Clinical trial NCT04896008
Conditions: Pulmonary Arterial Hypertension
Keywords: Pulmonary, hypertension, sotatercept
Sponsor: Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
Start date: 2021-12-01; Completion date: 2025-02-18
Enrollment: 173 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this study is to evaluate the effects of sotatercept (MK-7962, formerly called ACE-011) treatment (plus maximum tolerated background pulmonary arterial hypertension \[PAH\] therapy) versus placebo (plus maximum tolerated background PAH therapy) on time to first event of all cause death, lung transplantation, or PAH worsening-related hospitalization of ≥24 hours, in participants with World Health Organization (WHO) functional class (FC) III or FC IV PAH at high risk of mortality.

Detailed description:
This is a phase 3, randomized, double-blind, placebo-controlled study to evaluate sotatercept when added to maximum tolerated background PAH therapy on time to first event of all-cause death, lung transplantation, or PAH worsening related hospitalization of ≥24 hours, in participants with WHO FC III PAH or WHO FC IV PAH at high risk of mortality.

Participants with symptomatic PAH (WHO FC III or FC IV at high risk of mortality) who present with idiopathic or heritable PAH, PAH associated with connective tissue diseases (CTD), drug- or toxin-induced, post-shunt correction PAH, or PAH presenting at least 1 year following the correction of congenital heart defect. Participants must have a Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) Lite 2.0 risk score of ≥9 and be on maximum tolerated combination background PAH therapy.

Arms: arm 1: Participants on background PAH therapy will be administered placebo by SC injection every 21 days arm 2: Participants on background PAH therapy will be administered sotatercept by SC injection at a starting dose of 0.3 mg/kg, with a target dose of 0.7 mg/kg, every 21 days
Interventions: intervention 1: Sotatercept intervention 2: Placebo
Intervention descriptions: intervention 1: SC injection intervention 2: Placebo-matched SC injection

Protocol documents:
Prot_000.pdf: 
Official Protocol Title:
NCT number:
Document Date:           23-Apr-2024
NCT04896008
A Phase 3, Randomized, Double-Blind, Placebo-Controlled 
Study to Evaluate Sotatercept When Added to Maximum 
Tolerated Background Therapy in Participants With 
Pulmonary Arterial Hypertension (PAH) World Health 
Organization (WHO) Functional Class (FC) III or FC IV at 
High Risk of Mortality 


