Clinical trial NCT03496207
Conditions: Pulmonary Arterial Hypertension
Keywords: PAH
Sponsor: Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
Start date: 2018-06-13; Completion date: 2022-03-09
Enrollment: 106 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Study A011-09 is designed to assesses the efficacy and safety of sotatercept (ACE-011) relative to placebo in adults with pulmonary arterial hypertension (PAH). Eligible participants will receive study treatment for 24 weeks during the placebo-controlled treatment period, and then will be eligible to enroll into a 30-month extension period during which all participants will receive sotatercept. All treated patients will also undergo a follow-up period after last study drug treatment.

Detailed description:
This is a Phase 2, double-blind, randomized, placebo-controlled, parallel-group study of sotatercept plus standard of care (SOC) versus placebo plus SOC in participants with PAH of World Health Organization (WHO) Group 1, functional class II-III. Participants will be randomly assigned in a 3:3:4 ratio to receive placebo, sotatercept 0.3 mg/kg, or sotatercept 0.7 mg/kg by subcutaneous (SC) injection every 21 days for a period of 24 weeks in the placebo-controlled treatment period of the study while on SOC therapy. Evaluations will include changes in pulmonary vascular resistance (PVR), 6-minute walk distance (6MWD), quality of life questionnaires, echocardiographic parameters, and safety. Participants who have not discontinued early from the placebo-controlled treatment period and have had their post-treatment period PVR assessment will be able to continue into the 30-month extension period in which sotatercept-treated participants will receive their latest dose level of sotatercept SC every 21 days and placebo-treated participants will be re-randomized 1:1 to receive sotatercept 0.3 mg/kg SC or sotatercept 0.7 mg/kg SC every 21 days while on SOC therapy.

Arms: arm 1: Participants will receive placebo plus SOC by SC injection during the 24-week treatment period. Dosing will occur once every 3 weeks. arm 2: Participants will receive sotatercept 0.3 mg/kg plus SOC by SC injection during the 24-week treatment period. Per protocol, participants may have their doses titrated. Dosing will occur once every 3 weeks. arm 3: Participants will receive sotatercept 0.7 mg/kg plus SOC by SC injection during the 24-week treatment period. Per protocol, participants may have their doses titrated. Dosing will occur once every 3 weeks.
Interventions: intervention 1: Placebo intervention 2: Sotatercept intervention 3: SOC
Intervention descriptions: intervention 1: Placebo intervention 2: Sotatercept (ACE-011) is a recombinant fusion protein consisting of the extracellular domain of the human activin receptor type IIA linked to the Fc piece of human IgG1. intervention 3: SOC therapy refers to approved PAH-specific medications and may consist of monotherapy or combination therapy with endothelin-receptor antagonists, phosphodiesterase 5 (PDE5) inhibitors, soluble guanylate cyclase stimulators, and/or prostacyclin analogues or receptor agonists.

Protocol documents:
Prot_000.pdf: 
Official Protocol Title: 
NCT number: 
Document Date: 
A Phase 2, Double-Blind, Placebo-Controlled, Randomized Study to 
Compare the Efficacy and Safety of Sotatercept (ACE-011) Versus 
Placebo When Added to Standard of Care for the Treatment of 
Pulmonary Arterial Hypertension (PAH)
31 July 2020
NCT03496207


Clinical Study Protocol 
Sotatercept (ACE-011) 
Study No: A011-09 
Revision: 07D 
31 July 2020  
Acceleron Pharma Inc. 
Page 1 of 100 
CONFIDENTIAL 
Protocol A011-09 
Protocol Title: 
A Phase 2, Double-Blind, Placebo-Controlled, Randomized Study to Compare the Efficacy and 
Safety of Sotatercept (ACE-011) Versus Placebo When Added to Standard of Care for the 
Treatment of Pulmonary Arterial Hypertension (PAH) 
Short Title: 
A Phase 2 Study of Sotatercept for the Treatment of PAH 
SPONSOR: 
Acceleron Pharma Inc. 
128 Sidney Street 
Cambridge, MA 02139 USA 
Tel: 617-649-9200 
Regulatory Agency  
IND 136150 
Identifying Number(s): 
EudraCT 2017-004738-27 
ORIGINAL PROTOCOL DATE:  
15 December 2017 
PROTOCOL AMENDMENT 01B: 
15 February 2018 
PROTOCOL AMENDMENT 02B: 
30 April 2018 
PROTOCOL AMENDMENT 03B: 
24 May 2018 
PROTOCOL AMENDMENT 04C: 
14 June 2018 
PROTOCOL AMENDMENT 05D: 
12 August 2018 
PROTOCOL AMENDMENT 06D: 
18 December 2018 
PROTOCOL AMENDMENT 07D: 
31 July 2020 
Confidentiality Statement  
This confidential information in this document is provided to you as an investigator or consultant for 
review by you, your staff, and the applicable Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC).  Your acceptance of this document constitutes agreement that you will not disclose the 
information contained herein to others without written authorization from Acceleron Pharma Inc. 
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Clinical Study Protocol 
 
Sotatercept (ACE-011) 
Study No: A011-09 
Revision: 07D 
31 July 2020  
Acceleron Pharma Inc. 
Page 3 of 100 
CONFIDENTIAL 
PROCEDURES IN CASE OF EMERGENCY 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Contact Information 
Medical Monitor 
Janethe de Oliveira Pena, MD, 
PhD 
Acceleron Pharma Inc. 
128 Sidney Street 
Cambridge, MA 02139 USA 
Direct Line: + 617-649-9210 
Mobile: 617-909-6241 
jpena@acceleronpharma.com 
Medical Monitor, PPD 
Edward Matheis, MD, 
FCCP 
 
PPD 
3900 South Paramount Parkway 
3rd floor 
Morrisville, NC 27560-8408 USA 
Phone +888 483 7729 
edward.matheis@ppdi.com 
Pharmacovigilance 
Various 
PPD Safety Hotline 
Granta Park 
Great Abington, Cambridge CB21 6GQ 
England, UK 
Phone: +44 122 337 4240 
 
 
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Clinical Study Protocol 
 
Sotatercept (ACE-011) 
Study No: A011-09 
Revision: 07D 
31 July 2020  
Acceleron Pharma Inc. 
Page 4 of 100 
CONFIDENTIAL 
Protocol Amendment Summary of Changes Table 
Substantive changes from Amendment 6D (18 December 2018) to Protocol Amendment 7D 
(31 July 2020) are detailed below.  Minor edits are not included.  See Appendix 8 for the rest of 
the Protocol Amendment History. 
Protocol Location 
Description of Change 
Brief Rationale 
Title Page 
Added:  
PROTOCOL AMENDMENT 07D: 
Dated 31 July 2020 
Protocol amendment identifier 
and release date. 
Table 1, page3  
Updated Contact for the 
Pharmacovigilance safety contact. 
The Pharmacovigilance safety 
contact has changed.  The contact 
information has been updated. 
Section 1, Synopsis 
Section 4.1, Overall 
Design 
Objectives, endpoints, and study 
design were updated. 
Sections were updated to include 
study design modifications to 
assess long-term benefit and 
persistence of the effect of 
sotatercept. 
Section 1, Synopsis 
Section 2, Schedule of 
Events  
Section 4.1, Overall 
Design 
Figure 1  
 
Eighteen-month Extension Period 
was extended by an additional 
12 months to a 30-month Extension 
Period. 
It was revised to accommodate 
patients completing the 18-month 
Extension Period that would like 
to continue study treatment at the 
investigator’s discretion. 
Change to Extension Period from 
blinded to unblinded. 
Upon completion of primary 
endpoint analysis, the extension 
will be unblinded for patient 
transparency and to allow 
investigators to up titrate dose 
level up to 0.7 mg/kg dose level 
as needed.   
Upon completion of the study, 
participants will be provided the 
opportunity to transition into a 
separate Sotatercept Long-Term 
Follow-Up Study.  
Permits participants in the 
extension period of this study to 
continue sotatercept therapy after 
the completion of this clinical 
study. 
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Clinical Study Protocol 
 
Sotatercept (ACE-011) 
Study No: A011-09 
Revision: 07D 
31 July 2020  
Acceleron Pharma Inc. 
Page 5 of 100 
CONFIDENTIAL 
Protocol Location 
Description of Change 
Brief Rationale 
Section 2, Schedule of 
Events 
Additional 3rd RHC will be done at 
C25.  For participants who passed 
C25, RHC should be done at the 
next possible visit up to C33. 
The additional RHC has been 
added to C25 to assess long-term 
benefits and persistence of the 
effect of sotatercept.  
Add the evaluation of RHC 
Add Cycle 42 and Cycle 51  
Add the assessment of 12-lead ECG. 
RHC and 12-lead ECG during the 
extension visit will further 
evaluate the safety and efficacy of 
the study drug.  RHC added to 
assess long-term benefits and 
durability of the effect of 
sotatercept treatment. 
Add Cycles 35, 36, 37, 38, 39, 40, 
41, 43, 44, 45, 46, 47, 48, 49, and 
50. 
Remove the evaluation of serum 
chemistry, and anti-drug antibody. 
Serum chemistry and anti-drug 
antibody are not needed as 
frequently for safety monitoring 
in the extension period of the 
study. 
Corrected UA and UACR 
assessments in the Extension Period 
(Table 4).  
To clarify that UACR will be 
performed in combination with 
UA up to C33 but will not be 
performed at C42 or C51 in the 
Extension Period. 
Added footnote to the Schedule of 
Events for the Extension Period 
(Table 4). 
To clarify that participants are 
eligible, upon completion of the 
third RHC, to enroll in the 
Sotatercept Long-Term Follow-
Up Study. 
Updated SOE to include ECHO, 
6MWD, WHO FC, pre-dose PK, 
and NT-proBNP evaluations at the 
respective third RHC visit. 
Additional echocardiography 
imaging, 6MWT, WHO FC, 
pre-dose PK, and NT-proBNP 
were added to support 
maintenance of clinical benefits 
including the beneficial effect of 
sotatercept on right ventricular 
function and structure. 
Synopsis 
Section 4.1, Overall 
Design 
Section 6.3, Dose 
Modification 
Section 6.5, 
Randomization and 
Blinding  
Section 8.2, Efficacy 
Assessments 
Added additional Cycles 35 to 51 
and additional assessment, safety 
monitoring evaluations, dose 
modification adjustments, and 
updated blinding process and study 
schematic (Figure 1)  
Provide additional treatment and 
follow-up evaluations/visits and 
updated the unblinding process 
for transparency and align 
language to reflect these sections.  
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Study No: A011-09 
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Page 6 of 100 
CONFIDENTIAL 
Protocol Location 
Description of Change 
Brief Rationale 
Section 6.2, 
Treatment Administration 
and Schedule 
Added: “Where rounding is 
necessary to calculate the total 
volume to be administered based on 
weight, rounding should be at 
1 decimal place.  Please refer to the 
IRT manual for details.” 
This has been a common question 
Investigator Sites have asked 
Pharmaceutical Product 
Development (PPD) for additional 
clarification. 
Section 6.3, Dose 
Modification 
Corrected guidance for dose 
modifications and dose delay 
(Figure 2 and Figure 3). 
To clarify that participants are to 
RESTART/CONTINUE on the 
same dose level administered 
prior to the dose delay. 
Amended text: “Upon approval of 
Protocol Amendment 07D and 
unblinding of study sites and 
participants, study treatment dose 
may be escalated up to 0.7 mg/kg.  
If dose reductions are conducted due 
to an AE not related to study 
treatment, the dose can be escalated 
when the AE resolves.  In cases of 
dose reduction due to an increase in 
Hgb or decrease in platelets, the 
dose can be escalated after 2 
consecutive cycles in which Hgb or 
platelet values are stable.” 
To clarify the dose modification 
guidelines. 
Section 6.3, Dose 
Modification 
Section 8.3, Adverse 
Events 
Section 8.4., Monitoring 
of Identified, Potential, 
and Adverse Events of 
Special Interest 
Dose modification “rules” were 
revised to guidance. 
Hgb and thrombocytopenia guidance 
was revised due to the 1-year 
extension of study treatment.  AEs, 
leukocytopenia, neutropenia, and 
blood pressure guidances were 
removed from this section and 
moved to Section 8.3, Adverse 
Events and Section 8.4, Monitoring 
of Identified, Potential, and Adverse 
Event of Special Interest.  Moved 
management of leukocytopenia, 
neutropenia, and AESI per DMC 
decisions.  
Safety monitoring due to ongoing 
patient review and an extended 
1-year duration in study treatment.  
AESIs, neutropenia, and 
leukocytopenia 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 6.5., 
Randomization and 
Blinding 
Added unblinding process: 
Following the conduct and results of 
the C9D1 primary endpoint and the 
approval of Protocol A011-09 
amendment 07D, the study treatment 
This assists the investigator in 
using discretion on SOC treatment 
during the Extension Period. 
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Sotatercept (ACE-011) 
Study No: A011-09 
Revision: 07D 
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Page 7 of 100 
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Protocol Location 
Description of Change 
Brief Rationale 
will be unblinded to study teams, 
investigators, and study participants. 
Section 6.9., Concomitant 
Therapy 
During the Extension Period, 
following Protocol Amendment 
07D, the decision criteria for 
permitting concomitant medications 
additions, removal, or adjustments 
for PAH or other chronic conditions 
will be based on the investigator’s 
discretion.  This includes the 
decision to adjust or discontinue 
sotatercept study treatment.  If 
changes occur for concomitant 
medications, it should be recorded in 
the appropriate eCRF. 
This revision allows the 
investigator the decision to adjust 
or discontinue sotatercept study 
treatment while adding, removing, 
or adjusting the dose of SOC 
concomitant medications (for any 
chronic conditions or PAH 
worsening).  
The criteria are more permissible 
since during the Extension Period, 
the study will be unblinded, and 
C9D1 primary endpoint results 
will have been collected at this 
time. 
Section 7.1., 
Discontinuation of Study 
Treatment 
Section 7.2., Withdrawal 
from the Study 
Remove loss of treatment effect. 
At this time, the effect is not 
known, and we cannot define the 
effect.  Therefore, the reference to 
the loss of treatment effect has 
been deleted.  
Section 8.2.1., Pulmonary 
Vascular Resistance by 
Right Heart 
Catheterization 
Revised with an additional RHC 
performed at C25.  For participants 
who passed C25, RHC should be 
done at the next possible visit up to 
C33. 
Revised to reflect the additional 
RHC added to assess long-term 
durability and efficacy of 
sotatercept. 
Section 8.2.3., 
Echocardiogram 
Parameters 
Added LVEF. 
LVEF to be measured in the 
placebo-controlled period. 
Section 8.3., Adverse 
Event 
Further defined the following: 
Unexpected AE: (added bold) 
An unexpected AE, the nature, 
severity, specificity, or outcome of 
which is not consistent with the 
current IB under the Reference 
Safety Information (added 
specificity) 
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 E2: 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 
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Sotatercept (ACE-011) 
Study No: A011-09 
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Page 8 of 100 
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Protocol Location 
Description of Change 
Brief Rationale 
Updated safety monitoring moved 
AESIs to Section 8.4. 
Deleted other irrelevant materials. 
Reporting, and AESI and SAE 
requirements.  
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 Phase 3 Acceleron 
PAH clinical programs.  
Section 8.3.9, 
Transmission of an 
Infectious Agent 
Added language in the case of a 
virus or infectious particles 
pathogenic or nonpathogenic, is 
considered an infectious agent and 
reporting instructions 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 or 
blinded therapy should be reported 
as an SAE. 
Safety monitoring and reporting 
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 trial. 
Section 9.3, Statistical 
Analyses 
Updated to refer include the 
statistical analysis plan (SAP) for 
the Extension Period. 
The Extension Period SAP is 
added in this section to address 
the study updated design. 
Appendix 2, Standard of 
Care Therapy  
Added: 
“During the Extension Period, 
PAH-specific medications can be 
modified (substituted, removed, or 
adjust the dose), including 
supplemental oxygen 
discontinuation of sotatercept study 
drug discontinuation is based on 
investigator’s discretion.” 
In the Extension Period, 
participants under investigator’s 
supervision are allowed to 
substitute, remove, or adjust the 
dose of SOC concomitant 
medications (for any chronic 
conditions or PAH worsening). 
The criteria are more permissible 
since, during the Extension 
Period, the study will be 
unblinded and C9D1 primary 
endpoint results will have been 
collected at this time. 
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Clinical Study Protocol 
 
Sotatercept (ACE-011) 
Study No: A011-09 
Revision: 07D 
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Page 9 of 100 
CONFIDENTIAL 
Protocol Location 
Description of Change 
Brief Rationale 
Appendix 8, Protocol 
Amendment History 
Moved amendments 03A, 04A, and 
05A Protocol Amendment history 
from Summary of Changes to 
Appendix 8. 
Weight is collected and recorded 
in the eCRF as a part of the vital 
signs.  Amendment history was 
provided for amendment 05A in 
the Summary of Changes section 
of the protocol and was moved to 
Appendix 8. 
Appendix 1, Clinical 
Laboratory Tests, 
Table 12, 
Protocol-Required Safety 
Laboratory Assessments 
In Table 12, Chemistry section,  
Added bicarbonate, reads “carbon 
dioxide/bicarbonate.” 
Added bicarbonate to 
accommodate regional differences 
in chemistry testing for carbon 
dioxide. 
AE = adverse event; AESI = adverse event of special interest; Cx = Cycle x; DMC = Data Monitoring Committee; 
ECG = electrocardiogram; ECHO = echocardiogram; eCRF = electronic case report form; EOT = End of Treatment; 
FC = functional class; GCP = Good Clinical Practice; Hgb = hemoglobin; ICH = International Council for 
Harmonisation; IRB/EC = institutional review board/ethics committee; IRT = interactive response technology; 
LVEF = left ventricular ejection fraction; PAH = pulmonary arterial hypertension; PK = pharmacokinetic; 
PPD = Pharmaceutical Product Development; RHC = right heart catheterization; SAP = statistical analysis plan; 
SAE = adverse event; SAP = statistical analysis plan; SOC = standard of care; SOE = Schedule of Events 
UA = urinalysis; UACR = urine albumin creatinine ratio. 
 
 
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Clinical Study Protocol 
 
Sotatercept (ACE-011) 
Study No: A011-09 
Revision: 07D 
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TABLE OF CONTENTS 
PROCEDURES IN CASE OF EMERGENCY ...............................................................................3 
Protocol Amendment Summary of Changes Table .........................................................................4 
TABLE OF CONTENTS ...............................................................................................................10 
LIST OF TABLES .........................................................................................................................13 
LIST OF FIGURES .......................................................................................................................13 
1. 
SYNOPSIS .................................................................................................................14 
2. 
SCHEDULE OF EVENTS .........................................................................................18 
3. 
INTRODUCTION ......................................................................................................24 
3.1. 
Study Rationale ...........................................................................................................24 
3.2. 
Background .................................................................................................................25 
3.3. 
Benefit/Risk Assessment ............................................................................................26 
4. 
STUDY DESIGN .......................................................................................................28 
4.1. 
Overall Design ............................................................................................................28 
4.2. 
End of Study Definition ..............................................................................................33 
4.3. 
Justification for Dose ..................................................................................................33 
5. 
STUDY POPULATION .............................................................................................35 
5.1. 
Participant and Study Completion ..............................................................................35 
5.2. 
Inclusion Criteria ........................................................................................................35 
5.3. 
Exclusion Criteria .......................................................................................................36 
5.4. 
Screen Failures ............................................................................................................38 
6. 
TREATMENTS ..........................................................................................................40 
6.1. 
Treatments Administered ............................................................................................40 
6.2. 
Treatment Administration and Schedule ....................................................................40 
6.3. 
Dose Modification ......................................................................................................41 
6.4. 
Method of Treatment Assignment ..............................................................................44 
6.5. 
Randomization and Blinding ......................................................................................44 
6.6. 
Packaging and Labeling ..............................................................................................45 
6.7. 
Preparation/Handling/Storage/Accountability ............................................................45 
6.8. 
Treatment Compliance ................................................................................................45 
6.9. 
Concomitant Therapy .................................................................................................46 
7. 
DISCONTINUATION/WITHDRAWAL CRITERIA ...............................................47 
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7.1. 
Discontinuation of Study Treatment ...........................................................................47 
7.2. 
Withdrawal from the Study ........................................................................................47 
7.3. 
Lost to Follow-Up .......................................................................................................48 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................49 
8.1. 
Screening Procedures ..................................................................................................49 
8.2. 
Efficacy Assessments .................................................................................................49 
8.2.1. 
Pulmonary Vascular Resistance by Right Heart Catheterization ...............................49 
8.2.2. 
Six-Minute-Walk Distance .........................................................................................50 
8.2.3. 
Echocardiogram Parameters .......................................................................................50 
8.2.4. 
Quality of Life Assessments .......................................................................................51 
8.3. 
Adverse Events ...........................................................................................................51 
8.3.1. 
Severity .......................................................................................................................53 
8.3.2. 
Relationship to Study Treatment ................................................................................53 
8.3.3. 
Documentation and Methods of Detecting Adverse Events and Serious 
Adverse Events ...........................................................................................................54 
8.3.4. 
Documentation of Serious Adverse Events ................................................................54 
8.3.5. 
Reporting Period and Monitoring of Participants with Adverse Events ....................55 
8.3.6. 
Notification About Serious Adverse Events ...............................................................55 
8.3.7. 
Safety Reporting to Health Authorities, Independent Ethics Committees, 
Institutional Review Boards, and Investigators ..........................................................55 
8.3.8. 
Overdose .....................................................................................................................56 
8.3.9. 
Transmission of an Infectious Agent ..........................................................................56 
8.3.10. 
Pregnancy ...................................................................................................................57 
8.4. 
Monitoring of Identified, Potential, and Adverse Events of Special Interest .............57 
8.4.1. 
Identified Risks ...........................................................................................................58 
8.4.2. 
Potential Risks ............................................................................................................58 
8.4.3. 
Adverse Events of Special Interest .............................................................................59 
8.5. 
Safety Assessments .....................................................................................................60 
8.5.1. 
Physical Examinations ................................................................................................60 
8.5.2. 
Vital Signs ..................................................................................................................61 
8.5.3. 
Electrocardiograms .....................................................................................................61 
8.5.4. 
Clinical Worsening .....................................................................................................61 
8.5.5. 
Rescue Therapy Criteria .............................................................................................62 
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8.5.6. 
Clinical Safety Laboratory Assessments ....................................................................62 
8.6. 
Pharmacokinetics ........................................................................................................63 
8.7. 
Pharmacodynamics .....................................................................................................63 
8.8. 
Genetic Testing ...........................................................................................................63 
8.9. 
Seminal Fluid Analyses ..............................................................................................63 
9. 
STATISTICAL CONSIDERATIONS .......................................................................65 
9.1. 
Sample Size Determination ........................................................................................65 
9.2. 
Populations for Analyses ............................................................................................65 
9.3. 
Statistical Analyses .....................................................................................................65 
9.3.1. 
Efficacy Analyses .......................................................................................................66 
9.3.2. 
Safety Analyses ..........................................................................................................66 
9.3.3. 
Other Analyses ............................................................................................................67 
9.3.4. 
Data Monitoring Committee .......................................................................................67 
9.3.5. 
Primary Endpoint Analysis .........................................................................................67 
9.3.6. 
Extension Period Analysis ..........................................................................................67 
9.3.6.1. 
Delayed-start Efficacy Analysis .................................................................................69 
9.3.6.2. 
Placebo-Crossed Efficacy Analysis ............................................................................69 
10. 
REFERENCES ...........................................................................................................70 
11. 
APPENDICES ............................................................................................................71 
ABBREVIATIONS AND SPECIALIST TERMS ........................................................................72 
APPENDIX 1. CLINICAL LABORATORY TESTS ................................................................75 
APPENDIX 2. STANDARD OF CARE THERAPY .................................................................76 
APPENDIX 3. SIX-MINUTE-WALK TEST .............................................................................77 
APPENDIX 4. STUDY GOVERNANCE CONSIDERATIONS ..............................................80 
APPENDIX 5. CONTRACEPTIVE GUIDANCE AND COLLECTION OF 
PREGNANCY INFORMATION ...............................................................................84 
APPENDIX 6. GENETICS .........................................................................................................88 
APPENDIX 7. NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY 
CRITERIA FOR ADVERSE EVENTS VERSION 4.0 .............................................89 
APPENDIX 8. PROTOCOL AMENDMENT HISTORY ..........................................................90 
 
 
 
