interest .............................................................................51 
8.5. 
Safety Assessments .....................................................................................................52 
8.5.1. 
Physical Examinations ................................................................................................52 
8.5.2. 
Vital Signs ..................................................................................................................52 
8.5.3. 
Electrocardiograms .....................................................................................................53 
8.5.4. 
Clinical Worsening .....................................................................................................53 
8.5.5. 
Rescue Therapy Criteria .............................................................................................53 
8.5.6. 
Clinical Safety Laboratory Assessments ....................................................................54 
8.6. 
Pharmacokinetics ........................................................................................................54 
8.7. 
Pharmacodynamics .....................................................................................................55 
8.8. 
Genetic Testing ...........................................................................................................55 
9. 
STATISTICAL CONSIDERATIONS .......................................................................56 
9.1. 
Sample Size Determination ........................................................................................56 
9.2. 
Populations for Analyses ............................................................................................56 
9.3. 
Statistical Analyses .....................................................................................................56 
9.3.1. 
Efficacy Analyses .......................................................................................................57 
9.3.2. 
Safety Analyses ..........................................................................................................57 
9.3.3. 
Other Analyses ............................................................................................................58 
9.3.4. 
Primary Endpoint Analysis .........................................................................................58 
9.3.5. 
Extension Period Analysis ..........................................................................................58 
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Clinical Study Protocol 
 
Sotatercept (ACE-011) 
Study No: A011-10 
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10. 
REFERENCES ...........................................................................................................59 
11. 
APPENDICES ............................................................................................................61 
APPENDIX 1. ABBREVIATIONS AND SPECIALIST TERMS .............................................62 
APPENDIX 2. CLINICAL LABORATORY TESTS ................................................................66 
APPENDIX 3. STANDARD OF CARE THERAPY .................................................................67 
APPENDIX 4. SIX-MINUTE WALK TEST .............................................................................68 
APPENDIX 5. CARDIOPULMONARY EXERCISE TEST .....................................................71 
APPENDIX 6. CARDIAC MAGNETIC RESONANCE IMAGING ........................................72 
APPENDIX 7. STUDY GOVERNANCE CONSIDERATIONS...............................................73 
APPENDIX 8. CONTRACEPTIVE GUIDANCE AND COLLECTION OF 
PREGNANCY INFORMATION ...............................................................................77 
APPENDIX 9. GENETICS .........................................................................................................80 
APPENDIX 10. PROTOCOL AMENDMENT HISTORY ........................................................81 
 
 
 
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Clinical Study Protocol 
 
Sotatercept (ACE-011) 
Study No: A011-10 
Revision: 05 
Page 9 of 93 
CONFIDENTIAL 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Objectives and Endpoints ...........................................................................................11 
Table 3: 
Schedule of Events .....................................................................................................13 
Table 4: 
Schedule of Events: Extension and Follow-Up Periods .............................................16 
Table 5: 
Objectives and Endpoints ...........................................................................................23 
Table 6: 
Dose Reductions for Sotatercept ................................................................................37 
Table 7: 
Identified Risks ...........................................................................................................50 
Table 8: 
Potential Risks ............................................................................................................51 
Table 9: 
Adverse Events of Special Interest .............................................................................51 
Table 10: Statistical Analysis of Endpoints ................................................................................57 
Table 11: Protocol-Required Safety Laboratory Assessments ...................................................66 
Table 12: Highly Effective Contraceptive Methods ...................................................................78 
Table 13: Protocol Amendment 03A to Protocol Amendment 04 Amendment History ............81 
Table 14: Protocol Amendment 02 to Protocol Amendment 03A Amendment History ............86 
Table 15: Protocol Amendment 01 to Protocol Amendment 02 Amendment History ...............91 
Table 16: The Original Protocol to Protocol Amendment 01 Amendment History ...................93 
 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................27 
Figure 2: 
Platelet Count Dose Modification: Dose Delay, Dose Reduction and 
Discontinuation Guidelines ........................................................................................35 
Figure 3: 
Hemoglobin Dose Modification: Dose Delay, Dose Reduction and 
Discontinuation Guidelines ........................................................................................36 
 
 
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Clinical Study Protocol 
 
Sotatercept (ACE-011) 
Study No: A011-10 
Revision: 05 
12 August 2021 
Acceleron Pharma Inc. 
Page 10 of 93 
CONFIDENTIAL 
1. 
SYNOPSIS 
Protocol Title 
A Phase 2a Single-Arm, Open-Label, Multicenter Exploratory Study to Assess the Effects of 
Sotatercept (ACE-011) for the Treatment of Pulmonary Arterial Hypertension 
Short Title 
A Phase 2a Open-Label Exploratory Study of Sotatercept for the Treatment of PAH 
Clinical Sites 
 
Approximately five clinical sites in the United States. 
Rationale 
Study A011-10 is a Phase 2a, single-arm, open-label, multicenter exploratory study to determine 
the effects of sotatercept (ACE-011) in adults with World Health Organization (WHO) Group 1 
functional class III pulmonary hypertension or pulmonary arterial hypertension (PAH).  These 
patients experience marked limitations in physical activity and are at significant risk for disease 
progression and death.1  Data from rodent models of PAH suggest that treatment with sotatercept 
may reduce muscularization and thickness of pulmonary vessel walls, right-sided heart pressures, 
and right-to-left ventricle weight ratios.2  These improvements may be accompanied by 
reductions in pulmonary vascular resistance as well as increases in functional capacity, and right 
ventricular mechanics and function, all of which will be measured during the study. 
 
 
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Clinical Study Protocol 
Sotatercept (ACE-011) 
Study No: A011-10 
Revision: 05 
12 August 2021 
Acceleron Pharma Inc. 
Page 11 of 93 
CONFIDENTIAL 
The main objectives and endpoints for this study are found in Table 2. 
Table 2: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To evaluate the effect of sotatercept on an 
invasive cardiopulmonary exercise test 
(iCPET) measure in PAH patients treated with 
sotatercept plus standard of care (SOC) 
Change from baseline in VO2 max at 24 weeks 
Secondary 
•
To evaluate the effect of sotatercept on
additional measures in PAH patients
treated with sotatercept plus SOC
•
To evaluate effects of sotatercept on
right ventricular stroke volume
(RV SV), RV end-systolic volume
(RV ESV), RV end-diastolic volume
(RV EDV), RV ejection fraction
(RV EF), RV stroke volume index
(RV SVI), and RV mass in PAH
patients treated with sotatercept plus
SOC
•
Exercise measures, including change in
VE/VCO2 slope (ventilatory efficiency),
cardiac index, mean pulmonary arterial
pressure, and Ca-vO2 (arteriovenous O2 
content difference) at 24 weeks
•
Change from baseline in RV SV, RV ESV,
RV EDV, RV EF, RV SVI, and RV mass
by cardiac magnetic resonance (MR)
imaging at 24 weeks
iCPET = invasive cardiopulmonary exercise test; PAH = pulmonary arterial hypertension; PVR = pulmonary 
vascular resistance; RV EDV = right ventricular end-diastolic volume; RV EF = right ventricular ejection fraction; 
RV ESV = right ventricular end-systolic volume; RV SV = right ventricular stroke volume; RV SVI = right 
ventricular stroke volume index; SOC = standard of care; VO2=peak oxygen uptake. 
Overall Design 
This is a Phase 2a, single-arm, open-label, multicenter, exploratory study assessing the efficacy 
and safety of sotatercept for the treatment of WHO Group 1 functional class III PAH. 
Number of Participants 
Approximately 25 participants will be enrolled. 
Treatment Groups and Duration 
Each eligible participant will receive standard of care (SOC) plus sotatercept at a dose of 
0.3 mg/kg SC for Cycle 1 and escalating to 0.7 mg/kg at Cycle 2 and for the remainder of the 
treatment period.  Dosing will be every 3 weeks for 24 weeks.  During the Extension Period, 
sotatercept dosing will be every 3 weeks for 18 months.  
Standard of care (SOC) therapy refers to combination therapy consisting of drugs from two or 
more 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.  Patients receiving monotherapy are not to be enrolled. 
During the Extension Period, participants under investigator’s supervision can substitute, 
remove, or adjust the dose of SOC for PAH-worsening and chronic concomitant medications, 
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Clinical Study Protocol 
 
Sotatercept (ACE-011) 
Study No: A011-10 
Revision: 05 
12 August 2021 
Acceleron Pharma Inc. 
Page 12 of 93 
CONFIDENTIAL 
including supplemental oxygen.  Investigator discretion will be used to determine if sotatercept 
study drug discontinuation is necessary.  Additional SOC details can be found in Section 4.3 and 
Appendix 3. 
The study is divided into the Screening Period of up to 28 days, a Treatment Period of 24 weeks, 
followed by an 18-month Extension Period and an 8-week Follow-Up Period.  
Participants will have the opportunity to transition into the sotatercept long-term follow-up study 
following the completion of the third invasive cardiopulmonary exercise test (iCPET). 
 
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Clinical Study Protocol 
 
Sotatercept (ACE-011) 
Study No: A011-10 
Revision: 05 
12 August 2021 
Acceleron Pharma Inc. 
Page 13 of 93 
CONFIDENTIAL 
2. 
SCHEDULE OF EVENTS 
Table 3: 
Schedule of Events 
 
Screening 
Period 
(up to 28 
days 
before 
Cycle 1 
Day 1) 
Treatment Period (24 Weeks)1 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycles 
6-7 
Cycle 8 
Cycle 9 
Day 1 
Day 8 
Day 22 
Day 29 
Day 43 
Day 64 
Day 85 
Day 106; 
Day 127 
Day 148 
Day 169 
±3 
days 
±3 
days 
±3 
days 
±3 
days 
±3 
days 
±3 
days 
±3 
days 
±3 
days 
±3 
days 
±3 
days 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/ exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Physical examination2 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test3 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Hematology4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistry 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Urinalysis 
 
X 
 
 
 
 
 
X 
 
 
X 
12-lead ECG 
X 
X 
 
X 
 
 
 
 
 
 
 
Pulmonary tests5 
X 
 
 
 
 
 
 
 
 
 
 
Anti-drug antibody 
(ADA) 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Genetic sample 
 
X 
 
 
 
 
 
 
 
 
 
Cardiac MR6 
X 
 
 
 
 
 
 
 
 
 
X 
6MWT7 
X 
 
 
 
 
 
 
X 
 
 
X 
RHC + CPET (iCPET)8 
X 
 
 
 
 
 
 
 
 
 
X 
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Clinical Study Protocol 
 
Sotatercept (ACE-011) 
Study No: A011-10 
Revision: 05 
12 August 2021 
Acceleron Pharma Inc. 
Page 14 of 93 
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Screening 
Period 
(up to 28 
days 
before 
Cycle 1 
Day 1) 
Treatment Period (24 Weeks)1 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycles 
6-7 
Cycle 8 
Cycle 9 
Day 1 
Day 8 
Day 22 
Day 29 
Day 43 
Day 64 
Day 85 
Day 106; 
Day 127 
Day 148 
Day 169 
±3 
days 
±3 
days 
±3 
days 
±3 
days 
±3 
days 
±3 
days 
±3 
days 
±3 
days 
±3 
days 
±3 
days 
Transpulmonary flux 
biomarkers9 
X 
 
 
 
 
 
 
 
 
 
X 
WHO Functional Class 
Assessment 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Clinical worsening 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
PK collection 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
PD blood biomarkers 
 
X 
 
X 
 
 
 
X 
 
X 
X 
Study drug 
administration10 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
AE/SAE review11 
X11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: 6MWT = 6-minute walk test; ADA = anti-drug antibody; AE = adverse event; CTPA = computed tomography pulmonary angiogram; 
ECG = electrocardiogram; eCRF = electronic case report form; Hgb = hemoglobin; iCPET = invasive cardiopulmonary exercise test; MR = magnetic resonance; 
PD = pharmacodynamic(s); PK = pharmacokinetic(s); RHC = right heart catheterization; SAE = serious adverse event; VQ = ventilation-perfusion; 
WHO = World Health Organization. 
1 All visit day windows should be considered relative to the date of the previous dose of study drug.  Cycles are every 3 weeks (±3 days) and there must be at 
least 7 days between each dose. 
2 A full physical examination should be completed at the Screening visit.  A targeted cardiopulmonary examination should be completed at all other indicated 
visits. 
3 Pregnancy test (urine or serum) is required for female participants of childbearing potential at Screening and prior to each dose of study drug (see Appendix 8 
for information regarding pregnancy follow-up). 
4 Results from the hematology panel should be evaluated prior to study drug administration. For C1D1 and C2D22 visits, blood samples should be taken and 
assessed for Hgb levels on the same day as study drug administration.  For all other dosing cycles, blood samples may be taken and assessed for Hgb levels on 
the same day as study drug administration or 1 day prior to dosing. If Hgb is ≥ 17.0 g/dL during Cycles 1 and 2, participant should return weekly for Hgb 
monitoring (and continue to follow Dose Modification Guidance for dosing days [Section 6.3]). 
5 Additional screening procedures to include pulmonary function tests and VQ/CT pulmonary angiogram (CTPA) or pulmonary angiography as per inclusion 
criteria 5 and 6 (Section 5.1), if historical readings are unavailable. 
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Clinical Study Protocol 
 
Sotatercept (ACE-011) 
Study No: A011-10 
Revision: 05 
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6 Cardiac MR and iCPET may be done on separate days.  If performed on the same day, iCPET should be performed before cardiac MR, with ≥ 1-hour interval 
between procedures. 
7 6MWT: to be performed twice during the Screening Period at least 4 hours (but no longer than 1 week) apart and distances must be within 15% of each other, 
calculated from the higher number. 
8 RHC with CPET (iCPET) to be completed within 10 days prior to Cycle 1, Day 1.  A participant will not receive more than 3 iCPET assessments during the 
study.  If other assessments are occurring on the same day, iCPET should be performed after all other procedures (Exception: cardiac MR). 
9 Transpulmonary flux biomarkers will be collected during iCPET as described in Section 8.7. 
10 Study procedures and sample collection must be done prior to administration of study drug.  Dosing: The dose must be calculated based on the participant’s 
weight on the day of dosing. Dose-modification guidelines must be reviewed and implemented prior to dosing as required per protocol (see Section 6.3). 
11 AEs and SAEs occurring after the signing of the informed consent form and before Cycle 1, Day 1 will be reported and documented on the AE eCRF.  If 
related to protocol procedures (S)AEs should be indicated as such in the eCRF.
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Table 4: 
Schedule of Events: Extension and Follow-Up Periods 
 
Extension Period (18 Months)1  
Follow-Up Period (8 Weeks) 
Cycle 10 
Cycles 
11-13 
Cycle 
14 
Cycles 
15-16,  
18-20, 22-24, 
26-28, 30-33 
Cycle 
17 
Cycles 
21, 25, 29, 
342 
End of Treatment11 
At time of early 
discontinuation or 4 weeks 
(±7 days) post last dose of 
study drug 
End of Study 
8 weeks (±7 days) post last 
dose of study drug 
±3 days 
±3 days 
±3 days 
±3 days 
±3 days 
±3 days 
(±7 days) 
(±7 days) 
Physical examination2 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs (including 
weight) 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test3 
X 
X 
X 
X 
X 
X 
 
 
Hematology4 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistry 
X 
 
X 
 
X 
X 
X 
X 
Urinalysis 
X 
 
X 
 
X 
X 
X 
X 
12-lead ECG 
X 
 
X  
 
X 
X 
X 
X 
Anti-drug antibody (ADA) 5 
X 
 
X 
 
 
X 
 
X 
Cardiac MR6 
 
 
 
 
X 
 
 
 
6MWT 
X 
 
X 
 
X 
X 
X 
X 
RHC + CPET (iCPET) 6,7 
 
 
 
 
X 
 
 
 
Transpulmonary flux 
biomarkers8 
 
 
 
 
X 
 
 
 
WHO Functional Class 
Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical worsening 
X 
X 
X 
X 
X 
X 
X 
X 
PD blood biomarkers 
X 
 
X 
 
 
X 
 
X 
Study drug administration9 
X 
X 
X 
X 
X 
X 
 
 
AE/SAE review10 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
review 
X 
X 
X 
X 
X 
X 
X 
X 
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Abbreviations: 6MWT = 6-minute walk test; ADA = anti-drug antibody; AE = adverse event; CPET = cardiopulmonary exercise test; ECG = electrocardiogram; 
eCRF = electronic case report form; EOT = end of treatment; Hgb = hemoglobin; iCPET = invasive cardiopulmonary exercise test; MR = magnetic resonance; 
PD = pharmacodynamics; RHC = right heart catheterization; SAE = serious adverse event; WHO = World Health Organization. 
1 All visit day windows should be considered relative to the date of the previous dose of study drug. Cycles are every 21 days (±3 days). 
2 Targeted cardiopulmonary examination only. 
3 Pregnancy test (urine or serum) is required for female participants of childbearing potential prior to each dose of study drug (see Appendix 8 for pregnancy 
follow-up). 
4 Results from the hematology panel should be evaluated prior to study drug administration.  For all dosing cycles, blood samples may be taken and assessed for 
Hgb levels on the same day as study drug administration or 1 day prior to dosing.  If Hgb is ≥ 17.0 g/dL, participants should return weekly for Hgb monitoring 
(and continue to follow Dose Modification guidance for dosing days [Section 6.3]). 
5 If a participant has a positive ADA result at the EOT assessment, the participant may be asked to return approximately every 3 months for additional testing, 
until a negative result is obtained or the result is considered stabilized. 
6 Cardiac MR and iCPET may be done on separate days.  If performed on the same day, iCPET should be performed before cardiac MR, with ≥ 1-hour interval 
between procedures. 
7 A participant will not receive more than 3 iCPET assessments during the study.  The iCPETs, 2 in the Treatment Period and 1 in the Extension Period, must 
occur within 10 days prior to Cycle 1 (during the Screening Period), and within 10 days prior to Cycle 9 (during treatment period), and Cycle 14 during the 
Extension Period.  For patients discontinuing the study prior to Cycle 9, an iCPET should be performed ± 10 days of the EOT visit.  The third iCPET is to be 
performed at the time of early discontinuation if prior to Cycle 14.  If other assessments are occurring on the same day, the iCPET should be performed after all 
other procedures (Exception: cardiac MR imaging). 
8 Transpulmonary flux biomarkers will be collected during iCPET as described in Section 8.7. 
9 Study procedures should be done prior to administration of study drug. Dose must be calculated based on the participant’s weight on the day of dosing. Dose 
modification Guidance must be reviewed and implemented prior to dosing (Section 6.3). 
10 AEs and SAEs occurring after the signing of the informed consent form will be reported and documented on the AE eCRF.  If related to protocol procedures, 
(S)AEs should be indicated as such in the eCRF. 
11 Participants who complete the third iCPET and consent to the sotatercept long-term follow-up study will be asked to complete the EOT Visit only. 
 