CLINICAL STUDY PROTOCOL
SOTATERCEPT (ACE-011)
STUDY A011-14, AMENDMENT 03, VERSION 4.0 (MK-7962-006-07)
23 April 2024
Acceleron Pharma Inc.
Page 1 of 117
CONFIDENTIAL
PROTOCOL A011-14 (ZENITH)
PROTOCOL TITLE:
A Phase 3, Randomized, Double-Blind, Placebo-
Controlled Study to Evaluate Sotatercept When 
Added to Maximum Tolerated Background Therapy 
in Participants With Pulmonary Arterial Hypertension 
(PAH) World Health Organization (WHO) Functional 
Class (FC) III or FC IV at High Risk of Mortality 
SHORT TITLE:
A Phase 3 Study of Sotatercept in Participants with 
PAH WHO FC III or FC IV at High Risk of Mortality
REGULATORY AGENCY 
IDENTIFYING NUMBERS:
IND 136150
EudraCT 2021-001498-21
SPONSOR:
Acceleron Pharma, Inc., a wholly-owned subsidiary of 
Merck & Co., Inc., Rahway, NJ, USA 
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
ORIGINAL PROTOCOL 
DATE:
08 April 2021
PROTOCOL AMENDMENT 
01 DATE (MK-7962-006-01):
16 June 2022
PROTOCOL AMENDMENT 
02 DATE (MK-7962-006-06):
29 June 2023
PROTOCOL AMENDMENT 
03 DATE (MK-7962-006-07):
23 April 2024
See Appendix 5 for nomenclature mapping
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., a wholly-owned subsidiary of Merck & 
Co., Inc., Rahway, NJ, USA (henceforth referred to as Acceleron Pharma Inc. or Acceleron).
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CLINICAL STUDY PROTOCOL
SOTATERCEPT (ACE-011)
STUDY A011-14, AMENDMENT 03, VERSION 4.0 (MK-7962-006-07)
23 April 2024
Acceleron Pharma Inc.
Page 2 of 117
CONFIDENTIAL
PROTOCOL SIGNATURE PAGE
Acceleron Pharma Inc. Approval
Signature:
Date:
Name (print):
Investigator Agreement: 
The information contained in this protocol and all other information relevant to sotatercept 
are the confidential and proprietary information of Acceleron Pharma Inc., and except as 
may be required by federal, state or local laws or regulation, may not be disclosed to 
others without prior written permission of Acceleron Pharma Inc.
I have read the protocol and agree to conduct the study as outlined in the protocol. The 
study will be conducted in accordance with current United States (US) Food and Drug 
Administration (FDA) regulations, International Council for Harmonisation (ICH) 
Guidelines, Good Clinical Practices (GCP), the Declaration of Helsinki, and local ethical 
and legal requirements.
Signature:
Date:
Name (print):
Institution Name and Address:
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CLINICAL STUDY PROTOCOL
SOTATERCEPT (ACE-011)
STUDY A011-14, AMENDMENT 03, VERSION 4.0 (MK-7962-006-07)
23 April 2024
Acceleron Pharma Inc.
Page 3 of 117
CONFIDENTIAL
PROCEDURES IN CASE OF EMERGENCY
Table 1
Emergency Contact Information
Role in Study
Name
Contact Information
Medical Monitor
Details provided in the 
Regulatory Binder
Details provided in the Regulatory 
Binder
Pharmacovigilance
Acceleron Safety Reporting 
Hotline
EMEA/Asia Tel #: +44 1223 374 
240 
EMEA/Asia Fax #: +44 1223 374 
102
Emeaasiasafetycentral.sm@ppd.com
LA Tel #: +55 11 4504 4801
LA Fax #: +55 11 4504 4802
LATSafety@ppd.com
RTP Tel #: +1 888 483 7729
RTP Fax #: +1 888 529 3580
RTPSafety@ppd.com
Wilmington Tel #: +1 800 201 8725
Wilmington Fax #: +1 888 488 9697
WILSafety@ppd.com
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CLINICAL STUDY PROTOCOL
SOTATERCEPT (ACE-011)
STUDY A011-14, AMENDMENT 03, VERSION 4.0 (MK-7962-006-07)
23 April 2024
Acceleron Pharma Inc.
Page 4 of 117
CONFIDENTIAL
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
This protocol amendment was created primarily to add dose modification instructions due to
serious bleeding events, add event adjudication language, and update the risk/benefit section. 
Changes from the Version 3.0 (29 June 2023) to Version 4.0 (23 April 2024) are detailed 
below. Minor edits are not included.
Protocol 
Location
Description of Change
Brief Rationale
Section 2, 
Table 2
Added details to footnote ‘h’ stating 
that hematology assessments are 
required after a dose modification 
prior to the next dose administration
for participants on HHC and non-
quarterly site visits (full text not 
shown).
To facilitate hematology 
assessments after dose 
modification and before the 
next dose for participants on 
HHC and non-quarterly visits.
Section 2, 
Table 3
Changed footnote ‘e’ to read,
“Participants may be asked to return 
for additional ADA testing after their 
last visit if there is any indication of 
potential immunogenicity-related 
safety concern.” The previous 
statement was deleted.
To provide flexibility in post-
study ADA sampling across all 
Sotatercept studies.
Section 3.2
Updated the language on the 
important risks of sotatercept.
To reflect the potential risk of 
serious bleeding as added to the
sotatercept core risk profile.
Section 8.3
Changed text, “Dose delays should 
always precede dose reductions, as 
summarized in Figure 3 and Figure 4. 
While g Guidance for dose 
modifications and dose delays are 
summarized in Figure 3 and Figure 4, 
. For safety reasons other than those 
listed in Figure 3 and Figure 4, dose 
delays orfollowed by dose reductions
can be implemented for safety 
reasons at any time per the 
investigators assessment and are not 
limited to the dose modification 
guidance provided.”
To facilitate the correct 
application of the dose 
modification guidelines.
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CLINICAL STUDY PROTOCOL
SOTATERCEPT (ACE-011)
STUDY A011-14, AMENDMENT 03, VERSION 4.0 (MK-7962-006-07)
23 April 2024
Acceleron Pharma Inc.
Page 5 of 117
CONFIDENTIAL
Protocol 
Location
Description of Change
Brief Rationale
Section 8.3.2
Changed the text to read, “If Hgb 
level increase more than 4 g/dL 
above the participant’s baseline 
value, the study Medical Monitor 
should be consulted, and treatment 
discontinuation should be 
considered;…”
To align the body text with 
Figure 3.
Section 8.3.5
Added a new section (Dose Delays 
due to SAEs of Bleeding) and the 
text, “In cases of serious active 
bleeding, the dose of study 
intervention should be delayed until 
the event resolves. If more than one 
dose delay due to a serious bleeding 
event occurs, then the Medical 
Monitor should be consulted.” The 
subsequent section headings 
increased by one sequential number 
as a result.
See Section 3.2 rationale.
Section 9.2.1
Deleted text, 
“Measurements/assessments taken 
during Screening Period will be 
recorded as the baseline values for 
study assessment of endpoints unless 
described otherwise.”
To indicate that Section 9.2.1 is 
not intended for defining 
analysis details.
Section 9.3.14
Changed text, “Participants who have 
a new or higher titer-positive ADA 
result at their last visit may be asked 
to return for additional ADA testing
after their last visit if there is any 
indication of potential 
immunogenicity-related safety 
concern approximately every 3 
months until response is negative or 
result is considered stabilized.”
See Section 2, Table 3
rationale.
Section 9.3.18
Added a new section (Clinical Event
Information) to describe the 
collection of clinical events (full text 
not shown).
To add details regarding how 
clinical event information will 
be collected before an eDMC 
review or an interim/final 
analysis.
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CLINICAL STUDY PROTOCOL
SOTATERCEPT (ACE-011)
STUDY A011-14, AMENDMENT 03, VERSION 4.0 (MK-7962-006-07)
23 April 2024
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Page 6 of 117
CONFIDENTIAL
Protocol 
Location
Description of Change
Brief Rationale
Section 10.5,
Section 10.6
Changed text, “For overdose and
cancer (serious and non-serious) and
all SAEs, a paper SAE Report Form 
must be completed with a concise 
account of the event as much 
information as possible and submitted 
within the timeframe described in this 
section.”
To emphasize overdose and 
cancer as reportable events.
Section 10.7
Added text, “Additionally, the 
Serious Adverse Event Reporting 
Form must be submitted within the 
same timeframe. This form is to be 
submitted to the PPD PVG at the 
email address found at the bottom of 
the form.”.
To clarify that overdose should
be reported using the Serious 
Adverse Event Reporting Form
within 24 hours.
Section 10.9.1
Removed the risk language from this 
section (full text not shown).
To prevent redundancy with 
Section 3.2.
Section 11.10
Added a paragraph detailing the 
adjudication of events (full text not 
shown).
To provide specific information 
on the adjudication of events.
ADA = anti-drug antibodies; eDMC = external data monitoring committee; Hgb = hemoglobin; HHC = home 
health care; IB = Investigator’s Brochure; PAH = pulmonary arterial hypertension; PVG = pharmacovigilance;
SAE = serious adverse event.
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CLINICAL STUDY PROTOCOL
SOTATERCEPT (ACE-011)
STUDY A011-14, AMENDMENT 03, VERSION 4.0 (MK-7962-006-07)
23 April 2024
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Page 7 of 117
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TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ................................4
1
PROTOCOL SYNOPSIS..............................................................................................13
1.1
Study Schematic...................................................................................................22
2
SCHEDULE OF EVENTS............................................................................................23
3
INTRODUCTION: BACKGROUND AND STUDY RATIONALE ........................29
3.1
Background ..........................................................................................................29
3.2
Risks and/or Benefits to Participants.................................................................30
3.3
Study Rationale....................................................................................................31
4
STUDY OBJECTIVES..................................................................................................33
5
STUDY ENDPOINTS AND RATIONALE.................................................................34
5.1
Endpoints Reported in Previous PAH Studies..................................................34
5.2
Primary Efficacy Endpoint and Rationale ........................................................34
5.3
Secondary Efficacy Endpoints and Rationale...................................................35
5.3.1
N-Terminal Prohormone B-Type Natriuretic Peptide Rationale.................35
5.3.2
Six-Minute Walk Distance Rationale ..........................................................35
5.3.3
Pulmonary Vascular Resistance Rationale ..................................................36
5.3.4
Hemodynamic Parameters Rationale...........................................................36
5.3.5
REVEAL Lite 2.0 Risk Score Rationale......................................................36
5.3.6
World Health Organization Functional Class Rationale..............................37
5.3.7
Quality of Life Assessments Rationale........................................................37
5.4
Exploratory Endpoints........................................................................................38
5.5
Safety Endpoints ..................................................................................................38
6
STUDY DESIGN............................................................................................................39
6.1
Study Description.................................................................................................39
6.2
Duration of Study.................................................................................................39
6.3
Rationale for Dose Selection ...............................................................................39
6.4
Study Design, Stratification, and Treatment Assignment................................40
6.5
Home Health Care Visits.....................................................................................41
6.6
Randomization and Blinding ..............................................................................42
7
STUDY POPULATION ................................................................................................43
7.1
Rationale for Selected Population ......................................................................43
7.2
Background PAH Therapy .................................................................................43
7.3
Inclusion Criteria.................................................................................................43
7.4
Exclusion Criteria................................................................................................45
7.5
Screen Failures.....................................................................................................46
8
STUDY DRUG TREATMENT ....................................................................................47
8.1
Study Drug Description.......................................................................................47
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SOTATERCEPT (ACE-011)
STUDY A011-14, AMENDMENT 03, VERSION 4.0 (MK-7962-006-07)
23 April 2024
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Page 8 of 117
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8.1.1
Clinical Drug Product ..................................................................................47
8.1.2
Formulation..................................................................................................47
8.2
Study Drug Management ....................................................................................47
8.2.1
Storage .........................................................................................................47
8.2.2
Packaging and Shipment..............................................................................47
8.2.3
Dose and Administration .............................................................................48
8.3
Dose Modification ................................................................................................50
8.3.1
Escalation to Target Dose (0.7 mg/kg) ........................................................50
8.3.2
Dose Modifications Due to Hemoglobin Increase.......................................50
8.3.3
Dose Modifications Due to Low Platelet Count..........................................50
8.3.4
Dose Modifications Due to Adverse Events of Telangiectasia ...................51
8.3.5
Dose Delays Due to SAEs of Bleeding........................................................51
8.3.6
Dose Re-escalation Following Dose Reduction ..........................................51
8.3.7
Accountability..............................................................................................55
9
STUDY CONDUCT.......................................................................................................56
9.1
General Instructions............................................................................................56
9.2
Study Procedures .................................................................................................56
9.2.1
Screening Period (Up to 4 Weeks Prior to Visit 1)......................................56
9.2.2
Double-blind, Placebo-controlled Treatment Period (Until Event 
Occurrence)..................................................................................................57
9.2.2.1
Visit 1.................................................................................................57
9.2.2.2
Visit 2 (21 ± 3 days)...........................................................................58
9.2.2.3
Visits 3 and 4 (21 ± 3 days) ...............................................................59
9.2.2.4
Visit 5 (21 ± 3 days)...........................................................................59
9.2.2.5
Visits 6 Through 8 (21 ± 3 days) .......................................................60
9.2.2.6
Visit 9 (21 ± 3 days)...........................................................................60
9.2.2.7
Visits 10 Through 12 (21 ± 3 days) ...................................................61
9.2.2.8
Visit 13 (21± 3 days)..........................................................................61
9.2.2.9
Visits 14 Onward (21 ± 3 days).........................................................62
9.2.3
Follow-up Period (up to 8 Weeks)...............................................................63
9.2.3.1
End of Treatment Visit (21 ± 7 Days from Last Dose)......................63
9.2.3.2
End of Study Visit (5 Weeks ± 7 Days After EOT Visit)..................63
9.3
Description of Study Procedures........................................................................64
9.3.1
12-Lead Electrocardiogram .........................................................................64
9.3.2
Six-Minute Walk Test..................................................................................64
9.3.3
Borg Dyspnea Scale.....................................................................................65
9.3.4
World Health Organization Functional Class Assessment for Pulmonary 
Hypertension................................................................................................65
9.3.5
REVEAL Lite 2.0 Risk Score......................................................................66
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SOTATERCEPT (ACE-011)
STUDY A011-14, AMENDMENT 03, VERSION 4.0 (MK-7962-006-07)
23 April 2024
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9.3.6
COMPERA 2.0 Four-Strata Risk Score.......................................................66
9.3.7
Echocardiogram Parameters ........................................................................66
9.3.8
Patient-reported Outcomes...........................................................................67
9.3.8.1
EuroQoL - 5 Dimensions Scale 5 Levels Assessment.......................67
9.3.9
Physical Examination...................................................................................67
9.3.10
Vital Signs....................................................................................................67
9.3.11
NT-proB-type Natriuretic Peptide ...............................................................68
9.3.12
Activin A Assessments ................................................................................68
9.3.13
C-Reactive Protein.......................................................................................68
9.3.14
Anti-Drug Antibody Assessments ...............................................................69
9.3.15
Pharmacokinetics Measurements.................................................................69
9.3.16
Right Heart Catheterization Assessment .....................................................69
9.3.17
Clinical Laboratory Tests.............................................................................70
9.3.17.1
Hematology........................................................................................70
9.3.17.2
Serum Chemistry ...............................................................................70
9.3.17.3
Urinalysis...........................................................................................71
9.3.17.4
Pregnancy Testing..............................................................................71
9.3.18
Clinical Event Information ..........................................................................71
9.4
Discontinuation and Withdrawal Criteria.........................................................71
9.4.1
Participant Early Discontinuation................................................................71
9.4.2
End of Study Definition...............................................................................72
9.5
Participants Lost to Follow-Up...........................................................................73
9.6
Concomitant Medication and Therapy During Study Conduct......................73
9.7
Treatment Compliance........................................................................................73
9.8
Criteria for Study Termination..........................................................................74
9.8.1
Study and Site Closure.................................................................................74
10
SAFETY ASSESSMENT, REPORTING, AND MONITORING.............................75
10.1
Adverse Events.....................................................................................................75
10.1.1
Definitions of Adverse Event.......................................................................75
10.1.1.1
Unexpected Adverse Events ..............................................................75
10.1.1.2
Events Not Considered As Adverse Events.......................................75
10.2
Serious Adverse Events .......................................................................................76
10.2.1
Definition of Serious Adverse Events..........................................................76
10.2.2
Definition of Serious Adverse Event Terms................................................76
10.3
Assessment of Severity.........................................................................................77
10.4
Assessment of Causality ......................................................................................78
10.5
Documenting Adverse Events.............................................................................78
10.6
Reporting Serious Adverse Events.....................................................................79
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STUDY A011-14, AMENDMENT 03, VERSION 4.0 (MK-7962-006-07)
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10.6.1
Reporting Period and Monitoring of Participants with Adverse Events......80
10.6.2
Safety Reporting to Health Authorities, Independent Ethics 
Committees, Institutional Review Boards, and Investigators......................80
10.7
Overdose ...............................................................................................................81
10.8
Pregnancy .............................................................................................................81
10.9
Monitoring of Identified Risks, Potential Risks, and Adverse Events of 
Special Interest.....................................................................................................82
10.9.1
Adverse Event of Special Interest................................................................82
11
STATISTICAL ANALYSES ........................................................................................83
11.1
Overview...............................................................................................................83
11.2
Sample Size Determination.................................................................................83
11.3
Populations for Analysis......................................................................................83
11.4
Statistical Methods...............................................................................................84
11.5
Study Endpoints...................................................................................................84
11.5.1
Primary Endpoint.........................................................................................84
11.5.1.1
Handling of Censored Data................................................................84
11.5.2
Secondary Endpoints ...................................................................................84
11.5.3
Exploratory Endpoints .................................................................................85
11.5.4
Estimands.....................................................................................................86
11.5.4.1
Estimand for Time-to-Event Endpoints.............................................86
11.5.4.2
Estimand for Continuous Secondary Endpoints ................................86
11.5.4.3
Estimand for Binary Secondary Endpoints........................................87
11.6
Analysis of Safety.................................................................................................87
11.7
Pharmacokinetic Analysis...................................................................................88
11.8
Interim Analysis...................................................................................................88
11.9
Subgroup Analysis ...............................................................................................89
11.10 Event Adjudication Committee and Data Monitoring Committee.................90
12
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................91
12.1
Study Monitoring.................................................................................................91
12.2
Audits and Inspections ........................................................................................91
13
ETHICS AND RESPONSIBILITIES ..........................................................................92
13.1
Good Clinical Practice.........................................................................................92
13.2
Regulatory and Ethical Considerations.............................................................92
13.3
Institutional Review Board/Independent Ethics Committee...........................92
13.4
Informed Consent ................................................................................................93
14
DATA HANDLING AND RECORD KEEPING........................................................94
14.1
Source Documentation.........................................................................................94
14.2
Data Quality Assurance.......................................................................................94
15
STUDY REPORT AND PUBLICATIONS .................................................................95
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SOTATERCEPT (ACE-011)
STUDY A011-14, AMENDMENT 03, VERSION 4.0 (MK-7962-006-07)
23 April 2024
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16
CONFIDENTIALITY ...................................................................................................96
16.1
Data Protection.....................................................................................................96
17
REFERENCES...............................................................................................................97
18
APPENDICES..............................................................................................................106
Appendix 1
Abbreviations and Specialist Terms.............................................106
Appendix 2
REVEAL Lite 2.0 Updated PAH Risk Score Calculator ...........109
Appendix 3
Contraceptive Guidance and Collection of Pregnancy 
Information.........................................................................................................110
Appendix 4
Six-Minute Walk Test....................................................................114
Appendix 5
Protocol Nomenclature Mapping .................................................117
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SOTATERCEPT (ACE-011)
STUDY A011-14, AMENDMENT 03, VERSION 4.0 (MK-7962-006-07)
23 April 2024
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Page 12 of 117
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LIST OF TABLES
Table 1
Emergency Contact Information....................................................................3
Table 2
Schedule of Events: Screening and Double-Blind Placebo-Controlled 
Treatment Periods..................................................................................................24
Table 3
Schedule of Events: Follow-up Period ........................................................27
Table 4
Study Interventions......................................................................................49
Table 5
NYHA/WHO FC Assessment for PAH.......................................................65
Table 6
Monitoring of Adverse Events of Special Interest.......................................82
Table 7
Efficacy and Futility Boundaries and Properties for the Primary 
Endpoint.................................................................................................................89
Table 8
Highly Effective Contraceptive Methods ..................................................112
LIST OF FIGURES
Figure 1
Schematic of ZENITH.................................................................................22
Figure 2
Guidelines for Target Dose Escalation (0.7 mg/kg) ....................................52
Figure 3
Guidelines for Dose Modification Due to Hemoglobin Increase From 
Visit 3 Onward.......................................................................................................53
Figure 4
Guidelines for Dose Modification Due to Low Platelet Count From 
Visit 3 Onward.......................................................................................................54
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CLINICAL STUDY PROTOCOL
SOTATERCEPT (ACE-011)
STUDY A011-14, AMENDMENT 03, VERSION 4.0 (MK-7962-006-07)
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1
PROTOCOL SYNOPSIS
Protocol Title 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study 
to Evaluate Sotatercept When Added to Maximum Tolerated 
Background Therapy in Participants With Pulmonary Arterial 
Hypertension (PAH) World Health Organization (WHO) 
Functional Class (FC) III or FC IV at High Risk of Mortality
Short Title
A Phase 3 Study of Sotatercept in Participants With PAH WHO FC
III or FC IV at High Risk of Mortality
Protocol Number
A011-14/MK-7962-006-06 (ZENITH)
Study Type
Phase 3, randomized, double-blind, placebo-controlled, 
multicenter, parallel-group study.
Rationale 
PAH is a progressive, fatal disease that causes marked limitations 
in physical activity and quality of life, even when treated with 
approved therapies. This Phase 3 study is supported by data from 
the Phase 2 Study A011-09 (PULSAR; NCT03496207), in which 
participants taking any approved single or combination therapy for 
PAH were randomized to receive additional sotatercept or placebo 
for 24 weeks. The PULSAR study demonstrated a statistically 
significant improvement in its primary endpoint, pulmonary 
vascular resistance (PVR). Additionally, improvements were 
observed in 6-minute walk distance (6MWD), N-terminal 
prohormone B-type natriuretic peptide (NT-proBNP), and other 
endpoints.
Study Objective
The objective of this study is to evaluate the effects of sotatercept 
treatment (plus maximum tolerated background PAH therapy) 
versus placebo (plus maximum tolerated background PAH therapy) 
on time to first event of all-cause death, lung transplantation, or 
PAH worsening-related hospitalization of ≥24 hours, in 
participants with WHO FC III or FC IV PAH at high risk of 
mortality.
Study Population
Participants with symptomatic PAH (WHO FC III or FC IV at high 
risk of mortality) who present with idiopathic or heritable PAH, 
PAH associated with connective tissue diseases (CTD), drug- or 
toxin-induced, post-shunt correction PAH, or PAH presenting at 
least 1 year following the correction of congenital heart defect
(CHD). Participants must have a Registry to Evaluate Early and 
Long-Term PAH Disease Management (REVEAL) Lite 2.0 risk 
score of ≥9 and be on maximum tolerated combination background 
PAH therapy.
Number of 
Participants
Up to 166 participants will be randomly assigned in a 1:1 ratio to 
the 2 study treatment groups (83 participants per arm).
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Study Design
The study is divided into a Screening Period (up to 4 weeks) 
followed by a Double-blind Placebo-controlled (DBPC) Treatment 
Period. Participants who experience an event of PAH 
worsening-related hospitalization of ≥24 hours will complete an 
End of Treatment (EOT) Visit and may be eligible to enroll in the
open-label, long-term follow-up (LTFU) study, A011-12 
(SOTERIA). At the end of the DBPC Treatment Period, which will 
occur when the required number of participants have experienced a 
primary endpoint event (time to first event of all-cause death, lung 
transplantation, or PAH worsening-related hospitalization of 
≥24 hours), all participants who do not experience a primary 
endpoint event will complete an EOT Visit and may be eligible to 
enroll into the open-label, LTFU Study A011-12 SOTERIA. If the 
participant does not choose to enroll into the SOTERIA study, they 
will complete the Follow-up Period of the study that will include 
both the EOT and the End of Study (EOS) Visits (Figure 1).
Each study-eligible participant will be randomized in a 1:1 ratio to 
1 of the 2 treatment arms prior to starting the DBPC Treatment 
Period.
•
Arm 1: Placebo administered subcutaneously (SC) every 
21 days plus background PAH therapy
•
Arm 2: Sotatercept at a starting dose of 0.3 mg/kg, with a 
target dose of 0.7 mg/kg, administered SC every 21 days 
plus background PAH therapy
Each participant will remain in the DBPC Treatment Period until 1
of the following occurs, whichever comes first: 1) they experience 
the first event of all-cause death, lung transplantation, or PAH 
worsening-related hospitalization of ≥24 hours; 2) the time when 
the required number of primary events are accrued for the final 
analysis; 3) the study is stopped early at the interim analysis (IA)
for either efficacy or futility. The planned IA will occur when 
approximately 59 participants have experienced a primary endpoint 
event (roughly 50% of the required number of events). Study 
participants who have not experienced an event will remain in the 
DBPC Treatment Period until the required number of participants 
have experienced a first event of all-cause death, lung 
transplantation, or PAH worsening-related hospitalization.
Upon experiencing an event of PAH worsening-related 
hospitalization of ≥24 hours or at the time of study unblinding, 
participants will complete an EOT Visit and may enroll into the 
LTFU study, A011-12 (SOTERIA). If the SOTERIA study is not 
yet activated at study site, participants will remain in the ZENITH 
DBPC Treatment Period until SOTERIA has been activated. 
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Participants who experience an event of lung transplantation or 
who elect not to continue into the LTFU study, A011-12 
(SOTERIA), will complete the Follow-up Period including both 
EOT and the EOS Visits. 
Participants who discontinue from the DBPC Treatment Period 
early without experiencing a primary endpoint event, or before the 
trial is unblinded, should complete the EOT Visit at the time of 
discontinuation as specified in the SoE (Section 2) and EOS Visit 
(described in Section 9.2.3.2), provided that consent is not 
withdrawn. Following the EOT and EOS, or if the participant 
refuses to attend additional study visits, they will receive quarterly 
telephone contacts for vital status until the study is unblinded. 
These participants will not be eligible to enroll into the LTFU study 
A011-12 (SOTERIA).
Estimated 
Duration of the 
Study
Maximum study duration for a given participant in this study will 
be up to approximately 43 months as follows: 
•
Screening Period (up to 4 weeks)
•
DBPC Treatment Period (up to approximately 
40 months)
•
Follow-up Period (up to 8 weeks)
Inclusion Criteria
Eligible participants must meet all of the following inclusion 
criteria to be enrolled in the study:
1. Age 18 to 75 years, inclusive
2. Documented diagnostic right heart catheterization prior to 
screening confirming the diagnosis of WHO PAH Group 1 in 
any of the following subtypes:
•
Idiopathic PAH 
•
Heritable PAH
•
Drug/toxin-induced PAH
•
PAH associated with CTD
•
PAH associated with simple, congenital 
systemic-to-pulmonary shunts at least 1 year following 
repair
3. Symptomatic PAH classified as WHO FC III or IV
4. REVEAL Lite 2.0 risk score of ≥9
5. Right heart catheterization performed during screening (or 
within 2 weeks prior to screening, if done at the clinical study 
site) documenting a minimum PVR of ≥5 Wood units and a 
pulmonary capillary wedge pressure (PCWP) or left ventricular 
end-diastolic pressure (LVEDP) of ≤ 15 mmHg
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6. Clinically stable and on stable doses of maximum tolerated (per 
investigator’s judgment) double or triple background PAH 
therapies for at least 30 days prior to screening
7. Females of childbearing potential must: 
•
Have 2 negative urine or serum pregnancy tests as 
verified by the investigator prior to starting study 
therapy; must agree to ongoing urine or serum 
pregnancy testing during the course of the study and 
until 8 weeks after the last dose of the study drug
•
If sexually active with a male partner
-
Used highly effective contraception without 
interruption; for at least 28 days prior to starting the 
investigational product AND
-
Agree to use the same highly effective contraception 
in combination with a barrier method during the 
study (including dose interruptions), and for 
16 weeks (112 days) after discontinuation of study 
treatment
•
Refrain from breastfeeding a child or donating blood, 
eggs, or ovum for the duration of the study and for at 
least 16 weeks (112 days) after the last dose of study 
treatment
8. Male participants must: 
•
Agree to use a condom, defined as a male latex condom 
or nonlatex condom NOT made out of natural (animal) 
membrane (e.g., polyurethane), during sexual contact 
with a pregnant female or a female of childbearing 
potential while participating in the study, during dose 
interruptions, and for at least 16 weeks (112 days) 
following investigational product discontinuation, even 
if he has undergone a successful vasectomy
•
Refrain from donating blood or sperm for the duration 
of the study and for 16 weeks (112 days) after the last 
dose of study treatment
9. Ability to adhere to study visit schedule and understand and 
comply with all protocol requirements
10. Ability to understand and provide written informed consent
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Exclusion Criteria
1. Diagnosis of PH WHO Groups 2, 3, 4, or 5
2. Diagnosis of the following PAH Group 1 subtypes: human 
immunodeficiency virus-associated PAH and PAH associated 
with portal hypertension
3. Diagnosis of pulmonary veno-occlusive diseases or pulmonary 
capillary hemangiomatosis or overt signs of capillary and/or 
venous involvement
4. Hemoglobin at screening above gender-specific upper limit of 
normal (ULN), per local laboratory test
5. Baseline platelet count < 50,000/mm3 (< 50.0 × 109/L) at 
screening 
6. Baseline systolic blood pressure < 85 mmHg at Screening
7. Pregnant or breastfeeding women
8. Serum alanine aminotransferase, aspartate aminotransferase, or 
total bilirubin levels > 3.0 × ULN
9. Currently enrolled in or have completed any other 
investigational product study within 30 days for small-molecule 
drugs or within 5 half-lives for biologics prior to the date of 
signed informed consent
10. Prior exposure to sotatercept or known allergic reaction to 
sotatercept, its excipients, or luspatercept 
11. History of pneumonectomy
12. This criterion has been removed
13. Untreated more than mild obstructive sleep apnea 
14. History of known pericardial constriction
15. History of restrictive or congestive cardiomyopathy
16. Electrocardiogram (ECG) with Fridericia’s corrected QT 
interval (QTcF) > 500 ms during the Screening Period
17. Personal or family history of long QT syndrome or sudden 
cardiac death
18. Left ventricular ejection fraction < 45% on historical 
echocardiogram within 1 year prior to the Screening Visit 
19. 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 the Screening 
Visit
20. Cerebrovascular accident within 3 months prior to the 
Screening Visit
21. Significant (≥ 2+ regurgitation) mitral regurgitation or aortic 
regurgitation valvular disease
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22. Currently on dialysis or anticipated need for dialysis within the 
next 12 months
Efficacy Endpoints
Primary Efficacy Endpoint
The primary efficacy endpoint is the time to first event of all-cause 
death, lung transplantation, or PAH worsening-related 
hospitalization of ≥24 hours.
All events will be adjudicated by a blinded, independent committee 
of clinical experts.
Secondary Efficacy Endpoints
The secondary endpoints are ranked as follows:
1. Overall survival
2. Transplant-free survival
3. Proportion of participants who experienced a mortality
event at EOS
4. Change from baseline in REVEAL Lite 2.0 risk score at 
Week 24
5. Proportion of participants achieving a low or intermediate 
(≤7) REVEAL Lite 2.0 risk score at Week 24
6. Change from baseline in NT-proBNP levels at Week 24
7. Change from baseline in mean pulmonary artery pressure 
(mPAP) at Week 24 
8. Change from baseline in PVR at Week 24
9. Proportion of participants who improve in WHO FC at the 
end of the DBPC Treatment Period
10. Change from baseline in 6MWD at Week 24
11. Change from baseline in cardiac output (CO) at Week 24
12. Change from baseline in EuroQoL-5 dimensions scale 
5 levels (EQ-5D-5L) index score at Week 24
Exploratory Endpoints
•
Number of PAH-related hospital days during the study
•
Change from baseline in right ventricular (RV)-
pulmonary artery (PA) coupling at Week 24
•
Change from baseline in biomarkers; including, but not 
limited to, serum biomarkers such as C-reactive protein 
(CRP) and Activin A at Week 24
•
Proportion of participants achieving a low or 
intermediate-low COMPERA 2.0 4-strata risk score 
(Section 9.3.6) at Week 24 
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Safety Endpoints
Safety will be evaluated by collecting the following information:
•
Adverse events (AEs)
•
Anti-drug antibodies (ADAs)
•
Laboratory assessments (hematology, serum chemistry, 
and urinalysis)
•
Vital signs
•
Physical examination
•
12-lead ECG
Sample Size 
Determination and 
Power Calculations
The sample size determination is based on the primary efficacy 
endpoint of time to first event of all-cause death, lung 
transplantation, or PAH worsening-related hospitalization 
of ≥24 hours using EAST® version 6.4. In STELLAR, the hazard 
ratio for time to death or non-fatal clinical worsening in the 
sotatercept group compared with the placebo group was 0.16 (95% 
CI: 0.08 to 0.35) [Hoeper, M. M., et al 2023]. Given the differences 
in the populations and definitions of endpoints between STELLAR 
and this study, the hazard ratio is assumed to be 0.55 in this study 
[Hoeper, M. M., et al 2023]. Given a 1:1 randomization, a 1-sided 
0.025 Type 1 error rate, 90% power, and with a planned IA at 
approximately 50% of the required number of events with the 
option to stop the study for futility, approximately 118 events will 
be required based on the log-rank test.
Given that approximately 166 participants are planned to be 
enrolled in this study, the accrual period is approximately 
26 months, assuming an accrual rate of approximately 
6.5 participants per month. In addition, assuming a dropout rate of 
0.04% per month (0.5% per year), and the probability of observing 
an event for placebo is 0.45 for the first year, 0.60 for the second 
year, and 0.90 for the third year and later, the projected time of the 
IA will occur around 26 months. If the study continues after the IA, 
the final analysis will happen around 40 months. Median 
participant time on study must be at least 6 months in order for 
analyses following the occurrence of the required number of 
events.
Stratified 
Randomization 
Factors
Randomization will be stratified by: 
•
REVEAL Lite 2.0 risk score (9 to 10 or ≥11) at 
Screening
•
PAH subtype (CTD-associated or not CTD-associated) 
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Statistical Methods
Efficacy Analyses: All efficacy analyses will be based on the Full 
Analysis Set (FAS), which is defined as all randomized 
participants. 
Safety Analyses: All safety analyses will be based on the Safety 
Set, which is defined as all participants who receive at least 1 dose 
of study treatment. All participants will be analyzed according to 
the treatment they are administered.
Analysis of Study Endpoints:
Efficacy Endpoints
Interim Analysis
An IA of the primary efficacy endpoint is planned to occur when 
approximately 59 participants have experienced a primary endpoint 
event (roughly 50% of the required number of events) have 
occurred. A stratified log-rank test with randomization factors as
strata will be used for the analysis of the primary efficacy endpoint. 
The point estimate of the hazard ratio with 95% confidence interval 
(CI) will be estimated by a Cox regression model stratified by the 
randomization factors.
Primary Endpoint:
Time to first event of all-cause death, lung transplantation, or PAH 
worsening-related hospitalization of ≥ 24 hours, will be analyzed 
using the stratified log-rank test with the randomization factors as 
strata. The point estimate of the hazard ratio with 95% CI will be 
estimated by a Cox regression model stratified by the 
randomization factors.
Secondary Endpoints:
The aligned rank stratified Wilcoxon test will be used for 
continuous variables; the Cochran-Mantel-Haenszel test will be 
used for dichotomous variables, and the log-rank test and Cox 
regression methods will be used for time-to-event variables. A 
gatekeeping method will be used to control the Type 1 error rate in 
secondary endpoints by testing in the order of the secondary 
endpoints listed below, after successful testing for the primary 
endpoint. Secondary endpoint testing will be performed using a 1-
sided alpha = 0.025 level proceeding successively in the order of 
the secondary endpoints listed above after each of the preceding 
endpoints is tested to be statistically significant: 
•
Overall survival
•
Transplant-free survival
•
The change in REVEAL Lite 2.0 risk score at 24 weeks 
from baseline
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•
The proportion of participants achieving a low or 
intermediate (≤7) REVEAL Lite 2.0 risk score at 24 weeks
•
The proportion of participants who experience a mortality 
event at EOS
•
The change in NT-proBNP levels at 24 weeks from baseline
•
The change in mPAP at 24 weeks from baseline
•
The change in PVR at 24 weeks from baseline
•
The proportion of participants who improve in WHO FC at 
the end of the DBPC Treatment Period
•
The change in 6MWD at 24 weeks from baseline
•
The change in CO at 24 weeks from baseline
•
The change in the EQ-5D-5L index score at 24 weeks from 
baseline
Exploratory Endpoints:
•
The number of PAH-related hospital days during the study 
will be analyzed using a Poisson regression model.
•
The change in echocardiogram parameter data describing 
RV-PA coupling (tricuspid annular plane systolic 
excursion/ pulmonary arterial systolic pressure) at 24 weeks 
from baseline will be summarized using descriptive 
statistics.
•
The change in biomarker data at 24 weeks from baseline 
will be summarized using descriptive statistics.
•
The proportion of participants achieving a low or 
intermediate-low COMPERA 2.0 4-strata risk score 
(Section 9.3.6) at 24 weeks will be summarized using 
descriptive statistics.
No adjustments for multiplicity will be performed for statistical 
analyses of exploratory endpoints.
Safety Endpoints
Safety data will be summarized descriptively by treatment arm.
Safety and 
Pharmacovigilance
An unblinded, external, independent Data Monitoring Committee 
(DMC) will monitor participant safety throughout the course of the 
study.
Internal data review of safety-related data will occur in a blinded 
manner at a preplanned frequency throughout the study duration.
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1.1
Study Schematic
Figure 1
Schematic of ZENITH
EOT = end of treatment; EOS = end of study; LTFU = long-term follow-up; PAH = pulmonary arterial hypertension.
⁎Assessments will be collected at the 6-month visit (Visit 9) for secondary endpoint analysis.
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2
SCHEDULE OF EVENTS
The schedules of events (SoEs), which provide an overview of the study periods and 
procedures, are presented in Table 2 for the Screening and Double-blind Placebo-controlled 
(DBPC) Treatment Periods and Table 3 for the Follow-up Period.
Specific information on visits and assessments during the Screening, DBPC Treatment, and 
Follow-up Periods are discussed in Section 9.
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Table 2
Schedule of Events: Screening and Double-Blind Placebo-Controlled Treatment Periods
Study Procedure/
Assessmenta,b
Screening 
Period
(up to 4 
weeks 
prior to 
Visit 1)
Visit 1
(Study 
Day 1)
Visit 2
(21±3 
days)
Visits 3 
and 4 
(21±3 
days)
Visit 5
(21±3 
days)
Visits 6-8
(21±3 
days)
Visit 9
(6 month 
Visit)
(21±3 
days)
Visits 
10-12
(21±3 
days)
Visit 13
(Quarterly 
Site Visit)
(21±3 days)
Visits 14-
onward 
until the 
end of the 
DBPC 
Treatment 
Period
(21±3 
days)
Informed consent
X
Repeat 
Visits 
10-13 until 
the end of 
the DBPC 
Treatment 
Period
Inclusion/exclusion 
criteria
X
Randomization
X
Medical historyc
X
Physical examinationd
X
X
X
X
X
ECG (12-lead)e
X
X
Vital signs including 
weightf
X
X
X
X
X
X
X
Pregnancy test (urine or 
serum)g
X
X
X
X
X
X
X
X
X
Hematology (CBC)h
X
X
X
X
X
X
Serum chemistryi
X
X
X
X
X
Urinalysis
X
X
X
X
6MWTj
X
X
X
X
X
X
Borg Dyspnea Scale 
(pre- and post-6MWT)
X
X
X
X
X
X
WHO FC assessment
X
X
X
X
X
X
X
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Study Procedure/
Assessmenta,b
Screening 
Period
(up to 4 
weeks 
prior to 
Visit 1)
Visit 1
(Study 
Day 1)
Visit 2
(21±3 
days)
Visits 3 
and 4 
(21±3 
days)
Visit 5
(21±3 
days)
Visits 6-8
(21±3 
days)
Visit 9
(6 month 
Visit)
(21±3 
days)
Visits 
10-12
(21±3 
days)
Visit 13
(Quarterly 
Site Visit)
(21±3 days)
Visits 14-
onward 
until the 
end of the 
DBPC 
Treatment 
Period
(21±3 
days)
EQ-5D-5L assessment
X
X
X
X
X
Repeat 
Visits 10-
13 until 
the end of 
the DBPC 
Treatment 
Period
NT-proBNP and CRP 
sample collection
X
X
X
X
X
X
X
REVEAL Lite 2.0 risk 
score assessmentk
X
ADA sample collection
X
X
X
X
X
X
X
PK and Activin A 
sample collectionl
X
X
X
X
X
X
Right heart 
catheterizationm
X
X
Echocardiogramn
X
X
Study drug 
administrationa, b, o
X
X
X
X
X
X
X
X
AE/SAE reviewo
X
X
X
X
X
X
X
X
X
Concomitant 
medication reviewo
X
X
X
X
X
X
X
X
X
6MWT = 6-minute walk test; ADA = anti-drug antibody; AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood 
urea nitrogen; CBC = complete blood cell (count); CRP = C-reactive protein; DBPC = double-blind placebo-controlled; ECG = electrocardiogram; 
EDC = electronic data capture; EOT = end of treatment; EQ-5D-5L = EuroQoL-5 dimensions scale 5 levels; FC = functional class; HCO3 = bicarbonate; 
Hct = hematocrit; Hgb = hemoglobin; HHC= home health care; NT-proBNP = N-terminal prohormone B-type natriuretic peptide; PAH = pulmonary arterial 
hypertension; PK = pharmacokinetic(s); RBC = red blood cell; REVEAL = Registry to Evaluate Early and Long-Term PAH Disease Management; 
SAE = serious adverse event; WBC = white blood cell; WHO = World Health Organization.
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a
All study procedures must be performed prior to study drug administration. Dose must be calculated based on the participant’s weight on the day of 
dosing. Dose modification guidelines should be reviewed and implemented prior to dosing (Section 8.3).
b
All participants will receive study drug every 21 days (±3 days), either at the study site (Visits 1 to 5, Visit 9, and quarterly site visits for all participants) 
or at home (Visit 6 onwards, except for Visit 9 and quarterly site visits, for participants who consent and are approved for optional home health administration of 
study drug).
c
Medical history review includes confirmation of disease history associated with PAH.
d
Perform full physical examination at the Screening Visit only. For all other visits, perform targeted cardiopulmonary and skin examinations.
e
ECG will be performed at Screening and at Visits 9 and EOT. At visits where both ECGs and 6MWT assessments are done, ECGs should be performed 
prior to 6MWT.
f
For dosing visits at which weight is not collected, the most recently collected weight should be utilized for dose calculation.
g
Two pregnancy tests are required for female participants of childbearing potential at the Screening Visit. A single pregnancy test is required prior to 
study drug administration at all other visits.
h
Complete blood count includes RBCs, absolute WBCs, Hgb, Hct, and platelet count. Results are evaluated at Screening Visit and prior to study drug 
administration (or up to 3 days prior if available) for Visits 2 to 5, 9, and quarterly site visits. For HHC visits and non-quarterly site visits starting at Visit 6, 
hematology results are not required to be evaluated prior to study drug administration. However, if there is a dose modification based on Hgb levels and platelet 
count (Sections 8.3.2 and 8.3.3) during non-quarterly visits, a hematology assessment should be performed prior to the next dose administration (or up to 3 days 
prior if available) , and onsite visits are required (Section 6.5). Hematology results collected per SoE and Section 8.3 should be recorded in the EDC.
i
Creatinine, BUN, total bilirubin, direct bilirubin, AST, ALT, alkaline phosphatase, sodium, potassium, chloride, calcium, phosphorous, glucose, 
magnesium, follicle-stimulating hormone, albumin, and HCO3 will be measured.
j
The 6MWT should be performed twice during the Screening Period, at least 4 hours, but no longer than 1 week, apart. All 6MWTs performed from 
