A Phase 3 Non-randomized, Non-controlled, Open Label Clinical Study to Evaluate the Efficacy and Safety of MK-7962 (Sotatercept) add-on to Background Therapy in Japanese Participants With Pulmonary Arterial Hypertension (PAH)
Phase: PHASE3
Conditions: Pulmonary Arterial Hypertension
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT Number:               NCT05818137
Document Date:           24-Apr-2024
A Phase 3 Non-randomized, Non-controlled, Open 
Label Clinical Study to Evaluate the Efficacy and 
Safety of MK-7962 (Sotatercept) add-on to 
Background Therapy in Japanese Participants with 
Pulmonary Arterial Hypertension (PAH)

PRODUCT: MK-7962
1
PROTOCOL/AMENDMENT NO.: 020-01
MK-7962-020-01 FINAL PROTOCOL
24-APR-2024
TITLE PAGE
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 3 Non-randomized, Non-controlled, Open Label Clinical Study to 
Evaluate the Efficacy and Safety of MK-7962 (Sotatercept) add-on to Background Therapy 
in Japanese Participants with Pulmonary Arterial Hypertension (PAH)
Protocol Number: 020-01
Compound Number: MK-7962
Sponsor Name: Merck Sharp & Dohme LLC (hereafter called the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
NCT
NCT05818137
EU CT
Not Applicable
EudraCT
Not Applicable
JRCT
jRCT2031230046
WHO
Not Applicable
UTN
Not Applicable
IND
Not Applicable
Approval Date:   24 April 2024
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study 
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 01
24-APR-2024
This amendment was created primarily to add 
dose modification instructions in the event of 
serious bleeding events and to update the 
risk/benefit section.
Original Protocol
01-FEB-2023
Not applicable
PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 01
Overall Rationale for the Amendment:
This amendment was created primarily to add dose modification instructions in the event of 
serious bleeding events and to update the risk/benefit section.
Summary of Changes Table
Section Number and 
Name
Description of Change
Brief Rationale
Primary Reason for Amendment
Section 6.6.5, Dose 
Delays Due to SAEs of 
Bleeding 
New treatment modification guidance for 
the participants who experienced serious 
bleeding events included.
This change was made to reflect the potential 
risk of serious bleeding as added to the 
sotatercept core risk profile. 
Section Number and 
Name
Description of Change
Brief Rationale
Additional Changes
Throughout
The structure of the protocol has been 
updated.
To comply with current industry regulations 
and guidelines. This restructuring does not 
affect the clinical or regulatory integrity of 
the protocol. All other changes and their 
reasons are included for completeness.
Throughout
Minor administrative, formatting, 
grammatical, and/or typographical changes 
were made throughout the document.
To ensure clarity and accurate interpretation 
of the intent of the protocol.
Section 2.1, Study 
Rationale
New information added.
New data have become available.
Section 2.2.2, Preclinical 
and Clinical Studies
New information added.
Refer to Section 2.1 rationale.
Section 2.3, Benefit/Risk 
Assessment
New information added.
Refer to Section 2.1 rationale.
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Section Number and 
Name
Description of Change
Brief Rationale
Section 9.2, 
Responsibility for 
Analyses/In-house 
Blinding
Reference to an additional analysis after all 
participants have completed Week 54 or 
discontinued prior to Week 54 was added. 
To obtain an additional data cut for 
evaluation of selected efficacy and safety 
data.
Section 9.4.1, Efficacy 
Endpoints
The endpoints of WHO FC have been 
updated from “improvement or 
maintenance” to “improvement”.
To correct description errors and align with 
study objectives.
Section 9.6.1, Statistical 
Methods for Efficacy 
Analyses
The endpoints of WHO FC have been 
updated from “improvement or 
maintenance” to “improvement”.
Refer to Section 9.4.1 rationale.
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................3
1
PROTOCOL SUMMARY ............................................................................................13
1.1
Synopsis.................................................................................................................13
1.2
Schema ..................................................................................................................16
1.3
Schedule of Activities...........................................................................................17
2
INTRODUCTION..........................................................................................................21
2.1
Study Rationale....................................................................................................21
2.2
Background ..........................................................................................................22
2.2.1
Pharmaceutical and Therapeutic Background .............................................22
2.2.2
Preclinical and Clinical Studies ...................................................................22
2.2.3
Ongoing Clinical Studies.............................................................................23
2.3
Benefit/Risk Assessment......................................................................................24
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................25
4
STUDY DESIGN............................................................................................................27
4.1
Overall Design......................................................................................................27
4.2
Scientific Rationale for Study Design.................................................................27
4.2.1
Rationale for Endpoints ...............................................................................27
4.2.1.1
Efficacy Endpoints.............................................................................27
4.2.1.2
Safety Endpoints................................................................................28
4.2.1.3
Pharmacokinetic Endpoints ...............................................................28
4.2.1.4
Planned Exploratory Biomarker Research.........................................29
4.2.1.4.1
Planned Genetic Analysis ........................................................29
4.2.1.5
Future Biomedical Research..............................................................29
4.3
Justification for Dose...........................................................................................29
4.4
Beginning and End-of-Study Definition ............................................................30
4.4.1
Clinical Criteria for Early Study Termination .............................................30
5
STUDY POPULATION ................................................................................................31
5.1
Inclusion Criteria.................................................................................................31
5.2
Exclusion Criteria................................................................................................33
5.3
Lifestyle Considerations......................................................................................36
5.3.1
Caffeine, Alcohol, and Tobacco Restrictions ..............................................36
5.4
Screen Failures.....................................................................................................36
5.5
Participant Replacement Strategy......................................................................36
6
STUDY INTERVENTION............................................................................................37
6.1
Study Intervention(s) Administered...................................................................37
6.1.1
Medical Devices...........................................................................................39
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6.2
Preparation/Handling/Storage/Accountability .................................................39
6.2.1
Dose Preparation..........................................................................................39
6.2.2
Handling, Storage, and Accountability........................................................39
6.3
Measures to Minimize Bias: Randomization and Blinding..............................40
6.3.1
Intervention Assignment..............................................................................40
6.3.2
Stratification.................................................................................................40
6.3.3
Blinding........................................................................................................40
6.4
Study Intervention Compliance..........................................................................40
6.5
Concomitant Therapy..........................................................................................40
6.5.1
Background PAH Therapy and Diuretics ....................................................41
6.5.2
Rescue Medications and Supportive Care ...................................................41
6.6
Dose Modification (Escalation/Titration/Other)...............................................41
6.6.1
Escalation to Target Dose (0.7 mg/kg) ........................................................42
6.6.2
Dose Modifications Due to Hemoglobin Increase.......................................42
6.6.3
Dose Modifications Due to Low Platelet Count..........................................42
6.6.4
Dose Modifications Due to AE of Telangiectasia .......................................42
6.6.5
Dose Delays Due to SAEs of Bleeding........................................................43
6.6.6
Dose Re-escalation Following Dose Reduction ..........................................43
6.7
Intervention After the End of the Study............................................................47
6.8
Clinical Supplies Disclosure................................................................................47
6.9
Standard Policies..................................................................................................47
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................48
7.1
Discontinuation of Study Intervention...............................................................48
7.2
Participant Withdrawal From the Study...........................................................48
7.3
Lost to Follow-up .................................................................................................49
8
STUDY ASSESSMENTS AND PROCEDURES........................................................50
8.1
Administrative and General Procedures ...........................................................50
8.1.1
Informed Consent.........................................................................................50
8.1.1.1
General Informed Consent.................................................................51
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................51
8.1.2
Inclusion/Exclusion Criteria ........................................................................51
8.1.3
Participant Identification Card.....................................................................51
8.1.4
Medical History ...........................................................................................52
8.1.5
Prior and Concomitant Medications Review...............................................52
8.1.5.1
Prior Medications...............................................................................52
8.1.5.2
Concomitant Medications..................................................................52
8.1.6
Assignment of Screening Number...............................................................52
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8.1.7
Assignment of Treatment/Randomization Number.....................................52
8.1.8
Study Intervention Administration ..............................................................52
8.1.8.1
Timing of Dose Administration.........................................................52
8.1.8.1.1
Optional self-administration ....................................................53
8.1.9
Discontinuation and Withdrawal .................................................................53
8.1.9.1
Withdrawal From Future Biomedical Research ................................53
8.1.10
Participant Blinding/Unblinding..................................................................54
8.1.11
Calibration of Equipment.............................................................................54
8.2
Efficacy/Immunogenicity Assessments ..............................................................54
8.2.1
Right Heart Catheterization .........................................................................54
8.2.2
Six-Minute Walk Test (6MWT) ..................................................................55
8.2.3
World Health Organization Functional Class Assessment for Pulmonary 
Hypertension................................................................................................55
8.2.4
N-Terminal pro-B-type Natriuretic Peptide.................................................56
8.2.5
Echocardiogram (ECHO) parameters..........................................................56
8.2.6
8.2.7
Patient-Reported Outcomes .........................................................................57
8.2.7.1
Borg Dyspnea Scale (Borg CR 10 Scale) ..........................................57
8.2.7.2
8.2.8
8.3
Safety Assessments...............................................................................................58
8.3.1
Physical Examinations.................................................................................58
8.3.2
Vital Signs....................................................................................................58
8.3.3
Electrocardiograms ......................................................................................58
8.3.4
Clinical Safety Laboratory Assessments .....................................................59
8.3.5
Pregnancy Testing........................................................................................59
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................59
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................60
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......62
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...62
8.4.4
Regulatory Reporting Requirements for SAE .............................................62
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................63
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................63
8.4.7
Events of Clinical Interest............................................................................63
8.5
Treatment of Overdose........................................................................................64
8.6
Pharmacokinetics.................................................................................................64
CCI
CCI
CCI
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8.6.1
Blood Collection for Serum sotatercept.......................................................64
8.7
Pharmacodynamics..............................................................................................64
8.8
Biomarkers ...........................................................................................................64
8.8.1
Planned Genetic Analysis Sample Collection..............................................64
8.9
Future Biomedical Research Sample Collection...............................................65
8.10
Health Economics Medical Resource Utilization and Health Economics.......65
8.11
Visit Requirements...............................................................................................65
8.11.1
Screening......................................................................................................65
8.11.2
Rescreening..................................................................................................65
8.11.3
Treatment Period Visit.................................................................................65
8.11.3.1
Primary Treatment Period (Visit 2 to 10) ..........................................66
8.11.3.2
Extension Treatment Period (Visit 11 and later) ...............................66
8.11.4
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ................................................................................66
8.11.4.1
End of Treatment Visit.......................................................................66
8.11.4.2
End of Study Visit..............................................................................67
9
KEY STATISTICAL CONSIDERATIONS ...............................................................68
9.1
Statistical Analysis Plan Summary.....................................................................68
9.2
Responsibility for Analyses/In-house Blinding .................................................69
9.3
Hypotheses/Estimation ........................................................................................69
9.4
Analysis Endpoints...............................................................................................69
9.4.1
Efficacy Endpoints.......................................................................................69
9.4.2
Safety Endpoints..........................................................................................70
9.4.3
9.5
Analysis Populations............................................................................................70
9.5.1
Efficacy Analysis Populations.....................................................................70
9.5.2
Safety Analysis Populations ........................................................................71
9.6
Statistical Methods...............................................................................................71
9.6.1
Statistical Methods for Efficacy Analyses...................................................71