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3. 
INTRODUCTION 
Pulmonary arterial hypertension (PAH) represents 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.3,4  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 pulmonary vascular resistance and, eventually, right-sided heart failure.5  In the 
absence of treatment, the majority of patients succumb to heart failure within a few years of 
diagnosis.6  There is currently no pharmacological cure for PAH; treatment involves relieving 
symptoms by increasing blood flow through the pulmonary vasculature through pharmacologic 
manipulation of various pathways and slowing clinical worsening of the disease.  Current 
disease-specific treatments for PAH include vasodilator-type agents such as endothelin-receptor 
antagonists (ERAs), phosphodiesterase type 5 (PDE5) inhibitors, and prostanoids and are used to 
supplement general supportive care agents (e.g., anticoagulants, diuretics, digoxin).  
Genetic mutations in the bone morphogenetic protein type II receptor (BMPR2) are associated 
with the majority of the familial forms of PAH7,8 and approximately 25% of idiopathic PAH.  
Specifically, impairment of the BMPR2-associated signal pathway appears to lead to 
uncontrolled proliferation of pulmonary VSMCs.  These data strongly suggest a key role of 
transforming growth factor-beta (TGF-β) superfamily members in the pathogenesis of PAH.  
Sotatercept (ACE-011) is a first-in-class human fusion protein consisting of the extracellular 
domain of the activin receptor type IIA (ActRIIA) linked to the Fc domain of human 
immunoglobulin G1 (IgG1).  Sotatercept works by targeting molecules in the TGF-β 
superfamily, which includes activins, growth and differentiation factors (GDFs), and BMPs.  
Sotatercept may improve pulmonary vascular remodeling by restoring balance to SMAD 
signaling.8 
3.1. 
Study Rationale 
Study A011-10 is a Phase 2a, single-arm, open-label, multicenter exploratory study to determine 
the effects of sotatercept (ACE-011) in adults with World Health Organization (WHO) Group 1 
PAH. 
This study is designed to evaluate whether sotatercept has the potential to modify the clinical 
course of PAH, as assessed by changes in various measures obtained in invasive 
cardiopulmonary exercise testing (iCPET), various imaging parameters collected via cardiac 
magnetic resonance (MR) imaging, and correlation with other functional measures and 
assessments of clinical worsening. 
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3.2. 
Rationale for Patient Population 
Patients with WHO Group 1 pulmonary hypertension (i.e., PAH associated with idiopathic, 
heritable, drug-induced, connective tissue diseases, or post-shunt correction) and meet the WHO 
functional assessment definition for Class III PAH will be the population studied. 
The WHO Functional Classification9 (FC) is based on an assessment of the degree of physical 
activity limitation due primarily to associated dyspnea: 
• FC I: Patients with pulmonary hypertension but without resulting limitation of 
physical activity.  Ordinary physical activity does not cause undue dyspnea or fatigue, 
chest pain or near syncope. 
• FC II: Patients with pulmonary hypertension 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. 
• FC III: Patients with pulmonary hypertension 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. 
• FC IV: Patients with pulmonary hypertension 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.  Discomfort is increased by any 
physical activity.  
Previously diagnosed patients in FC I, II, III, and IV had an estimated 5-year survival rate of 
88.0%, 75.6%, 57.0%, and 27.2%, respectively, compared with 72.2%, 71.7%, 60.0%, and 
43.8% for newly diagnosed patients in FC I, II, III, and IV, respectively.1 
Patients with functional class III PAH comprise approximately half of all previously diagnosed 
PAH patients in the REVEAL registry.1  It is expected that the treatment effect of sotatercept can 
be more easily ascertained in this population.  Patients with functional class I PAH are typically 
excluded from interventional studies due to their relative low identification rate, low prevalence, 
and mild symptomatology.  Patients with functional class II PAH are typically enrolled in PAH 
studies, but are not as impaired physiologically, thus a treatment effect may be more challenging 
to ascertain compared with functional class III PAH patients.  There is a relatively low 
prevalence of patients with class IV PAH due to higher mortality and transplant rates compared 
with other functional classes; given their severe disease burden, these class IV patients have 
limited ability to participate in longer interventional studies.  Eligibility criteria for this study are 
consistent with those of other interventional studies in this population. 
3.3. 
Rationale for Study Endpoints 
The primary endpoint of the study is the change from baseline in peak oxygen uptake 
(VO2 max), as measured by cardiopulmonary exercise test (CPET).  This endpoint was chosen 
because of the importance of VO2 max in describing overall cardiopulmonary health, and its 
correlation with cardiopulmonary hemodynamics.  The final common pathophysiologic pathway 
to account for most organic causes of exertional dyspnea involves insufficient O2 supply to 
skeletal muscle or impaired uptake of O2 by skeletal muscle cells, which, collectively, may be 
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attributable to abnormal cardiac, pulmonary vascular, or neuromuscular function.  The integrated 
function of these systems is broadly assessed by measuring the peak oxygen uptake (V̇ O2), 
which is calculated as the product of minute ventilation (VE) and the difference in inspired and 
expired fractions of O2.  Thus, a fundamental objective of noninvasive (or invasive) CPET is 
quantification of maximum VO2, which is considered abnormal when < 80% of predicted for the 
patient’s age, gender, and height.10 
In a study of patients with WHO Group 2 pulmonary hypertension and systolic heart failure 
(mean [standard deviation (SD)] age 58 [13] years; depressed left ventricular [LV] ejection 
fraction [EF] 0.27 [±0.05]; and VO2 max 11.2 [±3.2] mL/kg/min), the patients underwent 
incremental CPET with simultaneous hemodynamic monitoring and first-pass radionuclide 
ventriculography before and after 12 weeks of treatment with sildenafil, a selective pulmonary 
vasodilator, or placebo.  Sildenafil was associated with an approximate 28% decrease in 
pulmonary vascular resistance (PVR), an approximate 10% increase in VO2 and an approximate 
10% decrease in VE/VCO2.11 
An important CPET secondary endpoint is change from baseline in ventilatory efficiency 
(VE/VCO2) slope.  If, as predicted by the preclinical model data, treatment with sotatercept 
results in modification of pulmonary vascular wall architecture, improvement in right-sided lung 
perfusion pressures, and reduction in right heart mechanics, then gas exchange efficiency should 
be improved.  This should result in an improved oxygen uptake rate VO2, as well as a reduction 
in pulmonary dead space and an improved ventilatory efficiency (as measured by VE/VCO2). 
Another important secondary endpoint is change in right ventricular (RV) stroke volume (SV) at 
24 weeks from baseline, which is designed to assess the effect of sotatercept on RV function.  
Given the pivotal role RV function has in determining much of the morbidity and mortality of 
PAH, a significant improvement in RV function on cardiac MR imaging could demonstrate that 
the clinical course of the subject’s PAH has been meaningfully improved.  Cardiac MR imaging 
is particularly suitable for accurately assessing the anatomical structure as well as function of the 
RV, and it is regarded as the gold standard test for quantifying ventricular volume, mass, 
structure, and function.  It is non-invasive, and does not involve the use of ionizing radiation.  
Cardiac MR imaging provides high-resolution, 3-dimensional images that avoid the need for the 
geometrical assumptions required for some calculations when using echocardiography.  
However, cardiac MR imaging is also associated with the following range of limitations: higher 
cost, more limited availability relative to other methods, the need for more intensive and 
time-consuming analysis, and the requirement for significant technical support and expertise.  In 
addition, cardiac MR imaging is incompatible with pacemakers and infusion pumps, and the 
need for breath holding may be difficult for PAH patients.  However, given the relevance of the 
right heart in PAH, the advantages of the method outweigh these disadvantages in the monitoring 
of patients with established PAH and in assessment of treatment response in clinical trials.  The 
clinical relevance of cardiac MR imaging in PAH was demonstrated in a study of 111 PAH 
patients evaluating the effect of implementing standard-of-care (SOC) therapy on cardiac MR 
imaging assessments of changes in stroke volume and correlating them with concurrent changes 
in 6-minute walk distance (6MWD), a frequently used measure of activity/function in PAH 
patients.  The study found that an improvement in RV SV of as little as 10 mL was 
prognostically significant and correlated with a meaningful improvement in 6MWD in PAH 
patients.12 
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In addition, assessment of RV SV may correlate with other functional and physiologic measures 
commonly assessed in treated PAH patients (e.g., cardiac index, mean pulmonary arterial 
pressure [PAP], VO2 max, Ca-vO2, VE/VCO2 slope, PVR, and N-terminal prohormone of brain 
natriuretic peptide [NT-proBNP]).  
Other secondary endpoints in this study include change in RV end-systolic volume (ESV), 
RV end-diastolic volume (EDV), change in RV EF, change in RV stroke volume index (SVI), 
change in RV mass by cardiac MR imaging at 24 weeks from baseline, iCPET results for 
exercise hemodynamic measures (including change in cardiac index, mean PAP, Ca-vO2 
[arteriovenous O2 content difference], VE/VCO2 slope [ventilatory efficiency], evaluation of 
changes in PVR, changes in 6MWD, clinical worsening (including changes in WHO functional 
class assessment and hospitalizations), pharmacokinetic (PK) results, pharmacodynamic (PD) 
results, and safety.  With the modification of pulmonary vessel wall architecture and pulmonary 
vessel pressure and patency, it is hypothesized that improvements in RV performance and 
structural measures, arteriovenous oxygen differences, ventilatory efficiency, and pulmonary 
vascular resistance will result.  The relevant downstream clinical benefits of these improvements 
should also include improvement in 6MWD and quality of life and reduction in clinical 
worsening events.  Of note, 6MWD and change in WHO functional class are predictors of 
mortality in PAH.1,13,14  Safety will be assessed by evaluating adverse events (AEs) and 
laboratory results, which will be graded for severity using the current version of the National 
Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE). 
3.4. 
Rationale for Dose Level and Frequency Selection 
3.4.1. 
Treatment Period 
A dose regimen of 0.3 mg/kg sotatercept SC for Cycle 1 and escalating to 0.7 mg/kg at Cycle 2 
SC every 3 weeks (Q3W) was selected after reviewing all relevant PK, safety, and efficacy data 
for sotatercept.  Based on population PK/PD modeling of data from a Phase 1 healthy volunteer 
study, exposure modeling of sotatercept from preclinical models of PAH, and t½ of sotatercept 
(~23 days), Q3W dosing is expected to result in the maintenance of target drug levels in patients 
with PAH.  See Section 4.10.  
3.4.2. 
Extension Period 
In the 18-month Extension Period, a dose regimen of every 3 weeks (Q3W) will be evaluated. 
Comparable dose levels based on exposure-matching will be selected to maintain steady-state 
exposures through the Extension Period. 
3.5. 
Background 
PAH applies to a group of diseases causing a progressive increase in PVR, resulting in RV 
dysfunction and ultimately failure as well as premature death.3,4  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 VSMCs in 
pulmonary arterioles, which results in progressive pulmonary vascular remodeling, increased 
PVR and, progressive, right-sided heart failure.5  In the absence of treatment, the majority of 
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patients succumb to heart failure within a few years of diagnosis.6  There is currently no 
pharmacological cure for PAH; treatment involves relieving symptoms, principally by increasing 
blood flow through the pulmonary vasculature with 1 or more vasodilators and slowing clinical 
worsening of the disease.  Current disease-specific treatments for PAH include vasodilator-type 
agents such as endothelin-receptor antagonists (ERAs), phosphodiesterase 5 (PDE5) inhibitors, 
and prostanoids, which are used to supplement general supportive care agents (e.g., 
anticoagulants, diuretics, digoxin).  Recent preclinical data suggest that sotatercept (murine 
analogue, RAP-011) may positively affect vascular remodelling in animal models of PAH.2  
Affected animals treated with RAP-011 showed substantial improvements in pulmonary vascular 
and cardiac hemodynamic measurements that are comparable or superior to approved agents for 
treatment of PAH.  Importantly, the animal models provide evidence of a disease-modifying 
effect, that is, a substantial reduction in the proliferation of pulmonary VSMCs in 
RAP-011-treated animals and a resultant reduction in pulmonary vascular wall thickness 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 of 
PAH, even when administered to rats with established disease.  These preclinical data suggest 
that sotatercept is a mechanism-targeted, non-vasodilator PAH therapy that may positively affect 
vascular remodelling.2 
A detailed description of the chemistry, pharmacology, efficacy, and safety of sotatercept is 
provided in the Investigator’s Brochure (IB). 
3.6. 
Benefit/Risk Assessment 
The study will be conducted in participants who require treatment for the management of PAH. 
The study design, inclusion/exclusion criteria, and procedures have been developed in a manner 
to protect participant safety. 
The evidence for potential benefits comes from data observed in rodent models of PAH.  These 
potential clinical benefits include reduced muscularization and thickness of pulmonary vessel 
walls, reduced right-sided heart pressures, and reduced right-to-left ventricle weight ratios.2  
These clinical improvements might be accompanied by benefit in hemodynamic measures such 
as reductions in PVR as well as increases in functional capacity, which will also be measured 
during the study. 
Possible risks to participants observed in prior clinical studies with sotatercept include increases 
in hemoglobin (Hgb), hematocrit, red blood cell (RBC) count, and blood pressure (BP).  These 
will be diligently monitored and managed during the study, and interruption or adjustments of 
dosing as necessary (in addition to medical treatment) to ameliorate these risks.  Potential risks 
of development of anti-drug antibodies (ADAs), reproductive effects, and renal injury, though 
not seen in clinical studies of sotatercept but observed in some preclinical studies, will also be 
monitored.  Thorough monitoring of all AEs experienced by any participant will also be 
employed in this study. 
In prior sotatercept clinical oncology studies in chemotherapy-induced anemia and osteolytic 
bone disease in multiple myeloma, the following have been described as treatment-emergent 
adverse events (TEAEs): leukopenia, neutropenia (including febrile neutropenia), 
granulocytopenia, and thrombocytopenia.  As a result of the decrease in white blood cells and 
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infection and as a consequence of thrombocytopenia, bleeding may be a potential risk.  Per 
health authority request, leukopenia, neutropenia, and thrombocytopenia have been identified as 
adverse events of special interest in this study (see Section 6.3 Dose Modification and 
Section 8.3 Adverse Events). 
More detailed information about the known and expected benefits and risks and possible AEs of 
sotatercept can be found in the IB.  
Table 5 indicates the objectives and endpoints of the study.   
Table 5: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary  
• 
To evaluate the effect of sotatercept on an 
invasive cardiopulmonary exercise test 
(iCPET) measure in PAH patients treated 
with sotatercept plus standard of care 
(SOC) 
• 
Change from baseline in VO2 max at 24 weeks 
Secondary  
• 
To evaluate the effect of sotatercept on 
additional iCPET measures in PAH patients 
treated with sotatercept plus SOC 
• 
Exercise measures, including change in 
VE/VCO2 slope (ventilatory efficiency), cardiac 
index, mean pulmonary arterial pressure, Ca-vO2 
(arteriovenous O2 content difference) at 24 
weeks  
• 
To evaluate effects of sotatercept on right 
ventricular stroke volume (RV SV), 
RV end-systolic volume (RV ESV), 
RV end-diastolic volume (RV EDV), 
RV ejection fraction (RV EF), RV stroke 
volume index (RV SVI), and RV mass by 
cardiac MR imaging in PAH patients 
treated with sotatercept plus SOC 
• 
Change from baseline in RV SV, RV ESV, 
RV EDV, RV EF, RV SVI, and RV mass by 
cardiac magnetic resonance (MR) imaging at 
24 weeks 
• 
To evaluate the effect of sotatercept on 
pulmonary vascular resistance (PVR) in 
PAH patients treated with sotatercept plus 
SOC 
• 
Change from baseline in PVR at 24 weeks 
• 
To assess the PK of sotatercept in PAH 
patients treated with sotatercept plus SOC 
• 
Population PK parameters of sotatercept 
• 
To evaluate the effect of sotatercept on 
6-minute walk distance (6MWD) in PAH 
patients treated with sotatercept plus SOC 
• 
Change from baseline in 6MWD at 24 weeks 
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Table 5: 
Objectives and Endpoints (Continued) 
Objectives 
Endpoints 
• 
To evaluate the effect of sotatercept on PD 
biomarker(s) in PAH patients treated with 
sotatercept plus SOC 
• 
Change from baseline in NT-proBNP at 
24 weeks 
• 
Change from baseline in WHO functional class 
at 24 weeks 
• 
To assess the safety and tolerability of 
sotatercept in PAH patients treated with 
sotatercept plus SOC 
• 
Clinical worsening (e.g., hospitalizations, change 
in WHO functional class) 
• 
Occurrence of adverse events 
Exploratory 
• 
To assess additional biomarkers in PAH 
patients treated with sotatercept plus SOC 
• 
Change from baseline in PAH-related 
biomarkers 
• 
To evaluate the primary and secondary 
endpoints during the Extension Period in 
PAH patients treated with sotatercept plus 
SOC 
• 
Change in selected primary and secondary 
endpoints during the Extension Period 
• 
Exercise hemodynamic measures in PAH 
patients treated with sotatercept plus SOC 
• 
RV-pulmonary arterial (PA) coupling ratio 
(based on single beat assessment), VO2 at 
anaerobic threshold (O2 consumption at 
anaerobic threshold), heart rate recovery 
(> 12 beats at 1 minute recovery), exercise 
oscillatory ventilation (present or absent as 
defined by AHA consensus statement), 
distensibility, resting and peak exercise end tidal 
CO2 
6MWD = 6-minute walk distance; AHA = American Heart Association; Ca-vO2 = arteriovenous O2 content 
difference; iCPET = invasive cardiopulmonary exercise test; MR = magnetic resonance; NT-proBNP = N-terminal 
prohormone of brain natriuretic peptide; PA = pulmonary arterial; PAH = pulmonary arterial hypertension; 
PD = pharmacodynamic; PK = pharmacokinetics; PVR = pulmonary vascular resistance; RV = right ventricular; RV 
EDV = right ventricular end-diastolic volume; RV EF = right ventricular ejection fraction; RV ESV = right 
ventricular end-systolic volume; RV SV = right ventricular stroke volume; RV SVI = right ventricular stroke 
volume index; SOC = standard of care; VE/VCO2 = ventilator efficiency; VO2 max = peak oxygen uptake; 
WHO = World Health Organization. 
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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a Phase 2a, single-arm, open-label, multicenter, exploratory study assessing the efficacy 
and safety of sotatercept for the treatment of WHO functional class III PAH. 
Study duration for each participant includes a Screening Period of up to 28 days, a 24-week 
Treatment Period, an 18-month Extension Period, and an 8-week Follow-Up Period.  
4.2. 
Clinical Sites 
This study will be conducted at approximately 5 clinical sites in the United States. 
4.3. 
Standard of Care 
In the Treatment Period, SOC therapy refers to combination therapy consisting of drugs from 
two or more of the following drug classes: an ERA, a PDE5 inhibitor, a soluble guanylate 
cyclase stimulator, and/or a prostacyclin analogue or receptor agonist.  Small adjustments or 
titrations are routine SOC for PAH therapies and are considered stable dosing.  Patients receiving 
monotherapy are not to be enrolled.  The SOC details can be found in Appendix 3. 
During the Extension Period, participants under investigator’s supervision can substitute, 
remove, or adjust the dose of SOC for PAH-worsening and chronic concomitant medications, 
including supplemental oxygen.  Investigator discretion will be used to determine if sotatercept 
study drug discontinuation is necessary. 
4.4. 
Screening Period 
Upon giving written informed consent, participants will enter the Screening Period to determine 
eligibility.  Participant screening procedures are to take place within 28 days prior to the first dose 
of study drug.  During the Screening Period, participants will undergo assessments to determine 
eligibility for the study and to obtain baseline measurements, including cardiac MR imaging 
parameters.  Right heart catheterization (RHC) for assessment of baseline CPET, PVR, 
pulmonary capillary wedge pressure (PCWP), and right-sided heart pressures is to be completed 
within 10 days prior to first dose of study drug. 
4.5. 
Treatment Period 
Approximately 25 participants will receive standard of care plus a starting dose of sotatercept 
0.3 mg/kg subcutaneously (SC) for Cycle 1 and escalate to 0.7 mg/kg SC at Cycle 2 Q3W for a 
total treatment duration of 24 weeks. 
4.6. 
Extension Period 
Participants who have not discontinued early from the 24-week Treatment Period may continue  
to an 18-month Extension Period.  Participants will continue to receive sotatercept at comparable 
dose levels, based on exposure-matching, to maintain steady-state exposures through the 
Extension Period, plus SOC. 
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Study drug will be administered subcutaneously Q3W for 18 months. 
4.7. 
Follow-Up Period 
Participants will enter into a Follow-Up Period for 8 weeks after the last dose of study treatment 
during the Extension Period.   
Participants who discontinue early, including during the 24-week Treatment Period or the 
18-month Extension Period, will be asked to return for End-of-Treatment (EOT) and 
End-of-Study (EOS) visits. 
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Figure 1: 
Study Design 
 