Visit 1 onward can be performed at the study visit day or within 10 days prior to study drug administration.
k
Sites will receive central laboratory NT-proBNP results from the screening sample only; therefore, sites will only be required to calculate the REVEAL 
Lite 2.0 risk score during the Screening Period. Sites will use this score to ensure that entry criterion 4: REVEAL Lite 2.0 risk score ≥9, is met by the participant 
at enrollment. Acceleron will calculate the REVEAL Lite 2.0 risk score for all other study visits (Visits 1 to 5, Visit 9, quarterly site visits, EOT Visit, and EOS 
Visits).
l
Samples for PK and Activin A testing will be collected on Day 1, predose and at 1 to 2, 2 to 4, and 4 to 8 hours postdose. On other visits, samples for 
PK and Activin A testing will be collected prior to study drug administration.
m
Right heart catheterization should be performed last when possible if other assessments are occurring on the same day. All right heart catheterizations 
performed after Screening may be performed on the day of study visit or within 1 week prior to study drug administration. 
n
Echocardiograms will be performed at Screening and at Visits 9, 25, and EOT only. All echocardiograms performed after Screening can be performed 
on the day of the study visit or within 1 week prior to study drug administration. If an echocardiogram has been performed in the past 3 months, it may be 
exempted at the EOT Visit. 
o
Documentation of concomitant medications as well as occurrence of any AEs, medication errors, accidental exposure of others, or product complaints 
will occur at these visits. See Section 6.5 for details regarding HHC visits.
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Table 3
Schedule of Events: Follow-up Period
Follow-up Perioda
(Study Completion or Early Discontinuation)
Study Procedure/Assessment
EOT Visit
(21 ± 7 days from last dose)
EOS Visit
(5 weeks ± 7 days after EOT Visit)
(early discontinuation, lung 
transplantation, or not in LTFU 
only)
Physical examinationb
X
X
ECG (12-lead)
X
Vital signs including weight
X
X
Pregnancy test (urine or serum)
X
X
Hematology (CBC)c
X
X
Serum chemistryd
X
X
Urinalysis
X
X
6MWT
X
X
Borg Dyspnea Scale (pre- and post-
6MWT)
X
X
WHO FC assessment
X
X
EQ-5D-5L assessment
X
X
NT-proBNP and CRP sample collection
X
X
ADA sample collectione
X
X
PK and Activin A sample collection
X
Echocardiogramf
X
AE/SAE review
X
X
Concomitant medication review
X
X
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6MWT = 6-minute walk test; ADA = anti-drug antibody; AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
CBC = complete blood cell (count); CRP = C-reactive protein; DBPC = double-blind placebo-controlled; ECG = electrocardiogram; EOS = end of study; 
EOT = end of treatment; EQ5D-5L = EuroQoL-5 dimensions scale 5 levels; FC = functional class; FSH = follicle-stimulating hormone; HCO3 = bicarbonate; 
Hct = hematocrit; Hgb = hemoglobin; LTFU = long-term follow-up; NT-proBNP = N-terminal prohormone B-type natriuretic peptide; PAH = pulmonary arterial 
hypertension; PK = pharmacokinetic(s); RBC = red blood cell; SAE = serious adverse event; WBC = white blood cell; WHO = World Health Organization.
a
Participants who experience an event of lung transplantation, who discontinue early, or who elect not to continue into the LTFU study, A011-12 
(SOTERIA), will complete both the EOT and the EOS Visits, provided that consent is not withdrawn. Refer to Section 9.4.1for early discontinuation criteria. 
Participants who have completed all DBPC Treatment Period visits, or who have experienced an event of PAH worsening-related hospitalization of ≥24 hours, 
and will continue into the LTFU Study, A011-12 (SOTERIA) will be asked to complete the EOT Visit only. The EOT Visit is recommended to occur 21 days 
(±7 days) after the last study drug administration in the DBPC Treatment Period. The EOS Visit is recommended to occur 5 weeks (± 7 days) after the EOT 
Visit.
b
Perform full physical examination at the Screening Visit only. For all other visits, perform targeted cardiopulmonary and skin examinations.
c
CBC includes RBCs, absolute WBCs, Hgb, Hct, and platelet count.
d
BUN, creatinine, total bilirubin, direct bilirubin, AST, ALT, alkaline phosphatase, sodium, potassium, chloride, calcium, phosphorous, glucose, 
magnesium, FSH, albumin, and HCO3 will be measured. 
e
Participants may be asked to return for additional ADA testing after their last visit if there is any indication of potential immunogenicity-related safety 
concern.
f
Echocardiograms will be performed at Screening Visit, Visits 9, 25, and the EOT Visit. If an echocardiogram has been performed in the past 3 months, 
it may be exempted at the EOT Visit. 
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3
INTRODUCTION: BACKGROUND AND STUDY RATIONALE
3.1
Background
Pulmonary arterial hypertension (PAH) applies to a group of diseases causing a progressive 
increase in pulmonary vascular resistance (PVR), resulting in right ventricular (RV) 
dysfunction, and ultimately failure as well as premature death [Rubin, L. J. 1997] 
[Simonneau, G., et al 2004]. The pathophysiology of PAH involves pulmonary endothelial 
dysfunction, resulting in impaired production of vasodilators, such as nitric oxide and 
prostacyclin, and overexpression of vasoconstrictors, such as endothelin-1. The 
pathophysiology of PAH also entails the abnormal proliferation of pulmonary vascular 
smooth muscle cells (VSMCs) in pulmonary arterioles, which results in progressive 
pulmonary vascular remodeling, increased PVR, and, eventually, right-sided heart failure 
[Schermuly, R. T., et al 2011]. In the absence of treatment, the majority of patients succumb 
to heart failure within a few years of diagnosis [Vonk-Noordegraaf, A., et al 2013]. There is 
currently no pharmacological cure for PAH. Current background PAH therapy involves 
increasing blood flow through the pulmonary vasculature via pharmacologic manipulation of 
various pathways to relieve symptoms and slow clinical worsening of the disease. In addition 
to general supportive care agents (e.g., anticoagulants, diuretics, and digoxin), current 
disease-specific treatments for PAH include vasodilator-type agents, such as endothelin-
receptor antagonists, phosphodiesterase inhibitors, and prostanoids.
Genetic mutations in the bone-morphogenetic protein type II receptor (BMPR2) are 
associated with the majority of cases of the familial form of PAH [Morrell, N. W. 2006] 
[Machado RD, Aldred MA, James V,  Harrison RE, Patel B, Schwalbeet EC 2006] and 
approximately 25% of idiopathic PAH cases. Specifically, impairment of the BMPR2-
associated signal pathway appears to lead to uncontrolled proliferation of pulmonary 
VSMCs, the principal cause of PAH. These data strongly suggest a key role of transforming 
growth factor-β family members in the pathogenesis of PAH. Sotatercept acts to block 
activin ligands and growth and differentiation factors (GDFs), may attenuate bone-
morphogenetic proteins (BMPs), and improve pulmonary vascular remodeling by restoring 
balance to Smad signaling [Yung, L., et al 2017].
Sotatercept (ACE-011) is a novel first-in-class fusion protein comprising the extracellular 
domain of human activin receptor type IIA linked to the Fc domain of human 
immunoglobulin G1 [Ruckle, J., et al 2009]. It has previously been tested in chemotherapy-
induced anemia [Raftopoulos, H., et al 2016], multiple myeloma [Abdulkadyrov, K. M., et al 
2014], bone loss [Ruckle, J., et al 2009], myelodysplastic syndromes [Komrokji, R., et al 
2018], β-thalassemia [Cappellini MD, Porter J, Origa R, Forni GL, Voskaridou E, Galactéros 
F 2019], end-stage kidney disease [Coyne, D. W., et al 2019], as an erythropoietic agent 
[Sherman, M. L., et al 2013], in pulmonary hypertension (PH), and has been shown to be 
well tolerated and consistent with its known and potential risks. 
Sotatercept binds select ligands in the transforming growth factor-β superfamily, such as 
activins A and B and GDF-8 and -11, to suppress their signaling and restore balance between 
the opposing growth-promoting activin/GDF and growth-inhibiting BMP pathways [Yung, 
L., et al 2017] [Yung, L., et al 2018]. Preclinical data suggest that sotatercept (murine analog, 
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RAP-011) may positively affect vascular remodeling in animal models of PAH. RAP-011 
was evaluated in both preventative and therapeutic disease models. Affected animals treated 
with RAP-011 showed substantial improvements in pulmonary vascular and cardiac 
hemodynamic measurements that were either comparable or superior to agents approved for 
treatment of PAH. Importantly, a substantial reduction in the proliferation of pulmonary 
VSMCs was observed in RAP-011 treated animals as assessed by histologic evaluation in 
both preventative and therapeutic disease models. Taken together, these data indicate that 
RAP-011 can attenuate the development and progression of PAH, even when administered to 
animals with established disease. These preclinical data suggest that sotatercept is a 
mechanism-targeted nonvasodilator therapy that may positively affect vascular remodeling 
associated with PAH [Yung, L., et al 2017]. Detailed descriptions of the chemistry, 
pharmacology, efficacy, and safety of sotatercept are provided in the Investigator’s Brochure 
(IB).
3.2
Risks and/or Benefits to Participants
The evidence for potential benefits of sotatercept is supported by data observed in preclinical 
studies in rodent models of PAH, clinical results from the Phase 2 Study A011-09 (PULSAR; 
NCT03496207) and clinical results from the Phase 3 pivotal study (STELLAR
NCT04576988).
Preclinical studies in rodent models of PAH have shown reduced muscularization and 
thickness of pulmonary vessel walls, reduced right-sided heart pressures, and reduced 
right-to-left ventricle weight ratios. These improvements observed in rodent models are 
thought to be associated with reductions in PVR as well as increases in functional capacity 
and quality of life in humans, which have been assessed in the PULSAR study, in which 
participants taking any approved single or combination therapy for PAH were randomized to 
receive additional sotatercept or placebo for 24 weeks.
Results from the PULSAR study demonstrated a statistically significant improvement in 
PVR at 24 weeks when compared to baseline (the study’s primary endpoint) [Badesch, D. B., 
et al 2020]. PVR was reduced in both sotatercept dose groups versus placebo (least squares 
mean difference [standard error [Ghofrani, H. A., et al 2013]]) (sotatercept 0.3 mg/kg: 
−145.8 [48.6] dyn·s/cm5, p = 0.0027; sotatercept 0.7 mg/kg: −239.5 [45.8] dyn·s/cm5, 
p < 0.0001).
Six-minute walk distance (6MWD) was the key secondary endpoint at 24 weeks. The least 
squares mean increase from baseline in 6MWD was 58.1 meters (m) for sotatercept 0.3 
mg/kg, 50.1 m for sotatercept 0.7 mg/kg, and 28.7 m for placebo. Combined, sotatercept 
produced a least squares mean difference versus placebo of 24.9 m (95% confidence interval 
[CI]: 3.1 to 46.6). Sotatercept also improved N-terminal prohormone B-type natriuretic 
peptide (NT-proBNP) levels. In addition, a greater proportion of participants in the 
sotatercept treatment groups improved in the World Health Organization (WHO) functional 
class (FC) compared with placebo.
Results from Study A011-11 (STELLAR), the pivotal Phase 3 study of sotatercept in PAH, 
further support those from PULSAR. STELLAR was a randomized, double-blind, 
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placebo-controlled study in participants with PAH (WHO Group 1 pulmonary hypertension 
[PH]) on stable background PAH therapy. STELLAR demonstrated a statistically significant 
and clinically meaningful improvement in 6MWD from baseline at 24 weeks. Eight of 
9 secondary efficacy outcome measures achieved statistical significance, including the 
outcome measure of proportion of participants achieving multicomponent improvement 
(defined as improvement in 6MWD, NT-proBNP level, and either improvement in WHO FC 
or maintenance of WHO FC II), and the outcome measure of time to death or the first 
occurrence of a clinical worsening event. For time to death or non-fatal clinical worsening 
event, and after a median follow-up of 32.7 weeks across the treatment groups, the hazard 
ratio in the sotatercept group as compared with the placebo group was 0.16 (95% CI: 0.08 to 
0.35). 
The current important risks for sotatercept in participants with PAH include erythrocytosis, 
severe thrombocytopenia, and serious bleeding. Erythrocytosis and thrombocytopenia were 
mostly nonserious, manageable, and tolerable. Participants with serious bleeding events were 
more likely to be on prostacyclin background therapy and/or anticoagulants, or to have had 
low platelet counts. Potential risks of embryo-fetal toxicity and impaired fertility are based 
on nonclinical observations. Details about contraception and collection of pregnancy 
information can be found in Appendix 3. Details about the known and expected benefits and 
risks of sotatercept may be found in the current IB.
3.3
Study Rationale
Study A011-14 is a Phase 3, randomized, double-blind, placebo-controlled, multicenter, 
parallel-group study to evaluate sotatercept versus placebo in participants with PAH WHO 
FC III or FC IV who are at high risk of mortality.
This Phase 3 study is supported by data from the PULSAR study as described in Section 3.2.
In the PULSAR study, more than 90% of participants at baseline were receiving double or 
triple background PAH therapy, targeting multiple existing therapeutic pathways. Sotatercept 
was able to demonstrate hemodynamic and functional improvements in these participants, 
including those receiving maximal PAH therapy with double/triple drug combinations and 
intravenous prostacyclin.
Treatment with sotatercept in addition to background PAH therapies was well tolerated, with 
thrombocytopenia and increased hemoglobin (Hgb) levels being the most commonly reported 
drug-related AEs. The treatment-induced increases in Hgb levels and decrease in platelet 
count observed in the PULSAR study are consistent with the effects of sotatercept in 
previous clinical studies described in Section 3.1 [Ruckle, J., et al 2009] [Raftopoulos, H., et 
al 2016] [Abdulkadyrov, K. M., et al 2014] [Komrokji, R., et al 2018] [Cappellini MD, 
Porter J, Origa R, Forni GL, Voskaridou E, Galactéros F 2019] [Coyne, D. W., et al 2019] 
[Sherman, M. L., et al 2013].
The current study will assess the effects of sotatercept treatment (plus maximum tolerated 
background PAH therapy) versus placebo (plus maximum tolerated background PAH 
therapy) on time to first event of all-cause death, lung transplantation, or PAH worsening-
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related hospitalization of ≥24 hours, in participants with WHO FC III and FC IV PAH at 
high risk of mortality. High-risk patients have a higher likelihood of events of PAH 
progression, and thus the benefit of adding sotatercept to background PAH therapy may be 
more evident in this patient population.
There is an unmet need for additional PAH therapies because despite available therapeutic 
options, the disease continues to progress in most patients. Through a novel mechanism of 
action, sotatercept targets an imbalance in activin/GDF and BMP pathway signaling, opening 
a new treatment paradigm for PAH. This Phase 3 study is being conducted to assess the 
risk-benefit profile of sotatercept in participants with WHO FC III or FC IV who are at high 
risk of mortality.
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4
STUDY OBJECTIVES
The objective of this study is to evaluate the effects of sotatercept treatment (plus maximum 
tolerated background PAH therapy) versus placebo (plus maximum tolerated background 
PAH therapy) on time to first event of all-cause death, lung transplantation, or PAH 
worsening-related hospitalization of ≥ 24 hours, in participants with WHO FC III and FC IV 
PAH at high risk of mortality.
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5
STUDY ENDPOINTS AND RATIONALE
5.1
Endpoints Reported in Previous PAH Studies
Pivotal clinical trials for many drugs approved for PAH used 6MWD as a primary endpoint 
to assess exercise capacity. Secondary endpoints commonly measured include invasive 
hemodynamics to demonstrate improvement in PVR, WHO FC to assess symptoms, and 
NT-proBNP to assess cardiac function [Sitbon, O., et al 2020].
However, these endpoints did not consistently correlate with indicators of disease 
progression, such as PAH-related hospitalization and death. This led to the preference toward
morbidity and mortality as primary endpoints, which were used in the following more recent 
Phase 3 clinical trials for PAH: AC-055-302/SERAPHIN (NCT00660179), AMBITION 
(NCT01178073), GRIPHON (NCT01106014), and FREEDOM-EV (NCT01560624) 
[Pulido, T., et al 2013] [Galie, N., et al 2015] [Sitbon, O., et al 2015] [Tapson, V. F., et al 
2019]. Despite the limitations of 6MWD and improvement in WHO FC as standalone 
endpoints, it is noteworthy that all 4 trials referenced include 6MWD and FC in the definition 
of clinical worsening.
Assessment of risk in PAH has been proposed using variables that are routinely measured in 
PAH, with a recommendation first issued by the European Society for Cardiology and
European Respiratory Society, followed by validation and simplified versions using registry 
data [Sitbon, O., et al 2015]. The indices that consistently show the most significant 
predictive effect across the different risk scores are 6MWD, WHO FC, and NT-proBNP.
Please refer to Section 11 for details on study endpoints calculations.
5.2
Primary Efficacy Endpoint and Rationale
This time-to-event trial will have a composite primary efficacy endpoint of time to first event 
of all-cause death, lung transplantation, or PAH worsening-related hospitalization of 
≥24 hours.
All events will be adjudicated by a blinded, independent committee of clinical experts.
Time to PAH worsening can be used to assess disease progression associated with PAH and, 
therefore, presents a relevant measurement to patients, clinicians, and regulatory agencies. 
The majority of clinical trials in PAH have included time to worsening as a secondary 
endpoint. Some of the more recent clinical trials have demonstrated a treatment-related delay 
in time to worsening, and while others have not [Galie, N., et al 2010], recent results suggest 
that time to worsening shows promise in detecting disease progression [Pulido, T., et al 
2013] [Galie, N., et al 2015] [Sitbon, O., et al 2015] [Tapson, V. F., et al 2019].
The events chosen as components in the composite primary efficacy endpoint were included 
due to their robustness and their relative independence from differences in local practice.
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5.3
Secondary Efficacy Endpoints and Rationale
Secondary Efficacy Endpoints
The secondary endpoints are ranked as follows:
1. Overall survival
2. Transplant-free survival
3. Proportion of participants who experienced a mortality event at EOS
4. Change from baseline in Registry to Evaluate Early and Long-Term PAH Disease 
Management (REVEAL) Lite 2.0 risk score at Week 24
5. Proportion of participants achieving a low or intermediate (≤ 7) REVEAL Lite 2.0
risk score at Week 24
6. Change from baseline in NT-proBNP levels at Week 24
7. Change from baseline in mean pulmonary artery pressure (mPAP) at Week 24
8. Change from baseline in PVR at Week 24
9. Proportion of participants who improve in WHO FC at the end of the DBPC 
Treatment Period
10. Change from baseline in 6MWD at Week 24
11. Change from baseline in cardiac output (CO) at Week 24
12. Change from baseline in EuroQoL-5 dimensions scale 5 levels (EQ-5D-5L) index 
score at Week 24
5.3.1
N-Terminal Prohormone B-Type Natriuretic Peptide Rationale
N-terminal prohormone B-type Natriuretic Peptide is secreted by cardiomyocytes in response 
to ventricular stretch and is an established noninvasive marker of ventricular dysfunction in 
patients with PAH. Plasma NT-proBNP levels correlate with functional capacity, RV 
function, and echocardiographic and hemodynamic variables, and it has been consistently 
shown to be an independent predictor of survival in PAH [Tiede, H., et al 2013] [Souza, R., 
et al 2007] [Souza, R., et al 2005]. In addition, the 2 largest studies of investigational new 
therapies in PAH to date, which used an outcomes-based primary endpoint, have shown that 
improvement in NT-proBNP correlated with lower risk of morbidity/mortality [Galie, N., et 
al 2017] [Chin, K. M., et al 2019].
5.3.2
Six-Minute Walk Distance Rationale
The 6MWD has been the most commonly used primary endpoint in clinical trials of PH 
therapies, beginning with the first randomized controlled trial for regulatory approval of 
epoprostenol [Barst, R. J., et al 1996]. However, the utility of improvement in 6MWD as a 
primary outcome measure in clinical trials has become limited, particularly in more 
contemporary trials involving sequential, add-on therapies. In these studies, the change from 
baseline in 6MWD was smaller than the clinically relevant thresholds of around 30 m 
[Mathai, S. C., et al 2012], despite the significance achieved by morbidity and mortality 
outcomes [Pulido, T., et al 2013] [Galie, N., et al 2015] [Sitbon, O., et al 2015]. The 6MWD 
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is a component of many prognostic risk scores, but is generally included as absolute 
thresholds (for example, < 165 m, 165 to 440 m, and > 440 m) [Galiè N, Humbert M, 
Vachiery JL, Gibbs S, Lang I, Torbicki A 2016] instead of changes from baseline.
5.3.3
Pulmonary Vascular Resistance Rationale
The term PAH describes a group of PH patients characterized hemodynamically by the 
presence of precapillary PH, defined by a pulmonary artery wedge pressure (PAWP) of 
≤ 15 mmHg and a PVR > 3 Wood units (WU) [Tiede, H., et al 2013]. Generally, PVR values 
< 5 WU are considered to be of good prognostic value. This parameter is in fact part of the 
calculation of the REVEAL risk score [Benza, R. L., et al 2019].
Earlier trials have used PVR as part of their endpoints, mostly as the key secondary endpoint, 
or in substudies as in the pivotal trials of the more recently approved PAH therapies.
Decreases in PVR in response to treatment have been associated with long-term transplant-
free survival [Tiede, H., et al 2013].
5.3.4
Hemodynamic Parameters Rationale
Three prognostic hemodynamic variables will be assessed by right heart catheterization. The 
first of these is PVR, the values of which are used in the diagnosis and assessment of the 
prognosis of PAH. In general, WHO PAH Group 1 describes a group of PH patients 
characterized hemodynamically by the presence of precapillary PH, which is defined by a 
PAWP of ≤ 15 mmHg and a PVR> 3 WU [Chin, K. M., et al 2019]. Generally, PVR values 
< 5 WU are considered to be of good prognostic value. PVR is also a component used in the 
calculation of the REVEAL risk score [Souza, R., et al 2007]. Earlier trials, including 
PULSAR, have also used PVR as an endpoint, and decreases in PVR in response to treatment 
are positively associated with long-term transplant-free survival.
Mean pulmonary arterial pressure (mPAP) is essential to a diagnosis of PAH. Based on the 
6th World Symposium on Pulmonary Hypertension, patients are at risk of PAH with an 
mPAP of 21 to 25 mmHg. Above a pressure of 25 mmHg, a diagnosis of PAH can be made if 
in conjunction with the above PAWP and PVR criteria.
Cardiac Output is a component of the PVR calculation. Along with right atrial pressure, it is 
the most important invasive measure to reflect prognosis. As such, it is a component of the 
REVEAL Risk Calculator. There is a very high risk of morbidity/mortality associated with 
reduced CO, and values of 4.0 to 8.0 L/min are considered normal.
5.3.5
REVEAL Lite 2.0 Risk Score Rationale
Risk assessment is important for the management of patients with PAH, and achievement of 
a low mortality risk status is the current goal of PAH treatment [Galiè N, Humbert M, 
Vachiery JL, Gibbs S, Lang I, Torbicki A 2016] [Benza, R. L., et al 2019] [Benza, R. L., et al 
2021] [Benza, R. L., et al 2012] [McLaughlin, V. V., et al 2018] [Hoeper, M. M., et al 2017]. 
The REVEAL risk calculator is commonly used to guide treatment decisions in this patient 
population, and has been validated to discriminate risk at diagnosis and throughout the course 
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of treatment. The REVEAL 2.0 and the REVEAL Lite 2.0 can predict both clinical 
worsening as well as mortality. The REVEAL Lite 2.0 is an abridged version of the 
REVEAL 2.0 that includes only noninvasive variables: renal insufficiency (by estimated 
glomerular filtration rate [eGFR]), WHO FC, systolic blood pressure (BP), heart rate, 
6MWD, and NT-proBNP. Scores are assigned to each of these variables based upon their 
presentation and contribution to mortality risk, and a total score is obtained. Total scores of 
≥8 indicate high risk; scores of 6 to 7 indicate intermediate risk, and scores of ≤5 indicate 
low risk. REVEAL 2.0 shows greater risk discrimination (c-index 0.76) than the 
Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension 
method (c-index 0.62) or the French Pulmonary Hypertension Registry method (c-index 
0.64). The development and validation of the REVEAL Lite 2.0 identified that the REVEAL 
Lite 2.0 risk assessment approximates the REVEAL 2.0 at discriminating low, intermediate, 
and high risk of mortality in patients in the REVEAL registry (c-index 0.73). The simplicity 
of this instrument makes it ideal for routine implementation in clinical practice to guide 
treatment decisions as well as appropriate for use as an endpoint for evaluating the effects of 
novel treatments on risk of morbidity/mortality. The REVEAL Lite 2.0 risk score calculator 
is presented in Appendix 2.
5.3.6
World Health Organization Functional Class Rationale
The WHO FC, despite its interobserver variability [Taichman, D. B., et al 2009], remains one
of the most powerful predictors of survival not only at diagnosis but also during follow-up 
[Sitbon, O., et al 2002] [Nickel, N., et al 2012] [Barst, R. J., et al 2013]. A worsening FC is 
one of the most alarming indicators of disease progression, which should trigger further 
diagnostic studies to identify the causes of clinical deterioration [Nickel, N., et al 2012] 
[Barst, R. J., et al 2013] [Benza, R. L., et al 2010].
The WHO FC is also a powerful predictor of survival as the WHO FC categories (I to IV) 
represent a scale to measure the severity of PAH. Studies have shown that a poor WHO FC 
status at presentation is associated with a lower 5-year survival rate and is, therefore, an 
important prognostic factor in the risk scores.
5.3.7
Quality of Life Assessments Rationale
Patient-reported outcome (PRO) instruments are essential tools to evaluate disease, 
treatment, and quality of life. Quality of life for PAH participants in this study will be 
assessed using the PRO measure EQ-5D-5L index score.
The EQ-5D-5L is a standardized measure of health status that provides a simple, generic 
measure of health for clinical and economic appraisal. It is designed for self-completion and 
captures information directly from the respondent, thereby generating data that conforms to 
the general requirement of all PRO measures.
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5.4
Exploratory Endpoints
In addition to the primary and secondary endpoints, the following will be analyzed:
•
Number of PAH-related hospital days during the study
•
Change from baseline in RV-pulmonary artery (PA) coupling at Week 24
•
Change from baseline in biomarkers; including, but not limited to, serum 
biomarkers such as C-reactive protein (CRP) and Activin A at Week 24
•
Proportion of participants achieving a low or intermediate-low COMPERA 2.0 4-
strata risk score (Section 9.3.6) at Week 24
5.5
Safety Endpoints
Safety will be evaluated by collecting the following:
•
AEs
•
Anti-drug antibodies (ADAs)
•
Laboratory assessments (hematology, serum chemistry, and urinalysis)
•
Vital signs
•
Physical examination
•
12-lead electrocardiogram (ECG)
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6
STUDY DESIGN
6.1
Study Description
This is a Phase 3, randomized, double-blind, placebo-controlled, multicenter, parallel-group 
study to evaluate sotatercept versus placebo in participants with PAH WHO FC III or FC IV 
who are at high risk of mortality. 
The study population includes participants with symptomatic PAH (WHO FC III or FC IV at 
high risk of mortality) who present with idiopathic or heritable PAH, PAH associated with 
connective tissue diseases (CTD), drug- or toxin-induced, post-shunt correction PAH, or 
PAH presenting at least 1 year following the correction of congenital heart defects (CHD). 
Participants must have a REVEAL Lite 2.0 risk score of ≥ 9 and be on maximum tolerated 
combination background PAH therapy.
6.2
Duration of Study
Each participant will be enrolled in the study for up to approximately 43 months as follows:
•
Screening Period (up to 4 weeks)
•
DBPC Treatment Period (up to approximately 40 months)
•
Follow-up Period (up to 8 weeks)
6.3
Rationale for Dose Selection
The PULSAR study demonstrated that both the 0.3 and 0.7 mg/kg sotatercept doses are 
pharmacologically active and that both resulted in statistically significant improvements 
across a number of study endpoints compared to placebo. However, comprehensive 
exposure-response (E R) analyses demonstrated that a concentration-effect relationship exists 
for PVR, 6MWD, and NT-proBNP for efficacy and Hgb for safety. Simulations based on 
these E-R models suggest a higher probability of achieving clinically meaningful targets for 
6MWD, PVR, and NT-proBNP with the 0.7 mg/kg dose level compared to 0.3 mg/kg. 
Consistent with these, in PULSAR data, 55% of participants in the 0.7 mg/kg group achieved 
a ≥ 30% reduction in PVR (PULSAR primary endpoint) compared to 25% in the 0.3 mg/kg 
dose group as of the preplanned interim data cutoff of 14 January 2020.
Acceleron Pharma Inc.’s interpretation of the PULSAR safety data is that both dose levels 
are generally safe and well tolerated in participants with PAH, which is consistent with 
previous experience with sotatercept in other indications. While a concentration-effect 
relationship was also demonstrated for Hgb increases, no significant difference at steady state 
was observed between sotatercept dose levels in the PULSAR study; the mean change from 
baseline in Hgb at Week 24 was 1.2 and 1.5 g/dL in the 0.3 and 0.7 mg/kg groups, 
respectively. The PULSAR study demonstrated that excursions in Hgb concentration above 
the upper limit of normal (ULN) can be effectively managed by sotatercept dose 
modification guidelines. Simulations based on the E-R model for Hgb suggest a very low 
probability (< 10%) of crossing Hgb safety thresholds defined in the PULSAR study.
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Clinical trial simulations from the pharmacokinetic (PK)/pharmacodynamic model for Hgb 
suggested that the probability of having Hgb ≥ 18 g/dL and an increase in Hgb ≥ 2 g/dL is 
higher during the first 21 days after a dose of 0.7 mg/kg than after a dose of 0.3 mg/kg. 
Therefore, for this study, sotatercept will be administered at a starting dose of 0.3 mg/kg, 
with a target dose of 0.7 mg/kg, subcutaneously (SC) every 21 days plus background PAH 
therapy.
6.4
Study Design, Stratification, and Treatment Assignment
The study is divided into a Screening Period (up to 4 weeks), a DBPC Treatment Period 
(up to approximately 40 months), and a Follow-up Period (up to 8 weeks). Participants who 
have documented informed consent and meet all eligibility criteria will be stratified by 
REVEAL Lite 2.0 risk score and PAH subtype and then randomized to receive either placebo 
plus background PAH therapy or sotatercept plus background PAH therapy, as described in 
Section 6.6. Up to 166 participants will be randomly assigned in a 1:1 ratio to the 2 study 
treatment groups (83 participants per arm) to receive SC injections of either placebo or 
sotatercept every 21 ± 3 days, at a starting dose of 0.3 mg/kg SC at Visit 1. Participants will 
then be escalated to the target dose level of 0.7 mg/kg SC at Visit 2 and will remain at this 
target dose level for all subsequent DBPC Treatment Period visits. All participants will 
remain on background PAH therapy during the study. Median participant time on study must 
be at least 6 months in order for analyses following the occurrence of the required number of 
events.
Study participants who have not experienced an event will remain in the DBPC Treatment 
Period until the required number of participants have experienced a first event of all-cause 
death, lung transplantation, or PAH worsening-related hospitalization and the study is 
unblinded. During the DBPC Treatment Period, selected study visits may be performed as 
home health care (HHC) visits as described in Section 6.5. 
When a participant experiences an event of PAH worsening-related hospitalization of 
≥24 hours, the investigator must complete the Primary Endpoint Event Assessment
electronic case report form (eCRF) page. An independent blinded adjudication committee 
will then adjudicate the event to determine whether the hospitalization is due to PAH. Upon 
confirmation, the participant will complete the EOT Visit and may be eligible to enroll into
the open-label, long-term follow-up (LTFU) study, A011-12 (SOTERIA). 
Rollover after site reporting of an event of PAH worsening-related hospitalization but prior 
to confirmation from the adjudication committee can be considered and will require 
consultation and written approval from the Sponsor. Upon written approval from the 
Sponsor, the participant will complete the EOT Visit and may be eligible to enroll into the 
open-label, LTFU study, A011-12 (SOTERIA). 
Participants who experience an event of PAH worsening-related hospitalization of ≥24 hours 
and who do not wish to participate in the LTFU study A011-12 (SOTERIA) will complete 
the Follow-up Period including both the EOT and EOS Visits (Figure 1).
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Participants who experience an event of lung transplantation will complete the Follow-up 
Period including both the EOT and EOS Visits ( Figure 1). 
The end of the DBPC Treatment Period will occur when the required number of participants 
have experienced a primary endpoint event, either for the interim analysis (IA) or the final 
analysis. If the Sponsor decides to stop the study early following the IA and Data Monitoring 
Committee (DMC) recommendation, all participants in the DBPC Treatment Period will be 
called in for their final visit(s), and the study will be terminated. If the study continues after 
the IA, the end of the DBPC Treatment Period will occur when the required number of 
participants have experienced a primary endpoint event for the final analysis.
At the end of the DBPC Treatment Period, participants who are currently on treatment 
(sotatercept or placebo) may be eligible to enroll into the LTFU study, A011-12 (SOTERIA) 
following completion of the EOT Visit. For these participants, the EOS Visit will be waived. 
If the participant does not choose to enroll into SOTERIA, they will complete the Follow-up 
Period including both the EOT and EOS Visits (Figure 1).
Participants who discontinue the DBPC Treatment Period early, without experiencing a 
primary endpoint event, will complete the EOT Visit at the time of discontinuation as 
specified in the SoE (Section 2) and EOS Visit (described in Section 9.2.3.2), provided that 
consent is not withdrawn. Following the EOT and EOS, or if the participant refuses to attend 
additional study visits, they will receive quarterly telephone contacts for vital status until the 
study is unblinded. These participants will not be eligible to enroll into the LTFU study,
A011-12 (SOTERIA).
6.5
Home Health Care Visits
Select study visits (Visits 6 onward, except for Visit 9 and quarterly site visits) may be 
performed at the participant’s home by a qualified health care professional if permitted by 
local and institutional regulations and requested by study participants that meet the criteria 
for HHC visits.
Starting at Visit 6, participants are eligible for HHC visits if dose modification/delays did not 
occur in the previous 2 consecutive visits. Guidelines for dose modification are described in 
Section 8.3.
If a dose modification is required at any time during the DBPC Treatment Period, the next 
2 visits must be performed on site. The participant will be eligible for HHC visits again 
following 2 consecutive on-site visits without dose modification.
For example, if a dose modification is required at Visit 13, then Visits 14 and 15 must be 
performed on site. If no further dose modifications are required at Visits 14 and 15, then 
Visit 16 may be performed as an HHC visit. 
For HHC visits, hematology results are not required to be evaluated prior to study drug 
administration.
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6.6
Randomization and Blinding
Participants who have documented informed consent and who meet all eligibility criteria will 
be stratified by REVEAL Lite 2.0 risk score and PAH subtype. They will then be randomized 
to receive either placebo to add to their background PAH therapy, or sotatercept to add to 
their background PAH therapy. Randomization assignments will be generated through a 
computerized system provided through Interactive Response Technology (IRT) (see the IRT 
Manual for details).
In the event of a medical emergency for an individual participant, where knowledge of the 
study drug is critical to the participant’s medical management, the investigator may break the
blind for that participant via the IRT (see the IRT Manual for further instruction). If the 
nature of the emergency does not permit consultation with the Medical Monitor prior to 
breaking the blind, the investigator must inform the Medical Monitor that the blind has been 
broken at the earliest opportunity. In non-urgent situations, the investigator is recommended 
to discuss the issue with the study Medical Monitor prior to breaking the blind. Only if 
knowledge of the participant’s treatment assignment is necessary for the medical 
management of that participant should the blind be broken.
If the blind is broken, the participant will be discontinued from the study and will not be 
eligible to enroll into the LTFU study, A011-12 (SOTERIA). The investigator should not 
inform the participant of their treatment assignment under any circumstances.
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7
STUDY POPULATION
7.1
Rationale for Selected Population
Participants diagnosed with symptomatic PAH (WHO FC III or IV at high risk of mortality), 
who present with idiopathic or heritable PAH, PAH associated with CTD, drug- or 
toxin-induced, post-shunt correction PAH, or PAH presenting at least 1 year following the 
correction of CHDs, will be eligible for this study. Participants must have a REVEAL 
Lite 2.0 risk score of ≥9 and be on maximum tolerated combination background PAH 
therapy.
PAH is considered a relatively rare condition, with approximately 80% of PAH patients 
presenting as WHO FC II to III. There is a low prevalence of PAH patients with WHO FC 
IV, and given their severe disease burden and their need for maximum PAH therapy, these 
patients have had a limited ability to participate in interventional studies. The study 
population selected will be receiving the maximum available standard-of-care therapies, 
which will provide the opportunity to assess the effects of sotatercept, on top of maximum 
available approved PAH therapies, on mortality and morbidity in a population with advanced 
PAH and limited to no opportunity for additional interventions.
This Phase 3 study is supported by data from the Phase 2 Study A011-09 (PULSAR; 
NCT03496207), in which participants taking any approved single or combination therapy for 
PAH were randomized to receive additional sotatercept or placebo for 24 weeks. The 
PULSAR study demonstrated a statistically significant improvement in its primary endpoint, 
PVR. Additionally, improvements were observed in 6MWD, NT-proBNP, and other 
endpoints.
7.2
Background PAH Therapy
Background PAH therapy refers to approved PAH-specific medications. Study participants 
must be stable on maximum tolerated double or triple combination background PAH therapy 
(per the investigator’s judgment) for at least 30 days prior to the Screening Visit. 
Adjustments in parenteral prostacyclin doses by up to 10% are permitted and should not 
affect therapy stability determination.
This background PAH therapy should be combination therapy consisting of at least 2 agents 
(each from a different class) from a list including: endothelin-receptor antagonists, 
phosphodiesterase 5 inhibitors, soluble guanylate cyclase stimulators, and/or prostacyclin 
analogs or receptor agonists. 
7.3
Inclusion Criteria
Eligible participants must meet all of the following criteria to be enrolled in the study:
1. Age 18 to 75 years, inclusive
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2. Documented diagnostic right heart catheterization prior to screening confirming the
diagnosis of WHO PAH Group 1 in any of the following subtypes:
•
Idiopathic PAH 
•
Heritable PAH
•
Drug/toxin-induced PAH
•
PAH associated with CTD
•
PAH associated with simple, congenital systemic-to-pulmonary shunts at least 1 
year following repair
3. Symptomatic PAH classified as WHO FC III or IV
4.
REVEAL Lite 2.0 risk score of ≥9
5. Right heart catheterization performed during screening (or within 2 weeks prior to 
screening, if done at the clinical study site) documenting a minimum PVR of 
≥5 Wood units and a pulmonary capillary wedge pressure (PCWP) or left ventricular 
end-diastolic pressure (LVEDP) of ≤ 15 mmHg
6. Clinically stable and on stable doses of maximum tolerated (per investigator’s 
judgment) double or triple background PAH therapies for at least 30 days prior to 
screening
7. Females of childbearing potential must: 
•
Have 2 negative urine or serum pregnancy tests as verified by the investigator 
prior to starting study therapy; must agree to ongoing urine or serum pregnancy 
testing during the course of the study and until 8 weeks after the last dose of the 
study drug
•
If sexually active with a male partner:
-
Used highly effective contraception without interruption; for at least 28 days 
prior to starting the investigational product AND
-
Agree to use the same highly effective contraception in combination with a 
barrier method during the study (including dose interruptions), and for 
16 weeks (112 days) after discontinuation of study treatment
•
Refrain from breastfeeding a child or donating blood, eggs, or ovum for the 
duration of the study and for at least 16 weeks (112 days) after the last dose of 
study treatment
8. Male participants must: 
•
Agree to use a condom, defined as a male latex condom or nonlatex condom NOT 
made out of natural (animal) membrane (e.g., polyurethane), during sexual 
contact with a pregnant female or a female of childbearing potential while 
participating in the study, during dose interruptions, and for at least 16 weeks 
(112 days) following investigational product discontinuation, even if he has 
undergone a successful vasectomy
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•
Refrain from donating blood or sperm for the duration of the study and for 
16 weeks (112 days) after the last dose of study treatment
9. Ability to adhere to study visit schedule and understand and comply with all protocol 
requirements
10. Ability to understand and provide written informed consent
7.4
Exclusion Criteria
1. Diagnosis of PH WHO Groups 2, 3, 4, or 5
2. Diagnosis of the following PAH Group 1 subtypes: human immunodeficiency 
virus-associated PAH and PAH associated with portal hypertension
3. Diagnosis of pulmonary veno-occlusive diseases or pulmonary capillary 
hemangiomatosis or overt signs of capillary and/or venous involvement
4. Hemoglobin at screening above gender-specific upper limit of normal (ULN), per 
local laboratory test
5. Baseline platelet count < 50,000/mm3 (< 50.0 x 109/L) at screening 
6. Baseline systolic blood pressure < 85 mmHg at Screening
7. Pregnant or breastfeeding women
8. Serum alanine aminotransferase, aspartate aminotransferase, or total bilirubin levels 
> 3.0 × ULN
9. Currently enrolled in or have completed any other investigational product study 
within 30 days for small-molecule drugs or within 5 half-lives for biologics prior to 
the date of signed informed consent
10. Prior exposure to sotatercept or known allergic reaction to sotatercept, its excipients, 
or luspatercept 
11. History of pneumonectomy
12. This criterion has been removed
13. Untreated more than mild obstructive sleep apnea 
14. History of known pericardial constriction
15. History of restrictive or congestive cardiomyopathy
16. Electrocardiogram (ECG) with Fridericia’s corrected QT interval (QTcF) > 500 ms 
during the Screening Period
17. Personal or family history of long QT syndrome or sudden cardiac death
18. Left ventricular ejection fraction < 45% on historical echocardiogram within 1 year 
prior to the Screening Visit 
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19. 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 the Screening Visit
20. Cerebrovascular accident within 3 months prior to the Screening Visit
21. Significant (≥ 2+ regurgitation) mitral regurgitation or aortic regurgitation valvular 
disease
22. Currently on dialysis or anticipated need for dialysis within the next 12 months
7.5
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomized to receive study treatment. Electronic case report forms
(eCRFs) must be completed for all participants who provide documented informed consent. 
A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure participants to meet the Consolidated Standards of Reporting Trials publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, reason for screen failure, and AEs.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once with the approval of the study Medical Monitor. Rescreening must occur at 
least 1 week after the initial screening attempt. Rescreened participants will be assigned a 
new participant number.
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8
STUDY DRUG TREATMENT
8.1
Study Drug Description
Sotatercept is a homodimeric recombinant fusion protein consisting of the extracellular 
domain of the human activin receptor type IIA linked to the human immunoglobulin G1 Fc 
domain. Sotatercept is the generic name assigned to ActRIIA-IgG1Fc. The laboratory code is 
ACE-011. The Chemical Abstracts Service Registry number for sotatercept is 1001080-50-7; 
the United States (US) Adopted Name and the International Nonproprietary Name is 
sotatercept.
8.1.1
Clinical Drug Product
The clinical drug product consists of sotatercept (60 mg/vial) in 10 mM citrate buffer, 
pH 5.8, 8% w/v sucrose, and 0.02% w/v polysorbate 80. The matching placebo consists of 
10 mM citrate buffer, pH 5.8, 2% w/v sucrose, 3% w/v mannitol, and 0.02% w/v polysorbate 
80. Both the clinical drug product containing sotatercept and its matching placebo are 
supplied as a lyophilized powder in labeled, rubber-stoppered, type I glass vials. Both the 
investigator and the participant will be blinded as described in Section 6.6.
PAH background therapy will not be provided as study treatment during the study. To be 
enrolled in the study, participants must be on stable PAH background therapy according to 
local practice. More details on PAH background therapy are provided in Section 7.2.
8.1.2
Formulation
Sotatercept (60 mg/vial) clinical drug product and placebo will be provided by Acceleron 
Pharma Inc. as a lyophilized powder.
8.2
Study Drug Management
8.2.1
Storage
The recommended storage temperature for sotatercept lyophilized drug product and matching 
placebo is 2°C to 8°C. Refer to the Pharmacy Manual for additional details.
8.2.2
Packaging and Shipment
Sotatercept or its matching placebo will be packaged in single-use kits. Each kit will contain 
1 vial of sotatercept (60 mg/vial) or its matching placebo product and 1 prefilled syringe of 
sterile water for injection for reconstituting the lyophilized sotatercept or its matching 
placebo. Each kit also contains ancillary components as follows:
•
A swabable vial adapter to aid reconstitution and withdrawal of required drug or 
placebo solution from the vial
•
A syringe and needle for SC injection
•
Alcohol swabs
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Each vial, prefilled syringe, and kit will be labeled for clinical trial use only, with 
country-specific required label text. Each kit will be assigned a serialized Medication ID 
number for identification. The kit will be tamper sealed. Kits will be stored at a depot and 
shipped under refrigerated conditions until the time of dispensation.
8.2.3
Dose and Administration
Each eligible participant will be randomly assigned in a 1:1 ratio to 1 of the following 
2 treatment arms:
•
Arm 1: Placebo administered SC every 21 days plus background PAH therapy
•
Arm 2: Sotatercept at a starting dose of 0.3 mg/kg, with a target dose of 
0.7 mg/kg, administered SC every 21 days plus background PAH therapy
Prior to administration, the lyophilized sotatercept drug product (60 mg/vial) or matching 
placebo will be reconstituted with 1.3 mL of sterile water for injection. Reconstituted 
sotatercept yields a 50 mg/mL solution of sotatercept. Study intervention details are in 
Table 4.
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Table 4
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/Treatment 
Period/Vaccination 
Regimen
Use
IMP or 
NIMP/
AxMP
Sourcing
Placebo 
(Arm 1)
Placebo 
Comparator
Placebo
Placebo
Injection, 
Powder, 
Lyophilized, 
For Solution
0 mg
0 mg 
Q3W
SC
V1 to EOT/EOS
Placebo IMP
Central
Sotatercept 
(Arm 2)
Experimental Sotatercept
Biological/Vaccine Injection, 
Powder, 
Lyophilized, 
For Solution
60 mg/vial
0.3 
mg/kg
Q3W
SC
V1
Test 
Product
IMP
Central
Sotatercept 
(Arm 2)
Experimental Sotatercept
Biological/Vaccine Injection, 
Powder, 
Lyophilized, 
For Solution
60 mg/vial
0.7 
mg/kg 
Q3W
SC
V2 to EOT/EOS
Test 
Product
IMP
Central
EOS=end of study; EOT=end of treatment; IMP=investigational medicinal product; NIMP/AxMP=noninvestigational/auxiliary medicinal product; Q3W=every 3 weeks; 
SC=subcutaneous; TBD=to-be-determined; V=Visit.
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the European Economic Area. A. 
Country differences with respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
Sotatercept dose reductions (from 0.7 to 0.3 mg/kg) due to a safety event are described in Section 8.3.2, 8.3.3 and 8.3.4. Sotatercept dose re-escalation may occur according to 
Section 8.3.6.
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8.3
Dose Modification
Dose delay, reduction, or discontinuation may be performed in any treatment arm 
(sotatercept or placebo). Dose delays should always precede dose reductions. Guidance for 
dose modifications and dose delays are summarized in Figure 3 and Figure 4. For safety 
reasons other than those listed in Figure 3 and Figure 4, dose delays followed by dose 
reductions can be implemented at any time per the investigator’s assessment.
Blood samples must be taken and assessed for Hgb and platelet count levels on the same day 
of study drug administration or up to 3 days prior to that day if available, except for Visit 1.
8.3.1
Escalation to Target Dose (0.7 mg/kg)
All participants will begin treatment at a starting dose of 0.3 mg/kg at Visit 1. At Visit 2, the 
dose will be escalated to the target dose of 0.7 mg/kg and remain at 0.7 mg/kg for the 
duration of the treatment period, unless dose reduction criteria as described in Section 8.3.2
or Section 8.3.3 are met. However, if at Visit 2 Hgb increases by more than 2.0 g/dL from the 
previous dosing visit and this value is above the gender-specific ULN per local laboratory 
test, dosing should be delayed. All other study procedures, with the exception of study drug 
administration, should be performed. At Visit 3, if Hgb has increased by less than 2.0 g/dL 
from the previous dosing visit or Hgb value is below the gender-specific ULN per local 
laboratory test, dosing should be restarted at 0.3 mg/kg. At Visit 4, if Hgb has increased by 
less than 2.0 g/dL from the previous dosing visit or Hgb value is below the gender-specific 
ULN per local laboratory test, the dose will be escalated to the target dose of 0.7 mg/kg. 
Refer to Figure 2 for additional details. 
8.3.2
Dose Modifications Due to Hemoglobin Increase
From Visit 3 onward, if Hgb level increases by more than 2 g/dL from the previous dosing 
visit and this value is above the gender-specific ULN per local laboratory test, then a 
maximum of 3 consecutive dose delays are allowed during the DBPC Treatment Period. 
After the third dose delay, if Hgb level persists at more than 2 g/dL above the previous 
dosing visit and this value is above the gender-specific ULN per local laboratory test, then 
the dose should be reduced to 0.3 mg/kg. If the participant is already at a dose of 0.3 mg/kg, 
the study Medical Monitor should be consulted, and study drug discontinuation should be 