 
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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Objectives and Endpoints ...........................................................................................14 
Table 3: 
Schedule of Events: Placebo-Controlled Treatment Period .......................................18 
Table 4: 
Schedule of Events: Extension and Follow-Up Periods .............................................21 
Table 5: 
Objectives and Endpoints ...........................................................................................31 
Table 6: 
Dose Reductions for Study Treatment ........................................................................44 
Table 7: 
Identified Risks ...........................................................................................................58 
Table 8: 
Potential Risks ............................................................................................................59 
Table 9: 
Adverse Events of Special Interest .............................................................................60 
Table 10: Statistical Analysis of Endpoints ................................................................................66 
Table 11: Notation: Efficacy Measurement at Different Timepoints .........................................68 
Table 12: Protocol-Required Safety Laboratory Assessments ...................................................75 
Table 13: Highly Effective Contraceptive Methods ...................................................................86 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................30 
Figure 2 
Platelet Count Dose Modification: Dose Delay, Dose Reduction, and 
Discontinuation Guidelines ........................................................................................42 
Figure 3 
Hemoglobin Dose Modification: Dose Delay, Dose Reduction, and 
Discontinuation Guidelines ........................................................................................43 
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1. 
SYNOPSIS 
Protocol Title 
A Phase 2, Double-Blind, Placebo-Controlled Randomized Study to Compare the Efficacy and 
Safety of Sotatercept (ACE-011) Versus Placebo When Added to Standard of Care for the 
Treatment of Pulmonary Arterial Hypertension (PAH) 
Short Title 
A Phase 2 Study of Sotatercept for the Treatment of PAH 
Rationale 
Study A011-09 is a Phase 2, double-blind, randomized, placebo-controlled, multicenter, 
parallel-group study to determine the efficacy and safety of Sotatercept (ACE-011) plus standard 
of care (SOC) versus placebo plus SOC in adults with pulmonary arterial hypertension (PAH) 
(World Health Organization [WHO] Group 1).  The study is divided into the Screening Period, 
Placebo-Controlled Treatment Period, Extension Period, and Follow-Up Period. 
Table 2: 
Objectives and Endpoints 
Primary -– Placebo-Controlled Treatment and Extension Periods 
Primary Objective 
Primary Endpoints 
Placebo-Controlled Treatment Period 
• 
To evaluate the effect on PVR in WHO 
functional class II-III PAH patients treated 
with sotatercept plus SOC compared with 
placebo plus SOC 
Placebo-Controlled Treatment Period 
• 
Change in PVR at 24 weeks (C9D1A) vs. 
screening PVR 
Extension Period 
• 
To evaluate the disease-modifying effect 
of sotatercept and additional efficacy 
analysis 
• 
To evaluate the long-term safety of 
sotatercept in WHO FC II-III PAH 
participants 
Extension Period 
• 
Change from baseline in PVR at Cycle 25 (or 
next cycles up to Cycle 33) for the Delayed 
Start efficacy analysis 
• 
Change from baseline in PVR at Cycle 25 (or 
next cycles up to Cycle 33) for the 
Placebo-Crossed treatment group 
• 
Safety and tolerability assessments based on 
AEs, clinical laboratory values, and vital signs 
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Sotatercept (ACE-011) 
Study No: A011-09 
Revision: 07D 
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Secondary – Placebo-Controlled Treatment and Extension Periods 
Secondary Objectives 
Secondary Endpoints 
• 
To assess the effects of sotatercept plus 
SOC on functional and PD endpoints in 
patients with PAH compared with placebo 
plus SOC 
• 
To assess the safety and tolerability of 
sotatercept in participants with PAH 
• 
To assess the PK of sotatercept in 
participants with PAH 
Placebo-Controlled Treatment Period 
Key Secondary Endpoint: 
• 
Change from baseline (screening or C1D1) in 
6MWD at 24 weeks (C9D1A) 
Other Secondary Endpoints: 
• 
Change from baseline (C1D1) in NT-proBNP at 
24 weeks (C9D1A) 
• 
Change from baseline (C1D1) in TAPSE at 
24 weeks (C9D1A)  
• 
Clinical worsening (e.g., hospitalizations, 
change in WHO functional class, and as defined 
in Section 8.5.4) from C1D1 to C9D1A 
• 
Change in WHO functional class at 24 weeks 
(C9D1A) vs. screening  
• 
Change from baseline (C1D1) in QoL 
(CAMPHOR, SF-36) at 24 weeks (C9D1A) 
• 
Safety and tolerability assessments based on 
adverse events (AEs), clinical laboratory values, 
vital signs, electrocardiograms (ECGs) 
• 
Population PK parameters of sotatercept 
Extension Period 
• 
To evaluate the disease modifying effect of 
sotatercept and additional efficacy analysis 
Extension Period 
Key Secondary Endpoints: 
• 
Change from baseline in 6MWD at Cycle 25 (or 
next cycles up to Cycle 33) for the 
Delayed-Start efficacy analysis 
• 
Change from baseline in 6MWD at Cycle 25 (or 
next cycles up to Cycle 33) for the 
Placebo-Crossed efficacy analysis 
Other Secondary Endpoints: 
• 
Change from baseline in WHO FC at Cycle 25 
(or next cycles up to Cycle 33) for the 
Delayed-Start efficacy analysis 
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Clinical Study Protocol 
 
Sotatercept (ACE-011) 
Study No: A011-09 
Revision: 07D 
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• 
Change from baseline in WHO FC at Cycle 25 
(or next cycles up to Cycle 33) for the 
Placebo-Crossed efficacy analysis 
Exploratory – Placebo-Controlled Treatment and Extension Periods 
Exploratory Objectives 
Exploratory Endpoints 
• 
To assess relevant biomarkers for PAH 
• 
To assess efficacy parameters in 
participants with PAH 
• 
Change from baseline (C1D1) in TGF-β ligands 
(e.g., activin A) and other PAH-related 
biomarkers at 24 weeks (C9D1A)  
• 
Change from baseline (historical or C1D1) in 
ECHO parameters (e.g., RVEF, PAP) at 
24 weeks (C9D1A)  
• 
Correlation of clinical efficacy vs. BMPR2 
expression in PBMCs 
• 
Correlation of clinical efficacy vs. sex hormone 
levels in males and females (e.g., estradiol 
metabolites) 
6MWD = 6-minute-walk distance; AE = adverse event; BMPR2 = bone morphogenetic protein receptor type II; 
CAMPHOR = Cambridge Pulmonary Hypertension Outcome Review; CxDy = Cycle x Day y; 
ECG = electrocardiogram; ECHO = echocardiogram; FC = functional class; NT-proBNP = N-terminal prohormone 
of brain natriuretic peptide; PAH = pulmonary arterial hypertension; PAP = pulmonary arterial pressure; 
PBMC = peripheral blood mononuclear cell; PD = pharmacodynamic(s); PK = pharmacokinetic(s); 
PVR = pulmonary vascular resistance; QoL = quality of life; RVEF = right ventricular ejection fraction; 
SF-36 = 36-Item Short Form Health Survey; SOC = standard of care; TAPSE = tricuspid annular plane systolic 
excursion; TGF-β = transforming growth factor-beta; WHO = World Health Organization 
Overall Design 
This is a Phase 2, double-blind, randomized, placebo-controlled, parallel-group study of 
sotatercept plus SOC versus placebo plus SOC in participants with PAH of WHO functional 
class (FC) II-III.  Participants will remain on SOC therapies during all periods of the study. 
In the Placebo-Controlled Treatment Period, participants will be randomly assigned in a 3:3:4 
ratio to receive subcutaneous (SC) injections of placebo, sotatercept 0.3 mg/kg, or sotatercept 
0.7 mg/kg, respectively, every 21 days for a period of 24 weeks.  During all periods of the study, 
all participants will also remain on SOC therapies.  Participants who have not discontinued early 
from the Placebo-Controlled Treatment Period and have had a Cycle 9 Day 1A (C9D1A) 
pulmonary vascular resistance (PVR) assessment will continue into the 30-month Extension 
Period.  After the primary endpoint analysis is completed, the trial will be unblinded and 
extended for an additional 12 months.  Investigators will be provided with the treatment 
assignments of their respective patients.  In the Extension Period, participants who received 
sotatercept in the Placebo-Controlled Treatment Period will continue to receive their current dose 
of sotatercept SC every 21 days plus SOC.  Participants who received placebo will be 
re-randomized 1:1 to receive either sotatercept 0.3 mg/kg SC or sotatercept 0.7 mg/kg SC every 
21 days plus SOC (see Section 6.5 for details). 
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Sotatercept (ACE-011) 
Study No: A011-09 
Revision: 07D 
31 July 2020  
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Page 17 of 100 
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Participants will have the opportunity to transition into a future sotatercept long-term follow-up 
study following completion of the third right heart catheterization (RHC). 
An independent Data Monitoring Committee (DMC) will be used to provide unblinded safety 
monitoring, see Section 9.3.4 for the DMC review details, after at least 15 participants have been 
enrolled and completed Cycle 2, and at 6-month intervals thereafter.  Section 9.3.3 and a detailed 
charter will outline all activities of the DMC (including, but not limited to, type of data to be 
reviewed, DMC responsibilities, and frequency of meetings). 
The primary endpoint analysis will be performed when all participants have completed the 
Cycle 9 Day 1 (C9D1A) PVR assessment or End of Treatment (EOT) PVR (for those subjects to 
discontinue early in the Placebo-Controlled Treatment Period).  Further information is available 
in Section 9.3.5.  After primary endpoint analysis is completed, the trial will be unblinded, and 
the DMC will continue to provide safety monitoring at approximately 6-month intervals, or ad 
hoc as necessary thereafter throughout the Extension Period. 
Number of Participants 
Approximately 100 participants will be randomly assigned in a 3:3:4 ratio to the 3 treatment 
groups.  
Randomization Stratification Factor 
Randomization will be stratified based on baseline (C1D1) WHO FC classification (II or III) as 
described in the Study Manual. 
Treatment Groups and Duration 
Study participation for each participant includes a Screening Period of 28 days, a 24-week, 
double-blind, Placebo-Controlled Treatment Period, and, if applicable, a 30-month Extension 
Period.  The Follow-Up Period will last 8 weeks following the last dose of study treatment. 
Each eligible participant will be randomly assigned in a 3:3:4 ratio to 1 of the 3 treatment groups 
during the Placebo-Controlled Treatment Period: 
• Arm 1: Placebo SC every 21 days plus SOC for 24 weeks 
• Arm 2: Sotatercept (0.3 mg/kg, SC) every 21 days plus SOC for 24 weeks 
• Arm 3: Sotatercept (0.7 mg/kg, SC) every 21 days plus SOC for 24 weeks 
Standard of care therapy refers to approved PAH-specific medications and may consist of 
monotherapy or combination therapy with endothelin-receptor antagonists (ERAs), 
phosphodiesterase 5 (PDE5) inhibitors, soluble guanylate cyclase stimulators, and/or 
prostacyclin analogues or receptor agonists.  Additional SOC details can be found in Appendix 2.  
Participants who have not discontinued early from the Placebo-Controlled Treatment Period and 
have had the 24-week (C9D1A) PVR assessment will continue into the 30-month Extension 
Period and will be treated as follows: 
• Placebo participants will be randomized 1:1 to receive either 0.3 or 0.7 mg/kg, 
sotatercept every 21 days plus SOC 
• Sotatercept-treated participants will continue on their current dose every 21 days plus 
SOC 
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Sotatercept (ACE-011) 
Study No: A011-09 
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2. 
SCHEDULE OF EVENTS 
Table 3: 
Schedule of Events: Placebo-Controlled Treatment Period 
 
Screening 
Period (up to 
28 days 
before Cycle 
1 Day 1) 
 
Placebo-Controlled Treatment Period (24 Weeks)1 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Cycle 7 
Cycle 8 
Cycle 9 
Day 1A2 
Day 1 
±3 
days 
Day 8 
±3 
days 
Day 1 
±3 
days 
Day 8 
±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 examination3 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Vital signs including weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test4  
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Hematology5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistry 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Urinalysis/urine albumin creatinine ratio 
 
X 
 
 
 
 
 
X 
 
 
 
X 
12-lead ECG 
X 
X 
 
X 
 
 
 
 
 
 
 
X 
Pulmonary tests (if necessary)6 
X 
 
 
 
 
 
 
 
 
 
 
 
Anti-drug antibody 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
Genetic sample (optional) 
 
X 
 
 
 
 
 
 
 
 
 
 
Right heart catheterization (RHC)7 
X 
 
 
 
 
 
 
 
 
 
 
X 
ECHO8 
X 
X 
 
X 
 
X 
 
X 
 
 
 
X 
6MWT9, 10 
X9 
X 
 
 
 
 
X 
 
X 
 
X 
X 
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Clinical Study Protocol 
 
Sotatercept (ACE-011) 
Study No: A011-09 
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CONFIDENTIAL 
Table 3: 
Schedule of Events: Placebo-Controlled Treatment Period (Continued) 
 
Screening 
Period (up to 
28 days 
before Cycle 
1 Day 1) 
 
Placebo-Controlled Treatment Period (24 Weeks)1 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Cycle 7 
Cycle 8 
Cycle 9 
Day 1A2 
Day 1 
±3 
days 
Day 8 
±3 
days 
Day 1 
±3 
days 
Day 8 
±3 
days 
±3 
days 
±3 days 
±3 days 
±3 
days 
±3 
days 
±3 
days 
±3 days 
QoL10 
 
X 
 
X 
 
 
X 
 
X 
 
X 
X 
WHO Functional class assessment 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Clinical worsening 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Pre-dose (or no dose) PK collection 
 
X 
X 
X 
X 
X 
 
X 
 
 
X 
X 
Post-dose PK collection11 
 
X 
 
 
 
 
 
X 
 
 
 
 
PD blood biomarkers 
 
X 
 
X 
 
 
 
X 
 
 
X 
X 
Seminal fluid collection (optional)12 
X 
 
 
 
 
 
 
 
 
 
 
 
Study treatment administration13 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
AE/SAE review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
6MWT = 6-meter walking test; AE = adverse event; CT = computed tomography; CxDy = cycle x day y; ECG = electrocardiogram; ECHO = echocardiogram; 
Hgb = hemoglobin; LVEF = left ventricular ejection fraction; PAP = pulmonary arterial pressure; PD = pharmacodynamics; PK = pharmacokinetic; 
QoL =quality of life; RHC = right heart catheterization; SAE = serious adverse event; TAPSE = tricuspid annular plan systolic excursion; VQ = ventilation-
perfusion (scan). 
1 All visit day windows should be considered relative to the date of the previous dose of study treatment.  Cycles are every 21 days (±3 days) except for RHC and 
ECHO as noted below.  
2 C9D1A procedures are to occur prior to C9D1B procedures on the same day except for RHC and ECHO, which may be performed earlier per protocol.  
3A full physical examination should be completed at the Screening Visit; a targeted cardiopulmonary exam should be completed at all other visits. 
4 Pregnancy test (urine or serum) is required for female participants of childbearing potential at Screening and prior to each dose of study treatment. (See 
Appendix 5 for pregnancy follow-up). 
5 Results from the hematology panel should be evaluated prior to study treatment administration.  For C1D1, C2D1, C9D1A/B, and C10D1 visits, blood samples 
should be taken and assessed for Hgb levels on the same day as study treatment administration.  For all other dosing cycles, blood samples may be taken and 
assessed for Hgb levels on the same day as study treatment administration or 1 day prior.  If Hgb is ≥ 17.0 g/dL at Day 8 visits for Cycles 1 or 2, participants 
should return weekly for Hgb monitoring (and continue to follow Dose Modification guidance for dosing days [Section 6.3]). 
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Clinical Study Protocol 
 
Sotatercept (ACE-011) 
Study No: A011-09 
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Acceleron Pharma Inc. 
Page 20 of 100 
CONFIDENTIAL 
6 Additional screening procedures to include pulmonary functional tests (PFTs) and VQ/CT pulmonary angiogram (CTPA) as per Inclusion criteria 5 and 6 
(Section 5.1) if historical readings are unavailable. 
7 Three RHCs should be performed during the course of this study.  The RHCs in the Placebo-Controlled Treatment Period must occur within 10 days prior to 
C1D1 (during the Screening Period) and C9D1A.  For participants discontinuing the study before C9D1A, an RHC should be performed ± 10 days of the EOT 
visit.  If other assessments are occurring on the same day, RHC should be performed last.  
8 ECHO parameters include but are not limited to: TAPSE, PAP, right ventricular ejection fraction, and LVEF.  Additional screening procedures to include 
ECHO as per exclusion criterion 16 (Section 5.2) if historical readings are unavailable.  If an ECHO is performed during screening, these values may be used as 
the baseline for this study and an additional ECHO is not required for these participants at C1D1.  If a historical ECHO is evaluated during the Screening Period, 
the participant should receive an ECHO at the C1D1 visit which will serve as the baseline for the study for these participants.  All ECHOs from C1D1 onward 
may be performed within 1 week of study visit.   
9 6MWT to be performed twice during the Screening Period at least 4 hours (but no longer than 1 week) apart.  6MWT may also be done twice based on criteria 
outlined for clinical worsening (Section 8.5.4).  If screening 6MWT is done within 10 days of C1D1, this value can serve as the baseline value and an additional 
6MWT does not need to be conducted at C1D1.  If the screening 6MWT is conducted > 10 days prior to C1D1, then the 6MWT should be done as part of the 
C1D1 assessments. 
10 QoL: Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR), SF36, should be performed before 6MWT, blood draws, AE discussions, and 
RHC. 
11 The post-dose PK sample will be collected within 4 hours of dosing (minimum of 15 minutes from dose administration). 
12 Seminal fluid collection is optional for male participants (Section 8.9).   
13 Study procedures should be done prior to the administration of study treatment except for postdose PK collection.  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). 
 
 
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Clinical Study Protocol 
 
Sotatercept (ACE-011) 
Study No: A011-09 
Revision: 07D 
 
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Table 4: 
Schedule of Events: Extension and Follow-Up Periods 
 
Extension Period (30 months)1,13 
Follow-Up Period  
(8 Weeks) 
Cycle 9 
Cycle 10 
Cycles 
11-12, 14-
16, 18-20, 
22-24 
Cycles 
13, 17, 
21 
Cycles 
25-33 
Cycle 
34 
Cycles 
35, 37, 
39, 41, 
43, 45, 
47, 49 
Cycles 
36, 38, 
40, 44, 
46, 48, 
50 
Cycles 
42 and 
51 
End of 
Treatment13 
End of 
Study13 
Day 
1B2 
±3 
days 
Day 8 
±3 
days 
Day 1 
±3 
days 
Day 8 
±3 days 
±3 days 
±3 
days 
±3 
days 
±3 
days 
±3 days 
±3 
days 
±3 
days 
4 weeks2 or at 
the time of 
early 
discontinuation 
(±3 days) 
8 weeks 
(±7 days) 
post last 
dose of 
study 
treatment) 
Physical examination3  
 
 
X 
 
X 
X 
X 
X 
 
 
X 
 
X 
Vital signs (including weight) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Pregnancy test4 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Hematology5 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Serum chemistry 
 
 
X 
 
X 
X 
X 
X 
 
 
X 
 
X 
Urinalysis 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
Urine albumin-creatinine ratio 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
12-lead ECG 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
Anti-drug antibody 
 
 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
Randomization 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Right heart catheterization  
 
 
 
 
 
 
X6 
 
 
 
 
X 
 
ECHO7 
 
 
X 
 
 
X 
X14 
 
 
 
X 
X 
X 
6MWT8 
 
 
X 
 
X14 
X 
X 
 
 
 
X 
X 
X 
QoL9 
 
 
X 
 
 
X 
 
 
 
 
X 
X 
X 
WHO Functional Class Assessment 
 
 
X 
 
X 
X 
X 
X 
 
 
X 
X 
X 
Clinical worsening 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pre-dose (or no dose) PK collection 
 
X 
X 
X 
X14 
X 
X14 
X 
 
 
 
X 
X 
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Clinical Study Protocol 
 
Sotatercept (ACE-011) 
Study No: A011-09 
Revision: 07D 
 
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Extension Period (30 months)1,13 
Follow-Up Period  
(8 Weeks) 
Cycle 9 
Cycle 10 
Cycles 
11-12, 14-
16, 18-20, 
22-24 
Cycles 
13, 17, 
21 
Cycles 
25-33 
Cycle 
34 
Cycles 
35, 37, 
39, 41, 
43, 45, 
47, 49 
Cycles 
36, 38, 
40, 44, 
46, 48, 
50 
Cycles 
42 and 
51 
End of 
Treatment13 
End of 
Study13 
Day 
1B2 
±3 
days 
Day 8 
±3 
days 
Day 1 
±3 
days 
Day 8 
±3 days 
±3 days 
±3 
days 
±3 
days 
±3 
days 
±3 days 
±3 
days 
±3 
days 
4 weeks2 or at 
the time of 
early 
discontinuation 
(±3 days) 
8 weeks 
(±7 days) 
post last 
dose of 
study 
treatment) 
Post-dose PK collection10 
X 
 
 
 
 
X 
 
X 
 
 
 
 
 
PD blood biomarkers 
 
 
X 
 
X14 
X 
X14 
X 
 
 
 
 
X 
Seminal fluid collections 
(optional)11 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study treatment administration12 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
 
AE/SAE review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
6MWT = 6-meter walking test; AE = adverse event; CT = computed tomography; CxDy = cycle x day y; ECG = electrocardiogram; ECHO = echocardiogram; 
EOS = End of Study; EOT = End of Treatment; Hgb = hemoglobin; IRB/IEC = Institutional Review Board/Independent Ethics Committee; LVEF = left 
ventricular ejection fraction; NT-proBNP = N-terminal prohormone of brain natriuretic peptide; PAP = pulmonary arterial pressure; PD = pharmacodynamics; 
PK = pharmacokinetic; QoL = quality of life; RHC = right heart catheterization; SAE = serious adverse event; TAPSE = tricuspid annular plan systolic 
excursion; VQ = ventilation-perfusion (scan); WHO = World Health Organization. 
1All visit day windows should be considered relative to the date of the previous dose of study treatment.  Cycles are every 21 days (±3 days) except for ECHO as 
noted below.  Upon IRB/IEC approval of the updated protocol (amendment 07D), investigators will be unblinded for treatment assignments of their participants.  
2 Cycle 9 Day 1A (C9D1A) procedures are to occur prior to Cycle 9 Day 1B (C9D1B) procedures on the same day except for RHC and ECHO, which may be 
performed earlier per protocol.  
3 Targeted cardiopulmonary exam only. 
4 Pregnancy test (urine or serum) is required for female participants of childbearing potential at Screening, prior to each dose of study treatment (see 
Appendix 5 or pregnancy follow-up). 
5 Results from the hematology panel should be evaluated prior to study treatment administration.  For C9D1A/B and C10D1 visits, blood samples should be 
taken and assessed for Hgb levels on the same day as study treatment administration.  For all other dosing cycles, blood samples may be taken and assessed for 
Hgb levels on the same day as study treatment administration or 1 day prior to dosing.  If Hgb is ≥ 17.0 g/dL at Day 8 visits for Cycles 9 or 10, participants 
should return weekly for Hgb monitoring (and continue to follow Dose Modification guidance for dosing days [Section 6.3]). 
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Clinical Study Protocol 
 
Sotatercept (ACE-011) 
Study No: A011-09 
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6 If a participant has previously completed Cycle 25, the third RHC is to be completed at the next possible dosing visit up to Cycle 33 and should be performed 
within 3 days of that visit.  Procedures to accompany the third RHC include pre-dose PK, NT-proBNP, ECHO, and 6MWT; RHC should be performed last.  No 
more than 3 RHCs are to be performed in total during the study: baseline, C9D1A, and at Cycle 25 (or first available dosing after Cycle 25 [up to Cycle 33]) or 
EOT if discontinued early from extension. 
7 ECHO parameters include but are not limited to: TAPSE, PAP, right ventricular ejection fraction, and LVEF.  ECHO may be performed within 1 week of study 
visit.   
8 6MWT may be done twice based on criteria outlined for clinical worsening (Section 8.5.4).  
9 QoL: Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR), 36-item short form survey (SF36), should be performed before 6MWT, blood 
draws, AE discussions, and RHC. 
10 The post-dose PK sample will be collected within 4 hours of dosing (minimum of 15 minutes from dose administration). 
11 Seminal fluid collection is optional for male participants (Section 8.9).   
12 Study procedures should be done prior to the administration of study treatment except for post-dose PK collection.  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).  
13 Participants who complete the third RHC and consent to sotatercept long-term follow-up study will roll over directly without completing EOT/EOS. 
14 If third RHC will be performed at this visit, the procedure should be performed prior to the RHC.  For participants whose third RHC assessment is performed 
at the next available dosing visit after C25D1 up to C33D1, ECHO may be performed within 1 week of the third RHC visit.  The ECHO procedure should only 
be performed once during this period matching the third RHC visit.  For PD biomarkers, only NT-proBNP is to be performed. 
 