9.6.2
Statistical Methods for Safety Analyses ......................................................72
9.6.2.1
Overall Safety Assessment ................................................................72
9.6.2.2
Assessment of Safety Topics of Special Interest ...............................73
9.6.3
Summary of Baseline Characteristics, Demographics, and Other 
Analyses.......................................................................................................73
9.7
Interim Analyses ..................................................................................................73
9.8
Multiplicity ...........................................................................................................73
9.9
Sample Size and Power Calculations .................................................................74
9.9.1
Sample Size and Power for Efficacy Analyses............................................74
9.9.2
Sample Size and Power for Safety Analyses ...............................................74
CCI
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9.10
Subgroup Analyses...............................................................................................75
9.11
Compliance (Medication Adherence).................................................................75
9.12
Extent of Exposure...............................................................................................75
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................76
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........76
10.1.1
Code of Conduct for Interventional Clinical Trials .....................................76
10.1.2
Financial Disclosure.....................................................................................79
10.1.3
Data Protection.............................................................................................80
10.1.3.1
Confidentiality of Data ......................................................................80
10.1.3.2
Confidentiality of Participant Records...............................................80
10.1.3.3
Confidentiality of IRB/IEC Information............................................81
10.1.4
Committees Structure...................................................................................81
10.1.5
Publication Policy........................................................................................81
10.1.6
Compliance with Study Registration and Results Posting Requirements ...81
10.1.7
Compliance with Law, Audit, and Debarment ............................................82
10.1.8
Data Quality Assurance ...............................................................................82
10.1.9
Source Documents .......................................................................................83
10.1.10
Study and Site Closure.................................................................................84
10.2
Appendix 2: Clinical Laboratory Tests..............................................................85
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................87
10.3.1
Definitions of Medication Error, Misuse, and Abuse..................................87
10.3.2
Definition of AE ..........................................................................................87
10.3.3
Definition of SAE ........................................................................................88
10.3.4
Additional Events Reported.........................................................................89
10.3.5
Recording AE and SAE ...............................................................................90
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................93
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ..............................................................................................................94
10.5
Appendix 5: Contraceptive Guidance................................................................95
10.5.1
Definitions....................................................................................................95
10.5.2
Contraceptive Requirements........................................................................96
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................97
10.7
Appendix 7: Country-specific Requirements..................................................101
10.8
Appendix 8: Manual for 6MWT.......................................................................102
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10.9
Appendix 9: Abbreviations ...............................................................................106
11
REFERENCES.............................................................................................................109
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LIST OF TABLES
Table 1
Study Interventions......................................................................................38
Table 2
World Health Organization Functional Class Assessment for Pulmonary 
Hypertension ...............................................................................................56
Table 3
Reporting Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events ............................................................................61
Table 4
Analysis Strategy for Key Efficacy Variables.............................................72
Table 5
Analysis Strategy for Safety Parameters......................................................73
Table 6
Half-Widths of 95% CIs for Change From Baseline in PVR 
(dyn∙sec/cm5) at Week 24 Given Various SD Estimates (31 
Participants).................................................................................................74
Table 7
Protocol-required Safety Laboratory Assessments......................................85
Table 8
Blood volumes for central laboratory tests ..................................................86
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LIST OF FIGURES
Figure 1
Study Schema...............................................................................................16
Figure 2
Guidelines for Target Dose Escalation (0.7 mg/kg) ....................................44
Figure 3
Guidelines for Dose Modification Due to Hemoglobin Increase ................45
Figure 4
Guidelines for Dose Modification Due to Low Platelet Count....................46
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3 Non-randomized, Non-controlled, Open Label Clinical Study to 
Evaluate the Efficacy and Safety of MK-7962 (Sotatercept) add-on to Background Therapy 
in Japanese Participants with Pulmonary Arterial Hypertension (PAH)
Short Title: A Phase 3 Study of Sotatercept in Japanese PAH Participants
Acronym: Not applicable
Hypotheses, Objectives, and Endpoints:
There are no hypotheses for this study.
The study has the following objectives in patients aged ≥18 years with WHO Group 1 PH 
(PAH) who are on stable background therapy.
Note: The primary population of this study consists of participants with WHO functional 
class (FC) II and III. Participants with WHO FC I or IV are considered as other populations 
and will be evaluated separately.
Primary Objective
Primary Endpoint
To evaluate the efficacy of sotatercept in 
reducing PVR at Week 24
PVR
To evaluate the safety and tolerability of 
sotatercept
-AEs
-Discontinuation of study intervention due 
to AEs
Secondary Objectives
Secondary Endpoints
To evaluate the efficacy of sotatercept in 
improving 6MWD at Week 24
6MWD
To evaluate the efficacy of sotatercept
based on the functional improvements at 
Week 24
WHO FC
To evaluate the efficacy of sotatercept 
based on the prognostic biomarker at Week 
24
NT-proBNP
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Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
Pulmonary arterial hypertension
Population
Adult Japanese Participants with WHO 
Group1 PAH and currently on stable 
background therapy
Study Type
Interventional
Intervention Model
Single Group
This is a multi site study.
Type of Control
No Treatment Control
Study Blinding
Unblinded open-label
Blinding Roles
No blinding
Estimated Duration of Study
The Sponsor estimates that the study will 
require approximately 3 years from the time 
the first participant (or their legally 
acceptable representative) provides 
documented informed consent until the last 
participant’s last study-related contact.
Number of Participants:
Approximately 35 PAH participants with WHO FC II or III will be allocated and evaluated 
as primary population. PAH participants with WHO FC I or IV are able to be enrolled in this 
study and evaluated separately as other populations.
Enrollment of participants using infusion prostacyclin will not exceed approximately 50% of 
primary population.
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Intervention Groups and Duration:
Arm Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
Sotatercept
MK-7962 
(sotatercept)
60 mg/vial
0.3 mg/kg, 
Q3W
SC
V2
Test Product
Sotatercept
MK-7962 
(sotatercept)
60 mg/vial
0.7 mg/kg, 
Q3W
SC
V3 to EOT
Test Product
EOT=End of Treatment; Q3W=every 3 weeks; SC=subcutaneous; V=visit
All participants receive sotatercept at a starting dose of 0.3 mg/kg with a target dose of 0.7 mg/kg every 3 weeks.
Dose delay, reductions (from 0.7 to 0.3 mg/kg) due to safety events and dose re-escalation are described in Section 6.6
Other current or former name(s) or alias(es) for study intervention(s) are as follows: 
ActRIIA-IgG1Fc, ACE-011.
Total Number of Intervention Groups/Arms
1
Duration of Participation
Each participant will participate in the study 
from the time the participant provides 
documented informed consent through the 
final contact as follows. After a screening
phase of up to 4 weeks, each participant will 
receive study intervention for 24 weeks as 
Primary Treatment Period and is able to 
continue until approval of sotatercept in 
Japan. If participants discontinue early, they
will be followed for approximately 8 weeks
after End of Treatment visit.
Study Governance Committees:
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Participants: No
A list of abbreviations is in Appendix 9.
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1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Schema
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1.3
Schedule of Activities
Study Period
Screening
Primary Treatment Period
Extension Treatment Period a
Follow-up
Notes
Visit Number
1
2
3
4, 5
6
7-9
10 
(1°EP 
Evalua
tion)
11
12
13-15
16-70
End of 
Treatment 
(EOT)
End of 
Study 
(EOS)
During the Treatment 
Period, visit intervals 
(21 days ± 3 days) are 
relative to the date of 
the previous dose of 
study intervention.
Scheduled Week
0
(Day 1)
3
6, 9
12
15, 18, 
21
24
27
30
33, 36, 
39
every 3 
weeks
3 weeks 
from the 
last dose
8 weeks 
from EOT
Visit Window
≤28 days
±3 days
±7 days
Administrative Procedures
Informed Consent
X
Repeat 
V12 to 
V15.
Inclusion/
Exclusion Criteria
X
X
Participant 
Identification Card
X
Medical History 
(includes disease 
history of PAH)
X
Prior/
Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
Allocation
X
Study intervention
Administration/
Dispensing
X
X
X
X
X
X
X
X
X
All study procedures 
must be done prior to 
study intervention 
administration. Dose 
must be calculated 
based on the 
participant’s weight on 
the day of dosing. Dose 
modification guidelines 
are in Section 6.6.
Eligible participants 
start self-administration 
from Visit 12 or later. 
Refer to the details in 
Section 8.1.8.1.
CCI
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Study Period
Screening
Primary Treatment Period
Extension Treatment Period a
Follow-up
Notes
Visit Number
1
2
3
4, 5
6
7-9
10 
(1°EP 
Evalua
tion)
11
12
13-15
16-70
End of 
Treatment 
(EOT)
End of 
Study 
(EOS)
During the Treatment 
Period, visit intervals 
(21 days ± 3 days) are 
relative to the date of 
the previous dose of 
study intervention.
Scheduled Week
0
(Day 1)
3
6, 9
12
15, 18, 
21
24
27
30
33, 36, 
39
every 3 
weeks
3 weeks 
from the 
last dose
8 weeks 
from EOT
Visit Window
≤28 days
±3 days
±7 days
Self-administration 
Training (Optional)
X
X
X
X
Repeat 
V12 to 
V15.
Training for self-
administration can be 
start from Visit 10 or 
later if participants 
eligible and wish to 
self-administration. 
Participants will be 
trained at least 3 
consequent visits. 
Refer to the details in 
Section 8.1.8.1
Study Intervention 
Accountability 
Confirmation for 
Self-administration
X
Efficacy Procedures
Right heart 
catheterization
X
X
Repeat 
V12 to 
V15.
(X)
RHC at EOT visit 
should be done for 
participants who 
discontinued prior to 
Visit 10, but in other 
case, it is optional.
6MWT/Borg 
Dyspnea Scale (pre 
and post 6MWT)
X
X
X
X
X
X
X
WHO FC 
assessment
X
X
X
X
X
X
X
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Study Period
Screening
Primary Treatment Period
Extension Treatment Period a
Follow-up
Notes
Visit Number
1
2
3
4, 5
6
7-9
10 
(1°EP 
Evalua
tion)
11
12
13-15
16-70
End of 
Treatment 
(EOT)
End of 
Study 
(EOS)
During the Treatment 
Period, visit intervals 
(21 days ± 3 days) are 
relative to the date of 
the previous dose of 
study intervention.
Scheduled Week
0
(Day 1)
3
6, 9
12
15, 18, 
21
24
27
30
33, 36, 
39
every 3 
weeks
3 weeks 
from the 
last dose
8 weeks 
from EOT
Visit Window
≤28 days
±3 days
±7 days
Clinical worsening 
assessment
X
X
X
X
Repeat 
V12 to 
X
X
Clinical worsening 
events occurs between 
the prespecified 
assessment visits 
should also be reported.
Safety Procedures
Physical 
examination 
including height 
and weight
X
X
X
X
X
X
X
X
X
X
Repeat 
V12 to 
V15.
X
X
Perform full physical 
examination at 
Screening, Visit 10, 
and at the EOT/EOS 
visits. For all other 
visits, perform targeted 
cardiopulmonary and 
skin examinations.
Height is measured 
only at Visit 1
Vital Signs 
X
X
X
X
X
X
X
X
X
X
X
X
Includes pulse, blood 
pressure, temperature, 
and respiratory rate.
12-lead ECG
X
X
X
X
X
X
Pulmonary function 
test
X
PFT will be done if the 
most recent test was 
performed more than 6 
months prior to the 
screening visit.
Echocardiogram
X
X
X
X
X
X
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Study Period
Screening
Primary Treatment Period
Extension Treatment Period a
Follow-up
Notes
Visit Number
1
2
3
4, 5
6
7-9
10 
(1°EP 
Evalua
tion)
11
12
13-15
16-70
End of 
Treatment 
(EOT)
End of 
Study 
(EOS)
During the Treatment 
Period, visit intervals 
(21 days ± 3 days) are 
relative to the date of 
the previous dose of 
study intervention.
Scheduled Week
0
(Day 1)
3
6, 9
12
15, 18, 
21
24
27
30
33, 36, 
39
every 3 
weeks
3 weeks 
from the 
last dose
8 weeks 
from EOT
Visit Window
≤28 days
±3 days
±7 days
Urine Pregnancy 
Test (POCBP only)
X
X
X
X
X
X
X
X
X
X
Repeat 
V12 to 
V15.
X
X
Confirm with serum 
test if urine test is 
positive.
A negative pregnancy 
test is required for 
POCBP prior to every 
study drug 
administration 
including self-
administration at home.
FSH - (as needed in 
PONCBP only)
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
Chemistry
X
X
X
X
X
X
AE/SAE review
X
X
X
X
X
X
X
X
X
X
X
Include injection-site 
reactions.
Pharmacokinetics/Pharmacodynamics/Biomarkers
follicle-stimulating hormone; NT-proBNP=N-terminal pro-B-type natriuretic peptide; PAH=pulmonary arterial hypertension; PFT=pulmonary function test; PK=pharmacokinetic; POCBP=participant 
of childbearing potential; PONCBP= participant of nonchildbearing potential; RHC=right heart catheterization; SAE=serious adverse event; WHO=World Health Organization; V=Visit; 6MWT=six-
minute walk test; 
a For participants who are eligible and trained for self-administration may be allowed to return to the study site every 4 visits (12 weeks) after Visit 12 at the earliest.
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2
INTRODUCTION
Pulmonary hypertension (PH) is a chronic disease with a variety of etiologies, which if not 
treated, leads to right heart failure and death due to sustained elevation of pulmonary arterial 
pressure [Rubin, L. J. 1997]. According to the latest clinical classification, PH is divided into 
5 types, and pulmonary arterial hypertension (PAH) is classified into WHO group 1
[Simonneau, G., et al 2013]. In Japan, PAH is designated as a specific disease (intractable 
disease) defined by Ministry of Health, Labour and Welfare (MHLW), and it is reported that 
the number of patients who received the certificate for the recipient of the specific medical 
expenses (designated intractable/rare diseases) for PAH in 2020 was 4320 [Japan Intractable 
Diseases Information Center 2020]. Currently, treatment of PAH is mainly drug therapy with 
PAH-specific drugs while providing supportive care with diuretics and oxygen. Although 
drugs have been approved for the treatment of PAH and widely used in Japan, all of them are 
vasodilators targeting the pathways that directly or indirectly increase blood flow in the 
pulmonary vascular system. Existing drugs for the treatment of PAH fall into three main 
classes: prostacyclin analogues or receptor agonists, endothelin receptor antagonists, and 
phosphodiesterase 5 inhibitors. The combination of these drugs has improved the survival 
rate of patients with PAH. However, a recent study also reported that the transplant-free 
survival rate at 5 years was 74.0% even though most PAH patients received the best 
treatment with combination of 2 or 3 PAH drugs including prostacyclin injection [Kozu, K., 
et al 2020]. In other words, there is a certain number of patients who do not sufficiently 
respond to vasodilators alone. The underlying cause of PAH is the unregulated growth of 
pulmonary vascular smooth muscle cells (VSMCs) in the pulmonary artery, leading to 
progressive pulmonary vascular remodeling and increased pulmonary vascular resistance 
(PVR). New drugs targeting the root causes of PAH could potentially be disease-modifying 
agents as well as improving symptoms. The development of therapeutic drugs for disease-