6MWT = 6-minute walk test; EOS = end of study; EOT = end of treatment; iCPET = invasive cardiopulmonary exercise test; MR = magnetic resonance; 
PD = pharmacodynamic; PK = pharmacokinetic; SC = subcutaneously; SOC = standard of care. 
Refer to Section 8 for a full list of study procedures/assessments. 
 
 
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4.8. 
Participant and Study Completion 
Approximately 25 participants will receive SOC plus sotatercept at a starting dose level of 
0.3 mg/kg for Cycle 1 and then 0.7 mg/kg at Cycle 2 and Q3W for the remainder of the 24-week 
Treatment Period. 
4.8.1. 
Extension Period 
All participants will continue into the 18-month Extension Period.  In the Extension Period, a 
dose regimen of Q3W will be continued. 
Upon completion of the study, participants will be provided the opportunity to transition into  the 
long-term follow-up study. 
4.9. 
End of Study Definition 
A participant is considered to have completed the study if he/she has completed all periods of the 
study, including the EOT and EOS visits. 
End of Study visits are only required for participants who discontinue the study early or decline 
transition to a future sotatercept long-term follow-up study.  The End of Study is defined as 
when the last participant completes the last visit. 
4.10. 
Justification for Dose 
Selection of the dose and dosing frequency are based on data from studies in healthy volunteers 
and patients with other chronic diseases.  In 2 completed Phase 1 studies (Studies A011-01 and 
A011-02), single doses of sotatercept up to 3.0 mg/kg intravenous (IV) and multiple doses of 
sotatercept up to 1.0 mg/kg SC were generally well tolerated in healthy postmenopausal women. 
Consistent with observations from nonclinical safety studies, many of the observed PD effects in 
the Phase 1 clinical studies were attributable to the expected biologic activity of activin 
inhibition (e.g., dose-dependent decreases in circulating follicle-stimulating hormone [FSH], and 
transient, reversible effects on red blood cell [RBC] parameters such as Hgb).  Using data from 
the Phase 1 studies, a PK/PD model for Hgb as a surrogate marker for target engagement was 
developed.  Simulations from this model also showed that the probability of having Hgb 
≥ 18 g/dL and an increase in Hgb ≥ 2 g/dL is higher during the first 3 weeks after a dose of 
0.7 mg/kg than after a dose of 0.3 mg/kg.  Therefore, a starting dose level of 0.3 mg/kg was 
selected for Cycle 1 and a dose level of 0.7 mg/kg was selected at Cycle 2 and for the remainder 
of treatment, all administered SC Q3W.  Simulations suggest that this dosing regimen may 
reduce the number of participants with increase in Hgb ≥ 2 g/dL. 
Based on the PK model developed from the Phase 1 data, the projected mean Ctrough level at 
steady state is 8.1 μg/mL at this dose and frequency.  This projected exposure is similar to the 
Cmax after the first dose of 1.0 mg/kg (7.4 μg/mL) in Study A011-02.  At the planned dose and 
frequency in this study, the projected Cmax and AUC21d are 12.4 μg/mL and 217 day*μg/mL, 
respectively. 
The risk of AEs due to Hgb increase will be ameliorated by implementation of dose reduction, 
delay, and stopping guidance in the subsequent treatment cycles (Section 6.3). 
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5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted, unless within the FDA Guidance on Conduct of 
Clinical Trials of Medical Products during COVID-19 Pandemic Guidance for Industry, 
Investigators, and Institutional Review Boards; March 2020 (FDA 2020)18.  
5.1. 
Inclusion Criteria 
Participants must satisfy all of the following criteria to be enrolled in the study: 
1. Age ≥ 18 years
2. Documented findings on right heart catheterization (RHC) at any time prior to Screening
consistent with a diagnosis of WHO pulmonary hypertension Group 1: PAH of any of the
following subtypes:
−
Idiopathic PAH
−
Heritable PAH
−
Drug- or toxin-induced PAH
−
PAH associated with connective tissue disease
−
PAH associated with simple, congenital systemic-to-pulmonary shunts at least
1 year following shunt repair
3. Symptomatic pulmonary hypertension classified as WHO functional class III
4. Screening Period RHC (within 10 days prior to C1D1 visit) documenting a minimum
PVR of ≥ 4 Wood units
5. Pulmonary function tests within 6 months prior to Screening as follows:
a.
Total lung capacity > 70% predicted; or if between 60% to 70% predicted, or not
possible to be determined, confirmatory high-resolution computed tomography (CT)
indicating no more than mild interstitial lung disease per investigator interpretation;
or,
b. Forced expiratory volume (first second) (FEV1)/forced vital capacity (FVC) > 70%
predicted
c.
For subjects with a history of lobectomy or pneumonectomy, and for whom there are
no population-based normalization methods, assessment based on residual lung
volume will be permitted to assess eligibility.
6. Ventilation-perfusion (VQ) scan (or, if unavailable, a negative CT pulmonary angiogram
[CTPA] or pulmonary angiography result), any time prior to Screening or conducted
during the Screening Period, with normal or low probability result
7. 6MWD ≥ 100 and ≤ 550 meters repeated twice during Screening Period and both values
within 15% of each other, calculated from the highest value (see Appendix 4)
8. Combination PAH therapy at stable (per SOC) dose levels as defined in Section 4.3 for at
least 90 days prior to Cycle 1 Day 1 (C1D1)
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9. Females of childbearing potential (defined in Appendix 8) must: 
a. Have 2 negative pregnancy tests as verified by the investigator prior to starting study 
and must agree to ongoing pregnancy testing during the course of the study and at end 
of study treatment. 
b. If sexually active, have used, and agree to continue to use, highly effective 
contraception** without interruption, for at least 28 days prior to starting 
investigational product (IP), during the study (including dose interruptions), and for 
16 weeks (112 days) after discontinuation of study treatment. 
c. Refrain from breastfeeding a child or donating blood, eggs, or ovum for the duration 
of the study and for at least 112 days after the last dose of study treatment. 
** (see Appendix 8 for additional contraceptive information) 
10. Male participants must: 
a. Agree to use a condom, defined as a male latex condom or nonlatex condom NOT 
made out of natural (animal) membrane (for example, polyurethane), during sexual 
contact with a pregnant female or a female of childbearing potential while 
participating in the study, during dose interruptions, and for at least 112 days 
following IP discontinuation, even if he has undergone a successful vasectomy. 
(see Appendix 8 for additional contraceptive information) 
b. Refrain from donating sperm for the duration of the study and for 112 days after the 
last dose of study treatment.  
11. Ability to adhere to the study visit schedule and understand and comply with all protocol 
requirements 
12. Ability to understand and provide written informed consent 
5.2. 
Exclusion Criteria 
Participants will be excluded from the study if they meet any of the following criteria: 
1. Started or stopped receiving any general supportive therapy for pulmonary hypertension 
(e.g., diuretics, oxygen, anticoagulants, digoxin) within 60 days prior to C1D1 
2. Received IV inotropes (e.g., dobutamine, dopamine, norepinephrine, vasopressin) within 
30 days prior to C1D1 
3. History of atrial septostomy within 180 days prior to Screening Visit 
4. History of more than mild obstructive sleep apnea that is untreated 
5. History of portal hypertension or chronic liver disease, defined as mild to severe hepatic 
impairment (Child-Pugh Classes A to C) 
6. History of human immunodeficiency virus infection-associated PAH 
7. Prior exposure to sotatercept (ACE-011) or luspatercept (ACE-536) 
8. Initiation of an exercise program for cardiopulmonary rehabilitation within 90 days prior 
to C1D1 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) 
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9. Uncontrolled systemic hypertension as evidenced by sitting systolic BP > 160 mm Hg or
sitting diastolic BP > 100 mm Hg during Screening Visit after a period of rest
10. Systolic BP < 90 mm Hg during Screening Visit or at baseline (C1D1)
11. History of known pericardial constriction
12. RHC contraindicated during the study per investigator
13. Electrocardiogram (ECG) with QTcF > 480 msec during Screening or C1D1
14. Personal or family history of long QTc syndrome or sudden cardiac death
15. Cerebrovascular accident within 3 months of C1D1
16. History of restrictive or constrictive cardiomyopathy
17. Left ventricular ejection fraction < 45% on historical echocardiogram performed within
6 months prior to Screening Period (or done as a part of the Screening Period) or PCWP
> 15 mmHg as determined in the Screening Period RHC
18. Any current symptomatic coronary disease (myocardial infarction, percutaneous coronary
intervention, coronary artery bypass graft surgery, or cardiac anginal chest pain in the
past 6 months prior to Screening Visit)
19. Acutely decompensated heart failure within 30 days prior to C1D1, as per investigator
assessment
20. Significant (≥ 2+ regurgitation) mitral regurgitation or aortic regurgitation valvular
disease
21. Any of the following clinical laboratory values during the Screening Period prior to
C1D1:
a.
Baseline Hgb > 16.0 g/dL within 28 days of C1D1
b. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels
> 3  upper limit of normal (ULN) or total bilirubin > 1.5  ULN within 28 days of
C1D1
c.
Estimated glomerular filtration rate < 30 mL/min/1.73 m2 (4-variable Modification of
Diet in Renal Disease equation) within 28 days of C1D1 or required renal
replacement therapy within 90 days
22. History of opportunistic infection (e.g., invasive candidiasis or Pneumocystis pneumonia)
within 6 months prior to Screening; serious local infection (e.g., cellulitis, abscess) or
systemic infection (e.g., septicemia) within 3 months prior to Screening
23. History of severe allergic or anaphylactic reaction or hypersensitivity to recombinant
proteins or excipients in IP
24. Major surgery within 8 weeks prior to C1D1. Participants must have completely
recovered from any previous surgery prior to C1D1
25. Prior heart or heart-lung transplants or life expectancy of < 12 months
26. Pregnant or breastfeeding females
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27. At any time in the 30 days prior to the Screening Period received > 20 mg/day of
prednisone (or equivalent) or started or changed the dose of a systemic corticosteroid.
Participants receiving stable doses of ≤ 20 mg prednisone (or equivalent) in 30 days prior
to the Screening Period are permitted in the study.
28. History of active malignancy, with the exception of fully excised or treated basal cell
carcinoma, cervical carcinoma in-situ, or ≤ 2 squamous cell carcinomas of the skin
29. History of clinically significant (as determined by the investigator) non-PAH related
cardiac, endocrine, hematologic, hepatic, immune, metabolic, urologic, pulmonary,
neurologic, neuromuscular, dermatologic, psychiatric, renal, and/or other disease that
may limit participation in the study
30. Participation in another clinical trial involving intervention with another investigational
drug, approved therapy for investigational use, or investigational device within 4 weeks
prior to C1D1, or if the half-life of the previous product is known, within 5× the half-life
prior to C1D1, whichever is longer
31. Unwillingness or inability to comply with the protocol-required procedures
5.3. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not eligible to receive study treatment.  Electronic case report forms need to be completed for all 
patients who sign the informed consent.  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 (CONSORT) publishing requirements and to respond to queries from 
regulatory authorities.  Minimal information includes demography, reason for screen failure 
adverse events, eligibility criteria. 
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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6. 
TREATMENTS 
Study treatment is defined as any investigational treatment intended to be administered to a study 
participant according to the study protocol. 
6.1. 
Treatments Administered 
Sotatercept clinical drug product will be provided by the sponsor as a lyophilized powder.  
The clinical drug product consists of sotatercept in 10 mM citrate buffer, pH 5.8, 8% sucrose, 
and 0.02% polysorbate 80.  It is supplied as a lyophilized powder in labeled, rubber stoppered, 
3-mL glass vials.  The recommended storage temperature for sotatercept lyophilized drug 
product is 2°C to 8°C.  Prior to administration, the lyophilized drug product is reconstituted with 
1 mL water for injection.  The reconstituted drug product consists of a 50 mg/mL solution of 
sotatercept.  The reconstituted sotatercept, in its original container closure system, may be held 
for up to 6 hours at 2°C to 8°C.  For details, refer to the Pharmacy Manual provided under a 
separate cover. 
SOC treatments will be provided by the treating physician based on local treatment guidelines 
and participants must remain on the same SOC treatments during the course of the study 
(see Appendix 3 for more details on SOC). 
6.2. 
Treatment Administration and Schedule 
Subcutaneous (SC) sotatercept will be administered after reconstitution as an SC injection to 
participants by the study staff at the clinical site and administration will be documented in the 
study source record.  Subcutaneous injections will be given in the upper arm, abdomen, or thigh.  
Where rounding the weight and total volume is necessary, please refer to the Pharmacy Manual 
for further details. 
Sotatercept dosing is weight based therefore an overdose would only be considered if the dose 
exceeds the no-observed-adverse-effect level (NOAEL) of 1 mg/kg.  For information on 
overdose, refer to Section 8.3.8. 
Standard of care treatments will be provided by the treating physician based on local treatment 
guidelines and participants must remain on the same SOC treatments during the study (see 
Section 4.3 and Appendix 3 for more details on SOC). 
6.3. 
Dose Modification 
Dose delay and/or reduction or discontinuation may be required for sotatercept. Guidance for 
dose modifications and dose delay are summarized in Figure 2 and Figure 3.  The details of Dose 
Modification Guidance are based on the results of platelet and Hgb values during the Treatment 
and Extension Periods.  Dose delays and reductions can be implemented for safety reasons at any 
time per Investigator’s assessment, not being restricted to the Dose Modification Guidance 
provided. 
A maximum of 3 dose delays are allowed based on safety monitoring during the study.  
If a fourth dose delay is required, the study treatment should be discontinued.  
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Questions regarding the applicability of the dose adjustment guidelines to specific situations 
must be directed to the medical monitor.   
Results from the hematology panel should be evaluated prior to study drug administration.  For 
C1D1 and C2D22 visits, blood samples should be taken and assessed for Hgb levels on the same 
day as study drug administration or 1 day prior.  If Hgb increases are > 4.0 g/dL above the 
participant baseline value, the medical monitor should be consulted, and study drug 
discontinuation should be considered. 
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Figure 2: 
Platelet Count Dose Modification: Dose Delay, Dose Reduction and Discontinuation Guidelines 
 