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Sotatercept (ACE-011) 
Study No: A011-09 
Revision: 07D 
 
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CONFIDENTIAL 
3. 
INTRODUCTION 
Sotatercept (ACE-011) is a first-in-class human fusion protein consisting of the extracellular 
domain of the activin receptor IIA linked to the Fc domain of human immunoglobulin G1.  
Sotatercept works by targeting molecules in the transforming growth factor-beta (TGF-β) 
superfamily, which includes activins and bone morphogenetic proteins (BMPs).  Aberrant TGF-β 
superfamily signaling is associated with a wide range of human pathologies, including 
autoimmune, fibrotic diseases, cancer, and cardiovascular disorders such as pulmonary arterial 
hypertension (PAH).  Disruptions in TGF-β and BMP signaling are associated with the 
development of PAH.  
3.1. 
Study Rationale 
Study A011-09 is a Phase 2, double-blind, randomized, placebo-controlled, multicenter, 
parallel-group study to determine the efficacy and safety of sotatercept plus standard of care 
(SOC) versus placebo plus SOC in adults with PAH (World Health Organization [WHO] 
Group 1).  The study is divided into the Screening Period, Treatment Period, Extension Period, 
and Follow-Up Period. 
The design of this study will control bias in the assignment of study treatment as well as in data 
interpretation, particularly of the measures that may have clinical variability (e.g., PVR and 
6-minute-walk distance [6MWD]). 
Rationale for Participant Population 
Patients with diagnostic WHO Group I PAH associated with idiopathic/heritable, drug-induced, 
connective tissue diseases, or post-shunt correction PAH within the WHO functional class II-III 
PAH will be selected for this study.  PAH is considered a rare condition, with approximately 
80% of patients presenting as class II-III PAH.  It is expected that the treatment effect of 
sotatercept can be more easily detected in this patient population.  Patients with class I PAH are 
typically excluded from interventional studies due to their relatively low identification rate, low 
prevalence, and mild symptomatology.  Similarly, there is a low prevalence of patients with 
class IV PAH, and given their severe disease burden, those patients have limited ability to 
participate in longer interventional studies.  Eligibility criteria for this study are consistent with 
those of other studies in this population. 
Rationale for Study Endpoints 
The primary endpoint is change in PVR at 24 weeks Cycle 9 Day 1A (C9D1A) as compared to 
the PVR value obtained during the Screening Period.  This analysis will assess change in 
resistance to flow across the pulmonary vasculature; a reduction is anticipated based on the 
activity of sotatercept in animal models and the hypothesized mechanism of action and activity 
of sotatercept in patients with PAH.  Secondary objectives include evaluation of changes in 
6MWD, echocardiogram (ECHO) parameters, such as tricuspid annular plane systolic excursion 
(TAPSE), clinical worsening (including WHO Functional class assessment and hospitalizations), 
quality of life (QoL; 36-Item Short Form Health Survey [SF-36]), Cambridge Pulmonary 
Hypertension Outcome Review (CAMPHOR), and safety.  TAPSE, 6MWD, and WHO 
functional class have been established as having significant mortality prognostic capacity.1-3  
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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; Appendix 7). 
Rationale for Comparator 
The choice of placebo as the comparator is to enable robust assessments of the effectiveness and 
safety of sotatercept in a controlled setting.  Participants in the placebo group (and sotatercept 
groups) will be on stable doses of SOC therapies for PAH prior to study entry and will maintain 
SOC therapies during the study, thus ensuring that participants randomized to the placebo arm 
are treated and managed as per established treatment guidelines. 
Rationale for Dose and Frequency Selection 
Selection of the dose and frequency are based on estimates of biologically active sotatercept 
doses and frequencies studied in several patient populations with other chronic diseases.  The 
doses proposed for the Phase 2 study in PAH are 0.3 and 0.7 mg/kg.  Doses in this range have 
been associated with pharmacodynamic (PD) effects and an acceptable safety profile.  The 
projected mean exposure levels at the steady state are 93 day*μg/mL for AUC21d and 5.3 μg/mL 
for Cmax at 0.3 mg/kg every 21 days, and 217 day*μg/mL for AUC28d and 12.4 μg/mL for Cmax at 
0.7 mg/kg every 21 days.  Pharmacokinetic (PK) modeling data showed every 21-day and every 
28-day dosing to be similar in terms of predicted hemoglobin (Hgb) response but different in 
regards to exposure. 
3.2. 
Background 
Genetic mutations in the bone morphogenetic protein receptor type II (BMPR2) are associated 
with the majority of the familial form of PAH4,5 and approximately 25% of idiopathic PAH.  
Specifically, the impairment of the BMPR2-associated signal pathway appears to lead to the 
uncontrolled proliferation of pulmonary vascular smooth muscle cells (VSMCs), the principal 
cause of PAH.  These data strongly suggest a key role of TGF-β family members in the 
pathogenesis of PAH.  Sotatercept acts to block activin ligands and growth and differentiation 
factors (GDFs), may attenuate BMPs, and improve pulmonary vascular remodeling by restoring 
balance to SMAD signaling.6  
PAH applies to a group of diseases causing a progressive increase in PVR, resulting in right 
ventricular dysfunction and ultimately failure as well as premature death.7,8  The PAH 
pathophysiology involves pulmonary endothelial dysfunction, resulting in impaired production 
of vasodilators, such as nitric oxide and prostacyclin, and overexpression of vasoconstrictors, 
such as endothelin-1.  The pathophysiology of PAH also entails the abnormal proliferation of 
pulmonary VSMCs in pulmonary arterioles, which results in progressive pulmonary vascular 
remodeling, increased PVR and, eventually, right-sided heart failure.9  In the absence of 
treatment, the majority of patients succumb to heart failure within a few years of diagnosis.10  
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 ERAs, phosphodiesterase 5 (PDE5) 
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inhibitors, and prostanoids and 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.  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 the treatment of PAH.  
Importantly, the animal models provide evidence of a disease-modifying effect - a substantial 
reduction in the proliferation of pulmonary VSMCs in RAP-011-treated animals, as assessed by 
histologic evaluation, in both preventative and therapeutic disease models. 
RAP-011, was evaluated in both preventative and therapeutic disease models.  Affected animals 
treated with RAP-011 showed substantial improvements in pulmonary vascular and cardiac 
hemodynamic measurements that are comparable or superior to approved agents for the 
treatment of PAH.  Importantly, a substantial reduction in the proliferation of pulmonary VSMCs 
was observed in RAP-011 treated animals as assessed by histologic evaluation in both 
preventative and therapeutic disease models.  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 potentially may positively affect vascular remodelling.6 
A detailed description of the chemistry, pharmacology, efficacy, and safety of sotatercept is 
provided in the Investigator Brochure. 
3.3. 
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 to protect 
participant safety. 
The evidence for potential benefits comes from data observed in rodent models of PAH.  These 
include reduced muscularization and thickness of pulmonary vessel walls, reduced right-sided 
heart pressures, and reduced right-to-left ventricle weight ratios.  These improvements might be 
accompanied by reductions in PVR as well as increases in functional capacity and QoL, which 
will also be measured during the study. 
Possible risks to participants observed in prior clinical studies with sotatercept include increases 
in Hgb, hematocrit (Hct), red blood cell count (RBC), and blood pressure.  These will be 
diligently monitored during the study, and adjustment to dosing made as necessary (following 
medical treatment) to ameliorate these risks.  Potential risks of development of anti-drug 
antibodies, reproductive effects, and renal injury, though not experienced as AEs in other 
sotatercept clinical studies (but observed in some preclinical studies), will also be monitored.  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 treatment-emergent adverse 
events (TEAEs).  As a consequence of the decrease in white blood cells (WBCs), infection 
maybe a potential risk and as a consequence of the decrease in platelets, bleeding maybe a 
potential risk.  Per health authority request, leukopenia, neutropenia, and thrombocytopenia have 
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been identified as adverse events of special interest (AESIs) in this study (see Section 8.4).  
Thorough monitoring of all AEs experienced by any participant will also be employed in this 
study. 
More detailed information about the known and expected benefits and risks and possible AEs of 
sotatercept may be found in the IB. 
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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a Phase 2, double-blind, randomized, placebo-controlled, parallel-group study of 
sotatercept plus SOC versus placebo plus SOC in participants with PAH of WHO functional 
class II-III.  Participants will remain on SOC therapies during all periods of the study.   
Standard of care therapy refers to approved PAH-specific medications, and may consist of 
monotherapy or combination therapy with ERAs, PDE5 inhibitors, soluble guanylate cyclase 
stimulators, and/or prostacyclin analogues or receptor agonists.  Additional SOC details can be 
found in Appendix 2.  
For the 24-week Placebo-Controlled Treatment Period, participants will be randomly assigned in 
a 3:3:4 ratio to receive placebo subcutaneously (SC) every 21 days plus SOC, sotatercept 
0.3 mg/kg SC every 21 days plus SOC or sotatercept 0.7 mg/kg SC every 21 days plus SOC.  
Participants who have not discontinued early from the double-blind Placebo-Controlled 
Treatment Period and have had the 24-week (C9D1A) PVR assessment will continue into the 
30-month Extension Period.  After the primary C9D1 endpoint analysis is completed, the trial 
will be unblinded.  In the Extension Period, participants who received sotatercept during the 
Placebo-Controlled Treatment Period will continue at their current dose, plus SOC, and 
participants who received placebo during the Placebo-Controlled Treatment Period will be 
randomized 1:1 to receive sotatercept, either 0.3 or 0.7 mg/kg, SC every 21 days plus SOC. 
Study duration for each participant includes a Screening Period of 28 days, a 24-week, 
double-blind, Placebo-Controlled Treatment Period, a 30-month Extension Period, and an 
8-week Follow-Up Period after the last dose of study treatment. 
Upon approval of protocol amendment 07D, participants will be presented with an informed 
consent form (ICF) for the additional 12-months in Extension Period. 
Approximately 100 eligible participants will be randomly assigned in a 3:3:4 ratio to 1 of the 3 
treatment groups in the Placebo-Controlled Treatment Period: 
• Arm 1: Placebo SC every 21 days plus SOC for 24 weeks 
• Arm 2: Sotatercept (0.3 mg/kg, SC) every 21 days plus SOC for 24 weeks 
• Arm 3: Sotatercept (0.7 mg/kg, SC) every 21 days plus SOC for 24 weeks 
Participants who have not discontinued early from the Placebo-Controlled Treatment Period and 
have had the 24-week (C9D1A) PVR assessment will continue into the 30-month Extension 
Period and will be treated as follows:  
• Placebo participants will be randomized 1:1 to receive either 0.3 or 0.7 mg/kg 
sotatercept every 21 days plus SOC. 
• Sotatercept-treated participants will continue on their current dose every 21 days plus 
SOC. 
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• Upon approval of amendment 07D, investigators will be allowed to increase a 
participant’s study treatment dose up to 0.7 mg/kg at the investigator’s discretion 
based on clinical assessments and in compliance with the dose modification guideline 
outlined in Section 6.3. 
Randomization will be stratified based on baseline (C1D1) WHO functional class classification 
(II or III) as described in the Study Manual. 
Screening Period 
Upon giving written informed consent, participants will enter the Screening Period to determine 
eligibility for the study.  Participant screening procedures are to take place within 28 days prior to 
randomization (C1D1).   
Placebo-Controlled Treatment Period 
Participants will receive either placebo plus SOC, sotatercept 0.3 mg/kg SC plus SOC, or 
sotatercept 0.7 mg/kg plus SOC as per randomization assignment.  Study treatment will be 
administered SC every 21 days for 24 weeks.  Safety analyses will be performed for the Data 
Monitoring Committee (DMC) review (Section 9.3.4 for more details). 
Extension Period 
Participants who have not discontinued early from the Placebo-Controlled Treatment Period will 
continue directly into the Extension Period.  Participants who have been on sotatercept will 
continue to receive sotatercept at their current dose SC plus SOC.  Participants who were in the 
placebo arm will be re-randomized 1:1 to receive sotatercept 0.3 or 0.7 mg/kg SC plus SOC.  
Study treatment will be administered SC every 21 days for 30 months.  Following the approval 
protocol amendment 07D, investigators and patients will be unblinded to the current dose (see 
Section 6.5 for additional details). 
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 the study early, including during either the Placebo-Controlled 
Treatment Period or the Extension Period, will be asked to return for EOT and End of Study 
(EOS) visits.  Additional safety assessments, including urinalysis (UA) and hematology, as 
determined by the investigator, may be done at this time. 
 
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Figure 1: 
Study Design 
 
 
C09 = Cycle 9; EOS = End of Study; EOT = End of Treatment; N = number; PBO = placebo; PVR = pulmonary vascular resistance; Q = every; RHC = right 
heart catheterization; SC = subcutaneously; SOC = standard of care. 
Refer to Section 8 for a full list of study assessments/procedures. 
 
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Table 5: 
Objectives and Endpoints 
Primary – Placebo-Controlled Treatment and Extension Periods 
Primary Objectives 
Primary Endpoints 
Placebo-Controlled Treatment Period 
• 
To evaluate the effect on PVR in WHO 
functional class II-III PAH participants 
treated with sotatercept plus SOC 
compared with placebo plus SOC 
Placebo-Controlled Treatment Period 
• 
Change in PVR at 24 weeks (C9D1A) vs. 
screening PVR  
Extension Period 
• 
To evaluate the disease-modifying effect 
of sotatercept and additional efficacy 
analysis  
• 
To evaluate the long-term safety of 
sotatercept in WHO functional class II-III 
PAH participants 
Extension Period 
• 
Change from baseline in PVR at Cycle 25 (or 
next cycles up to Cycle 33) for the 
Delayed-start efficacy analysis 
• 
Change from baseline in PVR at Cycle 25 (or 
next cycles up to Cycle 33) for the 
Placebo-Crossed efficacy analysis 
• 
Safety and tolerability assessments based on 
AEs, clinical laboratory values, and vital signs. 
 
 
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Table 5: 
Objectives and Endpoints (Continued) 
Secondary – Placebo-Controlled Treatment and Extension Periods 
Secondary Objectives  
Secondary Endpoints 
Placebo-Controlled Treatment Period 
• 
To assess the effects of sotatercept plus 
SOC on functional and PD endpoints in 
participants with PAH compared with 
placebo plus SOC 
• 
To assess the safety and tolerability of 
sotatercept in participants with PAH 
• 
To assess the PK of sotatercept in 
participants with PAH 
 
Placebo-Controlled Treatment Period 
Key Secondary Endpoint: 
• 
Change from baseline (screening or C1D1) in 
6MWD at 24 weeks (C9D1A) 
Other Secondary Endpoints: 
• 
Change from baseline (C1D1) in NT-proBNP 
at 24 weeks (C9D1A) 
• 
Change from baseline (C1D1) in TAPSE at 
24 weeks (C9D1A) 
• 
Clinical worsening (e.g., hospitalizations, 
change in WHO functional class, and as 
defined in Section 8.5.4) from C1D1 to C9D1A 
• 
Change in WHO functional class at 24 weeks 
(C9D1A) vs. screening 
• 
Change from baseline (C1D1) in QoL 
(CAMPHOR, SF-36) at 24 weeks (C9D1A) 
• 
Safety and tolerability assessments based on 
AEs, clinical laboratory values, vital signs, and 
electrocardiograms (ECGs) 
• 
Population PK parameters of sotatercept 
Extension Period 
• 
To evaluate the disease-modifying effect of 
sotatercept and additional efficacy analysis 
 
Extension Period 
Key Secondary Endpoint: 
• 
Change from baseline in 6MWD at Cycle 25 
(or next cycles up to Cycle 33) for the 
Delayed-Start efficacy analysis 
• 
Change from baseline in 6MWD at Cycle 25 
(or next cycles up to Cycle 33) for the 
Placebo-Crossed efficacy analysis 
Other Secondary Endpoints: 
• 
Change from baseline in WHO FC at Cycle 25 
(or next cycles up to Cycle 33) for the 
Delayed-Start efficacy analysis  
• 
Change from baseline in WHO FC at Cycle 25 
(or next cycles up to Cycle 33) for the 
Placebo-Crossed efficacy analysis 
 
 
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Table 5: 
Objectives and Endpoints (Continued) 
Exploratory– Placebo-Controlled Treatment and Extension Periods 
Exploratory Objectives 
Exploratory Endpoints 
• 
To assess relevant biomarkers for PAH 
• 
To assess efficacy parameters in 
participants with PAH  
• 
Change from baseline (C1D1) in TGF-β 
ligands (e.g., activin A) and other PAH-related 
biomarkers at 24 weeks (C9D1A) 
• 
Change from baseline (historical or C1D1) in 
ECHO parameters (e.g., RVEF, PAP) at 
24 weeks (C9D1A) 
• 
Correlation of clinical efficacy vs. BMPR2 
expression (in PBMCs) 
• 
Correlation of clinical efficacy vs. sex hormone 
levels in males and females (e.g., estradiol 
metabolites)  
6MWD = 6-minute-walk distance; AE = adverse event; BMPR2 = bone morphogenetic protein receptor type II; 
CAMPHOR = Cambridge Pulmonary Hypertension Outcome Review; CxDy = Cycle x Day y; 
ECG = electrocardiogram; ECHO = echocardiogram; FC = functional class; NT-proBNP = N-terminal prohormone 
of brain natriuretic peptide; PAH = pulmonary arterial hypertension; PAP = pulmonary arterial pressure; 
PBMC = peripheral blood mononuclear cell; PD = pharmacodynamic(s); PK = pharmacokinetic(s); 
PVR = pulmonary vascular resistance; QoL = quality of life; RVEF = right ventricular ejection fraction; 
SF-36 = 36-Item Short Form Health Survey; SOC = standard of care; TAPSE = tricuspid annular plane systolic 
excursion; TGF-β = transforming growth factor-beta; WHO = World Health Organization. 
4.2. 
End of Study Definition 
A participant is considered to have completed the study if he/she has completed all phases of the 
study, including the EOT and 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. 
4.3. 
Justification for Dose 
For the current study, doses of 0.3 and 0.7 mg/kg were selected and will be administered SC 
every 21 days (i.e., every 3 weeks [Q3W]).  The projected mean exposure levels at the steady 
state are 3.5 and 8.1 μg/mL for 0.3 and 0.7 mg/kg Q3W, respectively.  These projected exposures 
are comparable to those observed in healthy volunteers who received SC 0.3 mg/kg Q4W 
(Cmax = 2.4 μg/mL) and 1.0 mg/kg doses Q4W (Cmax = 7.4 μg/mL).  In the current protocol, the 
starting exposure levels (i.e., after the first dose) are estimated to be approximately half of that at 
the steady state. 
Simulations based on population PK model show that there will be an adequate separation in the 
systemic sotatercept exposure between the currently selected doses of 0.3 and 0.7 mg/kg Q3W 
[mean (5th, 95th percentile): 3.5 μg/mL (2.00, 4.90) versus 8.10 μg/mL (4.80, 11.4)].  This will 
facilitate the evaluation of the dose-response relationship for effectiveness and toxicity.  
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Based on the safety data from the 2 completed Phase 1 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 
0.3 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 Phase 1 clinical 
studies were attributable to the expected biologic activity of activin inhibition, i.e., 
dose-dependent decreases in circulating follicle-stimulating hormone (FSH), and transient, 
reversible effects on RBC parameters.  In Study A011-02, 1 participant experienced persistent, 
progressive hypertension, which was reported as a treatment-related serious adverse event 
(SAE), together with headaches approximately 1 week following her second dose of 1.0 mg/kg 
sotatercept SC that were attributable to a rapid and significant rise in Hgb.   
Using data from these Phase 1 studies, an indirect response PK/PD model for Hgb following IV 
or SC administration of sotatercept was developed.  The final PK/PD model was used to 
calculate the individual-predicted values of Hgb at each of the virtual sample times.  Summary 
statistics of Hgb at steady state and the associated sotatercept concentrations were calculated 
stratified by population, dose level, and dosing interval.  For simulations, PAH patients were 
assumed to be similar to healthy volunteers in terms of baseline Hgb level and likely Hgb 
responses to sotatercept dosing.  Mean (90% confidence interval) predicted steady state Hgb was 
15.4 g/dL (13.7, 17) and 16.0 g/dL (14.4, 17.4) for 0.3  and 0.7 mg/kg Q3W, respectively.  These 
projected Hgb levels appeared to be similar to the Hgb levels observed in 2 Phase 1 studies.  
Though simulations show that doses in the range of 0.3  and 0.7 mg/kg are expected to be safe 
overall, AE rates due to sotatercept-mediated Hgb increases will be further ameliorated by the 
implementation of dose reduction, delay, and stopping rules in the subsequent treatment cycles 
(Section 6.3).  In addition, a comprehensive safety monitoring plan will be incorporated into the 
study to mitigate risk.  This will include comprehensive dose-modification guidance as well as 
the incorporation of study oversight by both a scientific steering committee as well as an 
independent DMC to assess safety events on an ongoing basis. 
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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. 
5.1. 
Participant and Study Completion 
Approximately 100 participants will be randomly assigned in a 3:3:4 ratio to receive placebo 
plus SOC, sotatercept 0.3 mg/kg plus SOC, or sotatercept 0.7 mg/kg plus SOC. 
Additional details are provided in Section 9. 
5.2. 
Inclusion Criteria 
Participants must satisfy all of the following criteria to be enrolled in the study: 
1. Age ≥ 18 years 
2. Documented diagnostic RHC at any time prior to Screening confirming the diagnosis of 
WHO diagnostic pulmonary hypertension Group I: PAH in 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 II or III 
4. Baseline RHC performed within 10 days prior to C1D1 visit during the Screening Period 
documenting a minimum PVR of ≥ 400 dyn·sec/cm5 (5 Wood units) 
5. Pulmonary function tests (PFTs) within 6 months prior to the Screening Visit 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)/ forced vital capacity > 70% predicted 
6. Ventilation-perfusion (VQ) scan (or, if unavailable a negative CT pulmonary angiogram 
result or pulmonary angiography result), any time prior to Screening Visit or conducted 
during the Screening Period, with normal or low probability result 
7. No contraindication per investigator for RHC during the study 
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8. Six-Minute-Walk Distance ≥ 150 and ≤ 550 meters repeated twice during the Screening 
Period and both values within 15% of each other, calculated from the highest value 
(Appendix 3) 
9. PAH therapy at stable (per investigator) dose levels of SOC therapies as defined in 
Section 6.2 or at least 90 days prior to C1D1. 
10. Females of childbearing potential (defined in Appendix 5) must: 
a. Have 2 negative pregnancy tests as verified by the investigator prior to starting study 
therapy.  She must agree to ongoing pregnancy testing during the course of the study 
and until 8 weeks after the last dose of study treatment. 
b. If sexually active, have used, and agree to continue to use highly effective 
contraception (See Appendix 5 for definitions) without interruption, for at least 
28 days prior to starting investigational product, 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 5 for additional contraceptive information. 
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 investigational product discontinuation, even if he has undergone a 
successful vasectomy. (see Appendix 5 for additional contraceptive information). 
b. Refrain from donating blood or 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 
5.3. 
Exclusion Criteria 
Participants will be excluded from the study if they meet any of the following criteria: 
1. Stopped receiving any pulmonary hypertension chronic general supportive therapy 
(e.g., diuretics, oxygen, anticoagulants, digoxin) within 60 days prior to C1D1 
2. Received intravenous 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 
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5. Known history of portal hypertension or chronic liver disease, including hepatitis B 
and/or hepatitis C (with evidence of recent infection and/or active virus replication), 
defined as mild to severe hepatic impairment (Child-Pugh Class A-C) 
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).  
9. Uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure 
> 160 mm Hg or sitting diastolic blood pressure > 100 mm Hg during Screening after a 
period of rest 
10. Systolic blood pressure < 90 mmHg during Screening Visit or at baseline (C1D1) 
11. History of known pericardial constriction 
12. Electrocardiogram (ECG) with Fridericia’s corrected QT interval (QTcF) > 480 msec 
during Screening Period or C1D1 
13. Personal or family history of long corrected QT (QTc) syndrome or sudden cardiac death 
14. Cerebrovascular accident within 3 months of C1D1 
15. History of restrictive or congestive cardiomyopathy 
16. Left ventricular ejection fraction (LVEF) < 45% on historical ECHO within 6 months 
prior to the Screening Period (or done as part of the Screening Period), or pulmonary 
capillary wedge pressure (PCWP) > 15 mmHg as determined in the Screening Period 
RHC 
17. Any current or prior history of symptomatic coronary disease (prior myocardial 
infarction, percutaneous coronary intervention, coronary artery bypass graft surgery, or 
cardiac anginal chest pain) in the past 6 months prior to Screening Visit. 
18. Acutely decompensated heart failure within 30 days prior to C1D1, as per investigator 
assessment 
19. Significant (≥ 2+ regurgitation) mitral regurgitation or aortic regurgitation valvular 
disease 
20. Any of the following clinical laboratory values during the Screening Period prior to 
C1D1: 
a. Baseline Hgb > 16.0 g/dL  
b. Serum alanine aminotransferase or aspartate aminotransferase levels > 3X upper limit 
of normal (ULN) or total bilirubin > 1.5X ULN within 28 days of C1D1 
c. WBC count < 4000/mm3  
d. Platelets < 100,000/µL  
e. Absolute neutrophil count < 1500/mm3 
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21. 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 
22. History of severe allergic or anaphylactic reaction or hypersensitivity to recombinant 
proteins or excipients in the investigational product 
23. Major surgery within 8 weeks prior to C1D1.  Participants must have completely 
recovered from any previous surgery prior to C1D1. 
24. Prior heart or heart-lung transplants or life expectancy of < 12 months 
25. Pregnant or breastfeeding females 
26. If on corticosteroids, and at any time in the last 30 days prior to the Screening Period: 
have been receiving doses of > 20 mg/day of prednisone (or equivalent) or on a new or 
changing dose of ≤ 20 mg/day; only participants receiving stable doses of ≤ 20 mg 
prednisone (or equivalent) in last 30 days prior to the Screening Period permitted in the 
study 
27. 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 
28. History of clinically significant (as determined by the investigator) non-PAH related 
cardiac, endocrine, hematologic, hepatic, (auto)immune, metabolic, urologic, pulmonary, 
neurologic, neuromuscular, dermatologic, psychiatric, renal, and/or another disease that 
may limit participation in the study.  Autoimmune diseases are excluded with the 
exception of those related to PAH etiologies included in this study. 
29. 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 times the 
half-life prior to C1D1, whichever is longer 
30. Weight > 140 kg at Screening 
31. History of renal disease, including:  
a. Chronic renal disease at any time prior to screening; or  
b.  Any episode of acute renal failure, with or without a prior history of renal disease, 
occurring within the 3 months prior to screening in which acute dialysis (e.g., 
intermittent hemodialysis or continuous veno-venous hemofiltration ) was required 
32. History of rare hereditary fructose intolerance, glucose / galactose malabsorption, or 
sucrose / isomaltase deficiency 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized to study treatment.  Electronic case report forms (eCRFs) must be 
completed for all participants 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 
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Consolidated Standards of Reporting Trials publishing requirements and to respond to queries 
from regulatory authorities.  Minimal information includes demography, the reason for screen 
failure, AEs, and 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, or placebo 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 of 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 
separate cover. 
Placebo to be used in the study will be sterile normal saline (0.9% sodium chloride for injection).  
Sterile, normal saline should be supplied by the site.  The investigational site’s designated 
individuals will prepare the placebo syringes to match the active syringes.  The investigator and 
participants will be blinded during the Treatment Period, and unblinded during the Extension 
Period (see Section 6.5 for additional details).  The manufacturer’s directions for storage and 
handling are to be followed, as are standard clinical practices for ensuring sterility of the 
placebo. 
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 Appendix 2 for more details on SOC). 
6.2. 
Treatment Administration and Schedule 
There will be unblinded site personnel at each site designated for preparing the investigational 
product during the Placebo-Controlled Treatment Period.  Sotatercept or placebo will be 
administered after reconstitution as an SC (subcutaneous) 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.  Each injection will 
not exceed 1.0 mL; a minimum of 2 injections will be required per dose.  Where rounding weight 
and total volume is necessary, please refer to the pharmacy manual and interactive response 
technology (IRT) 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) = 1 mg/kg (for information on overdose 
refer to Section 8.3.8). 
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6.3. 
Dose Modification 
Dose delay and/or reduction or discontinuation may be required in any treatment arm 
(sotatercept or placebo).  Guidance for dose modifications and dose delay are summarized in 
Figure 2 and Figure 3.   
A maximum of 3 dose delays are allowed during the study.  If a fourth dose delay is required, the 
study treatment should be discontinued.  Questions regarding the applicability of the dose 
adjustment guidance to specific situations must be directed to the PPD medical monitor for 
assessment.   
Results from the hematology panel should be evaluated prior to study treatment administration.  
For C1D1, C2D1, C9D1A/B, and C10D1 visits, blood samples should be taken and assessed for 
Hgb levels on the same day as study treatment administration.  For all other dosing cycles, blood 
samples may be taken and assessed for Hgb levels on the same day as study treatment 
administration or 1 day prior.   
After the primary endpoint analysis, dose modification guidelines were revised to address only 
changes in platelet and hemoglobin values (Figure 2 and Figure 3).  If Hgb increases are 
> 4.0 g/dL above participant baseline value, consult the medical monitor and consider study 
treatment discontinuation.  
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.
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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 
 
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. 
Hgb = hemoglobin. 
 