modifying PAH is extremely important and it was mentioned at the 6th World Symposium 
on Pulmonary Hypertension [Sitbon, O., et al 2019].
Sotatercept (ActRIIA-IgG1Fc, ACE-011 or MK-7962) 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, and is being developed for treatment of PAH.
2.1
Study Rationale
This is an open-label uncontrolled study to evaluate the efficacy and safety of sotatercept in 
Japanese patients with PAH.
As described above, 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/growth and 
differentiation factors (GDF) and bone morphogenetic protein (BMP) pathway signaling, 
opening a new treatment paradigm for PAH (see 2.2.1 and IB for details). 
Currently, in participants with PAH, two global phase 2 studies (PULSAR [PN001] and 
SPECTRA [PN002] trials) and one phase 3 study (STELLAR [PN003]) have been 
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completed, and three global phase 3 studies (HYPERION [PN005], ZENITH [PN006] and 
SOTERIA [PN004] trials) are ongoing overseas. 
In Japan, this local Phase 3 study is planned to confirm the efficacy and safety in Japanese 
PAH participants. The primary population of this study is Japanese PAH participants with 
WHO FC II or III while the study includes PAH participants with WHO FC I or IV as other 
populations.
2.2
Background
Refer to the IB for detailed background information on MK-7962 (sotatercept).
2.2.1
Pharmaceutical and Therapeutic Background
Members of the TGF-β superfamily have been implicated in the abnormal proliferation of 
pulmonary vascular endothelial cells and pulmonary VSMCs that underlie the pathogenesis 
of PAH. It is reported that genetic mutations in the BMP type II receptor (BMPR2) are 
associated with the majority of the familial form of PAH and approximately 25% of 
idiopathic PAH [Morrell, N. W. 2006] [Thomson, J. R., et al 2000]. Specifically, impairment 
of the BMPR2-associated signal pathway appears to lead to uncontrolled proliferation of 
pulmonary VSMCs, the principal cause of PAH. 
Sotatercept traps Activin A, Activin B, and GDF-11, which are its family members, and 
ligands for ActRIIA, and by blocking pro-proliferative signaling, restores the balance 
between anti-proliferative signaling mediated by BMPs and BMPR2. As a result, it prevents 
abnormal remodeling of the pulmonary vascular system and improves pulmonary 
hemodynamics. PAH drugs available in the markets are drugs that improve symptoms by 
their vasodilating actions, however, since sotatercept acts on the underlying pathogenesis of 
PAH with a novel mechanism of action, it is expected not only to improve symptoms but also
to be a disease-modifying drug.
2.2.2
Preclinical and Clinical Studies
Recent preclinical data suggest that sotatercept (murine analogue, RAP-011) may positively 
affect vascular remodeling in animal models of PAH. RAP-011 was evaluated in both 
preventative and therapeutic disease models. Affected animals treated with RAP-011 showed 
substantial improvements in pulmonary vascular and cardiac hemodynamic measurements 
that were either comparable or superior to agents approved for treatment of PAH. 
Importantly, a substantial reduction in the proliferation of pulmonary VSMCs was observed 
in RAP-011-treated animals as assessed by histologic evaluation in both preventative and 
therapeutic disease models. 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. 
Results from the PULSAR trial demonstrated a statistically significant improvement in PVR 
at 24 weeks when compared to baseline (the study’s primary endpoint). PVR was reduced in 
both sotatercept dose groups versus placebo (least squares mean difference [standard error]) 
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(sotatercept 0.3 mg/kg: −145.8 [48.6] dyn·s/cm5, p = 0.0027; sotatercept 0.7 mg/kg: −239.5 
[45.8] dyn·s/cm5, p < 0.0001). Six-Minute Walk Distance (6MWD) was the key secondary 
endpoint at 24 weeks. The least squares mean increase from baseline in 6MWD was 58.1 m 
for sotatercept 0.3 mg/kg, 50.1 m for sotatercept 0.7 mg/kg, and 28.7 m for placebo. 
Combined, sotatercept produced a least squares mean difference versus placebo of 24.9 m 
(95% confidence interval [CI]: 3.1, 46.6 m). Sotatercept also improved N-terminal proB-type 
natriuretic peptide (NT-proBNP) levels. In addition, a greater proportion of participants in 
the sotatercept treatment groups improved in WHO functional class (FC) compared with 
placebo.
The most commonly reported AEs in clinical studies with sotatercept include headache, 
nausea, vomiting, hypertension and diarrhoea, and tended to occur at similar rates in 
sotatercept versus placebo arms in the PULSAR trial. Haemoglobin increased, however, was 
reported in 10.8% of participants receiving sotatercept versus 0 on placebo. Increases in 
hemoglobin are related to the mechanism of action of sotatercept. Thrombocytopenia was 
reported in 9.5% of participants receiving sotatercept vs 0 in placebo. There was no apparent 
association with bleeding. The emerging safety profile of sotatercept in the PAH population 
is reasonably well tolerated and manageable with routine clinical monitoring and dose 
modifications.
In the STELLAR trial, a Phase 3 study subsequently conducted after PULSAR, sotatercept 
also demonstrated the efficacy and was well-tolerated. In this trial, sotatercept significantly 
improved exercise capacity, increasing 6MWD by 40.8 meters (95% CI, 27.5-54.1; p<0.001) 
from baseline at week 24 comparing the placebo group, the study’s primary endpoint. In 
addition, sotatercept demonstrated statistically significant and clinically meaningful 
improvements in eight of nine secondary outcome measures, including improvements in 
WHO functional class (WHO FC) and pulmonary vascular resistance (PVR). Sotatercept 
reduced the risk of clinical worsening or death by 84% compared to placebo with a median 
follow-up of 32.7 weeks (HR=0.16 [95% CI, 0.08-0.35]; p<0.001).  The safety profile of 
sotatercept was generally consistent with that observed in previous studies with sotatercept.
Overall, the preclinical and clinical pharmacology findings suggest that sotatercept may have 
a therapeutic effect in the treatment of PAH. Further details may be found in the IB.
2.2.3
Ongoing Clinical Studies
P019 is a Phase 1, double-blind, randomized, placebo-controlled study in healthy Japanese 
participants to evaluate the safety, tolerability, and PK of single SC doses of sotatercept
0.3 mg/kg and 0.7 mg/kg. This phase 3 study (P020) will proceed if there is no safety 
concern, and there is no obvious difference in safety and pharmacokinetics between Japan 
and ex-Japan studies.
For PAH, there are three ex-Japan trials ongoing:
SOTERIA trial is a Phase 3 open-label long-term follow-up study to evaluate the effects of 
sotatercept when added to background PAH therapy for the treatment of PAH participants
rolling over from parent PAH sotatercept clinical studies. 
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HYPERION trial is a Phase 3, randomized, double-blind, placebo-controlled study to 
evaluate sotatercept when added to background PAH therapy in newly diagnosed 
intermediate-and high-risk PAH participants.
ZENITH trial is a Phase 3, randomized, double-blind, placebo-controlled study to evaluate 
sotatercept when added to maximum tolerated background therapy in participants with PAH 
WHO FC III or FC IV at high risk of mortality.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
In the PULSAR trial, more than 90% of patients at baseline were receiving double or triple 
background PAH therapy, targeting multiple existing therapeutic pathways. Sotatercept was 
able to demonstrate hemodynamic and functional improvements in these patients, including 
those receiving maximal PAH therapy with double/triple drug combinations and intravenous 
prostacyclin.
Treatment with sotatercept in addition to background PAH therapies was well tolerated, with 
thrombocytopenia and increased hemoglobin levels being the most common drug-related side 
effects. The treatment-induced increases in hemoglobin levels and decreases in platelet count 
observed in the PULSAR trial are consistent with effects of sotatercept in previous clinical 
studies. Each of these risks were monitored during the PULSAR and STELLAR trials, and 
dosing adjustments were made as necessary to mitigate these risks. 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. Another important potential risk in this study is recurrent medication error by 
health care practitioner (HCP)-trained lay user causing overdose and leading to 
erythrocytosis. Potential risks of reproductive effects and renal injury were also monitored, 
and no clinically meaningful changes were observed. Anti-drug antibodies (ADA) were 
detected but without associated adverse effects. As other potential risk, cutaneous 
telangiectasia emerged and these events have been carefully monitored in phase 3 program.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
There are no hypotheses for this study.
The study has the following objectives in patients aged ≥18 years with WHO Group 1 PH 
(PAH) who are on stable background therapy.
Note: The primary population of this study consists of participants with WHO functional 
class (FC) II and III. Participants with WHO FC I or IV are considered as other populations 
and will be evaluated separately.
Primary Objective
Primary Endpoint
To evaluate the efficacy of sotatercept in 
reducing PVR at Week 24
PVR
To evaluate the safety and tolerability of 
sotatercept
-AEs
-Discontinuation of study intervention due 
to AEs
Secondary Objectives
Secondary Endpoints
To evaluate the efficacy of sotatercept in 
improving 6MWD at Week 24
6MWD
To evaluate the efficacy of sotatercept
based on the functional improvements at 
Week 24
WHO FC
To evaluate the efficacy of sotatercept 
based on the prognostic biomarker at Week 
24
NT-proBNP
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4
STUDY DESIGN
4.1
Overall Design
This is a non-randomized, non-controlled, multisite, open-label study of Sotatercept in 
Japanese participants with PAH.
The study is divided into a Screening Period (up to 4 weeks), Primary Treatment Period (24 
weeks), Extension Treatment Period (until approval or participants discontinue the study 
treatments), and a Follow-Up Period (at least 8 weeks). Each study eligible participant will 
be assigned allocation number and initiate the study intervention. Sotatercept is administered 
subcutaneously (SC) starting at a dose of 0.3 mg/kg with a target dose of 0.7 mg/kg every 3 
weeks (21days) along with background PAH therapy that participants have been taking prior 
to study entry. Please refer to the details of background therapy in Section 6.5.1.
Escalation to target dose and dose modification (delay, reduction, or discontinuation) is 
performed according to the guidance prespecified in this protocol (Section 6.6). Dose 
modifications may occur at any time per the investigator’s assessment and are not limited to 
the dose modification guidance. Blood samples must be taken and assessed for Hgb and 
platelet count on the same day of study intervention administration or up to 3 days prior to 
that day if available.
Participants who complete the Primary Treatment Period and are considered eligible for 
optional self-administration of study intervention at home will receive appropriate training 
(including successful self-administration on-site under the supervision of investigators). 
Actual self-administration can be determined and started at Visit 12 (±3 days) or later. The 
details of requirement and procedure for self-administration is provided Section 8.1.8.1.1.
Participants who complete the Primary Treatment Period but do not wish to participate in the 
extension period or who discontinue the study treatment before this study is completed will 
complete the Follow-up Period consisting of the End of Treatment (EOT) and the End of 
Study (EOS) visits.
Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 of the SoA. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
Hemodynamic improvements, especially PVR, are one of the efficacy parameters commonly 
used for development of PAH drugs as well as confirming the treatment effects in clinical 
practice. Decreases in PVR in response to treatment have been associated with long-term 
transplant-free survival [Tiede, H., et al 2013]. The primary endpoint of change from 
baseline in PVR at 24 weeks is designed to assess reduction in resistance to flow across the 
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pulmonary vasculature, which is anticipated based on the activity of sotatercept in animal 
models and the hypothesized mechanism of action and activity of sotatercept in patients with 
PAH. In addition to that, PVR is an objective parameter measured by right heart 
catheterization (RHC), it is an appropriate primary endpoint given that this is an open-label 
non-randomized study. Other hemodynamic parameters are also used for efficacy evaluation 
as exploratory endpoints.
The 6MWD has been commonly used as an endpoint in clinical trials of PH therapies [Barst, 
R. J., et al 1996] and is an important prognostic factor in the risk scores[Galiè, N., et al 
2016].
NT-proBNP is secreted by cardiomyocytes in response to ventricular stretch and is an 
established noninvasive marker of ventricular dysfunction in patients with PAH. Plasma NT-
proBNP levels correlate with functional capacity, right ventricular function, and 
echocardiographic and hemodynamic variables, and this biomarker has been consistently 
shown to be an independent predictor of survival in PAH [Souza, R., et al 2007] [Souza, R., 
et al 2005].
The WHO FC, despite its interobserver variability, 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, and should trigger further diagnostic studies to identify the 
causes of clinical deterioration.
4.2.1.2
Safety Endpoints
AEs, AEs leading to discontinuation of study intervention, physical examinations (including 
vital signs), laboratory tests (ADA, hematology, chemistry, and urinalysis) and
electrocardiogram (ECG) will be assessed to provide a comprehensive safety evaluation of 
sotatercept in Japanese participants with PAH. Potential drug-induced liver injury (DILI)
events and AEs of telangiectasia will be captured as events of clinical interest (ECIs) per the 
standard requirement of Sponsor studies (Section 8.4.7). AEs will be evaluated at each visit 
and assessed according to the guidelines in Section 8.4 and Appendix 3. Participants may be 
asked to return for unscheduled visits to perform additional safety monitoring.
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4.3
Justification for Dose
The same dosing method for ex-Japan Phase 3 studies is used in this study.
The PULSAR study demonstrated that both the 0.3 mg/kg and 0.7 mg/kg sotatercept doses 
are pharmacologically active and that both resulted in statistically significant improvements 
across several study endpoints compared to placebo. However, comprehensive 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. 
While a concentration-effect relationship was also demonstrated for Hgb increases, no 
significant difference at steady state was observed between sotatercept dose levels in the 
PULSAR study; mean change from baseline in Hgb at Week 24 was 1.2 g/dL and 1.5 g/dL in 
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the 0.3 mg/kg 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. 
Clinical trial simulations from the pharmacokinetic (PK)/pharmacodynamic (PD) model for 
Hgb suggested that the probability of having Hgb ≥ 18 g/dL and an increase in Hgb ≥ 2 g/dL 
is higher during the first 21 days after a dose of 0.7 mg/kg than after a dose of 0.3 mg/kg. 
Therefore, for this study, a starting dose of 0.3 mg/kg was selected and will be administered 
at Visit 2 and a target dose of 0.7 mg/kg will be administered at Visit 3 and for the remainder 
of the treatment period. All doses will be administered subcutaneously every 3 weeks in 
accordance with dose modification guidelines (Section 6.6).
Prior to the initiation of Japan Phase 3 study (P020), the data from P019, a Japan Phase 1 
study, will be evaluated to determine if there are any differences in the safety and PK 
between Japanese and non-Japanese populations. There is unlikely to be ethnic difference in 
the PK of sotatercept because sotatercept, a fusion protein, is mainly eliminated through 
catabolic pathways. In addition, sotatercept is administered as a dose per body weight, which 
can reduce the effect of body size on the changes of the exposure.
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (Section 
7.3). For purposes of analysis and reporting, the overall study ends when the Sponsor 
receives the last laboratory test result or at the time of final contact with the last participant, 
whichever comes last.
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects is such that the risk/benefit ratio to the study population as a whole is 
unacceptable. In addition, further recruitment in the study or at (a) particular study site(s) 
may be stopped as described in Appendix 1.10.
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5
STUDY POPULATION
As stated in the Code of Conduct for Clinical Trials (Appendix 1.1), this study includes 
participants of varying age (as applicable), race, ethnicity, and sex (as applicable). The 
collection and use of these demographic data will follow all local laws and participant 
confidentiality guidelines while supporting the study of the disease, its related factors, and 
the IMP under investigation.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
An individual is eligible for inclusion in the study if the individual meets all of the following 
criteria:
Type of Participant and Disease Characteristics
1. Documented diagnostic RHC at any time prior to screening confirming the diagnosis of 
WHO PAH Group 1 in any of the following subtypes:

Idiopathic PAH

Heritable PAH

Drug/toxin-induced PAH

PAH associated with connective tissue disease

PAH associated with simple, congenital systemic-to-pulmonary shunts at least 1 year 
following repair
2. PAH classified as WHO FC I or symptomatic PAH classified as WHO FC II to IV
3. Baseline RHC performed during the Screening Period documenting a minimum PVR of ≥ 
400 dyn･sec/cm5（5 Wood unit）
4. On stable doses of background PAH therapy (i.e., patient-specific dose goal for each 
therapy already achieved) and diuretics (if applicable) for at least 90 days prior to 
screening (Refer to Section 6.5 for details).
5. 6MWD ≥ 150 and ≤ 500 m repeated twice at screening (measured at least 4 hours apart, 
but no longer than 1 week), and both values are within 15% of each other (calculated
from the highest value).
Demographics
6. Is an individual of any sex/gender and ≥18 years of age at the time of providing informed 
consent.
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Participants Assigned Male Sex at Birth
7. If capable of producing sperm, the participant, agrees to the following during the 
intervention period and for at least 16 weeks (112 days) after the last dose of study 
intervention:
•
Abstains from penile-vaginal intercourse as their preferred and usual lifestyle (abstinent 
on a long-term and persistent basis) and agrees to remain abstinent
OR
•
Uses contraception as detailed below unless confirmed to be azoospermic (vasectomized 
or secondary to medical cause, documented from the site personnel’s review of the 
participant’s medical records, medical examination, or medical history interview):
-
Uses a penile/external condom when having penile-vaginal intercourse with a 
nonparticipant of childbearing potential who is not currently pregnant and should also 
be advised of the benefit for that partner to use an additional method of contraception, 
as a condom may break or leak. 
Note: Participants capable of producing ejaculate whose partner is pregnant or 
breastfeeding must agree to use a penile/external condom during each episode of 
sexual activity in which the partner is at risk of drug exposure via ejaculate.
-
Contraceptive use by participants capable of producing sperm should be consistent 
with local regulations regarding the methods of contraception for those participating 
in clinical studies. If the contraception requirements in the local label for any of the 
study interventions are more stringent than the requirements above, the local label 
requirements are to be followed.
Participants Assigned Female Sex at Birth
8. A participant assigned female sex at birth is eligible to participate if not pregnant or 
breastfeeding, and at least one of the following conditions applies: 
•
Is not a POCBP
OR
•
Is a POCBP and:
-
Uses a contraceptive method that is highly effective (with a failure rate of <1% per 
year), with low user dependency, or is abstinent from penile-vaginal intercourse as 
their preferred and usual lifestyle (abstinent on a long-term and persistent basis), as 
described in Appendix 5 during the intervention period and for at least 16 weeks (112 
days) after the last dose of study intervention.The investigator should evaluate the 
potential for contraceptive method failure (ie, noncompliance, recently initiated) in 
relationship to the first dose of study intervention. Contraceptive use by POCBPs 
should be consistent with local regulations regarding the methods of contraception for 
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those participating in clinical studies. If the contraception requirements in the local 
label for any of the study interventions are more stringent than the requirements 
above, the local label requirements are to be followed.
-
Has a negative highly sensitive pregnancy test (as required by local regulations) 
within 24 hours before the first dose of study intervention. If a urine test cannot be 
confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. 
In such cases, the participant must be excluded from participation if the serum 
pregnancy result is positive. Additional requirements for pregnancy testing during 
and after study intervention are in Section 8.3.5.
-
Abstains from breastfeeding during the study intervention period and for at least 16 
weeks (112 days) after study intervention.
-
Medical history, menstrual history, and recent sexual activity has been reviewed by 
the investigator to decrease the risk for inclusion of a POCBP with an early 
undetected pregnancy.
Additional Categories
10. If participants assigned male sex at birth, agrees to refrain from donating blood or sperm 
for the duration of the study and for 16 weeks (112 days) after the last dose of study 
intervention.
11. If participants assigned female sex at birth, agrees to refrain from 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 intervention.
12. Ability to adhere to study visit schedule and understand and comply with all protocol 
requirements.
5.2
Exclusion Criteria
An individual must be excluded from the study if the individual meets any of the following 
criteria:
Medical Conditions
1. Diagnosis of PH WHO Groups 2, 3, 4, or 5.
2. Diagnosis of the following PAH Group 1 subtypes:

human immunodeficiency virus (HIV)-associated PAH
CCI
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
PAH associated with portal hypertension