PLT = platelet. 
 
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Figure 3: 
Hemoglobin Dose Modification: Dose Delay, Dose Reduction and Discontinuation Guidelines 
Hgb = hemoglobin 
Once Hgb returns to the required value for dose administration, the re-starting dose will be administered at the next planned cycle or if it is the first cycle, after a 
3-week dose delay.
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Leukopenia and neutropenia are defined as AESI in Section 8.4. 
A dose reduction of study drug will be maintained unless subsequent dose reductions are 
indicated.  No more than 2 dose reductions are allowed.  If dose reductions were done due to an 
AE not related to study drug, the dose can be escalated when the AE is resolved.  In cases of 
dose reduction due to increases in Hgb, the dose can be re-escalated after 2 consecutive cycles in 
which Hgb values are stable and equal or lower than the upper limit of normal. 
Table 6: 
Dose Reductions for Sotatercept 
Starting Dose Level 
First Dose Level 
Reduction 
Second Dose Level 
Reduction 
0.3 mg/kg
0.1 mg/kg
0.05 mg/kg
No additional dose 
reductions permitted; 
discontinue treatment 
0.7 mg/kg
0.3 mg/kg
0.1 mg/kg
6.4. 
Method of Treatment Assignment 
This is a non-randomized, open-label, single treatment study.  Participants who meet all 
inclusion and none of the exclusion criteria will receive all study treatments according to the 
Schedule of Events (Table 3). 
6.5. 
Randomization and Blinding 
This is an open-label, non-randomized study. 
6.6. 
Packaging and Labeling 
The study drug will be labeled per local requirements. 
6.7. 
Preparation/Handling/Storage/Accountability 
Accountability for study drug that is administered during the course of the study is the 
responsibility of the investigator or designee.  Investigational clinical supplies must be received 
by a designated person at the clinical site and kept in a secure and temperature-controlled 
location.  The investigational site must maintain accurate records demonstrating dates and 
amounts of study drug received, to whom it was administered (participant-by-participant 
accounting), and accounts of any sotatercept accidentally or deliberately destroyed or returned.  
Accurate recording of all study drug administration is to be made in the appropriate section of 
the participant’s electronic case report form (eCRF) and source documents.  Unless otherwise 
notified, all vials of study drug, both used and unused, must be saved for drug accountability.  
The used vials may be discarded, per the institution’s standard practice, after drug accountability 
has been completed by the monitor.  The investigator must return all unused vials of study drug 
to the sponsor at the end of the study, or the study drug may be destroyed at the clinical site with 
permission of the sponsor.  For either scenario, the outcome must be documented on the drug 
accountability log.  The sponsor or designee will provide direction for the outcome of all unused 
vials. 
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Acceleron (or designee) will review with the investigator and relevant site personnel the process 
for IP return, disposal, and/or destruction including responsibilities for the site versus Acceleron 
(or designee). 
Refer to the Pharmacy Manual for further instructions for preparation of study treatments and 
information regarding disposition of unused study treatments. 
6.8. 
Treatment Compliance 
Each dose of study treatment will be administered by SC injection(s) at the clinical site by the 
study staff and is to be documented in the study source record.  Accurate recording of all study 
drug administration will be made in the appropriate section of the participant’s eCRF and source 
documents.  The investigator or designee is responsible for accounting for all study drug that is 
administered during the course of the study. 
Standard of care treatment 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 SOC exactly as prescribed and by stating that compliance is necessary for the 
participant’s safety and the validity of the study.  The participant should be instructed to contact 
the investigator if he/she is unable for any reason to take their SOC medication as prescribed 
(see Appendix 3 for more details regarding SOC). 
SOC in the Extension Period is per the Investigator’s discretion (see Section 6.9). 
6.9. 
Concomitant Therapy 
During screening and throughout the Treatment Period of the study, participants may take stable 
doses of medications for chronic conditions that are not specifically excluded by the protocol.  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 chronic condition, concurrent therapy may 
be administered at the discretion of the investigator.  If the new medication is a PAH-specific 
medication that is being added for clinical worsening (i.e., rescue therapy, refer to Section 8.5.5 
for suggested criteria), or is disallowed by entry criteria (e.g., systemic corticosteroid), the 
investigator will need to discontinue study drug treatment and perform EOT visit assessments as 
directed by the protocol.  The investigator may consult the medical monitor regarding what 
constitutes a stable dose or a chronic condition.  Information regarding concomitant medications 
will be collected after signing of the ICF and will include all medications taken during the 
Screening Period to C1D1. 
During the Extension Period, participants under investigator’s supervision can substitute, 
remove, or adjust the dose of SOC for PAH-worsening and chronic concomitant medications, 
including supplemental oxygen.  Investigator discretion will be used to determine if sotatercept 
study drug discontinuation is necessary. 
If patients need additional concomitant medications, it should be recorded in the appropriate 
eCRF.  Study drug can be adjusted or discontinued due to concomitant therapy based on the 
Investigator’s discretion.  The investigator may consult the medical monitor regarding 
discontinuation or modification of study treatment on a case-by-case basis.  
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7. 
DISCONTINUATION/WITHDRAWAL CRITERIA 
The reason for treatment discontinuation/study withdrawal must be recorded in the 
corresponding participant’s eCRF.  The investigator must notify the sponsor and medical 
monitor when a participant has discontinued treatment or been withdrawn from the study.  All 
participants who are discontinued/withdrawn from the study prior to the EOT visit should 
complete the tests and evaluations scheduled for the EOT visit at the time of 
discontinuation/withdrawal and will be asked to return to the clinic to complete the remaining 
Follow-Up EOS visit. 
7.1. 
Discontinuation of Study Treatment 
Reasons that may lead to discontinuation of study treatment include the following: 
• Completion of treatment 
• AE or serious adverse event (SAE) 
• Participant request (withdrawal of consent) 
• Clinical worsening requiring rescue therapy with a PAH agent 
• Pregnancy 
• Protocol deviation 
• Study terminated by sponsor 
• QTcF > 500 ms during treatment period 
Clinical worsening, pregnancy, and QTcF > 500 ms should be recorded as an AE, see 
Section 8.3.  
The sponsor may terminate study treatment or a dose level after consultation with the 
investigator at any time for safety or administrative reasons.  The sponsor will terminate the 
study if the occurrence of SAEs or other findings suggests unacceptable risk to the health of the 
participants.  Refer to Section 6.3, Dose Modification, for further information regarding AEs that 
can lead to discontinuation. 
7.2. 
Withdrawal from the Study 
Reasons that may lead to a participant’s withdrawal from the study include: 
• Participant’s request (withdrawal of consent) 
• Screen failure 
• Participant’s unwillingness or inability to comply with the protocol 
• AE with an outcome of death 
• Death 
• Lost to follow-up 
• Study termination by the sponsor 
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• AE or SAE 
• Pregnancy 
Serious Adverse Events and AEs, including those with an outcome of death or pregnancy, should 
be recorded as an (S)AE (see Section 8.3).   
If the participant withdraws from the study and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such withdrawal 
of consent. 
If a participant discontinues due to an AE or other medical reason, the participant must continue 
to be followed at regular intervals until the AE normalizes or returns to the participant’s baseline 
condition, as per Section 8.3.5. 
Participants to whom rescue therapy is administered (see Section 8.5.5) after demonstrating 
clinical worsening criteria (Section 8.5.4) must discontinue study drug and must be withdrawn 
from the study.  
7.3. 
Lost to Follow-Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• 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 
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).  These contact attempts should be documented 
in the participant’s study source record. 
• Should the participant continue to be unreachable, 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. 
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8. 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarized in the Schedule of Events (SoE) 
(Section 2). 
• No protocol waivers or exemptions will be allowed for eligibility criteria. 
Assessments performed outside of their defined windows will be handled as protocol 
deviations. 
• Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment. 
• Adherence to the study design requirements, including those specified in the SoE 
(Section 2), is essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria.  The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
• Procedures conducted as part of the participant’s routine clinical management 
(e.g., blood count) and obtained before signing of the ICF may be utilized for 
screening or baseline purposes provided the procedures met the protocol-specified 
criteria and were performed within the timeframe defined in the SoE (Section 2). 
• All protocol assessments are to be recorded on the participant’s source 
documentation. 
• EOS Assessment visit is the point at which the post 24-week Treatment Period and 
post-18-month Extension Period outcome measures are assessed.   
8.1. 
Screening Procedures 
• Screening procedures are to be performed as per the SoE (Section 2) and are to be 
completed and reviewed by investigator prior to dosing to confirm the participant 
meets eligibility criteria. 
• Procedures also include review of participant’s medical, surgical, and family history; 
collection of demographics, race, and ethnicity; and requests for medical records for 
external procedures. 
8.2. 
Efficacy Assessments 
8.2.1. 
iCPET 
Invasive CPET (iCPET) will be performed at the Screening, Cycle 9, and Cycle 17 visits.  
Appendix 5 provides further instructions on iCPET.  During Screening, if performed on the same 
day, the iCPET should take place after other assessments.  
At the end of the 24-week Treatment Period (Cycle 9, Day 169), Cycle 17 of the 18-month 
Extension Period, the cardiac MR imaging and iCPET may be done on separate days.  If 
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performed on the same day, iCPET should be performed before cardiac MR, with ≥ 1 hr interval 
between procedures. 
RHC will be performed as per the iCPET manual.  Zero-pressure calibration will be performed at 
the mid-axillary line with the patient in a supine position.  Superior vena cava (SVC), right atrial 
(RA), right ventricular (RV), PCW, and PA pressures will be measured, and mean vascular 
pressures will be calculated based on systolic and diastolic pressure measurements.  Heart rate 
and vascular pressures are monitored continuously.  Cardiac output is measured by the Fick 
method.  Diastolic and transpulmonary pressure gradients are obtained, systemic and PVRs are 
calculated.  
8.2.2. 
Cardiac Magnetic Resonance Imaging 
Cardiac MR imaging will be performed at Screening and at multiple time points throughout the 
study as per the SoE (Section 2).  Cardiac MR imaging must include the first bullet below.  
Assessment of cardiac structure and function (SSFP sequences).  The subsequent analyses are to 
be collected, if possible: 
• Assessment of cardiac structure and function (SSFP sequences); 
• Hemodynamic assessment of valvular flow (phase-contrast imaging), including 
pulmonary-systemic flow ratio (Qp/Qs); 
• Assessment of diffuse fibrosis (using T1 mapping); 
• Pulmonary artery (PA) compliance and vessel wall remodeling (using high-temporal 
resolution sequences). 
Specific cardiac MR imaging measurements relevant to the PAH pathophysiology include the 
following: structural anatomy and morphology of cardiac chambers; functional performance of 
the RV and the LV; anatomy and morphology of great vessels; anatomic and hemodynamic 
findings suggestive of an intra-cardiac shunt; presence of scar/fibrosis of the LV and/or RV.   
In addition to the views collected according to established methods and protocols, the following 
views and series are of vital interest and must be collected, if possible, for evaluation: 
a. 3-plane loc 
b. Transaxial black blood from above arch to diaphragm 
c. 2-chamber cine localizer 
d. Short-axis cine localizer 
e. 4-chamber cine stack and localizer 
f. 2-chamber cine  
g. Short-axis cine 
h. Short-axis T1 map of base and mid ventricle 
i. Rvot cine 
j. Oblique cines of the RT, LT, and main pulmonary art 
k. Velocity encoding (vencs) of the pulmonary artery, ascending aorta, and the mitral 
and tricuspid valves 
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Further details of the cardiac MR imaging can be found in the imaging protocol.  
Cardiac MR images will be centrally read and details of central read can be found in the imaging 
review charter.  Cardiac MR and iCPET should be done on separate days.  If performed on the 
same day, iCPET should be performed before cardiac MR, with ≥ 1 hr interval between 
procedures. 
8.2.3. 
Pulmonary Vascular Resistance by Right Heart Catheterization  
Pulmonary vascular resistance will be measured by RHC at the Screening, Cycle 9, and Cycle 17 
visits.  For participants who discontinue from the Treatment Period early, PVR will be assessed 
at their EOT visit at the time of their discontinuation.  If performed on the same day, the RHC 
should take place after other assessments (i.e., 6-meter walking test [6MWT]) have been 
completed. 
The first RHC must be performed within 10 days prior to Cycle 1 (during the Screening Period), 
the second RHC should be performed within 10 days prior to the 24-week Treatment 
Period/Cycle 9 visit (during the Treatment Period), and the third RHC should be performed 
within 10 days of Cycle 17 (during the Extension Period).  RHC should be performed ±10 days 
of the EOT visit or at the time of their discontinuation for participants who discontinue prior to 
24 weeks/Cycle 9.  RHC will assess the long-term benefits and durability of the effect of 
sotatercept treatment.   
A participant will not receive more than 3 RHC assessments during the study.  
Right heart catheterization will be performed according to the iCPET manual and is to assess 
several prognostic hemodynamic variables in addition to PVR, including right atrial pressure 
(RAP), mean PAP, mean PCWP, and cardiac output (CO).  The following hemodynamic 
parameters will be assessed when the participant is in a stable hemodynamic rest state (as 
demonstrated by 3 consecutive mean PAP and CO measurements within 10% of each other) 
while the participant is breathing ambient air or oxygen: 
• RAP, mean PAP, mean PCWP, systolic pulmonary artery pressure, diastolic 
pulmonary artery pressure, systolic BP, diastolic BP, heart rate (HR) 
• CO measured in triplicate by the Fick method  
Pulmonary vascular resistance 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 selected sites. 
8.2.4. 
Six-Minute Walk Distance 
Six minute walk distance will be measured by the 6MWT at Screening and at multiple time 
points throughout the study as per Section 2 SoE.  During the Screening visit, the 6MWT is to be 
performed twice at least 4 hours but no more than 1 week apart and 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 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.  If occurring on the same day, 6MWT should be performed before 
RHC.  Appendix 4 provides further instructions on 6MWT.  For assessment of clinical 
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worsening, a decrease of ≥ 15% in 6MWD at any time point 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. 
8.3. 
Adverse Events 
8.3.1. 
Adverse Event Definitions 
8.3.1.1. 
Adverse Events 
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 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. 
8.3.1.2. 
Unexpected Adverse Events 
An unexpected AE is an AE that, the nature, severity, specificity, or outcome of which is not 
consistent with the summary of product characteristics described in the IB under the Reference 
Safety Information. 
8.3.1.3. 
Events Not to Be Considered as Adverse Events 