considered. 
If Hgb level increase more than 4 g/dL above the participant’s baseline value, the study 
Medical Monitor should be consulted, and treatment discontinuation should be considered; if 
Hgb increases greater than 2g/dL and above the gender-specific ULN, dose hold should be 
applied for at least 1 visit, and the Medical Monitor should be consulted. Refer to Figure 3
for additional details.
8.3.3
Dose Modifications Due to Low Platelet Count
From Visit 3 onwards, if platelet count is less than 50,000/mm3, dose delay is allowed for up 
to 3 visits. If platelet count remains less than 50,000/mm3 after 3 consecutive dose delays, 
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then study treatment should be discontinued/not restarted. At the visit following each dose 
delay, if platelet count is more than 50,000/mm3, then the dose should be reduced to 
0.3 mg/kg and study treatment should be restarted. If the participant is already at a dose of 
0.3 mg/kg, study treatment should be restarted at 0.3 mg/kg. Refer to Figure 4 for additional 
details.
8.3.4
Dose Modifications Due to Adverse Events of Telangiectasia
In cases of the identification of new events of telangiectasia that are of moderate or greater 
severity/intensity or for the progression of a telangiectasia event from mild to moderate, the 
dose of study drug should be delayed for 1 visit if the participant was receiving 0.7 mg/kg 
study drug, or for 3 visits if the participant was receiving 0.3 mg/kg at the time of the event. 
If, following the dose hold(s), there has been no progression in the severity of the event of 
telangiectasia, dosing of study drug may be resumed at a dose level of 0.3 mg/kg. If the event 
of telangiectasia progresses during the time in which study drug dosing has been delayed, the 
investigator should consult the Medical Monitor and consider discontinuation from study 
drug.
8.3.5
Dose Delays Due to SAEs of Bleeding
In cases of serious active bleeding, the dose of study intervention should be delayed until the 
event resolves. If more than one dose delay due to a serious bleeding event occurs, then the 
Medical Monitor should be consulted.
8.3.6
Dose Re-escalation Following Dose Reduction
In cases of dose reduction due to an AE not related to study drug, the dose can be re-
escalated when the AE is resolved. In cases of dose reduction due to increases in Hgb, the 
dose will be re-escalated to 0.7 mg/kg after 2 consecutive visits at which Hgb values are 
stable and equal to or lower than the ULN (refer to Figure 3). Similarly, in cases of dose 
reduction due to decrease in platelet count, the dose will be re-escalated to 0.7 mg/kg after 
2 consecutive visits at which platelet counts are stable and more than 50,000/mm3, with no 
association with AEs of bleeding (Figure 4). In cases of dose reduction due to events of 
telangiectasia, the dose may be re-escalated to 0.7 mg/kg only if the event has completely 
resolved.
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Figure 2
Guidelines for Target Dose Escalation (0.7 mg/kg)
AE = adverse event; Hgb = hemoglobin.
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Figure 3
Guidelines for Dose Modification Due to Hemoglobin Increase From Visit 3 Onward
AE = adverse event; Hgb = hemoglobin.
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Figure 4
Guidelines for Dose Modification Due to Low Platelet Count From Visit 3 Onward
AE = adverse event; PLT = platelet.
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8.3.7
Accountability
Accountability for study drug during the study is the responsibility of the investigator or 
designee. Investigational clinical supplies must be received by a designated person at the 
clinical site and kept in a secure and temperature-controlled location. The investigational site 
must maintain accurate records with dates and amounts of study drug received, to whom it 
was administered (participant-by-participant accounting), and accounts of any study drug 
accidentally or deliberately damaged, destroyed, or returned. Accurate recording of all study 
drug administration must be made in the appropriate section of the participant’s eCRF and 
source documents. Unless otherwise notified, all vials of study drug, both used and unused, 
must be saved to allow for drug accountability to be completed by the monitor. The used 
vials may be discarded, per the institution’s standard practice, after drug accountability has 
been completed. The investigator must return all unused vials of study drug to Acceleron 
Pharma Inc. at the end of the study, or the study drug may be destroyed at the clinical site 
after Acceleron Pharma Inc.’s approval. Either method must be documented on the drug 
accountability log.
The study will meet all applicable regulatory requirements for study drug accountability.
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9
STUDY CONDUCT
9.1
General Instructions
•
Study procedures and their timing are summarized in the SoEs (Section 2).
•
Prospective approval of protocol deviations to recruitment and eligibility criteria, 
also known as protocol waivers or exemptions, are not permitted.
•
Assessments performed outside of their defined windows must be handled as 
protocol deviations.
•
Immediate safety concerns must be discussed with the Medical Monitor 
immediately upon occurrence or awareness to determine whether the participant 
should continue or discontinue study treatment.
•
Adherence to the study design requirements, including those specified in the 
SoEs, is essential and required for study conduct.
•
All protocol assessment data must be recorded in the participant’s source 
documentation.
9.2
Study Procedures
9.2.1
Screening Period (Up to 4 Weeks Prior to Visit 1)
Potential participants must provide documented ICF before any study-specific Screening 
tests are conducted. Informed consent must be provided before any Screening procedures are 
undertaken.
All Screening procedures must be performed per the SoE (Table 2) and are to be completed 
and reviewed by the investigator to confirm participant eligibility prior to dosing.
The investigator will maintain a screening log to record details of all participants screened to 
confirm eligibility and record reasons for screening failure, as applicable.
Any screening clinical laboratory values considered abnormal may be repeated once during 
the Screening Period but prior to the right heart catheterization, when possible (right heart 
catheterization should be performed last and after all other Screening procedures are done, 
when possible, as described below and in the SoE).
Screening procedures may be performed and completed over the course of several days for 
the Screening Visit, as long as all Screening procedures are completed within the 4 weeks 
(28 days) immediately preceding Visit 1. 
Screening will include a review of the participant’s medical, surgical, and family history, and 
collecting of demographics, race, ethnicity, and medical record requests for relevant external 
procedures.
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Screening procedures include the following: 
•
Informed consent
•
Inclusion/exclusion criteria
•
Medical history review
•
Physical examination
•
12-lead ECG
•
Vital signs, including weight
•
Two serum or urine pregnancy tests (where applicable)
•
Hematology (complete blood cell [CBC] count) 
•
Serum chemistry
•
Urinalysis 
•
Six-Minute Walk Test (6MWT)
•
Borg Dyspnea Scale (pre- and post-6MWT)
•
WHO FC assessment
•
EQ-5D-5L assessment
•
NT-proBNP and CRP sample collection
•
REVEAL Lite 2.0 risk score assessment
•
ADA sample collection
•
Right heart catheterization
•
Echocardiogram
•
AE/serious adverse event (SAE) review
•
Concomitant medication review
9.2.2
Double-blind, Placebo-controlled Treatment Period (Until Event Occurrence)
Study procedures for Visits 1 to 9 vary dependent on the visit number and must be completed 
per the SoEs (Table 2). All study procedures/assessments must be performed prior to the 
administration of the study drug unless otherwise noted.
9.2.2.1
Visit 1
Visit 1 procedures include the following:
•
Randomization
•
Targeted cardiopulmonary and skin physical examinations
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•
Vital signs, including weight
•
Serum or urine pregnancy test (where applicable)
•
Serum chemistry
•
6MWT
•
Borg Dyspnea Scale (pre- and post-6MWT)
•
WHO FC assessment
•
EQ-5D-5L assessment
•
NT-proBNP and CRP sample collection
•
ADA sample collection
•
PK and Activin A sample collection; samples will be collected predose and at 1 to 
2 hours, 2 to 4 hours, and 4 to 8 hours postdose
•
Study drug administration
•
AE/SAE review
•
Concomitant medication review
9.2.2.2
Visit 2 (21 ± 3 days)
Visit day windows are relative to the date of the previous dose of study drug: every 21 days 
(± 3 days). Visit 2 procedures include the following: 
•
Vital signs, including weight
•
Serum or urine pregnancy test (where applicable)
•
Hematology (CBC)
•
6MWT
•
Borg Dyspnea Scale (pre- and post- 6MWT)
•
WHO FC assessment
•
NT-proBNP and CRP sample collection
•
ADA sample collection
•
PK and Activin A sample collection 
•
Study drug administration
•
AE/SAE review
•
Concomitant medication review
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9.2.2.3
Visits 3 and 4 (21 ± 3 days)
Visit day windows are relative to the date of the previous dose of study drug: every 21 days 
(± 3 days). Visit 3 and 4 procedures include the following: 
•
Vital signs, including weight
•
Serum or urine pregnancy test (where applicable)
•
Hematology (CBC)
•
WHO FC assessment
•
NT-proBNP and CRP sample collection
•
ADA sample collection
•
PK and Activin A sample collection 
•
Study drug administration
•
AE/SAE review
•
Concomitant medication review
9.2.2.4
Visit 5 (21 ± 3 days)
Visit 5 procedures include the following:
•
Targeted cardiopulmonary and skin physical examinations
•
Vital signs, including weight
•
Serum or urine pregnancy test (where applicable)
•
Hematology (CBC)
•
Serum chemistry
•
Urinalysis 
•
6MWT
•
Borg Dyspnea Scale (pre- and post-6MWT)
•
WHO FC assessment
•
EQ-5D-5L assessment
•
NT-proBNP and CRP sample collection
•
ADA sample collection
•
PK and Activin A sample collection 
•
Study drug administration
•
AE/SAE review
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•
Concomitant medication review
9.2.2.5
Visits 6 Through 8 (21 ± 3 days)
Visits 6 through 8 may be performed as HHC visits for eligible participants; refer to 
Section 6.5 for details.
Visits 6 through 8 procedures include the following:
•
Serum or urine pregnancy test (where applicable)
•
Study drug administration
•
AE/SAE review
•
Concomitant medication review
9.2.2.6
Visit 9 (21 ± 3 days)
The procedures at Visit 9 (6-month site visit) include the following:
•
Targeted cardiopulmonary and skin physical examinations
•
12-lead ECG
•
Vital signs, including weight
•
Serum or urine pregnancy test (where applicable)
•
Hematology (CBC)
•
Serum chemistry
•
Urinalysis 
•
6MWT
•
Borg Dyspnea Scale (pre- and post-6MWT)
•
WHO FC assessment
•
EQ-5D-5L assessment
•
NT-proBNP and CRP sample collection
•
ADA sample collection
•
PK and Activin A sample collection 
•
Right heart catheterization
•
Echocardiogram
•
Study drug administration
•
AE/SAE review
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•
Concomitant medication review
9.2.2.7
Visits 10 Through 12 (21 ± 3 days)
Visits 10 through 12 (HHC eligible) procedures include the following: 
•
Serum or urine pregnancy test (where applicable)
•
Study drug administration
•
AE/SAE review
•
Concomitant medication review
9.2.2.8
Visit 13 (21± 3 days)
The procedures at Visit 13 include the following:
•
Targeted cardiopulmonary and skin physical examinations
•
Vital signs, including weight
•
Serum or urine pregnancy test (where applicable)
•
Hematology (CBC) 
•
Serum chemistry
•
Urinalysis 
•
6MWT
•
Borg Dyspnea Scale (pre- and post-6MWT)
•
WHO FC assessment
•
EQ-5D-5L assessment
•
NT-proBNP and CRP sample collection
•
ADA sample collection
•
PK and Activin A sample collection 
•
Study drug administration
•
AE/SAE review
•
Concomitant medication review
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9.2.2.9
Visits 14 Onward (21 ± 3 days)
Visits 14 onward, except for quarterly site visits, may be performed as HHC visits for 
eligible participants.
The procedures for non-quarterly visits (Visits 14, 15, 16, 18, 19, 20, etc.) include the 
following:
•
Serum or urine pregnancy test (where applicable)
•
Study drug administration
•
AE/SAE review
•
Concomitant medication review
The procedures for quarterly site visits (Visits 17, 21, 25, etc.) include the following:
•
Targeted cardiopulmonary and skin physical examinations
•
Vital signs, including weight
•
Serum or urine pregnancy test (where applicable)
•
Hematology (CBC)
•
Serum chemistry
•
Urinalysis
•
6MWT
•
Borg Dyspnea Scale (pre- and post-6MWT)
•
WHO FC assessment
•
EQ-5D-5L assessment
•
NT-proBNP and CRP sample collection
•
ADA sample collection
•
PK and Activin A sample collection
•
Echocardiogram (Visit 25 only)
•
Study drug administration
•
AE/SAE review
•
Concomitant medication review
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9.2.3
Follow-up Period (up to 8 Weeks)
9.2.3.1
End of Treatment Visit (21 ± 7 Days from Last Dose)
The EOT Visit is recommended to occur 21 days (±7 days) after the last study drug 
administration in the DBPC Treatment Period. The procedures at the EOT Visit include the 
following:
•
Targeted cardiopulmonary and skin physical examinations
•
12-lead ECG
•
Vital signs, including weight
•
Serum or urine pregnancy test (where applicable)
•
Hematology (CBC)
•
Serum chemistry
•
Urinalysis
•
6MWT
•
Borg Dyspnea Scale (pre- and post-6MWT)
•
WHO FC assessment
•
EQ-5D-5L assessment
•
NT-proBNP and CRP sample collection
•
ADA sample collection
•
PK and Activin A sample collection 
•
Echocardiogram (if an echocardiogram has been performed in the past 3 months, 
it may be exempted at the EOT Visit)
•
AE/SAE review
•
Concomitant medication review
9.2.3.2
End of Study Visit (5 Weeks ± 7 Days After EOT Visit)
Participants who discontinue early, experience an event of lung transplantation, or do not 
wish to participate in the LTFU study, A011-12 (SOTERIA), will complete both the EOT 
and the EOS Visits. The EOS Visit is recommended to occur 5 weeks (± 7 days) after the
EOT Visit. Reasons for early discontinuation are described in Section 9.4.1.
The procedures for the EOS Visit include the following:
•
Targeted cardiopulmonary and skin physical examinations
•
Vital signs, including weight
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•
Serum or urine pregnancy test (where applicable)
•
Hematology (CBC)
•
Serum chemistry
•
Urinalysis
•
6MWT
•
Borg Dyspnea Scale (pre- and post-6MWT)
•
WHO FC assessment
•
EQ-5D-5L assessment
•
NT-proBNP and CRP sample collection
•
ADA sample collection
•
AE/SAE review
•
Concomitant medication review
9.3
Description of Study Procedures
9.3.1
12-Lead Electrocardiogram
A single 12-lead ECG will be obtained at study visits as outlined in the SoEs and will be 
transferred to a central laboratory for reading and interpretations. Parameters obtained will be 
heart rate, QRS, and QT interval (QTcF).
•
Clinically significant abnormal findings will be reported as AEs.
•
At visits where both ECGs and 6MWT assessments are done ECGs should be 
performed prior to 6MWT.
9.3.2
Six-Minute Walk Test
The 6MWD will be measured by the 6MWT during the Screening period and at multiple 
timepoints (See Table 2). During the Screening Period, the 6MWT should be performed 
twice, unless deemed inappropriate by the investigator based on the participant’s disease 
state, at least 4 hours, but no longer than 1 week, apart. The average of the two 6MWDs 
should be used for the REVEAL Lite 2.0 calculation (Appendix 2).
The 6MWT should be performed indoors, along a long, flat, straight, enclosed corridor with a 
hard surface that is seldom traveled. The walking course should be 30 m in length (or at least 
15 m) and should be at the same location that is used for all study visits [Singh, S. J., et al 
2014] [American Thoracic Society 2002]. The length of the corridor should be marked every 
3 m. The turnaround points should be marked (e.g., with a cone). A starting line, which 
marks the beginning and end of each 60-m lap, should be marked on the floor (e.g., using 
brightly colored tape).
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If the participant discontinues the test prematurely, the time (mm:ss) and distance walked 
will be recorded. Requirement of acute supportive rescue medication (e.g., oxygen therapy) 
and any AEs occurring during the 6MWT must be recorded. If a participant is on chronic 
oxygen therapy, oxygen should be administered at their standard rate or as directed by the 
investigator. During the study, the 6MWT should be performed at approximately the same 
time of day to avoid diurnal variation. The 6MWT should be performed under the same 
conditions at least between the Screening Visit and Visit 9, including chronic oxygen therapy 
and the use of walking aids or face coverings (the latter as required by local regulations). All 
6MWTs performed from Visit 1 onward can be performed at the study visit day or within 
10 days prior to study drug administration. Refer to Appendix 4 for additional details.
9.3.3
Borg Dyspnea Scale
The Borg Dyspnea Scale (Borg CR10 Scale) will be measured pre- and post-6MWT.
9.3.4
World Health Organization Functional Class Assessment for Pulmonary 
Hypertension
The modified NYHA/WHO classification of functional status is used to provide information 
about how affected an individual is by their disease [Stuart, R. 1998]. The 4 FCs that are used 
to rate how ill a PAH participant is are detailed in Table 5.
Table 5
NYHA/WHO FC Assessment for PAH
NYHA/WHO
Functional
Class
Description
Class I
Patients with PAH but without resulting limitation of physical activity
Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or 
near syncope.
Class II
Patients with PAH resulting in a slight limitation of physical activity
They are comfortable at rest. Ordinary physical activity causes undue dyspnea or 
fatigue, chest pain, or near syncope.
Class III
Patients with PAH resulting in marked limitation of physical activity
They are comfortable at rest. Less than ordinary activity causes undue dyspnea or 
fatigue, chest pain, or near syncope.
Class IV
Patients with PAH with inability to carry out any physical activity without 
symptoms.
These patients manifest signs of right heart failure. Dyspnea and/or fatigue may 
even be present at rest. Any physical activity leads to increased discomfort.
FC = functional class; NYHA = New York Heart Association; PAH = pulmonary arterial hypertension; WHO = 
World Health Organization; 
Note: NYHA/WHO functional class is modified after NYHA functional assessment.
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9.3.5
REVEAL Lite 2.0 Risk Score
REVEAL Lite 2.0 [Benza, R. L., et al 2019] [Benza, R. L., et al 2021] risk score assessment 
uses noninvasive variables to determine the risk score for classification into a risk category.
REVEAL Lite 2.0 will be calculated using central laboratory NT-proBNP, central laboratory 
eGFR, WHO FC, systolic BP, heart rate, and 6MWD (Appendix 2). Sites will use this score 
to ensure that entry criterion 4: REVEAL Lite 2.0 risk score ≥9, is met by the participant at 
enrollment. Sites will only be required to calculate the REVEAL Lite 2.0 risk score at
Screening. The Sponsor will calculate the REVEAL Lite 2.0 risk score for all other study 
visits (Visits 1 to 5, Visit 9, quarterly site visits, EOT Visit, and EOS Visits). Importantly, the 
Screening NT-proBNP and eGFR samples should be taken at the initial Screening Visit and 
should be submitted to the central laboratory for analysis as soon as possible to ensure 
availability of results prior to randomization.
9.3.6
COMPERA 2.0 Four-Strata Risk Score
The Comparative, Prospective Registry of Newly Initiated Therapies for PH (COMPERA) 
2.0 4-strata risk score is based on WHO FC, 6MWD and NT-proBNP. This 4-strata model 
was developed and validated in PAH patients for whom all 3 variables are available. Based 
on the cut-off levels proposed in the 2022 ESC/ERS guidelines [Humbert, M., et al 2022], 
each variable is graded from 1 to 4, where 1 defines low risk, 2 intermediate-low risk, 3 
intermediate-high risk and 4 high risk. The final risk score value is calculated by dividing the 
sum of all grades by the number of variables and rounding to the next integer. Participants 
will be categorized as low, intermediate–low, intermediate–high, or high risk depending on 
the final risk score value. Sites will not be required to calculate the COMPERA 2.0 4-strata
risk score. The Sponsor will calculate the 4-strata risk score risk score at Screening and Visit 
9 [Hoeper, M. M., et al 2022] [Boucly, A., et al 2022].
9.3.7
Echocardiogram Parameters
Two-dimensional echocardiogram parameters will include but not be limited to: tricuspid 
annular plane systolic excursion (TAPSE), pulmonary artery systolic pressure (PASP), RV 
fractional area change, and RV end diastolic area. An echocardiogram performed during the 
Screening Period is used as the baseline for this study. Right ventricular-pulmonary artery 
coupling will be assessed by evaluating the relationship between TAPSE and PASP 
(TAPSE/PASP). Right ventricular-pulmonary artery coupling is a noninvasive measure of 
end systolic arterial elastance and is a reflection of RV diastolic stiffness. Prognosis declines 
with a value < 0.31 mm/mmHg.
All echocardiograms performed after Screening can be performed on the day of the study 
visit or within 1 week prior to study drug administration. The echocardiogram parameters 
review process will be performed by a central vendor, according to the Study Manual. 
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9.3.8
Patient-reported Outcomes
9.3.8.1
EuroQoL - 5 Dimensions Scale 5 Levels Assessment
EuroQoL - 5 dimensions scale 5 levels is a standardized measure of health status developed 
to provide a simple generic measure of health for clinical and economic appraisal. The 
EQ-5D-5L questionnaire is designed for self-completion and captures information directly 
from the respondent, thereby generating data that conform to the general requirement of all 
PRO measures.
The EQ-5D-5L questionnaire has the following 2 components: health state description and 
evaluation.
In the description part, health status is measured in terms of 5 dimensions: mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression. The “mobility” dimension 
asks about the person’s walking ability. The “self-care” dimension asks about the ability to 
wash or dress by oneself, and the “usual activities” dimension measures performance in 
“work, study, housework, family or leisure activities.” The “pain/discomfort” dimension asks 
how much pain or discomfort an individual has, while the “anxiety/depression” dimension 
asks how anxious or depressed the individual is. Respondents self-rate their level of severity 
for each dimension using the 5-level (EQ-5D-5L) scale.
In the evaluation part, the respondents evaluate their overall health status using the visual 
analog scale.
Participants will complete the EQ-5D-5L questionnaire prior to study drug administration 
during the study visits outlined in the SoEs. Refer to the Study Manual for more details.
9.3.9
Physical Examination
•
A full physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, skin, and neurological systems. A full 
physical examination will be completed at the Screening Visit only.
•
A targeted physical examination will include, at a minimum, assessments of the 
cardiovascular and pulmonary systems, as well as the skin, and will be completed 
at visits that occur after Screening.
•
Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
9.3.10
Vital Signs
Vitals signs will be collected before blood collection and study treatment administration and 
include the following (refer to the Study Manual for more details):
•
Temperature, pulse rate, respiratory rate, BP, and weight will be assessed at study 
visits as outlined in the SoEs. Weight will be measured in indoor clothing but 
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without shoes. Dose will be calculated based on the participant’s most recently 
recorded weight. 
•
BP and pulse measurements will be assessed while seated after a period of rest in 
a quiet setting with no distractions (e.g., television and cell phones). The same 
method of collection (manual or automated) should be used throughout the study. 
Manual techniques will be used only if an automated device is not available. 
•
Clinically significant abnormal findings will be reported as AEs (Section 10.1).
9.3.11
NT-proB-type Natriuretic Peptide
B-type natriuretic peptide (BNP) is a hormone produced by the heart. NT-proBNP is a 
nonactive prohormone that is released from the same molecule that produces BNP. Both 
BNP and NT-proBNP are released in response to changes in pressure inside the heart. 
NT-proBNP levels are primarily used to help detect, support diagnosis, and, in some 
instances, evaluate the severity of heart failure.
Samples for NT-proBNP analysis will be collected as described in the SoEs and will be 
shipped and analyzed by a central laboratory. The Screening NT-proBNP sample should be 
taken at the initial Screening Visit and should be submitted to the central laboratory for 
analysis as soon as possible to ensure availability of results prior to randomization.
9.3.12
Activin A Assessments
Genetic mutations in the BMPR2 are associated with the majority of the familial form of 
PAH and approximately 25% of idiopathic PAH. Specifically, the impairment of the 
BMPR2-associated signal pathway appears to lead to the uncontrolled proliferation of 
pulmonary VSMCs, the principal cause of PAH. These data strongly suggest a key role of 
transforming growth factor-β family members in the pathogenesis of PAH. Sotatercept acts 
to block activin ligands and GDFs, may attenuate BMPs, and improve pulmonary vascular 
remodeling by restoring balance to Smad signaling. The assessment of ligand-trapping 
activity of sotatercept is therefore important and can provide better understanding in its role 
in disease modification.
Activin A is a ligand that is bound by sotatercept. Serum Activin A levels correlate with 
sotatercept ligand-trapping activity. Samples for analysis of Activin A will be collected as 
described in the SoEs and will be shipped and analyzed by a central laboratory.
9.3.13
C-Reactive Protein
C-reactive protein is a non-specific marker of inflammation and tissue damage and is a well-
accepted indicator of cardiovascular risk [Quarck, R., et al 2009] [Labarrere, C. A. 2004] 
[Elstein, D., et al 2005]. Elevated CRP predicts risk of recurrent ischemia and death in 
patients with atherosclerosis and is associated with systemic inflammation in patients with 
chronic obstructive pulmonary disease. Circulating CRP is increased in PAH patients as 
compared to control patients. In a small study analyzing data from 57 participants with PAH, 
a potential role of CRP levels in predicting response to therapy and in survival was identified. 
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In this study, the participants who exhibited CRP levels that were decreased to under the 
ULN following treatment initiation had significantly better survival, a decrease in New York 
Heart Association FC, and an increase in cardiac index.
Samples for CRP analysis will be collected as described in the SoEs and will be shipped and 
analyzed by a central laboratory.
9.3.14
Anti-Drug Antibody Assessments
Anti-drug antibody samples will be collected as outlined in the SoEs and will be analyzed by 
a central laboratory. Participants may be asked to return for additional ADA testing after 
their last visit if there is any indication of potential immunogenicity-related safety concern. 
9.3.15
Pharmacokinetics Measurements
Serum samples will be collected for measurement of serum concentrations of sotatercept as 
specified in the SoEs. Samples may be collected at additional timepoints during the study if 
warranted and agreed upon between the investigator and Acceleron Pharma Inc.
Instructions for the collection and handling of biological samples will be provided by
Acceleron Pharma Inc. The actual date and time (24-hour clock time) of each sample 
collection will be recorded. Samples will be used to evaluate the PK of sotatercept. Samples 
collected for analyses of sotatercept serum concentration may also be used to evaluate the 
safety or efficacy aspects related to concerns arising during or after the study.
Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded. Samples collected 
for analyses of sotatercept serum concentration may also be used to determine concentrations 
of concomitant medications in the background PAH therapy.
9.3.16
Right Heart Catheterization Assessment
Right heart catheterization assessments will be performed as outlined in the right heart 
catheterization manual and will assess several prognostic hemodynamic variables in addition 
to PVR, including right atrial pressure, mPAP, mean PCWP, mixed venous saturation of 
oxygen (SvO2), and CO. Left ventricular end-diastolic pressure may be substituted for mean 
PCWP if mean PCWP is not reliable. The following hemodynamic parameters will be 
assessed when the participant is in a stable hemodynamic rest state (as demonstrated by 3 
consecutive CO measurements within 10% of each other) while the participant is breathing 
ambient air or oxygen:
•
Right atrial pressure, mPAP, mean PCWP, systolic pulmonary artery pressure 
(PAP), diastolic PAP, SvO2, and heart rate
•
Cardiac output measured in triplicate by the thermodilution technique or by the 
Fick method (the same method must be used for all right heart catheterization 
assessments for each participant) 
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PVR will be calculated and populated in the eCRF. RV pressure data from the right heart 
catheterization with simultaneously recorded ECG recordings may be collected and digitally 
stored at the clinical sites.
In order to reduce invasive procedures for participants prior to confirming eligibility, right 
heart catheterization at the Screening Period should be performed last and after all Screening 
tests for eligibility are done, when possible. All right heart catheterizations performed after 
Screening may be performed on the day of study visit or within 1 week prior to study drug 
administration. If other assessments are performed on the same day, right heart 
catheterization should be performed last, when possible. 
9.3.17
Clinical Laboratory Tests
The investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study in the AE section of the case report 
form (CRF). These steps should be completed by the investigator prior to study drug 
administration from Visit 1 onwards.
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 significant and/or abnormal during 
participation in the study or within 6 weeks after the last dose of study treatment should be 
repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or Medical Monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and Acceleron Pharma Inc. notified.
All protocol-required laboratory assessments must be conducted in accordance with the 
SoEs. Please refer to the SoEs (Section 2) for the timing and frequency of clinical laboratory 
tests.
9.3.17.1
Hematology
Hematology (CBC) laboratory assessments will be collected and analyzed locally at the 
investigative sites and will be measured at every visit as outlined in the SoEs. Complete 
blood cell count includes red blood cells (RBCs), absolute white blood cells (WBCs), Hgb, 
hematocrit (Hct), and platelet count.
9.3.17.2
Serum Chemistry
A central laboratory will be used for the analysis of all chemistry laboratory specimens 
collected.
Blood samples for laboratory evaluations will be collected per the SoEs and should be drawn 
prior to dosing. Blood urea nitrogen (BUN), creatinine, total bilirubin, direct bilirubin, AST, 
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ALT, alkaline phosphatase, sodium, potassium, chloride, calcium, phosphorous, glucose, 
magnesium, follicle-stimulating hormone (FSH), albumin, and HCO3 will be measured. 
Investigators must review the results to monitor the participant’s safety.
9.3.17.3
Urinalysis
Urinalysis will be performed per the SoEs using dipsticks provided to sites by the central 
laboratory to evaluate pH, specific gravity, protein, glucose, bilirubin, ketones, blood, 
leukocytes, urobilinogen, and nitrite.
9.3.17.4
Pregnancy Testing
Pregnancy testing (urine or serum) will be performed per the SoEs for all females of 
childbearing potential prior to each dose administration. See Appendix 3 for further 
information.
9.3.18
Clinical Event Information
To ensure current and complete clinical event information is available at the time of database 
locks, updated information may be requested during the study by the Sponsor. For example, 
occurrence of clinical events including efficacy, safety, hospitalizations, lung transplantation, 
and death may be requested before but not limited to, an external Data Monitoring 
Committee (eDMC) review, interim and/or final analysis. Upon Sponsor notification, all 
participants who do not/will not have a scheduled study visit or study contact during the 
Sponsor-defined period will be contacted for their clinical information.
If a participant withdraws consent or is lost to follow-up, vital status (survival information) 
can be conducted by review of medical records or public records when vital status is in 
question in accordance with local regulations, unless the participant has specifically 
withdrawn consent for collection of vital status data.
9.4
Discontinuation and Withdrawal Criteria
9.4.1
Participant Early Discontinuation
Early discontinuation of study treatment refers to permanently stopping study drug 
administration without experiencing lung transplantation or PAH worsening-related 
hospitalization of ≥24 hours during the DBPC Treatment Period, or before the trial has been 
unblinded for participants to rollover into the LTFU Study, A011-12 (SOTERIA).
The reason for early discontinuation from treatment must be recorded in the corresponding 
participant’s eCRF. The investigator must notify Acceleron Pharma Inc. and the Medical 
Monitor when a participant discontinues treatment or withdraws from the study. Reasons that 
may lead to discontinuation from the study treatment include the following:
•
AE If a participant discontinues due to a drug-related SAE or other medical 
reason(s), the participant should be followed at regular intervals until the AE 
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normalizes or the participant returns to their baseline condition, as per 
Section 10.6
•
Participant request (withdrawal of consent): If the participant withdraws from the 
study and withdraws consent for disclosure of future information, no further 
evaluations are to be performed and no additional data are to be collected, and this 
will be recorded as the EOS Visit; Acceleron Pharma Inc. may retain and continue 
to use any data collected before such withdrawal of consent
•
Participant’s unwillingness or inability to comply with the protocol
•
An increase in QTcF of > 60 ms that results in QTcF > 500 ms (or > 550 ms if a 
right bundle branch abnormality is present) during the treatment period
•
More than 3 dose delays required per dose adjustment guidelines (Section 8.3)
•
Pregnancy
•
Women of childbearing potential not using adequate combination of effective 
contraception methods throughout the study
•
Men with a partner of childbearing potential not accepting to use contraceptive 
methods throughout the study
•
Study terminated by sponsor
•
Lost to follow-up
•
Death
All participants who discontinue study treatment early, without experiencing a primary 
endpoint event, should complete the EOT Visit at the time of discontinuation as specified in 
the SoE (Section 2) and EOS Visit (described in Section 9.2.3.2), provided that consent is not 
withdrawn. Following the EOT and EOS Visits, or if the participant refuses to attend 
additional study visits, they will receive quarterly telephone contacts for vital status until the 
study is unblinded. These participants will not be eligible to enroll into the LTFU study,
A011-12 (SOTERIA).
9.4.2
End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study, including the EOT and/or EOS Visits.
A participant who experiences an event of PAH worsening-related hospitalization of 
≥24 hours is considered to have completed the study if they completed the EOT Visit and 
enroll into the LTFU study, A011-12 (SOTERIA), or if they decline enrollment into 
SOTERIA and completed the Follow-up Period including both the EOT and EOS Visits. 
A participant who experiences an event of lung transplantation is considered to have 
completed the study if they completed the Follow-up Period including both the EOT and 
EOS Visits. 
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Participants who discontinue the study early, who experience an event of lung 
transplantation, and who decline enrollment into the LTFU study, A011-12 (SOTERIA) will 
be asked to return to the clinic for the EOS Visit. The end of the study is defined as when the 
last participant completes the last visit.
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.
9.5
Participants Lost to Follow-Up
A participant will be considered lost to follow-up if he/she stops attending scheduled visits 
and is unable to be contacted by the study site.
The following actions must be taken if a participant stops attending study visits:
•
The site must attempt to contact the participant and reschedule the missed visit as
soon as possible, 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). Each attempt at contact must be 
documented in the participant’s study record.
•
If the participant continues to be unreachable after the mentioned attempts, he/she 
will be considered to have withdrawn from the study with a primary reason of lost 
to follow-up, which should be noted on the participant’s eCRF.
9.6
Concomitant Medication and Therapy During Study Conduct
During Screening and throughout the study, participants may take stable doses of 
medications for chronic conditions, including for PAH, as outlined in the study inclusion 
criteria (Section 7.3). There are no restrictions on concomitant medications in this study. 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. The investigator 
may consult the Medical Monitor regarding what constitutes a stable dose or a chronic 
condition. After documenting the ICF, information regarding concomitant medications will 
be collected in the eCRF.
9.7
Treatment Compliance
Each dose of study treatment will be administered by SC injection(s) and must be 
documented in the study record. Accurate recording of all study drug administration must be 
made in the appropriate section of the participant’s eCRF and source documents. 
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Background PAH therapy compliance will be the responsibility of each participant and 
his/her treating physician. The investigator should promote compliance by instructing the 
participant to take their background PAH therapy exactly as prescribed and by stating that 
compliance is necessary for the participant’s safety and the validity of the study. The 
participant is expected to adhere to their background PAH therapy throughout the study and 
should be instructed to contact the investigator if he/she is unable for any reason to take their 
background PAH therapy as prescribed. 
9.8
Criteria for Study Termination
Both Acceleron Pharma Inc. and the Principal Investigator reserve the right to terminate the 
study at any time. Should this be necessary, Acceleron Pharma Inc. or a specified designee 
will inform the appropriate regulatory authorities of the termination of the study and the 
reasons for its termination, and the Principal Investigator will inform the Institutional Review 
Board (IRB)/Independent Ethics Committee (IEC) of the same. In terminating the study, 
Acceleron Pharma Inc. and the Principal Investigator will assure that adequate consideration 
is given to the protection of the participants’ interests.
9.8.1
Study and Site Closure
Acceleron Pharma Inc. reserves the right to close the study site or terminate the study at any 
time for any reason at its sole discretion.
The investigator may initiate study site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by Acceleron Pharma Inc. may include but are 
not limited to the following:
•
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, Acceleron Pharma Inc.’s procedures, or Good 
Clinical Practice (GCP) regulations.
•
Inadequate recruitment of participants by the investigator
•
Discontinuation of further study treatment development
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10
SAFETY ASSESSMENT, REPORTING, AND MONITORING
10.1
Adverse Events
10.1.1
Definitions of Adverse Event
An AE is any untoward medical occurrence in a clinical investigation participant 
administered a study drug, which does not necessarily have a causal relationship with this 
treatment. An AE can, therefore, be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of the 
study drug whether or not it is considered related to the study drug.
Abnormal laboratory and other abnormal investigational findings (e.g., physical examination 
and ECG) should not be reported as AEs unless they are associated with clinical signs and 
symptoms, lead to treatment discontinuation, or are otherwise considered clinically relevant 
by the investigator. In cases of surgical or diagnostic procedures, the condition/illness leading 
to such a procedure is considered as the AE rather than the procedure itself. In case of a 
fatality, the cause of death is considered as the AE, and the death is considered as its 
outcome.
10.1.1.1
Unexpected Adverse Events
An unexpected AE is an event the nature, severity, or outcome of which is not consistent 
with the Reference Safety Information in the current IB.
10.1.1.2
Events Not Considered As Adverse Events
Pre-existing medical conditions/signs/symptoms present 30 days prior to the initial study 
drug administration (Visit 1) that do not worsen in severity or frequency during the study are 
defined as baseline medical conditions and are not to be considered AEs. Anticipated day-to-
day fluctuations of pre-existing conditions, including the disease under study, that do not 
represent a clinically significant exacerbation or worsening need not be considered AEs.
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10.2
Serious Adverse Events
10.2.1
Definition of Serious Adverse Events
An SAE is any event that meets any of the following criteria:
•
Results in death
•
Life threatening
•
Inpatient hospitalization or prolongation of existing hospitalization
•
Results in persistent or significant disability/incapacity
•
Congenital anomaly/birth defect
•
Other: Important medical events that may not result in death, be life threatening, 
or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the participant and may 
require medical or surgical intervention to prevent 1 of the outcomes listed in this 
definition
10.2.2
Definition of Serious Adverse Event Terms
Death: An AE that results in death.
Life threatening: An AE in which the participant was at risk of death at the time of the 
event; it does not refer to an event that, hypothetically, might have caused death if it were 
more severe.
Hospitalization: An AE that requires inpatient hospitalization or prolongation of existing 
hospitalization; however, a hospitalization for an elective procedure will not be considered an 
SAE.
Hospitalization for planned surgery prior to providing documented ICF or routine clinical 
procedures that are not the result of an AE are not to be considered SAEs. If anything 
untoward is reported during the procedure, that occurrence must be reported as an AE, either 
“serious” or “nonserious” according to the usual criteria.
In general, hospitalization signifies that the participant has been detained (usually involving 
at least an overnight stay) at the hospital or emergency ward for observation and/or treatment 
that would not have been appropriate in the physician’s office or outpatient setting. When in 
doubt as to whether “hospitalization” occurred or was necessary, the AE should be 
considered serious.
Events not to be considered as SAEs are hospitalizations related to any of the following:
•
A standard procedure for protocol therapy administration; however, 
hospitalization or prolonged hospitalization for a complication of therapy 
administration will be reported as an SAE
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•
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, and bone marrow sampling); however, 
hospitalization or prolonged hospitalization for a complication of such procedures 
remains a reportable SAE
•
Hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE
•
An elective treatment of a 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
Disability/incapacitating: An AE is incapacitating or disabling if the experience results in a 
substantial and/or permanent disruption of the participant’s ability to carry out normal life 
functions.
Congenital anomaly/birth defect: Congenital anomaly/birth defect in a child of a 
participant or its partner that was exposed to study drug prior to conception or during 
pregnancy.
Important medical event: An important medical event is an event that may not result in 
death, be life threatening, or require hospitalization but may be considered an SAE when, 
based upon appropriate medical judgment, it may jeopardize the participant and may require 
medical or surgical intervention to prevent 1 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. 
10.3
Assessment of Severity
Investigators must evaluate the severity/intensity of AEs and SAEs. If there is a change in 
severity of an AE, it must be recorded as a separate event.
Mild:
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated; usually transient in nature and generally not 
interfering with normal activities
Moderate:
Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (preparing meals, 
shopping for groceries or clothes, using the telephone, managing money, etc.); 
sufficiently discomforting to interfere with normal activities
Severe:
Severe or medically significant; incapacitating; potentially life threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
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prevents normal activities limiting self-care activities of daily living (bathing, 
dressing and undressing, feeding self, using the toilet, taking medications, and 
not bedridden) 
The term “severe” is often used to describe the intensity of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively 
minor medical significance (such as severe headache). This criterion is not the same as 
“serious,” which is based on participant/event outcome or action criteria associated with 
events that pose a threat to a participant’s life or functioning.
10.4
Assessment of Causality
The investigator must determine the relationship between the administration of study drug 
and the occurrence of an AE/SAE as “not suspected” or “suspected” as defined below. 
Factors for the assessment of causal relationship include, but are not limited to, temporal 
relationship between the AE and the administration of study drug, including PK properties of 
sotatercept, known side effects of study drug, medical history, concomitant therapy, course of 
the underlying disease, and pertinent study procedures. Median time to maximum sotatercept 
concentration (Tmax) ranged from 5 to 8 days since first dose. After every 21-day dosing, 
sotatercept concentrations are expected to reach 95% steady state by Week 15 and Tmax at 
steady state can occur relatively early in the first few days after dose.
Not suspected:Means a causal relationship of the AE to study drug administration is unlikely 
or remote, or other medications, therapeutic interventions, or underlying 
conditions provide a sufficient explanation for the observed event.
Suspected:
Means there is a reasonable possibility that the administration of study drug 
caused the AE. “Reasonable possibility” means there is evidence to suggest a 
causal relationship between the study drug and the AE.
10.5
Documenting Adverse Events
It is the responsibility of the investigator to document all AEs that occur during the study. 
Participants will be evaluated and questioned generally for AEs during the course of the 
study starting when documented informed consent is provided. Care will be taken not to 
introduce bias when detecting AEs and/or SAEs. Open-ended and nonleading verbal 
questioning of the participant is the preferred method to inquire about AE occurrences. The 
investigator must report in detail all adverse signs and symptoms that are either volunteered 
by participants or observed during or following the course of investigational product 
administration on the appropriate CRF page. All clearly related signs, symptoms, and 
abnormal results from diagnostic procedures should be recorded under one diagnosis. All 
AEs and SAEs reported after documented informed consent is provided 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 
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procedures will be recorded on the AE eCRF. Any clinically relevant changes in laboratory 
assessments or other clinical findings as described are considered AEs and must be recorded 
on the AE eCRF. 
It is important that each AE report includes a description of the event, duration (onset and 
resolution dates), severity, relationship with study drug, any other potential causal factors, 
any treatment given or other action taken (including dose modification or discontinuation of 
study drug), and outcome. In addition, SAEs should be identified, and the appropriate 
seriousness criteria should be documented. 
Specific guidance can be found in the eCRF Completion Guidelines provided by Acceleron 
Pharma Inc. or designee.
For overdose and cancer (serious and non-serious) and all SAEs, a paper SAE Report Form 
must be completed with a concise account of the event and submitted within the timeframe 
described in Section 10.6.
When new significant information is obtained as well as when the outcome of an event is 
known, the investigator should record the information on a new paper SAE Report Form. If 
the participant was hospitalized, a summary from the investigator should be included as part 
of the participant medical file. In all instances, the investigator should follow up with 
participants until the outcome of the SAE is known.
10.6
Reporting Serious Adverse Events
If an SAE occurs during the reporting period, the investigator must immediately, within a 
maximum of 24 hours after becoming aware of the event, inform Acceleron Pharma Inc. via 
the contract research organization by entry on the eCRF or, if not available, by telephone or 
email. An initial study-specific paper SAE Report Form must also be submitted within 
24 hours of becoming aware of the event.
All written reports must be transmitted using the study-specific paper SAE Report Form, 
which must be completed by the investigator following specific completion instructions. 
Names, addresses, email addresses, and telephone numbers for SAE reporting are located on 
the paper 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 email. Reporting procedures and timelines for 
follow-up information are the same as for the initially reported SAE.
Relevant pages from the CRF may be provided in parallel (e.g., medical history and 
concomitant therapy). In all cases, the information provided in the paper SAE Report Form 
must be consistent with the data that are recorded in the corresponding sections of the CRF.
The investigator/reporter must respond to any request for follow-up information or to any 
question Acceleron Pharma Inc. or designee may have on the (S)AE within the same 
timelines as described for initial reports. This is necessary to permit a prompt assessment of 
the event by Acceleron Pharma Inc. and (as applicable) to allow Acceleron Pharma Inc. to 
meet regulatory timelines associated with expedited reporting obligations.
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Requests for follow-up will usually be made by the responsible clinical research associate or 
Medical Monitor, or an Acceleron Pharma Inc. pharmacovigilance representative who may 
contact the investigator directly to obtain clarification on a particularly critical event.
For overdose and cancer (serious and non-serious) and all SAEs, a paper SAE Report Form 
must be completed with a concise account of the event and submitted within the timeframe 
described in this section.
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 paper SAE Report Form. If 
the participant was hospitalized, a summary from the investigator should be included as part 
of the participant medical file. In all instances, the investigator should follow up with 
participants until the outcome of the SAE is known.
10.6.1
Reporting Period and Monitoring of Participants with Adverse Events
All AEs must be recorded in the eCRF from the signing of the ICF up until the EOS Visit. 
All participants who took at least 1 dose of study drug, whether they completed the DBPC 