schistosomiasis-associated PAH

PAH with features of significant venous/capillary (PVOD/PCH) involvement
3. Is on the waiting list for lung transplant
Note: patient who was registered to the list within 12 months prior to the screening or 
currently pending (temporally out of) the waiting list is eligible.
4. Uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure > 160 
mmHg or sitting diastolic blood pressure > 100 mmHg during screening visit after a 
period of rest
5. Baseline systolic blood pressure < 90 mmHg at screening.
6. Pregnant or breastfeeding women.
7. History of full or partial pneumonectomy.
8. Pulmonary function test (PFT) values of forced vital capacity (FVC) < 60% predicted at 
the screening visit or within 6 months prior to the screening visit.
9. Initiation of an exercise program for cardiopulmonary rehabilitation within 90 days prior 
to the screening visit or planned initiation during the study (participants who are stable in
the maintenance phase of a program and who will continue for the duration of the study
are eligible).
10. History of more than mild obstructive sleep apnea that is untreated.
11. Known history of portal hypertension or chronic liver disease, including hepatitis B 
and/or hepatitis C (with evidence of recent infection and/or active virus replication),
defined as mild to severe hepatic impairment (Child-Pugh Class A-C).
12. History of restrictive, constrictive, or congestive cardiomyopathy.
13. History of atrial septostomy within 180 days prior to the screening visit.
14. ECG with Fridericia’s corrected QT interval (QTcF) > 500 ms during the Screening 
Period.
15. Personal or family history of long QT syndrome (LQTS) or sudden cardiac death.
16. Left ventricular ejection fraction (LVEF) < 45% on historical ECHO within 6 months 
prior to the screening visit or pulmonary arterial wedge pressure (PAWP) > 15mmHg at 
the baseline RHC performed during the Screening Period.
17. Any symptomatic coronary disease events (prior myocardial infarction, percutaneous 
coronary intervention, coronary artery bypass graft surgery, or cardiac anginal chest pain)
within 6 months prior to the screening visit. Note: Anginal pain can be ignored as an 
exclusion criterion if coronary angiography shows no obstructions.
18. Cerebrovascular accident within 3 months prior to the screening visit.
19. Acutely decompensated heart failure within 30 days prior to the screening visit, as per 
investigator assessment.
20. Significant (≥ 2+ regurgitation) mitral regurgitation or aortic regurgitation valvular 
disease, mitral stenosis and more than mild aortic valve stenosis.
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21. Prior exposure to sotatercept or luspatercept or history of allergic or anaphylactic reaction 
or hypersensitivity to recombinant proteins (including sotatercept or luspatercept) or 
excipients in investigational product.
Prior/Concomitant Therapy
22. Received intravenous inotropes (e.g., dobutamine, dopamine, norepinephrine,
vasopressin) within 30 days prior to the screening visit.
Prior/Concurrent Clinical Study Experience
23. 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.
Diagnostic Assessments
24. Has exclusionary laboratory values at the screening visit as listed in the table below.
Laboratory Assessment
Exclusionary Values
AST
>3 × ULN
ALT
>3 × ULN
Total bilirubin
>3 × ULN
Estimated glomerular filtration 
rate (eGFR)
<30 mL/min/m2 based on the calculation with formula:  
eGFR (mL/min/1.73 m2) = 194 x Cr-1.094 x Age-0.287
(x0.739 if female)
Hemoglobin
> gender-specific ULN
Platelet count
<50,000/ mm3
25. Weight at the screening is over 85 kg.
Other Exclusions
26. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
27. Has a severe, acute or chronic medical condition or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator or Sponsor, would make the participant inappropriate for 
entry into this study.
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5.3
Lifestyle Considerations
5.3.1
Caffeine, Alcohol, and Tobacco Restrictions
No restrictions are required.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently entered in the study. A minimal set of screen-failure information is 
required to ensure transparent reporting of screen-failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen-failure details, eligibility criteria, and any AEs or 
SAEs meeting reporting requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention or withdraws from the study will not 
be replaced.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies [study intervention(s) provided by the Sponsor] will be packaged to support 
enrollment of study participant. Clinical supplies will be affixed with a clinical label in 
accordance with regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study is outlined in Table 1.
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Table 1
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
Sotatercept Experimental MK-7962 
(sotatercept)
Biological/
Vaccine
Injection, 
Powder, 
Lyophilized, 
For Solution
60 mg/vial
0.3 
mg/kg, 
Q3W
SC
V2
Test 
Product
IMP
Central
Sotatercept Experimental MK-7962 
(sotatercept)
Biological/
Vaccine
Injection, 
Powder, 
Lyophilized, 
For Solution
60 mg/vial
0.7 
mg/kg, 
Q3W
SC
V3 to EOT
Test 
Product
IMP
Central
EEA=European Economic Area; EOT=End of Treatment; IMP=investigational medicinal product; NIMP/AxMP=noninvestigational/auxiliary medicinal product; Q3W=every 3 
weeks; SC=subcutaneous; 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 EEA. Country differences with 
respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
Note: Sotatercept dose delay, reductions (from 0.7 to 0.3 mg/kg) due to a safety events and dose re-escalation are described in Section 6.6.
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All supplies indicated in Table 1 will be provided per the “Sourcing” column depending on 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.1.1
Medical Devices
No medical devices are tested in this study.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Specific calculations or evaluations required to be performed to administer the proper dose to 
each participant are outlined in a separate document provided by the Sponsor. The rationale 
for selection of doses to be used in this study is in Section 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Participants in this study will be allocated by non-random assignment using IRT. There is 1 
study intervention arm.
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the intervention administered.
6.4
Study Intervention Compliance
Each dose of study intervention will be administered by SC injection(s) and will be 
documented in the appropriate eCRF and source documents. Interruptions from the protocol-
specified treatment plan are acceptable for participants who dose delay due to a safety event, 
as described in Section 6.6. Study sites should consult with the Sponsor Clinical Director for 
participants who meet study intervention discontinuation criteria (Section 7.1) due to dose 
delays (see Section 6.6).
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed
during time periods specified by this protocol for that medication. If there is a clinical 
indication for any medications specifically prohibited, discontinuation from study
intervention may be required. The investigator should discuss any questions regarding this 
with the Sponsor Clinical Director. The final decision on any supportive therapy or 
vaccination rests with the investigator and/or the participant’s primary physician. However, 
the decision to continue the participant on study intervention requires the mutual agreement 
of the investigator, the Sponsor, and the participant.
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements or other specific categories of interest) that the participant is 
receiving at the time of enrollment or receives during the study must be recorded along with:
•
Reason for use
•
Dates of administration including start and end dates
•
Dosage information including dose and frequency
During screening and throughout the study, participants may take stable doses of medications 
for chronic conditions. If there is an immediate clinical need during the study to prescribe a 
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new medication or a new dosage of an existing medication for either a new or worsening 
preexisting condition, concurrent therapy may be administered at the discretion of the 
investigator. The investigator may consult the Sponsor Clinical Director regarding what 
constitutes a stable dose or a chronic condition.
6.5.1
Background PAH Therapy and Diuretics
Background PAH therapy refers to approved PAH-specific medications and may consist of 
monotherapy or double- or triple- combination therapy with ERA, PDE5 inhibitors, soluble 
guanylate cyclase stimulators, or prostacyclin analogues or receptor agonists. Background 
PAH therapy as well as diuretics used as supportive therapy should be stable at least 90 days 
prior to screening and remain stable throughout the study. For infusion prostacyclin, dose 
adjustment within 10% of optimal dose is allowed per medical practice. If the patient is on 
diuretic therapy, stable diuretic therapy is defined as no addition of a new diuretic and no 
switching of a pre-existent oral diuretic to parenteral administration; however, dose 
adjustments (up or down) in pre-existent oral diuretics are acceptable.
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.
Participants under investigator’s supervision can substitute, add, or increase the dose (for 
infusion prostacyclin, increase the dose by 10% or more) of background therapy for PAH-
worsening including diuretics and supplemental oxygen. Clinical worsening must be 
captured if background therapy is increased due to PAH-worsening.
The Sponsor Clinical Director should be contacted if there are any questions regarding 
concomitant or prior therapy.
6.5.2
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
6.6
Dose Modification (Escalation/Titration/Other)
Dose delay, reduction, or discontinuation may be performed according to Figure 2, Figure 3
and Figure 4. Dose delays should always precede dose reductions. While guidance for dose 
modifications and dose delay are summarized in Figure 3 and Figure 4, dose delays or 
reductions can be implemented for safety reasons at any time per the investigator’s 
assessment and are not limited to the dose modification guidance provided.
Blood samples must be taken and assessed for Hgb and platelet count on the same day of 
study intervention administration or up to 3 days prior to that day if available.
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6.6.1
Escalation to Target Dose (0.7 mg/kg)
All participants will begin treatment at a starting dose of 0.3 mg/kg at Visit 2. At Visit 3, 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 6.6.2 
and Section 6.6.3 are met. However, if at Visit 3 Hgb increases by more than 2.0 g/dL from 
baseline and this value is above the gender-specific ULN per local laboratory test, dosing 
should be delayed. All other study procedures, with the exception of study intervention 
administration, should be performed. At Visit 4, if Hgb has increased by less than 2.0 g/dL 
from baseline or Hgb value is below the gender-specific ULN per local laboratory test, 
dosing should be restarted at 0.3 mg/kg. At Visit 5, if Hgb has increased by less than 2.0 g/dL 
from baseline or Hgb value is below the gender-specific ULN per local laboratory test, the 
dose will be escalated to the target dose of 0.7 mg/kg. Refer to Figure 2 for additional details.
6.6.2
Dose Modifications Due to Hemoglobin Increase
From Visit 4 onward, if Hgb 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 study treatment period. After the third dose 
delay, if Hgb 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 Sponsor Clinical Director 
should be consulted, and study intervention discontinuation should be considered. 
If Hgb increases more than 4 g/dL above the participant’s baseline value, the Sponsor 
Clinical Director should be consulted, and study intervention discontinuation should be 
considered. Refer to for Figure 3 additional details.
6.6.3
Dose Modifications Due to Low Platelet Count
If platelet count is less than 50,000/mm3, dose delay is allowed for up to 3 visits. If platelet 
count remains less than 50,000/mm3 after 3 consecutive dose delays, then study intervention 
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 intervention 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.
6.6.4
Dose Modifications Due to AE 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 intervention should be delayed for one visit if the participant was receiving 0.7 
mg/kg study intervention, or for three visits if the participant was receiving 0.3 mg/kg at the 
time of the event. If, following the dose hold(s), there has been no progression in the severity 
of the event of telangiectasia, dosing of study intervention may be resumed at a dose level of 
0.3 mg/kg. If the event of telangiectasia progresses during the time in which study 
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intervention dosing has been delayed, the investigator should consult the Sponsor Clinical 
Director and consider discontinuation from study intervention.
6.6.5
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 
Sponsor Clinical Director should be consulted.
6.6.6
Dose Re-escalation Following Dose Reduction
In cases of dose reduction due to an AE not related to study intervention, the dose can be re-
escalated when the AE is resolved. In cases of dose reduction due to increases in Hgb, the 
dose will be re-escalated to 0.7 mg/kg after 2 consecutive visits at which Hgb values are 
stable and equal or lower than the ULN normal (refer to Figure 3). Similarly, in cases of dose 
reduction due to decrease in platelet count, the dose will be re-escalated to 0.7 mg/kg after 2 
consecutive visits at which platelet counts are stable and more than 50,000/mm3, with no 
association with AEs of bleeding (refer to Figure 4). In cases of dose reduction due to events 
of telangiectasia, the dose may be re-escalated to 0.7 mg/kg only if the event has completely 
resolved.
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Figure 2
Guidelines for Target Dose Escalation (0.7 mg/kg)
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Figure 3
Guidelines for Dose Modification Due to Hemoglobin Increase
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Figure 4
Guidelines for Dose Modification Due to Low Platelet Count
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6.7
Intervention After the End of the Study
There is no study-specified intervention after the end of the study.
6.8
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study-site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention (name, strength, or potency) is included 
in the label text; random code/disclosure envelopes or lists are not provided.
6.9
Standard Policies
Not applicable
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention before completion of the protocol-specified treatment 
period will still continue to be monitored in the study and participate in the study visits and 
procedures as specified in Section 1.3 and Section 8.11.4 unless the participant has 
withdrawn from the study as specified in Section 7.2.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons.
A participant must be discontinued from study intervention, but continue to be monitored in 
the study for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.
•
The participant has a confirmed positive serum pregnancy test.
•
The participant meets study intervention discontinuation criteria or decided to discontinue 
as a result of consultation with the Sponsor Clinical Director according to dose 
modification guidelines (Section 6.6)
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as
are outlined in 
Section 8.1.9. The procedures to be performed should a participant repeatedly fail to return 
CCI
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for scheduled visits and/or if the study site is unable to contact the participant are outlined in
Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
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8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be used for screening or baseline purposes 
provided the procedures meet the protocol-specified criteria and were performed within 
the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
•
The maximum amount of blood collected for central laboratory tests from each 
participant will be approximately 130 mL in Screening Period and Primary Treatment 
Period and 23 mL per visit in Extension treatment Period (only for visits with blood 
sampling) and Follow-up Period (see appendix 2)). The amount of blood collected for 
local laboratory tests varies according to each laboratory requirements.
•
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples.
8.1
Administrative and General Procedures
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8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study-site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention allocation,
site personnel will add the treatment/randomization number to the participant identification 
card.
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The participant ID card also contains contact information for the emergency unblinding call 
center so that a health care provider can obtain information about study intervention in 
emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use and record prior 
medication taken by the participant within 28 days before the first dose of study intervention.
Regardless of timing, all prior PAH therapy used must be recorded.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur before intervention allocation. Each 
participant will be assigned only 1 screening number. Screening numbers must not be reused 
for different participants.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be allocated, by nonrandom assignment, and will receive a 
treatment/allocation number. The treatment/allocation number identifies the participant for 
all procedures occurring after treatment allocation. Once a treatment/allocation number is 
assigned to a participant, it can never be reassigned to another participant.
A single participant cannot be assigned more than 1 treatment/allocation number.
8.1.8
Study Intervention Administration
Study intervention(s) will be administered by the investigator and/or an appropriately 
qualified designee according to the specifications within the pharmacy manual.
8.1.8.1
Timing of Dose Administration
Study intervention will be provided as per Table 1 (Section 6.1) and dispensed through the
IRT system at visits indicated in the SoA (Section 1.3).
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The first dose of study intervention will be administered at the study site at Visit 2 (Day 1). 
Subsequent dosing will be performed once per 3 weeks at the study site.
8.1.8.1.1
Optional self-administration
Participants who complete the Primary Treatment Period and are eligible for self-
administration (see below for criteria) can start training for consecutive 3 visits at Visit 10 or 
later. By the investigators’ judgement, participants considered eligible and well trained can
start self-administration from Visit 12 at the earliest. Those participants may be allowed to 
return to the study sites every 4 visits after start of self-administration. 
At the visit in which self-administration is started (i.e., Visit 12 or later), participants will 
self-administer the study intervention at the study site and then will be dispensed up to 3 
additional doses for self-administration at home.
Participants who meet all of the following criteria may be eligible for voluntary subsequent 
self-administration of study intervention at home: 
・Successfully completed on-site visits through Visit 10
・Received the provided training for self-administration of study intervention (including 
successful self-administration on-site under the supervision of the investigators) 
・Have stable Hgb and platelet count for at least 3 consecutive visits and throughout the 
duration of the training period
Each self-administration of study intervention at home will be accompanied by a phone call 
from the study site to confirm proper storage, dosing, and administration of study 
intervention and to document medication ID numbers, concomitant medications, as well as 
incidence of any AEs, medication errors, accidental exposure of others, or product inquiries.
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention before completion of the treatment period 