Pre-existing medical conditions/signs/symptoms present 30 days prior to the Screening Period 
that do not worsen in severity or frequency during the study are defined as Baseline Medical 
Conditions and are not to be considered AEs.  Anticipated day-to-day fluctuations of pre-existing 
conditions, including the disease under study, that do not represent a clinically significant 
exacerbation or worsening need not be considered AEs. 
8.3.1.4. 
Serious Adverse Event 
An SAE is any AE, occurring at any dose level/regimen and regardless of causality that: 
• Death: An adverse event that results in death e.g., cardiac arrest. 
• Life threatening: Is an AE in which the patient was at risk of death at the time of the 
event; it does not refer to an event which hypothetically might have caused death if it 
were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization; 
however, a hospitalization for an elective procedure will not be considered an SAE. 
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•
Results in persistent or significant disability/incapacity.  An AE is incapacitating or
disabling if the experience results in a substantial and/or permanent disruption of the
subject's ability to carry out normal life functions.
•
Is a congenital anomaly/birth defect: Congenital anomaly/birth defect in a child of a
subject or its partner that was exposed to study drug prior to conception or during
pregnancy.
•
Other, is an important medical event: An important medical event is an event that
may not result in death, be life-threatening, or require hospitalization but may be
considered an SAE when, based upon appropriate medical judgment, it may
jeopardize the patient and may require medical or surgical intervention to prevent one
of the outcomes listed in the definitions for SAEs.  Examples of such medical events
include allergic bronchospasm requiring intensive treatment in an emergency room or
at home, blood dyscrasias, or convulsions that do not result in inpatient
hospitalization, or the development of drug dependency or drug abuse.
For the purposes of reporting per regulations, any suspected transmission of an infectious agent 
via a medical product is by default a suspected unexpected serious adverse reaction (SUSAR) 
and should be reported in an expedited manner as described in Section 8.3.7. 
8.3.1.5. 
Events Not to Be Considered as Serious Adverse Events are Hospitalizations for: 
•
A standard procedure for protocol therapy administration.  However, hospitalization
or prolonged hospitalization for a complication of therapy administration will be
reported as an SAE.
•
Routine treatment or monitoring of the studied indication not associated with any
deterioration in condition.
•
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.
•
A procedure that is planned (i.e., planned prior to starting of treatment on study);
must be documented in the source document and the eCRF.  Hospitalization or
prolonged hospitalization for a complication remains a reportable SAE.
•
An elective treatment of a pre-existing condition unrelated to the studied indication.
•
Emergency outpatient treatment or observation that does not result in admission,
unless fulfilling other seriousness criteria above.
If an AE is considered serious, both the AE page/screen of the eCRF and the SAE Report Form 
must be completed. 
For each SAE, the investigator will provide information on severity, start and stop dates, 
relationship to IP, rationale of the causality, the action taken regarding IP, and outcome. 
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8.3.1.6. 
Severity 
Investigators must evaluate the severity/intensity of AEs and SAEs according to the current 
active version of the NCI-CTCAE (NCI-CTCAE), preferentially using the graded scales.  If 
there is a change in severity of an AE, it must be recorded as a separate event.  If a particular 
AE’s severity/intensity is not specifically graded, the investigator should apply the general 
guidelines for determination of Grade 1 through Grade 5 as listed in the NCI-CTCAE cover page 
(as shown below), using their best medical judgment: 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting age 
appropriate- instrumental activities of daily living (preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.). 
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
activities of daily living (bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden). 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
Grade 5: Death related to AE. 
The term “severe” is often used to describe the intensity of a specific event (as in mild, moderate, 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache).  This criterion is not the same as “serious,” which is 
based on subject/event outcome or action criteria associated with events that pose a threat to a 
subject’s life or functioning. 
Seriousness, not severity, serves as a guide for defining regulatory obligations. 
8.3.2. 
Relationship to Study Drug 
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, known side effects of study drug, concomitant 
therapy, course of the underlying disease and pertinent study procedures. 
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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8.3.3. 
Documentation and Methods of Detecting Adverse Events and Serious 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 non-leading verbal questioning of the participant is 
the preferred method to inquire about AE occurrences.  All clearly related signs and symptoms 
which are either volunteered by participants or are observed during or following the course of 
investigational product administration must be reported on the appropriate eCRF.  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 eCRF.  Any clinically relevant changes in laboratory assessments or 
other clinical findings as described in Section 8.3.1.1  are considered AEs and must be recorded 
on the AE eCRF.  AEs are to be followed for resolution as described in Section 8.3.5. 
It is important that each AE report include a description of the event, duration (onset and 
resolution dates), severity, relationship with sotatercept, any other potential causal factors, any 
treatment given or other action taken (including dose modification or discontinuation of 
sotatercept), and outcome.  In addition, SAEs should be identified and the appropriate 
seriousness criteria documented.  AEs categorized as SAEs must also be documented within the 
appropriate SAE section in the eCRF or a paper SAE form if the system is down or otherwise 
unavailable, as described in Section 8.3.4.  Note that both methods should not be used beside 
each other, the paper SAE Form is for back up reporting only.  
Specific guidance can be found in the eCRF Completion Guidelines provided by the sponsor or 
designee. 
8.3.4. 
Documentation of Serious Adverse Events 
For all SAEs, an SAE form must be completed with as much information as possible and 
submitted within the time frame described in Section 8.3.6. 
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. 
8.3.5. 
Reporting Period and Monitoring of Participants with AEs 
As described in Section 8.3.3, all AEs must be recorded in the eCRF from the signing of the 
informed consent up until the EOS visit.  All participants who took at least 1 dose of study drug, 
whether they completed the Treatment Period or not, should complete the EOT and EOS visits. 
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.  
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Follow-up data for SAEs obtained after clinical database lock will be incorporated into the 
sotatercept safety database. 
8.3.6. 
Notification About Serious Adverse Events 
If an SAE occurs during the reporting period, the investigator must immediately, within a 
maximum 24 hours after becoming aware of the event, inform the sponsor via the contract 
research organization (CRO) by telephone, fax, or email.  Per Section 8.3.3, paper SAE forms 
should be used to report an SAE if the eCRF is unavailable. 
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, and telephone and fax numbers for SAE reporting are located on the SAE 
Report Form and in the completion, instructions provided for the Investigator Site File.  When an 
SAE (or follow-up information) is reported by telephone, a written report must be sent 
immediately thereafter by fax or email.  Reporting procedures and timelines for follow-up 
information are the same as for the initially reported SAE. 
Relevant pages from the eCRF 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 eCRF. 
The investigator/reporter must respond to any request for follow-up information or to any 
question the sponsor or designee may have on the AE within the same timelines as described for 
initial reports.  This is necessary to permit a prompt assessment of the event by the sponsor and 
(as applicable) to allow the sponsor to meet regulatory timelines associated with expedited 
reporting obligations. 
Requests for follow-up will usually be made by the responsible clinical research associate or 
medical monitor, or an Acceleron pharmacovigilance representative who may contact the 
investigator directly to obtain clarification on a particularly critical event. 
8.3.7. 
Safety Reporting to Health Authorities, Independent Ethics Committees, 
Institutional Review Boards, and Investigators 
The sponsor will send appropriate safety notifications to Health Authorities in accordance with 
applicable laws and regulations. 
The investigator must comply with any applicable site-specific requirements related to the 
reporting of SAEs involving his/her participants to the IEC that approved the study. 
In accordance with International Council for Harmonisation (ICH) Good Clinical Practice (GCP) 
guidelines, the sponsor 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 continue the study.” 
The sponsor will inform the investigator of AEs that are both serious and unexpected and are 
considered to be related to sotatercept (SUSARs).  The investigator should place copies of these 
Safety Reports in the Investigator Site File.  National regulations with regard to Safety Report 
notifications to investigators will be followed. 
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When specifically required by regulations and guidelines, the sponsor will provide appropriate 
Safety Reports directly to the concerned lead IEC and will maintain records of these 
notifications.  When direct reporting by the sponsor is not clearly defined by national or 
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. 
8.3.8. 
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 purpose of this trial, an overdose is defined as 
any dose that has exposures in excess of monkey NOAEL dose of 1 mg/kg (IB Edition 14, 
Section 3.3.2, Table 4), which was also the highest dose tested in human volunteers study 
(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 or a specified designee within 24 hours and be fully 
documented as an AE in the eCRF.  
There is no antidote for sotatercept, and it is not dialyzable from blood, therefore in case of 
overdose patients should be monitored/treated as per clinical practice based on symptoms of 
identified and potential risks as described in the IB. 
8.3.9. 
Transmission of an Infectious Agent 
Definition: Transmission of an infectious agent via study drug administration.  Any organism, 
virus, or infectious particle (e.g., protein transmitting transmissible spongiform encephalopathy), 
pathogenic or non-pathogenic, is considered an infectious agent.   
Transmission of an infectious agent may be suspected from clinical signs or symptoms or 
laboratory findings indicating an infection in a patient exposed to study drug.  As in the case of 
suspected adverse reactions and adverse reactions, the terms suspected transmission and 
transmission are considered synonymous. 
In the context of evaluating a suspected transmission of an infectious agent via study drug 
administration, care should be taken to discriminate, whenever possible, between the cause 
(e.g., injection/administration) and the source (e.g., contamination) of the infection and the 
clinical conditions of the patient at the time of the infection (immune-suppressed/vaccine). 
Any instance of transmission of an infectious agent must be communicated to Acceleron or a 
specified designee within 24 hours to the sponsor using appropriate channels (e.g., telephone, 
email) and be fully documented as an AE in the eCRF, or as an SAE if associated SAE occurs 
(see Section 8.3 for further instruction). 
8.3.10. 
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 
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and up until 112 days after last dose of study drug treatment.  The pregnancy information will be 
recorded on the appropriate form and must be submitted to the sponsor 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 the sponsor 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 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 
112 days after the last dose. 
•
If a pregnancy is reported, the investigator must inform the sponsor within 24 hours
of learning of the pregnancy and should follow the procedures outlined in
Appendix 8.
•
Additional pregnancy, breastfeeding, and sperm/ovum donor information is provided
in Appendix 8.
8.4. 
Monitoring of Identified, Potential and Adverse Events of Special 
Interest 
The risks outlined below are consistent with the list in Sotatercept IB (IB Edition 14).  The AESI 
are considered important parameters to be monitored in order to assess the overall safety of the 
PAH patient population, therefore, added for safety monitoring in the sotatercept clinical trial. 
The 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 the study schedule 
or upon an unscheduled visit if applicable.  Section 6.3 provides details for dose modifications 
due to decreases in platelets and Hgb. 
Additional reviews will be performed periodically as part of standard safety signal detection and 
medical monitoring. 
8.4.1. 
Identified Risk 
Table 7 describes the identified risks that could occur during the study drug treatment. 
Table 7: 
Identified Risks 
Description 
Monitor Parameter 
Planned Action 
Blood pressure 
increase 
Hypertension SMQ 
(Narrow and broad) 
Monitor the vital signs for any hypertension 
trending in combination with the events reported. 
Additionally, review for risk factors of systemic 
hypertension (diabetes, metabolic syndrome, and 
obesity), concomitant medications, and previous 
medical history of hypertension. 
SMQ = standardized MedDRA queries 
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8.4.2. 
Potential Risks 
Laboratory data and AEs are measured as per protocol schedule or upon an unscheduled visit if 
applicable.  Section 6.3 provides details for dose modifications due to decreases in hematocrit 
and/or platelets.  Table 8 provides potential risks that could occur during study drug treatment. 
Table 8: 
Potential Risks 
Description 
Monitor Parameter 
Planned Action 
Increase in RBC 
 
RBC parameters  
(RBC, Hgb, and Hct) 
• 
Careful monitoring of RBC parameters is 
performed and in case of Hct ≤ 55% 
• 
Dose hold and/or dose decrease guidance 
is to be followed 
Additionally 
• 
Monitor by safety and Acceleron clinical 
physician using laboratory data (Hgb/Hct) 
• 
The medical monitor will ensure dosage 
adjustment according to the protocol 
• 
Monthly review of Hct/Hgb listings by 
safety team member (hematology expert) 
Immunogenicity for 
biologic 
Compound 
Anaphylactic reaction 
(SMQ) (Narrow and 
broad) and 
Hypersensitivity (SMQ) 
(Narrow and broad) 
• 
Immunogenicity will continue to be 
evaluated on reported events  
• 
The study sampling of anti-drug antibody 
is to be reviewed at the end of the study 
Renal toxicity 
Acute renal failure 
(SMQ) (Narrow and 
broad) 
• 
Renal monitoring of AEs in a combination 
of laboratory data monitoring of UA of 
protein/blood and eGFR 
AE = adverse event; eGFR = estimated glomerular filtration rate; Hct = hematocrit; Hgb = hemoglobin; RBC = red 
blood cell; SMQ = standardized MedDRA queries; UA = urinalysis  
8.4.3. 
Adverse Events of Special Interest 
Table 9 describes AESIs that may occur during study drug treatment. 
Table 9: 
Adverse Events of Special Interest 
Description 
Monitor Parameter 
Planned Action 
Fertility disorders 
with a focus on 
suppression of FSH 
SMQ fertility disorders 
Fertility disorders with a focus on FSH monitoring 
of AEs and laboratory data review of FSH 
 
Hepatic toxicity 
Hepatic disorders 
(SMQ) (Narrow and 
broad) 
Hepatic monitoring of AEs in combination of 
laboratory data Hy’s law laboratory data 
monitoring AST, ALT, ALP 
Cardiac events and 
Embolic and 
thrombotic events  
Ischaemic heart disease 
(SMQ) 
Monitor of AEs in combination of risk factors of 
systemic hypertension (diabetes, metabolic 
syndrome, obesity), concomitant medications, 
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Description 
Monitor Parameter 
Planned Action 
Embolic and thrombotic 
events (SMQ) 
previous medical history of heart and embolic, 
thrombotic events 
Thrombocytopenia, 
leukopenia, and 
neutropenia 
 