Treatment Period or not, should complete the EOS Visit unless they are transitioning into the 
LTFU study, A011-12 (SOTERIA), provided that consent is not withdrawn. 
All AEs will be followed until return to screening baseline, resolution, or clinical database 
lock. All SAEs will undergo active follow-up until resolved or the event becomes chronic or 
stable. Follow-up data for SAEs obtained after clinical database lock will be incorporated 
into the sotatercept safety database.
10.6.2
Safety Reporting to Health Authorities, Independent Ethics Committees, 
Institutional Review Boards, and Investigators
Acceleron Pharma Inc. will submit appropriate safety notifications to Health Authorities in 
accordance with applicable laws and regulations.
The investigator must comply with any applicable site-specific requirements related to the 
reporting of safety events involving his/her participants to the IEC that approved the study.
In accordance with International Council for Harmonisation (ICH) GCP guidance, Acceleron 
Pharma Inc. will inform the investigator of findings that could adversely affect the safety of 
participants, impact the conduct of the study, or alter the IEC’s approval/favorable opinion to 
continue the study.
Acceleron Pharma Inc. will inform the investigator of AEs that are both serious and 
unexpected and are considered to be related to study drug (suspected unexpected serious 
adverse reactions [SUSARs]). The investigator should place copies of these Safety Reports in 
the Investigator Site File, if applicable. National regulations with regard to Safety Report 
notifications to investigators will be followed.
When specifically required by regulations and guidelines, Acceleron Pharma Inc. will 
provide appropriate Safety Reports directly to the concerned lead IEC and will maintain 
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records of these notifications. When direct reporting by Acceleron Pharma Inc. is not clearly 
defined by national or site-specific regulations, the investigator will be responsible for 
promptly notifying the concerned IEC of any Safety Reports and for filing copies of all 
related correspondence in the Investigator Site File.
For studies covered by the European Union Clinical Trials Directive 2001/20/EC, Acceleron 
Pharma Inc.’s responsibilities regarding the reporting of SAEs/SUSARs will be carried out in 
accordance with that Directive and with the related Detailed Guidances.
10.7
Overdose
An overdose is defined as the administration of a quantity of a medicinal product given per 
administration or cumulatively which is above the maximum recommended dose according 
to the authorized product information.
Sotatercept dosing is weight-based. Any dose exceeding that of the study-prescribed dose is 
considered an overdose (see current IB).
Any instance of overdose (suspected or confirmed and irrespective of whether or not it 
involved sotatercept) as defined in the protocol, with or without an AE, must be 
communicated to Acceleron Pharma Inc. or a specified designee within 24 hours and be fully 
documented as an AE in the CRF. Additionally, the Serious Adverse Event Reporting Form 
must be submitted within the same timeframe. This form is to be submitted to the PPD PVG 
at the email address found at the bottom of the form.
There is no antidote for sotatercept, and it is not dialyzable from blood. Therefore, in case of 
overdose, participants should be monitored/treated as per clinical practice based on 
symptoms of potential risks as described in the current IB.
10.8
Pregnancy
The investigator will attempt to collect pregnancy information if a female participant or a 
male participant’s female partner becomes pregnant while the participant is participating in 
this study and up to 16 weeks (112 days) after last dose of study treatment, unless the 
participant is enrolled in the SOTERIA study. If the participant is enrolled in SOTERIA after 
completion of this study, pregnancy will be reported and followed up in SOTERIA. The 
pregnancy information will be recorded on the appropriate form and must be submitted to 
Acceleron Pharma Inc. within 24 hours of learning of the pregnancy. The participant or 
partner will be followed for the outcome of the pregnancy. Information on the status of the 
mother and child will be forwarded to Acceleron Pharma Inc. or designee. Generally, follow-
up will be no longer than 6 to 8 weeks following the estimated delivery date. Any premature 
termination of the pregnancy will be reported as an AE. Abnormal pregnancy outcomes (e.g., 
spontaneous abortion [includes miscarriage and missed abortion], fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy, and neonatal death) are considered SAEs. Any 
neonatal death that occurs within 1 month of birth should be reported, without regard to 
causality, as an SAE. Details of all pregnancies in female participants and female partners of 
male participants will be collected after the start of study treatment and until 16 weeks 
(112 days) after the last dose.
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If a pregnancy is reported, the investigator must inform Acceleron Pharma Inc. within 
24 hours of learning of the pregnancy. If pregnancy is reported, the participant will be 
discontinued from the study treatment.
10.9
Monitoring of Identified Risks, Potential Risks, and Adverse Events of Special 
Interest
Adverse events of special interest (AESIs) are considered important parameters to be 
monitored in order to assess the overall safety of the PAH population and therefore will be 
included in safety monitoring in the sotatercept clinical trial. For further information, consult 
the current IB.
Laboratory data and vital signs are monitored on an ongoing basis by the investigator and 
Medical Monitor in the study. Laboratory data and AEs are measured as per study schedule 
or upon an unscheduled visit, if applicable. Details regarding dose modifications due to 
decreases in platelets, increases in Hgb, and events of moderate or severe telangiectasia are 
provided in Section 8.3.
Additional reviews will be performed periodically as part of standard safety signal detection 
and medical monitoring. Finally, an independent DMC will be convened to monitor the 
safety of the study participants. An independent blinded adjudication committee will 
adjudicate clinical events up to the end of the study, including death, to determine whether 
these events are due to PAH.
10.9.1
Adverse Event of Special Interest
Monitoring of the AESI is detailed in Table 6. 
Based on review of safety data from the PULSAR and STELLAR studies, and the adequacy 
of routine safety monitoring described above, hepatic toxicity, leukopenia, and neutropenia 
are no longer considered as AESIs and will be followed by routine medical monitoring and 
signal detection activities.
Table 6
Monitoring of Adverse Events of Special Interest
Description
Monitoring Parameters
Telangiectasia
Any investigator who reports an AE of telangiectasia 
(spider veins, spider naevi) must complete a customized 
page in the eCRF. Investigators are strongly encouraged to 
have the participant evaluated by a dermatologist, or other 
appropriate specialist, and to consider photo-
documentation of the affected skin.
AE = adverse event; eCRF = electronic case report form
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11
STATISTICAL ANALYSES
11.1
Overview
This is a Phase 3, randomized, double-blind, placebo-controlled, multicenter, parallel-group 
study to evaluate sotatercept when added to maximum tolerated background PAH therapy in 
participants with PAH WHO FC III or IV at high risk of mortality.
Planned statistical analyses to be conducted are outlined in the sections that follow.
Additional details will be described in the statistical analysis plan (SAP) and will include, but 
not necessarily be limited to, the analysis populations to be used in the analyses as well as 
additional details of procedures for accounting for missing data as needed. Modifications 
and/or clarifications to protocol-specified statistical analyses as well as any other additional 
statistical analyses will be added to the SAP. The SAP will be developed and finalized before 
the study is unblinded and the database is locked.
11.2
Sample Size Determination
The sample size determination is based on the primary efficacy endpoint of time to first event 
of all-cause death, lung transplantation, or PAH worsening-related hospitalization 
of ≥24 hours using EAST® version 6.4. In STELLAR, the hazard ratio in the sotatercept 
group compared with the placebo group was 0.16 (95% CI: 0.08 to 0.35) [Hoeper, M. M., et 
al 2023]. Given the differences in the populations and definitions of endpoints between 
STELLAR and this study, the hazard ratio is assumed to be 0.55 in this study. Assuming a 
hazard ratio of 0.55, a 1:1 randomization, a 1-sided 0.025 Type 1 error rate, 90% power, and 
with a planned IA at approximately 50% of the required number of events with the option to 
stop the study for futility, approximately 118 events will be required based on the log-rank 
test. 
Given that approximately 166 participants are planned to be enrolled in this study, the 
accrual period is approximately 26 months, assuming an accrual rate of approximately 
6.5 participants per month. In addition, assuming a dropout rate of 0.04% per month (0.5% 
per year), and the probability of observing an event for placebo is 0.45 for the first year, 0.60 
for the second year, and 0.90 for the third year and later, the projected time of the IA will 
occur around 26 months. If the study continues after IA, the final analysis will happen around 
40 months. Another criterion for conducting the IA is that median participant time on study 
must be at least 6 months in order for analyses following the occurrence of the required 
number of events.
11.3
Populations for Analysis
The populations to be used for statistical analyses are listed below.
•
Full Analysis Set (FAS): All randomized participants. All participants will be 
analyzed according to the treatment arm to which the participant is randomized.
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•
Safety Set: All participants who receive at least 1 dose of study treatment. All 
participants will be analyzed according to the treatment they are administered.
11.4
Statistical Methods
The SAP will be developed and finalized before database lock and will describe the 
populations to be used in the analyses and additional details of procedures for accounting for 
missing, unused, and spurious data as needed. In general, the aligned rank stratified 
Wilcoxon test [Mehrotra, D. V., et al 2010] [Hodges, J. L., Jr. and Lehmann, E. L. 1962] will 
be used for continuous variables; Cochran-Mantel-Haenszel test will be used for 
dichotomous variables; the stratified log-rank test by the randomization factor and Cox 
regression methods will be used for time-to-event variables. For the primary endpoint, 
efficacy results are deemed to be statistically significant after consideration of controlling the 
overall 1-sided Type 1 error to be at 0.025. For the secondary endpoints, statistical tests 
performed will use 1-sided tests at the 0.025 significance level. Statistical analyses of 
efficacy data will be performed on the FAS. Pooling strategy of the randomization strata 
might be added in the SAP if the data is too sparse across the strata. 
11.5
Study Endpoints
11.5.1
Primary Endpoint
Time to first event of all-cause death, lung transplantation, or PAH worsening-related 
hospitalization of ≥ 24 hours, will be analyzed using a stratified log-rank test with 
randomization factors as strata.
The point estimate of the hazard ratio with 95% CI will be estimated by a Cox regression 
model stratified by the randomization factors.
11.5.1.1
Handling of Censored Data
Participants who do did not experience any of the components of the primary endpoint at the 
time of the data cutoff will be censored. Participants who withdraw from the study or lost to 
follow-up before experiencing any of the components of the primary endpoint will be 
censored at the last known study contact record. Additional details on the handling of 
censored data will be described in the SAP.
11.5.2
Secondary Endpoints
The secondary endpoints are ranked and analyzed as follows:
1. Overall survival will be analyzed using the stratified log-rank test with randomization 
factors as strata. Supportive analyses will include the inverse probability of censoring
weights (IPCW) [Robins, J. M. and Finkelstein, D. M. 2000] and 2-stage, rank 
preserving structural failure time (RPSFT) methods [Robins JM, Tsiatis AA. 1991]. 
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2. Transplant-free survival will be primarily analyzed using the stratified log-rank test 
with randomization factors as strata. Supportive analyses will include the IPCW and 
2-stage, RPSFT methods [Robins JM, Tsiatis AA. 1991].
3. Proportion of participants who experience a mortality event at EOS will be analyzed 
using the Cochran-Mantel-Haenszel test, stratified by the randomization factors.
4. Change in REVEAL Lite 2.0 risk score at 24 weeks from baseline will be analyzed 
using an aligned rank stratified Wilcoxon test with the randomization factors as strata.
5. Proportion of participants achieving a low or intermediate (≤7) REVEAL Lite 2.0 risk 
score at 24 weeks will be analyzed using the Cochran-Mantel-Haenszel test, stratified 
by the randomization factors.
6. Change in NT-proBNP levels at 24 weeks from baseline will be analyzed using the
aligned rank stratified Wilcoxon test with the randomization factors as strata.
7. Change in mPAP at 24 weeks from baseline will be analyzed using the aligned rank 
stratified Wilcoxon test with the randomization factors as strata.
8. Change in PVR at 24 weeks from baseline will be analyzed using the aligned rank 
stratified Wilcoxon test with the randomization factors as strata.
9. Proportion of participants who improve in WHO FC at the end of the DBPC 
Treatment Period will be analyzed using the Cochran-Mantel-Haenszel test, stratified 
by the randomization factors.
10. Change in 6MWD at 24 weeks from baseline will be analyzed using the aligned rank 
stratified Wilcoxon test with the randomization factors as strata.
11. Change in CO at 24 weeks from baseline will be analyzed using the aligned rank 
stratified Wilcoxon test with the randomization factors as strata.
12. Change in EQ-5D-5L index score at 24 weeks from baseline will be analyzed using 
the aligned rank stratified Wilcoxon test with the randomization factors as strata.
A gatekeeping method will be used to control the Type 1 error rate in secondary endpoints by 
testing in the order of the secondary endpoints listed above, after successful testing for the 
primary endpoint at IA or final analysis. Secondary endpoint testing will be performed using 
a 1-sided alpha = 0.025 level proceeding successively in the order of the secondary endpoints 
listed above after each of the preceding endpoints is tested to be statistically significant.
The handling of missing data for missing secondary endpoints will be described in the SAP.
11.5.3
Exploratory Endpoints
Other endpoints of interest are the following:
•
The number of PAH-related hospital days during the study will be analyzed using 
a Poisson regression model.
•
The change in echocardiogram parameter data describing RV-PA coupling 
(TAPSE/PASP) at 24 weeks from baseline 
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•
The change in biomarker data at 24 weeks from baseline
•
Proportion of participants achieving a low or intermediate-low COMPERA 2.0 
4-strata risk score (Section 9.3.6) at 24 weeks
All exploratory endpoints will be summarized using descriptive statistics. No adjustments for 
multiplicity will be performed for statistical analyses of exploratory endpoints.
11.5.4
Estimands
The estimands of this study were constructed in accordance with ICH E9 (R1).
The Treatment and Population attributes of all estimands in this study are as follows:
Treatment: Sotatercept or placebo on top of background PAH therapy.
Population: Adults with PAH WHO FC III or FC IV.
The Endpoint, Intercurrent Events, and Population-level Summary attributes for each 
estimand are provided below.
11.5.4.1
Estimand for Time-to-Event Endpoints
Endpoints:
•
Primary endpoint: Time to first event of all-cause death, lung transplantation, or 
PAH worsening-related hospitalization of ≥24 hours.
•
Secondary endpoints:
-
Overall survival, defined as the time to date of death due to any cause
-
Transplant-free survival, defined as the time to the first lung transplantation or 
death from any cause
Intercurrent events: Changes in treatment (dose reduction, dose delay, discontinuation from 
sotatercept or placebo, or changes to background PAH therapy); a treatment policy strategy 
will be used. Thus, the endpoint is of interest regardless of changes in treatment.
Population-level summary: Hazard ratio (sotatercept relative to placebo)
11.5.4.2
Estimand for Continuous Secondary Endpoints
Endpoints: Change from baseline at Week 24 in each of the following, with death prior to 
Week 24 represented quantitatively by any fixed worst-rank change from baseline to reflect 
the worst clinical outcome:
•
REVEAL Lite 2.0 risk score
•
NT-proBNP
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•
mPAP
•
PVR
•
6MWD
•
CO
•
EQ-5D-5L index score
Intercurrent events:
•
Changes in treatment: Same as for the estimand for the time-to-event endpoints.
•
Death: A composite strategy will be implemented, in which the occurrence of 
death is incorporated into the definition of the endpoint.
Population-level summary: The midpoint of the distribution of the variable/endpoint noted 
above, compared between treatment conditions using a difference (sotatercept minus 
placebo) in midpoints; this between-treatment difference is referred to in statistical terms as 
the location-shift parameter.
11.5.4.3
Estimand for Binary Secondary Endpoints
Endpoints: Indicator (yes/no) of meeting each of the following:
•
Achievement of a low or intermediate [≤7] REVEAL Lite 2.0 risk score at 
Week 24, where death prior to Week 24 is defined as not having met the criteria
•
Mortality event
•
Improvement in WHO FC, where death prior to the end of the DBPC Treatment 
Period is defined as not having met the criteria
Intercurrent events:
•
Changes in treatment: Same as for the estimand for the time-to-event endpoints
•
Death (applicable to only the first and third binary endpoints): A composite 
strategy will be used, such that anyone who dies prior to Week 24 without having 
had the endpoint is considered to be a failure.
Population-level summary: The difference (sotatercept minus placebo) in proportions of 
patients achieving responses.
11.6
Analysis of Safety
All safety analyses will be performed on the Safety Set. All participants will be analyzed 
according to the treatment they are administered.
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AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). AE
listings will include the verbatim term and the MedDRA preferred term. Treatment-emergent 
adverse events are defined as an AE that starts after the first administration of study drug up 
to 8 weeks after the last dose and summarized by worst severity grade, system organ class, 
and preferred term. Treatment-emergent adverse events (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 arm. Clinically 
significant laboratory abnormalities will be listed and summarized by treatment arm. 
Chemistry and hematology laboratory tests will be collected regularly and reviewed 
periodically. Descriptive statistics (mean, standard deviation, standard error of the mean, 
median, minimum, and maximum) will be provided for each timepoint of the collection by 
treatment arm for each timepoint analyzed. 
Vital sign measurements will be listed for each participant at each visit. Descriptive statistics 
for vital signs, both observed values and changes from baseline, will be summarized by 
treatment arm.
Immunogenicity (incidence/titer of ADA) will also be analyzed.
11.7
Pharmacokinetic Analysis
Population PK analysis will be performed using nonlinear mixed-effect modeling. 
Concentration data obtained from this study and other studies will be combined to develop a 
population PK model that describes the PK exposure data and the associated variability. 
Participant-specific factors (demographics, baseline characteristics, markers for organ 
function, ADAs against sotatercept, etc.) will be explored as covariates for their potential to 
influence sotatercept PK parameters. Empiric individual Bayesian estimates of PK 
parameters will be generated, and using the final population PK model, appropriate measures 
of sotatercept exposure (area under the curve, maximum plasma concentration, or other 
exposure metrics of interest) will be computed for each participant. The relationship between 
serum sotatercept exposure and the primary efficacy endpoint, AEs of interest, or other 
selected secondary endpoints will be explored as appropriate.
Full details will be included in a separate PK and PK/PD Data Analysis Plan.
11.8
Interim Analysis
An IA of the primary efficacy endpoint is planned to occur when approximately 59
participants have experienced a primary endpoint event (roughly 50% of the required number 
of events) and the median participant follow-up time is at least 6 months. A stratified log-
rank test with randomization factors as strata will be used for the analysis of the primary 
efficacy endpoint. The point estimate of the hazard ratio with 95% CI will be estimated by a 
Cox regression model stratified by the randomization factors.
The IA will be performed by an unblinded independent statistics provider and will be 
presented to the DMC where a recommendation will be communicated to the Executive 
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Oversight Committee (EOC), which is comprised of members of Sponsor Senior 
Management. The EOC will receive and decide upon any recommendations made by the 
DMC regarding the study. Table 7 shows the boundary properties for the planned interim and 
final analysis of the primary endpoint. The efficacy boundary is derived using a Lan-DeMets 
spending function approximating O’Brien-Fleming bounds [Lan, K. K. G. and DeMets, D. L. 
1983] and the futility boundary is derived using a gamma family spending function 
approximating Hwang-Shi-Decani bounds [Hwang, I. K., et al 1990] with gamma = -7. If the 
actual number of events at the IA and final analysis differ from those specified in the table, 
the bounds will be adjusted using this spending function evaluated at the observed 
information fraction (fraction of observed over expected final events) at each analysis.
Table 7
Efficacy and Futility Boundaries and Properties for the Primary Endpoint
Analysis
Value
Efficacy
Futility
IA: 50% a
information fraction
Required events: 59
Timing: 26 months
N: 166
Z
2.963
-0.458
p (1-sided)b
0.0015
0.677
HR at boundaryc
0.461
1.127
Final Analysis:
Required events: 118
Timing: 40 months
N: 166
Z
1.969
NA
p (1-sided)
0.0245
NA
HR at boundary
0.695
NA
HR = hazard ratio; IA = interim analysis. The number of events and timings are estimated.
a
Percentage of total planned events at the IA.
b
p (1-sided) is the nominal α for group sequential testing.
c
The HR at boundary is the approximate HR required to reach an efficacy/futility bound.
If the efficacy boundary is crossed for the primary endpoint at the IA, then analyses of 
secondary endpoints will be performed using a gatekeeping method as described for 
secondary endpoints in Section 11.5.2. The 1-sided Type 1 error rate for the evaluation of 
secondary endpoints should be 0.025.
11.9
Subgroup Analysis
Analyses of the primary endpoint will be conducted on the following subgroups provided the 
sample size in the subgroup category is at least 16:
•
Baseline REVEAL Lite 2.0 risk score (9 to 10 or ≥11) at Screening Visit
•
PAH subtype (CTD-associated or not CTD-associated)
•
Baseline WHO FC (III or IV)
Additional subgroups may be considered and will be listed in the SAP.
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11.10 Event Adjudication Committee and Data Monitoring Committee
An independent blinded adjudication committee will adjudicate clinical events up to the end 
of the study, including death, to determine whether these events are due to PAH. The 
adjudication of potential events will be based on available source documentation, including 
but not limited to anonymized individual clinical study data, office visit notes, hospital 
records, laboratory analysis, discharge/death summaries, procedural reports and imaging, 
and/or death certificates. All personnel involved in the adjudication process will remain 
blinded to study drug allocation throughout the study. The assessment of events will be 
conducted in compliance with study-specific procedures, manuals, GCP, and all other 
applicable regulatory requirements, including the archiving of essential documents. The 
adjudication guidance and clinical endpoint definitions are described in detail in the
adjudication committee charter.
An external, independent DMC will review unblinded safety data throughout the course of 
the study. A detailed charter will outline all activities of the DMC (including, but not limited 
to, the composition of the DMC, the type of data to be reviewed, the DMC responsibilities, 
and the frequency of meetings). Internal data review of safety-related data will occur in a 
blinded manner at a preplanned frequency throughout the study duration.
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12
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
12.1
Study Monitoring
Acceleron Pharma Inc. personnel (or designee) will monitor each site throughout the study at 
predetermined intervals to check for study progress, to identify any problems, and to ensure 
compliance with the protocol, GCP, and other regulations. 
Source document verification will be performed against entries on the eCRFs according to 
the study monitoring plan (see Section 14.1 for additional details on source documentation). 
12.2
Audits and Inspections
Acceleron Pharma Inc. or the IRB/IEC may audit the investigator’s records both during and 
after the study. The purpose of the audit is to ensure that ethics, regulatory, and quality 
requirements are fulfilled in all studies sponsored by Acceleron Pharma Inc. 
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13
ETHICS AND RESPONSIBILITIES
13.1
Good Clinical Practice
This study will be conducted in accordance with the standard of ICH GCP, an international 
ethical and scientific quality standard for designing, conducting, recording, and reporting 
studies that involve human participants. Compliance with these standards provides assurance 
that the rights, safety, and well-being of study participants are protected, consistent with the 
principles in the Declaration of Helsinki, and that the clinical study data are credible. All 
applicable country and local regulations will also be observed.
13.2
Regulatory and Ethical Considerations
The following regulatory and ethical considerations will be applied:
•
This study will be conducted in accordance with the protocol and with the 
following: 
-
Consensus ethical principles derived from international guidelines including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences International Ethical Guidelines 
-
ICH GCP guidance and regulations 
-
Applicable laws and regulations 
•
The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 
•
Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 
•
The investigator will be responsible for the following: 
-
Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/IEC 
-
Notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures 
-
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations Part 312, ICH guidelines, 
IRB/IEC, European Regulation 536/2014 for clinical studies (when 
applicable), European Union Clinical Trials Directive 2001/20/EC (when 
applicable), and all other applicable local regulations 
13.3
Institutional Review Board/Independent Ethics Committee
It is the responsibility of the investigator to ensure that the appropriate IRB/IEC has reviewed 
and approved this protocol prior to initiating the study. The investigator must provide 
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Acceleron Pharma Inc. or Acceleron Pharma Inc.’s representative with current and revised 
IRB/IEC membership rosters that include the members’ occupations and qualifications. Sites 
within the US may provide a copy of the US Department of Health and Human Services 
Assurance Number.
The IRB/IEC must also review and approve the clinical site’s ICF, other written information 
provided to the participant, and all advertisements that may be used for study recruitment. 
The investigator will provide the study monitor with copies of these documents and of dated 
IRB/IEC approval(s) prior to the start of the study.
If the protocol or the ICF is amended during the study, the investigator is responsible for 
ensuring that the IRB/IEC has reviewed and approved these amended documents. Approval 
of the amended documents must be obtained from the IRB/IEC before implementation and 
before new participants are consented to participate in the study using the amended version 
of the ICF. The investigator must provide Acceleron Pharma Inc. with the dated IRB/IEC 
approval of the amended documents as soon as available.
13.4
Informed Consent
Prior to study entry, the investigator or designee will explain the nature, purpose, benefits, 
and risks of participation in the study to each participant, participant’s legally acceptable 
representative, or impartial witness. Participants must be informed that their participation is 
voluntary. Documented informed consent must be obtained prior to the participant entering 
the study (before initiation of any study-related Screening procedure). Sufficient time will be 
allowed to discuss any questions raised by the participant. The ICF, which will contain all 
US federally required elements, all ICH-required elements, and Health Insurance Portability 
and Accountability Act authorization information in a language that is understandable to the 
participant, must be documented by all participants. The authorized person obtaining the 
informed consent must also document and date the ICF. A copy of the ICF(s) must be 
provided to the participant or the participant’s legally authorized representative, and such 
action must be documented according to local requirements. The process of documenting 
consent will be in compliance with all applicable local and country regulations and ICH 
requirements.
If the ICF is amended during the study, the investigator must follow all applicable regulatory 
requirements pertaining to IRB/IEC approval of the amended form. The clinical site must use 
the amended ICF for all new participants and must reconsent any ongoing participants with 
the amended ICF, if instructed to do so by the IRB/IEC.
The consent and reconsent process must be properly documented in the source 
documentation. The medical record must include a statement that documented informed 
consent was obtained before the participant was enrolled in the study as well as the time and 
date the written consent was obtained.
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STUDY A011-14, AMENDMENT 03, VERSION 4.0 (MK-7962-006-07)
23 April 2024
Acceleron Pharma Inc.
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14
DATA HANDLING AND RECORD KEEPING
14.1
Source Documentation
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available for source data verification.
14.2
Data Quality Assurance
The following data quality assurance considerations will be applied:
•
All participant data relating to the study will be recorded on an eCRF unless 
transmitted to Acceleron Pharma Inc. or designee electronically (e.g., laboratory 
data). The investigator is responsible for verifying that data entries are accurate 
and correct by electronically documenting the eCRF. 
•
The investigator must maintain accurate documentation (source data) that 
supports the information entered in the eCRF. 
•
The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 
•
Acceleron Pharma Inc. or designee is responsible for the data management of this 
study including quality checking of the data. 
•
Study monitors will perform ongoing source data verification as indicated to 
confirm that data entered into the eCRF by authorized site personnel are accurate, 
complete, and verifiable from source documents; that the safety and rights of 
participants are being protected; and that the study is being conducted in 
accordance with the currently approved protocol and any other study agreements, 
ICH GCP, and all applicable regulatory requirements. 
•
Records and documents, including documented ICFs, pertaining to the conduct of 
this study must be retained by the investigator for 2 years after the last marketing 
application approval or 2 years after formal discontinuation of the clinical
development of the investigational product, unless local regulations or 
institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of Acceleron 
Pharma Inc. No records may be transferred to another location or party without 
written notification to Acceleron Pharma Inc. 
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CLINICAL STUDY PROTOCOL
SOTATERCEPT (ACE-011)
STUDY A011-14, AMENDMENT 03, VERSION 4.0 (MK-7962-006-07)
23 April 2024
Acceleron Pharma Inc.
Page 95 of 117
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15
STUDY REPORT AND PUBLICATIONS
Acceleron Pharma Inc. is responsible for preparing and providing the appropriate regulatory 
authorities with clinical study reports (CSRs) according to the applicable regulatory 
requirements.
The publication policy of Acceleron Pharma Inc. is discussed in the investigator’s Clinical 
Research Agreement.
All information concerning sotatercept is considered confidential and shall remain the sole 
property of Acceleron Pharma Inc. The investigator agrees to use this information only in 
conducting the study and shall not use it for any other purposes without the written approval 
of Acceleron Pharma Inc. The investigator agrees not to disclose Acceleron Pharma Inc.’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 Acceleron Pharma Inc. in connection with the development of sotatercept, 
and therefore may be disclosed as required to regulatory agencies. To allow for the use of the 
information derived from clinical studies, it is understood that there is an obligation to 
provide Acceleron Pharma Inc. with complete test results and all data developed in the study.
No publication or disclosure of study results will be permitted except as specified in a 
separate, written agreement between Acceleron Pharma Inc. and the investigator.
Acceleron Pharma Inc. will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practices, Acceleron Pharma Inc. 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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CLINICAL STUDY PROTOCOL
SOTATERCEPT (ACE-011)
STUDY A011-14, AMENDMENT 03, VERSION 4.0 (MK-7962-006-07)
23 April 2024
Acceleron Pharma Inc.
Page 96 of 117
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16
CONFIDENTIALITY
All information generated in this study is considered highly confidential and must not be 
disclosed to any person or entity not directly involved with the study unless prior written 
consent is gained from Acceleron Pharma Inc. However, authorized regulatory officials, 
IRB/IEC personnel, Acceleron Pharma Inc., and its authorized representatives are allowed 
full access to the study records.
Identification of participants and CRFs shall be by initials and screening and treatment 
numbers only. If required, the participant’s full name may be made known to an authorized 
regulatory agency or other authorized official.
16.1
Data Protection
The following data protection considerations will be applied:
•
Participants will be assigned a unique identifier by Acceleron Pharma Inc. Any 
participant records or datasets that are transferred to Acceleron Pharma Inc. will 
contain the identifier only; participant names or any information that would make 
the participant identifiable will not be transferred. 
•
The participant must be informed that his/her personal study-related data will be 
used by Acceleron Pharma Inc. in accordance with local data protection law. The 
level of disclosure must also be explained to the participant. 
•
The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed by 
Acceleron Pharma Inc., by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities. 
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CLINICAL STUDY PROTOCOL
SOTATERCEPT (ACE-011)
STUDY A011-14, AMENDMENT 03, VERSION 4.0 (MK-7962-006-07)
23 April 2024
Acceleron Pharma Inc.
Page 97 of 117
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17
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CLINICAL STUDY PROTOCOL
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STUDY A011-14, AMENDMENT 03, VERSION 4.0 (MK-7962-006-07)
23 April 2024
Acceleron Pharma Inc.
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CLINICAL STUDY PROTOCOL
SOTATERCEPT (ACE-011)
STUDY A011-14, AMENDMENT 03, VERSION 4.0 (MK-7962-006-07)
23 April 2024
Acceleron Pharma Inc.
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CLINICAL STUDY PROTOCOL
SOTATERCEPT (ACE-011)
STUDY A011-14, AMENDMENT 03, VERSION 4.0 (MK-7962-006-07)
23 April 2024
Acceleron Pharma Inc.
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CLINICAL STUDY PROTOCOL
SOTATERCEPT (ACE-011)
STUDY A011-14, AMENDMENT 03, VERSION 4.0 (MK-7962-006-07)
23 April 2024
Acceleron Pharma Inc.
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CLINICAL STUDY PROTOCOL
SOTATERCEPT (ACE-011)
STUDY A011-14, AMENDMENT 03, VERSION 4.0 (MK-7962-006-07)
23 April 2024
Acceleron Pharma Inc.
Page 102 of 117
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CLINICAL STUDY PROTOCOL
SOTATERCEPT (ACE-011)
STUDY A011-14, AMENDMENT 03, VERSION 4.0 (MK-7962-006-07)
23 April 2024
Acceleron Pharma Inc.
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CLINICAL STUDY PROTOCOL
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CLINICAL STUDY PROTOCOL
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18
APPENDICES
Appendix 1
Abbreviations and Specialist Terms
6MWD
6-minute walk distance
6MWT
6-minute walk test
ADA
Anti-drug antibody
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
BMP
Bone morphogenetic protein
BMPR2
Bone morphogenetic protein type II receptor
BNP
B-type natriuretic peptide
BP
Blood pressure
BUN
Blood urea nitrogen
CBC
Complete blood cell (count)
CHD
Congenital heart defects
CI
Confidence interval
CO
Cardiac output
CRF
Case report form
CRP
C-reactive protein
CSR
Clinical study report
CTD
Connective tissue diseases
DBPC
Double-blind placebo-controlled
DMC
Data monitoring committee
ECG
Electrocardiogram
eCRF
Electronic case report form
eDMC
External Data Monitoring Committee
eGFR
Estimated glomerular filtration rate
EOC
Executive Oversight Committee 
EOS
End of Study
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EOT
End of Treatment
EQ-5D-5L
EuroQoL-5 dimensions scale 5 levels
E-R
Exposure-response
FAS
Full analysis set
FC
Functional class
FDA
Food and Drug Administration
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
GDF
Growth and differentiation factor
HCO3
Bicarbonate
Hct
Hematocrit
Hgb
Hemoglobin
HHC
Home health care
HRT
Hormone replacement therapy
IA
Interim analysis
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IPCW
Inverse probability of censoring weights
IRB
Institutional Review Board
IRT
Interactive Response Technology
LTFU
Long-term follow-up
LVEDP
Left ventricular end-diastolic pressure
m
meters
MedDRA
Medical Dictionary for Regulatory Activities
mPAP
Mean pulmonary artery pressure
NT-proBNP
N-terminal prohormone B-type natriuretic peptide
PA
Pulmonary artery
PAH
Pulmonary arterial hypertension
PAP
Pulmonary artery pressure
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PASP
Pulmonary artery systolic pressure
PAWP
Pulmonary artery wedge pressure
PCWP
Pulmonary capillary wedge pressure
PH
Pulmonary hypertension
PK
Pharmacokinetic(s)
PRO
Patient-reported outcome
PVR
Pulmonary vascular resistance
QTcF
Fridericia’s corrected QT interval
RBC
Red blood cell
REVEAL
Registry to Evaluate Early and Long-Term PAH Disease 
Management
RPSFT
Rank preserving structural failure time
RV
Right ventricular
SAE
Serious adverse event
SAP
Statistical analysis plan
SC
Subcutaneous(ly)
SoE
Schedule of Events
SpO2
Oxygen saturation
SUSAR
Suspected unexpected serious adverse reaction
SvO2
Mixed venous saturation of oxygen
TAPSE
Tricuspid annular plane systolic excursion
TEAE
Treatment-emergent adverse event
Tmax
Time to maximum sotatercept concentration
ULN
Upper limit of normal
US
United States
VSMC
Vascular smooth muscle cell
WBC
White blood cell
WHO
World Health Organization
WOCBP
Woman of childbearing potential
WU
Wood units
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Appendix 2
REVEAL Lite 2.0 Updated PAH Risk Score Calculator
Sites will use this score to ensure that entry criterion 4: REVEAL Lite 2.0 risk score ≥9, is 
met by the participant at enrollment. The Sponsor will calculate the REVEAL Lite 2.0 risk 
score for all other study visits (Visits 1 to 5, Visit 9, quarterly site visits, EOT Visit, and EOS 
Visits).
Importantly, the Screening NT-proBNP and eGFR samples taken at the initial Screening 
Visit should be submitted to the central laboratory for analysis as soon as possible to ensure 
availability of results prior to randomization. 
BPM = beats per minute; eGFR = estimated glomerular filtration rate; HR = heart rate; 
NT-proBNP = N-terminal prohormone B-type natriuretic peptide; NYHA = New York Heart Association; 
PAH = pulmonary arterial hypertension; REVEAL = Registry to Evaluate Early and Long-Term PAH Disease 
Management; SBP = systolic blood pressure; WHO = World Health Organization.
¹The average of the 2 Screening 6MWDs should be used for score calculation as described in Section 9.3.2.
²Central laboratory NT-proBNP result from Screening Visit should be used for score calculation as described in 
Section 9.3.11. Sources:[Benza, R. L., et al 2019] [Benza, R. L., et al 2021]
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Appendix 3
Contraceptive Guidance and Collection of Pregnancy Information
DEFINITIONS
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Premenopausal female with 1 of the following:
•
Documented hysterectomy
•
Documented bilateral salpingectomy
•
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview.
3. Postmenopausal female 
•
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high 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.
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CONTRACEPTION GUIDANCE 
Male Participants
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to 1 of the following (during the protocol-defined time frame in Section 6.1):
•
Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent
•
Agree to use a male condom when having penile-vaginal intercourse with a 
WOCBP who is not currently pregnant
Men with a partner who is pregnant, breastfeeding, or of childbearing potential 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 16 weeks (112 days) after the 
last dose of study treatment. Refrain from donating blood or sperm for the duration of the 
study and for 16 weeks (112 days) after the last dose of study treatment.
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 8.
Females who are exclusively in same-sex relationships are exempt for contraception 
guidelines. 
Female participants of childbearing potential must agree to use highly effective forms of 
birth control for at least 28 days prior to starting the investigational product and agree to use 
the same highly effective contraception in combination with a barrier method while 
participating in the study, and for at least 16 weeks (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 16 weeks (112 days) after the last dose of study 
treatment.
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Table 8
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependenta
Failure rate < 1% per year when used consistently and correctly
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulation
•
Oral
•
Intravaginal
•
Transdermal
Progestogen-only hormonal contraception associated with inhibition of ovulation
•
Oral
•
Injectable
Highly Effective Methods That Are User Independenta
Implantable progestogen-only hormonal contraception associated with inhibition of ovulation
•
Intrauterine device
•
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.
WOCBP = woman of childbearing potential
a
Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for participants participating in 
clinical studies.
Pregnancy Testing
•
A WOCBP 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 as described in Section 10.8.
•
After obtaining the necessary documented informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the appropriate 
form and submit it to Acceleron Pharma Inc. 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 Acceleron Pharma Inc. 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 as described in Section 10.8.
Information will be recorded on the appropriate form and submitted to Acceleron 
Pharma Inc. 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 Acceleron Pharma Inc. 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 Acceleron Pharma Inc. as 
described in Section 10.8. While the investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
•
Any female participant who becomes pregnant while participating in the study will 
discontinue study treatment.
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Appendix 4
Six-Minute Walk Test
The 6MWT should be performed indoors, along a long, flat, straight, enclosed corridor with a 
hard surface that is seldom traveled. The walking course must be 30 m in length (or at least 
15 m) and should be at the same location that is used for all study visits. The length of the 
corridor should be marked every 3 m. The turnaround points should be marked (e.g., with a 
cone). A starting line, which marks the beginning and end of each 60-m lap, should be 
marked on the floor (e.g., using brightly colored tape).
REQUIRED EQUIPMENT
1. Countdown timer (or stopwatch)
2. Mechanical lap counter 
3. Two small cones to mark the turnaround points
4. A chair that can be easily moved along the walking course
5. Worksheets on a clipboard
6. A source of oxygen
7. Sphygmomanometer
8. Telephone
9. Automated electronic defibrillator
10. Portable pulse oximeter
PARTICIPANT PREPARATION
1. Comfortable clothing should be worn.
2. Appropriate shoes for walking should be worn.
3. Participants should use their usual walking aids during the test (cane, walker, etc.).
4. The participant’s usual medical regimen should be continued.
5. A light meal is acceptable before early morning or early afternoon tests.
6. Participants should not have exercised vigorously within 2 hours of beginning the 
test.
MEASUREMENTS 
1. Repeat testing should be performed about the same time of day to minimize intraday 
variability.
2. A “warm-up” period before the test should not be performed.
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3. The participant should sit at rest in a chair, located near the starting position, for at 
least 10 minutes before the test starts. During this time, check for contraindications, 
measure pulse and BP, and make sure that clothing and shoes are appropriate. Record 
in the source documents.
4. Measure and record baseline heart rate and oxygen saturation (SpO2) and follow the 
manufacturer’s instructions to maximize the signal and to minimize motion artifact.
Make sure the readings are stable before recording. Note pulse regularity and whether 
the oximeter signal quality is acceptable.
5. Have the participant stand and rate their baseline dyspnea using the Borg Dyspnea 
Scale (Borg CR10 Scale).
a.
Show the scale to the participant and ask the participant this: “Please grade your 
level of shortness of breath using this scale.” Record the pre-walk Borg Dyspnea 
Scale level.
b. At the end of the exercise, remind the participant of the breathing number that 
they chose before the exercise and ask the participant to grade their breathing 
level again.
Instruct the Participant as Follows: 
“The object of this test is to walk as far as possible for 6 minutes. You will walk back and 
forth in this hallway. Six minutes is a long time to walk, so you will be exerting yourself.
You will probably get out of breath or become exhausted. You are permitted to slow down, 
to stop, and to rest as necessary. You may lean against the wall while resting but resume 
walking as soon as you are able. 
You will be walking back and forth around the cones. You should pivot briskly around the 
cones and continue back the other way without hesitation. Now I’m going to show you.
Please watch the way I turn without hesitation.” 
Demonstrate by walking 1 lap yourself. Walk and pivot around a cone briskly. 
“Are you ready to do that? I am going to use this counter to keep track of the number of laps 
you complete. I will click it each time you turn around at this starting line. Remember that 
the object is to walk AS FAR AS POSSIBLE for 6 minutes, but don’t run or jog. Start now, 
or whenever you are ready.” 
1. Position the participant at the starting line. You should also stand near the starting 
line during the test. Do not walk with the participant. As soon as the participant starts 
to walk, start the timer. 
2. Do not talk to anyone during the walk. Use an even tone of voice when using the 
standard phrases of encouragement. Watch the participant. Do not get distracted and 
lose count of the laps. Each time the participant returns to the starting line, click the 
lap counter once (or mark the lap on the worksheet). Let the participant see you do it.
Exaggerate the click using body language, like using a stopwatch at a race. 
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After the first minute, tell the participant the following (in even tones): “You are doing well.
You have 5 minutes to go.” 
When the timer shows 4 minutes remaining, tell the participant the following: “Keep up the 
good work. You have 4 minutes to go.”
When the timer shows 3 minutes remaining, tell the participant the following: “You are 
doing well. You are halfway done.” 
When the timer shows 2 minutes remaining, tell the participant the following: “Keep up the 
good work. You have only 2 minutes left.” 
When the timer shows only 1 minute remaining, tell the participant: “You are doing well. 
You have only 1 minute to go.” 
Do not use other words of encouragement (or body language) to speed up. 
If the participant stops walking during the test and needs a rest, say this: “You can lean 
against the wall if you would like; then continue walking whenever you feel able.” Do not 
stop the timer. 
If the participant stops before the 6 minutes are up and refuses to continue (or you decide that 
they should not continue), wheel the chair over for the participant to sit on, discontinue the 
walk, and note on the worksheet the distance, the time stopped, and the reason for stopping 
prematurely. 
When the timer is 15 seconds from completion, say this: “In a moment I’m going to tell you 
to stop. When I do, just stop right where you are, and I will come to you.” 
When the timer rings (or buzzes), say this: “Stop!” Walk over to the participant. Consider 
taking the chair if they look exhausted. Mark the spot where they stopped by placing a bean 
bag or a piece of tape on the floor.
Post-Test: 
1. Remind the participant of their breathing number pretest and ask the participant to 
rate their level of shortness of breath again. Record the post-walk Borg Dyspnea 
Scale level.
2. Measure SpO2 and pulse rate from the oximeter and then remove the sensor.
3. Record the number of laps from the counter.
4. Record the additional distance covered (the number of meters in the final partial lap) 
using the markers on the wall as distance guides.
5. Calculate the total distance walked, rounding to the nearest meter, and record it on the 
worksheet.
6. Congratulate the participant on good effort and offer a drink of water.
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Appendix 5
Protocol Nomenclature Mapping
Acceleron Protocol Description 
(A011-14)
Date
Merck REDS Number 
(MK-7962-006)
Original Protocol (v1.0)
08 April 2021
MK-7962-006-00
Global Amendment 01 (v2.0)
16 June 2022
MK-7962-006-01
Original Protocol (France)
16 December 2021
MK-7962-006-02
Original Protocol (United Kingdom)
22 October 2021
MK-7962-006-03
Original Protocol (United Kingdom)
03 November 2021
MK-7962-006-04
Global Amendment 02 (v3.0)
10 April 2023
MK-7962-006-05
Global Amendment 02 (v3.0)
29 June 2023
MK-7962-006-06
Global Amendment 03 (v4.0)
23 April 2024
MK-7962-006-07
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SAP_001.pdf: 
Official Protocol Title:
NCT number:                NCT04896008
Document Date:            16-Oct-2024
A Phase 3, Randomized, Double-Blind, Placebo-
Controlled Study to Evaluate Sotatercept When Added 
to Maximum Tolerated Background Therapy in 
Participants With Pulmonary Arterial Hypertension 
(PAH) World Health Organization (WHO) Functional 
Class (FC) III or FC IV at High Risk of Mortality