 
 
 
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Upon approval of Protocol Amendment 07D and unblinding of study sites and participants, study 
treatment dose may be escalated up to 0.7 mg/kg.  If dose reductions are conducted due to an AE 
not related to study treatment, the dose can be escalated when the AE resolves.  In cases of dose 
reduction due to an increase in Hgb or decrease in platelets, the dose can be escalated after 
2 consecutive cycles in which Hgb or platelet values are stable. 
Table 6: 
Dose Reductions for Study Treatment 
Starting Dose 
Level 
First Dose Level 
Reduction 
Second Dose Level 
Reduction 
No additional dose 
reductions permitted; 
discontinue treatment 
0.3 mg/kg 
0.1 mg/kg 
0.05 mg/kg 
0.7 mg/kg 
0.3 mg/kg 
0.1 mg/kg 
6.4. 
Method of Treatment Assignment 
6.5. 
Randomization and Blinding 
Participants who have signed the informed consent and met all eligibility criteria will be 
stratified by WHO functional class and then randomized to receive placebo plus SOC, 
sotatercept 0.3 mg/kg plus SOC, or sotatercept 0.7 mg/kg plus SOC in the Placebo-Controlled 
Treatment Period.  Randomization assignments will be generated through a computerized 
system, provided by IRT.  After the completion of the 24-week Placebo-Controlled Treatment 
Period, placebo participants will be re-randomized 1:1 to treatment with sotatercept 0.3 mg/kg 
plus SOC or sotatercept 0.7 mg/kg plus SOC and sotatercept-treated participants will continue on 
their current dose in the Extension Period. 
Among study personnel, the pharmacist or his/her designee who prepares the study treatment 
(sotatercept or placebo), and the study team at each site, and a sponsor clinical trial manager 
and/or designee will be unblinded to the participant treatment assignments during the 
Placebo-Controlled Treatment Period.  All other study personnel (including but not limited to the 
sponsor, the sponsor’s representatives, investigators, study coordinators, nursing staff, and 
clinical monitors) and all participants will remain blinded to the study treatment assignments 
until all participants in the Treatment Period have completed their post-Placebo-Controlled 
Treatment Period (C9D1A/24 week) PVR assessment. 
During the Extension Period, following the conduct and results of the C9 primary endpoint, and 
the approval of Protocol A011-09 Amendment 07D, study treatment will be unblinded to study 
teams, investigators, and study participants.  Investigators will be provided with treatment 
assignments by the site designee of study treatment.  All investigators will be allowed, at the 
investigator’s discretion, to increase study treatment dose up to 0.7 mg/kg based on the 
investigator’s clinical assessment. 
In the event of a medical emergency for an individual participant in which knowledge of the 
study treatment is critical to the participant’s medical management (Section 8.3.4), the 
investigator may break the blind for that participant by contacting IRT (see the IRT User Manual 
for further instructions).  The investigator is free to break the blind if it is required to manage the 
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participant’s medical emergency based on their judgment.  In non-urgent situations, the 
investigator is encouraged where possible to discuss with the study medical monitor prior to 
breaking the blind.  Where the investigator has broken the blind without prior discussion they are 
requested to inform the sponsor/medical monitor at the earliest opportunity.  Further, it must be 
determined by the investigator that breaking the treatment blind is necessary information for the 
medical management of that participant.  If the blind is broken, the investigator can consult with 
the medical monitor as needed.  Investigator discretion should be used to determine if the 
participant should continue on treatment or be discontinued from the study. 
6.6. 
Packaging and Labeling 
The study treatment will be labeled per local requirements. 
6.7. 
Preparation/Handling/Storage/Accountability 
Accountability for the study treatment 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 treatment 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 treatment administration will be made in the appropriate section 
of the participant’s eCRF and source documents.  Unless otherwise notified, all vials of study 
treatment, 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 and expired vials of study treatment to the 
sponsor at the end of the study, or the study treatment may be destroyed at the clinical site with 
the permission of the sponsor.  For either scenario, the outcome must be documented on the drug 
accountability log.  The sponsor or designee will provide direction for the outcome of all unused 
vials. 
Acceleron (or designee) will review with the investigator and relevant site personnel the process 
for the investigational product return, disposal, and/or destruction including responsibilities for 
the site versus Acceleron (or designee). 
Refer to the Pharmacy Manual for further instructions for the preparation of study treatments and 
information regarding the 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 will be documented in the study record.  Accurate recording of all study treatment 
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 treatment 
that is administered during the study. 
Standard of care treatment compliance will be the responsibility of each participant and his or 
her treating physician.  The investigator should promote compliance by instructing the 
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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 as prescribed (see 
Appendix 2 for more details regarding SOC). 
6.9. 
Concomitant Therapy 
During the screening and throughout the Placebo-Controlled 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 worsening 
pre-existing 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 during the Placebo-Controlled Treatment Period (i.e., rescue therapy; please refer to 
Section 8.5.5 for suggested criteria), the investigator will need to discontinue study treatment and 
perform EOT visit assessments as directed by the protocol.  The investigator may consult the 
PPD medical monitor regarding what constitutes a stable dose or a chronic condition.  
Information regarding concomitant medications will be collected beginning after signing ICF 
and will include all medications taken during Screening Period to C1D1. 
During the Extension Period, any concomitant medications including PAH medication and 
supplemental oxygen can be modified (removed, substituted, or dose adjusted) and should be 
recorded in the concomitant medication eCRF.  
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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 evaluation 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.  Additional safety assessments, including UA and hematology, as 
determined by the investigator, may be done at this time. 
7.1. 
Discontinuation of Study Treatment 
Reasons that may lead to discontinuation of study treatment include: 
• Completion of treatment 
• AE or SAE 
• Participant request (withdrawal of consent) 
• Clinical worsening requiring rescue therapy with a PAH agent 
• Pregnancy 
• Protocol deviation 
• Study terminated by the sponsor 
• QTcF > 500 ms during the Treatment Period 
Clinical worsening, pregnancy, and QTcF > 500 ms will need to be recorded as an AE (see 
Section 8.3). 
The sponsor may terminate study treatment or a dose level after consultation with the 
investigator and the DMC at any time for safety or administrative reasons.  The sponsor will 
terminate the study if the occurrence of SAEs or other findings suggests an 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 
• An AE with an outcome of death 
• Lost to follow-up 
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• Study terminated by the sponsor 
• AE or SAE 
• Pregnancy 
Serious adverse events/adverse events, including the outcome of death or pregnancy, will need to 
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, attempts to follow participants 
should be made, at regular intervals, until the AE normalizes or returns to the participant’s 
baseline condition, as per Section 8.3.5. 
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 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, 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 Treatment 
Period and the Extension Period. 
• All protocol assessments are to be recorded on the participant’s source 
documentation. 
8.1. 
Screening Procedures 
• Screening procedures are to be performed as per the SoE (Section 2) and are to be 
completed and reviewed by the investigator to confirm the participant met eligibility 
criteria prior to dosing. 
• Procedures also include a review of participant’s medical, surgical, and family 
history; collecting of demographics, race, ethnicity; medical record requests for 
external procedures. 
8.2. 
Efficacy Assessments 
8.2.1. 
Pulmonary Vascular Resistance by Right Heart Catheterization  
Pulmonary vascular resistance will be measured by the RHC procedure.  There will be a total of 
3 RHCs to assess pulmonary vascular resistance (PVR).  The first RHC must be performed 
within 10 days prior to C1D1 (during the Screening Period), and the second RHC should be 
performed within 10 days prior to the 24 weeks/C9D1A visit (during the Treatment Period).  The 
third RHC should be performed within 3 days of C25D1 or at the next available dosing visit 
upon consent to Protocol Amendment 07D, up to C33D1 (during the Extension Period).  If a 
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participant discontinues early from the Extension Period, a third RHC should be performed at 
EOT.  The third RHC has been added to assess the long-term benefits and durability of the effect 
of sotatercept treatment.  If performed on the same day at any of these timepoints, the RHC 
should take place after other assessments (i.e., 6-minute-walk test [6MWT]) have been 
completed and prior to dosing.  
A participant will not receive more than 3 RHC assessments during the study. 
Right heart catheterization will be performed according to the RHC manual and will assess 
several prognostic hemodynamic variables in addition to PVR, including right atrial pressure 
(RAP), mean pulmonary arterial pressure (PAP), mean pulmonary wedge pressure (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 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, heart rate 
• CO measured in triplicate by the thermodilution technique or by the Fick method (the 
same method must be used for all RHC assessments for each participant). 
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.  
8.2.2. 
Six-Minute-Walk Distance 
Six-minute-walk distance (6MWD) will be measured by the 6MWT during the Screening Period 
and at multiple timepoints throughout the study as per the SoE.  During the Screening Period, 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, the 
6MWT should be performed after QoL and before RHC.  Appendix 3 provides further 
instructions on 6MWT.  For evaluation of clinical worsening, as indicated by the 6MWT, a 
decrease of ≥ 15% in 6MWD at any timepoint as compared to Screening must be confirmed by a 
second 6MWT performed at least 4 hours and no more than 1 week apart from the first.  If the 
screening 6MWT is performed within 10 days prior to C1D1, the value may serve as the baseline 
and an additional 6MWT is not required at C1D1. 
8.2.3. 
Echocardiogram Parameters 
ECHO assessments to include tricuspid annular plane systolic excursion (TAPSE), right 
ventricular ejection fraction (RVEF), left ventricular ejection fraction (LVEF), pulmonary artery 
pressure (PAP), as well as other parameters will be conducted at baseline (C1D1) and at multiple 
timepoints throughout the study as per the SoE.  If a historical ECHO reading is unavailable for 
evaluation during Screening, an ECHO may be performed during the Screening Period.  If an 
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ECHO is performed as a part of the Screening Period, these values may be used as the baseline 
for this study and an additional ECHO is not required for these participants at C1D1.  If a 
historical ECHO is evaluated during the Screening Period, the participant should receive an 
ECHO at the C1D1 visit, which will serve as the baseline for the study for these participants.  
Echocardiograms will be centrally read.  For participants whose third RHC assessment is 
performed at the next available dosing visit after C25D1 up to C33D1, ECHO may be performed 
within 1 week of the third RHC visit. 
8.2.4. 
Quality of Life Assessments 
The CAMPHOR and SF-36 QoL assessments will be given at the timepoints noted in the SoE.  If 
occurring on the same day, QoL assessments should be performed before 6MWT, blood draws, 
AEs discussions, and RHC.  
8.3. 
Adverse Events 
Adverse Event Definitions 
Adverse Event 
An AE is any untoward medical occurrence in a clinical investigation participant administered a 
study treatment, 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 treatment whether 
or not it is considered related to the study treatment. 
Abnormal laboratory and other abnormal investigational findings (e.g., physical exam, ECG) 
should not be reported as AEs unless they are associated with clinical signs and symptoms, lead 
to treatment discontinuation, or are otherwise considered clinically relevant by the investigator.  
In cases of surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself.  In the case of a fatality, the cause of death 
is considered as the AE, and death is considered as its outcome. 
Unexpected Adverse Events 
An unexpected AE, the nature, severity, specificity, or outcome of which is not consistent with 
the summary of product characteristics, is described in the IB under the Reference Safety 
Information. 
Events Not to Be Considered as Adverse Events 
Pre-existing medical conditions/signs/symptoms present 30 days prior 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 as AEs. 
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Serious Adverse Event 
An SAE is any AE, occurring at any dose level/regimen and regardless of causality that: 
• Results in death. 
• Is life-threatening: Life-threatening means that the participant was at immediate risk 
of death from the reaction as it occurred, it does not include a reaction, which 
hypothetically might have caused death had it occurred in a more severe form. 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
• 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 participant’s ability to carry out normal life functions. 
• Is a congenital anomaly/birth defect: Congenital anomaly/birth defect in a child of 
a participant or its partner that was exposed to study treatment 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 on appropriate medical judgment, it may jeopardize 
the participant and may require medical or surgical intervention to prevent one of the 
outcomes listed in the definitions for SAEs.  Examples 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. 
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 the absence of an AE. 
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• A procedure that is planned (i.e., planned prior to starting of treatment on the 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. 
8.3.1. 
Severity 
Investigators must evaluate the severity/intensity of AEs and SAEs according to the active minor 
version of the NCI-CTCAE v4.0, preferentially using the graded scales.  If there is a change in 
the severity of an AE, it must be recorded as a separate event.  If a particular AE’s 
severity/intensity is not specifically graded, the investigator should apply the general guidelines 
for determination of Grade 1 through Grade 5 as listed in the NCI-CTCAE v4.0 cover page 
(as shown below), using their best medical judgment: 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (preparing meals, shopping for 
groceries or clothes, using the telephone, managing money, etc.). 
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of 
daily living (bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden). 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
Grade 5: Death related to AE. 
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 the participant/event outcome or action criteria associated with events that pose a threat 
to a participant’s life or functioning. 
8.3.2. 
Relationship to Study Treatment 
The investigator must determine the relationship between the administration of study treatment 
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, the temporal relationship 
between the AE and the administration of study treatment, known side effects of study treatment, 
medical history, concomitant therapy, course of the underlying disease and pertinent study 
procedures. 
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Not Suspected: Means a causal relationship of the AE to study treatment 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 treatment 
caused the AE.  ‘Reasonable possibility’ means there is evidence to suggest a causal relationship 
between the study treatment and the AE. 
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.  The investigator must report in detail all 
adverse signs and symptoms which are either volunteered by participants or observed during or 
following the course of investigational product administration on the appropriate eCRF page.  
All clearly related signs, symptoms, and abnormal diagnostic procedures results should be 
recorded under 1 diagnosis.  All AEs and SAEs reported from the signing of the ICF to the EOS 
visit are to be reported and documented on the AE eCRF.  Any AE related to a protocol 
procedure should be marked as such on the eCRF. 
All AEs spontaneously reported by the participant and/or in response to an open question from 
study personnel or revealed by observation, physical examination or other diagnostic procedures 
will be recorded on the AE eCRF.  Any clinically relevant changes in laboratory assessments or 
other clinical findings as described in Section 8.3.1 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 study treatment, any other potential causal factors, 
any treatment given or other action taken (including dose modification or discontinuation of 
study treatment) 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 both methods should not be used beside each 
other; the paper is for backup reporting only. 
Specific guidance can be found in the CRF 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 timeframe described in Section 8.3.6 (Notification about SAEs). 
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 
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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 Adverse Events 
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 
treatment, 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.  
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 of 24 hours after becoming aware of the event, inform the sponsor via the contract 
research organization by the entry on the eCRF, or if not available, by telephone, fax, or email.  
Paper SAE forms should be used to report an SAE if the eCRF is down or otherwise 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, 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. 
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The investigator must comply with any applicable site-specific requirements related to the 
reporting of SAEs involving his/her participants to the independent ethics committee (IEC) that 
approved the study. 
In accordance with International Council for Harmonisation (ICH) 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 study treatment (SUSARs).  The investigator should place copies of 
these Safety Reports in the Investigator Site File.  National regulations with regard to Safety 
Report notifications to investigators will be followed. 
When specifically required by regulations and guidelines, the sponsor will provide appropriate 
Safety Reports directly to the concerned lead IEC and will maintain records of these 
notifications.  When direct reporting by the sponsor is not clearly defined by national or 
site-specific regulations, the investigator will be responsible for promptly notifying the 
concerned IEC of any Safety Reports and for filing copies of all related correspondence in the 
Investigator Site File. 
For studies covered by the European Union Clinical Trials Directive 2001/20/EC, the sponsor’s 
responsibilities regarding the reporting of SAEs/SUSARs will be carried out in accordance with 
that Directive and with the related Detailed Guidances. 
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, and therefore, for the purpose of this trial, an overdose is 
defined as any dose that has exposures in excess of the monkey NOAEL dose of 1 mg/kg (IB, 
Section 3.3.2, Table 4), which was also the highest dose tested in a human volunteer 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, participants 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 treatment administration.  Any 
organism, virus, or infectious particle (e.g., protein transmitting Transmissible Spongiform 
Encephalopathy), pathogenic or non-pathogenic, is considered an infectious agent. 
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Transmission of an infectious agent may be suspected from clinical signs or symptoms or 
laboratory findings indicating an infection in a participant exposed to study treatment.  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 treatment 
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 participant 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., electronic 
protocol inquiry portal) and be fully documented as an AE in the eCRF, or as an SAE if an 
associated SAE occurs (see Section 8.3 for further instructions). 
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 
and up until 112 days after the last dose of study 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 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 5. 
• Additional pregnancy, breastfeeding, and sperm/ovum donor information are 
provided in Appendix 5. 
8.4. 
Monitoring of Identified, Potential, and Adverse Events of Special 
Interest 
The risks outlined below are consistent with the list in Sotatercept IB (Edition 14.0).  The AESIs 
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 
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or upon an unscheduled visit if applicable.  Section 6.3 provides details for dose modifications 
related to platelets and Hgb. 
Additional reviews will be performed periodically as part of standard safety signal detection and 
medical monitoring; finally, an independent DMC will be convened to monitor the safety of the 
participants as described in Section 9.3.4 and a detailed charter. 
8.4.1. 
Identified Risks 
Table 7 describes the identified risks that could occur during study 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 
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 treatment. 
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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 (Hgb/Hct) 
• 
The medical monitor will ensure dosage 
adjustment according to the protocol 
• 
Monthly review of unblinded Hct/Hgb listings 
by Data Safety Monitoring Board 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 treatment. 
 
 
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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 
Ischemic heart disease 
(SMQ) 
Embolic and thrombotic 
events (SMQ) 
Monitoring of AEs in combination of risk factors 
of systemic hypertension (diabetes, metabolic 
syndrome, obesity), concomitant medications, and 
previous medical history of heart, embolic, and 
thrombotic events 
Thrombocytopenia, 
leukopenia, and 
neutropenia 
Thrombocytopenia, 
leukopenia, and 
neutropenia 
Careful monitoring of platelet counts is performed, 
and in case platelet count are < 50.000/mm3 
(< 50.0 × 109/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 
Per the request of the European Health Authority, thrombocytopenia, leukopenia, and neutropenia were added as 
AESIs. 
AE = adverse event; AESI = adverse event of special interest; ALP = alkaline phosphatase; ALT = alanine 
aminotransferase; AST = aspartate aminotransferase; FSH = follicle-stimulating hormone; SMQ = standardized 
MedDRA queries. 
8.5. 
Safety Assessments 
Planned timepoints for all safety assessments are provided in 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 exam 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. 
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• 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 blood pressure will be assessed 
at every visit.  Height will be measured once, during the Screening Period. 
• Blood pressure and pulse measurements will be assessed while seated with a 
completely automated device.  Manual techniques will be used only if an automated 
device is not available. 
• Vital signs (to be taken before blood collection for laboratory tests): blood pressure 
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 
obtained approximately 5 minutes apart.  The average of the blood pressure readings 
will be recorded on the eCRF. 
• Weight will be measured (in indoor clothing but without shoes) and recorded at each 
dosing visit.  Dose will be calculated based on the participant’s weight on the day of 
dosing. 
• Clinically significant abnormal findings will be reported as AEs (Section 6.3 and 
Section 8.4). 
8.5.3. 
Electrocardiograms 
• A single 12-lead ECG will be obtained at each timepoint as outlined in the SoE.  
Parameters obtained will be HR, PR, QRS, and QT:QTcF.  If the ECG machine does 
not automatically calculate QTcF, it should be manually calculated. 
• Clinically significant abnormal findings will be reported as AEs. 
• ECGs should be performed prior to 6MWT.  
8.5.4. 
Clinical Worsening 
Clinical worsening will be assessed by the investigator at each dosing visit and recorded on the 
eCRF. 
Assessments are: 
• 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) 
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•
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 (II to III, III to IV, II to IV, etc.)
•
Decrease in 6MWD by ≥ 15% (confirmed by two 6MWTs; Section 8.2.2)
•
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 (and therefore 
discontinue study treatment) include: 
8.5.6. 
•
Participants who experience worsening of PAH requiring hospitalization for more 
than 24 hours.
•
PAH functional deterioration (worsening of the WHO functional class by 1 or more 
levels and a decrease in 6MWD of 15% measured on 2 occasions).
Clinical Safety Laboratory Assessments
•
See Appendix 1 for the list of clinical laboratory tests to be performed and to the SoE 
for the timing and frequency.
•
If hemoglobin is ≥ 17 g/dL during Cycles 1-2 Day 8, or Cycles 9-10 Day 8, 
participants should return weekly for hemoglobin monitoring.  Clinically significant 
abnormal Hgb findings will be reported as AEs.  Dose modification guidance should 
be followed (see Figure 3).
•
Seminal fluid collection is optional; samples will be collected from male participants 
who consent to this assessment.
•
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 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 1, must be 
conducted in accordance with the laboratory manual and the SoE. 
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− 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 the 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 safety or 
efficacy aspects related to concerns arising during or after the study. 
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded. 
8.7. 
Pharmacodynamics 
Venous blood samples will be collected for measurement of PD biomarkers including but not 
limited to activin A, BMPR2, BMPR2 expression (via peripheral blood mononuclear cells), 
GDF15, matrix metalloproteinase-2 (MMP2), N-terminal prohormone of brain natriuretic 
peptide (NT--proBNP), TGF-β1, vascular endothelial growth factor receptor (VEGFR1), and sex 
hormone metabolites at timepoints listed in the 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. 
8.8. 
Genetic Testing 
Participants may opt to 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, potassium channel subfamily K member 5, and mothers against 
decapentaplegic homolog 9; otherwise known as SMAD9.  See Appendix 6 for more information 
regarding genetic testing.  
8.9. 
Seminal Fluid Analyses 
Male participants who have not undergone a successful vasectomy may opt to have seminal fluid 
samples taken to assess sperm count, sperm motility, and sperm morphology.  Since the effects 
of sotatercept on fertility are unknown, these analyses may provide insight into changes 
sotatercept may mediate in sperm concentration or function.  The initial baseline sample will be 
taken during the screening period, and a sample will be collected for comparison at the EOS 
visit.  If there is a clinically significant difference between the baseline and EOS samples with 
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regard to sperm count, motility, or morphology, as per the investigator’s assessment, the subject 
will be asked to return up to 232 days after the last dose of study treatment to provide an 
additional seminal fluid sample for analysis. 
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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Sample Size Determination 
The sample size calculation is based on the primary endpoint of change from baseline PVR 
measurement.  The baseline PVR is expected to be approximately 800 dyn sec/cm5 (standard 
deviation 400).  Assuming a decrease from baseline PVR at 24 weeks of 240 dyn sec/cm5 (30%) 
for sotatercept groups and 0% for placebo, with 1-sided alpha=0.10 and 80% power, the sample 
size is 26 per treatment group.  The dropout rates may be different from 3 treatment groups.  The 
placebo group and 0.3 mg/kg sotatercept group may have about a 15% dropout rate, but the 
0.7 mg/kg sotatercept group may have an increased dropout rate due to potential Hgb increase 
based on PK modeling (about 20% more) and hence the total dropout rate in this group may be 
about 35%.  Thus, the total sample after accounting for dropouts in the 3 arms: placebo, 0.3 
mg/kg sotatercept, and 0.7 mg/kg sotatercept is 3:3:4, respectively, for a total of 100. 
For the 6MWD at 24 weeks, assuming the change from baseline is 50 meters for the sotatercept 
group and 20 meters for the placebo group with a standard deviation of 50 meters, n = 26 per 
treatment group will provide approximately 80% power to detect the difference at 1-sided 
alpha = 0.10 level. 
9.2. 
Populations for Analyses 
Full Analysis Set (FAS): All randomized participants treated with correct treatment assignments. 
Evaluable Population: All participants in the FAS who received at least 6 doses of the same dose 
during the Placebo-Controlled Treatment Period and have had their baseline and 
post-Placebo-Controlled Treatment Period PVR assessments (24 weeks/C9D1A) or EOT PVR 
assessment.  Data from participants whose dose is down-titrated will be analyzed according to 
the dose received rather than the dose to which they were originally assigned.  
Safety Population: All randomized participants who receive at least 1 dose of study treatment.  
Participants will be analyzed according to the treatment they actually received. 
9.3. 
Statistical Analyses 
The statistical analysis plan (SAP) will be developed and finalized before topline (24 weeks) 
database lock and will describe the participant populations to be included in the analyses, and 
procedures for accounting for missing, unused, and spurious data as needed.  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 
ANCOVA will be used to compare the 24-week (C9D1A) change from baseline PVR 
data between sotatercept and placebo groups, with the randomization factor as the 
covariate.  The primary analysis will be performed on the evaluable population.  The 
non-evaluable rate will be blindly monitored, and adjustments to statistical methods 
may be considered based on this blinded data, as necessary.  Gatekeeping method will 
be used to control the overall type 1 error rate, i.e., higher sotatercept dose group will 
be compared with the placebo group at 1-sided alpha = 0.10 first.  If significant, then 
the lower sotatercept dose will be compared with the placebo group at 1-sided alpha = 
0.10.  If the sotatercept higher and lower dose groups data are similar, they may be 
combined together to compare with the placebo group.  
Key 
Secondary 
6MWD will be analyzed similarly as the primary endpoint of the evaluable population.  
ANCOVA will be used to compare the 24-week (C9D1A) 6MWD from baseline 
(C1D1) 6MWD data between sotatercept and placebo groups, with the randomization 
factor as the covariate.  The gatekeeping method will be used to control the overall 
type 1 error rate 
If the sotatercept higher and lower dose groups data are similar, they may be combined 
together to compare with the placebo group. 
Other 
Endpoints 
In general, continuous data will be summarized descriptively with mean, standard 
deviation, median, min, max, and tested with ANCOVA method if applicable.  
Response rate data will be summarized with counts and percentages, tested with CMH 
method if applicable.  Time to event data will be summarized with the Kaplan-Meier 
method, tested with the log-rank test, and the hazard ratio will be estimated with the 
Cox regression method. 
6MWD = 6-minute-walk distance; ANCOVA = analysis of covariance; CMH = Cochran-Mantel-Haenszel; 
CxDy = Cycle x Day y; PVR = pulmonary vascular resistance.  
9.3.2. 
Safety Analyses 
All safety analyses will be performed on the Safety Population. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse event listings will include the verbatim term and the MedDRA preferred 
term.  TEAEs will be defined in the SAP and summarized by the worst severity grade, system 
organ class, and preferred term.  TEAEs leading to death or discontinuation from treatment, 
TEAEs related to investigational product, and serious TEAEs will be summarized separately. 
Clinical laboratory results will be summarized descriptively by treatment groups.  Clinically 
significant laboratory abnormalities will be listed and summarized by treatment group.  Renal 
function laboratory tests (creatinine and urine albumin-creatinine ratio) will be collected 
regularly during the Placebo-Controlled Treatment Period and may be limited to creatinine in the 
Extension Period.  The descriptive statistics (mean, standard deviation, median, min, max) will 
be provided for each timepoint of the collection by the treatment group.  One graph will be 
presented for the mean of each renal function test over time by treatment.  A listing of abnormal 
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values will also be provided.  Renal function related AEs will be summarized by treatment 
group.  Change from baseline in renal function tests at each timepoint will be presented.  
Vital sign measurements will be listed for each participant at each visit.  Descriptive statistics for 
vital signs, both observed values and changes from baseline, will be summarized by treatment 
group. 
Immunogenicity (incidence/titer of anti-drug antibody) will also be analyzed. 
9.3.3. 
Other Analyses 
Pharmacokinetic, PD, and biomarker exploratory analyses will be described in the SAP that will 
be finalized before database lock.  Other analyses include the change in PVR from baseline, 
similar to the primary analysis, but on the FAS population and incorporating methods for 
handling missing data as detailed in SAP. 
9.3.4. 
Data Monitoring Committee 
The external, independent DMC will provide unblinded safety monitoring after at least 
15 participants have been enrolled in the Treatment Period and completed Cycle 2, and at 
approximately 6-month intervals thereafter throughout the Extension Period. 
A detailed charter will outline all activities of the DMC (including, but not limited to, the 
composition of the DMC, type of data to be reviewed, DMC responsibilities, and frequency of 
meetings). 
9.3.5. 
Primary Endpoint Analysis 
An analysis of the primary endpoint of change in PVR at 24 weeks (C9D1A) versus the 
screening PVR assessment will be performed on the evaluable population when all participants 
in the Placebo-Controlled Treatment Period have completed the 24-week (C9D1A) PVR 
assessment or EOT PVR for those participants who discontinue early in the Placebo-Controlled 
Treatment Period as described in Section 9.3.2. 
9.3.6. 
Extension Period Analysis 
A separate SAP will be developed for the details of the analyses in the Extension Period.  
Participants will have a total of 3 PVR assessments over the course of the study: PVR at Baseline 
(PVR0), PVR following completion of the 6-month Placebo-Controlled Treatment Period 
(PVR6), and PVR after 18 to 24 months post baseline (PVR-ext). 
Table 11 provides notation for efficacy measurements at different timepoints. 
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Table 11: 
Notation: Efficacy Measurement at Different Timepoints 
 