Thrombocytopenia, 
leukopenia, and 
neutropenia 
 
Careful monitoring of platelet counts is performed 
and in case platelet counts are < 50.000/mm3 
(< 50.0x109/L), the dose hold and/or dose decrease 
guidance is to be followed. 
Additionally: 
• 
Monitoring of leukopenia and neutropenia 
as part of medical and periodic review 
• 
Monitoring of AEs and the medical history 
and concomitant medications that may 
cause thrombocytopenia, leukopenia, and 
neutropenia 
AE = adverse event; AESI = adverse event of special interest; ALP = alkaline phosphatase; ALT = alanine 
aminotransferase; AST = aspartate aminotransferase; FSH = follicle-stimulating hormone; MedDRA = Medical 
Dictionary for Regulatory Activities; SMQ = standardized MedDRA queries. 
Per the request of the European Health Authority, thrombocytopenia, leukopenia, and neutropenia were added as 
AESIs. 
8.5. 
Safety Assessments 
Planned time points for all safety assessments are provided in Section 2, the SoE. 
8.5.1. 
Physical Examinations 
• A full physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, 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 and will be completed at all other visits after 
screening. 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
8.5.2. 
Vital Signs 
• Temperature, weight, pulse rate, respiratory rate, and BP will be assessed at every 
visit.  Height will be measured once, during the screening period. 
• BP and pulse measurements will be assessed with a completely automated device 
while seated.  Manual techniques will be used only if an automated device is not 
available. 
• Vital signs should be taken before blood collection for laboratory tests.  BP and pulse 
measurements should be preceded by approximately 10 minutes of rest for the 
participant in a quiet setting without distractions (e.g., television, cell phones) for the 
initial reading.  Blood pressure values should be confirmed by mean of 2 readings 
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obtained approximately 5 minutes apart.  The average of the BP readings will be 
recorded on the eCRF. 
• Clinically significant abnormal findings will be reported as AEs (see Section 6.3 and 
Section 8.4). 
8.5.3. 
Electrocardiograms 
• A 12-lead ECG will be obtained as outlined in the SoE.  Parameters obtained will be 
HR, PR, QRS, and QT; QTcF intervals will be calculated.  If the ECG machine does 
not automatically calculate QTcF, it should be manually calculated. 
• Clinically significant abnormal findings will be reported as AEs. 
• If scheduled on the same day, ECGs should be performed prior to 6MWT.  
8.5.4. 
Clinical Worsening 
• Clinical worsening will be assessed by the investigator at each visit outlined in the 
SoE (or at any other time at the Investigator’s discretion) and recorded on the eCRF. 
• Assessments are the following: 
− Death 
− Worsening-related listing for lung and/or heart transplant 
− Need to initiate rescue therapy (see below), with an approved PAH SOC therapy 
− Need for atrial septostomy 
− PAH-specific hospitalization (> 24 hours) 
− Functional deterioration as defined by both of the below events occurring together 
at any time, even if they began at different times, as compared to their Screening 
values: 
− Worsened WHO functional class (III to IV)  
and 
− Decrease in 6MWD by ≥ 15% as compared to Screening (confirmed by two 
6MWTs; Section 8.2.4) 
• Clinically significant abnormal findings will be reported as AEs. 
8.5.5. 
Rescue Therapy Criteria  
Suggested clinical worsening criteria for the investigator to initiate rescue therapy with an 
approved PAH SOC therapy (and therefore discontinue study drug) include the following: 
• Participants who experience worsening of PAH requiring hospitalization for more 
than 24 hours. 
• PAH functional deterioration (worsening of WHO functional class by 1 level and a 
decrease in 6MWD of 15% as compared to Screening measured on 2 occasions).  
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8.5.6. 
Clinical Safety Laboratory Assessments 
• See Appendix 2 for the list of clinical laboratory tests to be performed and refer to the 
SoE for the timing and frequency. 
• If Hgb is ≥ 17 g/dL during Cycle 1 (Day 8) or Cycle 2 (Day 29), participants should 
return weekly for Hgb monitoring.  Clinically significant abnormal Hgb findings will 
be reported as AEs.  Dose Modification Guidance should be followed (see Figure 3). 
• Clinically significant abnormal Hgb findings will be reported as AEs.   
• The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
eCRF.  The laboratory reports must be filed with the source documents.  Clinically 
significant abnormal laboratory findings are those which are 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 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 the sponsor 
notified. 
− All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and Section 2, SoE. 
− If laboratory values from non-protocol-specified laboratory assessments 
performed at the institution’s local laboratory require a change in participant 
management or are considered clinically significant by the investigator (e.g., SAE 
or AE or dose modification), then the results must be recorded in the eCRF. 
8.6. 
Pharmacokinetics 
• Serum samples will be collected for measurement of serum concentrations of 
sotatercept as specified in Section 2 SoE.  Instructions for the collection and handling 
of biological samples will be provided by the sponsor.  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 PK of other 
concomitant medications and safety or efficacy aspects related to concerns arising 
during or after the study. 
Participants who have already entered the Extension Period under Protocol Amendment 3A 
(Q4W dosing regimen) should have a pre-dose PK sample taken at an unscheduled visit before 
transitioning to Q3W dosing under this amendment. 
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8.7. 
Pharmacodynamics 
Venous blood samples will be collected for measurement of PD biomarkers including but not 
limited to NT-proBNP, transforming growth factor-βeta 1 (TGF-β1), vascular endothelial growth 
factor receptor (VEGFR1), and sex hormone metabolites N-terminal prohormone of brain 
natriuretic peptide (NT-proBNP), at time points listed in Section 2 SoE.  Samples collected for 
NT-proBNP analyses may also be used to evaluate safety or efficacy aspects related to concerns 
arising during or after the study. 
Transpulmonary Flux Biomarkers: Samples from the RHC and from the radial artery will be 
collected at rest, peak exercise, and post-exercise during the iCPET procedure at the time points 
listed in the SoE and as described in the iCPET manual.  These samples will be stored and may 
be analyzed at a later date for exploratory biomarkers. 
8.8. 
Genetic Testing 
Participants will have a genetic sample taken to assess the mutation status and allele frequency 
(e.g., BMPR2) at C1D1.  Since genetic mutations in BMPR2 are associated with PAH, this 
testing may provide insight into the genetic basis of PAH and potential response to sotatercept.  
Other potential genetic analyses include, but are not limited to, activin receptor-like kinase 1, 
caveolin 1, eukaryotic translation initiation factor 2-alpha kinase 4, endoglin, potassium channel 
subfamily K member 3, and mothers against decapentaplegic homolog 9; otherwise known as 
SMAD9.  See Appendix 9 for more information regarding genetic testing.  
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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Sample Size Determination 
Assuming the change from baseline of peak VO2 is 1.5 mL/min/kg, with a standard deviation of 
3 mL/min/kg, the sample size needed will be 19 participants with 1-sided alpha=0.10 level and 
80% power.  This approximate level of improvement in pulmonary hypertension patients has 
been associated with a 28% decrease in PVR.11 
This sample size of 19 participants will also provide 80% power to detect an increase from 
baseline of at least 10 mL in RV SV at 1-sided alpha=0.10 level, assuming the standard deviation 
of RV SV is 20 mL.  It is expected that a 10-mL improvement in SV correlates with an ability 
for the patient to walk and additional 41 m on 6MWT in patients with PAH.12 
Assuming a 25% drop-out rate, approximately 25 participants will be enrolled. 
9.2. 
Populations for Analyses 
Evaluable Population: All participants who have completed the Treatment Period and had the 
iCPET assessment and cardiac MR imaging at the 24-week time point, with no major protocol 
deviations, which includes major inclusion and exclusion criteria deviations, concomitant 
therapy or procedures that impact the efficacy evaluation, and other deviations that also have 
major impacts on the efficacy of the study treatment.  
Safety Population: All participants who receive at least 1 dose of study treatment. 
Pharmacokinetic Population: All participants who receive at least 1 dose of study treatment and 
have at least 1 PK sample analyzed. 
9.3. 
Statistical Analyses 
The Statistical Analysis Plan (SAP) will be developed and finalized before topline (24 weeks) 
database lock and will describe the analysis details.  Data will be reviewed as needed to support 
regulatory filings.  This section is a summary of the planned statistical analyses of the primary 
and key secondary endpoints.  A separate SAP for the extension period analysis will be 
developed and finalized before the final database lock. 
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9.3.1. 
Efficacy Analyses 
Table 10: 
Statistical Analysis of Endpoints 
Endpoint 
Statistical Analysis Methods 
Primary 
The mean and standard deviation for change from baseline of peak VO2 will be 
calculated together with the corresponding 95% CI.  The evaluable population will be 
used for the primary endpoint analyses. 
Secondary 
Descriptive statistics will be presented for secondary cardiac MR endpoints (RV SV, 
RV ESV, RV EDV, RV EF, RV SVI, and RV mass by cardiac MR imaging), iCPET 
endpoints (VE/VCO2, Ca-vO2), PVR, 6MWD, and biomarker endpoint NT-proBNP.  
Frequency summaries will be provided for WHO functional class assessments and 
participants with clinical worsening.  Nonlinear mixed effects modeling will be 
employed to determine population PK parameters of sotatercept. 
Exploratory 
Descriptive statistics will be presented for biomarker endpoint change from baseline in 
PAH-related biomarkers.  Change from baseline in selected primary and secondary 
endpoints during the 8-week Follow-Up Period will be summarized through descriptive 
statistics.  Exercise hemodynamic measures will be summarized through descriptive 
statistics. 
Other 
Endpoints 
In general, continuous data will be summarized descriptively for absolute values and 
change from baseline with n, mean, SD, median, minimum, maximum, and categorical 
data will be summarized with frequency and percentage. 
6MWD = six-minute walk distance; Ca-vO2 = content difference, arteriovenous O2; CI = confidence interval; 
iCPET = invasive cardiopulmonary exercise test; MR = magnetic resonance; NT-proBNP = N-terminal prohormone 
of brain natriuretic peptide, PAH = pulmonary arterial hypertension; PK = Pharmacokinetic; PVR = pulmonary 
vascular resistance; RV = right ventricular; RV EDV = right ventricular end-diastolic volume; RV EF = right 
ventricular ejection fraction; RV ESV = right ventricular end-systolic volume; RV SV = right ventricular stroke 
volume; RV SVI = right ventricular stroke volume index; SD = standard deviation; VE/VCO2 = ventilator 
efficiency; VO2 = peak O2 uptake; WHO = World Health Organization 
Details will be described in the statistical analysis plan and finalized before database lock. 
9.3.2. 
Safety Analyses 
All safety analyses will be performed on the Safety Population. 
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA). 
Adverse event listings will include the verbatim term and the MedDRA preferred term. 
Treatment-emergent AEs (TEAEs) will be summarized by worst severity grade, system organ 
class, and preferred term.  TEAEs related to the IP will also be summarized.  TEAEs leading to 
death or discontinuation from treatment and serious TEAEs will be listed separately. 
Clinical laboratory results will be summarized descriptively for the Safety Population.  Clinically 
significant laboratory abnormalities will be flagged in the listing.  Shift tables will be presented 
for hematology, serum chemistry, and urinalysis tests.  Renal function laboratory tests (creatinine 
and urine albumin creatinine ratio) will be collected regularly during the Treatment Period and 
may be limited to creatinine in the Extension Period.  The descriptive statistics (mean, SD, 
median, min, max) will be provided for each time point of the collection. 
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Vital sign measurements, ECG results, and physical examination data will be listed for each 
participant at each visit.  Descriptive statistics for vital signs and ECG parameters, both observed 
values and changes from baseline, will be summarized. 
Immunogenicity (incidence/titer of ADA) will also be analyzed. 
9.3.3. 
Other Analyses 
Pharmacokinetic, PD, and biomarker exploratory analyses will be described in the statistical 
analysis plan finalized before database lock. 
9.3.4. 
Primary Endpoint Analysis 
An analysis of the primary endpoint of change in VO2 at 24 weeks Treatment Period (Cycle 9) 
versus the screening assessment will be performed on the evaluable population when all 
participants during the Treatment Period have completed their 24-week (Cycle 9) iCPET 
assessment or EOT iCPET for those subjects who discontinue early during the Treatment Period, 
as described in Section 9.3.1. 
9.3.5. 
Extension Period Analysis 
All the endpoints will be analyzed in a similar way for the Extension Period as with the main 
analysis in the Treatment Period.  
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10. 
REFERENCES 
1. Farber HW, Miller DP, Poms AD, et al.  Five-year outcomes of patients enrolled in the 
REVEAL Registry. Chest 2015;148:1043-54. 
2. Yung L PR, Bocobo G, et al. Abstract 18906: ACTRIIA-Fc rebalances BMP and 
activin/TGF-β signaling to attenuate experimental pulmonary hypertension. Circulation 
2017; 2017;136(Suppl 1):A18906. 
3. Rubin LJ. Primary pulmonary hypertension. N Engl J Med 1997;336:111-7. 
4. Simonneau G, Galie N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. 
J Am Coll Cardiol 2004;43:5-12S. 
5. Schermuly RT, Ghofrani HA, Wilkins MR, et al. Mechanisms of disease: pulmonary 
arterial hypertension. Nat Rev Cardiol 2011;8:443-55. 
6. Vonk-Noordegraaf A, Haddad F, Chin KM, et al. Right heart adaptation to pulmonary 
arterial hypertension: physiology and pathobiology. J Am Coll Cardiol 2013;62:D22-33. 
7. Morrell NW. Pulmonary hypertension due to BMPR2 mutation: a new paradigm for tissue 
remodeling? Proc Am Thorac Soc 2006;3:680-6. 
8. Machado RD, Aldred MA, James V, et al. Mutations of the TGF-beta type II receptor 
BMPR2 in pulmonary arterial hypertension. Hum Mutat 2006;27:121-32. 
9. 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;37:67-119. 
10. Maron BA, Cockrill BA, Waxman AB, et al. The invasive cardiopulmonary exercise test. 
Circulation 2013;127:1157-64. 
11. Lewis GD, Shah RV, Pappagianopolas PP, et al. Determinants of ventilatory efficiency in 
heart failure: the role of right ventricular performance and pulmonary vascular tone. Circ 
Heart Fail 2008;1:227-33. 
12. van Wolferen SA, van de Veerdonk MC, Mauritz GJ, et al. Clinically significant change 
in stroke volume in pulmonary hypertension. Chest 2011;139:1003-9. 
13. Forfia PR, Fisher MR, Mathai SC, et al. Tricuspid annular displacement predicts survival 
in pulmonary hypertension. Am J Respir Crit Care Med 2006;174:1034-41. 
14. Gabler NB, French B, Strom BL, et al. Validation of 6-minute walk distance as a surrogate 
end point in pulmonary arterial hypertension trials. Circulation 2012;126:349-56. 
15. Brooks D SS, Gibbons WJ. ATS statement on 6-minute walk test. Am J Respir Crit Care 
Med 2003;167:1287. 
16. ATS Statement. Guidelines for the Six-Minute Walk Test. Am J Crit Care 2002;166:111-7. 
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17. Holland AE, Spruit MA, Troosters T, et al. An official European Respiratory 
Society/American Thoracic Society technical standard: field walking tests in chronic 
respiratory disease. Eur Respir J 2014;44(6):1428-46. 
18. Guidance for Industry, Investigators, and Institutional Review Boards: FDA Guidance on 
Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic. U.S. 
Department of Health and Human Services Food and Drug Administration Center for 
Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and 
Research (CBER). March 2020 (updated 16 April 2020). 
 