should be encouraged to continue to be followed for all remaining study visits as outlined in 
the SoA and Section 8.11.4.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the EOT at the time of withdrawal. Any AEs that are present at the 
time of withdrawal should be followed in accordance with the safety requirements outlined in
Section 8.4.
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8.1.10
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study. The emergency unblinding 
call center will be available so that a health care provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.11
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
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In order to reduce invasive procedures for participants prior to confirming eligibility, RHC in 
the Screening Period should be performed last and after all screening tests are done for 
eligibility, when possible. The RHC performed after screening may be performed on the day 
of study visit or within 1 week prior to study intervention administration. If other 
assessments are performed on the same day, RHC should be performed last, when possible.
8.2.2
Six-Minute Walk Test (6MWT)
The distance walked in 6 minutes (the 6MWD) will be measured during the Screening Period 
and at multiple timepoints throughout the study as per the SoA. During Screening Period, the 
6MWT is to be performed twice-at least 4 hours and no longer than 1 week apart; the 
distances must be within 15% of each other, based on the longer distance. If the difference 
between the first and second tests is > 15%, the test may be repeated once more, provided 
that the repeat test is within 1 week of the previous test. If the difference between the 
distances remains > 15%, the participant will be considered a screen failure.
The 6MWD will be calculated and recorded. If the participant discontinues the test 
prematurely, the time (mm:ss) and distance walked will be recorded. Requirement of acute 
supportive rescue medication (e.g., oxygen therapy) and any AEs occurring during the 
6MWT 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. The 6MWT should be 
performed under the same conditions at least between Screening and Visit 10, including 
chronic oxygen therapy, use of walking aids or face coverings. All 6MWTs performed from 
Visit 1 onward can be performed at the study visit day or within 10 days prior to study 
intervention administration. If possible, the 6MWT should be performed at approximately the 
same time of day to avoid diurnal variation. For each 6MWT, blood pressure, pulse rate and 
percutaneous oxygen saturation (SpO2) will also be measured pre and post 6MWT. Refer to 
Appendix 8 for additional details.
For evaluation of clinical worsening as indicated by the 6MWT, a decrease of ≥ 15% in 
6MWD at any timepoint, as compared to screening, must be confirmed by a second 6MWT 
performed at least 4 hours and no more than 1 week apart from the first. Average of two 
6MWT measurements at screening will be used as baseline 6MWD.
8.2.3
World Health Organization Functional Class Assessment for Pulmonary 
Hypertension
The WHO class system is used to provide information about how affected an individual is by 
their disease. The 4 FCs that are used to rate how ill a PAH participant is are detailed in 
Table 2.
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Table 2
World Health Organization Functional Class Assessment for Pulmonary 
Hypertension
WHO FC
Description
Class I
Patients with PH 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 PH 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 PH 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 PH 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; PH=pulmonary hypertension; WHO=World Health Organization
Adapted from the New York Heart Association functional assessment.
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8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood to be drawn/collected over the course of the study (from 
prestudy to poststudy visits), including approximate blood volumes drawn/collected by visit 
and by sample type per participant, can be found in Appendix 2.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) per institutional standard. At minimum, 
assessments of the skin as well as cardiovascular, respiratory, gastrointestinal, and 
neurological systems will be performed.
A full physical examination will be completed at Screening, Visit 10, and at the EOT/EOS 
visits. At all other visits, a targeted physical examination, which is consist of 
cardiopulmonary and skin examinations, will be conducted by an investigator or medically 
qualified designee (consistent with local requirements) per institutional standard.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
Height (only at Visit 1) and weight will also be measured and recorded.
8.3.2
Vital Signs
•
Axillary temperature, PR, RR, and BP will be assessed.
•
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions.
8.3.3
Electrocardiograms
Single 12-lead ECG will be obtained and reviewed by an investigator or medically qualified 
designee as outlined in the SoA using an ECG machine that automatically calculates the HR 
and measures PR, QRS, QT, and QTc intervals.
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8.3.4
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant’s condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation In the study or within 21 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
8.3.5
Pregnancy Testing
•
Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Pregnancy testing (urine and/or serum) should be conducted as per SoA for the time 
required to eliminate systemic exposure after the last dose of each study intervention
and should correspond with the time frame for participant’s contraception as noted in
Section 5.1. The length of time required to continue pregnancy testing for each study 
intervention is: 8 weeks.
-
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the participant’s participation in the study.
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant’s legally authorized 
representative).
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The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse.
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3. The investigator, who is a qualified physician, 
will assess events that meet the definition of an AE or SAE as well as other reportable safety 
events with respect to seriousness, intensity/toxicity, and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent, but before intervention allocation, must be reported by the 
investigator if the participant is receiving placebo run-in or other run-in treatment; if the 
event causes the participant to be excluded from the study, or is the result of a protocol-
specified intervention, including, but not limited to washout or discontinuation of usual 
therapy, diet, or a procedure.
From the time of intervention allocation through 11 weeks after cessation of study 
intervention, all AEs, SAEs, and other reportable safety events must be reported by the 
investigator.
Additionally, any SAE brought to the attention of an investigator at any time outside the 
period specified in the previous paragraph must be reported immediately to the Sponsor if the 
event is considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and the investigator 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 3.
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
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Table 3
Reporting Periods and Time Frames for Adverse Events and Other Reportable 
Safety Events
Type of Event
Reporting Period:
Consent to 
Randomization/
Allocation
Reporting Period:
Randomization/
Allocation 
Through 
Protocol-specified 
Follow-up Period
Reporting 
Period:
After the 
Protocol-
specified 
Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information to 
Sponsor
NSAE
Report if:
– due to protocol-
specified 
intervention
– causes exclusion
– participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Not required
Per data entry 
guidelines
SAE
Report if:
– due to protocol-
specified 
intervention
– causes exclusion
– participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Report if:
– drug/vaccine 
related.
(Follow 
ongoing to 
outcome)
Within 
24 hours of 
learning of 
event
Pregnancy/Lactation 
Exposure
Report if:
– participant has been 
exposed to any 
protocol-specified 
intervention (eg, 
procedure, washout,
or run-in treatment 
including placebo 
run-in)
Exception: A positive 
pregnancy test at the 
time of initial 
screening is not a 
reportable event.
Report all
Previously 
reported –
Follow to 
completion/
termination; 
report outcome
Within 
24 hours of 
learning of 
event
ECI (require 
regulatory reporting)
Report if:
– due to intervention
– causes exclusion
Report
– potential DILI
– require regulatory 
reporting
Not required
Within 
24 hours of 
learning of 
event
ECI (do not require 
regulatory reporting)
Report if:
– due to intervention
– causes exclusion
Report
– non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 
5 calendar days 
of learning of 
event
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Type of Event
Reporting Period:
Consent to 
Randomization/
Allocation
Reporting Period:
Randomization/
Allocation 
Through 
Protocol-specified 
Follow-up Period
Reporting 
Period:
After the 
Protocol-
specified 
Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information to 
Sponsor
Cancer
Report if:
– due to intervention
– causes exclusion
Report all
Not required
Within 
5 calendar days 
of learning of 
event (unless 
serious)
Overdose
Report if:
– receiving placebo 
run-in or other run-
in medication 
Report all
Not required
Within 
5 calendar days 
of learning of 
event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious 
adverse event.
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events, 
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in allocated participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities toward the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
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An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding (spontaneously reported to the 
investigator or their designee) that occurs in a participant during the study are reportable to 
the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
There are no disease-related events or outcomes not qualifying as an AE or SAE.
8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
Events of clinical interest for this study include:
1. Potential DILI events defined as an elevated AST or ALT laboratory value that is greater 
than or equal to 3× the ULN and an elevated total bilirubin laboratory value that is greater 
than or equal to 2× the ULN and, at the same time, an alkaline phosphatase laboratory 
value that is less than 2× the ULN, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note: These criteria are based on available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology. The study-site guidance for assessment 
and follow-up of these criteria can be found in the Investigator Study File Binder (or 
equivalent).
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2. An AE of telangiectasia (spider veins, spider naevi) 
Note: 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.
8.5
Treatment of Overdose
In this study, an overdose is any dose higher than the prescribed dose.
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 the Sponsor within 5 calendar days of learning of event and be fully 
documented as an AE in the CRF.
There is no antidote for sotatercept and it is not dialyzable from blood. Therefore, in case of 
overdose, participants should be monitored/treated as per clinical practice based on 
symptoms of potential risks as described in the IB.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Sponsor Clinical Director based on the clinical evaluation of the 
participant.
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8.10
Health Economics Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics are not evaluated in this study.
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Screening
Approximately 4 weeks before intervention allocation, potential participants will be 
evaluated to determine that they fulfill the entry requirements as set forth in Section 5. 
Screening procedures may be repeated after consultation with the Sponsor.
8.11.2
Rescreening
If a participant screen-fails (Section 5.4), the participant may be rescreened once based on
investigator judgment, and after consultation with the Sponsor. Participants who are
rescreened will retain the same screening number assigned at the initial screening visit
(Section 8.1.6).
8.11.3
Treatment Period Visit
All procedures and their timing should be completed as per the SoA (Section 1.3). 
The treatment period consists of 24 weeks of Primary Treatment Period and Extension 
Treatment Period (until approval or participants discontinue the study treatments).
Visit intervals (21 days ± 3 days) are relative to the date of the previous dose of study 
intervention.
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8.11.3.1
Primary Treatment Period (Visit 2 to 10)
Study procedures/assessments for Visits 2 to 10 vary depending on the visit number and will 
be completed per the SoA (Section 1.3). All study procedures/assessments should be 
performed before administration of the study intervention. Study intervention should not be 
administered until after results from local Hgb and platelet assessments are available from a 
sample taken at the same visit or within 3 days before the visit.
8.11.3.2
Extension Treatment Period (Visit 11 and later)
Participants who complete the 24-week Primary Treatment Period on study intervention will 
be encouraged to continue treatment in the Extension Treatment Period. Study procedures for 
this period vary depending on the visit type and will be completed per the SoA (Section 1.3). 
All study procedures/assessments should be performed before administration of the study 
intervention. Study intervention should not be administered until after results from local Hgb 
and platelet assessments are available from a sample taken at the same visit or within 3 days 
before the visit.
Participants who are eligible (refer to Section 8.1.8.1.1 for details) for self-administration can 
start training for 3 consecutive visits at the time of Visit 10 or later. By the investigators’ 
judgement, participants considered eligible and well trained can start self-administration 
from Visit 12 at the earliest. Those participants may be allowed to return to the study sites 
every 4 visits after start of self-administration. Even in this case, a negative pregnancy test is 
required for POCBP prior to each self-administration at home.
All participants, regardless of opt-in for self-administration are required to return to the study 
site at Visit 11 and Visit 12 and every 4 visits thereafter (i.e., Visit 16, Visit 20, etc.). All 
those visits occur on a 21 ± 3 days cycle.
8.11.4
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study
A participant must be discontinued from study intervention but continue to be monitored for 
any of the reasons listed in Section 7.1. Once a participant discontinues from the study, they
will not be eligible to re-enter the study.
When it is determined that discontinuation from study intervention is appropriate, the
participant should have both an EOT visit (Section 8.11.4.1) and an EOS visit (Section 
8.11.4.2) conducted. After the visit procedures are completed, the participant will be 
withdrawn from the study and managed for treatment of PAH by the investigator per local 
standard-of-care.
8.11.4.1
End of Treatment Visit
Participants who discontinue treatment for any reason should have an EOT visit as outlined 
in Section 1.3. If discontinuation occurs during the timeframe of a scheduled study visit, the 
assessments for the EOT visit should be conducted.
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8.11.4.2
End of Study Visit
Participants who discontinue treatment should have EOS visit approximately 8 weeks after 
the EOT visit as outlined in Section 1.3.
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9
KEY STATISTICAL CONSIDERATIONS
This section outlines the statistical analysis strategy and procedures for the study. Changes to 
analyses made after the protocol has been finalized, but prior to the database lock for the 
primary timepoint analysis will be documented in a supplemental statistical analysis plan 
(SAP) and referenced in the clinical study report (CSR) for the study. Post hoc exploratory 
analyses will be clearly identified in the CSR.
9.1
Statistical Analysis Plan Summary
Key elements of the SAP are summarized below; the comprehensive plan is provided in 
Sections 9.2 through 9.12.
Study Design Overview
A Phase 3 Non-randomized, Non-controlled, Open Label Clinical Study to 
Evaluate the Efficacy and Safety of MK-7962 (Sotatercept) add-on to 
Background Therapy in Japanese Participants with Pulmonary Arterial 
Hypertension (PAH)
Treatment Assignment
All eligible participants will be treated with sotatercept.
Analysis Populations
Efficacy: Full Analysis Set (FAS)
Safety: All Participants as Treated (APaT)
The primary participant population of interest is WHO FC II and III
Primary endpoint
Change from baseline in PVR at Week 24
Key secondary endpoint
Change from baseline in 6MWD at Week 24
Statistical Methods for 
Key Efficacy Analyses
WHO FC II and III
The mean and the corresponding 95% CI based on a t-distribution will be 
calculated for change from baseline in PVR at Week 24, the primary efficacy 
endpoint for the study. If a serious departure from normality is observed, the 
median and the corresponding 95% CI based on the Hodges-Lehmann method 
will be provided instead.
The key secondary endpoint, change from baseline in 6MWD at Week 24, will 
be analyzed using the Hodges-Lehmann method.
WHO FC I, IV
The individual data will be listed. If the number of participants enrolled 
warrants statistical analysis, the point estimates and 95% CIs will be calculated 
in the same manner as WHO FC II and III.
Statistical Methods for 
Key Safety Analyses
The overall safety evaluation will include a summary of the number and 
percentage of participants with at least one AE, drug-related AE, SAE, drug-
related SAE, discontinuation from study intervention due to an AE, and an AE 
resulting in death.
The number and percentage of participants with specific AEs, including 
telangiectasia (event of special interest), will also be provided.
Interim Analyses
No interim analysis is planned.
Multiplicity
No adjustment for multiplicity is planned.
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Sample Size and Power
A minimum of 35 participants with WHO FC II and III will be enrolled and 
receive study intervention. 
With 35 participants enrolled, it is expected that change from baseline in PVR 
at Week 24 will be obtained from 31 participants, assuming a discontinuation 
rate of ~10%. If the standard deviation (SD) estimate is 200 (400) dyn∙sec/cm5,
the half-width of the 95% CI will be 73 (147) dyn∙sec/cm5.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the
Clinical Biostatistics department of the Sponsor.
This study is being conducted as a non-randomized, open-label study, i.e., participants, 
investigators, and Sponsor personnel will be aware of participant treatment assignments after 
each participant is enrolled and treatment is assigned.
The primary timepoint analysis will be performed after all participants have completed Week 
24 or discontinued. The data available at that point, including the data beyond Week 24 that 
are collected on or before the cutoff date, will be used to prepare the CSR. An additional 
analysis will also be performed to provide selected efficacy and safety results after all 
participants have completed Week 54 or discontinued prior to Week 54. After the Extension 
Treatment Period has been completed, the CSR will be amended to include those results.
If population PK analysis is performed, a separate analysis plan will be prepared by the 
Quantitative Pharmacology and Pharmacometrics group, and the analysis results will be 
provided as a separate report.
9.3
Hypotheses/Estimation
Objectives of the study are stated in Section 3.
9.4
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated for within-treatment differences are 
listed below. Unless otherwise noted, baseline is defined as the last available measurement 
prior to the first dose of study intervention, which is typically the measurement at Visit 1 
(Screening) or Visit 2 depending on the endpoint. 
9.4.1
Efficacy Endpoints
Primary endpoint