PVR 
6MWD 
FC 
FC Numeric Version 
Month 0 (baseline) 
PVR0 
6MWD0 
FC0 
FCn0 
Month 6 
PVR6 
6MWD6 
FC6 
FCn6 
Months 18-24 
PVR-ext 
6MWD-ext 
FC-ext 
FCn-ext 
6MWD = 6-minute-walk distance; FC = functional class; PVR = pulmonary vascular resistance.  
Two Analysis Treatment Groups in the Extension Period: 
• Continued sotatercept treatment group: Participants randomized to either dose group 
(0.3 and 0.7 mg/kg) of sotatercept at the beginning of the Placebo-Controlled Period.  
They continued to receive sotatercept in the Extension Period. 
• Placebo-Crossed treatment group: Participants randomized to placebo at the 
beginning of the Placebo-Controlled Period and then randomized to either 0.3 or 
0.7 mg/kg of sotatercept in the Extension Period. 
Two Statistical Efficacy Analyses: 
• Delayed-start efficacy analysis: Compare the efficacy endpoints between the 2 
treatment groups in the Extension Period. 
• Placebo-crossed efficacy analysis: Compare postbaseline (Months 18 to 24) versus 
baseline (Month 0) values of efficacy endpoints within the Placebo-Crossed treatment 
group. 
The overall type I error rate will be 2-sided 0.05.  Recycle method will be used to control the 
overall type I error rate.14  
The set of Placebo-crossed efficacy analyses will be tested first at 2-sided 0.025 level.  
Gatekeeping method will be used to sequentially test each efficacy endpoint.  PVR will be tested 
first at 0.025 level.  If successful, 6MWD will be tested second at 0.025.  If both PVR and 
6MWD are successfully tested, FC improvement will then be tested at 2-sided 0.025 level.  
If all 3 efficacy endpoints in the Placebo-crossed efficacy analyses are statistically significant, 
then the type I error rate of 0.025 will be recycled.  The set of Delayed-start efficacy analysis 
will be tested at 0.025 + 0.025 = 0.05 2-sided level.  Otherwise, if at least 1 of the 3 tests is not 
significant, they will be tested sequentially at 2-sided 0.025 level.  Each endpoints in the 
Delayed-start efficacy analysis will be tested similarly as the placebo-crossed efficacy analyses. 
The sotatercept 0.3- and 0.7-mg/kg groups will be pooled into 1 sotatercept group Extension 
Period analysis. 
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9.3.6.1. 
Delayed-start Efficacy Analysis 
The primary analysis is to compare the change from baseline (PVR-ext – PVR0) between the 
Continued sotatercept treatment group and the Placebo-Crossed treatment group to evaluate 
disease-modifying effect with a type I error rate of 2-sided 0.025.  ANCOVA will be used with 
PVR0 and FC0 as covariates.  Normality will be tested using Shapiro-Wilk test.  If normal 
distribution is rejected, a non-parametric Wilcoxon rank sum test stratified by FC0 will be used.  
Multiple imputation method will be used to handle the missing data.  
The key secondary analysis is to compare change from baseline (6MWD-ext – 6MWD0) 
between the Continued sotatercept treatment group and Placebo-Crossed treatment group after 
the successful testing on primary PVR analysis with a type I error rate of 2-sided 0.025.  
ANCOVA will be used with 6MWD0 and FC0 as covariates.  The normality check and missing 
data handling method will be similar to the primary analysis. 
The other secondary analysis is to compare FC-ext improvement from baseline (FC0) between 
the Continued sotatercept treatment group and Placebo-Crossed treatment group after the 
successful testing on primary PVR and key secondary 6MWD analysis, with a type I error rate of 
2-sided 0.025.  Cochran-Mantel Haenszel (CMH) test will be used with FC0 as the stratum. 
9.3.6.2. 
Placebo-Crossed Efficacy Analysis 
The primary analysis is to evaluate PVR-ext – PVR0 in the Placebo-Crossed treatment group 
with a type I error rate of 2-sided 0.025.  ANCOVA will be used to test the intercept with 
PVR0-average (PVR0) as the covariate.  Normality will be tested using Shapiro-Wilk test.  If 
normal distribution is rejected, a non-parametric Wilcoxon signed rank test will be used.  
Multiple imputation method will be used to handle the missing data.  
The key secondary analysis is to evaluate 6MWD-ext - 6MWD0 in the Placebo-Crossed 
treatment group after the successful testing on primary PVR analysis, with a type I error rate of 
2-sided 0.025.  ANCOVA will be used to test the intercept with 6MWD0-average (6MWD0) as 
the covariate.  The normality check and missing data handling method will be similar to the 
primary analysis. 
The other secondary analysis is to evaluate FCn-ext – FCn0 in the Placebo-Crossed treatment 
group after the successful testing on primary PVR and key secondary 6MWD analysis, with a 
type I error rate of 2-sided 0.025.  ANCOVA will be used to test the intercept with FCn0-average 
(FCn0) as the covariate.  The FC categories are converted to numerical values, I = 1, II = 2, 
III = 3, and IV = 4.  The numerical values will be used in this analysis.  This conversion is made 
in order to increase the statistical power of the ANCOVA analysis. 
 
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10. 
REFERENCES  
1. 
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. 
2. 
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. 
3. 
Farber HW, Miller DP, Poms AD, et al. Five-Year outcomes of patients enrolled in the 
REVEAL Registry. Chest. 2015;148:1043-54. 
4. 
Morrell NW. Pulmonary hypertension due to BMPR2 mutation: a new paradigm for 
tissue remodeling? Proc Am Thorac Soc. 2006;3:680-6. 
5. 
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. 
6. 
Yung LM, Pearsall RS, Bocobo G. Abstract 18906: ACTRIIA-Fc Rebalances BMP and 
Activin/TGF-β Signaling to Attenuate Experimental Pulmonary Hypertension. Circulation. 
2017;136:A18906. 
7. 
Rubin LJ. Primary pulmonary hypertension. N Engl J Med. 1997;336:111-7. 
8. 
Simonneau G, Galie N, Rubin LJ, et al. Clinical classification of pulmonary 
hypertension. J Am Coll Cardiol. 2004;43:5S-12S. 
9. 
Schermuly RT, Ghofrani HA, Wilkins MR, et al. Mechanisms of disease: pulmonary 
arterial hypertension. Nat Rev Cardiol. 2011;8:443-55. 
10. 
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. 
11. 
Brooks D SS, Gibbons WJ. ATS Statement on 6-minute walk test. Am J Respir Crit Care 
Med. 2003;167:1287. 
12. 
ATS Statement. Guidelines for the Six-Minute Walk Test. Am J Crit Care. 
2002;166:111-17. 
13. 
Holland AE, Spruit MA, Trotters T, et al. An official European Respiratory 
Society/American Thoracic Society technical standard: field walking tests in chronic respiratory 
disease. Eur Respir J. 2014 Dec;44(6):1428-46. 
14. 
Ouyang J, Zhang P, Koch G, et al. Comparisons of global tests on intersection hypotheses 
and their application in matched parallel gatekeeping procedures. J Biopharmaceutical Statistics. 
2019;1520:5711(online). 
 
 
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11. 
APPENDICES 
 
 
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ABBREVIATIONS AND SPECIALIST TERMS 
Abbreviation or Specialist Term 
Explanation 
6MWD 
Six-Minute-Walk Distance 
6MWT 
Six-Minute-Walk Test 
ACE-011 
Sotatercept 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate Aminotransferase 
BMP 
Bone Morphogenetic Protein 
BMPR2 
Bone Morphogenetic Protein Receptor type II 
CAMPHOR 
Cambridge Pulmonary Hypertension Outcome Review 
CBC 
Cell Blood Count 
CFR 
Code of Federal Regulations 
CO 
Cardiac Output 
CxDy 
Cycle x Day y 
CMH 
Cochran-Mantel-Haenszel (method) 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ECHO 
Echocardiogram 
eGFR 
Estimated Glomerular Filtration Rate 
ERA 
Endothelin-Receptor Antagonist 
EOS 
End of Study 
EOT 
End of Treatment 
ETE 
Embolic and Thrombotic Events 
FAS 
Full Analysis Set 
FC 
Functional Class 
FDA 
Food and Drug Administration 
FSH 
Follicle-Stimulating Hormone 
GCP 
Good Clinical Practice 
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Abbreviation or Specialist Term 
Explanation 
GDF 
Growth and Differentiation Factor  
GEE 
Generalized Estimating Equation 
Hgb 
Hemoglobin 
Hct 
Hematocrit 
HRT 
Hormone Replacement Therapy 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Council For Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
LVEF 
Left Ventricular Ejection Fraction 
MedDRA 
Medical Dictionary for Medical Activities 
MMP2 
Matrix Metalloproteinase-2 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse 
Events 
NI 
Non-Inferiority 
NOAEL 
No-Observed-Adverse-Effect Level 
NT-proBNP 
N-terminal prohormone of brain natriuretic peptide 
PAH 
Pulmonary Arterial Hypertension 
PAP 
Pulmonary Arterial Pressure 
PBMC 
Peripheral Blood Mononuclear Cell 
PCWP 
Pulmonary Capillary Wedge Pressure 
PD 
Pharmacodynamic(s) 
PDE5 
Phosphodiesterase 5 
PK 
Pharmacokinetic(s) 
PPD 
Pharmaceutical Product Development 
PVR 
Pulmonary Vascular Resistance 
PVR0 
Pulmonary Vascular Resistance at Baseline 
PVR6 
Pulmonary Vascular Resistance Following Completion of the 6-Month 
Placebo-Controlled Treatment Period 
PVR-ext 
Pulmonary Vascular Resistance After 12 to 18 Months on Treatment in 
the Extension Period 
QTc 
Corrected QT 
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Abbreviation or Specialist Term 
Explanation 
QTcF 
Fridericia’s Corrected QT formula 
QoL 
Quality of Life 
QxW 
Every X Weeks 
RBC 
Red Blood Cell 
RHC 
Right Heart Catheterization 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous(ly) 
SMQ 
Standardized MedDRA Queries 
SOC 
Standard of Care 
SoE 
Schedule of Events 
sPAP 
Systolic Pulmonary Artery Pressure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TAPSE 
Tricuspid Annular Plane Systolic Excursion 
TEAE 
Treatment-Emergent Adverse Event 
TGF-β 
Transforming Growth Factor-βeta 
UA 
Urinalysis 
UACR 
Urine Albumin Creatinine Ratio 
ULN 
Upper Limit of Normal 
VEGFR1 
Vascular Endothelial Growth Factor Receptor 1 
VQ 
Ventilation-Perfusion (Scan) 
WBC 
White Blood Cell 
WHO 
World Health Organization 
WOCBP 
Woman of Childbearing Potential 
 
 
 
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APPENDIX 1. CLINICAL LABORATORY TESTS 
The tests detailed in Table 12 will be performed by local laboratories at the timepoints specified 
in the Schedule of Events (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 12: 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
CBC with differential: CBC includes RBCs, WBCs, Hgb, Hct, mean 
corpuscular volume, mean corpuscular hemoglobin, mean corpuscular 
hemoglobin concentration, platelet count 
Chemistry 
Albumin, ALP, ALT, AST, blood urea nitrogen, calcium, chloride, carbon 
dioxide/bicarbonate, creatinine, glucose, phosphorus, potassium, sodium, 
total bilirubin, direct bilirubin 
Urinalysis 
UA, UACR 
Seminal fluid collection Sperm count, Sperm Motility, Sperm Morphology 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CBC = complete 
blood count; Hgb = hemoglobin; Hct = hematocrit; RBC = red blood cell; UA = urinalysis; WBC = white blood cell 
Investigators must document their review of each laboratory safety report. 
 
 
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APPENDIX 2. STANDARD OF CARE THERAPY 
Standard of care (SOC) therapy refers to approved PAH-specific medications and may consist of 
monotherapy or combination therapy with endothelin-receptor antagonists, phosphodiesterase 5 
(PDE5) inhibitors, soluble guanylate cyclase stimulators, and/or prostacyclin analogues or 
receptor agonists.  Standard of care therapy should remain stable throughout the study.  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 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 a participant may stay on study treatment.  
During the Extension Period, PAH-specific medications can be modified (substituted, removed, 
or dose adjusted), including supplemental oxygen.  Investigator discretion will be used to 
determine if sotatercept study treatment discontinuation is necessary. 
 
 
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APPENDIX 3. SIX-MINUTE-WALK TEST 
A standardized 6-minute-walk test (6MWT) will be performed in accordance with the guidelines 
of the American Thoracic Society.11-13  The 6MWT should be performed indoors, along a long, 
flat, straight, enclosed corridor with a hard surface that is seldom traveled.  The walking course 
must be 30 meters in length.  The length of the corridor should be marked every 3 meters.  The 
turnaround points should be marked (e.g., with a cone).  A starting line, which marks the 
beginning and end of each 60-meter lap, should be marked on the floor (e.g., using brightly 
colored tape). 
The 6-minute-walk distance will be calculated and recorded.  If the participant discontinues the 
test prematurely, the time (mm:ss) and distance walked will be recorded.  Requirement of acute 
supportive rescue medication (e.g., oxygen therapy) and any adverse events (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 blood pressure, and make sure that clothing and shoes are appropriate.  Record 
in the source documents. 
4. Measure and record baseline heart rate and oxygen saturation (SpO2) and follow 
manufacturer's instructions to maximize the signal and to minimize motion artifact. 
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 1 lap yourself.  Walk and pivot around a cone briskly. 
“Are you ready to do that?  I am going to use this counter to keep track of the number of laps you 
complete.  I will click it each time you turn around at this starting line.  Remember that the 
object is to walk AS FAR AS POSSIBLE for 6 minutes, but don't run or jog.  Start now, or 
whenever you are ready.” 
1. Position the participant at the starting line.  You should also stand near the starting line 
during the test.  Do not walk with the participant.  As soon as the participant starts to 
walk, start the timer. 
2. Do not talk to anyone during the walk.  Use an even tone of voice when using the 
standard phrases of encouragement.  Watch the participant.  Do not get distracted and 
lose count of the laps.  Each time the participant returns to the starting line, click the lap 
counter once (or mark the lap on the worksheet).  Let the participant see you do it.  
Exaggerate the click using body language, like using a stopwatch at a race. 
After the first minute, tell the participant the following (in even tones): “You are doing well.  
You have 5 minutes to go.” 
When the timer shows 4 minutes remaining, tell the participant the following: “Keep up the good 
work.  You have 4 minutes to go.” 
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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 4. 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 International Ethical Guidelines 
− Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
− Applicable laws and regulations 
• The protocol, protocol amendments, informed consent form (ICF), Investigator 
Brochure, and other relevant documents (e.g., advertisements) must be submitted to 
an institutional review board (IRB)/independent ethics committee (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 serious adverse events (SAEs) or other significant 
safety findings as required by IRB/IEC procedures 
− Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (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 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. 
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• Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study. 
• 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. 
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Data Quality Assurance 
• All participant data relating to the study will be recorded on printed or electronic case 
report form (eCRF) unless transmitted to the sponsor or designee electronically (e.g., 
laboratory data).  The investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the eCRF. 
• The investigator must maintain accurate documentation (source data) that supports 
the information entered in the eCRF. 
• The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• 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 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. 
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Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
• 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 5. CONTRACEPTIVE GUIDANCE AND COLLECTION OF 
PREGNANCY INFORMATION 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  A high follicle-stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormone replacement therapy (HRT).  However, in 
the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. 
• Females on HRT and whose menopausal status is in doubt will be required to use 1 of 
the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study.  Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
Contraception Guidance 
Male Participants 
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to 1 of the following (during the protocol-defined time frame in Section 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 a minimum of 112 days after the last dose of study treatment.  Refrain from 
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donating blood or sperm for the duration of the study and for a minimum of 112 days after the 
last dose of study treatment. 
Female Participants 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 13.  
Females who are exclusively in same-sex relationships are exempt for contraception guidelines. 
Female participants must agree to use highly effective forms of birth control for at least 28 days 
prior to starting the study, while participating in the study, and for at least 112 days after the last 
dose of study treatment. 
Participants should refrain from breastfeeding a child, donating blood, eggs, or ovum for the 
duration of the study and for at least 112 days after the last dose of study treatment. 
 
 
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Table 13: 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent a 
Failure rate of < 1% per year when used consistently and correctly  
Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulationb 
• Oral 
• Intravaginal 
• Transdermal 
Progestogen only hormonal contraception associated with inhibition of ovulation 
• Oral 
• Injectable  
Highly Effective Methods That Are User Independent a  
Implantable progestogen only hormonal contraception associated with inhibition of ovulationb 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system 
Bilateral tubal occlusion 
Vasectomized Partner 
A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed.  If 
not, an additional highly effective method of contraception should be used.  
Sexual Abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment.  
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
study and the preferred and usual lifestyle of the participant.  
a Typical use failure rates may differ from those when used consistently and correctly.  Use should be consistent with 
local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the efficacy 
of the contraceptive method.  In this case, 2 highly effective methods of contraception should be utilized during the 
study and for at least 112 days after the last dose of study treatment 
WOCBP = woman of childbearing potential. 
Pregnancy Testing 
• A Woman f Child-Bearing Potential should only be included in the study after 2 
confirmed negative pregnancy tests. 
• Additional pregnancy testing should be performed prior to study treatment 
administration at each dosing visit during the study and as required locally. 
Pregnancy testing will also be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected. 
 
 
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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 6. GENETICS 
Use/Analysis of Deoxyribonucleic Acid 
• 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.  
• Optional deoxyribonucleic acid (DNA) samples that are collected 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 1 or more candidate genes or the analysis of genetic markers throughout 
the genome (as appropriate). 
• DNA samples that are collected will be analyzed for bone morphogenetic protein 
receptor type II (BMPR2; and other potential genes of interest) mutational status and 
variant allele frequency 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 optional genetic samples will be tested to characterize any associations between 
mutational status of pulmonary hypertension genes and the response of participants to 
study treatment, as well as potential susceptibility to, severity and progression of the 
disease in aggregate.  Summary tables and figures will be generated to facilitate the 
understanding of the data.  There is no analysis plan to focus on specific individual 
mutational information.  The planned genetic analysis will help the future 
development of sotatercept in the indication of PAH.  
• 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.  All optional genetic samples collected will be 
analyzed at the bioanalytical laboratory shortly after receipt.  Any remnants from the 
analysis will be stored until end of the study or as per local regulations.  The 
information obtained from individual participants will be de-identified by labeling the 
samples with a unique participant identifier (participant number) prior to shipment to 
the analysis laboratory. 
 
 
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APPENDIX 7. NATIONAL CANCER INSTITUTE COMMON 
TERMINOLOGY CRITERIA FOR ADVERSE EVENTS 
VERSION 4.0 
Currently active minor version of the National Cancer Institute-Common Terminology Criteria 
for Adverse Events , version 4.0: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40 
 
 
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APPENDIX 8. PROTOCOL AMENDMENT HISTORY 
The Protocol Amendment Summary of Changes Tables  
Substantive changes from Protocol Amendment 05D (12 August 2018) to Protocol Amendment 
06D (18 December 2018) are detailed below.  Minor edits are not included.   
Protocol Location 
Description of Change 
Brief Rationale 
Synopsis,  
Section 2., Schedule of Events,  
Section 4.1., Overall Design,  
Figure 1 
Changed Double-Blind Treatment 
Period to Placebo-Controlled 
Treatment Period 
Change in nomenclature of study 
periods to clarify that the difference 
between the study periods is defined by 
the presence of a placebo arm rather 
than the study blinding. 
Synopsis,  
Section 3.1., Study Rationale,  
Section 4.1., Overall Design,  
Section 6.3., Dose Modification,  
Section 6.5., Randomization and 
Blinding; 
Section 8.2., Efficacy 
Assessments,  
Section 9.2., Populations for 
Analyses 
Added cycle and day numbers to 
the descriptions of timepoints. 
To align language in the protocol with 
the Schedule of Events and to clarify 
that the 24-week timepoint is Cycle 9 
Day 1A (C9D1A).  
Synopsis,  
Section 4.1., Overall Design,  
Figure 1,  
Section 9.1., Sample Size 
Determination 
Changed sample size to 
approximately 100 participants to 
be enrolled in a 3:3:4 
randomization ratio.  
Added approximately 10 participants to 
be randomized to the 0.7 mg/kg 
sotatercept dose level group in order to 
ensure that a sufficient number of 
participants are evaluable in the higher 
dose level group. 
Synopsis,  
Section 4.1., Overall Design,  
Section 5.2., Exclusion Criteria,  
Appendix 3:  Standard of Care 
Therapy 
Removed cap of 25% for the 
percentage of participants on 
monotherapy.  Clarified definitions 
of SOC. 
It is unnecessary to cap the percentage 
of participants who are receiving 
monotherapy to treat PAH.  
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Section 2., Schedule of Events 
Separated the SOE into 2 distinct 
tables: The Placebo-Controlled 
Treatment Period (Table 3) and the 
Extension and Follow-Up Periods 
(Table 4).  Cycle 9 Day 1 is split 
into Cycle 9 Day 1A and Cycle 9 
Day 1B.  Cycle 9 Day 1A is within 
the Placebo-Controlled Treatment 
Period and includes all assessments 
scheduled for the day.  Cycle 9 
Day 1B is the first column in the 
Extension Period and includes 
study treatment administration. 
Clarified timing and order of 
assessments, including 6MWT, 
ECHO, and RHC. 
Removed footnotes. 
To improve readability and 
functionality of the SOE while 
maintaining the necessary level of 
detail.  Footnotes composed of 
unnecessary or redundant information 
were removed. 
Section 2., Schedule of Events,  
Section 8.4.2., Clinical 
Laboratory Assessments,  
Section 8.8., Seminal Fluid 
Analyses;  
Appendix 2: Clinical 
Laboratory Tests  
Allowed seminal fluid collection to 
be optional for male participants.  
Added a section to explain seminal 
fluid collection and analyses 
(Section 8.8). 
Comply with health authority request 
while allowing for operational 
feasibility.  Clarified parameters to be 
evaluated for seminal fluid. 
Section 4.1., Overall Design 
Redundant and unnecessary 
language was removed from 
explanations of the study periods. 
To improve clarity. 
Section 5.1., Inclusion Criteria 
Inclusion criterion 4: added 
language about the timing of RHC 
assessments 
 
Inclusion criterion 5: added 
language around pulmonary 
function tests for total lung 
capacity 
 
Inclusion criterion 6: added 
language regarding options for 
To clarify when RHC assessments will 
be conducted. 
 