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11. 
APPENDICES 
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APPENDIX 1. ABBREVIATIONS AND SPECIALIST TERMS 
Abbreviation or Specialist Term 
Explanation 
6MWD 
Six-minute walk distance 
6MWT 
Six-minute walk test 
ACE-011 
Sotatercept 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AHA 
American Heart Association 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC21d 
Area under the concentration-time curve from time zero to Day 21 
BMP 
Bone morphogenetic protein 
BMPR2 
Bone morphogenetic protein type II receptor 
BP 
Blood pressure 
Ca-vO2 
Content difference, arteriovenous O2 
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
Cmax 
Maximum concentration 
CMR 
Cardiac Magnetic Resonance Imaging 
CO 
Cardiac output 
CONSORT 
Consolidated Standards of Reporting Trials 
CPET 
Cardiopulmonary exercise test 
CRF 
Case report form 
CRO 
Contract research organization 
CT 
Computed tomography 
CTPA 
Computed tomography pulmonary angiogram 
Ctrough 
Minimum concentration before dosing 
CxDy 
Cycle x Day y 
DBP 
Diastolic blood pressure 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EF 
Ejection fraction 
EOS 
End of study 
EOT 
End of treatment 
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Abbreviation or Specialist Term 
Explanation 
ERA 
Endothelin-receptor antagonist 
FC 
Functional classification 
FDA 
Food and Drug Administration 
FEV1 
Forced expiratory volume in 1 second 
FSH 
Follicle-stimulating hormone 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
Hgb 
Hemoglobin 
HR 
Heart rate 
HRT 
Hormone replacement therapy 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
iCPET 
Invasive cardiopulmonary exercise test 
IEC 
Independent ethics committee 
IgG1 
Immunoglobulin G1 
IP 
Investigational product 
IRB 
Institutional review board 
IUD 
Intrauterine device 
IV 
Intravenous 
LV 
Left ventricular 
MedDRA 
Medical Dictionary for Regulatory Activities 
MR 
Magnetic resonance 
NOAEL 
no-observed-adverse-effect level 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse 
Events 
NT-proBNP 
N-terminal prohormone of brain natriuretic peptide 
PA 
Pulmonary artery 
PAH 
Pulmonary arterial hypertension 
PAP 
Pulmonary arterial pressure 
PCWP 
Pulmonary capillary wedge pressure 
PD 
Pharmacodynamic 
PDE5 
Phosphodiesterase type 5 
PK 
Pharmacokinetic 
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Abbreviation or Specialist Term 
Explanation 
PPD 
PPD Safety Hotline, medical monitor for this study 
PVR 
Pulmonary vascular resistance 
Q3W 
Every 3 weeks 
Q4W 
Every 4 weeks 
Qp/Qs 
Pulmonary-Systemic Flow Ratio 
RA 
Right atrial 
RAP 
Right atrial pressure 
RBC 
Red blood cell 
RHC 
Right heart catheterization 
RV 
Right ventricular 
RV EDV 
Right ventricular end-diastolic volume 
RV EF 
Right ventricular ejection fraction 
RV ESV 
Right ventricular end-systolic volume 
RV PA 
Right ventricular pulmonary artery 
RV SV 
Right ventricular stroke volume 
RV SVI 
Right ventricular stroke volume index 
SBP 
Systolic blood pressure 
SAE 
Serious adverse event 
SC 
Subcutaneous(ly) 
SD 
Standard deviation 
SOC 
Standard of care 
SoE 
Schedule of Events 
SSFP 
Structure and Function Sequences 
SUSAR 
Suspected unexpected serious adverse reaction 
SV 
Stroke volume 
SVC 
Superior vena cava 
TEAE 
Treatment-emergent adverse event 
TGF-β 
Transforming growth factor-beta 
UA 
Urinalysis 
UACR 
Urine albumin creatinine ratio 
ULN 
Upper limit of normal 
VAF 
Variant allele frequency 
VE/VCO2 
Ventilator efficiency 
Venc 
Velocity encoding (cardiac motion view via MRI) 
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Abbreviation or Specialist Term 
Explanation 
VO2 max 
Peak O2 uptake 
VQ 
Ventilation-perfusion 
VSMC 
Vascular smooth muscle cell 
WHO 
World Health Organization 
WOCBP 
Woman of childbearing potential 
 
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APPENDIX 2. CLINICAL LABORATORY TESTS 
The tests detailed in Table 11 will be performed by local laboratories at the time points specified 
in the Schedule of Events (SoE, Section 2). 
Additional tests may be performed at any time during the study as determined necessary by the 
investigator or required by local regulations. 
Table 11: 
Protocol-Required Safety Laboratory Assessments 
Laboratory Assessments 
Parameters 
Hematology 
Complete blood count (CBC) with differential: CBC includes RBCs, 
white blood cells (WBCs), platelets, hemoglobin, hematocrit, mean 
corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean 
corpuscular hemoglobin concentration (MCHC), reticulocyte count, and 
platelet count 
Serum chemistry 
Albumin, alkaline phosphatase (ALP), ALT, AST, blood urea nitrogen 
(BUN), calcium, chloride, carbon dioxide, creatinine, glucose, 
phosphorus, potassium, sodium, total bilirubin, direct bilirubin 
Urinalysis 
Urinalysis 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CBC = complete 
blood count; CR = creatinine; Hgb = hemoglobin; Hct = hematocrit; RBC = red blood cell; WBC = white blood cell 
Investigators must document their review of each laboratory safety report. 
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APPENDIX 3. STANDARD OF CARE THERAPY 
Standard of care therapy refers to combination therapy consisting of at least 2 agents (each from 
a different class) from a list including the following: an ERA, a PDE5 inhibitor, a soluble 
guanylate cyclase stimulator, and/or a prostacyclin analogue or receptor agonist. 
Standard of Care should remain stable throughout the study.  Small adjustments or titrations are 
routine SOC for PAH therapies and are considered stable dosing.  If a participant has an event of 
clinical worsening requiring rescue therapy (see Section 8.5.5), SOC therapy may be altered as 
per the treating physician’s decision, and the participant will be discontinued from study drug 
treatment.  Any other changes (aside from rescue therapy for clinical worsening) to a 
participant’s SOC should be discussed with the medical monitor on a case-by-case basis to 
determine if the participant may stay on study treatment. 
During the Extension Period, participants under investigator’s supervision can substitute, 
remove, or adjust the dose of SOC for PAH-worsening and chronic concomitant medications, 
including supplemental oxygen.  Investigator discretion will be used to determine if sotatercept 
study drug discontinuation is necessary.  
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APPENDIX 4. SIX-MINUTE WALK TEST 
A standardized 6MWT will be performed in accordance with the guidelines of the American 
Thoracic Society.15-17  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 
preferably be 30 m in length.  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 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 AEs occurring during the 6MWT will be recorded.  If 
a participant is on chronic oxygen therapy, oxygen should be given at their standard rate or as 
directed by the investigator.  During the study, the 6MWT should be done about the same time of 
day to avoid diurnal variation.  
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. 
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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 BP, and make sure that clothing and shoes are appropriate.  Complete portion 
of eCRF. 
4. Measure and record baseline HR and oxygen saturation (SpO2) and follow manufacturer's 
instructions to maximize the signal and to minimize motion artifact. 
5. Make sure the readings are stable before recording.  Note pulse regularity and whether 
the oximeter signal quality is acceptable. 
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 one 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." 
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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." 
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. Measure SpO2 and pulse rate from the oximeter and then remove the sensor. 
2. Record the number of laps from the counter 
3. Record the additional distance covered (the number of meters in the final partial lap) 
using the markers on the wall as distance guides.  
4. Calculate the total distance walked, rounding to the nearest meter, and record it on the 
worksheet. 
5. Congratulate the participant on good effort and offer a drink of water. 
 
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APPENDIX 5. CARDIOPULMONARY EXERCISE TEST 
Right Heart Catheterization 
Resting supine RHC will be performed according to the iCPET manual.  Zero-pressure 
calibration will be performed at the mid-axillary line with the patient in a supine position.  SVC, 
RA, RV, PCW, and PA pressures will be measured, and mean vascular pressures will be 
calculated based on systolic and diastolic pressure measurements.  Heart rate and vascular 
pressures are monitored continuously.  Cardiac output is measured by the Fick method.  Diastolic 
and transpulmonary pressure gradients are obtained, systemic and PVRs are calculated.   
Physiologic Measurements: iCPET 
Maximum symptom-limited incremental iCPET is performed using an upright cycle ergometer 
and a breath-by-breath metabolic cart with subjects breathing room air. 
Minute ventilation, breath-by-breath pulmonary gas exchange, HR, radial arterial BP, RAP, RV 
pressure, and PAP are measured throughout the test.  PAWP is obtained at rest and at the end of 
each minute of exercise.   
By co-oximetry, oxygen saturation, Hgb concentration, and O2 content (CaO2 and CvO2, 
respectively) are measured for each blood sample.  CO is then calculated by the Fick principle 
using a simultaneously measured VO2.  Predicted COMAX was calculated from predicted VO2MAX 
and an assumed maximal arterial-mixed venous O2 content difference equivalent to a normal 
(Hgb) of 14 g/dL for healthy subjects. 
The full iCPET guideline will be included in a separate charter. 
 
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APPENDIX 6. CARDIAC MAGNETIC RESONANCE IMAGING 
Secondary endpoints of interest include change from baseline in RV SV, RV EF, RV ESV, RV 
EDV, RV SVI, and RV mass.  The central imaging vendor will perform review of site images 
and will qualify sites prior to any subject enrollment.  Site cardiac MR equipment, test images, 
and the capability to transmit cardiac MR images for central reader review are validated for 
qualification.  Only sites who are prequalified by the central imaging vendor are permitted to 
participate in the study.  The quality of site cardiac MR imaging is continually monitored to 
maintain consistency and minimize variability throughout the study.  A study-specific cardiac 
MR imaging manual in agreement with the imaging charter will be provided for consistency in 
imaging performance, reporting format, and image transmission. 
 
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APPENDIX 7. STUDY GOVERNANCE CONSIDERATIONS 
Regulatory and Ethical Considerations 
• 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 (CIOMS) International Ethical Guidelines 
− Applicable ICH Good Clinical Practice (GCP) Guidelines 
− Applicable laws and regulations 
• The protocol, protocol amendments, ICF, Investigator’s Brochure (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 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations 
Informed Consent Process 
• The investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study. 
• Participants must be informed that their participation is voluntary.  Participants will 
be required to sign a statement of informed consent that meets the requirements of 
21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or 
study center. 
• The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained.  The authorized person obtaining the informed consent must 
also sign the ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study. 
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• A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative. 
Data Protection 
• Participants will be assigned a unique identifier by the sponsor.  Any participant 
records or datasets that are transferred to the sponsor will contain the identifier only; 
participant names or any information which 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 the sponsor 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 the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
Publication Policy 
• All information concerning sotatercept is considered confidential and shall remain the 
sole property of the sponsor.  The investigator agrees to use this information only in 
conducting the study and shall not use it for any other purposes without the sponsor’s 
written approval.  The investigator agrees not to disclose the sponsor’s confidential 
information to anyone except to persons involved in the study that need such 
information to assist in conducting the study, and then only on like terms of 
confidentiality and non-use. 
• It is understood by the investigator that the information developed from this clinical 
study will be used by the sponsor 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 the sponsor with complete test results and all data developed in 
the study. 
• No publication or disclosure of study results will be permitted except as specified in a 
separate, written, agreement between the sponsor and the investigator. 
• The sponsor will comply with the requirements for publication of study results.  In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support 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. 
Data Quality Assurance 
• All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the sponsor or designee electronically (e.g., laboratory data).  
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The investigator is responsible for verifying that data entries are accurate and correct 
by physically or electronically signing the CRF. 
• 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. 
• The sponsor 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 the sponsor.  No records may be 
transferred to another location or party without written notification to the sponsor. 
Source Documents 
• 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. 
Study and Site Closure 
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor.  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 the sponsor or investigator may include but are 
not limited to: 
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• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of participants by the investigator 
• Discontinuation of further study treatment development 
 
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APPENDIX 8. 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 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 one 
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 ONE of the following (during the protocol-defined time frame in Section 5.1): 
• 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 
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 sperm 
for the duration of the study and for 112 days after the last dose of study treatment. 
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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 12.  
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. 
Table 12: 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent1 
Failure rate of < 1% per year when used consistently and correctly 
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of 
ovulation2 
• 
Oral 
• 
Intravaginal 
• 
Transdermal 
Progestogen only hormonal contraception associated with inhibition of ovulation 
• 
Oral 
• 
Injectable  
Highly Effective Methods That Are User Independent1 
Implantable progestogen only hormonal contraception associated with inhibition of ovulation2 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
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.  
1 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. 
2 Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the efficacy 
of the contraceptive method.  In this case, two highly effective methods of contraception should be utilized during 
the study and for at least 112 days after the last dose of study treatment. 
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Pregnancy Testing 
• WOCBP should only be included in the study after two confirmed negative 
pregnancy tests. 
• Additional pregnancy testing should be performed prior to study drug administration 
at each dosing visit during the study as required locally. 
Pregnancy testing will also be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected. 
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 8.3.10.  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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APPENDIX 9. GENETICS 
Use/Analysis of DNA 
• Genetic variation may impact a participant’s response to therapy, susceptibility to, 
and severity and progression of disease.  Variable response to therapy may be due to 
genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular 
subtype of the disease being treated.  
• DNA samples will be used for research related to PAH.  They may also be used to 
develop tests/assays including diagnostic tests related to sotatercept and PAH.  
Genetic research may consist of the analysis of one or more candidate genes or the 
analysis of genetic markers throughout the genome (as appropriate). 
• DNA samples will be analyzed for BMPR2 (and other potential genes of interest) 
mutational status and variant allele frequency (VAF) at baseline. 
• The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to sotatercept or study treatments of this class to understand 
study disease or related conditions. 
• The results of genetic analyses may be reported in the clinical study report or in a 
separate study summary and may be shared with regulatory authorities such as the 
Food and Drug Administration and the European Medicines Agency. 
• The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
 
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APPENDIX 10. PROTOCOL AMENDMENT HISTORY 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents.   
Substantive changes from Protocol Amendment 3A (31 October 2019) to Protocol 
Amendment 04 (18 June 2020) are detailed below.  Minor edits are not included. 
Table 13: 
Protocol Amendment 03A to Protocol Amendment 04 Amendment History 
Protocol Location 
Description of Change 
Brief Rationale 
Cover Page 
Added:  
PROTOCOL AMENDMENT 04 
Dated 18 June 2020 
This is the protocol amendment 
identifier and release date. 
Section 3.6, Benefit/Risk 
Assessment 
In prior sotatercept clinical 
oncology studies in chemotherapy-
induced anemia and osteolytic bone 
disease in multiple myeloma, 
leukopenia, neutropenia (including 
febrile neutropenia), 
granulocytopenia, and 
thrombocytopenia have been 
described as TEAEs.  As a 
consequence of the decrease in 
WBCs, infection maybe a potential 
risk and, as a consequence of 
thrombocytopenia, bleeding may be 
a potential risk.  Per health 
authority request, leukopenia, 
neutropenia, and thrombocytopenia 
have been identified as AESIs in 
this study (see Section 6.3, Dose 
Modification and Section 8.3, 
Adverse Events). 
The language regarding risks added 
to better synchronize between 
information presented in the IB and 
information presented in the ICF. 
Section 1, Synopsis 
Table 4, Schedule of 
Events: Extension and 
Follow-Up Periods 
Section 3.4.2, Extension 
Period 
Figure 1, Study Design 
Dosing in the Extension Period was 
changed from every 4-week dosing 
to every 3-week dosing. 
Q3W is selected to be consistent 
with PULSAR OLE and Phase 3 
A011-11 study.   
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Table 13: 
Protocol Amendment 03A to Protocol Amendment 04 Amendment History 
Protocol Location 
Description of Change 
Brief Rationale 
Section 1, Synopsis 
Section 4.3, Standard of 
Care  
Section 6.9, Concomitant 
Therapy 
Appendix 3, Standard of 
Care Therapy 
Added: “During the Extension 
Period, participants under 
investigator’s supervision can 
substitute, remove, or adjust the 
dose of SOC for PAH-worsening 
and chronic concomitant 
medications, including 
supplemental oxygen.  Investigator 
discretion will be used to determine 
if sotatercept study drug 
discontinuation is necessary.”  
This revision allows the investigator 
to use his clinical judgement during 
this extended period of study 
treatment in an open-label setting. 
 