MK-7962
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PROTOCOL NO A011-14/ 006-07 (ZENITH)
SAP AMENDMENT 03
STATISTICAL ANALYSIS PLAN
PHASE III
VERSION: Amendment 3
DATE OF PLAN:
16-Oct-2024
BASED ON:
Protocol Revision 4.0 Amendment 03 of April 23, 2024 (MK-7962-006-07)
STUDY DRUG:
Sotatercept
PROTOCOL NUMBER (STUDY NAME):
A011-14/MK-7962-006(ZENITH)
STUDY TITLE:
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate Sotatercept 
When Added to Maximum Tolerated Background Therapy in Participants With Pulmonary 
Arterial Hypertension (PAH) World Health Organization (WHO) Functional Class (FC) III 
or FC IV at High Risk of Mortality
SPONSOR:
Acceleron Pharma Inc., a wholly owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA
120 East Lincoln Avenue
P.O Box 2000
Rahway, NJ 07065 USA
This study is being conducted in compliance with good clinical practice, including the 
archiving of essential documents.
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TABLE OF CONTENTS
TABLE OF CONTENTS ........................................................................................................2
LIST OF TABLES...................................................................................................................5
1
LIST OF ABBREVIATIONS .........................................................................................6
2
INTRODUCTION............................................................................................................8
2.1
Changes From Statistical Section of the Protocol...............................................8
2.2
Summary of Changes from Previous Versions of the SAP ................................9
3
STUDY OBJECTIVES AND ENDPOINTS................................................................13
3.1
Study Objectives...................................................................................................13
3.2
Study Endpoints...................................................................................................13
3.2.1
Primary Endpoint.........................................................................................13
3.2.2
Secondary Endpoints ...................................................................................13
3.2.3
Exploratory Endpoints .................................................................................14
3.2.4
Safety Endpoints..........................................................................................16
4
STUDY DESIGN............................................................................................................16
4.1
Summary of Study Design...................................................................................16
4.2
Definition of Study Drugs....................................................................................17
4.3
Sample Size Considerations ................................................................................17
4.3.1
Sample Size Justification.............................................................................17
4.4
Randomization .....................................................................................................18
4.5
Clinical Assessments............................................................................................18
5
PLANNED ANALYSES................................................................................................18
5.1
Interim Analyses ..................................................................................................18
5.2
Final Analyses.......................................................................................................20
6
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND HANDLING....20
6.1
General Summary Table and Individual Participant Data Listing 
Considerations......................................................................................................20
6.2
General Post Text Summary Table, Figure, and Individual Participant 
Data Listing Format Considerations..................................................................20
6.3
Data Management................................................................................................20
6.4
Data Presentation Conventions ..........................................................................21
6.5
Analysis Populations............................................................................................21
6.5.1
Screen Failures.............................................................................................21
6.5.2
Safety Set .....................................................................................................22
6.5.3
Full Analysis Set..........................................................................................22
6.5.4
Patient Report Outcome Full Analysis Set (PRO FAS)...............................22
6.6
Baseline Definition ...............................................................................................22
6.6.1
Secondary Efficacy Endpoints.....................................................................22
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6.6.2
Exploratory Efficacy Endpoints...................................................................23
6.6.3
Safety data....................................................................................................23
6.7
Derived and Transformed Data..........................................................................24
6.7.1
Study Day.....................................................................................................24
6.7.2
Change from Baseline..................................................................................24
6.7.3
Analysis Visit Windows ..............................................................................24
6.8
Handling of Missing Data....................................................................................27
6.8.1
Missing Efficacy Endpoints.........................................................................27
6.8.1.1
Primary Efficacy Endpoint ................................................................27
6.8.1.2
Secondary endpoints..........................................................................27
6.8.2
Missing Dates for Prior and Concomitant Medications and Adverse 
Events...........................................................................................................28
6.8.3
Missing Dates for Disease Diagnosis Date..................................................30
6.8.4
Handling of Data Limits ..............................................................................30
7
STUDY POPULATION ................................................................................................30
7.1
Participant Disposition........................................................................................30
7.2
Screen Failures.....................................................................................................31
7.3
Protocol Deviations..............................................................................................31
7.4
Demographic, Baseline Characteristics, and Disease History .........................31
7.5
Listing of Participant Inclusion and Exclusion Criteria ..................................31
7.6
Medical History and Medical Conditions Present at Entry.............................31
8
EFFICACY.....................................................................................................................32
8.1
General Considerations.......................................................................................32
8.2
Testing Statistical Assumptions..........................................................................32
8.3
Statement of the Null and Alternate Hypotheses..............................................33
8.4
Subgroup Analyses...............................................................................................33
8.5
Multiple Comparisons and Multiplicity.............................................................34
8.6
Analysis of the Primary Efficacy Endpoint.......................................................34
8.6.1
Estimand ......................................................................................................34
8.6.2
Primary Efficacy Analyses ..........................................................................34
8.6.3
Sensitivity Analyses of the Primary Efficacy Results .................................36
8.7
Analysis of the Secondary Efficacy Endpoints..................................................38
8.7.1
Estimand ......................................................................................................38
8.7.1.1
Estimand for Secondary Time-to-Event Endpoints ...........................38
8.7.1.2
Estimand for Continuous Secondary Endpoints ................................38
8.7.1.3
Estimand for Binary Secondary Endpoints........................................39
8.7.2
Secondary Efficacy Analyses ......................................................................39
9
SAFETY ANALYSIS.....................................................................................................46
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9.1
Adverse Events.....................................................................................................47
9.2
Anti-drug Antibodies...........................................................................................51
9.3
Laboratory Evaluations.......................................................................................52
9.4
Vital Signs.............................................................................................................54
9.5
Electrocardiogram (ECG)...................................................................................54
10
STUDY MEDICATION................................................................................................55
10.1
Compliance (Medication Adherence).................................................................55
10.2
Extent of Exposure...............................................................................................55
11
REFERENCES...............................................................................................................56
12
APPENDIX.....................................................................................................................58
12.1
REVEAL Lite 2.0 PAH Risk Score Calculator.................................................58
12.2
COMPERA 2.0 Risk Score Calculator ..............................................................59
12.3
SAS Code for the Aligned Rank Stratified Wilcoxon Test ..............................60
12.4
Approval Information .........................................................................................61
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LIST OF TABLES
Table 1
List of Abbreviations .....................................................................................6
Table 2
Changes from Statistical Section of Protocol ................................................8
Table 3  Efficacy and Futility Boundaries and Properties of the Primary Endpoint .........19
Table 4
Evaluation Frequency for Each Endpoints ..................................................25
Table 5
Analysis Visit Windows ..............................................................................26
Table 6
Primary Analysis Strategy for the Primary Efficacy Endpoint....................35
Table 7
Sensitivity Analyses for the Primary Efficacy Endpoint.............................36
Table 8
Analysis Strategy for the Time-to-Event Secondary Efficacy Endpoints ...40
Table 9
Analysis Strategy for the Non-Time-to-Event Secondary Efficacy 
Endpoints .....................................................................................................................42
Table 10
Analysis Strategy for Safety Parameters......................................................47
Table 11
Search Criteria for AESI / AEOI .................................................................50
Table 12
SMQ Information for the Selected Adverse Events ....................................52
Table 13
CTCAE Version 4.03 Severity Grade Classifications for Selected 
Laboratory Parameters.................................................................................................53
Table 14
CTCAE Version 4.03 Severity Grade Classification for Vital Signs..........54
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1
LIST OF ABBREVIATIONS
Table 1
List of Abbreviations
Abbreviation
Term
6MWD
Six-minute walk distance
6MWT
Six-minute walk test
ADA
Anti-drug Antibody
AE
Adverse Event
AEOI
Adverse Events of Interest
AESI
Adverse Events of Special Interest
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophils Count
ANCOVA
Analysis of Covariance
AST
Aspartate Aminotransferase
BMI
Body Mass Index
CMH
Cochran Mantel-Haenszel
CRF
Case Report Form
CRP
C-reactive protein
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
DBP
Diastolic Blood Pressure
DBPC
Double-blind Placebo-controlled
DMC
Data Monitoring Committee
DOB
Date of Birth
ECG
Electrocardiogram
EQ-5D-5L
EuroQol – 5 dimensions scale 5 levels
eGFR
estimated Glomerular Filtration Rate
FAS
Full Analysis Set
FCS
Fully Conditional Specification
GGT
Gamma-Glutamyl Transferase
Hgb
Hemoglobin
IA
Interim Analysis
ICH
International Conference on Harmonization
IRT
Interactive Response Therapy
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Abbreviation
Term
LLN
Lower Limit of Normal
LTDB
Long Term Double-blind
MAR
Missing at Random
MedDRA
Medical Dictionary for Regulatory Activities Terminology
MI
Multiple Imputation
N
Total Sample Size
PAH
Pulmonary Arterial Hypertension
PC
Platelet Counts
PRO FAS
Patient Report Output Full Analysis Set
PT
Preferred Term
PVR
Pulmonary Vascular Resistance
REVEAL
Registry to Evaluate Early and Long-Term PAH Disease Management
RVSP
Right Ventricular Systolic Pressure
SAP
Statistical Analysis Plan
SAE
Serious Adverse Event
SAS
Statistical Analysis System 
SBP
Systolic Blood Pressure
SD
Standard Deviation
SEM
Standard Error of the Mean
SMQ
Standard MedDRA Queries
SOC
System Organ Class
TAPSE
Tricuspid Annular Plane Systolic Excursion
TEAE
Treatment Emergent Adverse Events
TTCW
Time to Clinical Worsening
ULN
Upper Limit of Normal
VAS
Visual Analogue Scale
WBC
White Blood Cell Count
WHO
World Health Organization 
WHO FC
World Health Organization Functional Class
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2
INTRODUCTION
The statistical analysis plan (SAP) is based on:
•
Protocol No. A011-14 (MK-7962-006) (ZENITH), Global Amendment 03 (v4.0) 
approved on April 23, 2024
•
ICH guidelines E9 (Statistical Principles for Clinical Trials) and E9(R1) (Addendum on 
Estimands and Sensitivity Analysis in Clinical Trials to the Guideline on Statistical 
Principles for Clinical Trials)
The purpose of this document is to provide details on study populations and on how the 
variables will be derived, how missing data will be handled as well as details on statistical 
methods to be used to analyze the safety and efficacy data.
The SAP will be finalized and approved before the database is locked. Deviations from the 
final approved plan will be noted in the clinical study report.
2.1
Changes From Statistical Section of the Protocol 
Table 2
Changes from Statistical Section of Protocol
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2.2
Summary of Changes from Previous Versions of the SAP
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3
STUDY OBJECTIVES AND ENDPOINTS
3.1
Study Objectives
The objective of this study is to evaluate the efficacy and safety of sotatercept (plus 
maximum tolerated background PAH therapy) versus placebo (plus maximum tolerated 
background PAH therapy) on time to first event of all-cause death, lung transplantation, or 
PAH worsening-related hospitalization of ≥24 hours, in participants with WHO FC III or FC 
IV PAH at high risk of mortality.
3.2
Study Endpoints
3.2.1
Primary Endpoint
The primary efficacy endpoint is the time to first event of all-cause death, lung 
transplantation, or PAH worsening-related hospitalization of ≥ 24 hours. An independent 
blinded adjudication committee will adjudicate all clinical worsening events, including death 
that occurred while the participants are in the study and deaths caused by any serious adverse 
events (SAE) during the study, up to the end of the study to determine whether these events 
are due to PAH. Only adjudication-confirmed lung transplantation and hospitalization of ≥ 
24 hours will be included in the primary analysis. All deaths that are a first event for a 
participant, whether occurring during the study or following early discontinuation, will be 
included regardless of adjudication.
3.2.2
Secondary Endpoints
The following are the secondary efficacy endpoints, listed according to the order in which 
they will be tested:
1. Overall survival. The primary approach for this endpoint will include all deaths up to 
the data cutoff date, except for those that occurred after enrollment in the long-term 
follow-up study (SOTERIA) or after lung transplantation. Deaths that were 
obtained by the collection of vital status among participants who (1) completed the 
study or discontinued prematurely and (2) did not enroll in SOTERIA, will be 
included. 
2. Transplant-free survival. The primary approach for this endpoint will include all 
events that occurred prior to the cutoff date, including deaths that were obtained by 
the collection of vital status for participants who completed the study or withdrew 
prematurely without lung transplantation. Deaths that occurred after enrollment in 
SOTERIA will not be included in the primary analysis.
3. Proportion of participants who experienced a mortality event at end of study (EOS).
This endpoint will include the same events as defined for the primary approach for 
the overall survival.
4. Change from baseline in Registry to Evaluate Early and Long-Term PAH Disease 
Management (REVEAL) Lite 2.0 risk score at Week 24
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a.
The REVEAL Lite 2.0 risk score is calculated based on the values of the 
following variables: renal insufficiency (by estimated glomerular filtration rate 
[eGFR]), WHO FC, systolic blood pressure (SBP), heart rate, 6-minute walk 
distance (6MWD), and N-terminal prohormone B-type natriuretic peptide 
(NT-proBNP). Scores are assigned to each of these variables based upon their 
presentation and contribution to mortality risk, and a total score is obtained. See 
[Appendix 12.1] for the details of the REVEAL Lite 2.0 risk score calculator. 
5. Proportion of participants achieving a low or intermediate (≤7) REVEAL Lite 2.0 risk 
score at Week 24: only participants with a REVEAL Lite 2.0 risk score > 7 at 
baseline will be included in the analyses.
6. Change from baseline in NT-proBNP levels at Week 24
7. Change from baseline in mean pulmonary artery pressure (mPAP) at Week 24 
8. Change from baseline in PVR at Week 24
9. Proportion of participants who improve in WHO FC at the end of the double-blind 
placebo-controlled (DBPC) Treatment Period
10.
Change from baseline in 6MWD at Week 24
11.
Change from baseline in cardiac output (CO) at Week 24
12.
Change from baseline in EuroQoL-5 dimensions scale 5 levels (EQ-5D-5L) index 
score at Week 24
3.2.3
Exploratory Endpoints
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3.2.4
Safety Endpoints
Safety endpoints include the following:
•
Adverse events (AEs)
•
Anti-drug antibodies (ADAs)
•
Laboratory assessments (hematology, serum chemistry, and urinalysis)
•
Vital signs (systolic blood pressure, diastolic blood pressure, pulse rate, 
respiratory rate, temperature, weight, body mass index)
•
Physical examination
•
12-lead electrocardiogram (ECG)
4
STUDY DESIGN
4.1
Summary of Study Design
This is a Phase 3, randomized, double-blind, placebo-controlled, multicenter, parallel-group 
study to evaluate sotatercept versus placebo in participants with PAH WHO FC III or FC IV 
who are at high risk of mortality. 
The study population includes participants with symptomatic PAH (WHO FC III or FC IV at 
high risk of mortality) who present with idiopathic or heritable PAH, PAH associated with 
connective tissue diseases (CTD), drug- or toxin-induced, post-shunt correction PAH, or 
PAH presenting at least 1 year following the correction of congenital heart defects (CHD). 
Participants must have a REVEAL Lite 2.0 risk score of ≥ 9 and be on maximum tolerated 
combination background PAH therapy.
A planned interim analysis (IA) will occur when approximately 59 participants have 
experienced a primary endpoint event (roughly 50% of the required number of events) and 
median participant time on study is at least 6 months. The time on study for each participant 
is calculated from the randomization date to the database cutoff date, study discontinuation 
date, or the onset date of the primary endpoint, whichever comes first. If the study continues 
after the IA, the final analysis will happen when approximately 118 participants have 
experienced a primary endpoint.
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Each participant will be enrolled in the study for up to approximately 43 months as follows:
•
Screening Period (up to 4 weeks)
•
DBPC Treatment Period (up to approximately 40 months)
•
Follow-up Period (up to 8 weeks)
Each participant will remain in the DBPC Treatment Period until one of the following 
occurs, whichever comes first: 1) they experience the first event of all-cause death, lung 
transplantation, or PAH worsening-related hospitalization of ≥24 hours; 2) the time when the 
required number of primary events are accrued for the final analysis; 3) the study is stopped 
early at the IA for either efficacy or futility. Study participants who have not experienced an 
event will remain in the DBPC Treatment Period until the required number of participants 
have experienced a first event of all-cause death, lung transplantation, or PAH worsening-
related hospitalization.
The DBPC treatment period starts when the first participant receives the first dose of the 
treatment and ends when the first of the following occurs: 1) at least 118 participants have 
experienced a primary endpoint event for the final analysis; 2) the study is stopped early at 
the IA for either efficacy or futility. 
4.2
Definition of Study Drugs
Investigational treatments include:
•
Placebo administered subcutaneously (SC) every 21±3 days plus background 
PAH therapy
•
Sotatercept at a starting dose of 0.3 mg/kg SC with a target dose of 0.7 mg/kg SC 
every 21±3 days plus background PAH therapy
Background PAH therapy refers to approved PAH-specific medications. Study participants 
must be stable on maximum tolerated double or triple combination background PAH therapy 
(per the investigator’s judgment) for at least 30 days prior to the Screening Visit. 
Adjustments in parenteral prostacyclin doses by up to 10% are permitted and should not 
affect therapy stability determination.
4.3
Sample Size Considerations
4.3.1
Sample Size Justification
The sample size determination is based on the primary efficacy endpoint of time to first event 
of all-cause death, lung transplantation, or PAH worsening-related hospitalization 
of ≥24 hours using EAST® version 6.4. In STELLAR, the hazard ratio (HR) in the 
sotatercept group compared with the placebo group was 0.16 (95% CI: 0.08 to 0.35) 
[Hoeper, M. M., et al 2023]. Given the differences in the populations and definitions of 
endpoints between STELLAR and this study, the HR is assumed to be 0.55 in this study. 
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Assuming a HR of 0.55, a 1:1 randomization, a 1-sided 0.025 Type 1 error rate, 90% power, 
and with a planned IA at approximately 50% of the required number of events with the 
option to stop the study for futility, approximately 118 events will be required based on the 
log-rank test. 
Given that approximately 166 participants are planned to be enrolled in this study, the 
accrual period is approximately 26 months, assuming an accrual rate of approximately 
6.5 participants per month. In addition, assuming a dropout hazard rate of 0.04% per month 
(0.5% per year), and the probability of observing an event for placebo is 0.45 for the first 
year, 0.60 for the second year, and 0.90 for the third year and later, the projected time of the 
IA will occur around 26 months. If the study continues after IA, the final analysis will 
happen around 40 months. Median participant time on study must be at least 6 months in 
order for analyses following the occurrence of the required number of events.
4.4
Randomization
The randomization schedule is stratified by REVEAL Lite 2.0 risk score (9 to 10 or ≥11) and 
PAH subtype (CTD-associated or not CTD-associated) at screening. Additional details on the 
randomization schedule can be found in the randomization specifications document in the 
study trial master file.
Participants who have signed the informed consent and meet all eligibility criteria will be 
stratified by REVEAL Lite 2.0 risk score and PAH subtype and then randomized in a 
1:1 ratio to receive placebo plus maximum tolerated background PAH therapy or sotatercept 
plus maximum tolerated background PAH therapy.
Randomization assignments will be generated through a computerized system, provided by 
an Interactive Response Technology (IRT).
4.5
Clinical Assessments
The schedule of clinical assessments can be found in the study protocol (Section 2).
5
PLANNED ANALYSES
5.1
Interim Analyses
One IA of the primary efficacy endpoint is planned to occur when approximately 59 
participants have experienced a primary endpoint event (roughly 50% of the required number 
of events). The IA will include data only up to a cutoff date defined prior to the interim 
database lock. The stratified log-rank test with randomization factors as strata will be used 
for the analysis of the primary efficacy endpoint. The point estimate of the HR with 95% CI 
will be estimated by a Cox regression model stratified by the randomization factors.
The IA will be performed by an unblinded independent statistics provider and will be 
presented to the data monitoring committee (DMC) where a recommendation will be 
communicated to the Executive Oversight Committee (EOC), which is comprised of 
members of Sponsor Senior Management. The EOC will receive and decide upon any 
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recommendations made by the DMC regarding the study. [Table 3] shows the boundary 
properties for the planned interim and final analysis of the primary endpoint. The efficacy 
boundary is derived using a Lan-DeMets spending function approximating O’Brien-Fleming 
bounds and the futility boundary is derived using a gamma family spending function 
approximating Hwang-Shi-Decani bounds with gamma = -7. 
Table 3  Efficacy and Futility Boundaries and Properties of the Primary Endpoint
Analysis
Value
Efficacy
Futility
IA: 50% a information fraction
Required events: 59
Timing: 26 months
N: 166
Z
2.963
-0.458
p (1-sided)b
0.0015
0.677
HR at boundaryc
0.461
1.127
Final Analysis:
Required events: 118
Timing: 40 months
N: 166
Z
1.969
NA
p (1-sided)
0.0245
NA
HR at boundary
0.695
NA
HR = hazard ratio; IA = interim analysis. The number of events and timings are estimated.
a
Percentage of total planned events at the IA.
b
p (1-sided) is the nominal α for group sequential testing.
c
The HR at boundary is the approximate HR required to reach an efficacy/futility bound.
In the scenario that the event accumulation at IA is different from expected, i.e., the number 
of observed events at the time of database lock (DBL) is more than 59, the alpha spending at 
the IA will be based on the information fraction calculated as the actual number of events at 
IA over the target number of events at final analysis.
If the efficacy boundary is crossed for the primary endpoint at the IA, then analyses of 
secondary endpoints will be performed using a gatekeeping method. The 1-sided type 1 error 
rate for the evaluation of secondary endpoints will be the same as that used for the primary 
hypothesis at the IA. More details of the analysis methods for secondary endpoints are 
described in (Section 8.7).
The DMC has responsibility for assessment of overall risk/benefit. As such, the DMC may 
request to look at efficacy data at times other than the prespecified IA. If an unplanned 
efficacy look is prompted by safety concerns without the potential to stop for efficacy before 
the prespecified interim analysis, this will not require a multiplicity adjustment typically 
associated with the planned efficacy interim analysis; however, to account for any 
multiplicity concerns in this case, a sensitivity analysis that reduces the final alpha by 0.0001 
(1-sided) will be conducted. If an unplanned efficacy look is conducted with the potential to 
stop the study for (positive) efficacy before the prespecified interim analysis, an alpha of 
0.0001 (1-sided) will be applied to the primary endpoint at the time of the analysis, and if the 
study is not stopped, the same alpha will be deducted from the alpha specified for the 
planned interim analysis and the final analysis.
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5.2
Final Analyses
If the study continues after the IA, the final analysis is planned to occur when approximately 
118 participants have experienced a primary endpoint event. The final analysis will use the 
remaining type I error that was not spent at the earlier analysis. The p-value bound at the 
final primary analysis will be calculated by considering the type I error spending using the 
information fraction as determined by the actual number of events at IA of the study and the 
expected number of events (118) at the final analysis, with the correlations of the test 
statistics between IA and FA as well as the HR boundary adjusted if the actual number of 
final events differs from 118.
If the efficacy boundary is crossed for the primary endpoint at the final analyses, then analyses 
of secondary endpoints will be performed using a gatekeeping method. For all secondary 
endpoints except for the proportion of participants who experienced a mortality event at EOS 
(secondary endpoint 3) and the proportion of participants who improve in WHO FC at the end 
of DBPC (secondary endpoint 9), the p-value boundary for the secondary endpoints will be 
updated using the same remaining type I error spending as used for the primary endpoint, with 
the correlations determined by the observed information at the final and interim analyses. For 
the secondary endpoints 3 and 9, for which the information fraction and correlation are not 
clearly defined, the p-value boundary at the final analysis will be adjusted using the Bonferroni 
adjustment, i.e., 0.025 minus the p-value boundary from the IA. This is a conservative 
adjustment for secondary endpoints 3 and 9 that does not attempt to take advantage of the 
correlation between the interim and final analyses.
6
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND HANDLING
6.1
General Summary Table and Individual Participant Data Listing 
Considerations
All summary tables and figures as well as individual participant data listings will include a 
“footer” that will include the data source.
6.2
General Post Text Summary Table, Figure, and Individual Participant Data 
Listing Format Considerations
The default convention is to number summary tables, figures, and listings using a decimal 
system to reflect main levels of unique tables, figures, and listings and sub-levels of replicate 
tables and listings with two digits per level (e.g., Table XX. Y. Z. …). In general, summary 
tables and figures will occupy Appendix 14 of the CSR so that the table or figure number 
should start with 14 (e.g., Table 14. Y. Z. …). Individual participant data listings will occupy 
Appendix 16 of the CSR so that the listing number should start with 16 (e.g., Listing 16. Y.
Z. …).
6.3
Data Management
Derived datasets will be created using SAS® software. Derived datasets, summary tables, 
summary figures, statistical analyses, and individual participant data listings will be 
generated using SAS version 9.4 or above.
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6.4
Data Presentation Conventions
Continuous variables (e.g., age) are summarized using descriptive statistics (the number of 
participants with available data, the mean, standard deviation (SD), median and minimum 
and maximum). Categorical variables (e.g., race) are summarized using counts and 
percentages. Percentages are calculated using the total participants per treatment group.
The following conventions are applied to all data presentations and summaries.
•
For continuous variables, all mean and median values are formatted to one more 
decimal place than the measured value. Standard deviation values are formatted to 
two more decimal places than the measured value. Minimum and maximum 
values are presented with the same number of decimal places as the measured 
value.
•
For categorical variables, the number and percentage of responses are presented in 
the form XX (XX.X) where the percentage is in the parentheses.
•
Date variables are formatted as DDMMMYYYY for presentation. Time is 
formatted in military time as HH:MM for presentation.
•
Wherever possible, data will be decimal aligned.
•
P-values, if applicable, will be presented to 3 decimal places. If the p-value is less 
than 0.001 then it will be presented as <0.001. If the rounded result is a value of 
1.000, it will be displayed as >0.999.
•
Unless otherwise stated, any statistical tests performed will use 2-sided tests at the 
5% significance level.
6.5
Analysis Populations
6.5.1
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomized to receive study treatment.
Individuals who do not meet the criteria for participation in the study (screen failure) may be 
rescreened once with the approval of the study medical monitor. A rescreened participant
will be assigned a new participant number. The two participant numbers are linked in the 
data so that each participant will be counted once in the summaries. A participant is 
considered as randomized if the participant is screen failed the first time and meet the criteria 
for participating in the study in the re-screening process.
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6.5.2
Safety Set
The Safety Set is defined as all participants who receive at least one dose of study treatment. 
All participants will be analyzed according to the treatment they received.
6.5.3
Full Analysis Set
The Full Analysis Set (FAS) is defined as all randomized participants, regardless of whether 
study treatment was administered, with the exception of one participant who was randomized 
in error and immediately discontinued by the site. This participant was never dosed and it is 
the only participant that did not receive any dose of the study treatment. Participants in the 
FAS will be analyzed according to the treatment group to which they were randomized.
6.5.4
Patient Report Outcome Full Analysis Set (PRO FAS)
The EQ-5D-5L analyses will be performed in the PRO FAS population. This population is 
the subset of FAS participants who had at least one dose of study medication and completed 
at least one baseline or post-baseline PRO assessment. Participants will be included in the 
treatment group to which they are randomized for the analyses of PRO data using the PRO 
FAS population.
6.6
Baseline Definition
6.6.1
Secondary Efficacy Endpoints
The baseline REVEAL Lite 2.0 risk score is calculated based on the values of the following 
variables measured prior to the first dose: eGFR, WHO FC, SBP, heart rate, 6MWD, 
NT-proBNP. 
For the eGFR, WHO FC, systolic BP, and heart rate, measurements taken at Visit 1 will be 
used as the baseline values; if the measurements at Visit 1 are missing, the corresponding 
values at Screening will be used.
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The baseline 6MWD is derived using the data from the 6-minute walk test (6MWT)
performed at Visit 1 or Screening, prior to the first dose. If a participant discontinues the 
6MWT prematurely, the total distance walked at the time of discontinuation will be the 
6MWD used in the analysis. The Screening 6MWT is performed twice at least 4 hours apart, 
but no longer than 1 week apart. The following rules will describe how the baseline 6MWD 
is to be derived in general scenarios:
•
If at least one 6MWD measurement is present prior to the first study drug 
administration at Visit 1, then the corresponding last measurement prior to the 
time of the first dose will be used as the baseline. 
•
If the 6MWD measurement at Visit 1 is not available then:
-
If the two 6MWD screening measurements are present, then the average of 
the two screening 6MWD measurements will be used as the baseline.
-
If one of the two 6MWD screening measurements is missing and there is no 
other 6MWT done prior to the first study drug administration, then the non-
missing 6MWD measurement will be used as the baseline.
The baseline for mPAP, PVR, CO is the assessment taken at Screening. If the Screening 
assessment is missing, then an unscheduled assessment may be used if it was done prior to 
the first dose of study medication. No imputations will be performed for missing data.
For all other variables such as NT-proBNP, WHO FC, EQ-5D-5L index score, the baseline is 
the last value on or before Visit 1 (pre-dose).
6.6.2
Exploratory Efficacy Endpoints
6.6.3
Safety data
For safety data (vital signs, laboratory data, ECG), the baseline is defined as the last 
observation prior to the first dose of study treatment.
The first dose date will serve as the reference from which the non-missing pre-treatment 
measurements would be identified. For participants that are randomized but do not receive 
any study drug administration, the date of randomization will be the baseline reference.
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6.7
Derived and Transformed Data
6.7.1
Study Day
If the date of interest occurs on or after the first dose/randomization date, then study day will 
be calculated as (date of interest – date of first dose/randomization) + 1. If the date of interest 
occurs prior to the first dose/randomization date, then study day will be calculated as (date of 
interest – date of first dose/randomization). There is no study day 0.
6.7.2
Change from Baseline
Change from baseline is calculated as (post-baseline result – baseline result).
6.7.3
Analysis Visit Windows
Depending on the frequency of the measurements of the endpoints [Table 4], the analyses 
windows are different across endpoints. [Table 5] gives a summary of the endpoints 
measured at each visit per schedule of events (Section 2) in the protocol.
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Table 4
Evaluation Frequency for Each Endpoints
Visit 
schedule
Analysis Visit
Efficacy Endpoints
Safety Endpoints
Visit 
Schedule 1
Every 4 visits starting from 
Visit 1