 
To clarify that pulmonary function test 
of total lung capacity may be 
substituted by a chest computed 
tomography scan showing no more than 
mild interstitial lung disease (ILD) by 
investigator interpretation. 
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ventilation-perfusion scan if 
unavailable 
 
Inclusion criterion 8: 6MWD upper 
limit changed to 550 m 
 
 
Inclusion criterion 10: 
Contraceptive guidelines language 
clarified.  Changed the timing of 
the requirement for effective 
contraception use prior to starting 
investigational product from 
5 weeks to 28 days. 
To clarify that pulmonary angiography 
result may be used. 
 
 
 
6MWD distance upper threshold was 
increased to better reflect the patient 
population on treatment with SOC.  
 
To align inclusion criterion with the 
Appendix 6 guidelines and definitions.  
To align contraception guidelines with 
study timelines. 
Section 5.2., Exclusion Criteria 
Exclusion criterion 16: Clarified 
that if a historical ECHO is 
unavailable, a participant may 
receive 1 during the Screening 
Period. 
 
Exclusion criterion 20: 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 clarify timing of ECHO 
assessments. 
 
 
 
 
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 
adverse events and frequency of 
rescreening for screen failures.   
To clarify that adverse event details are 
to be captured for screen failures and 
that rescreening is allowed only once.  
Section 6.3., Dose Modification 
Table 5: Changed the dose 
modification rules for AE, 
hemoglobin, and blood pressure. 
To align with updated 
inclusion/exclusion criteria and to 
clarify when doses of study treatment 
should be delayed or reduced. 
Section 6.5., Randomization and 
Blinding 
Language added regarding timing 
of unblinding.  
To clarify that unblinding will occur for 
everyone when all participants have had 
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their post-Placebo-Controlled Period 
(C9D1) PVR assessment. 
Section 8.2., Efficacy 
Assessments 
Added information about the 
timing of the RHC (Section 8.2.1) 
and ECHO (Section 8.2.3) 
assessments. 
To improve clarity of the timing of 
these assessments and to promote 
alignment with the SoE. 
Section 8.3., Adverse Events 
All AEs (serious and non-serious, 
related and non-related) are to be 
recorded on the eCRF from the 
time of signing of consent to the 
EOS visit. 
Clarification on the intent of capturing 
all AEs.  
 
Section 8.4., Safety 
Assessments 
Weight was moved from the 
physical examination section 
(Section 8.4.1) to the vital signs 
section (Section 8.4.2). 
Weight is collected and recorded in the 
eCRF as a part of the vital signs. 
Section 8.4.3., 
Electrocardiograms 
Added language regarding details 
of ECGs.  
To clarify that single not triplicate 
ECGs are to be obtained and that 
manual calculations are to be made if 
automatic ones are not available. 
Section 8.4.6., Clinical Safety 
Laboratory Assessments 
Added, “If hemoglobin is 
≥ 17 g/dL during Cycles 1-2 or 
Cycles 9-10, participants should 
return weekly for hemoglobin 
monitoring.” 
To ensure that participants whose 
hemoglobin levels become high are 
appropriately monitored. 
6MWD = 6-minute-walk distance; 6MWT = 6-minute-walk test; AE = adverse event; AESI = adverse event of 
special interest; ANC = absolute neutrophil count; CKD = chronic kidney disease; CT = computed tomography; 
CxDy = Cycle x Day x; DMC = Data Monitoring Committee; ECG = electrocardiogram; ECHO = echocardiogram; 
eCRF = electronic case report form; eGFR = estimated glomerular filtration rate; EOS = End of Study; 
Hgb = hemoglobin; ICF = informed consent form; PAH = pulmonary arterial hypertension; PVR = pulmonary 
vascular resistance; QoL = quality of life; QTcF = Fridericia’s corrected QT formula; RHC = right heart 
catheterization; SOC = standard of care; SOE = Schedule of Events; TEAE = treatment-emergent adverse event; 
UA = urinalysis; UACR = urine albumin creatinine ratio; VQ = ventilation-perfusion; WBC = white blood cell. 
 
 
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Substantive changes from Protocol Amendment 04C (14 June 2018) to Protocol Amendment 5D 
(12 August 2018) are detailed below.  Minor edits are not included.  
Protocol Location 
Description of Change 
Brief Rationale 
Synopsis 
Section 4.1 Overall Design, 
Section 5.2 Exclusion Criteria, 
and Appendix 3: Standard of 
Care Therapy 
Removed any exclusion of 
prostacyclin treatment as part of 
standard of care 
Sponsor acknowledges standard of care 
may include monotherapy with 
prostacyclin 
Section 2., Schedule of Event, 
Section 8.4.2., Clinical 
Laboratory Assessments, 
Appendix 2: Clinical 
Laboratory Tests and 
Appendix 6: Contraceptive 
Guidance and Collection of 
Pregnancy Information 
Include seminal fluid collection 
pre-dose and post-dose and 
increase follow-up monitoring time 
Comply with health authority request 
Section 4.1., Overall Design 
Remove interim analysis language. 
Administrative change.  Removal of 
interim analysis language that was 
inadvertently missed from last 
amendment.   
Section 5.2., Exclusion Criteria 
number 32 
Exclude patient with history of rare 
hereditary fructose intolerance and 
other genetic deficiencies of sugar 
metabolism 
Comply with health authority request 
Section 7.1., Discontinuation of 
Study Treatment 
Add QTcF > 500ms during 
treatment period 
Comply with health authority request 
Section 8.4.2., Vital Signs 
Add additional blood pressure 
measurements 
To ensure accurate readings, for dose 
modifications rules pertaining to blood 
pressure as with all on – study blood 
pressure measurement 3 readings are 
required 
Section 8.4.6., Clinical Safety 
Laboratory Assessments 
Add all hematology findings 
Clarify that all clinically significant 
abnormal hematology lab findings will 
be reported as adverse events 
QTcF = Fridericia’s corrected QT formula. 
 
 
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CONFIDENTIAL 
Substantive changes from Protocol Amendment 03B (24 May 2018) to Protocol Amendment 
04C (14 June 2018) are listed below.  Minor edits are not included. 
Protocol Location 
Description of Change 
Brief Rationale 
Synopsis 
Section 9.3.5 Interim 
Analysis 
Interim analysis removed 
Upon further review, the interim 
analysis was not expected to 
provide meaningful additional 
benefit over standard DMC 
monitoring. 
Section 5.2 Exclusion 
Criteria. 
Replaced exclusion criterion 20c with 
exclusion criterion 31:  
History of renal disease, including:  
a. Chronic renal disease at 
any time prior to 
screening; or  
b.  Any episode of acute 
renal failure, with or 
without a prior history of 
renal disease, occurring 
within the 3 months prior 
to screening in which 
acute dialysis 
(e.g., intermittent 
hemodialysis or 
continuous veno-venous 
hemofiltration) was 
required 
To reduce the risk of enrolling 
participants with baseline chronic 
renal impairment or a recent acute 
renal failure episode. 
Section 6.3 Dose 
Modification 
Added separate rows for leukopenia 
and thrombocytopenia. 
To clarify actions to be taken 
whether these events were deemed 
related or not. 
Section 9.3.2 Safety 
Analyses 
Added language regarding creatinine 
and UACR. 
To describe planned analyses for 
renal function tests.  
DMC = Data Monitoring Committee; UACR = urine albumin creatinine ratio. 
 
 
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Sotatercept (ACE-011) 
Study No: A011-09 
Revision: 07D 
 
31 July 2020 
Acceleron Pharma Inc. 
Page 96 of 100 
CONFIDENTIAL 
Substantive changes from the Protocol Amendment 02B (dated 30 April 2018) to amendment 
03B (dated 24 May 2018) are listed below.  Amendment 03B was approved internally and 
submitted to VHP but never implemented at any site.  Minor edits are not included.  
Protocol Location 
Description of Change 
Brief Rationale 
Section 2., Schedule of 
Events 
Added urinalysis (UA) and urine 
albumin creatinine ratio (UACR) 
assessments 
 
Edited timing of quality of life 
(QoL) assessments to be consistent 
with timing of 6-minute-walk test 
(6MWT) 
UA and UACR added to provide 
additional renal function monitoring 
 
To provide for the opportunity to 
investigate any correlations of QoL 
with 6MWT  
Section 5.2., Exclusion 
Criteria 
Exclusion criterion 16: added 
timing around ECHO - to be 
historical within 6 months prior to 
Screening 
 
 
Exclusion criterion 20: added 
lower entry limits for white blood 
cell (WBC) count, platelets, and 
absolute neutrophil count (ANC).  
Edited eGFR threshold to 
< 45 ml/min/1.73m2. 
Exclusion criterion 28: added 
“(auto)” in front of immune and 
“Autoimmune diseases are 
excluded with the exception of 
those related to PAH etiologies 
included in this study” 
To clarify that historical ECHO (within 
6 months) is to be used for eligibility 
(further clarified in Schedule of Events 
footnote 10) 
 
To limit baseline infection and bleeding 
risk of participants entering the study 
and to reduce the risk of enrolling 
participants with baseline significant 
renal impairment (i.e., CKD Stage 3B 
or worse excluded).  
To clarify that the presence of 
autoimmune conditions are also 
exclusionary, but not those which are 
associated with the particular subtypes 
of PAH disease included in this study.  
Section 3.3., 
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 
Language regarding risks added to 
better synchronize between information 
presented in the Investigator’s Brochure 
and informed consent form.  
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Sotatercept (ACE-011) 
Study No: A011-09 
Revision: 07D 
 
31 July 2020 
Acceleron Pharma Inc. 
Page 97 of 100 
CONFIDENTIAL 
thrombocytopenia have been 
described as treatment-emergent 
adverse events.  As a consequence 
of the decrease in white blood 
cells, infection maybe a potential 
risk and as a consequence of 
thrombocytopenia, bleeding maybe 
a potential risk.  Per health 
authority request, leukopenia, 
neutropenia, and 
thrombocytopenia have been 
identified as adverse events of 
special interest (AESI) in this 
study (see Section 6.3 Dose 
Modifications and 8.3 Adverse 
Events). 
Section 6.3. Dose 
Modifications 
Guidance for AESI have been 
added to Table 5 
To provide management of the events 
added to Section 3.3.  
Section 8.3. Adverse 
Events 
Added details regarding AESI 
To provide details of the events added 
to Section 3.3. 
Appendix 8: National 
Cancer Institute (NCI) 
Common Terminology 
Criteria for Adverse 
Events (CTCAE) 
Version 4.0 
Added link to NCI-CTCAE 
For clarification purposes with 
additions to Sections 6.3 and 8.3. 
6MWT = 6-minute-walk test; AESI = adverse event of special interest; ANC = absolute neutrophil count; CKD = 
chronic kidney disease; ECHO = echocardiogram; NCI-CTCAE = National Cancer Institute Common Terminology 
Criteria for Adverse Events; PAH = pulmonary arterial hypertension; QoL = quality of life; UA = urinalysis; 
UACR = urine albumin creatinine ratio; WBC = white blood cell. 
 
 
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Clinical Study Protocol 
 
Sotatercept (ACE-011) 
Study No: A011-09 
Revision: 07D 
 
31 July 2020 
Acceleron Pharma Inc. 
Page 98 of 100 
CONFIDENTIAL 
Substantive changes from the Protocol Amendment 01B (dated 15 February 2018) to amendment 
02B (dated 30 April 2018) are listed below.  Minor edits are not included.  
Protocol Location 
Description of Change 
Brief Rationale 
Section 2. Schedule of 
Events, footnote 13.  
Added: “Additionally, PK will be 
collected on the following non-
dosing days within the Treatment 
and Extension Periods: C1D8, 
C2D8, C9D8 and C10D8.” 
Clarification of PK collection visits (no 
assessments added or removed) 
Section 5.1. Inclusion 
Criteria 
Included information regarding 
sperm donation and oocyte 
donation into Inclusion Criteria 10 
To provide more comprehensive 
information in the body of the 
document in addition to that in 
Appendix 6 
Section 6.2. Treatment 
Administration and 
Schedule 
Added: “Each injection will not 
exceed 1.0 mL; a minimum of 2 
injections will be required per 
dose.” 
Clarified the number of injections in 
order to align with Exclusion Criteria 
30 from the last protocol amendment 
and the Pharmacy Manual.  
Section 9.3.5. Interim 
Analysis 
“The first full interim analysis…” 
changed to “An interim 
analysis…” 
 
 
Removal of language detailing 
potential actions the sponsor could 
take after the interim analysis (IA).  
Only one interim analysis is planned. 
Language was clarified to accurately 
express this intent.   
 
Simplification of the protocol text in 
order to clarify that if decisions are 
made post IA by the sponsor, any 
amendment to the protocol would take 
into consideration all operational and 
statistical requirements.  
Section 11.7. 
Appendix 7. Genetics 
Added descriptions for the use and 
long-term storage of genetic 
samples 
To provide further details of the intent 
and logistics of the genetic testing 
CxDy = Cycle x Day x; PK = pharmacokinetic. 
 
 
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Study No: A011-09 
Revision: 07D 
 
31 July 2020 
Acceleron Pharma Inc. 
Page 99 of 100 
CONFIDENTIAL 
Substantive changes from the original protocol (dated 15 December 2017) to amendment 01B 
(dated 15 February 2018) are listed below.  Minor edits are not included.  
Protocol Location 
Description of Change 
Brief Rationale 
Synopsis. Overall Design.  
Section 4.1. Study Design. 
Section 11.3. Appendix 3. 
Standard of Care. 
Deleted “SC/inhaled/PO” as a 
restriction on prostacyclin analogue 
or receptor agonist for Standard of 
Care.  
 
Participants receiving IV 
prostanoids as part of their 
Standard of Care will be 
allowed. 
Section 2. Schedule of 
Events 
Added WHO functional class 
assessments at multiple timepoints 
To be able to capture events of 
WHO functional class 
improvement as well as WHO 
functional class deterioration 
(already being assessed as part 
of clinical worsening).  
Section 2. Schedule of 
Events, footnote 4 
 
Added “If hemoglobin is ≥ 17 g/dL 
during Cycles 1-2 or Cycles 9-10, 
participant should return weekly for 
hemoglobin monitoring (and 
continue to follow Dose 
Modification rules for dosing days 
(Section 6.3).” 
Additional monitoring for 
safety to ensure hemoglobin 
levels are not rising while 
participants are reaching steady 
state.  Cycles 9-10 will be the 
first time placebo participants 
receive sotatercept.  
Section 2. Schedule of 
Events, footnote 7 
Section 8.7. Genetic Testing 
Appendix 7: Genetics 
Added language to clarify that 
genetic testing is optional.  
Genetic testing is now an 
optional procedure per protocol.  
Section 2. Schedule of 
Events, footnote 14 
Section 8.6. 
Pharmacodynamics 
Updated list of PD biomarkers to: 
“activin A, BMPR2 (via PBMCs), 
GDF15, MMP2, NT-proBNP, TGF-
β1, VEGFR1, and sex hormone 
metabolites”. 
PD biomarkers testing plan has 
been revised. 
Section 5.2. Exclusion 
Criteria 
 
Added exclusion criteria #30: 
“Weight > 140 kg at Screening” 
The weight restriction ensures 
participants will receive 2 
injections per dose, as detailed 
in the Pharmacy Manual.  
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Sotatercept (ACE-011) 
Study No: A011-09 
Revision: 07D 
 
31 July 2020 
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Page 100 of 100 
CONFIDENTIAL 
Section 8.2.2. 
Six-Minute-Walk Distance 
Added, “For assessment of clinical 
worsening, a decrease of ≥ 15% in 
6MWD at any timepoint as 
compared to Screening must be 
confirmed by a second 6MWT 
performed at least 4 hours and no 
more than 1 week apart from the 
first.” 
Clarification of the timing of 
the repeat 6MWT as needed for 
assessment of clinical 
worsening.  
Section 8.4.4. Clinical 
Worsening 
Added to the functional 
deterioration assessment, “…both of 
the below events occurring together 
at any time, even if they began at 
different times, as compared to their 
Screening values.” 
To clarify that the paired 
assessments for functional 
deterioration as part of the 
clinical worsening 
determination need not occur 
within the same cycle.  
6MWD = six-minute-walk distance; 6MWT = six-minute-walk test; BMPR2 = bone morphogenetic protein 
receptor type II; GDF = growth and differentiation factor; IV = intravenous; MMP2 = matrix metalloproteinase-2; 
NT-proBNP = N-terminal prohormone of brain natriuretic peptide; PBMC = peripheral blood mononuclear cell; 
PO = oral; SC = subcutaneous; TGF-β1 = transforming growth factor-beta 1; VEGFR1 = vascular endothelial 
growth factor receptor 1; WHO = World Health Organization. 
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SAP_001.pdf: 
Official Protocol Title: 
NCT number: 
NCT03496207 
Document Date: 
18-Jan-2022
A Phase 2, Double-Blind, Placebo-Controlled, Randomized Study to 
Compare the Efficacy and Safety of Sotatercept (ACE-011) Versus 
Placebo When Added to Standard of Care for the Treatment of 
Pulmonary Arterial Hypertension (PAH)


Confidential and Proprietary 
1 
Acceleron Pharma Inc. 
Statistical Analysis Plan 
Extension Period: A Phase 2, Double-Blind, Placebo-Controlled, 
Randomized Study to Compare the Efficacy and Safety of 
Sotatercept (ACE-011) Versus Placebo When Added to Standard 
of Care for the Treatment of Pulmonary Arterial Hypertension 
(PAH) 
Sponsor: 
Acceleron Pharma Inc. 
128 Sidney Street 
Cambridge, MA 02139 USA 
Tel: +1 617-649-9200 
Fax: +1 617-576-0479 
Investigational Product: 
Sotatercept (ACE-011) 
Protocol Number: 
A011-09 Extension Period 
EudraCT Number: 
2017-004738-27 
Version Number: 
1.2 
Date: 
18 January 2022 
CONFIDENTIALITY STATEMENT 
The information contained in this document, especially unpublished data, is the property of 
Acceleron Pharma Inc. (or under its control), and therefore provided to you in confidence for 
review by you and/or your staff.  It is understood that this information will not be disclosed to 
others without written authorization from Acceleron.
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ACCELERON PHARMA SIGNATURE PAGE 
The undersigned have approved this Statistical Analysis Plan Version 1.2 for use in this 
study. 
 
 
 
Signature: 
 
Date: 
 
 
Solaiappan Manimaran, Ph.D.  
Senior Manager, Biostatistics 
Acceleron Pharma Inc. 
 
 
DD/MMM/YYYY 
 
 
Signature: 
 
Date: 
 
 
Janethe de Oliveira Pena, MD  
Vice President, Medical Research 
Acceleron Pharma Inc. 
 
DD/MMM/YYYY 
 
 
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SAP SUMMARY OF CHANGES TABLE 
The changes from Extension Period SAP Version 1.1 (30 April 2021) to Extension Period SAP 
Version 1.2 (18 January 2022) are detailed below.  Minor edits are not included. 
Location 
Description of Change 
Brief Rationale 
Section 5.6.1.4. 
Supportive Analysis 
Added analysis with Month-6 
window for Placebo-controlled 
period. 
Added to support the End of 
Period analysis. 
Section 5.6.4. Subgroup Analysis Added subgroup analysis for the 
subgroups of Baseline Cardiac 
Index (< 2.5 or >= 2.5 L/min/m2 at 
baseline) 
Baseline Cardiac Index < 2.5 
represents an important 
intermediate/high risk category 
and Baseline Cardiac Index 
> = 2.5 L/min/m2 represents an
important low risk category.
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TABLE OF CONTENTS 
SAP SUMMARY OF CHANGES TABLE .....................................................................................3
1.
INTRODUCTION ........................................................................................................7
2.
STUDY OBJECTIVES ................................................................................................7
3.
OVERALL STUDY DESIGN ......................................................................................8
3.1.
Extension Period Study Design ....................................................................................8
3.2.
Rerandomization ...........................................................................................................8
3.3.
Treatment Discontinuation ...........................................................................................9
3.4.
Sample Size and Power Calculation .............................................................................9
4.
ANALYSIS POPULATIONS ....................................................................................10
4.1.
Full Analysis Set for the Extension Period (FAS-E) ..................................................10
4.2.
Safety Population for the Extension Period ................................................................10
4.3.
PK Population for the Extension Period .....................................................................10
4.4.
Per Protocol Set for the Extension Period (PPS-E) ....................................................10
5.
STATISTICAL METHODOLOGY ...........................................................................11
5.1.
General Considerations ...............................................................................................11
5.2.
Disposition of Patients ................................................................................................11
5.3.
Demographic, Baseline Characteristics, and Disease History ....................................11
5.4.
Study Drug Exposure ..................................................................................................11
5.5.
Prior and Concomitant Medication and Procedures ...................................................11
5.5.1.
Prior and Concomitant Medication .............................................................................11
5.5.2.
Non-Medication Procedures .......................................................................................12
5.6.
Efficacy Analyses .......................................................................................................12
5.6.1.
Extension Period Analysis ..........................................................................................12
5.6.1.1.
Placebo-crossed Efficacy Analysis .............................................................................13
5.6.1.2.
Delayed-start Efficacy Analysis .................................................................................14
5.6.1.3.
Sensitivity Analysis ....................................................................................................14
5.6.1.4.
Supportive Analysis ....................................................................................................14
5.6.2.
Other Extension Period Analysis ................................................................................15
5.6.2.1.
Six-minute walk distance (6MWD) at 12-Months .....................................................15
5.6.2.2.
WHO Functional Class Change at 12-Months ...........................................................15
5.6.2.3.
Other Secondary Efficacy Endpoints at 12-Months and aligned with 3rd RHC 
(Month 18-24) .............................................................................................................16
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5.6.3. 
Exploratory Endpoints ................................................................................................17 
5.6.4. 
Subgroup Analysis ......................................................................................................19 
5.6.5. 
Additional Sensitivity Analysis ..................................................................................20 
5.6.6. 
Special Handling for COVID-19 ................................................................................22 
5.7. 
Safety Analysis ...........................................................................................................22 
5.7.1. 
Adverse Events ...........................................................................................................22 
5.7.2. 
Laboratory Evaluations ...............................................................................................23 
5.7.3. 
Vital Signs ..................................................................................................................24 
5.7.4. 
Electrocardiogram (ECG) Results ..............................................................................24 
5.7.5. 
Physical Examination .................................................................................................25 
5.8. 
Pharmacokinetics ........................................................................................................25 
5.8.1. 
Pharmacokinetic Sampling Schedule .........................................................................25 
5.8.2. 
Pharmacokinetic Data Handling .................................................................................26 
5.8.3. 
Pharmacokinetic Analysis ..........................................................................................26 
5.9. 
Pharmacodynamics .....................................................................................................26 
5.10. 
Interim Analysis ..........................................................................................................26 
5.11. 
Protocol Deviations ....................................................................................................26 
5.12. 
Data Handling .............................................................................................................27 
5.12.1. 
Analysis Visit Window ...............................................................................................27 
5.12.2. 
Handling of Missing Data ...........................................................................................27 
5.12.2.1. 
Missing Dates for Adverse Event and Concomitant Medication ...............................27 
5.12.2.2. 
Missing Dates for Disease Diagnosis Date .................................................................29 
5.12.3. 
Handling of Data Limits .............................................................................................29 
5.13. 
Changes in Conduct or Planned Analyses from the Protocol .....................................29 
6. 
REFERENCES ...........................................................................................................30 
7. 
APPENDICES ............................................................................................................31 
7.1. 
Appendix 1 - List of Abbreviations ............................................................................31 
7.2. 
Appendix 2 - Schedule of Events (SoE) .....................................................................33 
 
 
 
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LIST OF TABLES 
Table 1: 
Notation: Efficacy Measurement at Different Time Points ........................................12 
Table 2: 
Patients Blood Sample Collection Schedule...............................................................25 
 