Section 1, Synopsis 
Section 4.7.12, Extension 
Period 
Section 4.8.1, Treatment 
Extension Period 
Upon completion of the study 
participants will be provided the 
opportunity to transition into a 
future long-term follow-up study. 
This open-label study permits 
participants in the extension period 
of this study to continue sotatercept 
therapy after the completion of this 
clinical study. 
Section 5, Study 
Population 
Added: “Prospective approval of 
protocol deviations to recruitment 
and enrollment criteria, also known 
as protocol waivers or exemptions, 
is not permitted, unless within the 
FDA Guidance on Conduct of 
Clinical Trials of Medical Products 
during COVID-19 Pandemic 
Guidance for Industry, 
Investigators, and Institutional 
Review Boards; March 2020 (FDA 
2020).”  
To align with sotatercept clinical 
programs and the new COVID-19 
guidelines. 
Section 6.2, Treatment 
Administration and 
Schedule 
Added: “Where rounding the 
weight and total volume is 
necessary, please refer to the 
Pharmacy Manual for further 
details.” 
This has been a common question 
clinical sites have asked 
Pharmaceutical Product 
Development (PPD) to clarify.  
Section 6.3, Dose 
Modification 
Dose modification ‘rules’ were 
revised to guidance. 
Hgb and platelet guidance were 
revised after reviewing safety data 
Safety monitoring due to ongoing 
patient review and an extended 
1-year duration in study drug.  
AESIs, including leukocytopenia, 
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Table 13: 
Protocol Amendment 03A to Protocol Amendment 04 Amendment History 
Protocol Location 
Description of Change 
Brief Rationale 
Section 8.3, Adverse 
Events 
Section 8.4, Monitoring 
of Identified, Potential 
Risks, and AESI 
of participants who have been 
administered sotatercept.  AEs and 
blood pressure guidance were 
removed from this section and 
moved to Section 8.3 and 
Section 8.4.  Regarding the 
monitoring of identified, potential, 
risks and AESI the management of 
leukocytopenia, neutropenia and 
thrombocytopenia AESI were 
added per safety review decisions.  
neutropenia, and thrombocytopenia 
will continue to be monitored.  
Safety monitoring guidance on 
these items can be found in 
Section 8.4, which covers the 
monitoring of identified, potential, 
and AESIs. 
  
Section 7.1, 
Discontinuation  
Section 7.2, Withdrawal 
from Study 
Removed “loss of treatment 
effect’’. 
At this time, the effect is not known, 
and the effect cannot be defined.  
Therefore, the reference to the loss 
of treatment effect has been deleted. 
Section 8.2.3, Pulmonary 
Vascular resistance by 
Right Heart 
Catheterization 
Section 2, Schedule of 
Events 
Added hemodynamic variables 
• 
Systolic pulmonary artery 
pressure 
Diastolic pulmonary artery pressure 
These were added following safety 
review. 
Section 8.3, Adverse 
Event 
Further defined the following: 
Unexpected AE: updates below are 
indicated in bold font)  
An unexpected AE is an AE that, 
the nature, severity, specificity, or 
outcome of which, is not consistent 
with the summary of product 
characteristics described in the IB 
under the Reference Safety 
Information. 
SAE: Hospitalization 
Added: A hospitalization for an 
elective procedure will not be 
considered an SAE 
Incapacity or Disability:  
Updated according to the reporting 
requirements for safety monitoring, 
and ICH Topic E 2: A Clinical 
Safety Data Management. 
 
Added the word “specificity’’ to 
align with GCP guidance .and the 
summary of product characteristics 
to be used only for the marketed 
product. 
 
Updated according to Definitions 
and Standards for Expedited 
Reporting, and AESI and SAE 
requirements.  
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Table 13: 
Protocol Amendment 03A to Protocol Amendment 04 Amendment History 
Protocol Location 
Description of Change 
Brief Rationale 
Updated safety monitoring moved 
AESIs to Section 8.4. 
Deleted other irrelevant materials. 
Section 8.3.8, Overdose 
Specified the definition of 
Overdose for sotatercept dosing 
based on weight.  
Added to the definition of overdose 
and recently standardize language 
from Acceleron PAH clinical 
programs.  
Section 8.3.9, 
Transmission of an 
Infectious Agent 
Added language in the case that a 
virus or infectious particle, 
pathogenic or non-pathogenic, is 
considered an infectious agent, in 
addition to instructions for 
reporting within 24 hours.  
Preparation for an infectious disease 
during the study. 
Section 8.3.10, 
Pregnancy 
Removed: Any infant death that is 
assessed as possibly related to the 
in utero exposure to sotatercept 
therapy should be reported as an 
SAE. 
Removal is reflective of ICH safety 
reporting for pregnancy.  
Section 8.4, Monitoring 
of Identified, Potential, 
and Adverse Events of 
Special Interest 
Updated AESI safety monitoring 
parameters and guidelines after 
reviewing active and past AESIs 
experienced by sotatercept 
administered PAH patients. 
Ongoing monitoring and evaluation 
of active and past sotatercept 
patient’s AESIs are necessary to 
assess the overall safety of the PAH 
patient population; therefore, a 
detail section for safety monitoring 
AESIs was added to this sotatercept 
clinical study. 
Section 9.3.5, Extension 
Period Analysis 
Added the analysis for the 
Extension Period.  All the 
endpoints will be analyzed in a 
similar way for the Extension 
Period as with the main analysis in 
the Treatment Period. 
The Extension Period will be 
analyzed and will have a separate 
statistical analysis plan (SAP). 
Section 9.3.4, Primary 
Endpoint Analysis 
Added: An analysis of the primary 
endpoint of change in VO2 at 
24 weeks Treatment Period 
(Cycle 9) versus the screening 
This addition gives further 
clarification of the Primary 
Endpoint Analysis.  
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Table 13: 
Protocol Amendment 03A to Protocol Amendment 04 Amendment History 
Protocol Location 
Description of Change 
Brief Rationale 
assessment will be performed on 
the evaluable population when all 
participants during the Treatment 
Period have completed their 
24-week (Cycle 9) iCPET 
assessment or EOT iCPET for those 
subjects who discontinue early 
during the Treatment Period, as 
described in Section 9.3.1. 
Appendix 10, Protocol 
Amendment History 
Moved the Protocol Amendments 
02 and 03A history from the 
Summary of Changes section to 
Appendix 10. 
Amendment history was provided 
for Protocol Amendment 04 in the 
Summary of Changes section and 
was moved to Appendix 10. 
 
 
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Clinical Study Protocol 
 
Sotatercept (ACE-011) 
Study No: A011-10 
Revision: 05 
12 August 2021 
Acceleron Pharma Inc. 
Page 87 of 93 
CONFIDENTIAL 
Table 14: 
Protocol Amendment 02 to Protocol Amendment 03A Amendment History 
(Continued) 
Protocol Location 
Description of Change 
Brief Rationale 
Section 4.3, Standard of 
Care, page 25; 
Section 5.1, Inclusion 
Criteria, page 30;  
Section 8.5.5, Rescue 
Therapy Criteria, 
page 50; Appendix 3, 
page 63 
Definition of stable standard of care 
for PAH clarified 
Small adjustments to routine 
standard of care (SOC) for PAH are 
considered stable. However, 
changes, removal, or addition of 
PAH therapies during 90 days prior 
to enrollment are considered 
unstable SOC, and these subjects do 
not meet inclusion criteria 8. 
Section 4.6, Extension 
Period, page 25 
18-month Extension Period inserted To present the 18-month Extension 
Period for all participants enrolled 
Section 4.7, Follow-up 
Period, page 26, 
Follow-Up Period revised to 
describe follow-up for participants 
who terminate early from the study, 
participant in the 24-week 
Treatment Period but choose not to 
enter the 18-month Extension 
Period, and participants who 
complete the 24-week Treatment 
Period and the 18-month Extension 
Period 
To clarify the Follow-Up Period for 
all participants enrolled 
Figure 1, page 27 
Figure 1 edited to remove “placebo-
controlled treatment period” from 
the 24-week Treatment Period, 
remove the 16-week Off Study 
Drug Follow-Up Period, include the 
18-month Extension Period, and the 
8-week Follow-Up Period 
This Phase 2a study is open-label, 
not placebo controlled, changed to 
“Treatment Period” 
To reflect study design 
modifications as described for all 
participants 
Section 4.8.1, Extension 
Period, page 28 
Extension Period section inserted to 
describe the Q4W dosing schedule 
during the 18-month Extension 
Period 
In the 18-month Extension Period, a 
dose regimen of Q4W will be 
evaluated, with dose adjustment as 
needed to maintain equivalent 
exposure 
 
 
082WBL

Clinical Study Protocol 
 
Sotatercept (ACE-011) 
Study No: A011-10 
Revision: 05 
12 August 2021 
Acceleron Pharma Inc. 
Page 88 of 93 
CONFIDENTIAL 
Table 14: 
Protocol Amendment 02 to Protocol Amendment 03A Amendment History 
(Continued) 
Protocol Location 
Description of Change 
Brief Rationale 
Section 4.10, Justification 
for Dose, pages 28-29 
Justification For Dose during the 
24-week Treatment Period (Q3W 
dosing) and the 18-month 
Extension Period (Q4W dosing) 
edited to clarify exposures and 
exposure-matching during these 
treatment periods 
To justify the 2 different dosing 
intervals, and the data modeling to 
explain exposure-matching during 
the 18-month Extension Period. 
Justification for the Off 
Study Drug Period 
Removed Justification for the Off 
Study Drug Period  
All participants transition directly 
from the 24-week Treatment Period 
to the 18-month Extension Period 
without an Off-Study Drug Period 
Section 5.1, Inclusion 
Criteria, page 30 
Pulmonary function test clarified 
for Inclusion criterion 5 
Normalization of FVC (% predicted 
FVC) and FEV1/FVC (% predicted 
FEV1/FVC) are based on measure 
pulmonary function in a healthy 
normal population with 2 lungs. 
There is no population-based 
normalization method for patients 
who have less than complete lungs. 
Therefore, further adjustment will 
be permitted, based on the 
remaining fraction of lung volume 
in subjects with a history of 
lobectomy or pneumonectomy.  
 
 
082WBL

Clinical Study Protocol 
 
Sotatercept (ACE-011) 
Study No: A011-10 
Revision: 05 
12 August 2021 
Acceleron Pharma Inc. 
Page 89 of 93 
CONFIDENTIAL 
Table 14: 
Protocol Amendment 02 to Protocol Amendment 03A Amendment History 
(Continued) 
Protocol Location 
Description of Change 
Brief Rationale 
Table 6, pages 35-36 
Dose modifications clarified 
If target blood pressure (BP) is 
maintained at the subsequent cycle, 
dose can be escalated, if applicable.  
Consider phlebotomy until 
hemoglobin (Hgb) < 16.0 g/dL; 
delay dose for 1 cycle.  
At the next cycle, if Hgb is: 
a) < 18.0 g/dL, reduce study 
drug by 1 dose level and 
restart dosing.  
If dose reductions were done due to 
an adverse event not related to 
study medication, the dose can be 
escalated when the adverse event is 
resolved. In cases of dose reduction 
due to increases in Hgb, the dose 
can be re-escalated after 2 
consecutive cycles in which Hgb 
values are stable and equal or lower 
than the upper limit of normal. 
To clarify dose modifications due to 
adverse events 
Section  7.2, Withdrawal 
from Study, page 39 
Withdrawal from the Study section 
revised to clarify rescue therapy 
and study withdrawal 
To ensure that patients who need 
rescue therapy due to clinical 
worsening are withdrawn from the 
study 
Section 8, Study 
Assessments and 
Procedures, page 41 
Study assessments revised to define 
End of Study (EOS) assessment and 
8-week Follow-Up for all 
participants 
Study assessments revised to define 
EOS and 8-week Follow-Up Period 
in the 18-month Extension Period  
Section 8.2.1, (iCPET), 
page 41 
Invasive Cardiopulmonary Exercise 
Test (iCPET) Assessment clarified 
for participants at Cycle 9, 
Day 169, in the 24-week Treatment 
Period, and Cycle 14 in the 
18-month Extension Period  
iCPET Assessment clarified for 
participants to reflect changes in the 
SoE (Tables 3 and 4)  
082WBL

Clinical Study Protocol 
 
Sotatercept (ACE-011) 
Study No: A011-10 
Revision: 05 
12 August 2021 
Acceleron Pharma Inc. 
Page 90 of 93 
CONFIDENTIAL 
Table 14: 
Protocol Amendment 02 to Protocol Amendment 03A Amendment History 
(Continued) 
Protocol Location 
Description of Change 
Brief Rationale 
Section 8.2.2, Cardiac 
Magnetic Resonance 
Imaging, page 42 
Cardiac Magnetic Resonance 
Imaging expanded to include 
measures to support Secondary and 
Exploratory Objectives 
Cardiac Magnetic Resonance 
Imaging expanded to include 
request for additional measures to 
support Secondary and Exploratory 
Objectives of the study 
Throughout 
Mention of secondary endpoint RV 
SWI removed from synopsis and 
body of the protocol. 
Not calculated via cardiac magnetic 
resonance imaging as pressure 
values are not obtained via CMR, 
which are required in order to 
calculate RVSWI. 
Throughout 
Additional section headers inserted 
in order to include sections in Table 
of Contents 
To assist investigative personnel 
with more rapid searching for 
sections of interest 
 
 
082WBL

Clinical Study Protocol 
 
Sotatercept (ACE-011) 
Study No: A011-10 
Revision: 05 
12 August 2021 
Acceleron Pharma Inc. 
Page 91 of 93 
CONFIDENTIAL 
Substantive changes from the Protocol Amendment 01 (13 September 2018) to Protocol 
Amendment 02 (05 December 2018) are detailed below.  Minor edits are not included. 
Table 15: 
Protocol Amendment 01 to Protocol Amendment 02 Amendment History 
Protocol Location 
Description of Change 
Brief Rationale 
Table 2, Schedule of 
Events 
Section 8.2, Efficacy 
Assessments 
Assessments and timepoints 
rearranged and clarified. 
Some footnotes were removed 
 
Assessments and timepoints have 
been edited to better capture 
meaningful changes and timepoints 
throughout the study.  Other edits of 
Treatment Period, Follow-Up 
Period, and EOS have been made 
for clarity.  Redundant and 
unnecessary footnotes were 
removed. 
Section 5.1, Inclusion 
Criteria 
Inclusion criterion 8: increase 
6MWD upper limit  
 
 
Inclusion criterion 10: Contraceptive 
guidelines language clarified.  
Changed timing of the requirement 
for effective contraception use prior 
to starting investigational product 
from 5 weeks to 28 days. 
6MWD distance upper threshold 
increased to accommodate for effect 
from stable SOC. 
 
To align inclusion criterion with the 
Appendix 8 guidelines and 
definitions.  To align contraception 
guidelines with study timelines. 
Section 5.2, Exclusion 
Criteria 
Exclusion criterion 10: Changed the 
baseline hemoglobin level for 
exclusion for women from > 15 g/dL 
to > 16 g/dL 
Exclusion criterion 24: removed 
“active on the lung transplant list.” 
To align the hemoglobin exclusion 
criterion for both genders. 
 
To allow participants to enroll in the 
study if they are active on the lung 
transplant list and meet all other 
inclusion/exclusion criteria. 
Section 5.3, Screen 
Failures 
Added details regarding capturing 
AEs and frequency of rescreening 
for screen failures. 
To clarify that AE details are to be 
captured for screen failures and 
rescreening is allowed only once.  
Section 6.3, Dose 
Modification 
Table 5: Changed the dose 
modification rules for AEs, 
hemoglobin, and blood pressure. 
To align with updated 
inclusion/exclusion criteria and to 
clarify when doses of study drug 
should be delayed, reduced, or 
escalated. 
Section 7.1, 
Discontinuation of 
Study Treatment 
Added that discontinuation of study 
treatment would occur if a subject 
has a QTcF > 500ms during the 
treatment period. 
To ensure that participants who 
meet this threshold are discontinued 
appropriately.  
082WBL

Clinical Study Protocol 
 
Sotatercept (ACE-011) 
Study No: A011-10 
Revision: 05 
12 August 2021 
Acceleron Pharma Inc. 
Page 92 of 93 
CONFIDENTIAL 
Table 15: 
Protocol Amendment 01 to Protocol Amendment 02 Amendment History 
(Continued) 
Protocol Location 
Description of Change 
Brief Rationale 
Section 8.4, Safety 
Assessments. 
Weight was moved from the 
physical exam section (8.4.1) to the 
vital signs section (8.4.2). 
Weight is collected and recorded in 
the eCRF as a part of the vital signs. 
Section 8.4.6, Clinical 
Safety Laboratory 
Assessments 
Added, “If hemoglobin is ≥ 17 g/dL 
during Cycle 1 (Day 8) or Cycle 2 
(Day 30), participants should return 
weekly for hemoglobin monitoring.” 
To ensure that participants whose 
hemoglobin levels become high are 
appropriately monitored. 
Appendix 8, 
Contraceptive Guidance 
and Collection of 
Pregnancy Information 
Contraceptive guidelines language 
clarified.   
To align with Inclusion Criteria and 
study timelines. 
 
 
082WBL

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