REVEAL List 2.0 risk score
(Consists of eGFR, WHO FC, BP, 
heart rate, 6MWD, NT-proBNP)

EQ-5D-5L

Serum 
chemistry

Urinalysis
Visit 
Schedule 2
Visit 1, Visit 2, Visit 3, Visit 
4, Visit 5 and every 4 visits 
after Visit 4

NT-proBNP

WHO FC

ADA

Vital Signs

Hematology
Visit 
Schedule 3
Visit 1, Visit 2, Visit 5, and 
every 4 visits after Visit 5

6MWD
Visit 
Schedule 4
Screening Visit, Visit 9

mPAP

PVR

CO

ECG
The analysis window for each endpoint is defined by following the rule below:
•
Target day of each visit is defined as the first day of the week the participant 
should come in for that visit. For example, Visit 1 is defined as Day 1, 
correspondingly Visit 2 should happen in Week 3, therefore target day of Visit 2 
is Day 22 (1 + 3 × 7). 
•
The starting day of the analysis window is defined as the floor (average of the 
target day of current visit and previous visit according to the respective visit 
schedule). For example, the start day of Visit 3 is 2I//%(
PQR

) = 32, where 
43 = 1 + 6 × 7 is the target day of Visit 3 (if the endpoint is measured at Visit 3). 
•
To avoid any gap between the analysis window for two consecutive analysis 
visits, the end day of the analysis window is defined as the starting day of the 
analysis window for the next visit – 1. For example, the end day of Visit 2 is 
2I//% U
QRP

V −1 = 31.
Based on the above definition, [Table 5] provides an example of the analysis windows for 
REVEAL Lite 2.0 risk score. 
For measurements that are analyzed/summarized at specific time points, the value of 
measurements at each time point used in the analysis will be determined using visit windows
as defined above rather than the name of the visit in database. 
If there are multiple measurements for a participant within an analysis window, the
measurement that is closest to the target day will be used. If days to the target day are the 
same between the two measurements, the measurement that is taken later will be used. If 
there are multiple measurements collected on the same day, the average measurement will be 
used.
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Table 5
Analysis Visit Windows
Visit Schedule 1
Analysis Visit
Target Day
Analysis Window
[Study Day Relative to First Dose]
Screening
-28
Screening visit
Baseline
1
Last observation prior to first dosea
Visit 5 (Week 12)
85
2 to 126
Visit 9 (Week 24)
169
127 to 210
Visit 13 (Week 36)
253
211 to 294
Visit 17 (Week 48)
337
295 to 378
Visit 21 (Week 60)
421
379 to 462
Visit 25 (Week 72)
505
463 to 546
Visit Schedule 2
Analysis Visit
Target Day
Analysis Window
[Study Day Relative to First Dose]
Screening
-28
Screening visit
Baseline
1
Last observation prior to first dose
Visit 2 (Week 3)
22
2 to 31
Visit 3 (Week 6)
43
32 to 52
Visit 4 (Week 9)
64
53 to 73
Visit 5 (Week 12)
85
74 to 126
Visit 9 (Week 24)
169
127 to 210
Visit 13 (Week 36)
253
211 to 294
Visit 17 (Week 48)
337
295 to 378
Visit 21 (Week 60)
421
379 to 462
Visit 25 (Week 72)
505
463 to 546
Visit Schedule 3
Analysis Visit
Target Day
Analysis Window
[Study Day Relative to First Dose]
Screening
-28
Screening visit
Baseline
1
Last observation prior to first dose
Visit 2 (Week 3)
22
2 to 52
Visit 5 (Week 12)
85
53 to 126
Visit 9 (Week 24)
169
127 to 210
Visit 13 (Week 36)
253
211 to 294
Visit 17 (Week 48)
337
295 to 378
Visit 21 (Week 60)
421
379 to 462
Visit 25 (Week 72)
505
463 to 546
Visit Schedule 4
Analysis Visit
Target Day
Analysis Window
[Study Day Relative to First Dose]
Screening (Baseline)
-28
Last observation prior to first dose
Visit 9 (Week 24)
169
127 to 210b
[a] The analysis window for baseline starts at Day 1 but after the first dose. 
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[b] For the endpoints that are measured under visit schedule 4, if there is any measurement conducted at Visit 9 
that is after Day 210 (visit out of window), the measurements will be included in the analyses given there is no 
future visits scheduled for the measurements. 
6.8
Handling of Missing Data
6.8.1
Missing Efficacy Endpoints
6.8.1.1
Primary Efficacy Endpoint
Participants who are in the study and do not experience any of the components of the primary 
endpoint at the time of the data cutoff will be censored at the time of the data cutoff. 
Participants who discontinue from the study or are lost to follow-up before experiencing any 
of the components of the primary endpoint will be censored at the last known study contact 
record. This can be 1) the study withdrawal date or 2) the database cutoff date, whichever 
comes first. Other censoring rules of the primary endpoint for the sensitivity analyses are 
described in [Sec. 8.6.3].
6.8.1.2
Secondary endpoints
Time-to-event endpoints
For the primary analysis of the overall survival endpoint, participants who have a lung 
transplantation in ZENITH will be censored at the date of lung transplantation; participants 
who enroll to SOTERIA will be censored at the ZENITH study completion date; other 
participants who do not report a death at the time of the data cutoff will be censored at the 
earlier of the data cutoff date and last known alive. The last known alive date can be 1) the 
last contact date in the vital status follow-up (if available) or 2) the study discontinuation 
date, whichever is later.
For transplant-free survival, the censoring rule for the primary analysis is the same as the 
primary endpoint. 
Other censoring rules of for the sensitivity analyses for the above two endpoints are 
described in [Table 8].
Continuous endpoints
For continuous endpoints, multiple imputation (MI) will be used to impute missing data for 
reasons other than death or a non-fatal clinical worsening event. For those with non-existent 
data due to death or missing data due to a non-fatal clinical worsening event, 
[Sec. 8.7] describes details of handling these data.
For the IA, data will not be imputed for ongoing participants who had not completed Week 
24 at the time of the database cutoff as the non-existent change from baseline at Week 24 is 
missing completely at random.
The Missing at Random (MAR) assumption is made to perform Multiple Imputation (MI). It 
has been shown [Mogg, R. and Mehrotra, D. V. 2007] that MAR-based imputation under 
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non-MAR conditions is unlikely to impact the overall treatment-level mean ranks. For 
missing points, Fully Conditional Specification (FCS) regression [van Buuren, S., et al 2006]
[van Buuren, S. 2007] is used to fill in the missing points in the order of timepoints using 
measurements calculated at the previous timepoints. The analysis involves the following 
steps:
1. The missing data are filled in m times to generate m (where m = 100) complete 
datasets using an FCS regression model accounting for the baseline measurement, 
treatment group, and prior to the efficacy assessment at time point “X” that is to be 
imputed. For each participant requiring imputation, this imputation will be 
performed within the relevant stratum (defined by the participant’s screening 
REVEAL Lite 2.0 risk score and PAH subtype).
2. The m complete datasets are analyzed by using the analysis described in [Sec. 8.7.2]
3. The results from the m complete datasets are combined for the inference.
If there are not enough non-missing observations for imputation when using 2 randomization 
factors as strata, only the screening REVEAL Lite 2.0 risk score will be used in the FCS 
regression if this does not cause any issues in the missing data imputation procedure. 
Otherwise, only the baseline PAH subtype will be used in the FCS regression.
For participants who die, the worst-rank score will be assigned for the non-existent change 
from baseline at Week 24. For participants with missing values at Week 24 on account of an
event other than all-cause mortality, the next worst-rank score will be used to impute the 
missing change from baseline at Week 24 for continuous endpoints [Lachin, J. M. 1999]. 
The random number seed used for all imputations will be 7962006.
Sensitivity analyses are described in [Sec. 8.7.2].
Additionally, for the NT-proBNP endpoint, a log transform, y = log(x), will be applied to the 
data before using the standard MI method.
Categorical / Qualitative endpoints
The handling of missing data for categorical / qualitative endpoints is described in [Sec. 8.7]
for each of the applicable endpoints.
6.8.2
Missing Dates for Prior and Concomitant Medications and Adverse Events
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 dosing date will be assigned to the missing fields.
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•
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 the first dosing date, 
then the first dosing 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 
the partial 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 the 
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 needed. The corresponding AE will be included as a 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 then 
December 31 will be assigned to the missing fields.
•
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.
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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 the 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.
6.8.3
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.
6.8.4
Handling of Data Limits
The following rules will be applied:
•
Measurements reported as less than Lower Limits of Quantification (LLOQ) will 
be imputed to a value of LLOQ/2 for purposes of summarization.
•
Measurements reported as less than some numerical value “X” will be imputed to 
“0.5 * X” for purposes of summarization.
•
Percentage measurements reported as greater than 99% will be assigned a value of 
99.5% during summarization.
Actual measurements will appear in the individual participant data listings, not the imputed 
measurements used for summarization.
7
STUDY POPULATION
7.1
Participant Disposition
Individual participant disposition data will be listed for all screened participants.
The number and percentage of participants receiving study treatment who completed the 
DBPC treatment periods along with the associated reasons for discontinuation from treatment 
and/or withdrawal from study will be presented.
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The disposition summary table will also include a count of the number of participants who 
terminated the study as screen failures.
7.2
Screen Failures
A summary of the number of participants screened will be provided in the disposition table 
and the following information will be available in a separate table:
•
Participants who failed the first screening
•
Participants who were rescreened
•
Participants who were rescreened and then randomized
•
Participants who screen failed
This includes the number of participants who failed a second rescreening as well 
as those who failed initial screening and not subsequently rescreened. In such 
cases, these participants terminate the study as screen failures.
7.3
Protocol Deviations
A listing of all protocol deviations by type of deviation will be provided.
7.4
Demographic, Baseline Characteristics, and Disease History
Demographic and baseline characteristics data, medical history, and disease history data will 
be listed for each participant.
Demographic and baseline characteristics will be summarized by descriptive statistics for all 
the randomized participants as randomized by treatment group.
7.5
Listing of Participant Inclusion and Exclusion Criteria
A listing of participants meeting all eligibility criteria for entry into the study will be 
provided. If a participant did not meet all eligibility criteria, then the individual inclusion and 
exclusion criteria that the participant did not meet will be listed.
7.6
Medical History and Medical Conditions Present at Entry
A listing of past medical history and medical conditions present at entry will be provided. A 
summary of medical history conditions by MedDRA preferred term for each treatment group 
will also be provided.
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8
EFFICACY 
8.1
General Considerations
All efficacy endpoints will be analyzed using the FAS unless otherwise specified. In the 
change from baseline analyses, participants who do not have baseline measurements will be 
excluded from the analyses.
Per protocol, randomization is stratified by REVEAL Lite 2.0 risk score (9 to 10 or ≥11) at 
screening and PAH subtypes (CTD-associated or not CTD-associated). Participants who are 
mis-stratified at the time of randomization will be analyzed using the “as intended”/“correct” 
stratum to which they were supposed to be randomized for all analyses, unless otherwise 
specified. Participants with screening REVEAL Lite 2.0 risk scores ≤9 will be grouped into 
the 9 to 10 category. If there are more than 10% participants mis-stratified, sensitivity 
analyses for all endpoints with a statistically significant outcome may be conducted using the 
stratum assigned at the time of randomization.
8.2
Testing Statistical Assumptions 
The proportional hazards assumption of the Cox model will be examined using both 
graphical and analytical methods if warranted. The log[-log] of the survival function vs. time 
for first event will be plotted for the comparation between sotatercept and the placebo arm. If 
the curves are not parallel, indicating the hazards are not proportional, supportive analyses 
may be conducted to account for the possible non-proportional hazards effect, for example, 
using the Restricted Mean Survival Time (RMST) method [Anderson, K. M. 1991], and 
parametric method [Mehrotra, D. V., et al 2012].
The RMST is the population average of the amount of event-free survival time experienced 
during the study follow up time. This quantity can be estimated by the area under the KM 
curve up to the follow up time. The difference of two RMSTs for two treatment groups will 
be estimated and 95% confidence interval will be provided.
In addition, it is likely that a parametric model will fit data well and can be used as an 
alternative approach to comparing two group event rates over time. A Weibull model 
[Anderson KM. 1991] that allows the shape parameter to be a function of the covariates can 
also be used to examine the proportional hazards assumption where event rates change over 
time; these will be fit with the gamlss.cens R package (package and reference are available 
from CRAM the R library at http://cran.r-project.org).
One assumption for the stratified Cox proportional hazard model is that the treatment hazard 
ratio (HR) is constant across the strata. In case of a strong deviation from the assumption, 
which can result in a notably biased and/or less powerful analysis, a sensitivity analysis may 
be performed based on a two-step weighted Cox model approach by Mehrotra (2012) 
[Uno, H., et al 2014]. The first step is to estimate the treatment effect for each stratum and 
then the stratum specific estimates are combined to make overall inference using sample size 
weights.
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8.3
Statement of the Null and Alternate Hypotheses
The null and alternate hypotheses for the primary and secondary efficacy endpoints are as 
follows:
•
Ho: Sotatercept does not have a differential effect compared to placebo
•
HA: Sotatercept does have a differential effect compared to placebo
8.4
Subgroup Analyses
Subgroups are defined as follows:
•
Age (<65 vs ≥65 years)
•
Sex (male and female)
•
PAH subtype (CTD-associated or not CTD-associated)
•
Screening WHO functional class (III or IV)
•
Screening REVEAL Lite 2.0 risk score (9 to 10 or ≥11): Participants with 
baseline REVEAL Lite 2.0 risk scores < 9 will be grouped into the 9 to 10 
category.
•
Double vs. Triple combination therapy at Screening
•
Prostacyclin Infusion Therapy vs. Non-Prostacyclin Infusion at Screening
•
Screening PVR (≤ 800 or >800 dynes*sec/cm5)
•
eGFR at baseline (0-30; >30-60; > 60 ml/min/1.73m2)
Subgroup analyses will be performed on the primary efficacy endpoint and any secondary 
efficacy endpoints that demonstrate statistical significance.
For the primary endpoint, the between-group treatment with a nominal 95% CI by treatment 
group will be estimated using Cox regression and plotted within each category of the 
subgroups described above. 
For the secondary endpoints, the consistency of the treatment effect will be assessed using 
the unstratified analysis based on the corresponding analysis method for the endpoint as 
specified in [Sec. 8.7] for each category of the subgroup variables listed above. If the number 
of participants in subgroup category is less than 10% of FAS, the subgroup analysis will not 
be performed for this category of the subgroup variable, and this subgroup variable will not 
be displayed in the forest plot.
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8.5
Multiple Comparisons and Multiplicity
A gatekeeping method will be used to control the Type I error rate in the primary and 
secondary efficacy endpoints by testing starting with the primary efficacy endpoint and then 
proceeding in the order of the secondary efficacy endpoints as listed in [Sec. 3.2.2].The p-
value boundaries to be used at the IA and FA are described in Section 5.1 and Section 5.2, 
respectively.
8.6
Analysis of the Primary Efficacy Endpoint
8.6.1
Estimand
Following ICH E9(R1) , the estimand for the primary efficacy endpoint contains the 
following attributes:
Treatment: Sotatercept or placebo on top of background PAH therapy.
Population: Adults with PAH WHO FC III or IV. 
Endpoint: Time to first event of all-cause death, lung transplantation, or PAH worsening-
related hospitalization of ≥24 hours.
Intercurrent events: Changes in treatment (dose reduction, dose delay, discontinuation from 
sotatercept or placebo, or changes to background PAH therapy); a treatment policy strategy 
will be used. Thus, the endpoint is of interest regardless of changes in treatment.
Population-level summary: HR (sotatercept relative to placebo)
8.6.2
Primary Efficacy Analyses
The primary efficacy endpoint will be evaluated by comparing sotatercept to placebo with 
respect to time to first event. The stratified log-rank test with randomization factors as strata 
will be used to calculate the p-value. The treatment difference in survival will be assessed by 
the stratified log-rank test with randomization stratification factors as strata. The HR and its 
95% confidence interval (CI) will be estimated using a stratified Cox proportional hazard 
model with Efron’s method of tie handling. The non-parametric Kaplan-Meier method 
without stratification will be used to estimate the survival curve in each treatment group. 
For the first event meeting the primary composite endpoint event definition, the onset date 
reported by the site in the CRF will be used for analyses. Specifically, for participants who 
die, the date of death will be used; for participants who report a PAH worsening-related 
hospitalization of ≥24 hours, the start date of the AE that leads to hospitalization will be used 
as the onset date of the event; for participants who had a lung transplantation, the date of the 
procedure will be used as the onset date of the event. 
PAH-related hospitalization and lung transplant data are collected only during the study, 
whereas deaths are collected both during the study and post-study. In participants who do not 
have a primary event during the study, follow-up time for the primary analysis will be 
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censored at the earlier of the data cutoff date and the study discontinuation (or study 
completion date) except for participants who died post-study and prior to the data cutoff date.
For such participants, the death (and follow-up time up to the death) will be included in the 
primary analysis. Follow-up time (and events) in SOTERIA are ineligible for the primary 
analysis because all participants who enter SOTERIA had a primary event in ZENITH.
The number and proportion of participants with a primary endpoint event, as well as 
incidence rates per 100 patient-years of follow up, will be provided by treatment group.
To support the primary analysis, a summary of the individual component events contributing 
to the first event of the composite primary endpoint will be provided by treatment group and 
overall. In the event multiple first component events occur on the same day for a participant 
the unique combination of these first component events will be summarized as separate 
categories.
Table 6
Primary Analysis Strategy for the Primary Efficacy Endpoint
Statistical Method
Event Inclusion Criteria and Censoring 
Rules
Missing Data Approach
Testing: stratified log-rank test
Estimation: stratified Cox 
regression
Include the first event of adjudication-
confirmed PAH worsening-related 
hospitalization ≥24 hours, lung 
transplantation, or all-cause death prior to 
the cutoff date. All pre-cutoff deaths
will be eligible, regardless of 
adjudication and regardless of whether 
they occurred during or post ZENITH.
Follow-up time will be censored at the 
earlier of the data cutoff date and the date 
of study discontinuation (or study 
completion) except that post-study deaths 
(and follow-up time) before the data 
cutoff date will be included for 
participants whose first event was a post-
study death occurring before the cutoff.
No imputation of missing data.
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8.6.3
Sensitivity Analyses of the Primary Efficacy Results
The following sensitivity analyses are planned for the primary efficacy endpoints. [Table 7]
provides an overview of each method and the missing data approach. Missing data are 
defined as follow-up time and potential events between the date of discontinuation and the 
data cutoff date among participants who discontinued prematurely without having had a 
primary endpoint. 
Table 7
Sensitivity Analyses for the Primary Efficacy Endpoint
Sensitivity Analysis
Statistical 
Method
Event Inclusion Criteria and 
Censoring rules
Missing Data Approach
Sensitivity #1
Testing: 
stratified log-
rank test
Estimation: 
stratified Cox 
regression
Same as in [Table 6] except 
that deaths obtained after study 
discontinuation (that are not 
adjudicated) will be excluded, 
and post-study follow-up time
will be excluded.
No imputation of missing data. 
Sensitivity #2
Same as in [Table 6]
Impute missing follow-up time 
and events using the retrieved 
dropout method[1]
Sensitivity #3
Same as in [Table 6]
Impute missing follow-up time 
and events using the jump to 
reference method.
Sensitivity #4
Same as in [Table 6]
Impute missing follow-up time 
and events using the tipping 
point method.
[1] This method will be performed only if there are more than 5 such participants with retrieved dropout data.
A sensitivity analysis (Sensitivity #1) will be conducted restricted to events that are 
confirmed via adjudication. Post-study events (i.e., deaths) are the only events not subject to 
adjudication, so this analysis can equivalently be described as an analysis that excludes post-
study events and post-study follow-up time.
A simulation approach will be used to assess the influence of missing data on the primary 
endpoint. The following is a detailed description of the planned analyses (Sensitivity #2-
Sensitivity #4):
1. Counting the number of participants with missing follow-up data
Any participant who did not have a reported event prior to the data cutoff date and who 
discontinued the study prior to the cutoff date will be considered as having missing follow-
up. The number of participants with missing follow up data will be summarized by treatment 
group.
2. Counting missing follow up time for the primary efficacy endpoint
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Lost follow-up time will be calculated as the time from the last visit with full assessment of 
efficacy endpoints to the data cutoff date. The total amount of lost follow-up time will be 
summarized by treatment group and compared to the total potential follow-up time in a 
complete study where every patient is observed to have a primary outcome event, died while 
being actively followed or followed-up until the end of study.
3. Multiple imputation analysis of lost follow-up time
Missing follow-up data on the primary endpoint will be simulated based on the assumption 
that the time to first primary event will have a similar survival distribution pattern as the
observed data. Parametric regression analysis will be used to estimate the survival curve 
using all available follow-up data. Parametric distributions such as Weibull distribution and
exponential distribution will be explored to fit the distribution of the time to first primary 
efficacy event.
The following scenarios will be explored on the hazard rate of the primary endpoint in 
missing follow-up data:
1. Missing at random (MAR), Sensitivity #2: the missing follow-up data from both 
treatment groups have the same hazard rate as the observed data from patients from 
retrieved dropouts. Retrieved dropouts are participants who do not develop an event 
prior to treatment discontinuation and remain in study until the end of DBPC [He, J., 
et al 2023]. This method will only be performed only if there are more than 5 such 
participants with retrieved dropout data.
2. Missing not at random (MNAR), using the following approaches:
i. Sensitivity #3: The missing follow-up data from both treatment groups have the 
same hazard rate as the observed data from placebo group (Jump to Reference 
approach);
ii. Sensitivity #4: Tipping point analyses to assess the degree of robustness of 
statistical significance of the observed treatment effect, as follows:
-
The hazard rate in the placebo group missing data will be fixed at the 
placebo group’s observed rate. The hazard rate in the sotatercept group 
missing data will be varied over a range of values and will be compared to 
the hazard rate in the placebo group with missing data to determine the point 
at which the log-rank test (based on imputed + observed data) is no longer 
significant. 
The time-to-event analysis on the combined data (observed + imputed) using the same one-
sided log-rank test stratified by stratification factors for primary efficacy analysis will be
performed, and p-values and confidence intervals will be obtained using Rubin’s approach 
for multiple imputation analysis.
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8.7
Analysis of the Secondary Efficacy Endpoints
8.7.1
Estimand
The Treatment and Population attributes of all secondary endpoints estimands are as follows:
Treatment: sotatercept or placebo on top of background PAH therapy.
Population: Adults with PAH WHO FC III or IV.
The Endpoint, Intercurrent Events, and Population-level Summary attributes for each 
estimand are provided below.
8.7.1.1
Estimand for Secondary Time-to-Event Endpoints
Endpoints:
•
Overall survival, defined as the time to date of death due to any cause
•
Transplant-free survival, defined as the time to the first lung transplantation or 
death from any cause
Intercurrent events: Changes in treatment (dose reduction, dose delay, discontinuation from 
sotatercept or placebo, or changes to background PAH therapy); a treatment policy strategy 
will be used. Thus, the endpoint is of interest regardless of changes in treatment.
Population-level summary: Hazard ratio (sotatercept relative to placebo)
8.7.1.2
Estimand for Continuous Secondary Endpoints
Endpoints: Change from baseline at Week 24 in each of the following, with death prior to 
Week 24 represented quantitatively by any fixed worst-rank change from baseline to reflect 
the worst clinical outcome:
•
REVEAL Lite 2.0 risk score
•
NT-proBNP
•
mPAP
•
PVR
•
6MWD
•
CO
•
EQ-5D-5L index score
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Intercurrent events:
•
Changes in treatment: Same as for the estimand for the time-to-event endpoints.
•
Death: A composite strategy will be implemented, in which the occurrence of 
death is incorporated into the definition of the endpoint.
Population-level summary: The midpoint of the distribution of the variable/endpoint noted 
above, compared between treatment conditions using a difference (sotatercept minus 
placebo) in midpoints; this between-treatment difference is referred to in statistical terms as 
the location-shift parameter.
8.7.1.3
Estimand for Binary Secondary Endpoints
Endpoints: Indicator (yes/no) of meeting each of the following:
•
Achievement of a low or intermediate [≤7] REVEAL Lite 2.0 risk score at 
Week 24, where death prior to Week 24 is defined as not having met the criteria
•
Mortality event
•
Improvement in WHO FC, where death prior to the end of the DBPC Treatment 
Period is defined as not having met the criteria
Intercurrent events:
•
Changes in treatment: Same as the estimand for the time-to-event endpoints
•
Death (applicable to only the first and third binary endpoints): A composite 
strategy will be used, such that anyone who dies prior to Week 24 without having 
had the endpoint is considered to be a failure.
Population-level summary: The difference (sotatercept minus placebo) in proportions of 
patients achieving responses.
8.7.2
Secondary Efficacy Analyses
[Table 8] and [Table 9] present an overview of the analysis strategy for the secondary 
efficacy endpoints. Details of the analyses can be found below.
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Table 8
Analysis Strategy for the Time-to-Event Secondary Efficacy Endpoints
Endpoint
Type
Statistical 
Method
Event Inclusion Criteria and 
Censoring Rules
Missing Data Approach
Overall 
survival
P
Testing: 
stratified 
log-rank 
test
Estimation: 
stratified 
Cox 
regression
Include all deaths up to the data cutoff 
date, except for those occurring after 
lung transplantation or enrollment in 
SOTERIA.
-Participants who have a pre-cutoff lung 
transplantation will be censored at the 
date of lung transplantation;
-Participants who enroll in SOTERIA 
will be censored at date of ZENITH 
study completion;
-Other participants who do not report a 
pre-cutoff death in ZENITH will be 
censored at the earlier of the data cutoff 
date and the last known alive date 
(study discontinuation date or last vital 
status contact date, whichever is later).
No imputation for missing 
data. 
S1
Include all deaths occurring prior to the 
data cutoff date (even those occurring 
post lung transplantation or in 
SOTERIA). 
-Participants without a reported pre-
cutoff death will be censored at the 
earlier of the data cutoff date and the 
last known alive date.
No imputation for missing 
data. 
S2
Include all deaths occurring prior to the 
data cutoff date (even those occurring 
post lung transplantation or in 
SOTERIA).
-Participants without a reported pre-
cutoff death and being followed up as 
of the data cutoff date will be censored 
at the earlier of the data cutoff date and 
the last known alive date.
Impute the missing follow-
up time and events using 
tipping point method.
S3
Same as S2.
Impute the missing follow-
up time and events using 
jump to reference method.
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Endpoint
Type
Statistical 
Method
Event Inclusion Criteria and 
Censoring Rules
Missing Data Approach
Transplant-
free 
survival
P
Testing: 
stratified 
log-rank 
test
Estimation: 
stratified 
Cox 
regression
Include all lung transplantations 
reported up to the data cutoff. 
Include all pre-cutoff deaths reported in 
the study or after study discontinuation.
Exclude deaths that happened after 
enrollment in SOTERIA.
Participants who do not have pre-cutoff 
event will be censored at the earlier of 
the data cutoff and the last known 
event-free date (data study 
discontinuation or study completion). 
Post-study follow-up time will not be 
included.
No imputation for missing 
data. 
S1
Same as the primary approach (P) 
except that post-study events and 
follow-up time will be excluded.
No imputation for missing 
data. 
S2
Include all lung transplantations;
Include all deaths reported in the study, 
after study discontinuation/completion, 
or after enrollment in SOTERIA.
Participants who do not have a pre-
cutoff event will be censored at the 
earlier of the data cutoff and the last 
known event-free date (data study 
discontinuation or study completion). 
Post-study follow-up time (whether in, 
or not in, SOTERIA, will be included.
No imputation for missing 
data. 
S3
Include all lung transplantations;
Include all deaths reported in the study, 
after study discontinuation/completion, 
or after enrollment in SOTERIA.
-Participants who do not have a pre-
cutoff event and being in the study will 
be censored at the data cutoff date.
Impute the missing follow-
up time and events using 
jump to reference method.
P = Primary; S = Sensitivity
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Table 9
Analysis Strategy for the Non-Time-to-Event Secondary Efficacy 
Endpoints
Endpoint
Type
Statistical Method
Missing Data Approach
Participants who 
experienced a 
mortality event at 
the end of the study
P
Stratified CMH
For participants that do not consider as a death as 
the overall survival primary analysis,
-Impute as a non-death case if a participant is lost to 
follow-up prior to the date cutoff of IA or the end of 
DBPC
Change from 
baseline in 
REVEAL Lite 2.0 
risk score at Week 
24
P
ARSW
MI[1]
S
ARSW
Pattern mixture control-based
Participants 
achieving a low or 
intermediate (≤7) 
REVEAL Lite 2.0 
risk score at Week 
24
P
Stratified CMH
Impute as a non-responder
Change from 
baseline in NT-
proBNP levels at 
Week 24
P
ARSW
MI[1]
S
ARSW
Pattern mixture control-based
Change from 
baseline in mPAP at 
Week 24
P
ARSW
MI[1]
S
ARSW
Pattern mixture control-based
Change from 
baseline in PVR at 
Week 24
P
ARSW
MI[1]
S
ARSW
Pattern mixture control-based
Participants who 
improve in WHO 
FC at the end of 
DBPC treatment 
period
P
Stratified CMH
Impute as a non-improver
Change from 
baseline in 6MWD 
at Week 24
P
ARSW
MI[1]
S
ARSW
Pattern mixture control-based
Change from 
baseline in CO at 
Week 24
P
ARSW
MI[1]
S
ARSW
Pattern mixture control-based
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Endpoint
Type
Statistical Method
Missing Data Approach
Change from 
baseline in EQ-5D-
5L index score at 
Week 24
P
ARSW
MI[1]
P = Primary; S = Sensitivity; CMH = Cochran-Mantel-Haenszel; ARSW = Aligned Rank Stratified 
Wilcoxon, MI = Multiple Imputation; 
[1] Change from baseline at Week 24 for participants who died will be assigned a value that will receive the 
worst rank. Change from baseline at Week 24 for participants who have missing data due to a non-fatal 
clinical worsening event will be imputed to receive the next worst-rank.
Overall Survival
The overall survival (time to death) will be analyzed using the same approach as the primary 
endpoint. In addition, Kaplan-Meier curves will be generated for each arm with 
randomization factors as strata.
[Table 8] describes the primary and supportive analyses for the overall survival. Details of 
the multiple imputations are the same as the corresponding sensitivity analyses for primary 
endpoint, see [Sec. 8.6.3] for details.
Any participant with unknown vital status as of the data cutoff date will be considered as 
having missing follow-up.
Transplant-free survival
The analysis approach for the time to lung transplantation is analogous to that for the overall 
survival.
The details for the primary and supportive analyses for this endpoint are described in
[Table 8]
Any participant who discontinued the study prior to the data cutoff date and did not have a 
reported lung transplantation or death prior to the data cutoff will be considered as having 
missing follow-up. 
Participants who experienced a mortality event at the end of the study
This endpoint is defined identically to the overall survival endpoint. 
The Cochran-Mantel-Haenszel test, stratified by the randomization factors, will be used to 
provide the p-value. The treatment difference will be provided with the 95% CI using the 
Miettinen and Nurminen method [Miettinen, O. and Nurminen, M. 1985] stratified by the 
randomization factors with Cochran-Mantel-Haenszel weights. 
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Change from baseline in REVEAL Lite 2.0 risk score at Week 24
Descriptive statistics will be provided for the baseline, Week 24, and the change from 
baseline at Week 24 for REVEAL Lite 2.0 risk score. 
At the IA, the analysis will include only those participants who were randomized more than 
24 weeks prior to the database cutoff. At the final analysis, all participants will be included in 
the analyses. 
The change in REVEAL Lite 2.0 risk score at Week 24 from baseline will be analyzed using 
the aligned rank stratified Wilcoxon test [Hodges, J. L., Jr. and Lehmann, E. L. 1962]
[Mehrotra, D. V., et al 2010] with the randomization stratification factors as strata (PAH 
subtype only since REVEAL Lite 2.0 risk score is the other stratification factor). In this test, 
the endpoint values are first aligned across the randomization strata using the stratum-level 
Hodges-Lehmann location shift estimates, and the aligned values are then analyzed using a 
Wilcoxon rank sum test. The output from this analysis will be used to provide a 2-sided p-
value and corresponding Hodges-Lehmann location-shift estimate of the overall treatment 
difference with 95% CI. SAS implementation code for the aligned rank stratified Wilcoxon 
test is provided in [Appendix 12.3]. 
A sensitivity analysis using a control-based pattern mixture model will be performed if the 
result from the primary analysis approach is statistically significant. For the IA, data will not 
be imputed for ongoing participants who had not completed Week 24 at the time of the 
database cutoff as the non-existent change from baseline at Week 24 is missing completely at 
random. Non-existent REVEAL Lite 2.0 risk score at Week 24 due to death and missing data 
following a non-fatal primary endpoint event will be handled in the same way as the primary 
analyses described in [Sec. 6.8.1.2]. Missing data due to other reasons for both treatment 
arms will be imputed using placebo data only. Missing data will be filled in m (m=100) times 
using FCS regression accounting for the baseline measurement within each stratum. The 
complete datasets will be analyzed using the aligned rank test stratified Wilcoxon test with 
randomization factors as strata. The results from the m complete datasets will be combined 
for the inference.
Participants achieved a low or intermediate (≤7) REVEAL Lite 2.0 risk score at Week 
24
The analysis approach for this endpoint is analogous to that for participants experienced a 
mortality event at the end of DBPC Treatment Period. PAH subtype is the only stratification 
factor to be used since REVEAL Lite 2.0 risk score is the other stratification factor). At the 
IA, the analysis will include only those participants who were randomized more than 24 
weeks prior to the database cutoff. At the final analysis, all participants will be included in
the analyses. 
Achieving a low or intermediate risk score at Week 24 means that the criterion outline above 
are satisfied at Week 24, regardless of the score calculated at baseline. Participants who do 
not have the risk score at Week 24 will be considered as non-responder. Participants who had 
a REVEAL Lite 2.0 risk score ≤ 7 at baseline will not be included in the analyses. 
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Change from baseline for the following endpoints at Week 24
•
NT-proBNP
•
mPAP
•
PVR
•
6MWD
•
CO
The analysis approach for these endpoints is analogous to that for change from baseline in 
REVEAL Lite 2.0 risk score at Week 24. For 6MWD, if a participant discontinues the 
6MWT prematurely, the total distance walked at the time of discontinuation will be the 
6MWD used in the analysis.
Participants improved in WHO FC at the end of DBPC Treatment Period
The analysis approach for this endpoint is analogous to that for participants who experienced 
a mortality event at the end of DBPC Treatment Period. 
Participants who die prior to the date for the data cutoff will be considered as non-improvers. 
For participants who complete or discontinue the study prior to the cutoff date, the last 
measurement that was taken prior to the end of the study will be used. For the participants 
that are in the study at the time of DBL, the last measurement prior to cutoff date will be 
used. 
Change from baseline in EQ-5D-5L index score 
The EQ-5D-5L consists of 5 dimensions (Mobility, Self-Care, Usual Activities, 
Pain/Discomfort, and Anxiety/Depression). Each dimension has 5 response levels (no 
problems, slight problems, moderate problems, severe problems, and unable to/extreme 
problems). Each response level is coded from 1 to 5 with ‘1’ assigned to “No problems”, ‘2’ 
assigned to “Slight problems”, and so on up to ‘5’ assigned to “Unable to/extreme problems”.
Individual responses from subjects at each time the questionnaire is completed are coded as 
single-digit numbers expressing the severity level selected in each dimension. For example, 
“21111” means slight problems in the mobility dimensions and no problems in any of the 
other dimensions. This 5-digit code is often referred to as a health state. Such 5-digit codes 
should not be added to obtain any kind of overall score.
The summary index score is derived from an appropriate “value set”. Value sets represent the 
average measurements of a sample of people. Usually this is for the general public of a 
particular country/region.
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9
SAFETY ANALYSIS
[Table 10] below summarizes the analysis strategy for safety endpoints.
CCI
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Table 10
Analysis Strategy for Safety Parameters
Analysis Part
Safety Endpoint
Descriptive
Statistics
95%
Between-
group CIa
Overall Safety Assessment
Any TEAE
X
X
Any serious TEAE
X
X
Any suspected drug related TEAE
X
X
Any serious and drug related TEAE
X
X
Discontinuation due to TEAE
X
X
Death
X
X
SOC (incidence ≥4 participants in any 
treatment group)
X
X
AE PT (incidence ≥4 participants in any 
treatment group)
X
X
SOC, AE PT (incidence <4 in both treatment 
groups)
X
Change from baseline results (laboratory 
tests, vital signs, ECG)
X
Xb
Assessment of safety topics of 
special interest
telangiectasia
X
X
AEOI
X
X
AE=adverse event; AEOI=adverse events of interest; CI=confidence interval, SOC=system organ class, PT=preferred 
term, ECG=electrocardiogram, X=results to be provided 
a 95% between-treatment group CI will be provided using the Miettinen and Nurminen method [Miettinen, 
O. and Nurminen, M. 1985].
b Only to be provided for selected vital sign summaries described in [Sec. 9.4].
The safety endpoints will be summarized using the Safety Set. The safety endpoints include 
treatment emergent adverse events, laboratory tests, vital signs, immunogenicity, and ECGs. 
In the change from baseline analyses, both measurements at baseline and the relevant post-
baseline timepoint will be required for a participant to be included in the analyses.
For participants who have either discontinued or completed study intervention, all
measurements within 56 days (8 weeks) following the last dose of study intervention will be 
considered to be on-treatment measurements. For participants who are on study intervention 
(i.e., have not discontinued or completed study intervention), all measurements will be 
considered to be on-treatment measurements.
9.1
Adverse Events
All adverse events (AEs) and SAEs reported from the signing of the informed consent form 
to the end-of-study visit will be reported on the AE CRF and present in the study database. 
All AEs that started or worsened from the time of first dosing of study medication to 8 weeks 
after the last dose of study medication will be considered as treatment emergent adverse 
events (TEAE).
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Any partial dates will be imputed based on the rules described in [Sec. 6.8.2].
A drug related TEAE is defined as any TEAE that is “suspected” to be related to study 
treatment as reported on the CRF or with missing assessment of the relationship to study 
treatment.
The following summaries will be presented for each treatment group:
•
Overall summary of TEAEs
•
Number and percentage of participants reporting each TEAE, categorized by 
System Organ Class (SOC) and Preferred Term (PT)