 
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1. 
INTRODUCTION 
This statistical analysis plan (SAP) describes the statistical methods to be used for the analysis of 
Extension Period of Acceleron Protocol A011-09.  This SAP should be read in conjunction with 
the study protocol and electronic case report form (eCRF).  This version of the plan has been 
developed using the protocol amendment 07A dated 17 July 2020.  Any further changes to the 
protocol may necessitate updates to the SAP. 
This SAP will be signed off before the study database lock of the Extension period.  Any 
deviations from the SAP will be described and justified in the final clinical study report (CSR). 
2. 
STUDY OBJECTIVES 
The primary objectives of the Extension period are: 
• To compare the efficacy endpoints between the continued sotatercept treatment group 
and placebo-crossed treatment group in the extension period using delayed-start 
efficacy analysis. 
• To compare post-baseline (Month 18-24) vs baseline (Month 0) values of efficacy 
endpoints within the placebo-crossed treatment group using placebo-crossed efficacy 
analysis. 
• To evaluate the long-term safety and tolerability of sotatercept in WHO functional 
class II-III PAH patients 
The secondary objectives for the extension periods are: 
• To assess the long-term effects on patients with PAH continuing sotatercept plus SOC 
on functional and pharmacodynamic endpoints compared with those transitioning 
from placebo plus SOC to sotatercept plus SOC. 
• To assess the Pharmacokinetics (PK) of sotatercept in patients with PAH 
The exploratory objectives for the extension periods are: 
• To assess relevant biomarkers for PAH 
• To assess efficacy parameters in patients with PAH 
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3. 
OVERALL STUDY DESIGN 
This is a Phase 2, double-blind, randomized, placebo-controlled, parallel-group study of 
sotatercept plus SOC versus placebo plus SOC in participants with PAH of WHO functional 
class II-III with an extension period where the placebo participants are rerandomized to one of 
the dose groups of sotatercept plus SOC.  
3.1. 
Extension Period Study Design 
In this study, 106 participants were randomly assigned in a 3:3:4 ratio to one of the 3 treatment 
groups in the Placebo-Controlled Treatment Period with 32 participants in Arm 1: Placebo SC 
every 21 days plus SOC for 24 weeks, 32 participants in Arm 2: Sotatercept (0.3 mg/kg, SC) 
every 21 days plus SOC for 24 weeks and 42 participants in Arm 3: Sotatercept (0.7 mg/kg, SC) 
every 21 days plus SOC for 24 weeks.  Out of the 32 participants originally randomized to 
Placebo, 30 participants entered the Extension period with 15 of the participants rerandomized to 
0.3 dose group and 15 participants rerandomized to 0.7 dose group.  Out of the 32 participants 
originally randomized to 0.3 dose group, 31 participants entered the Extension period and out of 
the 42 participants originally randomized to 0.7 dose group, 36 participants entered the 
Extension period.  Study duration for the extension period is up to 30 months with a 8-week 
Follow-Up Period after the last dose of study drug. 
Participants who have not discontinued early from the Placebo-Controlled Treatment Period will 
continue directly into the Extension Period.  Participants who have been on sotatercept will 
continue to receive sotatercept at their current dose level SC plus SOC.  Participants who were in 
the placebo arm will be re-randomized to receive sotatercept 0.3 or 0.7 mg/kg SC plus SOC.  
Study drug will be administered subcutaneously every 21 days for up to 30 months. 
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 the study early (including during either the Placebo-Controlled 
Treatment Period or the Extension Period) will be asked to return for EOT and EOS visits.  
Additional safety assessments, including urinalysis and hematology, as determined by the 
investigator, may be done at this time. 
The independent Data Monitoring Committee (DMC) used during Placebo-controlled period will 
continue monitoring at 6-month intervals during the extension period.  A detailed charter will 
outline all activities of the DMC (including, but not limited to, type of data to be reviewed, DMC 
responsibilities, and frequency of meetings). 
The main analysis including Delayed-start efficacy analysis and Placebo-crossed efficacy 
analysis of the extension period will be performed on the primary and secondary endpoints after 
the last patient has completed the third right-heart catheterization or has passed the Month 18-24 
window for the 3rd RHC or has an early EOT. 
3.2. 
Rerandomization 
Following the completion of the 24-week Placebo-Controlled Treatment Period, placebo 
participants will be re-randomized 1:1 to treatment with sotatercept 0.3 mg/kg plus SOC or 
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sotatercept 0.7 mg/kg plus SOC through the computerized system, provided by the Interactive 
Response Technology (IRT), and sotatercept-treated participants will continue on their current 
dose in the Extension Period in a blinded manner. 
3.3. 
Treatment Discontinuation 
Reasons that may lead to discontinuation of study treatment include: 
• Completion of treatment 
• Adverse event 
• Participant request (withdrawal of consent) 
• Loss of treatment effect 
• Clinical worsening requiring rescue therapy with a PAH agent 
• Pregnancy 
• Protocol deviation 
• Study terminated by sponsor 
• QTcF > 500ms during treatment period  
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 
• Loss of treatment effect 
• Death 
• Lost to follow-up 
• Study terminated by sponsor 
• Adverse event 
The sponsor may terminate study treatment or a dose level after consultation with the 
investigator and the DMC 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. 
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. 
3.4. 
Sample Size and Power Calculation 
For the delayed-start efficacy analysis of the extension period, with 30 participants in the placebo 
arm transition to sotatercept (out of the 32 participants randomized to placebo, two participants 
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discontinued early and did not reach the Extension period) and about 60 participants continuing 
on the sotatercept treatment with values after third right heart catheterization, with an assumed 
difference in PVR of 100 dyn·sec/cm5 (-150 dyn·sec/cm5 in placebo transitioning to sotatercept 
arm and -250 dyn·sec/cm5 in continuing sotatercept arm) and a standard deviation of 220, there 
is a power of about 40% to detect the difference at 2-sided alpha = 0.025 level in PVR between 
the arms.  
And with an assumed difference in 6MWD of 30 meters (30 meters in placebo transitioning to 
sotatercept arm and 60 meters in continuing sotatercept arm) and a standard deviation of 50, 
there is a power of about 65% to detect the difference at 2-sided alpha = 0.025 level in 6MWD 
between the arms. 
For the Placebo-crossed efficacy analysis of the extension period, with 30 participants in the 
placebo arm transition to sotatercept, with an assumed change from baseline in PVR of -
220 dyn·sec/cm5 that is sustained after third right heart catheterization in the Extension period 
and a standard deviation of 220, there is a power > 99% to at 2-sided alpha = 0.025 level in PVR. 
4. 
ANALYSIS POPULATIONS 
4.1. 
Full Analysis Set for the Extension Period (FAS-E) 
The Full Analysis Set consists of all randomized participants treated with correct treatment 
assignment who transitioned to extension period. 
4.2. 
Safety Population for the Extension Period 
All randomized participants who receive at least 1 dose of study treatment.  Participants will be 
analyzed according to the treatment they actually received who transitioned to extension period. 
All ACE-011-treated is the set of all participants who received sotatercept at any time.  This set 
is also used to study the overall safety of sotatercept. 
4.3. 
PK Population for the Extension Period 
PK population will include all participants who have received at least 1 dose of sotatercept and 
have sufficient pharmacokinetic samples collected and assayed for PK analysis who transitioned 
to extension period. 
4.4. 
Per Protocol Set for the Extension Period (PPS-E) 
PPS includes all participants in the Full Analysis Set (FAS-E) who transitioned to extension 
period and had their Extension Period PVR assessment, with no failure to perform key 
procedures (RHC and 6MWT) during the 3rd RHC window (Month 18-24), without missing 3 
consecutive doses immediately before 3rd RHC, and with no other deviations that also have 
major impacts on the efficacy of the study treatment. 
 
 
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5. 
STATISTICAL METHODOLOGY 
5.1. 
General Considerations 
Unless otherwise noted, continuous data will be summarized with the following descriptive 
statistics: number of observations (n), mean, standard deviation (STD), minimum, median, and 
maximum.  Categorical data will be summarized with frequencies (n) and percentages (%).  In 
cases where missing data cause percentages sum to less than 100, a missing data row will be 
provided.  Percentages will use column totals as the denominator unless otherwise indicated. 
All study data will be included in study data listings.  Missing data will generally be treated as 
missing, not imputed, unless otherwise stated. 
5.2. 
Disposition of Patients 
The number and percentage of patients receiving study treatment who completed the treatment 
period and study period along with the associated reasons for discontinuation from treatment 
and/or withdrawal from study will be presented. 
5.3. 
Demographic, Baseline Characteristics, and Disease History 
Baseline and demographic characteristics will be summarized by descriptive statistics for all the 
randomized patients as randomized by treatment groups.  Partially missing diagnosis dates will 
be imputed based on the rules mentioned in the Data Handling section. 
Demographic and baseline data, medical history, and disease history data will be listed for each 
patient. 
5.4. 
Study Drug Exposure 
Study drug exposure will be descriptively summarized for safety population and will present the 
duration of exposure, the number of treatment cycles, the total dose administered, and the 
number of patients with dose delay and reduction. 
The duration of exposure will be calculated as (last dose date – first dose date) + 21. 
The total number of cycles will be summarized by presenting the number and percentage of 
patients in each category. 
The total dose administered is the total amount in mg a patient received during the treatment 
period. 
Study drug administration details will be listed for each patient. 
5.5. 
Prior and Concomitant Medication and Procedures 
5.5.1. 
Prior and Concomitant Medication 
The prior and concomitant medications are coded with WHO dictionary.  The medications will 
be summarized for the safety population. 
Medications will be assigned as prior or concomitant based on the following rules with the 
partial missing dates imputed based on the rules mentioned in the Data Handling section below: 
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• If both the start and stop date exist and are before the first dose date of study drug, the 
medication will be counted as prior. 
• If the start date is on or after the first dose date of study drug, the medication will be 
counted as concomitant. 
• If the start date is before the first dose date of study drug and the stop date is after the 
first dose date of study drug or the medication is ongoing, the medication will be 
counted as concomitant. 
• If the start date is missing and the stop date is before the first dose of study drug, the 
medication will be counted as prior. 
• If the start date is missing and the stop date is after the first dose of study drug or the 
medication is ongoing, the medication will be counted as concomitant. 
• If the start and stop dates are missing, the medication will be counted as concomitant. 
All prior and concomitant medications will be listed for each patient. 
5.5.2. 
Non-Medication Procedures 
Non-medication procedures will be coded using MedDRA.  All non-medication procedures will 
be listed for each patient. 
5.6. 
Efficacy Analyses 
All efficacy endpoints in the extension period will be analyzed using Full Analysis Set for the 
Extension Period (FAS-E) and Per Protocol Set for the Extension Period (PPS-E) population 
unless otherwise specified.  Analysis on Full Analysis Set for the Extension Period (FAS-E) will 
be considered as primary for the extension period analysis. 
5.6.1. 
Extension Period Analysis 
Participants will have a total of three PVR assessments over the course of the study: PVR at 
Baseline (PVR0), PVR following completion of the 6-month Placebo-Controlled Treatment 
Period (PVR6), and PVR from 3rd Right Heart Catheterization done at Month 18-24 window post 
baseline (PVR-ext.).  The 6MWD and WHO Functional Class (FC) measurements taken at or 
closest around the same timepoint as PVR within the Month 18-24 window or the first 
measurement within the Month 18-24 window if no PVR measurement are also analyzed 
similarly.  Table 1 provides notation for efficacy measurements at different time points.  
Table 1: 
Notation: Efficacy Measurement at Different Time Points 
 
PVR 
6MWD 
FC 
FC numeric 
version 
Month 0 (baseline) 
PVR0 
6MWD0 
FC0 
FCn0 
Month 6 
PVR6 
6MWD6 
FC6 
FCn6 
Month 18-24 
PVR-ext 
6MWD-ext 
FC-ext 
FCn-ext 
6MWD = 6-minute-walk distance; FC = functional class; PVR = pulmonary vascular resistance.  
 
 
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Two Analysis Treatment Groups in the Extension Period: 
• Continued sotatercept treatment group: Participants randomized to either dose group 
(0.3 mg/kg and 0.7 mg/kg) of sotatercept at the beginning of the Placebo-Controlled 
Period.  They continued to receive sotatercept in the Extension Period. 
• Placebo-Crossed treatment group: Participants randomized to Placebo at the beginning of 
Placebo-Controlled Period and then randomized to either 0.3 mg/kg or 0.7 mg/kg of 
sotatercept in the Extension Period. 
Two Statistical Efficacy Analyses:  
• Delayed-start efficacy analysis: Compare the efficacy endpoints between the two 
treatment groups in the Extension Period. 
• Placebo-crossed efficacy analysis: Compare post-baseline (Month 18-24) vs baseline 
(Month 0) values of efficacy endpoints within the Placebo-Crossed treatment group. 
The overall type I error rate will be 2-sided 0.05. Recycle method will be used to control the 
overall type I error rate.1 
The set of Placebo-crossed efficacy analyses will be tested first at 2-sided 0.025 level.  Gate 
keeping method will be used to sequentially test each efficacy endpoint.  PVR will be tested first 
at 0.025 level.  If successful, 6MWD will be tested second at 2-sided 0.025 level.  If both PVR 
and 6MWD are successfully tested, FC improvement will then be tested at 2-sided 0.025 level.  
If all three efficacy endpoints in the Placebo-crossed efficacy analyses are statistically 
significant, then the type I error rate of 0.025 will be recycled.  The set of Delayed-start efficacy 
analysis will be tested at 0.025 + 0.025 = 0.05 2-sided level.  Otherwise, if at least one of the 
three tests is not significant, they will be tested sequentially at 2-sided 0.025 level.  Each 
endpoint in Delayed-start efficacy analysis will be tested similarly as the sotatercept placebo-
crossed efficacy analyses. 
The sotatercept 0.3 mg/kg group and 0.7 mg/kg group will be pooled into one sotatercept group 
Extension Period analysis. 
5.6.1.1. 
Placebo-crossed Efficacy Analysis 
The primary analysis is to evaluate PVR-ext - PVR0 in Placebo-Crossed treatment group with 
type I error rate of 2-sided 0.025.  ANCOVA will be used to test the intercept with 
PVR0˗average (PVR0) as the covariate.  Normality will be tested using Shapiro-Wilk test.  If 
normal distribution is rejected, a non-parametric Wilcoxon signed rank test will be used.  
Multiple imputation method will be used to handle the missing data.  
The key secondary analysis is to evaluate 6MWD-ext - 6MWD0 in Placebo-Crossed treatment 
group after the successful testing on primary PVR analysis, with type I error rate of 2-sided 
0.025.  ANCOVA will be used to test the intercept with 6MWD0-average (6MWD0) as the 
covariate.  The normality check and missing data handling method will be similar to primary 
analysis. 
The other secondary analysis is to evaluate FCn-ext – FCn0 in the Placebo-Crossed treatment 
group after the successful testing on primary PVR and key secondary 6MWD analysis, with type 
I error rate of 2-sided 0.025.  ANCOVA will be used to test the intercept with FCn0-average 
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(FCn0) as the covariate.  The FC categories are converted to numerical values, I = 1, II = 2, 
III = 3 and IV = 4.  The numerical values will be used in this analysis.  This conversion is made 
in order to increase statistical power of the ANCOVA analysis. 
5.6.1.2. 
Delayed-start Efficacy Analysis  
The primary analysis is to compare the change from baseline (PVR-ext – PVR0) between the 
Continued sotatercept treatment group and the Placebo-Crossed treatment group to evaluate 
disease modifying effect with type I error rate of 2-sided 0.025.  ANCOVA will be used with 
PVR0 and FC0 as covariates.  Normality will be tested using Shapiro-Wilk test.  If normal 
distribution is rejected, a non-parametric Wilcoxon rank sum test stratified by FC0 will be used.  
Multiple imputation method will be used to handle the missing data.  
The key secondary analysis is to compare change from baseline (6MWD-ext – 6MWD0) 
between the Continued sotatercept treatment group and Placebo-Crossed treatment group after 
the successful testing on primary PVR analysis with type I error rate of 2-sided 0.025.  
ANCOVA will be used with 6MWD0 and FC0 as covariates.  The normality check and missing 
data handling method will be similar to primary analysis. 
The other secondary analysis is to compare FC-ext improvement from baseline (FC0) between 
the Continued sotatercept treatment group and Placebo-Crossed treatment group after the 
successful testing on primary PVR and key secondary 6MWD analysis, with type I error rate of 
2-sided 0.025.  Cochran-Mantel-Haenszel (CMH) test will be used with FC0 as the stratum. 
5.6.1.3. 
Sensitivity Analysis  
For the participants who missed the third right heart catheterization during the Month 18-24 but 
was performed later, the Delayed-start Efficacy Analysis and Placebo-crossed Efficacy Analysis 
will be repeated with those out-of-window visit values as a sensitivity analysis. 
5.6.1.4. 
Supportive Analysis  
The Placebo-crossed Efficacy Analysis will also be repeated with Month-6 (Cycle 9) as baseline 
in order to analyze the effect of sotatercept on participants after transitioning from placebo to 
sotatercept at Month-6 (Cycle 9).  A similar analysis with Month-6 (Cycle 9) as baseline will 
also be conducted on the continued sotatercept (combined and by dose arms) in order to evaluate 
the continued effect of sotatercept in the long term. 
In order to characterize the combined difference between sotatercept treatment arms and placebo 
after the placebo participants crossing over to sotatercept, aligned supportive analysis will be 
performed by combining the results of change from baseline after 6 months for participants on 
the original sotatercept treated arms with the results of change from baseline at Month-12 for 
additional placebo to sotatercept participants after 6 months in sotatercept and comparing with 
the results of change from baseline after first 6 months for participants originally randomized to 
placebo group.  This analysis will be done on the secondary endpoints of Six-minute walk 
distance (6MWD), WHO Functional Class, NT-proBNP and Multi-component improvement 
endpoints. 
In addition, because of the same participants being present in the placebo group and also in the 
placebo-crossed sotatercept group, and there is also correlation between the repeated 
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measurements on participants at baseline and Month-6, and at Month-12, additional supportive 
analysis to explore the treatment difference in continuous secondary endpoints of Six-minute 
walk distance (6MWD), and NT-proBNP will be performed using MMRM model (proc mixed in 
SAS with repeated statement) and binary enpoints of WHO Functional Class Improvement and 
Multi-component Improvement endpoint are analyzed using GEE logistic regression (proc 
genmod in SAS with repeated statement), with just the values from baseline, Month-6 and 
Month-12 for all the participants. 
Additional placebo-controlled period supportive analysis is performed on 6MWD using a 
Month-6 window defined as follows.  Month-6 measurement is defined as one occurring in a 
window of Day 147-189 excluding any measurements after a subject has crossed over from 
Placebo to Sotatercept in the extension period.  If there are multiple measurements, then the 
closest measurement to Day 168 is used.  The Month-6 window supportive analysis is performed 
on Full Analysis Sets using an ANCOVA model with standard multiple imputation.  Normality 
distribution assumption is tested using Shapiro-Wilk method and if significant, a non-parametric 
stratified Wilcoxon-rank sum test is performed.  In addition, a Worst Rank Analysis method is 
performed, in which, for the participants who missed the measurement due to death, their missed 
post-baseline measurement will be imputed as -2000.  And for those participants who missed the 
measurement due to clinical worsening, their missed post-baseline measurement will be imputed 
as -1000. 
5.6.2. 
Other Extension Period Analysis 
5.6.2.1. 
Six-minute walk distance (6MWD) at 12-Months 
The average of the distance in the two-screening measurement will be used as the baseline. 
The Delayed-Start analysis and Placebo-Crossed analysis performed after third right heart 
catheterization as described in the sections above will also be performed for 6MWD at 
12-months in the Full Analysis Set for the Extension Period (FAS-E).  In addition, the above 
exploratory analysis will be performed for each dose group separately.  
In addition, several methods for missing value handling will be explored as described in the 
Additional Sensitivity Analysis section below. 
5.6.2.2. 
WHO Functional Class Change at 12-Months 
The average of the distance in the two-screening measurement will be used as the baseline. 
The Delayed-Start analysis and Placebo-Crossed analysis performed after third right heart 
catheterization as described in the sections above will also be performed for WHO Functional 
Class at 12-months in the Full Analysis Set for the Extension Period (FAS-E).  In addition, the 
above exploratory analysis will be performed for each dose group separately.  
In addition, several methods for missing value handling will be explored as described in the 
Additional Sensitivity Analysis section below. 
 
 
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5.6.2.3. 
Other Secondary Efficacy Endpoints at 12-Months and aligned with 3rd RHC 
(Month 18-24)  
Change in NT-ProBNP from Baseline 
The Delayed-Start analysis and Placebo-Crossed analysis performed after third right heart 
catheterization will also be performed for NT-proBNP at 12-months and aligned with 3rd RHC 
(Month 18-24) in the Full Analysis Set for the Extension Period (FAS-E).  In addition, the above 
exploratory analysis will be performed for each dose group separately.  
In addition, several methods for missing value handling will be explored as described in the 
Additional Sensitivity Analysis section below. 
Simplified French Risk Score 
The simplified French risk scoring system is based on the 2015 ESC/ERS Guidelines for the 
diagnosis and treatment of pulmonary hypertension.  In this study, the noninvasive parameters 
will be used to determine the score.  “Low risk” is defined as attaining or maintaining all 3 
low-risk criteria: WHO FC I or II, 6MWD > 440 m, and NT-proBNP < 300 ng/L.  The 
proportion of participants who attain low risk is analyzed. 
Echo Parameters 
The Echo parameters of interest are Change from baseline in the following parameters: Tricuspid 
Annular Plane Systolic Excursion (TAPSE), Pulmonary Artery Pressure (PAP), Pulmonary 
Artery Systolic Pressure (PASP), Right Ventricular Pulmonary Artery contractile-pressure 
coupling (RV-PA coupling), Right Ventricular End Systolic Area (RVESA), Right Ventricular 
End Diastolic Area (RVEDA) and Right Ventricular Fractional Area Change (RVFAC). 
Clinical Worsening 
Clinical worsening will be assessed by the investigator at each visit and recorded on the CRF.  
Assessments are: 
• 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 (II to III, III to IV, II to IV, etc.) 
and 
− Decrease in 6MWD by ≥ 15% (confirmed by two 6MWTs) 
Clinically significant abnormal findings will be reported as adverse events. 
Number of patients and percentages with clinical worsening will be summarized by visit and 
overall during the treatment period. 
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Time to clinical worsening will be summarized using Kaplan-Meier estimates (median and its 
95% confidence interval).  Participant who has no clinical worsening will be censored at the last 
visit on treatment.  Stratified log-rank test will be used to test the treatment difference of each 
active treatment arm versus placebo arm separately.  Cox proportional hazard model stratified by 
randomization factors will be used to estimate the hazard ratio and its 2-sided 80% and 95% CIs 
will be provided. 
Change in QoL (CAMPHOR, SF-36) at 12-Months and aligned with 3rd RHC (Month 
18-24) vs. Baseline 
QoL will be measured using CAMPHOR and SF-36.  Change in individual subscale scores and 
total scores comparing to baseline will be summarized by visit and treatment.  The change in all 
the three components of CAMPHOR score: Symptom (impairment) score, Activity (disability) 
score and Quality of life (QoL) score and the overall score, which is the sum of the above three 
component scores will be analyzed using stratified Wilcoxon's rank-sum test stratified by 
randomization factors.  The change in SF-36 score and the individual component scores 
(Physical Component Scores (PCS) and Mental Component Scores (MCS)) will be formally 
analyzed using ANCOVA model with randomization factors as covariates.  
Population PK Parameters of Sotatercept 
Sotatercept concentration data will be summarized per Section 5.8.  
5.6.3. 
Exploratory Endpoints 
Multi-component Improvement Endpoint  
Improvement in the lives of PAH patients will be assessed at each visit using Multi-component 
improvement endpoint. 
Multi-component Improvement Endpoint is defined by the number of patients who exhibit all 
three of the following criteria: 
• Any Improvement in WHO Functional Class or maintenance of WHO Functional 
Class II 
• Improvement in NT Pro-BNP by at least 30% (≤-30% from baseline) 
• Improvement in 6MWD by at least 30 meters (≥ 30m from baseline) 
The Multi-component Improvement Endpoint is compared in each of the treatment groups.  
Multi-component Improvement Endpoint defined by the number of patients who exhibit at least 
two of the above criteria is also analyzed as an additional analysis.  Missing values will be 
treated as non-responder by default unless special handling rule for COVID-19 as mentioned in 
Section 5.6.6 applies. 
Other Exploratory Endpoints 
In addition to the clinical improvement endpoints, the following exploratory endpoints will be 
summarized by visit for each treatment group using descriptive statistics. 
• Change from baseline in TGF-β ligands (e.g., activin A) and other PAH-related 
biomarkers (GDF15, TGFB1, VEGRF1 and MMP2) as well as variance in related 
genes and transcript expressions of BMPR2 
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• Mortality Risk Assessment 
• Renal Risk Assessment using Estimated Glomerular Filtration Rate (eGFR) 
• Change in ECHO parameters other than the one listed above (TAPSE, PAP, PASP, 
RV-PA coupling, RVESA, RVEDA and RVFAC), if any 
• Change in Cardiac Index calculated using the following formula2: 
𝐶𝑎𝑟𝑑𝑖𝑎𝑐 𝐼𝑛𝑑𝑒𝑥 =  𝐶𝑎𝑟𝑑𝑖𝑎𝑐 𝑂𝑢𝑡𝑝𝑢𝑡 (𝐶𝑂) / 𝐵𝑜𝑑𝑦 𝑆𝑢𝑟𝑓𝑎𝑐𝑒 𝐴𝑟𝑒𝑎 (𝐵𝑆𝐴) 
𝐵𝑜𝑑𝑦 𝑆𝑢𝑟𝑓𝑎𝑐𝑒 𝐴𝑟𝑒𝑎 (𝐵𝑆𝐴) = √(ℎ𝑒𝑖𝑔ℎ𝑡 (𝑐𝑚) ∗ 𝑤𝑒𝑖𝑔ℎ𝑡 (𝑘𝑔)
3600
) 
The details of PAH related biomarkers and PK/PD analysis will be described in detail in separate 
analysis plans. 
 