The primary efficacy endpoint will be change from baseline in PVR at Week 24. Percent 
change from baseline in PVR at Week 24 will also be evaluated as a supportive 
approach.
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Secondary endpoints
The key secondary efficacy endpoint will be change from baseline in 6MWD at Week 24. 
The average of two measurements at screening, which are within 15% of each other, will be 
used as baseline. Percent change from baseline in 6MWD at Week 24 will also be evaluated 
as a supportive approach.
The other secondary efficacy endpoints include:

Proportion of participants with improvement in WHO FC at Week 24

Change from baseline in NT-proBNP at Week 24
Exploratory endpoints
9.4.2
Safety Endpoints
Refer to Section 4.2.1.2 Safety Endpoints.
9.5
Analysis Populations
The primary participant population of interest is WHO FC II and III.
9.5.1
Efficacy Analysis Populations
Efficacy analyses will be conducted in the FAS population, which consists of all participants 
who received at least one dose of study intervention. The number of participants contributing 
to the analyses may vary by endpoint, depending on the degree of missing data.
CCI
CCI
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9.5.2
Safety Analysis Populations
Safety analyses will be conducted in the APaT population, which consists of all participants 
who received at least one dose of study intervention.
9.6
Statistical Methods
All analyses will be conducted separately by WHO FC [(1) WHO FC II and III, (2) WHO FC 
I, (3) WHO FC IV] at baseline.
9.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory objectives will be described in the supplemental 
SAP.
WHO FC II and III
The mean and the corresponding 95% CI based on a t-distribution will be calculated for 
change from baseline in PVR at Week 24, the primary efficacy endpoint for the study. If a 
serious departure from normality (p <0.001 with a Shapiro-Wilk test) is observed, the median 
and the corresponding 95% CI based on the Hodges-Lehmann method will be provided 
instead.
As a supportive approach, percent change from baseline in PVR at Week 24 will also be 
evaluated. The individual ratios (Week 24/baseline) will be natural log-transformed, and the 
mean and the corresponding 95% CI based on a t-distribution will be calculated. The results 
will be transformed back to the original scale for reporting.
The key secondary efficacy endpoint, change from baseline in 6MWD at Week 24, will be 
analyzed using the Hodges-Lehmann method. Percent change from baseline at Week 24 will 
be analyzed in the same manner as PVR.
The data obtained after the addition, increase or substitute of background PAH therapy will 
be excluded from the analysis. As a supportive approach, the analysis without excluding the 
data obtained after the addition, increase or substitute of background PAH therapy will also 
be performed.
Missing data will not be imputed for any analyses.
CCI
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WHO FC I, IV
The individual data will be listed. If the number of participants enrolled warrants statistical 
analysis, the point estimates and 95% CIs will be calculated in the same manner as WHO FC 
II and III.
Table 4 summarizes key efficacy analyses.
Table 4
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
(Description, time Point)
Primary vs. 
Supportive
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary Objective
Change from baseline in 
PVR at Week 24
P
CI based on t-distribution/
Hodges-Lehmann method a
FAS
Data as 
observed
Percent change from 
baseline in PVR at Week 
24
S
CI based on t-distribution
FAS
Data as 
observed
Secondary Objective #1
Change from baseline in 
6MWD at Week 24
P
Hodges-Lehmann method
FAS
Data as 
observed
Percent change from 
baseline in 6MWD at 
Week 24
S
CI based on t-distribution
FAS
Data as 
observed
Secondary Objective #2
Proportion of participants 
with improvement in 
WHO FC at Week 24
P
CI based on the method of 
Clopper and Pearson
FAS
Data as 
observed
Secondary Objective #3
Change from baseline in 
NT-proBNP at Week 24
P
CI based on t-distribution/
Hodges-Lehmann method a
FAS
Data as 
observed
P = primary, S = supportive.
a Methods that will be used under serious departure from normality (p <0.001 with a Shapiro-Wilk test)
9.6.2
Statistical Methods for Safety Analyses
9.6.2.1
Overall Safety Assessment
The overall safety evaluation will include a summary of the number and percentage of 
participants with at least one AE, drug-related AE, SAE, drug-related SAE, discontinuation 
from study intervention due to an AE, and an AE resulting in death.
The number and percentage of participants with specific AEs, system organ classes and 
predefined limits of change (PDLCs) will also be provided.
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For continuous safety measures, such as change from baseline in laboratory, vital signs and 
ECG parameters, summary statistics for baseline, on-treatment, and change from baseline 
values will be provided.
Immunogenicity (incidence/titer of ADA) will also be analyzed.
9.6.2.2
Assessment of Safety Topics of Special Interest
The AE of telangiectasia (spider veins, spider naevi) will be considered an event of special 
interest in this study. The number and percentage of participants with an event will be 
summarized.
Table 5 summarizes analysis strategy for safety endpoints in this study.
Table 5
Analysis Strategy for Safety Parameters
Analysis Part
Safety Endpoint
Descriptive 
Statistics
Overall 
Safety Assessment
Any AE
X
Any drug-related AE
Any SAE
Any drug-related SAE
Discontinuation from study intervention due to an AE
AE resulting in death
Specific AEs, system organ classes, PDLCs
Change from baseline results (labs, vital signs, ECGs)
AE of Special Interest
AE of telangiectasia (spider veins, spider naevi)
X
9.6.3
Summary of Baseline Characteristics, Demographics, and Other Analyses
Demographic variables and other baseline characteristics, participant disposition, medical 
history, as well as prior and concomitant medications, will be summarized either by 
descriptive statistics or categorical tables.
9.7
Interim Analyses
No interim analysis is planned.
9.8
Multiplicity
No adjustment for multiplicity is planned.
CCI
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9.9
Sample Size and Power Calculations
A minimum of 35 participants with WHO FC II and III will be enrolled and receive study 
intervention. If this is achieved in less than 1 year from the first dose of study intervention in 
the study, the enrollment will continue until either of the following has been achieved:

One (1) year has elapsed from the first dose of study intervention in the study

Forty (40) participants have been enrolled and received study intervention
The proportion of participants using infusion prostacyclin will not exceed approximately 
50% of the WHO FC II and III participants enrolled.
No minimum or maximum number of participants will be pre-specified for WHO FC I or IV.
9.9.1
Sample Size and Power for Efficacy Analyses
With 35 participants enrolled and treated, it is expected that change from baseline in PVR at 
Week 24 will be obtained from 31 participants, assuming a discontinuation rate of ~10%. 
The half-widths of 95% CIs for change from baseline given various SD estimates will be as 
follows. For example, if the SD estimate is 200 (400) dyn∙sec/cm5, the half-width of the 95% 
CI will be 73 (147) dyn∙sec/cm5.
Table 6
Half-Widths of 95% CIs for Change From Baseline in PVR (dyn∙sec/cm5) at 
Week 24 Given Various SD Estimates (31 Participants)
SD Estimate
Half-width of 95% CI
115
42
200
73
300
110
400
147
500
183
600
220
700
257
9.9.2
Sample Size and Power for Safety Analyses
There is a >99% chance of observing at least one SAE among 35 participants if the 
underlying incidence of SAE is approximately 24% (1 of every ~4.2 participants receiving 
the study intervention), which is consistent with the 0.7 mg/kg group in the PULSAR trial. If 
no SAEs are observed among 35 participants, this study will provide 95% confidence that the 
underlying percentage of participants with an SAE is less than approximately 8.2% (one in 
every 12.2 participants).
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9.10
Subgroup Analyses
The consistency of the treatment effect will be assessed descriptively via summary statistics 
by subgroup for the classification variables listed below.

Sex (male, female)

PAH Etiological Subgroups (iPAH [idiopathic PAH], hPAH [heritable PAH], 
Drug/Toxin, Connective Tissue Disease, congenital heart disease with s/p Shunt Repair)

Background PAH therapy at baseline (monotherapy, double combination, triple 
combination)

WHO FC at baseline (II, III)