Number and percentage of participants reporting each TEAE with incidence ≥4 
by SOC and PT

Number and percentage of participants with TEAE that were suspected to be 
related to study drug by SOC and PT.
•
Number and percentage of participants reporting SAE, categorized by SOC and 
PT
•
Number and percentage of participants reporting SAE that are suspected to be 
related to study drug by SOC and PT
•
Number and percentage of participants reporting TEAE leading to death by SOC 
and PT
•
Number and percentage of participants reporting severe TEAE, categorized by 
SOC and PT
•
Number and percentage of participants reporting TEAE leading to study drug 
withdrawal, categorized by SOC and PT
•
Number and percentage of participants with treatment emergent adverse events of 
special interest (AESI) and adverse events of interest (AEOI)
•
Number and percentage of participants with AESI that are suspected to be related 
to study drug by SOC and PT
•
Number and percentage of participants with TEAE by SOC and PT indicating 
severity of the TEAE
•
Number and percentage of TEAE/AEOI/AESI categorized by 1) background 
therapy at baseline (Double vs. Triple combination), 2) prostacyclin therapy at 
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baseline (Prostacyclin Infusion Therapy vs. Non-Prostacyclin Infusion), and 3) 
Age (<65 years of old vs ≥65 years of old).
Counting will be by numbers of participants, not events, and participants will be counted 
once within each applicable SOC or PT. If a participant experiences the same AE at more 
than one severity or with more than one relationship to study drug, the severity rating or 
relationship that is more severe or stronger to study drug will be given precedence in 
summaries that consider severity or drug relationship. Any missing severity, causality, or 
outcome will not be imputed and classed as unknown.
In addition to the summaries described above, point estimates and 95% CIs for the 
differences between treatment groups in the percentages of participants will be provided for 
selected AE summaries in accordance with what is outlined in [Table 10] above that occur in 
at least 4 participants in any treatment group. This threshold was chosen because the 95% CI 
for the between-group difference in percent incidence will always include zero when fewer 
participants per group have events and thus would add little to the interpretation of 
potentially meaningful differences.
Confidence intervals for between-treatment group differences will be provided using the 
unstratified Miettinen and Nurminen method [Miettinen, O. and Nurminen, M. 1985].
No adjustments for multiplicity are planned.
Adverse events of interest (AEOI) and the AESI (Telangiectasia) are presented in [Table 11]
with the corresponding search strategies. 
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Table 11
Search Criteria for AESI / AEOI
AESI / AEOI
SMQ(s)
[MedDRA 27.0] 
Scope
(if applicable)
Description
Increased hemoglobin 
(increased hematocrit, 
increased RBC count)
N/A
N/A
Preferred terms:

Haemoglobin increased

RBC count increased

Full blood count increased

Haematocrit increased

Polycythaemia

Stress polycythaemia
Thrombocytopenia
Haematopoietic 
thrombocytopenia
Narrow
N/A
Immunogenicity

Anaphylactic reaction

Hypersensitivity
Narrow
SMQ and Preferred term:

Preferred terms: Drug 
specific antibody

Preferred terms: Drug 
specific antibody present

SMQ Anaphylactic reaction

SMQ Hypersensitivity
Increased blood 
pressure / hypertension
Hypertension
Broad+Narrow
N/A
Thrombo-embolic 
events
Embolic and thrombotic events
Narrow
N/A
Bleeding events
Haemorrhages 
SMQ and Preferred term:

SMQ Haemorrhages (excluding 
laboratory terms)

Preferred term: Anemia
Renal toxicity

Acute renal failure

Proteinuria

Chronic kidney disease
Narrow
N/A
Telangiectasia
N/A
N/A
Preferred Terms:

Telangiectasia

Spider vein

Spider naevi

Nasal mucosal telangiectasia
Hepatic toxicity
Hepatic disorders
Narrow
N/A
Cardiac events
Ischaemic heart disease
Narrow
SMQ and HLGT:

SMQ Ischaemic heart disease

HLGT Heart failures

HLGT Pericardial disorders
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All AEs will be listed.
9.2
Anti-drug Antibodies
Individual anti-drug antibody (ADA) data will be listed.
The frequency and percentage of ADA responses will be summarized by treatment group and 
scheduled time.
The frequency and percentage of all patients testing positive for ADA (anti-sotatercept) at 
any point during the study (i.e., ADA prevalence) will be summarized by treatment group. In 
addition, for sotatercept ADA, a summary of the prevalence of sotatercept ADA and titer 
summary (median, minimum, and maximum value) will be provided by scheduled visit and 
antibody follow-up visit (as applicable).
The frequency and percentage of patients with neutralizing antibodies (NAb) will also be 
summarized by treatment group.
In addition, the following tables will be provided by ADA status

Primary efficacy endpoint

Serum concentration

Adverse event summary, including a summary of the safety events selected based on 
the [Table 12]

Number and percentage of participants with AESI/AEOI
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Table 12
SMQ Information for the Selected Adverse Events
Selected Safety Events
SMQ(s)
[MedDRA 27.0] 
Scope
(if 
applicable)
Description
Hypersensitivity-like 
reactions

Anaphylactic reaction

Hypersensitivity
Narrow
Administration site
reactions (related to
sotatercept)
N/A
N/A
HLGT: Administration site reactions
Additional analyses may be performed as appropriate.
9.3
Laboratory Evaluations
The following laboratory parameters will be analyzed over time, for urinalysis, only a listing 
will be provided:
Hematology
Hematology data consists of complete blood counts of red blood cells, absolute white blood 
cells, hemoglobin, hematocrit, and platelet counts. Such data will be collected and analyzed 
locally at the investigative sites.
Serum Chemistry
Serum chemistry data consists of blood urea, creatinine, total bilirubin, direct bilirubin, AST, 
ALT, alkaline phosphatase, sodium, potassium, chloride, calcium, phosphorous, glucose, 
magnesium, CO2, and FSH. Such data will be analyzed at a central laboratory.
Actual measurements and changes in laboratory measurements from baseline will be 
summarized by timepoint.
Shift tables based on CTCAE criterion [Table 13] by the worst post-baseline grade value for 
the following parameters will be presented by treatment group:
Hematology: Platelets, and Hemoglobin
Serum Chemistry: ALT, AST, creatinine, alkaline phosphatase, total bilirubin, and eGFR
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Table 13
CTCAE Version 4.03 Severity Grade Classifications for Selected 
Laboratory Parameters
Category
Parameter
Grade 1
Grade 2
Grade 3
Grade 4
Hematology
Hemoglobin 
(Hgb)
[Anemia]
10.0 g/dL ≤ Hgb 
< LLN
8.0 ≤ Hgb < 10.0 
g/dL
Hgb < 8.0 g/dL
Life-threatening 
consequences; 
urgent 
intervention 
indicated a
Hemoglobin 
increased
0 < Increase ≤ 2 
g/dL above ULN 
or above 
baseline if 
baseline is above 
ULN
2 < Increase ≤ 4 
g/dL above ULN 
or above baseline 
if baseline is 
above ULN
Increase > 4 g/dL 
above ULN or 
above baseline if 
baseline is above 
ULN
N/A
Platelet counts
(PC)
75.0 x 10e9 /L ≤ 
PC < LLN
50.0 x 10e9 ≤ PC 
< 75.0 x 10e9 /L
25.0 x 10e9 ≤ PC 
< 50.0 x 10e9 /L
PC < 25.0 x 10e9 
/L
Serum 
Chemistry
Creatinine
>ULN and ≤1.5x 
ULN
>1.5xULN and 
≤3x ULN
>3xULN and ≤6x 
ULN
>6x ULN
Total bilirubin
>ULN and ≤1.5x 
ULN
>1.5x ULN and 
≤3x ULN
>3x ULN and 
≤10x ULN
>10x ULN
Direct bilirubin
>ULN and ≤1.5x 
ULN
>1.5x ULN and 
≤3x ULN
>3x ULN and 
≤10x ULN
>10x ULN
AST
>ULN and ≤3x 
ULN
>3x ULN and ≤5x 
ULN
>5x ULN and 
≤20x ULN
>20x ULN
ALT
>ULN and ≤3x 
ULN
>3x ULN and ≤5x 
ULN
>5x ULN and 
≤20x ULN
>20x ULN
Alkaline 
Phosphatase
Increased
>ULN - 2.5 x 
ULN
>2.5 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
eGFR
< LLN – 60 
ml/min/1.73m2
30-59 
ml/min/1.73m2
15-29 
ml/min/1.73m2
<15 
ml/min/1.73m2
a No grade 4 will be assigned given the assignment of the severity grade is based on the numeric values of 
hemoglobin.
Grade 0 will be assigned if the values are outside the defined ranges above. 
A boxplot of the raw data and change from baseline will be provided for the following 
hematology parameters: hemoglobin, leukocytes, neutrophils, platelets, and hemoglobin (by 
gender) and chemistry parameters: ALT, alkaline phosphatase, AST, total bilirubin, calcium, 
chloride, creatinine, direct bilirubin, glucose, phosphorus, potassium, sodium, urea nitrogen.
A plot of the peak total bilirubin versus peak ALT/AST will be provided.
All laboratory measurements will be listed for all participants.
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9.4
Vital Signs
Vital sign parameters include temperature, pulse rate, respiratory rate, and blood pressure.
For each parameter at each timepoint, the change from baseline will be summarized. Vital 
signs will also be listed for all participants including height at screening and weight at all 
dosing visits.
The number and percentage of participants with the following changes in systolic blood 
pressure (SBP) and diastolic blood pressure (DBP) will be summarized by visit:
•
Change from baseline SBP >20 mmHg and SBP ≥140 mmHg
•
Change from baseline SBP >40 mmHg and SBP ≥140 mmHg
•
Change from baseline DBP >10 mmHg and DBP ≥90 mmHg
•
Change from baseline DBP >20 mmHg and DBP ≥90 mmHg
BMI will be calculated using the formula: BMI (kg/m2) = weight (kg) / [height (m)]2.
A boxplot of raw data as well as a boxplot of change from baseline will be provided for each 
vital sign parameter and treatment group.
Shift tables using vital sign parameters according to version 5.0 of the CTCAE criteria will 
be provided by treatment group as outlined in [Table 14].
Table 14
CTCAE Version 4.03 Severity Grade Classification for Vital Signs
9.5
Electrocardiogram (ECG)
ECG parameters include heart rate (HR), QRS, QT, and QTcF and will consist of a single 
12-lead ECG that will be centrally read.
ECG parameters will be summarized at each timepoint.
ECG interpretation (normal, abnormal) will be presented for actual measurements and 
changes from baseline to each post baseline visit [expressed as Improvement, No Change, 
and Deterioration].
Classification
Grade 1
Grade 2
Grade 3
Hypertension
Systolic BP 
120 - 139 mm 
Hg or 
diastolic BP 
80 - 89 mm 
Hg
Systolic BP 140 - 159 mm Hg or diastolic 
BP 90 - 99 mm Hg 
Systolic BP >=160 mm Hg 
or diastolic BP >=100 mm 
Hg
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Note that:
•
Improvement = Abnormal to Normal
•
Deterioration = Normal to Abnormal
•
No Change = Abnormal to Abnormal or Normal to Normal
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 participants.
10
STUDY MEDICATION
10.1
Compliance (Medication Adherence)
Percent compliance will be calculated according to the following formula and summarized 
using descriptive statistics. 
Compliance (%) is calculated by the following: 
100*
Number of visits where study medication was administered
Number of visits in the Treatment Period where study medication should have been administered
The study medication is administered every 3 weeks. For a participant who is followed for 
the entire study treatment period, the “Number of Visits in the Treatment Period Where 
Study Medication Should Have Been Administered” is the total number of visits that should 
be done from randomization to the last scheduled day for treatment administration for that 
participant, excluding the number of dose delays/holds per protocol. For a participant who 
discontinues from the study treatment, the “Number of Visits in the Treatment Period Where 
Study Medication Should Have Been Administered” is the total number of visits that should 
be done from randomization to the date of the last visit, excluding the number of dose 
delays/holds per protocol.
10.2
Extent of Exposure
The duration of exposure in days and number of treatment visits will be summarized by 
treatment group with descriptive statistics. The total dose administered in mg will also be 
summarized by treatment group with descriptive statistics and is calculated as a function of 
the individual participant’s weight in kg.
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11
REFERENCES
[Anderson, K. M. 1991]
Anderson KM. A nonproportional hazards 
weibull accelerated failure time regression 
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[00TH4Z]
[He, J., et al 2023]
He J, Crackel R, Koh W, Chen LW, Li F, 
Zhang J, et al. Retrieved-dropout-based 
multiple imputation for time-to-event data in 
cardiovascular outcome trials. J Biopharm Stat. 
2023;33(2):234-52.
[089NSQ]
[Hodges, J. L., Jr. and 
Lehmann, E. L. 1962]
Hodges JL, Jr., Lehmann EL. Rank methods for 
combination of independent experiments in 
analysis of variance. The Annals of 
Mathematical Statistics 1962;33(2):482-97.
[03R277]
[Hoeper, M. M., et al 
2023]
Hoeper MM, Badesch DB, Ghofrani HA, Gibbs 
JSR, Gomberg-Maitland M, McLaughlin VV, et 
al. Phase 3 trial of sotatercept for treatment of 
pulmonary arterial hypertension. N Engl J Med. 
In press 2023.
[088BQF]
[Humbert, M., et al 2022]
Humbert M, Kovacs G, Hoeper MM, 
Badagliacca R, Berger RMF, Brida M, et al. 
2022 ESC/ERS Guidelines for the diagnosis 
and treatment of pulmonary hypertension. Eur 
Heart J. 2022;43:3618-731.
[085V4Z]
[Lachin, J. M. 1999]
Lachin JM. Worst-rank score analysis with 
informatively missing observations in clinical 
trials. Control Clin Trials 1999;20:408-22.
[03PYVK]
[Mehrotra, D. V., et al 
2010]
Mehrotra DV, Lu X, Li X. Rank-based analyses 
of stratified experiments: alternatives to the van 
Elteren test. Am Stat. 2010 May;64(2):121-30.
[055P90]
[Mehrotra, D. V., et al 
2012]
Mehrotra DV, Su SC, Li X. An efficient 
alternative to the stratified Cox model analysis. 
Stat Med. 2012 Jul 30;31(17):1849-56.
[0422HQ]
[Miettinen, O. and 
Nurminen, M. 1985]
Miettinen O and Nurminen M. Comparative 
analysis of two rates. Stat Med 1985;4:213-26.
[00VMQY]
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[Mogg, R. and Mehrotra, 
D. V. 2007]
Mogg R, Mehrotra DV. Analysis of 
antiretroviral immunotherapy trials with 
potentially non-normal and incomplete 
longitudinal data. Stat Med 2007;26:484-97.
[03RBNV]
[Mosteller, R. D. 1987]
Mosteller RD. Simplified calculation of body-
surface area [Letter to the Editor] [Abstract]. N 
Engl J Med 1987;1098.
[03QGHG]
[Uno, H., et al 2014]
Uno H, Claggett B, Tian L, Inoue E, Gallo P, 
Miyata T, et al. Moving beyond the hazard ratio 
in quantifying the between-group difference in 
survival analysis. J Clin Oncol. 2014 Aug 
1;32(22):2380-5.
[045X5X]
[van Buuren, S. 2007]
van Buuren S. Multiple imputation of discrete 
and continuous data by fully conditional 
specification. Stat Methods Med Res. 
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[0826M5]
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APPENDIX
12.1
REVEAL Lite 2.0 PAH Risk Score Calculator
BPM = beats per minute; eGFR = estimated glomerular filtration rate; HR = heart rate; 
NT-proBNP = N-terminal prohormone B-type natriuretic peptide; NYHA = New York Heart Association; 
PAH = pulmonary arterial hypertension; REVEAL = Registry to Evaluate Early and Long-Term PAH Disease 
Management; SBP = systolic blood pressure; WHO = World Health Organization.
¹The average of the two Screening 6MWDs should be used for score calculation;
²Central laboratory NT-proBNP result from Screening Visit should be used for score calculation.
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12.2
COMPERA 2.0 Risk Score Calculator
6MWD = 6-minute walk distance; NT-proBNP = N-terminal prohormone B-type natriuretic peptide; 
WHO = World Health Organization.
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12.3
SAS Code for the Aligned Rank Stratified Wilcoxon Test
PROC NPAR1WAY DATA=mimpdata WILCOXON ALIGN=STRATA(HL) HL 
CORRECT=NO;
CLASS trt;
VAR resp;
STRATA strat;
BY impnumber;
ODS OUTPUT HodgesLehmann=hlstats_a;
RUN;
PROC MIANALYZE DATA=hlstats_a;
MODELEFFECTS shift;
STDERR stderr;
ODS OUTPUT ParameterEstimates=results;
RUN;
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12.4
Approval Information
The SAP amendment 03 of Protocol MK7962-006-07 was approved by the BARDS TA 
head. 
Name: 
                                                                             Date:16-Oct-2024
PPD
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