 
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Mortality Risk Assessment 
Different approaches will be explored to assess risk in PAH3 such as the use of risk variables 
according to the 2015 European Society of Cardiology (ESC)/European Respiratory Society 
(ERS) pulmonary hypertension (PH) guidelines with 1-year mortality risk classified as Low risk 
< 5%, Intermediate risk 5–10% and High risk > 10% based on the available parameters, and the 
use of a risk score such as the simplified REVEAL 2.0 (Registry to Evaluate Early And 
Long-term PAH Disease Management) registry risk score with the available parameters and 
REVEAL Lite 2.0 scores. 
Renal Risk Assessment using eGFR 
Estimated Glomerular Filtration Rate (eGFR) is used to measure the condition of renal 
functionality with respect to any effect due to the treatment.  The eGFR is calculated from four 
inputs - Serum Creatinine (SerumCr), Gender, Race (Black or Not) and Age as follows: 
𝑒𝐺𝐹𝑅 𝑖𝑛 𝑚𝐿/𝑚𝑖𝑛 𝑝𝑒𝑟  1.73𝑚2
= 175 ∗𝑆𝑒𝑟𝑢𝑚𝐶𝑟−1.154 ∗𝐴𝑔𝑒−0.203 ∗1.212(𝑖𝑓 𝑝𝑎𝑡𝑖𝑒𝑛𝑡 𝑖𝑠 𝑏𝑙𝑎𝑐𝑘)
∗0.742 (𝑖𝑓 𝑓𝑒𝑚𝑎𝑙𝑒) 
Compare the improvement in eGFR from baseline for patients who have eGFR < 60 mL/min per 
1.73 m2 at baseline, in each of the treatment groups.  Compute the number of patients for whom 
there is an improvement of at least 20 points. 
Hematocrit Adjusted PVR 
In order to study the effect of hemoglobin increase on PVR, the analysis on the primary endpoint 
is repeated on Hematocrit adjusted PVR, which is calculated using the following formula:5 
[𝑎𝑑𝑗𝑢𝑠𝑡𝑒𝑑 𝑃𝑉𝑅] =
𝑚𝑃𝐴𝑃
𝐶𝑂∗𝑒[2(𝜑𝑚𝑒𝑎𝑠𝑢𝑟𝑒𝑑− 𝜑𝑟𝑒𝑓] − 𝑃𝐴𝑊𝑃
𝐶𝑂
 
[𝑎𝑑𝑗𝑢𝑠𝑡𝑒𝑑 𝑃𝑉𝑅]: 𝑃𝑢𝑙𝑚𝑜𝑛𝑎𝑟𝑦 𝑉𝑎𝑠𝑐𝑢𝑙𝑎𝑟 𝑅𝑒𝑠𝑖𝑠𝑡𝑎𝑛𝑐𝑒 (𝑊𝑜𝑜𝑑 𝑈𝑛𝑖𝑡𝑠) 
𝜑𝑟𝑒𝑓(𝐻𝑒𝑚𝑎𝑡𝑜𝑐𝑟𝑖𝑡 𝑟𝑒𝑓𝑒𝑟𝑒𝑛𝑐𝑒 𝑙𝑒𝑣𝑒𝑙) = 0.45, 𝑖. 𝑒. 45% 
𝜑𝑚𝑒𝑎𝑠𝑢𝑟𝑒𝑑: 𝐻𝑒𝑚𝑎𝑡𝑜𝑐𝑟𝑖𝑡 𝑚𝑒𝑎𝑠𝑢𝑟𝑒𝑑 
𝑚𝑃𝐴𝑃: 𝑚𝑒𝑎𝑛 𝑃𝑢𝑙𝑚𝑜𝑛𝑎𝑟𝑦 𝐴𝑟𝑡𝑒𝑟𝑦 𝑃𝑟𝑒𝑠𝑠𝑢𝑟𝑒 (𝑚𝑚𝐻𝑔) 
𝑃𝐴𝑊𝑃: 𝑃𝑢𝑙𝑚𝑜𝑛𝑎𝑟𝑦 𝐴𝑟𝑡𝑒𝑟𝑦 𝑊𝑒𝑑𝑔𝑒 𝑃𝑟𝑒𝑠𝑠𝑢𝑟𝑒 (𝑚𝑚𝐻𝑔), 𝑒𝑞𝑢𝑖𝑣𝑎𝑙𝑒𝑛𝑡 𝑡𝑜  
𝑃𝐶𝑊𝑃: 𝑃𝑢𝑙𝑚𝑜𝑛𝑎𝑟𝑦 𝐶𝑎𝑝𝑖𝑙𝑙𝑎𝑟𝑦 𝑊𝑒𝑑𝑔𝑒 𝑃𝑟𝑒𝑠𝑠𝑢𝑟𝑒 (𝑚𝑚𝐻𝑔) 
𝐶𝑂: 𝐶𝑎𝑟𝑑𝑖𝑎𝑐 𝑂𝑢𝑡𝑝𝑢𝑡 (𝐿/𝑚𝑖𝑛) 
5.6.4. 
Subgroup Analysis 
Subgroup analyses of change of the Primary and Secondary Endpoints at 3rd RHC and applicable 
endpoints at 12 months and 18 months might be performed with the following baseline factors if 
the sample size in the subgroup category is ≥ 10: 
• Sex (male and female) 
• Known pathological mutations (including BMPR2 mutation) vs Wild Type at 
baseline 
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• PAH Etiological Subgroups (iPAH, hPAH (heritable PAH), Drug/Toxin, Connective 
Tissue Disease, congenital heart disease with s/p Shunt Repair) 
• Monotherapy vs Double vs. Triple combination therapy at baseline 
• Prostacyclin Infusion Therapy vs. Non-Prostacyclin Infusion at baseline 
• WHO functional class (II or III) 
• Baseline PVR (≤ 800 or > 800 dyn*sec/cm5 at baseline) 
• Baseline Cardiac Index (< 2.5 or > = 2.5 L/min/m2 at baseline) 
Subgroup analyses of change of the Primary and Secondary Endpoints for the above subgroups 
including baseline Cardiac Index < 2.5 and >= 2.5 L/min/m2 are also performed for the Placebo-
controlled period at 24 weeks. 
5.6.5. 
Additional Sensitivity Analysis 
Several methods for missing value handling including the following techniques will be explored 
to conduct sensitivity analysis on the primary, key secondary endpoints and other secondary 
endpoints as appropriate: 
• Standard Multiple Imputation 
• Pattern Mixture Model 
• Tipping Point Analysis 
For the comparison between the treatment arms of the change from baseline for the primary 
endpoint, ANCOVA with the randomization stratification factor as the covariate will be used.  
For the secondary endpoints, ANCOVA with the randomization stratification factor as the 
covariate model and a Mixed effect Model Repeat Measure (MMRM) model will be used.  The 
MMRM model includes the baseline endpoint value and the randomization stratification factor as 
covariate; treatment group, time point, and treatment group-by-time point interaction as fixed 
effects.  An unstructured covariance structure will be used to model the within-patient covariance 
across visits. 
Standard Multiple Imputation 
Missing at Random (MAR) assumption is made to perform standard Multiple Imputation (MI).  
For missing points, monotonous regression is used to fill in the missing points in the order of 
time points using values calculated at the previous time points.  The analysis involves the 
following steps: 
1. The missing data are filled in m times to generate m complete data sets using 
monotonous regression model accounting for baseline value, randomization stratification 
factor, and if necessary, additional covariates such as age and other secondary endpoints 
at different visits in the imputation model. 
2. The m complete data sets are analyzed by using standard procedures.  ANCOVA with the 
randomization stratification factor and baseline value as the covariate and Mixed effect 
Model Repeat Measure (MMRM) model as mentioned above will be used for analysis 
here. 
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3. The results from the m complete data sets are combined for the inference. 
Pattern Mixture Model 
Pattern Mixture Model with control-based pattern imputation will be used to perform sensitivity 
analysis, if the p-value is highly significant at a 1-sided alpha of 0.025.  The analysis includes the 
following steps: 
1. When imputing missing values for time-point t, the input dataset should include all 
placebo participants, and only those participants from the experimental arm that have 
values at time-point t missing (only those that need imputation at time-point t).  
Imputation model will be estimated using placebo participants only.  This way, 
participants from experimental arm will be imputed based on the control participants’ 
model.  Note that treatment arm should not be included as an effect in this model.  The 
missing data are filled in m times using monotonous regression model accounting for 
baseline value, randomization stratification factor, and if necessary, additional covariates 
such as age and other secondary endpoints at different visits in the imputation model to 
generate m complete data sets using this Pattern Mixture Model. 
2. The m complete data sets are analyzed by using standard procedures.  ANCOVA with the 
randomization stratification factor as the covariate and Mixed effect Model Repeat 
Measure (MMRM) model as mentioned above will be used for analysis here. 
3. The results from the m complete data sets are combined for the inference. 
Tipping Point Analysis 
Tipping point analysis will be used to perform sensitivity analysis, if the p-value is highly 
significant at a 1-sided alpha of 0.025.  Tipping point analysis include the following steps.  The 
first three steps are the standard multiple imputation (MI) steps: 
1. The missing data are filled in m times to generate m complete data sets using the Pattern 
Mixture model as mentioned above. 
2. The m complete data sets are analyzed by using standard procedures.  ANCOVA with the 
randomization stratification factor and baseline value as the covariate and Mixed effect 
Model Repeat Measure (MMRM) model as mentioned above will be used for analysis 
here. 
3. The results from the m complete data sets are combined for the inference. 
4. Repeat the step 1 to generate multiple imputed data sets, with a specified shift parameter 
that adjust the imputed values for observations in the treatment group, not the placebo 
group). 
5. Repeat the step 2 for the imputed data sets with shift parameter applied. 
6. Repeat the step 3 to obtain the p-value and check statistical significance. 
7. Repeat the steps 4-6 with more stringent shift parameter applied until the p-value 
becomes not significant. 
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5.6.6. 
Special Handling for COVID-19 
Several methods for missing value handling of visits missed due to COVID-19 are applied as 
follows: For the main analysis after 3rd Right Heart Catheterization, the participants who missed 
assessments in the Month 18-24 window due to COVID-19 will be taken out of the denominator 
for binary endpoints such as WHO Functional Class improvement and Multi-component 
Improvement Endpoint.  For the Multi-component Improvement Endpoint with three 
components, if a response could be established based on the components with available values, 
that response of responder or non-responder will be used for that participant.  Otherwise, if a 
response could not be established based on the components with available values and some 
components are missing due to COVID-19 the participant will be taken out of the denominator.  
For the 12-Month analysis, for a subject who missed the 12-Month visit due to COVID-19, the 
values if available from the next available visit within a 12-week window may be used, 
otherwise will be taken out of the denominator for binary endpoints. 
5.7. 
Safety Analysis 
The safety endpoints will be summarized using the Safety Population.  The safety endpoints 
include treatment emergent adverse events, changes in laboratory tests, vital signs, 
immunogenicity, and ECG’s. 
Severity of AEs will be coded using National Cancer Institute Common Toxicity Criteria for 
Adverse Events version 4.0 (NCI-CTCAE v4.0).4 
5.7.1. 
Adverse Events 
All AEs and SAEs reported from C1D1 to the EOS visit are to be reported and documented on 
the AE CRF.  All AEs worsened or started between C1D1 and 8 weeks safety follow-up visit 
after the last dose will be considered as treatment emergent adverse events (TEAE).  Any partial 
dates will be imputed based on the rules in Data Handling section below.  A drug-related TEAE 
is defined as any TEAE related to the study medication as assessed by the investigator or with 
missing assessment of the causal relationship. 
The following summaries will be presented for all dosed: 
• Number and percentage of patients reporting each TEAE, categorized by System 
Organ Class (SOC) and Preferred Term (PT) 
• Number and percentage of patients reporting each TEAE experienced by ≥ 5% and 
≥ 10% of patients in all patients by PT 
• Number and percentage of patients reporting SAE, categorized by SOC and PT 
• Number and percentage of patients reporting Grade ≥ 3 TEAE, categorized by SOC 
and PT 
• Number and percentage of patients reporting related TEAE, categorized by SOC and 
PT 
• Number and percentage of patients reporting related SAE, categorized by SOC and 
PT 
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• Number and percentage of patients reporting TEAE leading to drug withdrawal, 
categorized by SOC and PT 
• Number and percentage of TEAE of special interest (AESI) 
• Number and percentage of TEAE by severity 
• Number and percentage of TEAE categorized by Monotherapy vs Double vs Triple 
combination therapy at baseline 
• Number and percentage of TEAE categorized by Prostacyclin Infusion Therapy vs 
Non-Prostacyclin Infusion at baseline 
• All AEs will also be summarized by last dose received prior to the event. 
Note that counting will be by patient, not event, and patients are only counted once within each 
SOC or PT.  If a patient experiences the same AE at more than one severity, or with more than 
one relationship to study drug, the most severe rating or the stronger causal relationship to study 
drug will be given precedence.  Any missing severity, causality, or outcome will not be imputed 
and classed as unknown. 
Events to be considered adverse events of special interest (AESI) in this study, according to 
National Cancer Institute-Common Toxicity Criteria for Adverse Events, version 4.0 
(NCI-CTCAE v4.0)4, are SMQ fertility disorders, Hepatic disorders (SMQ) (Narrow and broad), 
Ischemic heart disease (SMQ) Embolic and thrombotic events (SMQ) and the following: 
• Leukopenia 
• Neutropenia (including febrile neutropenia) 
• Thrombocytopenia 
All AEs will be listed.  The following listings will also be provided:  
1. patients with SAEs;  
2. patients with Grade ≥ 3 AEs;  
3. patients with AEs leading to study drug discontinuation;  
4. patients with AEs leading to death; 
5. Patients with AEs leading to dose modifications. 
In addition, Time-at-risk Exposure-adjusted Incidence Rate6 analysis will also be performed on 
the summarized AEs.  Exposure Adjusted Incidence Rates (EAIRs) are calculated as number of 
participants with an AE divided by the sum of the individual times at risk for the first occurrence 
of an AE of all participants in the safety set from start of treatment during Extension period to 
first onset of AE during Extension period before switch (or end of Extension period if no 
switch), date of switch, end of Extension period or death, whichever occurs first. 
5.7.2. 
Laboratory Evaluations 
The following laboratory parameters will be measured over time: 
 
 
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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, 
platelet count. 
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 
Urine Creatinine, urine albumin creatinine ratio (UACR). 
Actual values and changes in laboratory values from baseline will be summarized by time point.   
Shift tables for the following parameters comparing values above, within and below the normal 
reference range overtime will be presented using standard reference ranges: 
Hematology: RBC, WBC, Platelets, Hemoglobin and Hematocrit 
Chemistry: ALT, AST, BUN, Creatinine and Total Bilirubin 
Urinalysis: UACR 
All laboratory values will be listed for all patients. 
5.7.3. 
Vital Signs 
Vital signs parameters include temperature, pulse rate, respiratory rate, and blood pressure.  For 
each parameter at each time point, the change from baseline to post baseline will be summarized. 
Vital signs will also be listed for all patients.  This includes height at screening and weight at all 
dosing visits. 
BMI will be calculated using the formula: BMI = weight (kg) / [height (m)]2 
5.7.4. 
Electrocardiogram (ECG) Results 
The quantitative ECG assessments (ventricular rate, PR interval, QRS duration, QRS Interval 
and QTcF interval) will be summarized at each time point. 
ECG overall interpretation (normal, abnormal not clinically significant and abnormal clinically 
significant) will be presented for actual values and changes from baseline to each post baseline 
visit [expressed as Improvement, No Change, and Deterioration]. 
Note: 
• Improvement = Abnormal Clinically Significant (CS) to Abnormal Not Clinically 
Significant (NCS)/Normal, Abnormal NCS to Normal  
• Deterioration = Normal to Abnormal NCS/CS, Abnormal NCS to Abnormal CS  
• No change = Normal to Normal, Abnormal NCS to Abnormal NCS, Abnormal CS to 
Abnormal CS 
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If either result is missing or unknown for any patient, then the corresponding 
‘Missing’/ ‘Unknown’ category will also be presented. 
ECG results will be listed for all patients. 
5.7.5. 
Physical Examination 
Physical exam details will be listed only. 
5.8. 
Pharmacokinetics 
5.8.1. 
Pharmacokinetic Sampling Schedule 
Blood samples will be collected from all patients at the schedule presented in Table 2. 
Table 2: 
Patients Blood Sample Collection Schedule 
N/A = Not Applicable 
 
 
Visit 
Study Day (± 3days) 
Pre-dose or No dose 
4-hourPost-dose 
Cycle 1 Day 1 
1 
Yes 
Yes  
Cycle 1 Day 8 
8 
Yes 
No 
Cycle 2 Day 1 
22 
Yes 
No 
Cycle 2 Day 8 
29 
Yes 
No 
Cycle 3 Day 1 
43 
Yes 
No 
Cycle 5 Day 1 
85 
Yes 
Yes  
Cycle 8 Day 1 
148 
Yes 
No 
Cycle 9 Day 1 
169 
Yes 
Yes  
Cycle 9 Day 8 
176 
Yes 
No 
Cycle 10 Day 1 
190 
Yes 
No 
Cycle 10 Day 8 
197 
Yes 
No 
Cycle 13 Day 1 
253 
Yes 
Yes  
Cycle 17 Day 1 
337 
Yes 
Yes  
Cycle 21 Day 1 
421 
Yes 
Yes  
Cycle 25 Day 1 
526 
Yes 
No 
Cycle 29 Day 1 
610 
Yes 
Yes 
Cycle 34 Day 1 
715 
Yes 
Yes 
EOT 
N/A 
Yes 
No 
EOS 
N/A 
Yes 
No 
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5.8.2. 
Pharmacokinetic Data Handling 
The following rules regarding concentration values below the limit of quantitation (BLQ) and 
other data handling rules regarding concentration data are only intended for listings and 
summary of concentration data.  Data handling rules for population PK and population PK/PD 
analyses will be presented in a separate analysis plan. 
Concentrations that are BLQ prior to the first dose will be assigned a numerical value of zero.  
Post-treatment concentrations that are BLQ will be treated as missing. 
Concentrations assigned a value of missing will be omitted from the descriptive statistics.  A 
concentration value of zero will be excluded from the computation of the geometric mean 
(geometric CV%).  If any patients are found to be noncompliant with respect to dosing, have 
incomplete data, or encounter other circumstances that would affect the evaluation of 
pharmacokinetics, a decision will be made on a case-by-case basis as to their inclusion in the 
pharmacokinetic analysis.  Data excluded from pharmacokinetic analysis will be included in the 
data listings, but not in the summaries. 
In tables and listings for the derived pharmacokinetic data, there should be four decimal places 
for numerical values below 1, three decimal places for numeric values below 10 but above 1, and 
two decimal places for numeric values above 10.  However, the listings of raw data should not 
have more decimal places than the actual data. 
5.8.3. 
Pharmacokinetic Analysis 
All sotatercept serum concentrations will be listed by patient and scheduled time (visit and 
study).  Actual dosing/sampling time, sample time relative to first dosing time, visit, and 
concentration will be presented in the listing. 
The sotatercept serum concentrations will be summarized by scheduled time, including N 
(number of observations), arithmetic mean, arithmetic standard deviation (SD), arithmetic 
coefficient of variation (CV%), geometric mean, geometric CV%, minimum, median, and 
maximum.  Mean (SD) serum concentration-time profiles will be presented on linear scales. 
5.9. 
Pharmacodynamics 
Venous blood samples will be collected for measurement of PD biomarkers including but not 
limited to activin A, NT-proBNP, estrogen (e2) 16-alpha-hydroxyesterone, 2-methoxyestradioal, 
2-hydroestradiao, testosterone, FSH, and estradiol at timepoints listed in the SoE.  PD 
biomarkers will be summarized using descriptive statistics by visits for each treatment group.  
5.10. 
Interim Analysis 
There are no Interim Analysis planned for the study.  There are only planned DMC safety 
reviews. 
5.11. 
Protocol Deviations 
All major protocol deviations will be listed and summarized. 
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5.12. 
Data Handling 
5.12.1. 
Analysis Visit Window 
Baseline is defined as the last observation on or prior to the first dose of study drug, unless 
otherwise specified.  For the purpose of Extension Period Analysis, the following rules will be 
followed: 
1. Month 18-24 window corresponds to Day 548 – 730. 
2. Enlarged window of Day 480-730 is used to include 3rd RHC PVR measurements. 
3. 6MWD and WHO Functional Class measured on the same day or closest to the PVR 
measurement will be used.  
4. If there is no 3rd RHC PVR measurement, then the first measurement of 6MWD and 
WHO Functional Class in the Day 548 – 730 window will be used. 
5. Other efficacy parameters such as NT-proBNP and Multi-component Improvement 
endpoint will be handled similarly. 
5.12.2. 
Handling of Missing Data  
As a general principle, no imputation of missing data will be done unless otherwise specified. 
Exceptions are the start and stop dates of AEs and concomitant medication with the rules listed 
below.  The imputed dates will be used to allocate the medication as prior or concomitant 
medications and to determine whether an AE is/is not treatment emergent.  Listings of the AEs 
and concomitant medications will present the actual partial dates; imputed dates will not be 
shown. 
In addition, partial disease diagnosis dates are imputed to calculate time since disease diagnosis.  
The listing will present the actual partial dates. 
5.12.2.1. Missing Dates for Adverse Event and Concomitant Medication 
Incomplete Start Date 
Missing day and month 
• If the year is the same as the year of the first dosing date, then the day and month of 
the first doing date will be assigned to the missing fields. 
• If the year is prior to the year of first dosing date, then December 31 will be assigned 
to the missing fields. 
• If the year is after the year of first dosing, then January 1 will be assigned to the 
missing fields. 
Missing day only  
• If the month and year are the same as the year and month of first dosing date, then the 
first doing date will be assigned to the missing day. 
• If either the year of the partial date is before the year of the first dosing date or the 
years of the partial date and the first dosing date are the same, but the month of partial 
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date is before the month of the first dosing date, then the last day of the month will be 
assigned to the missing day. 
• If either the year of the partial date is after the year of the first dosing date or the 
years of the partial date and the first dose date are the same, but the month of partial 
date is after the month of the first dosing date, then the first day of the month will be 
assigned to the missing day. 
• If the stop date is not missing, and the imputed start date is after the stop date, the 
start date will be imputed by the stop date.  
Missing day, month, and year 
• No imputation is needed.  The corresponding AE will be included as TEAE.  
Incomplete Stop Date: If the imputed stop date is before the start date, then the imputed stop 
date will be equal to the start date. 
Missing day and month 
• If the year of the incomplete stop date is the same as the year of the last dosing date, 
then the day and month of the last dosing date will be assigned to the missing fields.  
• If the year of the incomplete stop date is prior to the year of the last dosing date or 
prior to the year of the first dosing date, then December 31 will be assigned to the 
missing fields.  
• If the year of the incomplete stop date is prior to the year of the last dosing date but 
is the same as the year of the first dosing date, then the first dosing date will be 
assigned to the missing date.  
• If the year of the incomplete stop date is after the year of the last dosing date, then 
January 1 will be assigned to the missing fields. 
Missing day only  
• If the month and year of the incomplete stop date are the same as the month and year 
of the last dosing date, then the day of the last dosing date will be assigned to the 
missing day.  
If either the year of the partial date is not equal to the year of the last dosing date or the years of 
the partial date and the last dosing date are the same but the month of partial date is not equal to 
the month of the last dosing date, then the last day of the month will be assigned to the missing 
day. 
 
 
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5.12.2.2. Missing Dates for Disease Diagnosis Date 
For disease diagnosis dates, the imputation rules are: 
a. If day is missing, use 15th of the month 
b. If both day and month are missing, impute as January 1st 
c. If month is missing, impute as January 
d. If year is missing, set to missing 
5.12.3. 
Handling of Data Limits  
All the PD values reported as less than Lower Limits of Quantification (LLOQ) will be assigned 
a value of LLOQ/2 during summarization.  Percentage values reported as greater than 99% will 
be assigned a value of 99.5% during summarization. 
5.13. 
Changes in Conduct or Planned Analyses from the Protocol 
The text for the dose assignment in the Evaluable population is updated to refer to the dose 
received at least 6 times rather than the dose to which they were originally assigned. 
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6. 
REFERENCES 
1. 
Comparisons of global tests on intersection hypotheses and their application in matched 
parallel gatekeeping procedures, Ouyang J, Zhang P, Koch G, et al., J Biopharmaceutical 
Statistics. 2019;1520:5711 (online). 
2. 
Simplified Calculation of Body-Surface Area, R.D. Mosteller M.D., Akron City Hospital, 
1987, The New England Journal of Medicine. 
3. 
Risk assessment in pulmonary arterial hypertension, Amresh Raina and Marc Humbert, 
2016, The European Respiratory Review. 
4. 
National Cancer Institute Common Toxicity Criteria for Adverse Events, version 4.0 
(NCI-CTCAE v4.0). 
5. 
Hematocrit-corrected Pulmonary Vascular Resistance, Rebecca R. Vanderpool and 
Robert Naeije, 2018, American Thoracic Society. 
6. 
Risk-based and Exposure-based Adjusted Safety Incidence Rates; Qiuhong Jia, Fang-
Ting Kuo, Chia-Ling Ally Wu, and Ping Xu, Seattle Genetics, Inc; PharmaSUG 2020 - 
Paper SA-103. 
 
 
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7. 
APPENDICES 
7.1. 
Appendix 1 - List of Abbreviations 
Abbreviation or Specialist Term 
Explanation 
6MWD 
Six-minute-walk distance 
6MWT 
Six-minute-walk test 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BMP 
Bone morphogenetic protein 
BP 
Blood Bone morphogenetic protein pressure 
CAMPHOR 
Cambridge Pulmonary Hypertension Outcome Review 
CRF 
Case report form 
CxDy 
Cycle x Day y 
CO 
Cardiac Output 
DBP 
Diastolic blood pressure 
DLT 
Dose limiting toxicity 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
eGFR 
Estimated Glomerular Filtration Rate 
ERA 
Endothelin-receptor antagonist 
EOS 
End of study 
EOT 
End of treatment 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
FST 
Follistatin 
IgG2 
Immunoglobulin G2 
IP 
Investigational product 
mPAP 
Mean Pulmonary Artery Pressure 
MMRM 
Mixed effect model repeat measurement 
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Abbreviation or Specialist Term 
Explanation 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for 
Adverse Events 
NT-proBNP 
N-terminal-prohormone of brain natriuretic peptide 
PAH 
Pulmonary arterial hypertension 
PAP 
Pulmonary arterial pressure 
PAWP 
Pulmonary Artery Wedge Pressure 
PCWP 
Pulmonary Capillary Wedge Pressure 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PPS 
Per Protocol Set 
PVR 
Pulmonary vascular resistance 
RBC 
Red blood cell 
RHC 
Right heart catheterization 
RVEF 
Right ventricular ejection fraction 
RVFA 
Right ventricular fractional area 
SAE 
Serious adverse event 
SBP 
Systolic blood pressure 
SD 
Standard deviation 
SOC 
Standard of care 
SoE 
Schedule of Events 
TAPSE 
Tricuspid annular plane systolic excursion 
TGF-β 
Transforming growth factor-beta 
UACR 
Urine Albumin-to-Creatinine Ratio 
ULN 
Upper limit of normal 
VAF 
Variant allele frequency 
WHO 
World Health Organization 
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7.2. 
Appendix 2 - Schedule of Events (SoE) 
Refer to A011-09 Protocol Amendment 07A, dated 17 April 2020, Section 2. 
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