PVR (dyn∙sec/cm5) at baseline (≤800, >800)
The subgroup analysis will be performed for the primary and key secondary efficacy 
endpoints in participants with WHO FC II and III.
9.11
Compliance (Medication Adherence)
Percent compliance will be calculated according to the following formula and summarized
using descriptive statistics.
Compliance (%) = 100x
Number of visits where study intervention was 
administered
Number of visits in the treatment period where 
study intervention should have been 
administered
The study intervention 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 
intervention should have been administered” is the total number of visits that should be done 
from allocation 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 
intervention should have been administered” is the total number of visits that should be done 
from allocation to the date of the last visit, excluding the number of dose delays/holds per 
protocol.
9.12
Extent of Exposure
The duration of exposure and the total dose administered (mg) will be summarized with 
descriptive statistics.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Interventional Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
I.
Introduction
A. Purpose
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD), through its subsidiaries, 
conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, planning, conducting, analyzing, 
and reporting these trials in compliance with the highest ethical and scientific 
standards. Protection of participants in clinical trials is the overriding concern in the 
design and conduct of clinical trials. In all cases, MSD clinical trials will be 
conducted in compliance with MSD’s global standards, local and/or national 
regulations (including all applicable data protection laws and regulations), and 
International Council for Harmonisation Good Clinical Practice (ICH GCP) E6 and 
ICH General Considerations for Clinical Studies E8, and in accordance with the 
ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical 
interventional investigations sponsored by MSD irrespective of the party (parties) 
employed for their execution (e.g., contract research organizations, collaborative 
research efforts). This Code is not intended to apply to trials that are observational in 
nature, or which are retrospective. Further, this Code does not apply to investigator-
initiated trials, which are not under the full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-
driven to assess safety, efficacy, and/or pharmacokinetic or pharmacodynamic 
indices of MSD or comparator products. Alternatively, MSD may conduct 
outcomes research trials, trials to assess or validate various endpoint measures, or 
trials to determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be 
adequate to address the specific purpose of the trial and shall respect the data 
protection rights of all participants, trial site staff and, where applicable, third 
parties. Input may be considered from a broad range of stakeholders, including 
patient advocacy groups/patients representing the trial population, caregivers, and 
healthcare providers to ensure operational feasibility. Trial design also includes 
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proactive identification of critical to quality factors utilizing a risk-based 
approach. Plans are then developed to assess and mitigate risks to those factors as 
appropriate during the trial. All trial protocols are and will be assessed for the 
need and capability to enroll underrepresented groups. Participants must meet 
protocol entry criteria to be enrolled in the trial.
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in 
diverse populations, including people of varying age, race, ethnicity, gender, and 
accounting for other potential disease related factors. MSD selects investigative 
sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary 
considerations. Prior to trial initiation, sites are evaluated by MSD personnel (or 
individuals acting on behalf of MSD) to assess the ability to successfully conduct 
the trial. Individuals involved in trial conduct receive training commensurate with 
their role prior to their becoming involved in the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD 
will make concerted efforts to raise awareness of clinical trial opportunities in 
various communities. MSD will seek to engage underrepresented groups and 
those disproportionately impacted by the disease under study. MSD will support 
clinical trial investigators to enroll underrepresented groups and expand access to 
those who will ultimately use the products under investigation.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol 
and Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, 
completeness, and consistency. Data are verified versus source documentation 
according to standard operating procedures. Per MSD policies and procedures, if 
potential fraud, scientific/research misconduct, privacy incidents/breaches or 
Clinical Trial-related Significant Quality Issues are reported, such matters are 
investigated. When necessary, appropriate corrective and/or preventative actions 
are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary 
results of its registered trials of marketed products in which treatment is assigned, 
according to the pre-specified plans for data analysis. To the extent scientifically 
appropriate, MSD seeks to publish the results of other analyses it conducts that are 
important to patients, physicians, and payers. Some early phase or pilot trials are 
intended to be hypothesis generating rather than hypothesis testing; in such cases, 
publication of results may not be appropriate since the trial may be underpowered and 
the analyses complicated by statistical issues such as multiplicity.
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MSD’s policy on authorship is consistent with the recommendations published by the 
International Committee of Medical Journal Editors (ICMJE). In summary, 
authorship should reflect significant contribution to the design and conduct of the 
trial, performance or interpretation of the analysis, and/or writing of the manuscript. 
All named authors must be able to defend the trial results and conclusions. MSD 
funding of a trial will be acknowledged in publications.
III.Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board 
[IRB]/Independent Ethics Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory 
authority acceptance/authorization prior to implementation of the trial or amendment, 
in compliance with local and/or national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s 
brochure, and other relevant trial documents must be reviewed and approved by an 
IRB/IEC before being implemented at each site, in compliance with local and/or 
national regulations and ICH Guidelines. Changes to the protocol that are required 
urgently to eliminate an immediate hazard and to protect participant safety may be 
enacted in anticipation of ethics committee approval. MSD will inform regulatory 
authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is 
of primary importance. Potential participants will be informed of the risks and 
benefits of, as well as alternatives to, trial participation. At a minimum, trial designs 
will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only 
after informed consent is obtained. Trial designs include procedures and systems for 
the identification, monitoring, and reporting of safety concerns. Participants may 
withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
During trial planning, the need for an independent Data Monitoring Committee 
(DMC) is assessed. DMC review of data accumulated during the conduct of the trial 
is integral to the well-being of trial participants.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent 
possible, as well as all applicable data protection rights. Unless required by law, only 
the investigator, Sponsor (or individuals acting on behalf of MSD), ethics committee, 
and/or regulatory authorities will have access to confidential medical records that 
might identify the participant by name.
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D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed 
consent authorized by an ethics committee.
E. Trial Results
At the time of providing informed consent and in accordance with local laws and 
regulations, participants should be informed about the plans for availability of trial 
results.
IV.Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate 
investigators (or the sponsoring institution) in a fair manner for the work performed 
in support of MSD trials. MSD does not pay incentives to enroll participants in its 
trials. However, when enrollment is particularly challenging, additional payments 
may be made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate 
referring physicians for time spent on medical record review and medical evaluation 
to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the 
investigator or sponsoring institution is being paid or provided a grant for performing 
the trial. However, the local ethics committee may wish to alter the wording of the 
disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source 
of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, 
investigator meetings, etc) will be consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the 
trial protocol, and in signing the protocol, agree to support these ethical and scientific 
standards.
10.1.2
Financial Disclosure
Financial disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor’s responsibility to determine, based on these regulations, whether a request for 
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financial disclosure information is required. It is the investigator’s/subinvestigator’s 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide their financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, frequently known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that their personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
The Sponsor has EU-approved Binding Corporate Rules since 2017, covering all aspects of 
its Global Privacy Program (Corporate Policy 20), and is self-certified pursuant to the EU-US 
Data Privacy Framework.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee, affiliated institution, and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution, and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
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process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked before transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules, 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
There are no committees in this study.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with ICMJE authorship 
requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trials Regulation 536/2014, the
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu, https://euclinicaltrials.eu, or other local registries. MSD, as 
Sponsor of this study, will review this protocol and submit the information necessary to 
fulfill these requirements. MSD entries are not limited to FDAAA or the EMA clinical trials 
Regulation 536/2014 mandated trials. Information posted will allow participants to identify 
potentially appropriate studies for their disease conditions and pursue participation by calling 
a central contact number for further information on appropriate study locations and study-site 
contact information.
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By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials Regulation 536/2014, or other locally mandated registries 
are that of the Sponsor and agrees not to submit any information about this study or its results 
to those registries.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol, generally accepted standards of GCP 
(eg, ICH GCP: Consolidated Guideline and other generally accepted standards of GCP), and 
all applicable federal, state, and local laws, rules, and regulations relating to the conduct of 
the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority.
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
For investigators located in countries with serious breach reporting requirements, investigator 
will promptly report to the Sponsor any serious breach or suspected serious breach that 
occurs in compliance with those requirements. Unless more specifically defined in the 
applicable requirements, a serious breach is any breach of the applicable clinical trial 
regulation or of the clinical trial protocol which is likely to affect to a significant degree: (i) 
the safety or rights of a trial participant, or (ii) the reliability and robustness of the data 
generated in the clinical trial.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
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or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF 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 participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). 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 
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investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study-site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
•
Hematology parameters listed in Table 7 will be collected and analyzed locally.
•
Except for hematology parameters, parameters in Table 7 will be analyzed by a central 
laboratory. Local assessment may be performed in the event that the central laboratory 
results are not available in time for study intervention administration and/or response 
evaluation. Additionally, if local laboratory results are used to make either a study 
intervention decision or response evaluation, the results must be entered into the CRF.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5.1 and 5.2 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 7
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
MCV
MCH
Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
BUN
Potassium
AST/SGOT
Total bilirubin (and direct 
bilirubin, if total bilirubin is 
above the ULN)
Albumin
Bicarbonate
Chloride
Phosphorous
Creatinine
Sodium
ALT/SGPT
Total Protein
Glucose 
(nonfasting)
Calcium
Alkaline 
phosphatase
Magnesium
Uric acid
Routine Urinalysis
Specific gravity
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen
Microscopic examination (if blood or protein is abnormal)
Pregnancy Testing
Highly sensitive serum or urine hCG pregnancy test (as needed for POCBP)
Other Screening Tests
FSH (as needed in PONCBP only)
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; FSH=follicle-
stimulating hormone; hCG=human chorionic gonadotropin; MCH=mean corpuscular hemoglobin; MCV=mean 
corpuscular volume; RBC=red blood cell; SGOT=serum glutamic-oxaloacetic transaminase; SGPT=serum 
glutamic-pyruvic transaminase; ULN=upper limit of normal; POCBP=Participants of childbearing potential; 
PONCBP=Participants of nonchildbearing potential; WBC=white blood cell
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
Blood volumes for central laboratory tests are listed in Table 8.
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Table 8
Blood volumes for central laboratory tests
Study 
Period
Screening
Primary Treatment Period
Extension Treatment 
Period
Follow-up
Visit 
Number
1
2
3
4
5
6
7-9
10 (1°EP 
Evaluation)
11
12
13-
15
16, 
20, 24
End of 
Treatment 
(EOT)
End 
of 
Study 
(EOS)
Scheduled 
Week
0
(Day 
1)
3
6
9
12
15, 
18, 
21
24
27
30
33, 
36, 
39
every 
12 
weeks 
3 weeks 
from the 
last dose
8 
weeks 
from 
EOT
Visit 
Window
≤28 days
±3 days
±7 days
NT-
proBNP/
Activin A
4
4
4
4
4
4
4
4
Chemistry
7
7
7
7
7
7
7
Total
19
24.5
16
12
12
23
0
23
0
23
0
23
23
23
CCI
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic intentional, excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired nontherapeutic 
effect.
10.3.2
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
Note: For purposes of AE definition, study intervention includes any pharmaceutical 
product, biological product, vaccine, diagnostic agent, medical device, combination 
product, or protocol-specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.
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•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer or progression of existing cancer.
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
-
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
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c.
Requires inpatient hospitalization or prolongation of existing hospitalization
-
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a preexisting condition that has not 
worsened is not an SAE.) A preexisting condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
-
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
-
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
-
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
-
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
-
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.4
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a cancer.
•
Is associated with an overdose.
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10.3.5
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following 
categories:
-
Mild: An event that is easily tolerated by the participant, causing minimal discomfort, 
and not interfering with everyday activities (for pediatric studies, awareness of 
symptoms, but easily tolerated).
-
Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies, definitely acting like something is wrong).
-
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category used for rating the 
intensity of an event; and both AE and SAE can be assessed as severe (for pediatric 
studies, extremely distressed or unable to do usual activities).
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Assessment of causality
•
Did the study intervention cause the AE?
•
The determination of the likelihood that the study intervention caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
study intervention and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the study 
intervention caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the study 
intervention such as: reliable history, acceptable compliance assessment (pill count, 
diary, etc), expected pharmacologic effect, or measurement of drug/metabolite in 
bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the study intervention? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal product)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the study intervention discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the study 
intervention; (3) the study is a single-dose drug study; or (4) study intervention (s) 
is/are only used 1 time.)
-
Rechallenge: Was the participant reexposed to the study intervention in this study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability; (2) the study is a single-dose drug study; or (3) study 
intervention (s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE STUDY INTERVENTION, OR IF REEXPOSURE 
TO THE STUDY INTERVENTION POSES ADDITIONAL POTENTIAL SIGNIFICANT 
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RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the study intervention or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to their best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a study intervention relationship).
-
Yes, there is a reasonable possibility of study intervention relationship:
◦
There is evidence of exposure to the study intervention. The temporal sequence of 
the AE onset relative to the administration of the study intervention is reasonable. 
The AE is more likely explained by the study intervention than by another cause.
-
No, there is not a reasonable possibility of study intervention relationship:
◦
Participant did not receive the study intervention OR temporal sequence of the AE 
onset relative to administration of the study intervention is not reasonable OR the 
AE is more likely explained by another cause than the study intervention. (Also 
entered for a participant with overdose without an associated AE.)
•
The investigator must review and provide an assessment of causality for each AE/SAE
and document this in the medical notes.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change their opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
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•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
-
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure email of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device and Drug–Device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not applicable
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Participants of Childbearing Potential (POCBP)
A participant assigned female sex at birth is considered fertile following menarche and 
capable of becoming pregnant until becoming postmenopausal unless permanently sterile 
(see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Participants assigned female sex at birth who are in the following categories are not capable 
of becoming pregnant and, therefore, not considered POCBP:
•
Premenarchal
•
Premenopausal with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Müllerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal
-
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 participants assigned female sex at birth who are not 
using hormonal contraception or HRT. However, in the absence of 12 months of 
amenorrhea, confirmation with 2 FSH measurements in the postmenopausal range 
is required.
-
Participants assigned female sex at birth who are on HRT and whose menopausal 
status is in doubt will be required to use one of the nonhormonal 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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10.5.2
Contraceptive Requirements
Contraceptives allowed during the study include:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
• IUSa,b
• Nonhormonal IUD
• Bilateral tubal occlusion
• Azoospermic partner(s) (vasectomized or secondary to medical cause).
All sexual partner(s) of the POCBP must be azoospermic. The participant must provide verbal 
confirmation of partner azoospermia during Medical History. If not, an additional highly effective method 
of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Sexual Abstinence
• Sexual abstinence is considered a highly effective method only if defined as refraining from penile-vaginal
intercourse with partner(s) capable of producing sperm during the entire period of risk associated with the 
study intervention. The reliability of sexual abstinence needs to be evaluated in relation to the duration of 
the study and the preferred and usual lifestyle of the participant.
a
Penile/external condoms must be used in addition to POCBP’s hormonal contraception.
b
IUS is a progestin releasing IUD.
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2. Scope of Future Biomedical Research3, 4
The specimens consented and/or collected in this study as outlined in Section 8.9 will be 
used in various experiments to understand:
-
The biology of how drugs/vaccines work
-
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
-
Other pathways with which drugs/vaccines may interact
-
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease, and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research3, 4
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study 
visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
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A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research3, 4
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participants’ clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history, and intervention outcomes is
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number that does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
5. Biorepository Specimen Usage3, 4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses using the future biomedical research specimens may be performed by 
the Sponsor, or an additional third party (eg, a university investigator) designated by the 
Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy and 
confidentiality requirements. Any contracted third-party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
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8. Data Security3, 4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
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If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.7
Appendix 7: Country-specific Requirements
Not applicable
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10.8
Appendix 8: Manual for 6MWT
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 (eg, with a
cone). A starting line, which marks the beginning and end of each 60 m lap, should be
marked on the floor (eg, using brightly colored tape).
Required Equipment
a.
Countdown timer (or stopwatch)
b.
Mechanical lap counter
c.
Two small cones to mark the turnaround points
d.
A chair that can be easily moved along the walking course
e.
Worksheets on a clipboard
f.
A source of oxygen
g.
Sphygmomanometer
h.
Telephone
i.
Automated electronic defibrillator
j.
Portable pulse oximeter
Participant Preparation
a.
Comfortable clothing should be worn.
b. Appropriate shoes for walking should be worn.
c.
Participants should use their usual walking aids during the test (eg, cane, walker, etc.).
d. The participant’s usual medical regimen should be continued.
e.
A light meal is acceptable before early morning or early afternoon tests.
f.
Participants should not have exercised vigorously within 2 hours of beginning the test. 
Measurements
a.
Repeat testing should be performed about the same time of day to minimize intraday
variability.
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b. A “warm-up” period before the test should not be performed.
c.
The participant should sit at rest in a chair located near the starting position for at least 10 
minutes before the test starts. During this time, check for contraindications, measure 
pulse and blood pressure, and ensure that clothing and shoes are appropriate. Record in 
the source documents.
d. Measure and record baseline heart rate and SpO2, and follow the manufacturer’s 
instructions to maximize the signal and minimize motion artifact. Make sure the readings 
are stable before recording. Note pulse regularity and whether the oximeter signal quality 
is acceptable.
e.
Have the participant stand and rate their baseline dyspnea using the Borg dyspnea scale
(Borg CR10 Scale).

Show the scale to the participant and ask the participant this: “Please grade your 
level of shortness of breath using this scale.” Record the pre-walk Borg dyspnea 
level.

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 should
resume walking as soon as you are able to do so.
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 objective is to walk AS FAR AS POSSIBLE for 6 minutes but not run or jog. Start 
now or whenever you are ready.”
a.
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.
b. 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
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the laps. Each time the participant returns to the starting line, click the lap counter once
(or mark the lap on the worksheet). Let the participant see you do it. Exaggerate the click 
using body language, like using a stopwatch at a race.
After the first minute, tell the participant the following (in even tones): “You are doing well.
You have 5 minutes to go.”
When the timer shows 4 minutes remaining, tell the participant: “Keep up the good work. 
You have 4 minutes to go.”
When the timer shows 3 minutes remaining, tell the participant: “You are doing well. You 
are halfway done.”
When the timer shows 2 minutes remaining, tell the participant: “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, tell them: “You can lean
against the wall if you would like, then continue walking whenever you feel able to do so.”
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, tell the participant: “In a moment, I am 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), tell the participant: “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
a.
Remind the participant of their breathing number pretest and ask the participant to rate 
their level of shortness of breath again. Record the post-walk Borg dyspnea level.
b. Measure SpO2 and pulse rate from the oximeter and then remove the sensor.
c.
Record the number of laps from the counter.
d. Record the additional distance covered (the number of meters in the final partial lap) 
using the markers on the wall as distance guides.
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e.
Calculate the total distance walked rounding to the nearest meter and record it on the 
worksheet.
f.
Congratulate the participant on good effort and offer a drink of water.
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10.9
Appendix 9: Abbreviations
Abbreviation
Expanded Term
6MWD
six-minute walk distance
6MWT
six-minute walk test
ADME
absorption, distribution, metabolism, and excretion
AE
adverse event 
ALT
alanine aminotransferase
APaT
All-Participants-as-Treated
AST
aspartate aminotransferase
BMP
bone morphogenetic protein
CI
confidence interval
CO
cardiac output
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case Report Form 
CSR
Clinical Study Report
DILI
drug-induced liver injury
DNA
deoxyribonucleic acid 
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
EDC
electronic data collection 
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
E-R
exposure response
FC
functional class
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FAS
Full Analysis Set
FSH
follicle-stimulating hormone 
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Abbreviation
Expanded Term
FVC
forced vital capacity
GCP
Good Clinical Practice 
GDF
growth and differentiation factors
hCG
human chorionic gonadotropin
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
interactive response technology
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
NT-proBNP
N-terminal proB-type natriuretic peptide
PAH
pulmonary arterial hypertension
PAP
pulmonary artery pressure
PAWP
pulmonary artery wedge pressure
PD
pharmacodynamic
PDLC
predefined limits of change
PK
pharmacokinetic
POCBP
participant/participants of childbearing potential
PONCBP
participant/participants of nonchildbearing potential
PRO
patient-reported outcome
PVR
pulmonary vascular resistance
QoL
quality of life
RAP
right atrial pressure
RHC
right heart catheterization
RNA
ribonucleic acid
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Abbreviation
Expanded Term
RVP
right ventricular pressure
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SD
standard deviation
SGOT
serum glutamic-oxaloacetic transaminase
SGPT
serum glutamic-pyruvic transaminase
SLAB
Supplemental laboratory test(s)
SoA
schedule of activities
SpO2
percutaneous oxygen saturation
SUSAR
suspected unexpected serious adverse reaction
SvO2
mixed venous saturation of oxygen
ULN
upper limit of normal
VAS
Visual Analog Scale
VSMC(s)
vascular smooth muscle cell(s)
WHO
World Health Organization
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